[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