[Federal Register Volume 67, Number 105 (Friday, May 31, 2002)]
[Rules and Regulations]
[Pages 37988-37998]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 02-13583]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 314 and 601
[Docket No. 98N-0237]
RIN 0910-AC05
New Drug and Biological Drug Products; Evidence Needed to
Demonstrate Effectiveness of New Drugs When Human Efficacy Studies Are
Not Ethical or Feasible
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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SUMMARY: The Food and Drug Administration (FDA) is amending its new
drug and biological product regulations to allow appropriate studies in
animals in certain cases to provide
[[Page 37989]]
substantial evidence of the effectiveness of new drug and biological
products used to reduce or prevent the toxicity of chemical,
biological, radiological, or nuclear substances. This rule will apply
when adequate and well-controlled clinical studies in humans cannot be
ethically conducted and field efficacy studies are not feasible. In
these situations, certain new drug and biological products that are
intended to reduce or prevent serious or life-threatening conditions
may be approved for marketing based on evidence of effectiveness
derived from appropriate studies in animals and any additional
supporting data.
DATES: This rule is effective July 1, 2002.
FOR FURTHER INFORMATION CONTACT:
Wayne H. Mitchell, Center for Drug Evaluation and Research (HFD-7),
Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857,
301-594-2041;
or Karen L. Goldenthal, Center for Biologics Evaluation and
Research (HFM-475), 1401 Rockville Pike, suite 370 North, Rockville, MD
20852, 301-827-3070.
SUPPLEMENTARY INFORMATION:
I. Introduction
In the Federal Register of October 5, 1999 (64 FR 53960), we (FDA)
proposed to amend our new drug and biological product regulations to
identify the information needed to provide substantial evidence of the
effectiveness of certain new drug and biological products used to
reduce or prevent the toxicity of chemical, biological, radiological,
or nuclear substances. We are finalizing that proposed rule by adding
subpart I to part 314 (21 CFR part 314) and subpart H to part 601 (21
CFR part 601).
This final rule provides for approval of certain new drug and
biological products based on animal data when adequate and well-
controlled efficacy studies in humans cannot be ethically conducted
because the studies would involve administering a potentially lethal or
permanently disabling toxic substance or organism to healthy human
volunteers and field trials are not feasible prior to approval. Under
this rule, in these situations, certain new drug and biological
products that are intended to reduce or prevent serious or life-
threatening conditions can be approved for marketing based on evidence
of effectiveness derived from appropriate studies in animals, without
adequate and well-controlled efficacy studies in humans (Sec. 314.126).
In assessing the sufficiency of animal data, the agency may take into
account other data, including human data, available to the agency.
Under this rule, FDA can rely on the evidence from animal studies to
provide substantial evidence of the effectiveness of these products
when:
1. There is a reasonably well-understood pathophysiological
mechanism for the toxicity of the chemical, biological, radiological,
or nuclear substance and its amelioration or prevention 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 (meaning the model has
been adequately evaluated for its responsiveness) for predicting the
response in humans;
3. The animal study endpoint is clearly related to the desired
benefit in humans, which is generally the enhancement of survival or
prevention of major morbidity; and
4. The data or information on the pharmacokinetics and
pharmacodynamics of the product or other relevant data or information
in animals and humans is sufficiently well understood to allow
selection of an effective dose in humans, and it is therefore
reasonable to expect the effectiveness of the product in animals to be
a reliable indicator of its effectiveness in humans.
All studies subject to this rule must be conducted in accordance
with preexisting requirements under the good laboratory practices (21
CFR part 58) regulations and the Animal Welfare Act (7 U.S.C. 2131 et.
seq.).
Safety evaluation of products is not addressed in this rule.
Products evaluated for effectiveness under subpart I of part 314 and
subpart H of part 601 will be evaluated for safety under preexisting
requirements for establishing the safety of new drug and biological
products. The agency believes that the safety of most of these products
can be studied in human volunteers similar to the people who would be
exposed to the product. FDA recognizes that some safety data, such as
data on possible adverse interactions between the toxic substance
itself and the new product, may not be available. This is not expected
to keep the agency from making an adequate safety evaluation. FDA's
procedures and standards for evaluating the safety of new drug and
biological products are sufficiently flexible to provide for the safety
evaluation of products evaluated for efficacy under subpart I of part
314 and subpart H of part 601.
This rule will not apply if product approval can be based on
standards described elsewhere in our regulations (for example,
accelerated approval based on human surrogate markers or clinical
endpoints other than survival or irreversible morbidity).\1\
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\1\ An example of a drug approval based on human surrogate
markers is our August 30, 2000, approval of an efficacy supplement
for ciprofloxacin. Ciprofloxacin HCl was approved for postexposure
management of inhalational anthrax. The approval was based, in part,
on human studies demonstrating that ciprofloxacin achieved serum
concentrations reaching or exceeding levels associated with improved
survival of animals exposed to aerosolized Bacillus anthracis
spores. The results from these studies were combined with the
knowledge of effectiveness in humans of ciprofloxacin for other
bacterial infections, including pneumonia. The validity of the human
surrogate marker was supported by animal studies.
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II. Comments on the Proposed Rule and Our Response
We received comments on the proposed rule from two pharmaceutical
companies and one physician affiliated with a university. We also
received comments from the National Institutes of Health (NIH). The NIH
comments were based on a prepublication draft of the proposed rule, but
the comments were received too late to be addressed in the proposed
rule. The NIH comments have been placed in the docket for this rule and
are addressed in this document.
In addition to the changes we have made in response to comments, we
have changed the titles of subpart I of part 314 and subpart H
(formerly subpart G) of part 601 to better describe the scope of the
subparts. Subpart I of part 314 is now entitled ``Approval of New Drugs
When Human Efficacy Studies Are Not Ethical or Feasible'' and subpart H
of part 601 is now entitled ``Approval of Biological Products When
Human Efficacy Studies Are Not Ethical or Feasible.'' Proposed subpart
G has been redesignated as subpart H in the final rule because subpart
G has since been designated for regulations on postmarketing studies.
Proposed Secs. 601.60 through 601.65 have been renumbered Secs.
601.90 through 601.95 in subpart H.
We have also changed, on our own initiative, the requirements
proposed in Secs. 314.610(c) and 601.61(c) (Secs. 314.610(b)(3) and
601.91(b)(3) in this final rule). We have deleted the requirement that
self-administered drug products approved under this rule be in unit-of-
use packaging with attached patient labeling. In addition, we have
eliminated the distinction between self-
[[Page 37990]]
administered products and products administered by health
professionals.
Whether a product is self-administered or administered by a health
professional, it is important to inform patient recipients that a
product approved under this rule has not been studied for efficacy in
humans because of ethical or feasibility reasons.\2\ It is also
important that patient recipients receive information about
indications, dosage and administration, contraindications, reasonably
foreseeable risks, adverse reactions, anticipated benefits, and drug
interactions. This rule requires that all of this information be
provided to patient recipients of products approved under subpart I of
part 314 and subpart H of part 601.
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\2\ In some cases, however, such as with anti-infective drug
products, it would usually be expected that human data on safety and
effectiveness for other indications may be available.
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We believe, however, that the proposed unit-of-use packaging and
attached patient-labeling requirement could have had the unintended
effect of hampering the distribution and dispensing of these products
in the event of an emergency. The added bulk of unit-of-use packaging
could have made stockpiling and transporting more difficult in many
cases. The proposed requirement might also have hampered the speedy
distribution of products for additional indications previously approved
outside of this rule.
Applicants may meet the requirements of new Secs. 314.610(b)(3)
and 601.91(b)(3) in a variety of ways, as long as sponsors make
provisions to get the information to patients. For example, the sponsor
could provide reproducible master copies of labeling information or
presentations for patient recipients that would be appropriate in the
event of an emergency.
We have also changed proposed Secs. 314.610(c) and 601.61(c) (Secs.
314.610(b) and 601.91(b) in this final rule) to require that the
patient labeling explain that, for ethical or feasibility reasons, the
product's approval was based on efficacy studies conducted only in
animals. This explanation will better inform patient recipients about
the nature and ethical basis of the product approval under this rule
and how that approval differs from approval of products based on
standard human efficacy studies.
Finally, we have added to Secs. 314.610(b)(1) and 601.91(b)(1)
(proposed Secs. 314.610(a) and 601.61(a)) a requirement that
applicants include a plan or approach to fulfilling postmarketing study
commitments as part of their application. We recognize that such
studies normally will not be conducted unless an emergency arises that
requires the product's use. Furthermore, when the product is used in an
emergency, it may not be feasible for sponsors to conduct postmarketing
studies in a timely manner, nor is it our intention to require sponsors
to send investigators into areas of exposure. We do, however, believe
that applicants can plan a postmarketing study approach, in
consultation with the agency, as part of an overall response to an
event.
The requirement to submit a plan for postmarketing studies is
consistent with the requirements for sponsors under the accelerated
approval process provided for in subpart H of part 314.
The procedures in subpart H and in this rule are similar because,
to assess efficacy, both allow use of an endpoint that is not a
clinical endpoint showing a benefit. Instead the rules under subpart H
allow for reliance on a clinical surrogate endpoint and this rule
allows for the use of animal data as an endpoint.
Postmarketing studies are critical in both of these situations to
verify and describe the clinical benefit of the drug or biological
product. The postmarketing studies may provide us with data that
directly verify that the product provides the desired benefit in
humans, such as increased survival or prevention of major morbidity.
(Comment 1) One comment suggested that we define ``lethal'' and
``permanently disabling.'' The comment expressed concern that without
such definitions, subpart I of part 314 and subpart H of part 601 will
be misapplied in situations where clinical testing can and should be
carried out.
The definitions of ``lethal'' and ``permanently disabling'' would
seem to be well understood. Although we share the concern that too
expansive an interpretation of ``lethal'' or ``permanently disabling''
could lead to attempts to apply this rule when human studies are, in
fact, feasible, we are also concerned that too restrictive a definition
of ``lethal'' or ``permanently disabling'' could lead to failure to
apply subpart I of part 314 and subpart H of part 601 in situations
where they should be applied to protect the public health. We believe
that, as a general matter, we must rely on the good sense and
responsibility of those health professionals who will be seeking to
apply subpart I of part 314 and subpart H of part 601 in the future,
and on responsible review of specific cases by FDA. Nevertheless, we
can provide guidance for applying subpart I of part 314 and subpart H
of part 601 by clarifying that a ``lethal substance'' is one that is
likely to kill at least some of the humans who have been exposed to the
substance and a ``permanently disabling substance'' is one that is
likely to cause a permanent physical or mental impairment that
substantially limits one or more of the major life activities in at
least some of the humans who have been exposed to the substance.
(Comment 2) One comment stated that the rule does not explicitly
cover infectious substances and pointed out that not all infectious
substances produce toxins. The comment suggested replacing ``toxic''
with ``toxic and/or infectious'' in proposed Secs. 314.600 and 601.60
(Sec. 601.90 in this final rule).
The rule is certainly intended to cover products for treatment of
infections. At some level, an infectious agent that is lethal or
permanently disabling is toxic to its host, even if that agent is not
itself a ``toxin'' or a producer of ``toxins'' within a strict
definition of the word. Because we do not use ``toxin'' in the rule,
and ``toxic'' is accurate, we do not believe we need to replace
``toxic'' with ``toxic and/or infectious'' to indicate that products
for the treatment of infections may be approved under this rule.
(Comment 3) One comment noted that the proposed rule did not
discuss criteria that should be applied in determining if ``an
important medical need is not adequately met by currently available
therapies.'' The comment suggested that we state that we will use the
criteria given in our guidance for industry entitled ``Fast Track Drug
Development Programs--Designation, Development, and Application
Review'' (September 1998).
We have decided to eliminate the requirement that ``products would
be expected to provide meaningful therapeutic benefits to patients over
existing treatments,'' as well as the limitation that the toxic agent
be ``without a proven treatment'' (proposed Secs. 314.600 and 601.60).
Recent events involving the multiple exposures to anthrax in our
population, and deaths resulting from those infections, have indicated
a need for a wide range of therapeutic options that, in some instances,
might be inappropriately limited by requiring new products to have a
therapeutic benefit over existing treatments, or to be used only in the
absence of a proven treatment. Availability of a variety of drug and
biological products is important because, for example, patient
recipients may be allergic to one product and require another, may be
intolerant of a product because of side effects, or may respond more
favorably to one product
[[Page 37991]]
than another. We also believe that a wider variety of therapeutic
choices will limit potential problems with availability, accessibility,
and distribution of products. We have modified the final rule to
address these concerns and help ensure the availability of more than
one therapeutic option.
(Comment 4) One comment requested that antivenin and antitoxin
products of animal origin be considered for inclusion specifically on
the list of new drugs and biological products to which the rule
applies.
There is no list of products that may be approved based on evidence
of effectiveness from efficacy studies in animals. The rule provides
criteria to determine if evidence of effectiveness from efficacy
studies in animals may support approval of a product. If an antivenin
or antitoxin product of animal origin meets the criteria specified in
the rule, it may be approved on the basis of evidence of effectiveness
from efficacy studies in animals.
(Comment 5) One comment requested that we revise proposed
Secs. 314.610 and 601.61 (Sec. 601.91 in this final rule) to state that
substantiation in multiple animal species is required only where
appropriate. The comment stated we should not limit ourselves to
approvals only when there is substantiation in ``multiple'' animal
species. The comment contended that where independent studies in a
single species meet the general principles of independent
substantiation as described in the guidance for industry entitled
``Providing Clinical Evidence of Effectiveness for Human Drugs and
Biological Products'' (May 1998), those studies are sufficient to
substantiate effectiveness as a matter of science and a requirement of
substantiation in multiple species would result in an unnecessary delay
of agency approval. According to the comment, these concerns are
particularly important where viruses have a narrow host range and
conducting efficacy trials in more than one animal species in such
cases either is not feasible or provides only limited additional
information that is relevant to the full-blown disease in humans. The
comment suggested that the requirement of substantiation in multiple
species in a given case should depend on the known host range and the
availability of animal model systems.
We share some of the concerns expressed in the comment, but we
believe the proposed remedy goes too far. Approval of the use of a drug
lacking human evidence of effectiveness represents a significant
departure from ordinary practice. There are countless examples of
treatments with favorable effects in animals that did not prove
effective in humans. Although this rule does, for good reason, allow
reliance on animal studies when human studies cannot be conducted, in
general we expect that the evidence, to be persuasive, should be
developed in more than one animal species unless the effect is
demonstrated in a single animal species that represents a sufficiently
well-characterized animal model for predicting the response in humans.
We recognize that conducting studies in more than one species can
result in added expense, but we believe this is warranted because of
the additional assurance they would provide.
Furthermore, reliance on our guidance entitled ``Providing Clinical
Evidence of Effectiveness for Human Drugs and Biological Products'' is
misplaced. That guidance was drafted to provide advice on the quantity
of data from clinical studies needed to support a finding of
effectiveness and, specifically, on when the agency ought to rely on a
single human study. The guidance addressed cases in which the issue is
the credibility of the data itself, not the relevance of the data to
humans. In this rule, the issue is the ability of results from animal
studies to predict the human response, and not the credibility of the
animal finding itself (although, of course, the animal studies should
be replicated or substantiated in each species as needed to ensure
credible results). The need for multiple species in certain cases is to
enhance the likelihood that the data are pertinent to humans.
We do recognize, however, that the multiple species requirement
could be inappropriate or unnecessary in certain situations. For
example, there may be only one species capable of reacting with a
response predictive for humans. This would occur where there is only
one nonhuman host for the targeted microorganism. There may also be
other situations in which studies in a particular species are
specifically well recognized as predictors of effectiveness in humans.
Thus, circumstances in which the agency will rely on evidence from
studies in one animal species to provide substantial evidence of the
effectiveness of these products in humans would generally be limited to
situations where the study model is sufficiently well-recognized so as
to render studies in multiple species unnecessary. In addition, other
human data for the product could provide support for such approvals.
Accordingly, we have changed proposed Secs. 314.610 and 601.61
(Sec. 601.91(c) in this final rule) to require that approval be based
on studies in more than one animal species unless the effect is
demonstrated in a single animal species that represents a sufficiently
well-characterized animal model for predicting the response in humans.
The agency believes that demonstrating effectiveness in studies
conducted in a single animal species using a well-characterized animal
model will most often be done for anti-infective drug products. The
pathophysiological mechanisms of infectious diseases are usually very
well understood, and animal models for many infectious diseases have
been studied for years and are very well characterized.
(Comment 6) One comment suggested we remove the requirement that
there be a reasonably well-understood pathophysiological mechanism of
the toxicity of the substance and its prevention or substantial
reduction by the product. The comment stated it is hard to say when we
understand something reasonably well and that, if we decide to retain
the requirement, we should state at what level (e.g., cellular,
molecular) the mechanism must be understood.
A disease's or toxin's mechanism of action does not need to be
understood before a safe and effective treatment or preventative can be
devised. Quinine and Jenner's smallpox vaccine were both developed
before the acceptance of the germ theory of disease. Neither is there a
general requirement that an applicant who is relying on human testing
to establish effectiveness demonstrate the mechanism of action of the
drug or biological product that is the subject of the marketing
application. It is generally sufficient to demonstrate that a product
is safe and effective. It is generally not required that an applicant
demonstrate how or why the product is safe and effective.
It is true that a pathophysiologic understanding of a disease and
treatment is not required when human studies are used to support
approval. In the case of human drug or biological products approved on
the basis of evidence of effectiveness from studies in animals,
however, we are requiring an understanding of the mechanism of the
toxic substance or infectious organism and its prevention or reduction
by the product. This understanding helps provide assurance that the
efficacy data from studies in animals can be applied to humans. We have
not specified exactly what degree of pathophysiologic understanding is
needed, and that will be a matter of judgment. The level of
understanding could range from a complete understanding of how a toxic
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substance works at the cellular level in both human and animal cells
together with a clear understanding of what the antidote does at the
molecular level to a less complete understanding. The level of required
understanding of the mechanism of action of the toxic substance or
infectious organism and the product may vary from toxic substance to
toxic substance or infectious organism to infectious organism and could
even vary from one product to another intended to treat the same
condition.
(Comment 7) One comment suggested that an institutional review
board (IRB) or other ethical scientific review body determine if it
would be unethical to conduct studies in humans. The comment also said
we do not mention who would make the determination that it would be
unethical to conduct studies in humans.
The final determination that it is unethical to conduct studies in
humans will be made by the reviewing officials in FDA. We anticipate
that in most cases the determination as to whether it would be
unethical to conduct studies in humans will not be difficult. In those
cases that are difficult, the views of one or more IRBs, individual
ethicists and clinicians, and FDA advisory committees could be sought
by a sponsor or FDA. A case where such a consultation could be useful
is one in which a putatively subtoxic dose would be used in humans to
establish at least a mechanism for protection, if not actual
protection.
(Comment 8) One comment noted that we said in the proposed rule:
The agency also intends in most cases to consult on applications
to market such products with an advisory committee, supplemented
with appropriate expert consultants, in meetings open to the public
in order to receive expert advice on whether a particular set of
animal data support efficacy of a product under this rule (64 FR
53960 at 53964 and 53965).
The comment asked us to consider requiring consultation with an
advisory committee either before conducting the animal studies or
before approval of the product, or both.
We want to reiterate our statement in the proposed rule that we
intend usually to consult with an advisory committee during the
approval process. Indeed, we may consult with an advisory committee
more than once on a single product if circumstances warrant it.
Consultation with an advisory committee could occur early in the
development process, to discuss whether the concept of using certain
animal data to support efficacy is reasonable.
Even though consultation with an advisory committee is generally
desirable, it is not always practical. For example, products reviewed
under this rule may be part of the response to a public health
emergency; therefore, there may not be time to convene an advisory
committee. Accordingly, we believe that it would be inappropriate to
absolutely require consultation with an advisory committee.
(Comment 9) One comment questioned whether patient labeling is
adequate to inform patients that a product has been approved on the
basis of animal efficacy data, particularly in situations where
military personnel are ordered to take a product approved under this
rule. The comment did not suggest an alternative to the provisions of
the rule.
Sections 314.610(b)(3) and 609.91(b)(3) provide that for products
or specific indications approved under this rule, applicants must
prepare, as part of their proposed labeling, labeling to be provided to
patients or potential patients. The patient labeling, written in
language that can be easily understood by the general public, must
explain that, for ethical or feasibility reasons, the product's
approval was based on efficacy studies conducted in animals alone. The
labeling must give the product'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. If possible, the patient labeling must be
available with the product to be provided to patients or potential
patients prior to administration or dispensing of the product for the
use approved under this rule. We intend that in interpreting
Sec. Sec. 314.610(b)(3) and 601.91(b)(3), the word ``possible'' be
given its ordinary and literal meaning. Situations in which it would be
inconvenient or require some effort to make the labeling available for
patients should not be equated with situations in which it would be
impossible to do so.
These provisions, coupled with communications within a health care
provider-patient relationship should, as a general matter in both
civilian and military contexts, adequately ensure that patients are
informed that the product they are taking has been approved based on
animal efficacy data.
(Comment 10) One comment suggested that labeling a drug or
biological product approved on the basis of evidence of effectiveness
from studies in animals as ``FDA approved'' is misleading, because
patients would assume that the product had been approved based on human
studies. The comment suggested that we treat the product as an
investigational new drug, but waive certain requirements generally
applied to investigational new drugs, if those requirements would
provide obstacles to the product's use in an emergency.
We agree that the labeling would be misleading if information were
not included to explain to patients or potential patients that the
effectiveness of the product was demonstrated in animals not humans,
and that this reliance on animal efficacy data was based on ethical and
feasibility concerns. Therefore, under sections 502(a) and 701(a) of
the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 352(a)
and 372(a)) (and consistent with the legal authority cited in the
preamble to the proposed rule (64 FR 53960 at 53964)), we have revised
the language in Secs. 314.610(b)(3) and 601.91(b)(3) to require that
this information be included in the patient labeling.
Where the evidence of effectiveness comes from studies in animals,
regulating new drug or biological products as investigational drugs
presents several difficulties. These difficulties have led us to this
rulemaking. The proposed rule describes our concerns with relying
solely on the investigational new drug regulations (64 FR 53960 at
53963) for such approvals. There may be cases, however, when an
application does not meet the criteria of this rule, and approval of
the product is not feasible. Should an emergency situation arise under
such circumstances, it is conceivable that the product could be used
under the investigational new drug regulations.
(Comment 11) Another comment suggested that, unless ``lay persons''
may use the product, we prohibit advertising of drug or biological
products approved on the basis of evidence of effectiveness from
studies in animals. The comment further recommended stringent controls
on the advertising of products that could be used by ``lay persons.''
Such a sweeping prohibition would likely give rise to
constitutional issues regarding the regulation of commercial speech. In
addition, the suggestion presents serious public health concerns. A
prohibition on advertising could limit health care providers' and
public health and emergency preparedness officials' awareness of the
products approved under this rule. Limiting awareness of these
products, which are intended to
[[Page 37993]]
reduce or prevent life-threatening or disabling toxicity, does not seem
desirable or appropriate.
We believe that the advertising provisions in Secs. 314.640 and
601.94 of this rule provide adequate protection against false or
misleading advertising, and no additional requirements are needed. As
discussed in the preamble to the proposed rule (64 FR 53960 at 53964),
we proposed the requirements pertaining to promotional materials in
order to provide for the safe and effective use of these products.
These requirements, along with others, are similar to those in the
accelerated approval regulations in subpart H of part 314 and in
subpart E of part 601. In issuing the accelerated approval regulations,
we stated that the special circumstances under which those products
would be approved and the possibility that promotional materials could
adversely affect the sensitive risk/benefit balance justified review of
promotional materials before and after approval (57 FR 58942 at 58949).
Similarly, the special circumstances of all product approvals under
subpart I of part 314 and subpart H of part 601 and the possibility
that promotional materials could adversely affect the even more
sensitive risk/benefit balance justifies advance review of promotional
materials.
We intend to review all such promotional materials under these new
regulations promptly, and to notify the applicant of any identified
problems as soon as possible (see also 57 FR 58942 at 58950). Also as
with the accelerated approval regulations' requirements for promotional
materials (Secs. 314.560 and 601.46), FDA may terminate the
requirements for advance submission of promotional materials under
these new regulations at Secs. 314.650 and 601.95 if the agency
determines, on its own initiative or in response to a petition
submitted by the sponsor, that the requirements are no longer necessary
for safe and effective use of the product. When we remove the
requirement for advance submission of promotional materials, we will
continue to offer a prompt review of all voluntarily submitted
promotional materials.
(Comment 12) We received some comments addressing questions posed
in section VII, ``Discussion,'' of the proposed rule. In this final
rule, we have addressed comments that dealt with the rule itself.
Comments that dealt with questions related to the application of this
rule, rather than the requirements, will be addressed if and when we
draft a guidance on this subject.
III. Legal Authority
We did not receive any comments discussing our legal authority to
approve new drugs and biological products based on evidence of
effectiveness from studies in animals. We have concluded, for the
reasons set out in section V of the proposed rule, ``Legal Authority,''
(64 FR 53960 at 53964), that we have the legal authority to approve new
drugs and biological products based on evidence of effectiveness from
studies in animals.
(Comment 13) We received a comment asserting that under the court's
holding in American Pharmaceutical Association v. Weinberger, 377
F.Supp. 824 (D.C.D.C. 1974) aff'd sub nom. American Pharmaceutical
Association v. Mathews, 530 F.2d 1054 (D.C. Cir. 1976) (per curiam), we
do not have the legal authority to impose the distribution controls
proposed in Secs. 314.610(b) and 601.61(b) (Secs. 314.610(b)(2) and
601.91(b)(2) in this final rule). The comment asked that, if we
disagree with their characterization of the law, distribution controls
not be applied just because a product was approved under the provisions
of this rule. The comment also asked that we give examples of
situations where we would impose distribution restrictions.
For a full discussion of FDA's authority to impose distribution
restrictions to ensure the safe use of drug products, see the agency's
proposed and final rules amending part 314 by adding subpart H on
accelerated approval of new drugs for serious or life-threatening
illnesses (proposed rule at 57 FR 13234, April 15, 1992; final rule at
57 FR 59842, December 11, 1992). Those rules relied on sections 501,
502, 503, 505, and 701 of the act (21 U.S.C. 351, 352, 353, 355, and
372) as authority for FDA to issue regulations to help ensure the
safety and effectiveness of new drugs.
We agree with the comment that distribution controls should not be
placed on a product solely because it is approved under the provisions
of this rule. New Secs. 314.610(b)(2) and 601.91(b)(2) authorize
distribution controls--they do not require them.
We do not believe it would be useful to give examples of situations
where distribution controls may be necessary to ensure safe use of the
product. Products approved under this rule could be indicated for
widely differing conditions, and those products could be used in unique
circumstances presenting many distinct safety concerns. It would not be
practical to try to devise a list of representative examples of
situations where distribution controls would be appropriate.
IV. Environmental Impact
The agency has determined under 21 CFR 25.30(h) that this action is
of a type that does not individually or cumulatively have a significant
effect on the human environment. Therefore, neither an environmental
assessment nor an environmental impact statement is required.
V. Federalism
FDA has analyzed this final rule in accordance with the principles
set forth in Executive Order 13132. FDA has determined that the rule
does not contain policies that have substantial direct effects on the
States, on the relationship between the National Government and the
States, or on the distribution of power and responsibilities among the
various levels of government. Accordingly, the agency has concluded
that the rule does not contain policies that have federalism
implications as defined in the Executive order and, consequently, a
federalism summary impact statement is not required.
VI. Analysis of Impacts
FDA has examined the impacts of the final rule under Executive
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612) (as
amended by subtitle D of the Small Business Regulatory Fairness Act of
1996 (Public Law 104-121)) and the Unfunded Mandates Reform Act of 1995
(Public Law 104-4). Executive Order 12866 directs agencies to assess
all costs and benefits of available regulatory alternatives and, when
regulation is necessary, to select regulatory approaches that maximize
net benefits (including potential economic, environmental, public
health and safety, and other advantages; distributive impacts; and
equity). Unless the agency certifies that the rule is not expected to
have a significant economic impact on a substantial number of small
entities, the Regulatory Flexibility Act requires agencies to analyze
regulatory options that would minimize any significant economic impact
of a rule on small entities. Section 202 of the Unfunded Mandates
Reform Act (Public Law 104-4) requires that agencies prepare an
assessment of anticipated costs and benefits before proposing any rule
that may result in expenditure by State, local, and tribal governments,
in the aggregate, or by the private sector, of $100 million in any one
year (adjusted annually for inflation).
[[Page 37994]]
The agency has determined that the rule is consistent with the
principles set forth in the Executive order and in these statutes. FDA
finds that this rule will not have an effect on the economy that
exceeds $100 million in any one year (adjusted for inflation). The
current inflation-adjusted statutory threshold is about $110 million.
Therefore, no further analysis is required under the Unfunded Mandates
Reform Act. Because this rule does not impose any new costs on small
entities, FDA certifies that this rule will not result in a significant
economic impact on a substantial number of small entities. Thus, the
agency need not prepare a Regulatory Flexibility Analysis. The agency
reached the same conclusions in its proposed rule. FDA has not received
any new information or comments that would alter its previous
determinations.
VII. The Paperwork Reduction Act of 1995
This final rule contains information collection provisions that are
subject to review by the Office of Management and Budget (OMB) under
the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520). The title,
description, and respondent description of the information collection
provisions are shown below with an estimate of the annual reporting and
recordkeeping burden. Included in the estimate is the time for
reviewing instructions, searching existing data sources, gathering and
maintaining the data needed, and completing and reviewing each
collection of information.
Title: New Drug and Biological Products; Animal Efficacy Studies.
Description: FDA is amending its new drug and biological product
regulations to allow appropriate studies in animals in certain cases to
provide substantial evidence of effectiveness of new drug and
biological products used to reduce or prevent the toxicity of chemical,
biological, radiological, or nuclear substances when adequate and well-
controlled efficacy studies in humans cannot be ethically conducted
because the studies would involve administering a potentially lethal or
permanently disabling toxic substance or organism to healthy human
volunteers and field trials are not feasible prior to approval. In
these circumstances, when it may be impossible to demonstrate
effectiveness through adequate and well-controlled studies in humans,
FDA is providing that certain new drug and biological products intended
to treat or prevent serious or life-threatening conditions could be
approved for marketing based on studies in animals, without the
traditional efficacy studies in humans. FDA is taking this action
because it recognizes the importance of improving medical response
capabilities to the use of lethal or permanently disabling chemical,
biological, radiological, and nuclear substances in order to protect
individuals exposed to these substances.
Respondent Description: Businesses and other for-profit
organizations, and nonprofit institutions.
Table 1.--Estimated Annual Reporting Burden\1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
Annual Frequency Total Annual
21 CFR Section No. of Respondents per Response Responses Hours per Response Total Hours
--------------------------------------------------------------------------------------------------------------------------------------------------------
314.610(b)(2) and 314.630 601.91(b)(2) and 601.93 1 1 1 5 5
314.610(b) and 314.640 601.91(b) and 601.94 1 1 1 240 240
-------------------
Total 245
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.
Table 2.--Estimated Annual Disclosure/Recordkeeping Burden\1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
No. of Annual Frequency Total Annual Hours per
21 CFR Section Recordkeepers per Recordkeeping Records Recordkeeper Total Hours
--------------------------------------------------------------------------------------------------------------------------------------------------------
314.610(b)(2) and 314.630 601.91(b)(2) and 601.93 1 1 1 1 1
314.610(b) 601.91(b) 1 1 1 1 1
-------------------
Total 2
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\There are no capital costs or operating and maintenance costs with this collection of information.
FDA estimates that only one application of this nature may be
submitted every 3 years; however, for calculation purposes, FDA is
estimating the submission of one application annually. FDA estimates
240 hours for a manufacturer of a new drug or biological product to
develop patient labeling and to submit the appropriate information and
promotional labeling to FDA. At this time, FDA cannot estimate the
number of postmarketing reports for adverse drug or biological
experiences associated with a newly approved drug or biological
product. Therefore, FDA is using one report for purposes of this
information collection. These reports are required under parts 310 and
600 (21 CFR parts 310 and 600), and 314. Any burdens associated with
these requirements will be reported under the adverse experience
reporting (AER) information collection requirements. The estimated
hours for postmarketing reports range from 1 to 5 hours based on
previous estimates for AER; however FDA is estimating 5 hours for the
purpose of this information collection.
The majority of the burden for developing the patient labeling is
included under the reporting requirements; therefore, minimal burden is
calculated for providing the guide to patients. As discussed
previously, no burden can be calculated at this time for the number of
AER reports that may be submitted after approval of a new drug or
biologic. Therefore, the number of records that may be maintained also
cannot be determined. Any burdens associated with these requirements
will be reported under the AER information collection requirements. The
estimated recordkeeping burden of 1 hour is based on previous estimates
for the recordkeeping requirements associated with the AER system.
[[Page 37995]]
The information collection provisions in this final rule have been
approved under OMB control number 0910-0423. This approval expires
December 31, 2002. An agency may not conduct or sponsor, and a person
is not required to respond to, a collection of information unless it
displays a currently valid OMB control number.
List of Subjects
21 CFR Part 314
Administrative practice and procedure, Confidential business
information, Drugs, Reporting and recordkeeping requirements.
21 CFR Part 601
Administrative practice and procedure, Biologics, Confidential
business information.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, 21 CFR parts
314 and 601 are amended as follows:
PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG
1. The authority citation for 21 CFR part 314 continues to read as
follows:
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 355a, 356,
356a, 356b, 356c, 371, 374, 379e.
2. Subpart I, consisting of Secs. 314.600 through 314.650, is added
to read as follows:
Subpart I--Approval of New Drugs When Human Efficacy Studies Are
Not Ethical or Feasible
Sec.
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.
Subpart I--Approval of New Drugs When Human Efficacy Studies Are
Not Ethical or Feasible
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.
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;
(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
[[Page 37996]]
(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 Secs. 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 Secs. 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 Secs. 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 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 601--LICENSING
3. The authority citation for 21 CFR part 601 continues to read as
follows:
Authority: 15 U.S.C. 1451-1561; 21 U.S.C. 321, 351, 352, 353,
355, 356b, 360, 360c-360f, 360h-360j, 371, 374, 379e, 381; 42 U.S.C.
216, 241, 262, 263, 264; sec. 122, Pub. L. 105-115, 111 Stat. 2322
(21 U.S.C. 355 note).
4. Subpart H, consisting of Secs. 601.90 through 601.95, is added
to read as follows:
Subpart H--Approval of Biological Products When Human Efficacy
Studies Are Not Ethical or Feasible
Sec.
601.90 Scope.
601.91 Approval based on evidence of effectiveness from studies in
animals.
601.92 Withdrawal procedures.
601.93 Postmarketing safety reporting.
601.94 Promotional materials.
601.95 Termination of requirements.
Subpart H--Approval of Biological Products When Human Efficacy
Studies Are Not Ethical or Feasible
Sec. 601.90 Scope.
This subpart applies to certain biological 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 biological
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 efficacy 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.
Sec. 601.91 Approval based on evidence of effectiveness from studies
in animals.
(a) FDA may grant marketing approval for a biological product for
which safety has been established and for which the requirements of
Sec. 601.90 are met based on adequate and well-controlled animal
studies when the results of those animal studies establish that the
biological 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
[[Page 37997]]
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 biological
product'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 biological 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 biological product, commensurate with the specific safety
concerns presented by the biological 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
biological 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 biological
product's approval was based on efficacy studies conducted in animals
alone and must give the biological product'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 biological product for the use
approved under this subpart, if possible.
Sec. 601.92 Withdrawal procedures.
(a) Reasons to withdraw approval. For biological products 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;
(3) Use after marketing demonstrates that postmarketing
restrictions are inadequate to ensure safe use of the biological
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 biological 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 Biologics Evaluation and Research (CBER) will give the applicant
notice of an opportunity for a hearing on CBER'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 Secs. 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 CBER 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. 601.93 Postmarketing safety reporting.
Biological products approved under this subpart are subject to the
postmarketing recordkeeping and safety reporting applicable to all
approved biological products.
Sec. 601.94 Promotional materials.
For biological 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.
[[Page 37998]]
601.95 Termination of requirements.
If FDA determines after approval under this subpart that the
requirements established in Secs. 601.91(b)(2), 601.92, and 601.93 are
no longer necessary for the safe and effective use of a biological
product, FDA will so notify the applicant. Ordinarily, for biological
products approved under Sec. 601.91, these requirements will no longer
apply when FDA determines that the postmarketing study verifies and
describes the biological product's clinical benefit. For biological
products approved under Sec. 601.91, the restrictions would no longer
apply when FDA determines that safe use of the biological 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.
Dated: May 23, 2002.
Lester M. Crawford,
Deputy Commissioner.
[FR Doc. 02-13583 Filed 5-30-02; 8:45 am]
BILLING CODE 4160-01-S