[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.

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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,

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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

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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\
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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 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.
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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 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,

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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