[Federal Register Volume 63, Number 216 (Monday, November 9, 1998)]
[Notices]
[Pages 60353-60356]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-29748]
[[Page 60353]]
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 97N-0447]
Protection of Human Subjects: Categories of Research That May Be
Reviewed by the Institutional Review Board (IRB) Through an Expedited
Review Procedure
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
-----------------------------------------------------------------------
SUMMARY: On November 10, 1997, the Food and Drug Administration (FDA),
in consultation with the Office for Protection from Research Risks
(OPRR) at the National Institutes of Health, requested written comments
relating to the proposed republication of the list that identifies
certain research activities involving human subjects that may be
reviewed by the Institutional Review Board (IRB) through the expedited
review procedure authorized in 21 CFR 56.110. The comment period closed
on March 10, 1998. FDA and OPRR received a combined total of 108
comments. After a review of the comments, FDA and OPRR are now
simultaneously publishing identical revised lists of categories of
research activities that may be reviewed by the IRB through the
expedited review procedure.
EFFECTIVE DATE: The revised list is effective November 9, 1998.
FOR FURTHER INFORMATION CONTACT: Paul W. Goebel, Jr., Office of Health
Affairs (HFY-20), Food and Drug Administration, 5600 Fishers Lane,
Rockville, MD 20857, 301-827-1685.
SUPPLEMENTARY INFORMATION: The FDA regulations for protection of human
subjects can be found under part 50 (21 CFR part 50), and the
regulations for the IRB's can be found under part 56 (21 CFR part 56).
The regulations require, with limited exceptions, obtaining and
documenting legally effective informed consent for all human subjects
of research on FDA regulated products and review of research involving
human subjects by an IRB.
Section 56.110 provides for expedited IRB review procedures for
certain categories of research involving no more than minimal risk, and
for minor changes in previously approved research during the period for
which approval is authorized. The list that is referenced in
Sec. 56.110(a) was originally published in the Federal Register of
January 27, 1981 (46 FR 8980), as a notice of a list of research
activities that could be reviewed by the IRB through the expedited
review procedures set forth in the FDA's regulations. OPRR has a
separate codification that references the Expedited Review List for
matters under the Department of Health and Human Services' (HHS)
jurisdiction (45 CFR part 46). The HHS list was published in the
Federal Register on January 26, 1981 (46 FR 8392). The FDA and HHS
lists published in 1981 differ slightly, in that item nine on the HHS
list, concerning research on individual or group behavior, pertains
only to 45 CFR 46.110. Because behavioral research is not specifically
regulated by FDA, that category was not included in the list published
by FDA.
The comments received in response to the November 10, 1997 (62 FR
60607), proposal by FDA and OPRR to revise the 1981 expedited review
list overwhelmingly supported the proposed revision of the list. Three
comments indicated that there should be no expedited review available
at all. These comments misunderstood the purpose of expedited review,
expressing concern that allowing expedited IRB review also removes the
requirement for informed consent of study subjects. FDA and OPRR
disagree with these three comments and believe that expedited review is
an appropriate part of the IRB review process. In addition, deleting
the expedited review process would require a regulatory change to
section 110 of the Federal Policy, which is beyond the scope of this
revision. However, in response to these comments paragraph (E) has been
added to the Applicability section I of this document to make it clear
that the standard requirements for informed consent must be met
regardless of the type of review--expedited or convened--utilized by
the IRB.
The following discussion summarizes the 108 comments received and
the resulting changes. In response to over 40 comments expressing
concern that the general principles that apply to all research
categories could be easily misinterpreted, the introductory paragraph
to the 1981 list has been reformatted into six general principles that
apply to the entire list. The parenthetical in the introductory
sentence to the 1981 list ``(carried out through standard methods)''
has been deleted in response to comments that this phrase served no
particular purpose in the 1981 list.
The reformatted general principles are set forth in paragraphs (A)
through (G). Paragraph (C) makes it clear that the IRB must consider,
for all categories, whether identification of the subjects or their
responses would reasonably place them at risk of criminal or civil
liability or be damaging to the subjects' financial standing,
employability, insurability, reputation, or be stigmatizing, unless
reasonable and appropriate protections will be implemented so that
risks related to invasion of privacy and breach of confidentiality are
no greater than minimal. At the time of the publication of the 1981
list, FDA routinely considered only the medical risk to subjects in
determining whether a study imparted greater than minimal risk. Since
that time, the scope of research projects that are under FDA purview
has expanded to include activities that could place the subjects at
risk for the harms listed in paragraph (C). Therefore, the IRB's
reviewing studies of FDA regulated products may need to consider the
listed nonmedical harms. For certain studies subject to regulation
under 45 CFR part 46, these concerns have always been implicit in
determining whether an activity is a minimal risk activity. The words
``insurability'' and ``be stigmatizing'' have been added to the new
list to help ensure that the IRB's consider these potential risks
during their review.
Two comments point out that classified research must be reviewed by
the IRB at a convened meeting. FDA and OPRR agree and have added
paragraph (D), which prohibits expedited review for classified research
involving human subjects. This is in accordance with the March 27,
1997, Presidential memorandum that proposed the elimination of an
expedited review procedure for all classified research involving human
subjects.
Paragraph (E) serves as a reminder to the IRB's that informed
consent and expedited review are two totally separate issues. This
responds to concerns that allowing an increase in the scope of research
eligible for expedited review would result in more waivers of informed
consent. Research reviewed under the expedited review procedure is not
necessarily eligible for waiver or alteration of informed consent. All
research, regardless of whether it meets the conditions for expedited
IRB review, must conform to the applicable requirements for obtaining
and documenting informed consent. Informed consent must be obtained and
documented unless the research meets one of the conditions for waiving,
excepting, or otherwise altering the informed consent requirements that
are set forth in 45 CFR 46.116 and 46.117, and Secs. 50.23, 50.24, and
56.109(c).
The list of research eligible for expedited review continues to
fall into nine categories. Category one,
[[Page 60354]]
enumerated as category nine on the 1981 list, addresses the
availability of expedited review for marketed drugs and devices. This
category now contains citations to the investigational drug and device
regulations and provides when expedited review of research on marketed
drugs (including biologics) would not be appropriate. This modification
was in response to five comments that raised questions about these
issues. FDA and OPRR on their own initiative have added wording to set
out in greater detail the conditions that must be met in order for an
IRB to review research with a medical device using expedited
procedures.
Over 45 comments suggested certain changes to proposed category
two, formerly category four in the 1981 list, addressing the collection
of blood. The suggested changes include addition of many specific
conditions, including limits on the amount withdrawn, collection
procedures, and limits on the physical condition of the subjects. In
response to these suggestions, the category has been reorganized to set
general limits that the specific procedure must meet. The procedures
for the collection of blood now include finger stick, heel stick, ear
stick, and venipuncture. The four proposed subcategories were
recombined as two separate subcategories. The critical issues to be
considered include weight, physical condition, and amount of blood to
be collected. The first subcategory (a) concerns healthy nonpregnant
adults. The second subcategory (b) concerns all other adults and
children. For this second subcategory, the IRB will need to make
certain judgments including: Consideration for the age, weight, and
health of the subjects in light of the amount of blood to be collected,
the frequency with which it will be collected, and the collection
procedure. The final sentence of subcategory (b) reads: ``For these
subjects, the amount drawn may not exceed the lesser of 50 mL or 3 mL
per kg in an 8-week period and collection may not occur more than 2
times per week.'' While an expedited review of research involving
pregnant women is permissible under the revised section, this last
sentence makes it clear that the amount of blood that can be drawn is
subject to limitations greater than those on healthy nonpregnant
adults. Also in response to public comment, the proposed phrase
``medically vulnerable adults'' has been deleted.
More than 24 comments were received regarding category three, which
was previously categories one and two in the 1981 list, addressing the
collection of biological specimens. Some of the comments requested
inclusion of specific procedures, such as throat cultures and pap
smears. Some of the comments requested the category be rephrased as a
general limit, setting out as examples the types of specimens and
conditions for collection. In response to these comments, new category
three has been reorganized to limit the manner of collection to
noninvasive means. The list of specific types of biological specimens
is now included as examples of the types of procedures that could fall
within this category.
Categories four and five on the proposed list have been combined
into one new category, category five, addressing research involving
materials collected or which will be collected solely for nonresearch
purposes. This new category five was formed in response to comments
that raised questions about why the two categories separated out
existing and prospectively collected materials. The term ``nonresearch
purposes'' was maintained in new category five to describe the origins
of the research materials.
An explanatory note has been added to categories five and seven to
clarify that some research described in these categories may be exempt
from the IRB review under 45 CFR 46.101 of the HHS regulations for the
protection of human subjects. Thus, the listing of those categories
refers only to nonexempt research.
Category six on the list proposed in November 1997 has become
category four on the revised list and addresses the collection of data
through noninvasive procedures. In response to several comments that
raised concerns about the use of anesthesia and sedation with magnetic
resonance imaging procedures, expedited review will not be allowed for
any procedure employing anesthesia or sedation. In response to more
than 24 comments, the general term ``noninvasive procedures'' now
applies to all procedures in this category. The specific procedures to
which expedited review was limited in proposed category six, are
included in new category four as examples of the types of procedures
that could qualify for expedited review. FDA and OPRR, on their own
initiative, added wording to clarify that studies intended to evaluate
the safety and effectiveness of medical devices or using medical
devices that are not cleared or approved for marketing by FDA are
generally not eligible for expedited review.
Category seven on the proposed list is now category six on the
revised list and deals with the collection of data from voice, video,
digital, or image recordings. In the proposal, the IRB was to consider
certain risks to the subjects in this category before granting
expedited review. In response to several comments that inquired why
only this type of research should receive this consideration, it was
incorporated as a guiding principle in the Applicability section I of
this document and is no longer simply specific to this category.
Category eight on the proposed list is now category seven on the
revised list. This category was added to the 1981 list with the
proposal and concerns research on individual or group characteristics
or behavior. At the time of the publication of the 1981 list, this
category was not included in the FDA list because FDA routinely
considered only the medical risk to subjects in determining whether a
study imparted greater than minimal risk. Since that time, the scope of
research projects that are under FDA purview has expanded to include
activities that are listed in new category seven. Therefore, studies
related to FDA-regulated products might employ such methodology.
Over 30 comments requested this category be simplified and
rephrased so that researchers and IRB's could more readily determine
whether their study is eligible for expedited review. In response, the
following changes have been made. The condition that the research does
not involve ``stress'' has been deleted; the subsections in the
proposed list have been combined to eliminate the distinction between
research involving adults and research involving children; research on
oral history has been included in response to six comments; and
specific research and research techniques have been noted. The category
has been reorganized to include research involving motivation,
identity, language, communication, cultural beliefs or practices, and
social behavior as examples of research on individual or group
characteristics or behavior. Methods of conducting such research are
now separately listed and have been expanded to include oral history,
program evaluation, human factors evaluation, and quality assurance
methodologies. As in new category six, the qualification that requires
consideration of certain kinds of risks to subjects has been deleted
from this category, as it is now a general guiding principle, (C),
which applies to the entire list.
Category nine on the proposed list, research previously approved by
the convened IRB, received more than 50 comments explicitly applauding
this category. It has now been divided into new categories eight and
nine. New
[[Page 60355]]
category eight identifies three situations in which research that is
greater than minimal risk and has been initially reviewed by the
convened IRB, could undergo subsequent continuing review by the
expedited review procedure. The new category nine concerns continuing
review of research that is not greater than minimal risk, but had to
undergo initial review by a convened IRB because it did not meet the
criteria of categories two through seven on this list.
Certain other minimal changes have been made for editorial purposes
or to clarify certain words that were used in the proposed list.
Accordingly, the list of categories of research which may be reviewed
by the IRB through an expedited review procedure is amended as set
forth:
Categories of Research That May Be Reviewed by the Institutional
Review Board (IRB) Through an Expedited Review Procedure \1\
---------------------------------------------------------------------------
\1\ An expedited review procedure consists of a review of
research involving human subjects by the IRB chairperson or by one
or more experienced reviewers designated by the chairperson from
among members of the IRB in accordance with the requirements set
forth in 45 CFR 46.110.
---------------------------------------------------------------------------
Applicability
(A) Research activites that (1) present no more than mimimal risk
to human subjects, and (2) involve only procedures listed in one or
more of the following categories, may be reviewed by the IRB through
the expedited review procedure authorized by 45 CFR 46.110 and 21 CFR
56.110. The activities listed should not be deemed to be of minimal
risk simply because they are included on this list. Inclusion on this
list merely means that the activity is eligible for review through the
expedited review procedure when the specific circumstances of the
proposed research involve no more than minimal risk to human subjects.
(B) The categories in this list apply regardless of the age of
subjects, except as noted.
(C) The expedited review procedure may not be used where
identification of the subjects and/or their responses would reasonably
place them at risk of criminal or civil liability or be damaging to the
subjects' financial standing, employability, insurability, reputation,
or be stigmatizing, unless reasonable and appropriate protections will
be implemented so that risks related to invasion of privacy and breach
of confidentiality are no greater than minimal.
(D) The expedited review procedure may not be used for classified
research involving human subjects.
(E) IRBs are reminded that the standard requirements for informed
consent (or its waiver, alteration, or exception) apply regardless of
the type of review--expedited or convened--utilized by the IRB.
(F) Categories one (1) through seven (7) pertain to both initial
and continuing IRB review.
Research Categories
(1) Clinical studies of drugs and medical devices only when
condition (a) or (b) is met.
(a) Research on drugs for which an investigational new drug
application (21 CFR Part 312) is not required.
(Note: Research on marketed drugs that significantly increases the
risks or decreases the acceptability of the risks associated with
the use of the product is not eligible for expedited review.)
(b) Research on medical devices for which (i) an investigational
device exemption application (21 CFR Part 812) is not required; or (ii)
the medical device is cleared/approved for marketing and the medical
device is being used in accordance with its cleared/approved labeling.
(2) Collection of blood samples by finger stick, heel stick, ear
stick, or venipuncture as follows:
(a) From healthy, nonpregnant adults who weigh at least 110 pounds.
For these subjects, the amounts drawn may not exceed 550 ml in an 8
week period and collection may not occur more frequently than 2 times
per week; or
(b) from other adults and children,\2\ considering the age, weight,
and health of the subjects, the collection procedure, the amount of
blood to be collected, the frequency with which it will be collected.
For these subjects, the amount drawn may not exceed the lesser of 50 ml
or 3 ml per kg in an 8 week period and collection may not occur more
frequently than 2 times per week.
---------------------------------------------------------------------------
\2\ Children are defined in the HHS regulations as ``persons who
have not attained the legal age for consent to treatments or
procedures involved in the research, under the applicable law of the
jurisdiction in which the research will be conducted.'' 45 CFR
46.402(a).
---------------------------------------------------------------------------
(3) Prospective collection of biological specimens for research
purposes by noninvasive means.
Examples: (a) hair and nail clippings in a nondisfiguring manner;
(b) deciduous teeth at time of exfoliation or if routine patient care
indicates a need for extraction; (c) permanent teeth if routine patient
care indicates a need for extraction; (d) excreta and external
secretions (including sweat); (e) uncannulated saliva collected either
in an unstimulated fashion or stimulated by chewing gumbase or wax or
by applying a dilute citric solution to the tongue; (f) placenta
removed at delivery; (g) amniotic fluid obtained at the time of rupture
of the membrane prior to or during labor; (h) supra- and subgingival
dental plaque and calculus, provided the collection procedure is not
more invasive than routine prophylatic scaling of the teeth and the
process is accomplished in accordance with accepted prophylactic
techniques; (i) mucosal and skin cells collected by buccal scraping or
swab, skin swab, or mouth washings; (j) sputum collected after saline
mist nebulization.
(4) Collection of data through noninvasive procedures (not
involving general anesthesia or sedation) routinely employed in
clinical practice, excluding procedures involving x-rays or microwaves.
Where medical devices are employed, they must be cleared/approved for
marketing. (Studies intended to evaluate the safety and effectiveness
of the medical device are not generally eligible for expedited review,
including studies of cleared medical devices for new indications.)
Examples: (a) physical sensors that are applied either to the
surface of the body or at a distance and do not involve input of
significant amounts of energy into the subject or an invasion of the
subject's privacy; (b) weighing or testing sensory acuity; (c) magnetic
resonance imaging; (d) electrocardiography, electroencephalography,
thermography, detection of naturally occurring radioactivity,
electroretinography, ultrasound, diagnostic infrared imaging, doppler
blood flow, and echocardiography; (e) moderate exercise, muscular
strength testing, body composition assessment, and flexibility testing
where appropriate given the age, weight, and health of the individual.
(5) Research involving materials (data, documents, records, or
specimens) that have been collected or will be collected solely for
nonresearch purposes (such as medical treatment or diagnosis).
(Note: Some research in this category may be exempt from the HHS
regulations for the protection of human subjects. 45 CFR
46.101(b)(4). This listing refers only to research that is not
exempt.)
(6) Collection of data from voice, video, digital, or image
recordings made for research purposes.
(7) Research on individual or group characteristics or behavior
(including, but not limited to, research on perception, cognition,
motivation, identity, language, communication, cultural beliefs or
practices, and social behavior) or research employing survey,
interview, oral history, focus group,
[[Page 60356]]
program evaluation, human factors evaluation, or quality assurance
methodologies.
(Note: Some research in this category may be exempt from the HHS
regulations for the protection of human subjects. 45 CFR
46.101(b)(2) and (b)(3). This listing refers only to research that
is not exempt.)
(8) Continuing review of research previously approved by the
convened IRB as follows:
(a) Where (i) the research is permanently closed to the enrollment
of new subjects; (ii) all subjects have completed all research-related
interventions; and (iii) the research remains active only for long-term
follow-up of subjects; or
(b) Where no subjects have been enrolled and no additional risks
have been identified; or
(c) Where the remaining research activities are limited to data
analysis.
(9) Continuing review of research, not conducted under an
investigational new drug application or investigational device
exemption where categories two (2) through eight (8) do not apply but
the IRB has determined and documented at a convened meeting that the
research involves no greater than minimal risk and no additional risks
have been identified.
Dated: November 2, 1998.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 98-29748 Filed 11-6-98; 8:45 am]
BILLING CODE 4160-01-M