NOTE: NOTE: THIS GUIDANCE HAS BEEN REPLACED BY
OHRP�S JANUARY 15, 2007 GUIDANCE ON CONTINUING REVIEW. CLICK
HERE FOR THE JANUARY 15, 2007
GUIDANCE. THIS GUIDANCE HAD REPLACED THE FOLLOWING OHRP GUIDANCE: 1.
"CONTINUING REVIEW � INSTITUTIONAL AND
INSTITUTIONAL REVIEW BOARD RESPONSIBILITIES" (JANUARY 10, 1995) CLICK
HERE; 2.
"IRB APPROVAL PERIODS AND CONTINUING REVIEW OF
RESEARCH" (JANUARY 20, 2000) CLICK HERE;
AND 3.
"CONTINUING REVIEW OF DSMB-MONITORED CLINICAL
TRIALS" (MAY 22, 2000) CLICK HERE.
Office for Human Research Protections Guidance on Continuing Review Date: July 11, 2002 Scope: This document describes the requirements of
Department of Health and Human Services (HHS) regulations at 45 CFR 46.109(e)
for the continuing review of human subjects research by an Institutional
Review Board (IRB) at intervals appropriate to the degree of risk, but not
less than once per year. In particular, OHRP offers guidance on the following
topics:
Target Audience: IRBs, investigators,
research institutions, and sponsors. The HHS regulations for the protection of
human subjects (45 CFR Part 46) require that, among other things, (1)
institutions have written procedures which the IRB will follow for (a)
conducting its continuing review of research and for reporting its findings
and actions to investigators and the institution, and (b) determining which
projects require review more often than annually (45 CFR 46.103(b)(4)); (2)
except when an expedited review procedure is used, each IRB reviews proposed
research at convened meetings at which a majority of the members of the IRB
are present, including at least one member whose primary concerns are in the
nonscientific areas (45 CFR 46.108(b)); and (3) an IRB conducts continuing
review of research at intervals appropriate to the degree of risk, but not
less often than once a year (45 CFR 46.109(e)). WHAT CONSTITUTES SUBSTANTIVE AND MEANINGFUL Continuing review of research must be
substantive and meaningful. In accordance with HHS regulations at 45 CFR
46.108(b) and at 46.115(a)(2), continuing review by the convened IRB, with
recorded vote on each study, is required unless the research is otherwise
appropriate for expedited review under Section 46.110 (see below).
Furthermore, HHS regulations at 45 CFR 46.111 set forth the criteria that
must be satisfied in order for the IRB to approve research. These criteria include,
among other things, determinations by the IRB regarding risks, potential
benefits, informed consent, and safeguards for human subjects. The IRB must
ensure that these criteria are satisfied at the time of both initial and
continuing review. The procedures for continuing review by the convened IRB
may include a primary reviewer system. In conducting continuing review of
research not eligible for expedited review, all IRB members should at least
receive and review a protocol summary and a status report on the progress of
the research, including:
At least one member of the IRB (i.e., a
primary reviewer) also should receive a copy of the complete protocol including
any modifications previously approved by the IRB. Furthermore, upon request,
any IRB member also should have access to the complete IRB protocol file and
relevant IRB minutes prior to or during the convened IRB meeting. When reviewing the current informed
consent document(s), the IRB should ensure the following:
Review of currently approved or newly
proposed consent documents must occur during the scheduled continuing review
of research by the IRB, but informed consent documents should be reviewed
whenever new information becomes available that would require modification of
information in the informed consent document. Furthermore, the minutes of IRB meetings
should document separate deliberations, actions, and votes for each protocol
undergoing continuing review by the convened IRB. When reviewing research under an expedited
review procedure, the IRB Chair (or designated IRB member(s)) should receive
and review all of the above-referenced documentation, including the complete
protocol. WHAT ARE SOME ADDITIONAL CONSIDERATIONS
FOR CONTINUING As noted above, continuing review of
research by the IRB should include consideration of adverse events, interim findings,
and any recent literature that may be relevant to the research. OHRP recognizes that such information may
not be readily available to local investigators participating in multi-center
clinical trials or to their local IRBs. However,
OHRP notes that such trials are often subject to oversight by a Data and
Safety Monitoring Board (DSMB), Data Monitoring Committee (DMC), other
similar body, or sponsor whose responsibilities include review of adverse
events, interim findings, and relevant literature. In such circumstances, IRBs
conducting continuing review of research may rely on a current statement from
the DSMB or sponsor indicating that it has reviewed study-wide adverse
events, interim findings, and any recent literature that may be relevant to
the research, in lieu of requiring that this information be submitted
directly to the IRB. The IRB must still receive and review reports of local,
on-site adverse events and unanticipated problems involving risks to subjects
or others and any other information needed to ensure that its continuing
review is substantive and meaningful. In addition, institutions and IRBs may require additional information for continuing
review at their discretion. WHEN MAY EXPEDITED REVIEW PROCEDURES BE USED The HHS human subjects regulations at 45
CFR 46.110(b)(1) limit the use of expedited review procedures to specific
research categories published in the Federal Register at 63 FR 60364-60367
(see http://www.hhs.gov/ohrp/humansubjects/guidance/expedited98.htm),
and to the review of minor changes in previously approved research during the
period (of one year or less) for which approval is authorized. IRBs are permitted to use expedited review for the
continuing review of research that involves solely one or more of the
activities published at 63 FR 60364-60367. Generally, if research did not qualify for
expedited review at the time of initial review, it does not qualify for
expedited review at the time of continuing review, except in limited
circumstances described by expedited review categories (8) and (9) at 63 FR
60364-60367. It is also possible that research activities that previously
qualified for expedited review in accordance with Section 46.110,
have changed or will change, such that expedited IRB review would no longer
be permitted for continuing review. Expedited Review Category (8): Under Category (8), an expedited review
procedure may be used for the continuing review of research previously
approved by the convened IRB as follows:
Of note, category (8) identifies three
situations in which research that is greater than minimal risk and has been
initially reviewed by a convened IRB may undergo subsequent continuing review
by the expedited review procedure. For a multi-center protocol, an expedited
review procedure may be used by the IRB at a particular site whenever the
conditions of category (8)(a), (b), or (c) are
satisfied for that site. However, with respect to category 8(b), while the
criterion that "no subjects have been enrolled" is interpreted to
mean that no subjects have ever been enrolled at a particular site, the
criterion that "no additional risks have been identified" is
interpreted to mean that neither the investigator nor the IRB at a particular
site has identified any additional risks from any site or other relevant
source. Expedited Review Category (9): Under Category (9), an expedited review
procedure may be used for continuing review of research not conducted under
an investigational new drug application or investigational device exemption
where categories (2) through (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. The determination that "no additional
risks have been identified" does not need to be made by the convened
IRB. HOW IS THE CONTINUING REVIEW DATE DETERMINED? HHS regulations at 45 CFR 46.108(b) and
109(e) require, respectively, that (1) except when an expedited review
procedure is used, each IRB must review proposed research at convened
meetings at which a majority of the members of the IRB are present, including
at least one member whose primary concerns are in nonscientific areas; and
(2) an IRB must conduct continuing review of research at intervals
appropriate to the degree of risk, but not less frequently than once per
year. The IRB should decide the frequency of continuing review for each study
protocol necessary to ensure the continued protection of the rights and
welfare of research subjects. Several scenarios for determining the date
of continuing review apply for protocols reviewed by the IRB at a convened
meeting. To determine the date by which continuing review must occur, focus
on the date of the convened meeting at which IRB approval occurs. (These
examples presume the IRB has determined that it will conduct continuing
review no sooner than within 1 year).
Expedited Review For a study approved under expedited
review, continuing review must occur within 1 year of the date the IRB Chair
or IRB member(s) designated by the Chair gives final approval to the
protocol. Review of a change in a protocol
ordinarily does not alter the date by which continuing review must occur.
This is because continuing review is review of the full protocol, not simply
a change to it. The regulations make no provision for any
grace period extending the conduct of research beyond the expiration date of
IRB approval. Therefore, continuing review and re-approval of research must
occur on or before the date when IRB approval expires. OHRP recognizes the
logistical advantages of keeping the IRB approval period constant from year
to year throughout the life of each project. When continuing review occurs
annually and the IRB performs continuing review within 30 days before the IRB
approval period expires, the IRB may retain the anniversary date as the date
by which the continuing review must occur. This would be, for example,
October 1, 2003, in the above Scenarios 1 and 2, and October 29, 2003, in
Scenario 3, even if the continuing reviews took place up to 30 days prior to
these dates. WHAT OCCURS IF THERE IS A LAPSE IN CONTINUING REVIEW? The IRB and investigators must plan ahead
to meet required continuing review dates. If an investigator has failed to
provide continuing review information to the IRB or the IRB has not reviewed
and approved a research study by the continuing review date specified by the
IRB, the research must stop, unless the IRB finds that it is in the best
interests of individual subjects to continue participating in the research
interventions or interactions. Enrollment of new subjects cannot occur after
the expiration of IRB approval. When continuing review of a research
protocol does not occur prior to the end of the approval period specified by
the IRB, IRB approval expires automatically. Such expiration of IRB approval
does not need to be reported to OHRP as a suspension of IRB approval under
HHS regulations. WHAT IS THE REQUIRED COMPOSITION OF IRBS OHRP is aware that some institutions have
designated one or more IRBs for the sole purpose of
conducting continuing review. While OHRP acknowledges that such a practice is
permissible under the HHS regulations for the protection of human subjects,
OHRP reminds institutions that such IRBs must
comply with the IRB membership requirements stipulated by HHS regulations at
45 CFR 46.107. In particular, HHS regulations at 45 CFR 46.107(a) require the
following for all IRBs, including IRBs that are solely responsible for continuing review: The IRB must have at least five members
with varying backgrounds to promote complete and adequate review of research
activities commonly conducted by the institution. The IRB must be
sufficiently qualified through the experience and expertise of its members,
and the diversity of members, including consideration of race, gender, and
cultural backgrounds and sensitivity to such issues as community attitudes,
to promote respect for its advice and counsel in safeguarding the rights and
welfare of human subjects. In addition to possessing the professional
competence necessary to review specific research activities, the IRB shall be
able to ascertain the acceptability of proposed research in terms of
institutional commitments and regulations, applicable law, and standards of
professional conduct and practice. The IRB must therefore include persons
knowledgeable in these areas. If the IRB regularly reviews research that
involves a vulnerable category of subjects, such as children, prisoners,
pregnant women, or handicapped or mentally disabled persons, consideration
shall be given to the inclusion of one or more individuals who are
knowledgeable about and experienced in working with these subjects. In addition, it should be noted that the
other requirements for IRB membership at 45 CFR 46.107(b)-(f) also apply to IRBs conducting continuing review. For FDA-regulated research, see 21 CFR 50, and 21 CFR 56. |