[Federal Register Volume 63, Number 216 (Monday, November 9, 1998)]
[Notices]
[Pages 60364-60367]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-29749]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
National Institutes of Health
Protection of Human Subjects: Categories of Research That May Be
Reviewed by the Institutional Review Board (IRB) Through an Expedited
Review Procedure
AGENCY: Office for Protection from Research Risks, National Institutes
of Health, HHS.
ACTION: Notice.
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SUMMARY: On November 10, 1997, the Office for Protection from Research
Risks (OPRR), in consultation with the Food and Drug Administration
(FDA), requested written comments relating to the proposed
republication of the list that identifies certain research activities
involving human subjects which may be reviewed by the Institutional
Review Board (IRB) through the expedited review procedure authorized in
45 CFR 46.110. The comment period closed on March 10, 1998. OPRR and
FDA received a combined total of 108 comments. After a review of the
comments, OPRR and FDA 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 DATES: The revised list is effective as of November 9, 1998.
FOR FURTHER INFORMATION CONTACT: Michele Russell-Einhorn, Director of
Regulatory Affairs, Office for Protection from Research Risks (OPRR),
National Institutes of Health, 6100 Executive Blvd., Suite 3B01,
Rockville, MD 20892-7507 or telephone (301) 435-5649 (not a toll-free
number).
SUPPLEMENTARY INFORMATION: The Federal Policy (Common Rule) for the
Protection of Human Subjects was published in the Federal Register on
June 18, 1991 (56 FR 28003) and is employed by 17 Executive Branch
agencies. This Federal Policy requires adherence to certain
requirements by Federal agencies 1 and institutions
receiving support from those agencies for research activities involving
human subjects. The Federal Policy has three cornerstones: review of
any research involving human subjects by an IRB with limited
exceptions, informed consent of all research subjects; and formal,
written assurance of institutional compliance with the Policy. The
Department of Health and Human Services' (HHS) codification of the
Federal Policy can be found at 45 CFR Part 46, Subpart A.
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\1\ The following agencies have adopted the Common Rule:
Department of Agriculture, Department of Energy, National
Aeronautics and Space Administration, Department of Commerce,
Consumer Product Safety Commission, International Development
Cooperation Agency-Agency for International Development, Department
of Housing and Urban Development, Department of Justice, Department
of Defense, Department of Health and Human Services, Department of
Education, Department of Veterans Affairs, Environmental Protection
Agency, National Science Foundation, Department of Transportation,
Central Intelligence Agency, Social Security Administration.
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Section ________.110 of the Federal Policy provides for expedited
review procedures for certain categories of research involving no more
than minimal risk, and for minor changes in approved research. This
same section gives the Secretary, HHS, the authority to amend and
republish the expedited review list as needed after consultation with
the departments and agencies that are subject to the Federal Policy.
The expedited review list that is referenced in the Federal Policy was
originally published by the Secretary, HHS in 1981 (46 FR 8392, 46 FR
8980). It listed categories of research that could be reviewed by the
IRB through an expedited review procedure. The FDA also references an
expedited review list (21 CFR Part 56) for matters under FDA's
jurisdiction. The HHS and FDA lists have differed slightly, in that
item nine (9) on the 1981 HHS expedited review list regarding certain
types of behavioral research is not included in the list referenced in
21 CFR 56.110.
The comments received in response to the OPRR and FDA proposed
revision of the 1981 expedited review list that was published on
November 10, 1997 (62 FR 60607) overwhelmingly supported the proposed
revision of the list. Three commenters suggested that there should be
no expedited review available at all. OPRR and FDA disagree with these
three comments and believe that expedited review is an appropriate part
of the IRB review process. In addition, a deletion of the expedited
review process would require a regulatory change to Section 110 which
is beyond the scope of this revision. Several commenters suggested
changing the exemptions found at Section 101(b), a topic also outside
the scope of this revision.
[[Page 60365]]
The following discussion summarizes the 108 comments received and
the resulting changes. In response to over forty comments, the
introductory paragraph to the 1981 list has been reformatted into five
general principles. The parenthetical in the introductory sentence in
the 1981 list ``(carried out through standard methods)'' has been
deleted in response to comments that this phrase served no particular
purpose.
The reformatted general principles are set forth in paragraphs (A)
through (F). 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. OPRR does not consider this to be a new or
additional consideration. These concerns have always been an implicit
part of the determination of whether an activity is a minimal risk
activity. The words ``insurability'' and ``be stigmatizing'' have been
added and are designed to serve as an aid to IRBs when genetic research
is presented for review in an expedited review procedure. These changes
were made in response to concerns raised in several comments that
genetic testing may have consequences beyond those normally considered
by the IRB.
Consistent with two comments, paragraph (D) prohibits expedited
review for classified research involving human subjects. This is also
in accordance with a March 27, 1997 Presidential Memorandum which
proposed the elimination of an expedited review procedure for all
classified research involving human subjects.
Paragraph (E) serves as a reminder to IRBs 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 pursuant to an expedited review procedure is not
necessarily eligible for waiver or alteration of informed consent. All
research, whether reviewed by the full IRB or by way of expedited
review, must conform to the applicable requirements for obtaining and
documenting prospective informed consent, unless the research meets the
conditions for waiving, excepting, or otherwise altering the informed
consent requirements that are set forth in 45 CFR 46.116 and 117, 21
CFR 50.23 and 24, or 21 CFR 56.109(c).
Category one (1) preserves category ten (10) on the 1981 list. It
also contains a new sentence that addresses the availability of the
expedited review procedure for marketed drugs in research as well as
specific citations in response to five comments that raised questions
about these issues.
The following changes have been made to category two (2) in
response to over 45 comments which supported enhanced expedited review
concerning collection of blood, but which suggested certain
refinements. Collection of blood now includes finger stick, heel stick,
or ear stick as well as venipuncture. The four proposed subcategories
were recombined as two separate subcategories. The critical issues to
be considered by the IRB 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 individuals, 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 phrase ``medically
vulnerable adults'' that was proposed in November 1997 has been
deleted.
In response to more than 24 comments, category three (3)
(previously category one (1) in the 1981 list) has been changed in the
following manner. The words ``noninvasive means'' have been added to
clarify the manner of collection of research materials; and, the
procedures outlined are set out as examples to the IRB of the types of
procedures that could fall within this category.
Categories four (4) and five (5) on the proposed list have been
combined into one new category five (5) on the 1998 list. This new
section is added in response to comments that raised questions about
the relationship of proposed categories four (4) and five (5) to exempt
research and about separating out existing and prospectively collected
materials. The term ``nonresearch purposes'' was maintained in new
category five (5) to describe the origins of the research materials. An
explanatory note has been added to categories five (5) and seven (7) to
clarify that some research described in these categories may be exempt
from IRB review under 45 CFR 46.101(b) of the HHS regulations for the
protection of human subjects (there is no comparable exemption
provision in the FDA regulations). Thus, the listing of those
categories refers only to nonexempt research.
Category six (6), proposed in November 1997, is now category four
(4) on the 1998 list and addresses the collection of data through
noninvasive procedures. The words ``noninvasive procedures'' have been
added and apply to all procedures that would fall within this category.
Because of several comments that raised concerns about MRIs and the use
of anesthesia and sedation, expedited review would not be allowed for
any procedure employing either of these. In response to more than 24
comments, this category lists procedures as examples for the IRB of the
types of procedures that would qualify for expedited review.
Category seven (7) on the list proposed in November 1997 is now
category six (6) on the 1998 list and deals with the collection of data
from voice, digital, or image recordings. The qualification that was
proposed in November of 1998 requiring consideration of certain risks
to subjects is now a general guiding principle. It has been
incorporated into the general Applicability section in response to
several comments that questioned limiting this consideration to this
type of research.
Category eight (8) on the proposed list is now category seven (7)
on the revised list. In response to over 30 comments, the following
changes have been made. The word ``stress'' has been deleted; the
subsections in the proposed list have been combined; research on oral
history has been included in response to approximately six comments;
and specific research and research techniques have been noted. As in
new category six (6), the qualification that requires consideration of
certain kinds of risks to subjects has been deleted as it is now a
general guiding principle for the entire list.
Category nine (9) on the proposed list received more than 50
comments
[[Page 60366]]
explicitly applauding this additional category. It has been divided
into two categories. Category eight (8) 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. New category nine (9)
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 (2) through seven (7) on the
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 the expedited review procedure is amended as set
forth below.
Categories of Research That May Be Reviewed by the Institutional
Review Board (IRB) Through an Expedited Review Procedure
1
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\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.
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Applicability
(A) Research activities that (1) present no more than minimal 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, and 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.
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\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).
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(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 prophylactic 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
[[Page 60367]]
behavior) or research employing survey, interview, oral history, focus
group, 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.
Gary B. Ellis,
Director, Office for Protection from Research Risks.
[FR Doc. 98-29749 Filed 11-6-98; 8:45 am]
BILLING CODE 4140-01-P