Protection of Human Subjects: Categories of Research That May Be Reviewed by the Institutional Review Board (IRB) Through an Expedited Review Procedure: Guidance for Institutional Review Boards and Clinical Investigators

Administrative guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

60353	Federal Register / Vol. 63, No. 216 / Monday, November 9, 1998 / Notices
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 § 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 §§ 50.23, 50.24,
and 56.109(c).
The list of research eligible for
expedited review continues to fall into
nine categories. Category one,

60354 	Federal Register / Vol. 63, No. 216 / Monday, November 9, 1998 / Notices
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

60355	Federal Register / Vol. 63, No. 216 / Monday, November 9, 1998 / Notices
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.
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).
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
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.
(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,

60356 	Federal Register / Vol. 63, No. 216 / Monday, November 9, 1998 / Notices
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
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Health Care Financing Administration
[Document Identifier: HCFA–0670]
Agency Information Collection
Activities: Proposed Collection;
Comment Request
AGENCY: Health Care Financing
Administration, HHS.
In compliance with the requirement
of section 3506(c)(2)(A) of the
Paperwork Reduction Act of 1995, the
Health Care Financing Administration
(HCFA), Department of Health and
Human Services, is publishing the
following summary of proposed
collections for public comment.
Interested persons are invited to send
comments regarding this burden
estimate or any other aspect of this
collection of information, including any
of the following subjects: (1) The
necessity and utility of the proposed
information collection for the proper
performance of the agency’s functions;
(2) the accuracy of the estimated
burden; (3) ways to enhance the quality,
utility, and clarity of the information to
be collected; and (4) the use of
automated collection techniques or
other forms of information technology to
minimize the information collection
burden.
Type of Information Collection
Request: Extension of a currently
approved collection; Title of
Information Collection: Team
Composition and Workload Report and
Supporting Regulations in 42 CFR
493.1–493.2001; Form No.: HCFA–0670
(OMB# 0938–0583); Use: This form
requests resource utilization
information on Medicare and Medicaid
providers, suppliers, and CLIA
laboratories. The data is used to
determine Federal reimbursement for all
participating health care facilities that
accept Medicare and Medicaid
beneficiaries.; Frequency: As needed;
Affected Public: State, Local, and Tribal
Government, Business or other for-
profit, and Not-for-profit institutions;
Number of Respondents: 53; Total
Annual Responses: 449,252; Total
Annual Hours: 71,667.
To obtain copies of the supporting
statement and any related forms for the
proposed paperwork collections
referenced above, access HCFA’s Web
Site address at http://www.hcfa.gov/
regs/prdact95.htm, or E-mail your
request, including your address, phone
number, OMB number, and HCFA
document identifier, to
Paperwork@hcfa.gov, or call the Reports
Clearance Office on (410) 786–1326.
Written comments and
recommendations for the proposed
information collections must be mailed
within 60 days of this notice directly to
the HCFA Paperwork Clearance Officer
designated at the following address:
HCFA, Office of Information Services,
Security and Standards Group, Division
of HCFA Enterprise Standards,
Attention: Louis Blank, Room N2–14–
26, 7500 Security Boulevard, Baltimore,
Maryland 21244–1850.
Dated: November 2, 1998.
John P. Burke III,
HCFA Reports Clearance Officer, HCFA Office
of Information Services, Security and
Standards Group, Division of HCFA
Enterprise Standards.
[FR Doc. 98–29959 Filed 11–6–98; 8:45 am]
BILLING CODE 4120–03–P
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Health Care Financing Administration
[Document Identifier: HCFA–R–250]
Agency Information Collection
Activities: Proposed Collection;
Comment Request
AGENCY : Health Care Financing
Administration.
In compliance with the requirement
of section 3506(c)(2)(A) of the
Paperwork Reduction Act of 1995, the
Health Care Financing Administration
(HCFA), Department of Health and
Human Services, is publishing the
following summary of proposed
collections for public comment.
Interested persons are invited to send
comments regarding this burden
estimate or any other aspect of this
collection of information, including any
of the following subjects: (1) The
necessity and utility of the proposed
information collection for the proper
performance of the agency’s functions;
(2) the accuracy of the estimated
burden; (3) ways to enhance the quality,
utility, and clarity of the information to
be collected; and (4) the use of
automated collection techniques or
other forms of information technology to
minimize the information collection
burden.
Type of Information Collection
Request: Extension of a currently
approved collection.
Title of Information Collection:
Skilled Nursing Facility (SNF) Resident
Assessment MDS Data and Supporting
Regulations in 42 CFR 413.343 and
424.32.
Form No.: HCFA–R–250 (OMB#
0938–0739).
Use: Skilled Nursing Facilities (SNF’s)
are required to submit Resident
Assessment Data as described at 42 CFR,
483.20 in the manner necessary to
administer the payment rate
methodology described in 42 CFR,
413.337. Pursuant to sections 4204(b)
and 4214(d) of OBRA 1987, the current
requirements related to the submission
and retention of resident assessment
data for the 5th, 30th and 60th days
following admission, necessary to
administer the payment rate
methodology described in 413.337, is
subject to the Paperwork Reduction Act.
Frequency: Monthly.
Affected Public: Business or other for-
profit, and Not-for-profit.
Number of Respondents: 17,000.
Total Annual Responses: 204,000.
Total Annual Hours: 3,865,885.
To obtain copies of the supporting
statement and any related forms for the