[Title 21 CFR ]
[Code of Federal Regulations (annual edition) - April 1, 2024 Edition]
[From the U.S. Government Publishing Office]
[[Page i]]
Title 21
Food and Drugs
________________________
Parts 300 to 499
Revised as of April 1, 2024
Containing a codification of documents of general
applicability and future effect
As of April 1, 2024
Published by the Office of the Federal Register
National Archives and Records Administration as a
Special Edition of the Federal Register
[[Page ii]]
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[[Page iii]]
Table of Contents
Page
Explanation................................................. v
Title 21:
Chapter I--Food and Drug Administration, Department
of Health and Human Services (Continued) 3
Finding Aids:
Table of CFR Titles and Chapters........................ 361
Alphabetical List of Agencies Appearing in the CFR...... 381
List of CFR Sections Affected........................... 391
[[Page iv]]
----------------------------
Cite this Code: CFR
To cite the regulations in
this volume use title,
part and section number.
Thus, 21 CFR 300.50 refers
to title 21, part 300,
section 50.
----------------------------
[[Page v]]
EXPLANATION
The Code of Federal Regulations is a codification of the general and
permanent rules published in the Federal Register by the Executive
departments and agencies of the Federal Government. The Code is divided
into 50 titles which represent broad areas subject to Federal
regulation. Each title is divided into chapters which usually bear the
name of the issuing agency. Each chapter is further subdivided into
parts covering specific regulatory areas.
Each volume of the Code is revised at least once each calendar year
and issued on a quarterly basis approximately as follows:
Title 1 through Title 16.................................as of January 1
Title 17 through Title 27..................................as of April 1
Title 28 through Title 41...................................as of July 1
Title 42 through Title 50................................as of October 1
The appropriate revision date is printed on the cover of each
volume.
LEGAL STATUS
The contents of the Federal Register are required to be judicially
noticed (44 U.S.C. 1507). The Code of Federal Regulations is prima facie
evidence of the text of the original documents (44 U.S.C. 1510).
HOW TO USE THE CODE OF FEDERAL REGULATIONS
The Code of Federal Regulations is kept up to date by the individual
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To determine whether a Code volume has been amended since its
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the daily Federal Register. These two lists will identify the Federal
Register page number of the latest amendment of any given rule.
EFFECTIVE AND EXPIRATION DATES
Each volume of the Code contains amendments published in the Federal
Register since the last revision of that volume of the Code. Source
citations for the regulations are referred to by volume number and page
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OMB CONTROL NUMBERS
The Paperwork Reduction Act of 1980 (Pub. L. 96-511) requires
Federal agencies to display an OMB control number with their information
collection request.
[[Page vi]]
Many agencies have begun publishing numerous OMB control numbers as
amendments to existing regulations in the CFR. These OMB numbers are
placed as close as possible to the applicable recordkeeping or reporting
requirements.
PAST PROVISIONS OF THE CODE
Provisions of the Code that are no longer in force and effect as of
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Code users may find the text of provisions in effect on any given date
in the past by using the appropriate List of CFR Sections Affected
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the Code prior to the LSA listings at the end of the volume, consult
previous annual editions of the LSA. For changes to the Code prior to
2001, consult the List of CFR Sections Affected compilations, published
for 1949-1963, 1964-1972, 1973-1985, and 1986-2000.
``[RESERVED]'' TERMINOLOGY
The term ``[Reserved]'' is used as a place holder within the Code of
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INCORPORATION BY REFERENCE
What is incorporation by reference? Incorporation by reference was
established by statute and allows Federal agencies to meet the
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This material, like any other properly issued regulation, has the force
of law.
What is a proper incorporation by reference? The Director of the
Federal Register will approve an incorporation by reference only when
the requirements of 1 CFR part 51 are met. Some of the elements on which
approval is based are:
(a) The incorporation will substantially reduce the volume of
material published in the Federal Register.
(b) The matter incorporated is in fact available to the extent
necessary to afford fairness and uniformity in the administrative
process.
(c) The incorporating document is drafted and submitted for
publication in accordance with 1 CFR part 51.
What if the material incorporated by reference cannot be found? If
you have any problem locating or obtaining a copy of material listed as
an approved incorporation by reference, please contact the agency that
issued the regulation containing that incorporation. If, after
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CFR INDEXES AND TABULAR GUIDES
A subject index to the Code of Federal Regulations is contained in a
separate volume, revised annually as of January 1, entitled CFR Index
and Finding Aids. This volume contains the Parallel Table of Authorities
and Rules. A list of CFR titles, chapters, subchapters, and parts and an
alphabetical list of agencies publishing in the CFR are also included in
this volume.
An index to the text of ``Title 3--The President'' is carried within
that volume.
[[Page vii]]
The Federal Register Index is issued monthly in cumulative form.
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the daily Federal Register.
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the revision dates of the 50 CFR titles.
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INQUIRIES
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Oliver A. Potts,
Director,
Office of the Federal Register
April 1, 2024.
[[Page ix]]
THIS TITLE
Title 21--Food and Drugs is composed of nine volumes. The parts in
these volumes are arranged in the following order: Parts 1-99, 100-169,
170-199, 200-299, 300-499, 500-599, 600-799, 800-1299 and 1300 to end.
The first eight volumes, containing parts 1-1299, comprise Chapter I--
Food and Drug Administration, Department of Health and Human Services.
The ninth volume, containing part 1300 to end, includes Chapter II--Drug
Enforcement Administration, Department of Justice, and Chapter III--
Office of National Drug Control Policy. The contents of these volumes
represent all current regulations codified under this title of the CFR
as of April 1, 2024.
For this volume, Susannah C. Hurley was Chief Editor. The Code of
Federal Regulations publication program is under the direction of John
Hyrum Martinez, assisted by Stephen J. Frattini.
[[Page 1]]
TITLE 21--FOOD AND DRUGS
(This book contains parts 300 to 499)
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Part
chapter i--Food and Drug Administration, Department of
Health and Human Services (Continued)..................... 300
[[Page 3]]
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES (CONTINUED)
--------------------------------------------------------------------
Editorial Note: Nomenclature changes to chapter I appear at 59 FR
14366, Mar. 28, 1994, and 69 FR 13717, Mar. 24, 2004.
SUBCHAPTER D--DRUGS FOR HUMAN USE
Part Page
300 General..................................... 5
310 New drugs................................... 6
312 Investigational new drug application........ 52
314 Applications for FDA approval to market a
new drug................................ 94
315 Diagnostic radiopharmaceuticals............. 192
316 Orphan drugs................................ 194
317 Qualifying pathogens........................ 206
320 Bioavailability and bioequivalence
requirements............................ 207
328 Over-the-counter drug products intended for
oral ingestion that contain alcohol..... 221
329 Nonprescription human drug products subject
to section 760 of the Federal food,
drug, and cosmetic act.................. 223
330 Over-the-counter (OTC) human drugs which are
generally recognized as safe and
effective and not misbranded............ 224
331 Antacid products for over-the-counter (OTC)
human use............................... 244
332 Antiflatulent products for over-the-counter
human use............................... 247
333 Topical antimicrobial drug products for
over-the-counter human use.............. 248
335 Antidiarrheal drug products for over-the-
counter human use....................... 256
336 Antiemetic drug products for over-the-
counter human use....................... 258
338 Nighttime sleep-aid drug products for over-
the-counter human use................... 260
[[Page 4]]
340 Stimulant drug products for over-the-counter
human use............................... 261
341 Cold, cough, allergy, bronchodilator, and
antiasthmatic drug products for over-
the-counter human use................... 262
343 Internal analgesic, antipyretic, and
antirheumatic drug products for over-
the-counter human use................... 286
344 Topical otic drug products for over-the-
counter human use....................... 294
346 Anorectal drug products for over-the-counter
human use............................... 296
347 Skin protectant drug products for over-the-
counter human use....................... 301
348 External analgesic drug products for over-
the-counter human use................... 309
349 Ophthalmic drug products for over-the-
counter human use....................... 310
350 Antiperspirant drug products for over-the-
counter human use....................... 316
352 Sunscreen drug products for over-the-counter
human use [stayed indefinitely]......... 318
355 Anticaries drug products for over-the-
counter human use....................... 328
357 Miscellaneous internal drug products for
over-the-counter human use.............. 333
358 Miscellaneous external drug products for
over-the-counter human use.............. 337
361 Prescription drugs for human use generally
recognized as safe and effective and not
misbranded: Drugs used in research...... 346
369 Interpretative statements re warnings on
drugs and devices for over-the-counter
sale.................................... 351
370-499
[Reserved]
[[Page 5]]
SUBCHAPTER D_DRUGS FOR HUMAN USE
PART 300_GENERAL--Table of Contents
Subpart A [Reserved]
Subpart B_Combination Drugs
Sec.
300.50 Fixed-combination prescription drugs for humans.
Subpart C_Substances Generally Prohibited From Drugs
300.100 Chlorofluorocarbon propellants.
Subpart D_Annual Summary Reporting Requirements.
Sec.
300.200 Annual summary requirements under the Right to Try Act.
Authority: 21 U.S.C. 331, 351, 352, 355, 360b, 360bbb-0a, 371.
Subpart A [Reserved]
Subpart B_Combination Drugs
Sec. 300.50 Fixed-combination prescription drugs for humans.
The Food and Drug Administration's policy in administering the new-
drug, antibiotic, and other regulatory provisions of the Federal Food,
Drug, and Cosmetic Act regarding fixed combination dosage form
prescription drugs for humans is as follows:
(a) Two or more drugs may be combined in a single dosage form when
each component makes a contribution to the claimed effects and the
dosage of each component (amount, frequency, duration) is such that the
combination is safe and effective for a significant patient population
requiring such concurrent therapy as defined in the labeling for the
drug. Special cases of this general rule are where a component is added:
(1) To enhance the safety or effectiveness of the principal active
component; and
(2) To minimize the potential for abuse of the principal active
component.
(b) If a combination drug presently the subject of an approved new-
drug application has not been recognized as effective by the
Commissioner of Food and Drugs based on his evaluation of the
appropriate National Academy of Sciences-National Research Council panel
report, or if substantial evidence of effectiveness has not otherwise
been presented for it, then formulation, labeling, or dosage changes may
be proposed and any resulting formulation may meet the appropriate
criteria listed in paragraph (a) of this section.
(c) A fixed-combination prescription drug for humans that has been
determined to be effective for labeled indications by the Food and Drug
Administration, based on evaluation of the NAS-NRC report on the
combination, is considered to be in compliance with the requirements of
this section.
[40 FR 13496, Mar. 27, 1975, as amended at 64 FR 401, Jan. 5, 1999]
Subpart C_Substances Generally Prohibited From Drugs
Sec. 300.100 Chlorofluorocarbon propellants.
The use of chlorofluorocarbons in human drugs as propellants in
self-pressurized containers is generally prohibited except as provided
by Sec. 2.125 of this chapter.
[43 FR 11317, Mar. 17, 1978]
Subpart D_Annual Summary Reporting Requirements.
Source: 87 FR 56276, Sept. 14, 2022, unless otherwise noted.
Sec. 300.200 Annual summary requirements under the Right to Try Act.
(a) Definitions: The following definitions of terms apply only to
this section:
(1) Eligible investigational drug. An eligible investigational drug
is as defined in section 561B(a)(2) of the Federal Food, Drug, and
Cosmetic Act.
(2) Eligible patient. An eligible patient is as defined in section
561B(a)(1) of the Federal Food, Drug, and Cosmetic Act.
[[Page 6]]
(3) Investigational New Drug (IND). An IND is as defined in Sec.
312.3 of this chapter.
(4) Known serious adverse event. A serious adverse event (as defined
in Sec. 312.32 of this chapter) is considered ``known'' if the
manufacturer or sponsor is aware of it.
(5) Manufacturer or sponsor. A manufacturer or sponsor is the person
who:
(i) Meets the definition of ``sponsor'' in Sec. 312.3 of this
chapter for the eligible investigational drug;
(ii) Has submitted an application for the eligible investigational
drug under section 505(b) of the Federal Food, Drug, and Cosmetic Act or
section 351(a) of the Public Health Service Act; or
(iii) Is other than a contract manufacturer acting on behalf of a
manufacturer or sponsor, producing the eligible investigational drug
provided to an eligible patient on behalf of the persons described in
paragraph (a)(5)(i) or (ii) of this section.
(b)(1) Except as described in paragraph (b)(2) of this section, a
manufacturer or sponsor of an eligible investigational drug shall submit
to the Food and Drug Administration (FDA), no later than March 31 of
each year, an annual summary of any use of eligible investigational
drugs supplied to any eligible patient under section 561B of the Federal
Food, Drug, and Cosmetic Act for the period of January 1 through
December 31 of the preceding year.
(2) For a manufacturer or sponsor of an eligible investigational
drug that has supplied an eligible patient with an eligible
investigational drug under section 561B of the Federal Food, Drug, and
Cosmetic Act between the period from enactment of section 561B (May 30,
2018) and December 31, 2022, the manufacturer or sponsor shall submit to
FDA a first annual summary covering that period no later than March 31,
2023.
(c) For each eligible investigational drug, the annual summary must
include:
(1) The name of the eligible investigational drug and applicable IND
number. The name and IND number of the eligible investigational drug
supplied by the manufacturer or sponsor for use under section 561B of
the Federal Food, Drug, and Cosmetic Act.
(2) Number of doses supplied. The total number of doses supplied by
the manufacturer or sponsor to eligible patients for use under section
561B of the Federal Food, Drug, and Cosmetic Act. Each dose of an
eligible investigational drug supplied for an eligible patient shall be
counted as a dose supplied.
(3) Number of patients treated. The total number of eligible
patients for whom the manufacturer or sponsor provided the eligible
investigational drug for use under section 561B of the Federal Food,
Drug, and Cosmetic Act. An eligible patient treated more than one time
or with multiple doses of an eligible investigational drug shall be
counted as a single patient.
(4) Use for which the eligible investigational drug was made
available. A tabular summary identifying the diseases or conditions for
which the eligible investigational drug was made available for use under
section 561B of the Federal Food, Drug, and Cosmetic Act.
(5) Any known serious adverse events and outcomes. A tabular summary
of any known serious adverse events, including resulting outcomes,
experienced by patients treated with the eligible investigational drug
under section 561B of the Federal Food, Drug, and Cosmetic Act.
(d) Annual summaries submitted pursuant to this section shall be
submitted in an electronic format that FDA can process, review, and
archive, and shall be sent directly to a designated point of contact for
submissions made under section 561B of the Federal Food, Drug, and
Cosmetic Act. The annual summaries must be submitted to the designated
point of contact and shall not be submitted to a particular
investigational new drug application. FDA will specify the designated
point of contact for submission of the annual summary on FDA's website,
as described at https://www.fda.gov.
PART 310_NEW DRUGS--Table of Contents
Subpart A_General Provisions
Sec.
310.3 Definitions and interpretations.
[[Page 7]]
310.4 Biologics; products subject to license control.
310.6 Applicability of ``new drug'' or safety or effectiveness findings
in drug efficacy study implementation notices and notices of
opportunity for hearing to identical, related, and similar
drug products.
Subpart B_Specific Administrative Rulings and Decisions
310.100 New drug status opinions; statement of policy.
310.103 New drug substances intended for hypersensitivity testing.
Subpart C_New Drugs Exempted From Prescription-Dispensing Requirements
310.200 Prescription-exemption procedure.
310.201 Exemption for certain drugs limited by new drug applications to
prescription sale.
Subpart D_Records and Reports
310.305 Records and reports concerning adverse drug experiences on
marketed prescription drugs for human use without approved new
drug applications.
310.306 Notification of a permanent discontinuance or an interruption in
manufacturing of marketed prescription drugs for human use
without approved new drug applications.
Subpart E_Requirements for Specific New Drugs or Devices
310.501 Patient package inserts for oral contraceptives.
310.502 Certain drugs accorded new drug status through rulemaking
procedures.
310.503 Requirements regarding certain radioactive drugs.
310.509 Parenteral drug products in plastic containers.
310.515 Patient package inserts for estrogens.
310.517 Labeling for oral hypoglycemic drugs of the sulfonylurea class.
310.518 Drug products containing iron or iron salts.
310.519 Drug products marketed as over-the-counter (OTC) daytime
sedatives.
310.527 Drug products containing active ingredients offered over-the-
counter (OTC) for external use as hair growers or for hair
loss prevention.
310.528 Drug products containing active ingredients offered over-the-
counter (OTC) for use as an aphrodisiac.
310.529 Drug products containing active ingredients offered over-the-
counter (OTC) for oral use as insect repellents.
310.530 Topically applied hormone-containing drug products for over-the-
counter (OTC) human use.
310.531 Drug products containing active ingredients offered over-the-
counter (OTC) for the treatment of boils.
310.532 Drug products containing active ingredients offered over-the-
counter (OTC) to relieve the symptoms of benign prostatic
hypertrophy.
310.533 Drug products containing active ingredients offered over-the-
counter (OTC) for human use as an anticholinergic in cough-
cold drug products.
310.534 Drug products containing active ingredients offered over-the-
counter (OTC) for human use as oral wound healing agents.
310.536 Drug products containing active ingredients offered over-the-
counter (OTC) for use as a nailbiting or thumbsucking
deterrent.
310.537 Drug products containing active ingredients offered over-the-
counter (OTC) for oral administration for the treatment of
fever blisters and cold sores.
310.538 Drug products containing active ingredients offered over-the-
counter (OTC) for use for ingrown toenail relief.
310.540 Drug products containing active ingredients offered over-the-
counter (OTC) for use as stomach acidifiers.
310.541 Over-the-counter (OTC) drug products containing active
ingredients offered for use in the treatment of
hypophosphatemia.
310.542 Over-the-counter (OTC) drug products containing active
ingredients offered for use in the treatment of
hyperphosphatemia.
310.543 Drug products containing active ingredients offered over-the-
counter (OTC) for human use in exocrine pancreatic
insufficiency.
310.544 Drug products containing active ingredients offered over-the-
counter (OTC) for use as a smoking deterrent.
310.545 Drug products containing certain active ingredients offered
over-the-counter (OTC) for certain uses.
310.546 Drug products containing active ingredients offered over-the-
counter (OTC) for the treatment and/or prevention of nocturnal
leg muscle cramps.
310.547 Drug products containing quinine offered over-the-counter (OTC)
for the treatment and/or prevention of malaria.
310.548 Drug products containing colloidal silver ingredients or silver
salts offered over-the-counter (OTC) for the treatment and/or
prevention of disease.
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360b-360f, 360j,
360hh-360ss, 361(a), 371, 374, 375, 379e, 379k-l; 42 U.S.C. 216, 241,
242(a), 262.
[[Page 8]]
Subpart A_General Provisions
Sec. 310.3 Definitions and interpretations.
As used in this part:
(a) The term act means the Federal Food, Drug, and Cosmetic Act, as
amended (secs. 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C.
321-392).
(b) Department means the Department of Health and Human Services.
(c) Secretary means the Secretary of Health and Human Services.
(d) Commissioner means the Commissioner of Food and Drugs.
(e) The term person includes individuals, partnerships,
corporations, and associations.
(f) The definitions and interpretations of terms contained in
section 201 of the act shall be applicable to such terms when used in
the regulations in this part.
(g) New drug substance means any substance that when used in the
manufacture, processing, or packing of a drug, causes that drug to be a
new drug, but does not include intermediates used in the synthesis of
such substance.
(h) The newness of a drug may arise by reason (among other reasons)
of:
(1) The newness for drug use of any substance which composes such
drug, in whole or in part, whether it be an active substance or a
menstruum, excipient, carrier, coating, or other component.
(2) The newness for a drug use of a combination of two or more
substances, none of which is a new drug.
(3) The newness for drug use of the proportion of a substance in a
combination, even though such combination containing such substance in
other proportion is not a new drug.
(4) The newness of use of such drug in diagnosing, curing,
mitigating, treating, or preventing a disease, or to affect a structure
or function of the body, even though such drug is not a new drug when
used in another disease or to affect another structure or function of
the body.
(5) The newness of a dosage, or method or duration of administration
or application, or other condition of use prescribed, recommended, or
suggested in the labeling of such drug, even though such drug when used
in other dosage, or other method or duration of administration or
application, or different condition, is not a new drug.
(i) [Reserved]
(j) The term sponsor means the person or agency who assumes
responsibility for an investigation of a new drug, including
responsibility for compliance with applicable provisions of the act and
regulations. The ``sponsor'' may be an individual, partnership,
corporation, or Government agency and may be a manufacturer, scientific
institution, or an investigator regularly and lawfully engaged in the
investigation of new drugs.
(k) The phrase related drug(s) includes other brands, potencies,
dosage forms, salts, and esters of the same drug moiety, including
articles prepared or manufactured by other manufacturers: and any other
drug containing a component so related by chemical structure or known
pharmacological properties that, in the opinion of experts qualified by
scientific training and experience to evaluate the safety and
effectiveness of drugs, it is prudent to assume or ascertain the
liability of similar side effects and contraindications.
(l) Special packaging as defined in section 2(4) of the Poison
Prevention Packaging Act of 1970 means packaging that is designed or
constructed to be significantly difficult for children under 5 years of
age to open or obtain a toxic or harmful amount of the substance
contained therein within a reasonable time and not difficult for normal
adults to use properly, but does not mean packaging which all such
children cannot open or obtain a toxic or harmful amount within a
reasonable time.
(m) [Reserved]
(n) The term radioactive drug means any substance defined as a drug
in section 201(g)(1) of the Federal Food, Drug, and Cosmetic Act which
exhibits spontaneous disintegration of unstable nuclei with the emission
of nuclear particles or photons and includes any nonradioactive reagent
kit or nuclide generator which is intended to be used in the preparation
of any such substance but does not include drugs such as carbon-
containing compounds or potassium-containing salts which contain trace
quantities of naturally occurring
[[Page 9]]
radionuclides. The term ``radioactive drug'' includes a ``radioactive
biological product'' as defined in Sec. 600.3(ee) of this chapter.
[39 FR 11680, Mar. 29, 1974, as amended at 39 FR 20484, June 11, 1974;
40 FR 31307, July 25, 1975; 46 FR 8952, Jan. 27, 1981; 50 FR 7492, Feb.
22, 1985]
Sec. 310.4 Biologics; products subject to license control.
(a) If a drug has an approved license under section 351 of the
Public Health Service Act (42 U.S.C. 262 et seq.) or under the animal
virus, serum, and toxin law of March 4, 1913 (21 U.S.C. 151 et seq.), it
is not required to have an approved application under section 505 of the
act.
(b) To obtain marketing approval for radioactive biological products
for human use, as defined in Sec. 600.3(ee) of this chapter,
manufacturers must comply with the provisions of Sec. 601.2(a) of this
chapter.
[64 FR 56448, Oct. 20, 1999, as amended at 70 FR 14981, Mar. 24, 2005]
Sec. 310.6 Applicability of ``new drug'' or safety or effectiveness
findings in drug efficacy study implementation notices and notices of
opportunity for hearing to identical, related, and similar drug products.
(a) The Food and Drug Administration's conclusions on the
effectiveness of drugs are currently being published in the Federal
Register as Drug Efficacy Study Implementation (DESI) Notices and as
Notices of Opportunity for Hearing. The specific products listed in
these notices include only those that were introduced into the market
through the new drug procedures from 1938-62 and were submitted for
review by the National Academy of Sciences-National Research Council
(NAS-NRC), Drug Efficacy Study Group. Many products which are identical
to, related to, or similar to the products listed in these notices have
been marketed under different names or by different firms during this
same period or since 1962 without going through the new drug procedures
or the Academy review. Even though these products are not listed in the
notices, they are covered by the new drug applications reviewed and thus
are subject to these notices. All persons with an interest in a product
that is identical, related, or similar to a drug listed in a drug
efficacy notice or a notice of opportunity for a hearing will be given
the same opportunity as the applicant to submit data and information, to
request a hearing, and to participate in any hearing. It is not feasible
for the Food and Drug Administration to list all products which are
covered by an NDA and thus subject to each notice. However, it is
essential that the findings and conclusions that a drug product is a
``new drug'' or that there is a lack of evidence to show that a drug
product is safe or effective be applied to all identical, related, and
similar drug products to which they are reasonably applicable. Any
product not in compliance with an applicable drug efficacy notice is in
violation of section 505 (new drugs) and/or section 502 (misbranding) of
the act.
(b)(1) An identical, related, or similar drug includes other brands,
potencies, dosage forms, salts, and esters of the same drug moiety as
well as of any drug moiety related in chemical structure or known
pharmacological properties.
(2) Where experts qualified by scientific training and experience to
evaluate the safety and effectiveness of drugs would conclude that the
findings and conclusions, stated in a drug efficacy notice or notice of
opportunity for hearing, that a drug product is a ``new drug'' or that
there is a lack of evidence to show that a drug product is safe or
effective are applicable to an identical, related, or similar drug
product, such product is affected by the notice. A combination drug
product containing a drug that is identical, related, or similar to a
drug named in a notice may also be subject to the findings and
conclusions in a notice that a drug product is a ``new drug'' or that
there is a lack of evidence to show that a drug product is safe or
effective.
(3) Any person may request an opinion on the applicability of such a
notice to a specific product by writing to the Food and Drug
Administration at the address shown in paragraph (e) of this section.
(c) Manufacturers and distributors of drugs should review their
products as
[[Page 10]]
drug efficacy notices are published and assure that identical, related,
or similar products comply with all applicable provisions of the
notices.
(d) The published notices and summary lists of the conclusions are
of particular interest to drug purchasing agents. These agents should
take particular care to assure that the same purchasing policy applies
to drug products that are identical, related, or similar to those named
in the drug efficacy notices. The Food and Drug Administration applies
the same regulatory policy to all such products. In many instances a
determination can readily be made as to the applicability of a drug
efficacy notice by an individual who is knowledgeable about drugs and
their indications for use. Where the relationships are more subtle and
not readily recognized, the purchasing agent may request an opinion by
writing to the Food and Drug Administration at the address shown in
paragraph (e) of this section.
(e) Interested parties may submit to the Food and Drug
Administration, Center for Drug Evaluation and Research, Office of
Compliance, 10903 New Hampshire Ave., Silver Spring, MD 20993-0002, the
names of drug products, and of their manufacturers or distributors, that
should be the subject of the same purchasing and regulatory policies as
those reviewed by the Drug Efficacy Study Group. Appropriate action,
including referral to purchasing officials of various government
agencies, will be taken.
(f) This regulation does not apply to OTC drugs identical, similar,
or related to a drug in the Drug Efficacy Study unless there has been or
is notification in the Federal Register that a drug will not be subject
to an OTC panel review pursuant to Sec. Sec. 330.10, 330.11, and 330.5
of this chapter.
[39 FR 11680, Mar. 29, 1974, as amended at 48 FR 2755, Jan. 21, 1983; 50
FR 8996, Mar. 6, 1985; 55 FR 11578, Mar. 29, 1990; 74 FR 13113, Mar. 26,
2009]
Subpart B_Specific Administrative Rulings and Decisions
Sec. 310.100 New drug status opinions; statement of policy.
(a) Over the years since 1938 the Food and Drug Administration has
given informal advice to inquirers as to the new drug status of
preparations. These drugs have sometimes been identified only by general
statements of composition. Generally, such informal opinions were
incorporated in letters that did not explicitly relate all of the
necessary conditions and qualifications such as the quantitative formula
for the drug and the conditions under which it was prescribed,
recommended, or suggested. This has contributed to misunderstanding and
misinterpretation of such opinions.
(b) These informal opinions that an article is ``not a new drug'' or
``no longer a new drug'' require reexamination under the Kefauver-Harris
Act (Public Law 87-781; 76 Stat. 788-89). In particular, when approval
of a new drug application is withdrawn under provisions of section
505(e) of the Federal Food, Drug, and Cosmetic Act, a drug generally
recognized as safe may become a ``new drug'' within the meaning of
section 201(p) of said act as amended by the Kefauver-Harris Act on
October 10, 1962. This is of special importance by reason of proposed
actions to withdraw approval of new drug applications for lack of
substantial evidence of effectiveness as a result of reports of the
National Academy of Sciences--National Research Council on its review of
drug effectiveness; for example, see the notice published in the Federal
Register of January 23, 1968 (33 FR 818), regarding rutin, quercetin, et
al.
(c) Any marketed drug is a ``new drug'' if any labeling change made
after October 9, 1962, recommends or suggests new conditions of use
under which the drug is not generally recognized as safe and effective
by qualified experts. Undisclosed or unreported side effects as well as
the emergence of new knowledge presenting questions with respect to the
safety or effectiveness of a drug may result in its becoming a ``new
drug'' even though it was previously considered ``not a new drug.''
[[Page 11]]
Any previously given informal advice that an article is ``not a new
drug'' does not apply to such an article if it has been changed in
formulation, manufacture control, or labeling in a way that may
significantly affect the safety of the drug.
(d) For these reasons, all opinions previously given by the Food and
Drug Administration to the effect that an article is ``not a new drug''
or is ``no longer a new drug'' are hereby revoked. This does not mean
that all articles that were the subjects of such prior opinions will be
regarded as new drugs. The prior opinions will be replaced by opinions
of the Food and Drug Administration that are qualified and current on
when an article is ``not a new drug,'' as set forth in this subchapter.
[39 FR 11680, Mar. 29, 1974]
Sec. 310.103 New drug substances intended for hypersensitivity testing.
(a) The Food and Drug Administration is aware of the need in the
practice of medicine for the ingredients of a new drug to be available
for tests of hypersensitivity to such ingredients and therefore will not
object to the shipment of a new drug substance, as defined in Sec.
310.3(g), for such purpose if all of the following conditions are met:
(1) The shipment is made as a result of a specific request made to
the manufacturer or distributor by a practitioner licensed by law to
administer such drugs, and the use of such drugs for patch testing is
not promoted by the manufacturer or distributor.
(2) The new drug substance requested is an ingredient in a marketed
new drug and is not one that is an ingredient solely in a new drug that
is legally available only under the investigational drug provisions of
this part.
(3) The label bears the following prominently placed statements in
lieu of adequate directions for use and in addition to complying with
the other labeling provisions of the act:
(i) ``Rx only''; and
(ii) ``For use only in patch testing''.
(4) The quantity shipped is limited to an amount reasonable for the
purpose of patch testing in the normal course of the practice of
medicine and is used solely for such patch testing.
(5) The new drug substance is manufactured by the same procedures
and meets the same specifications as the component used in the finished
dosage form.
(6) The manufacturer or distributor maintains records of all
shipments for this purpose for a period of 2 years after shipment and
will make them available to the Food and Drug Administration on request.
(b) When the requested new drug substance is intended for
investigational use in humans or the substance is legally available only
under the investigational drug provisions of part 312 of this chapter,
the submission of an ``Investigational New Drug Application'' (IND) is
required. The Food and Drug Administration will offer assistance to any
practitioner wishing to submit an Investigational New Drug Application.
(c) This section does not apply to drugs or their components that
are subject to the licensing requirements of the Public Health Service
Act of 1944, as amended. (See subchapter F--Biologics, of this chapter.)
[39 FR 11680, Mar. 29, 1974, as amended at 55 FR 11578, Mar. 29, 1990;
67 FR 4907, Feb. 1, 2002]
Subpart C_New Drugs Exempted From Prescription-Dispensing Requirements
Sec. 310.200 Prescription-exemption procedure.
(a) Duration of prescription requirement. Any drug limited to
prescription use under section 503(b)(1)(B) of the act remains so
limited until it is exempted as provided in paragraph (b) or (e) of this
section.
(b) Prescription-exemption procedure for drugs limited by a new drug
application. Any drug limited to prescription use under section
503(b)(1)(B) of the act shall be exempted from prescription-dispensing
requirements when the Commissioner finds such requirements are not
necessary for the protection of the public health by reason of the
drug's toxicity or other potentiality for harmful effect, or the method
of its use, or the collateral measures necessary to its use, and he
finds that the drug is safe and effective for use in self-medication as
directed in proposed
[[Page 12]]
labeling. A proposal to exempt a drug from the prescription-dispensing
requirements of section 503(b)(1)(B) of the act may be initiated by the
Commissioner or by any interested person. Any interested person may file
a petition seeking such exemption, which petition may be pursuant to
part 10 of this chapter, or in the form of a supplement to an approved
new drug application.
(c) New drug status of drugs exempted from the prescription
requirement. A drug exempted from the prescription requirement under the
provisions of paragraph (b) of this section is a ``new drug'' within the
meaning of section 201(p) of the act until it has been used to a
material extent and for a material time under such conditions except as
provided in paragraph (e) of this section.
(d) Prescription legend not allowed on exempted drugs. The use of
the prescription caution statement quoted in section 503(b) (4) of the
act, in the labeling of a drug exempted under the provisions of this
section, constitutes misbranding. Any other statement or suggestion in
the labeling of a drug exempted under this section, that such drug is
limited to prescription use, may constitute misbranding.
(e) Prescription-exemption procedure of OTC drug review. A drug
limited to prescription use under section 503(b)(1)(B) of the act may
also be exempted from prescription-dispensing requirements by the
procedure set forth in Sec. 330.13 of this chapter.
[39 FR 11680, Mar. 29, 1974, as amended at 41 FR 32582, Aug. 4, 1976; 42
FR 4714, Jan. 25, 1977; 42 FR 15674, Mar. 22, 1977; 72 FR 15043, Mar.
30, 2007]
Sec. 310.201 Exemption for certain drugs limited by new-drug
applications to prescription sale.
(a) The prescription-dispensing requirements of section503(b)(1)(B)
of the Federal Food, Drug, and Cosmetic Act are not necessary for the
protection of the public health with respect to the following drugs
subject to new drug applications:
(1) N-Acetyl-p-aminophenol (acetaminophen, p-hydroxy-acetanilid)
preparations meeting all the following conditions:
(i) The N-acetyl-p-aminophenol is prepared, with or without other
drugs, in tablet or other dosage form suitable for oral use in self-
medication, and containing no drug limited to prescription sale under
the provisions of section 503(b)(1) of the act.
(ii) The N-acetyl-p-aminophenol and all other components of the
preparation meet their professed standards of identity, strength,
quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to
section 505 (b) of the act is approved for it.
(iv) The preparation contains not more than 0.325 gram (5 grains) of
N-acetyl-p-aminophenol per dosage unit, or if it is in liquid form not
more than 100 milligrams of N-acetyl-p-aminophenol per milliliter.
(v) The preparation is labeled with adequate directions for use in
minor conditions as a simple analgesic.
(vi) The dosages of N-acetyl-p-aminophenol recommended or suggested
in the labeling do not exceed: For adults, 0.65 gram (10 grains) per
dose or 2.6 grams (40 grains) per 24-hour period: for children 6 to 12
years of age, one-half of the maximum adult dose or dosage; for children
3 to 6 years of age, one-fifth of the maximum adult dose or dosage.
(vii) The labeling bears, in juxtaposition with the dosage
recommendations, a clear warning statement against administration of the
drug to children under 3 years of age and against use of the drug for
more than 10 days, unless such uses are directed by a physician.
(viii) If the article is offered for use in arthritis or rheumatism,
the labeling prominently bears a statement that the beneficial effects
claimed are limited to the temporary relief of minor aches and pains of
arthritis and rheumatism and, in juxtaposition with directions for use
in such conditions, a conspicuous warning statement, such as ``Caution:
If pain persists for more than 10 days, or redness is present, or in
conditions affecting children under 12 years of age, consult a physician
immediately''.
(2) Sodium gentisate (sodium-2, 5-dihydroxybenzoate) preparations
meeting all the following conditions:
(i) The sodium gentisate is prepared, with or without other drugs,
in tablet or other dosage form suitable for oral
[[Page 13]]
use in self-medication, and containing no drug limited to prescription
sale under the provisions of section 503(b)(1) of the act.
(ii) The sodium gentisate and all other components of the
preparation meet their professed standards of identity, strength,
quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to
section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 0.5 gram (7.7 grains) of
anhydrous sodium gentisate per dosage unit.
(v) The preparation is labeled with adequate directions for use in
minor conditions as a simple analgesic.
(vi) The dosages of sodium gentisate recommended or suggested in the
labeling do not exceed: For adults, 0.5 gram (7.7 grains) per dose of
2.0 grams (31 grains) per 24-hour period; for children 6 to 12 years of
age, one-half of the maximum adult dose or dosage.
(vii) The labeling bears, in juxtaposition with the dosage
recommendations, a clear warning statement against administration of the
drug to children under 6 years of age and against use of the drug for a
prolonged period, except as such uses may be directed by a physician.
(3) Isoamylhydrocupreine and zolamine hydrochloride (N, N-dimethyl-
N'-2-thiazolyl-N'-p-methoxybenzyl-ethyl- enediamine hydrochloride)
preparations meeting all the following conditions:
(i) The isoamylhydrocupreine and zolamine hydrochloride are prepared
in dosage form suitable for self-medication as rectal suppositories or
as an ointment and containing no drug limited to prescription sale under
the provisions of section 503(b)(1) of the act.
(ii) The isoamylhydrocupreine, zola-amine hydrochloride, and all
other components of the preparation meet their professed standards of
identity, strength, quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to
section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 0.25 percent of
isoamylhydrocupreine and 1.0 percent of zolamine hydrochloride.
(v) If the preparation is in suppository form, it contains not more
than 5.0 milligrams of isoamylhydrocupreine and not more than 20.0
milligrams of zolamine hydrochloride per suppository.
(vi) The preparation is labeled with adequate directions for use in
the temporary relief of local pain and itching associated with
hemorrhoids.
(vii) The directions provide for the use of not more than two
suppositories or two applications of ointment in a 24-hour period.
(viii) The labeling bears, in juxtaposition with the dosage
recommendations, a clear warning statement against use of the
preparation in case of rectal bleeding, as this may indicate serious
disease.
(4) Phenyltoloxamine dihydrogen citrate (N,N-dimethyl-(a-phenyl-O-
toloxy) ethylamine dihydrogen citrate), preparations meeting all the
following conditions:
(i) The phenyltoloxamine dihydrogen citrate is prepared, with or
without other drugs, in tablet or other dosage form suitable for oral
use in self-medication, and containing no drug limited to prescription
sale under the provisions of section 503(b)(1) of the act.
(ii) The phenyltoloxamine dihydrogen citrate and all other
components of the preparation meet their professed standards of
identity, strength, quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to
section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 88 milligrams of
phenyltoloxamine dihydrogen citrate (equivalent to 50 milligrams of
phenyltoloxamine) per dosage unit.
(v) The preparation is labeled with adequate directions for use in
the temporary relief of the symptoms of hay fever and/or the symptoms of
other minor conditions in which it is indicated.
(vi) The dosages recommended or suggested in the labeling do not
exceed: For adults, 88 milligrams of phenyltoloxamine dihydrogen citrate
(equivalent to 50 milligrams of phenyltoloxamine) per dose or 264
milligrams of phenyltoloxamine dihydrogen citrate
[[Page 14]]
(equivalent to 150 milligrams of phenyltoloxamine) per 24-hour period;
for children 6 to 12 years of age, one-half of the maximum adult dose or
dosage.
(vii) The labeling bears, in juxtaposition with the dosage
recommendations:
(a) Clear warning statements against administration of the drug to
children under 6 years of age, except as directed by a physician, and
against driving a car or operating machinery while using the drug, since
it may cause drowsiness.
(b) If the article is offered for temporary relief of the symptoms
of colds, a statement that continued administration for such use should
not exceed 3 days, except as directed by a physician.
(5)-(7) [Reserved]
(8) Dicyclomine hydrochloride (1-cyclohexylhexahydrobenzoic acid.
[beta]-diethylaminoethyl ester hydrochloride; diethylaminocarbethoxy-
bicyclohexyl hydrochloride) preparations meeting all the following
conditions:
(i) The dicyclomine hydrochloride is prepared with suitable antacid
and other components, in tablet or other dosage form for oral use in
self-medication, and containing no drug limited to prescription sale
under the provisions of section 503(b)(1) of the act.
(ii) The dicyclomine hydrochloride and all other components of the
preparation meet their professed standards of identity, strength,
quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to
section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 5 milligrams of
dicyclomine hydrochloride per dosage unit, or if it is in liquid form
not more than 0.5 milligram of dicyclomine hydrochloride per milliliter.
(v) The preparation is labeled with adequate directions for use only
by adults and children over 12 years of age, in the temporary relief of
gastric hyperacidity.
(vi) The dosages recommended or suggested in the directions for use
do not exceed 10 milligrams of dicyclomine hydrochloride per dose or 30
milligrams in a 24-hour period.
(vii) The labeling bears, in juxtaposition with the dosage
recommendations, clear warning statements against:
(a) Exceeding the recommended dosage.
(b) Prolonged use, except as directed by a physician, since
persistent or recurring symptoms may indicate a serious disease
requiring medical attention.
(c) Administration to children under 12 years of age except as
directed by a physician.
(9)-(10) [Reserved]
(11) Hexadenol (a mixture of tetracosanes and their oxidation
products) preparations meeting all the following conditions:
(i) The hexadenol is prepared and packaged, with or without other
drugs, solvents, and propellants, in a form suitable for self-medication
by external application to the skin as a spray, and containing no drug
limited to prescription sale under the provisions of section 503(b)(1)
of the act.
(ii) The hexadenol and all other components of the preparation meet
their professed standards of identity, strength, quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to
section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 5 percent by weight of
hexadenol.
(v) The preparation is labeled with adequate directions for use by
external application in the treatment of minor burns and minor skin
irritations.
(vi) The labeling bears, in juxtaposition with the directions for
use, clear warning statements against:
(a) Use on serious burns or skin conditions or prolonged use, except
as directed by a physician.
(b) Spraying the preparation in the vicinity of eyes, mouth, nose,
or ears.
(12) Sulfur dioxide preparations meeting all the following
conditions:
(i) The sulfur dioxide is prepared with or without other drugs, in
an aqueous solution packaged in a hermetic container suitable for use in
self-medication by external application to the skin, and containing no
drug limited to prescription sale under the provisions of section
503(b)(1) of the act.
[[Page 15]]
(ii) The sulfur dioxide and all other components of the preparation
meet their professed standards of identity, strength, quality, and
purity.
(iii) If the preparation is a new drug, an application pursuant to
section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 5 grams of sulfur
dioxide per 100 milliliters of solution.
(v) The preparation is labeled with adequate directions for use by
external application to the smooth skin in the prevention or treatment
of minor conditions in which it is indicated.
(vi) The directions for use recommend or suggest not more than two
applications a day for not more than 1 week, except as directed by a
physician.
(13)-(15) [Reserved]
(16) Tuaminoheptane sulfate (2-aminoheptane sulfate) preparations
meeting all the following conditions:
(i) The tuaminoheptane sulfate is prepared, with or without other
drugs, in an aqueous vehicle suitable for administration in self-
medication as nose drops, and containing no drug limited to prescription
sale under the provisions of section 503(b)(1) of the act.
(ii) The preparation is packaged with a style of container or
assembly suited to self-medication by the recommended route of
administration, and delivering not more than 0.1 milliliter of the
preparation per drop.
(iii) The tuaminoheptane sulfate and all other components of the
preparation meet their professed standards of identity, strength,
quality, and purity.
(iv) If the preparation is a new drug, an application pursuant to
section 505(b) of the act is approved for it.
(v) The tuaminoheptane sulfate content of the preparation does not
exceed 10 milligrams per milliliter.
(vi) The preparation is labeled with adequate directions for use in
the temporary relief of nasal congestion.
(vii) The dosages recommended or suggested in the directions for use
do not exceed the equivalent: For adults, 5 drops of a 1 percent
solution per nostril per dose, and 5 doses in a 24-hour period; for
children 1 to 6 years of age, 3 drops of a 1 percent solution per
nostril per dose, and 5 doses in a 24-hour period; for infants under 1
year of age, 2 drops of a 1 percent solution per nostril per dose, and 5
doses in a 24-hour period.
(viii) The labeling bears, in juxtaposition with the dosage
recommendations:
(a) Clear warning statements against use of more than 5 doses daily,
and against use longer than 4 days unless directed by a physician.
(b) A clear warning statement to the effect that frequent use may
cause nervousness or sleeplessness, and that individuals with high blood
pressure, heart disease, diabetes, or thyroid disease should not use the
preparation unless directed by a physician.
(17) [Reserved]
(18) Vibesate (a mixture of copolymers of hydroxy-vinyl
chlorideacetate, sebacic acid, and modified maleic rosin ester)
preparations meeting all the following conditions.
(i) The vibesate is prepared and packaged, with or without other
drugs, solvents, and propellants, in a form suitable for self-medication
by external application to the skin as a spray, and containing no drug
limited to prescription sale under the provisions of section 503(b)(1)
of the act.
(ii) The vibesate and all other components of the preparation meet
their professed standards of identity, strength, quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to
section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 13 percent by weight of
vibesate.
(v) The preparation is labeled with adequate directions for use by
external application as a dressing for minor burns, minor cuts, or other
minor skin irritations.
(vi) The labeling bears in juxtaposition with the directions for use
clear warning statements against:
(a) Use on serious burns and on infected, deep, and puncture wounds
unless directed by a physician.
(b) Spraying the preparation near the eyes or other mucous
membranes.
(c) Inhaling the preparation.
(d) Use near open flames.
(e) Puncturing the container or throwing the container into fire.
[[Page 16]]
(19) Pramoxine hydrochloride (4-N-butoxyphenyl [gamma]-
morpholinopropyl ether hydrochloride) preparations meeting all the
following conditions:
(i) The pramoxine hydrochloride is prepared, with or without other
drugs, in a dosage form suitable for use in self-medication by external
application to the skin, and containing no drug limited to prescription
sale under the provisions of section 503(b)(1) of the act.
(ii) The pramoxine hydrochloride and all other components of the
preparation meet their professed standards of identity, strength,
quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to
section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 1.0 percent of pramoxine
hydrochloride.
(v) The preparation is labeled with adequate directions for use by
external application to the skin for the temporary relief of pain or
itching due to minor burns and sunburn, nonpoisonous insect bites, and
minor skin irritations.
(vi) The directions for use recommend or suggest not more than four
applications of the preparation per day, unless directed by a physician.
(vii) The labeling bears, in juxtaposition with the directions for
use, clear warning statements against:
(a) Prolonged use.
(b) Application to large areas of the body.
(c) Continued use if redness, irritation, swelling, or pain persists
or increases, unless directed by a physician.
(d) Use in the eyes or nose.
(20) [Reserved]
(21) Pamabrom (2-amino-2-methylpropanol-1-8-bromotheophyllinate)
preparations meeting all the following conditions:
(i) The pamabrom is prepared with appropriate amounts of a suitable
analgesic and with or without other drugs, in tablet or other dosage
form suitable for oral use in self-medication, and containing no drug
limited to prescription sale under the provisions of section 503(b)(1)
of the act.
(ii) The pamabrom and all other components of the preparation meet
their professed standards of identity, strength, quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to
section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 50 milligrams of
pamabrom per dosage unit.
(v) The preparation is labeled with adequate directions for use in
the temporary relief of the minor pains and discomforts that may occur a
few days before and during the menstrual period.
(vi) The dosages recommended or suggested in the labeling do not
exceed 50 milligrams of pamabrom per dose or 200 milligrams per 24-hour
period.
(22) Diphemanil methylsulfate (4-diphenylmethylene-1,1-dimethyl-
piperidinium methylsulfate) preparations meeting all the following
conditions:
(i) The diphemanil methylsulfate is prepared, with or without other
drugs, in a dosage form suitable for use in self-medication by external
application to the skin, and containing no drug limited to prescription
sale under the provisions of section 503(b)(1) of the act.
(ii) The diphemanil methylsulfate and all other components of the
preparation meet their professed standards of identity, strength,
quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to
section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 2.0 percent of
diphemanil methylsulfate.
(v) The preparation is labeled with adequate directions for use by
external application to the skin for the relief of symptoms of mild
poison ivy, oak, and sumac and other minor irritations and itching of
the skin.
(vi) The directions for use recommend or suggest not more than four
applications of the preparation per day, unless directed by a physician.
(vii) The labeling bears, in juxtaposition with the directions for
use, a clear warning statement, such as: ``Caution: If redness,
irritation, swelling, or pain persists or increases, discontinue use and
consult physician.''
[[Page 17]]
(23) Dyclonine hydrochloride (4-butoxy-3-piperidinopropiophenone
hydrochloride; 4-n-butoxy-[beta]-piperidonopropiophenone hydrochloride)
preparations meeting all the following conditions:
(i) The dyclonine hydrochloride is prepared, with or without other
drugs, in a dosage form suitable for use as a cream or ointment in self-
medication by external application to the skin, or rectally, and
contains no drug limited to prescription sale under the provisions of
section 503(b)(1) of the act.
(ii) The dyclonine hydrochloride and all other components of the
preparation meet their professed standards of identity, strength,
quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to
section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 1.0 percent of dyclonine
hydrochloride.
(v) The preparation is labeled with adequate directions for use:
(a) By external application to the skin for the temporary relief of
pain and itching in sunburn, nonpoisonous insect bites, minor burns,
cuts, abrasions, and other minor skin irritations.
(b) [Reserved]
(c) In the prevention or treatment of other minor conditions in
which it is indicated.
(vi) The labeling bears, in juxtaposition with the directions for
use, clear warning statements against:
(a) Continued use if redness, irritation, swelling, or pain persists
or increases, unless directed by a physician.
(b) Use in case of rectal bleeding, as this may indicate serious
disease.
(c) Use in the eyes.
(d) Prolonged use.
(e) Application to large areas of the body.
(f) Use for deep or puncture wounds or serious burns.
(24) Chlorothen citrate (chloromethapyrilene citrate; N,N-dimethyl-
N'-(2-pyridyl)-N'-(5-chloro-2-thenyl) ethylenediamine citrate)
preparations meeting all the following conditions:
(i) The chlorothen citrate is prepared, with or without other drugs,
in tablet or other dosage form suitable for oral use in self-medication,
and containing no drug limited to prescription sale under the provisions
of section 503(b)(1) of the act.
(ii) The chlorothen citrate and all other components of the
preparation meet their professed standards of identity, strength,
quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to
section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 25 milligrams of
chlorothen citrate per dosage unit.
(v) The preparation is labeled with adequate directions for use in
the temporary relief of the symptoms of hay fever and/or the symptoms of
other minor conditions in which it is indicated.
(vi) The dosages recommended or suggested in the labeling do not
exceed: For adults, 25 milligrams of chlorothen citrate per dose or 150
milligrams of chlorothen citrate per 24-hour period; for children 6 to
12 years of age, one-half of the maximum adult dose or dosage.
(vii) The labeling bears, in juxtaposition with the dosage
recommendations:
(a) Clear warning statements against administration of the drug to
children under 6 years of age or exceeding the recommended dosage,
unless directed by a physician, and against driving a car or operating
machinery while using the drug, since it may cause drowsiness.
(b) If the article is offered for the temporary relief of symptoms
of colds, a statement that continued administration for such use should
not exceed 3 days, unless directed by a physician.
(25) [Reserved]
(26) Methoxyphenamine hydrochloride ([beta]-(o-methoxyphenyl)-
isopropyl-methylamine hydrochloride; 1-(o-methoxyphenyl)- 2-methylamino-
propane hydrochloride) preparations meeting all the following
conditions:
(i) The methoxyphenamine hydrochloride is prepared with appropriate
amounts of a suitable antitussive, with or without other drugs, in a
dosage form suitable for oral use in self-medication, and containing no
drug limited to prescription sale under the provisions of section
503(b)(1) of the act.
(ii) The methoxyphenamine hydrochloride and all other components of
the preparation meet their professed
[[Page 18]]
standards of identity, strength, quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to
section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 3.5 milligrams of
methoxyphenamine hydrochloride per milliliter.
(v) The preparation is labeled with adequate directions for use in
the temporary relief of cough due to minor conditions in which it is
indicated.
(vi) The dosages recommended or suggested in the labeling do not
exceed: For adults, 35 milligrams of methoxyphenamine hydrochloride per
dose or 140 milligrams of methoxyphenamine hydrochloride per 24-hour
period; for children 6 to 12 years of age, one-half of the maximum adult
dose or dosage.
(vii) The label bears a conspicuous warning to keep the drug out of
the reach of children, and the labeling bears, in juxtaposition with the
dosage recommendations:
(a) A clear warning statement against administration of the drug to
children under 6 years of age, unless directed by a physician.
(b) A clear warning statement to the effect that frequent or
prolonged use may cause nervousness, restlessness, or drowsiness, and
that individuals with high blood pressure, heart disease, diabetes, or
thyroid disease should not use the preparation unless directed by a
physician.
(c) A clear warning statement against use of the drug in the
presence of high fever or if cough persists, since persistent cough as
well as high fever may indicate the presence of a serious condition.
(27) Biphenamine hydrochloride ([beta]-diethylaminoethyl-3-phenyl-2-
hydroxybenzoate hydrochloride) preparations meeting all the following
conditions:
(i) The biphenamine hydrochloride is prepared in a form suitable for
use as a shampoo and contains no drug limited to prescription sale under
the provisions of section 503(b)(1) of the act.
(ii) The biphenamine hydrochloride meets its professed standards of
identity, strength, quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to
section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 1 percent of biphenamine
hydrochloride.
(v) The preparation is labeled with adequate directions for use for
the temporary relief of itching and scaling due to dandruff.
(vi) The label bears a conspicuous warning to keep the drug out of
the reach of children.
(28) Tyloxapol (an alkylarylpolyether alcohol) and benzalkonium
chloride ophthalmic preparations meeting all the following conditions:
(i) The tyloxapol and benzalkonium chloride are prepared, with other
appropriate ingredients which are not drugs limited to prescription sale
under the provisions of section 503(b)(1) of the act, as a sterile,
isotonic aqueous solution suitable for use in self-medication on eye
prostheses.
(ii) The preparation is so packaged as to volume and type of
container as to afford adequate protection and be suitable for self-
medication with a minimum risk of contamination of the solution during
use. Any dispensing unit is sterile and so packaged as to maintain
sterility until the package is opened.
(iii) The tyloxapol, benzalkonium chloride, and other ingredients
used to prepare the isotonic aqueous solution meet their professed
standards of identity, strength, quality, and purity.
(iv) An application pursuant to section 505(b) of the act is
approved for the drug.
(v) The preparation contains 0.25 percent of tyloxapol and 0.02
percent of benzalkonium chloride.
(vi) The label bears a conspicuous warning to keep the drug out of
the reach of children and the labeling bears, in juxtaposition with the
dosage recommendations, a clear warning that if irritation occurs,
persists, or increases, use of the drug should be discontinued and a
physician consulted. The labeling includes a statement that the dropper
or other dispensing tip should not touch any surface, since this may
contaminate the solution.
(29) [Reserved]
[[Page 19]]
(b) [Reserved]
[39 FR 11680, Mar. 29, 1974, as amended at 42 FR 36994, July 19, 1977;
52 FR 15892, Apr. 30, 1987; 52 FR 30055, Aug. 12, 1987; 55 FR 31779,
Aug. 3, 1990; 57 FR 58374, Dec. 9, 1992; 58 FR 49898, Sept. 23, 1993; 59
FR 4218, Jan. 28, 1994; 60 FR 52507, Oct. 6, 1995; 72 FR 15043, Mar. 30,
2007; 72 FR 67640, Nov. 30, 2007]
Subpart D_Records and Reports
Sec. 310.305 Records and reports concerning adverse drug experiences
on marketed prescription drugs for human use without approved new drug
applications.
(a) Scope. FDA is requiring manufacturers, packers, and distributors
of marketed prescription drug products that are not the subject of an
approved new drug or abbreviated new drug application to establish and
maintain records and make reports to FDA of all serious, unexpected
adverse drug experiences associated with the use of their drug products.
Any person subject to the reporting requirements of paragraph (c) of
this section must also develop written procedures for the surveillance,
receipt, evaluation, and reporting of postmarketing adverse drug
experiences to FDA.
(b) Definitions. The following definitions of terms apply to this
section:
Adverse drug experience. Any adverse event associated with the use
of a drug in humans, whether or not considered drug related, including
the following: An adverse event occurring in the course of the use of a
drug product in professional practice; an adverse event occurring from
drug overdose whether accidental or intentional; an adverse event
occurring from drug abuse; an adverse event occurring from drug
withdrawal; and any failure of expected pharmacological action.
Disability. A substantial disruption of a person's ability to
conduct normal life functions.
Individual case safety report (ICSR). A description of an adverse
drug experience related to an individual patient or subject.
ICSR attachments. Documents related to the adverse drug experience
described in an ICSR, such as medical records, hospital discharge
summaries, or other documentation.
Life-threatening adverse drug experience. Any adverse drug
experience that places the patient, in the view of the initial reporter,
at immediate risk of death from the adverse drug experience as it
occurred, i.e., it does not include an adverse drug experience that, had
it occurred in a more severe form, might have caused death.
Serious adverse drug experience. Any adverse drug experience
occurring at any dose that results in any of the following outcomes:
Death, a life-threatening adverse drug experience, inpatient
hospitalization or prolongation of existing hospitalization, a
persistent or significant disability/incapacity, or a congenital
anomaly/birth defect. Important medical events that may not result in
death, be life-threatening, or require hospitalization may be considered
a serious adverse drug experience when, based upon appropriate medical
judgment, they may jeopardize the patient or subject and may require
medical or surgical intervention to prevent one of the outcomes listed
in this definition. Examples of such medical events include allergic
bronchospasm requiring intensive treatment in an emergency room or at
home, blood dyscrasias or convulsions that do not result in inpatient
hospitalization, or the development of drug dependency or drug abuse.
Unexpected adverse drug experience. Any adverse drug experience that
is not listed in the current labeling for the drug product. This
includes events that may be symptomatically and pathophysiologically
related to an event listed in the labeling, but differ from the event
because of greater severity or specificity. For example, under this
definition, hepatic necrosis would be unexpected (by virtue of greater
severity) if the labeling only referred to elevated hepatic enzymes or
hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis
would be unexpected (by virtue of greater specificity) if the labeling
only listed cerebral vascular accidents. ``Unexpected,'' as used in this
definition, refers to an adverse drug experience that has not been
previously observed (i.e., included in the labeling) rather than from
the perspective of such experience
[[Page 20]]
not being anticipated from the pharmacological properties of the
pharmaceutical product.
(c) Reporting requirements. Each person identified in paragraph
(c)(1)(i) of this section must submit to FDA adverse drug experience
information as described in this section. Except as provided in
paragraph (e)(2) of this section, 15-day ``Alert reports'' and followup
reports, including ICSRs and any ICSR attachments, must be submitted to
the Agency in electronic format as described in paragraph (e)(1) of this
section.
(1) Postmarketing 15-day ``Alert reports''. (i) Any person whose
name appears on the label of a marketed prescription drug product as its
manufacturer, packer, or distributor must report to FDA each adverse
drug experience received or otherwise obtained that is both serious and
unexpected as soon as possible, but no later than 15 calendar days from
initial receipt of the information by the person whose name appears on
the label. Each report must be accompanied by the current content of
labeling in electronic format as an ICSR attachment unless it is already
on file at FDA.
(ii) A person identified in paragraph (c)(1)(i) of this section is
not required to submit a 15-day ``Alert report'' for an adverse drug
experience obtained from a postmarketing study (whether or not conducted
under an investigational new drug application) unless the applicant
concludes that there is a reasonable possibility that the drug caused
the adverse experience.
(2) Postmarketing 15-day ``Alert reports''--followup. Each person
identified in paragraph (c)(1)(i) of this section must promptly
investigate all serious, unexpected adverse drug experiences that are
the subject of these postmarketing 15-day Alert reports and must submit
followup reports within 15 calendar days of receipt of new information
or as requested by FDA. If additional information is not obtainable,
records should be maintained of the unsuccessful steps taken to seek
additional information.
(3) Submission of reports. To avoid unnecessary duplication in the
submission of, and followup to, reports required in this section, a
packer's or distributor's obligations may be met by submission of all
reports of serious adverse drug experiences to the manufacturer of the
drug product. If a packer or distributor elects to submit these adverse
drug experience reports to the manufacturer rather than to FDA, it must
submit, by any appropriate means, each report to the manufacturer within
5 calendar days of its receipt by the packer or distributor, and the
manufacturer must then comply with the requirements of this section even
if its name does not appear on the label of the drug product. Under this
circumstance, the packer or distributor must maintain a record of this
action which must include:
(i) A copy of each adverse drug experience report;
(ii) The date the report was received by the packer or distributor;
(iii) The date the report was submitted to the manufacturer; and
(iv) The name and address of the manufacturer.
(4) [Reserved]
(5) A person identified in paragraph (c)(1)(i) of this section is
not required to resubmit to FDA adverse drug experience reports
forwarded to that person by FDA; however, the person must submit all
followup information on such reports to FDA.
(d) Information reported on ICSRs. ICSRs include the following
information:
(1) Patient information.
(i) Patient identification code;
(ii) Patient age at the time of adverse drug experience, or date of
birth;
(iii) Patient gender; and
(iv) Patient weight.
(2) Adverse drug experience.
(i) Outcome attributed to adverse drug experience;
(ii) Date of adverse drug experience;
(iii) Date of ICSR submission;
(iv) Description of adverse drug experience (including a concise
medical narrative);
(v) Adverse drug experience term(s);
(vi) Description of relevant tests, including dates and laboratory
data; and
(vii) Other relevant patient history, including preexisting medical
conditions.
(3) Suspect medical product(s).
(i) Name;
[[Page 21]]
(ii) Dose, frequency, and route of administration used;
(iii) Therapy dates;
(iv) Diagnosis for use (indication);
(v) Whether the product is a combination product as defined in Sec.
3.2(e) of this chapter;
(vi) Whether the product is a prescription or nonprescription
product;
(vii) Whether adverse drug experience abated after drug use stopped
or dose reduced;
(viii) Whether adverse drug experience reappeared after
reintroduction of drug;
(ix) Lot number;
(x) Expiration date;
(xi) National Drug Code (NDC) number; and
(xii) Concomitant medical products and therapy dates.
(4) Initial reporter information.
(i) Name, address, and telephone number;
(ii) Whether the initial reporter is a health care professional; and
(iii) Occupation, if a health care professional.
(5) Manufacturer, packer, or distributor information.
(i) Manufacturer, packer, or distributor name and contact office
address;
(ii) Telephone number;
(iii) Report source, such as spontaneous, literature, or study;
(iv) Date the report was received by manufacturer, packer, or
distributor;
(v) Whether the ICSR is a 15-day ``Alert report'';
(vi) Whether the ICSR is an initial report or followup report; and
(vii) Unique case identification number, which must be the same in
the initial report and any subsequent followup report(s).
(e) Electronic format for submissions. (1) Each report required to
be submitted to FDA under this section, including the ICSR and any ICSR
attachments, must be submitted in an electronic format that FDA can
process, review, and archive. FDA will issue guidance on how to provide
the electronic submission (e.g., method of transmission, media, file
formats, preparation and organization of files).
(2) Each person identified in paragraph (c)(1)(i) of this section
may request, in writing, a temporary waiver of the requirements in
paragraph (e)(1) of this section. These waivers will be granted on a
limited basis for good cause shown. FDA will issue guidance on
requesting a waiver of the requirements in paragraph (e)(1) of this
section.
(f) Patient privacy. Manufacturers, packers, and distributors should
not include in reports under this section the names and addresses of
individual patients; instead, the manufacturer, packer, and distributor
should assign a unique code for identification of the patient. The
manufacturer, packer, and distributor should include the name of the
reporter from whom the information was received as part of the initial
reporter information, even when the reporter is the patient. The names
of patients, individual reporters, health care professionals, hospitals,
and geographical identifiers in adverse drug experience reports are not
releasable to the public under FDA's public information regulations in
part 20 of this chapter.
(g) Recordkeeping. (1) Each manufacturer, packer, and distributor
must maintain for a period of 10 years records of all adverse drug
experiences required under this section to be reported, including raw
data and any correspondence relating to the adverse drug experiences,
and the records required to be maintained under paragraph (c)(3) of this
section.
(2) Manufacturers and packers may retain the records required in
paragraph (f)(1) of this section as part of its complaint files
maintained under Sec. 211.198 of this chapter.
(3) Manufacturers, packers, and distributors must permit any
authorized FDA employee, at all reasonable times, to have access to and
copy and verify the records established and maintained under this
section.
(h) Disclaimer. A report or information submitted by a manufacturer,
packer, or distributor under this section (and any release by FDA of
that report or information) does not necessarily reflect a conclusion by
the manufacturer, packer, or distributor, or by FDA, that the report or
information constitutes an admission that the
[[Page 22]]
drug caused or contributed to an adverse effect. The manufacturer,
packer, or distributor need not admit, and may deny, that the report or
information submitted under this section constitutes an admission that
the drug caused or contributed to an adverse effect.
[51 FR 24479, July 3, 1986, as amended at 52 FR 37936, Oct. 13, 1987; 55
FR 11578, Mar. 29, 1990; 57 FR 17980, Apr. 28, 1992; 62 FR 34167, June
25, 1997; 62 FR 52249, Oct. 7, 1997; 67 FR 9585, Mar. 4, 2002; 74 FR
13113, Mar. 26, 2009; 79 FR 33087, June 10, 2014]
Sec. 310.306 Notification of a permanent discontinuance or an
interruption in manufacturing of marketed prescription drugs for human
use without approved new drug applications.
(a) Applicability. Marketed prescription drug products that are not
the subject of an approved new drug or abbreviated new drug application
are subject to this section.
(b) Notification of a permanent discontinuance or an interruption in
manufacturing. The manufacturer of each product subject to this section
must make the notifications required under Sec. 314.81(b)(3)(iii) of
this chapter and otherwise comply with Sec. 314.81(b)(3)(iii) of this
chapter. If the manufacturer of a product subject to this section fails
to provide notification as required under Sec. 314.81(b)(3)(iii), FDA
will send a letter to the manufacturer and otherwise follow the
procedures set forth under Sec. 314.81(b)(3)(iii)(e).
(c) Drug shortages list. FDA will include on the drug shortages list
required by Sec. 314.81(b)(3)(iii)(d) drug products that are subject to
this section that it determines to be in shortage. For such drug
products, FDA will provide the names of each manufacturer rather than
the names of each applicant. With respect to information collected under
this paragraph, FDA will observe the confidentiality and disclosure
provisions set forth in Sec. 314.81(b)(3)(iii)(d)(2).
[80 FR 38938, July 8, 2015]
Subpart E_Requirements for Specific New Drugs or Devices
Sec. 310.501 Patient package inserts for oral contraceptives.
(a) Requirement for a patient package insert. The safe and effective
use of oral contraceptive drug products requires that patients be fully
informed of the benefits and the risks involved in their use. An oral
contraceptive drug product that does not comply with the requirements of
this section is misbranded under section 502 of the Federal Food, Drug,
and Cosmetic Act. Each dispenser of an oral contraceptive drug product
shall provide a patient package insert to each patient (or to an agent
of the patient) to whom the product is dispensed, except that the
dispenser may provide the insert to the parent or legal guardian of a
legally incompetent patient (or to the agent of either). The patient
package insert is required to be placed in or accompany each package
dispensed to the patient.
(b) Distribution requirements. (1) For oral contraceptive drug
products, the manufacturer and distributor shall provide a patient
package insert in or with each package of the drug product that the
manufacturer or distributor intends to be dispensed to a patient.
(2) Patient package inserts for oral contraceptives dispensed in
acute-care hospitals or long-term care facilities will be considered to
have been provided in accordance with this section if provided to the
patient before administration of the first oral contraceptive and every
30 days thereafter, as long as the therapy continues.
(c) Contents of patient package insert. A patient package insert for
an oral contraceptive drug product is required to contain the following:
(1) The name of the drug.
(2) A summary including a statement concerning the effectiveness of
oral contraceptives in preventing pregnancy, the contraindications to
the drug's use, and a statement of the risks and benefits associated
with the drug's use.
(3) A statement comparing the effectiveness of oral contraceptives
to other methods of contraception.
[[Page 23]]
(4) A boxed warning concerning the increased risks associated with
cigarette smoking and oral contraceptive use.
(5) A discussion of the contraindications to use, including
information that the patient should provide to the prescriber before
taking the drug.
(6) A statement of medical conditions that are not contraindications
to use but deserve special consideration in connection with oral
contraceptive use and about which the patient should inform the
prescriber.
(7) A warning regarding the most serious side effects of oral
contraceptives.
(8) A statement of other serious adverse reactions and potential
safety hazards that may result from the use of oral contraceptives.
(9) A statement concerning common, but less serious side effects
which may help the patient evaluate the benefits and risks from the use
of oral contraceptives.
(10) Information on precautions the patients should observe while
taking oral contraceptives, including the following:
(i) A statement of risks to the mother and unborn child from the use
of oral contraceptives before or during early pregnancy;
(ii) A statement concerning excretion of the drug in human milk and
associated risks to the nursing infant;
(iii) A statement about laboratory tests which may be affected by
oral contraceptives; and
(iv) A statement that identifies activities and drugs, foods, or
other substances the patient should avoid because of their interactions
with oral contraceptives.
(11) Information about how to take oral contraceptives properly,
including information about what to do if the patient forgets to take
the product, information about becoming pregnant after discontinuing use
of the drug, a statement that the drug product has been prescribed for
the use of the patient and should not be used for other conditions or
given to others, and a statement that the patient's pharmacist or
practitioner has a more technical leaflet about the drug product that
the patient may ask to review.
(12) A statement of the possible benefits associated with oral
contraceptive use.
(13) The following information about the drug product and the
patient package insert:
(i) The name and place of business of the manufacturer, packer, or
distributor, or the name and place of business of the dispenser of the
product.
(ii) The date, identified as such, of the most recent revision of
the patient package insert placed prominently immediately after the last
section of the labeling.
(d) Other indications. The patient package insert may identify
indications in addition to contraception that are identified in the
professional labeling for the drug product.
(e) Labeling guidance texts. The Food and Drug Administration issues
informal labeling guidance texts under Sec. 10.90(b)(9) of this chapter
to provide assistance in meeting the requirements of this section. A
request for a copy of the guidance texts should be directed to the
Center for Drug Evaluation and Research, Division of Reproductive and
Urologic Products, Food and Drug Administration, 10903 New Hampshire
Ave., Silver Spring, MD 20993-0002.
(f) Requirement to supplement approved application. Holders of
approved applications for oral contraceptive drug products that are
subject to the requirements of this section are required to submit
supplements under Sec. 314.70(c) of this chapter to provide for the
labeling required by this section. Such labeling may be put into use
without advance approval by the Food and Drug Administration.
[54 FR 22587, May 25, 1989, as amended at 74 FR 13113, Mar. 26, 2009]
Sec. 310.502 Certain drugs accorded new drug status through rulemaking
procedures.
(a) The drugs listed in this paragraph (a) have been determined by
rulemaking procedures to be new drugs within the meaning of section
201(p) of the Federal Food, Drug, and Cosmetic Act. An approved new drug
application under section 505 of the Federal Food, Drug, and Cosmetic
Act and part 314 of this chapter is required for marketing the following
drugs:
[[Page 24]]
(1) Aerosol drug products for human use containing 1,1,1-
trichloroethane.
(2) Aerosol drug products containing zirconium.
(3) Amphetamines (amphetamine, dextroamphetamine, and their salts,
and levamfetamine and its salts) for human use.
(4) Camphorated oil drug products.
(5) Certain halogenated salicylanilides (tribromsalan (TBS, 3,4',5-
tribromosalicylanilide), dibromsalan (DBS, 4', 5-dibromosalicylanilide),
metabromsalan (MBS, 3, 5-dibromosalicylanilide), and 3,3', 4,5'-
tetrachlorosalicylanilide (TC-SA)) as an ingredient in drug products.
(6) Chloroform used as an ingredient (active or inactive) in drug
products.
(7) Cobalt preparations intended for use by man.
(8) Intrauterine devices for human use for the purpose of
contraception that incorporate heavy metals, drugs, or other active
substances.
(9) Oral prenatal drugs containing fluorides intended for human use.
(10) Parenteral drug products in plastic containers.
(11) [Reserved]
(12) Sweet spirits of nitre drug products.
(13) Thorium dioxide for drug use.
(14) Timed release dosage forms.
(15) Vinyl chloride as an ingredient, including propellant, in
aerosol drug products.
(b) [Reserved]
[62 FR 12084, Mar. 14, 1997, as amended at 64 FR 401, Jan. 5, 1999; 84
FR 68334, Dec. 16, 2019]
Sec. 310.503 Requirements regarding certain radioactive drugs.
(a) On January 8, 1963 (28 FR 183), the Commissioner of Food and
Drugs exempted investigational radioactive new drugs from part 312 of
this chapter provided they were shipped in complete conformity with the
regulations issued by the Nuclear Regulatory Commission. This exemption
also applied to investigational radioactive biologics.
(b) It is the opinion of the Nuclear Regulatory Commission, and the
Food and Drug Administration that this exemption should not apply for
certain specific drugs and that these drugs should be appropriately
labeled for uses for which safety and effectiveness can be demonstrated
by new drug applications or through licensing under the Public Health
Service Act (42 U.S.C. 262 et seq.) in the case of biologics. Continued
distribution under the investigational exemption when the drugs are
intended for established uses will not be permitted.
(c) Based on its experience in regulating investigational
radioactive pharmaceuticals, the Nuclear Regulatory Commission has
compiled a list of reactor-produced isotopes for which it considers that
applicants may reasonably be expected to submit adequate evidence of
safety and effectiveness for use as recommended in appropriate labeling.
Such use may include, among others, the uses in this tabulation:
------------------------------------------------------------------------
Isotope Chemical form Use
------------------------------------------------------------------------
Chromium 51........... Chromate............... Spleen scans.
Do................... ......do............... Placenta localization.
Do................... ......do............... Red blood cell labeling
and survival studies.
Do................... Labeled human serum Gastrointestinal
albumin. protein loss studies.
Do................... ......do............... Placenta localization.
Do................... Labeled red blood cells Do.
Cobalt 58 or Cobalt 60 Labeled cyanocobalamin. Intestinal absorption
studies.
Gold 198.............. Colloidal.............. Liver scans.
Do................... ......do............... Intracavitary treatment
of pleural effusions
and/or ascites.
Do................... ......do............... Interstitial treatment
of cancer.
Iodine 131............ Iodide................. Diagnosis of thyroid
functions.
Do................... ......do............... Thyroid scans.
Do................... ......do............... Treatment of
hyperthyroidism and/or
cardiac dysfunction.
Do................... ......do............... Treatment of thyroid
carcinoma.
Do................... Iodinated human serum Blood volume
albumin. determinations.
Do................... ......do............... Cisternography.
Do................... ......do............... Brain tumor
localization.
Do................... ......do............... Placenta localization.
Do................... ......do............... Cardiac scans for
determination of
pericardial effusions.
Do................... Rose Bengal............ Liver function studies.
Do................... ......do............... Liver scans.
[[Page 25]]
Do................... Iodopyracet, sodium Kidney function studies
iodohippurate, sodium and kidney scans.
diatrizoate,
diatrizoate
methylglucamine,
sodium diprotrizoate,
sodium acetrizoate, or
sodium iothalamate.
Do................... Labeled fats and/or Fat absorption studies.
fatty acids.
Do................... Cholografin............ Cardiac scans for
determination of
pericardial effusions.
Do................... Macroaggregated Lung scans.
iodinated human serum
albumin.
Do................... Colloidal Liver scans.
microaggregated human
serum albumin.
Iodine 125............ Iodide................. Diagnosis of thyroid
function.
Do................... Iodinated human serum Blood volume
albumin. determinations.
Do................... Rose Bengal............ Liver function studies.
Do................... Iodopyracet, sodium Kidney function
iodohippurate, sodium studies.
diatrizoate,
diatrizoate methyl-
glucamine, sodium
diprotrizoate, sodium
acetrizoate, or sodium
iothalamate.
Do................... Labeled fats and/or Fat absorption studies.
fatty acids.
Iron 59............... Chloride, citrate and/ Iron turnover studies.
or sulfate.
Krypton 85............ Gas.................... Diagnosis of cardiac
abnormalities.
Mercury 197........... Chlormerodrin.......... Kidney scans.
Do................... ......do............... Brain scans.
Mercury 203 \1\....... ......do............... Kidney scans.
Do................... ......do............... Brain scans.
Phosphorus 32......... Soluble phosphate...... Treatment of
polycythemia vera.
Do................... ......do............... Treatment of leukemia
and bone metastasis.
Do................... Colloidal chromic Intracavitary treatment
phosphate. of pleural effusions
and/or ascites.
Do................... ......do............... Interstitial treatment
of cancer.
Potassium 42.......... Chloride............... Potassium space
studies.
Selenium 75........... Labeled methionine..... Pancreas scans.
Strontium 85.......... Nitrate or chloride.... Bone scans on patients
with diagnosed cancer.
Technetium 99m........ Pertechnetate.......... Brain scans.
Do................... ......do............... Thyroid scans.
Do................... Sulfur colloid......... Liver and spleen scans.
Do................... Pertechnetate.......... Placenta localization.
Do................... ......do............... Blood pool scans.
Do................... ......do............... Salivary gland scans.
Do................... Diethylenetri-amine Kidney scans.
pentaacetic acid
(DTPA).
Xenon 133............. Gas.................... Diagnosis of cardia
abnormalities.
Cerebral bloodflow
studies. Pulmonary
function studies.
Muscle bloodflow
studies.
------------------------------------------------------------------------
\1\ This item has been removed from the AEC list for kidney scans but is
included as the requirements of this order are applicable.
(d)(1) In view of the extent of experience with the isotopes listed
in paragraph (c) of this section, the Nuclear Regulatory Commission and
the Food and Drug Administration conclude that such isotopes should not
be distributed under investigational-use labeling when they are actually
intended for use in medical practice.
(2) The exemption referred to in paragraph (a) of this section, as
applied to any drug or biologic containing any of the isotopes listed in
paragraph (c) of this section, in the ``chemical form'' and intended for
the uses stated, is terminated on March 3, 1972, except as provided in
paragraph (d)(3) of this section.
(3) The exemption referred to in paragraph (a) of this section, as
applied to any drug or biologic containing any of the isotopes listed in
paragraph (c) of this section, in the ``chemical form'' and intended for
the uses stated, for which drug a new drug application or a
``Investigational New Drug Application'' was submitted prior to March 3,
1972, or for which biologic an application for product license or
``Investigational New Drug Application'' was submitted prior to March 3,
1972, is terminated on August 20, 1976, unless an approvable notice was
issued on or before August 20, 1976, in which case the exemption is
terminated either upon the subsequent issuance of a nonapprovable notice
for the new drug application or on November 20, 1976, whichever occurs
first.
(e) No exemption from section 505 of the act or from part 312 of
this chapter is in effect or has been in effect for radioactive drugs
prepared from accelerator-produced radioisotopes, naturally occurring
isotopes, or nonradioactive substances used in conjunction with
isotopes.
[[Page 26]]
(f)(1) Based on its experience in regulating investigational
radioactive pharmaceuticals, the Nuclear Regulatory Commission has
compiled a list of reactor-produced isotopes for which it considers that
applicants may reasonably be expected to submit adequate evidence of
safety and effectiveness for use as recommended in appropriate labeling;
such use may include, among others, the uses in this tabulation:
------------------------------------------------------------------------
Isotope Chemical form Use
------------------------------------------------------------------------
Fluorine 18........... Fluoride............... Bone imaging.
Indium-113m........... Diethylenetriamine Brain imaging; kidney
pentaacetic acid imaging.
(DTPA).
Do................... Chloride............... Placenta imaging; blood
pool imaging.
Technetium 99m........ Human serum albumin Lung imaging.
microspheres.
Do................... Diethylenetriamine Kidney imaging; kidney
pentaacetic acid (Sn). function studies.
Do................... ......do............... Brain imaging.
Do................... Polyphosphates......... Bone imaging.
Do................... Technetated aggregated Lung imaging.
albumin (human).
Do................... Disodium etidronate.... Bone imaging.
------------------------------------------------------------------------
(2) In view of the extent of experience with the isotopes listed in
paragraph (f)(1) of this section, the Nuclear Regulatory Commission and
the Food and Drug Administration conclude that they should not be
distributed under investigational-use labeling when they are actually
intended for use in medical practice.
(3) Any manufacturer or distributor interested in continuing to ship
in interstate commerce drugs containing the isotopes listed in paragraph
(f)(1) of this section for any of the indications listed, shall submit,
on or before August 25, 1975 to the Center for Drug Evaluation and
Research, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD
20857, a new drug application or a ``Investigational New Drug
Application'' for each such drug for which the manufacturer or
distributor does not have an approved new drug application pursuant to
section 505(b) of the act. If the drug is a biologic, a
``Investigational New Drug Application'' or an application for a license
under section 351 of the Public Health Service Act shall be submitted to
the Food and Drug Administration, Center for Biologics Evaluation and
Research, Document Control Center, 10903 New Hampshire Ave., Bldg. 71,
Rm. G112, Silver Spring, MD 20993-0002, in lieu of any submission to the
Center for Drug Evaluation and Research.
(4) The exemption referred to in paragraph (a) of this section, as
applied to any drug or biologic containing any of the isotopes listed in
paragraph (f)(1) of this section, in the ``chemical form'' and intended
for the uses stated, is terminated on August 26, 1975 except as provided
in paragraph (f)(5) of this section.
(5)(i) Except as provided in paragraph (f)(5)(ii) of this section,
the exemption referred to in paragraph (a) of this section, as applied
to any drug containing any of the isotopes listed in paragraph (f)(1) of
this section, in the ``chemical form'' and intended for the uses stated,
for which drug a new drug application or ``Investigational New Drug
Application'' was submitted to the Center for Drug Evaluation and
Research on or before August 25, 1975 is terminated on August 20, 1976,
unless an approvable notice was issued on or before August 20, 1976, in
which case the exemption is terminated either upon the subsequent
issuance of a nonapprovable notice for the new drug application or on
November 20, 1976, whichever occurs first.
(ii) The exemption referred to in paragraph (a) of this section, as
applied to any biologic containing any of the isotopes listed in
paragraph (f)(1) of this section in the ``chemical form'' and intended
for the uses stated, for which biologic an application for product
license or ``Investigational New Drug Application'' was submitted to the
Center for Biologics Evaluation and Research on or before August 25,
1975 is terminated on October 20, 1976, unless an approvable notice was
issued on or before October 20, 1976, in which case the exemption is
terminated either upon the subsequent issuance of a nonapprovable notice
for the new drug application or on January 20, 1977, whichever occurs
first.
(g) The exemption referred to in paragraph (a) of this section, as
applied to any drug intended solely for investigational use as part of a
research project, which use had been approved on or before July 25, 1975
in accordance
[[Page 27]]
with 10 CFR 35.11 (or equivalent regulation of an Agreement State) is
terminated on February 20, 1976 if the manufacturer of such drug or the
sponsor of the investigation of such drug submits on or before August
25, 1975 to the Food and Drug Administration, Bureau of Drugs, HFD-150,
5600 Fishers Lane, Rockville, MD 20857, the following information:
(1) The research project title;
(2) A brief description of the purpose of the project;
(3) The name of the investigator responsible;
(4) The name and license number of the institution holding the
specific license under 10 CFR 35.11 (or equivalent regulation of an
Agreement State);
(5) The name and maximum amount per subject of the radionuclide
used;
(6) The number of subjects involved; and
(7) The date on which the administration of the radioactive drugs is
expected to be completed.
(h) The exemption referred to in paragraph (a) of this section, as
applied to any drug not referred to in paragraphs (d), (f), and (g) of
this section, is terminated on August 26, 1975.
[39 FR 11680, Mar. 29, 1974, as amended at 40 FR 31307, July 25, 1975;
40 FR 44543, Sept. 29, 1975; 41 FR 35171, Aug. 20, 1976; 41 FR 42947,
Sept. 29, 1976; 50 FR 8996, Mar. 6, 1985; 55 FR 11578, Mar. 29, 1990; 64
FR 56449, Oct. 20, 1999; 80 FR 18091, Apr. 3, 2015]
Sec. 310.509 Parenteral drug products in plastic containers.
(a) Any parenteral drug product packaged in a plastic immediate
container is not generally recognized as safe and effective, is a new
drug within the meaning of section 201(p) of the act, and requires an
approved new drug application as a condition for marketing. An
``Investigational New Drug Application'' set forth in part 312 of this
chapter is required for clinical investigations designed to obtain
evidence of safety and effectiveness.
(b) As used in this section, the term ``large volume parenteral drug
product'' means a terminally sterilized aqueous drug product packaged in
a single-dose container with a capacity of 100 milliliters or more and
intended to be administered or used intravenously in a human.
(c) Until the results of compatibility studies are evaluated, a
large volume parenteral drug product for intravenous use in humans that
is packaged in a plastic immediate container on or after April 16, 1979,
is misbranded unless its labeling contains a warning that includes the
following information:
(1) A statement that additives may be incompatible.
(2) A statement that, if additive drugs are introduced into the
parenteral system, aseptic techniques should be used and the solution
should be thoroughly mixed.
(3) A statement that a solution containing an additive drug should
not be stored.
(d) This section does not apply to a biological product licensed
under the Public Health Service Act of July 1, 1944 (42 U.S.C. 201).
[62 FR 12084, Mar. 14, 1997]
Sec. 310.515 Patient package inserts for estrogens.
(a) Requirement for a patient package insert. FDA concludes that the
safe and effective use of drug products containing estrogens requires
that patients be fully informed of the benefits and risks involved in
the use of these drugs. Accordingly, except as provided in paragraph (e)
of this section, each estrogen drug product restricted to prescription
distribution, including products containing estrogens in fixed
combinations with other drugs, shall be dispensed to patients with a
patient package insert containing information concerning the drug's
benefits and risks. An estrogen drug product that does not comply with
the requirements of this section is misbranded under section 502(a) of
the Federal Food, Drug, and Cosmetic Act.
(b) Distribution requirements. (1) For estrogen drug products, the
manufacturer and distributor shall provide a patient package insert in
or with each package of the drug product that the manufacturer or
distributor intends to be dispensed to a patient.
(2) In the case of estrogen drug products in bulk packages intended
for multiple dispensing, and in the case of
[[Page 28]]
injectables in multiple-dose vials, a sufficient number of patient
labeling pieces shall be included in or with each package to assure that
one piece can be included with each package or dose dispensed or
administered to every patient. Each bulk package shall be labeled with
instructions to the dispensor to include one patient labeling piece with
each package dispensed or, in the case of injectables, with each dose
administered to the patient. This section does not preclude the
manufacturer or labeler from distributing additional patient labeling
pieces to the dispensor.
(3) Patient package inserts for estrogens dispensed in acute-care
hospitals or long-term care facilities will be considered to have been
provided in accordance with this section if provided to the patient
before administration of the first estrogen and every 30 days
thereafter, as long as the therapy continues.
(c) Patient package insert contents. A patient package insert for an
estrogen drug product is required to contain the following information:
(1) The name of the drug.
(2) The name and place of business of the manufacturer, packer, or
distributor.
(3) A statement regarding the benefits and proper uses of estrogens.
(4) The contraindications to use, i.e., when estrogens should not be
used.
(5) A description of the most serious risks associated with the use
of estrogens.
(6) A brief summary of other side effects of estrogens.
(7) Instructions on how a patient may reduce the risks of estrogen
use.
(8) The date, identified as such, of the most recent revision of the
patient package insert.
(d) Guidance language. The Food and Drug Administration issues
informal labeling guidance texts under Sec. 10.90(b)(9) of this chapter
to provide assistance in meeting the requirements of paragraph (c) of
this section. Requests for a copy of the guidance text should be
directed to the Center for Drug Evaluation and Research, Division of
Reproductive and Urologic Products, Food and Drug Administration, 10903
New Hampshire Ave., Silver Spring, MD 20993-0002.
(e) Exemptions. This section does not apply to estrogen-progestogen
oral contraceptives. Labeling requirements for these products are set
forth in Sec. 310.501.
(f) Requirement to supplement approved application. Holders of
approved applications for estrogen drug products that are subject to the
requirements of this section must submit supplements under Sec.
314.70(c) of this chapter to provide for the labeling required by
paragraph (a) of this section. Such labeling may be put into use without
advance approval by the Food and Drug Administration.
[55 FR 18723, May 4, 1990, as amended at 74 FR 13113, Mar. 26, 2009]
Sec. 310.517 Labeling for oral hypoglycemic drugs of the sulfonylurea
class.
(a) The University Group Diabetes Program clinical trial has
reported an association between the administration of tolbutamide and
increased cardiovascular mortality. The Food and Drug Administration has
concluded that this reported association provides adequate basis for a
warning in the labeling. In view of the similarities in chemical
structure and mode of action, the Food and Drug Administration also
believes it is prudent from a safety standpoint to consider that the
possible increased risk of cardiovascular mortality from tolbutamide
applies to all other sulfonylurea drugs as well. Therefore, the labeling
for oral hypoglycemic drugs of the sulfonylurea class shall include a
warning concerning the possible increased risk of cardiovascular
mortality associated with such use, as set forth in paragraph (b) of
this section.
(b) Labeling for oral hypoglycemic drugs of the sulfonylurea class
shall include in boldface type at the beginning of the ``Warnings''
section of the labeling the following statement:
Special Warning on Increased Risk of Cardiovascular Mortality
The administration of oral hypoglycemic drugs has been reported to
be associated with increased cardiovascular mortality as compared to
treatment with diet alone or diet plus insulin. This warning is based on
the study conducted by the University Group
[[Page 29]]
Diabetes Program (UGDP), a long-term prospective clinical trial designed
to evaluate the effectiveness of glucose-lowering drugs in preventing or
delaying vascular complications in patients with non-insulin-dependent
diabetes. The study involved 823 patients who were randomly assigned to
one of four treatment groups (Diabetes, 19 (supp. 2): 747-830, 1970).
UGDP reported that patients treated for 5 to 8 years with diet plus
a fixed dose of tolbutamide (1.5 grams per day) had a rate of
cardiovascular mortality approximately 2\1/2\ times that of patients
treated with diet alone. A significant increase in total mortality was
not observed, but the use of tolbutamide was discontinued based on the
increase in cardiovascular mortality, thus limiting the opportunity for
the study to show an increase in overall mortality. Despite controversy
regarding the interpretation of these results, the findings of the UGDP
study provide an adequate basis for this warning. The patient should be
informed of the potential risks and advantages of (name of drug) and of
alternative modes of therapy.
Although only one drug in the sulfonylurea class (tolbutamide) was
included in this study, it is prudent from a safety standpoint to
consider that this warning may also apply to other oral hypoglycemic
drugs in this class, in view of their close similarities in mode of
action and chemical structure.
[49 FR 14331, Apr. 11, 1984]
Sec. 310.518 Drug products containing iron or iron salts.
Drug products containing elemental iron or iron salts as an active
ingredient in solid oral dosage form, e.g., tablets or capsules shall
meet the following requirements:
(a) Labeling. (1) The label of any drug in solid oral dosage form
(e.g., tablets or capsules) that contains iron or iron salts for use as
an iron source shall bear the following statement:
WARNING: Accidental overdose or iron-containing products is a
leading cause of fatal poisoning in children under 6. Keep this product
out of reach of children. In case of accidental overdose, call a doctor
or poison control center immediately.
(2)(i) The warning statement required by paragraph (a)(1) of this
section shall appear prominently and conspicuously on the information
panel of the immediate container label.
(ii) If a drug product is packaged in unit-dose packaging, and if
the immediate container bears labeling but not a label, the warning
statement required by paragraph (a)(1) of this section shall appear
prominently and conspicuously on the immediate container labeling in a
way that maximizes the likelihood that the warning is intact until all
of the dosage units to which it applies are used.
(3) Where the immediate container is not the retail package, the
warning statement required by paragraph (a)(1) of this section shall
also appear prominently and conspicuously on the information panel of
the retail package label.
(4) The warning statement shall appear on any labeling that contains
warnings.
(5) The warning statement required by paragraph (a)(1) of this
section shall be set off in a box by use of hairlines.
(b) The iron-containing inert tablets supplied in monthly packages
of oral contraceptives are categorically exempt from the requirements of
paragraph (a) of this section.
[68 FR 59715, Oct. 17, 2003]
Sec. 310.519 Drug products marketed as over-the-counter (OTC) daytime
sedatives.
(a) Antihistamines, bromides, and scopolamine compounds, either
singly or in combinations, have been marketed as ingredients in over-
the-counter (OTC) drug products for use as daytime sedatives. The
following claims have been made for daytime sedative products:
``occasional simple nervous tension,'' ``nervous irritability,''
``nervous tension headache,'' ``simple nervousness due to common every
day overwork and fatigue,'' ``a relaxed feeling,'' ``calming down and
relaxing,'' ``gently soothe away the tension,'' ``calmative,''
``resolving that irritability that ruins your day,'' ``helps you
relax,'' ``restlessness,'' ``when you're under occasional stress . . .
helps you work relaxed.'' Based on evidence presently available, there
are no ingredients that can be generally recognized as safe and
effective for use as OTC daytime sedatives.
(b) Any OTC drug product that is labeled, represented, or promoted
as an OTC daytime sedative (or any similar or related indication) is
regarded as a new drug within the meaning of section 201(p) of the
Federal Food, Drug, and
[[Page 30]]
Cosmetic Act for which an approved new drug application under section
505 of the act and part 314 of this chapter is required for marketing.
(c) Clinical investigations designed to obtain evidence that any
drug product labeled, represented, or promoted as an OTC daytime
sedative (or any similar or related indication) is safe and effective
for the purpose intended must comply with the requirements and
procedures governing the use of investigational new drugs set forth in
part 312 of this chapter.
(d) Any OTC daytime sedative drug product introduced into interstate
commerce after December 24, 1979, that is not in compliance with this
section is subject to regulatory action.
[44 FR 36380, June 22, 1979; 45 FR 47422, July 15, 1980, as amended at
55 FR 11579, Mar. 29, 1990]
Sec. 310.527 Drug products containing active ingredients offered
over-the-counter (OTC) for external use as hair growers or for hair
loss prevention.
(a) Amino acids, aminobenzoic acid, ascorbic acid, benzoic acid,
biotin and all other B-vitamins, dexpanthenol, estradiol and other
topical hormones, jojoba oil, lanolin, nucleic acids, polysorbate 20,
polysorbate 60, sulfanilamide, sulfur 1 percent on carbon in a fraction
of paraffinic hydrocarbons, tetracaine hydrochloride, urea, and wheat
germ oil have been marketed as ingredients in OTC drug products for
external use as hair growers or for hair loss prevention. There is a
lack of adequate data to establish general recognition of the safety and
effectiveness of these or any other ingredients intended for OTC
external use as a hair grower or for hair loss prevention. Based on
evidence currently available, all labeling claims for OTC hair grower
and hair loss prevention drug products for external use are either
false, misleading, or unsupported by scientific data. Therefore, any OTC
drug product for external use containing an ingredient offered for use
as a hair grower or for hair loss prevention cannot be considered
generally recognized as safe and effective for its intended use.
(b) Any OTC drug product that is labeled, represented, or promoted
for external use as a hair grower or for hair loss prevention is
regarded as a new drug within the meaning of section 201(p) of the
Federal Food, Drug, and Cosmetic Act (the act), for which an approved
new drug application under section 505 of the act and part 314 of this
chapter is required for marketing. In the absence of an approved new
drug application, such product is also misbranded under section 502 of
the act.
(c) Clinical investigations designed to obtain evidence that any
drug product labeled, represented, or promoted for OTC external use as a
hair grower or for hair loss prevention is safe and effective for the
purpose intended must comply with the requirements and procedures
governing the use of investigational new drugs set forth in part 312 of
this chapter.
(d) After January 8, 1990, any such OTC drug product initially
introduced or initially delivered for introduction into interstate
commerce that is not in compliance with this section is subject to
regulatory action.
[54 FR 28777, July 7, 1989]
Sec. 310.528 Drug products containing active ingredients offered
over-the-counter (OTC) for use as an aphrodisiac.
(a) Any product that bears labeling claims that it will arouse or
increase sexual desire, or that it will improve sexual performance, is
an aphrodisiac drug product. Anise, cantharides, don qual, estrogens,
fennel, ginseng, golden seal, gotu kola, Korean ginseng, licorice,
mandrake, methyltestosterone, minerals, nux vomica, Pega Palo,
sarsaparilla, strychnine, testosterone, vitamins, yohimbine, yohimbine
hydrochloride, and yohimbinum have been present as ingredients in such
drug products. Androgens (e.g., testosterone and methyltestosterone) and
estrogens are powerful hormones when administered internally and are not
safe for use except under the supervision of a physician. There is a
lack of adequate data to establish general recognition of the safety and
effectiveness of any of these ingredients, or any other ingredient, for
OTC use as an aphrodisiac. Labeling claims for aphrodisiacs for OTC use
are either false, misleading, or
[[Page 31]]
unsupported by scientific data. The following claims are examples of
some that have been made for aphrodisiac drug products for OTC use:
``acts as an aphrodisiac;'' ``arouses or increases sexual desire and
improves sexual performance;'' ``helps restore sexual vigor, potency,
and performance;'' ``improves performance, staying power, and sexual
potency;'' and ``builds virility and sexual potency.'' Based on evidence
currently available, any OTC drug product containing ingredients for use
as an aphrodisiac cannot be generally recognized as safe and effective.
(b) Any OTC drug product that is labeled, represented, or prompted
for use as an aphrodisiac is regarded as a new drug within the meaning
of section 201(p) of the Federal Food, Drug, and Cosmetic Act, (the
act), for which an approved new drug application under section 505 of
the act and part 314 of this chapter is required for marketing. In the
absence of an approved new drug application, such product is also
misbranded under section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any
drug product labeled, represented, or promoted for OTC use as an
aphrodisiac is safe and effective for the purpose intended must comply
with the requirements and procedures governing the use of
investigational new drugs set forth in part 312 of this chapter.
(d) After January 8, 1990, any such OTC drug product initially
introduced or initially delivered for introduction into interstate
commerce that is not in compliance with this section is subject to
regulatory action.
[54 FR 28786, July 7, 1989]
Sec. 310.529 Drug products containing active ingredients offered
over-the-counter (OTC) for oral use as insect repellents.
(a) Thiamine hydrochloride (vitamin B-1) has been marketed as an
ingredient in over-the-counter (OTC) drug products for oral use as an
insect repellent (an orally administered drug product intended to keep
insects away). There is a lack of adequate data to establish the
effectiveness of this, or any other ingredient for OTC oral use as an
insect repellent. Labeling claims for OTC orally administered insect
repellent drug products are either false, misleading, or unsupported by
scientific data. The following claims are examples of some that have
been made for orally administered OTC insect repellent drug products:
``Oral mosquito repellent,'' ``mosquitos avoid you,'' ``bugs stay
away,'' ``keep mosquitos away for 12 to 24 hours,'' and ``the newest way
to fight mosquitos.'' Therefore, any drug product containing ingredients
offered for oral use as an insect repellent cannot be generally
recognized as safe and effective.
(b) Any OTC drug product that is labeled, represented, or promoted
for oral use as an insect repellent is regarded as a new drug within the
meaning of section 201(p) of the Federal Food, Drug and Cosmetic Act for
which an approved new drug application under section 505 of the act and
part 314 of this chapter is required for marketing. In the absence of an
approved new drug application, such product is also misbranded under
section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any
drug product labeled, represented, or promoted OTC for oral use as an
insect repellent is safe and effective for the purpose intended must
comply with the requirements and procedures governing the use of
investigational new drugs set forth in part 312 of this chapter.
(d) Any such drug product in interstate commerce after December 17,
1985, that is not in compliance with this section is subject to
regulatory action.
[40 FR 25171, June 17, 1985, as amended at 55 FR 11579, Mar. 29, 1990]
Sec. 310.530 Topically applied hormone-containing drug products for
over-the-counter (OTC) human use.
(a) The term ``hormone'' is used broadly to describe a chemical
substance formed in some organ of the body, such as the adrenal glands
or the pituitary, and carried to another organ or tissue, where it has a
specific effect. Hormones include, for example, estrogens, progestins,
androgens, anabolic steroids, and adrenal corticosteroids,
[[Page 32]]
and synthetic analogs. Estrogens, progesterone, pregnenolone, and
pregnenolone acetate have been present as ingredients in OTC drug
products marketed for topical use as hormone creams. However, there is a
lack of adequate data to establish effectiveness for any OTC drug use of
these ingredients. Therefore, with the exception of those hormones
identified in paragraph (e) of this section, any OTC drug product
containing an ingredient offered for use as a topically applied hormone
cannot be considered generally recognized as safe and effective for its
intended use. The intended use of the product may be inferred from the
product's labeling, promotional material, advertising, and any other
relevant factor. The use of the word ``hormone'' in the text of the
labeling or in the ingredient statement is an implied drug claim. The
claim implied by the use of this term is that the product will have a
therapeutic or some other physiological effect on the body. Therefore,
reference to a product as a ``hormone cream'' or any statement in the
labeling indicating that ``hormones'' are present in the product, or any
statement that features or emphasizes the presence of a hormone
ingredient in the product, will be considered to be a therapeutic claim
for the product, or a claim that the product will affect the structure
or function of the body, and will consequently cause the product to be a
drug.
(b) Any OTC drug product that is labeled, represented, or promoted
as a topically applied hormone-containing product for drug use, with the
exception of those hormones identified in paragraph (e) of this section,
is regarded as a new drug within the meaning of section 201(p) of the
act, for which an approved application or abbreviated application under
section 505 of the act and part 314 of this chapter is required for
marketing. In the absence of an approved new drug application or
abbreviated new drug application, such product is also misbranded under
section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any
drug product labeled, represented, or promoted for OTC use as a
topically applied hormone-containing drug product is safe and effective
for the purpose intended must comply with the requirements and
procedures governing the use of investigational new drugs set forth in
part 312 of this chapter.
(d) After March 9, 1994, any such OTC drug product initially
introduced or initially delivered for introduction into interstate
commerce that is not in compliance with this section is subject to
regulatory action.
(e) This section does not apply to hydrocortisone and hydrocortisone
acetate labeled, represented, or promoted for OTC topical use in
accordance with part 348 of this chapter.
[58 FR 47610, Sept. 9, 1993]
Sec. 310.531 Drug products containing active ingredients offered
over-the-counter (OTC) for the treatment of boils.
(a) Aminacrine hydrochloride, benzocaine, bismuth subnitrate,
calomel, camphor, cholesterol, ergot fluid extract, hexachlorophene,
ichthammol, isobutamben, juniper tar (oil of cade), lanolin, magnesium
sulfate, menthol, methyl salicylate, oxyguinoline sulfate, petrolatum,
phenol, pine tar, rosin, rosin cerate, sassafras oil, sulfur, thymol,
triclosan, and zinc oxide have been present in OTC boil treatment drug
products. There is a lack of adequate data to establish general
recognition of the safety and effectiveness of these or any other
ingredient for OTC use for the treatment of boils. Treatment is defined
as reducing the size of a boil or reducing an infection related to a
boil. Treatment has involved the use of ``drawing salves'' for these
purposes. These ``drawing salves'' contained various ingredients. Based
on evidence currently available, any OTC drug product offered for the
treatment of boils cannot be considered generally recognized as safe and
effective.
(b) Any OTC drug product that is labeled, represented, or promoted
for the treatment of boils is regarded as a new drug within the meaning
of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act),
for which an approved application or abbreviated application under
section 505 of the act and part 314 of this chapter is required
[[Page 33]]
for marketing. In the absence of an approved new drug application or
abbreviated new drug application, such product is also misbranded under
section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any OTC
boil treatment drug product is safe and effective for the purpose
intended must comply with the requirements and procedures governing the
use of investigational new drugs set forth in part 312 of this chapter.
(d) After May 7, 1991, any such OTC drug product that contains
aminacrine hydrochloride, bismuth subnitrate, calomel, camphor,
cholesterol, ergot fluid extract, hexachlorophene, isobutamben, juniper
tar (oil of cade), lanolin, magnesium sulfate, menthol, methyl
salicylate, oxyguinoline sulfate, petrolatum, phenol, pine tar, rosin,
rosin cerate, sassafras oil, thymol, or zinc oxide initially introduced
or initially delivered for introduction into interstate commerce that is
not in compliance with this section is subject to regulatory action.
(e) After May 16, 1994, any such OTC drug product that contains
benzocaine, ichthammol, sulfur, or triclosan initially introduced or
initially delivered for introduction into interstate commerce that is
not in compliance with this section is subject to regulatory action.
(f) This section does not apply to drug products that contain
benzocaine labeled, represented, or promoted for OTC topical use in
accordance with part 348 of this chapter.
[58 FR 60336, Nov. 15, 1993]
Sec. 310.532 Drug products containing active ingredients offered
over-the-counter (OTC) to relieve the symptoms of benign prostatic
hypertrophy.
(a) The amino acids glycine, alanine, and glutamic acid (alone or in
combination) and the ingredient sabal have been present in over-the-
counter (OTC) drug products to relieve the symptoms of benign prostatic
hypertrophy, e.g., urinary urgency and frequency, excessive urinating at
night, and delayed urination. There is a lack of adequate data to
establish general recognition of the safety and effectiveness of these
or any other ingredients for OTC use in relieving the symptoms of benign
prostatic hypertrophy. In addition, there is no definitive evidence that
any drug product offered for the relief of the symptoms of benign
prostatic hypertrophy would alter the obstructive or inflammatory signs
and symptoms of this condition. Therefore, self-medication with OTC drug
products might unnecessarily delay diagnosis and treatment of
progressive obstruction and secondary infections. Based on evidence
currently available, any OTC drug product containing ingredients offered
for use in relieving the symptoms of benign prostatic hypertrophy cannot
be generally recognized as safe and effective.
(b) Any OTC drug product that is labeled, represented, or promoted
to relieve the symptoms of benign prostatic hypertrophy is regarded as a
new drug within the meaning of section 201(p) of the Federal Food, Drug,
and Cosmetic Act (the act), for which an approved application under
section 505 of the act and part 314 of this chapter is required for
marketing. In the absence of an approved application, such product is
also misbranded under section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any
drug product labeled, represented, or promoted for OTC use to relieve
the symptoms of benign prostatic hypertrophy is safe and effective for
the purpose intended must comply with the requirements and procedures
governing the use of investigational new drugs set forth in part 312 of
this chapter.
(d) After August 27, 1990, any such OTC drug product initially
introduced or initially delivered for introduction into interstate
commerce that is not in compliance with this section is subject to
regulatory action.
[55 FR 6930, Feb. 27, 1990]
[[Page 34]]
Sec. 310.533 Drug products containing active ingredients offered
over-the-counter (OTC) for human use as an anticholinergic in cough-cold
drug products.
(a) Atropine sulfate, belladonna alkaloids, and belladonna alkaloids
as contained in Atropa belladonna and Datura stramonium have been
present as ingredients in cough-cold drug products for use as an
anticholinergic. Anticholinergic drugs have been marketed OTC in cough-
cold drug products to relieve excessive secretions of the nose and eyes,
symptoms that are commonly associated with hay fever, allergy, rhinitis,
and the common cold. Atropine sulfate for oral use as an anticholinergic
is probably safe at dosages that have been used in marketed cough-cold
products (0.2 to 0.3 milligram); however, there are inadequate data to
establish general recognition of the effectiveness of this ingredient.
The belladonna alkaloids, which contain atropine (d, dl hyoscyamine) and
scopolamine (l- hyoscine), are probably safe for oral use at dosages
that have been used in marketed cough-cold products (0.2 milligram) but
there are inadequate data to establish general recognition of the
effectiveness of these ingredients as an anticholinergic for cough-cold
use. Belladonna alkaloids for inhalation use, as contained in Atropa
belladonna and Datura stramonium, are neither safe nor effective as an
OTC anticholinergic. There are inadequate safety and effectiveness data
to establish general recognition of the safety and/or effectiveness or
any of these ingredients, or any other ingredient, for OTC use as an
anticholinergic in cough-cold drug products.
(b) Any OTC cough-cold drug product that is labeled, represented, or
promoted for use as an anticholinergic is regarded as a new drug within
the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic
Act, for which an approved new drug application under section 505 of the
act and part 314 of this chapter is required for marketing. In the
absence of an approved new drug application, such product is also
misbranded under section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any
cough-cold drug product labeled, represented, or promoted for OTC use as
an anticholinergic is safe and effective for the purpose intended must
comply with the requirements and procedures governing the use of
investigational new drugs set forth in part 312 of this chapter.
(d) After the effective date of the final regulation, any such OTC
cough-cold drug product that is labeled, represented, or promoted for
use as an anticholinergic may not be initially introduced or initially
delivered for introduction into interstate commerce unless it is the
subject of an approved new drug application.
[50 FR 46587, Nov. 8, 1985, as amended at 55 FR 11579, Mar. 29, 1990]
Sec. 310.534 Drug products containing active ingredients offered
over-the-counter (OTC) for human use as oral wound healing agents.
(a) Allantoin, carbamide peroxide in anhydrous glycerin, water
soluble chlorophyllins, and hydrogen peroxide in aqueous solution have
been present in oral mucosal injury drug products for use as oral wound
healing agents. Oral wound healing agents have been marketed as aids in
the healing of minor oral wounds by means other than cleansing and
irrigating, or by serving as a protectant. Allantoin, carbamide peroxide
in anhydrous glycerin, water soluble chlorophyllins, and hydrogen
peroxide in aqueous solution are safe for use as oral wound healing
agents, but there are inadequate data to establish general recognition
of the effectiveness of these ingredients as oral wound healing agents.
(b) Any OTC drug product that is labeled, represented, or promoted
for use as an oral wound healing agent is regarded as a new drug within
the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic
Act, for which an approved new drug application under section 505 of the
act and part 314 of this chapter is required for marketing. In the
absence of an approved new drug application, such product is also
misbranded under section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any
drug product labeled, represented, or promoted for OTC use as an oral
wound healing
[[Page 35]]
agent is safe and effective for the purpose intended must comply with
the requirements and procedures governing the use of investigational new
drugs set forth in part 312 of this chapter.
(d) After the effective date of the final regulation, any OTC drug
product that is labeled, represented, or promoted for use as an oral
wound healing agent may not be initially introduced or initially
delivered for introduction into interstate commerce unless it is the
subject of an approved new drug application.
[51 FR 26114, July 18, 1986, as amended at 55 FR 11579, Mar. 29, 1990]
Sec. 310.536 Drug products containing active ingredients offered
over-the-counter (OTC) for use as a nailbiting or thumbsucking deterrent.
(a) Denatonium benzoate and sucrose octaacetate have been present in
OTC nailbiting and thumbsucking deterrent drug products. There is a lack
of adequate data to establish general recognition of the safety and
effectiveness of these and any other ingredients (e.g., cayenne pepper)
for OTC use as a nailbiting or thumbsucking deterrent. Based on evidence
currently available, any OTC drug product containing ingredients offered
for use as a nailbiting or thumbsucking deterrent cannot be generally
recognized as safe and effective.
(b) Any OTC drug product that is labeled, represented, and promoted
as a nailbiting or thumbsucking deterrent is regarded as a new drug
within the meaning of section 201(p) of the Federal Food, Drug, and
Cosmetic Act (the act) for which an approved application or abbreviated
application under section 505 of the act and part 314 of this chapter is
required for marketing. In the absence of an approved new drug
application or abbreviated new drug application, such product is also
misbranded under section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any
drug product labeled, represented, or promoted for OTC use as a
nailbiting or thumbsucking deterrent is safe and effective for the
purpose intended must comply with the requirements and procedures
governing the use of investigational new drugs set forth in part 312 of
this chapter.
(d) After March 2, 1994, any such OTC drug product initially
introduced or initially delivered for introduction into interstate
commerce that is not in compliance with this section is subject to
regulatory action.
[58 FR 46754, Sept. 2, 1993]
Sec. 310.537 Drug products containing active ingredients offered
over-the-counter (OTC) for oral administration for the treatment of
fever blisters and cold sores.
(a) l-lysine (lysine, lysine hydrochloride), Lactobacillus
acidophilus, and Lactobacillus bulgaricus have been present in orally
administered OTC drug products to treat fever blisters and cold sores.
There is a lack of adequate data to establish general recognition of the
safety and effectiveness of these or any other orally administered
ingredients for OTC use to treat or relieve the symptoms or discomfort
of fever blisters and cold sores. Based on evidence currently available,
any OTC drug product for oral administration containing ingredients
offered for use in treating or relieving the symptoms or discomfort of
fever blisters and cold sores cannot be generally recognized as safe and
effective.
(b) Any OTC drug product for oral administration that is labeled,
represented, or promoted to treat or relieve the symptoms or discomfort
of fever blisters and cold sores is regarded as a new drug within the
meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act
(the act), for which an approved application under section 505 of the
act and part 314 of this chapter is required for marketing. In the
absence of an approved application, such product is also misbranded
under section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any
drug product for oral administration labeled, represented, or promoted
for OTC use to treat or relieve the symptoms or discomfort of fever
blisters and cold sores is safe and effective for the purpose intended
must comply with the requirements and procedures governing the use of
investigational new drugs set forth in part 312 of this chapter.
[[Page 36]]
(d) After December 30, 1992, any such OTC drug product initially
introduced or initially delivered for introduction into interstate
commerce that is not in compliance with this section is subject to
regulatory action.
[57 FR 29173, June 30, 1992]
Sec. 310.538 Drug products containing active ingredients offered
over-the-counter (OTC) for use for ingrown toenail relief.
(a) Any product that bears labeling claims such as for ``temporary
relief of discomfort from ingrown toenails,'' or ``ingrown toenail
relief product,'' or ``ingrown toenail reliever,'' or similar claims is
considered an ingrown toenail relief drug product. Benzocaine,
chlorobutanol, chloroxylenol, dibucaine, tannic acid, and urea have been
present as ingredients in such products. There is lack of adequate data
to establish general recognition of the safety and effectiveness of
these or any other ingredients for OTC use for ingrown toenail relief.
Based on evidence currently available, any OTC drug product containing
ingredients offered for use for ingrown toenail relief cannot be
generally recognized as safe and effective.
(b) Any OTC drug product that is labeled, represented, or promoted
for ingrown toenail relief is regarded as a new drug within the meaning
of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act),
for which an approved application or abbreviated application under
section 505 of the act and part 314 of this chapter is required for
marketing. In the absence of an approved new drug application or
abbreviated new drug application, such product is also misbranded under
section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any
drug product labeled, represented, or promoted for OTC use for ingrown
toenail relief is safe and effective for the purpose intended must
comply with the requirements and procedures governing the use of
investigational new drugs set forth in part 312 of this chapter.
(d) After March 9, 1994, any such OTC drug product initially
introduced or initially delivered for introduction into interstate
commerce that is not in compliance with this section is subject to
regulatory action.
(e) This section does not apply to sodium sulfide labeled,
represented, or promoted for OTC topical use for ingrown toenail relief
in accordance with part 358, subpart D of this chapter, after June 6,
2003.
[58 FR 47605, Sept. 9, 1993, as amended at 68 FR 24348, May 7, 2003]
Sec. 310.540 Drug products containing active ingredients offered
over-the-counter (OTC) for use as stomach acidifiers.
(a) Betaine hydrochloride, glutamic acid hydrochloride, diluted
hydrochloric acid, and pepsin have been present as ingredients in over-
the-counter (OTC) drug products for use as stomach acidifiers. Because
of the lack of adequate data to establish the effectiveness of these or
any other ingredients for use in treating achlorhydria and
hypochlorhydria, and because such conditions are asymptomatic, any OTC
drug product containing ingredients offered for use as a stomach
acidifier cannot be considered generally recognized as safe and
effective.
(b) Any OTC drug product that is labeled, represented, or promoted
for use as a stomach acidifier is regarded as a new drug within the
meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act,
for which an approved new drug application under section 505 of the act
and part 314 of this chapter is required for marketing. In the absence
of an approved new drug application, such product is also misbranded
under section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any
drug product labeled, represented, or promoted as a stomach acidifier
for OTC use is safe and effective for the purpose intended must comply
with the requirements and procedures governing the use of
investigational new drugs set forth in part 312 of this chapter.
(d) After the effective date of the final regulation, any such OTC
drug product initially introduced or initially delivered for
introduction into interstate commerce that is not in compliance with
this section is subject to regulatory action.
[53 FR 31271, Aug. 17, 1988]
[[Page 37]]
Sec. 310.541 Over-the-counter (OTC) drug products containing active
ingredients offered for use in the treatment of hypophosphatemia.
(a) Hypophosphatemia is a condition in which an abnormally low
plasma level of phosphate occurs in the blood. This condition is not
amenable to self-diagnosis or self-treatment. Treatment of this
condition should be restricted to the supervision of a physician. For
this reason, any drug product containing ingredients offered for OTC use
in the treatment of hypophosphatemia cannot be considered generally
recognized as safe and effective.
(b) Any drug product that is labeled, represented, or promoted for
OTC use in the treatment of hypophosphatemia is regarded as a new drug
within the meaning of section 201(p) of the Federal Food, Drug, and
Cosmetic Act (the act), for which an approved application under section
505 of the act and part 314 of this chapter is required for marketing.
In the absence of an approved application, such product is also
misbranded under section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any
drug product labeled, represented, or promoted for OTC use in the
treatment of hypophosphatemia is safe and effective for the purpose
intended must comply with the requirements and procedures governing the
use of investigational new drugs set forth in part 312 of his chapter.
(d) After November 12, 1990, any such OTC drug product initially
introduced or initially delivered for introduction into interstate
commerce that is not in compliance with this section is subject to
regulatory action.
[55 FR 19858, May 11, 1990]
Sec. 310.542 Over-the-counter (OTC) drug products containing active
ingredients offered for use in the treatment of hyperphosphatemia.
(a) Hyperphosphatemia is a condition in which an abnormally high
plasma level of phosphate occurs in the blood. This condition in not
amenable to self-diagnosis or self-treatment. Treatment of this
condition should be restricted to the supervision of a physician. For
this reason, any drug product containing ingredients offered for OTC use
in the treatment of hyperphosphatemia cannot be considered generally
recognized as safe and effective.
(b) Any drug product that is labeled, represented, or promoted for
OTC use in the treatment of hyperphosphatemia is regarded as a new drug
within the meaning of section 201(p) of the Federal Food, Drug, and
Cosmetic Act (the act), for which an approved application under section
505 of the act and part 314 of this chapter is required for marketing.
In the absence of an approved application, such product is also
misbranded under section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any
drug product labeled, represented, or promoted for use in the treatment
of hyperphosphatemia is safe and effective for the purpose intended must
comply with the requirements and procedures governing use of
investigational new drugs set forth in part 312 of this chapter.
(d) After November 12, 1990, any such OTC drug product initially
introduced or initially delivered for introduction into interstate
commerce that is not in compliance with this section is subject to
regulatory action.
[55 FR 19858, May 11, 1990]
Sec. 310.543 Drug products containing active ingredients offered
over-the-counter (OTC) for human use in exocrine pancreatic insufficiency.
(a) Hemicellulase, pancreatin, and pancrelipase have been present as
ingredients in exocrine pancreatic insufficiency drug products.
Pancreatin and pancrelipase are composed of enzymes: amylase, trypsin
(protease), and lipase. Significant differences have been shown in the
bioavailability of marketed exocrine pancreatic insufficiency drug
products produced by different manufacturers. These differences raise a
potential for serious risk to patients using these drug products. The
bioavailability of pancreatic enzymes is dependent on the process used
to manufacture the drug products. Information on this process is not
included in an OTC drug monograph. Therefore, the safe and effective use
of these enzymes for treating exocrine pancreatic insufficiency cannot
be regulated adequately by an OTC drug monograph.
[[Page 38]]
Information on the product's formulation, manufacture, quality control
procedures, and final formulation effectiveness testing are necessary in
an approved application to ensure that a company has the ability to
manufacture a proper bioactive formulation. In addition, continuous
physician monitoring of patients who take these drug products is a
collateral measure necessary to the safe and effective use of these
enzymes, causing such products to be available by prescription only.
(b) Any drug product that is labeled, represented, or promoted for
OTC use in the treatment of exocrine pancreatic insufficiency is
regarded as a new drug within the meaning of section 201(p) of the
Federal Food, Drug, and Cosmetic Act (the act), for which an approved
application under section 505 of the act and part 314 of this chapter is
required for marketing. In the absence of an approved application, such
product is also misbranded under section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any
drug product labeled, represented, or promoted for OTC use in the
treatment of exocrine pancreatic insufficiency is safe and effective for
the purpose intended must comply with the requirements and procedures
governing the use of investigational new drugs set forth in part 312 of
this chapter.
(d) After May 7, 1991, any such OTC drug product that contains
hemicellulase initially introduced or initially delivered for
introduction into interstate commerce that is not in compliance with
this section is subject to regulatory action.
(e) After October 24, 1995, any such OTC drug product that contains
pancreatin or pancrelipase initially introduced or initially delivered
for introduction into interstate commerce that is not in compliance with
this section is subject to regulatory action.
[60 FR 20165, Apr. 24, 1995]
Sec. 310.544 Drug products containing active ingredients offered
over-the-counter (OTC) for use as a smoking deterrent.
(a) Any product that bears labeling claims that it ``helps stop or
reduce the cigarette urge,'' ``helps break the cigarette habit,''
``helps stop or reduce smoking,'' or similar claims is a smoking
deterrent drug product. Cloves, coriander, eucalyptus oil, ginger
(Jamaica), lemon oil (terpeneless), licorice root extract, lobeline (in
the form of lobeline sulfate or natural lobelia alkaloids or Lobelia
inflata herb), menthol, methyl salicylate, povidone-silver nitrate,
quinine ascorbate, silver acetate, silver nitrate, and thymol have been
present as ingredients in such drug products. There is a lack of
adequate data to establish general recognition of the safety and
effectiveness of these or any other ingredients for OTC use as a smoking
deterrent. Based on evidence currently available, any OTC drug product
containing ingredients offered for use as a smoking deterrent cannot be
generally recognized as safe and effective.
(b) Any OTC drug product that is labeled, represented, or promoted
as a smoking deterrent is regarded as a new drug within the meaning of
section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act),
for which an approved application or abbreviated application under
section 505 of the act and part 314 of this chapter is required for
marketing. In the absence of an approved new drug application or
abbreviated new drug application, such product is also misbranded under
section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any
drug product labeled, represented, or promoted for OTC use as a smoking
deterrent is safe and effective for the purpose intended must comply
with the requirements and procedures governing the use of
investigational new drugs set forth in part 312 of this chapter.
(d) After May 7, 1991, any such OTC drug product containing cloves,
coriander, eucalyptus oil, ginger (Jamaica), lemon oil (terpeneless),
licorice root extract, menthol, methyl salicylate, quinine ascorbate,
silver nitrate, and/or thymol initially introduced or initially
delivered for introduction into interstate commerce that is not in
compliance with this section is subject to regulatory action. After
December 1, 1993, any such OTC drug product containing lobeline (in the
form of lobeline sulfate or natural lobelia alkaloids or
[[Page 39]]
Lobelia inflata herb), povidone-silver nitrate, silver acetate, or any
other ingredients initially introduced or initially delivered for
introduction into interstate commerce that is not in compliance with
this section is subject to regulatory action.
[58 FR 31241, June 1, 1993]
Sec. 310.545 Drug products containing certain active ingredients
offered over-the-counter (OTC) for certain uses.
(a) A number of active ingredients have been present in OTC drug
products for various uses, as described below. However, based on
evidence currently available, there are inadequate data to establish
general recognition of the safety and effectiveness of these ingredients
for the specified uses:
(1) Topical acne drug products.
Alcloxa
Alkyl isoquinolinium bromide
Aluminum chlorohydrex
Aluminum hydroxide
Benzocaine
Benzoic acid
Boric acid
Calcium polysulfide
Calcium thiosulfate
Camphor
Chloroxylenol
Cloxyquin
Coal tar
Dibenzothiophene
Estrone
Magnesium aluminum silicate
Magnesium sulfate
Phenol
Phenolate sodium
Phenyl salicylate
Povidone-iodine
Pyrilamine maleate
Resorcinol (as single ingredient)
Resorcinol monoacetate (as single ingredient)
Salicylic acid (over 2 up to 5 percent)
Sodium borate
Sodium thiosulfate
Tetracaine hydrochloride
Thymol
Vitamin E
Zinc oxide
Zinc stearate
Zinc sulfide
(2) Anticaries drug products--(i) Approved as of May 7, 1991.
Hydrogen fluoride
Sodium carbonate
Sodium monofluorophosphate (6 percent rinse)
Sodium phosphate
(ii) Approved as of October 7, 1996.
Calcium sucrose phosphate
Dicalcium phosphate dihydrate
Disodium hydrogen phosphate \1\
---------------------------------------------------------------------------
\1\ These ingredients are nonmonograph except when used to prepare
acidulated phosphate fluoride treatment rinses identified in Sec.
355.10(a)(3) of this chapter.
---------------------------------------------------------------------------
Phosphoric acid \1\
Sodium dihydrogen phosphate
Sodium dihydrogen phosphate monohydrate
Sodium phosphate, dibasic anhydrous reagent \1\
(3) Antidiarrheal drug products--(i) Approved as of May 7, 1991.
Aluminum hydroxide
Atropine sulfate
Calcium carbonate
Carboxymethylcellulose sodium
Glycine
Homatropine methylbromide
Hyoscyamine sulfate
Lactobacillus acidophilus
Lactobacillus bulgaricus
Opium, powdered
Opium tincture
Paregoric
Phenyl salicylate
Scopolamine hydrobromide
Zinc phenolsulfonate
(ii) Approved as of April 19, 2004; April 18, 2005, for products
with annual sales less than $25,000.
Attapulgite, activated
Bismuth subnitrate
Calcium hydroxide
Calcium polycarbophil
Charcoal (activated)
Pectin
Polycarbophil
Potassium carbonate
Rhubarb fluidextract
(4) Antiperspirant drug products--(i) Ingredients--Approved as of
May 7, 1991.
Alum, potassium
Aluminum bromohydrate
Aluminum chloride (alcoholic solutions)
Aluminum chloride (aqueous solution) (aerosol only)
Aluminum sulfate
Aluminum sulfate, buffered (aerosol only)
Sodium aluminum chlorohydroxy lactate
(ii) Approved as of December 9, 2004; June 9, 2005, for products
with annual sales less than $25,000.
Aluminum sulfate buffered with sodium aluminum lactate
[[Page 40]]
(5) [Reserved]
(6) Cold, cough, allergy, bronchodilator, and antiasthmatic drug
products--(i) Antihistamine drug products--(A) Ingredients.
Methapyrilene hydrochloride
Methapyrilene fumarate
Thenyldiamine hydrochloride
(B) Ingredients.
Phenyltoloxamine dihydrogen citrate
Methapyrilene hydrochloride
Methapyrilene fumarate
Thenyldiamine hydrochloride
(ii) Nasal decongestant drug products--(A) Approved as of May 7,
1991.
Allyl isothiocyanate
Camphor (lozenge)
Creosote, beechwood (oral)
Eucalyptol (lozenge)
Eucalyptol (mouthwash)
Eucalyptus oil (lozenge)
Eucalyptus oil (mouthwash)
Menthol (mouthwash)
Peppermint oil (mouthwash)
Thenyldiamine hydrochloride
Thymol
Thymol (lozenge)
Thymol (mouthwash)
Turpentine oil
(B) Approved as of August 23, 1995.
Bornyl acetate (topical)
Cedar leaf oil (topical)
Creosote, beechwood (topical)
Ephedrine (oral)
Ephedrine hydrochloride (oral)
Ephedrine sulfate (oral)
Racephedrine hydrochloride (oral/topical)
(C) Approved as of April 11, 2007; October 11, 2007, for products
with annual sales less than $25,000. Any ingredient(s) labeled with
claims or directions for use for sinusitis or for relief of nasal
congestion associated with sinusitis.
(iii) Expectorant drug products.
Ammonium chloride
Antimony potassium tartrate
Beechwood creosote
Benzoin preparations (compound tincture of benzoin, tincture of benzoin)
Camphor
Chloroform
Eucalyptol/eucalyptus oil
Horehound
Iodides (calcium iodide anyhydrous, hydroidic acid syrup, iodized lime,
potassium iodide)
Ipecac
Ipecac fluidextract
Ipecac syrup
Menthol/peppermint oil
Pine tar preparations (extract white pine compound, pine tar, syrup of
pine tar, compound white pine syrup, white pine)
Potassium guaiacolsulfonate
Sodium citrate
Squill preparations (squill, squill extract)
Terpin hydrate preparations (terpin hydrate, terpin hydrate elixir)
Tolu preparations (tolu, tolu balsam, tolu balsam tincture)
Turpentine oil (spirits of turpentine)
(iv) Bronchodilator drug products--(A) Approved as of October 2,
1987.
Aminophylline
Belladonna alkaloids
Euphorbia pilulifera
Metaproterenol sulfate
Methoxyphenamine hydrochloride
Pseudoephedrine hydrochloride
Pseudoephedrine sulfate
Theophylline, anhydrous
Theophylline calcium salicylate
Theophylline sodium glycinate
(B) Approved as of January 29, 1996. Any combination drug product
containing theophylline (e.g., theophylline and ephedrine, or
theophylline and ephedrine and phenobarbital).
(C) Approved as of June 19, 1996. Any ingredient(s) in a pressurized
metered-dose inhaler container.
(D) Approved as of October 29, 2001. Any oral bronchodilator active
ingredient (e.g., ephedrine, ephedrine hydrochloride, ephedrine sulfate,
racephedrine hydrochloride, or any other ephedrine salt) in combination
with any analgesic(s) or analgesic-antipyretic(s), anticholinergic,
antihistamine, oral antitussive, or stimulant active ingredient.
(7) Dandruff/seborrheic dermatitis/psoriasis drug products.
Alkyl isoquinolinium bromide
Allantoin
Benzalkonium chloride
Benzethonium chloride
Boric acid
Calcium undecylenate
Captan
Chloroxylenol
Colloidal oatmeal
Cresol, saponated
Ethohexadiol
Eucalyptol
Juniper tar
Lauryl isoquinolinium bromide
Menthol
Mercury oleate
Methylbenzethonium chloride
Methyl salicylate
[[Page 41]]
Phenol
Phenolate sodium
Pine tar
Povidone-iodine
Resorcinol
Sodium borate
Sodium salicylate
Thymol
Undecylenic acid
(8) Digestive aid drug products--(i) Approved as of May 7, 1991.
Bismuth sodium tartrate
Calcium carbonate
Cellulase
Dehydrocholic acid
Dihydroxyaluminum sodium carbonate
Duodenal substance
Garlic, dehydrated
Glutamic acid hydrochloride
Hemicellulase
Homatropine methylbromide
Magnesium hydroxide
Magnesium trisilicate
Ox bile extract
Pancreatin
Pancrelipase
Papain
Peppermint oil
Pepsin
Sodium bicarbonate
Sodium citrate
Sorbitol
(ii) Approved as of November 10, 1993.
Alcohol
Aluminum hydroxide
Amylase
Anise seed
Aromatic powder
Asafetida
Aspergillus oryza enzymes (except lactase enzyme derived from
Aspergillus oryzae)
Bacillus acidophilus
Bean
Belladonna alkaloids
Belladonna leaves, powdered extract
Betaine hydrochloride
Bismuth subcarbonate
Bismuth subgallate
Black radish powder
Blessed thistle (cnicus benedictus)
Buckthorn
Calcium gluconate
Capsicum
Capsicum, fluid extract of
Carbon
Cascara sagrada extract
Catechu, tincture
Catnip
Chamomile flowers
Charcoal, wood
Chloroform
Cinnamon oil
Cinnamon tincture
Citrus pectin
Diastase
Diastase malt
Dog grass
Elecampane
Ether
Fennel acid
Galega
Ginger
Glycine
Hydrastis canadensis (golden seal)
Hectorite
Horsetail
Huckleberry
Hydrastis fluid extract
Hydrochloric acid
Iodine
Iron ox bile
Johnswort
Juniper
Kaolin, colloidal
Knotgrass
Lactic acid
Lactose
Lavender compound, tincture of
Linden
Lipase
Lysine hydrochloride
Mannitol
Mycozyme
Myrrh, fluid extract of
Nettle
Nickel-pectin
Nux vomica extract
Orthophosphoric acid
Papaya, natural
Pectin
Peppermint
Peppermint spirit
Phenacetin
Potassium bicarbonate
Potassium carbonate
Protease
Prolase
Rhubarb fluid extract
Senna
Sodium chloride
Sodium salicylate
Stem bromelain
Strawberry
Strychnine
Tannic acid
Trillium
Woodruff
(iii) Charcoal, activated
(9) [Reserved]
(10) External analgesic drug products--(i) Analgesic and anesthetic
drug products.
Aspirin
Chloral hydrate
Chlorobutanol
Cyclomethycaine sulfate
Eugenol
Hexylresorcinol
Methapyrilene hydrochloride
[[Page 42]]
Salicylamide
Thymol
(ii) Counterirritant drug products.
Chloral hydrate
Eucalyptus oil
(iii) Male genital desensitizer drug products.
Benzyl alcohol
Camphorated metacresol
Ephedrine hydrochloride
(iv) Diaper rash drug products. Any ingredient(s) labeled with
claims or directions for use in the treatment and/or prevention of
diaper rash.
(v) Fever blister and cold sore treatment drug products.
Allyl isothiocyanate
Aspirin
Bismuth sodium tartrate
Camphor (exceeding 3 percent)
Capsaicin
Capsicum
Capsicum oleoresin
Chloral hydrate
Chlorobutanol
Cyclomethycaine sulfate
Eucalyptus oil
Eugenol
Glycol salicylate
Hexylresorcinol
Histamine dihydrochloride
Menthol (exceeding 1 percent)
Methapyrilene hydrochloride
Methyl nicotinate
Methyl salicylate
Pectin
Salicylamide
Strong ammonia solution
Tannic acid
Thymol
Tripelennamine hydrochloride
Trolamine salicylate
Turpentine oil
Zinc sulfate
(vi) Insect bite and sting drug products.
Alcohol
Alcohol, ethoxylated alkyl
Benzalkonium chloride
Calamine
Ergot fluidextract
Ferric chloride
Panthenol
Peppermint oil
Pyrilamine maleate
Sodium borate
Trolamine salicylate
Turpentine oil
Zinc oxide
Zirconium oxide
(vii) Poison ivy, poison oak, and poison sumac drug products.
Alcohol
Aspirin
Benzethonium chloride
Benzocaine (0.5 to 1.25 percent)
Bithionol
Calamine
Cetalkonium chloride
Chloral hydrate
Chlorobutanol
Chlorpheniramine maleate
Creosote, beechwood
Cyclomethycaine sulfate
Dexpanthenol
Diperodon hydrochloride
Eucalyptus oil
Eugenol
Glycerin
Glycol salicylate
Hectorite
Hexylresorcinol
Hydrogen peroxide
Impatiens biflora tincture
Iron oxide
Isopropyl alcohol
Lanolin
Lead acetate
Merbromin
Mercuric chloride
Methapyrilene hydrochloride
Panthenol
Parethoxycaine hydrochloride
Phenyltoloxamine dihydrogen citrate
Povidone-vinylacetate copolymers
Pyrilamine maleate
Salicylamide
Salicylic acid
Simethicone
Sulfur
Tannic acid
Thymol
Trolamine salicylate
Turpentine oil
Zirconium oxide
Zyloxin
(11) [Reserved]
(12) Laxative drug products--(i)(A) Bulk laxatives.
Agar
Carrageenan (degraded)
Carrageenan (native)
Guar gun
(i)(B) Bulk laxatives--Approved as of March 29, 2007.
Granular dosage forms containing psyllium (hemicellulose), psyllium
hydrophilic mucilloid, psyllium seed, psyllium seed (blond), psyllium
seed husks, plantago husks, or plantago seed including, but not limited
to, any granules that are:
(1) Swallowed dry prior to drinking liquid,
(2) Dispersed, suspended, or partially dissolved in liquid prior to
swallowing,
[[Page 43]]
(3) Chewed, partially chewed, or unchewed, and then washed down (or
swallowed) with liquid, or
(4) Sprinkled over food.
(ii) Saline laxative.
Tartaric acid
(iii) Stool softener.
Poloxamer 188
(iv)(A) Stimulant laxatives--Approved as of May 7, 1991.
Aloin
Bile salts/acids
Calcium pantothenate
Calomel
Colocynth
Elaterin resin
Frangula
Gamboge
Ipomea
Jalap
Ox bile
Podophyllum resin
Prune concentrate dehydrate
Prune powder
Rhubarb, Chinese
Sodium Oleate
(iv)(B) Stimulant laxatives--Approved as of January 29, 1999.
Danthron
Phenolphthalein
(C) Stimulant laxatives--Approved as of November 5, 2002.
Aloe ingredients (aloe, aloe extract, aloe flower extract)
Cascara sagrada ingredients (casanthranol, cascara fluidextract
aromatic, cascara sagrada bark, cascara sagrada extract, cascara sagrada
fluidextract).
(13) [Reserved]
(14) Oral health care drug products (nonantimicrobial).
Antipyrine
Camphor
Cresol
Dibucaine
Dibucaine hydrochloride
Eucalyptol
Lidocaine
Lidocaine hydrochloride
Methly salicylate
Myrrh tincture
Pyrilamine maleate
Sorbitol
Sugars
Tetracaine
Tetracaine hydrochloride
Thymol
(15) Topical otic drug products--(i) For the prevention of swimmer's
ear and for the drying of water-clogged ears, approved as of May 7,
1991.
Acetic acid
(ii) For the prevention of swimmer's ear, approved as of August 15,
1995.
Glycerin and anhydrous glycerin
Isopropyl alcohol
(16) Poison treatment drug products.
Ipecac fluidextract
Ipecac tincture
Zinc sulfate
(17) Skin bleaching drug products.
Mercury, ammoniated
(18) Skin protectant drug products--(i)(A) Ingredients--Approved as
of May 7, 1991.
Allantoin (wound healing claims only)
Sulfur
Tannic acid
Zinc acetate (wound healing claims only)
(B) Ingredients--Approved as of June 4, 2004; June 6, 2005, for
products with annual sales less than $25,000.
Beeswax
Bismuth subnitrate
Boric acid
Cetyl alcohol
Glyceryl stearate
Isopropyl palmitate
Live yeast cell derivative
Shark liver oil
Stearyl alcohol
(ii) Astringent drug products.
Acetone
Alcohol
Alum, ammonium
Alum, potassium
Aluminum chlorhydroxy complex
Aromatics
Benzalkonium chloride
Benzethonium chloride
Benzocaine
Benzoic acid
Boric acid
Calcium acetate (except calcium acetate monohydrate when combined with
aluminum sulfate tetradecahydrate to provide an aluminum acetate
solution as described in Sec. 347.20(b) of this chapter)
Camphor gum
Clove oil
Colloidal oatmeal
Cresol
Cupric sulfate
Eucalyptus oil
Eugenol
[[Page 44]]
Ferric subsulfate (Monsel's Solution)
Honey
Isopropyl alcohol
Menthol
Methyl salicylate
Oxyquinoline sulfate
P-t-butyl-m-cresol
Peppermint oil
Phenol
Polyoxeythylene laurate
Potassium ferrocyanide
Sage oil
Silver nitrate
Sodium borate
Sodium diacetate
Talc
Tannic acid glycerite
Thymol
Topical starch
Zinc chloride
Zinc oxide
Zinc phenolsulfonate
Zinc stearate
Zinc sulfate
(iii) Diaper rash drug products.
Aluminum hydroxide
Cocoa butter
Cysteine hydrochloride
Glycerin
Protein hydrolysate
Racemethionine
Sulfur
Tannic acid
Zinc acetate
Zinc carbonate
(iv) Fever blister and cold sore treatment drug products.
Bismuth subnitrate
Boric acid
Pyridoxine hydrochloride
Sulfur
Tannic acid
Topical starch
Trolamine
Zinc sulfate
(v) Insect bite and sting drug products--(A) Ingredients--Approved
as of November 10, 1993.
Alcohol
Alcohol, ethoxylated alkyl
Ammonia solution, strong
Ammonium hydroxide
Benzalkonium chloride
Camphor
Ergot fluid extract
Ferric chloride
Menthol
Peppermint oil
Phenol
Pyrilamine maleate
Sodium borate
Trolamine
Turpentine oil
Zirconium oxide
(B) Ingredients--Approved as of June 4, 2004; June 6, 2005, for
products with annual sales less than $25,000.
Beeswax
Bismuth subnitrate
Boric acid
Cetyl alcohol
Glyceryl stearate
Isopropyl palmitate
Live yeast cell derivative
Shark liver oil
Stearyl alcohol
(vi) Poison ivy, poison oak, and poison sumac drug products--(A)
Ingredients--Approved as of November 10, 1993.
Alcohol
Anion and cation exchange resins buffered
Benzethonium chloride
Benzocaine
Benzyl alcohol
Bismuth subnitrate
Bithionol
Boric acid
Camphor
Cetalkonium chloride
Chloral hydrate
Chlorpheniramine maleate
Creosote
Diperodon hydrochloride
Diphenhydramine hydrochloride
Eucalyptus oil
Ferric chloride
Glycerin
Hectorite
Hydrogen peroxide
Impatiens biflora tincture
Iron oxide
Isopropyl alcohol
Lanolin
Lead acetate
Lidocaine
Menthol
Merbromin
Mercuric chloride
Panthenol
Parethoxycaine hydrochloride
Phenol
Phenyltoloxamine dihydrogen citrate
Povidone-vinylacetate copolymers
Salicylic acid
Simethicone
Tannic acid
Topical starch
Trolamine
Turpentine oil
Zirconium oxide
Zyloxin
(B) Ingredients--Approved as of June 4, 2004; June 6, 2005, for
products with annual sales less than $25,000.
Beeswax
[[Page 45]]
Bismuth subnitrate
Boric acid
Cetyl alcohol
Glyceryl stearate
Isopropyl palmitate
Live yeast cell derivative
Shark liver oil
Stearyl alcohol
(19) [Reserved]
(20) Weight control drug products.
Alcohol
Alfalfa
Alginic acid
Anise oil
Arginine
Ascorbic acid
Bearberry
Biotin
Bone marrow, red
Buchu
Buchu, potassium extract
Caffeine
Caffeine citrate
Calcium
Calcium carbonate
Calcium caseinate
Calcium lactate
Calcium pantothenate
Carboxymethylcellulose sodium
Carrageenan
Cholecalcierol
Choline
Chondrus
Citric acid
Cnicus benedictus
Copper
Copper gluconate
Corn oil
Corn syrup
Corn silk, potassium extract
Cupric sulfate
Cyanocobalamin (vitamin B12)
Cystine
Dextrose
Docusate sodium
Ergocalciferol
Ferric ammonium citrate
Ferric pyrophosphate
Ferrous fumarate
Ferrous gluconate
Ferrous sulfate (iron)
Flax seed
Folic acid
Fructose
Guar gum
Histidine
Hydrastis canadensis
Inositol
Iodine
Isoleucine
Juniper, potassium extract
Karaya gum
Kelp
Lactose
Lecithin
Leucine
Liver concentrate
Lysine
Lysine hydrochloride
Magnesium
Magnesium oxide
Malt
Maltodextrin
Manganese citrate
Mannitol
Methionine
Methylcellulose
Mono- and di-glycerides
Niacinamide
Organic vegetables
Pancreatin
Pantothenic acid
Papain
Papaya enzymes
Pepsin
Phenacetin
Phenylalanine
Phosphorus
Phytolacca
Pineapple enzymes
Plantago seed
Potassium citrate
Pyridoxine hydrochloride (vitamin B6)
Riboflavin
Rice polishings
Saccharin
Sea minerals
Sesame seed
Sodium
Sodium bicarbonate
Sodium caseinate
Sodium chloride (salt)
Soybean protein
Soy meal
Sucrose
Thiamine hydrochloride (vitamin B1)
Thiamine mononitrate (vitamin B1 mononitrate)
Threonine
Tricalcium phosphate
Tryptophan
Tyrosine
Uva ursi, potassium extract
Valine
Vegetable
Vitamin A
Vitamin A acetate
Vitamin A palmitate
Vitamin E
Wheat germ
Xanthan gum
Yeast
(21) Ophthalmic drug products. (i) Ophthalmic anesthetic drug
products.
Antipyrine
Piperocaine hydrochloride
(ii) Ophthalmic anti-infective drug products.
Boric acid
[[Page 46]]
Mild silver protein
Yellow mercuric oxide
(iii) Ophthalmic astringent drug products.
Infusion of rose petals
(iv) Ophthalmic demulcent drug products.
Polyethylene glycol 6000
(v) Ophthalmic vasoconstrictor drug products.
Phenylephrine hydrochloride (less than 0.08 percent)
(22) Topical antifungal drug products. (i) Diaper rash drug
products. Any ingredient(s) labeled with claims or directions for use in
the treatment and/or prevention of diaper rash.
(ii) Ingredients.
Alcloxa
Alum, potassium
Aluminum sulfate
Amyltricresols, secondary
Basic fuchsin
Benzethonium chloride
Benzoic acid
Benzoxiquine
Boric acid
Camphor
Candicidin
Chlorothymol
Coal tar
Dichlorophen
Menthol
Methylparaben
Oxyquinoline
Oxyquinoline sulfate
Phenol
Phenolate sodium
Phenyl salicylate
Propionic acid
Propylparaben
Resorcinol
Salicylic acid
Sodium borate
Sodium caprylate
Sodium propionate
Sulfur
Tannic acid
Thymol
Tolindate
Triacetin
Zinc caprylate
Zinc propionate
(iii) Any ingredient(s) labeled with claims or directions for use on
the scalp or on the nails.
(iv) Ingredients.
Camphorated metacresol
Chloroxylenol
m-cresol
Nystatin
(23) Internal analgesic drug products--(i) Approved as of November
10, 1993.
Aminobenzoic acid
Antipyrine
Aspirin, aluminum
Calcium salicylate
Codeine
Codeine phosphate
Codeine sulfate
Iodoantipyrine
Lysine aspirin
Methapyrilene fumarate
Phenacetin
Pheniramine maleate
Pyrilamine maleate
Quinine
Salsalate
Sodium aminobenzoate
(ii) Approved as of February 22, 1999.
Any atropine ingredient
Any ephedrine ingredient
(24) Orally administered menstrual drug products--(i) Approved as of
November 10, 1993.
Alcohol
Alfalfa leaves
Aloes
Asclepias tuberosa
Asparagus
Barosma
Bearberry (extract of uva ursi)
Bearberry fluidextract (extract of bearberry)
Blessed thistle (cnicus benedictus)
Buchu powdered extract (extract of buchu)
Calcium lactate
Calcium pantothenate
Capsicum oleoresin
Cascara fluidextract, aromatic (extract of cascara)
Chlorprophenpyridamine maleate
Cimicifuga racemosa
Codeine
Collinsonia (extract stone root)
Corn silk
Couch grass
Dog grass extract
Ethyl nitrite
Ferric chloride
Ferrous sulfate
Gentiana lutea (gentian)
Glycyrrhiza (licorice)
Homatropine methylbromide
Hydrangea, powdered extract (extract of hydrangea)
Hydrastis canadensis (golden seal)
Hyoscyamine sulfate
Juniper oil (oil of juniper)
Magnesium sulfate
Methapyrilene hydrochloride
Methenamine
Methylene blue
[[Page 47]]
Natural estrogenic hormone
Niacinamide
Nutmeg oil (oil of nutmeg)
Oil of erigeron
Parsley
Peppermint spirit
Pepsin, essence
Phenacetin
Phenindamine tartrate
Phenyl salicylate
Piscidia erythrina
Pipsissewa
Potassium acetate
Potassium nitrate
Riboflavin
Saw palmetto
Senecio aureus
Sodium benzoate
Sodium nitrate
Sucrose
Sulferated oils of turpentine
Taraxacum officinale
Theobromine sodium salicylate
Theophylline
Thiamine hydrochloride
Triticum
Turpentine, venice (venice turpertine)
Urea
(ii) Approved as of February 22, 1999.
Any atropine ingredient
Any ephedrine ingredient
(25) Pediculicide drug products--(i) Approved as of November 10,
1993.
Benzocaine
Benzyl alcohol
Benzyl benzoate
Chlorophenothane (dichlorodiphenyl trichloroethane)
Coconut oil soap, aqueous
Copper oleate
Docusate sodium
Formic acid
Isobornyl thiocyanoacetate
Picrotoxin
Propylene glycol
Sabadilla alkaloids
Sulfur, sublimed
Thiocyanoacetate
(ii) Approved as of June 14, 1994. The combination of pyrethrum
extract (formerly named pyrethrins) and piperonyl butoxide in an aerosol
dosage formulation.
(26) Anorectal drug products--(i) Anticholinergic drug products.
Atropine
Belladonna extract
(ii) Antiseptic drug products.
Boric acid
Boroglycerin
Hydrastis
Phenol
Resorcinol
Sodium salicylic acid phenolate
(iii) Astringent drug products.
Tannic acid
(iv) Counterirritant drug products.
Camphor (greater than 3 to 11 percent)
Hydrastis
Menthol (1.25 to 16 percent)
Turpentine oil (rectified) (6 to 50 percent)
(v) Keratolytic drug products.
Precipitated sulfur
Sublimed sulfur
(vi) Local anesthetic drug products.
Diperodon
Phenacaine hydrochloride
(vii) Other drug products.
Collinsonia extract
Escherichia coli vaccines
Lappa extract
Leptandra extract
Live yeast cell derivative
Mullein
(viii) Protectant drug products.
Bismuth oxide
Bismuth subcarbonate
Bismuth subgallate
Bismuth subnitrate
Lanolin alcohols
(ix) Vasoconstrictor drug products.
Epinephrine undecylenate
(x) Wound healinq drug products.
Cholecalciferol
Cod liver oil
Live yeast cell derivative
Peruvian balsam
Shark liver oil
Vitamin A
(xi) Combination drug products. Any combination drug product
containing hydrocortisone and pramoxine hydrochloride.
(27) Topical antimicrobial drug products--(i) First aid antiseptic
drug products.
Ammoniated mercury
Calomel (mercurous chloride)
Merbromin (mercurochrome)
Mercufenol chloride (ortho-chloromercuriphenol, ortho-
hydroxyphenylmercuric chloride)
Mercuric chloride (bichloride of mercury, mercury chloride)
Mercuric oxide, yellow
Mercuric salicylate
[[Page 48]]
Mercuric sulfide, red
Mercury
Mercury oleate
Mercury sulfide
Nitromersol
Para-chloromercuriphenol
Phenylmercuric nitrate
Thimerosal
Vitromersol
Zyloxin
(ii) Diaper rash drug products.
Para-chloromercuriphenol
Any other ingredient containing mercury
(iii) Consumer antiseptic hand wash drug products. Approved as of
September 6, 2017.
Cloflucarban
Fluorosalan
Hexachlorophene
Hexylresorcinol
Iodine complex (ammonium ether sulfate and polyoxyethylene sorbitan
monolaurate)
Iodine complex (phosphate ester of alkylaryloxy polyethylene glycol)
Methylbenzethonium chloride
Nonylphenoxypoly (ethyleneoxy) ethanoliodine
Phenol (greater than 1.5 percent)
Phenol (less than 1.5 percent)
Poloxamer iodine complex
Povidone-iodine (5 to 10 percent)
Secondary amyltricresols
Sodium oxychlorosene
Tribromsalan
Triclocarban
Triclosan
Triple Dye
Undecoylium chloride iodine complex
(iv) Consumer antiseptic body wash drug products. Approved as of
September 6, 2017.
Cloflucarban
Fluorosalan
Hexachlorophene
Hexylresorcinol
Iodine complex (phosphate ester of alkylaryloxy polyethylene glycol)
Iodine tincture
Methylbenzethonium chloride
Nonylphenoxypoly (ethyleneoxy) ethanoliodine
Phenol (greater than 1.5 percent)
Phenol (less than 1.5 percent)
Poloxamer iodine complex
Povidone-iodine (5 to 10 percent)
Secondary amyltricresols
Sodium oxychlorosene
Tribromsalan
Triclocarban
Triclosan
Triple Dye
Undecoylium chloride iodine complex
(v) [Reserved]
(vi) Health care personnel hand wash drug products. Approved as of
December 20, 2018.
Cloflucarban
Fluorosalan
Hexachlorophene
Hexylresorcinol
Iodine complex (ammonium ether sulfate and polyoxyethylene sorbitan
monolaurate)
Iodine complex (phosphate ester of alkylaryloxy polyethylene glycol)
Methylbenzethonium chloride
Nonylphenoxypoly (ethyleneoxy) ethanoliodine
Phenol
Poloxamer-iodine complex
Secondary amyltricresols
Sodium oxychlorosene
Tribromsalan
Triclocarban
Triclosan
Undecoylium chloride iodine complex
(vii) [Reserved]
(viii) Surgical hand scrub drug products. Approved as of December
20, 2018.
Cloflucarban
Fluorosalan
Hexachlorophene
Hexylresorcinol
Iodine complex (ammonium ether sulfate and polyoxyethylene sorbitan
monolaurate)
Iodine complex (phosphate ester of alkylaryloxy polyethylene glycol)
Methylbenzethonium chloride
Nonylphenoxypoly (ethyleneoxy) ethanoliodine
Phenol
Poloxamer-iodine complex
Secondary amyltricresols
Sodium oxychlorosene
Tribromsalan
Triclocarban
Triclosan
Undecoylium chloride iodine complex
(ix) [Reserved]
(x) Patient antiseptic skin preparation drug products. Approved as
of December 20, 2018.
Cloflucarban
Fluorosalan
Hexachlorophene
Hexylresorcinol
Iodine complex (phosphate ester of alkylaryloxy polyethylene glycol)
Iodine tincture (USP)
Iodine topical solution (USP)
Mercufenol chloride
Methylbenzethonium chloride
Nonylphenoxypoly (ethyleneoxy) ethanoliodine
[[Page 49]]
Phenol
Poloxamer-iodine complex
Secondary amyltricresols
Sodium oxychlorosene
Tribromsalan
Triclocarban
Triclosan
Triple dye
Undecoylium chloride iodine complex
Combination of calomel, oxyquinoline benzoate, triethanolamine, and
phenol derivative
Combination of mercufenol chloride and secondary amyltricresols in 50
percent alcohol
(28) Vaginal contraceptive drug products--(i) Approved as of October
22, 1998.
Dodecaethylene glycol monolaurate (polyethylene glycol 600 monolaurate)
Laureth 10S
Methoxypolyoxyethyleneglycol 550 laurate
Phenylmercuric acetate
Phenylmercuric nitrate
Any other ingredient containing mercury
(ii) Approved as of November 5, 2002.
Octoxynol 9
(29) Sunscreen drug products. (i) Ingredients.
Diethanolamine methoxycinnamate
Digalloyl trioleate
Ethyl 4-[bis(hydroxypropyl)] aminobenzoate
Glyceryl aminobenzoate
Lawsone with dihydroxyacetone
Red petrolatum
(ii) Any ingredients labeled with any of the following or similar
claims. Instant protection or protection immediately upon application.
Claims for ``all-day'' protection or extended wear claims citing a
specific number of hours of protection that is inconsistent with the
directions for application in 21 CFR 201.327.
(30) [Reserved]
(b) Any OTC drug product that is labeled, represented, or promoted
for the uses specified and containing any active ingredient(s) as
specified in paragraph (a) of this section is regarded as a new drug
within the meaning of section 210(p) of the Federal Food, Drug, and
Cosmetic Act (the Act), for which an approved new drug application under
section 505 of the Act and part 314 of this chapter is required for
marketing. In the absence of an approved new drug application, such
product is also misbranded under section 502 of the Act.
(c) Clinical investigations designed to obtain evidence that any
drug product labeled, represented, or promoted for the OTC uses and
containing any active ingredient(s) as specified in paragraph (a) of
this section is safe and effective for the purpose intended must comply
with the requirements and procedures governing the use of
investigational new drugs set forth in part 312 of this chapter.
(d) Any OTC drug product that is not in compliance with this section
is subject to regulatory action if initially introduced or initially
delivered for introduction into interstate commerce after the dates
specified in paragraphs (d)(1) through (d)(42) of this section.
(1) May 7, 1991, for products subject to paragraphs (a)(1) through
(a)(2)(i), (a)(3)(i), (a)(4)(i), (a)(6)(i)(A), (a)(6)(ii)(A), (a)(7)
(except as covered by paragraph (d)(3) of this section), (a)(8)(i),
(a)(10)(i) through (a)(10)(iii), (a)(12)(i)(A), (a)(12)(ii) through
(a)(12)(iv)(A), (a)(14) through (a)(15)(i), (a)(16) through
(a)(18)(i)(A), (a)(18)(ii) (except as covered by paragraph (d)(22) of
this section), (a)(18)(iii), (a)(18)(iv), (a)(18)(v)(A), and
(a)(18)(vi)(A) of this section.
(2) February 10, 1992, for products subject to paragraph (a)(20) of
this section.
(3) December 4, 1992, for products subject to paragraph (a)(7) of
this section that contain menthol as an antipruritic in combination with
the antidandruff ingredient coal tar identified in Sec. 358.710(a)(1)
of this chapter. This section does not apply to products allowed by
Sec. 358.720(b) of this chapter after April 5, 2007.
(4) February 28, 1990, for products subject to paragraph (a)(6)(iii)
of this section, except those that contain ipecac.
(5) September 14, 1993, for products subject to paragraph
(a)(6)(iii) of this section that contain ipecac.
(6) December 9, 1993, for products subject to paragraph (a)(6)(i)(B)
of this section.
(7) March 6, 1989, for products subject to paragraph (a)(21) of this
section, except those that contain ophthalmic anti-infective ingredients
listed in paragraph (a)(21)(ii).
(8) June 18, 1993, for products subject to paragraph (a)(21) of this
section that
[[Page 50]]
contain ophthalmic anti-infective ingredients.
(9) June 18, 1993, for products subject to paragraph (a)(10)(iv) of
this section.
(10) June 18, 1993, for products subject to paragraph (a)(22)(i) of
this section.
(11) November 10, 1993, for products subject to paragraphs
(a)(8)(ii), (a)(10)(v) through (a)(10)(vii), (a)(18)(ii) (except
products that contain ferric subsulfate as covered by paragraph (d)(22)
of this section and except products that contain calcium acetate
monohydrate as covered by paragraph (d)(39) of this section) through
(a)(18)(v)(A), (a)(18)(vi)(A), (a)(22)(ii), (a)(23)(i), (a)(24)(i), and
(a)(25) of this section.
(12) March 2, 1994, for products subject to paragraph (a)(22)(iii)
of this section.
(13) August 5, 1991, for products subject to paragraph (a)(26) of
this section, except for those that contain live yeast cell derivative
and a combination of hydrocortisone and pramoxine hydrochloride.
(14) September 2, 1994, for products subject to paragraph
(a)(26)(vii) and (a)(26)(x) of this section that contain live yeast cell
derivative.
(15) September 23, 1994, for products subject to paragraph
(a)(22)(iv) of this section.
(16) June 14, 1994, for products subject to paragraph (a)(25)(ii) of
this section.
(17) April 19, 2004, for products subject to paragraph (a)(3)(ii) of
this section. April 18, 2005, for products with annual sales less than
$25,000.
(18) August 15, 1995, for products subject to paragraph (a)(15)(ii)
of this section.
(19) October 2, 1987, for products subject to paragraph
(a)(6)(iv)(A) of this section.
(20) January 29, 1996, for products subject to paragraph
(a)(6)(iv)(B) of this section.
(21) April 21, 1994, for products subject to paragraph (a)(8)(iii)
of this section.
(22) April 21, 1993, for products subject to paragraph (a)(18)(ii)
of this section that contain ferric subsulfate.
(23) August 23, 1995, for products subject to paragraph
(a)(6)(ii)(B) of this section.
(24) October 7, 1996, for products subject to paragraph (a)(2)(ii)
of this section.
(25) June 19, 1996, for products subject to paragraph (a)(6)(iv)(C)
of this section.
(26) February 22, 1999, for products subject to paragraphs
(a)(23)(ii) and (a)(24)(ii) of this section.
(27) [Reserved]
(28) October 22, 1998, for products subject to paragraphs (a)(27)
and (a)(28)(i) of this section.
(29) January 29, 1999, for products subject to paragraph
(a)(12)(iv)(B) of this section.
(30) November 5, 2002, for products subject to paragraph
(a)(12)(iv)(C) of this section.
(31) December 31, 2002, for products subject to paragraph (a)(29)(i)
of this section.
(32) June 4, 2004, for products subject to paragraphs (a)(18)(i)(B),
(a)(18)(v)(B), and (a)(18)(vi)(B) of this section. June 6, 2005, for
products with annual sales less than $25,000.
(33) October 29, 2001, for products subject to paragraph
(a)(6)(iv)(D) of this section.
(34) December 9, 2004, for products subject to paragraph (a)(4)(ii)
of this section. June 9, 2005, for products with annual sales less than
$25,000.
(35) [Reserved]
(36) November 5, 2002, for products subject to paragraph (a)(28)(ii)
of this section.
(37) September 25, 2003, for products subject to paragraph
(a)(26)(xi) of this section.
(38) October 1, 2007, for products subject to paragraph
(a)(12)(i)(B) of this section.
(39) September 6, 2010, for products subject to paragraph
(a)(18)(ii) of this section that contain calcium acetate monohydrate,
except as provided in Sec. 347.20(b) of this chapter.
(40) December 17, 2012, for products subject to paragraph
(a)(29)(ii) of this section. December 17, 2013, for products with annual
sales less than $25,000.
(41) September 6, 2017, for products subject to paragraph
(a)(27)(iii) or (iv) of this section.
[[Page 51]]
(42) December 20, 2018, for products subject to paragraphs
(a)(27)(vi) through (x) of this section.
[55 FR 46919, Nov. 7, 1990]
Editorial Note: For Federal Register citations affecting Sec.
310.545, see the List of CFR Sections Affected, which appears in the
Finding Aids section of the printed volume and at www.govinfo.gov.
Effective Date Note: At 61 FR 9571, Mar. 8, 1996, in Sec. 310.545
in paragraph (a)(6)(ii)(B), the entry for ``l-desoxyephedrine
(topical)'' was stayed until further notice.
Sec. 310.546 Drug products containing active ingredients offered
over-the-counter (OTC) for the treatment and/or prevention of nocturnal
leg muscle cramps.
(a) Quinine sulfate alone or in combination with vitamin E has been
present in over-the-counter (OTC) drug products for the treatment and/or
prevention of nocturnal leg muscle cramps, i.e., a condition of
localized pain in the lower extremities usually occurring in middle life
and beyond with no regular pattern concerning time or severity. There is
a lack of adequate data to establish general recognition of the safety
and effectiveness of quinine sulfate, vitamin E, or any other
ingredients for OTC use in the treatment and/or prevention of nocturnal
leg muscle cramps. In the doses used to treat or prevent this condition,
quinine sulfate has caused adverse events such as transient visual and
auditory disturbances, dizziness, fever, nausea, vomiting, and diarrhea.
Quinine sulfate may cause unpredictable serious and life-threatening
hypersensitivity reactions requiring medical intervention and
hospitalization; fatalities have been reported. The risk associated with
use of quinine sulfate, in the absence of evidence of its effectiveness,
outweighs any potential benefit in treating and/or preventing this
benign, self-limiting condition. Based upon the adverse benefit-to-risk
ratio, any drug product containing quinine or quinine sulfate cannot be
considered generally recognized as safe for the treatment and/or
prevention of nocturnal leg muscle cramps.
(b) Any OTC drug product that is labeled, represented, or promoted
for the treatment and/or prevention of nocturnal leg muscle cramps is
regarded as a new drug within the meaning of section 201(p) of the
Federal Food, Drug, and Cosmetic Act (the act), for which an approved
application or abbreviated application under section 505 of the act and
part 314 of this chapter is required for marketing. In the absence of an
approved new drug application or abbreviated new drug application, such
product is also misbranded under section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any
drug product labeled, represented, or promoted for OTC use for the
treatment and/or prevention of nocturnal leg muscle cramps is safe and
effective for the purpose intended must comply with the requirements and
procedures governing the use of investigational new drugs set forth in
part 312 of this chapter.
(d) After February 22, 1995, any such OTC drug product initially
introduced or initially delivered for introduction into interstate
commerce that is not in compliance with this section is subject to
regulatory action.
[59 FR 43252, Aug. 22, 1994]
Sec. 310.547 Drug products containing quinine offered over-the-counter
(OTC) for the treatment and/or prevention of malaria.
(a) Quinine and quinine salts have been used OTC for the treatment
and/or prevention of malaria, a serious and potentially life-threatening
disease. Quinine is no longer the drug of choice for the treatment and/
or prevention of most types of malaria. In addition, there are serious
and complicating aspects of the disease itself and some potentially
serious and life-threatening risks associated with the use of quinine at
doses employed for the treatment of malaria. There is a lack of adequate
data to establish general recognition of the safety of quinine drug
products for OTC use in the treatment and/or prevention of malaria.
Therefore, quinine or quinine salts cannot be safely and effectively
used for the treatment and/or prevention of malaria except under the
care and supervision of a doctor.
(b) Any OTC drug product containing quinine or quinine salts that is
labeled, represented, or promoted for the treatment and/or prevention of
malaria is
[[Page 52]]
regarded as a new drug within the meaning of section 201(p) of the act,
for which an approved application or abbreviated application under
section 505 of the act and part 314 of this chapter is required for
marketing. In the absence of an approved new drug application or
abbreviated new drug application, such product is also misbranded under
section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any
drug product labeled, represented, or promoted for OTC use for the
treatment and/or prevention of malaria is safe and effective for the
purpose intended must comply with the requirements and procedures
governing the use of investigational new drugs set forth in part 312 of
this chapter.
(d) After April 20, 1998, any such OTC drug product initially
introduced or initially delivered for introduction into interstate
commerce that is not in compliance with this section is subject to
regulatory action.
[63 FR 13528, Mar. 20, 1998]
Sec. 310.548 Drug products containing colloidal silver ingredients
or silver salts offered over-the-counter (OTC) for the treatment and/or
prevention of disease.
(a) Colloidal silver ingredients and silver salts have been marketed
in over-the-counter (OTC) drug products for the treatment and prevention
of numerous disease conditions. There are serious and complicating
aspects to many of the diseases these silver ingredients purport to
treat or prevent. Further, there is a lack of adequate data to establish
general recognition of the safety and effectiveness of colloidal silver
ingredients or silver salts for OTC use in the treatment or prevention
of any disease. These ingredients and salts include, but are not limited
to, silver proteins, mild silver protein, strong silver protein, silver,
silver ion, silver chloride, silver cyanide, silver iodide, silver
oxide, and silver phosphate.
(b) Any OTC drug product containing colloidal silver ingredients or
silver salts that is labeled, represented, or promoted for the treatment
and/or prevention of any disease is regarded as a new drug within the
meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act
(the act) for which an approved application or abbreviated application
under section 505 of the act and part 314 of this chapter is required
for marketing. In the absence of an approved new drug application or
abbreviated new drug application, such product is also misbranded under
section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any
drug product containing colloidal silver or silver salts labeled,
represented, or promoted for any OTC drug use is safe and effective for
the purpose intended must comply with the requirements and procedures
governing the use of investigational new drugs as set forth in part 312
of this chapter.
(d) After September 16, 1999, any such OTC drug product containing
colloidal silver or silver salts initially introduced or initially
delivered for introduction into interstate commerce that is not in
compliance with this section is subject to regulatory action.
[64 FR 44658, Aug. 17, 1999]
PART 312_INVESTIGATIONAL NEW DRUG APPLICATION--Table of Contents
Subpart A_General Provisions
Sec.
312.1 Scope.
312.2 Applicability.
312.3 Definitions and interpretations.
312.6 Labeling of an investigational new drug.
312.7 Promotion of investigational drugs.
312.8 Charging for investigational drugs under an IND.
312.10 Waivers.
Subpart B_Investigational New Drug Application (IND)
312.20 Requirement for an IND.
312.21 Phases of an investigation.
312.22 General principles of the IND submission.
312.23 IND content and format.
312.30 Protocol amendments.
312.31 Information amendments.
312.32 IND safety reporting.
312.33 Annual reports.
312.38 Withdrawal of an IND.
[[Page 53]]
Subpart C_Administrative Actions
312.40 General requirements for use of an investigational new drug in a
clinical investigation.
312.41 Comment and advice on an IND.
312.42 Clinical holds and requests for modification.
312.44 Termination.
312.45 Inactive status.
312.47 Meetings.
312.48 Dispute resolution.
Subpart D_Responsibilities of Sponsors and Investigators
312.50 General responsibilities of sponsors.
312.52 Transfer of obligations to a contract research organization.
312.53 Selecting investigators and monitors.
312.54 Emergency research under Sec. 50.24 of this chapter.
312.55 Informing investigators.
312.56 Review of ongoing investigations.
312.57 Recordkeeping and record retention.
312.58 Inspection of sponsor's records and reports.
312.59 Disposition of unused supply of investigational drug.
312.60 General responsibilities of investigators.
312.61 Control of the investigational drug.
312.62 Investigator recordkeeping and record retention.
312.64 Investigator reports.
312.66 Assurance of IRB review.
312.68 Inspection of investigator's records and reports.
312.69 Handling of controlled substances.
312.70 Disqualification of a clinical investigator.
Subpart E_Drugs Intended to Treat Life-threatening and Severely-
debilitating Illnesses
312.80 Purpose.
312.81 Scope.
312.82 Early consultation.
312.83 Treatment protocols.
312.84 Risk-benefit analysis in review of marketing applications for
drugs to treat life-threatening and severely-debilitating
illnesses.
312.85 Phase 4 studies.
312.86 Focused FDA regulatory research.
312.87 Active monitoring of conduct and evaluation of clinical trials.
312.88 Safeguards for patient safety.
Subpart F_Miscellaneous
312.110 Import and export requirements.
312.120 Foreign clinical studies not conducted under an IND.
312.130 Availability for public disclosure of data and information in an
IND.
312.140 Address for correspondence.
312.145 Guidance documents.
Subpart G_Drugs for Investigational Use in Laboratory Research Animals
or in Vitro Tests
312.160 Drugs for investigational use in laboratory research animals or
in vitro tests.
Subpart H [Reserved]
Subpart I_Expanded Access to Investigational Drugs for Treatment Use
312.300 General.
312.305 Requirements for all expanded access uses.
312.310 Individual patients, including for emergency use.
312.315 Intermediate-size patient populations.
312.320 Treatment IND or treatment protocol.
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360bbb, 371; 42
U.S.C. 262.
Source: 52 FR 8831, Mar. 19, 1987, unless otherwise noted.
Editorial Note: Nomenclature changes to part 312 appear at 69 FR
13717, Mar. 24, 2004.
Subpart A_General Provisions
Sec. 312.1 Scope.
(a) This part contains procedures and requirements governing the use
of investigational new drugs, including procedures and requirements for
the submission to, and review by, the Food and Drug Administration of
investigational new drug applications (IND's). An investigational new
drug for which an IND is in effect in accordance with this part is
exempt from the premarketing approval requirements that are otherwise
applicable and may be shipped lawfully for the purpose of conducting
clinical investigations of that drug.
(b) References in this part to regulations in the Code of Federal
Regulations are to chapter I of title 21, unless otherwise noted.
Sec. 312.2 Applicability.
(a) Applicability. Except as provided in this section, this part
applies to all clinical investigations of products that are subject to
section 505 of the Federal Food, Drug, and Cosmetic Act or to the
[[Page 54]]
licensing provisions of the Public Health Service Act (58 Stat. 632, as
amended (42 U.S.C. 201 et seq.)).
(b) Exemptions. (1) The clinical investigation of a drug product
that is lawfully marketed in the United States is exempt from the
requirements of this part if all the following apply:
(i) The investigation is not intended to be reported to FDA as a
well-controlled study in support of a new indication for use nor
intended to be used to support any other significant change in the
labeling for the drug;
(ii) If the drug that is undergoing investigation is lawfully
marketed as a prescription drug product, the investigation is not
intended to support a significant change in the advertising for the
product;
(iii) The investigation does not involve a route of administration
or dosage level or use in a patient population or other factor that
significantly increases the risks (or decreases the acceptability of the
risks) associated with the use of the drug product;
(iv) The investigation is conducted in compliance with the
requirements for institutional review set forth in part 56 and with the
requirements for informed consent set forth in part 50; and
(v) The investigation is conducted in compliance with the
requirements of Sec. 312.7.
(2)(i) A clinical investigation involving an in vitro diagnostic
biological product listed in paragraph (b)(2)(ii) of this section is
exempt from the requirements of this part if (a) it is intended to be
used in a diagnostic procedure that confirms the diagnosis made by
another, medically established, diagnostic product or procedure and (b)
it is shipped in compliance with Sec. 312.160.
(ii) In accordance with paragraph (b)(2)(i) of this section, the
following products are exempt from the requirements of this part: (a)
blood grouping serum; (b) reagent red blood cells; and (c) anti-human
globulin.
(3) A drug intended solely for tests in vitro or in laboratory
research animals is exempt from the requirements of this part if shipped
in accordance with Sec. 312.160.
(4) FDA will not accept an application for an investigation that is
exempt under the provisions of paragraph (b)(1) of this section.
(5) A clinical investigation involving use of a placebo is exempt
from the requirements of this part if the investigation does not
otherwise require submission of an IND.
(6) A clinical investigation involving an exception from informed
consent under Sec. 50.24 of this chapter is not exempt from the
requirements of this part.
(c) Bioavailability studies. The applicability of this part to in
vivo bioavailability studies in humans is subject to the provisions of
Sec. 320.31.
(d) Unlabeled indication. This part does not apply to the use in the
practice of medicine for an unlabeled indication of a new drug product
approved under part 314 or of a licensed biological product.
(e) Guidance. FDA may, on its own initiative, issue guidance on the
applicability of this part to particular investigational uses of drugs.
On request, FDA will advise on the applicability of this part to a
planned clinical investigation.
[52 FR 8831, Mar. 19, 1987, as amended at 61 FR 51529, Oct. 2, 1996; 64
FR 401, Jan. 5, 1999]
Sec. 312.3 Definitions and interpretations.
(a) The definitions and interpretations of terms contained in
section 201 of the Act apply to those terms when used in this part:
(b) The following definitions of terms also apply to this part:
Act means the Federal Food, Drug, and Cosmetic Act (secs. 201-902,
52 Stat. 1040 et seq., as amended (21 U.S.C. 301-392)).
Clinical investigation means any experiment in which a drug is
administered or dispensed to, or used involving, one or more human
subjects. For the purposes of this part, an experiment is any use of a
drug except for the use of a marketed drug in the course of medical
practice.
Contract research organization means a person that assumes, as an
independent contractor with the sponsor, one or more of the obligations
of a sponsor, e.g., design of a protocol, selection or
[[Page 55]]
monitoring of investigations, evaluation of reports, and preparation of
materials to be submitted to the Food and Drug Administration.
FDA means the Food and Drug Administration.
IND means an investigational new drug application. For purposes of
this part, ``IND'' is synonymous with ``Notice of Claimed
Investigational Exemption for a New Drug.''
Independent ethics committee (IEC) means a review panel that is
responsible for ensuring the protection of the rights, safety, and well-
being of human subjects involved in a clinical investigation and is
adequately constituted to provide assurance of that protection. An
institutional review board (IRB), as defined in Sec. 56.102(g) of this
chapter and subject to the requirements of part 56 of this chapter, is
one type of IEC.
Investigational new drug means a new drug or biological drug that is
used in a clinical investigation. The term also includes a biological
product that is used in vitro for diagnostic purposes. The terms
``investigational drug'' and ``investigational new drug'' are deemed to
be synonymous for purposes of this part.
Investigator means an individual who actually conducts a clinical
investigation (i.e., under whose immediate direction the drug is
administered or dispensed to a subject). In the event an investigation
is conducted by a team of individuals, the investigator is the
responsible leader of the team. ``Subinvestigator'' includes any other
individual member of that team.
Marketing application means an application for a new drug submitted
under section 505(b) of the act or a biologics license application for a
biological product submitted under the Public Health Service Act.
Sponsor means a person who takes responsibility for and initiates a
clinical investigation. The sponsor may be an individual or
pharmaceutical company, governmental agency, academic institution,
private organization, or other organization. The sponsor does not
actually conduct the investigation unless the sponsor is a sponsor-
investigator. A person other than an individual that uses one or more of
its own employees to conduct an investigation that it has initiated is a
sponsor, not a sponsor-investigator, and the employees are
investigators.
Sponsor-Investigator means an individual who both initiates and
conducts an investigation, and under whose immediate direction the
investigational drug is administered or dispensed. The term does not
include any person other than an individual. The requirements applicable
to a sponsor-investigator under this part include both those applicable
to an investigator and a sponsor.
Subject means a human who participates in an investigation, either
as a recipient of the investigational new drug or as a control. A
subject may be a healthy human or a patient with a disease.
[52 FR 8831, Mar. 19, 1987, as amended at 64 FR 401, Jan. 5, 1999; 64 FR
56449, Oct. 20, 1999; 73 FR 22815, Apr. 28, 2008]
Sec. 312.6 Labeling of an investigational new drug.
(a) The immediate package of an investigational new drug intended
for human use shall bear a label with the statement ``Caution: New
Drug--Limited by Federal (or United States) law to investigational
use.''
(b) The label or labeling of an investigational new drug shall not
bear any statement that is false or misleading in any particular and
shall not represent that the investigational new drug is safe or
effective for the purposes for which it is being investigated.
(c) The appropriate FDA Center Director, according to the procedures
set forth in Sec. Sec. 201.26 or 610.68 of this chapter, may grant an
exception or alternative to the provision in paragraph (a) of this
section, to the extent that this provision is not explicitly required by
statute, for specified lots, batches, or other units of a human drug
product that is or will be included in the Strategic National Stockpile.
[52 FR 8831, Mar. 19, 1987, as amended at 72 FR 73599, Dec. 28, 2007]
Sec. 312.7 Promotion of investigational drugs.
(a) Promotion of an investigational new drug. A sponsor or
investigator, or any person acting on behalf of a sponsor or
[[Page 56]]
investigator, shall not represent in a promotional context that an
investigational new drug is safe or effective for the purposes for which
it is under investigation or otherwise promote the drug. This provision
is not intended to restrict the full exchange of scientific information
concerning the drug, including dissemination of scientific findings in
scientific or lay media. Rather, its intent is to restrict promotional
claims of safety or effectiveness of the drug for a use for which it is
under investigation and to preclude commercialization of the drug before
it is approved for commercial distribution.
(b) Commercial distribution of an investigational new drug. A
sponsor or investigator shall not commercially distribute or test market
an investigational new drug.
(c) Prolonging an investigation. A sponsor shall not unduly prolong
an investigation after finding that the results of the investigation
appear to establish sufficient data to support a marketing application.
[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 19476, May 22, 1987; 67
FR 9585, Mar. 4, 2002; 74 FR 40899, Aug. 13, 2009]
Sec. 312.8 Charging for investigational drugs under an IND.
(a) General criteria for charging. (1) A sponsor must meet the
applicable requirements in paragraph (b) of this section for charging in
a clinical trial or paragraph (c) of this section for charging for
expanded access to an investigational drug for treatment use under
subpart I of this part, except that sponsors need not fulfill the
requirements in this section to charge for an approved drug obtained
from another entity not affiliated with the sponsor for use as part of
the clinical trial evaluation (e.g., in a clinical trial of a new use of
the approved drug, for use of the approved drug as an active control).
(2) A sponsor must justify the amount to be charged in accordance
with paragraph (d) of this section.
(3) A sponsor must obtain prior written authorization from FDA to
charge for an investigational drug.
(4) FDA will withdraw authorization to charge if it determines that
charging is interfering with the development of a drug for marketing
approval or that the criteria for the authorization are no longer being
met.
(b) Charging in a clinical trial--(1) Charging for a sponsor's drug.
A sponsor who wishes to charge for its investigational drug, including
investigational use of its approved drug, must:
(i) Provide evidence that the drug has a potential clinical benefit
that, if demonstrated in the clinical investigations, would provide a
significant advantage over available products in the diagnosis,
treatment, mitigation, or prevention of a disease or condition;
(ii) Demonstrate that the data to be obtained from the clinical
trial would be essential to establishing that the drug is effective or
safe for the purpose of obtaining initial approval of a drug, or would
support a significant change in the labeling of an approved drug (e.g.,
new indication, inclusion of comparative safety information); and
(iii) Demonstrate that the clinical trial could not be conducted
without charging because the cost of the drug is extraordinary to the
sponsor. The cost may be extraordinary due to manufacturing complexity,
scarcity of a natural resource, the large quantity of drug needed (e.g.,
due to the size or duration of the trial), or some combination of these
or other extraordinary circumstances (e.g., resources available to a
sponsor).
(2) Duration of charging in a clinical trial. Unless FDA specifies a
shorter period, charging may continue for the length of the clinical
trial.
(c) Charging for expanded access to investigational drug for
treatment use. (1) A sponsor who wishes to charge for expanded access to
an investigational drug for treatment use under subpart I of this part
must provide reasonable assurance that charging will not interfere with
developing the drug for marketing approval.
(2) For expanded access under Sec. 312.320 (treatment IND or
treatment protocol), such assurance must include:
(i) Evidence of sufficient enrollment in any ongoing clinical
trial(s) needed for marketing approval to reasonably assure FDA that the
trial(s) will be successfully completed as planned;
[[Page 57]]
(ii) Evidence of adequate progress in the development of the drug
for marketing approval; and
(iii) Information submitted under the general investigational plan
(Sec. 312.23(a)(3)(iv)) specifying the drug development milestones the
sponsor plans to meet in the next year.
(3) The authorization to charge is limited to the number of patients
authorized to receive the drug under the treatment use, if there is a
limitation.
(4) Unless FDA specifies a shorter period, charging for expanded
access to an investigational drug for treatment use under subpart I of
this part may continue for 1 year from the time of FDA authorization. A
sponsor may request that FDA reauthorize charging for additional
periods.
(d) Costs recoverable when charging for an investigational drug. (1)
A sponsor may recover only the direct costs of making its
investigational drug available.
(i) Direct costs are costs incurred by a sponsor that can be
specifically and exclusively attributed to providing the drug for the
investigational use for which FDA has authorized cost recovery. Direct
costs include costs per unit to manufacture the drug (e.g., raw
materials, labor, and nonreusable supplies and equipment used to
manufacture the quantity of drug needed for the use for which charging
is authorized) or costs to acquire the drug from another manufacturing
source, and direct costs to ship and handle (e.g., store) the drug.
(ii) Indirect costs include costs incurred primarily to produce the
drug for commercial sale (e.g., costs for facilities and equipment used
to manufacture the supply of investigational drug, but that are
primarily intended to produce large quantities of drug for eventual
commercial sale) and research and development, administrative, labor, or
other costs that would be incurred even if the clinical trial or
treatment use for which charging is authorized did not occur.
(2) For expanded access to an investigational drug for treatment use
under Sec. Sec. 312.315 (intermediate-size patient populations) and
312.320 (treatment IND or treatment protocol), in addition to the direct
costs described in paragraph (d)(1)(i) of this section, a sponsor may
recover the costs of monitoring the expanded access IND or protocol,
complying with IND reporting requirements, and other administrative
costs directly associated with the expanded access IND.
(3) To support its calculation for cost recovery, a sponsor must
provide supporting documentation to show that the calculation is
consistent with the requirements of paragraphs (d)(1) and, if
applicable, (d)(2) of this section. The documentation must be
accompanied by a statement that an independent certified public
accountant has reviewed and approved the calculations.
[74 FR 40899, Aug. 13, 2009]
Sec. 312.10 Waivers.
(a) A sponsor may request FDA to waive applicable requirement under
this part. A waiver request may be submitted either in an IND or in an
information amendment to an IND. In an emergency, a request may be made
by telephone or other rapid communication means. A waiver request is
required to contain at least one of the following:
(1) An explanation why the sponsor's compliance with the requirement
is unnecessary or cannot be achieved;
(2) A description of an alternative submission or course of action
that satisfies the purpose of the requirement; or
(3) Other information justifying a waiver.
(b) FDA may grant a waiver if it finds that the sponsor's
noncompliance would not pose a significant and unreasonable risk to
human subjects of the investigation and that one of the following is
met:
(1) The sponsor's compliance with the requirement is unnecessary for
the agency to evaluate the application, or compliance cannot be
achieved;
(2) The sponsor's proposed alternative satisfies the requirement; or
(3) The applicant's submission otherwise justifies a waiver.
[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 67
FR 9585, Mar. 4, 2002]
[[Page 58]]
Subpart B_Investigational New Drug Application (IND)
Sec. 312.20 Requirement for an IND.
(a) A sponsor shall submit an IND to FDA if the sponsor intends to
conduct a clinical investigation with an investigational new drug that
is subject to Sec. 312.2(a).
(b) A sponsor shall not begin a clinical investigation subject to
Sec. 312.2(a) until the investigation is subject to an IND which is in
effect in accordance with Sec. 312.40.
(c) A sponsor shall submit a separate IND for any clinical
investigation involving an exception from informed consent under Sec.
50.24 of this chapter. Such a clinical investigation is not permitted to
proceed without the prior written authorization from FDA. FDA shall
provide a written determination 30 days after FDA receives the IND or
earlier.
[52 FR 8831, Mar. 19, 1987, as amended at 61 FR 51529, Oct. 2, 1996; 62
FR 32479, June 16, 1997]
Sec. 312.21 Phases of an investigation.
An IND may be submitted for one or more phases of an investigation.
The clinical investigation of a previously untested drug is generally
divided into three phases. Although in general the phases are conducted
sequentially, they may overlap. These three phases of an investigation
are a follows:
(a) Phase 1. (1) Phase 1 includes the initial introduction of an
investigational new drug into humans. Phase 1 studies are typically
closely monitored and may be conducted in patients or normal volunteer
subjects. These studies are designed to determine the metabolism and
pharmacologic actions of the drug in humans, the side effects associated
with increasing doses, and, if possible, to gain early evidence on
effectiveness. During Phase 1, sufficient information about the drug's
pharmacokinetics and pharmacological effects should be obtained to
permit the design of well-controlled, scientifically valid, Phase 2
studies. The total number of subjects and patients included in Phase 1
studies varies with the drug, but is generally in the range of 20 to 80.
(2) Phase 1 studies also include studies of drug metabolism,
structure-activity relationships, and mechanism of action in humans, as
well as studies in which investigational drugs are used as research
tools to explore biological phenomena or disease processes.
(b) Phase 2. Phase 2 includes the controlled clinical studies
conducted to evaluate the effectiveness of the drug for a particular
indication or indications in patients with the disease or condition
under study and to determine the common short-term side effects and
risks associated with the drug. Phase 2 studies are typically well
controlled, closely monitored, and conducted in a relatively small
number of patients, usually involving no more than several hundred
subjects.
(c) Phase 3. Phase 3 studies are expanded controlled and
uncontrolled trials. They are performed after preliminary evidence
suggesting effectiveness of the drug has been obtained, and are intended
to gather the additional information about effectiveness and safety that
is needed to evaluate the overall benefit-risk relationship of the drug
and to provide an adequate basis for physician labeling. Phase 3 studies
usually include from several hundred to several thousand subjects.
Sec. 312.22 General principles of the IND submission.
(a) FDA's primary objectives in reviewing an IND are, in all phases
of the investigation, to assure the safety and rights of subjects, and,
in Phase 2 and 3, to help assure that the quality of the scientific
evaluation of drugs is adequate to permit an evaluation of the drug's
effectiveness and safety. Therefore, although FDA's review of Phase 1
submissions will focus on assessing the safety of Phase 1
investigations, FDA's review of Phases 2 and 3 submissions will also
include an assessment of the scientific quality of the clinical
investigations and the likelihood that the investigations will yield
data capable of meeting statutory standards for marketing approval.
(b) The amount of information on a particular drug that must be
submitted in an IND to assure the accomplishment of the objectives
described in paragraph (a) of this section depends
[[Page 59]]
upon such factors as the novelty of the drug, the extent to which it has
been studied previously, the known or suspected risks, and the
developmental phase of the drug.
(c) The central focus of the initial IND submission should be on the
general investigational plan and the protocols for specific human
studies. Subsequent amendments to the IND that contain new or revised
protocols should build logically on previous submissions and should be
supported by additional information, including the results of animal
toxicology studies or other human studies as appropriate. Annual reports
to the IND should serve as the focus for reporting the status of studies
being conducted under the IND and should update the general
investigational plan for the coming year.
(d) The IND format set forth in Sec. 312.23 should be followed
routinely by sponsors in the interest of fostering an efficient review
of applications. Sponsors are expected to exercise considerable
discretion, however, regarding the content of information submitted in
each section, depending upon the kind of drug being studied and the
nature of the available information. Section 312.23 outlines the
information needed for a commercially sponsored IND for a new molecular
entity. A sponsor-investigator who uses, as a research tool, an
investigational new drug that is already subject to a manufacturer's IND
or marketing application should follow the same general format, but
ordinarily may, if authorized by the manufacturer, refer to the
manufacturer's IND or marketing application in providing the technical
information supporting the proposed clinical investigation. A sponsor-
investigator who uses an investigational drug not subject to a
manufacturer's IND or marketing application is ordinarily required to
submit all technical information supporting the IND, unless such
information may be referenced from the scientific literature.
Sec. 312.23 IND content and format.
(a) A sponsor who intends to conduct a clinical investigation
subject to this part shall submit an ``Investigational New Drug
Application'' (IND) including, in the following order:
(1) Cover sheet (Form FDA-1571). A cover sheet for the application
containing the following:
(i) The name, address, and telephone number of the sponsor, the date
of the application, and the name of the investigational new drug.
(ii) Identification of the phase or phases of the clinical
investigation to be conducted.
(iii) A commitment not to begin clinical investigations until an IND
covering the investigations is in effect.
(iv) A commitment that an Institutional Review Board (IRB) that
complies with the requirements set forth in part 56 will be responsible
for the initial and continuing review and approval of each of the
studies in the proposed clinical investigation and that the investigator
will report to the IRB proposed changes in the research activity in
accordance with the requirements of part 56.
(v) A commitment to conduct the investigation in accordance with all
other applicable regulatory requirements.
(vi) The name and title of the person responsible for monitoring the
conduct and progress of the clinical investigations.
(vii) The name(s) and title(s) of the person(s) responsible under
Sec. 312.32 for review and evaluation of information relevant to the
safety of the drug.
(viii) If a sponsor has transferred any obligations for the conduct
of any clinical study to a contract research organization, a statement
containing the name and address of the contract research organization,
identification of the clinical study, and a listing of the obligations
transferred. If all obligations governing the conduct of the study have
been transferred, a general statement of this transfer--in lieu of a
listing of the specific obligations transferred--may be submitted.
(ix) The signature of the sponsor or the sponsor's authorized
representative. If the person signing the application does not reside or
have a place of business within the United States, the IND is required
to contain the name and address of, and be countersigned
[[Page 60]]
by, an attorney, agent, or other authorized official who resides or
maintains a place of business within the United States.
(2) A table of contents.
(3) Introductory statement and general investigational plan. (i) A
brief introductory statement giving the name of the drug and all active
ingredients, the drug's pharmacological class, the structural formula of
the drug (if known), the formulation of the dosage form(s) to be used,
the route of administration, and the broad objectives and planned
duration of the proposed clinical investigation(s).
(ii) A brief summary of previous human experience with the drug,
with reference to other IND's if pertinent, and to investigational or
marketing experience in other countries that may be relevant to the
safety of the proposed clinical investigation(s).
(iii) If the drug has been withdrawn from investigation or marketing
in any country for any reason related to safety or effectiveness,
identification of the country(ies) where the drug was withdrawn and the
reasons for the withdrawal.
(iv) A brief description of the overall plan for investigating the
drug product for the following year. The plan should include the
following: (a) The rationale for the drug or the research study; (b) the
indication(s) to be studied; (c) the general approach to be followed in
evaluating the drug; (d) the kinds of clinical trials to be conducted in
the first year following the submission (if plans are not developed for
the entire year, the sponsor should so indicate); (e) the estimated
number of patients to be given the drug in those studies; and (f) any
risks of particular severity or seriousness anticipated on the basis of
the toxicological data in animals or prior studies in humans with the
drug or related drugs.
(4) [Reserved]
(5) Investigator's brochure. If required under Sec. 312.55, a copy
of the investigator's brochure, containing the following information:
(i) A brief description of the drug substance and the formulation,
including the structural formula, if known.
(ii) A summary of the pharmacological and toxicological effects of
the drug in animals and, to the extent known, in humans.
(iii) A summary of the pharmacokinetics and biological disposition
of the drug in animals and, if known, in humans.
(iv) A summary of information relating to safety and effectiveness
in humans obtained from prior clinical studies. (Reprints of published
articles on such studies may be appended when useful.)
(v) A description of possible risks and side effects to be
anticipated on the basis of prior experience with the drug under
investigation or with related drugs, and of precautions or special
monitoring to be done as part of the investigational use of the drug.
(6) Protocols. (i) A protocol for each planned study. (Protocols for
studies not submitted initially in the IND should be submitted in
accordance with Sec. 312.30(a).) In general, protocols for Phase 1
studies may be less detailed and more flexible than protocols for Phase
2 and 3 studies. Phase 1 protocols should be directed primarily at
providing an outline of the investigation--an estimate of the number of
patients to be involved, a description of safety exclusions, and a
description of the dosing plan including duration, dose, or method to be
used in determining dose--and should specify in detail only those
elements of the study that are critical to safety, such as necessary
monitoring of vital signs and blood chemistries. Modifications of the
experimental design of Phase 1 studies that do not affect critical
safety assessments are required to be reported to FDA only in the annual
report.
(ii) In Phases 2 and 3, detailed protocols describing all aspects of
the study should be submitted. A protocol for a Phase 2 or 3
investigation should be designed in such a way that, if the sponsor
anticipates that some deviation from the study design may become
necessary as the investigation progresses, alternatives or contingencies
to provide for such deviation are built into the protocols at the
outset. For example, a protocol for a controlled short-term study might
include a plan for an early crossover of nonresponders to an alternative
therapy.
[[Page 61]]
(iii) A protocol is required to contain the following, with the
specific elements and detail of the protocol reflecting the above
distinctions depending on the phase of study:
(a) A statement of the objectives and purpose of the study.
(b) The name and address and a statement of the qualifications
(curriculum vitae or other statement of qualifications) of each
investigator, and the name of each subinvestigator (e.g., research
fellow, resident) working under the supervision of the investigator; the
name and address of the research facilities to be used; and the name and
address of each reviewing Institutional Review Board.
(c) The criteria for patient selection and for exclusion of patients
and an estimate of the number of patients to be studied.
(d) A description of the design of the study, including the kind of
control group to be used, if any, and a description of methods to be
used to minimize bias on the part of subjects, investigators, and
analysts.
(e) The method for determining the dose(s) to be administered, the
planned maximum dosage, and the duration of individual patient exposure
to the drug.
(f) A description of the observations and measurements to be made to
fulfill the objectives of the study.
(g) A description of clinical procedures, laboratory tests, or other
measures to be taken to monitor the effects of the drug in human
subjects and to minimize risk.
(7) Chemistry, manufacturing, and control information. (i) As
appropriate for the particular investigations covered by the IND, a
section describing the composition, manufacture, and control of the drug
substance and the drug product. Although in each phase of the
investigation sufficient information is required to be submitted to
assure the proper identification, quality, purity, and strength of the
investigational drug, the amount of information needed to make that
assurance will vary with the phase of the investigation, the proposed
duration of the investigation, the dosage form, and the amount of
information otherwise available. FDA recognizes that modifications to
the method of preparation of the new drug substance and dosage form and
changes in the dosage form itself are likely as the investigation
progresses. Therefore, the emphasis in an initial Phase 1 submission
should generally be placed on the identification and control of the raw
materials and the new drug substance. Final specifications for the drug
substance and drug product are not expected until the end of the
investigational process.
(ii) It should be emphasized that the amount of information to be
submitted depends upon the scope of the proposed clinical investigation.
For example, although stability data are required in all phases of the
IND to demonstrate that the new drug substance and drug product are
within acceptable chemical and physical limits for the planned duration
of the proposed clinical investigation, if very short-term tests are
proposed, the supporting stability data can be correspondingly limited.
(iii) As drug development proceeds and as the scale or production is
changed from the pilot-scale production appropriate for the limited
initial clinical investigations to the larger-scale production needed
for expanded clinical trials, the sponsor should submit information
amendments to supplement the initial information submitted on the
chemistry, manufacturing, and control processes with information
appropriate to the expanded scope of the investigation.
(iv) Reflecting the distinctions described in this paragraph (a)(7),
and based on the phase(s) to be studied, the submission is required to
contain the following:
(a) Drug substance. A description of the drug substance, including
its physical, chemical, or biological characteristics; the name and
address of its manufacturer; the general method of preparation of the
drug substance; the acceptable limits and analytical methods used to
assure the identity, strength, quality, and purity of the drug
substance; and information sufficient to support stability of the drug
substance during the toxicological studies and the planned clinical
studies. Reference to the current edition of the United
[[Page 62]]
States Pharmacopeia--National Formulary may satisfy relevant
requirements in this paragraph.
(b) Drug product. A list of all components, which may include
reasonable alternatives for inactive compounds, used in the manufacture
of the investigational drug product, including both those components
intended to appear in the drug product and those which may not appear
but which are used in the manufacturing process, and, where applicable,
the quantitative composition of the investigational drug product,
including any reasonable variations that may be expected during the
investigational stage; the name and address of the drug product
manufacturer; a brief general description of the manufacturing and
packaging procedure as appropriate for the product; the acceptable
limits and analytical methods used to assure the identity, strength,
quality, and purity of the drug product; and information sufficient to
assure the product's stability during the planned clinical studies.
Reference to the current edition of the United States Pharmacopeia--
National Formulary may satisfy certain requirements in this paragraph.
(c) A brief general description of the composition, manufacture, and
control of any placebo used in a controlled clinical trial.
(d) Labeling. A copy of all labels and labeling to be provided to
each investigator.
(e) Environmental analysis requirements. A claim for categorical
exclusion under Sec. 25.30 or 25.31 or an environmental assessment
under Sec. 25.40.
(8) Pharmacology and toxicology information. Adequate information
about pharmacological and toxicological studies of the drug involving
laboratory animals or in vitro, on the basis of which the sponsor has
concluded that it is reasonably safe to conduct the proposed clinical
investigations. The kind, duration, and scope of animal and other tests
required varies with the duration and nature of the proposed clinical
investigations. Guidance documents are available from FDA that describe
ways in which these requirements may be met. Such information is
required to include the identification and qualifications of the
individuals who evaluated the results of such studies and concluded that
it is reasonably safe to begin the proposed investigations and a
statement of where the investigations were conducted and where the
records are available for inspection. As drug development proceeds, the
sponsor is required to submit informational amendments, as appropriate,
with additional information pertinent to safety.
(i) Pharmacology and drug disposition. A section describing the
pharmacological effects and mechanism(s) of action of the drug in
animals, and information on the absorption, distribution, metabolism,
and excretion of the drug, if known.
(ii) Toxicology. (a) An integrated summary of the toxicological
effects of the drug in animals and in vitro. Depending on the nature of
the drug and the phase of the investigation, the description is to
include the results of acute, subacute, and chronic toxicity tests;
tests of the drug's effects on reproduction and the developing fetus;
any special toxicity test related to the drug's particular mode of
administration or conditions of use (e.g., inhalation, dermal, or ocular
toxicology); and any in vitro studies intended to evaluate drug
toxicity.
(b) For each toxicology study that is intended primarily to support
the safety of the proposed clinical investigation, a full tabulation of
data suitable for detailed review.
(iii) For each nonclinical laboratory study subject to the good
laboratory practice regulations under part 58, a statement that the
study was conducted in compliance with the good laboratory practice
regulations in part 58, or, if the study was not conducted in compliance
with those regulations, a brief statement of the reason for the
noncompliance.
(9) Previous human experience with the investigational drug. A
summary of previous human experience known to the applicant, if any,
with the investigational drug. The information is required to include
the following:
(i) If the investigational drug has been investigated or marketed
previously, either in the United States or other countries, detailed
information about such experience that is relevant
[[Page 63]]
to the safety of the proposed investigation or to the investigation's
rationale. If the drug has been the subject of controlled trials,
detailed information on such trials that is relevant to an assessment of
the drug's effectiveness for the proposed investigational use(s) should
also be provided. Any published material that is relevant to the safety
of the proposed investigation or to an assessment of the drug's
effectiveness for its proposed investigational use should be provided in
full. Published material that is less directly relevant may be supplied
by a bibliography.
(ii) If the drug is a combination of drugs previously investigated
or marketed, the information required under paragraph (a)(9)(i) of this
section should be provided for each active drug component. However, if
any component in such combination is subject to an approved marketing
application or is otherwise lawfully marketed in the United States, the
sponsor is not required to submit published material concerning that
active drug component unless such material relates directly to the
proposed investigational use (including publications relevant to
component-component interaction).
(iii) If the drug has been marketed outside the United States, a
list of the countries in which the drug has been marketed and a list of
the countries in which the drug has been withdrawn from marketing for
reasons potentially related to safety or effectiveness.
(10) Additional information. In certain applications, as described
below, information on special topics may be needed. Such information
shall be submitted in this section as follows:
(i) Drug dependence and abuse potential. If the drug is a
psychotropic substance or otherwise has abuse potential, a section
describing relevant clinical studies and experience and studies in test
animals.
(ii) Radioactive drugs. If the drug is a radioactive drug,
sufficient data from animal or human studies to allow a reasonable
calculation of radiation-absorbed dose to the whole body and critical
organs upon administration to a human subject. Phase 1 studies of
radioactive drugs must include studies which will obtain sufficient data
for dosimetry calculations.
(iii) Pediatric studies. Plans for assessing pediatric safety and
effectiveness.
(iv) Other information. A brief statement of any other information
that would aid evaluation of the proposed clinical investigations with
respect to their safety or their design and potential as controlled
clinical trials to support marketing of the drug.
(11) Relevant information. If requested by FDA, any other relevant
information needed for review of the application.
(b) Information previously submitted. The sponsor ordinarily is not
required to resubmit information previously submitted, but may
incorporate the information by reference. A reference to information
submitted previously must identify the file by name, reference number,
volume, and page number where the information can be found. A reference
to information submitted to the agency by a person other than the
sponsor is required to contain a written statement that authorizes the
reference and that is signed by the person who submitted the
information.
(c) Material in a foreign language. The sponsor shall submit an
accurate and complete English translation of each part of the IND that
is not in English. The sponsor shall also submit a copy of each original
literature publication for which an English translation is submitted.
(d) Number of copies. The sponsor shall submit an original and two
copies of all submissions to the IND file, including the original
submission and all amendments and reports.
(e) Numbering of IND submissions. Each submission relating to an IND
is required to be numbered serially using a single, three-digit serial
number. The initial IND is required to be numbered 000; each subsequent
submission (e.g., amendment, report, or correspondence) is required to
be numbered chronologically in sequence.
(f) Identification of exception from informed consent. If the
investigation involves an exception from informed consent under Sec.
50.24 of this chapter, the sponsor shall prominently identify on the
cover sheet that the investigation
[[Page 64]]
is subject to the requirements in Sec. 50.24 of this chapter.
[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 53
FR 1918, Jan. 25, 1988; 61 FR 51529, Oct. 2, 1996; 62 FR 40599, July 29,
1997; 63 FR 66669, Dec. 2, 1998; 65 FR 56479, Sept. 19, 2000; 67 FR
9585, Mar. 4, 2002]
Sec. 312.30 Protocol amendments.
Once an IND is in effect, a sponsor shall amend it as needed to
ensure that the clinical investigations are conducted according to
protocols included in the application. This section sets forth the
provisions under which new protocols may be submitted and changes in
previously submitted protocols may be made. Whenever a sponsor intends
to conduct a clinical investigation with an exception from informed
consent for emergency research as set forth in Sec. 50.24 of this
chapter, the sponsor shall submit a separate IND for such investigation.
(a) New protocol. Whenever a sponsor intends to conduct a study that
is not covered by a protocol already contained in the IND, the sponsor
shall submit to FDA a protocol amendment containing the protocol for the
study. Such study may begin provided two conditions are met: (1) The
sponsor has submitted the protocol to FDA for its review; and (2) the
protocol has been approved by the Institutional Review Board (IRB) with
responsibility for review and approval of the study in accordance with
the requirements of part 56. The sponsor may comply with these two
conditions in either order.
(b) Changes in a protocol. (1) A sponsor shall submit a protocol
amendment describing any change in a Phase 1 protocol that significantly
affects the safety of subjects or any change in a Phase 2 or 3 protocol
that significantly affects the safety of subjects, the scope of the
investigation, or the scientific quality of the study. Examples of
changes requiring an amendment under this paragraph include:
(i) Any increase in drug dosage or duration of exposure of
individual subjects to the drug beyond that in the current protocol, or
any significant increase in the number of subjects under study.
(ii) Any significant change in the design of a protocol (such as the
addition or dropping of a control group).
(iii) The addition of a new test or procedure that is intended to
improve monitoring for, or reduce the risk of, a side effect or adverse
event; or the dropping of a test intended to monitor safety.
(2)(i) A protocol change under paragraph (b)(1) of this section may
be made provided two conditions are met:
(a) The sponsor has submitted the change to FDA for its review; and
(b) The change has been approved by the IRB with responsibility for
review and approval of the study. The sponsor may comply with these two
conditions in either order.
(ii) Notwithstanding paragraph (b)(2)(i) of this section, a protocol
change intended to eliminate an apparent immediate hazard to subjects
may be implemented immediately provided FDA is subsequently notified by
protocol amendment and the reviewing IRB is notified in accordance with
Sec. 56.104(c).
(c) New investigator. A sponsor shall submit a protocol amendment
when a new investigator is added to carry out a previously submitted
protocol, except that a protocol amendment is not required when a
licensed practitioner is added in the case of a treatment protocol under
Sec. 312.315 or Sec. 312.320. Once the investigator is added to the
study, the investigational drug may be shipped to the investigator and
the investigator may begin participating in the study. The sponsor shall
notify FDA of the new investigator within 30 days of the investigator
being added.
(d) Content and format. A protocol amendment is required to be
prominently identified as such (i.e., ``Protocol Amendment: New
Protocol'', ``Protocol Amendment: Change in Protocol'', or ``Protocol
Amendment: New Investigator''), and to contain the following:
(1)(i) In the case of a new protocol, a copy of the new protocol and
a brief description of the most clinically significant differences
between it and previous protocols.
(ii) In the case of a change in protocol, a brief description of the
change and reference (date and number) to the
[[Page 65]]
submission that contained the protocol.
(iii) In the case of a new investigator, the investigator's name,
the qualifications to conduct the investigation, reference to the
previously submitted protocol, and all additional information about the
investigator's study as is required under Sec. 312.23(a)(6)(iii)(b).
(2) Reference, if necessary, to specific technical information in
the IND or in a concurrently submitted information amendment to the IND
that the sponsor relies on to support any clinically significant change
in the new or amended protocol. If the reference is made to supporting
information already in the IND, the sponsor shall identify by name,
reference number, volume, and page number the location of the
information.
(3) If the sponsor desires FDA to comment on the submission, a
request for such comment and the specific questions FDA's response
should address.
(e) When submitted. A sponsor shall submit a protocol amendment for
a new protocol or a change in protocol before its implementation.
Protocol amendments to add a new investigator or to provide additional
information about investigators may be grouped and submitted at 30-day
intervals. When several submissions of new protocols or protocol changes
are anticipated during a short period, the sponsor is encouraged, to the
extent feasible, to include these all in a single submission.
[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 53
FR 1918, Jan. 25, 1988; 61 FR 51530, Oct. 2, 1996; 67 FR 9585, Mar. 4,
2002; 74 FR 40942, Aug. 13, 2009]
Sec. 312.31 Information amendments.
(a) Requirement for information amendment. A sponsor shall report in
an information amendment essential information on the IND that is not
within the scope of a protocol amendment, IND safety reports, or annual
report. Examples of information requiring an information amendment
include:
(1) New toxicology, chemistry, or other technical information; or
(2) A report regarding the discontinuance of a clinical
investigation.
(b) Content and format of an information amendment. An information
amendment is required to bear prominent identification of its contents
(e.g., ``Information Amendment: Chemistry, Manufacturing, and Control'',
``Information Amendment: Pharmacology-Toxicology'', ``Information
Amendment: Clinical''), and to contain the following:
(1) A statement of the nature and purpose of the amendment.
(2) An organized submission of the data in a format appropriate for
scientific review.
(3) If the sponsor desires FDA to comment on an information
amendment, a request for such comment.
(c) When submitted. Information amendments to the IND should be
submitted as necessary but, to the extent feasible, not more than every
30 days.
[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 53
FR 1918, Jan. 25, 1988; 67 FR 9585, Mar. 4, 2002]
Sec. 312.32 IND safety reporting.
(a) Definitions. The following definitions of terms apply to this
section:
Adverse event means any untoward medical occurrence associated with
the use of a drug in humans, whether or not considered drug related.
Life-threatening adverse event or life-threatening suspected adverse
reaction. An adverse event or suspected adverse reaction is considered
``life-threatening'' if, in the view of either the investigator or
sponsor, its occurrence places the patient or subject at immediate risk
of death. It does not include an adverse event or suspected adverse
reaction that, had it occurred in a more severe form, might have caused
death.
Serious adverse event or serious suspected adverse reaction. An
adverse event or suspected adverse reaction is considered ``serious''
if, in the view of either the investigator or sponsor, it results in any
of the following outcomes: Death, a life-threatening adverse event,
inpatient hospitalization or prolongation of existing hospitalization, a
persistent or significant incapacity or substantial disruption of the
ability to conduct normal life functions, or a congenital anomaly/birth
defect. Important medical events that may not result in death, be life-
threatening, or require hospitalization may
[[Page 66]]
be considered serious when, based upon appropriate medical judgment,
they may jeopardize the patient or subject and may require medical or
surgical intervention to prevent one of the outcomes listed in this
definition. Examples of such medical events include allergic
bronchospasm requiring intensive treatment in an emergency room or at
home, blood dyscrasias or convulsions that do not result in inpatient
hospitalization, or the development of drug dependency or drug abuse.
Suspected adverse reaction means any adverse event for which there
is a reasonable possibility that the drug caused the adverse event. For
the purposes of IND safety reporting, ``reasonable possibility'' means
there is evidence to suggest a causal relationship between the drug and
the adverse event. Suspected adverse reaction implies a lesser degree of
certainty about causality than adverse reaction, which means any adverse
event caused by a drug.
Unexpected adverse event or unexpected suspected adverse reaction.
An adverse event or suspected adverse reaction is considered
``unexpected'' if it is not listed in the investigator brochure or is
not listed at the specificity or severity that has been observed; or, if
an investigator brochure is not required or available, is not consistent
with the risk information described in the general investigational plan
or elsewhere in the current application, as amended. For example, under
this definition, hepatic necrosis would be unexpected (by virtue of
greater severity) if the investigator brochure referred only to elevated
hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and
cerebral vasculitis would be unexpected (by virtue of greater
specificity) if the investigator brochure listed only cerebral vascular
accidents. ``Unexpected,'' as used in this definition, also refers to
adverse events or suspected adverse reactions that are mentioned in the
investigator brochure as occurring with a class of drugs or as
anticipated from the pharmacological properties of the drug, but are not
specifically mentioned as occurring with the particular drug under
investigation.
(b) Review of safety information. The sponsor must promptly review
all information relevant to the safety of the drug obtained or otherwise
received by the sponsor from foreign or domestic sources, including
information derived from any clinical or epidemiological investigations,
animal or in vitro studies, reports in the scientific literature, and
unpublished scientific papers, as well as reports from foreign
regulatory authorities and reports of foreign commercial marketing
experience for drugs that are not marketed in the United States.
(c)(1) IND safety reports. The sponsor must notify FDA and all
participating investigators (i.e., all investigators to whom the sponsor
is providing drug under its INDs or under any investigator's IND) in an
IND safety report of potential serious risks, from clinical trials or
any other source, as soon as possible, but in no case later than 15
calendar days after the sponsor determines that the information
qualifies for reporting under paragraph (c)(1)(i), (c)(1)(ii),
(c)(1)(iii), or (c)(1)(iv) of this section. In each IND safety report,
the sponsor must identify all IND safety reports previously submitted to
FDA concerning a similar suspected adverse reaction, and must analyze
the significance of the suspected adverse reaction in light of previous,
similar reports or any other relevant information.
(i) Serious and unexpected suspected adverse reaction. The sponsor
must report any suspected adverse reaction that is both serious and
unexpected. The sponsor must report an adverse event as a suspected
adverse reaction only if there is evidence to suggest a causal
relationship between the drug and the adverse event, such as:
(A) A single occurrence of an event that is uncommon and known to be
strongly associated with drug exposure (e.g., angioedema, hepatic
injury, Stevens-Johnson Syndrome);
(B) One or more occurrences of an event that is not commonly
associated with drug exposure, but is otherwise uncommon in the
population exposed to the drug (e.g., tendon rupture);
(C) An aggregate analysis of specific events observed in a clinical
trial (such as known consequences of the underlying disease or condition
under investigation or other events that commonly occur in the study
population
[[Page 67]]
independent of drug therapy) that indicates those events occur more
frequently in the drug treatment group than in a concurrent or
historical control group.
(ii) Findings from other studies. The sponsor must report any
findings from epidemiological studies, pooled analysis of multiple
studies, or clinical studies (other than those reported under paragraph
(c)(1)(i) of this section), whether or not conducted under an IND, and
whether or not conducted by the sponsor, that suggest a significant risk
in humans exposed to the drug. Ordinarily, such a finding would result
in a safety-related change in the protocol, informed consent,
investigator brochure (excluding routine updates of these documents), or
other aspects of the overall conduct of the clinical investigation.
(iii) Findings from animal or in vitro testing. The sponsor must
report any findings from animal or in vitro testing, whether or not
conducted by the sponsor, that suggest a significant risk in humans
exposed to the drug, such as reports of mutagenicity, teratogenicity, or
carcinogenicity, or reports of significant organ toxicity at or near the
expected human exposure. Ordinarily, any such findings would result in a
safety-related change in the protocol, informed consent, investigator
brochure (excluding routine updates of these documents), or other
aspects of the overall conduct of the clinical investigation.
(iv) Increased rate of occurrence of serious suspected adverse
reactions. The sponsor must report any clinically important increase in
the rate of a serious suspected adverse reaction over that listed in the
protocol or investigator brochure.
(v) Submission of IND safety reports. The sponsor must submit each
IND safety report in a narrative format or on FDA Form 3500A or in an
electronic format that FDA can process, review, and archive. FDA will
periodically issue guidance on how to provide the electronic submission
(e.g., method of transmission, media, file formats, preparation and
organization of files). The sponsor may submit foreign suspected adverse
reactions on a Council for International Organizations of Medical
Sciences (CIOMS) I Form instead of a FDA Form 3500A. Reports of overall
findings or pooled analyses from published and unpublished in vitro,
animal, epidemiological, or clinical studies must be submitted in a
narrative format. Each notification to FDA must bear prominent
identification of its contents, i.e., ``IND Safety Report,'' and must be
transmitted to the review division in the Center for Drug Evaluation and
Research or in the Center for Biologics Evaluation and Research that has
responsibility for review of the IND. Upon request from FDA, the sponsor
must submit to FDA any additional data or information that the agency
deems necessary, as soon as possible, but in no case later than 15
calendar days after receiving the request.
(2) Unexpected fatal or life-threatening suspected adverse reaction
reports. The sponsor must also notify FDA of any unexpected fatal or
life-threatening suspected adverse reaction as soon as possible but in
no case later than 7 calendar days after the sponsor's initial receipt
of the information.
(3) Reporting format or frequency. FDA may require a sponsor to
submit IND safety reports in a format or at a frequency different than
that required under this paragraph. The sponsor may also propose and
adopt a different reporting format or frequency if the change is agreed
to in advance by the director of the FDA review division that has
responsibility for review of the IND.
(4) Investigations of marketed drugs. A sponsor of a clinical study
of a drug marketed or approved in the United States that is conducted
under an IND is required to submit IND safety reports for suspected
adverse reactions that are observed in the clinical study, at domestic
or foreign study sites. The sponsor must also submit safety information
from the clinical study as prescribed by the postmarketing safety
reporting requirements (e.g., Sec. Sec. 310.305, 314.80, and 600.80 of
this chapter).
(5) Reporting study endpoints. Study endpoints (e.g., mortality or
major morbidity) must be reported to FDA by the sponsor as described in
the protocol and ordinarily would not be reported under paragraph (c) of
this section.
[[Page 68]]
However, if a serious and unexpected adverse event occurs for which
there is evidence suggesting a causal relationship between the drug and
the event (e.g., death from anaphylaxis), the event must be reported
under Sec. 312.32(c)(1)(i) as a serious and unexpected suspected
adverse reaction even if it is a component of the study endpoint (e.g.,
all-cause mortality).
(d) Followup. (1) The sponsor must promptly investigate all safety
information it receives.
(2) Relevant followup information to an IND safety report must be
submitted as soon as the information is available and must be identified
as such, i.e., ``Followup IND Safety Report.''
(3) If the results of a sponsor's investigation show that an adverse
event not initially determined to be reportable under paragraph (c) of
this section is so reportable, the sponsor must report such suspected
adverse reaction in an IND safety report as soon as possible, but in no
case later than 15 calendar days after the determination is made.
(e) Disclaimer. A safety report or other information submitted by a
sponsor under this part (and any release by FDA of that report or
information) does not necessarily reflect a conclusion by the sponsor or
FDA that the report or information constitutes an admission that the
drug caused or contributed to an adverse event. A sponsor need not
admit, and may deny, that the report or information submitted by the
sponsor constitutes an admission that the drug caused or contributed to
an adverse event.
[75 FR 59961, Sept. 29, 2010]
Sec. 312.33 Annual reports.
A sponsor shall within 60 days of the anniversary date that the IND
went into effect, submit a brief report of the progress of the
investigation that includes:
(a) Individual study information. A brief summary of the status of
each study in progress and each study completed during the previous
year. The summary is required to include the following information for
each study:
(1) The title of the study (with any appropriate study identifiers
such as protocol number), its purpose, a brief statement identifying the
patient population, and a statement as to whether the study is
completed.
(2) The total number of subjects initially planned for inclusion in
the study; the number entered into the study to date, tabulated by age
group, gender, and race; the number whose participation in the study was
completed as planned; and the number who dropped out of the study for
any reason.
(3) If the study has been completed, or if interim results are
known, a brief description of any available study results.
(b) Summary information. Information obtained during the previous
year's clinical and nonclinical investigations, including:
(1) A narrative or tabular summary showing the most frequent and
most serious adverse experiences by body system.
(2) A summary of all IND safety reports submitted during the past
year.
(3) A list of subjects who died during participation in the
investigation, with the cause of death for each subject.
(4) A list of subjects who dropped out during the course of the
investigation in association with any adverse experience, whether or not
thought to be drug related.
(5) A brief description of what, if anything, was obtained that is
pertinent to an understanding of the drug's actions, including, for
example, information about dose response, information from controlled
trials, and information about bioavailability.
(6) A list of the preclinical studies (including animal studies)
completed or in progress during the past year and a summary of the major
preclinical findings.
(7) A summary of any significant manufacturing or microbiological
changes made during the past year.
(c) A description of the general investigational plan for the coming
year to replace that submitted 1 year earlier. The general
investigational plan shall contain the information required under Sec.
312.23(a)(3)(iv).
(d) If the investigator brochure has been revised, a description of
the revision and a copy of the new brochure.
[[Page 69]]
(e) A description of any significant Phase 1 protocol modifications
made during the previous year and not previously reported to the IND in
a protocol amendment.
(f) A brief summary of significant foreign marketing developments
with the drug during the past year, such as approval of marketing in any
country or withdrawal or suspension from marketing in any country.
(g) If desired by the sponsor, a log of any outstanding business
with respect to the IND for which the sponsor requests or expects a
reply, comment, or meeting.
[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 63
FR 6862, Feb. 11, 1998; 67 FR 9585, Mar. 4, 2002]
Sec. 312.38 Withdrawal of an IND.
(a) At any time a sponsor may withdraw an effective IND without
prejudice.
(b) If an IND is withdrawn, FDA shall be so notified, all clinical
investigations conducted under the IND shall be ended, all current
investigators notified, and all stocks of the drug returned to the
sponsor or otherwise disposed of at the request of the sponsor in
accordance with Sec. 312.59.
(c) If an IND is withdrawn because of a safety reason, the sponsor
shall promptly so inform FDA, all participating investigators, and all
reviewing Institutional Review Boards, together with the reasons for
such withdrawal.
[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 67
FR 9586, Mar. 4, 2002]
Subpart C_Administrative Actions
Sec. 312.40 General requirements for use of an investigational new
drug in a clinical investigation.
(a) An investigational new drug may be used in a clinical
investigation if the following conditions are met:
(1) The sponsor of the investigation submits an IND for the drug to
FDA; the IND is in effect under paragraph (b) of this section; and the
sponsor complies with all applicable requirements in this part and parts
50 and 56 with respect to the conduct of the clinical investigations;
and
(2) Each participating investigator conducts his or her
investigation in compliance with the requirements of this part and parts
50 and 56.
(b) An IND goes into effect:
(1) Thirty days after FDA receives the IND, unless FDA notifies the
sponsor that the investigations described in the IND are subject to a
clinical hold under Sec. 312.42; or
(2) On earlier notification by FDA that the clinical investigations
in the IND may begin. FDA will notify the sponsor in writing of the date
it receives the IND.
(c) A sponsor may ship an investigational new drug to investigators
named in the IND:
(1) Thirty days after FDA receives the IND; or
(2) On earlier FDA authorization to ship the drug.
(d) An investigator may not administer an investigational new drug
to human subjects until the IND goes into effect under paragraph (b) of
this section.
Sec. 312.41 Comment and advice on an IND.
(a) FDA may at any time during the course of the investigation
communicate with the sponsor orally or in writing about deficiencies in
the IND or about FDA's need for more data or information.
(b) On the sponsor's request, FDA will provide advice on specific
matters relating to an IND. Examples of such advice may include advice
on the adequacy of technical data to support an investigational plan, on
the design of a clinical trial, and on whether proposed investigations
are likely to produce the data and information that is needed to meet
requirements for a marketing application.
(c) Unless the communication is accompanied by a clinical hold order
under Sec. 312.42, FDA communications with a sponsor under this section
are solely advisory and do not require any modification in the planned
or ongoing clinical investigations or response to the agency.
[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 67
FR 9586, Mar. 4, 2002]
[[Page 70]]
Sec. 312.42 Clinical holds and requests for modification.
(a) General. A clinical hold is an order issued by FDA to the
sponsor to delay a proposed clinical investigation or to suspend an
ongoing investigation. The clinical hold order may apply to one or more
of the investigations covered by an IND. When a proposed study is placed
on clinical hold, subjects may not be given the investigational drug.
When an ongoing study is placed on clinical hold, no new subjects may be
recruited to the study and placed on the investigational drug; patients
already in the study should be taken off therapy involving the
investigational drug unless specifically permitted by FDA in the
interest of patient safety.
(b) Grounds for imposition of clinical hold--(1) Clinical hold of a
Phase 1 study under an IND. FDA may place a proposed or ongoing Phase 1
investigation on clinical hold if it finds that:
(i) Human subjects are or would be exposed to an unreasonable and
significant risk of illness or injury;
(ii) The clinical investigators named in the IND are not qualified
by reason of their scientific training and experience to conduct the
investigation described in the IND;
(iii) The investigator brochure is misleading, erroneous, or
materially incomplete; or
(iv) The IND does not contain sufficient information required under
Sec. 312.23 to assess the risks to subjects of the proposed studies.
(v) The IND is for the study of an investigational drug intended to
treat a life-threatening disease or condition that affects both genders,
and men or women with reproductive potential who have the disease or
condition being studied are excluded from eligibility because of a risk
or potential risk from use of the investigational drug of reproductive
toxicity (i.e., affecting reproductive organs) or developmental toxicity
(i.e., affecting potential offspring). The phrase ``women with
reproductive potential'' does not include pregnant women. For purposes
of this paragraph, ``life-threatening illnesses or diseases'' are
defined as ``diseases or conditions where the likelihood of death is
high unless the course of the disease is interrupted.'' The clinical
hold would not apply under this paragraph to clinical studies conducted:
(A) Under special circumstances, such as studies pertinent only to
one gender (e.g., studies evaluating the excretion of a drug in semen or
the effects on menstrual function);
(B) Only in men or women, as long as a study that does not exclude
members of the other gender with reproductive potential is being
conducted concurrently, has been conducted, or will take place within a
reasonable time agreed upon by the agency; or
(C) Only in subjects who do not suffer from the disease or condition
for which the drug is being studied.
(2) Clinical hold of a Phase 2 or 3 study under an IND. FDA may
place a proposed or ongoing Phase 2 or 3 investigation on clinical hold
if it finds that:
(i) Any of the conditions in paragraphs (b)(1)(i) through (b)(1)(v)
of this section apply; or
(ii) The plan or protocol for the investigation is clearly deficient
in design to meet its stated objectives.
(3) Clinical hold of an expanded access IND or expanded access
protocol. FDA may place an expanded access IND or expanded access
protocol on clinical hold under the following conditions:
(i) Final use. FDA may place a proposed expanded access IND or
treatment use protocol on clinical hold if it is determined that:
(A) The pertinent criteria in subpart I of this part for permitting
the expanded access use to begin are not satisfied; or
(B) The expanded access IND or expanded access protocol does not
comply with the requirements for expanded access submissions in subpart
I of this part.
(ii) Ongoing use. FDA may place an ongoing expanded access IND or
expanded access protocol on clinical hold if it is determined that the
pertinent criteria in subpart I of this part for permitting the expanded
access are no longer satisfied.
(4) Clinical hold of any study that is not designed to be adequate
and well-controlled. FDA may place a proposed or
[[Page 71]]
ongoing investigation that is not designed to be adequate and well-
controlled on clinical hold if it finds that:
(i) Any of the conditions in paragraph (b)(1) or (b)(2) of this
section apply; or
(ii) There is reasonable evidence the investigation that is not
designed to be adequate and well-controlled is impeding enrollment in,
or otherwise interfering with the conduct or completion of, a study that
is designed to be an adequate and well-controlled investigation of the
same or another investigational drug; or
(iii) Insufficient quantities of the investigational drug exist to
adequately conduct both the investigation that is not designed to be
adequate and well-controlled and the investigations that are designed to
be adequate and well-controlled; or
(iv) The drug has been studied in one or more adequate and well-
controlled investigations that strongly suggest lack of effectiveness;
or
(v) Another drug under investigation or approved for the same
indication and available to the same patient population has demonstrated
a better potential benefit/risk balance; or
(vi) The drug has received marketing approval for the same
indication in the same patient population; or
(vii) The sponsor of the study that is designed to be an adequate
and well-controlled investigation is not actively pursuing marketing
approval of the investigational drug with due diligence; or
(viii) The Commissioner determines that it would not be in the
public interest for the study to be conducted or continued. FDA
ordinarily intends that clinical holds under paragraphs (b)(4)(ii),
(b)(4)(iii) and (b)(4)(v) of this section would only apply to additional
enrollment in nonconcurrently controlled trials rather than eliminating
continued access to individuals already receiving the investigational
drug.
(5) Clinical hold of any investigation involving an exception from
informed consent under Sec. 50.24 of this chapter. FDA may place a
proposed or ongoing investigation involving an exception from informed
consent under Sec. 50.24 of this chapter on clinical hold if it is
determined that:
(i) Any of the conditions in paragraphs (b)(1) or (b)(2) of this
section apply; or
(ii) The pertinent criteria in Sec. 50.24 of this chapter for such
an investigation to begin or continue are not submitted or not
satisfied.
(6) Clinical hold of any investigation involving an exception from
informed consent under Sec. 50.23(d) of this chapter. FDA may place a
proposed or ongoing investigation involving an exception from informed
consent under Sec. 50.23(d) of this chapter on clinical hold if it is
determined that:
(i) Any of the conditions in paragraphs (b)(1) or (b)(2) of this
section apply; or
(ii) A determination by the President to waive the prior consent
requirement for the administration of an investigational new drug has
not been made.
(c) Discussion of deficiency. Whenever FDA concludes that a
deficiency exists in a clinical investigation that may be grounds for
the imposition of clinical hold FDA will, unless patients are exposed to
immediate and serious risk, attempt to discuss and satisfactorily
resolve the matter with the sponsor before issuing the clinical hold
order.
(d) Imposition of clinical hold. The clinical hold order may be made
by telephone or other means of rapid communication or in writing. The
clinical hold order will identify the studies under the IND to which the
hold applies, and will briefly explain the basis for the action. The
clinical hold order will be made by or on behalf of the Division
Director with responsibility for review of the IND. As soon as possible,
and no more than 30 days after imposition of the clinical hold, the
Division Director will provide the sponsor a written explanation of the
basis for the hold.
(e) Resumption of clinical investigations. An investigation may only
resume after FDA (usually the Division Director, or the Director's
designee, with responsibility for review of the IND) has notified the
sponsor that the investigation may proceed. Resumption of the affected
investigation(s) will be authorized when the sponsor corrects the
deficiency(ies) previously cited or otherwise satisfies the agency that
the investigation(s) can proceed.
[[Page 72]]
FDA may notify a sponsor of its determination regarding the clinical
hold by telephone or other means of rapid communication. If a sponsor of
an IND that has been placed on clinical hold requests in writing that
the clinical hold be removed and submits a complete response to the
issue(s) identified in the clinical hold order, FDA shall respond in
writing to the sponsor within 30-calendar days of receipt of the request
and the complete response. FDA's response will either remove or maintain
the clinical hold, and will state the reasons for such determination.
Notwithstanding the 30-calendar day response time, a sponsor may not
proceed with a clinical trial on which a clinical hold has been imposed
until the sponsor has been notified by FDA that the hold has been
lifted.
(f) Appeal. If the sponsor disagrees with the reasons cited for the
clinical hold, the sponsor may request reconsideration of the decision
in accordance with Sec. 312.48.
(g) Conversion of IND on clinical hold to inactive status. If all
investigations covered by an IND remain on clinical hold for 1 year or
more, the IND may be placed on inactive status by FDA under Sec.
312.45.
[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 19477, May 22, 1987; 57
FR 13249, Apr. 15, 1992; 61 FR 51530, Oct. 2, 1996; 63 FR 68678, Dec.
14, 1998; 64 FR 54189, Oct. 5, 1999; 65 FR 34971, June 1, 2000; 74 FR
40942, Aug. 13, 2009]
Sec. 312.44 Termination.
(a) General. This section describes the procedures under which FDA
may terminate an IND. If an IND is terminated, the sponsor shall end all
clinical investigations conducted under the IND and recall or otherwise
provide for the disposition of all unused supplies of the drug. A
termination action may be based on deficiencies in the IND or in the
conduct of an investigation under an IND. Except as provided in
paragraph (d) of this section, a termination shall be preceded by a
proposal to terminate by FDA and an opportunity for the sponsor to
respond. FDA will, in general, only initiate an action under this
section after first attempting to resolve differences informally or,
when appropriate, through the clinical hold procedures described in
Sec. 312.42.
(b) Grounds for termination--(1) Phase 1. FDA may propose to
terminate an IND during Phase 1 if it finds that:
(i) Human subjects would be exposed to an unreasonable and
significant risk of illness or injury.
(ii) The IND does not contain sufficient information required under
Sec. 312.23 to assess the safety to subjects of the clinical
investigations.
(iii) The methods, facilities, and controls used for the
manufacturing, processing, and packing of the investigational drug are
inadequate to establish and maintain appropriate standards of identity,
strength, quality, and purity as needed for subject safety.
(iv) The clinical investigations are being conducted in a manner
substantially different than that described in the protocols submitted
in the IND.
(v) The drug is being promoted or distributed for commercial
purposes not justified by the requirements of the investigation or
permitted by Sec. 312.7.
(vi) The IND, or any amendment or report to the IND, contains an
untrue statement of a material fact or omits material information
required by this part.
(vii) The sponsor fails promptly to investigate and inform the Food
and Drug Administration and all investigators of serious and unexpected
adverse experiences in accordance with Sec. 312.32 or fails to make any
other report required under this part.
(viii) The sponsor fails to submit an accurate annual report of the
investigations in accordance with Sec. 312.33.
(ix) The sponsor fails to comply with any other applicable
requirement of this part, part 50, or part 56.
(x) The IND has remained on inactive status for 5 years or more.
(xi) The sponsor fails to delay a proposed investigation under the
IND or to suspend an ongoing investigation that has been placed on
clinical hold under Sec. 312.42(b)(4).
(2) Phase 2 or 3. FDA may propose to terminate an IND during Phase 2
or Phase 3 if FDA finds that:
(i) Any of the conditions in paragraphs (b)(1)(i) through (b)(1)(xi)
of this section apply; or
(ii) The investigational plan or protocol(s) is not reasonable as a
bona fide scientific plan to determine whether or
[[Page 73]]
not the drug is safe and effective for use; or
(iii) There is convincing evidence that the drug is not effective
for the purpose for which it is being investigated.
(3) FDA may propose to terminate a treatment IND if it finds that:
(i) Any of the conditions in paragraphs (b)(1)(i) through (x) of
this section apply; or
(ii) Any of the conditions in Sec. 312.42(b)(3) apply.
(c) Opportunity for sponsor response. (1) If FDA proposes to
terminate an IND, FDA will notify the sponsor in writing, and invite
correction or explanation within a period of 30 days.
(2) On such notification, the sponsor may provide a written
explanation or correction or may request a conference with FDA to
provide the requested explanation or correction. If the sponsor does not
respond to the notification within the allocated time, the IND shall be
terminated.
(3) If the sponsor responds but FDA does not accept the explanation
or correction submitted, FDA shall inform the sponsor in writing of the
reason for the nonacceptance and provide the sponsor with an opportunity
for a regulatory hearing before FDA under part 16 on the question of
whether the IND should be terminated. The sponsor's request for a
regulatory hearing must be made within 10 days of the sponsor's receipt
of FDA's notification of nonacceptance.
(d) Immediate termination of IND. Notwithstanding paragraphs (a)
through (c) of this section, if at any time FDA concludes that
continuation of the investigation presents an immediate and substantial
danger to the health of individuals, the agency shall immediately, by
written notice to the sponsor from the Director of the Center for Drug
Evaluation and Research or the Director of the Center for Biologics
Evaluation and Research, terminate the IND. An IND so terminated is
subject to reinstatement by the Director on the basis of additional
submissions that eliminate such danger. If an IND is terminated under
this paragraph, the agency will afford the sponsor an opportunity for a
regulatory hearing under part 16 on the question of whether the IND
should be reinstated.
[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 55
FR 11579, Mar. 29, 1990; 57 FR 13249, Apr. 15, 1992; 67 FR 9586, Mar. 4,
2002]
Sec. 312.45 Inactive status.
(a) If no subjects are entered into clinical studies for a period of
2 years or more under an IND, or if all investigations under an IND
remain on clinical hold for 1 year or more, the IND may be placed by FDA
on inactive status. This action may be taken by FDA either on request of
the sponsor or on FDA's own initiative. If FDA seeks to act on its own
initiative under this section, it shall first notify the sponsor in
writing of the proposed inactive status. Upon receipt of such
notification, the sponsor shall have 30 days to respond as to why the
IND should continue to remain active.
(b) If an IND is placed on inactive status, all investigators shall
be so notified and all stocks of the drug shall be returned or otherwise
disposed of in accordance with Sec. 312.59.
(c) A sponsor is not required to submit annual reports to an IND on
inactive status. An inactive IND is, however, still in effect for
purposes of the public disclosure of data and information under Sec.
312.130.
(d) A sponsor who intends to resume clinical investigation under an
IND placed on inactive status shall submit a protocol amendment under
Sec. 312.30 containing the proposed general investigational plan for
the coming year and appropriate protocols. If the protocol amendment
relies on information previously submitted, the plan shall reference
such information. Additional information supporting the proposed
investigation, if any, shall be submitted in an information amendment.
Notwithstanding the provisions of Sec. 312.30, clinical investigations
under an IND on inactive status may only resume (1) 30 days after FDA
receives the protocol amendment, unless FDA notifies the sponsor that
the investigations described in the amendment are subject to a clinical
hold under Sec. 312.42, or (2) on earlier notification by FDA that the
clinical investigations described in the protocol amendment may begin.
[[Page 74]]
(e) An IND that remains on inactive status for 5 years or more may
be terminated under Sec. 312.44.
[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 67
FR 9586, Mar. 4, 2002]
Sec. 312.47 Meetings.
(a) General. Meetings between a sponsor and the agency are
frequently useful in resolving questions and issues raised during the
course of a clinical investigation. FDA encourages such meetings to the
extent that they aid in the evaluation of the drug and in the solution
of scientific problems concerning the drug, to the extent that FDA's
resources permit. The general principle underlying the conduct of such
meetings is that there should be free, full, and open communication
about any scientific or medical question that may arise during the
clinical investigation. These meetings shall be conducted and documented
in accordance with part 10.
(b) ``End-of-Phase 2'' meetings and meetings held before submission
of a marketing application. At specific times during the drug
investigation process, meetings between FDA and a sponsor can be
especially helpful in minimizing wasteful expenditures of time and money
and thus in speeding the drug development and evaluation process. In
particular, FDA has found that meetings at the end of Phase 2 of an
investigation (end-of-Phase 2 meetings) are of considerable assistance
in planning later studies and that meetings held near completion of
Phase 3 and before submission of a marketing application (``pre-NDA''
meetings) are helpful in developing methods of presentation and
submission of data in the marketing application that facilitate review
and allow timely FDA response.
(1) End-of-Phase 2 meetings--(i) Purpose. The purpose of an end-of-
phase 2 meeting is to determine the safety of proceeding to Phase 3, to
evaluate the Phase 3 plan and protocols and the adequacy of current
studies and plans to assess pediatric safety and effectiveness, and to
identify any additional information necessary to support a marketing
application for the uses under investigation.
(ii) Eligibility for meeting. While the end-of-Phase 2 meeting is
designed primarily for IND's involving new molecular entities or major
new uses of marketed drugs, a sponsor of any IND may request and obtain
an end-of-Phase 2 meeting.
(iii) Timing. To be most useful to the sponsor, end-of-Phase 2
meetings should be held before major commitments of effort and resources
to specific Phase 3 tests are made. The scheduling of an end-of-Phase 2
meeting is not, however, intended to delay the transition of an
investigation from Phase 2 to Phase 3.
(iv) Advance information. At least 1 month in advance of an end-of-
Phase 2 meeting, the sponsor should submit background information on the
sponsor's plan for Phase 3, including summaries of the Phase 1 and 2
investigations, the specific protocols for Phase 3 clinical studies,
plans for any additional nonclinical studies, plans for pediatric
studies, including a time line for protocol finalization, enrollment,
completion, and data analysis, or information to support any planned
request for waiver or deferral of pediatric studies, and, if available,
tentative labeling for the drug. The recommended contents of such a
submission are described more fully in FDA Staff Manual Guide 4850.7
that is publicly available under FDA's public information regulations in
part 20.
(v) Conduct of meeting. Arrangements for an end-of-Phase 2 meeting
are to be made with the division in FDA's Center for Drug Evaluation and
Research or the Center for Biologics Evaluation and Research which is
responsible for review of the IND. The meeting will be scheduled by FDA
at a time convenient to both FDA and the sponsor. Both the sponsor and
FDA may bring consultants to the meeting. The meeting should be directed
primarily at establishing agreement between FDA and the sponsor of the
overall plan for Phase 3 and the objectives and design of particular
studies. The adequacy of the technical information to support Phase 3
studies and/or a marketing application may also be discussed. FDA will
also provide its best judgment, at that time, of the pediatric studies
that will be required for the drug product
[[Page 75]]
and whether their submission will be deferred until after approval.
Agreements reached at the meeting on these matters will be recorded in
minutes of the conference that will be taken by FDA in accordance with
Sec. 10.65 and provided to the sponsor. The minutes along with any
other written material provided to the sponsor will serve as a permanent
record of any agreements reached. Barring a significant scientific
development that requires otherwise, studies conducted in accordance
with the agreement shall be presumed to be sufficient in objective and
design for the purpose of obtaining marketing approval for the drug.
(2) ``Pre-NDA'' and ``pre-BLA'' meetings. FDA has found that delays
associated with the initial review of a marketing application may be
reduced by exchanges of information about a proposed marketing
application. The primary purpose of this kind of exchange is to uncover
any major unresolved problems, to identify those studies that the
sponsor is relying on as adequate and well-controlled to establish the
drug's effectiveness, to identify the status of ongoing or needed
studies adequate to assess pediatric safety and effectiveness, to
acquaint FDA reviewers with the general information to be submitted in
the marketing application (including technical information), to discuss
appropriate methods for statistical analysis of the data, and to discuss
the best approach to the presentation and formatting of data in the
marketing application. Arrangements for such a meeting are to be
initiated by the sponsor with the division responsible for review of the
IND. To permit FDA to provide the sponsor with the most useful advice on
preparing a marketing application, the sponsor should submit to FDA's
reviewing division at least 1 month in advance of the meeting the
following information:
(i) A brief summary of the clinical studies to be submitted in the
application.
(ii) A proposed format for organizing the submission, including
methods for presenting the data.
(iii) Information on the status of needed or ongoing pediatric
studies.
(iv) Any other information for discussion at the meeting.
[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 55
FR 11580, Mar. 29, 1990; 63 FR 66669, Dec. 2, 1998; 67 FR 9586, Mar. 4,
2002]
Sec. 312.48 Dispute resolution.
(a) General. The Food and Drug Administration is committed to
resolving differences between sponsors and FDA reviewing divisions with
respect to requirements for IND's as quickly and amicably as possible
through the cooperative exchange of information and views.
(b) Administrative and procedural issues. When administrative or
procedural disputes arise, the sponsor should first attempt to resolve
the matter with the division in FDA's Center for Drug Evaluation and
Research or Center for Biologics Evaluation and Research which is
responsible for review of the IND, beginning with the consumer safety
officer assigned to the application. If the dispute is not resolved, the
sponsor may raise the matter with the person designated as ombudsman,
whose function shall be to investigate what has happened and to
facilitate a timely and equitable resolution. Appropriate issues to
raise with the ombudsman include resolving difficulties in scheduling
meetings and obtaining timely replies to inquiries. Further details on
this procedure are contained in FDA Staff Manual Guide 4820.7 that is
publicly available under FDA's public information regulations in part
20.
(c) Scientific and medical disputes. (1) When scientific or medical
disputes arise during the drug investigation process, sponsors should
discuss the matter directly with the responsible reviewing officials. If
necessary, sponsors may request a meeting with the appropriate reviewing
officials and management representatives in order to seek a resolution.
Requests for such meetings shall be directed to the director of the
division in FDA's Center for Drug Evaluation and Research or Center for
Biologics Evaluation and Research which is responsible for review of the
IND. FDA will make every attempt to grant requests for meetings that
involve important issues and that
[[Page 76]]
can be scheduled at mutually convenient times.
(2) The ``end-of-Phase 2'' and ``pre-NDA'' meetings described in
Sec. 312.47(b) will also provide a timely forum for discussing and
resolving scientific and medical issues on which the sponsor disagrees
with the agency.
(3) In requesting a meeting designed to resolve a scientific or
medical dispute, applicants may suggest that FDA seek the advice of
outside experts, in which case FDA may, in its discretion, invite to the
meeting one or more of its advisory committee members or other
consultants, as designated by the agency. Applicants may rely on, and
may bring to any meeting, their own consultants. For major scientific
and medical policy issues not resolved by informal meetings, FDA may
refer the matter to one of its standing advisory committees for its
consideration and recommendations.
[52 FR 8831, Mar. 19, 1987, as amended at 55 FR 11580, Mar. 29, 1990]
Subpart D_Responsibilities of Sponsors and Investigators
Sec. 312.50 General responsibilities of sponsors.
Sponsors are responsible for selecting qualified investigators,
providing them with the information they need to conduct an
investigation properly, ensuring proper monitoring of the
investigation(s), ensuring that the investigation(s) is conducted in
accordance with the general investigational plan and protocols contained
in the IND, maintaining an effective IND with respect to the
investigations, and ensuring that FDA and all participating
investigators are promptly informed of significant new adverse effects
or risks with respect to the drug. Additional specific responsibilities
of sponsors are described elsewhere in this part.
Sec. 312.52 Transfer of obligations to a contract research organization.
(a) A sponsor may transfer responsibility for any or all of the
obligations set forth in this part to a contract research organization.
Any such transfer shall be described in writing. If not all obligations
are transferred, the writing is required to describe each of the
obligations being assumed by the contract research organization. If all
obligations are transferred, a general statement that all obligations
have been transferred is acceptable. Any obligation not covered by the
written description shall be deemed not to have been transferred.
(b) A contract research organization that assumes any obligation of
a sponsor shall comply with the specific regulations in this chapter
applicable to this obligation and shall be subject to the same
regulatory action as a sponsor for failure to comply with any obligation
assumed under these regulations. Thus, all references to ``sponsor'' in
this part apply to a contract research organization to the extent that
it assumes one or more obligations of the sponsor.
Sec. 312.53 Selecting investigators and monitors.
(a) Selecting investigators. A sponsor shall select only
investigators qualified by training and experience as appropriate
experts to investigate the drug.
(b) Control of drug. A sponsor shall ship investigational new drugs
only to investigators participating in the investigation.
(c) Obtaining information from the investigator. Before permitting
an investigator to begin participation in an investigation, the sponsor
shall obtain the following:
(1) A signed investigator statement (Form FDA-1572) containing:
(i) The name and address of the investigator;
(ii) The name and code number, if any, of the protocol(s) in the IND
identifying the study(ies) to be conducted by the investigator;
(iii) The name and address of any medical school, hospital, or other
research facility where the clinical investigation(s) will be conducted;
(iv) The name and address of any clinical laboratory facilities to
be used in the study;
(v) The name and address of the IRB that is responsible for review
and approval of the study(ies);
(vi) A commitment by the investigator that he or she:
(a) Will conduct the study(ies) in accordance with the relevant,
current
[[Page 77]]
protocol(s) and will only make changes in a protocol after notifying the
sponsor, except when necessary to protect the safety, the rights, or
welfare of subjects;
(b) Will comply with all requirements regarding the obligations of
clinical investigators and all other pertinent requirements in this
part;
(c) Will personally conduct or supervise the described
investigation(s);
(d) Will inform any potential subjects that the drugs are being used
for investigational purposes and will ensure that the requirements
relating to obtaining informed consent (21 CFR part 50) and
institutional review board review and approval (21 CFR part 56) are met;
(e) Will report to the sponsor adverse experiences that occur in the
course of the investigation(s) in accordance with Sec. 312.64;
(f) Has read and understands the information in the investigator's
brochure, including the potential risks and side effects of the drug;
and
(g) Will ensure that all associates, colleagues, and employees
assisting in the conduct of the study(ies) are informed about their
obligations in meeting the above commitments.
(vii) A commitment by the investigator that, for an investigation
subject to an institutional review requirement under part 56, an IRB
that complies with the requirements of that part will be responsible for
the initial and continuing review and approval of the clinical
investigation and that the investigator will promptly report to the IRB
all changes in the research activity and all unanticipated problems
involving risks to human subjects or others, and will not make any
changes in the research without IRB approval, except where necessary to
eliminate apparent immediate hazards to the human subjects.
(viii) A list of the names of the subinvestigators (e.g., research
fellows, residents) who will be assisting the investigator in the
conduct of the investigation(s).
(2) Curriculum vitae. A curriculum vitae or other statement of
qualifications of the investigator showing the education, training, and
experience that qualifies the investigator as an expert in the clinical
investigation of the drug for the use under investigation.
(3) Clinical protocol. (i) For Phase 1 investigations, a general
outline of the planned investigation including the estimated duration of
the study and the maximum number of subjects that will be involved.
(ii) For Phase 2 or 3 investigations, an outline of the study
protocol including an approximation of the number of subjects to be
treated with the drug and the number to be employed as controls, if any;
the clinical uses to be investigated; characteristics of subjects by
age, sex, and condition; the kind of clinical observations and
laboratory tests to be conducted; the estimated duration of the study;
and copies or a description of case report forms to be used.
(4) Financial disclosure information. Sufficient accurate financial
information to allow the sponsor to submit complete and accurate
certification or disclosure statements required under part 54 of this
chapter. The sponsor shall obtain a commitment from the clinical
investigator to promptly update this information if any relevant changes
occur during the course of the investigation and for 1 year following
the completion of the study.
(d) Selecting monitors. A sponsor shall select a monitor qualified
by training and experience to monitor the progress of the investigation.
[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 61
FR 57280, Nov. 5, 1996; 63 FR 5252, Feb. 2, 1998; 67 FR 9586, Mar. 4,
2002]
Sec. 312.54 Emergency research under Sec. 50.24 of this chapter.
(a) The sponsor shall monitor the progress of all investigations
involving an exception from informed consent under Sec. 50.24 of this
chapter. When the sponsor receives from the IRB information concerning
the public disclosures required by Sec. 50.24(a)(7)(ii) and (a)(7)(iii)
of this chapter, the sponsor promptly shall submit to the IND file and
to Docket Number 95S-0158 in the Dockets Management Staff (HFA-305),
Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD
20852, copies of the information that was disclosed, identified by the
IND number.
[[Page 78]]
(b) The sponsor also shall monitor such investigations to identify
when an IRB determines that it cannot approve the research because it
does not meet the criteria in the exception in Sec. 50.24(a) of this
chapter or because of other relevant ethical concerns. The sponsor
promptly shall provide this information in writing to FDA, investigators
who are asked to participate in this or a substantially equivalent
clinical investigation, and other IRB's that are asked to review this or
a substantially equivalent investigation.
[61 FR 51530, Oct. 2, 1996, as amended at 68 FR 24879, May 9, 2003; 88
FR 45065, July 14, 2023]
Sec. 312.55 Informing investigators.
(a) Before the investigation begins, a sponsor (other than a
sponsor-investigator) shall give each participating clinical
investigator an investigator brochure containing the information
described in Sec. 312.23(a)(5).
(b) The sponsor shall, as the overall investigation proceeds, keep
each participating investigator informed of new observations discovered
by or reported to the sponsor on the drug, particularly with respect to
adverse effects and safe use. Such information may be distributed to
investigators by means of periodically revised investigator brochures,
reprints or published studies, reports or letters to clinical
investigators, or other appropriate means. Important safety information
is required to be relayed to investigators in accordance with Sec.
312.32.
[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 67
FR 9586, Mar. 4, 2002]
Sec. 312.56 Review of ongoing investigations.
(a) The sponsor shall monitor the progress of all clinical
investigations being conducted under its IND.
(b) A sponsor who discovers that an investigator is not complying
with the signed agreement (Form FDA-1572), the general investigational
plan, or the requirements of this part or other applicable parts shall
promptly either secure compliance or discontinue shipments of the
investigational new drug to the investigator and end the investigator's
participation in the investigation. If the investigator's participation
in the investigation is ended, the sponsor shall require that the
investigator dispose of or return the investigational drug in accordance
with the requirements of Sec. 312.59 and shall notify FDA.
(c) The sponsor shall review and evaluate the evidence relating to
the safety and effectiveness of the drug as it is obtained from the
investigator. The sponsors shall make such reports to FDA regarding
information relevant to the safety of the drug as are required under
Sec. 312.32. The sponsor shall make annual reports on the progress of
the investigation in accordance with Sec. 312.33.
(d) A sponsor who determines that its investigational drug presents
an unreasonable and significant risk to subjects shall discontinue those
investigations that present the risk, notify FDA, all institutional
review boards, and all investigators who have at any time participated
in the investigation of the discontinuance, assure the disposition of
all stocks of the drug outstanding as required by Sec. 312.59, and
furnish FDA with a full report of the sponsor's actions. The sponsor
shall discontinue the investigation as soon as possible, and in no event
later than 5 working days after making the determination that the
investigation should be discontinued. Upon request, FDA will confer with
a sponsor on the need to discontinue an investigation.
[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 67
FR 9586, Mar. 4, 2002]
Sec. 312.57 Recordkeeping and record retention.
(a) A sponsor shall maintain adequate records showing the receipt,
shipment, or other disposition of the investigational drug. These
records are required to include, as appropriate, the name of the
investigator to whom the drug is shipped, and the date, quantity, and
batch or code mark of each such shipment.
(b) A sponsor shall maintain complete and accurate records showing
any financial interest in Sec. 54.4(a)(3)(i), (a)(3)(ii), (a)(3)(iii),
and (a)(3)(iv) of this chapter paid to clinical investigators by the
sponsor of the covered study. A sponsor shall also maintain complete and
accurate records concerning all
[[Page 79]]
other financial interests of investigators subject to part 54 of this
chapter.
(c) A sponsor shall retain the records and reports required by this
part for 2 years after a marketing application is approved for the drug;
or, if an application is not approved for the drug, until 2 years after
shipment and delivery of the drug for investigational use is
discontinued and FDA has been so notified.
(d) A sponsor shall retain reserve samples of any test article and
reference standard identified in, and used in any of the bioequivalence
or bioavailability studies described in, Sec. 320.38 or Sec. 320.63 of
this chapter, and release the reserve samples to FDA upon request, in
accordance with, and for the period specified in Sec. 320.38.
[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 58
FR 25926, Apr. 28, 1993; 63 FR 5252, Feb. 2, 1998; 67 FR 9586, Mar. 4,
2002]
Sec. 312.58 Inspection of sponsor's records and reports.
(a) FDA inspection. A sponsor shall upon request from any properly
authorized officer or employee of the Food and Drug Administration, at
reasonable times, permit such officer or employee to have access to and
copy and verify any records and reports relating to a clinical
investigation conducted under this part. Upon written request by FDA,
the sponsor shall submit the records or reports (or copies of them) to
FDA. The sponsor shall discontinue shipments of the drug to any
investigator who has failed to maintain or make available records or
reports of the investigation as required by this part.
(b) Controlled substances. If an investigational new drug is a
substance listed in any schedule of the Controlled Substances Act (21
U.S.C. 801; 21 CFR part 1308), records concerning shipment, delivery,
receipt, and disposition of the drug, which are required to be kept
under this part or other applicable parts of this chapter shall, upon
the request of a properly authorized employee of the Drug Enforcement
Administration of the U.S. Department of Justice, be made available by
the investigator or sponsor to whom the request is made, for inspection
and copying. In addition, the sponsor shall assure that adequate
precautions are taken, including storage of the investigational drug in
a securely locked, substantially constructed cabinet, or other securely
locked, substantially constructed enclosure, access to which is limited,
to prevent theft or diversion of the substance into illegal channels of
distribution.
Sec. 312.59 Disposition of unused supply of investigational drug.
The sponsor shall assure the return of all unused supplies of the
investigational drug from each individual investigator whose
participation in the investigation is discontinued or terminated. The
sponsor may authorize alternative disposition of unused supplies of the
investigational drug provided this alternative disposition does not
expose humans to risks from the drug. The sponsor shall maintain written
records of any disposition of the drug in accordance with Sec. 312.57.
[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 67
FR 9586, Mar. 4, 2002]
Sec. 312.60 General responsibilities of investigators.
An investigator is responsible for ensuring that an investigation is
conducted according to the signed investigator statement, the
investigational plan, and applicable regulations; for protecting the
rights, safety, and welfare of subjects under the investigator's care;
and for the control of drugs under investigation. An investigator shall
obtain the informed consent of each human subject to whom the drug is
administered, in accordance with part 50 of this chapter. Additional
specific responsibilities of clinical investigators are set forth in
this part and in parts 50 and 56 of this chapter.
[88 FR 88248, Dec. 21, 2023]
Sec. 312.61 Control of the investigational drug.
An investigator shall administer the drug only to subjects under the
investigator's personal supervision or under
[[Page 80]]
the supervision of a subinvestigator responsible to the investigator.
The investigator shall not supply the investigational drug to any person
not authorized under this part to receive it.
Sec. 312.62 Investigator recordkeeping and record retention.
(a) Disposition of drug. An investigator is required to maintain
adequate records of the disposition of the drug, including dates,
quantity, and use by subjects. If the investigation is terminated,
suspended, discontinued, or completed, the investigator shall return the
unused supplies of the drug to the sponsor, or otherwise provide for
disposition of the unused supplies of the drug under Sec. 312.59.
(b) Case histories. An investigator is required to prepare and
maintain adequate and accurate case histories that record all
observations and other data pertinent to the investigation on each
individual administered the investigational drug or employed as a
control in the investigation. Case histories include the case report
forms and supporting data including, for example, signed and dated
consent forms and medical records including, for example, progress notes
of the physician, the individual's hospital chart(s), and the nurses'
notes. The case history for each individual shall document that informed
consent was obtained prior to participation in the study.
(c) Record retention. An investigator shall retain records required
to be maintained under this part for a period of 2 years following the
date a marketing application is approved for the drug for the indication
for which it is being investigated; or, if no application is to be filed
or if the application is not approved for such indication, until 2 years
after the investigation is discontinued and FDA is notified.
[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 61
FR 57280, Nov. 5, 1996; 67 FR 9586, Mar. 4, 2002]
Sec. 312.64 Investigator reports.
(a) Progress reports. The investigator shall furnish all reports to
the sponsor of the drug who is responsible for collecting and evaluating
the results obtained. The sponsor is required under Sec. 312.33 to
submit annual reports to FDA on the progress of the clinical
investigations.
(b) Safety reports. An investigator must immediately report to the
sponsor any serious adverse event, whether or not considered drug
related, including those listed in the protocol or investigator brochure
and must include an assessment of whether there is a reasonable
possibility that the drug caused the event. Study endpoints that are
serious adverse events (e.g., all-cause mortality) must be reported in
accordance with the protocol unless there is evidence suggesting a
causal relationship between the drug and the event (e.g., death from
anaphylaxis). In that case, the investigator must immediately report the
event to the sponsor. The investigator must record nonserious adverse
events and report them to the sponsor according to the timetable for
reporting specified in the protocol.
(c) Final report. An investigator shall provide the sponsor with an
adequate report shortly after completion of the investigator's
participation in the investigation.
(d) Financial disclosure reports. The clinical investigator shall
provide the sponsor with sufficient accurate financial information to
allow an applicant to submit complete and accurate certification or
disclosure statements as required under part 54 of this chapter. The
clinical investigator shall promptly update this information if any
relevant changes occur during the course of the investigation and for 1
year following the completion of the study.
[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 63
FR 5252, Feb. 2, 1998; 67 FR 9586, Mar. 4, 2002; 75 FR 59963, Sept. 29,
2010]
Sec. 312.66 Assurance of IRB review.
An investigator shall assure that an IRB that complies with the
requirements set forth in part 56 will be responsible for the initial
and continuing review and approval of the proposed clinical study. The
investigator shall also assure that he or she will promptly report to
the IRB all changes in the research activity and all unanticipated
problems involving risk to human subjects or others, and that he or she
will not make any changes in the research
[[Page 81]]
without IRB approval, except where necessary to eliminate apparent
immediate hazards to human subjects.
[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 67
FR 9586, Mar. 4, 2002]
Sec. 312.68 Inspection of investigator's records and reports.
An investigator shall upon request from any properly authorized
officer or employee of FDA, at reasonable times, permit such officer or
employee to have access to, and copy and verify any records or reports
made by the investigator pursuant to Sec. 312.62. The investigator is
not required to divulge subject names unless the records of particular
individuals require a more detailed study of the cases, or unless there
is reason to believe that the records do not represent actual case
studies, or do not represent actual results obtained.
Sec. 312.69 Handling of controlled substances.
If the investigational drug is subject to the Controlled Substances
Act, the investigator shall take adequate precautions, including storage
of the investigational drug in a securely locked, substantially
constructed cabinet, or other securely locked, substantially constructed
enclosure, access to which is limited, to prevent theft or diversion of
the substance into illegal channels of distribution.
Sec. 312.70 Disqualification of a clinical investigator.
(a) If FDA has information indicating that an investigator
(including a sponsor-investigator) has repeatedly or deliberately failed
to comply with the requirements of this part, part 50 or part 56 of this
chapter, or has repeatedly or deliberately submitted to FDA or to the
sponsor false information in any required report, the Center for Drug
Evaluation and Research or the Center for Biologics Evaluation and
Research will furnish the investigator written notice of the matter
complained of and offer the investigator an opportunity to explain the
matter in writing, or, at the option of the investigator, in an informal
conference. If an explanation is offered and accepted by the applicable
Center, the Center will discontinue the disqualification proceeding. If
an explanation is offered but not accepted by the applicable Center, the
investigator will be given an opportunity for a regulatory hearing under
part 16 of this chapter on the question of whether the investigator is
eligible to receive test articles under this part and eligible to
conduct any clinical investigation that supports an application for a
research or marketing permit for products regulated by FDA.
(b) After evaluating all available information, including any
explanation presented by the investigator, if the Commissioner
determines that the investigator has repeatedly or deliberately failed
to comply with the requirements of this part, part 50 or part 56 of this
chapter, or has repeatedly or deliberately submitted to FDA or to the
sponsor false information in any required report, the Commissioner will
notify the investigator, the sponsor of any investigation in which the
investigator has been named as a participant, and the reviewing
institutional review boards (IRBs) that the investigator is not eligible
to receive test articles under this part. The notification to the
investigator, sponsor, and IRBs will provide a statement of the basis
for such determination. The notification also will explain that an
investigator determined to be ineligible to receive test articles under
this part will be ineligible to conduct any clinical investigation that
supports an application for a research or marketing permit for products
regulated by FDA, including drugs, biologics, devices, new animal drugs,
foods, including dietary supplements, that bear a nutrient content claim
or a health claim, infant formulas, food and color additives, and
tobacco products.
(c) Each application or submission to FDA under the provisions of
this chapter containing data reported by an investigator who has been
determined to be ineligible to receive FDA-regulated test articles is
subject to examination to determine whether the investigator has
submitted unreliable data that are essential to the continuation of an
investigation or essential to the approval of a marketing application,
or essential to the continued marketing of an FDA-regulated product.
[[Page 82]]
(d) If the Commissioner determines, after the unreliable data
submitted by the investigator are eliminated from consideration, that
the data remaining are inadequate to support a conclusion that it is
reasonably safe to continue the investigation, the Commissioner will
notify the sponsor, who shall have an opportunity for a regulatory
hearing under part 16 of this chapter. If a danger to the public health
exists, however, the Commissioner shall terminate the IND immediately
and notify the sponsor and the reviewing IRBs of the termination. In
such case, the sponsor shall have an opportunity for a regulatory
hearing before FDA under part 16 on the question of whether the IND
should be reinstated. The determination that an investigation may not be
considered in support of a research or marketing application or a
notification or petition submission does not, however, relieve the
sponsor of any obligation under any other applicable regulation to
submit to FDA the results of the investigation.
(e) If the Commissioner determines, after the unreliable data
submitted by the investigator are eliminated from consideration, that
the continued approval of the product for which the data were submitted
cannot be justified, the Commissioner will proceed to withdraw approval
of the product in accordance with the applicable provisions of the
relevant statutes.
(f) An investigator who has been determined to be ineligible under
paragraph (b) of this section may be reinstated as eligible when the
Commissioner determines that the investigator has presented adequate
assurances that the investigator will employ all test articles, and will
conduct any clinical investigation that supports an application for a
research or marketing permit for products regulated by FDA, solely in
compliance with the applicable provisions of this chapter.
[77 FR 25359, Apr. 30, 2012]
Subpart E_Drugs Intended to Treat Life-threatening and Severely-
debilitating Illnesses
Authority: 21 U.S.C. 351, 352, 353, 355, 371; 42 U.S.C. 262.
Source: 53 FR 41523, Oct. 21, 1988, unless otherwise noted.
Sec. 312.80 Purpose.
The purpose of this section is to establish procedures designed to
expedite the development, evaluation, and marketing of new therapies
intended to treat persons with life-threatening and severely-
debilitating illnesses, especially where no satisfactory alternative
therapy exists. As stated Sec. 314.105(c) of this chapter, while the
statutory standards of safety and effectiveness apply to all drugs, the
many kinds of drugs that are subject to them, and the wide range of uses
for those drugs, demand flexibility in applying the standards. The Food
and Drug Administration (FDA) has determined that it is appropriate to
exercise the broadest flexibility in applying the statutory standards,
while preserving appropriate guarantees for safety and effectiveness.
These procedures reflect the recognition that physicians and patients
are generally willing to accept greater risks or side effects from
products that treat life-threatening and severely-debilitating
illnesses, than they would accept from products that treat less serious
illnesses. These procedures also reflect the recognition that the
benefits of the drug need to be evaluated in light of the severity of
the disease being treated. The procedure outlined in this section should
be interpreted consistent with that purpose.
Sec. 312.81 Scope.
This section applies to new drug and biological products that are
being studied for their safety and effectiveness in treating life-
threatening or severely-debilitating diseases.
(a) For purposes of this section, the term ``life-threatening''
means:
(1) Diseases or conditions where the likelihood of death is high
unless the course of the disease is interrupted; and
(2) Diseases or conditions with potentially fatal outcomes, where
the end point of clinical trial analysis is survival.
(b) For purposes of this section, the term ``severely debilitating''
means diseases or conditions that cause major irreversible morbidity.
[[Page 83]]
(c) Sponsors are encouraged to consult with FDA on the applicability
of these procedures to specific products.
[53 FR 41523, Oct. 21, 1988, as amended at 64 FR 401, Jan. 5, 1999]
Sec. 312.82 Early consultation.
For products intended to treat life-threatening or severely-
debilitating illnesses, sponsors may request to meet with FDA-reviewing
officials early in the drug development process to review and reach
agreement on the design of necessary preclinical and clinical studies.
Where appropriate, FDA will invite to such meetings one or more outside
expert scientific consultants or advisory committee members. To the
extent FDA resources permit, agency reviewing officials will honor
requests for such meetings
(a) Pre-investigational new drug (IND) meetings. Prior to the
submission of the initial IND, the sponsor may request a meeting with
FDA-reviewing officials. The primary purpose of this meeting is to
review and reach agreement on the design of animal studies needed to
initiate human testing. The meeting may also provide an opportunity for
discussing the scope and design of phase 1 testing, plans for studying
the drug product in pediatric populations, and the best approach for
presentation and formatting of data in the IND.
(b) End-of-phase 1 meetings. When data from phase 1 clinical testing
are available, the sponsor may again request a meeting with FDA-
reviewing officials. The primary purpose of this meeting is to review
and reach agreement on the design of phase 2 controlled clinical trials,
with the goal that such testing will be adequate to provide sufficient
data on the drug's safety and effectiveness to support a decision on its
approvability for marketing, and to discuss the need for, as well as the
design and timing of, studies of the drug in pediatric patients. For
drugs for life-threatening diseases, FDA will provide its best judgment,
at that time, whether pediatric studies will be required and whether
their submission will be deferred until after approval. The procedures
outlined in Sec. 312.47(b)(1) with respect to end-of-phase 2
conferences, including documentation of agreements reached, would also
be used for end-of-phase 1 meetings.
[53 FR 41523, Oct. 21, 1988, as amended at 63 FR 66669, Dec. 2, 1998]
Sec. 312.83 Treatment protocols.
If the preliminary analysis of phase 2 test results appears
promising, FDA may ask the sponsor to submit a treatment protocol to be
reviewed under the procedures and criteria listed in Sec. Sec. 312.305
and 312.320. Such a treatment protocol, if requested and granted, would
normally remain in effect while the complete data necessary for a
marketing application are being assembled by the sponsor and reviewed by
FDA (unless grounds exist for clinical hold of ongoing protocols, as
provided in Sec. 312.42(b)(3)(ii)).
[53 FR 41523, Oct. 21, 1988, as amended at 76 FR 13880, Mar. 15, 2011]
Sec. 312.84 Risk-benefit analysis in review of marketing applications
for drugs to treat life-threatening and severely-debilitating illnesses.
(a) FDA's application of the statutory standards for marketing
approval shall recognize the need for a medical risk-benefit judgment in
making the final decision on approvability. As part of this evaluation,
consistent with the statement of purpose in Sec. 312.80, FDA will
consider whether the benefits of the drug outweigh the known and
potential risks of the drug and the need to answer remaining questions
about risks and benefits of the drug, taking into consideration the
severity of the disease and the absence of satisfactory alternative
therapy.
(b) In making decisions on whether to grant marketing approval for
products that have been the subject of an end-of-phase 1 meeting under
Sec. 312.82, FDA will usually seek the advice of outside expert
scientific consultants or advisory committees. Upon the filing of such a
marketing application under Sec. 314.101 or part 601 of this chapter,
FDA will notify the members of the relevant standing advisory committee
of the application's filing and its availability for review.
(c) If FDA concludes that the data presented are not sufficient for
marketing approval, FDA will issue a complete response letter under
Sec. 314.110 of
[[Page 84]]
this chapter or the biological product licensing procedures. Such
letter, in describing the deficiencies in the application, will address
why the results of the research design agreed to under Sec. 312.82, or
in subsequent meetings, have not provided sufficient evidence for
marketing approval. Such letter will also describe any recommendations
made by the advisory committee regarding the application.
(d) Marketing applications submitted under the procedures contained
in this section will be subject to the requirements and procedures
contained in part 314 or part 600 of this chapter, as well as those in
this subpart.
[53 FR 41523, Oct. 21, 1988, as amended at 73 FR 39607, July 10, 2008]
Sec. 312.85 Phase 4 studies.
Concurrent with marketing approval, FDA may seek agreement from the
sponsor to conduct certain postmarketing (phase 4) studies to delineate
additional information about the drug's risks, benefits, and optimal
use. These studies could include, but would not be limited to, studying
different doses or schedules of administration than were used in phase 2
studies, use of the drug in other patient populations or other stages of
the disease, or use of the drug over a longer period of time.
Sec. 312.86 Focused FDA regulatory research.
At the discretion of the agency, FDA may undertake focused
regulatory research on critical rate-limiting aspects of the
preclinical, chemical/manufacturing, and clinical phases of drug
development and evaluation. When initiated, FDA will undertake such
research efforts as a means for meeting a public health need in
facilitating the development of therapies to treat life-threatening or
severely debilitating illnesses.
Sec. 312.87 Active monitoring of conduct and evaluation of clinical
trials.
For drugs covered under this section, the Commissioner and other
agency officials will monitor the progress of the conduct and evaluation
of clinical trials and be involved in facilitating their appropriate
progress.
Sec. 312.88 Safeguards for patient safety.
All of the safeguards incorporated within parts 50, 56, 312, 314,
and 600 of this chapter designed to ensure the safety of clinical
testing and the safety of products following marketing approval apply to
drugs covered by this section. This includes the requirements for
informed consent (part 50 of this chapter) and institutional review
boards (part 56 of this chapter). These safeguards further include the
review of animal studies prior to initial human testing (Sec. 312.23),
and the monitoring of adverse drug experiences through the requirements
of IND safety reports (Sec. 312.32), safety update reports during
agency review of a marketing application (Sec. 314.50 of this chapter),
and postmarketing adverse reaction reporting (Sec. 314.80 of this
chapter).
Subpart F_Miscellaneous
Sec. 312.110 Import and export requirements.
(a) Imports. An investigational new drug offered for import into the
United States complies with the requirements of this part if it is
subject to an IND that is in effect for it under Sec. 312.40 and: (1)
The consignee in the United States is the sponsor of the IND; (2) the
consignee is a qualified investigator named in the IND; or (3) the
consignee is the domestic agent of a foreign sponsor, is responsible for
the control and distribution of the investigational drug, and the IND
identifies the consignee and describes what, if any, actions the
consignee will take with respect to the investigational drug.
(b) Exports. An investigational new drug may be exported from the
United States for use in a clinical investigation under any of the
following conditions:
(1) An IND is in effect for the drug under Sec. 312.40, the drug
complies with the laws of the country to which it is being exported, and
each person who receives the drug is an investigator in a study
submitted to and allowed to proceed under the IND; or
(2) The drug has valid marketing authorization in Australia, Canada,
Israel, Japan, New Zealand, Switzerland, South Africa, or in any country
in the European Union or the European
[[Page 85]]
Economic Area, and complies with the laws of the country to which it is
being exported, section 802(b)(1)(A), (f), and (g) of the act, and Sec.
1.101 of this chapter; or
(3) The drug is being exported to Australia, Canada, Israel, Japan,
New Zealand, Switzerland, South Africa, or to any country in the
European Union or the European Economic Area, and complies with the laws
of the country to which it is being exported, the applicable provisions
of section 802(c), (f), and (g) of the act, and Sec. 1.101 of this
chapter. Drugs exported under this paragraph that are not the subject of
an IND are exempt from the label requirement in Sec. 312.6(a); or
(4) Except as provided in paragraph (b)(5) of this section, the
person exporting the drug sends an email certification to the Office of
Global Policy and Strategy at OGPSExecSec@fda.hhs.gov, or a written
certification to the Office of Global Policy and Strategy (HFG-1), Food
and Drug Administration, 10903 New Hampshire Ave., Bldg. 31, Rm. 3420,
Silver Spring, MD 20993, at the time the drug is first exported and
maintains records documenting compliance with this paragraph (b)(4). The
certification shall describe the drug that is to be exported (i.e.,
trade name (if any), generic name, and dosage form), identify the
country or countries to which the drug is to be exported, and affirm
that:
(i) The drug is intended for export;
(ii) The drug is intended for investigational use in a foreign
country;
(iii) The drug meets the foreign purchaser's or consignee's
specifications;
(iv) The drug is not in conflict with the importing country's laws;
(v) The outer shipping package is labeled to show that the package
is intended for export from the United States;
(vi) The drug is not sold or offered for sale in the United States;
(vii) The clinical investigation will be conducted in accordance
with Sec. 312.120;
(viii) The drug is manufactured, processed, packaged, and held in
substantial conformity with current good manufacturing practices;
(ix) The drug is not adulterated within the meaning of section
501(a)(1), (a)(2)(A), (a)(3), (c), or (d) of the act;
(x) The drug does not present an imminent hazard to public health,
either in the United States, if the drug were to be reimported, or in
the foreign country; and
(xi) The drug is labeled in accordance with the foreign country's
laws.
(5) In the event of a national emergency in a foreign country, where
the national emergency necessitates exportation of an investigational
new drug, the requirements in paragraph (b)(4) of this section apply as
follows:
(i) Situations where the investigational new drug is to be
stockpiled in anticipation of a national emergency. There may be
instances where exportation of an investigational new drug is needed so
that the drug may be stockpiled and made available for use by the
importing country if and when a national emergency arises. In such
cases:
(A) A person may export an investigational new drug under paragraph
(b)(4) of this section without making an affirmation with respect to any
one or more of paragraphs (b)(4)(i), (b)(4)(iv), (b)(4)(vi),
(b)(4)(vii), (b)(4)(viii), and/or (b)(4)(ix) of this section, provided
that he or she:
(1) Provides a written statement explaining why compliance with each
such paragraph is not feasible or is contrary to the best interests of
the individuals who may receive the investigational new drug;
(2) Provides a written statement from an authorized official of the
importing country's government. The statement must attest that the
official agrees with the exporter's statement made under paragraph
(b)(5)(i)(A)(1) of this section; explain that the drug is to be
stockpiled solely for use of the importing country in a national
emergency; and describe the potential national emergency that warrants
exportation of the investigational new drug under this provision; and
(3) Provides a written statement showing that the Secretary of
Health and Human Services (the Secretary), or his or her designee,
agrees with the findings of the authorized official of the importing
country's government. Persons who wish to obtain a written
[[Page 86]]
statement from the Secretary should direct their requests to Secretary's
Operations Center, Office of Emergency Operations and Security Programs,
Office of Public Health Emergency Preparedness, Office of the Secretary,
Department of Health and Human Services, 200 Independence Ave. SW.,
Washington, DC 20201. Requests may be also be sent by FAX: 202-619-7870
or by e-mail: HHS.SOC@hhs.gov.
(B) Exportation may not proceed until FDA has authorized exportation
of the investigational new drug. FDA may deny authorization if the
statements provided under paragraphs (b)(5)(i)(A)(1) or (b)(5)(i)(A)(2)
of this section are inadequate or if exportation is contrary to public
health.
(ii) Situations where the investigational new drug is to be used for
a sudden and immediate national emergency. There may be instances where
exportation of an investigational new drug is needed so that the drug
may be used in a sudden and immediate national emergency that has
developed or is developing. In such cases:
(A) A person may export an investigational new drug under paragraph
(b)(4) of this section without making an affirmation with respect to any
one or more of paragraphs (b)(4)(i), (b)(4)(iv), (b)(4)(v), (b)(4)(vi),
(b)(4)(vii), (b)(4)(viii), (b)(4)(ix), and/or (b)(4)(xi), provided that
he or she:
(1) Provides a written statement explaining why compliance with each
such paragraph is not feasible or is contrary to the best interests of
the individuals who are expected to receive the investigational new drug
and
(2) Provides sufficient information from an authorized official of
the importing country's government to enable the Secretary, or his or
her designee, to decide whether a national emergency has developed or is
developing in the importing country, whether the investigational new
drug will be used solely for that national emergency, and whether prompt
exportation of the investigational new drug is necessary. Persons who
wish to obtain a determination from the Secretary should direct their
requests to Secretary's Operations Center, Office of Emergency
Operations and Security Programs, Office of Public Health Emergency
Preparedness, Office of the Secretary, Department of Health and Human
Services, 200 Independence Ave. SW., Washington, DC 20201. Requests may
be also be sent by FAX: 202-619-7870 or by e-mail: HHS.SOC@hhs.gov.
(B) Exportation may proceed without prior FDA authorization.
(c) Limitations. Exportation under paragraph (b) of this section may
not occur if:
(1) For drugs exported under paragraph (b)(1) of this section, the
IND pertaining to the clinical investigation is no longer in effect;
(2) For drugs exported under paragraph (b)(2) of this section, the
requirements in section 802(b)(1), (f), or (g) of the act are no longer
met;
(3) For drugs exported under paragraph (b)(3) of this section, the
requirements in section 802(c), (f), or (g) of the act are no longer
met;
(4) For drugs exported under paragraph (b)(4) of this section, the
conditions underlying the certification or the statements submitted
under paragraph (b)(5) of this section are no longer met; or
(5) For any investigational new drugs under this section, the drug
no longer complies with the laws of the importing country.
(d) Insulin and antibiotics. New insulin and antibiotic drug
products may be exported for investigational use in accordance with
section 801(e)(1) of the act without complying with this section.
[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 64
FR 401, Jan. 5, 1999; 67 FR 9586, Mar. 4, 2002; 70 FR 70729, Nov. 23,
2005; 88 FR 18037, Mar. 27, 2023]
Sec. 312.120 Foreign clinical studies not conducted under an IND.
(a) Acceptance of studies. (1) FDA will accept as support for an IND
or application for marketing approval (an application under section 505
of the act or section 351 of the Public Health Service Act (the PHS Act)
(42 U.S.C. 262)) a well-designed and well-conducted foreign clinical
study not conducted under an IND, if the following conditions are met:
(i) The study was conducted in accordance with good clinical
practice (GCP). For the purposes of this section,
[[Page 87]]
GCP is defined as a standard for the design, conduct, performance,
monitoring, auditing, recording, analysis, and reporting of clinical
trials in a way that provides assurance that the data and reported
results are credible and accurate and that the rights, safety, and well-
being of trial subjects are protected. GCP includes review and approval
(or provision of a favorable opinion) by an independent ethics committee
(IEC) before initiating a study, continuing review of an ongoing study
by an IEC, and obtaining and documenting the freely given informed
consent of the subject (or a subject's legally authorized
representative, if the subject is unable to provide informed consent)
before initiating a study. GCP does not require informed consent in
life-threatening situations when the IEC reviewing the study finds,
before initiation of the study, that informed consent is not feasible
and either that the conditions present are consistent with those
described in Sec. 50.23 or Sec. 50.24(a) of this chapter, or that the
measures described in the study protocol or elsewhere will protect the
rights, safety, and well-being of subjects; and
(ii) FDA is able to validate the data from the study through an
onsite inspection if the agency deems it necessary.
(2) Although FDA will not accept as support for an IND or
application for marketing approval a study that does not meet the
conditions of paragraph (a)(1) of this section, FDA will examine data
from such a study.
(3) Marketing approval of a new drug based solely on foreign
clinical data is governed by Sec. 314.106 of this chapter.
(b) Supporting information. A sponsor or applicant who submits data
from a foreign clinical study not conducted under an IND as support for
an IND or application for marketing approval must submit to FDA, in
addition to information required elsewhere in parts 312, 314, or 601 of
this chapter, a description of the actions the sponsor or applicant took
to ensure that the research conformed to GCP as described in paragraph
(a)(1)(i) of this section. The description is not required to duplicate
information already submitted in the IND or application for marketing
approval. Instead, the description must provide either the following
information or a cross-reference to another section of the submission
where the information is located:
(1) The investigator's qualifications;
(2) A description of the research facilities;
(3) A detailed summary of the protocol and results of the study and,
should FDA request, case records maintained by the investigator or
additional background data such as hospital or other institutional
records;
(4) A description of the drug substance and drug product used in the
study, including a description of the components, formulation,
specifications, and, if available, bioavailability of the specific drug
product used in the clinical study;
(5) If the study is intended to support the effectiveness of a drug
product, information showing that the study is adequate and well
controlled under Sec. 314.126 of this chapter;
(6) The name and address of the IEC that reviewed the study and a
statement that the IEC meets the definition in Sec. 312.3 of this
chapter. The sponsor or applicant must maintain records supporting such
statement, including records of the names and qualifications of IEC
members, and make these records available for agency review upon
request;
(7) A summary of the IEC's decision to approve or modify and approve
the study, or to provide a favorable opinion;
(8) A description of how informed consent was obtained;
(9) A description of what incentives, if any, were provided to
subjects to participate in the study;
(10) A description of how the sponsor(s) monitored the study and
ensured that the study was carried out consistently with the study
protocol; and
(11) A description of how investigators were trained to comply with
GCP (as described in paragraph (a)(1)(i) of this section) and to conduct
the study in accordance with the study protocol, and a statement on
whether written
[[Page 88]]
commitments by investigators to comply with GCP and the protocol were
obtained. Any signed written commitments by investigators must be
maintained by the sponsor or applicant and made available for agency
review upon request.
(c) Waivers. (1) A sponsor or applicant may ask FDA to waive any
applicable requirements under paragraphs (a)(1) and (b) of this section.
A waiver request may be submitted in an IND or in an information
amendment to an IND, or in an application or in an amendment or
supplement to an application submitted under part 314 or 601 of this
chapter. A waiver request is required to contain at least one of the
following:
(i) An explanation why the sponsor's or applicant's compliance with
the requirement is unnecessary or cannot be achieved;
(ii) A description of an alternative submission or course of action
that satisfies the purpose of the requirement; or
(iii) Other information justifying a waiver.
(2) FDA may grant a waiver if it finds that doing so would be in the
interest of the public health.
(d) Records. A sponsor or applicant must retain the records required
by this section for a foreign clinical study not conducted under an IND
as follows:
(1) If the study is submitted in support of an application for
marketing approval, for 2 years after an agency decision on that
application;
(2) If the study is submitted in support of an IND but not an
application for marketing approval, for 2 years after the submission of
the IND.
[73 FR 22815, Apr. 28, 2008]
Sec. 312.130 Availability for public disclosure of data and information
in an IND.
(a) The existence of an investigational new drug application will
not be disclosed by FDA unless it has previously been publicly disclosed
or acknowledged.
(b) The availability for public disclosure of all data and
information in an investigational new drug application for a new drug
will be handled in accordance with the provisions established in Sec.
314.430 for the confidentiality of data and information in applications
submitted in part 314. The availability for public disclosure of all
data and information in an investigational new drug application for a
biological product will be governed by the provisions of Sec. Sec.
601.50 and 601.51.
(c) Notwithstanding the provisions of Sec. 314.430, FDA shall
disclose upon request to an individual to whom an investigational new
drug has been given a copy of any IND safety report relating to the use
in the individual.
(d) The availability of information required to be publicly
disclosed for investigations involving an exception from informed
consent under Sec. 50.24 of this chapter will be handled as follows:
Persons wishing to request the publicly disclosable information in the
IND that was required to be filed in Docket Number 95S-0158 in the
Dockets Management Staff (HFA-305), Food and Drug Administration, 5630
Fishers Lane, rm. 1061, Rockville, MD 20852, shall submit a request
under the Freedom of Information Act.
[52 FR 8831, Mar. 19, 1987. Redesignated at 53 FR 41523, Oct. 21, 1988,
as amended at 61 FR 51530, Oct. 2, 1996; 64 FR 401, Jan. 5, 1999; 68 FR
24879, May 9, 2003; 88 FR 45065, July 14, 2023]
Sec. 312.140 Address for correspondence.
(a) A sponsor must send an initial IND submission to the Center for
Drug Evaluation and Research (CDER) or to the Center for Biologics
Evaluation and Research (CBER), depending on the Center responsible for
regulating the product as follows:
(1) For drug products regulated by CDER. Send the IND submission to
the Central Document Room, Center for Drug Evaluation and Research, Food
and Drug Administration, 5901-B Ammendale Rd., Beltsville, MD 20705-
1266.
(2) For biological products regulated by CDER. Send the IND
submission to the Central Document Room, Center for Drug Evaluation and
Research, Food and Drug Administration, 5901-B Ammendale Rd.,
Beltsville, MD 20705-1266.
(3) For biological products regulated by CBER. Send the IND
submission to the Food and Drug Administration, Center for Biologics
Evaluation and Research,
[[Page 89]]
Document Control Center, 10903 New Hampshire Ave., Bldg. 71, Rm. G112,
Silver Spring, MD 20993-0002.
(b) On receiving the IND, the responsible Center will inform the
sponsor which one of the divisions in CDER or CBER is responsible for
the IND. Amendments, reports, and other correspondence relating to
matters covered by the IND should be sent to the appropriate center at
the address indicated in this section and marked to the attention of the
responsible division. The outside wrapper of each submission shall state
what is contained in the submission, for example, ``IND Application'',
``Protocol Amendment'', etc.
(c) All correspondence relating to export of an investigational drug
under Sec. 312.110(b)(2) shall be submitted to the International
Affairs Staff (HFY-50), Office of Health Affairs, Food and Drug
Administration, 5600 Fishers Lane, Rockville, MD 20857.
[70 FR 14981, Mar. 24, 2005, as amended at 74 FR 13113, Mar. 26, 2009;
74 FR 55771, Oct. 29, 2009; 75 FR 37295, June 29, 2010; 80 FR 18091,
Apr. 3, 2015; 81 FR 17066, Mar. 28, 2016; 84 FR 6673, Feb. 28, 2019]
Sec. 312.145 Guidance documents.
(a) FDA has made available guidance documents under Sec. 10.115 of
this chapter to help you to comply with certain requirements of this
part.
(b) The Center for Drug Evaluation and Research (CDER) and the
Center for Biologics Evaluation and Research (CBER) maintain lists of
guidance documents that apply to the centers' regulations. The lists are
maintained on the Internet and are published annually in the Federal
Register. A request for a copy of the CDER list should be directed to
the Office of Training and Communications, Division of Drug Information,
Center for Drug Evaluation and Research, Food and Drug Administration,
10903 New Hampshire Ave., Silver Spring, MD 20993-0002. A request for a
copy of the CBER list should be directed to the Food and Drug
Administration, Center for Biologics Evaluation and Research, Office of
Communication, Outreach and Development, 10903 New Hampshire Ave., Bldg.
71, Rm. 3103, Silver Spring, MD 20993-0002.
[65 FR 56479, Sept. 19, 2000, as amended at 74 FR 13113, Mar. 26, 2009;
80 FR 18091, Apr. 3, 2015]
Subpart G_Drugs for Investigational Use in Laboratory Research Animals
or In Vitro Tests
Sec. 312.160 Drugs for investigational use in laboratory research
animals or in vitro tests.
(a) Authorization to ship. (1)(i) A person may ship a drug intended
solely for tests in vitro or in animals used only for laboratory
research purposes if it is labeled as follows:
CAUTION: Contains a new drug for investigational use only in
laboratory research animals, or for tests in vitro. Not for use in
humans.
(ii) A person may ship a biological product for investigational in
vitro diagnostic use that is listed in Sec. 312.2(b)(2)(ii) if it is
labeled as follows:
CAUTION: Contains a biological product for investigational in vitro
diagnostic tests only.
(2) A person shipping a drug under paragraph (a) of this section
shall use due diligence to assure that the consignee is regularly
engaged in conducting such tests and that the shipment of the new drug
will actually be used for tests in vitro or in animals used only for
laboratory research.
(3) A person who ships a drug under paragraph (a) of this section
shall maintain adequate records showing the name and post office address
of the expert to whom the drug is shipped and the date, quantity, and
batch or code mark of each shipment and delivery. Records of shipments
under paragraph (a)(1)(i) of this section are to be maintained for a
period of 2 years after the shipment. Records and reports of data and
shipments under paragraph (a)(1)(ii) of this section are to be
maintained in accordance with Sec. 312.57(b). The person who ships the
drug shall upon request from any properly authorized officer or employee
of the Food and Drug Administration, at reasonable times, permit such
officer or
[[Page 90]]
employee to have access to and copy and verify records required to be
maintained under this section.
(b) Termination of authorization to ship. FDA may terminate
authorization to ship a drug under this section if it finds that:
(1) The sponsor of the investigation has failed to comply with any
of the conditions for shipment established under this section; or
(2) The continuance of the investigation is unsafe or otherwise
contrary to the public interest or the drug is used for purposes other
than bona fide scientific investigation. FDA will notify the person
shipping the drug of its finding and invite immediate correction. If
correction is not immediately made, the person shall have an opportunity
for a regulatory hearing before FDA pursuant to part 16.
(c) Disposition of unused drug. The person who ships the drug under
paragraph (a) of this section shall assure the return of all unused
supplies of the drug from individual investigators whenever the
investigation discontinues or the investigation is terminated. The
person who ships the drug may authorize in writing alternative
disposition of unused supplies of the drug provided this alternative
disposition does not expose humans to risks from the drug, either
directly or indirectly (e.g., through food-producing animals). The
shipper shall maintain records of any alternative disposition.
[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987.
Redesignated at 53 FR 41523, Oct. 21, 1988; 67 FR 9586, Mar. 4, 2002]
Subpart H [Reserved]
Subpart I_Expanded Access to Investigational Drugs for Treatment Use
Source: 74 FR 40942, Aug. 13, 2009, unless otherwise noted.
Sec. 312.300 General.
(a) Scope. This subpart contains the requirements for the use of
investigational new drugs and approved drugs where availability is
limited by a risk evaluation and mitigation strategy (REMS) when the
primary purpose is to diagnose, monitor, or treat a patient's disease or
condition. The aim of this subpart is to facilitate the availability of
such drugs to patients with serious diseases or conditions when there is
no comparable or satisfactory alternative therapy to diagnose, monitor,
or treat the patient's disease or condition.
(b) Definitions. The following definitions of terms apply to this
subpart:
Immediately life-threatening disease or condition means a stage of
disease in which there is reasonable likelihood that death will occur
within a matter of months or in which premature death is likely without
early treatment.
Serious disease or condition means a disease or condition associated
with morbidity that has substantial impact on day-to-day functioning.
Short-lived and self-limiting morbidity will usually not be sufficient,
but the morbidity need not be irreversible, provided it is persistent or
recurrent. Whether a disease or condition is serious is a matter of
clinical judgment, based on its impact on such factors as survival, day-
to-day functioning, or the likelihood that the disease, if left
untreated, will progress from a less severe condition to a more serious
one.
Sec. 312.305 Requirements for all expanded access uses.
The criteria, submission requirements, safeguards, and beginning
treatment information set out in this section apply to all expanded
access uses described in this subpart. Additional criteria, submission
requirements, and safeguards that apply to specific types of expanded
access are described in Sec. Sec. 312.310 through 312.320.
(a) Criteria. FDA must determine that:
(1) The patient or patients to be treated have a serious or
immediately life-threatening disease or condition, and there is no
comparable or satisfactory alternative therapy to diagnose, monitor, or
treat the disease or condition;
(2) The potential patient benefit justifies the potential risks of
the treatment use and those potential risks are not unreasonable in the
context of the disease or condition to be treated; and
[[Page 91]]
(3) Providing the investigational drug for the requested use will
not interfere with the initiation, conduct, or completion of clinical
investigations that could support marketing approval of the expanded
access use or otherwise compromise the potential development of the
expanded access use.
(b) Submission. (1) An expanded access submission is required for
each type of expanded access described in this subpart. The submission
may be a new IND or a protocol amendment to an existing IND. Information
required for a submission may be supplied by referring to pertinent
information contained in an existing IND if the sponsor of the existing
IND grants a right of reference to the IND.
(2) The expanded access submission must include:
(i) A cover sheet (Form FDA 1571) meeting the requirements of Sec.
312.23(a);
(ii) The rationale for the intended use of the drug, including a
list of available therapeutic options that would ordinarily be tried
before resorting to the investigational drug or an explanation of why
the use of the investigational drug is preferable to the use of
available therapeutic options;
(iii) The criteria for patient selection or, for an individual
patient, a description of the patient's disease or condition, including
recent medical history and previous treatments of the disease or
condition;
(iv) The method of administration of the drug, dose, and duration of
therapy;
(v) A description of the facility where the drug will be
manufactured;
(vi) Chemistry, manufacturing, and controls information adequate to
ensure the proper identification, quality, purity, and strength of the
investigational drug;
(vii) Pharmacology and toxicology information adequate to conclude
that the drug is reasonably safe at the dose and duration proposed for
expanded access use (ordinarily, information that would be adequate to
permit clinical testing of the drug in a population of the size expected
to be treated); and
(viii) A description of clinical procedures, laboratory tests, or
other monitoring necessary to evaluate the effects of the drug and
minimize its risks.
(3) The expanded access submission and its mailing cover must be
plainly marked ``EXPANDED ACCESS SUBMISSION.'' If the expanded access
submission is for a treatment IND or treatment protocol, the applicable
box on Form FDA 1571 must be checked.
(c) Safeguards. The responsibilities of sponsors and investigators
set forth in subpart D of this part are applicable to expanded access
use under this subpart as described in this paragraph.
(1) A licensed physician under whose immediate direction an
investigational drug is administered or dispensed for an expanded access
use under this subpart is considered an investigator, for purposes of
this part, and must comply with the responsibilities for investigators
set forth in subpart D of this part to the extent they are applicable to
the expanded access use.
(2) An individual or entity that submits an expanded access IND or
protocol under this subpart is considered a sponsor, for purposes of
this part, and must comply with the responsibilities for sponsors set
forth in subpart D of this part to the extent they are applicable to the
expanded access use.
(3) A licensed physician under whose immediate direction an
investigational drug is administered or dispensed, and who submits an
IND for expanded access use under this subpart is considered a sponsor-
investigator, for purposes of this part, and must comply with the
responsibilities for sponsors and investigators set forth in subpart D
of this part to the extent they are applicable to the expanded access
use.
(4) Investigators. In all cases of expanded access, investigators
are responsible for reporting adverse drug events to the sponsor,
ensuring that the informed consent requirements of part 50 of this
chapter are met, ensuring that IRB review of the expanded access use is
obtained in a manner consistent with the requirements of part 56 of this
chapter, and maintaining accurate case histories and drug disposition
records and retaining records in a manner consistent with the
requirements of Sec. 312.62. Depending on the type of expanded access,
other investigator responsibilities under subpart D may also apply.
[[Page 92]]
(5) Sponsors. In all cases of expanded access, sponsors are
responsible for submitting IND safety reports and annual reports (when
the IND or protocol continues for 1 year or longer) to FDA as required
by Sec. Sec. 312.32 and 312.33, ensuring that licensed physicians are
qualified to administer the investigational drug for the expanded access
use, providing licensed physicians with the information needed to
minimize the risk and maximize the potential benefits of the
investigational drug (the investigator's brochure must be provided if
one exists for the drug), maintaining an effective IND for the expanded
access use, and maintaining adequate drug disposition records and
retaining records in a manner consistent with the requirements of Sec.
312.57. Depending on the type of expanded access, other sponsor
responsibilities under subpart D may also apply.
(d) Beginning treatment--(1) INDs. An expanded access IND goes into
effect 30 days after FDA receives the IND or on earlier notification by
FDA that the expanded access use may begin.
(2) Protocols. With the following exceptions, expanded access use
under a protocol submitted under an existing IND may begin as described
in Sec. 312.30(a).
(i) Expanded access use under the emergency procedures described in
Sec. 312.310(d) may begin when the use is authorized by the FDA
reviewing official.
(ii) Expanded access use under Sec. 312.320 may begin 30 days after
FDA receives the protocol or upon earlier notification by FDA that use
may begin.
(3) Clinical holds. FDA may place any expanded access IND or
protocol on clinical hold as described in Sec. 312.42.
Sec. 312.310 Individual patients, including for emergency use.
Under this section, FDA may permit an investigational drug to be
used for the treatment of an individual patient by a licensed physician.
(a) Criteria. The criteria in Sec. 312.305(a) must be met; and the
following determinations must be made:
(1) The physician must determine that the probable risk to the
person from the investigational drug is not greater than the probable
risk from the disease or condition; and
(2) FDA must determine that the patient cannot obtain the drug under
another IND or protocol.
(b) Submission. The expanded access submission must include
information adequate to demonstrate that the criteria in Sec.
312.305(a) and paragraph (a) of this section have been met. The expanded
access submission must meet the requirements of Sec. 312.305(b).
(1) If the drug is the subject of an existing IND, the expanded
access submission may be made by the sponsor or by a licensed physician.
(2) A sponsor may satisfy the submission requirements by amending
its existing IND to include a protocol for individual patient expanded
access.
(3) A licensed physician may satisfy the submission requirements by
obtaining from the sponsor permission for FDA to refer to any
information in the IND that would be needed to support the expanded
access request (right of reference) and by providing any other required
information not contained in the IND (usually only the information
specific to the individual patient).
(c) Safeguards. (1) Treatment is generally limited to a single
course of therapy for a specified duration unless FDA expressly
authorizes multiple courses or chronic therapy.
(2) At the conclusion of treatment, the licensed physician or
sponsor must provide FDA with a written summary of the results of the
expanded access use, including adverse effects.
(3) FDA may require sponsors to monitor an individual patient
expanded access use if the use is for an extended duration.
(4) When a significant number of similar individual patient expanded
access requests have been submitted, FDA may ask the sponsor to submit
an IND or protocol for the use under Sec. 312.315 or Sec. 312.320.
(d) Emergency procedures. If there is an emergency that requires the
patient to be treated before a written submission can be made, FDA may
authorize
[[Page 93]]
the expanded access use to begin without a written submission. The FDA
reviewing official may authorize the emergency use by telephone.
(1) Emergency expanded access use may be requested by telephone,
facsimile, or other means of electronic communications. For
investigational biological drug products regulated by the Center for
Biologics Evaluation and Research, the request should be directed to the
Office of Communication, Outreach and Development, Center for Biologics
Evaluation and Research, 240-402-8010 or 1-800-835-4709, e-mail:
ocod@fda.hhs.gov. For all other investigational drugs, the request for
authorization should be directed to the Division of Drug Information,
Center for Drug Evaluation and Research, 301-796-3400, e-mail:
druginfo@fda.hhs.gov. After normal working hours (8 a.m. to 4:30 p.m.),
the request should be directed to the FDA Emergency Call Center, 866-
300-4374, e-mail: emergency.operations@fda.hhs.gov.
(2) The licensed physician or sponsor must explain how the expanded
access use will meet the requirements of Sec. Sec. 312.305 and 312.310
and must agree to submit an expanded access submission within 15 working
days of FDA's authorization of the use.
[74 FR 40942, Aug. 13, 2009, as amended at 75 FR 32659, June 9, 2010; 80
FR 18091, Apr. 3, 2015]
Sec. 312.315 Intermediate-size patient populations.
Under this section, FDA may permit an investigational drug to be
used for the treatment of a patient population smaller than that typical
of a treatment IND or treatment protocol. FDA may ask a sponsor to
consolidate expanded access under this section when the agency has
received a significant number of requests for individual patient
expanded access to an investigational drug for the same use.
(a) Need for expanded access. Expanded access under this section may
be needed in the following situations:
(1) Drug not being developed. The drug is not being developed, for
example, because the disease or condition is so rare that the sponsor is
unable to recruit patients for a clinical trial.
(2) Drug being developed. The drug is being studied in a clinical
trial, but patients requesting the drug for expanded access use are
unable to participate in the trial. For example, patients may not be
able to participate in the trial because they have a different disease
or stage of disease than the one being studied or otherwise do not meet
the enrollment criteria, because enrollment in the trial is closed, or
because the trial site is not geographically accessible.
(3) Approved or related drug. (i) The drug is an approved drug
product that is no longer marketed for safety reasons or is unavailable
through marketing due to failure to meet the conditions of the approved
application, or
(ii) The drug contains the same active moiety as an approved drug
product that is unavailable through marketing due to failure to meet the
conditions of the approved application or a drug shortage.
(b) Criteria. The criteria in Sec. 312.305(a) must be met; and FDA
must determine that:
(1) There is enough evidence that the drug is safe at the dose and
duration proposed for expanded access use to justify a clinical trial of
the drug in the approximate number of patients expected to receive the
drug under expanded access; and
(2) There is at least preliminary clinical evidence of effectiveness
of the drug, or of a plausible pharmacologic effect of the drug to make
expanded access use a reasonable therapeutic option in the anticipated
patient population.
(c) Submission. The expanded access submission must include
information adequate to satisfy FDA that the criteria in Sec.
312.305(a) and paragraph (b) of this section have been met. The expanded
access submission must meet the requirements of Sec. 312.305(b). In
addition:
(1) The expanded access submission must state whether the drug is
being developed or is not being developed and describe the patient
population to be treated.
(2) If the drug is not being actively developed, the sponsor must
explain why the drug cannot currently be developed for the expanded
access use and
[[Page 94]]
under what circumstances the drug could be developed.
(3) If the drug is being studied in a clinical trial, the sponsor
must explain why the patients to be treated cannot be enrolled in the
clinical trial and under what circumstances the sponsor would conduct a
clinical trial in these patients.
(d) Safeguards. (1) Upon review of the IND annual report, FDA will
determine whether it is appropriate for the expanded access to continue
under this section.
(i) If the drug is not being actively developed or if the expanded
access use is not being developed (but another use is being developed),
FDA will consider whether it is possible to conduct a clinical study of
the expanded access use.
(ii) If the drug is being actively developed, FDA will consider
whether providing the investigational drug for expanded access use is
interfering with the clinical development of the drug.
(iii) As the number of patients enrolled increases, FDA may ask the
sponsor to submit an IND or protocol for the use under Sec. 312.320.
(2) The sponsor is responsible for monitoring the expanded access
protocol to ensure that licensed physicians comply with the protocol and
the regulations applicable to investigators.
Sec. 312.320 Treatment IND or treatment protocol.
Under this section, FDA may permit an investigational drug to be
used for widespread treatment use.
(a) Criteria. The criteria in Sec. 312.305(a) must be met, and FDA
must determine that:
(1) Trial status. (i) The drug is being investigated in a controlled
clinical trial under an IND designed to support a marketing application
for the expanded access use, or
(ii) All clinical trials of the drug have been completed; and
(2) Marketing status. The sponsor is actively pursuing marketing
approval of the drug for the expanded access use with due diligence; and
(3) Evidence. (i) When the expanded access use is for a serious
disease or condition, there is sufficient clinical evidence of safety
and effectiveness to support the expanded access use. Such evidence
would ordinarily consist of data from phase 3 trials, but could consist
of compelling data from completed phase 2 trials; or
(ii) When the expanded access use is for an immediately life-
threatening disease or condition, the available scientific evidence,
taken as a whole, provides a reasonable basis to conclude that the
investigational drug may be effective for the expanded access use and
would not expose patients to an unreasonable and significant risk of
illness or injury. This evidence would ordinarily consist of clinical
data from phase 3 or phase 2 trials, but could be based on more
preliminary clinical evidence.
(b) Submission. The expanded access submission must include
information adequate to satisfy FDA that the criteria in Sec.
312.305(a) and paragraph (a) of this section have been met. The expanded
access submission must meet the requirements of Sec. 312.305(b).
(c) Safeguard. The sponsor is responsible for monitoring the
treatment protocol to ensure that licensed physicians comply with the
protocol and the regulations applicable to investigators.
PART 314_APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG-
-Table of Contents
Subpart A_General Provisions
Sec.
314.1 Scope of this part.
314.2 Purpose.
314.3 Definitions.
Subpart B_Applications
314.50 Content and format of an NDA.
314.52 Notice of certification of invalidity, unenforceability, or
noninfringement of a patent.
314.53 Submission of patent information.
314.54 Procedure for submission of a 505(b)(2) application requiring
investigations for approval of a new indication for, or other
change from, a listed drug.
314.55 Pediatric use information.
314.60 Amendments to an unapproved application, supplement, or
resubmission.
314.65 Withdrawal by the applicant of an unapproved application.
314.70 Supplements and other changes to an approved NDA.
314.71 Procedures for submission of a supplement to an approved
application.
[[Page 95]]
314.72 Change in ownership of an application.
314.80 Postmarketing reporting of adverse drug experiences.
314.81 Other postmarketing reports.
314.90 Waivers.
Subpart C_Abbreviated Applications
314.92 Drug products for which abbreviated applications may be
submitted.
314.93 Petition to request a change from a listed drug.
314.94 Content and format of an ANDA.
314.95 Notice of certification of invalidity, unenforceability, or
noninfringement of a patent.
314.96 Amendments to an unapproved ANDA.
314.97 Supplements and other changes to an approved ANDA.
314.98 Postmarketing reports.
314.99 Other responsibilities of an applicant of an ANDA.
Subpart D_FDA Action on Applications and Abbreviated Applications
314.100 Timeframes for reviewing applications and abbreviated
applications.
314.101 Filing an NDA and receiving an ANDA.
314.102 Communications between FDA and applicants.
314.103 Dispute resolution.
314.104 Drugs with potential for abuse.
314.105 Approval of an NDA and an ANDA.
314.106 Foreign data.
314.107 Date of approval of a 505(b)(2) application or ANDA.
314.108 New drug product exclusivity.
314.110 Complete response letter to the applicant.
314.120 [Reserved]
314.122 Submitting an abbreviated application for, or a 505(j)(2)(C)
petition that relies on, a listed drug that is no longer
marketed.
314.125 Refusal to approve an NDA.
314.126 Adequate and well-controlled studies.
314.127 Refusal to approve an ANDA.
314.150 Withdrawal of approval of an application or abbreviated
application.
314.151 Withdrawal of approval of an abbreviated new drug application
under section 505(j)(5) of the act.
314.152 Notice of withdrawal of approval of an application or
abbreviated application for a new drug.
314.153 Suspension of approval of an abbreviated new drug application.
314.160 Approval of an application or abbreviated application for which
approval was previously refused, suspended, or withdrawn.
314.161 Determination of reasons for voluntary withdrawal of a listed
drug.
314.162 Removal of a drug product from the list.
314.170 Adulteration and misbranding of an approved drug.
Subpart E_Hearing Procedures for New Drugs
314.200 Notice of opportunity for hearing; notice of participation and
request for hearing; grant or denial of hearing.
314.201 Procedure for hearings.
314.235 Judicial review.
Subpart F [Reserved]
Subpart G_Miscellaneous Provisions
314.410 Imports and exports of new drugs.
314.420 Drug master files.
314.430 Availability for public disclosure of data and information in an
application or abbreviated application.
314.440 Addresses for applications and abbreviated applications.
314.445 Guidance documents.
Subpart H_Accelerated Approval of New Drugs for Serious or Life-
Threatening Illnesses
314.500 Scope.
314.510 Approval based on a surrogate endpoint or on an effect on a
clinical endpoint other than survival or irreversible
morbidity.
314.520 Approval with restrictions to assure safe use.
314.530 Withdrawal procedures.
314.540 Postmarketing safety reporting.
314.550 Promotional materials.
314.560 Termination of requirements.
Subpart I_Approval of New Drugs When Human Efficacy Studies Are Not
Ethical or Feasible
314.600 Scope.
314.610 Approval based on evidence of effectiveness from studies in
animals.
314.620 Withdrawal procedures.
314.630 Postmarketing safety reporting.
314.640 Promotional materials.
314.650 Termination of requirements.
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 355a, 355f, 356,
356a, 356b, 356c, 356e, 360cc, 371, 374, 379e, 379k-1.
Source: 50 FR 7493, Feb. 22, 1985, unless otherwise noted.
Editorial Note: Nomenclature changes to part 314 appear at 69 FR
13717, Mar. 24, 2004; 81 FR 69639, Oct. 6, 2016.
[[Page 96]]
Subpart A_General Provisions
Sec. 314.1 Scope of this part.
(a) This part sets forth procedures and requirements for the
submission to, and the review by, the Food and Drug Administration of
applications and abbreviated applications to market a new drug under
section 505 of the Federal Food, Drug, and Cosmetic Act, as well as
amendments, supplements, and postmarketing reports to them.
(b) This part does not apply to drug products subject to licensing
by FDA under the Public Health Service Act (58 Stat. 632 as amended (42
U.S.C. 201 et seq.)) and subchapter F of chapter I of title 21 of the
Code of Federal Regulations.
(c) References in this part to regulations in the Code of Federal
Regulations are to chapter I of title 21, unless otherwise noted.
[50 FR 7493, Feb. 22, 1985, as amended at 57 FR 17981, Apr. 28, 1992; 64
FR 401, Jan. 5, 1999]
Sec. 314.2 Purpose.
The purpose of this part is to establish an efficient and thorough
drug review process in order to: (a) Facilitate the approval of drugs
shown to be safe and effective; and (b) ensure the disapproval of drugs
not shown to be safe and effective. These regulations are also intended
to establish an effective system for FDA's surveillance of marketed
drugs. These regulations shall be construed in light of these
objectives.
Sec. 314.3 Definitions.
(a) The definitions and interpretations contained in section 201 of
the Federal Food, Drug, and Cosmetic Act apply to those terms when used
in this part and part 320 of this chapter.
(b) The following definitions of terms apply to this part and part
320 of this chapter:
180-day exclusivity period is the 180-day period beginning on the
date of the first commercial marketing of the drug (including the
commercial marketing of the reference listed drug) by any first
applicant. The 180-day period ends on the day before the date on which
an ANDA submitted by an applicant other than a first applicant could be
approved.
505(b)(2) application is an NDA submitted under section 505(b)(1) of
the Federal Food, Drug, and Cosmetic Act for a drug for which at least
some of the investigations described in section 505(b)(1)(A) of the
Federal Food, Drug, and Cosmetic Act and relied upon by the applicant
for approval of the NDA were not conducted by or for the applicant and
for which the applicant has not obtained a right of reference or use
from the person by or for whom the investigations were conducted.
Abbreviated application, abbreviated new drug application, or ANDA
is the application described under Sec. 314.94, including all
amendments and supplements to the application.
Acknowledgment letter is a written, postmarked communication from
FDA to an applicant stating that the Agency has determined that an ANDA
is sufficiently complete to permit a substantive review. An
acknowledgment letter indicates that the ANDA is regarded as received.
Act is the Federal Food, Drug, and Cosmetic Act (section 201 et seq.
(21 U.S.C. 301 et seq.)).
Active ingredient is any component that is intended to furnish
pharmacological activity or other direct effect in the diagnosis, cure,
mitigation, treatment, or prevention of disease, or to affect the
structure or any function of the body of man or other animals. The term
includes those components that may undergo chemical change in the
manufacture of the drug product and be present in the drug product in a
modified form intended to furnish the specified activity or effect.
Active moiety is the molecule or ion, excluding those appended
portions of the molecule that cause the drug to be an ester, salt
(including a salt with hydrogen or coordination bonds), or other
noncovalent derivative (such as a complex, chelate, or clathrate) of the
molecule, responsible for the physiological or pharmacological action of
the drug substance.
ANDA holder is the applicant that owns an approved ANDA.
Applicant is any person who submits an NDA (including a 505(b)(2)
application) or ANDA or an amendment or supplement to an NDA or ANDA
under this part to obtain FDA approval of a
[[Page 97]]
new drug and any person who owns an approved NDA (including a 505(b)(2)
application) or ANDA.
Application, new drug application, or NDA is the application
described under Sec. 314.50, including all amendments and supplements
to the application. An NDA refers to ``stand-alone'' applications
submitted under section 505(b)(1) of the Federal Food, Drug, and
Cosmetic Act and to 505(b)(2) applications.
Approval letter is a written communication to an applicant from FDA
approving an NDA or an ANDA.
Assess the effects of the change is to evaluate the effects of a
manufacturing change on the identity, strength, quality, purity, and
potency of a drug product as these factors may relate to the safety or
effectiveness of the drug product.
Authorized generic drug is a listed drug, as defined in this
section, that has been approved under section 505(c) of the Federal
Food, Drug, and Cosmetic Act and is marketed, sold, or distributed
directly or indirectly to the retail class of trade with labeling,
packaging (other than repackaging as the listed drug in blister packs,
unit doses, or similar packaging for use in institutions), product code,
labeler code, trade name, or trademark that differs from that of the
listed drug.
Bioavailability is the rate and extent to which the active
ingredient or active moiety is absorbed from a drug product and becomes
available at the site of drug action. For drug products that are not
intended to be absorbed into the bloodstream, bioavailability may be
assessed by scientifically valid measurements intended to reflect the
rate and extent to which the active ingredient or active moiety becomes
available at the site of drug action.
Bioequivalence is the absence of a significant difference in the
rate and extent to which the active ingredient or active moiety in
pharmaceutical equivalents or pharmaceutical alternatives becomes
available at the site of drug action when administered at the same molar
dose under similar conditions in an appropriately designed study. Where
there is an intentional difference in rate (e.g., in certain extended-
release dosage forms), certain pharmaceutical equivalents or
alternatives may be considered bioequivalent if there is no significant
difference in the extent to which the active ingredient or moiety from
each product becomes available at the site of drug action. This applies
only if the difference in the rate at which the active ingredient or
moiety becomes available at the site of drug action is intentional and
is reflected in the proposed labeling, is not essential to the
attainment of effective body drug concentrations on chronic use, and is
considered medically insignificant for the drug. For drug products that
are not intended to be absorbed into the bloodstream, bioequivalence may
be assessed by scientifically valid measurements intended to reflect the
rate and extent to which the active ingredient or active moiety becomes
available at the site of drug action.
Bioequivalence requirement is a requirement imposed by FDA for in
vitro and/or in vivo testing of specified drug products that must be
satisfied as a condition of marketing.
Class 1 resubmission is the resubmission of an NDA or efficacy
supplement, following receipt of a complete response letter, that
contains one or more of the following: Final printed labeling, draft
labeling, certain safety updates, stability updates to support
provisional or final dating periods, commitments to perform
postmarketing studies (including proposals for such studies), assay
validation data, final release testing on the last lots used to support
approval, minor reanalyses of previously submitted data, and other
comparatively minor information.
Class 2 resubmission is the resubmission of an NDA or efficacy
supplement, following receipt of a complete response letter, that
includes any item not specified in the definition of ``Class 1
resubmission,'' including any item that would require presentation to an
advisory committee.
Commercial marketing is the introduction or delivery for
introduction into interstate commerce of a drug product described in an
ANDA, outside the control of the ANDA applicant, except that the term
does not include transfer of the drug product for investigational use
under part 312 of this chapter or
[[Page 98]]
transfer of the drug product to parties identified in the ANDA for
reasons other than sale. Commercial marketing includes the introduction
or delivery for introduction into interstate commerce of the reference
listed drug by the ANDA applicant.
Complete response letter is a written communication to an applicant
from FDA usually describing all of the deficiencies that the Agency has
identified in an NDA or ANDA that must be satisfactorily addressed
before it can be approved.
Component is any ingredient intended for use in the manufacture of a
drug product, including those that may not appear in such drug product.
Date of approval is the date on the approval letter from FDA stating
that the NDA or ANDA is approved, except that the date of approval for
an NDA described in section 505(x)(1) of the Federal Food, Drug, and
Cosmetic Act is determined as described in section 505(x)(2) of the
Federal Food, Drug, and Cosmetic Act. ``Date of approval'' refers only
to a final approval and not to a tentative approval.
Dosage form is the physical manifestation containing the active and
inactive ingredients that delivers a dose of the drug product. This
includes such factors as:
(1) The physical appearance of the drug product;
(2) The physical form of the drug product prior to dispensing to the
patient;
(3) The way the product is administered; and
(4) The design features that affect frequency of dosing.
Drug product is a finished dosage form, e.g., tablet, capsule, or
solution, that contains a drug substance, generally, but not
necessarily, in association with one or more other ingredients.
Drug substance is an active ingredient that is intended to furnish
pharmacological activity or other direct effect in the diagnosis, cure,
mitigation, treatment, or prevention of disease or to affect the
structure or any function of the human body, but does not include
intermediates used in the synthesis of such ingredient.
Efficacy supplement is a supplement to an approved NDA proposing to
make one or more related changes from among the following changes to
product labeling:
(1) Add or modify an indication or claim;
(2) Revise the dose or dose regimen;
(3) Provide for a new route of administration;
(4) Make a comparative efficacy claim naming another drug product;
(5) Significantly alter the intended patient population;
(6) Change the marketing status from prescription to over-the-
counter use;
(7) Provide for, or provide evidence of effectiveness necessary for,
the traditional approval of a product originally approved under subpart
H of this part; or
(8) Incorporate other information based on at least one adequate and
well-controlled clinical study.
FDA or Agency is the Food and Drug Administration.
First applicant is an ANDA applicant that, on the first day on which
a substantially complete application containing a paragraph IV
certification is submitted for approval of a drug, submits a
substantially complete application that contains, and for which the
applicant lawfully maintains, a paragraph IV certification for the drug.
Inactive ingredient is any component other than an active
ingredient.
Listed drug is a new drug product that has been approved under
section 505(c) of the Federal Food, Drug, and Cosmetic Act for safety
and effectiveness or under section 505(j) of the Federal Food, Drug, and
Cosmetic Act, which has not been withdrawn or suspended under section
505(e)(1) through (5) or section 505(j)(6) of the Federal Food, Drug,
and Cosmetic Act, and which has not been withdrawn from sale for what
FDA has determined are reasons of safety or effectiveness. Listed drug
status is evidenced by the drug product's identification in the current
edition of FDA's ``Approved Drug Products With Therapeutic Equivalence
Evaluations'' (the list) as an approved drug. A drug product is deemed
to be a listed drug on the date of approval for the NDA or ANDA for that
drug product.
[[Page 99]]
NDA holder is the applicant that owns an approved NDA.
Newly acquired information is data, analyses, or other information
not previously submitted to the Agency, which may include (but is not
limited to) data derived from new clinical studies, reports of adverse
events, or new analyses of previously submitted data (e.g., meta-
analyses) if the studies, events, or analyses reveal risks of a
different type or greater severity or frequency than previously included
in submissions to FDA.
Original application or original NDA is a pending NDA for which FDA
has never issued a complete response letter or approval letter, or an
NDA that was submitted again after FDA had refused to file it or after
it was withdrawn without being approved.
Paragraph IV acknowledgment letter is a written, postmarked
communication from FDA to an applicant stating that the Agency has
determined that a 505(b)(2) application or ANDA containing a paragraph
IV certification is sufficiently complete to permit a substantive
review. A paragraph IV acknowledgment letter indicates that the
505(b)(2) application is regarded as filed or the ANDA is regarded as
received.
Paragraph IV certification is a patent certification of invalidity,
unenforceability, or noninfringement described in Sec.
314.50(i)(1)(i)(A)(4) or Sec. 314.94(a)(12)(i)(A)(4).
Patent owner is the owner of the patent for which information is
submitted for an NDA.
Pharmaceutical alternatives are drug products that contain the
identical therapeutic moiety, or its precursor, but not necessarily in
the same amount or dosage form or as the same salt or ester. Each such
drug product individually meets either the identical or its own
respective compendial or other applicable standard of identity,
strength, quality, and purity, including potency and, where applicable,
content uniformity, disintegration times, and/or dissolution rates.
Pharmaceutical equivalents are drug products in identical dosage
forms and route(s) of administration that contain identical amounts of
the identical active drug ingredient, i.e., the same salt or ester of
the same therapeutic moiety, or, in the case of modified-release dosage
forms that require a reservoir or overage or such forms as prefilled
syringes where residual volume may vary, that deliver identical amounts
of the active drug ingredient over the identical dosing period; do not
necessarily contain the same inactive ingredients; and meet the
identical compendial or other applicable standard of identity, strength,
quality, and purity, including potency and, where applicable, content
uniformity, disintegration times, and/or dissolution rates.
Postmark is an independently verifiable evidentiary record of the
date on which a document is transmitted, in an unmodifiable format, to
another party. For postmarks made by the U.S. Postal Service or a
designated delivery service, the date of transmission is the date on
which the document is received by the domestic mail service of the U.S.
Postal Service or by a designated delivery service. For postmarks
documenting an electronic event, the date of transmission is the date
(in a particular time zone) that FDA sends the electronic transmission
on its host system as evidenced by a verifiable record. If the sender
and the intended recipient are located in different time zones, it is
the sender's time zone that provides the controlling date of electronic
transmission.
Reference listed drug is the listed drug identified by FDA as the
drug product upon which an applicant relies in seeking approval of its
ANDA.
Reference standard is the drug product selected by FDA that an
applicant seeking approval of an ANDA must use in conducting an in vivo
bioequivalence study required for approval.
Resubmission, in the context of a complete response letter, is
submission by the applicant of all materials needed to fully address all
deficiencies identified in the complete response letter. An NDA or ANDA
for which FDA issued a complete response letter, but which was withdrawn
before approval and later submitted again, is not a resubmission.
Right of reference or use is the authority to rely upon, and
otherwise use, an investigation for the purpose of obtaining approval of
an NDA, including the
[[Page 100]]
ability to make available the underlying raw data from the investigation
for FDA audit, if necessary.
Same drug product formulation is the formulation of the drug product
submitted for approval and any formulations that have minor differences
in composition or method of manufacture from the formulation submitted
for approval, but are similar enough to be relevant to the Agency's
determination of bioequivalence.
Specification is the quality standard (i.e., tests, analytical
procedures, and acceptance criteria) provided in an approved NDA or ANDA
to confirm the quality of drug substances, drug products, intermediates,
raw materials, reagents, components, in-process materials, container
closure systems, and other materials used in the production of a drug
substance or drug product. For the purpose of this definition,
acceptance criteria means numerical limits, ranges, or other criteria
for the tests described.
Strength is the amount of drug substance contained in, delivered, or
deliverable from a drug product, which includes:
(1)(i) The total quantity of drug substance in mass or units of
activity in a dosage unit or container closure (e.g., weight/unit dose,
weight/volume or weight/weight in a container closure, or units/volume
or units/weight in a container closure); and/or, as applicable.
(ii) The concentration of the drug substance in mass or units of
activity per unit volume or mass (e.g., weight/weight, weight/volume, or
units/volume); or
(2) Such other criteria the Agency establishes for determining the
amount of drug substance contained in, delivered, or deliverable from a
drug product if the weights and measures described in paragraph (i) of
this definition do not apply (e.g., certain drug-device combination
products for which the amount of drug substance is emitted per use or
unit time).
Substantially complete application is an ANDA that on its face is
sufficiently complete to permit a substantive review. Sufficiently
complete means that the ANDA contains all the information required under
section 505(j)(2)(A) of the Federal Food, Drug, and Cosmetic Act and
does not contain a deficiency described in Sec. 314.101(d) and (e).
Tentative approval is notification that an NDA or ANDA otherwise
meets the requirements for approval under the Federal Food, Drug, and
Cosmetic Act, but cannot be approved because there is a 7-year period of
orphan exclusivity for a listed drug under section 527 of the Federal
Food, Drug, and Cosmetic Act and Sec. 316.31 of this chapter, or that a
505(b)(2) application or ANDA otherwise meets the requirements for
approval under the Federal Food, Drug, and Cosmetic Act, but cannot be
approved until the conditions in Sec. 314.107(b)(1)(iii), (b)(3), or
(c) are met; because there is a period of exclusivity for the listed
drug under Sec. 314.108; because there is a period of pediatric
exclusivity for the listed drug under section 505A of the Federal Food,
Drug, and Cosmetic Act; because there is a period of exclusivity for the
listed drug under section 505E of the Federal Food, Drug, and Cosmetic
Act; or because a court order pursuant to 35 U.S.C. 271(e)(4)(A) orders
that the NDA or ANDA may be approved no earlier than the date specified.
A drug product that is granted tentative approval is not an approved
drug and will not be approved until FDA issues an approval letter after
any necessary additional review of the NDA or ANDA.
The list is the list of approved drug products published in FDA's
current ``Approved Drug Products With Therapeutic Equivalence
Evaluations,'' available electronically on FDA's Web site at http://
www.fda.gov/cder.
Therapeutic equivalents are approved drug products that are
pharmaceutical equivalents for which bioequivalence has been
demonstrated, and that can be expected to have the same clinical effect
and safety profile when administered to patients under the conditions
specified in the labeling.
[81 FR 69636, Oct. 6, 2016]
Subpart B_Applications
Sec. 314.50 Content and format of an NDA.
NDAs and supplements to approved NDAs are required to be submitted
in the form and contain the information,
[[Page 101]]
as appropriate for the particular submission, required under this
section. Three copies of the NDA are required: An archival copy, a
review copy, and a field copy. An NDA for a new chemical entity will
generally contain an application form, an index, a summary, five or six
technical sections, case report tabulations of patient data, case report
forms, drug samples, and labeling, including, if applicable, any
Medication Guide required under part 208 of this chapter. Other NDAs
will generally contain only some of those items, and information will be
limited to that needed to support the particular submission. These
include an NDA of the type described in section 505(b)(2) of the Federal
Food, Drug, and Cosmetic Act, an amendment, and a supplement. The NDA is
required to contain reports of all investigations of the drug product
sponsored by the applicant, and all other information about the drug
pertinent to an evaluation of the NDA that is received or otherwise
obtained by the applicant from any source. FDA will maintain guidance
documents on the format and content of NDAs to assist applicants in
their preparation.
(a) Application form. The applicant must submit a completed and
signed application form that contains the following:
(1) The name and address of the applicant; the date of the NDA; the
NDA number if previously issued (for example, if the NDA is a
resubmission or an amendment or supplement); the name of the drug
product, including its established, proprietary, code, and chemical
names; the dosage form and strength; the route of administration; the
identification numbers of all INDs (as defined in Sec. 312.3(b) of this
chapter) that are referenced in the NDA; the identification numbers of
all drug master files and other applications under this part that are
referenced in the NDA; and the drug product's proposed indications for
use.
(2) A statement whether the submission is an original submission, a
505(b)(2) application, a resubmission, or a supplement to an application
under Sec. 314.70.
(3) A statement whether the applicant proposes to market the drug
product as a prescription or an over-the-counter product.
(4) A check-list identifying what enclosures required under this
section the applicant is submitting.
(5) The applicant, or the applicant's attorney, agent, or other
authorized official must sign the NDA. If the person signing the NDA
does not reside or have a place of business within the United States,
the NDA is required to contain the name and address of, and be
countersigned by, an attorney, agent, or other authorized official who
resides or maintains a place of business within the United States.
(b) Index. The archival copy of the NDA is required to contain a
comprehensive index by volume number and page number to the summary
under paragraph (c) of this section, the technical sections under
paragraph (d) of this section, and the supporting information under
paragraph (f) of this section.
(c) Summary. (1) An NDA is required to contain a summary of the NDA
in enough detail that the reader may gain a good general understanding
of the data and information in the NDA, including an understanding of
the quantitative aspects of the data. The summary is not required for
supplements under Sec. 314.70. Resubmissions of an NDA should contain
an updated summary, as appropriate. The summary should discuss all
aspects of the NDA, and synthesize the information into a well-
structured and unified document. The summary should be written at
approximately the level of detail required for publication in, and meet
the editorial standards generally applied by, refereed scientific and
medical journals. In addition to the agency personnel reviewing the
summary in the context of their review of the NDA, FDA may furnish the
summary to FDA advisory committee members and agency officials whose
duties require an understanding of the NDA. To the extent possible, data
in the summary should be presented in tabular and graphic forms. FDA has
prepared a guideline under Sec. 10.90(b) that provides information
about how to prepare a summary. The summary required under this
paragraph may be used by FDA or the applicant to prepare the Summary
Basis
[[Page 102]]
of Approval document for public disclosure (under Sec.
314.430(e)(2)(ii)) when the NDA is approved.
(2) The summary is required to contain the following information:
(i) The proposed text of the labeling, including, if applicable, any
Medication Guide required under part 208 of this chapter, for the drug,
with annotations to the information in the summary and technical
sections of the NDA that support the inclusion of each statement in the
labeling, and, if the NDA is for a prescription drug, statements
describing the reasons for omitting a section or subsection of the
labeling format in Sec. 201.57 of this chapter.
(ii) A statement identifying the pharmacologic class of the drug and
a discussion of the scientific rationale for the drug, its intended use,
and the potential clinical benefits of the drug product.
(iii) A brief description of the marketing history, if any, of the
drug outside the United States, including a list of the countries in
which the drug has been marketed, a list of any countries in which the
drug has been withdrawn from marketing for any reason related to safety
or effectiveness, and a list of countries in which applications for
marketing are pending. The description is required to describe both
marketing by the applicant and, if known, the marketing history of other
persons.
(iv) A summary of the chemistry, manufacturing, and controls section
of the NDA.
(v) A summary of the nonclinical pharmacology and toxicology section
of the NDA.
(vi) A summary of the human pharmacokinetics and bioavailability
section of the NDA.
(vii) A summary of the microbiology section of the NDA (for anti-
infective drugs only).
(viii) A summary of the clinical data section of the NDA, including
the results of statistical analyses of the clinical trials.
(ix) A concluding discussion that presents the benefit and risk
considerations related to the drug, including a discussion of any
proposed additional studies or surveillance the applicant intends to
conduct postmarketing.
(d) Technical sections. The NDA is required to contain the technical
sections described below. Each technical section is required to contain
data and information in sufficient detail to permit the agency to make a
knowledgeable judgment about whether to approve the NDA or whether
grounds exist under section 505(d) of the Federal Food, Drug, and
Cosmetic Act to refuse to approve the NDA. The required technical
sections are as follows:
(1) Chemistry, manufacturing, and controls section. A section
describing the composition, manufacture, and specification of the drug
substance and the drug product, including the following:
(i) Drug substance. A full description of the drug substance
including its physical and chemical characteristics and stability; the
name and address of its manufacturer; the method of synthesis (or
isolation) and purification of the drug substance; the process controls
used during manufacture and packaging; and the specifications necessary
to ensure the identity, strength, quality, and purity of the drug
substance and the bioavailability of the drug products made from the
substance, including, for example, tests, analytical procedures, and
acceptance criteria relating to stability, sterility, particle size, and
crystalline form. The NDA may provide additionally for the use of
alternatives to meet any of these requirements, including alternative
sources, process controls, and analytical procedures. Reference to the
current edition of the U.S. Pharmacopeia and the National Formulary may
satisfy relevant requirements in this paragraph.
(ii)((a)) Drug product. A list of all components used in the
manufacture of the drug product (regardless of whether they appear in
the drug product) and a statement of the composition of the drug
product; the specifications for each component; the name and address of
each manufacturer of the drug product; a description of the
manufacturing and packaging procedures and in-process controls for the
drug product; the specifications necessary to ensure the identity,
strength, quality, purity, potency, and bioavailability of the drug
product, including, for example, tests,
[[Page 103]]
analytical procedures, and acceptance criteria relating to sterility,
dissolution rate, container closure systems; and stability data with
proposed expiration dating. The NDA may provide additionally for the use
of alternatives to meet any of these requirements, including alternative
components, manufacturing and packaging procedures, in-process controls,
and analytical procedures. Reference to the current edition of the U.S.
Pharmacopeia and the National Formulary may satisfy relevant
requirements in this paragraph.
(b) Unless provided by paragraph (d)(1)(ii)(a) of this section, for
each batch of the drug product used to conduct a bioavailability or
bioequivalence study described in Sec. 320.38 or Sec. 320.63 of this
chapter or used to conduct a primary stability study: The batch
production record; the specification for each component and for the drug
product; the names and addresses of the sources of the active and
noncompendial inactive components and of the container and closure
system for the drug product; the name and address of each contract
facility involved in the manufacture, processing, packaging, or testing
of the drug product and identification of the operation performed by
each contract facility; and the results of any test performed on the
components used in the manufacture of the drug product as required by
Sec. 211.84(d) of this chapter and on the drug product as required by
Sec. 211.165 of this chapter.
(c) The proposed or actual master production record, including a
description of the equipment, to be used for the manufacture of a
commercial lot of the drug product or a comparably detailed description
of the production process for a representative batch of the drug
product.
(iii) Environmental impact. The NDA is required to contain either a
claim for categorical exclusion under Sec. 25.30 or 25.31 of this
chapter or an environmental assessment under Sec. 25.40 of this
chapter.
(iv) The applicant may, at its option, submit a complete chemistry,
manufacturing, and controls section 90 to 120 days before the
anticipated submission of the remainder of the NDA. FDA will review such
early submissions as resources permit.
(v) The applicant must include a statement certifying that the field
copy of the NDA has been provided to the applicant's home FDA district
office.
(2) Nonclinical pharmacology and toxicology section. A section
describing, with the aid of graphs and tables, animal and in vitro
studies with drug, including the following:
(i) Studies of the pharmacological actions of the drug in relation
to its proposed therapeutic indication and studies that otherwise define
the pharmacologic properties of the drug or are pertinent to possible
adverse effects.
(ii) Studies of the toxicological effects of the drug as they relate
to the drug's intended clinical uses, including, as appropriate, studies
assessing the drug's acute, subacute, and chronic toxicity;
carcinogenicity; and studies of toxicities related to the drug's
particular mode of administration or conditions of use.
(iii) Studies, as appropriate, of the effects of the drug on
reproduction and on the developing fetus.
(iv) Any studies of the absorption, distribution, metabolism, and
excretion of the drug in animals.
(v) For each nonclinical laboratory study subject to the good
laboratory practice regulations under part 58 a statement that it was
conducted in compliance with the good laboratory practice regulations in
part 58, or, if the study was not conducted in compliance with those
regulations, a brief statement of the reason for the noncompliance.
(3) Human pharmacokinetics and bioavailability section. A section
describing the human pharmacokinetic data and human bioavailability
data, or information supporting a waiver of the submission of in vivo
bioavailability data under subpart B of part 320, including the
following:
(i) A description of each of the bioavailability and pharmacokinetic
studies of the drug in humans performed by or on behalf of the applicant
that includes a description of the analytical procedures and statistical
methods used in each study and a statement
[[Page 104]]
with respect to each study that it either was conducted in compliance
with the institutional review board regulations in part 56, or was not
subject to the regulations under Sec. 56.104 or Sec. 56.105, and that
it was conducted in compliance with the informed consent regulations in
part 50.
(ii) If the NDA describes in the chemistry, manufacturing, and
controls section tests, analytical procedures, and acceptance criteria
needed to assure the bioavailability of the drug product or drug
substance, or both, a statement in this section of the rationale for
establishing the tests, analytical procedures, and acceptance criteria,
including data and information supporting the rationale.
(iii) A summarizing discussion and analysis of the pharmacokinetics
and metabolism of the active ingredients and the bioavailability or
bioequivalence, or both, of the drug product.
(4) Microbiology section. If the drug is an anti-infective drug, a
section describing the microbiology data, including the following:
(i) A description of the biochemical basis of the drug's action on
microbial physiology.
(ii) A description of the antimicrobial spectra of the drug,
including results of in vitro preclinical studies to demonstrate
concentrations of the drug required for effective use.
(iii) A description of any known mechanisms of resistance to the
drug, including results of any known epidemiologic studies to
demonstrate prevalence of resistance factors.
(iv) A description of clinical microbiology laboratory procedures
(for example, in vitro sensitivity discs) needed for effective use of
the drug.
(5) Clinical data section. A section describing the clinical
investigations of the drug, including the following:
(i) A description and analysis of each clinical pharmacology study
of the drug, including a brief comparison of the results of the human
studies with the animal pharmacology and toxicology data.
(ii) A description and analysis of each controlled clinical study
pertinent to a proposed use of the drug, including the protocol and a
description of the statistical analyses used to evaluate the study. If
the study report is an interim analysis, this is to be noted and a
projected completion date provided. Controlled clinical studies that
have not been analyzed in detail for any reason (e.g., because they have
been discontinued or are incomplete) are to be included in this section,
including a copy of the protocol and a brief description of the results
and status of the study.
(iii) A description of each uncontrolled clinical study, a summary
of the results, and a brief statement explaining why the study is
classified as uncontrolled.
(iv) A description and analysis of any other data or information
relevant to an evaluation of the safety and effectiveness of the drug
product obtained or otherwise received by the applicant from any source,
foreign or domestic, including information derived from clinical
investigations, including controlled and uncontrolled studies of uses of
the drug other than those proposed in the NDA, commercial marketing
experience, reports in the scientific literature, and unpublished
scientific papers.
(v) An integrated summary of the data demonstrating substantial
evidence of effectiveness for the claimed indications. Evidence is also
required to support the dosage and administration section of the
labeling, including support for the dosage and dose interval
recommended. The effectiveness data must be presented by gender, age,
and racial subgroups and must identify any modifications of dose or dose
interval needed for specific subgroups. Effectiveness data from other
subgroups of the population of patients treated, when appropriate, such
as patients with renal failure or patients with different levels of
severity of the disease, also must be presented.
(vi) A summary and updates of safety information, as follows:
(a) The applicant must submit an integrated summary of all available
information about the safety of the drug product, including pertinent
animal data, demonstrated or potential adverse effects of the drug,
clinically significant drug/drug interactions, and other safety
considerations, such as data from epidemiological studies of related
drugs. The safety data must be
[[Page 105]]
presented by gender, age, and racial subgroups. When appropriate, safety
data from other subgroups of the population of patients treated also
must be presented, such as for patients with renal failure or patients
with different levels of severity of the disease. A description of any
statistical analyses performed in analyzing safety data should also be
included, unless already included under paragraph (d)(5)(ii) of this
section.
(b) The applicant must, under section 505(i) of the Federal Food,
Drug, and Cosmetic Act, update periodically its pending NDA with new
safety information learned about the drug that may reasonably affect the
statement of contraindications, warnings, precautions, and adverse
reactions in the draft labeling and, if applicable, any Medication Guide
required under part 208 of this chapter. These ``safety update reports''
must include the same kinds of information (from clinical studies,
animal studies, and other sources) and must be submitted in the same
format as the integrated summary in paragraph (d)(5)(vi)(a) of this
section. In addition, the reports must include the case report forms for
each patient who died during a clinical study or who did not complete
the study because of an adverse event (unless this requirement is
waived). The applicant must submit these reports (1) 4 months after the
initial submission; (2) in a resubmission following receipt of a
complete response letter; and (3) at other times as requested by FDA.
Before submitting the first such report, applicants are encouraged to
consult with FDA regarding further details on its form and content.
(vii) If the drug has a potential for abuse, a description and
analysis of studies or information related to abuse of the drug,
including a proposal for scheduling under the Controlled Substances Act.
A description of any studies related to overdosage is also required,
including information on dialysis, antidotes, or other treatments, if
known.
(viii) An integrated summary of the benefits and risks of the drug,
including a discussion of why the benefits exceed the risks under the
conditions stated in the labeling.
(ix) A statement with respect to each clinical study involving human
subjects that it either was conducted in compliance with the
institutional review board regulations in part 56, or was not subject to
the regulations under Sec. 56.104 or Sec. 56.105, and that it was
conducted in compliance with the informed consent regulations in part
50.
(x) If a sponsor has transferred any obligations for the conduct of
any clinical study to a contract research organization, a statement
containing the name and address of the contract research organization,
identification of the clinical study, and a listing of the obligations
transferred. If all obligations governing the conduct of the study have
been transferred, a general statement of this transfer--in lieu of a
listing of the specific obligations transferred--may be submitted.
(xi) If original subject records were audited or reviewed by the
sponsor in the course of monitoring any clinical study to verify the
accuracy of the case reports submitted to the sponsor, a list
identifying each clinical study so audited or reviewed.
(6) Statistical section. A section describing the statistical
evaluation of clinical data, including the following:
(i) A copy of the information submitted under paragraph (d)(5)(ii)
of this section concerning the description and analysis of each
controlled clinical study, and the documentation and supporting
statistical analyses used in evaluating the controlled clinical studies.
(ii) A copy of the information submitted under paragraph
(d)(5)(vi)(a) of this section concerning a summary of information about
the safety of the drug product, and the documentation and supporting
statistical analyses used in evaluating the safety information.
(7) Pediatric use section. A section describing the investigation of
the drug for use in pediatric populations, including an integrated
summary of the information (the clinical pharmacology studies,
controlled clinical studies, or uncontrolled clinical studies, or other
data or information) that is relevant to the safety and effectiveness
and benefits and risks of the drug in pediatric
[[Page 106]]
populations for the claimed indications, a reference to the full
descriptions of such studies provided under paragraphs (d)(3) and (d)(5)
of this section, and information required to be submitted under Sec.
314.55.
(e) Samples and labeling. (1) Upon request from FDA, the applicant
must submit the samples described below to the places identified in the
Agency's request. FDA generally will ask applicants to submit samples
directly to two or more Agency laboratories that will perform all
necessary tests on the samples and validate the applicant's analytical
procedures.
(i) Four representative samples of the following, each sample in
sufficient quantity to permit FDA to perform three times each test
described in the NDA to determine whether the drug substance and the
drug product meet the specifications given in the NDA:
(a) The drug product proposed for marketing;
(b) The drug substance used in the drug product from which the
samples of the drug product were taken; and
(c) Reference standards and blanks (except that reference standards
recognized in an official compendium need not be submitted).
(ii) Samples of the finished market package, if requested by FDA.
(2) The applicant must submit the following in the archival copy of
the NDA:
(i) Three copies of the analytical procedures and related
descriptive information contained in the chemistry, manufacturing, and
controls section under paragraph (d)(1) of this section for the drug
substance and the drug product that are necessary for FDA's laboratories
to perform all necessary tests on the samples and to validate the
applicant's analytical procedures. The related descriptive information
includes a description of each sample; the proposed regulatory
specifications for the drug; a detailed description of the methods of
analysis; supporting data for accuracy, specificity, precision and
ruggedness; and complete results of the applicant's tests on each
sample.
(ii) Copies of the label and all labeling for the drug product
(including, if applicable, any Medication Guide required under part 208
of this chapter) for the drug product (4 copies of draft labeling or 12
copies of final printed labeling).
(f) Case report forms and tabulations. The archival copy of the NDA
is required to contain the following case report tabulations and case
report forms:
(1) Case report tabulations. The NDA is required to contain
tabulations of the data from each adequate and well-controlled study
under Sec. 314.126 (Phase 2 and Phase 3 studies as described in
Sec. Sec. 312.21 (b) and (c) of this chapter), tabulations of the data
from the earliest clinical pharmacology studies (Phase 1 studies as
described in Sec. 312.21(a) of this chapter), and tabulations of the
safety data from other clinical studies. Routine submission of other
patient data from uncontrolled studies is not required. The tabulations
are required to include the data on each patient in each study, except
that the applicant may delete those tabulations which the agency agrees,
in advance, are not pertinent to a review of the drug's safety or
effectiveness. Upon request, FDA will discuss with the applicant in a
``pre-NDA'' conference those tabulations that may be appropriate for
such deletion. Barring unforeseen circumstances, tabulations agreed to
be deleted at such a conference will not be requested during the conduct
of FDA's review of the NDA. If such unforeseen circumstances do occur,
any request for deleted tabulations will be made by the director of the
FDA division responsible for reviewing the NDA, in accordance with
paragraph (f)(3) of this section.
(2) Case report forms. The NDA is required to contain copies of
individual case report forms for each patient who died during a clinical
study or who did not complete the study because of an adverse event,
whether believed to be drug related or not, including patients receiving
reference drugs or placebo. This requirement may be waived by FDA for
specific studies if the case report forms are unnecessary for a proper
review of the study.
(3) Additional data. The applicant must submit to FDA additional
case report forms and tabulations needed to conduct a proper review of
the NDA, as requested by the director of the FDA division responsible
for reviewing the
[[Page 107]]
NDA. The applicant's failure to submit information requested by FDA
within 30 days after receipt of the request may result in the agency
viewing any eventual submission as a major amendment under Sec. 314.60
and extending the review period as necessary. If desired by the
applicant, the FDA division director will verify in writing any request
for additional data that was made orally.
(4) Presentation and format. Applicants are invited to meet with FDA
before submitting an NDA to discuss the presentation and format of
supporting information. If the applicant and FDA agree, the applicant
may submit tabulations of patient data and case report forms in an
alternate form.
(g) Other. The following general requirements apply to the
submission of information within the summary under paragraph (c) of this
section and within the technical sections under paragraph (d) of this
section.
(1) The applicant ordinarily is not required to resubmit information
previously submitted, but may incorporate the information by reference.
A reference to information submitted previously is required to identify
the file by name, reference number, volume, and page number in the
agency's records where the information can be found. A reference to
information submitted to the agency by a person other than the applicant
is required to contain a written statement that authorizes the reference
and that is signed by the person who submitted the information.
(2) The applicant must submit an accurate and complete English
translation of each part of the NDA that is not in English. The
applicant must submit a copy of each original literature publication for
which an English translation is submitted.
(3) If an applicant who submits an NDA under section 505(b) of the
Federal Food, Drug, and Cosmetic Act obtains a ``right of reference or
use,'' as defined under Sec. 314.3(b), to an investigation described in
clause (A) of section 505(b)(1) of the Federal Food, Drug, and Cosmetic
Act, the applicant must include in its NDA a written statement signed by
the owner of the data from each such investigation that the applicant
may rely on in support of the approval of its NDA, and provide FDA
access to, the underlying raw data that provide the basis for the report
of the investigation submitted in its NDA.
(h) Patent information. The NDA is required to contain the patent
information described under Sec. 314.53.
(i) Patent certification--(1) Contents. A 505(b)(2) application is
required to contain the following:
(i) Patents claiming drug substance, drug product, or method of use.
(A) An appropriate patent certification or statement with respect to
each patent issued by the U.S. Patent and Trademark Office that, in the
opinion of the applicant and to the best of its knowledge, claims the
drug substance or drug product on which investigations that are relied
upon by the applicant for approval of its 505(b)(2) application were
conducted or that claims an approved use for such drug and for which
information is required to be filed under section 505(b) and (c) of the
Federal Food, Drug, and Cosmetic Act and Sec. 314.53. For each such
patent, the applicant must provide the patent number and certify, in its
opinion and to the best of its knowledge, one of the following
circumstances:
(1) That the patent information has not been submitted to FDA. The
applicant must entitle such a certification ``Paragraph I
Certification'';
(2) That the patent has expired. The applicant must entitle such a
certification ``Paragraph II Certification'';
(3) The date on which the patent will expire. The applicant must
entitle such a certification ``Paragraph III Certification''; or
(4)(i) That the patent is invalid, unenforceable, or will not be
infringed by the manufacture, use, or sale of the drug product for which
the 505(b)(2) application is submitted. The applicant must entitle such
a certification ``Paragraph IV Certification''. This certification must
be submitted in the following form:
I, (name of applicant), certify that Patent No. ____ (is invalid,
unenforceable, or will not be infringed by the manufacture, use, or sale
of) (name of proposed drug product) for which this 505(b)(2) application
is submitted.
[[Page 108]]
(ii) The certification must be accompanied by a statement that the
applicant will comply with the requirements under Sec. 314.52(a) with
respect to providing a notice to each owner of the patent or its
representative and to the NDA holder (or, if the NDA holder does not
reside or maintain a place of business within the United States, its
attorney, agent, or other authorized official) for the drug product that
is claimed by the patent or a use of which is claimed by the patent and
with the requirements under Sec. 314.52(b) with respect to sending the
notice and under Sec. 314.52(c) with respect to the content of the
notice.
(B) If the drug on which investigations that are relied upon by the
applicant were conducted is itself a licensed generic drug of a patented
drug first approved under section 505(b) of the Federal Food, Drug, and
Cosmetic Act, an appropriate patent certification or statement under
this section with respect to each patent that claims the first-approved
patented drug or that claims an approved use for such a drug.
(C) If, before the date of submission of an original 505(b)(2)
application, there is a drug product approved in an NDA that is
pharmaceutically equivalent to the drug product for which the original
505(b)(2) application is submitted, an appropriate patent certification
or statement under this section with respect to each patent that claims
the drug substance or drug product or that claims an approved use for
one such drug product.
(ii) No relevant patents. If, in the opinion of the applicant and to
the best of its knowledge, there are no patents described in paragraph
(i)(1)(i) of this section, a certification in the following form:
In the opinion and to the best knowledge of (name of applicant),
there are no patents that claim the drug or drugs on which
investigations that are relied upon in this 505(b)(2) application were
conducted or that claim a use of such drug or drugs.
(iii) Method-of-use patent. (A) If information that is submitted
under section 505(b) or (c) of the Federal Food, Drug, and Cosmetic Act
and Sec. 314.53 is for a method-of-use patent, and the labeling for the
drug product for which the applicant is seeking approval does not
include an indication or other condition of use that is covered by the
method-of-use patent, a statement explaining that the method-of-use
patent does not claim a proposed indication or other condition of use.
(B) If the labeling of the drug product for which the applicant is
seeking approval includes an indication or other condition of use that,
according to the patent information submitted under section 505(b) or
(c) of the Federal Food, Drug, and Cosmetic Act and Sec. 314.53 or in
the opinion of the applicant, is claimed by a method-of-use patent, the
applicant must submit an applicable certification under paragraph
(i)(1)(i) of this section.
(2) [Reserved]
(3) Licensing agreements. If a 505(b)(2) application is submitted
for a drug or method of using a drug claimed by a patent and the
applicant has a licensing agreement with the patent owner, the applicant
must submit a paragraph IV certification as to that patent and a
statement that the applicant has been granted a patent license. If the
patent owner consents to approval of the 505(b)(2) application (if
otherwise eligible for approval) as of a specific date, the 505(b)(2)
application must contain a written statement from the patent owner that
it has a licensing agreement with the applicant and that it consents to
approval of the 505(b)(2) application as of a specific date.
(4) Untimely filing of patent information. (i) If a patent described
in paragraph (i)(1)(i)(A) of this section is issued and the holder of
the approved NDA for the patented drug does not file with FDA the
required information on the patent within 30 days of issuance of the
patent, an applicant who submitted a 505(b)(2) application that, before
the submission of the patent information, contained an appropriate
patent certification or statement is not required to submit a patent
certification or statement to address the patent or patent information
that is late-listed with respect to the pending 505(b)(2) application.
Except as provided in Sec. 314.53(f)(1), an NDA holder's amendment to
the description of the approved method(s) of use claimed by the patent
will be considered untimely filing of patent information unless:
[[Page 109]]
(A) The amendment to the description of the approved method(s) of
use claimed by the patent is submitted within 30 days of patent
issuance;
(B) The amendment to the description of the approved method(s) of
use claimed by the patent is submitted within 30 days of approval of a
corresponding change to product labeling; or
(C) The amendment to the description of the approved method(s) of
use claimed by the patent is submitted within 30 days of a decision by
the U.S. Patent and Trademark Office or by a Federal district court, the
Court of Appeals for the Federal Circuit, or the U.S. Supreme Court that
is specific to the patent and alters the construction of a method-of-use
claim(s) of the patent, and the amendment contains a copy of the
decision.
(ii) An applicant whose 505(b)(2) application is submitted after the
NDA holder's untimely filing of patent information or whose 505(b)(2)
application was previously filed but did not contain an appropriate
patent certification or statement at the time of the patent submission
must submit a certification under paragraph (i)(1)(i) of this section
and/or a statement under paragraph (i)(1)(iii) of this section as to
that patent.
(5) Disputed patent information. If an applicant disputes the
accuracy or relevance of patent information submitted to FDA, the
applicant may seek a confirmation of the correctness of the patent
information in accordance with the procedures under Sec. 314.53(f).
Unless the patent information is withdrawn, the applicant must submit an
appropriate certification or statement for each listed patent.
(6) Amended certifications. A patent certification or statement
submitted under paragraphs (i)(1)(i) through (iii) of this section may
be amended at any time before the approval of the 505(b)(2) application.
An applicant must submit an amended certification as an amendment to a
pending 505(b)(2) application. If an applicant with a pending 505(b)(2)
application voluntarily makes a patent certification for an untimely
filed patent, the applicant may withdraw the patent certification for
the untimely filed patent. Once an amendment is submitted to change the
certification, the 505(b)(2) application will no longer be considered to
contain the prior certification.
(i) After finding of infringement. An applicant who has submitted a
paragraph IV certification and is sued for patent infringement must
submit an amendment to change its certification if a court enters a
final decision from which no appeal has been or can be taken, or signs
and enters a settlement order or consent decree in the action that
includes a finding that the patent is infringed, unless the final
decision, settlement order, or consent decree also finds the patent to
be invalid. In its amendment, the applicant must certify under paragraph
(i)(1)(i)(A)(3) of this section that the patent will expire on a
specific date or, with respect to a patent claiming a method of use, the
applicant may instead provide a statement under paragraph (i)(1)(iii) of
this section if the applicant amends its 505(b)(2) application such that
the applicant is no longer seeking approval for a method of use claimed
by the patent. Once an amendment for the change has been submitted, the
505(b)(2) application will no longer be considered to contain a
paragraph IV certification to the patent. If a final decision finds the
patent to be invalid and infringed, an amended certification is not
required.
(ii) After request to remove a patent or patent information from the
list. If the list reflects that an NDA holder has requested that a
patent or patent information be removed from the list and no ANDA
applicant is eligible for 180-day exclusivity based on a paragraph IV
certification to that patent, the patent or patent information will be
removed and any applicant with a pending 505(b)(2) application
(including a tentatively approved 505(b)(2) application) who has made a
certification with respect to such patent must submit an amendment to
withdraw its certification. In the amendment, the applicant must state
the reason for withdrawing the certification or statement (that the
patent has been removed from the list). If the list reflects that an NDA
holder has requested that a patent or patent information be removed from
the list and one or more
[[Page 110]]
first applicants are eligible for 180-day exclusivity based on a
paragraph IV certification to that patent, the patent will remain listed
until any 180-day exclusivity based on that patent has expired or has
been extinguished. A 505(b)(2) applicant is not required to provide or
maintain a certification to a patent or patent information that remains
listed only for purposes of a first applicant's 180-day exclusivity for
its ANDA. Once an amendment to withdraw the certification has been
submitted, the 505(b)(2) application will no longer be considered to
contain a paragraph IV certification to the patent. If removal of a
patent from the list results in there being no patents listed for the
listed drug(s) identified in the 505(b)(2) application, the applicant
must submit an amended certification reflecting that there are no listed
patents.
(iii) Other amendments. (A) Except as provided in paragraphs (i)(4)
and (i)(6)(iii)(B) of this section:
(1) An applicant must amend a submitted certification or statement
if, at any time before the approval of the 505(b)(2) application, the
applicant learns that the submitted certification or statement is no
longer accurate; and
(2) An applicant must submit an appropriate patent certification or
statement under paragraph (i)(1) of this section if, after submission of
the 505(b)(2) application, a new patent is issued by the U.S. Patent and
Trademark Office that, in the opinion of the applicant and to the best
of its knowledge, claims a listed drug relied upon or that claims an
approved use for such listed drug for which information is required to
be filed under section 505(b) and (c) of the Federal Food, Drug, and
Cosmetic Act and Sec. 314.53.
(B) An applicant is not required to submit a supplement to change a
submitted certification when information on an otherwise applicable
patent is submitted after the approval of the 505(b)(2) application.
(j) Claimed exclusivity. A new drug product, upon approval, may be
entitled to a period of marketing exclusivity under the provisions of
Sec. 314.108. If an applicant believes its drug product is entitled to
a period of exclusivity, it must submit with the NDA prior to approval
the following information:
(1) A statement that the applicant is claiming exclusivity.
(2) A reference to the appropriate paragraph under Sec. 314.108
that supports its claim.
(3) If the applicant claims exclusivity under Sec. 314.108(b)(2),
information to show that, to the best of its knowledge or belief, a drug
has not previously been approved under section 505(b) of the Federal
Food, Drug, and Cosmetic Act containing any active moiety in the drug
for which the applicant is seeking approval.
(4) If the applicant claims exclusivity under Sec. 314.108(b)(4) or
(b)(5), the following information to show that the NDA contains ``new
clinical investigations'' that are ``essential to approval of the NDA or
supplement'' and were ``conducted or sponsored by the applicant:''
(i) ``New clinical investigations.'' A certification that to the
best of the applicant's knowledge each of the clinical investigations
included in the NDA meets the definition of ``new clinical
investigation'' set forth in Sec. 314.108(a).
(ii) ``Essential to approval.'' A list of all published studies or
publicly available reports of clinical investigations known to the
applicant through a literature search that are relevant to the
conditions for which the applicant is seeking approval, a certification
that the applicant has thoroughly searched the scientific literature
and, to the best of the applicant's knowledge, the list is complete and
accurate and, in the applicant's opinion, such published studies or
publicly available reports do not provide a sufficient basis for the
approval of the conditions for which the applicant is seeking approval
without reference to the new clinical investigation(s) in the NDA, and
an explanation as to why the studies or reports are insufficient.
(iii) ``Conducted or sponsored by.'' If the applicant was the
sponsor named in the Form FDA 1571 for an IND under which the new
clinical investigation(s) that is essential to the approval of its NDA
was conducted, identification of the IND by number. If the applicant was
not the sponsor of the IND under which the clinical investigation(s) was
[[Page 111]]
conducted, a certification that the applicant or its predecessor in
interest provided substantial support for the clinical investigation(s)
that is essential to the approval of its NDA, and information supporting
the certification. To demonstrate ``substantial support,'' an applicant
must either provide a certified statement from a certified public
accountant that the applicant provided 50 percent or more of the cost of
conducting the study or provide an explanation of why FDA should
consider the applicant to have conducted or sponsored the study if the
applicant's financial contribution to the study is less than 50 percent
or the applicant did not sponsor the investigational new drug. A
predecessor in interest is an entity, e.g., a corporation, that the
applicant has taken over, merged with, or purchased, or from which the
applicant has purchased all rights to the drug. Purchase of nonexclusive
rights to a clinical investigation after it is completed is not
sufficient to satisfy this definition.
(k) Financial certification or disclosure statement. The NDA must
contain a financial certification or disclosure statement or both as
required by part 54 of this chapter.
(l) Format of an original NDA--(1) Archival copy. The applicant must
submit a complete archival copy of the NDA that contains the information
required under paragraphs (a) through (f) of this section. FDA will
maintain the archival copy during the review of the NDA to permit
individual reviewers to refer to information that is not contained in
their particular technical sections of the NDA, to give other agency
personnel access to the NDA for official business, and to maintain in
one place a complete copy of the NDA. Except as required by paragraph
(l)(1)(i) of this section, applicants may submit the archival copy on
paper or in electronic format provided that electronic submissions are
made in accordance with part 11 of this chapter.
(i) Labeling. The content of labeling required under Sec.
201.100(d)(3) of this chapter (commonly referred to as the package
insert or professional labeling), including all text, tables, and
figures, must be submitted to the agency in electronic format as
described in paragraph (l)(5) of this section. This requirement is in
addition to the requirements of paragraph (e)(2)(ii) of this section
that copies of the formatted label and all labeling be submitted.
Submissions under this paragraph must be made in accordance with part 11
of this chapter, except for the requirements of Sec. 11.10(a), (c)
through (h), and (k), and the corresponding requirements of Sec. 11.30.
(ii) [Reserved]
(2) Review copy. The applicant must submit a review copy of the NDA.
Each of the technical sections, described in paragraphs (d)(1) through
(6) of this section, in the review copy is required to be separately
bound with a copy of the application form required under paragraph (a)
of this section and a copy of the summary required under paragraph (c)
of this section.
(3) Field copy. The applicant must submit a field copy of the NDA
that contains the technical section described in paragraph (d)(1) of
this section, a copy of the application form required under paragraph
(a) of this section, a copy of the summary required under paragraph (c)
of this section, and a certification that the field copy is a true copy
of the technical section described in paragraph (d)(1) of this section
contained in the archival and review copies of the NDA.
(4) Binding folders. The applicant may obtain from FDA sufficient
folders to bind the archival, the review, and the field copies of the
NDA.
(5) Electronic format submissions. Electronic format submissions
must be in a form that FDA can process, review, and archive. FDA will
periodically issue guidance on how to provide the electronic submission
(e.g., method of transmission, media, file formats, preparation and
organization of files).
[50 FR 7493, Feb. 22, 1985]
Editorial Note: For Federal Register citations affecting Sec.
314.50, see the List of CFR Sections Affected, which appears in the
Finding Aids section of the printed volume and at www.govinfo.gov.
Sec. 314.52 Notice of certification of invalidity, unenforceability,
or noninfringement of a patent.
(a) Notice of certification. For each patent that claims the listed
drug or
[[Page 112]]
drugs relied upon or that claims a use for such listed drug or drugs and
for which the 505(b)(2) applicant submits a paragraph IV certification,
the applicant must send notice of such certification by registered or
certified mail, return receipt requested, or by a designated delivery
service, as defined in paragraph (g) of this section, to each of the
following persons:
(1) Each owner of the patent that is the subject of the
certification or the representative designated by the owner to receive
the notice. The name and address of the patent owner or its
representative may be obtained from the U.S. Patent and Trademark
Office; and
(2) The holder of the approved NDA under section 505(b) of the
Federal Food, Drug, and Cosmetic Act for each drug product which is
claimed by the patent or a use of which is claimed by the patent and for
which the applicant is seeking approval, or, if the NDA holder does not
reside or maintain a place of business within the United States, the NDA
holder's attorney, agent, or other authorized official. The name and
address of the NDA holder or its attorney, agent, or authorized official
may be obtained by sending a written or electronic communication to the
Central Document Room, Attn: Orange Book Staff, Center for Drug
Evaluation and Research, Food and Drug Administration, 5901-B Ammendale
Rd., Beltsville, MD 20705-1266, or to the Orange Book Staff at the email
address listed on the Agency's Web site at http://www.fda.gov.
(3) This paragraph (a) does not apply to a method-of-use patent that
does not claim a use for which the applicant is seeking approval.
(4) An applicant may send notice by an alternative method only if
FDA has agreed in advance that the method will produce an acceptable
form of documentation.
(b) Sending the notice. (1) Except as provided under paragraph (d)
of this section, the applicant must send the notice required by
paragraph (a) of this section on or after the date of filing described
in Sec. 314.101(a)(2) or (3), as applicable, but not later than 20 days
after the date of the postmark on the paragraph IV acknowledgment
letter. The 20-day clock described in this paragraph (b) begins on the
day after the date of the postmark on the paragraph IV acknowledgment
letter. When the 20th day falls on Saturday, Sunday, or a Federal
holiday, the 20th day will be the next day that is not a Saturday,
Sunday, or Federal holiday.
(2) Any notice required by paragraph (a) of this section is invalid
if it is sent before the date of filing described in Sec. 314.101(a)(2)
or, if FDA notifies the applicant that FDA has refused to file the
505(b)(2) application, before the date described in Sec. 314.101(a)(3)
on which the 505(b)(2) application is filed. The applicant will not have
complied with this paragraph (b) until it sends valid notice.
(3) The applicant must submit to FDA an amendment to its 505(b)(2)
application that includes a statement certifying that the notice has
been provided to each person identified under paragraph (a) of this
section and that the notice met the content requirement under paragraph
(c) of this section. A copy of the notice itself need not be submitted
to the Agency.
(c) Content of a notice. In the notice, the applicant must cite
section 505(b)(3)(D) of the Federal Food, Drug, and Cosmetic Act and the
notice must include, but is not limited to, the following information:
(1) A statement that a 505(b)(2) application that contains any
required bioavailability or bioequivalence studies has been submitted by
the applicant and filed by FDA.
(2) The NDA number.
(3) The established name, if any, as defined in section 502(e)(3) of
the Federal Food, Drug, and Cosmetic Act, of the proposed drug product.
(4) The active ingredient, strength, and dosage form of the proposed
drug product.
(5) The patent number and expiration date of each patent on the list
alleged to be invalid, unenforceable, or not infringed.
(6) A detailed statement of the factual and legal basis of the
applicant's opinion that the patent is not valid, unenforceable, or will
not be infringed. The applicant must include in the detailed statement:
(i) For each claim of a patent alleged not to be infringed, a full
and detailed
[[Page 113]]
explanation of why the claim is not infringed.
(ii) For each claim of a patent alleged to be invalid or
unenforceable, a full and detailed explanation of the grounds supporting
the allegation.
(7) If the applicant alleges that the patent will not be infringed
and the applicant seeks to preserve the option to later file a civil
action for declaratory judgment in accordance with section 505(c)(3)(D)
of the Federal Food, Drug, and Cosmetic Act, then the notice must be
accompanied by an offer of confidential access to the 505(b)(2)
application for the sole and limited purpose of evaluating possible
infringement of the patent that is the subject of the paragraph IV
certification.
(8) If the applicant does not reside or have a place of business in
the United States, the name and address of an agent in the United States
authorized to accept service of process for the applicant.
(d) Amendment or supplement to a 505(b)(2) application. (1) If,
after the date of filing described in Sec. 314.101(a)(2) or (3), as
applicable, an applicant submits an amendment or supplement to its
505(b)(2) application that includes a paragraph IV certification, the
applicant must send the notice required by paragraph (a) of this section
at the same time that the amendment or supplement to the 505(b)(2)
application is submitted to FDA, regardless of whether the applicant has
already given notice with respect to another such certification
contained in the 505(b)(2) application or in an amendment or supplement
to the 505(b)(2) application.
(2) If, before the date of filing described in Sec. 314.101(a)(2)
or (3), as applicable, an applicant submits a paragraph IV certification
in an amendment, the applicant must send the notice required by
paragraph (a) of this section in accordance with the procedures in
paragraph (b) of this section.
(3) An applicant that submits an amendment or supplement to seek
approval of a different strength must provide notice of any paragraph IV
certification in accordance with paragraph (d)(1) or (2) of this
section, as applicable.
(e) Documentation of timely sending and receipt of notice. The
applicant must amend its 505(b)(2) application to provide documentation
of the date of receipt of the notice required under paragraph (a) of
this section by each person provided the notice. The amendment must be
submitted to FDA within 30 days after the last date on which notice was
received by a person described in paragraph (a) of this section. The
applicant's amendment also must include documentation that its notice
was sent on a date that complies with the timeframe required by
paragraph (b) or (d) of this section, as applicable. FDA will accept, as
adequate documentation of the date the notice was sent, a copy of the
registered mail receipt, certified mail receipt, or receipt from a
designated delivery service, as defined in paragraph (g) of this
section. FDA will accept as adequate documentation of the date of
receipt a return receipt, a signature proof of delivery by a designated
delivery service, or a letter acknowledging receipt by the person
provided the notice. An applicant may rely on another form of
documentation only if FDA has agreed to such documentation in advance. A
copy of the notice itself need not be submitted to the Agency.
(f) Forty-five day period after receipt of notice. If the
requirements of this section are met, the Agency will presume the notice
to be complete and sufficient and will count the day following the date
of receipt of the notice by the patent owner or its representative and
by the approved NDA holder or its attorney, agent, or other authorized
official as the first day of the 45-day period provided for in section
505(c)(3)(C) of the Federal Food, Drug, and Cosmetic Act. FDA may, if
the applicant amends its 505(b)(2) application with a written statement
that a later date should be used, count from such later date.
(g) Designated delivery services. (1) For purposes of this section,
the term ``designated delivery service'' is any delivery service
provided by a trade or business that the Agency determines:
(i) Is available to the general public throughout the United States;
(ii) Records electronically to its database, kept in the regular
course of its business, or marks on the cover in which any item referred
to in this section is to be delivered, the date on
[[Page 114]]
which such item was given to such trade or business for delivery; and
(iii) Provides overnight or 2-day delivery service throughout the
United States.
(2) FDA may periodically issue guidance regarding designated
delivery services.
[81 FR 69641, Oct. 6, 2016, as amended at 84 FR 6673, Feb. 28, 2019]
Sec. 314.53 Submission of patent information.
(a) Who must submit patent information. This section applies to any
applicant who submits to FDA an NDA or an amendment to it under section
505(b) of the Federal Food, Drug, and Cosmetic Act and Sec. 314.50 or a
supplement to an approved NDA under Sec. 314.70, except as provided in
paragraph (d)(2) of this section.
(b) Patents for which information must be submitted and patents for
which information must not be submitted--(1) General requirements. An
applicant described in paragraph (a) of this section must submit to its
NDA the required information, on the required FDA declaration form, set
forth in paragraph (c) of this section for each patent that claims the
drug or a method of using the drug that is the subject of the NDA or
amendment or supplement to it and with respect to which a claim of
patent infringement could reasonably be asserted if a person not
licensed by the owner of the patent engaged in the manufacture, use, or
sale of the drug product. For purposes of this part, such patents
consist of drug substance (active ingredient) patents, drug product
(formulation and composition) patents, and method-of-use patents. For
patents that claim the drug substance, the applicant must submit
information only on those patents that claim the drug substance that is
the subject of the pending or approved NDA or that claim a drug
substance that is the same as the active ingredient that is the subject
of the approved or pending NDA. For patents that claim only a polymorph
that is the same as the active ingredient described in the approved or
pending NDA, the applicant must certify in the required FDA declaration
form that the applicant has test data, as set forth in paragraph (b)(2)
of this section, demonstrating that a drug product containing the
polymorph will perform the same as the drug product described in the
NDA. For patents that claim a drug product, the applicant must submit
information only on those patents that claim the drug product, as is
defined in Sec. 314.3, that is described in the pending or approved
NDA. For patents that claim a method of use, the applicant must submit
information only on those patents that claim indications or other
conditions of use for which approval is sought or has been granted in
the NDA. The applicant must separately identify each pending or approved
method of use and related patent claim(s). For approved NDAs, the NDA
holder's description of the patented method of use required by paragraph
(c)(2)(ii)(P)(3) of this section must describe only the approved
method(s) of use claimed by the patent for which a claim of patent
infringement could reasonably be asserted if a person not licensed by
the owner of the patent engaged in the manufacture, use, or sale of the
drug product. If the method(s) of use claimed by the patent does not
cover an indication or other approved condition of use in its entirety,
the applicant must describe only the specific approved method of use
claimed by the patent for which a claim of patent infringement could
reasonably be asserted if a person not licensed by the owner of the
patent engaged in the manufacture, use, or sale of the drug product. For
approved NDAs, the NDA holder submitting information on the method-of-
use patent must identify with specificity the section(s) and
subsection(s) of the approved labeling that describes the method(s) of
use claimed by the patent submitted. Process patents, patents claiming
packaging, patents claiming metabolites, and patents claiming
intermediates are not covered by this section, and information on these
patents must not be submitted to FDA.
(2) Test data for submission of patent information for patents that
claim only a polymorph. The test data, referenced in paragraph (b)(1) of
this section, must include the following:
[[Page 115]]
(i) A full description of the polymorphic form of the drug
substance, including its physical and chemical characteristics and
stability; the method of synthesis (or isolation) and purification of
the drug substance; the process controls used during manufacture and
packaging; and such specifications and analytical methods as are
necessary to assure the identity, strength, quality, and purity of the
polymorphic form of the drug substance;
(ii) The executed batch record for a drug product containing the
polymorphic form of the drug substance and documentation that the batch
was manufactured under current good manufacturing practice requirements;
(iii) Demonstration of bioequivalence between the executed batch of
the drug product that contains the polymorphic form of the drug
substance and the drug product as described in the NDA;
(iv) A list of all components used in the manufacture of the drug
product containing the polymorphic form and a statement of the
composition of the drug product; a statement of the specifications and
analytical methods for each component; a description of the
manufacturing and packaging procedures and in-process controls for the
drug product; such specifications and analytical methods as are
necessary to assure the identity, strength, quality, purity, and
bioavailability of the drug product, including release and stability
data complying with the approved product specifications to demonstrate
pharmaceutical equivalence and comparable product stability; and
(v) Comparative in vitro dissolution testing on 12 dosage units each
of the executed test batch and the NDA product.
(c) Reporting requirements--(1) General requirements. An applicant
described in paragraph (a) of this section must submit the required
patent information described in paragraph (c)(2) of this section for
each patent that meets the requirements described in paragraph (b) of
this section. We will not accept the patent information unless it is
submitted on the appropriate form, Form FDA 3542 or 3542a, and contains
the information required in paragraph (c)(2) of this section. These
forms may be obtained on the Internet at http://www.fda.gov by searching
for ``forms''.
(2) Drug substance (active ingredient), drug product (formulation or
composition), and method-of-use patents--(i) Original declaration. For
each patent that claims a drug substance (active ingredient), drug
product (formulation and composition), or method of use, the applicant
must submit Form FDA 3542a. The following information and verification
is required, subject to the exceptions listed in paragraph (c)(2)(i)(S)
of this section:
(A) NDA number;
(B) The NDA applicant's name, full address, phone number and, if
available, fax number and email address;
(C) Trade name (or proposed trade name) of new drug;
(D) Active ingredient(s) of new drug;
(E) Strength(s) of new drug;
(F) Dosage form(s) and route(s) of administration of new drug, and
whether the applicant proposes to market the new drug for prescription
use or over-the-counter use;
(G) U.S. patent number, issue date, and expiration date of patent
submitted;
(H) The patent owner's name, full address, phone number and, if
available, fax number and email address;
(I) The name, full address, phone number and, if available, fax
number and email address of an agent or representative who resides or
maintains a place of business within the United States authorized to
receive notice of patent certification under section 505(b)(3) and
(j)(2)(B) of the Federal Food, Drug, and Cosmetic Act and Sec. Sec.
314.52 and 314.95 (if patent owner or NDA applicant or holder does not
reside or have a place of business within the United States);
(J) Information on whether the patent has been submitted previously
for the NDA or supplement;
(K) If the patent has been submitted previously for listing,
identify all change(s) from the previously submitted patent information
and specify whether the change is related to the patent or related to an
FDA action or procedure;
(L) Information on whether the patent is a product-by-process patent
in which the product claimed is novel;
[[Page 116]]
(M) Information on the drug substance (active ingredient) patent,
including the following:
(1) Whether the patent claims a drug substance that is an active
ingredient in the drug product described in the NDA or supplement;
(2) Whether the patent claims only a polymorph that is the same
active ingredient that is described in the pending NDA or supplement;
(3) Whether the applicant has test data, described in paragraph
(b)(2) of this section, demonstrating that a drug product containing
only the polymorph will perform the same as the drug product described
in the NDA or supplement, and a description of the polymorphic form(s)
claimed by the patent for which such test data exist;
(4) Whether the patent claims only a metabolite of the active
ingredient; and
(5) Whether the patent claims only an intermediate;
(N) Information on the drug product (composition/formulation)
patent, including the following:
(1) Whether the patent claims the drug product for which approval is
being sought, as defined in Sec. 314.3; and
(2) Whether the patent claims only an intermediate;
(O) Information on each method-of-use patent, including the
following:
(1) Whether the patent claims one or more methods of using the drug
product for which approval is being sought and a description of each
pending method of use and related patent claim of the patent being
submitted;
(2) Identification of the specific section(s) and subsection(s) of
the proposed labeling for the drug product that describes the method of
use claimed by the patent submitted; and
(3) An applicant that submits information for a patent that claims
one or more methods of using the drug product must also submit
information described in either paragraph (c)(2)(i)(M) or (N) of this
section, regarding whether that patent also claims either the drug
substance (active ingredient) or the drug product (composition/
formulation).
(P) Whether there are no relevant patents that claim the drug
substance (active ingredient), drug product (formulation or
composition), or method(s) of use, for which the applicant is seeking
approval and with respect to which a claim of patent infringement could
reasonably be asserted if a person not licensed by the owner of the
patent engaged in the manufacture, use, or sale of the drug product;
(Q) A signed verification that states:
The undersigned declares that this is an accurate and complete
submission of patent information for the NDA, amendment, or supplement
pending under section 505 of the Federal Food, Drug, and Cosmetic Act.
This time-sensitive patent information is submitted pursuant to 21 CFR
314.53. I attest that I am familiar with 21 CFR 314.53 and this
submission complies with the requirements of the regulation. I verify
under penalty of perjury that the foregoing is true and correct.
(R) Information on whether the applicant, patent owner or attorney,
agent, representative, or other authorized official signed the form; the
name of the person; and the full address, phone number and, if
available, the fax number and email address; and
(S) Exceptions to required submission of patent information:
(1) If an applicant submits the information described in paragraph
(c)(2)(i)(M) of this section for a patent that claims the drug substance
(active ingredient) and meets the requirements for listing on that
basis, then the applicant is not required to provide the information
described in paragraph (c)(2)(i)(N) of this section on whether that
patent also claims the drug product (composition/formulation);
(2) If an applicant submits the information described in paragraph
(c)(2)(i)(N) of this section for a patent that claims the drug product
(composition/formulation) and meets the requirements for listing on that
basis, then the applicant is not required to provide the information
described in paragraph (c)(2)(i)(M) of this section on whether that
patent also claims the drug substance (active ingredient);
(3) If the applicant submits a supplement for a change other than
one of the changes listed under paragraph (d)(2)(i) of this section,
then the patent information submission requirements of paragraph
(d)(2)(ii) of this section apply.
[[Page 117]]
(ii) Submission of patent information upon and after approval.
Within 30 days after the date of approval of its NDA or supplement, the
applicant must submit Form FDA 3542 for each patent that claims the drug
substance (active ingredient), drug product (formulation and
composition), or approved method of use. FDA will not list or publish
patent information if it is not provided on this form or if the patent
declaration does not contain the required information or indicates the
patent is not eligible for listing. Patent information must also be
submitted for patents issued after the date of approval of the NDA as
required in paragraph (c)(2)(ii) of this section. As described in
paragraph (d)(3) of this section, to be timely filed, patent information
for patents issued after the date of approval of the NDA must be
submitted to FDA within 30 days of the date of issuance of the patent.
If the applicant submits the required patent information within the 30
days, but we notify an applicant that a declaration form is incomplete
or shows that the patent is not eligible for listing, the applicant must
submit an acceptable declaration form within 15 days of FDA notification
to be considered timely filed. The following information and
verification statement is required, subject to the exceptions listed in
paragraph (c)(2)(ii)(T) of this section:
(A) NDA number;
(B) The NDA holder's name, full address, phone number and, if
available, fax number and email address;
(C) Trade name of new drug;
(D) Active ingredient(s) of new drug;
(E) Strength(s) of new drug;
(F) Dosage form(s) and route(s) of administration of new drug, and
whether the new drug is approved for prescription use or over-the-
counter use;
(G) Approval date of NDA or supplement;
(H) U.S. patent number, issue date, and expiration date of patent
submitted;
(I) The patent owner's name, full address, phone number and, if
available, fax number and email address;
(J) The name, full address, phone number and, if available, fax
number and email address of an agent or representative who resides or
maintains a place of business within the United States authorized to
receive notice of patent certification under section 505(b)(3) and
(j)(2)(B) of the Federal Food, Drug, and Cosmetic Act and Sec. Sec.
314.52 and 314.95 (if patent owner or NDA applicant or holder does not
reside or have a place of business within the United States);
(K) Information on whether the patent has been submitted previously
for the NDA or supplement;
(L) If the patent has been submitted previously for listing,
identify all change(s) from the previously submitted patent information
and specify whether the change is related to the patent or related to an
FDA action or procedure;
(M) Information on whether the patent is a product-by-process patent
in which the product claimed is novel;
(N) Information on the drug substance (active ingredient) patent,
including the following:
(1) Whether the patent claims a drug substance that is an active
ingredient in the drug product described in the approved NDA;
(2) Whether the patent claims only a polymorph that is the same as
the active ingredient that is described in the approved NDA;
(3) Whether the applicant has test data, described in paragraph
(b)(2) of this section, demonstrating that a drug product containing
only the polymorph will perform the same as the drug product described
in the approved NDA and a description of the polymorphic form(s) claimed
by the patent for which such test data exist;
(4) Whether the patent claims only a metabolite of the active
ingredient; and
(5) Whether the patent claims only an intermediate;
(O) Information on the drug product (composition/formulation)
patent, including the following:
(1) Whether the patent claims the approved drug product as defined
in Sec. 314.3; and
(2) Whether the patent claims only an intermediate;
(P) Information on each method-of-use patent, including the
following:
(1) Whether the patent claims one or more approved methods of using
the
[[Page 118]]
approved drug product and a description of each approved method of use
and related patent claim of the patent being submitted;
(2) Identification of the specific section(s) and subsection(s) of
the approved labeling for the drug product that describes the method of
use claimed by the patent submitted;
(3) The description of the patented method of use as required for
publication, which must contain adequate information to assist 505(b)(2)
and ANDA applicants in determining whether a listed method-of-use patent
claims a use for which the 505(b)(2) or ANDA applicant is not seeking
approval (for example, if the method(s) of use claimed by the patent
does not cover an indication or other approved condition of use in its
entirety, then the applicant must describe only the specific approved
method of use claimed by the patent for which a claim of patent
infringement could reasonably be asserted if a person not licensed by
the owner of the patent engaged in the manufacture, use, or sale of the
drug product); and
(4) An applicant that submits information for a patent that claims
one or more methods of using the drug product must also submit
information described in either paragraph (c)(2)(ii)(N) or (O) of this
section, regarding whether that patent also claims either the drug
substance (active ingredient) or the drug product (composition/
formulation).
(Q) Whether there are no relevant patents that claim the approved
drug substance (active ingredient), the approved drug product
(formulation or composition), or approved method(s) of use and with
respect to which a claim of patent infringement could reasonably be
asserted if a person not licensed by the owner of the patent engaged in
the manufacture, use, or sale of the drug product;
(R) A signed verification that states:
The undersigned declares that this is an accurate and complete
submission of patent information for the NDA, amendment, or supplement
approved under section 505 of the Federal Food, Drug, and Cosmetic Act.
This time-sensitive patent information or response to a request under 21
CFR 314.53(f)(1) is submitted pursuant to 21 CFR 314.53. I attest that I
am familiar with 21 CFR 314.53 and this submission complies with the
requirements of the regulation. I verify under penalty of perjury that
the foregoing is true and correct.
(S) Information on whether the applicant, patent owner or attorney,
agent, representative, or other authorized official signed the form; the
name of the person; and the full address, phone number and, if
available, the fax number and email address; and
(T) Exceptions to required submission of patent information:
(1) If an applicant submits the information described in paragraph
(c)(2)(ii)(N) of this section for a patent that claims the drug
substance (active ingredient) and meets the requirements for listing on
that basis, then the applicant is not required to provide the
information described in paragraph (c)(2)(ii)(O) of this section on
whether that patent also claims the drug product (composition/
formulation).
(2) If an applicant submits the information described in paragraph
(c)(2)(ii)(O) of this section for a patent that claims the drug product
(composition/formulation) and meets the requirements for listing on that
basis, then the applicant is not required to provide the information
described in paragraph (c)(2)(ii)(N) of this section on whether that
patent also claims the drug substance (active ingredient).
(3) If the applicant submits a supplement for a change other than
one of the changes listed under paragraph (d)(2)(i) of this section,
then the patent information submission requirements of paragraph
(d)(2)(ii) of this section apply.
(3) No relevant patents. If the applicant believes that there are no
relevant patents that claim the drug substance (active ingredient), drug
product (formulation or composition), or the method(s) of use for which
the applicant has received approval, and with respect to which a claim
of patent infringement could reasonably be asserted if a person not
licensed by the owner of the patent engaged in the manufacture, use, or
sale of the drug product, the applicant will verify this information in
the appropriate form, Form FDA 3542 or 3542a.
(4) Authorized signature. The declarations required by this section
must be signed by the applicant or patent
[[Page 119]]
owner, or the applicant's or patent owner's attorney, agent
(representative), or other authorized official.
(d) When and where to submit patent information--(1) Original NDA.
An applicant must submit with its original NDA submitted under this
part, the information described in paragraph (c) of this section on each
drug substance (active ingredient), drug product (formulation and
composition), and method-of-use patent issued before the NDA is filed
with FDA and for which patent information is required to be submitted
under this section. If a patent is issued after the NDA is filed with
FDA but before the NDA is approved, the applicant must, within 30 days
of the date of issuance of the patent, submit the required patent
information in an amendment to the NDA under Sec. 314.60.
(2) Supplements. (i) An applicant must submit patent information
required under paragraph (c) of this section for a patent that claims
the drug substance, drug product, or method of use for which approval is
sought in any of the following supplements:
(A) To add or change the dosage form or route of administration;
(B) To add or change the strength; or
(C) To change the drug product from prescription use to over-the-
counter use.
(ii) If the applicant submits a supplement for a change other than
one of the changes listed under paragraph (d)(2)(i) of this section (for
example, to change the formulation, to add a new indication or other
condition of use, or to make any other patented change regarding the
drug substance, drug product, or any method of use), the following
patent information submission requirements apply:
(A) If existing patents for which information required by paragraph
(c) of this section has already been submitted to FDA for the product
approved in the original NDA claim the changed product, the applicant is
not required to resubmit this patent information pursuant to paragraph
(c) of this section unless the published description of the patented
method of use would change upon approval of the supplement, and FDA will
continue to list this patent information for the product;
(B) If one or more existing patents for which information has
already been submitted to FDA no longer claim the changed product, the
applicant must submit a request under paragraph (f)(2)(iv) of this
section to remove that patent information from the list at the time of
approval of the supplement;
(C) If one or more existing drug substance (active ingredient), drug
product (formulation and composition), or method-of-use patents claim
the changed product for which approval is sought in the supplement and
such patent information has not been submitted to FDA, the applicant
must submit the patent information required under paragraph (c) of this
section.
(3) Newly issued patents. If a patent is issued for a drug
substance, drug product, or method of use after an NDA is approved, the
applicant must submit to FDA, as described in paragraph (d)(4) of this
section, the required patent information within 30 days of the date of
issuance of the patent. If the required patent information is not
submitted within 30 days of the issuance of the patent, FDA will list
the patent, but patent certifications or statements will be governed by
the provisions regarding untimely filed patent information at Sec. Sec.
314.50(i)(4) and (6) and 314.94(a)(12)(vi) and (viii).
(4) Submission of Forms FDA 3542a and 3542--(i) Patent information
submitted with the filing of an NDA, amendment, or supplement. The
applicant must submit patent information required by paragraphs (c)(1)
and (c)(2)(i) of this section and Sec. 314.50(h) or Sec. 314.70(f) on
Form FDA 3542a to the Central Document Room, Center for Drug Evaluation
and Research, Food and Drug Administration, 5901-B Ammendale Rd.,
Beltsville, MD 20705-1266, or to FDA in an electronic format submission
that complies with Sec. 314.50(l)(5). Form FDA 3542a should not be
submitted to the Orange Book Staff in the Office of Generic Drugs.
(ii) Patent information submitted upon and after approval of an NDA
or supplement. The applicant must submit patent information required by
paragraphs (c)(1) and (c)(2)(ii) of this section on
[[Page 120]]
Form FDA 3542 to the Central Document Room, Center for Drug Evaluation
and Research, Food and Drug Administration, 5901-B Ammendale Rd.,
Beltsville, MD 20705-1266, or to FDA in an electronic format submission
that complies with Sec. 314.50(l)(5). Form FDA 3542 should not be
submitted to the Orange Book Staff in the Office of Generic Drugs.
(5) Submission date. Patent information will be considered to be
submitted to FDA for purposes of paragraph (d)(3) of this section as of
the earlier of the date the information submitted on Form FDA 3542 is
date-stamped by the Central Document Room, or officially received by FDA
in an electronic format submission that complies with Sec.
314.50(l)(5).
(6) Identification. Each submission of patent information, except
information submitted with an original NDA, must bear prominent
identification as to its contents, i.e., ``Patent Information,'' or, if
submitted after approval of an NDA, ``Time Sensitive Patent
Information.''
(e) Public disclosure of patent information. FDA will publish in the
list the patent number and expiration date of each patent that is
required to be, and is, submitted to FDA by an applicant, and for each
method-of-use patent, the description of the method of use claimed by
the patent as required by Sec. 314.53(c)(2)(ii)(P)(3). FDA will publish
such patent information upon approval of the NDA, or, if the patent
information is submitted by the applicant after approval of an NDA as
provided under paragraph (d)(2) of this section, as soon as possible
after the submission to the Agency of the patent information. A request
for copies of the submitted patent information must be sent in writing
to the Freedom of Information Staff at the address listed on the
Agency's Web site at http://www.fda.gov. The submitted patent
information, and requests to remove a patent or patent information from
the list, may be subject to public disclosure.
(f) Correction of patent information errors--(1) Requests by persons
other than the NDA holder. If any person disputes the accuracy or
relevance of patent information submitted to the Agency under this
section and published by FDA in the list, or believes that an NDA holder
has failed to submit required patent information, that person must first
notify the Agency in a written or electronic communication titled
``314.53(f) Patent Listing Dispute.'' The patent listing dispute
communication must include a statement of dispute that describes the
specific grounds for disagreement regarding the accuracy or relevance of
patent information for FDA to send to the applicable NDA holder. For a
dispute regarding the accuracy or relevance of patent information
regarding an approved method of using the drug product, this statement
of dispute must be only a narrative description (no more than 250 words)
of the person's interpretation of the scope of the patent. This
statement of dispute must only contain information for which the person
consents to disclosure because FDA will send the text of the statement
to the applicable NDA holder without review or redaction. The patent
listing dispute communication should be directed to the Central Document
Room, Attn: Orange Book Staff, Center for Drug Evaluation and Research,
Food and Drug Administration, 5901-B Ammendale Rd., Beltsville, MD
20705-1266, or to the Orange Book Staff at the email address listed on
the Agency's Web site at http://www.fda.gov.
(i) Communication with the NDA holder--(A) Drug substance or drug
product claim. For requests submitted under this paragraph (f)(1) that
are directed to the accuracy or relevance of submitted patent
information regarding a drug substance or drug product claim, the Agency
will send the statement of dispute to the applicable NDA holder. The NDA
holder must confirm the correctness of the patent information and
include the signed verification required by paragraph (c)(2)(ii)(R) of
this section or withdraw or amend the patent information in accordance
with paragraph (f)(2) of this section within 30 days of the date on
which the Agency sends the statement of dispute. Unless the NDA holder
withdraws or amends its patent information in response to the patent
listing dispute, the Agency will not change the patent information in
the Orange Book.
[[Page 121]]
(B) Method-of-use claim. For requests submitted under this paragraph
(f)(1) that are directed to the accuracy or relevance of submitted
patent information regarding an approved method of using the drug
product, FDA will send the statement of dispute to the NDA holder. The
NDA holder must confirm the correctness of its description of the
approved method of use claimed by the patent that has been included as
the ``Use Code'' in the Orange Book, or withdraw or amend the patent
information in accordance with paragraph (f)(2) of this section, provide
a narrative description (no more than 250 words) of the NDA holder's
interpretation of the scope of the patent that explains why the existing
or amended ``Use Code'' describes only the specific approved method of
use claimed by the patent for which a claim of patent infringement could
reasonably be asserted if a person not licensed by the owner of the
patent engaged in the manufacture, use, or sale of the drug product, and
include the signed verification required by paragraph (c)(2)(ii)(R) of
this section within 30 days of the date on which the Agency sends the
statement of dispute. The narrative description must only contain
information for which the NDA holder consents to disclosure because FDA
will send the text of the statement to the person who submitted the
patent listing dispute without review or redaction.
(1) If the NDA holder confirms the correctness of the patent
information, provides the narrative description required by paragraph
(f)(1)(i)(B) of this section, and includes the signed verification
required by paragraph (c)(2)(ii)(R) of this section within 30 days of
the date on which the Agency sends the statement of dispute, the Agency
will not change the patent information in the Orange Book.
(2) If the NDA holder responds to the patent listing dispute with
amended patent information in accordance with paragraph (f)(2) of this
section, provides the narrative description required by paragraph
(f)(1)(i)(B) of this section, and includes the signed verification
required by paragraph (c)(2)(ii)(R) of this section within 30 days of
the date on which the Agency sends the statement of dispute, FDA will
update the Orange Book to reflect the amended patent information.
(ii) Patent certification or statement during and after patent
listing dispute. A 505(b)(2) application or ANDA must contain an
appropriate certification or statement for each listed patent, including
the disputed patent, during and after the patent listing dispute.
(iii) Information on patent listing disputes. FDA will promptly post
information on its Web site regarding whether a patent listing dispute
has been submitted for a published description of a patented method of
use for a drug product and whether the NDA holder has timely responded
to the patent listing dispute.
(2) Requests by the NDA holder--(i) Patents or patent claims that no
longer meet the statutory requirements for listing. If the NDA holder
determines that a patent or patent claim no longer meets the
requirements for listing in section 505(b)(1) or (c)(2) of the Federal
Food, Drug, and Cosmetic Act (including if there has been a judicial
finding of invalidity for a listed patent, from which no appeal has been
or can be taken), the NDA holder is required to promptly notify FDA to
amend the patent information or withdraw the patent or patent
information and request that the patent or patent information be removed
from the list. If the NDA holder is required by court order to amend
patent information or withdraw a patent from the list, it must submit an
amendment to its NDA that includes a copy of the order, within 14 days
of the date the order was entered, to the Central Document Room, Center
for Drug Evaluation and Research, Food and Drug Administration, 5901-B
Ammendale Rd., Beltsville, MD 20705-1266. The amendment to the NDA must
bear the identification described in paragraph (d)(6) of this section.
FDA will remove a patent or patent information from the list if there is
no first applicant eligible for 180-day exclusivity based on a paragraph
IV certification to that patent or after the 180-day exclusivity period
of a first applicant based on that patent has expired or has been
extinguished.
(ii) Patent term restoration. If the term of a listed patent is
extended pursuant to 35 U.S.C. 156(e), the NDA holder
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must submit on Form FDA 3542 a correction to the expiration date of the
patent. This correction must be submitted within 30 days of receipt of a
certificate of extension as described in 35 U.S.C. 156(e)(1) or
documentation of an extension of the term of the patent as described in
35 U.S.C. 156(e)(2).
(iii) Submission of corrections or changes to patent information.
Corrections or changes to previously submitted patent information, other
than withdrawal of a patent and requests to remove a patent from the
list, must be submitted on Form FDA 3542 or 3542a, as appropriate, in an
amendment or supplement to the NDA. The amendment or supplement to the
NDA must bear the identification described in paragraph (d)(6) of this
section. We will not accept the corrections or changes unless they are
submitted on the appropriate forms.
(iv) Submission of patent withdrawals and requests to remove a
patent from the list. Withdrawal of a patent and requests to remove a
patent from the list must be submitted to the same addresses described
in paragraph (d)(4)(ii) of this section, except that the withdrawal or
request to remove a patent from the list is not required to be submitted
on Form FDA 3542 and may be submitted by letter. Withdrawal of a patent
and a request to remove a patent from the list must contain the
following information:
(A) The NDA number to which the request applies;
(B) Each product(s) approved in the NDA to which the request
applies; and
(C) The patent number.
[81 FR 69643, Oct. 6, 2016, as amended at 84 FR 6673, Feb. 28, 2019]
Sec. 314.54 Procedure for submission of a 505(b)(2) application requiring
investigations for approval of a new indication for, or other change from,
a listed drug.
(a) The Federal Food, Drug, and Cosmetic Act does not permit
approval of an ANDA for a new indication, nor does it permit approval of
other changes in a listed drug if investigations, other than
bioavailability or bioequivalence studies, are essential to the approval
of the change. Any person seeking approval of a drug product that
represents a modification of a listed drug (e.g., a new indication or
new dosage form) and for which investigations, other than
bioavailability or bioequivalence studies, are essential to the approval
of the changes may, except as provided in paragraph (b) of this section,
submit a 505(b)(2) application. This 505(b)(2) application need contain
only that information needed to support the modification(s) of the
listed drug.
(1) The applicant must submit a complete archival copy of the
application that contains the following:
(i) The information required under Sec. 314.50(a), (b), (c),
(d)(1), (d)(3), (e), and (g), except that Sec. 314.50(d)(1)(ii)(c) must
contain the proposed or actual master production record, including a
description of the equipment, to be used for the manufacture of a
commercial lot of the drug product.
(ii) The information required under Sec. 314.50 (d)(2), (d)(4) (if
an anti-infective drug), (d)(5), (d)(6), and (f) as needed to support
the safety and effectiveness of the drug product.
(iii) Identification of each listed drug for which FDA has made a
finding of safety and effectiveness and on which finding the applicant
relies in seeking approval of its proposed drug product by established
name, if any, proprietary name, dosage form, strength, route of
administration, name of listed drug's application holder, and listed
drug's approved NDA number. The listed drug(s) identified as relied upon
must include a drug product approved in an NDA that:
(A) Is pharmaceutically equivalent to the drug product for which the
original 505(b)(2) application is submitted; and
(B) Was approved before the original 505(b)(2) application was
submitted.
(iv) If the applicant is seeking approval only for a new indication
and not for the indications approved for the listed drug on which the
applicant relies, a certification so stating.
(v) Any patent information required under section 505(b)(1) of the
Federal Food, Drug, and Cosmetic Act with respect to any patent which
claims the drug for which approval is sought or a method of using such
drug and to which a claim of patent infringement could reasonably be
asserted if a person
[[Page 123]]
not licensed by the owner of the patent engaged in the manufacture, use,
or sale of the drug product.
(vi) Any patent certification or statement required under section
505(b)(2) of the Federal Food, Drug, and Cosmetic Act with respect to
any relevant patents that claim the listed drug(s) on which
investigations relied on by the applicant for approval of the
application were conducted, or that claim a use for the listed drug(s).
A 505(b)(2) applicant seeking approval of a drug that is
pharmaceutically equivalent to a listed drug approved in an NDA
implicitly relies upon one such pharmaceutically equivalent listed drug.
(vii) If the applicant believes the change for which it is seeking
approval is entitled to a period of exclusivity, the information
required under Sec. 314.50(j).
(2) The applicant must submit a review copy that contains the
technical sections described in Sec. 314.50(d)(1), except that the
section described in Sec. 314.50(d)(1)(ii)(c) must contain the proposed
or actual master production record, including a description of the
equipment, to be used for the manufacture of a commercial lot of the
drug product, and Sec. 314.50(d)(3), and the technical sections
described in Sec. 314.50(d)(2), (d)(4) through (6), and (f) when needed
to support the modification. Each of the technical sections in the
review copy is required to be separately bound with a copy of the
information required under Sec. 314.50(a), (b), and (c) and a copy of
the proposed labeling.
(3) The information required by Sec. 314.50 (d)(2), (d)(4) (if an
anti-infective drug), (d)(5), (d)(6), and (f) for the listed drug on
which the applicant relies must be satisfied by reference to the listed
drug under paragraph (a)(1)(iii) of this section.
(4) The applicant must submit a field copy of the 505(b)(2)
application that contains the technical section described in Sec.
314.50(d)(1), a copy of the information required under Sec. 314.50(a)
and (c), and certification that the field copy is a true copy of the
technical section described in Sec. 314.50(d)(1) contained in the
archival and review copies of the 505(b)(2) application.
(b) A 505(b)(2) application may not be submitted under this section
for a drug product whose only difference from a listed drug is that:
(1) The extent to which its active ingredient(s) is absorbed or
otherwise made available to the site of action is less than that of the
listed drug; or
(2) The rate at which its active ingredient(s) is absorbed or
otherwise made available to the site of action is unintentionally less
than that of the listed drug.
[57 FR 17982, Apr. 28, 1992; 57 FR 61612, Dec. 28, 1992, as amended at
58 FR 47351, Sept. 8, 1993; 59 FR 50364, Oct. 3, 1994; 81 FR 69647, Oct.
6, 2016]
Sec. 314.55 Pediatric use information.
(a) Required assessment. Except as provided in paragraphs (b), (c),
and (d) of this section, each application for a new active ingredient,
new indication, new dosage form, new dosing regimen, or new route of
administration shall contain data that are adequate to assess the safety
and effectiveness of the drug product for the claimed indications in all
relevant pediatric subpopulations, and to support dosing and
administration for each pediatric subpopulation for which the drug is
safe and effective. Where the course of the disease and the effects of
the drug are sufficiently similar in adults and pediatric patients, FDA
may conclude that pediatric effectiveness can be extrapolated from
adequate and well-controlled studies in adults usually supplemented with
other information obtained in pediatric patients, such as
pharmacokinetic studies. Studies may not be needed in each pediatric age
group, if data from one age group can be extrapolated to another.
Assessments of safety and effectiveness required under this section for
a drug product that represents a meaningful therapeutic benefit over
existing treatments for pediatric patients must be carried out using
appropriate formulations for each age group(s) for which the assessment
is required.
(b) Deferred submission. (1) FDA may, on its own initiative or at
the request of an applicant, defer submission of some or all assessments
of safety and effectiveness described in paragraph (a) of this section
until after approval of the drug product for use in adults. Deferral may
be granted if, among other
[[Page 124]]
reasons, the drug is ready for approval in adults before studies in
pediatric patients are complete, or pediatric studies should be delayed
until additional safety or effectiveness data have been collected. If an
applicant requests deferred submission, the request must provide a
certification from the applicant of the grounds for delaying pediatric
studies, a description of the planned or ongoing studies, and evidence
that the studies are being or will be conducted with due diligence and
at the earliest possible time.
(2) If FDA determines that there is an adequate justification for
temporarily delaying the submission of assessments of pediatric safety
and effectiveness, the drug product may be approved for use in adults
subject to the requirement that the applicant submit the required
assessments within a specified time.
(c) Waivers--(1) General. FDA may grant a full or partial waiver of
the requirements of paragraph (a) of this section on its own initiative
or at the request of an applicant. A request for a waiver must provide
an adequate justification.
(2) Full waiver. An applicant may request a waiver of the
requirements of paragraph (a) of this section if the applicant certifies
that:
(i) The drug product does not represent a meaningful therapeutic
benefit over existing treatments for pediatric patients and is not
likely to be used in a substantial number of pediatric patients;
(ii) Necessary studies are impossible or highly impractical because,
e.g., the number of such patients is so small or geographically
dispersed; or
(iii) There is evidence strongly suggesting that the drug product
would be ineffective or unsafe in all pediatric age groups.
(3) Partial waiver. An applicant may request a waiver of the
requirements of paragraph (a) of this section with respect to a
specified pediatric age group, if the applicant certifies that:
(i) The drug product does not represent a meaningful therapeutic
benefit over existing treatments for pediatric patients in that age
group, and is not likely to be used in a substantial number of patients
in that age group;
(ii) Necessary studies are impossible or highly impractical because,
e.g., the number of patients in that age group is so small or
geographically dispersed;
(iii) There is evidence strongly suggesting that the drug product
would be ineffective or unsafe in that age group; or
(iv) The applicant can demonstrate that reasonable attempts to
produce a pediatric formulation necessary for that age group have
failed.
(4) FDA action on waiver. FDA shall grant a full or partial waiver,
as appropriate, if the agency finds that there is a reasonable basis on
which to conclude that one or more of the grounds for waiver specified
in paragraphs (c)(2) or (c)(3) of this section have been met. If a
waiver is granted on the ground that it is not possible to develop a
pediatric formulation, the waiver will cover only those pediatric age
groups requiring that formulation. If a waiver is granted because there
is evidence that the product would be ineffective or unsafe in pediatric
populations, this information will be included in the product's
labeling.
(5) Definition of ``meaningful therapeutic benefit''. For purposes
of this section and Sec. 201.23 of this chapter, a drug will be
considered to offer a meaningful therapeutic benefit over existing
therapies if FDA estimates that:
(i) If approved, the drug would represent a significant improvement
in the treatment, diagnosis, or prevention of a disease, compared to
marketed products adequately labeled for that use in the relevant
pediatric population. Examples of how improvement might be demonstrated
include, for example, evidence of increased effectiveness in treatment,
prevention, or diagnosis of disease, elimination or substantial
reduction of a treatment-limiting drug reaction, documented enhancement
of compliance, or evidence of safety and effectiveness in a new
subpopulation; or
(ii) The drug is in a class of drugs or for an indication for which
there is a need for additional therapeutic options.
(d) Exemption for orphan drugs. This section does not apply to any
drug for an indication or indications for which orphan designation has
been granted
[[Page 125]]
under part 316, subpart C, of this chapter.
[63 FR 66670, Dec. 2, 1998]
Sec. 314.60 Amendments to an unapproved NDA, supplement, or resubmission.
(a) Submission of NDA. FDA generally assumes that when an original
NDA, supplement to an approved NDA, or resubmission of an NDA or
supplement is submitted to the Agency for review, the applicant believes
that the Agency can approve the NDA, supplement, or resubmission as
submitted. However, the applicant may submit an amendment to an NDA,
supplement, or resubmission that has been filed under Sec. 314.101 but
is not yet approved.
(b) Submission of major amendment. (1) Submission of a major
amendment to an original NDA, efficacy supplement, or resubmission of an
NDA or efficacy supplement within 3 months of the end of the initial
review cycle constitutes an agreement by the applicant under section
505(c) of the Federal Food, Drug, and Cosmetic Act to extend the initial
review cycle by 3 months. (For references to a resubmission of an NDA or
efficacy supplement in paragraph (b) of this section, the timeframe for
reviewing the resubmission is the ``review cycle'' rather than the
``initial review cycle.'') FDA may instead defer review of the amendment
until the subsequent review cycle. If the agency extends the initial
review cycle for an original NDA, efficacy supplement, or resubmission
under this paragraph, the division responsible for reviewing the NDA,
supplement, or resubmission will notify the applicant of the extension.
The initial review cycle for an original NDA, efficacy supplement, or
resubmission of an NDA or efficacy supplement may be extended only once
due to submission of a major amendment. FDA may, at its discretion,
review any subsequent major amendment during the initial review cycle
(as extended) or defer review until the subsequent review cycle.
(2) Submission of a major amendment to an original NDA, efficacy
supplement, or resubmission of an NDA or efficacy supplement more than 3
months before the end of the initial review cycle will not extend the
cycle. FDA may, at its discretion, review such an amendment during the
initial review cycle or defer review until the subsequent review cycle.
(3) Submission of an amendment to an original NDA, efficacy
supplement, or resubmission of an NDA or efficacy supplement that is not
a major amendment will not extend the initial review cycle. FDA may, at
its discretion, review such an amendment during the initial review cycle
or defer review until the subsequent review cycle.
(4) Submission of a major amendment to a manufacturing supplement
within 2 months of the end of the initial review cycle constitutes an
agreement by the applicant under section 505(c) of the Federal Food,
Drug, and Cosmetic Act to extend the initial review cycle by 2 months.
FDA may instead defer review of the amendment until the subsequent
review cycle. If the agency extends the initial review cycle for a
manufacturing supplement under this paragraph, the division responsible
for reviewing the supplement will notify the applicant of the extension.
The initial review cycle for a manufacturing supplement may be extended
only once due to submission of a major amendment. FDA may, at its
discretion, review any subsequent major amendment during the initial
review cycle (as extended) or defer review until the subsequent review
cycle.
(5) Submission of an amendment to a supplement other than an
efficacy or manufacturing supplement will not extend the initial review
cycle. FDA may, at its discretion, review such an amendment during the
initial review cycle or defer review until the subsequent review cycle.
(6) A major amendment may not include data to support an indication
or claim that was not included in the original NDA, supplement, or
resubmission, but it may include data to support a minor modification of
an indication or claim that was included in the original NDA,
supplement, or resubmission.
(7) When FDA defers review of an amendment until the subsequent
review cycle, the agency will notify the applicant of the deferral in
the complete response letter sent to the applicant under Sec. 314.110
of this part.
[[Page 126]]
(c) Limitation on certain amendments.(1) An unapproved NDA may not
be amended if all of the following conditions apply:
(i) The unapproved NDA is for a drug for which a previous NDA has
been approved and granted a period of exclusivity in accordance with
section 505(c)(3)(E)(ii) of the Federal Food, Drug, and Cosmetic Act
that has not expired;
(ii) The applicant seeks to amend the unapproved NDA to include a
published report of an investigation that was conducted or sponsored by
the applicant entitled to exclusivity for the drug;
(iii) The applicant has not obtained a right of reference or use to
the investigation described in paragraph (c)(1)(ii) of this section; and
(iv) The report of the investigation described in paragraph
(c)(1)(ii) of this section would be essential to the approval of the
unapproved NDA.
(2) The submission of an amendment described in paragraph (c)(1) of
this section will cause the unapproved NDA to be deemed to be withdrawn
by the applicant under Sec. 314.65 on the date of receipt by FDA of the
amendment. The amendment will be considered a resubmission of the NDA,
which may not be accepted except as provided in accordance with section
505(c)(3)(E)(ii) of the Federal Food, Drug, and Cosmetic Act.
(d) Field copy. The applicant must submit a field copy of each
amendment to a section of the NDA described in Sec. 314.50(d)(1). The
applicant must include in its submission of each such amendment to FDA a
statement certifying that a field copy of the amendment has been sent to
the applicant's home FDA district office.
(e) Different drug. An applicant may not amend a 505(b)(2)
application to seek approval of a drug that is a different drug from the
drug in the original submission of the 505(b)(2) application. For
purposes of this paragraph (e), a drug is a different drug if it has
been modified to have a different active ingredient, different route of
administration, different dosage form, or difference in excipients that
requires either a separate clinical study to establish safety or
effectiveness or, for topical products, that requires a separate in vivo
demonstration of bioequivalence. However, notwithstanding the limitation
described in this paragraph (e), an applicant may amend the 505(b)(2)
application to seek approval of a different strength.
(f) Patent certification requirements. (1) An amendment to a
505(b)(2) application is required to contain an appropriate patent
certification or statement described in Sec. 314.50(i) or a
recertification for a previously submitted paragraph IV certification if
approval is sought for any of the following types of amendments:
(i) To add a new indication or other condition of use;
(ii) To add a new strength;
(iii) To make other than minor changes in product formulation; or
(iv) To change the physical form or crystalline structure of the
active ingredient.
(2) If the amendment to the 505(b)(2) application does not contain a
patent certification or statement, the applicant must verify that the
proposed change described in the amendment is not one of the types of
amendments described in paragraph (f)(1) of this section.
[50 FR 7493, Feb. 22, 1985, as amended at 57 FR 17983, Apr. 28, 1992; 58
FR 47352, Sept. 8, 1993; 63 FR 5252, Feb. 2, 1998; 69 FR 18764, Apr. 8,
2004; 73 FR 39608, July 10, 2008; 81 FR 69648, Oct. 6, 2016]
Sec. 314.65 Withdrawal by the applicant of an unapproved application.
An applicant may at any time withdraw an application that is not yet
approved by notifying the Food and Drug Administration in writing. If,
by the time it receives such notice, the agency has identified any
deficiencies in the application, we will list such deficiencies in the
letter we send the applicant acknowledging the withdrawal. A decision to
withdraw the application is without prejudice to refiling. The agency
will retain the application and will provide a copy to the applicant on
request under the fee schedule in Sec. 20.45 of FDA's public
information regulations.
[50 FR 7493, Feb. 22, 1985, as amended at 68 FR 25287, May 12, 2003; 73
FR 39609, July 10, 2008]
[[Page 127]]
Sec. 314.70 Supplements and other changes to an approved NDA.
(a) Changes to an approved NDA. (1)(i) Except as provided in
paragraph (a)(1)(ii) of this section, the applicant must notify FDA
about each change in each condition established in an approved NDA
beyond the variations already provided for in the NDA. The notice is
required to describe the change fully. Depending on the type of change,
the applicant must notify FDA about the change in a supplement under
paragraph (b) or (c) of this section or by inclusion of the information
in the annual report to the NDA under paragraph (d) of this section.
(ii) The submission and grant of a written request for an exception
or alternative under Sec. 201.26 of this chapter satisfies the
applicable requirements in paragraphs (a) through (c) of this section.
However, any grant of a request for an exception or alternative under
Sec. 201.26 of this chapter must be reported as part of the annual
report to the NDA under paragraph (d) of this section.
(2) The NDA holder must assess the effects of the change before
distributing a drug product made with a manufacturing change.
(3) Notwithstanding the requirements of paragraphs (b) and (c) of
this section, an applicant must make a change provided for in those
paragraphs in accordance with a regulation or guidance that provides for
a less burdensome notification of the change (for example, by submission
of a supplement that does not require approval prior to distribution of
the product or in an annual report).
(4) The applicant must promptly revise all promotional labeling and
advertising to make it consistent with any labeling change implemented
in accordance with paragraphs (b) and (c) of this section.
(5) Except for a supplement providing for a change in the labeling,
the applicant must include in each supplement and amendment to a
supplement providing for a change under paragraph (b) or (c) of this
section a statement certifying that a field copy has been provided in
accordance with Sec. 314.440(a)(4).
(6) A supplement or annual report must include a list of all changes
contained in the supplement or annual report. For supplements, this list
must be provided in the submission.
(b) Changes requiring supplement submission and approval prior to
distribution of the product made using the change (major changes). (1) A
supplement must be submitted for any change in the drug substance, drug
product, production process, quality controls, equipment, or facilities
that has a substantial potential to have an adverse effect on the
identity, strength, quality, purity, or potency of the drug product as
these factors may relate to the safety or effectiveness of the drug
product.
(2) These changes include, but are not limited to:
(i) Except those described in paragraphs (c) and (d) of this
section, changes in the qualitative or quantitative formulation of the
drug product, including inactive ingredients, or in the specifications
provided in the approved NDA;
(ii) Changes requiring completion of studies in accordance with part
320 of this chapter to demonstrate the equivalence of the drug product
to the drug product as manufactured without the change or to the
reference listed drug;
(iii) Changes that may affect drug substance or drug product
sterility assurance, such as changes in drug substance, drug product, or
component sterilization method(s) or an addition, deletion, or
substitution of steps in an aseptic processing operation;
(iv) Changes in the synthesis or manufacture of the drug substance
that may affect the impurity profile and/or the physical, chemical, or
biological properties of the drug substance;
(v) The following labeling changes:
(A) Changes in labeling, except those described in paragraphs
(c)(6)(iii), (d)(2)(ix), or (d)(2)(x) of this section;
(B) If applicable, any change to a Medication Guide required under
part 208 of this chapter, except for changes in the information
specified in Sec. 208.20(b)(8)(iii) and (b)(8)(iv) of this chapter; and
(C) Any change to the information required by Sec. 201.57(a) of
this chapter, with the following exceptions that may be reported in an
annual report under paragraph (d)(2)(x) of this section:
[[Page 128]]
(1) Removal of a listed section(s) specified in Sec. 201.57(a)(5)
of this chapter; and
(2) Changes to the most recent revision date of the labeling as
specified in Sec. 201.57(a)(15) of this chapter.
(vi) Changes in a drug product container closure system that
controls the drug product delivered to a patient or changes in the type
(e.g., glass to high density polyethylene (HDPE), HDPE to polyvinyl
chloride, vial to syringe) or composition (e.g., one HDPE resin to
another HDPE resin) of a packaging component that may affect the
impurity profile of the drug product.
(vii) Changes solely affecting a natural product, a recombinant DNA-
derived protein/polypeptide, or a complex or conjugate of a drug
substance with a monoclonal antibody for the following:
(A) Changes in the virus or adventitious agent removal or
inactivation method(s);
(B) Changes in the source material or cell line; and
(C) Establishment of a new master cell bank or seed.
(viii) Changes to a drug product under an NDA that is subject to a
validity assessment because of significant questions regarding the
integrity of the data supporting that NDA.
(3) The applicant must obtain approval of a supplement from FDA
prior to distribution of a drug product made using a change under
paragraph (b) of this section. Except for submissions under paragraph
(e) of this section, the following information must be contained in the
supplement:
(i) A detailed description of the proposed change;
(ii) The drug product(s) involved;
(iii) The manufacturing site(s) or area(s) affected;
(iv) A description of the methods used and studies performed to
assess the effects of the change;
(v) The data derived from such studies;
(vi) For a natural product, a recombinant DNA-derived protein/
polypeptide, or a complex or conjugate of a drug substance with a
monoclonal antibody, relevant validation protocols and a list of
relevant standard operating procedures must be provided in addition to
the requirements in paragraphs (b)(3)(iv) and (b)(3)(v) of this section;
and
(vii) For sterilization process and test methodologies related to
sterilization process validation, relevant validation protocols and a
list of relevant standard operating procedures must be provided in
addition to the requirements in paragraphs (b)(3)(iv) and (b)(3)(v) of
this section.
(4) An applicant may ask FDA to expedite its review of a supplement
for public health reasons or if a delay in making the change described
in it would impose an extraordinary hardship on the applicant. Such a
supplement should be plainly marked: ``Prior Approval Supplement-
Expedited Review Requested.''
(c) Changes requiring supplement submission at least 30 days prior
to distribution of the drug product made using the change (moderate
changes). (1) A supplement must be submitted for any change in the drug
substance, drug product, production process, quality controls,
equipment, or facilities that has a moderate potential to have an
adverse effect on the identity, strength, quality, purity, or potency of
the drug product as these factors may relate to the safety or
effectiveness of the drug product. If the supplement provides for a
labeling change under paragraph (c)(6)(iii) of this section, 12 copies
of the final printed labeling must be included.
(2) These changes include, but are not limited to:
(i) A change in the container closure system that does not affect
the quality of the drug product, except those described in paragraphs
(b) and (d) of this section; and
(ii) Changes solely affecting a natural protein, a recombinant DNA-
derived protein/polypeptide or a complex or conjugate of a drug
substance with a monoclonal antibody, including:
(A) An increase or decrease in production scale during finishing
steps that involves different equipment; and
(B) Replacement of equipment with that of a different design that
does not affect the process methodology or process operating parameters.
(iii) Relaxation of an acceptance criterion or deletion of a test to
comply with an official compendium that is
[[Page 129]]
consistent with FDA statutory and regulatory requirements.
(3) A supplement submitted under paragraph (c)(1) of this section is
required to give a full explanation of the basis for the change and
identify the date on which the change is to be made. The supplement must
be labeled ``Supplement--Changes Being Effected in 30 Days'' or, if
applicable under paragraph (c)(6) of this section, ``Supplement--Changes
Being Effected.''
(4) Pending approval of the supplement by FDA, except as provided in
paragraph (c)(6) of this section, distribution of the drug product made
using the change may begin not less than 30 days after receipt of the
supplement by FDA. The information listed in paragraphs (b)(3)(i)
through (b)(3)(vii) of this section must be contained in the supplement.
(5) The applicant must not distribute the drug product made using
the change if within 30 days following FDA's receipt of the supplement,
FDA informs the applicant that either:
(i) The change requires approval prior to distribution of the drug
product in accordance with paragraph (b) of this section; or
(ii) Any of the information required under paragraph (c)(4) of this
section is missing; the applicant must not distribute the drug product
made using the change until the supplement has been amended to provide
the missing information.
(6) The agency may designate a category of changes for the purpose
of providing that, in the case of a change in such category, the holder
of an approved NDA may commence distribution of the drug product
involved upon receipt by the agency of a supplement for the change.
These changes include, but are not limited to:
(i) Addition to a specification or changes in the methods or
controls to provide increased assurance that the drug substance or drug
product will have the characteristics of identity, strength, quality,
purity, or potency that it purports or is represented to possess;
(ii) A change in the size and/or shape of a container for a
nonsterile drug product, except for solid dosage forms, without a change
in the labeled amount of drug product or from one container closure
system to another;
(iii) Changes in the labeling to reflect newly acquired information,
except for changes to the information required in Sec. 201.57(a) of
this chapter (which must be made under paragraph (b)(2)(v)(C) of this
section), to accomplish any of the following:
(A) To add or strengthen a contraindication, warning, precaution, or
adverse reaction for which the evidence of a causal association
satisfies the standard for inclusion in the labeling under Sec.
201.57(c) of this chapter;
(B) To add or strengthen a statement about drug abuse, dependence,
psychological effect, or overdosage;
(C) To add or strengthen an instruction about dosage and
administration that is intended to increase the safe use of the drug
product;
(D) To delete false, misleading, or unsupported indications for use
or claims for effectiveness; or
(E) Any labeling change normally requiring a supplement submission
and approval prior to distribution of the drug product that FDA
specifically requests be submitted under this provision.
(7) If the agency disapproves the supplemental NDA, it may order the
manufacturer to cease distribution of the drug product(s) made with the
manufacturing change.
(d) Changes to be described in an annual report (minor changes). (1)
Changes in the drug substance, drug product, production process, quality
controls, equipment, or facilities that have a minimal potential to have
an adverse effect on the identity, strength, quality, purity, or potency
of the drug product as these factors may relate to the safety or
effectiveness of the drug product must be documented by the applicant in
the next annual report in accordance with Sec. 314.81(b)(2).
(2) These changes include, but are not limited to:
(i) Any change made to comply with a change to an official
compendium, except a change described in paragraph (c)(2)(iii) of this
section, that is consistent with FDA statutory and regulatory
requirements.
[[Page 130]]
(ii) The deletion or reduction of an ingredient intended to affect
only the color of the drug product;
(iii) Replacement of equipment with that of the same design and
operating principles except those equipment changes described in
paragraph (c) of this section;
(iv) A change in the size and/or shape of a container containing the
same number of dosage units for a nonsterile solid dosage form drug
product, without a change from one container closure system to another;
(v) A change within the container closure system for a nonsterile
drug product, based upon a showing of equivalency to the approved system
under a protocol approved in the NDA or published in an official
compendium;
(vi) An extension of an expiration dating period based upon full
shelf life data on production batches obtained from a protocol approved
in the NDA;
(vii) The addition or revision of an alternative analytical
procedure that provides the same or increased assurance of the identity,
strength, quality, purity, or potency of the material being tested as
the analytical procedure described in the approved NDA, or deletion of
an alternative analytical procedure;
(viii) The addition by embossing, debossing, or engraving of a code
imprint to a solid oral dosage form drug product other than a modified
release dosage form, or a minor change in an existing code imprint;
(ix) A change in the labeling concerning the description of the drug
product or in the information about how the drug product is supplied,
that does not involve a change in the dosage strength or dosage form;
and
(x) An editorial or similar minor change in labeling, including a
change to the information allowed by paragraphs (b)(2)(v)(C)(1) and (2)
of this section.
(3) For changes under this category, the applicant is required to
submit in the annual report:
(i) A statement by the holder of the approved NDA that the effects
of the change have been assessed;
(ii) A full description of the manufacturing and controls changes,
including the manufacturing site(s) or area(s) involved;
(iii) The date each change was implemented;
(iv) Data from studies and tests performed to assess the effects of
the change; and,
(v) For a natural product, recombinant DNA-derived protein/
polypeptide, complex or conjugate of a drug substance with a monoclonal
antibody, sterilization process or test methodology related to
sterilization process validation, a cross-reference to relevant
validation protocols and/or standard operating procedures.
(e) Protocols. An applicant may submit one or more protocols
describing the specific tests and studies and acceptance criteria to be
achieved to demonstrate the lack of adverse effect for specified types
of manufacturing changes on the identity, strength, quality, purity, and
potency of the drug product as these factors may relate to the safety or
effectiveness of the drug product. Any such protocols, if not included
in the approved NDA, or changes to an approved protocol, must be
submitted as a supplement requiring approval from FDA prior to
distribution of a drug product produced with the manufacturing change.
The supplement, if approved, may subsequently justify a reduced
reporting category for the particular change because the use of the
protocol for that type of change reduces the potential risk of an
adverse effect.
(f) Patent information. The applicant must comply with the patent
information requirements under section 505(c)(2) of the Federal Food,
Drug, and Cosmetic Act and Sec. 314.53.
(g) Claimed exclusivity. If an applicant claims exclusivity under
Sec. 314.108 upon approval of a supplement for change to its previously
approved drug product, the applicant must include with its supplement
the information required under Sec. 314.50(j).
(h) Different drug. An applicant may not supplement a 505(b)(2)
application to seek approval of a drug that is a different drug from the
drug in the approved 505(b)(2) application. For purposes of this
paragraph (h), a drug is a different drug if it has been modified to
[[Page 131]]
have a different active ingredient, different route of administration,
different dosage form, or difference in excipients that requires either
a separate clinical study to establish safety or effectiveness or, for
topical products, that requires a separate in vivo demonstration of
bioequivalence. However, notwithstanding the limitation described in
this paragraph (h), an applicant may supplement the 505(b)(2)
application to seek approval of a different strength.
[69 FR 18764, Apr. 8, 2004, as amended at 71 FR 3997, Jan. 24, 2006; 72
FR 73600, Dec. 28, 2007; 73 FR 49609, Aug. 22, 2008; 81 FR 69648, Oct.
6, 2016]
Sec. 314.71 Procedures for submission of a supplement to an approved
application.
(a) Only the applicant may submit a supplement to an application.
(b) All procedures and actions that apply to an application under
Sec. 314.50 also apply to supplements, except that the information
required in the supplement is limited to that needed to support the
change. A supplement is required to contain an archival copy and a
review copy that include an application form and appropriate technical
sections, samples, and labeling; except that a supplement for a change
other than a change in labeling is required also to contain a field
copy.
(c) All procedures and actions that apply to applications under this
part, including actions by applicants and the Food and Drug
Administration, also apply to supplements except as specified otherwise
in this part.
[50 FR 7493, Feb. 22, 1985, as amended at 50 FR 21238, May 23, 1985; 58
FR 47352, Sept. 8, 1993; 67 FR 9586, Mar. 4, 2002; 73 FR 39609, July 10,
2008]
Sec. 314.72 Change in ownership of an application.
(a) An applicant may transfer ownership of its application. At the
time of transfer the new and former owners are required to submit
information to the Food and Drug Administration as follows:
(1) The former owner shall submit a letter or other document that
states that all rights to the application have been transferred to the
new owner.
(2) The new owner shall submit an application form signed by the new
owner and a letter or other document containing the following:
(i) The new owner's commitment to agreements, promises, and
conditions made by the former owner and contained in the application;
(ii) The date that the change in ownership is effective; and
(iii) Either a statement that the new owner has a complete copy of
the approved application, including supplements and records that are
required to be kept under Sec. 314.81, or a request for a copy of the
application from FDA's files. FDA will provide a copy of the application
to the new owner under the fee schedule in Sec. 20.45 of FDA's public
information regulations.
(b) The new owner shall advise FDA about any change in the
conditions in the approved application under Sec. 314.70, except the
new owner may advise FDA in the next annual report about a change in the
drug product's label or labeling to change the product's brand or the
name of its manufacturer, packer, or distributor.
[50 FR 7493, Feb. 22, 1985; 50 FR 14212, Apr. 11, 1985, as amended at 50
FR 21238, May 23, 1985; 67 FR 9586, Mar. 4, 2002; 68 FR 25287, May 12,
2003]
Sec. 314.80 Postmarketing reporting of adverse drug experiences.
(a) Definitions. The following definitions of terms apply to this
section:
Adverse drug experience. Any adverse event associated with the use
of a drug in humans, whether or not considered drug related, including
the following: An adverse event occurring in the course of the use of a
drug product in professional practice; an adverse event occurring from
drug overdose whether accidental or intentional; an adverse event
occurring from drug abuse; an adverse event occurring from drug
withdrawal; and any failure of expected pharmacological action.
Individual case safety report (ICSR). A description of an adverse
drug experience related to an individual patient or subject.
ICSR attachments. Documents related to the adverse drug experience
described in an ICSR, such as medical
[[Page 132]]
records, hospital discharge summaries, or other documentation.
Disability. A substantial disruption of a person's ability to
conduct normal life functions.
Life-threatening adverse drug experience. Any adverse drug
experience that places the patient, in the view of the initial reporter,
at immediate risk of death from the adverse drug experience as it
occurred, i.e., it does not include an adverse drug experience that, had
it occurred in a more severe form, might have caused death.
Serious adverse drug experience. Any adverse drug experience
occurring at any dose that results in any of the following outcomes:
Death, a life-threatening adverse drug experience, inpatient
hospitalization or prolongation of existing hospitalization, a
persistent or significant disability/incapacity, or a congenital
anomaly/birth defect. Important medical events that may not result in
death, be life-threatening, or require hospitalization may be considered
a serious adverse drug experience when, based upon appropriate medical
judgment, they may jeopardize the patient or subject and may require
medical or surgical intervention to prevent one of the outcomes listed
in this definition. Examples of such medical events include allergic
bronchospasm requiring intensive treatment in an emergency room or at
home, blood dyscrasias or convulsions that do not result in inpatient
hospitalization, or the development of drug dependency or drug abuse.
Unexpected adverse drug experience. Any adverse drug experience that
is not listed in the current labeling for the drug product. This
includes events that may be symptomatically and pathophysiologically
related to an event listed in the labeling, but differ from the event
because of greater severity or specificity. For example, under this
definition, hepatic necrosis would be unexpected (by virtue of greater
severity) if the labeling only referred to elevated hepatic enzymes or
hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis
would be unexpected (by virtue of greater specificity) if the labeling
only listed cerebral vascular accidents. ``Unexpected,'' as used in this
definition, refers to an adverse drug experience that has not been
previously observed (i.e., included in the labeling) rather than from
the perspective of such experience not being anticipated from the
pharmacological properties of the pharmaceutical product.
(b) Review of adverse drug experiences. Each applicant having an
approved application under Sec. 314.50 or, in the case of a 505(b)(2)
application, an effective approved application, must promptly review all
adverse drug experience information obtained or otherwise received by
the applicant from any source, foreign or domestic, including
information derived from commercial marketing experience, postmarketing
clinical investigations, postmarketing epidemiological/surveillance
studies, reports in the scientific literature, and unpublished
scientific papers. Applicants are not required to resubmit to FDA
adverse drug experience reports forwarded to the applicant by FDA;
however, applicants must submit all followup information on such reports
to FDA. Any person subject to the reporting requirements under paragraph
(c) of this section must also develop written procedures for the
surveillance, receipt, evaluation, and reporting of postmarketing
adverse drug experiences to FDA.
(c) Reporting requirements. The applicant must submit to FDA adverse
drug experience information as described in this section. Except as
provided in paragraph (g)(2) of this section, these reports must be
submitted to the Agency in electronic format as described in paragraph
(g)(1) of this section.
(1)(i) Postmarketing 15-day ``Alert reports''. The applicant must
report each adverse drug experience that is both serious and unexpected,
whether foreign or domestic, as soon as possible but no later than 15
calendar days from initial receipt of the information by the applicant.
(ii) Postmarketing 15-day ``Alert reports''--followup. The applicant
must promptly investigate all adverse drug experiences that are the
subject of these postmarketing 15-day Alert reports and must submit
followup reports within 15 calendar days of receipt of new information
or as requested by FDA. If additional information is not
[[Page 133]]
obtainable, records should be maintained of the unsuccessful steps taken
to seek additional information.
(iii) Submission of reports. The requirements of paragraphs
(c)(1)(i) and (c)(1)(ii) of this section, concerning the submission of
postmarketing 15-day Alert reports, also apply to any person other than
the applicant whose name appears on the label of an approved drug
product as a manufacturer, packer, or distributor (nonapplicant). To
avoid unnecessary duplication in the submission to FDA of reports
required by paragraphs (c)(1)(i) and (c)(1)(ii) of this section,
obligations of a nonapplicant may be met by submission of all reports of
serious adverse drug experiences to the applicant. If a nonapplicant
elects to submit adverse drug experience reports to the applicant rather
than to FDA, the nonapplicant must submit, by any appropriate means,
each report to the applicant within 5 calendar days of initial receipt
of the information by the nonapplicant, and the applicant must then
comply with the requirements of this section. Under this circumstance,
the nonapplicant must maintain a record of this action which must
include:
(A) A copy of each adverse drug experience report;
(B) The date the report was received by the nonapplicant;
(C) The date the report was submitted to the applicant; and
(D) The name and address of the applicant.
(2) Periodic adverse drug experience reports. (i) The applicant must
report each adverse drug experience not reported under paragraph
(c)(1)(i) of this section at quarterly intervals, for 3 years from the
date of approval of the application, and then at annual intervals. The
applicant must submit each quarterly report within 30 days of the close
of the quarter (the first quarter beginning on the date of approval of
the application) and each annual report within 60 days of the
anniversary date of approval of the application. Upon written notice,
FDA may extend or reestablish the requirement that an applicant submit
quarterly reports, or require that the applicant submit reports under
this section at different times than those stated. For example, the
agency may reestablish a quarterly reporting requirement following the
approval of a major supplement. Followup information to adverse drug
experiences submitted in a periodic report may be submitted in the next
periodic report.
(ii) Each periodic report is required to contain:
(A) Descriptive information. (1) A narrative summary and analysis of
the information in the report;
(2) An analysis of the 15-day Alert reports submitted during the
reporting interval (all 15-day Alert reports being appropriately
referenced by the applicant's patient identification code, adverse
reaction term(s), and date of submission to FDA);
(3) A history of actions taken since the last report because of
adverse drug experiences (for example, labeling changes or studies
initiated); and
(4) An index consisting of a line listing of the applicant's patient
identification code, and adverse reaction term(s) for all ICSRs
submitted under paragraph (c)(2)(ii)(B) of this section.
(B) ICSRs for serious, expected, and nonserious adverse drug
experiences. An ICSR for each adverse drug experience not reported under
paragraph (c)(1)(i) of this section (all serious, expected and
nonserious adverse drug experiences). All such ICSRs must be submitted
to FDA (either individually or in one or more batches) within the
timeframe specified in paragraph (c)(2)(i) of this section. ICSRs must
only be submitted to FDA once.
(iii) Periodic reporting, except for information regarding 15-day
Alert reports, does not apply to adverse drug experience information
obtained from postmarketing studies (whether or not conducted under an
investigational new drug application), from reports in the scientific
literature, and from foreign marketing experience.
(d) Scientific literature. A 15-day Alert report based on
information in the scientific literature must be accompanied by a copy
of the published article. The 15-day reporting requirements in paragraph
(c)(1)(i) of this section (i.e., serious, unexpected adverse drug
experiences) apply only to reports found in scientific and medical
journals either
[[Page 134]]
as case reports or as the result of a formal clinical trial.
(e) Postmarketing studies. An applicant is not required to submit a
15-day Alert report under paragraph (c) of this section for an adverse
drug experience obtained from a postmarketing study (whether or not
conducted under an investigational new drug application) unless the
applicant concludes that there is a reasonable possibility that the drug
caused the adverse experience.
(f) Information reported on ICSRs. ICSRs include the following
information:
(1) Patient information.
(i) Patient identification code;
(ii) Patient age at the time of adverse drug experience, or date of
birth;
(iii) Patient gender; and
(iv) Patient weight.
(2) Adverse drug experience.
(i) Outcome attributed to adverse drug experience;
(ii) Date of adverse drug experience;
(iii) Date of ICSR submission;
(iv) Description of adverse drug experience (including a concise
medical narrative);
(v) Adverse drug experience term(s);
(vi) Description of relevant tests, including dates and laboratory
data; and
(vii) Other relevant patient history, including preexisting medical
conditions.
(3) Suspect medical product(s).
(i) Name;
(ii) Dose, frequency, and route of administration used;
(iii) Therapy dates;
(iv) Diagnosis for use (indication);
(v) Whether the product is a prescription or nonprescription
product;
(vi) Whether the product is a combination product as defined in
Sec. 3.2(e) of this chapter;
(vii) Whether adverse drug experience abated after drug use stopped
or dose reduced;
(viii) Whether adverse drug experience reappeared after
reintroduction of drug;
(ix) Lot number;
(x) Expiration date;
(xi) National Drug Code (NDC) number; and
(xii) Concomitant medical products and therapy dates.
(4) Initial reporter information.
(i) Name, address, and telephone number;
(ii) Whether the initial reporter is a health care professional; and
(iii) Occupation, if a health care professional.
(5) Applicant information.
(i) Applicant name and contact office address;
(ii) Telephone number;
(iii) Report source, such as spontaneous, literature, or study;
(iv) Date the report was received by applicant;
(v) Application number and type;
(vi) Whether the ICSR is a 15-day ``Alert report'';
(vii) Whether the ICSR is an initial report or followup report; and
(viii) Unique case identification number, which must be the same in
the initial report and any subsequent followup report(s).
(g) Electronic format for submissions. (1) Safety report
submissions, including ICSRs, ICSR attachments, and the descriptive
information in periodic reports, must be in an electronic format that
FDA can process, review, and archive. FDA will issue guidance on how to
provide the electronic submission (e.g., method of transmission, media,
file formats, preparation and organization of files).
(2) An applicant or nonapplicant may request, in writing, a
temporary waiver of the requirements in paragraph (g)(1) of this
section. These waivers will be granted on a limited basis for good cause
shown. FDA will issue guidance on requesting a waiver of the
requirements in paragraph (g)(1) of this section.
(h) Multiple reports. An applicant should not include in reports
under this section any adverse drug experiences that occurred in
clinical trials if they were previously submitted as part of the
approved application. If a report applies to a drug for which an
applicant holds more than one approved application, the applicant should
submit the report to the application that was first approved. If a
report refers to more than one drug marketed by an applicant, the
applicant should submit the report to the application for the drug
listed first in the report.
[[Page 135]]
(i) Patient privacy. An applicant should not include in reports
under this section the names and addresses of individual patients;
instead, the applicant should assign a unique code for identification of
the patient. The applicant should include the name of the reporter from
whom the information was received as part of the initial reporter
information, even when the reporter is the patient. The names of
patients, health care professionals, hospitals, and geographical
identifiers in adverse drug experience reports are not releasable to the
public under FDA's public information regulations in part 20 of this
chapter.
(j) Recordkeeping. The applicant must maintain for a period of 10
years records of all adverse drug experiences known to the applicant,
including raw data and any correspondence relating to adverse drug
experiences.
(k) Withdrawal of approval. If an applicant fails to establish and
maintain records and make reports required under this section, FDA may
withdraw approval of the application and, thus, prohibit continued
marketing of the drug product that is the subject of the application.
(l) Disclaimer. A report or information submitted by an applicant
under this section (and any release by FDA of that report or
information) does not necessarily reflect a conclusion by the applicant
or FDA that the report or information constitutes an admission that the
drug caused or contributed to an adverse effect. An applicant need not
admit, and may deny, that the report or information submitted under this
section constitutes an admission that the drug caused or contributed to
an adverse effect. For purposes of this provision, the term
``applicant'' also includes any person reporting under paragraph
(c)(1)(iii) of this section.
[50 FR 7493, Feb. 22, 1985; 50 FR 14212, Apr. 11, 1985, as amended at 50
FR 21238, May 23, 1985; 51 FR 24481, July 3, 1986; 52 FR 37936, Oct. 13,
1987; 55 FR 11580, Mar. 29, 1990; 57 FR 17983, Apr. 28, 1992; 62 FR
34168, June 25, 1997; 62 FR 52251, Oct. 7, 1997; 63 FR 14611, Mar. 26,
1998; 67 FR 9586, Mar. 4, 2002; 69 FR 13473, Mar. 23, 2004; 74 FR 13113,
Mar. 26, 2009; 79 FR 33088, June 10, 2014]
Sec. 314.81 Other postmarketing reports.
(a) Applicability. Each applicant shall make the reports for each of
its approved applications and abbreviated applications required under
this section and section 505(k) of the act.
(b) Reporting requirements. The applicant shall submit to the Food
and Drug Administration at the specified times two copies of the
following reports:
(1) NDA--Field alert report. The applicant shall submit information
of the following kinds about distributed drug products and articles to
the FDA district office that is responsible for the facility involved
within 3 working days of receipt by the applicant. The information may
be provided by telephone or other rapid communication means, with prompt
written followup. The report and its mailing cover should be plainly
marked: ``NDA--Field Alert Report.''
(i) Information concerning any incident that causes the drug product
or its labeling to be mistaken for, or applied to, another article.
(ii) Information concerning any bacteriological contamination, or
any significant chemical, physical, or other change or deterioration in
the distributed drug product, or any failure of one or more distributed
batches of the drug product to meet the specification established for it
in the application.
(2) Annual report. The applicant shall submit each year within 60
days of the anniversary date of U.S. approval of the application, two
copies of the report to the FDA division responsible for reviewing the
application. Each annual report is required to be accompanied by a
completed transmittal Form FDA 2252 (Transmittal of Periodic Reports for
Drugs for Human Use), and must include all the information required
under this section that the applicant received or otherwise obtained
during the annual reporting interval that ends on the U.S. anniversary
date. The report is required to contain in the order listed:
(i) Summary. A brief summary of significant new information from the
previous year that might affect the safety, effectiveness, or labeling
of the drug product. The report is also required to contain a brief
description of actions the applicant has taken or intends to
[[Page 136]]
take as a result of this new information, for example, submit a labeling
supplement, add a warning to the labeling, or initiate a new study. The
summary shall briefly state whether labeling supplements for pediatric
use have been submitted and whether new studies in the pediatric
population to support appropriate labeling for the pediatric population
have been initiated. Where possible, an estimate of patient exposure to
the drug product, with special reference to the pediatric population
(neonates, infants, children, and adolescents) shall be provided,
including dosage form.
(ii)(a) Distribution data. Information about the quantity of the
drug product distributed under the approved application, including that
distributed to distributors. The information is required to include the
National Drug Code (NDC) number, the total number of dosage units of
each strength or potency distributed (e.g., 100,000/5 milligram tablets,
50,000/10 milliliter vials), and the quantities distributed for domestic
use and the quantities distributed for foreign use. Disclosure of
financial or pricing data is not required.
(b) Authorized generic drugs. If applicable, the date each
authorized generic drug (as defined in Sec. 314.3) entered the market,
the date each authorized generic drug ceased being distributed, and the
corresponding trade or brand name. Each dosage form and/or strength is a
different authorized generic drug and should be listed separately. The
first annual report submitted on or after January 25, 2010 must include
the information listed in this paragraph for any authorized generic drug
that was marketed during the time period covered by an annual report
submitted after January 1, 1999. If information is included in the
annual report with respect to any authorized generic drug, a copy of
that portion of the annual report must be sent to the Food and Drug
Administration, Center for Drug Evaluation and Research, Office of New
Drug Quality Assessment, Bldg. 21, rm. 2562, 10903 New Hampshire Ave.,
Silver Spring, MD 20993-0002, and marked ``Authorized Generic
Submission'' or, by e-mail, to the Authorized Generics electronic
mailbox at AuthorizedGenerics@fda.hhs.gov with ``Authorized Generic
Submission'' indicated in the subject line. However, at such time that
FDA has required that annual reports be submitted in an electronic
format, the information required by this paragraph must be submitted as
part of the annual report, in the electronic format specified for
submission of annual reports at that time, and not as a separate
submission under the preceding sentence in this paragraph.
(iii) Labeling. (a) Currently used professional labeling, patient
brochures or package inserts (if any), and a representative sample of
the package labels.
(b) The content of labeling required under Sec. 201.100(d)(3) of
this chapter (i.e., the package insert or professional labeling),
including all text, tables, and figures, must be submitted in electronic
format. Electronic format submissions must be in a form that FDA can
process, review, and archive. FDA will periodically issue guidance on
how to provide the electronic submission (e.g., method of transmission,
media, file formats, preparation and organization of files). Submissions
under this paragraph must be made in accordance with part 11 of this
chapter, except for the requirements of Sec. 11.10(a), (c) through (h),
and (k), and the corresponding requirements of Sec. 11.30.
(c) A summary of any changes in labeling that have been made since
the last report listed by date in the order in which they were
implemented, or if no changes, a statement of that fact.
(iv) Chemistry, manufacturing, and controls changes. (a) Reports of
experiences, investigations, studies, or tests involving chemical or
physical properties, or any other properties of the drug (such as the
drug's behavior or properties in relation to microorganisms, including
both the effects of the drug on microorganisms and the effects of
microorganisms on the drug). These reports are only required for new
information that may affect FDA's previous conclusions about the safety
or effectiveness of the drug product.
(b) A full description of the manufacturing and controls changes not
requiring a supplemental application under Sec. 314.70 (b) and (c),
listed by date in the order in which they were implemented.
[[Page 137]]
(v) Nonclinical laboratory studies. Copies of unpublished reports
and summaries of published reports of new toxicological findings in
animal studies and in vitro studies (e.g., mutagenicity) conducted by,
or otherwise obtained by, the applicant concerning the ingredients in
the drug product. The applicant shall submit a copy of a published
report if requested by FDA.
(vi) Clinical data. (a) Published clinical trials of the drug (or
abstracts of them), including clinical trials on safety and
effectiveness; clinical trials on new uses; biopharmaceutic,
pharmacokinetic, and clinical pharmacology studies; and reports of
clinical experience pertinent to safety (for example, epidemiologic
studies or analyses of experience in a monitored series of patients)
conducted by or otherwise obtained by the applicant. Review articles,
papers describing the use of the drug product in medical practice,
papers and abstracts in which the drug is used as a research tool,
promotional articles, press clippings, and papers that do not contain
tabulations or summaries of original data should not be reported.
(b) Summaries of completed unpublished clinical trials, or
prepublication manuscripts if available, conducted by, or otherwise
obtained by, the applicant. Supporting information should not be
reported. (A study is considered completed 1 year after it is
concluded.)
(c) Analysis of available safety and efficacy data in the pediatric
population and changes proposed in the labeling based on this
information. An assessment of data needed to ensure appropriate labeling
for the pediatric population shall be included.
(vii) Status reports of postmarketing study commitments. A status
report of each postmarketing study of the drug product concerning
clinical safety, clinical efficacy, clinical pharmacology, and
nonclinical toxicology that is required by FDA (e.g., accelerated
approval clinical benefit studies, pediatric studies) or that the
applicant has committed, in writing, to conduct either at the time of
approval of an application for the drug product or a supplement to an
application, or after approval of the application or a supplement. For
pediatric studies, the status report shall include a statement
indicating whether postmarketing clinical studies in pediatric
populations were required by FDA under Sec. 201.23 of this chapter. The
status of these postmarketing studies shall be reported annually until
FDA notifies the applicant, in writing, that the agency concurs with the
applicant's determination that the study commitment has been fulfilled
or that the study is either no longer feasible or would no longer
provide useful information.
(a) Content of status report. The following information must be
provided for each postmarketing study reported under this paragraph:
(1) Applicant's name.
(2) Product name. Include the approved drug product's established
name and proprietary name, if any.
(3) NDA, ANDA, and supplement number.
(4) Date of U.S. approval of NDA or ANDA.
(5) Date of postmarketing study commitment.
(6) Description of postmarketing study commitment. The description
must include sufficient information to uniquely describe the study. This
information may include the purpose of the study, the type of study, the
patient population addressed by the study and the indication(s) and
dosage(s) that are to be studied.
(7) Schedule for completion and reporting of the postmarketing study
commitment. The schedule should include the actual or projected dates
for submission of the study protocol to FDA, completion of patient
accrual or initiation of an animal study, completion of the study,
submission of the final study report to FDA, and any additional
milestones or submissions for which projected dates were specified as
part of the commitment. In addition, it should include a revised
schedule, as appropriate. If the schedule has been previously revised,
provide both the original schedule and the most recent, previously
submitted revision.
(8) Current status of the postmarketing study commitment. The status
of each postmarketing study should be categorized using one of the
following terms that describes the study's status
[[Page 138]]
on the anniversary date of U.S. approval of the application or other
agreed upon date:
(i) Pending. The study has not been initiated, but does not meet the
criterion for delayed.
(ii) Ongoing. The study is proceeding according to or ahead of the
original schedule described under paragraph (b)(2)(vii)(a)(7) of this
section.
(iii) Delayed. The study is behind the original schedule described
under paragraph (b)(2)(vii)(a)(7) of this section.
(iv) Terminated. The study was ended before completion but a final
study report has not been submitted to FDA.
(v) Submitted. The study has been completed or terminated and a
final study report has been submitted to FDA.
(9) Explanation of the study's status. Provide a brief description
of the status of the study, including the patient accrual rate
(expressed by providing the number of patients or subjects enrolled to
date, and the total planned enrollment), and an explanation of the
study's status identified under paragraph (b)(2)(vii)(a)(8) of this
section. If the study has been completed, include the date the study was
completed and the date the final study report was submitted to FDA, as
applicable. Provide a revised schedule, as well as the reason(s) for the
revision, if the schedule under paragraph (b)(2)(vii)(a)(7) of this
section has changed since the last report.
(b) Public disclosure of information. Except for the information
described in this paragraph, FDA may publicly disclose any information
described in paragraph (b)(2)(vii) of this section, concerning a
postmarketing study, if the agency determines that the information is
necessary to identify the applicant or to establish the status of the
study, including the reasons, if any, for failure to conduct, complete,
and report the study. Under this section, FDA will not publicly disclose
trade secrets, as defined in Sec. 20.61 of this chapter, or
information, described in Sec. 20.63 of this chapter, the disclosure of
which would constitute an unwarranted invasion of personal privacy.
(viii) Status of other postmarketing studies. A status report of any
postmarketing study not included under paragraph (b)(2)(vii) of this
section that is being performed by, or on behalf of, the applicant. A
status report is to be included for any chemistry, manufacturing, and
controls studies that the applicant has agreed to perform and for all
product stability studies.
(ix) Log of outstanding regulatory business. To facilitate
communications between FDA and the applicant, the report may, at the
applicant's discretion, also contain a list of any open regulatory
business with FDA concerning the drug product subject to the application
(e.g., a list of the applicant's unanswered correspondence with the
agency, a list of the agency's unanswered correspondence with the
applicant).
(3) Other reporting--(i) Advertisements and promotional labeling.
The applicant shall submit specimens of mailing pieces and any other
labeling or advertising devised for promotion of the drug product at the
time of initial dissemination of the labeling and at the time of initial
publication of the advertisement for a prescription drug product.
Mailing pieces and labeling that are designed to contain samples of a
drug product are required to be complete, except the sample of the drug
product may be omitted. Each submission is required to be accompanied by
a completed transmittal Form FDA-2253 (Transmittal of Advertisements and
Promotional Labeling for Drugs for Human Use) and is required to include
a copy of the product's current professional labeling. Form FDA-2253 is
available on the Internet at http://www.fda.gov/opacom/morechoices/
fdaforms/cder.html.
(ii) Special reports. Upon written request the agency may require
that the applicant submit the reports under this section at different
times than those stated.
(iii) Notification of a permanent discontinuance or an interruption
in manufacturing. (a) An applicant of a prescription drug product must
notify FDA in writing of a permanent discontinuance of manufacture of
the drug product or an interruption in manufacturing of the drug product
that is likely to lead to a meaningful disruption in supply of that drug
in the United States if:
[[Page 139]]
(1) The drug product is life supporting, life sustaining, or
intended for use in the prevention or treatment of a debilitating
disease or condition, including any such drug used in emergency medical
care or during surgery; and
(2) The drug product is not a radiopharmaceutical drug product.
(b) Notifications required by paragraph (b)(3)(iii)(a) of this
section must be submitted to FDA electronically in a format that FDA can
process, review, and archive:
(1) At least 6 months prior to the date of the permanent
discontinuance or interruption in manufacturing; or
(2) If 6 months' advance notice is not possible because the
permanent discontinuance or interruption in manufacturing was not
reasonably anticipated 6 months in advance, as soon as practicable
thereafter, but in no case later than 5 business days after the
permanent discontinuance or interruption in manufacturing occurs.
(c) Notifications required by paragraph (b)(3)(iii)(a) of this
section must include the following information:
(1) The name of the drug subject to the notification, including the
NDC for such drug;
(2) The name of the applicant;
(3) Whether the notification relates to a permanent discontinuance
of the drug or an interruption in manufacturing of the drug;
(4) A description of the reason for the permanent discontinuance or
interruption in manufacturing; and
(5) The estimated duration of the interruption in manufacturing.
(d)(1) FDA will maintain a publicly available list of drugs that are
determined by FDA to be in shortage. This drug shortages list will
include the following information:
(i) The names and NDC(s) for such drugs;
(ii) The name of each applicant for such drugs;
(iii) The reason for the shortage, as determined by FDA from the
following categories: Requirements related to complying with good
manufacturing practices; regulatory delay; shortage of an active
ingredient; shortage of an inactive ingredient component;
discontinuation of the manufacture of the drug; delay in shipping of the
drug; demand increase for the drug; or other reason; and
(iv) The estimated duration of the shortage.
(2) FDA may choose not to make information collected to implement
this paragraph available on the drug shortages list or available under
section 506C(c) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C.
356c(c)) if FDA determines that disclosure of such information would
adversely affect the public health (such as by increasing the
possibility of hoarding or other disruption of the availability of the
drug to patients). FDA will also not provide information on the public
drug shortages list or under section 506C(c) of the Federal Food, Drug,
and Cosmetic Act that is protected by 18 U.S.C. 1905 or 5 U.S.C.
552(b)(4), including trade secrets and commercial or financial
information that is considered confidential or privileged under Sec.
20.61 of this chapter.
(e) If an applicant fails to submit a notification as required under
paragraph (b)(3)(iii)(a) of this section and in accordance with
paragraph (b)(3)(iii)(b) of this section, FDA will issue a letter to the
applicant informing it of such failure.
(1) Not later than 30 calendar days after the issuance of such a
letter, the applicant must submit to FDA a written response setting
forth the basis for noncompliance and providing the required
notification under paragraph (b)(3)(iii)(a) of this section and
including the information required under paragraph (b)(3)(iii)(c) of
this section; and
(2) Not later than 45 calendar days after the issuance of a letter
under paragraph (b)(3)(iii)(e) of this section, FDA will make the letter
and the applicant's response to the letter public, unless, after review
of the applicant's response, FDA determines that the applicant had a
reasonable basis for not notifying FDA as required under paragraph
(b)(3)(iii)(a) of this section.
(f) The following definitions of terms apply to paragraph
(b)(3)(iii) of this section:
Drug shortage or shortage means a period of time when the demand or
projected demand for the drug within the
[[Page 140]]
United States exceeds the supply of the drug.
Intended for use in the prevention or treatment of a debilitating
disease or condition means a drug product intended for use in the
prevention or treatment of a disease or condition associated with
mortality or morbidity that has a substantial impact on day-to-day
functioning.
Life supporting or life sustaining means a drug product that is
essential to, or that yields information that is essential to, the
restoration or continuation of a bodily function important to the
continuation of human life.
Meaningful disruption means a change in production that is
reasonably likely to lead to a reduction in the supply of a drug by a
manufacturer that is more than negligible and affects the ability of the
manufacturer to fill orders or meet expected demand for its product, and
does not include interruptions in manufacturing due to matters such as
routine maintenance or insignificant changes in manufacturing so long as
the manufacturer expects to resume operations in a short period of time.
(iv) Withdrawal of approved drug product from sale. (a) Within 30
calendar days of the withdrawal of an approved drug from sale,
applicants who are manufacturers, repackers, or relabelers subject to
part 207 of this chapter must submit the following information about the
drug, in accordance with the applicable requirements described in
Sec. Sec. 207.61 and 207.65:
(1) The National Drug Code (NDC);
(2) The identity of the drug by established name and by proprietary
name, if any;
(3) The new drug application number or abbreviated application
number;
(4) The date on which the drug is expected to be no longer in
commercial distribution. FDA requests that the reason for withdrawal of
the drug from sale be included with the information.
(b) Within 30 calendar days of the withdrawal of an approved drug
from sale, applicants who are not subject to part 207 of this chapter
must submit the information listed in paragraphs (b)(3)(iv)(a)(1)
through (4) of this section. The information must be submitted either
electronically or in writing to the Drug Registration and Listing
Office, Food and Drug Administration, Center for Drug Evaluation and
Research.
(c) Reporting under paragraph (b)(3)(iv)(a) of this section
constitutes compliance with the requirements of Sec. 207.57 of this
chapter to update drug listing information with respect to the
withdrawal from sale.
(c) General requirements--(1) Multiple applications. For all reports
required by this section, the applicant shall submit the information
common to more than one application only to the application first
approved, and shall not report separately on each application. The
submission is required to identify all the applications to which the
report applies.
(2) Patient identification. Applicants should not include in reports
under this section the names and addresses of individual patients;
instead, the applicant should code the patient names whenever possible
and retain the code in the applicant's files. The applicant shall
maintain sufficient patient identification information to permit FDA, by
using that information alone or along with records maintained by the
investigator of a study, to identify the name and address of individual
patients; this will ordinarily occur only when the agency needs to
investigate the reports further or when there is reason to believe that
the reports do not represent actual results obtained.
(d) Withdrawal of approval. If an applicant fails to make reports
required under this section, FDA may withdraw approval of the
application and, thus, prohibit continued marketing of the drug product
that is the subject of the application.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0001)
[50 FR 7493, Feb. 22, 1985; 50 FR 14212, Apr. 11, 1985, as amended at 50
FR 21238, May 23, 1985; 55 FR 11580, Mar. 29, 1990; 57 FR 17983, Apr.
28, 1992; 63 FR 66670, Dec. 2, 1998; 64 FR 401, Jan. 5, 1999; 65 FR
64617, Oct. 30, 2000; 66 FR 10815, Feb. 20, 2001; 68 FR 69019, Dec. 11,
2003; 69 FR 18766, Apr. 8, 2004; 69 FR 48775, Aug. 11, 2004; 72 FR
58999, Oct. 18, 2007; 74 FR 13113, Mar. 26, 2009; 74 FR 37167, July 28,
2009; 76 FR 78539, Dec. 19, 2011; 80 FR 38938, July 8, 2015; 81 FR
60221, Aug. 31, 2016]
[[Page 141]]
Sec. 314.90 Waivers.
(a) An applicant may ask the Food and Drug Administration to waive
under this section any requirement that applies to the applicant under
Sec. Sec. 314.50 through 314.81. An applicant may ask FDA to waive
under Sec. 314.126(c) any criteria of an adequate and well-controlled
study described in Sec. 314.126(b). A waiver request under this section
is required to be submitted with supporting documentation in an NDA, or
in an amendment or supplement to an NDA. The waiver request is required
to contain one of the following:
(1) An explanation why the applicant's compliance with the
requirement is unnecessary or cannot be achieved;
(2) A description of an alternative submission that satisfies the
purpose of the requirement; or
(3) Other information justifying a waiver.
(b) FDA may grant a waiver if it finds one of the following:
(1) The applicant's compliance with the requirement is unnecessary
for the agency to evaluate the NDA or compliance cannot be achieved;
(2) The applicant's alternative submission satisfies the
requirement; or
(3) The applicant's submission otherwise justifies a waiver.
(c) If FDA grants the applicant's waiver request with respect to a
requirement under Sec. Sec. 314.50 through 314.81, the waived
requirement will not constitute a basis for refusal to approve an NDA
under Sec. 314.125.
[50 FR 7493, Feb. 22, 1985, as amended at 50 FR 21238, May 23, 1985; 67
FR 9586, Mar. 4, 2002; 81 FR 69649, Oct. 6, 2016]
Subpart C_Abbreviated Applications
Source: 57 FR 17983, Apr. 28, 1992, unless otherwise noted.
Sec. 314.92 Drug products for which abbreviated applications may be
submitted.
(a) Abbreviated applications are suitable for the following drug
products within the limits set forth under Sec. 314.93:
(1) Drug products that are the same as a listed drug. A ``listed
drug'' is defined in Sec. 314.3. For determining the suitability of an
abbreviated new drug application, the term ``same as'' means identical
in active ingredient(s), dosage form, strength, route of administration,
and conditions of use, except that conditions of use for which approval
cannot be granted because of exclusivity or an existing patent may be
omitted. If a listed drug has been voluntarily withdrawn from or not
offered for sale by its manufacturer, a person who wishes to submit an
abbreviated new drug application for the drug shall comply with Sec.
314.122.
(2) [Reserved]
(3) Drug products that have been declared suitable for an
abbreviated new drug application submission by FDA through the petition
procedures set forth under Sec. 10.30 of this chapter and Sec. 314.93.
(b) FDA will publish in the list listed drugs for which abbreviated
applications may be submitted. The list is available from the
Superintendent of Documents, U.S. Government Printing Office,
Washington, DC 20402, 202-783-3238.
[57 FR 17983, Apr. 28, 1992, as amended at 64 FR 401, Jan. 5, 1999]
Sec. 314.93 Petition to request a change from a listed drug.
(a) The only changes from a listed drug for which the agency will
accept a petition under this section are those changes described in
paragraph (b) of this section. Petitions to submit ANDAs for other
changes from a listed drug will not be approved.
(b) A person who wants to submit an ANDA for a drug product which is
not identical to a listed drug in route of administration, dosage form,
and strength, or in which one active ingredient is substituted for one
of the active ingredients in a listed combination drug, must first
obtain permission from FDA to submit such an ANDA.
(c) To obtain permission to submit an ANDA for a change described in
paragraph (b) of this section, a person must submit and obtain approval
of a petition requesting the change. A person seeking permission to
request such a change from a reference listed drug
[[Page 142]]
shall submit a petition in accordance with Sec. 10.20 of this chapter
and in the format specified in Sec. 10.30 of this chapter. The petition
shall contain the information specified in Sec. 10.30 of this chapter
and any additional information required by this section. If any
provision of Sec. 10.20 or Sec. 10.30 of this chapter is inconsistent
with any provision of this section, the provisions of this section
apply.
(d) The petitioner shall identify a listed drug and include a copy
of the proposed labeling for the drug product that is the subject of the
petition and a copy of the approved labeling for the listed drug. The
petitioner may, under limited circumstances, identify more than one
listed drug, for example, when the proposed drug product is a
combination product that differs from the combination reference listed
drug with regard to an active ingredient, and the different active
ingredient is an active ingredient of a listed drug. The petitioner
shall also include information to show that:
(1) The active ingredients of the proposed drug product are of the
same pharmacological or therapeutic class as those of the reference
listed drug.
(2) The drug product can be expected to have the same therapeutic
effect as the reference listed drug when administered to patients for
each condition of use in the reference listed drug's labeling for which
the applicant seeks approval.
(3) If the proposed drug product is a combination product with one
different active ingredient, including a different ester or salt, from
the reference listed drug, that the different active ingredient has
previously been approved in a listed drug or is a drug that does not
meet the definition of ``new drug'' in section 201(p) of the Federal
Food, Drug, and Cosmetic Act.
(e) No later than 90 days after the date a petition that is
permitted under paragraph (a) of this section is submitted, FDA will
approve or disapprove the petition.
(1) FDA will approve a petition properly submited under this section
unless it finds that:
(i) Investigations must be conducted to show the safety and
effectiveness of the drug product or of any of its active ingredients,
its route of administration, dosage form, or strength which differs from
the reference listed drug; or
(ii) For a petition that seeks to change an active ingredient, the
drug product that is the subject of the petition is not a combination
drug; or
(iii) For a combination drug product that is the subject of the
petition and has an active ingredient different from the reference
listed drug:
(A) The drug product may not be adequately evaluated for approval as
safe and effective on the basis of the information required to be
submitted under Sec. 314.94; or
(B) The petition does not contain information to show that the
different active ingredient of the drug product is of the same
pharmacological or therapeutic class as the ingredient of the reference
listed drug that is to be changed and that the drug product can be
expected to have the same therapeutic effect as the reference listed
drug when administered to patients for each condition of use in the
listed drug's labeling for which the applicant seeks approval; or
(C) The different active ingredient is not an active ingredient in a
listed drug or a drug that meets the requirements of section 201(p) of
the Federal Food, Drug, and Cosmetic Act; or
(D) The remaining active ingredients are not identical to those of
the listed combination drug; or
(iv) Any of the proposed changes from the listed drug would
jeopardize the safe or effective use of the product so as to necessitate
significant labeling changes to address the newly introduced safety or
effectiveness problem; or
(v) FDA has determined that the reference listed drug has been
withdrawn from sale for safety or effectiveness reasons under Sec.
314.161, or the reference listed drug has been voluntarily withdrawn
from sale and the agency has not determined whether the withdrawal is
for safety or effectiveness reasons; or
(vi) A drug product is approved in an NDA for the change described
in the petition.
(2) For purposes of this paragraph, ``investigations must be
conducted''
[[Page 143]]
means that information derived from animal or clinical studies is
necessary to show that the drug product is safe or effective. Such
information may be contained in published or unpublished reports.
(3) If FDA approves a petition submitted under this section, the
agency's response may describe what additional information, if any, will
be required to support an ANDA for the drug product. FDA may, at any
time during the course of its review of an ANDA, request additional
information required to evaluate the change approved under the petition.
(f)(1) FDA may withdraw approval of a petition if the agency
receives any information demonstrating that the petition no longer
satisfies the conditions under paragraph (e) of this section.
(2) If, after approval of a petition and before approval of an ANDA
submitted pursuant to the approved petition, a drug product is approved
in an NDA for the change described in the petition, the petition and the
listed drug identified in the petition can no longer be the basis for
ANDA submission, irrespective of whether FDA has withdrawn approval of
the petition. A person seeking approval for such drug product must
submit a new ANDA that identifies the pharmaceutically equivalent
reference listed drug as the basis for ANDA submission and comply with
applicable regulatory requirements.
[57 FR 17983, Apr. 28, 1992, as amended at 81 FR 69649, Oct. 6, 2016]
Sec. 314.94 Content and format of an ANDA.
ANDAs are required to be submitted in the form and contain the
information required under this section. Three copies of the ANDA are
required, an archival copy, a review copy, and a field copy. FDA will
maintain guidance documents on the format and content of ANDAs to assist
applicants in their preparation.
(a) ANDAs. Except as provided in paragraph (b) of this section, the
applicant must submit a complete archival copy of the abbreviated new
drug application that includes the following:
(1) Application form. The applicant must submit a completed and
signed application form that contains the information described under
Sec. 314.50(a)(1), (a)(3), (a)(4), and (a)(5). The applicant must state
whether the submission is an ANDA under this section or a supplement to
an ANDA under Sec. 314.97.
(2) Table of contents. The archival copy of the ANDA is required to
contain a table of contents that shows the volume number and page number
of the contents of the submission.
(3) Basis for ANDA submission. An ANDA must refer to a listed drug.
Ordinarily, that listed drug will be the drug product selected by the
Agency as the reference standard for conducting bioequivalence testing.
The ANDA must contain:
(i) The name of the reference listed drug, including its dosage form
and strength. For an ANDA based on an approved petition under Sec.
10.30 of this chapter and Sec. 314.93, the reference listed drug must
be the same as the listed drug referenced in the approved petition.
(ii) A statement as to whether, according to the information
published in the list, the reference listed drug is entitled to a period
of marketing exclusivity under section 505(j)(5)(F) of the Federal Food,
Drug, and Cosmetic Act.
(iii) For an ANDA based on an approved petition under Sec. 10.30 of
this chapter and Sec. 314.93, a reference to the FDA-assigned docket
number for the petition and a copy of FDA's correspondence approving the
petition.
(4) Conditions of use. (i) A statement that the conditions of use
prescribed, recommended, or suggested in the labeling proposed for the
drug product have been previously approved for the reference listed
drug.
(ii) A reference to the applicant's annotated proposed labeling and
to the currently approved labeling for the reference listed drug
provided under paragraph (a)(8) of this section.
(5) Active ingredients. (i) For a single-active-ingredient drug
product, information to show that the active ingredient is the same as
that of the reference single-active-ingredient listed drug, as follows:
(A) A statement that the active ingredient of the proposed drug
product is the same as that of the reference listed drug.
[[Page 144]]
(B) A reference to the applicant's annotated proposed labeling and
to the currently approved labeling for the reference listed drug
provided under paragraph (a)(8) of this section.
(ii) For a combination drug product, information to show that the
active ingredients are the same as those of the reference listed drug
except for any different active ingredient that has been the subject of
an approved petition, as follows:
(A) A statement that the active ingredients of the proposed drug
product are the same as those of the reference listed drug, or if one of
the active ingredients differs from one of the active ingredients of the
reference listed drug and the ANDA is submitted under the approval of a
petition under Sec. 314.93 to vary such active ingredient, information
to show that the other active ingredients of the drug product are the
same as the other active ingredients of the reference listed drug,
information to show that the different active ingredient is an active
ingredient of another listed drug or of a drug that does not meet the
definition of ``new drug'' in section 201(p) of the Federal Food, Drug,
and Cosmetic Act, and such other information about the different active
ingredient that FDA may require.
(B) A reference to the applicant's annotated proposed labeling and
to the currently approved labeling for the reference listed drug
provided under paragraph (a)(8) of this section.
(6) Route of administration, dosage form, and strength. (i)
Information to show that the route of administration, dosage form, and
strength of the drug product are the same as those of the reference
listed drug except for any differences that have been the subject of an
approved petition, as follows:
(A) A statement that the route of administration, dosage form, and
strength of the proposed drug product are the same as those of the
reference listed drug.
(B) A reference to the applicant's annotated proposed labeling and
to the currently approved labeling for the reference listed drug
provided under paragraph (a)(8) of this section.
(ii) If the route of administration, dosage form, or strength of the
drug product differs from the reference listed drug and the ANDA is
submitted under an approved petition under Sec. 314.93, such
information about the different route of administration, dosage form, or
strength that FDA may require.
(7) Bioequivalence. (i) Information that shows that the drug product
is bioequivalent to the reference listed drug upon which the applicant
relies. A complete study report must be submitted for the bioequivalence
study upon which the applicant relies for approval. For all other
bioequivalence studies conducted on the same drug product formulation as
defined in Sec. 314.3(b), the applicant must submit either a complete
or summary report. If a summary report of a bioequivalence study is
submitted and FDA determines that there may be bioequivalence issues or
concerns with the product, FDA may require that the applicant submit a
complete report of the bioequivalence study to FDA; or
(ii) If the ANDA is submitted pursuant to a petition approved under
Sec. 314.93, the results of any bioavailability or bioequivalence
testing required by the Agency, or any other information required by the
Agency to show that the active ingredients of the proposed drug product
are of the same pharmacological or therapeutic class as those in the
reference listed drug and that the proposed drug product can be expected
to have the same therapeutic effect as the reference listed drug. If the
proposed drug product contains a different active ingredient than the
reference listed drug, FDA will consider the proposed drug product to
have the same therapeutic effect as the reference listed drug if the
applicant provides information demonstrating that:
(A) There is an adequate scientific basis for determining that
substitution of the specific proposed dose of the different active
ingredient for the dose of the member of the same pharmacological or
therapeutic class in the reference listed drug will yield a resulting
drug product whose safety and effectiveness have not been adversely
affected.
[[Page 145]]
(B) The unchanged active ingredients in the proposed drug product
are bioequivalent to those in the reference listed drug.
(C) The different active ingredient in the proposed drug product is
bioequivalent to an approved dosage form containing that ingredient and
approved for the same indication as the proposed drug product or is
bioequivalent to a drug product offered for that indication which does
not meet the definition of ``new drug'' under section 201(p) of the
Federal Food, Drug, and Cosmetic Act.
(iii) For each in vivo or in vitro bioequivalence study contained in
the ANDA:
(A) A description of the analytical and statistical methods used in
each study; and
(B) With respect to each study involving human subjects, a statement
that the study either was conducted in compliance with the institutional
review board regulations in part 56 of this chapter, or was not subject
to the regulations under Sec. 56.104 or Sec. 56.105 of this chapter,
and that it was conducted in compliance with the informed consent
regulations in part 50 of this chapter.
(8) Labeling--(i) Listed drug labeling. A copy of the currently
approved labeling (including, if applicable, any Medication Guide
required under part 208 of this chapter) for the listed drug referred to
in the ANDA, if the ANDA relies on a reference listed drug.
(ii) Copies of proposed labeling. Copies of the label and all
labeling for the drug product including, if applicable, any Medication
Guide required under part 208 of this chapter (4 copies of draft
labeling or 12 copies of final printed labeling).
(iii) Statement on proposed labeling. A statement that the
applicant's proposed labeling including, if applicable, any Medication
Guide required under part 208 of this chapter is the same as the
labeling of the reference listed drug except for differences annotated
and explained under paragraph (a)(8)(iv) of this section.
(iv) Comparison of approved and proposed labeling. A side-by-side
comparison of the applicant's proposed labeling including, if
applicable, any Medication Guide required under part 208 of this chapter
with the approved labeling for the reference listed drug with all
differences annotated and explained. Labeling (including the container
label, package insert, and, if applicable, Medication Guide) proposed
for the drug product must be the same as the labeling approved for the
reference listed drug, except for changes required because of
differences approved under a petition filed under Sec. 314.93 or
because the drug product and the reference listed drug are produced or
distributed by different manufacturers. Such differences between the
applicant's proposed labeling and labeling approved for the reference
listed drug may include differences in expiration date, formulation,
bioavailability, or pharmacokinetics, labeling revisions made to comply
with current FDA labeling guidelines or other guidance, or omission of
an indication or other aspect of labeling protected by patent or
accorded exclusivity under section 505(j)(5)(F) of the Federal Food,
Drug, and Cosmetic Act.
(9) Chemistry, manufacturing, and controls. (i) The information
required under Sec. 314.50(d)(1), except that the information required
under Sec. 314.50(d)(1)(ii)(c) must contain the proposed or actual
master production record, including a description of the equipment, to
be used for the manufacture of a commercial lot of the drug product.
(ii) Inactive ingredients. Unless otherwise stated in paragraphs
(a)(9)(iii) through (a)(9)(v) of this section, an applicant must
identify and characterize the inactive ingredients in the proposed drug
product and provide information demonstrating that such inactive
ingredients do not affect the safety or efficacy of the proposed drug
product.
(iii) Inactive ingredient changes permitted in drug products
intended for parenteral use. Generally, a drug product intended for
parenteral use must contain the same inactive ingredients and in the
same concentration as the reference listed drug identified by the
applicant under paragraph (a)(3) of this section. However, an applicant
may seek approval of a drug product that differs from the reference
listed drug in preservative, buffer, or antioxidant
[[Page 146]]
provided that the applicant identifies and characterizes the differences
and provides information demonstrating that the differences do not
affect the safety or efficacy of the proposed drug product.
(iv) Inactive ingredient changes permitted in drug products intended
for ophthalmic or otic use. Generally, a drug product intended for
ophthalmic or otic use must contain the same inactive ingredients and in
the same concentration as the reference listed drug identified by the
applicant under paragraph (a)(3) of this section. However, an applicant
may seek approval of a drug product that differs from the reference
listed drug in preservative, buffer, substance to adjust tonicity, or
thickening agent provided that the applicant identifies and
characterizes the differences and provides information demonstrating
that the differences do not affect the safety or efficacy of the
proposed drug product, except that, in a product intended for ophthalmic
use, an applicant may not change a buffer or substance to adjust
tonicity for the purpose of claiming a therapeutic advantage over or
difference from the listed drug, e.g., by using a balanced salt solution
as a diluent as opposed to an isotonic saline solution, or by making a
significant change in the pH or other change that may raise questions of
irritability.
(v) Inactive ingredient changes permitted in drug products intended
for topical use. Generally, a drug product intended for topical use,
solutions for aerosolization or nebulization, and nasal solutions shall
contain the same inactive ingredients as the reference listed drug
identified by the applicant under paragraph (a)(3) of this section.
However, an ANDA may include different inactive ingredients provided
that the applicant identifies and characterizes the differences and
provides information demonstrating that the differences do not affect
the safety or efficacy of the proposed drug product.
(10) Samples. The information required under Sec. 314.50(e)(1) and
(e)(2)(i). Samples need not be submitted until requested by FDA.
(11) Other. The information required under Sec. 314.50(g).
(12) Patent certification--(i) Patents claiming drug substance, drug
product, or method of use. (A) An appropriate patent certification or
statement with respect to each patent issued by the U.S. Patent and
Trademark Office that, in the opinion of the applicant and to the best
of its knowledge, claims the reference listed drug or that claims a use
of such listed drug for which the applicant is seeking approval under
section 505(j) of the Federal Food, Drug, and Cosmetic Act and for which
information is required to be filed under section 505(b) and (c) of the
Federal Food, Drug, and Cosmetic Act and Sec. 314.53. For each such
patent, the applicant must provide the patent number and certify, in its
opinion and to the best of its knowledge, one of the following
circumstances:
(1) That the patent information has not been submitted to FDA. The
applicant must entitle such a certification ``Paragraph I
Certification'';
(2) That the patent has expired. The applicant must entitle such a
certification ``Paragraph II Certification'';
(3) The date on which the patent will expire. The applicant must
entitle such a certification ``Paragraph III Certification''; or
(4)(i) That the patent is invalid, unenforceable, or will not be
infringed by the manufacture, use, or sale of the drug product for which
the ANDA is submitted. The applicant must entitle such a certification
``Paragraph IV Certification''. This certification must be submitted in
the following form:
I, (name of applicant), certify that Patent No. _____ (is invalid,
unenforceable, or will not be infringed by the manufacture, use, or sale
of) (name of proposed drug product) for which this ANDA is submitted.
(ii) The certification must be accompanied by a statement that the
applicant will comply with the requirements under Sec. 314.95(a) with
respect to providing a notice to each owner of the patent or its
representative and to the NDA holder (or, if the NDA holder does not
reside or maintain a place of business within the United States, its
attorney, agent, or other authorized official) for the listed drug, with
the requirements under Sec. 314.95(b) with respect to sending the
notice, and with
[[Page 147]]
the requirements under Sec. 314.95(c) with respect to the content of
the notice.
(B) If the ANDA refers to a listed drug that is itself a licensed
generic product of a patented drug first approved under section 505(b)
of the Federal Food, Drug, and Cosmetic Act, an appropriate patent
certification or statement under paragraph (a)(12)(i) and/or (iii) of
this section with respect to each patent that claims the first-approved
patented drug or that claims a use for such drug.
(ii) No relevant patents. If, in the opinion of the applicant and to
the best of its knowledge, there are no patents described in paragraph
(a)(12)(i) of this section, a certification in the following form:
In the opinion and to the best knowledge of (name of applicant),
there are no patents that claim the listed drug referred to in this ANDA
or that claim a use of the listed drug.
(iii) Method-of-use patent. (A) If patent information is submitted
under section 505(b) or (c) of the Federal Food, Drug, and Cosmetic Act
and Sec. 314.53 for a patent claiming a method of using the listed
drug, and the labeling for the drug product for which the applicant is
seeking approval does not include an indication or other condition of
use that is covered by the method-of-use patent, a statement explaining
that the method-of-use patent does not claim a proposed indication or
other condition of use.
(B) If the labeling of the drug product for which the applicant is
seeking approval includes an indication or other condition of use that,
according to the patent information submitted under section 505(b) or
(c) of the Federal Food, Drug, and Cosmetic Act and Sec. 314.53 or in
the opinion of the applicant, is claimed by a method-of-use patent, an
applicable certification under paragraph (a)(12)(i) of this section.
(iv) [Reserved]
(v) Licensing agreements. If the ANDA is for a drug or method of
using a drug claimed by a patent and the applicant has a licensing
agreement with the patent owner, the applicant must submit a paragraph
IV certification as to that patent and a statement that the applicant
has been granted a patent license. If the patent owner consents to
approval of the ANDA (if otherwise eligible for approval) as of a
specific date, the ANDA must contain a written statement from the patent
owner that it has a licensing agreement with the applicant and that it
consents to approval of the ANDA as of a specific date.
(vi) Untimely filing of patent information. (A) If a patent on the
listed drug is issued and the holder of the approved NDA for the listed
drug does not file with FDA the required information on the patent
within 30 days of issuance of the patent, an applicant who submitted an
ANDA for that drug that contained an appropriate patent certification or
statement before the submission of the patent information is not
required to submit a patent certification or statement to address the
patent or patent information that is late-listed with respect to the
pending ANDA. Except as provided in Sec. 314.53(f)(1), an NDA holder's
amendment to the description of the approved method(s) of use claimed by
the patent will be considered untimely filing of patent information
unless:
(1) The amendment to the description of the approved method(s) of
use claimed by the patent is submitted within 30 days of patent
issuance;
(2) The amendment to the description of the approved method(s) of
use claimed by the patent is submitted within 30 days of approval of a
corresponding change to product labeling; or
(3) The amendment to the description of the approved method(s) of
use claimed by the patent is submitted within 30 days of a decision by
the U.S. Patent and Trademark Office or by a Federal district court, the
Court of Appeals for the Federal Circuit, or the U.S. Supreme Court that
is specific to the patent and alters the construction of a method-of-use
claim(s) of the patent, and the amendment contains a copy of the
decision.
(B) An applicant whose ANDA is submitted after the NDA holder's
untimely filing of patent information, or whose pending ANDA was
previously submitted but did not contain an appropriate patent
certification or statement at the time of the patent submission, must
submit a certification under
[[Page 148]]
paragraph (a)(12)(i) of this section and/or a statement under paragraph
(a)(12)(iii) of this section as to that patent.
(vii) Disputed patent information. If an applicant disputes the
accuracy or relevance of patent information submitted to FDA, the
applicant may seek a confirmation of the correctness of the patent
information in accordance with the procedures under Sec. 314.53(f).
Unless the patent information is withdrawn, the applicant must submit an
appropriate certification or statement for each listed patent.
(viii) Amended certifications. A patent certification or statement
submitted under paragraphs (a)(12)(i) through (iii) of this section may
be amended at any time before the approval of the ANDA. If an applicant
with a pending ANDA voluntarily makes a patent certification for an
untimely filed patent, the applicant may withdraw the patent
certification for the untimely filed patent. An applicant must submit an
amended certification as an amendment to a pending ANDA. Once an
amendment is submitted to change a certification, the ANDA will no
longer be considered to contain the prior certification.
(A) After finding of infringement. An applicant who has submitted a
paragraph IV certification and is sued for patent infringement must
submit an amendment to change its certification if a court enters a
final decision from which no appeal has been or can be taken, or signs
and enters a settlement order or consent decree in the action that
includes a finding that the patent is infringed, unless the final
decision, settlement order, or consent decree also finds the patent to
be invalid. In its amendment, the applicant must certify under paragraph
(a)(12)(i)(A)(3) of this section that the patent will expire on a
specific date or, with respect to a patent claiming a method of use, the
applicant may instead provide a statement under paragraph (a)(12)(iii)
of this section if the applicant amends its ANDA such that the applicant
is no longer seeking approval for a method of use claimed by the patent.
Once an amendment for the change has been submitted, the ANDA will no
longer be considered to contain a paragraph IV certification to the
patent. If a final judgment finds the patent to be invalid and
infringed, an amended certification is not required.
(B) After request to remove a patent or patent information from the
list. If the list reflects that an NDA holder has requested that a
patent or patent information be removed from the list and no ANDA
applicant is eligible for 180-day exclusivity based on a paragraph IV
certification to that patent, the patent or patent information will be
removed and any applicant with a pending ANDA (including a tentatively
approved ANDA) who has made a certification with respect to such patent
must submit an amendment to withdraw its certification. In the
amendment, the applicant must state the reason for withdrawing the
certification or statement (that the patent has been removed from the
list). If the list reflects that an NDA holder has requested that a
patent or patent information be removed from the list and one or more
first applicants are eligible for 180-day exclusivity based on a
paragraph IV certification to that patent, the patent will remain listed
until any 180-day exclusivity based on that patent has expired or has
been extinguished. After any applicable 180-day exclusivity has expired
or has been extinguished, the patent or patent information will be
removed and any applicant with a pending ANDA (including a tentatively
approved ANDA) who has made a certification with respect to such patent
must submit an amendment to withdraw its certification. Once an
amendment to withdraw the certification has been submitted, the ANDA
will no longer be considered to contain a paragraph IV certification to
the patent. If removal of a patent from the list results in there being
no patents listed for the listed drug identified in the ANDA, the
applicant must submit an amended certification reflecting that there are
no relevant patents.
(C) Other amendments. (1) Except as provided in paragraphs
(a)(12)(vi) and (a)(12)(viii)(C)(2) of this section:
(i) An applicant must amend a submitted certification or statement
if, at any time before the date of approval of the ANDA, the applicant
learns that
[[Page 149]]
the submitted certification or statement is no longer accurate; and
(ii) An applicant must submit an appropriate patent certification or
statement under paragraph (a)(12)(i) and/or (iii) of this section if,
after submission of the ANDA, a new patent is issued by the U.S. Patent
and Trademark Office that, in the opinion of the applicant and to the
best of its knowledge, claims the reference listed drug or that claims
an approved use for such reference listed drug and for which information
is required to be filed under section 505(b) and (c) of the Federal
Food, Drug, and Cosmetic Act and Sec. 314.53. For a paragraph IV
certification, the certification must not be submitted earlier than the
first working day after the day the patent is published in the list.
(2) An applicant is not required to submit a supplement to change a
submitted certification when information on a patent on the listed drug
is submitted after the approval of the ANDA.
(13) Financial certification or disclosure statement. An ANDA must
contain a financial certification or disclosure statement as required by
part 54 of this chapter.
(b) Drug products subject to the Drug Efficacy Study Implementation
(DESI) review. If the ANDA is for a duplicate of a drug product that is
subject to FDA's DESI review (a review of drug products approved as safe
between 1938 and 1962) or other DESI-like review and the drug product
evaluated in the review is a listed drug, the applicant must comply with
the provisions of paragraph (a) of this section.
(c) [Reserved]
(d) Format of an ANDA. (1) The applicant must submit a complete
archival copy of the ANDA as required under paragraphs (a) and (c) of
this section. FDA will maintain the archival copy during the review of
the ANDA to permit individual reviewers to refer to information that is
not contained in their particular technical sections of the ANDA, to
give other Agency personnel access to the ANDA for official business,
and to maintain in one place a complete copy of the ANDA.
(i) Format of submission. An applicant may submit portions of the
archival copy of the ANDA in any form that the applicant and FDA agree
is acceptable, except as provided in paragraph (d)(1)(ii) of this
section.
(ii) Labeling. The content of labeling required under Sec.
201.100(d)(3) of this chapter (commonly referred to as the package
insert or professional labeling), including all text, tables, and
figures, must be submitted to the agency in electronic format as
described in paragraph (d)(1)(iii) of this section. This requirement
applies to the content of labeling for the proposed drug product only
and is in addition to the requirements of paragraph (a)(8)(ii) of this
section that copies of the formatted label and all proposed labeling be
submitted. Submissions under this paragraph must be made in accordance
with part 11 of this chapter, except for the requirements of Sec.
11.10(a), (c) through (h), and (k), and the corresponding requirements
of Sec. 11.30.
(iii) Electronic format submissions. Electronic format submissions
must be in a form that FDA can process, review, and archive. FDA will
periodically issue guidance on how to provide the electronic submission
(e.g., method of transmission, media, file formats, preparation and
organization of files).
(2) For ANDAs, the applicant must submit a review copy of the ANDA
that contains two separate sections. One section must contain the
information described under paragraphs (a)(2) through (6) and (8) and
(9) of this section and section 505(j)(2)(A)(vii) of the Federal Food,
Drug, and Cosmetic Act and a copy of the analytical procedures and
descriptive information needed by FDA's laboratories to perform tests on
samples of the proposed drug product and to validate the applicant's
analytical procedures. The other section must contain the information
described under paragraphs (a)(3), (7), and (8) of this section. Each of
the sections in the review copy is required to contain a copy of the
application form described under paragraph (a) of this section.
(3) [Reserved]
(4) The applicant may obtain from FDA sufficient folders to bind the
archival, the review, and the field copies of the ANDA.
(5) The applicant must submit a field copy of the ANDA that contains
the
[[Page 150]]
technical section described in paragraph (a)(9) of this section, a copy
of the application form required under paragraph (a)(1) of this section,
and a certification that the field copy is a true copy of the technical
section described in paragraph (a)(9) of this section contained in the
archival and review copies of the ANDA.
[57 FR 17983, Apr. 28, 1992; 57 FR 29353, July 1, 1992, as amended at 58
FR 47352, Sept. 8, 1993; 59 FR 50364, Oct. 3, 1994; 63 FR 5252, Feb. 2,
1998; 63 FR 66399, Dec. 1, 1998; 64 FR 401, Jan. 5, 1999; 65 FR 56479,
Sept. 19, 2000; 67 FR 77672, Dec. 19, 2002; 68 FR 69019, Dec. 11, 2003;
69 FR 18766, Apr. 8, 2004; 74 FR 2861, Jan. 16, 2009; 76 FR 13880, Mar.
15, 2011; 81 FR 69649, Oct. 6, 2016]
Sec. 314.95 Notice of certification of invalidity, unenforceability,
or noninfringement of a patent.
(a) Notice of certification. For each patent that claims the listed
drug or that claims a use for such listed drug for which the applicant
is seeking approval and for which the applicant submits a paragraph IV
certification, the applicant must send notice of such certification by
registered or certified mail, return receipt requested, or by a
designated delivery service, as defined in paragraph (g) of this section
to each of the following persons:
(1) Each owner of the patent that is the subject of the
certification or the representative designated by the owner to receive
the notice. The name and address of the patent owner or its
representative may be obtained from the U.S. Patent and Trademark
Office; and
(2) The holder of the approved NDA under section 505(b) of the
Federal Food, Drug, and Cosmetic Act for the listed drug that is claimed
by the patent and for which the applicant is seeking approval, or, if
the NDA holder does not reside or maintain a place of business within
the United States, the NDA holder's attorney, agent, or other authorized
official. The name and address of the NDA holder or its attorney, agent,
or authorized official may be obtained by sending a written or
electronic communication to the Central Document Room, Attn: Orange Book
Staff, Center for Drug Evaluation and Research, Food and Drug
Administration, 5901-B Ammendale Rd., Beltsville, MD 20705-1266 or to
the Orange Book Staff at the email address listed on the Agency's Web
site at http://www.fda.gov.
(3) This paragraph (a) does not apply to a method-of-use patent that
does not claim a use for which the applicant is seeking approval.
(4) An applicant may send notice by an alternative method only if
FDA has agreed in advance that the method will produce an acceptable
form of documentation.
(b) Sending the notice. (1) Except as provided under paragraph (d)
of this section, the applicant must send the notice required by
paragraph (a) of this section on or after the date it receives a
paragraph IV acknowledgment letter from FDA, but not later than 20 days
after the date of the postmark on the paragraph IV acknowledgment
letter. The 20-day clock described in this paragraph (b) begins on the
day after the date of the postmark on the paragraph IV acknowledgment
letter. When the 20th day falls on Saturday, Sunday, or a Federal
holiday, the 20th day will be the next day that is not a Saturday,
Sunday, or Federal holiday.
(2) Any notice required by paragraph (a) of this section is invalid
if it is sent before the applicant's receipt of a paragraph IV
acknowledgment letter, or before the first working day after the day the
patent is published in the list. The applicant will not have complied
with this paragraph (b) until it sends valid notice.
(3) The applicant must submit to FDA an amendment to its ANDA that
includes a statement certifying that the notice has been provided to
each person identified under paragraph (a) of this section and that the
notice met the content requirements under paragraph (c) of this section.
A copy of the notice itself need not be submitted to the Agency.
(c) Contents of a notice. In the notice, the applicant must cite
section 505(j)(2)(B)(iv) of the Federal Food, Drug, and Cosmetic Act and
the notice must include, but is not limited to, the following
information:
(1) A statement that FDA has received an ANDA submitted by the
applicant containing any required bioavailability or bioequivalence data
or information.
[[Page 151]]
(2) The ANDA number.
(3) A statement that the applicant has received the paragraph IV
acknowledgment letter for the ANDA.
(4) The established name, if any, as defined in section 502(e)(3) of
the Federal Food, Drug, and Cosmetic Act, of the proposed drug product.
(5) The active ingredient, strength, and dosage form of the proposed
drug product.
(6) The patent number and expiration date of each listed patent for
the reference listed drug alleged to be invalid, unenforceable, or not
infringed.
(7) A detailed statement of the factual and legal basis of the
applicant's opinion that the patent is not valid, unenforceable, or will
not be infringed. The applicant must include in the detailed statement:
(i) For each claim of a patent alleged not to be infringed, a full
and detailed explanation of why the claim is not infringed.
(ii) For each claim of a patent alleged to be invalid or
unenforceable, a full and detailed explanation of the grounds supporting
the allegation.
(8) If the applicant alleges that the patent will not be infringed
and the applicant seeks to preserve the option to later file a civil
action for declaratory judgment in accordance with section 505(j)(5)(C)
of the Federal Food, Drug, and Cosmetic Act, then the notice must be
accompanied by an offer of confidential access to the ANDA for the sole
and limited purpose of evaluating possible infringement of the patent
that is the subject of the paragraph IV certification.
(9) If the applicant does not reside or have a place of business in
the United States, the name and address of an agent in the United States
authorized to accept service of process for the applicant.
(d) Amendment or supplement to an ANDA. (1) If, after receipt of a
paragraph IV acknowledgment letter or acknowledgment letter, an
applicant submits an amendment or supplement to its ANDA that includes a
paragraph IV certification, the applicant must send the notice required
by paragraph (a) of this section at the same time that the amendment or
supplement to the ANDA is submitted to FDA, regardless of whether the
applicant has already given notice with respect to another such
certification contained in the ANDA or in an amendment or supplement to
the ANDA.
(2) If, before receipt of a paragraph IV acknowledgment letter, an
applicant submits an amendment to its ANDA that includes a paragraph IV
certification, the applicant must send the notice required by paragraph
(a) of this section in accordance with the procedures in paragraph (b)
of this section. If an ANDA applicant's notice of its paragraph IV
certification is timely provided in accordance with paragraph (b) of
this section and the applicant has not submitted a previous paragraph IV
certification, FDA will base its determination of whether the applicant
is a first applicant on the date of submission of the amendment
containing the paragraph IV certification.
(3) An applicant that submits an amendment or supplement to seek
approval of a different strength must provide notice of any paragraph IV
certification in accordance with paragraph (d)(1) or (2) of this
section, as applicable.
(e) Documentation of timely sending and receipt of notice. The
applicant must amend its ANDA to provide documentation of the date of
receipt of the notice required under paragraph (a) of this section by
each person provided the notice. The amendment must be submitted to FDA
within 30 days after the last date on which notice was received by a
person described in paragraph (a) of this section. The applicant's
amendment also must include documentation that its notice was sent on a
date that complies with the timeframe required by paragraph (b) or (d)
of this section, as applicable, and a dated printout of the entry for
the reference listed drug in FDA's ``Approved Drug Products With
Therapeutic Equivalence Evaluations'' (the list) that includes the
patent that is the subject of the paragraph IV certification. FDA will
accept, as adequate documentation of the date the notice was sent, a
copy of the registered mail receipt, certified mail receipt, or receipt
from a designated delivery service as defined in paragraph (g) of this
section. FDA will accept as adequate
[[Page 152]]
documentation of the date of receipt a return receipt, signature proof
of delivery by a designated delivery service, or a letter acknowledging
receipt by the person provided the notice. An applicant may rely on
another form of documentation only if FDA has agreed to such
documentation in advance. A copy of the notice itself need not be
submitted to the Agency.
(f) Forty-five day period after receipt of notice. If the
requirements of this section are met, FDA will presume the notice to be
complete and sufficient, and it will count the day following the date of
receipt of the notice by the patent owner or its representative and by
the approved NDA holder or its attorney, agent, or other authorized
official as the first day of the 45-day period provided for in section
505(j)(5)(B)(iii) of the Federal Food, Drug, and Cosmetic Act. FDA may,
if the applicant provides a written statement to FDA that a later date
should be used, count from such later date.
(g) Designated delivery services. (1) For purposes of this section,
the term ``designated delivery service'' means any delivery service
provided by a trade or business that the Agency determines:
(i) Is available to the general public throughout the United States;
(ii) Records electronically to its database, kept in the regular
course of its business, or marks on the cover in which any item referred
to in this section is to be delivered, the date on which such item was
given to such trade or business for delivery; and
(iii) Provides overnight or 2-day delivery service throughout the
United States.
(2) FDA may periodically issue guidance regarding designated
delivery services.
[81 FR 69651, Oct. 6, 2016, as amended at 84 FR 6673, Feb. 28, 2019]
Sec. 314.96 Amendments to an unapproved ANDA.
(a) ANDA. (1) An applicant may amend an ANDA that is submitted under
Sec. 314.94, but not yet approved, to revise existing information or
provide additional information. Amendments containing bioequivalence
studies must contain reports of all bioequivalence studies conducted by
the applicant on the same drug product formulation, unless the
information has previously been submitted to FDA in the ANDA. A complete
study report must be submitted for any bioequivalence study upon which
the applicant relies for approval. For all other bioequivalence studies
conducted on the same drug product formulation as defined in Sec. 314.3
of this chapter, the applicant must submit either a complete or summary
report. If a summary report of a bioequivalence study is submitted and
FDA determines that there may be bioequivalence issues or concerns with
the product, FDA may require that the applicant submit a complete report
of the bioequivalence study to FDA.
(2) Submission of an amendment containing significant data or
information before the end of the initial review cycle constitutes an
agreement between FDA and the applicant to extend the initial review
cycle only for the time necessary to review the significant data or
information and for no more than 180 days.
(b) Field copy. The applicant must submit a field copy of each
amendment under Sec. 314.94(a)(9). The applicant, other than a foreign
applicant, must include in its submission of each such amendment to FDA
a statement certifying that a field copy of the amendment has been sent
to the applicant's home FDA district office.
(c) Different listed drug. An applicant may not amend an ANDA to
seek approval of a drug referring to a listed drug that is different
from the reference listed drug identified in the ANDA. This paragraph
(c) applies if, at any time before the approval of the ANDA, a different
listed drug is approved that is the pharmaceutical equivalent to the
product in the ANDA and is designated as a reference listed drug. This
paragraph (c) also applies if changes are proposed in an amendment to
the ANDA such that the proposed product is a pharmaceutical equivalent
to a different listed drug than the reference listed drug identified in
the ANDA. A change of the reference listed drug must be submitted in a
new ANDA. However, notwithstanding the limitation described in this
paragraph (c), an applicant may amend the ANDA
[[Page 153]]
to seek approval of a different strength.
(d)(1) Patent certification requirements. An amendment to an ANDA is
required to contain an appropriate patent certification or statement
described in Sec. 314.94(a)(12) or a recertification for a previously
submitted paragraph IV certification if approval is sought for any of
the following types of amendments:
(i) To add a new indication or other condition of use;
(ii) To add a new strength;
(iii) To make other than minor changes in product formulation; or
(iv) To change the physical form or crystalline structure of the
active ingredient.
(2) If the amendment to the ANDA does not contain a patent
certification or statement, the applicant must verify that the proposed
change described in the amendment is not one of the types of amendments
described in paragraph (d)(1) of this section.
[57 FR 17983, Apr. 28, 1992, as amended at 58 FR 47352, Sept. 8, 1993;
64 FR 401, Jan. 5, 1999; 73 FR 39609, July 10, 2008; 74 FR 2861, Jan.
16, 2009; 81 FR 69652, Oct. 6, 2016]
Sec. 314.97 Supplements and other changes to an approved ANDA.
(a) General requirements. The applicant must comply with the
requirements of Sec. Sec. 314.70 and 314.71 regarding the submission of
supplemental ANDAs and other changes to an approved ANDA.
(b) Different listed drug. An applicant may not supplement an ANDA
to seek approval of a drug referring to a listed drug that is different
from the current reference listed drug identified in the ANDA. This
paragraph (b) applies if changes are proposed in a supplement to the
ANDA such that the proposed product is a pharmaceutical equivalent to a
different listed drug than the reference listed drug identified in the
ANDA. A change of reference listed drug must be submitted in a new ANDA.
However, notwithstanding the limitation described in this paragraph (b),
an applicant may supplement the ANDA to seek approval of a different
strength.
[81 FR 69653, Oct. 6, 2016]
Sec. 314.98 Postmarketing reports.
(a) Each applicant having an approved abbreviated new drug
application under Sec. 314.94 that is effective must comply with the
requirements of Sec. 314.80 regarding the reporting and recordkeeping
of adverse drug experiences.
(b) Each applicant must make the reports required under Sec. 314.81
and section 505(k) of the Federal Food, Drug, and Cosmetic Act for each
of its approved abbreviated applications.
[79 FR 33089, June 10, 2014]
Sec. 314.99 Other responsibilities of an applicant of an ANDA.
(a) An applicant must comply with the requirements of Sec. 314.65
regarding withdrawal by the applicant of an unapproved ANDA and Sec.
314.72 regarding a change in ownership of an ANDA.
(b) An applicant may ask FDA to waive under this section any
requirement that applies to the applicant under Sec. Sec. 314.92
through 314.99. The applicant must comply with the requirements for a
waiver under Sec. 314.90. If FDA grants the applicant's waiver request
with respect to a requirement under Sec. Sec. 314.92 through 314.99,
the waived requirement will not constitute a basis for refusal to
approve an ANDA under Sec. 314.127.
81 FR 69653, Oct. 6, 2016]
Subpart D_FDA Action on Applications and Abbreviated Applications
Source: 50 FR 7493, Feb. 22, 1985, unless otherwise noted.
Redesignated at 57 FR 17983, Apr. 28, 1992.
Sec. 314.100 Timeframes for reviewing applications and abbreviated
applications.
(a) Except as provided in paragraph (c) of this section, within 180
days of receipt of an application for a new drug under section 505(b) of
the act or an abbreviated application for a new drug under section
505(j) of the act, FDA will review it and send the applicant either an
approval letter under Sec. 314.105 or a complete response letter under
Sec. 314.110. This 180-day period is called the ``initial review
cycle.''
[[Page 154]]
(b) At any time before approval, an applicant may withdraw an
application under Sec. 314.65 or an abbreviated application under Sec.
314.99 and later submit it again for consideration.
(c) The initial review cycle may be adjusted by mutual agreement
between FDA and an applicant or as provided in Sec. Sec. 314.60 and
314.96, as the result of a major amendment.
[73 FR 39609, July 10, 2008]
Sec. 314.101 Filing an NDA and receiving an ANDA.
(a) Filing an NDA. (1) Within 60 days after FDA receives an NDA, the
Agency will determine whether the NDA may be filed. The filing of an NDA
means that FDA has made a threshold determination that the NDA is
sufficiently complete to permit a substantive review.
(2) If FDA finds that none of the reasons in paragraphs (d) and (e)
of this section for refusing to file the NDA apply, the Agency will file
the NDA and notify the applicant in writing. In the case of a 505(b)(2)
application that contains a paragraph IV certification, the applicant
will be notified via a paragraph IV acknowledgment letter. The date of
filing will be the date 60 days after the date FDA received the NDA. The
date of filing begins the 180-day period described in section 505(c) of
the Federal Food, Drug, and Cosmetic Act. This 180-day period is called
the ``filing clock.''
(3) If FDA refuses to file the NDA, the Agency will notify the
applicant in writing and state the reason under paragraph (d) or (e) of
this section for the refusal. If FDA refuses to file the NDA under
paragraph (d) of this section, the applicant may request in writing
within 30 days of the date of the Agency's notification an informal
conference with the Agency about whether the Agency should file the NDA.
If, following the informal conference, the applicant requests that FDA
file the NDA (with or without amendments to correct the deficiencies),
the Agency will file the NDA over protest under paragraph (a)(2) of this
section, notify the applicant in writing, and review it as filed. If the
NDA is filed over protest, the date of filing will be the date 60 days
after the date the applicant requested the informal conference. The
applicant need not resubmit a copy of an NDA that is filed over protest.
If FDA refuses to file the NDA under paragraph (e) of this section, the
applicant may amend the NDA and resubmit it, and the Agency will make a
determination under this section whether it may be filed.
(b)(1) Receiving an ANDA. An ANDA will be evaluated after it is
submitted to determine whether the ANDA may be received. Receipt of an
ANDA means that FDA has made a threshold determination that the
abbreviated application is substantially complete.
(2) If FDA finds that none of the reasons in paragraphs (d) and (e)
of this section for considering the ANDA not to have been received
applies, the ANDA is substantially complete and the Agency will receive
the ANDA and notify the applicant in writing. If FDA determines, upon
evaluation, that an ANDA was substantially complete as of the date it
was submitted to FDA, FDA will consider the ANDA to have been received
as of the date of submission. In the case of an ANDA that contains a
paragraph IV certification, the applicant will be notified via a
paragraph IV acknowledgment letter.
(3) If FDA considers the ANDA not to have been received under
paragraph (d) or (e) of this section, FDA will notify the applicant of
the refuse-to-receive decision. The applicant may then:
(i) Withdraw the ANDA under Sec. 314.99; or
(ii) Correct the deficiencies and resubmit the ANDA; or
(iii) Take no action, in which case FDA may consider the ANDA
withdrawn after 1 year.
(c) [Reserved]
(d) NDA or ANDA deficiencies. FDA may refuse to file an NDA or may
not consider an ANDA to be received if any of the following applies:
(1) The NDA or ANDA does not contain a completed application form.
(2) The NDA or ANDA is not submitted in the form required under
Sec. 314.50 or Sec. 314.94.
(3) The NDA or ANDA is incomplete because it does not on its face
contain information required under section 505(b) or section 505(j) of
the Federal Food, Drug, and Cosmetic Act and
[[Page 155]]
Sec. 314.50 or Sec. 314.94. In determining whether an ANDA is
incomplete on its face, FDA will consider the nature (e.g., major or
minor) of the deficiencies, including the number of deficiencies in the
ANDA.
(4) The applicant fails to submit a complete environmental
assessment, which addresses each of the items specified in the
applicable format under Sec. 25.40 of this chapter or fails to provide
sufficient information to establish that the requested action is subject
to categorical exclusion under Sec. 25.30 or Sec. 25.31 of this
chapter.
(5) The NDA or ANDA does not contain an accurate and complete
English translation of each part of the NDA or ANDA that is not in
English.
(6) The NDA or ANDA does not contain a statement for each
nonclinical laboratory study that the study was conducted in compliance
with the requirements set forth in part 58 of this chapter, or, for each
study not conducted in compliance with part 58 of this chapter, a brief
statement of the reason for the noncompliance.
(7) The NDA or ANDA does not contain a statement for each clinical
study that the study was conducted in compliance with the institutional
review board regulations in part 56 of this chapter, or was not subject
to those regulations, and that it was conducted in compliance with the
informed consent regulations in part 50 of this chapter, or, if the
study was subject to but was not conducted in compliance with those
regulations, the NDA or ANDA does not contain a brief statement of the
reason for the noncompliance.
(8) The drug product that is the subject of the submission is
already covered by an approved NDA or ANDA and the applicant of the
submission:
(i) Has an approved NDA or ANDA for the same drug product; or
(ii) Is merely a distributor and/or repackager of the already
approved drug product.
(9) The NDA is submitted as a 505(b)(2) application for a drug that
is a duplicate of a listed drug and is eligible for approval under
section 505(j) of the Federal Food, Drug, and Cosmetic Act.
(e) Regulatory deficiencies. The Agency will refuse to file an NDA
or will consider an ANDA not to have been received if any of the
following applies:
(1) The drug product is subject to licensing by FDA under the Public
Health Service Act (42 U.S.C. 201 et seq.) and subchapter F of this
chapter.
(2) Submission of a 505(b)(2) application or an ANDA is not
permitted under section 505(c)(3)(E)(ii), 505(j)(5)(F)(ii),
505A(b)(1)(A)(i)(I), 505A(c)(1)(A)(i)(I), or 505E(a) of the Federal
Food, Drug, and Cosmetic Act.
(f) Outcome of FDA review. (1) Within 180 days after the date of
filing, plus the period of time the review period was extended (if any),
FDA will either:
(i) Approve the NDA; or
(ii) Issue a notice of opportunity for a hearing if the applicant
asked FDA to provide it an opportunity for a hearing on an NDA in
response to a complete response letter.
(2) Within 180 days after the date of receipt, plus the period of
time the review clock was extended (if any), FDA will either approve or
disapprove the ANDA. If FDA disapproves the ANDA, FDA will issue a
notice of opportunity for hearing if the applicant asked FDA to provide
it an opportunity for a hearing on an ANDA in response to a complete
response letter.
(3) This paragraph (f) does not apply to NDAs or ANDAs that have
been withdrawn from FDA review by the applicant.
[81 FR 69653, Oct. 6, 2016]
Sec. 314.102 Communications between FDA and applicants.
(a) General principles. During the course of reviewing an
application or an abbreviated application, FDA shall communicate with
applicants about scientific, medical, and procedural issues that arise
during the review process. Such communication may take the form of
telephone conversations, letters, or meetings, whichever is most
appropriate to discuss the particular issue at hand. Communications
shall be appropriately documented in the application in accordance with
Sec. 10.65 of this chapter. Further details on the procedures for
communication between FDA and applicants are contained in a staff manual
guide that is publicly available.
[[Page 156]]
(b) Notification of easily correctable deficiencies. FDA reviewers
shall make every reasonable effort to communicate promptly to applicants
easily correctable deficiencies found in an application or an
abbreviated application when those deficiencies are discovered,
particularly deficiencies concerning chemistry, manufacturing, and
controls issues. The agency will also inform applicants promptly of its
need for more data or information or for technical changes in the
application or the abbreviated application needed to facilitate the
agency's review. This early communication is intended to permit
applicants to correct such readily identified deficiencies relatively
early in the review process and to submit an amendment before the review
period has elapsed. Such early communication would not ordinarily apply
to major scientific issues, which require consideration of the entire
pending application or abbreviated application by agency managers as
well as reviewing staff. Instead, major scientific issues will
ordinarily be addressed in a complete response letter.
(c) Ninety-day conference. Approximately 90 days after the agency
receives the application, FDA will provide applicants with an
opportunity to meet with agency reviewing officials. The purpose of the
meeting will be to inform applicants of the general progress and status
of their applications, and to advise applicants of deficiencies that
have been identified by that time and that have not already been
communicated. This meeting will be available on applications for all new
chemical entities and major new indications of marketed drugs. Such
meetings will be held at the applicant's option, and may be held by
telephone if mutually agreed upon. Such meetings would not ordinarily be
held on abbreviated applications because they are not submitted for new
chemical entities or new indications.
(d) End-of-review conference. At the conclusion of FDA's review of
an NDA as designated by the issuance of a complete response letter, FDA
will provide the applicant with an opportunity to meet with agency
reviewing officials. The purpose of the meeting will be to discuss what
further steps need to be taken by the applicant before the application
can be approved. Requests for such meetings must be directed to the
director of the division responsible for reviewing the application.
(e) Other meetings. Other meetings between FDA and applicants may be
held, with advance notice, to discuss scientific, medical, and other
issues that arise during the review process. Requests for meetings shall
be directed to the director of the division responsible for reviewing
the application or abbreviated application. FDA will make every attempt
to grant requests for meetings that involve important issues and that
can be scheduled at mutually convenient times. However, ``drop-in''
visits (i.e., an unannounced and unscheduled visit by a company
representative) are discouraged except for urgent matters, such as to
discuss an important new safety issue.
[57 FR 17988, Apr. 28, 1992; 57 FR 29353, July 1, 1992, as amended at 73
FR 39609, July 10, 2008]
Sec. 314.103 Dispute resolution.
(a) General. FDA is committed to resolving differences between
applicants and FDA reviewing divisions with respect to technical
requirements for applications or abbreviated applications as quickly and
amicably as possible through the cooperative exchange of information and
views.
(b) Administrative and procedural issues. When administrative or
procedural disputes arise, the applicant should first attempt to resolve
the matter with the division responsible for reviewing the application
or abbreviated application, beginning with the consumer safety officer
assigned to the application or abbreviated application. If resolution is
not achieved, the applicant may raise the matter with the person
designated as ombudsman, whose function shall be to investigate what has
happened and to facilitate a timely and equitable resolution.
Appropriate issues to raise with the ombudsman include resolving
difficulties in scheduling meetings, obtaining timely replies to
inquiries, and obtaining timely completion of pending reviews. Further
details on this procedure are contained in a staff manual guide that
[[Page 157]]
is publicly available under FDA's public information regulations in part
20.
(c) Scientific and medical disputes. (1) Because major scientific
issues are ordinarily communicated to applicants in a complete response
letter pursuant to Sec. 314.110, the ``end-of-review conference''
described in Sec. 314.102(d) will provide a timely forum for discussing
and resolving, if possible, scientific and medical issues on which the
applicant disagrees with the agency. In addition, the ``ninety-day
conference'' described in Sec. 314.102(c) will provide a timely forum
for discussing and resolving, if possible, issues identified by that
date.
(2) When scientific or medical disputes arise at other times during
the review process, applicants should discuss the matter directly with
the responsible reviewing officials. If necessary, applicants may
request a meeting with the appropriate reviewing officials and
management representatives in order to seek a resolution. Ordinarily,
such meetings would be held first with the Division Director, then with
the Office Director, and finally with the Center Director if the matter
is still unresolved. Requests for such meetings shall be directed to the
director of the division responsible for reviewing the application or
abrreviated application. FDA will make every attempt to grant requests
for meetings that involve important issues and that can be scheduled at
mutually convenient times.
(3) In requesting a meeting designed to resolve a scientific or
medical dispute, applicants may suggest that FDA seek the advice of
outside experts, in which case FDA may, in its discretion, invite to the
meeting one or more of its advisory committee members or other
consultants, as designated by the agency. Applicants may also bring
their own consultants. For major scientific and medical policy issues
not resolved by informal meetings, FDA may refer the matter to one of
its standing advisory committees for its consideration and
recommendations.
[50 FR 7493, Feb. 22, 1985; 50 FR 14212, Apr. 11, 1985, as amended at 57
FR 17989, Apr. 28, 1992; 73 FR 39609, July 10, 2008]
Sec. 314.104 Drugs with potential for abuse.
The Food and Drug Administration will inform the Drug Enforcement
Administration under section 201(f) of the Controlled Substances Act (21
U.S.C. 801) when an application or abbreviated application is submitted
for a drug that appears to have an abuse potential.
[57 FR 17989, Apr. 28, 1992]
Sec. 314.105 Approval of an NDA and an ANDA.
(a) FDA will approve an NDA and send the applicant an approval
letter if none of the reasons in Sec. 314.125 for refusing to approve
the NDA applies. FDA will issue a tentative approval letter if an NDA
otherwise meets the requirements for approval under the Federal Food,
Drug, and Cosmetic Act, but cannot be approved because there is a 7-year
period of orphan exclusivity for the listed drug under section 527 of
the Federal Food, Drug, and Cosmetic Act and Sec. 316.31 of this
chapter, or if a 505(b)(2) application otherwise meets the requirements
for approval under the Federal Food, Drug, and Cosmetic Act, but cannot
be approved until the conditions in Sec. 314.107(b)(3) are met; because
there is a period of exclusivity for the listed drug under Sec.
314.108; because there is a period of pediatric exclusivity for the
listed drug under section 505A of the Federal Food, Drug, and Cosmetic
Act; or because there is a period of exclusivity for the listed drug
under section 505E of the Federal Food, Drug, and Cosmetic Act. A drug
product that is granted tentative approval is not an approved drug and
will not be approved until FDA issues an approval after any necessary
additional review of the NDA. FDA's tentative approval of a drug product
is based on information available to FDA at the time of the tentative
approval letter (i.e., information in the 505(b)(2) application and the
status of current good manufacturing practices of the facilities used in
the manufacturing and testing of the drug product) and is therefore
subject to change on the basis of new information that may come to FDA's
attention. A new drug product may not be marketed until the date of
approval.
[[Page 158]]
(b) FDA will approve an NDA and issue the applicant an approval
letter on the basis of draft labeling if the only deficiencies in the
NDA concern editorial or similar minor deficiencies in the draft
labeling. Such approval will be conditioned upon the applicant
incorporating the specified labeling changes exactly as directed, and
upon the applicant submitting to FDA a copy of the final printed
labeling prior to marketing.
(c) FDA will approve an NDA after it determines that the drug meets
the statutory standards for safety and effectiveness, manufacturing and
controls, and labeling, and an ANDA after it determines that the drug
meets the statutory standards for manufacturing and controls, labeling,
and, where applicable, bioequivalence. While the statutory standards
apply to all drugs, the many kinds of drugs that are subject to the
statutory standards and the wide range of uses for those drugs demand
flexibility in applying the standards. Thus FDA is required to exercise
its scientific judgment to determine the kind and quantity of data and
information an applicant is required to provide for a particular drug to
meet the statutory standards. FDA makes its views on drug products and
classes of drugs available through guidance documents, recommendations,
and other statements of policy.
(d) FDA will approve an ANDA and send the applicant an approval
letter if none of the reasons in Sec. 314.127 for refusing to approve
the ANDA applies. FDA will issue a tentative approval letter if an ANDA
otherwise meets the requirements for approval under the Federal Food,
Drug, and Cosmetic Act, but cannot be approved because there is a 7-year
period of orphan exclusivity for the listed drug under section 527 of
the Federal Food, Drug, and Cosmetic Act and Sec. 316.31 of this
chapter, or cannot be approved until the conditions in Sec.
314.107(b)(3) or (c) are met; because there is a period of exclusivity
for the listed drug under Sec. 314.108; because there is a period of
pediatric exclusivity for the listed drug under section 505A of the
Federal Food, Drug, and Cosmetic Act; or because there is a period of
exclusivity for the listed drug under section 505E of the Federal Food,
Drug, and Cosmetic Act. A drug product that is granted tentative
approval is not an approved drug and will not be approved until FDA
issues an approval after any necessary additional review of the ANDA.
FDA's tentative approval of a drug product is based on information
available to FDA at the time of the tentative approval letter (i.e.,
information in the ANDA and the status of current good manufacturing
practices of the facilities used in the manufacturing and testing of the
drug product) and is therefore subject to change on the basis of new
information that may come to FDA's attention. A new drug product may not
be marketed until the date of approval.
[81 FR 69654, Oct. 6, 2016]
Sec. 314.106 Foreign data.
(a) General. The acceptance of foreign data in an application
generally is governed by Sec. 312.120 of this chapter.
(b) As sole basis for marketing approval. An application based
solely on foreign clinical data meeting U.S. criteria for marketing
approval may be approved if: (1) The foreign data are applicable to the
U.S. population and U.S. medical practice; (2) the studies have been
performed by clinical investigators of recognized competence; and (3)
the data may be considered valid without the need for an on-site
inspection by FDA or, if FDA considers such an inspection to be
necessary, FDA is able to validate the data through an on-site
inspection or other appropriate means. Failure of an application to meet
any of these criteria will result in the application not being
approvable based on the foreign data alone. FDA will apply this policy
in a flexible manner according to the nature of the drug and the data
being considered.
(c) Consultation between FDA and applicants. Applicants are
encouraged to meet with agency officials in a ``presubmission'' meeting
when approval based solely on foreign data will be sought.
[50 FR 7493, Feb. 22, 1985, as amended at 55 FR 11580, Mar. 29, 1990]
[[Page 159]]
Sec. 314.107 Date of approval of a 505(b)(2) application or ANDA.
(a) General. A drug product may be introduced or delivered for
introduction into interstate commerce when the 505(b)(2) application or
ANDA for the drug product is approved. A 505(b)(2) application or ANDA
for a drug product is approved on the date FDA issues an approval letter
under Sec. 314.105 for the 505(b)(2) application or ANDA.
(b) Effect of patent(s) on the listed drug. As described in
paragraphs (b)(1) and (2) of this section, the status of patents listed
for the listed drug(s) relied upon or reference listed drug, as
applicable, must be considered in determining the first possible date on
which a 505(b)(2) application or ANDA can be approved. The criteria in
paragraphs (b)(1) and (2) of this section will be used to determine, for
each relevant patent, the date that patent will no longer prevent
approval. The first possible date on which the 505(b)(2) application or
ANDA can be approved will be calculated for each patent, and the
505(b)(2) application or ANDA may be approved on the last applicable
date.
(1) Timing of approval based on patent certification or statement.
If none of the reasons in Sec. 314.125 or Sec. 314.127, as applicable,
for refusing to approve the 505(b)(2) application or ANDA applies, and
none of the reasons in paragraph (d) of this section for delaying
approval applies, the 505(b)(2) application or ANDA may be approved as
follows:
(i) Immediately, if the applicant certifies under Sec. 314.50(i) or
Sec. 314.94(a)(12) that:
(A) The applicant is aware of a relevant patent but the patent
information required under section 505(b) or (c) of the Federal Food,
Drug, and Cosmetic Act has not been submitted to FDA; or
(B) The relevant patent has expired; or
(C) The relevant patent is invalid, unenforceable, or will not be
infringed, except as provided in paragraphs (b)(3) and (c) of this
section, and the 45-day period provided for in section 505(c)(3)(C) and
(j)(5)(B)(iii) of the Federal Food, Drug, and Cosmetic Act has expired;
or
(D) There are no relevant patents.
(ii) Immediately, if the applicant submits an appropriate statement
under Sec. 314.50(i) or Sec. 314.94(a)(12) explaining that a method-
of-use patent does not claim an indication or other condition of use for
which the applicant is seeking approval, except that if the applicant
also submits a paragraph IV certification to the patent, then the
505(b)(2) application or ANDA may be approved as provided in paragraph
(b)(1)(i)(C) of this section.
(iii) On the date specified, if the applicant certifies under Sec.
314.50(i) or Sec. 314.94(a)(12) that the relevant patent will expire on
a specified date.
(2) Patent information filed after submission of 505(b)(2)
application or ANDA. If the holder of the approved NDA for the listed
drug submits patent information required under Sec. 314.53 after the
date on which the 505(b)(2) application or ANDA was submitted to FDA,
the 505(b)(2) applicant or ANDA applicant must comply with the
requirements of Sec. 314.50(i)(4) and (6) and Sec. 314.94(a)(12)(vi)
and (viii) regarding submission of an appropriate patent certification
or statement. If the applicant submits an amendment certifying under
Sec. 314.50(i)(1)(i)(A)(4) or Sec. 314.94(a)(12)(i)(A)(4) that the
relevant patent is invalid, unenforceable, or will not be infringed, and
complies with the requirements of Sec. 314.52 or Sec. 314.95, the
505(b)(2) application or ANDA may be approved immediately upon
submission of documentation of receipt of notice of paragraph IV
certification under Sec. 314.52(e) or Sec. 314.95(e). The 45-day
period provided for in section 505(c)(3)(C) and (j)(5)(B)(iii) of the
Federal Food, Drug, and Cosmetic Act does not apply in these
circumstances.
(3) Disposition of patent litigation--(i) Approval upon expiration
of 30-month period or 7\1/2\ years from date of listed drug approval.
(A) Except as provided in paragraphs (b)(3)(ii) through (viii) of this
section, if, with respect to patents for which required information was
submitted under Sec. 314.53 before the date on which the 505(b)(2)
application or ANDA was submitted to FDA (excluding an amendment or
supplement to the 505(b)(2) application or ANDA), the applicant
certifies under Sec. 314.50(i) or Sec. 314.94(a)(12) that the relevant
patent is invalid, unenforceable, or will not be
[[Page 160]]
infringed, and the patent owner or its representative or the exclusive
patent licensee brings suit for patent infringement within 45 days of
receipt of the notice of certification from the applicant under Sec.
314.52 or Sec. 314.95, the 505(b)(2) application or ANDA may be
approved 30 months after the later of the date of the receipt of the
notice of certification by any owner of the listed patent or by the NDA
holder (or its representative(s)) unless the court has extended or
reduced the period because of a failure of either the plaintiff or
defendant to cooperate reasonably in expediting the action; or
(B) If the patented drug product qualifies for 5 years of exclusive
marketing under Sec. 314.108(b)(2) and the patent owner or its
representative or the exclusive patent licensee brings suit for patent
infringement during the 1-year period beginning 4 years after the date
of approval of the patented drug and within 45 days of receipt of the
notice of certification from the applicant under Sec. 314.52 or Sec.
314.95, the 505(b)(2) application or ANDA may be approved at the
expiration of the 7\1/2\ years from the date of approval of the NDA for
the patented drug product.
(ii) Federal district court decision of invalidity,
unenforceability, or non-infringement. If before the expiration of the
30-month period, or 7\1/2\ years where applicable, the district court
decides that the patent is invalid, unenforceable, or not infringed
(including any substantive determination that there is no cause of
action for patent infringement or invalidity), the 505(b)(2) application
or ANDA may be approved on:
(A) The date on which the court enters judgment reflecting the
decision; or
(B) The date of a settlement order or consent decree signed and
entered by the court stating that the patent that is the subject of the
certification is invalid, unenforceable, or not infringed.
(iii) Appeal of Federal district court judgment of infringement. If
before the expiration of the 30-month period, or 7\1/2\ years where
applicable, the district court decides that the patent has been
infringed, and if the judgment of the district court is appealed, the
505(b)(2) application or ANDA may be approved on:
(A) The date on which the mandate is issued by the court of appeals
entering judgment that the patent is invalid, unenforceable, or not
infringed (including any substantive determination that there is no
cause of action for patent infringement or invalidity); or
(B) The date of a settlement order or consent decree signed and
entered by the court of appeals stating that the patent that is the
subject of the certification is invalid, unenforceable, or not
infringed.
(iv) Affirmation or non-appeal of Federal district court judgment of
infringement. If before the expiration of the 30-month period, or 7\1/2\
years where applicable, the district court decides that the patent has
been infringed, and if the judgment of the district court is not
appealed or is affirmed, the 505(b)(2) application or ANDA may be
approved no earlier than the date specified by the district court in an
order under 35 U.S.C. 271(e)(4)(A).
(v) Grant of preliminary injunction by Federal district court. If
before the expiration of the 30-month period, or 7\1/2\ years where
applicable, the district court grants a preliminary injunction
prohibiting the applicant from engaging in the commercial manufacture or
sale of the drug product until the court decides the issues of patent
validity and infringement, and if the court later decides that:
(A) The patent is invalid, unenforceable, or not infringed, the
505(b)(2) application or ANDA may be approved as provided in paragraph
(b)(3)(ii) of this section; or
(B) The patent is infringed, the 505(b)(2) application or ANDA may
be approved as provided in paragraph (b)(3)(iii) or (iv) of this
section, whichever is applicable.
(vi) Written consent to approval by patent owner or exclusive patent
licensee. If before the expiration of the 30-month period, or 7\1/2\
years where applicable, the patent owner or the exclusive patent
licensee (or their representatives) agrees in writing that the 505(b)(2)
application or ANDA may be approved any time on or after the date of the
consent, approval may be granted on or after that date.
[[Page 161]]
(vii) Court order terminating 30-month or 7\1/2\-year period. If
before the expiration of the 30-month period, or 7\1/2\ years where
applicable, the court enters an order requiring the 30-month or 7\1/2\-
year period to be terminated, the 505(b)(2) application or ANDA may be
approved in accordance with the court's order.
(viii) Court order of dismissal without a finding of infringement.
If before the expiration of the 30-month period, or 7\1/2\ years where
applicable, the court(s) enter(s) an order of dismissal, with or without
prejudice, without a finding of infringement in each pending suit for
patent infringement brought within 45 days of receipt of the notice of
paragraph IV certification sent by the 505(b)(2) or ANDA applicant, the
505(b)(2) application or ANDA may be approved on or after the date of
the order.
(4) Tentative approval. FDA will issue a tentative approval letter
when tentative approval is appropriate in accordance with this section.
In order for a 505(b)(2) application or ANDA to be approved under
paragraph (b)(3) of this section, the applicant must receive an approval
letter from the Agency. Tentative approval of an NDA or ANDA does not
constitute ``approval'' of an NDA or ANDA and cannot, absent an approval
letter from the Agency, result in an approval under paragraph (b)(3) of
this section.
(c) Timing of approval of subsequent ANDA. (1) If an ANDA contains a
paragraph IV certification for a relevant patent and the ANDA is not
that of a first applicant, the ANDA is regarded as the ANDA of a
subsequent applicant. The ANDA of a subsequent applicant will not be
approved during the period when any first applicant is eligible for 180-
day exclusivity or during the 180-day exclusivity period of a first
applicant. Any applicable 180-day exclusivity period cannot extend
beyond the expiration of the patent upon which the 180-day exclusivity
period was based.
(2) A first applicant must submit correspondence to its ANDA
notifying FDA within 30 days of the date of its first commercial
marketing of its drug product or the reference listed drug. If an
applicant does not notify FDA, as required in this paragraph (c)(2), of
this date, the date of first commercial marketing will be deemed to be
the date of the drug product's approval.
(3) If FDA concludes that a first applicant is not actively pursuing
approval of its ANDA, FDA may immediately approve an ANDA(s) of a
subsequent applicant(s) if the ANDA(s) is otherwise eligible for
approval.
(d) Delay due to exclusivity. The Agency will also delay the
approval of a 505(b)(2) application or ANDA if delay is required by the
exclusivity provisions in Sec. 314.108; section 527 of the Federal
Food, Drug, and Cosmetic Act and Sec. 316.31 of this chapter; section
505A of the Federal Food, Drug, and Cosmetic Act; or section 505E of the
Federal Food, Drug, and Cosmetic Act. When the approval of a 505(b)(2)
application or ANDA is delayed under this section and Sec. 314.108;
section 527 of the Federal Food, Drug, and Cosmetic Act and Sec. 316.31
of this chapter; section 505A of the Federal Food, Drug, and Cosmetic
Act; or section 505E of the Federal Food, Drug, and Cosmetic Act, the
505(b)(2) application or ANDA will be approved on the latest of the days
specified under this section and Sec. 314.108; section 527 of the
Federal Food, Drug, and Cosmetic Act and Sec. 316.31 of this chapter;
section 505A of the Federal Food, Drug, and Cosmetic Act; or section
505E of the Federal Food, Drug, and Cosmetic Act, as applicable.
(e) Notification of court actions or written consent to approval.
(1) The applicant must submit the following information to FDA, as
applicable:
(i) A copy of any judgment by the court (district court or mandate
of the court of appeals) or settlement order or consent decree signed
and entered by the court (district court or court of appeals) finding a
patent described in paragraph (b)(3) of this section invalid,
unenforceable, or not infringed, or finding the patent valid and
infringed;
(ii) Written notification of whether or not any action by the court
described in paragraph (e)(1)(i) of this section has been appealed
within the time permitted for an appeal;
(iii) A copy of any order entered by the court terminating the 30-
month or
[[Page 162]]
7\1/2\-year period as described in paragraph (b)(3)(i), (ii), (vii), or
(viii) of this section;
(iv) A copy of any written consent to approval by the patent owner
or exclusive patent licensee described in paragraph (b)(3)(vi) of this
section;
(v) A copy of any preliminary injunction described in paragraph
(b)(3)(v) of this section, and a copy of any subsequent court order
lifting the injunction; and
(vi) A copy of any court order pursuant to 35 U.S.C. 271(e)(4)(A)
ordering that a 505(b)(2) application or ANDA may be approved no earlier
than the date specified (irrespective of whether the injunction relates
to a patent described in paragraph (b)(3) of this section).
(2) All information required by paragraph (e)(1) of this section
must be sent to the applicant's NDA or ANDA, as appropriate, within 14
days of the date of entry by the court, the date of appeal or expiration
of the time for appeal, or the date of written consent to approval, as
applicable.
(f) Forty-five day period after receipt of notice of paragraph IV
certification--(1) Computation of 45-day time clock. The 45-day clock
described in paragraph (b)(3) of this section as to each recipient
required to receive notice of paragraph IV certification under Sec.
314.52 or Sec. 314.95 begins on the day after the date of receipt of
the applicant's notice of paragraph IV certification by the recipient.
When the 45th day falls on Saturday, Sunday, or a Federal holiday, the
45th day will be the next day that is not a Saturday, Sunday, or a
Federal holiday.
(2) Notification of filing of legal action. (i) The 505(b)(2) or
ANDA applicant must notify FDA in writing within 14 days of the filing
of any legal action filed within 45 days of receipt of the notice of
paragraph IV certification by any recipient. A 505(b)(2) applicant must
send the notification to its NDA. An ANDA applicant must send the
notification to its ANDA. The notification to FDA of the legal action
must include:
(A) The 505(b)(2) application or ANDA number.
(B) The name of the 505(b)(2) or ANDA applicant.
(C) The established name of the drug product or, if no established
name exists, the name(s) of the active ingredient(s), the drug product's
strength, and dosage form.
(D) A statement that an action for patent infringement, identified
by court, case number, and the patent number(s) of the patent(s) at
issue in the action, has been filed in an appropriate court on a
specified date.
(ii) A patent owner or NDA holder (or its representative(s)) may
also notify FDA of the filing of any legal action for patent
infringement. The notice should contain the information and be sent to
the offices or divisions described in paragraph (f)(2)(i) of this
section.
(iii) If the 505(b)(2) or ANDA applicant, the patent owner(s), the
NDA holder, or its representative(s) does not notify FDA in writing
before the expiration of the 45-day time period or the completion of the
Agency's review of the 505(b)(2) application or ANDA, whichever occurs
later, that a legal action for patent infringement was filed within 45
days of receipt of the notice of paragraph IV certification, the
505(b)(2) application or ANDA may be approved upon expiration of the 45-
day period (if the 505(b)(2) or ANDA applicant confirms that a legal
action for patent infringement has not been filed) or upon completion of
the Agency's review of the 505(b)(2) application or ANDA, whichever is
later.
(3) Waiver. If the patent owner or NDA holder who is an exclusive
patent licensee (or its representative(s)) waives its opportunity to
file a legal action for patent infringement within 45 days of a receipt
of the notice of certification and the patent owner or NDA holder who is
an exclusive patent licensee (or its representative(s)) submits to FDA a
valid waiver before the 45 days elapse, the 505(b)(2) application or
ANDA may be approved upon completion of the Agency's review of the NDA
or ANDA. FDA will only accept a waiver in the following form:
(Name of patent owner or NDA holder who is an exclusive patent
licensee or its representative(s)) has received notice from (name of
applicant) under (section 505(b)(3) or 505(j)(2)(B) of the Federal Food,
Drug, and Cosmetic Act)
[[Page 163]]
and does not intend to file an action for patent infringement against
(name of applicant) concerning the drug (name of drug) before (date on
which 45 days elapse). (Name of patent owner or NDA holder who is an
exclusive patent licensee) waives the opportunity provided by (section
505(c)(3)(C) or 505(j)(5)(B)(iii) of the Federal Food, Drug, and
Cosmetic Act) and does not object to FDA's approval of (name of
applicant)'s (505(b)(2) application or ANDA) for (name of drug) with an
approval date on or after the date of this submission.
(g) Conversion of approval to tentative approval. If FDA issues an
approval letter in error or a court enters an order requiring, in the
case of an already approved 505(b)(2) application or ANDA, that the date
of approval be delayed, FDA will convert the approval to a tentative
approval if appropriate.
[81 FR 69655, Oct. 6, 2016]
Sec. 314.108 New drug product exclusivity.
(a) Definitions. The definitions in Sec. 314.3 and the following
definitions of terms apply to this section:
Approved under section 505(b) means an NDA submitted under section
505(b) and approved on or after October 10, 1962, or an application that
was ``deemed approved'' under section 107(c)(2) of Public Law 87-781.
Bioavailability study means a study to determine the bioavailability
or the pharmacokinetics of a drug.
Clinical investigation means any experiment other than a
bioavailability study in which a drug is administered or dispensed to,
or used on, human subjects.
Conducted or sponsored by the applicant with regard to an
investigation means that before or during the investigation, the
applicant was named in Form FDA-1571 filed with FDA as the sponsor of
the investigational new drug application under which the investigation
was conducted, or the applicant or the applicant's predecessor in
interest, provided substantial support for the investigation. To
demonstrate ``substantial support,'' an applicant must either provide a
certified statement from a certified public accountant that the
applicant provided 50 percent or more of the cost of conducting the
study or provide an explanation why FDA should consider the applicant to
have conducted or sponsored the study if the applicant's financial
contribution to the study is less than 50 percent or the applicant did
not sponsor the investigational new drug. A predecessor in interest is
an entity, e.g., a corporation, that the applicant has taken over,
merged with, or purchased, or from which the applicant has purchased all
rights to the drug. Purchase of nonexclusive rights to a clinical
investigation after it is completed is not sufficient to satisfy this
definition.
Essential to approval means, with regard to an investigation, that
there are no other data available that could support approval of the
NDA.
New chemical entity means a drug that contains no active moiety that
has been approved by FDA in any other NDA submitted under section 505(b)
of the Federal Food, Drug, and Cosmetic Act.
New clinical investigation means an investigation in humans the
results of which have not been relied on by FDA to demonstrate
substantial evidence of effectiveness of a previously approved drug
product for any indication or of safety for a new patient population and
do not duplicate the results of another investigation that was relied on
by the agency to demonstrate the effectiveness or safety in a new
patient population of a previously approved drug product. For purposes
of this section, data from a clinical investigation previously submitted
for use in the comprehensive evaluation of the safety of a drug product
but not to support the effectiveness of the drug product would be
considered new.
(b) Submission of and timing of approval of a 505(b)(2) application
or ANDA. (1) [Reserved]
(2) If a drug product that contains a new chemical entity was
approved after September 24, 1984, in an NDA submitted under section
505(b) of the Federal Food, Drug, and Cosmetic Act, no person may submit
a 505(b)(2) application or ANDA under section 505(j) of the Federal
Food, Drug, and Cosmetic Act for a drug product that contains the same
active moiety as in the new chemical entity for a period of 5 years from
the date of approval of the first approved NDA, except that the
505(b)(2) application or ANDA may be submitted
[[Page 164]]
after 4 years if it contains a certification of patent invalidity or
noninfringement described in Sec. 314.50(i)(1)(i)(A)(4) or Sec.
314.94(a)(12)(i)(A)(4).
(3) The approval of a 505(b)(2) application or ANDA described in
paragraph (b)(2) of this section will occur as provided in Sec.
314.107(b)(1) or (2), unless the owner of a patent that claims the drug,
the patent owner's representative, or exclusive licensee brings suit for
patent infringement against the applicant during the 1-year period
beginning 48 months after the date of approval of the NDA for the new
chemical entity and within 45 days after receipt of the notice described
at Sec. 314.52 or Sec. 314.95, in which case, approval of the
505(b)(2) application or ANDA will occur as provided in Sec.
314.107(b)(3).
(4) If an NDA:
(i) Was submitted under section 505(b) of the Federal Food, Drug,
and Cosmetic Act;
(ii) Was approved after September 24, 1984;
(iii) Was for a drug product that contains an active moiety that has
been previously approved in another NDA under section 505(b) of the
Federal Food, Drug, and Cosmetic Act; and
(iv) Contained reports of new clinical investigations (other than
bioavailability studies) conducted or sponsored by the applicant that
were essential to approval of the application, for a period of 3 years
after the date of approval of the application, the Agency will not
approve a 505(b)(2) application or an ANDA for the conditions of
approval of the NDA, or an ANDA submitted pursuant to an approved
petition under section 505(j)(2)(C) of the Federal Food, Drug, and
Cosmetic Act that relies on the information supporting the conditions of
approval of an original NDA.
(5) If a supplemental NDA:
(i) Was approved after September 24, 1984; and
(ii) Contained reports of new clinical investigations (other than
bioavailability studies) that were conducted or sponsored by the
applicant that were essential to approval of the supplemental NDA, for a
period of 3 years after the date of approval of the supplemental
application, the Agency will not approve a 505(b)(2) application or an
ANDA for a change, or an ANDA submitted pursuant to an approved petition
under section 505(j)(2)(C) of the Federal Food, Drug, and Cosmetic Act
that relies on the information supporting a change approved in the
supplemental NDA.
[59 FR 50368, Oct. 3, 1994, as amended at 81 FR 69657, Oct. 6, 2016]
Sec. 314.110 Complete response letter to the applicant.
(a) Complete response letter. FDA will send the applicant a complete
response letter if the agency determines that we will not approve the
application or abbreviated application in its present form for one or
more of the reasons given in Sec. 314.125 or Sec. 314.127,
respectively.
(1) Description of specific deficiencies. A complete response letter
will describe all of the specific deficiencies that the agency has
identified in an application or abbreviated application, except as
stated in paragraph (a)(3) of this section.
(2) Complete review of data. A complete response letter reflects
FDA's complete review of the data submitted in an original application
or abbreviated application (or, where appropriate, a resubmission) and
any amendments that the agency has reviewed. The complete response
letter will identify any amendments that the agency has not yet
reviewed.
(3) Inadequate data. If FDA determines, after an application is
filed or an abbreviated application is received, that the data submitted
are inadequate to support approval, the agency might issue a complete
response letter without first conducting required inspections and/or
reviewing proposed product labeling.
(4) Recommendation of actions for approval. When possible, a
complete response letter will recommend actions that the applicant might
take to place the application or abbreviated application in condition
for approval.
(b) Applicant actions. After receiving a complete response letter,
the applicant must take one of following actions:
[[Page 165]]
(1) Resubmission. Resubmit the application or abbreviated
application, addressing all deficiencies identified in the complete
response letter.
(i) A resubmission of an application or efficacy supplement that FDA
classifies as a Class 1 resubmission constitutes an agreement by the
applicant to start a new 2-month review cycle beginning on the date FDA
receives the resubmission.
(ii) A resubmission of an application or efficacy supplement that
FDA classifies as a Class 2 resubmission constitutes an agreement by the
applicant to start a new 6-month review cycle beginning on the date FDA
receives the resubmission.
(iii) A resubmission of an NDA supplement other than an efficacy
supplement constitutes an agreement by the applicant to start a new
review cycle the same length as the initial review cycle for the
supplement (excluding any extension due to a major amendment of the
initial supplement), beginning on the date FDA receives the
resubmission.
(iv) A major resubmission of an abbreviated application constitutes
an agreement by the applicant to start a new 6-month review cycle
beginning on the date FDA receives the resubmission.
(v) A minor resubmission of an abbreviated application constitutes
an agreement by the applicant to start a new review cycle beginning on
the date FDA receives the resubmission.
(2) Withdrawal. Withdraw the application or abbreviated application.
A decision to withdraw an application or abbreviated application is
without prejudice to a subsequent submission.
(3) Request opportunity for hearing. Ask the agency to provide the
applicant an opportunity for a hearing on the question of whether there
are grounds for denying approval of the application or abbreviated
application under section 505(d) or (j)(4) of the act, respectively. The
applicant must submit the request to the Associate Director for Policy,
Center for Drug Evaluation and Research, Food and Drug Administration,
10903 New Hampshire Ave., Silver Spring, MD 20993. Within 60 days of the
date of the request for an opportunity for a hearing, or within a
different time period to which FDA and the applicant agree, the agency
will either approve the application or abbreviated application under
Sec. 314.105, or refuse to approve the application under Sec. 314.125
or abbreviated application under Sec. 314.127 and give the applicant
written notice of an opportunity for a hearing under Sec. 314.200 and
section 505(c)(1)(B) or (j)(5)(c) of the act on the question of whether
there are grounds for denying approval of the application or abbreviated
application under section 505(d) or (j)(4) of the act, respectively.
(c) Failure to take action. (1) An applicant agrees to extend the
review period under section 505(c)(1) or (j)(5)(A) of the act until it
takes any of the actions listed in paragraph (b) of this section. For an
application or abbreviated application, FDA may consider an applicant's
failure to take any of such actions within 1 year after issuance of a
complete response letter to be a request by the applicant to withdraw
the application, unless the applicant has requested an extension of time
in which to resubmit the application. FDA will grant any reasonable
request for such an extension. FDA may consider an applicant's failure
to resubmit the application within the extended time period or to
request an additional extension to be a request by the applicant to
withdraw the application.
(2) If FDA considers an applicant's failure to take action in
accordance with paragraph (c)(1) of this section to be a request to
withdraw the application, the agency will notify the applicant in
writing. The applicant will have 30 days from the date of the
notification to explain why the application should not be withdrawn and
to request an extension of time in which to resubmit the application.
FDA will grant any reasonable request for an extension. If the applicant
does not respond to the notification within 30 days, the application
will be deemed to be withdrawn.
[73 FR 39609, July 10, 2008]
[[Page 166]]
Sec. 314.120 [Reserved]
Sec. 314.122 Submitting an abbreviated application for, or a
505(j)(2)(C) petition that relies on, a listed drug that is no longer
marketed.
(a) An abbreviated new drug application that refers to, or a
petition under section 505(j)(2)(C) of the act and Sec. 314.93 that
relies on, a listed drug that has been voluntarily withdrawn from sale
in the United States must be accompanied by a petition seeking a
determination whether the listed drug was withdrawn for safety or
effectiveness reasons. The petition must be submitted under Sec. Sec.
10.25(a) and 10.30 of this chapter and must contain all evidence
available to the petitioner concerning the reasons for the withdrawal
from sale.
(b) When a petition described in paragraph (a) of this section is
submitted, the agency will consider the evidence in the petition and any
other evidence before the agency, and determine whether the listed drug
is withdrawn from sale for safety or effectiveness reasons, in
accordance with the procedures in Sec. 314.161.
(c) An abbreviated new drug application described in paragraph (a)
of this section will be disapproved, under Sec. 314.127(a)(11), and a
505(j)(2)(C) petition described in paragraph (a) of this section will be
disapproved, under Sec. 314.93(e)(1)(iv), unless the agency determines
that the withdrawal of the listed drug was not for safety or
effectiveness reasons.
(d) Certain drug products approved for safety and effectiveness that
were no longer marketed on September 24, 1984, are not included in the
list. Any person who wishes to obtain marketing approval for such a drug
product under an abbreviated new drug application must petition FDA for
a determination whether the drug product was withdrawn from the market
for safety or effectiveness reasons and request that the list be amended
to include the drug product. A person seeking such a determination shall
use the petition procedures established in Sec. 10.30 of this chapter.
The petitioner shall include in the petition information to show that
the drug product was approved for safety and effectiveness and all
evidence available to the petitioner concerning the reason that
marketing of the drug product ceased.
[57 FR 17990, Apr. 28, 1992; 57 FR 29353, July 1, 1992]
Sec. 314.125 Refusal to approve an NDA.
(a) The Food and Drug Administration will refuse to approve the NDA
and for a new drug give the applicant written notice of an opportunity
for a hearing under Sec. 314.200 on the question of whether there are
grounds for denying approval of the NDA under section 505(d) of the
Federal Food, Drug, and Cosmetic Act, if:
(1) FDA sends the applicant a complete response letter under Sec.
314.110;
(2) The applicant requests an opportunity for hearing for a new drug
on the question of whether the NDA is approvable; and
(3) FDA finds that any of the reasons given in paragraph (b) of this
section apply.
(b) FDA may refuse to approve an NDA for any of the following
reasons, unless the requirement has been waived under Sec. 314.90:
(1) The methods to be used in, and the facilities and controls used
for, the manufacture, processing, packing, or holding of the drug
substance or the drug product are inadequate to preserve its identity,
strength, quality, purity, stability, and bioavailability.
(2) The investigations required under section 505(b) of the Federal
Food, Drug, and Cosmetic Act do not include adequate tests by all
methods reasonably applicable to show whether or not the drug is safe
for use under the conditions prescribed, recommended, or suggested in
its proposed labeling.
(3) The results of the tests show that the drug is unsafe for use
under the conditions prescribed, recommended, or suggested in its
proposed labeling or the results do not show that the drug product is
safe for use under those conditions.
(4) There is insufficient information about the drug to determine
whether the product is safe for use under the conditions prescribed,
recommended, or suggested in its proposed labeling.
(5) There is a lack of substantial evidence consisting of adequate
and well-controlled investigations, as defined in
[[Page 167]]
Sec. 314.126, that the drug product will have the effect it purports or
is represented to have under the conditions of use prescribed,
recommended, or suggested in its proposed labeling.
(6) The proposed labeling is false or misleading in any particular.
(7) The NDA contains an untrue statement of a material fact.
(8) The drug product's proposed labeling does not comply with the
requirements for labels and labeling in part 201.
(9) The NDA does not contain bioavailability or bioequivalence data
required under part 320 of this chapter.
(10) A reason given in a letter refusing to file the NDA under Sec.
314.101(d), if the deficiency is not corrected.
(11) The drug will be manufactured in whole or in part in an
establishment that is not registered and not exempt from registration
under section 510 of the Federal Food, Drug, and Cosmetic Act and part
207.
(12) The applicant does not permit a properly authorized officer or
employee of the Department of Health and Human Services an adequate
opportunity to inspect the facilities, controls, and any records
relevant to the NDA.
(13) The methods to be used in, and the facilities and controls used
for, the manufacture, processing, packing, or holding of the drug
substance or the drug product do not comply with the current good
manufacturing practice regulations in parts 210 and 211.
(14) The NDA does not contain an explanation of the omission of a
report of any investigation of the drug product sponsored by the
applicant, or an explanation of the omission of other information about
the drug pertinent to an evaluation of the NDA that is received or
otherwise obtained by the applicant from any source.
(15) A nonclinical laboratory study that is described in the NDA and
that is essential to show that the drug is safe for use under the
conditions prescribed, recommended, or suggested in its proposed
labeling was not conducted in compliance with the good laboratory
practice regulations in part 58 of this chapter and no reason for the
noncompliance is provided or, if it is, the differences between the
practices used in conducting the study and the good laboratory practice
regulations do not support the validity of the study.
(16) Any clinical investigation involving human subjects described
in the NDA, subject to the institutional review board regulations in
part 56 of this chapter or informed consent regulations in part 50 of
this chapter, was not conducted in compliance with those regulations
such that the rights or safety of human subjects were not adequately
protected.
(17) The applicant or contract research organization that conducted
a bioavailability or bioequivalence study described in Sec. 320.38 or
Sec. 320.63 of this chapter that is contained in the NDA refuses to
permit an inspection of facilities or records relevant to the study by a
properly authorized officer or employee of the Department of Health and
Human Services or refuses to submit reserve samples of the drug products
used in the study when requested by FDA.
(18) For a new drug, the NDA failed to contain the patent
information required by section 505(b)(1) of the Federal Food, Drug, and
Cosmetic Act.
(19) The 505(b)(2) application failed to contain a patent
certification or statement with respect to each listed patent for a drug
product approved in an NDA that:
(i) Is pharmaceutically equivalent to the drug product for which the
original 505(b)(2) application is submitted; and
(ii) Was approved before the original 505(b)(2) application was
submitted.
(c) For drugs intended to treat life-threatening or severely-
debilitating illnesses that are developed in accordance with Sec. Sec.
312.80 through 312.88 of this chapter, the criteria contained in
paragraphs (b) (3), (4), and (5) of this section shall be applied
according to the considerations contained in Sec. 312.84 of this
chapter.
[50 FR 7493, Feb. 22, 1985, as amended at 53 FR 41524, Oct. 21, 1988; 57
FR 17991, Apr. 28, 1992; 58 FR 25926, Apr. 28, 1993; 64 FR 402, Jan. 5,
1999; 73 FR 39610, July 10, 2008; 74 FR 9766, Mar. 6, 2009; 81 FR 60221,
Aug. 31, 2016; 81 FR 69658, Oct. 6, 2016]
[[Page 168]]
Sec. 314.126 Adequate and well-controlled studies.
(a) The purpose of conducting clinical investigations of a drug is
to distinguish the effect of a drug from other influences, such as
spontaneous change in the course of the disease, placebo effect, or
biased observation. The characteristics described in paragraph (b) of
this section have been developed over a period of years and are
recognized by the scientific community as the essentials of an adequate
and well-controlled clinical investigation. The Food and Drug
Administration considers these characteristics in determining whether an
investigation is adequate and well-controlled for purposes of section
505 of the act. Reports of adequate and well-controlled investigations
provide the primary basis for determining whether there is ``substantial
evidence'' to support the claims of effectiveness for new drugs.
Therefore, the study report should provide sufficient details of study
design, conduct, and analysis to allow critical evaluation and a
determination of whether the characteristics of an adequate and well-
controlled study are present.
(b) An adequate and well-controlled study has the following
characteristics:
(1) There is a clear statement of the objectives of the
investigation and a summary of the proposed or actual methods of
analysis in the protocol for the study and in the report of its results.
In addition, the protocol should contain a description of the proposed
methods of analysis, and the study report should contain a description
of the methods of analysis ultimately used. If the protocol does not
contain a description of the proposed methods of analysis, the study
report should describe how the methods used were selected.
(2) The study uses a design that permits a valid comparison with a
control to provide a quantitative assessment of drug effect. The
protocol for the study and report of results should describe the study
design precisely; for example, duration of treatment periods, whether
treatments are parallel, sequential, or crossover, and whether the
sample size is predetermined or based upon some interim analysis.
Generally, the following types of control are recognized:
(i) Placebo concurrent control. The test drug is compared with an
inactive preparation designed to resemble the test drug as far as
possible. A placebo-controlled study may include additional treatment
groups, such as an active treatment control or a dose-comparison
control, and usually includes randomization and blinding of patients or
investigators, or both.
(ii) Dose-comparison concurrent control. At least two doses of the
drug are compared. A dose-comparison study may include additional
treatment groups, such as placebo control or active control. Dose-
comparison trials usually include randomization and blinding of patients
or investigators, or both.
(iii) No treatment concurrent control. Where objective measurements
of effectiveness are available and placebo effect is negligible, the
test drug is compared with no treatment. No treatment concurrent control
trials usually include randomization.
(iv) Active treatment concurrent control. The test drug is compared
with known effective therapy; for example, where the condition treated
is such that administration of placebo or no treatment would be contrary
to the interest of the patient. An active treatment study may include
additional treatment groups, however, such as a placebo control or a
dose-comparison control. Active treatment trials usually include
randomization and blinding of patients or investigators, or both. If the
intent of the trial is to show similarity of the test and control drugs,
the report of the study should assess the ability of the study to have
detected a difference between treatments. Similarity of test drug and
active control can mean either that both drugs were effective or that
neither was effective. The analysis of the study should explain why the
drugs should be considered effective in the study, for example, by
reference to results in previous placebo-controlled studies of the
active control drug.
(v) Historical control. The results of treatment with the test drug
are compared with experience historically derived from the adequately
documented natural history of the disease or condition, or from the
results of active
[[Page 169]]
treatment, in comparable patients or populations. Because historical
control populations usually cannot be as well assessed with respect to
pertinent variables as can concurrent control populations, historical
control designs are usually reserved for special circumstances. Examples
include studies of diseases with high and predictable mortality (for
example, certain malignancies) and studies in which the effect of the
drug is self-evident (general anesthetics, drug metabolism).
(3) The method of selection of subjects provides adequate assurance
that they have the disease or condition being studied, or evidence of
susceptibility and exposure to the condition against which prophylaxis
is directed.
(4) The method of assigning patients to treatment and control groups
minimizes bias and is intended to assure comparability of the groups
with respect to pertinent variables such as age, sex, severity of
disease, duration of disease, and use of drugs or therapy other than the
test drug. The protocol for the study and the report of its results
should describe how subjects were assigned to groups. Ordinarily, in a
concurrently controlled study, assignment is by randomization, with or
without stratification.
(5) Adequate measures are taken to minimize bias on the part of the
subjects, observers, and analysts of the data. The protocol and report
of the study should describe the procedures used to accomplish this,
such as blinding.
(6) The methods of assessment of subjects' response are well-defined
and reliable. The protocol for the study and the report of results
should explain the variables measured, the methods of observation, and
criteria used to assess response.
(7) There is an analysis of the results of the study adequate to
assess the effects of the drug. The report of the study should describe
the results and the analytic methods used to evaluate them, including
any appropriate statistical methods. The analysis should assess, among
other things, the comparability of test and control groups with respect
to pertinent variables, and the effects of any interim data analyses
performed.
(c) The Director of the Center for Drug Evaluation and Research may,
on the Director's own initiative or on the petition of an interested
person, waive in whole or in part any of the criteria in paragraph (b)
of this section with respect to a specific clinical investigation,
either prior to the investigation or in the evaluation of a completed
study. A petition for a waiver is required to set forth clearly and
concisely the specific criteria from which waiver is sought, why the
criteria are not reasonably applicable to the particular clinical
investigation, what alternative procedures, if any, are to be, or have
been employed, and what results have been obtained. The petition is also
required to state why the clinical investigations so conducted will
yield, or have yielded, substantial evidence of effectiveness,
notwithstanding nonconformance with the criteria for which waiver is
requested.
(d) For an investigation to be considered adequate for approval of a
new drug, it is required that the test drug be standardized as to
identity, strength, quality, purity, and dosage form to give
significance to the results of the investigation.
(e) Uncontrolled studies or partially controlled studies are not
acceptable as the sole basis for the approval of claims of
effectiveness. Such studies carefully conducted and documented, may
provide corroborative support of well-controlled studies regarding
efficacy and may yield valuable data regarding safety of the test drug.
Such studies will be considered on their merits in the light of the
principles listed here, with the exception of the requirement for the
comparison of the treated subjects with controls. Isolated case reports,
random experience, and reports lacking the details which permit
scientific evaluation will not be considered.
[50 FR 7493, Feb. 22, 1985, as amended at 50 FR 21238, May 23, 1985; 55
FR 11580, Mar. 29, 1990; 64 FR 402, Jan. 5, 1999; 67 FR 9586, Mar. 4,
2002]
Sec. 314.127 Refusal to approve an ANDA.
(a) FDA will refuse to approve an ANDA for a new drug under section
505(j) of the Federal Food, Drug, and Cosmetic Act for any of the
following
[[Page 170]]
reasons, unless the requirement has been waived under Sec. 314.99:
(1) The methods used in, or the facilities and controls used for,
the manufacture, processing, and packing of the drug product are
inadequate to ensure and preserve its identity, strength, quality, and
purity.
(2) Information submitted with the ANDA is insufficient to show that
each of the proposed conditions of use has been previously approved for
the listed drug referred to in the ANDA.
(3)(i) If the reference listed drug has only one active ingredient,
information submitted with the ANDA is insufficient to show that the
active ingredient is the same as that of the reference listed drug;
(ii) If the reference listed drug has more than one active
ingredient, information submitted with the ANDA is insufficient to show
that the active ingredients are the same as the active ingredients of
the reference listed drug; or
(iii) If the reference listed drug has more than one active
ingredient and if the ANDAis for a drug product that has an active
ingredient different from the reference listed drug:
(A) Information submitted with the ANDA is insufficient to show:
(1) That the other active ingredients are the same as the active
ingredients of the reference listed drug; or
(2) That the different active ingredient is an active ingredient of
a listed drug or a drug that does not meet the requirements of section
201(p) of the Federal Food, Drug, and Cosmetic Act; or
(B) No petition to submit an ANDA for the drug product with the
different active ingredient was approved under Sec. 314.93.
(4)(i) If the ANDA is for a drug product whose route of
administration, dosage form, or strength purports to be the same as that
of the listed drug referred to in the ANDA, information submitted in the
abbreviated new drug application is insufficient to show that the route
of administration, dosage form, or strength is the same as that of the
reference listed drug; or
(ii) If the ANDA is for a drug product whose route of
administration, dosage form, or strength is different from that of the
listed drug referred to in the application, no petition to submit an
ANDA for the drug product with the different route of administration,
dosage form, or strength was approved under Sec. 314.93.
(5) If the ANDA was submitted under the approval of a petition under
Sec. 314.93, the ANDA did not contain the information required by FDA
with respect to the active ingredient, route of administration, dosage
form, or strength that is not the same as that of the reference listed
drug.
(6)(i) Information submitted in the ANDA is insufficient to show
that the drug product is bioequivalent to the listed drug referred to in
the ANDA; or
(ii) If the ANDA was submitted under a petition approved under Sec.
314.93, information submitted in the ANDA is insufficient to show that
the active ingredients of the drug product are of the same
pharmacological or therapeutic class as those of the reference listed
drug and that the drug product can be expected to have the same
therapeutic effect as the reference listed drug when administered to
patients for each condition of use approved for the reference listed
drug.
(7) Information submitted in the ANDA is insufficient to show that
the labeling proposed for the drug is the same as the labeling approved
for the listed drug referred to in the ANDA except for changes required
because of differences approved in a petition under Sec. 314.93 or
because the drug product and the reference listed drug are produced or
distributed by different manufacturers or because aspects of the listed
drug's labeling are protected by patent, or by exclusivity, and such
differences do not render the proposed drug product less safe or
effective than the listed drug for all remaining, nonprotected
conditions of use.
(8)(i) Information submitted in the ANDA or any other information
available to FDA shows that:
(A) The inactive ingredients of the drug product are unsafe for use,
as described in paragraph (a)(8)(ii) of this section, under the
conditions prescribed, recommended, or suggested in the labeling
proposed for the drug product; or
[[Page 171]]
(B) The composition of the drug product is unsafe, as described in
paragraph (a)(8)(ii) of this section, under the conditions prescribed,
recommended, or suggested in the proposed labeling because of the type
or quantity of inactive ingredients included or the manner in which the
inactive ingredients are included.
(ii)(A) FDA will consider the inactive ingredients or composition of
a drug product unsafe and refuse to approve an ANDA under paragraph
(a)(8)(i) of this section if, on the basis of information available to
the agency, there is a reasonable basis to conclude that one or more of
the inactive ingredients of the proposed drug or its composition raises
serious questions of safety or efficacy. From its experience with
reviewing inactive ingredients, and from other information available to
it, FDA may identify changes in inactive ingredients or composition that
may adversely affect a drug product's safety or efficacy. The inactive
ingredients or composition of a proposed drug product will be considered
to raise serious questions of safety or efficacy if the product
incorporates one or more of these changes. Examples of the changes that
may raise serious questions of safety or efficacy include, but are not
limited to, the following:
(1) A change in an inactive ingredient so that the product does not
comply with an official compendium.
(2) A change in composition to include an inactive ingredient that
has not been previously approved in a drug product for human use by the
same route of administration.
(3) A change in the composition of a parenteral drug product to
include an inactive ingredient that has not been previously approved in
a parenteral drug product.
(4) A change in composition of a drug product for ophthalmic use to
include an inactive ingredient that has not been previously approved in
a drug for ophthalmic use.
(5) The use of a delivery or a modified release mechanism never
before approved for the drug.
(6) A change in composition to include a significantly greater
content of one or more inactive ingredients than previously used in the
drug product.
(7) If the drug product is intended for topical administration, a
change in the properties of the vehicle or base that might increase
absorption of certain potentially toxic active ingredients thereby
affecting the safety of the drug product, or a change in the lipophilic
properties of a vehicle or base, e.g., a change from an oleaginous to a
water soluble vehicle or base.
(B) FDA will consider an inactive ingredient in, or the composition
of, a drug product intended for parenteral use to be unsafe and will
refuse to approve the ANDA unless it contains the same inactive
ingredients, other than preservatives, buffers, and antioxidants, in the
same concentration as the listed drug, and, if it differs from the
listed drug in a preservative, buffer, or antioxidant, the ANDA contains
sufficient information to demonstrate that the difference does not
affect the safety or efficacy of the drug product.
(C) FDA will consider an inactive ingredient in, or the composition
of, a drug product intended for ophthalmic or otic use unsafe and will
refuse to approve the ANDA unless it contains the same inactive
ingredients, other than preservatives, buffers, substances to adjust
tonicity, or thickening agents, in the same concentration as the listed
drug, and if it differs from the listed drug in a preservative, buffer,
substance to adjust tonicity, or thickening agent, the ANDA contains
sufficient information to demonstrate that the difference does not
affect the safety or efficacy of the drug product and the labeling does
not claim any therapeutic advantage over or difference from the listed
drug.
(9) Approval of the listed drug referred to in the ANDA has been
withdrawn or suspended for grounds described in Sec. 314.150(a) or FDA
has published a notice of opportunity for hearing to withdraw approval
of the reference listed drug under Sec. 314.150(a).
(10) Approval of the listed drug referred to in the ANDA has been
withdrawn under Sec. 314.151 or FDA has proposed to withdraw approval
of the reference listed drug under Sec. 314.151(a).
(11) FDA has determined that the reference listed drug has been
withdrawn from sale for safety or effectiveness reasons under Sec.
314.161, or the reference
[[Page 172]]
listed drug has been voluntarily withdrawn from sale and the agency has
not determined whether the withdrawal is for safety or effectiveness
reasons, or approval of the reference listed drug has been suspended
under Sec. 314.153, or the agency has issued an initial decision
proposing to suspend the reference listed drug under Sec.
314.153(a)(1).
(12) The abbreviated new drug application does not meet any other
requirement under section 505(j)(2)(A) of the Federal Food, Drug, and
Cosmetic Act.
(13) The abbreviated new drug application contains an untrue
statement of material fact.
(14) For an ANDA submitted pursuant to an approved petition under
Sec. 10.30 of this chapter and Sec. 314.93, an NDA subsequently has
been approved for the change described in the approved petition.
(b) FDA may refuse to approve an ANDA for a new drug if the
applicant or contract research organization that conducted a
bioavailability or bioequivalence study described in Sec. 320.63 of
this chapter that is contained in the ANDA refuses to permit an
inspection of facilities or records relevant to the study by a properly
authorized officer or employee of the Department of Health and Human
Services or refuses to submit reserve samples of the drug products used
in the study when requested by FDA.
[57 FR 17991, Apr. 28, 1992; 57 FR 29353, July 1, 1992, as amended at 58
FR 25927, Apr. 28, 1993; 67 FR 77672, Dec. 19, 2002; 81 FR 69658, Oct.
6, 2016]
Sec. 314.150 Withdrawal of approval of an application or abbreviated
application.
(a) The Food and Drug Administration will notify the applicant, and,
if appropriate, all other persons who manufacture or distribute
identical, related, or similar drug products as defined in Sec. Sec.
310.6 and 314.151(a) of this chapter and for a new drug afford an
opportunity for a hearing on a proposal to withdraw approval of the
application or abbreviated new drug application under section 505(e) of
the act and under the procedure in Sec. 314.200, if any of the
following apply:
(1) The Secretary of Health and Human Services has suspended the
approval of the application or abbreviated application for a new drug on
a finding that there is an imminent hazard to the public health. FDA
will promptly afford the applicant an expedited hearing following
summary suspension on a finding of imminent hazard to health.
(2) FDA finds:
(i) That clinical or other experience, tests, or other scientific
data show that the drug is unsafe for use under the conditions of use
upon the basis of which the application or abbreviated application was
approved; or
(ii) That new evidence of clinical experience, not contained in the
application or not available to FDA until after the application or
abbreviated application was approved, or tests by new methods, or tests
by methods not deemed reasonably applicable when the application or
abbreviated application was approved, evaluated together with the
evidence available when the application or abbreviated application was
approved, reveal that the drug is not shown to be safe for use under the
conditions of use upon the basis of which the application or abbreviated
application was approved; or
(iii) Upon the basis of new information before FDA with respect to
the drug, evaluated together with the evidence available when the
application or abbreviated application was approved, that there is a
lack of substantial evidence from adequate and well-controlled
investigations as defined in Sec. 314.126, that the drug will have the
effect it is purported or represented to have under the conditions of
use prescribed, recommended, or suggested in its labeling; or
(iv) That the application or abbreviated application contains any
untrue statement of a material fact; or
(v) That the patent information prescribed by section 505(c) of the
act was not submitted within 30 days after the receipt of written notice
from FDA specifying the failure to submit such information; or
(b) FDA may notify the applicant, and, if appropriate, all other
persons who manufacture or distribute identical, related, or similar
drug products
[[Page 173]]
as defined in Sec. 310.6, and for a new drug afford an opportunity for
a hearing on a proposal to withdraw approval of the application or
abbreviated new drug application under section 505(e) of the act and
under the procedure in Sec. 314.200, if the agency finds:
(1) That the applicant has failed to establish a system for
maintaining required records, or has repeatedly or deliberately failed
to maintain required records or to make required reports under section
505(k) or 507(g) of the act and Sec. 314.80, Sec. 314.81, or Sec.
314.98, or that the applicant has refused to permit access to, or
copying or verification of, its records.
(2) That on the basis of new information before FDA, evaluated
together with the evidence available when the application or abbreviated
application was approved, the methods used in, or the facilities and
controls used for, the manufacture, processing, and packing of the drug
are inadequate to ensure and preserve its identity, strength, quality,
and purity and were not made adequate within a reasonable time after
receipt of written notice from the agency.
(3) That on the basis of new information before FDA, evaluated
together with the evidence available when the application or abbreviated
application was approved, the labeling of the drug, based on a fair
evaluation of all material facts, is false or misleading in any
particular, and the labeling was not corrected by the applicant within a
reasonable time after receipt of written notice from the agency.
(4) That the applicant has failed to comply with the notice
requirements of section 510(j)(2) of the act.
(5) That the applicant has failed to submit bioavailability or
bioequivalence data required under part 320 of this chapter.
(6) The application or abbreviated application does not contain an
explanation of the omission of a report of any investigation of the drug
product sponsored by the applicant, or an explanation of the omission of
other information about the drug pertinent to an evaluation of the
application or abbreviated application that is received or otherwise
obtained by the applicant from any source.
(7) That any nonclinical laboratory study that is described in the
application or abbreviated application and that is essential to show
that the drug is safe for use under the conditions prescribed,
recommended, or suggested in its labeling was not conducted in
compliance with the good laboratory practice regulations in part 58 of
this chapter and no reason for the noncompliance was provided or, if it
was, the differences between the practices used in conducting the study
and the good laboratory practice regulations do not support the validity
of the study.
(8) Any clinical investigation involving human subjects described in
the application or abbreviated application, subject to the institutional
review board regulations in part 56 of this chapter or informed consent
regulations in part 50 of this chapter, was not conducted in compliance
with those regulations such that the rights or safety of human subjects
were not adequately protected.
(9) That the applicant or contract research organization that
conducted a bioavailability or bioequivalence study described in Sec.
320.38 or Sec. 320.63 of this chapter that is contained in the
application or abbreviated application refuses to permit an inspection
of facilities or records relevant to the study by a properly authorized
officer or employee of the Department of Health and Human Services or
refuses to submit reserve samples of the drug products used in the study
when requested by FDA.
(10) That the labeling for the drug product that is the subject of
the abbreviated new drug application is no longer consistent with that
for the listed drug referred to in the abbreviated new drug application,
except for differences approved in the abbreviated new drug application
or those differences resulting from:
(i) A patent on the listed drug issued after approval of the
abbreviated new drug application; or
(ii) Exclusivity accorded to the listed drug after approval of the
abbreviated new drug application that do not render the drug product
less safe or effective than the listed drug for any remaining,
nonprotected condition(s) of use.
[[Page 174]]
(c) FDA will withdraw approval of an application or abbreviated
application if the applicant requests its withdrawal because the drug
subject to the application or abbreviated application is no longer being
marketed, provided none of the conditions listed in paragraphs (a) and
(b) of this section applies to the drug. FDA will consider a written
request for a withdrawal under this paragraph to be a waiver of an
opportunity for hearing otherwise provided for in this section.
Withdrawal of approval of an application or abbreviated application
under this paragraph is without prejudice to refiling.
(d) FDA may notify an applicant that it believes a potential problem
associated with a drug is sufficiently serious that the drug should be
removed from the market and may ask the applicant to waive the
opportunity for hearing otherwise provided for under this section, to
permit FDA to withdraw approval of the application or abbreviated
application for the product, and to remove voluntarily the product from
the market. If the applicant agrees, the agency will not make a finding
under paragraph (b) of this section, but will withdraw approval of the
application or abbreviated application in a notice published in the
Federal Register that contains a brief summary of the agency's and the
applicant's views of the reasons for withdrawal.
[57 FR 17993, Apr. 28, 1992, as amended at 58 FR 25927, Apr. 28, 1993;
64 FR 402, Jan. 5, 1999]
Sec. 314.151 Withdrawal of approval of an abbreviated new drug
application under section 505(j)(5) of the act.
(a) Approval of an abbreviated new drug application approved under
Sec. 314.105(d) may be withdrawn when the agency withdraws approval,
under Sec. 314.150(a) or under this section, of the approved drug
referred to in the abbreviated new drug application. If the agency
proposed to withdraw approval of a listed drug under Sec. 314.150(a),
the holder of an approved application for the listed drug has a right to
notice and opportunity for hearing. The published notice of opportunity
for hearing will identify all drug products approved under Sec.
314.105(d) whose applications are subject to withdrawal under this
section if the listed drug is withdrawn, and will propose to withdraw
such drugs. Holders of approved applications for the identified drug
products will be provided notice and an opportunity to respond to the
proposed withdrawal of their applications as described in paragraphs (b)
and (c) of this section.
(b)(1) The published notice of opportunity for hearing on the
withdrawal of the listed drug will serve as notice to holders of
identified abbreviated new drug applications of the grounds for the
proposed withdrawal.
(2) Holders of applications for drug products identified in the
notice of opportunity for hearing may submit written comments on the
notice of opportunity for hearing issued on the proposed withdrawal of
the listed drug. If an abbreviated new drug application holder submits
comments on the notice of opportunity for hearing and a hearing is
granted, the abbreviated new drug application holder may participate in
the hearing as a nonparty participant as provided for in Sec. 12.89 of
this chapter.
(3) Except as provided in paragraphs (c) and (d) of this section,
the approval of an abbreviated new drug application for a drug product
identified in the notice of opportunity for hearing on the withdrawal of
a listed drug will be withdrawn when the agency has completed the
withdrawal of approval of the listed drug.
(c)(1) If the holder of an application for a drug identified in the
notice of opportunity for hearing has submitted timely comments but does
not have an opportunity to participate in a hearing because a hearing is
not requested or is settled, the submitted comments will be considered
by the agency, which will issue an initial decision. The initial
decision will respond to the comments, and contain the agency's decision
whether there are grounds to withdraw approval of the listed drug and of
the abbreviated new drug applications on which timely comments were
submitted. The initial decision will be sent to each abbreviated new
drug application holder that has submitted comments.
(2) Abbreviated new drug application holders to whom the initial
decision was sent may, within 30 days of the
[[Page 175]]
issuance of the initial decision, submit written objections.
(3) The agency may, at its discretion, hold a limited oral hearing
to resolve dispositive factual issues that cannot be resolved on the
basis of written submissions.
(4) If there are no timely objections to the initial decision, it
will become final at the expiration of 30 days.
(5) If timely objections are submitted, they will be reviewed and
responded to in a final decision.
(6) The written comments received, the initial decision, the
evidence relied on in the comments and in the initial decision, the
objections to the initial decision, and, if a limited oral hearing has
been held, the transcript of that hearing and any documents submitted
therein, shall form the record upon which the agency shall make a final
decision.
(7) Except as provided in paragraph (d) of this section, any
abbreviated new drug application whose holder submitted comments on the
notice of opportunity for hearing shall be withdrawn upon the issuance
of a final decision concluding that the listed drug should be withdrawn
for grounds as described in Sec. 314.150(a). The final decision shall
be in writing and shall constitute final agency action, reviewable in a
judicial proceeding.
(8) Documents in the record will be publicly available in accordance
with Sec. 10.20(j) of this chapter. Documents available for examination
or copying will be placed on public display in the Dockets Management
Staff (HFA-305), Food and Drug Administration, room. 1-23, 12420
Parklawn Dr., Rockville, MD 20857, promptly upon receipt in that office.
(d) If the agency determines, based upon information submitted by
the holder of an abbreviated new drug application, that the grounds for
withdrawal of the listed drug are not applicable to a drug identified in
the notice of opportunity for hearing, the final decision will state
that the approval of the abbreviated new drug application for such drug
is not withdrawn.
[57 FR 17994, Apr. 28, 1992, as amended at 88 FR 45066, July 14, 2023]
Sec. 314.152 Notice of withdrawal of approval of an application or
abbreviated application for a new drug.
If the Food and Drug Administration withdraws approval of an
application or abbreviated application for a new drug, FDA will publish
a notice in the Federal Register announcing the withdrawal of approval.
If the application or abbreviated application was withdrawn for grounds
described in Sec. 314.150(a) or Sec. 314.151, the notice will announce
the removal of the drug from the list of approved drugs published under
section 505(j)(6) of the act and shall satisfy the requirement of Sec.
314.162(b).
[57 FR 17994, Apr. 28, 1992]
Sec. 314.153 Suspension of approval of an abbreviated new drug
application.
(a) Suspension of approval. The approval of an abbreviated new drug
application approved under Sec. 314.105(d) shall be suspended for the
period stated when:
(1) The Secretary of the Department of Health and Human Services,
under the imminent hazard authority of section 505(e) of the act or the
authority of this paragraph, suspends approval of a listed drug referred
to in the abbreviated new drug application, for the period of the
suspension;
(2) The agency, in the notice described in paragraph (b) of this
section, or in any subsequent written notice given an abbreviated new
drug application holder by the agency, concludes that the risk of
continued marketing and use of the drug is inappropriate, pending
completion of proceedings to withdraw or suspend approval under Sec.
314.151 or paragraph (b) of this section; or
(3) The agency, under the procedures set forth in paragraph (b) of
this section, issues a final decision stating the determination that the
abbreviated application is suspended because the listed drug on which
the approval of the abbreviated new drug application depends has been
withdrawn from sale for reasons of safety or effectiveness or has been
suspended under paragraph (b) of this section. The suspension will take
effect on the date stated in the decision and will remain in effect
until the agency determines that the marketing
[[Page 176]]
of the drug has resumed or that the withdrawal is not for safety or
effectiveness reasons.
(b) Procedures for suspension of abbreviated new drug applications
when a listed drug is voluntarily withdrawn for safety or effectiveness
reasons. (1) If a listed drug is voluntarily withdrawn from sale, and
the agency determines that the withdrawal from sale was for reasons of
safety or effectiveness, the agency will send each holder of an approved
abbreviated new drug application that is subject to suspension as a
result of this determination a copy of the agency's initial decision
setting forth the reasons for the determination. The initial decision
will also be placed on file with the Dockets Management Staff (HFA-305),
Food and Drug Administration, room 1-23, 12420 Parklawn Dr., Rockville,
MD 20857.
(2) Each abbreviated new drug application holder will have 30 days
from the issuance of the initial decision to present, in writing,
comments and information bearing on the initial decision. If no comments
or information is received, the initial decision will become final at
the expiration of 30 days.
(3) Comments and information received within 30 days of the issuance
of the initial decision will be considered by the agency and responded
to in a final decision.
(4) The agency may, in its discretion, hold a limited oral hearing
to resolve dispositive factual issues that cannot be resolved on the
basis of written submissions.
(5) If the final decision affirms the agency's initial decision that
the listed drug was withdrawn for reasons of safety or effectiveness,
the decision will be published in the Federal Register in compliance
with Sec. 314.152, and will, except as provided in paragraph (b)(6) of
this section, suspend approval of all abbreviated new drug applications
identified under paragraph (b)(1) of this section and remove from the
list the listed drug and any drug whose approval was suspended under
this paragraph. The notice will satisfy the requirement of Sec.
314.162(b). The agency's final decision and copies of materials on which
it relies will also be filed with the Dockets Management Staff (address
in paragraph (b)(1) of this section).
(6) If the agency determines in its final decision that the listed
drug was withdrawn for reasons of safety or effectiveness but, based
upon information submitted by the holder of an abbreviated new drug
application, also determines that the reasons for the withdrawal of the
listed drug are not relevant to the safety and effectiveness of the drug
subject to such abbreviated new drug application, the final decision
will state that the approval of such abbreviated new drug application is
not suspended.
(7) Documents in the record will be publicly available in accordance
with Sec. 10.20(j) of this chapter. Documents available for examination
or copying will be placed on public display in the Dockets Management
Staff (address in paragraph (b)(1) of this section) promptly upon
receipt in that office.
[57 FR 17995, Apr. 28, 1992, as amended at 88 FR 45066, July 14, 2023]
Sec. 314.160 Approval of an application or abbreviated application for
which approval was previously refused, suspended, or withdrawn.
Upon the Food and Drug Administration's own initiative or upon
request of an applicant, FDA may, on the basis of new data, approve an
application or abbreviated application which it had previously refused,
suspended, or withdrawn approval. FDA will publish a notice in the
Federal Register announcing the approval.
[57 FR 17995, Apr. 28, 1992]
Sec. 314.161 Determination of reasons for voluntary withdrawal of a
listed drug.
(a) A determination whether a listed drug that has been voluntarily
withdrawn from sale was withdrawn for safety or effectiveness reasons
may be made by the agency at any time after the drug has been
voluntarily withdrawn from sale, but must be made:
(1) Prior to approving an abbreviated new drug application that
refers to the listed drug;
(2) Whenever a listed drug is voluntarily withdrawn from sale and
abbreviated new drug applications that referred to the listed drug have
been approved; and
[[Page 177]]
(3) When a person petitions for such a determination under
Sec. Sec. 10.25(a) and 10.30 of this chapter.
(b) Any person may petition under Sec. Sec. 10.25(a) and 10.30 of
this chapter for a determination whether a listed drug has been
voluntarily withdrawn for safety or effectiveness reasons. Any such
petition must contain all evidence available to the petitioner
concerning the reason that the drug is withdrawn from sale.
(c) If the agency determines that a listed drug is withdrawn from
sale for safety or effectiveness reasons, the agency will, except as
provided in paragraph (d) of this section, publish a notice of the
determination in the Federal Register.
(d) If the agency determines under paragraph (a) of this section
that a listed drug is withdrawn from sale for safety and effectiveness
reasons and there are approved abbreviated new drug applications that
are subject to suspension under section 505(j)(5) of the act, FDA will
initiate a proceeding in accordance with Sec. 314.153(b).
(e) A drug that the agency determines is withdrawn for safety or
effectiveness reasons will be removed from the list, under Sec.
314.162. The drug may be relisted if the agency has evidence that
marketing of the drug has resumed or that the withdrawal is not for
safety or effectiveness reasons. A determination that the drug is not
withdrawn for safety or effectiveness reasons may be made at any time
after its removal from the list, upon the agency's initiative, or upon
the submission of a petition under Sec. Sec. 10.25(a) and 10.30 of this
chapter. If the agency determines that the drug is not withdrawn for
safety or effectiveness reasons, the agency shall publish a notice of
this determination in the Federal Register. The notice will also
announce that the drug is relisted, under Sec. 314.162(c). The notice
will also serve to reinstate approval of all suspended abbreviated new
drug applications that referred to the listed drug.
[57 FR 17995, Apr. 28, 1992]
Sec. 314.162 Removal of a drug product from the list.
(a) FDA will remove a previously approved new drug product from the
list for the period stated when:
(1) The agency withdraws or suspends approval of a new drug
application or an abbreviated new drug application under Sec.
314.150(a) or Sec. 314.151 or under the imminent hazard authority of
section 505(e) of the act, for the same period as the withdrawal or
suspension of the application; or
(2) The agency, in accordance with the procedures in Sec.
314.153(b) or Sec. 314.161, issues a final decision stating that the
listed drug was withdrawn from sale for safety or effectiveness reasons,
or suspended under Sec. 314.153(b), until the agency determines that
the withdrawal from the market has ceased or is not for safety or
effectiveness reasons.
(b) FDA will publish in the Federal Register a notice announcing the
removal of a drug from the list.
(c) At the end of the period specified in paragraph (a)(1) or (a)(2)
of this section, FDA will relist a drug that has been removed from the
list. The agency will publish in the Federal Register a notice
announcing the relisting of the drug.
[57 FR 17996, Apr. 28, 1992]
Sec. 314.170 Adulteration and misbranding of an approved drug.
All drugs, including those the Food and Drug Administration approves
under section 505 of the act and this part, are subject to the
adulteration and misbranding provisions in sections 501, 502, and 503 of
the act. FDA is authorized to regulate approved new drugs by regulations
issued through informal rulemaking under sections 501, 502, and 503 of
the act.
[50 FR 7493, Feb. 22, 1985. Redesignated at 57 FR 17983, Apr. 28, 1992,
and amended at 64 FR 402, Jan. 5, 1999]
Subpart E_Hearing Procedures for New Drugs
Source: 50 FR 7493, Feb. 22, 1985, unless otherwise noted.
Redesignated at 57 FR 17983, Apr. 28, 1992.
[[Page 178]]
Sec. 314.200 Notice of opportunity for hearing; notice of participation
and request for hearing; grant or denial of hearing.
(a) Notice of opportunity for hearing. The Director of the Center
for Drug Evaluation and Research, Food and Drug Administration, will
give the applicant, and all other persons who manufacture or distribute
identical, related, or similar drug products as defined in Sec. 310.6
of this chapter, notice and an opportunity for a hearing on the Center's
proposal to refuse to approve an application or to withdraw the approval
of an application or abbreviated application under section 505(e) of the
act. The notice will state the reasons for the action and the proposed
grounds for the order.
(1) The notice may be general (that is, simply summarizing in a
general way the information resulting in the notice) or specific (that
is, either referring to specific requirements in the statute and
regulations with which there is a lack of compliance, or providing a
detailed description and analysis of the specific facts resulting in the
notice).
(2) FDA will publish the notice in the Federal Register and will
state that the applicant, and other persons subject to the notice under
Sec. 310.6, who wishes to participate in a hearing, has 30 days after
the date of publication of the notice to file a written notice of
participation and request for hearing. The applicant, or other persons
subject to the notice under Sec. 310.6, who fails to file a written
notice of participation and request for hearing within 30 days, waives
the opportunity for a hearing.
(3) It is the responsibility of every manufacturer and distributor
of a drug product to review every notice of opportunity for a hearing
published in the Federal Register to determine whether it covers any
drug product that person manufactures or distributes. Any person may
request an opinion of the applicability of a notice to a specific
product that may be identical, related, or similar to a product listed
in a notice by writing to the Division of New Drugs and Labeling
Compliance, Office of Compliance, Center for Drug Evaluation and
Research, Food and Drug Administration, 10903 New Hampshire Ave., Silver
Spring, MD 20993-0002. A person shall request an opinion within 30 days
of the date of publication of the notice to be eligible for an
opportunity for a hearing under the notice. If a person requests an
opinion, that person's time for filing an appearance and request for a
hearing and supporting studies and analyses begins on the date the
person receives the opinion from FDA.
(b) FDA will provide the notice of opportunity for a hearing to
applicants and to other persons subject to the notice under Sec. 310.6,
as follows:
(1) To any person who has submitted an application or abbreviated
application, by delivering the notice in person or by sending it by
registered or certified mail to the last address shown in the
application or abbreviated application.
(2) To any person who has not submitted an application or
abbreviated application but who is subject to the notice under Sec.
310.6 of this chapter, by publication of the notice in the Federal
Register.
(c)(1) Notice of participation and request for a hearing, and
submission of studies and comments. The applicant, or any other person
subject to the notice under Sec. 310.6, who wishes to participate in a
hearing, shall file with the Dockets Management Staff (HFA-305), Food
and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD
20852, (i) within 30 days after the date of the publication of the
notice (or of the date of receipt of an opinion requested under
paragraph (a)(3) of this section) a written notice of participation and
request for a hearing and (ii) within 60 days after the date of
publication of the notice, unless a different period of time is
specified in the notice of opportunity for a hearing, the studies on
which the person relies to justify a hearing as specified in paragraph
(d) of this section. The applicant, or other person, may incorporate by
reference the raw data underlying a study if the data were previously
submitted to FDA as part of an application, abbreviated application, or
other report.
(2) FDA will not consider data or analyses submitted after 60 days
in determining whether a hearing is warranted unless they are derived
from
[[Page 179]]
well-controlled studies begun before the date of the notice of
opportunity for hearing and the results of the studies were not
available within 60 days after the date of publication of the notice.
Nevertheless, FDA may consider other studies on the basis of a showing
by the person requesting a hearing of inadvertent omission and hardship.
The person requesting a hearing shall list in the request for hearing
all studies in progress, the results of which the person intends later
to submit in support of the request for a hearing. The person shall
submit under paragraph (c)(1)(ii) of this section a copy of the complete
protocol, a list of the participating investigators, and a brief status
report of the studies.
(3) Any other interested person who is not subject to the notice of
opportunity for a hearing may also submit comments on the proposal to
withdraw approval of the application or abbreviated application. The
comments are requested to be submitted within the time and under the
conditions specified in this section.
(d) The person requesting a hearing is required to submit under
paragraph (c)(1)(ii) of this section the studies (including all
protocols and underlying raw data) on which the person relies to justify
a hearing with respect to the drug product. Except, a person who
requests a hearing on the refusal to approve an application is not
required to submit additional studies and analyses if the studies upon
which the person relies have been submitted in the application and in
the format and containing the summaries required under Sec. 314.50.
(1) If the grounds for FDA's proposed action concern the
effectiveness of the drug, each request for hearing is required to be
supported only by adequate and well-controlled clinical studies meeting
all of the precise requirements of Sec. 314.126 and, for combination
drug products, Sec. 300.50, or by other studies not meeting those
requirements for which a waiver has been previously granted by FDA under
Sec. 314.126. Each person requesting a hearing shall submit all
adequate and well-controlled clinical studies on the drug product,
including any unfavorable analyses, views, or judgments with respect to
the studies. No other data, information, or studies may be submitted.
(2) The submission is required to include a factual analysis of all
the studies submitted. If the grounds for FDA's proposed action concern
the effectiveness of the drug, the analysis is required to specify how
each study accords, on a point-by-point basis, with each criterion
required for an adequate well-controlled clinical investigation
established under Sec. 314.126 and, if the product is a combination
drug product, with each of the requirements for a combination drug
established in Sec. 300.50, or the study is required to be accompanied
by an appropriate waiver previously granted by FDA. If a study concerns
a drug or dosage form or condition of use or mode of administration
other than the one in question, that fact is required to be clearly
stated. Any study conducted on the final marketed form of the drug
product is required to be clearly identified.
(3) Each person requesting a hearing shall submit an analysis of the
data upon which the person relies, except that the required information
relating either to safety or to effectiveness may be omitted if the
notice of opportunity for hearing does not raise any issue with respect
to that aspect of the drug; information on compliance with Sec. 300.50
may be omitted if the drug product is not a combination drug product. A
financial certification or disclosure statement or both as required by
part 54 of this chapter must accompany all clinical data submitted. FDA
can most efficiently consider submissions made in the following format.
I. Safety data.
A. Animal safety data.
1. Individual active components.
a. Controlled studies.
b. Partially controlled or uncontrolled studies.
2. Combinations of the individual active components.
a. Controlled studies.
b. Partially controlled or uncontrolled studies.
B. Human safety data.
1. Individual active components.
a. Controlled studies.
b. Partially controlled or uncontrolled studies.
c. Documented case reports.
[[Page 180]]
d. Pertinent marketing experiences that may influence a
determination about the safety of each individual active component.
2. Combinations of the individual active components.
a. Controlled studies.
b. Partially controlled or uncontrolled studies.
c. Documented case reports.
d. Pertinent marketing experiences that may influence a
determination about the safety of each individual active component.
II. Effectiveness data.
A. Individual active components: Controlled studies, with an
analysis showing clearly how each study satisfies, on a point-by-point
basis, each of the criteria required by Sec. 314.126.
B. Combinations of individual active components.
1. Controlled studies with an analysis showing clearly how each
study satisfies on a point-by-point basis, each of the criteria required
by Sec. 314.126.
2. An analysis showing clearly how each requirement of Sec. 300.50
has been satisfied.
III. A summary of the data and views setting forth the medical
rationale and purpose for the drug and its ingredients and the
scientific basis for the conclusion that the drug and its ingredients
have been proven safe and/or effective for the intended use. If there is
an absence of controlled studies in the material submitted or the
requirements of any element of Sec. 300.50 or Sec. 314.126 have not
been fully met, that fact is required to be stated clearly and a waiver
obtained under Sec. 314.126 is required to be submitted.
IV. A statement signed by the person responsible for such submission
that it includes in full (or incorporates by reference as permitted in
Sec. 314.200(c)(2)) all studies and information specified in Sec.
314.200(d).
(Warning: A willfully false statement is a criminal offense, 18
U.S.C. 1001.)
(e) Contentions that a drug product is not subject to the new drug
requirements. A notice of opportunity for a hearing encompasses all
issues relating to the legal status of each drug product subject to it,
including identical, related, and similar drug products as defined in
Sec. 310.6. A notice of appearance and request for a hearing under
paragraph (c)(1)(i) of this section is required to contain any
contention that the product is not a new drug because it is generally
recognized as safe and effective within the meaning of section 201(p) of
the act, or because it is exempt from part or all of the new drug
provisions of the act under the exemption for products marketed before
June 25, 1938, contained in section 201(p) of the act or under section
107(c) of the Drug Amendments of 1962, or for any other reason. Each
contention is required to be supported by a submission under paragraph
(c)(1)(ii) of this section and the Commissioner of Food and Drugs will
make an administrative determination on each contention. The failure of
any person subject to a notice of opportunity for a hearing, including
any person who manufactures or distributes an identical, related, or
similar drug product as defined in Sec. 310.6, to submit a notice of
participation and request for hearing or to raise all such contentions
constitutes a waiver of any contentions not raised.
(1) A contention that a drug product is generally recognized as safe
and effective within the meaning of section 201(p) of the act is
required to be supported by submission of the same quantity and quality
of scientific evidence that is required to obtain approval of an
application for the product, unless FDA has waived a requirement for
effectiveness (under Sec. 314.126) or safety, or both. The submission
should be in the format and with the analyses required under paragraph
(d) of this section. A person who fails to submit the required
scientific evidence required under paragraph (d) waives the contention.
General recognition of safety and effectiveness shall ordinarily be
based upon published studies which may be corroborated by unpublished
studies and other data and information.
(2) A contention that a drug product is exempt from part or all of
the new drug provisions of the act under the exemption for products
marketed before June 25, 1938, contained in section 201(p) of the act,
or under section 107(c) of the Drug Amendments of 1962, is required to
be supported by evidence of past and present quantitative formulas,
labeling, and evidence of marketing. A person who makes such a
contention should submit the formulas, labeling, and evidence of
marketing in the following format.
I. Formulation.
A. A copy of each pertinent document or record to establish the
exact quantitative formulation of the drug (both active and inactive
ingredients) on the date of initial marketing of the drug.
B. A statement whether such formulation has at any subsequent time
been changed in
[[Page 181]]
any manner. If any such change has been made, the exact date, nature,
and rationale for each change in formulation, including any deletion or
change in the concentration of any active ingredient and/or inactive
ingredient, should be stated, together with a copy of each pertinent
document or record to establish the date and nature of each such change,
including, but not limited to, the formula which resulted from each such
change. If no such change has been made, a copy of representative
documents or records showing the formula at representative points in
time should be submitted to support the statement.
II. Labeling.
A. A copy of each pertinent document or record to establish the
identity of each item of written, printed, or graphic matter used as
labeling on the date the drug was initially marketed.
B. A statement whether such labeling has at any subsequent time been
discontinued or changed in any manner. If such discontinuance or change
has been made, the exact date, nature, and rationale for each
discontinuance or change and a copy of each pertinent document or record
to establish each such discontinuance or change should be submitted,
including, but not limited to, the labeling which resulted from each
such discontinuance or change. If no such discontinuance or change has
been made, a copy of representative documents or records showing
labeling at representative points in time should be submitted to support
the statement.
III. Marketing.
A. A copy of each pertinent document or record to establish the
exact date the drug was initially marketed.
B. A statement whether such marketing has at any subsequent time
been discontinued. If such marketing has been discontinued, the exact
date of each such discontinuance should be submitted, together with a
copy of each pertinent document or record to establish each such date.
IV. Verification.
A statement signed by the person responsible for such submission,
that all appropriate records have been searched and to the best of that
person's knowledge and belief it includes a true and accurate
presentation of the facts.
(Warning: A willfully false statement is a criminal offense, 18
U.S.C. 1001.)
(3) The Food and Drug Administration will not find a drug product,
including any active ingredient, which is identical, related, or
similar, as described in Sec. 310.6, to a drug product, including any
active ingredient for which an application is or at any time has been
effective or deemed approved, or approved under section 505 of the act,
to be exempt from part or all of the new drug provisions of the act.
(4) A contention that a drug product is not a new drug for any other
reason is required to be supported by submission of the factual records,
data, and information that are necessary and appropriate to support the
contention.
(5) It is the responsibility of every person who manufactures or
distributes a drug product in reliance upon a ``grandfather'' provision
of the act to maintain files that contain the data and information
necessary fully to document and support that status.
(f) Separation of functions. Separation of functions commences upon
receipt of a request for hearing. The Director of the Center for Drug
Evaluation and Research, Food and Drug Administration, will prepare an
analysis of the request and a proposed order ruling on the matter. The
analysis and proposed order, the request for hearing, and any proposed
order denying a hearing and response under paragraph (g) (2) or (3) of
this section will be submitted to the Office of the Commissioner of Food
and Drugs for review and decision. When the Center for Drug Evaluation
and Research recommends denial of a hearing on all issues on which a
hearing is requested, no representative of the Center will participate
or advise in the review and decision by the Commissioner. When the
Center for Drug Evaluation and Research recommends that a hearing be
granted on one or more issues on which a hearing is requested,
separation of functions terminates as to those issues, and
representatives of the Center may participate or advise in the review
and decision by the Commissioner on those issues. The Commissioner may
modify the text of the issues, but may not deny a hearing on those
issues. Separation of functions continues with respect to issues on
which the Center for Drug Evaluation and Research has recommended denial
of a hearing. The Commissioner will neither evaluate nor rule on the
Center's recommendation on such issues and such issues will not be
included in the notice of hearing. Participants in the hearing may make
a motion to the presiding officer for the inclusion of
[[Page 182]]
any such issue in the hearing. The ruling on such a motion is subject to
review in accordance with Sec. 12.35(b). Failure to so move constitutes
a waiver of the right to a hearing on such an issue. Separation of
functions on all issues resumes upon issuance of a notice of hearing.
The Office of the General Counsel, Department of Health and Human
Services, will observe the same separation of functions.
(g) Summary judgment. A person who requests a hearing may not rely
upon allegations or denials but is required to set forth specific facts
showing that there is a genuine and substantial issue of fact that
requires a hearing with respect to a particular drug product specified
in the request for hearing.
(1) Where a specific notice of opportunity for hearing (as defined
in paragraph (a)(1) of this section) is used, the Commissioner will
enter summary judgment against a person who requests a hearing, making
findings and conclusions, denying a hearing, if it conclusively appears
from the face of the data, information, and factual analyses in the
request for the hearing that there is no genuine and substantial issue
of fact which precludes the refusal to approve the application or
abbreviated application or the withdrawal of approval of the application
or abbreviated application; for example, no adequate and well-controlled
clinical investigations meeting each of the precise elements of Sec.
314.126 and, for a combination drug product, Sec. 300.50 of this
chapter, showing effectiveness have been identified. Any order entering
summary judgment is required to set forth the Commissioner's findings
and conclusions in detail and is required to specify why each study
submitted fails to meet the requirements of the statute and regulations
or why the request for hearing does not raise a genuine and substantial
issue of fact.
(2) When following a general notice of opportunity for a hearing (as
defined in paragraph (a)(1) of this section) the Director of the Center
for Drug Evaluation and Research concludes that summary judgment against
a person requesting a hearing should be considered, the Director will
serve upon the person requesting a hearing by registered mail a proposed
order denying a hearing. This person has 60 days after receipt of the
proposed order to respond with sufficient data, information, and
analyses to demonstrate that there is a genuine and substantial issue of
fact which justifies a hearing.
(3) When following a general or specific notice of opportunity for a
hearing a person requesting a hearing submits data or information of a
type required by the statute and regulations, and the Director of the
Center for Drug Evaluation and Research concludes that summary judgment
against the person should be considered, the Director will serve upon
the person by registered mail a proposed order denying a hearing. The
person has 60 days after receipt of the proposed order to respond with
sufficient data, information, and analyses to demonstrate that there is
a genuine and substantial issue of fact which justifies a hearing.
(4) If review of the data, information, and analyses submitted show
that the grounds cited in the notice are not valid, for example, that
substantial evidence of effectiveness exists, the Commissioner will
enter summary judgment for the person requesting the hearing, and
rescind the notice of opportunity for hearing.
(5) If the Commissioner grants a hearing, it will begin within 90
days after the expiration of the time for requesting the hearing unless
the parties otherwise agree in the case of denial of approval, and as
soon as practicable in the case of withdrawal of approval.
(6) The Commissioner will grant a hearing if there exists a genuine
and substantial issue of fact or if the Commissioner concludes that a
hearing would otherwise be in the public interest.
(7) If the manufacturer or distributor of an identical, related, or
similar drug product requests and is granted a hearing, the hearing may
consider whether the product is in fact identical, related, or similar
to the drug product named in the notice of opportunity for a hearing.
(8) A request for a hearing, and any subsequent grant or denial of a
hearing, applies only to the drug products named in such documents.
(h) FDA will issue a notice withdrawing approval and declaring all
[[Page 183]]
products unlawful for drug products subject to a notice of opportunity
for a hearing, including any identical, related, or similar drug product
under Sec. 310.6, for which an opportunity for a hearing is waived or
for which a hearing is denied. The Commissioner may defer or stay the
action pending a ruling on any related request for a hearing or pending
any related hearing or other administrative or judicial proceeding.
[50 FR 7493, Feb. 22, 1985; 50 FR 14212, Apr. 11, 1985, as amended at 50
FR 21238, May 23, 1985; 55 FR 11580, Mar. 29, 1990; 57 FR 17996, Apr.
28, 1992; 59 FR 14364, Mar. 28, 1994; 63 FR 5252, Feb. 2, 1998; 67 FR
9586, Mar. 4, 2002; 68 FR 24879, May 9, 2003; 69 FR 48775, Aug. 11,
2004; 74 FR 13113, Mar. 26, 2009; 88 FR 45066, July 14, 2023]
Sec. 314.201 Procedure for hearings.
Parts 10 through 16 apply to hearings relating to new drugs under
section 505 (d) and (e) of the act.
Sec. 314.235 Judicial review.
(a) The Commissioner of Food and Drugs will certify the transcript
and record. In any case in which the Commissioner enters an order
without a hearing under Sec. 314.200(g), the record certified by the
Commissioner is required to include the requests for hearing together
with the data and information submitted and the Commissioner's findings
and conclusion.
(b) A manufacturer or distributor of an identical, related, or
similar drug product under Sec. 310.6 may seek judicial review of an
order withdrawing approval of a new drug application, whether or not a
hearing has been held, in a United States court of appeals under section
505(h) of the act.
Subpart F [Reserved]
Subpart G_Miscellaneous Provisions
Source: 50 FR 7493, Feb. 22, 1985, unless otherwise noted.
Redesignated at 57 FR 17983, Apr. 28, 1992.
Sec. 314.410 Imports and exports of new drugs.
(a) Imports. (1) A new drug may be imported into the United States
if: (i) It is the subject of an approved application under this part; or
(ii) it complies with the regulations pertaining to investigational new
drugs under part 312; and it complies with the general regulations
pertaining to imports under subpart E of part 1.
(2) A drug substance intended for use in the manufacture,
processing, or repacking of a new drug may be imported into the United
States if it complies with the labeling exemption in Sec. 201.122
pertaining to shipments of drug substances in domestic commerce.
(b) Exports. (1) A new drug may be exported if it is the subject of
an approved application under this part or it complies with the
regulations pertaining to investigational new drugs under part 312.
(2) A new drug substance that is covered by an application approved
under this part for use in the manufacture of an approved drug product
may be exported by the applicant or any person listed as a supplier in
the approved application, provided the drug substance intended for
export meets the specification of, and is shipped with a copy of the
labeling required for, the approved drug product.
(3) Insulin or an antibiotic drug may be exported without regard to
the requirements in section 802 of the act if the insulin or antibiotic
drug meets the requirements of section 801(e)(1) of the act.
[50 FR 7493, Feb. 22, 1985. Redesignated at 57 FR 17983, Apr. 28, 1992,
and amended at 64 FR 402, Jan. 5, 1999; 69 FR 18766, Apr. 8, 2004]
Sec. 314.420 Drug master files.
(a) A drug master file is a submission of information to the Food
and Drug Administration by a person (the drug master file holder) who
intends it to be used for one of the following purposes: To permit the
holder to incorporate the information by reference when the holder
submits an investigational new drug application under part 312 or
submits an application or an abbreviated application or an amendment or
supplement to them under this part, or to permit the holder to authorize
other persons to rely on the information to support a submission to FDA
without the holder having to disclose the information to the person. FDA
ordinarily
[[Page 184]]
neither independently reviews drug master files nor approves or
disapproves submissions to a drug master file. Instead, the agency
customarily reviews the information only in the context of an
application under part 312 or this part. A drug master file may contain
information of the kind required for any submission to the agency,
including information about the following:
(1) [Reserved]
(2) Drug substance, drug substance intermediate, and materials used
in their preparation, or drug product;
(3) Packaging materials;
(4) Excipient, colorant, flavor, essence, or materials used in their
preparation;
(5) FDA-accepted reference information. (A person wishing to submit
information and supporting data in a drug master file (DMF) that is not
covered by Types II through IV DMF's must first submit a letter of
intent to the Drug Master File Staff, Food and Drug Administration,
5901-B Ammendale Rd., Beltsville, MD 20705-1266.) FDA will then contact
the person to discuss the proposed submission.
(b) An investigational new drug application or an application,
abbreviated application, amendment, or supplement may incorporate by
reference all or part of the contents of any drug master file in support
of the submission if the holder authorizes the incorporation in writing.
Each incorporation by reference is required to describe the incorporated
material by name, reference number, volume, and page number of the drug
master file.
(c) A drug master file is required to be submitted in two copies.
The agency has prepared guidance that provides information about how to
prepare a well-organized drug master file. If the drug master file
holder adds, changes, or deletes any information in the file, the holder
shall notify in writing, each person authorized to reference that
information. Any addition, change, or deletion of information in a drug
master file (except the list required under paragraph (d) of this
section) is required to be submitted in two copies and to describe by
name, reference number, volume, and page number the information affected
in the drug master file.
(d) The drug master file is required to contain a complete list of
each person currently authorized to incorporate by reference any
information in the file, identifying by name, reference number, volume,
and page number the information that each person is authorized to
incorporate. If the holder restricts the authorization to particular
drug products, the list is required to include the name of each drug
product and the application number, if known, to which the authorization
applies.
(e) The public availability of data and information in a drug master
file, including the availability of data and information in the file to
a person authorized to reference the file, is determined under part 20
and Sec. 314.430.
[50 FR 7493, Feb. 22, 1985, as amended at 50 FR 21238, May 23, 1985; 53
FR 33122, Aug. 30, 1988; 55 FR 28380, July 11, 1990; 65 FR 1780, Jan.
12, 2000; 65 FR 56479, Sept. 19, 2000; 67 FR 9586, Mar. 4, 2002; 69 FR
13473, Mar. 23, 2004]
Sec. 314.430 Availability for public disclosure of data and information
in an application or abbreviated application.
(a) The Food and Drug Administration will determine the public
availability of any part of an application or abbreviated application
under this section and part 20 of this chapter. For purposes of this
section, the application or abbreviated application includes all data
and information submitted with or incorporated by reference in the
application or abbreviated application, including investigational new
drug applications, drug master files under Sec. 314.420, supplements
submitted under Sec. 314.70 or Sec. 314.97, reports under Sec. 314.80
or Sec. 314.98, and other submissions. For purposes of this section,
safety and effectiveness data include all studies and tests of a drug on
animals and humans and all studies and tests of the drug for identity,
stability, purity, potency, and bioavailability.
(b) FDA will not publicly disclose the existence of an application
or abbreviated application before an approval letter is sent to the
applicant under Sec. 314.105 or tentative approval letter is sent to
the applicant under Sec. 314.107,
[[Page 185]]
unless the existence of the application or abbreviated application has
been previously publicly disclosed or acknowledged.
(c) If the existence of an unapproved application or abbreviated
application has not been publicly disclosed or acknowledged, no data or
information in the application or abbreviated application is available
for public disclosure.
(d)(1) If the existence of an application or abbreviated application
has been publicly disclosed or acknowledged before the agency sends an
approval letter to the applicant, no data or information contained in
the application or abbreviated application is available for public
disclosure before the agency sends an approval letter, but the
Commissioner may, in his or her discretion, disclose a summary of
selected portions of the safety and effectiveness data that are
appropriate for public consideration of a specific pending issue; for
example, for consideration of an open session of an FDA advisory
committee.
(2) Notwithstanding paragraph (d)(1) of this section, FDA will make
available to the public upon request the information in the
investigational new drug application that was required to be filed in
Docket Number 95S-0158 in the Dockets Management Staff (HFA-305), Food
and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD
20852, for investigations involving an exception from informed consent
under Sec. 50.24 of this chapter. Persons wishing to request this
information shall submit a request under the Freedom of Information Act.
(e) After FDA sends an approval letter to the applicant, the
following data and information in the application or abbreviated
application are immediately available for public disclosure, unless the
applicant shows that extraordinary circumstances exist. A list of
approved applications and abbreviated applications, entitled ``Approved
Drug Products with Therapeutic Equivalence Evaluations,'' is available
from the Government Printing Office, Washington, DC 20402. This list is
updated monthly.
(1) [Reserved]
(2) If the application applies to a new drug, all safety and
effectiveness data previously disclosed to the public as set forth in
Sec. 20.81 and a summary or summaries of the safety and effectiveness
data and information submitted with or incorporated by reference in the
application. The summaries do not constitute the full reports of
investigations under section 505(b)(1) of the act (21 U.S.C. 355(b)(1))
on which the safety or effectiveness of the drug may be approved. The
summaries consist of the following:
(i) For an application approved before July 1, 1975, internal agency
records that describe safety and effectiveness data and information, for
example, a summary of the basis for approval or internal reviews of the
data and information, after deletion of the following:
(a) Names and any information that would identify patients or test
subjects or investigators.
(b) Any inappropriate gratuitous comments unnecessary to an
objective analysis of the data and information.
(ii) For an application approved on or after July 1, 1975, a Summary
Basis of Approval (SBA) document that contains a summary of the safety
and effectiveness data and information evaluated by FDA during the drug
approval process. The SBA is prepared in one of the following ways:
(a) Before approval of the application, the applicant may prepare a
draft SBA which the Center for Drug Evaluation and Research will review
and may revise. The draft may be submitted with the application or as an
amendment.
(b) The Center for Drug Evaluation and Research may prepare the SBA.
(3) A protocol for a test or study, unless it is shown to fall
within the exemption established for trade secrets and confidential
commercial information in Sec. 20.61.
(4) Adverse reaction reports, product experience reports, consumer
complaints, and other similar data and information after deletion of the
following:
(i) Names and any information that would identify the person using
the product.
(ii) Names and any information that would identify any third party
involved
[[Page 186]]
with the report, such as a physician or hospital or other institution.
(5) A list of all active ingredients and any inactive ingredients
previously disclosed to the public as set forth in Sec. 20.81.
(6) An assay procedure or other analytical procedure, unless it
serves no regulatory or compliance purpose and is shown to fall within
the exemption established for trade secrets and confidential commercial
information in Sec. 20.61.
(7) All correspondence and written summaries of oral discussions
between FDA and the applicant relating to the application, under the
provisions of part 20.
(f) All safety and effectiveness data and information which have
been submitted in an application and which have not previously been
disclosed to the public are available to the public, upon request, at
the time any one of the following events occurs unless extraordinary
circumstances are shown:
(1) No work is being or will be undertaken to have the application
approved.
(2) A final determination is made that the application is not
approvable and all legal appeals have been exhausted.
(3) Approval of the application is withdrawn and all legal appeals
have been exhausted.
(4) A final determination has been made that the drug is not a new
drug.
(5) For applications submitted under section 505(b) of the act, the
effective date of the approval of the first abbreviated application
submitted under section 505(j) of the act which refers to such drug, or
the date on which the approval of an abbreviated application under
section 505(j) of the act which refers to such drug could be made
effective if such an abbreviated application had been submitted.
(6) For abbreviated applications submitted under section 505(j) of
the act, when FDA sends an approval letter to the applicant.
(g) The following data and information in an application or
abbreviated application are not available for public disclosure unless
they have been previously disclosed to the public as set forth in Sec.
20.81 of this chapter or they relate to a product or ingredient that has
been abandoned and they do not represent a trade secret or confidential
commercial or financial information under Sec. 20.61 of this chapter:
(1) Manufacturing methods or processes, including quality control
procedures.
(2) Production, sales distribution, and similar data and
information, except that any compilation of that data and information
aggregated and prepared in a way that does not reveal data or
information which is not available for public disclosure under this
provision is available for public disclosure.
(3) Quantitative or semiquantitative formulas.
(h) The compilations of information specified in Sec. 20.117 are
available for public disclosure.
[50 FR 7493, Feb. 22, 1985, as amended at 50 FR 21238, May 23, 1985; 55
FR 11580, Mar. 29, 1990; 57 FR 17996, Apr. 28, 1992; 61 FR 51530, Oct.
2, 1996; 64 FR 26698, May 13, 1998; 64 FR 402, Jan. 5, 1999; 66 FR 1832,
Jan. 10, 2001; 68 FR 24879, May 9, 2003; 69 FR 18766, Apr. 8, 2004; 73
FR 39610, July 10, 2008; 88 FR 45066, July 14, 2023]
Sec. 314.440 Addresses for applications and abbreviated applications.
(a) Applicants shall send applications, abbreviated applications,
and other correspondence relating to matters covered by this part,
except for products listed in paragraph (b) of this section, to the
appropriate office identified below:
(1) Except as provided in paragraph (a)(4) of this section, an
application under Sec. 314.50 or Sec. 314.54 submitted for filing
should be directed to the Central Document Room, 5901-B Ammendale Rd.,
Beltsville, MD 20705-1266. Applicants may obtain information about
folders for binding applications on the Internet at http://www.fda.gov/
cder/ddms/binders.htm. After FDA has filed the application, the agency
will inform the applicant which division is responsible for the
application. Amendments, supplements, resubmissions, requests for
waivers, and other correspondence about an application that has been
filed should be addressed to 5901-B Ammendale Rd., Beltsville, MD 20705-
1266, to the attention of the appropriate division.
[[Page 187]]
(2) Except as provided in paragraph (a)(4) of this section, an
abbreviated application under Sec. 314.94, and amendments, supplements,
and resubmissions should be directed to the Central Document Room,
Center for Drug Evaluation and Research, Food and Drug Administration,
5901-B Ammendale Rd., Beltsville, MD 20705-1266. This includes items
sent by parcel post or overnight courier service. Correspondence not
associated with an abbreviated application also should be addressed to
5901-B Ammendale Rd., Beltsville, MD 20705-1266.
(3) A request for an opportunity for a hearing under Sec. 314.110
on the question of whether there are grounds for denying approval of an
application, except an application under paragraph (b) of this section,
should be directed to the Associate Director for Policy (HFD-5).
(4) The field copy of an application, an abbreviated application,
amendments, supplements, resubmissions, requests for waivers, and other
correspondence about an application and an abbreviated application shall
be sent to the applicant's home FDA district office, except that a
foreign applicant shall send the field copy to the appropriate address
identified in paragraphs (a)(1) and (a)(2) of this section.
(b) Applicants shall send applications and other correspondence
relating to matters covered by this part for the drug products listed
below to the Food and Drug Administration, Center for Biologics
Evaluation and Research, Document Control Center, 10903 New Hampshire
Ave., Bldg. 71, Rm. G112, Silver Spring, MD 20993-0002, except
applicants shall send a request for an opportunity for a hearing under
Sec. 314.110 on the question of whether there are grounds for denying
approval of an application to the Center for Biologics Evaluation and
Research, ATTN: Director, at the same address.
(1) Ingredients packaged together with containers intended for the
collection, processing, or storage of blood and blood components;
(2) Plasma volume expanders and hydroxyethyl starch for
leukapheresis;
(3) Blood component processing solutions and shelf life extenders;
and
(4) Oxygen carriers.
[50 FR 7493, Feb. 22, 1985, as amended at 50 FR 21238, May 23, 1985; 55
FR 11581, Mar. 29, 1990; 57 FR 17997, Apr. 28, 1992; 58 FR 47352, Sept.
8, 1993; 62 FR 43639, Aug. 15, 1997; 69 FR 13473, Mar. 23, 2004; 70 FR
14981, Mar. 24, 2005; 73 FR 39610, July 10, 2008; 74 FR 13113, Mar. 26,
2009; 75 FR 37295, June 29, 2010; 80 FR 18091, Apr. 3, 2015; 84 FR 6673,
Feb. 28, 2019]
Sec. 314.445 Guidance documents.
(a) FDA has made available guidance documents under Sec. 10.115 of
this chapter to help you to comply with certain requirements of this
part.
(b) The Center for Drug Evaluation and Research (CDER) maintains a
list of guidance documents that apply to CDER's regulations. The list is
maintained on the Internet and is published annually in the Federal
Register. A request for a copy of the CDER list should be directed to
the Office of Training and Communications, Division of Drug Information,
Center for Drug Evaluation and Research, Food and Drug Administration,
10903 New Hampshire Ave., Silver Spring, MD 20993-0002.
[65 FR 56480, Sept. 19, 2000, as amended at 74 FR 13113, Mar. 26, 2009]
Subpart H_Accelerated Approval of New Drugs for Serious or Life-
Threatening Illnesses
Source: 57 FR 58958, Dec. 11, 1992, unless otherwise noted.
Sec. 314.500 Scope.
This subpart applies to certain new drug products that have been
studied for their safety and effectiveness in treating serious or life-
threatening illnesses and that provide meaningful therapeutic benefit to
patients over existing treatments (e.g., ability to treat patients
unresponsive to, or intolerant of, available therapy, or improved
patient response over available therapy).
[57 FR 58958, Dec. 11, 1992, as amended at 64 FR 402, Jan. 5, 1999]
[[Page 188]]
Sec. 314.510 Approval based on a surrogate endpoint or on an effect
on a clinical endpoint other than survival or irreversible morbidity.
FDA may grant marketing approval for a new drug product on the basis
of adequate and well-controlled clinical trials establishing that the
drug product has an effect on a surrogate endpoint that is reasonably
likely, based on epidemiologic, therapeutic, pathophysiologic, or other
evidence, to predict clinical benefit or on the basis of an effect on a
clinical endpoint other than survival or irreversible morbidity.
Approval under this section will be subject to the requirement that the
applicant study the drug further, to verify and describe its clinical
benefit, where there is uncertainty as to the relation of the surrogate
endpoint to clinical benefit, or of the observed clinical benefit to
ultimate outcome. Postmarketing studies would usually be studies already
underway. When required to be conducted, such studies must also be
adequate and well-controlled. The applicant shall carry out any such
studies with due diligence.
Sec. 314.520 Approval with restrictions to assure safe use.
(a) If FDA concludes that a drug product shown to be effective can
be safely used only if distribution or use is restricted, FDA will
require such postmarketing restrictions as are needed to assure safe use
of the drug product, such as:
(1) Distribution restricted to certain facilities or physicians with
special training or experience; or
(2) Distribution conditioned on the performance of specified medical
procedures.
(b) The limitations imposed will be commensurate with the specific
safety concerns presented by the drug product.
Sec. 314.530 Withdrawal procedures.
(a) For new drugs approved under Sec. Sec. 314.510 and 314.520, FDA
may withdraw approval, following a hearing as provided in part 15 of
this chapter, as modified by this section, if:
(1) A postmarketing clinical study fails to verify clinical benefit;
(2) The applicant fails to perform the required postmarketing study
with due diligence;
(3) Use after marketing demonstrates that postmarketing restrictions
are inadequate to assure safe use of the drug product;
(4) The applicant fails to adhere to the postmarketing restrictions
agreed upon;
(5) The promotional materials are false or misleading; or
(6) Other evidence demonstrates that the drug product is not shown
to be safe or effective under its conditions of use.
(b) Notice of opportunity for a hearing. The Director of the Center
for Drug Evaluation and Research will give the applicant notice of an
opportunity for a hearing on the Center's proposal to withdraw the
approval of an application approved under Sec. 314.510 or Sec.
314.520. The notice, which will ordinarily be a letter, will state
generally the reasons for the action and the proposed grounds for the
order.
(c) Submission of data and information. (1) If the applicant fails
to file a written request for a hearing within 15 days of receipt of the
notice, the applicant waives the opportunity for a hearing.
(2) If the applicant files a timely request for a hearing, the
agency will publish a notice of hearing in the Federal Register in
accordance with Sec. Sec. 12.32(e) and 15.20 of this chapter.
(3) An applicant who requests a hearing under this section must,
within 30 days of receipt of the notice of opportunity for a hearing,
submit the data and information upon which the applicant intends to rely
at the hearing.
(d) Separation of functions. Separation of functions (as specified
in Sec. 10.55 of this chapter) will not apply at any point in
withdrawal proceedings under this section.
(e) Procedures for hearings. Hearings held under this section will
be conducted in accordance with the provisions of part 15 of this
chapter, with the following modifications:
(1) An advisory committee duly constituted under part 14 of this
chapter will be present at the hearing. The committee will be asked to
review the issues involved and to provide advice
[[Page 189]]
and recommendations to the Commissioner of Food and Drugs.
(2) The presiding officer, the advisory committee members, up to
three representatives of the applicant, and up to three representatives
of the Center may question any person during or at the conclusion of the
person's presentation. No other person attending the hearing may
question a person making a presentation. The presiding officer may, as a
matter of discretion, permit questions to be submitted to the presiding
officer for response by a person making a presentation.
(f) Judicial review. The Commissioner's decision constitutes final
agency action from which the applicant may petition for judicial review.
Before requesting an order from a court for a stay of action pending
review, an applicant must first submit a petition for a stay of action
under Sec. 10.35 of this chapter.
[57 FR 58958, Dec. 11, 1992, as amended at 64 FR 402, Jan. 5, 1999]
Sec. 314.540 Postmarketing safety reporting.
Drug products approved under this program are subject to the
postmarketing recordkeeping and safety reporting applicable to all
approved drug products, as provided in Sec. Sec. 314.80 and 314.81.
Sec. 314.550 Promotional materials.
For drug products being considered for approval under this subpart,
unless otherwise informed by the agency, applicants must submit to the
agency for consideration during the preapproval review period copies of
all promotional materials, including promotional labeling as well as
advertisements, intended for dissemination or publication within 120
days following marketing approval. After 120 days following marketing
approval, unless otherwise informed by the agency, the applicant must
submit promotional materials at least 30 days prior to the intended time
of initial dissemination of the labeling or initial publication of the
advertisement.
Sec. 314.560 Termination of requirements.
If FDA determines after approval that the requirements established
in Sec. 314.520, Sec. 314.530, or Sec. 314.550 are no longer
necessary for the safe and effective use of a drug product, it will so
notify the applicant. Ordinarily, for drug products approved under Sec.
314.510, these requirements will no longer apply when FDA determines
that the required postmarketing study verifies and describes the drug
product's clinical benefit and the drug product would be appropriate for
approval under traditional procedures. For drug products approved under
Sec. 314.520, the restrictions would no longer apply when FDA
determines that safe use of the drug product can be assured through
appropriate labeling. FDA also retains the discretion to remove specific
postapproval requirements upon review of a petition submitted by the
sponsor in accordance with Sec. 10.30.
Subpart I_Approval of New Drugs When Human Efficacy Studies Are Not
Ethical or Feasible
Source: 67 FR 37995, May 31, 2002, unless otherwise noted.
Sec. 314.600 Scope.
This subpart applies to certain new drug products that have been
studied for their safety and efficacy in ameliorating or preventing
serious or life-threatening conditions caused by exposure to lethal or
permanently disabling toxic biological, chemical, radiological, or
nuclear substances. This subpart applies only to those new drug products
for which: Definitive human efficacy studies cannot be conducted because
it would be unethical to deliberately expose healthy human volunteers to
a lethal or permanently disabling toxic biological, chemical,
radiological, or nuclear substance; and field trials to study the
product's effectiveness after an accidental or hostile exposure have not
been feasible. This subpart does not apply to products that can be
approved based on efficacy standards described elsewhere in FDA's
regulations (e.g., accelerated approval based on surrogate markers or
clinical endpoints other than survival or irreversible morbidity), nor
does it address the safety evaluation for the products to which it does
apply.
[[Page 190]]
Sec. 314.610 Approval based on evidence of effectiveness from studies
in animals.
(a) FDA may grant marketing approval for a new drug product for
which safety has been established and for which the requirements of
Sec. 314.600 are met based on adequate and well-controlled animal
studies when the results of those animal studies establish that the drug
product is reasonably likely to produce clinical benefit in humans. In
assessing the sufficiency of animal data, the agency may take into
account other data, including human data, available to the agency. FDA
will rely on the evidence from studies in animals to provide substantial
evidence of the effectiveness of these products only when:
(1) There is a reasonably well-understood pathophysiological
mechanism of the toxicity of the substance and its prevention or
substantial reduction by the product;
(2) The effect is demonstrated in more than one animal species
expected to react with a response predictive for humans, unless the
effect is demonstrated in a single animal species that represents a
sufficiently well-characterized animal model for predicting the response
in humans;
(3) The animal study endpoint is clearly related to the desired
benefit in humans, generally the enhancement of survival or prevention
of major morbidity; and
(4) The data or information on the kinetics and pharmacodynamics of
the product or other relevant data or information, in animals and
humans, allows selection of an effective dose in humans.
(b) Approval under this subpart will be subject to three
requirements:
(1) Postmarketing studies. The applicant must conduct postmarketing
studies, such as field studies, to verify and describe the drug's
clinical benefit and to assess its safety when used as indicated when
such studies are feasible and ethical. Such postmarketing studies would
not be feasible until an exigency arises. When such studies are
feasible, the applicant must conduct such studies with due diligence.
Applicants must include as part of their application a plan or approach
to postmarketing study commitments in the event such studies become
ethical and feasible.
(2) Approval with restrictions to ensure safe use. If FDA concludes
that a drug product shown to be effective under this subpart can be
safely used only if distribution or use is restricted, FDA will require
such postmarketing restrictions as are needed to ensure safe use of the
drug product, commensurate with the specific safety concerns presented
by the drug product, such as:
(i) Distribution restricted to certain facilities or health care
practitioners with special training or experience;
(ii) Distribution conditioned on the performance of specified
medical procedures, including medical followup; and
(iii) Distribution conditioned on specified recordkeeping
requirements.
(3) Information to be provided to patient recipients. For drug
products or specific indications approved under this subpart, applicants
must prepare, as part of their proposed labeling, labeling to be
provided to patient recipients. The patient labeling must explain that,
for ethical or feasibility reasons, the drug's approval was based on
efficacy studies conducted in animals alone and must give the drug's
indication(s), directions for use (dosage and administration),
contraindications, a description of any reasonably foreseeable risks,
adverse reactions, anticipated benefits, drug interactions, and any
other relevant information required by FDA at the time of approval. The
patient labeling must be available with the product to be provided to
patients prior to administration or dispensing of the drug product for
the use approved under this subpart, if possible.
Sec. 314.620 Withdrawal procedures.
(a) Reasons to withdraw approval. For new drugs approved under this
subpart, FDA may withdraw approval, following a hearing as provided in
part 15 of this chapter, as modified by this section, if:
(1) A postmarketing clinical study fails to verify clinical benefit;
(2) The applicant fails to perform the postmarketing study with due
diligence;
[[Page 191]]
(3) Use after marketing demonstrates that postmarketing restrictions
are inadequate to ensure safe use of the drug product;
(4) The applicant fails to adhere to the postmarketing restrictions
applied at the time of approval under this subpart;
(5) The promotional materials are false or misleading; or
(6) Other evidence demonstrates that the drug product is not shown
to be safe or effective under its conditions of use.
(b) Notice of opportunity for a hearing. The Director of the Center
for Drug Evaluation and Research (CDER) will give the applicant notice
of an opportunity for a hearing on CDER's proposal to withdraw the
approval of an application approved under this subpart. The notice,
which will ordinarily be a letter, will state generally the reasons for
the action and the proposed grounds for the order.
(c) Submission of data and information. (1) If the applicant fails
to file a written request for a hearing within 15 days of receipt of the
notice, the applicant waives the opportunity for a hearing.
(2) If the applicant files a timely request for a hearing, the
agency will publish a notice of hearing in the Federal Register in
accordance with Sec. Sec. 12.32(e) and 15.20 of this chapter.
(3) An applicant who requests a hearing under this section must,
within 30 days of receipt of the notice of opportunity for a hearing,
submit the data and information upon which the applicant intends to rely
at the hearing.
(d) Separation of functions. Separation of functions (as specified
in Sec. 10.55 of this chapter) will not apply at any point in
withdrawal proceedings under this section.
(e) Procedures for hearings. Hearings held under this section will
be conducted in accordance with the provisions of part 15 of this
chapter, with the following modifications:
(1) An advisory committee duly constituted under part 14 of this
chapter will be present at the hearing. The committee will be asked to
review the issues involved and to provide advice and recommendations to
the Commissioner of Food and Drugs.
(2) The presiding officer, the advisory committee members, up to
three representatives of the applicant, and up to three representatives
of CDER may question any person during or at the conclusion of the
person's presentation. No other person attending the hearing may
question a person making a presentation. The presiding officer may, as a
matter of discretion, permit questions to be submitted to the presiding
officer for response by a person making a presentation.
(f) Judicial review. The Commissioner of Food and Drugs' decision
constitutes final agency action from which the applicant may petition
for judicial review. Before requesting an order from a court for a stay
of action pending review, an applicant must first submit a petition for
a stay of action under Sec. 10.35 of this chapter.
Sec. 314.630 Postmarketing safety reporting.
Drug products approved under this subpart are subject to the
postmarketing recordkeeping and safety reporting requirements applicable
to all approved drug products, as provided in Sec. Sec. 314.80 and
314.81.
Sec. 314.640 Promotional materials.
For drug products being considered for approval under this subpart,
unless otherwise informed by the agency, applicants must submit to the
agency for consideration during the preapproval review period copies of
all promotional materials, including promotional labeling as well as
advertisements, intended for dissemination or publication within 120
days following marketing approval. After 120 days following marketing
approval, unless otherwise informed by the agency, the applicant must
submit promotional materials at least 30 days prior to the intended time
of initial dissemination of the labeling or initial publication of the
advertisement.
Sec. 314.650 Termination of requirements.
If FDA determines after approval under this subpart that the
requirements established in Sec. Sec. 314.610(b)(2), 314.620, and
314.630 are no longer necessary for the safe and effective use of a drug
product, FDA will so notify the applicant. Ordinarily, for drug products
[[Page 192]]
approved under Sec. 314.610, these requirements will no longer apply
when FDA determines that the postmarketing study verifies and describes
the drug product's clinical benefit. For drug products approved under
Sec. 314.610, the restrictions would no longer apply when FDA
determines that safe use of the drug product can be ensured through
appropriate labeling. FDA also retains the discretion to remove specific
postapproval requirements upon review of a petition submitted by the
sponsor in accordance with Sec. 10.30 of this chapter.
PART 315_DIAGNOSTIC RADIOPHARMACEUTICALS--Table of Contents
Sec.
315.1 Scope.
315.2 Definition.
315.3 General factors relevant to safety and effectiveness.
315.4 Indications.
315.5 Evaluation of effectiveness.
315.6 Evaluation of safety.
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 371, 374, 379e;
sec. 122, Pub. L. 105-115, 111 Stat. 2322 (21 U.S.C. 355 note).
Source: 64 FR 26667, May 17, 1999, unless otherwise noted.
Sec. 315.1 Scope.
The regulations in this part apply to radiopharmaceuticals intended
for in vivo administration for diagnostic and monitoring use. They do
not apply to radiopharmaceuticals intended for therapeutic purposes. In
situations where a particular radiopharmaceutical is proposed for both
diagnostic and therapeutic uses, the radiopharmaceutical must be
evaluated taking into account each intended use.
Sec. 315.2 Definition.
For purposes of this part, diagnostic radiopharmaceutical means:
(a) An article that is intended for use in the diagnosis or
monitoring of a disease or a manifestation of a disease in humans and
that exhibits spontaneous disintegration of unstable nuclei with the
emission of nuclear particles or photons; or
(b) Any nonradioactive reagent kit or nuclide generator that is
intended to be used in the preparation of such article as defined in
paragraph (a) of this section.
Sec. 315.3 General factors relevant to safety and effectiveness.
FDA's determination of the safety and effectiveness of a diagnostic
radiopharmaceutical includes consideration of the following:
(a) The proposed use of the diagnostic radiopharmaceutical in the
practice of medicine,
(b) The pharmacological and toxicological activity of the diagnostic
radiopharmaceutical (including any carrier or ligand component of the
diagnostic radiopharmaceutical), and
(c) The estimated absorbed radiation dose of the diagnostic
radiopharmaceutical.
Sec. 315.4 Indications.
(a) For diagnostic radiopharmaceuticals, the categories of proposed
indications for use include, but are not limited to, the following:
(1) Structure delineation;
(2) Functional, physiological, or biochemical assessment;
(3) Disease or pathology detection or assessment; and
(4) Diagnostic or therapeutic patient management.
(b) Where a diagnostic radiopharmaceutical is not intended to
provide disease-specific information, the proposed indications for use
may refer to a biochemical, physiological, anatomical, or pathological
process or to more than one disease or condition.
Sec. 315.5 Evaluation of effectiveness.
(a) The effectiveness of a diagnostic radiopharmaceutical is
assessed by evaluating its ability to provide useful clinical
information related to its proposed indications for use. The method of
this evaluation varies depending upon the proposed indication(s) and may
use one or more of the following criteria:
(1) The claim of structure delineation is established by
demonstrating in a defined clinical setting the ability to locate
anatomical structures and to characterize their anatomy.
(2) The claim of functional, physiological, or biochemical
assessment is
[[Page 193]]
established by demonstrating in a defined clinical setting reliable
measurement of function(s) or physiological, biochemical, or molecular
process(es).
(3) The claim of disease or pathology detection or assessment is
established by demonstrating in a defined clinical setting that the
diagnostic radiopharmaceutical has sufficient accuracy in identifying or
characterizing the disease or pathology.
(4) The claim of diagnostic or therapeutic patient management is
established by demonstrating in a defined clinical setting that the test
is useful in diagnostic or therapeutic patient management.
(5) For a claim that does not fall within the indication categories
identified in Sec. 315.4, the applicant or sponsor should consult FDA
on how to establish the effectiveness of the diagnostic
radiopharmaceutical for the claim.
(b) The accuracy and usefulness of the diagnostic information is
determined by comparison with a reliable assessment of actual clinical
status. A reliable assessment of actual clinical status may be provided
by a diagnostic standard or standards of demonstrated accuracy. In the
absence of such diagnostic standard(s), the actual clinical status must
be established in another manner, e.g., patient followup.
Sec. 315.6 Evaluation of safety.
(a) Factors considered in the safety assessment of a diagnostic
radiopharmaceutical include, among others, the following:
(1) The radiation dose;
(2) The pharmacology and toxicology of the radiopharmaceutical,
including any radionuclide, carrier, or ligand;
(3) The risks of an incorrect diagnostic determination;
(4) The adverse reaction profile of the drug;
(5) Results of human experience with the radiopharmaceutical for
other uses; and
(6) Results of any previous human experience with the carrier or
ligand of the radiopharmaceutical when the same chemical entity as the
carrier or ligand has been used in a previously studied product.
(b) The assessment of the adverse reaction profile includes, but is
not limited to, an evaluation of the potential of the diagnostic
radiopharmaceutical, including the carrier or ligand, to elicit the
following:
(1) Allergic or hypersensitivity responses,
(2) Immunologic responses,
(3) Changes in the physiologic or biochemical function of the target
and nontarget tissues, and
(4) Clinically detectable signs or symptoms.
(c)(1) To establish the safety of a diagnostic radiopharmaceutical,
FDA may require, among other information, the following types of data:
(i) Pharmacology data,
(ii) Toxicology data,
(iii) Clinical adverse event data, and
(iv) Radiation safety assessment.
(2) The amount of new safety data required will depend on the
characteristics of the product and available information regarding the
safety of the diagnostic radiopharmaceutical, and its carrier or ligand,
obtained from other studies and uses. Such information may include, but
is not limited to, the dose, route of administration, frequency of use,
half-life of the ligand or carrier, half-life of the radionuclide, and
results of clinical and preclinical studies. FDA will establish
categories of diagnostic radiopharmaceuticals based on defined
characteristics relevant to risk and will specify the amount and type of
safety data that are appropriate for each category (e.g., required
safety data may be limited for diagnostic radiopharmaceuticals with a
well established, low-risk profile). Upon reviewing the relevant product
characteristics and safety information, FDA will place each diagnostic
radiopharmaceutical into the appropriate safety risk category.
(d) Radiation safety assessment. The radiation safety assessment
must establish the radiation dose of a diagnostic radiopharmaceutical by
radiation dosimetry evaluations in humans and appropriate animal models.
The maximum tolerated dose need not be established.
[[Page 194]]
PART 316_ORPHAN DRUGS--Table of Contents
Subpart A_General Provisions
Sec.
316.1 Scope of this part.
316.2 Purpose.
316.3 Definitions.
316.4 Address for submissions.
Subpart B_Written Recommendations for Investigations of Orphan Drugs
316.10 Content and format of a request for written recommendations.
316.12 Providing written recommendations.
316.14 Refusal to provide written recommendations.
Subpart C_Designation of an Orphan Drug
316.20 Content and format of a request for orphan-drug designation.
316.21 Verification of orphan-drug status.
316.22 Permanent-resident agent for foreign sponsor.
316.23 Timing of requests for orphan-drug designation; designation of
already approved drugs.
316.24 Deficiency letters and granting orphan-drug designation.
316.25 Refusal to grant orphan-drug designation.
316.26 Amendment to orphan-drug designation.
316.27 Change in ownership of orphan-drug designation.
316.28 Publication of orphan-drug designations.
316.29 Revocation of orphan-drug designation.
316.30 Annual reports of holder of orphan-drug designation.
Subpart D_Orphan-Drug Exclusive Approval
316.31 Scope of orphan-drug exclusive approval.
316.34 FDA recognition of exclusive approval.
316.36 Insufficient quantities of orphan drugs.
Subpart E_Open Protocols for Investigations
316.40 Treatment use of a designated orphan drug.
Subpart F_Availability of Information
316.50 Guidance documents.
316.52 Availability for public disclosure of data and information in
requests and applications.
Authority: 21 U.S.C. 360aa, 360bb, 360cc, 360dd, 371.
Source: 57 FR 62085, Dec. 29, 1992, unless otherwise noted.
Editorial Note: Nomenclature changes to part 316 appear at 69 FR
13717, Mar. 24, 2004.
Subpart A_General Provisions
Sec. 316.1 Scope of this part.
(a) This part implements sections 525, 526, 527, and 528 of the act
and provides procedures to encourage and facilitate the development of
drugs for rare diseases or conditions, including biological products and
antibiotics. This part sets forth the procedures and requirements for:
(1) Submissions to FDA of:
(i) Requests for recommendations for investigations of drugs for
rare diseases or conditions;
(ii) Requests for designation of a drug for a rare disease or
condition; and
(iii) Requests for gaining exclusive approval for a drug for a rare
disease or condition.
(2) Allowing a sponsor to provide an investigational drug under a
treatment protocol to patients who need the drug for treatment of a rare
disease or condition.
(b) This part does not apply to food, medical devices, or drugs for
veterinary use.
(c) References in this part to regulatory sections of the Code of
Federal Regulations are to chapter I of title 21, unless otherwise
noted.
[57 FR 62085, Dec. 29, 1992, as amended at 78 FR 35132, June 12, 2013]
Sec. 316.2 Purpose.
The purpose of this part is to establish standards and procedures
for determining eligibility for the benefits provided for in section 2
of the Orphan Drug Act, including written recommendations for
investigations of orphan drugs, a 7-year period of exclusive marketing,
and treatment use of investigational orphan drugs. This part is also
intended to satisfy Congress' requirements that FDA promulgate
procedures for the implementation of sections 525(a) and 526(a) of the
act.
[[Page 195]]
Sec. 316.3 Definitions.
(a) The definitions and interpretations contained in section 201 of
the act apply to those terms when used in this part.
(b) The following definitions of terms apply to this part:
(1) Act means the Federal Food, Drug, and Cosmetic Act as amended by
section 2 of the Orphan Drug Act (sections 525-528 (21 U.S.C. 360aa-
360dd)).
(2) Active moiety means the molecule or ion, excluding those
appended portions of the molecule that cause the drug to be an ester,
salt (including a salt with hydrogen or coordination bonds), or other
noncovalent derivative (such as a complex, chelate, or clathrate) of the
molecule, responsible for the physiological or pharmacological action of
the drug substance.
(3) Clinically superior means that a drug is shown to provide a
significant therapeutic advantage over and above that provided by an
approved drug (that is otherwise the same drug) in one or more of the
following ways:
(i) Greater effectiveness than an approved drug (as assessed by
effect on a clinically meaningful endpoint in adequate and well
controlled clinical trials). Generally, this would represent the same
kind of evidence needed to support a comparative effectiveness claim for
two different drugs; in most cases, direct comparative clinical trials
would be necessary; or
(ii) Greater safety in a substantial portion of the target
populations, for example, by the elimination of an ingredient or
contaminant that is associated with relatively frequent adverse effects.
In some cases, direct comparative clinical trials will be necessary; or
(iii) In unusual cases, where neither greater safety nor greater
effectiveness has been shown, a demonstration that the drug otherwise
makes a major contribution to patient care.
(4) Director means the Director of FDA's Office of Orphan Products
Development.
(5) FDA means the Food and Drug Administration.
(6) Holder means the sponsor in whose name an orphan drug is
designated and approved.
(7) IND means an investigational new drug application under part 312
of this chapter.
(8) Manufacturer means any person or agency engaged in the
manufacture of a drug that is subject to investigation and approval
under the act or the biologics provisions of the Public Health Service
Act (42 U.S.C. 262-263).
(9) Marketing application means an application for approval of a new
drug filed under section 505(b) of the act or an application for a
biologics license submitted under section 351 of the Public Health
Service Act (42 U.S.C. 262).
(10) Orphan drug means a drug intended for use in a rare disease or
condition as defined in section 526 of the act.
(11) Orphan-drug designation means FDA's act of granting a request
for designation under section 526 of the act.
(12) Orphan-drug exclusive approval or exclusive approval means
that, effective on the date of FDA approval as stated in the approval
letter of a marketing application for a sponsor of a designated orphan
drug, no approval will be given to a subsequent sponsor of the same drug
for the same use or indication for 7 years, except as otherwise provided
by law or in this part. A designated drug will receive orphan-drug
exclusive approval only if the same drug has not already been approved
for the same use or indication.
(13) Orphan subset of a non-rare disease or condition (``orphan
subset'') means that use of the drug in a subset of persons with a non-
rare disease or condition may be appropriate but use of the drug outside
of that subset (in the remaining persons with the non-rare disease or
condition) would be inappropriate owing to some property(ies) of the
drug, for example, drug toxicity, mechanism of action, or previous
clinical experience with the drug.
(14) Same drug means:
(i) If it is a drug composed of small molecules, a drug that
contains the same active moiety as a previously approved drug and is
intended for the same use as the previously approved drug, even if the
particular ester or salt (including a salt with hydrogen or coordination
bonds) or other noncovalent derivative such as a complex, chelate or
clathrate has not been
[[Page 196]]
previously approved, except that if the subsequent drug can be shown to
be clinically superior to the first drug, it will not be considered to
be the same drug.
(ii) If it is a drug composed of large molecules (macromolecules), a
drug that contains the same principal molecular structural features (but
not necessarily all of the same structural features) and is intended for
the same use as a previously approved drug, except that, if the
subsequent drug can be shown to be clinically superior, it will not be
considered to be the same drug. This criterion will be applied as
follows to different kinds of macromolecules:
(A) Two protein drugs would be considered the same if the only
differences in structure between them were due to post-translational
events or infidelity of translation or transcription or were minor
differences in amino acid sequence; other potentially important
differences, such as different glycosylation patterns or different
tertiary structures, would not cause the drugs to be considered
different unless the differences were shown to be clinically superior.
(B) Two polysaccharide drugs would be considered the same if they
had identical saccharide repeating units, even if the number of units
were to vary and even if there were postpolymerization modifications,
unless the subsequent drug could be shown to be clinically superior.
(C) Two polynucleotide drugs consisting of two or more distinct
nucleotides would be considered the same if they had an identical
sequence of purine and pyrimidine bases (or their derivatives) bound to
an identical sugar backbone (ribose, deoxyribose, or modifications of
these sugars), unless the subsequent drug were shown to be clinically
superior.
(D) Closely related, complex partly definable drugs with similar
therapeutic intent, such as two live viral vaccines for the same
indication, would be considered the same unless the subsequent drug was
shown to be clinically superior.
(15) Sponsor means the entity that assumes responsibility for a
clinical or nonclinical investigation of a drug, including the
responsibility for compliance with applicable provisions of the act and
regulations. A sponsor may be an individual, partnership, corporation,
or Government agency and may be a manufacturer, scientific institution,
or an investigator regularly and lawfully engaged in the investigation
of drugs. For purposes of the Orphan Drug Act, FDA considers the real
party or parties in interest to be a sponsor.
[57 FR 62085, Dec. 29, 1992, as amended at 64 FR 402, Jan. 5, 1999; 64
FR 56449, Oct. 20, 1999; 78 FR 35132, June 12, 2013]
Sec. 316.4 Address for submissions.
All correspondence and requests for FDA action under the provisions
of this rule should be addressed as follows: Office of Orphan Products
Development, Food and Drug Administration, Bldg. 32, Rm. 5271, 10903 New
Hampshire Ave., Silver Spring, MD 20993.
[78 FR 35133, June 12, 2013]
Subpart B_Written Recommendations for Investigations of Orphan Drugs
Sec. 316.10 Content and format of a request for written
recommendations.
(a) A sponsor's request for written recommendations from FDA
concerning the nonclinical and clinical investigations necessary for
approval of a marketing application shall be submitted in the form and
contain the information required in this section. FDA may require the
sponsor to submit information in addition to that specified in paragraph
(b) of this section if FDA determines that the sponsor's initial request
does not contain adequate information on which to base recommendations.
(b) A sponsor shall submit two copies of a completed, dated, and
signed request for written recommendations that contains the following:
(1) The sponsor's name and address.
(2) A statement that the sponsor is requesting written
recommendations on orphan-drug development under section 525 of the act.
(3) The name of the sponsor's primary contact person and/or resident
agent, and the person's title, address, and telephone number.
[[Page 197]]
(4) The generic name and trade name, if any, of the drug and a list
of the drug product's components or description of the drug product's
formulation, and chemical and physical properties.
(5) The proposed dosage form and route of administration.
(6) A description of the disease or condition for which the drug is
proposed to be investigated and the proposed indication or indications
for use for such disease or condition.
(7) Current regulatory and marketing status and history of the drug
product, including:
(i) Whether the product is the subject of an IND or a marketing
application (if the product is the subject of an IND or a marketing
application, the IND or marketing application numbers should be stated
and the investigational or approved indication or indications for use
specified);
(ii) Known marketing experience or investigational status outside
the United States;
(iii) So far as is known or can be determined, all indications
previously or currently under investigation anywhere;
(iv) All adverse regulatory actions taken by the United States or
foreign authorities.
(8) The basis for concluding that the drug is for a disease or
condition that is rare in the United States, including the following:
(i) The size and other known demographic characteristics of the
patient population affected and the source of this information.
(ii) For drugs intended for diseases or conditions affecting 200,000
or more people in the United States, or for a vaccine, diagnostic drug,
or preventive drug that would be given to 200,000 or more persons per
year, a summary of the sponsor's basis for believing that the disease or
condition described in paragraph (b)(6) of this section occurs so
infrequently that there is no reasonable expectation that the costs of
drug development and marketing will be recovered in future sales of the
drug in the United States. The estimated costs and sales data should be
submitted as provided for in Sec. 316.21(c).
(9) A summary and analysis of available data on the pharmacologic
effects of the drug.
(10) A summary and analysis of available nonclinical and clinical
data pertinent to the drug and the disease to be studied including
copies of pertinent published reports. When a drug proposed for orphan
drug designation is intended to treat a life-threatening or severely
debilitating illness, especially where no satisfactory alternative
therapy exists, the sponsor may wish voluntarily to provide this
information. A sponsor of such a drug may be entitled to expeditious
development, evaluation, and marketing under 21 CFR part 312, subpart E.
(11) An explanation of how the data summarized and analyzed under
paragraphs (b)(9) and (b)(10) of this section support the rationale for
use of the drug in the rare disease or condition.
(12) A definition of the population from which subjects will be
identified for clinical trials, if known.
(13) A detailed outline of any protocols under which the drug has
been or is being studied for the rare disease or condition and a summary
and analysis of any available data from such studies.
(14) The sponsor's proposal as to the scope of nonclinical and
clinical investigations needed to establish the safety and effectiveness
of the drug.
(15) Detailed protocols for each proposed United States or foreign
clinical investigation, if available.
(16) Specific questions to be addressed by FDA in its
recommendations for nonclinical laboratory studies and clinical
investigations.
[57 FR 62085, Dec. 29, 1992; 58 FR 6167, Jan. 26, 1993]
Sec. 316.12 Providing written recommendations.
(a) FDA will provide the sponsor with written recommendations
concerning the nonclinical laboratory studies and clinical
investigations necessary for approval of a marketing application if none
of the reasons described in Sec. 316.14 for refusing to do so applies.
(b) When a sponsor seeks written recommendations at a stage of drug
development at which advice on any clinical
[[Page 198]]
investigations, or on particular investigations would be premature,
FDA's response may be limited to written recommendations concerning only
nonclinical laboratory studies, or only certain of the clinical studies
(e.g., Phase 1 studies as described in Sec. 312.21 of this chapter).
Prior to providing written recommendations for the clinical
investigations required to achieve marketing approval, FDA may require
that the results of the nonclinical laboratory studies or completed
early clinical studies be submitted to FDA for agency review.
Sec. 316.14 Refusal to provide written recommendations.
(a) FDA may refuse to provide written recommendations concerning the
nonclinical laboratory studies and clinical investigations necessary for
approval of a marketing application for any of the following reasons:
(1) The information required to be submitted by Sec. 316.10(b) has
not been submitted, or the information submitted is incomplete.
(2) There is insufficient information about:
(i) The drug to identify the active moiety and its physical and
chemical properties, if these characteristics can be determined; or
(ii) The disease or condition to determine that the disease or
condition is rare in the United States; or
(iii) The reasons for believing that the drug may be useful for
treating the rare disease or condition with that drug; or
(iv) The regulatory and marketing history of the drug to determine
the scope and type of investigations that have already been conducted on
the drug for the rare disease or condition; or
(v) The plan of study for establishing the safety and effectiveness
of the drug for treatment of the rare disease or condition.
(3) The specific questions for which the sponsor seeks the advice of
the agency are unclear or are not sufficiently specific.
(4) On the basis of the information submitted and on other
information available to the agency, FDA determines that the disease or
condition for which the drug is intended is not rare in the United
States.
(5) On the basis of the information submitted and on other
information available to the agency, FDA determines that there is an
inadequate basis for permitting investigational use of the drug under
part 312 of this chapter for the rare disease or condition.
(6) The request for information contains an untrue statement of
material fact.
(b) A refusal to provide written recommendations will be in writing
and will include a statement of the reason for FDA's refusal. Where
practicable, FDA will describe the information or material it requires
or the conditions the sponsor must meet for FDA to provide
recommendations.
(c) Within 90 days after the date of a letter from FDA requesting
additional information or material or setting forth the conditions that
the sponsor is asked to meet, the sponsor shall either:
(1) Provide the information or material or amend the request for
written recommendations to meet the conditions sought by FDA; or
(2) Withdraw the request for written recommendations. FDA will
consider a sponsor's failure to respond within 90 days to an FDA letter
requesting information or material or setting forth conditions to be met
to be a withdrawal of the request for written recommendations.
Subpart C_Designation of an Orphan Drug
Sec. 316.20 Content and format of a request for orphan-drug designation.
(a) A sponsor that submits a request for orphan-drug designation of
a drug for a specified rare disease or condition shall submit each
request in the form and containing the information required in paragraph
(b) of this section. A sponsor may request orphan-drug designation of a
previously unapproved drug, or of a new use for an already marketed
drug. In addition, a sponsor of a drug that is otherwise the same drug
as an already approved drug may seek and obtain orphan-drug designation
for the subsequent drug for the same rare disease or condition if it can
present a plausible hypothesis that its
[[Page 199]]
drug may be clinically superior to the first drug. More than one sponsor
may receive orphan-drug designation of the same drug for the same rare
disease or condition, but each sponsor seeking orphan-drug designation
must file a complete request for designation as provided in paragraph
(b) of this section.
(b) A sponsor shall submit two copies of a completed, dated, and
signed request for designation that contains the following:
(1) A statement that the sponsor requests orphan-drug designation
for a rare disease or condition, which shall be identified with
specificity.
(2) The name and address of the sponsor; the name of the sponsor's
primary contact person and/or resident agent including title, address,
telephone number, and email address; the generic and trade name, if any,
of the drug, or, if neither is available, the chemical name or a
meaningful descriptive name of the drug; and the name and address of the
source of the drug if it is not manufactured by the sponsor.
(3) A description of the rare disease or condition for which the
drug is being or will be investigated, the proposed use of the drug, and
the reasons why such therapy is needed.
(4) A description of the drug, to include the identity of the active
moiety if it is a drug composed of small molecules, or of the principal
molecular structural features if it is composed of macromolecules; its
physical and chemical properties, if these characteristics can be
determined; and a discussion of the scientific rationale to establish a
medically plausible basis for the use of the drug for the rare disease
or condition, including all relevant data from in vitro laboratory
studies, preclinical efficacy studies conducted in an animal model for
the human disease or condition, and clinical experience with the drug in
the rare disease or condition that are available to the sponsor, whether
positive, negative, or inconclusive. Animal toxicology studies are
generally not relevant to a request for orphan-drug designation. Copies
of pertinent unpublished and published papers are also required.
(5) Where the sponsor of a drug that is otherwise the same drug as
an already approved drug seeks orphan-drug designation for the
subsequent drug for the same rare disease or condition, an explanation
of why the proposed variation may be clinically superior to the first
drug.
(6) Where a sponsor requests orphan-drug designation for a drug for
only a subset of persons with a particular disease or condition that
otherwise affects 200,000 or more people (``orphan subset''), a
demonstration that, due to one or more properties of the drug, the
remaining persons with such disease or condition would not be
appropriate candidates for use of the drug.
(7) A summary of the regulatory status and marketing history of the
drug in the United States and in foreign countries, e.g., IND and
marketing application status and dispositions, what uses are under
investigation and in what countries; for what indication is the drug
approved in foreign countries; what adverse regulatory actions have been
taken against the drug in any country.
(8) Documentation, with appended authoritative references, to
demonstrate that:
(i) The disease or condition for which the drug is intended affects
fewer than 200,000 people in the United States or, if the drug is a
vaccine, diagnostic drug, or preventive drug, the persons to whom the
drug will be administered in the United States are fewer than 200,000
per year as specified in Sec. 316.21(b), or
(ii) For a drug intended for diseases or conditions affecting
200,000 or more people, or for a vaccine, diagnostic drug, or preventive
drug to be administered to 200,000 or more persons per year in the
United States, there is no reasonable expectation that costs of research
and development of the drug for the indication can be recovered by sales
of the drug in the United States as specified in Sec. 316.21(c).
(c) Any of the information previously provided by the sponsor to FDA
under subpart B of this part may be referenced by specific page or
location if it duplicates information required elsewhere in this
section.
[57 FR 62085, Dec. 29, 1992, as amended at 78 FR 35133, June 12, 2013]
[[Page 200]]
Sec. 316.21 Verification of orphan-drug status.
(a) So that FDA can determine whether a drug qualifies for orphan-
drug designation under section 526(a) of the act, the sponsor shall
include in its request to FDA for orphan-drug designation under Sec.
316.20 either:
(1) Documentation as described in paragraph (b) of this section that
the number of people affected by the disease or condition for which the
drug is to be developed is fewer than 200,000 persons; or
(2) Documentation as described in paragraph (c) of this section that
demonstrates that there is no reasonable expectation that the sales of
the drug will be sufficient to offset the costs of developing the drug
for the U.S. market and the costs of making the drug available in the
United States.
(b) For the purpose of documenting that the number of people
affected by the disease or condition for which the drug is to be
developed is less than 200,000 persons, ``prevalence'' is defined as the
number of persons in the United States who have been diagnosed as having
the disease or condition at the time of the submission of the request
for orphan-drug designation. To document the number of persons in the
United States who have the disease or condition for which the drug is to
be developed, the sponsor shall submit to FDA evidence showing:
(1) The estimated prevalence of the disease or condition for which
the drug is being developed, together with a list of the sources
(including dates of information provided and literature citations) for
the estimate;
(2) Upon request by FDA, the estimated prevalence of any other
disease or condition for which the drug has already been approved or for
which the drug is currently being developed, together with an
explanation of the bases of these estimates; and
(3) The estimated number of people to whom the drug will be
administered annually if the drug is a vaccine or is a drug intended for
diagnosis or prevention of a rare disease or condition, together with an
explanation of the bases of these estimates (including dates of
information provided and literature citations).
(c) When submitting documentation that there is no reasonable
expectation that costs of research and development of the drug for the
disease or condition can be recovered by sales of the drug in the United
States, the sponsor shall submit to FDA:
(1) Data on all costs that the sponsor has incurred in the course of
developing the drug for the U.S. market. These costs shall include, but
are not limited to, nonclinical laboratory studies, clinical studies,
dosage form development, record and report maintenance, meetings with
FDA, determination of patentability, preparation of designation request,
IND/marketing application preparation, distribution of the drug under a
``treatment'' protocol, licensing costs, liability insurance, and
overhead and depreciation. Furthermore, the sponsor shall demonstrate
the reasonableness of the cost data. For example, if the sponsor has
incurred costs for clinical investigations, the sponsor shall provide
information on the number of investigations, the years in which they
took place, and on the scope, duration, and number of patients that were
involved in each investigation.
(2) If the drug was developed wholly or in part outside the United
States, in addition to the documentation listed in paragraph (c)(1) of
this section:
(i) Data on and justification for all costs that the sponsor has
incurred outside of the United States in the course of developing the
drug for the U.S. market. The justification, in addition to
demonstrating the reasonableness of the cost data, must also explain the
method that was used to determine which portion of the foreign
development costs should be applied to the U.S. market, and what percent
these costs are of total worldwide development costs. Any data submitted
to foreign government authorities to support drug pricing determinations
must be included with this information.
(ii) Data that show which foreign development costs were recovered
through cost recovery procedures that are allowed during drug
development in some foreign countries. For example, if the sponsor
charged patients for the drug during clinical investigations, the
[[Page 201]]
revenues collected by the sponsor must be reported to FDA.
(3) In cases where the drug has already been approved for marketing
for any indication or in cases where the drug is currently under
investigation for one or more other indications (in addition to the
indication for which orphan-drug designation is being sought), a clear
explanation of and justification for the method that is used to
apportion the development costs among the various indications.
(4) A statement of and justification for any development costs that
the sponsor expects to incur after the submission of the designation
request. In cases where the extent of these future development costs are
not clear, the sponsor should request FDA's advice and assistance in
estimating the scope of nonclinical laboratory studies and clinical
investigations and other data that are needed to support marketing
approval. Based on these recommendations, a cost estimate should be
prepared.
(5) A statement of and justification for production and marketing
costs that the sponsor has incurred in the past and expects to incur
during the first 7 years that the drug is marketed.
(6) An estimate of and justification for the expected revenues from
sales of the drug in the United States during its first 7 years of
marketing. The justification should assume that the total market for the
drug is equal to the prevalence of the disease or condition that the
drug will be used to treat. The justification should include:
(i) An estimate of the expected market share of the drug in each of
the first 7 years that it is marketed, together with an explanation of
the basis for that estimate;
(ii) A projection of and justification for the price at which the
drug will be sold; and
(iii) Comparisons with sales of similarly situated drugs, where
available.
(7) The name of each country where the drug has already been
approved for marketing for any indication, the dates of approval, the
indication for which the drug is approved, and the annual sales and
number of prescriptions in each country since the first approval date.
(8) A report of an independent certified public accountant in
accordance with Statement on Standards for Attestation established by
the American Institute of Certified Public Accountants on agreed upon
procedures performed with respect to the data estimates and
justifications submitted pursuant to this section. Cost data shall be
determined in accordance with generally accepted accounting principles.
(d) A sponsor that is requesting orphan-drug designation for a drug
designed to treat a disease or condition that affects 200,000 or more
persons shall, at FDA's request, allow FDA or FDA-designated personnel
to examine at reasonable times and in a reasonable manner all relevant
financial records and sales data of the sponsor and manufacturer.
[57 FR 62085, Dec. 29, 1992, as amended at 78 FR 35133, June 12, 2013]
Sec. 316.22 Permanent-resident agent for foreign sponsor.
Every foreign sponsor that seeks orphan-drug designation shall name
a permanent resident of the United States as the sponsor's agent upon
whom service of all processes, notices, orders, decisions, requirements,
and other communications may be made on behalf of the sponsor.
Notifications of changes in such agents or changes of address of agents
should preferably be provided in advance, but not later than 60 days
after the effective date of such changes. The permanent-resident agent
may be an individual, firm, or domestic corporation and may represent
any number of sponsors. The name of the permanent-resident agent,
address, telephone number, and email address shall be provided to:
Office of Orphan Products Development, Food and Drug Administration,
Bldg. 32, rm. 5271, 10903 New Hampshire Ave., Silver Spring, MD 20993.
[78 FR 35133, June 12, 2013]
Sec. 316.23 Timing of requests for orphan-drug designation; designation
of already approved drugs.
(a) A sponsor may request orphan-drug designation at any time in its
drug development process prior to the time that sponsor submits a
marketing
[[Page 202]]
application for the drug for the same rare disease or condition.
(b) A sponsor may request orphan-drug designation of an already
approved drug for an unapproved use without regard to whether the prior
marketing approval was for a rare disease or condition.
[78 FR 35133, June 12, 2013]
Sec. 316.24 Deficiency letters and granting orphan-drug designation.
(a) FDA will send a deficiency letter to the sponsor if the request
for orphan-drug designation lacks information required under Sec. Sec.
316.20 and 316.21, or contains inaccurate or incomplete information. FDA
may consider a designation request voluntarily withdrawn if the sponsor
fails to respond to the deficiency letter within 1 year of issuance of
the deficiency letter, unless within that same timeframe the sponsor
requests in writing an extension of time to respond. This request must
include the reason(s) for the requested extension and the length of time
of the requested extension. FDA will grant all reasonable requests for
an extension. In the event FDA denies a request for an extension of
time, FDA may consider the designation request voluntarily withdrawn. In
the event FDA considers a designation request voluntarily withdrawn, FDA
will so notify the sponsor in writing.
(b) FDA will grant the request for orphan-drug designation if none
of the reasons described in Sec. 316.25 for requiring or permitting
refusal to grant such a request applies.
(c) When a request for orphan-drug designation is granted, FDA will
notify the sponsor in writing and will publicize the orphan-drug
designation in accordance with Sec. 316.28.
(d) A sponsor may voluntarily withdraw an orphan-drug designation
request or an orphan-drug designation at any time after the request is
submitted or granted, respectively, by submitting a written request for
withdrawal to FDA. FDA will acknowledge such withdrawal in a letter to
the sponsor. Any benefits attendant to designation (such as orphan-
exclusive approval) will cease once designation is voluntarily
withdrawn, from the date of FDA's acknowledgement letter. If a sponsor
voluntarily withdraws designation, FDA will publicize such withdrawal in
accordance with Sec. 316.28.
[57 FR 62085, Dec. 29, 1992, as amended at 78 FR 35133, June 12, 2013]
Sec. 316.25 Refusal to grant orphan-drug designation.
(a) FDA will refuse to grant a request for orphan-drug designation
if any of the following reasons apply:
(1) The drug is not intended for a rare disease or condition
because:
(i) There is insufficient evidence to support the estimate that the
drug is intended for treatment of a disease or condition in fewer than
200,000 people in the United States, or that the drug is intended for
use in prevention or in diagnosis in fewer than 200,000 people annually
in the United States; or
(ii) Where the drug is intended for prevention, diagnosis, or
treatment of a disease or condition affecting 200,000 or more people in
the United States, the sponsor has failed to demonstrate that there is
no reasonable expectation that development and production costs will be
recovered from sales of the drug for such disease or condition in the
United States. A sponsor's failure to comply with Sec. 316.21 shall
constitute a failure to make the demonstration required in this
paragraph.
(2) There is insufficient information about the drug, or the disease
or condition for which it is intended, to establish a medically
plausible basis for expecting the drug to be effective in the
prevention, diagnosis, or treatment of that disease or condition.
(3) The drug is otherwise the same drug as an already approved drug
for the same rare disease or condition and the sponsor has not submitted
a medically plausible hypothesis for the possible clinical superiority
of the subsequent drug.
(b) FDA may refuse to grant a request for orphan-drug designation if
the request for designation contains an untrue statement of material
fact or omits material information or if the request is otherwise
ineligible under this part.
[57 FR 62085, Dec. 29, 1992, as amended at 78 FR 35133, June 12, 2013]
[[Page 203]]
Sec. 316.26 Amendment to orphan-drug designation.
(a) At any time prior to approval of a marketing application for a
designated orphan drug, the sponsor holding designation may apply for an
amendment to the designated use if the proposed change is due to new and
unexpected findings in research on the drug, information arising from
FDA recommendations, or unforeseen developments in treatment or
diagnosis of the disease or condition.
(b) FDA will grant the amendment if it finds that the initial
designation request was made in good faith and that the amendment is
intended to conform the orphan-drug designation to the results of
unanticipated research findings, to unforeseen developments in the
treatment or diagnosis of the disease or condition, or to changes based
on FDA recommendations, and that, as of the date of the submission of
the amendment request, the amendment would not result in exceeding the
prevalence or cost recovery thresholds in Sec. 316.21(a)(1) or (a)(2)
upon which the drug was originally designated.
[78 FR 35134, June 12, 2013]
Sec. 316.27 Change in ownership of orphan-drug designation.
(a) A sponsor may transfer ownership of or any beneficial interest
in the orphan-drug designation of a drug to a new sponsor. At the time
of the transfer, the new and former owners are required to submit the
following information to FDA:
(1) The former owner or assignor of rights shall submit a letter or
other document that states that all or some rights to the orphan-drug
designation of the drug have been transferred to the new owner or
assignee and that a complete copy of the request for orphan-drug
designation, including any amendments to the request, supplements to the
granted request, and correspondence relevant to the orphan-drug
designation, has been provided to the new owner or assignee.
(2) The new owner or assignee of rights shall submit a statement
accepting orphan-drug designation and a letter or other document
containing the following:
(i) The date that the change in ownership or assignment of rights is
effective;
(ii) A statement that the new owner has a complete copy of the
request for orphan-drug designation including any amendments to the
request, supplements to the granted request, and correspondence relevant
to the orphan-drug designation; and
(iii) A specific description of the rights that have been assigned
and those that have been reserved. This may be satisfied by the
submission of either a list of rights assigned and reserved or copies of
all relevant agreements between assignors and assignees; and
(iv) The name and address of a new primary contact person or
resident agent.
(b) No sponsor may relieve itself of responsibilities under the
Orphan Drug Act or under this part by assigning rights to another person
without:
(1) Assuring that the sponsor or the assignee will carry out such
responsibilities; or
(2) Obtaining prior permission from FDA.
[57 FR 62085, Dec. 29, 1992; 58 FR 6167, Jan. 26, 1993]
Sec. 316.28 Publication of orphan-drug designations.
Each month FDA will update a publicly available cumulative posting
of all drugs designated as orphan drugs. These postings will contain the
following information:
(a) The name and address of the sponsor;
(b) The generic name and trade name, if any, or, if neither is
available, the chemical name or a meaningful descriptive name of the
drug;
(c) The date of the granting of orphan-drug designation;
(d) The designated use in the rare disease or condition; and
(e) If the drug loses designation after August 12, 2013, the date of
it no longer having designation.
[78 FR 35134, June 12, 2013]
[[Page 204]]
Sec. 316.29 Revocation of orphan-drug designation.
(a) FDA may revoke orphan-drug designation for any drug if the
agency finds that:
(1) The request for designation contained an untrue statement of
material fact; or
(2) The request for designation omitted material information
required by this part; or
(3) FDA subsequently finds that the drug in fact had not been
eligible for orphan-drug designation at the time of submission of the
request therefor.
(b) For an approved drug, revocation of orphan-drug designation also
suspends or withdraws the sponsor's exclusive marketing rights for the
drug but not the approval of the drug's marketing application.
(c) Where a drug has been designated as an orphan drug because the
prevalence of a disease or condition (or, in the case of vaccines,
diagnostic drugs, or preventive drugs, the target population) is under
200,000 in the United States at the time of designation, its designation
will not be revoked on the ground that the prevalence of the disease or
condition (or the target population) becomes more than 200,000 persons.
(d) If FDA revokes orphan-drug designation, FDA will publicize that
the drug is no longer designated in accordance with Sec. 316.28(e).
[57 FR 62085, Dec. 29, 1992, as amended at 78 FR 35134, June 12, 2013]
Sec. 316.30 Annual reports of holder of orphan-drug designation.
Within 14 months after the date on which a drug was designated as an
orphan drug and annually thereafter until marketing approval, the
sponsor of a designated drug shall submit a brief progress report to the
FDA Office of Orphan Products Development on the drug that includes:
(a) A short account of the progress of drug development including a
review of preclinical and clinical studies initiated, ongoing, and
completed and a short summary of the status or results of such studies.
(b) A description of the investigational plan for the coming year,
as well as any anticipated difficulties in development, testing, and
marketing; and
(c) A brief discussion of any changes that may affect the orphan-
drug status of the product. For example, for products nearing the end of
the approval process, sponsors should discuss any disparity between the
probable marketing indication and the designated indication as related
to the need for an amendment to the orphan-drug designation pursuant to
Sec. 316.26.
Subpart D_Orphan-drug Exclusive Approval
Sec. 316.31 Scope of orphan-drug exclusive approval.
(a) FDA may approve a sponsor's marketing application for a
designated orphan drug for use in the rare disease or condition for
which the drug was designated, or for select indication(s) or use(s)
within the rare disease or condition for which the drug was designated.
Unless FDA previously approved the same drug for the same use or
indication, FDA will not approve another sponsor's marketing application
for the same drug for the same use or indication before the expiration
of 7 years from the date of such approval as stated in the approval
letter from FDA, except that such a marketing application can be
approved sooner if, and at such time as, any of the following occurs:
(1) Withdrawal of exclusive approval or revocation of orphan-drug
designation by FDA under any provision of this part; or
(2) Withdrawal for any reason of the marketing application for the
drug in question; or
(3) Consent by the holder of exclusive approval to permit another
marketing application to gain approval; or
(4) Failure of the holder of exclusive approval to assure a
sufficient quantity of the drug under section 527 of the act and Sec.
316.36.
(b) Orphan-drug exclusive approval protects only the approved
indication or use of a designated drug. If such approval is limited to
only particular indication(s) or uses(s) within the rare disease or
condition for which the drug
[[Page 205]]
was designated, FDA may later approve the drug for additional
indication(s) or uses(s) within the rare disease or condition not
protected by the exclusive approval. If the sponsor who obtains approval
for these new indication(s) or uses(s) has orphan-drug designation for
the drug for the rare disease or condition, FDA will recognize a new
orphan-drug exclusive approval for these new (not previously approved)
indication(s) or use(s) from the date of approval of the drug for such
new indication(s) or use(s).
(c) If a sponsor's marketing application for a drug product is
determined not to be approvable because approval is barred under section
527 of the Federal Food, Drug, and Cosmetic Act until the expiration of
the period of exclusive marketing of another drug, FDA will so notify
the sponsor in writing.
[57 FR 62085, Dec. 29, 1992, as amended at 78 FR 35134, June 12, 2013]
Sec. 316.34 FDA recognition of exclusive approval.
(a) FDA will send the sponsor (or, the permanent-resident agent, if
applicable) timely written notice recognizing exclusive approval once
the marketing application for a designated orphan-drug product has been
approved, if the same drug has not already been approved for the same
use or indication. The written notice will inform the sponsor of the
requirements for maintaining orphan-drug exclusive approval for the full
7-year term of exclusive approval.
(b) When a marketing application is approved under section 505 of
the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355) for a
designated orphan drug that qualifies for exclusive approval, FDA will
publish in its publication entitled ``Approved Drug Products With
Therapeutic Equivalence Evaluations'' information identifying the
sponsor, the drug, and the date of termination of the orphan-drug
exclusive approval. A subscription to this publication and its monthly
cumulative supplements is available from the Superintendent of
Documents, Government Printing Office, Washington, DC 20402-9325, and is
also available online at http://www.accessdata.fda.gov/scripts/cder/ob/
default.cfm.
(c) If a drug is otherwise the same drug as a previously approved
drug for the same use or indication, FDA will not recognize orphan-drug
exclusive approval if the sponsor fails to demonstrate upon approval
that the drug is clinically superior to the previously approved drug.
[78 FR 35135, June 12, 2013]
Sec. 316.36 Insufficient quantities of orphan drugs.
(a) Under section 527 of the act, whenever the Director has reason
to believe that the holder of exclusive approval cannot assure the
availability of sufficient quantities of an orphan drug to meet the
needs of patients with the disease or condition for which the drug was
designated, the Director will so notify the holder of this possible
insufficiency and will offer the holder one of the following options,
which must be exercised by a time that the Director specifies:
(1) Provide the Director in writing, or orally, or both, at the
Director's discretion, views and data as to how the holder can assure
the availability of sufficient quantities of the orphan drug within a
reasonable time to meet the needs of patients with the disease or
condition for which the drug was designated; or
(2) Provide the Director in writing the holder's consent for the
approval of other marketing applications for the same drug before the
expiration of the 7-year period of exclusive approval.
(b) If, within the time that the Director specifies, the holder
fails to consent to the approval of other marketing applications and if
the Director finds that the holder has not shown that it can assure the
availability of sufficient quantities of the orphan drug to meet the
needs of patients with the disease or condition for which the drug was
designated, the Director will issue a written order withdrawing the drug
product's exclusive approval. This order will embody the Director's
findings and conclusions and will constitute final agency action. An
order withdrawing the sponsor's exclusive marketing rights may issue
whether or not there are other sponsors that can
[[Page 206]]
assure the availability of alternative sources of supply. Once withdrawn
under this section, exclusive approval may not be reinstated for that
drug.
Subpart E_Open Protocols for Investigations
Sec. 316.40 Treatment use of a designated orphan drug.
Prospective investigators seeking to obtain treatment use of
designated orphan drugs may do so as provided in subpart I of this
chapter.
[74 FR 40945, Aug. 13, 2009]
Subpart F_Availability of Information
Sec. 316.50 Guidance documents.
FDA's Office of Orphan Products Development will maintain and make
publicly available a list of guidance documents that apply to the
regulations in this part. The list is maintained on the Internet and is
published annually in the Federal Register. A request for a copy of the
list should be directed to the Office of Orphan Products Development,
Food and Drug Administration, Bldg. 32, rm. 5271, 10903 New Hampshire
Ave., Silver Spring, MD 20993.
[78 FR 35135, June 12, 2013]
Sec. 316.52 Availability for public disclosure of data and information
in requests and applications.
(a) FDA will not publicly disclose the existence of a request for
orphan-drug designation under section 526 of the act prior to final FDA
action on the request unless the existence of the request has been
previously publicly disclosed or acknowledged.
(b) Whether or not the existence of a pending request for
designation has been publicly disclosed or acknowledged, no data or
information in the request are available for public disclosure prior to
final FDA action on the request.
(c) Upon final FDA action on a request for designation, FDA will
determine the public availability of data and information in the request
in accordance with part 20 and Sec. 314.430 of this chapter and other
applicable statutes and regulations.
(d) In accordance with Sec. 316.28, FDA will make a cumulative list
of all orphan drug designations available to the public and update such
list monthly.
(e) FDA will not publicly disclose the existence of a pending
marketing application for a designated orphan drug for the use for which
the drug was designated unless the existence of the application has been
previously publicly disclosed or acknowledged.
(f) FDA will determine the public availability of data and
information contained in pending and approved marketing applications for
a designated orphan drug for the use for which the drug was designated
in accordance with part 20 and Sec. 314.430 of this chapter and other
applicable statutes and regulations.
PART 317_QUALIFYING PATHOGENS--Table of Contents
Sec.
317.1 [Reserved]
317.2 List of qualifying pathogens that have the potential to pose a
serious threat to public health.
Authority: 21 U.S.C. 355f, 371.
Source: 79 FR 32480, June 5, 2014, unless otherwise noted.
Sec. 317.1 [Reserved]
Sec. 317.2 List of qualifying pathogens that have the potential to
pose a serious threat to public health.
The term ``qualifying pathogen'' in section 505E(f) of the Federal
Food, Drug, and Cosmetic Act is defined to mean any of the following:
(a) Acinetobacter species.
(b) Aspergillus species.
(c) Burkholderia cepacia complex.
(d) Campylobacter species.
(e) Candida species.
(f) Clostridium difficile.
(g) Coccidioides species.
(h) Cryptococcus species.
(i) Enterobacteriaceae.
(j) Enterococcus species.
(k) Helicobacter pylori.
(l) Mycobacterium tuberculosis complex.
(m) Neisseria gonorrhoeae.
(n) Neisseria meningitidis.
[[Page 207]]
(o) Non-tuberculous mycobacteria species.
(p) Pseudomonas species.
(q) Staphylococcus aureus.
(r) Streptococcus agalactiae.
(s) Streptococcus pneumoniae.
(t) Streptococcus pyogenes.
(u) Vibrio cholerae.
PART 320_BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS-
-Table of Contents
Subpart A_General Provisions
Sec.
320.1 Definitions.
Subpart B_Procedures for Determining the Bioavailability or
Bioequivalence of Drug Products
320.21 Requirements for submission of bioavailability and bioequivalence
data.
320.22 Criteria for waiver of evidence of in vivo bioavailability or
bioequivalence.
320.23 Basis for measuring in vivo bioavailability or demonstrating
bioequivalence.
320.24 Types of evidence to measure bioavailability or establish
bioequivalence.
320.25 Guidelines for the conduct of an in vivo bioavailability study.
320.26 Guidelines on the design of a single-dose in vivo bioavailability
or bioequivalence study.
320.27 Guidelines on the design of a multiple-dose in vivo
bioavailability study.
320.28 Correlation of bioavailability with an acute pharmacological
effect or clinical evidence.
320.29 Analytical methods for an in vivo bioavailability or
bioequivalence study.
320.30 Inquiries regarding bioavailability and bioequivalence
requirements and review of protocols by the Food and Drug
Administration.
320.31 Applicability of requirements regarding an ``Investigational New
Drug Application.''
320.32 Procedures for establishing or amending a bioequivalence
requirement.
320.33 Criteria and evidence to assess actual or potential
bioequivalence problems.
320.34 Requirements for batch testing and certification by the Food and
Drug Administration.
320.35 Requirements for in vitro testing of each batch.
320.36 Requirements for maintenance of records of bioequivalence
testing.
320.38 Retention of bioavailability samples.
320.63 Retention of bioequivalence samples.
Authority: 21 U.S.C. 321, 351, 352, 355, 371.
Subpart A_General Provisions
Sec. 320.1 Definitions.
The definitions contained in Sec. 314.3 of this chapter apply to
those terms when used in this part.
[81 FR 69658, Oct. 6, 2016]