NOTE:
THIS GUIDANCE REPLACES OHRP�S JULY 11, 2002 GUIDANCE ENTITLED �GUIDANCE ON
WRITTEN IRB PROCEDURES.� CLICK HERE
FOR THE JULY 11, 2002 GUIDANCE.� THIS GUIDANCE HAS BEEN UPDATED TO INCLUDE THE
FOLLOWING CHANGES:� (1) CONTENT REGARDING
CONTINUING REVIEW HAS BEEN REVISED TO BE CONSISTENT WITH THE CONTENT OF OHRP�S JANUARY
15, 2007 �GUIDANCE ON REVIEWING AND REPORTING UNANTICIPATED PROBLEMS INVOLVING
RISKS TO SUBJECTS OR OTHERS AND ADVERSE EVENTS;� (2) PARAGRAPH A.(4) UNDER �ADDITIONAL OHRP
GUIDANCE RELEVANT TO WRITTEN IRB PROCEDURES� HAS BEEN REVISED TO BE CONSISTENT
WITH OHRP�S POSITION REGARDING WHEN IRB�S MUST DEFER APPROVAL OF RESEARCH; AND
(3) FORMATTING CHANGES.
Office for Human Research Protections (OHRP)
Department of Health and Human Services
This guidance represents OHRP's current thinking on this topic and should be viewed as recommendations unless specific regulatory requirements are cited.� The use of the word must in OHRP guidance means that something is required under HHS regulations at 45 CFR part 46.� The use of the word should in OHRP guidance means that something is recommended or suggested, but not required.� An institution may use an alternative approach if the approach satisfies the requirements of the HHS regulations at 45 CFR part 46.� OHRP is available to discuss alternative approaches at 240-453-6900 or 866-447-4777.
������������������������������� Guidance
on Written IRB Procedures
Date: January
15, 2007
Scope: �This document outlines the required elements
of written Institutional Review Board (IRB) procedures under Department of
Health and Human Services (HHS) regulations for the protection of human
subjects (45 CFR Part 46) and provides an overview of relevant OHRP guidance
regarding each required element.
Target Audience:� This document
primarily is intended to assist IRB administrators, IRB chairpersons, and other
relevant institutional officials who may be responsible for preparing and
maintaining written IRB procedures.
BACKGROUND
OHRP
frequently receives requests for guidance and clarification regarding the
content of written IRB procedures.� In
order to assist institutions in developing adequate written IRB procedures,
OHRP has compiled the following summary of the relevant regulatory requirements
and guidance issued routinely by OHRP over the past several years.�
OHRP
has not developed a model written IRB procedures document for institutions to
adapt because procedures appropriately can vary significantly among
institutions as the result of differences in institution size, the type of
research activities, institutional administrative practices, number of IRBs,
and local and state laws and regulations.�
For each required element, the written IRB procedures should provide
sufficient step-by-step operational details so that an independent observer can
understand how an IRB operates and conducts its major functions.������
REGULATORY REQUIREMENTS
HHS
regulations at 45 CFR 46.103(b)(4) and (5) require that institutions have
written IRB procedures for each of the following:�
(1) the procedures which the IRB will follow
for conducting its initial review of research;
(2) the procedures which the IRB will follow
for conducting its continuing review of research;
(3) the procedures which the IRB will follow
for reporting its findings and actions to investigators and the institution;�
(4) the procedures which the IRB will follow
for determining which projects require review more often than annually;
(5) the procedures which the IRB will follow
for determining which projects need verification from sources other than the
investigators that no material changes have occurred since previous IRB review;
(6) the procedures which the IRB will follow
for ensuring prompt reporting to the IRB of proposed changes in a research
activity, and for ensuring that such changes in approved research, during the
period for which IRB approval has already been given, may not be initiated
without IRB review and approval except when necessary to eliminate apparent
immediate hazards to the subject; and
(7) the procedures for ensuring prompt
reporting to the IRB, appropriate institutional officials, any Department or
Agency head, and OHRP of:
(a) any unanticipated problems involving risks
to subjects or others (hereinafter referred to as unanticipated problems);
(b) any serious or continuing noncompliance
with 45 CFR Part 46 or the requirements or determinations of the IRB; and
(c) any suspension or termination of IRB
approval.
GUIDANCE ON OPERATIONAL DETAILS
Written
IRB procedures should provide a step-by-step description with key operational
details for each of the above procedures.�
Important operational details for the above procedures should include:
(1) a description of any primary reviewer
system used for initial review, continuing review, review of protocol changes,
and/or review of reports of unanticipated problems or of serious or continuing
noncompliance;
(2) lists of specific documents distributed to
primary reviewers (if applicable) and to all other IRB members for initial
review, continuing review, review of protocol changes, and review of reports of
unanticipated problems or of serious or continuing noncompliance;
(3) details of any process (e.g., a
subcommittee procedure) that may be used to supplement the IRB�s initial
review, continuing review, review of protocol changes, and/or review of reports
of unanticipated problems or of serious or continuing noncompliance;
����������� (4) the timing of document
distribution prior to IRB meetings;
�����������
(5) the range of possible actions taken by the
IRB for protocols undergoing initial or continuing review and protocol changes
undergoing review;
(6) a description of how expedited review is conducted and
how expedited approval actions are communicated to all IRB members;
(7) a description of the procedures for:
(a) communicating to investigators IRB action
regarding proposed research and any modifications or clarifications required by
the IRB as a condition for IRB approval of proposed research; and
(b) reviewing and acting upon investigators�
responses;
(8) a description of which institutional
office(s) and official(s) are notified of IRB findings and actions and how
notification to each is accomplished;
(9) a description, if applicable, of which
institutional office(s) or official(s) is responsible for further review and
approval or disapproval of research that is approved by the IRB; please note
that, in accordance with HHS regulations at 45 CFR 46.112, no other
institutional office or official may approve research that has not been
approved by the IRB;
(10) a specific procedure for how the IRB
determines which protocols require review more often than annually, including
specific criteria used to make these determinations (e.g., an IRB may set a
shorter approval period for high-risk protocols or protocols with a high
risk:potential benefit ratio);
(11) a specific procedure for how the IRB
determines which projects need verification from sources other than the
investigators that no material changes have occurred since previous IRB review,
including specific criteria used to make these determinations (e.g., such
criteria could include some or all of the following:
(a) randomly selected projects;
(b) complex projects involving unusual levels
or types of risk to subjects;
(c) projects conducted by investigators who
previously have failed to comply with the requirements
of the HHS regulations or the requirements or
determinations of the IRB; and
(d) projects where concern about possible
material changes occurring without IRB approval have been raised based upon
information provided in continuing review reports or from other sources);
(12) a description of what steps are taken to
ensure that investigators do not implement any protocol changes without prior
IRB review and approval, except when necessary to eliminate apparent immediate
hazards to subjects (e.g., this might be addressed through training programs
and materials for investigators, specific directives included in approval
letters to investigators, and random audits of research records);
(13) a description of which office(s) or
institutional official(s) is responsible for promptly reporting to the IRB,
appropriate institutional officials, any supporting Agency or Department heads,
and OHRP any:
(a) unanticipated problems;
(b) any serious or continuing noncompliance
with 45 CFR Part 46 or the requirements or determinations of the IRB; and
(c) any suspension or termination of IRB
approval;
(14) a description of the required time frame
for accomplishing the reporting requirements in the preceding paragraph; and
(15) the range of possible actions taken by the
IRB in response to reports of unanticipated problems or of serious or
continuing noncompliance.
ADDITIONAL OHRP GUIDANCE RELEVANT TO WRITTEN
IRB PROCEDURES
�
A. Guidance Relevant to Initial and Continuing
Review
(1) Requirement
for Review of Research by the IRB at Convened Meetings.� In accordance with HHS regulations at 45 CFR
46.108(b), initial and continuing reviews of research must be conducted by the
IRB 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 (i.e., a quorum), except where expedited review is
appropriate under HHS regulations at 45 CFR 46.110(b)(1) for the categories of
research listed in the Federal Register of November 9, 1998 (see 63 FR
60364-60367 at http://www.hhs.gov/ohrp/humansubjects/guidance/63fr60364.htm).� Approval of research is by a majority vote of
this quorum.� Should the quorum fail
during a meeting (e.g., loss of a majority through recusal of members with
conflicting interests or early departures, or absence of a nonscientist
member), the IRB may not take further actions or votes unless the quorum can be
restored.
(2) Research Review Materials
(a) Initial
Review Materials.� 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.�� In conducting the initial review of proposed
research, IRBs must obtain information in sufficient detail to make the
determinations required under HHS regulations at 45 CFR 46.111.� Materials should include the full protocol, a
proposed informed consent document, any relevant grant application(s), the
investigator's brochure (if one exists), and any recruitment materials,
including advertisements intended to be seen or heard by potential
subjects.� Furthermore, for HHS-supported
multicenter clinical trials, the IRB should receive and review a copy of the
HHS-approved sample informed consent document and the complete HHS-approved
protocol, if they exist.� Unless a
primary reviewer system is used, all members should receive a copy of the
complete documentation.� These materials
should be received by members sufficiently in advance of the meeting date to
allow review of this material.
If the IRB uses a primary reviewer system, the primary
reviewer(s) should do an in-depth review of all pertinent documentation (see
previous paragraph).� All other IRB
members should at least receive and review a protocol summary (of sufficient
detail to make the determinations required under HHS regulations at 45 CFR
46.111), the proposed informed consent document, and any recruitment materials,
including advertisements intended to be seen or heard by potential
subjects.� In addition, the complete
documentation should be available to all members for review.
(b) Continuing
Review Materials.� Continuing review
of research must be substantive and meaningful.�
The IRB must ensure that the criteria set forth by HHS regulations at 45
CFR 46.111 are satisfied at the time of 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 that
includes:
�
the number of subjects
accrued;
�
a summary of any unanticipated problems and
available information regarding adverse events (in many cases, such a summary could be a simple brief statement that there
have been no unanticipated problems and that adverse events have occurred at
the expected frequency and level of severity as documented in the research
protocol, the informed consent document, and any investigator brochure);
�
a summary of any
withdrawal of subjects from the research since the last IRB review;
�
a summary of any
complaints about the research since the last IRB review;
�
a summary of any
recent literature that may be relevant to the research and any amendments or modifications
to the research since the last IRB review;
�
any relevant
multi-center trial reports;
�
any other relevant
information, especially information about risks associated with the research;
and
�
a copy of the current
informed consent document and any newly proposed consent document.
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 members also should have
access to the complete IRB protocol file and relevant IRB minutes prior to or
during the convened IRB meeting.
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.�
For additional details about OHRP�s guidance on continuing
review, see
http://www.hhs.gov/ohrp/humansubjects/guidance/contrev0107.htm.
(3) IRB
Review in Emergency Situations.� HHS
regulations do not permit human subject research activities to be started, even
in an emergency, without prior IRB review and approval (see 45 CFR 46.103(b)
and 46.116(f) and OHRP guidance at http://www.hhs.gov/ohrp/humansubjects/guidance/hsdc91-01.htm).� When emergency medical care is initiated
without prior IRB review and approval, the patient may not be considered a
research subject under 45 CFR Part 46.�
Such emergency care may not be claimed as research, nor may any data� regarding such care be included in any report
of a prospectively conceived research activity.�
When emergency care involves investigational drugs, devices, or
biologics, U.S. Food and Drug Administration (FDA) requirements must be
satisfied.
(4) Contingent Approval of Research.�
Convened IRBs often set conditions under which a protocol can be
approved.� OHRP notes that when the
convened IRB requests substantive clarifications or modifications regarding the
protocol or informed consent process/documents that are directly relevant to
the determinations required by the IRB under HHS regulations at 45 CFR 46.111,
IRB approval of the proposed research must be deferred, pending subsequent
review by the convened IRB of responsive material.��
(5) Conflicting
Interest.� HHS regulations at 45 CFR
46.107(e) stipulate that no IRB member may participate in the IRB�s initial or
continuing review of a project in which the member has a conflicting interest,
except to provide information requested by the IRB.� OHRP recommends that except when requested by
the IRB to be present to provide information, IRB members absent themselves
from the meeting room when the IRB reviews research in which they have a
conflicting interest, and such should be noted in the IRB meeting minutes.
(6) Initial
and Continuing Expedited Review.�
OHRP recommends that documentation for initial and continuing reviews
conducted under an expedited review procedure include: (a) the specific
permissible categories (see 63 FR 60364-60367 at http://www.hhs.gov/ohrp/humansubjects/guidance/63fr60364.htm)
justifying the expedited review; and (b) documentation of the review and action
taken by the IRB chairperson or designated reviewer and any findings required
under the HHS regulations.
B. Guidance Relevant to IRB Records and
Documentation
(1) IRB
Protocol Records.� IRB protocol
records must include all the information stipulated by HHS regulations at 45
CFR 46.115(a)(1), (3), (4), and (7).�
(2) Minutes
of IRB Meetings.� The minutes of IRB
meetings must include all the information stipulated by HHS regulations at 45
CFR 46.115(a)(2).� The minutes of IRB
meetings should document, among other things:
(a) Separate deliberations,
actions, and votes for each protocol undergoing initial or continuing review by
the convened IRB.
(b) The vote on all IRB actions including the
number of members voting for, against, and abstaining.� In order to document the continued existence
of a quorum, OHRP recommends that votes be recorded in the minutes using the
following format: Total = 15; Vote: For-14, Opposed-0, Abstained-1.�
(3) Documentation
of Findings.� HHS regulations at 45
CFR 46.116(d) require that the IRB make and document four findings when
approving a consent procedure which does not include, or which alters, some or
all of the required elements of informed consent or when waiving the
requirement to obtain informed consent.�
OHRP recommends that when approving such a waiver for research reviewed
by the convened IRB, these findings be documented in the minutes of the IRB
meeting, including protocol-specific
information justifying each IRB finding.
Similarly, where HHS regulations require specific findings
on the part of the IRB, such as:
(a) approving a procedure which waives the
requirement for obtaining a signed consent form [see 45 CFR 46.117(c)];
(b) approving research involving pregnant
women, human fetuses, or neonates (see 45 CFR 46.204-207);
(c) approving research involving prisoners (see
45 CFR 46.305-306);or
(d) approving research involving children (see
45 CFR 46.404-407), the IRB should document such findings.�
OHRP recommends that for research approved by the convened
IRB, all required findings be fully documented in the minutes of the IRB
meeting, including protocol-specific information
justifying each IRB finding.�
For research reviewed under an expedited review procedure,
these findings should be documented by the IRB Chairperson or other designated
reviewer elsewhere in the IRB record.������������������������������
(4) Documentation
of Risk and Approval Period.� IRBs
must determine which protocols require continuing review more often than
annually, as appropriate to the degree of risk [see 45 CFR 46.103(b)(4) and
46.109(e)].� OHRP recommends that the
minutes of IRB meetings clearly reflect these determinations regarding risk and
approval period (review interval).
(5) Retention
of IRB Records.� HHS regulations at
45 CFR 46.115(b) require that IRB records be retained for at least 3 years, and
records relating to research which is conducted be retained for at least 3
years after completion of the research.�
All records must be accessible for inspection and copying by authorized
representatives of HHS at reasonable times and in a reasonable manner.
C. Guidance Relevant to Review of Protocol
Changes
(1) Requirement
for Review of Proposed Protocol Changes by the IRB at Convened Meetings.� In accordance with HHS regulations at 45 CFR
46.108(b), review of proposed protocol changes must be conducted by the IRB 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, except where expedited review is appropriate under HHS regulations at 45
CFR 46.110(b)(2).
(2) Expedited
Review of Minor Changes. OHRP recommends that institutions adopt policies
describing the types of minor changes in previously approved research which can
be approved under an expedited review procedure in accordance with HHS
regulations at 45 CFR 46.110(b)(2).
(3) Protocol
Revisions.� OHRP recommends that each
revision to a research protocol be incorporated into the written protocol.� This practice ensures that there is only one
complete protocol with the revision dates noted on each revised page and the
first page of the protocol itself.� This
procedure is consistent with the procedure used for revised and approved
informed consent documents which then supersede the previous one.
D. Miscellaneous Guidance
(1) Procedures
for Determining Exemptions.� OHRP
recommends that institutions adopt clear procedures under which the IRB (or
some authority other than the investigator) determines whether proposed
research is exempt from the human subjects regulations [see 45 CFR
46.101(b)].� Documentation should include
the specific category justifying the exemption.
(2) Informed
Consent Documents: Approval and Expiration Dates.� OHRP recommends that IRBs affix the approval
and expiration dates to all approved informed consent documents and stipulate
that copies of these dated documents must be used in obtaining consent.� This procedure helps ensure that only the
current, IRB-approved informed consent documents are presented to subjects and
serves as a reminder to the investigators of the need for continuing review.
(3) Applicability
of State and Local Laws to HHS-Supported Research.� The HHS regulations do not affect any
applicable State or local laws or regulations which provide additional
protections for human subjects [see 45 CFR 46.101(f)].� OHRP recommends that written IRB procedures
describe applicable State and local laws and regulations relevant to the
conduct of human subject research.
(4) Additional Considerations.�
Institutions may wish to consider including additional pertinent
information in their written IRB procedures, such as the following:
(a) important definitions
(e.g., the definition of research, human
subject, and minimal risk);
(b) a description of
procedures for implementing other relevant Federal regulations that apply to
human subject research (e.g., FDA and HIPAA regulations);
(c) procedures for selecting
and appointing the IRB chairperson and members in order to satisfy the
requirements of HHS regulations at 45 CFR 46.107;
(d) procedures for training
and educating IRB members and staff and investigators;
(e) a description of the
required elements of informed consent and criteria for waiving or altering
these requirements; and
(f) procedures for ensuring that the IRB possesses sufficient knowledge of the local research context.� ��