Guidance for Industry
Using a Centralized IRB Review Process in Multicenter Clinical
Trials
(PDF of this document)
U.S. Department of Health and Human Services
Food and Drug Administration
Good Clinical Practice Program, Office of the Commissioner (OC)
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
Office of Regulatory Affairs (ORA)
March 2006
Procedural
Guidance for Industry
Using a Centralized IRB Review Process in Multicenter Clinical
Trials
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(Tel) 800-835-4709 or 301-827-1800
U.S. Department of Health and Human Services
Food and Drug Administration
Good Clinical Practice Program, Office of the Commissioner (OC)
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
Office of Regulatory Affairs (ORA)
March 2006
Procedural
Guidance
for Industry
Using a Centralized IRB Review Process
in Multicenter Clinical Trials
This
guidance represents the Food and Drug Administration's (FDA's)
current thinking on this topic. It does not create or confer any
rights for or on any person and does not operate to bind FDA or
the public. You can use an alternative approach if the approach
satisfies the requirements of the applicable statutes and
regulations. If you want to discuss an alternative approach,
contact the FDA staff responsible for implementing this guidance.
If you cannot identify the appropriate FDA staff, call the
appropriate number listed on the title page of this guidance.
This guidance is intended to assist sponsors,
institutions, institutional review boards (IRBs), and clinical
investigators involved in multicenter clinical research in meeting
the requirements of 21 CFR part 56 by facilitating the use of a
centralized IRB review process (use of a single central IRB ),
especially in situations where centralized review could improve
efficiency of IRB review.
The guidance (1) describes the roles of the
participants in a centralized IRB review process, (2) offers
guidance on how a centralized IRB review process might consider the
concerns and attitudes of the various communities participating in a
multicenter clinical trial, (3) makes recommendations about
documenting agreements between a central IRB and the IRBs at
institutions involved in the centralized IRB review process
concerning the respective responsibilities of the central IRB and
each institution's IRB, (4) recommends that IRBs have procedures for
implementing a centralized review process, and (5) makes
recommendations for a central IRB's documentation of its reviews of
studies at clinical trial sites not affiliated with an IRB. This
guidance applies to clinical investigations conducted under 21 CFR
part 312 (investigational new drug application, or IND
regulations).
FDA's guidance documents, including this
guidance, do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency's current thinking on a topic
and should be viewed only as recommendations, unless specific
regulatory or statutory requirements are cited. The use of the word
should in Agency guidances means that something is suggested
or recommended, but not required.
Clinical investigations that are subject to the
requirements of IND regulations must be reviewed and approved by an
IRB in accordance with the requirements of 21 CFR part 56. The IRB
requirements evolved at a time when most clinical trials were
conducted at a single study site or at a small number of sites. In
the intervening years, there has been substantial growth in the
amount of clinical research generally, the number of multicenter
trials, and the size and complexity of late-stage clinical trials.
These changes have placed considerable burdens on IRBs and on
sponsors and clinical investigators who are seeking IRB review for
multicenter trials.,
For example, sometimes the IRB at each center of a multicenter trial
conducts a complete review of the protocol and informed consent.
Such multiple reviews by multiple IRBs can result in unnecessary
duplication of effort, delays, and increased expenses in the conduct
of multicenter clinical trials.,
,
Greater reliance on a centralized IRB review process, in
appropriate circumstances, could reduce IRB burdens and delays in
the conduct of multicenter trials.
Use of a centralized IRB review process is
consistent with the requirements of existing IRB regulations.
Section 56.114 (21 CFR 56.114, Cooperative Research) provides that,
“institutions involved in multi-institutional studies may use joint
review, reliance upon the review of another qualified IRB, or
similar arrangements aimed at avoidance of duplication of effort.”
When this rule was proposed, the preamble to the proposed rule
indicated that the purpose of this section is “to explicitly reduce
duplicative review of multi-institutional studies.”
The preamble to the final rule also stated that “the purpose of
this section is to assure IRBs that FDA will accept reasonable
methods of joint review.”
An IRB that is at a different location from the research site can
review the research, provided that the IRB is competent to
understand the local context of the research. As stated in 21 CFR
56.107(a), this would require sensitivity to community attitudes and
the ability to ascertain the acceptability of proposed research in
terms of institutional commitments and regulations, applicable law,
and standards of professional conduct and practice (see Section
IV).
A centralized IRB review
process involves an agreement under which multiple study sites in a
multicenter trial rely in whole or in part on the review of an IRB
other than the IRB affiliated with the research site.
Because the goal of the centralized process is to increase
efficiency and decrease duplicative efforts that do not contribute
to meaningful human subject protection, it will usually be
preferable that a central IRB take responsibility for all aspects of
IRB review at each site participating in the centralized review
process. Other approaches may be appropriate as well. For example,
an institution may permit a central IRB to be entirely responsible
for initial and continuing review of a study, or apportion IRB
review responsibilities between the central IRB and its own IRB.
The following sections describe the roles and
responsibilities of the principal parties as they relate to a
centralized IRB review process.
Under 21 CFR 56.114, institutions that
participate in multicenter studies can use joint review, rely on the
review of another qualified IRB, or establish other arrangements
aimed at reducing duplicative efforts. For example, the decision
could be made in a multicenter trial to rely primarily on the review
of a central IRB while establishing an agreement that all
site-specific IRBs will review their informed consent documents for
local concerns. Institutions should develop policies for
determining when and which studies conducted in the institution
would be appropriate for centralized review and how a centralized
review would be conducted for such studies.
An institution's IRB is the IRB
designated or formed by an institution for the purpose of reviewing
research conducted at the institution or with institutional
support. For multicenter studies, an institution’s IRB can serve as
a central IRB; an institution’s IRB can rely on the review of a
centralized IRB (in whole or in part) in place of its own IRB review
of the study; or it can conduct its own review of the study. The
institution’s policies will dictate under what circumstances the
institution’s IRB can participate in a centralized review process
and the role of the institution’s IRB in that process.
For studies conducted under an IND, 21 CFR part
312 provides that a sponsor is responsible for obtaining a
commitment from each investigator that he or she will ensure that
requirements in part 56 relating to IRB review and approval are met
with respect to the research conducted by the investigator (21 CFR
312.53(c)(1)(vi)(d)). Sponsors can also initiate plans for
use of a centralized IRB review process and facilitate agreements
and other necessary communications among the parties involved.
Under 21 CFR part 312, an investigator
is responsible for ensuring that there will be initial and
continuing review by a qualified IRB of research conducted by that
investigator (21 CFR 312.53(c)(1)(vi)(d); 312.66). If the
investigator is conducting clinical research as part of a
multicenter study at an institution with its own IRB and is subject
to the policies of that institution, those policies would dictate
how the investigator will ensure IRB review. Those policies may
provide that the investigator's responsibility can be met by
ensuring review through a centralized IRB review, through the
institution's IRB, or through apportionment of IRB review
responsibilities between a centralized IRB and the institution's IRB.
For multicenter
studies, the central IRB is the IRB that conducts reviews on
behalf of all study sites that agree to participate in the
centralized review process. For sites at institutions that have an
IRB that would ordinarily review research conducted at the site, the
central IRB should reach agreement with the individual institutions
participating in centralized review and those institutions' IRBs
about how to apportion the review responsibilities between local
IRBs and the central IRB (21 CFR 56.114).
The implementation of a centralized IRB review
process involves addressing a number of issues related to the
communities where the research will take place.The requirements for IRB membership in 21 CFR 56.107(a)
specify that the membership of an IRB must have sufficient
experience, expertise, and diversity to promote respect for its
advice and counsel in safeguarding the rights and welfare of human
subjects. This requirement was intended to implement a
recommendation of the National Commission for the Protection of
Human Subjects of Biomedical and Behavioral Research that IRB
members be “men and women of diverse backgrounds and sufficient
maturity, experience, and competence to assure that the Board will
be able to discharge its responsibilities and that its
determinations will be accorded respect by investigators and the
community served by the institution or in which it is located.”
In addition, IRB members must “be able to ascertain the
acceptability of the proposed research in terms of institutional
commitments and regulations, applicable law, and standards or
professional conduct and practice” (21 CFR 56.107(a)). Thus, IRB
review, through its membership, is intended to provide meaningful
consideration of various local factors in assessing research
activities, including the cultural backgrounds (e.g., ethnicity,
educational level, religious affiliations) of the population from
which research subjects will be drawn, community attitudes
about the nature of the proposed research, and the capacity of the
institution to conduct or support the proposed research.
Inter-community differences could influence, among other things,
assessments of whether mechanisms of subject selection will be
equitable, whether adequate provision is made to minimize risks to
vulnerable populations, and the adequacy of the informed consent
process.
The preamble to the final rule indicates that
where a centralized IRB review process is used (21 CFR 56.114), the
review should consider the ethical standards of the local community.
Therefore, a centralized IRB review process should include
mechanisms to ensure meaningful consideration of these relevant
local factors. Possible mechanisms include:
·
Provision of relevant local information to the central
IRB in writing by individuals or organizations familiar with the
local community, institution, and/or clinical research
·
Participation of consultants with relevant expertise,
or IRB members from the institution's own IRB, in the deliberations
of the central IRB
·
Limited review of a central IRB-reviewed study by the
institution's own IRB, with that limited review focusing on issues
that are of concern to the local community
Other mechanisms may also be appropriate.
IRB meeting minutes or other records should document how relevant
community issues were considered in the review (21 CFR 56.115(a))
(see section V).
IRBs and institutions are required to prepare
and maintain adequate documentation of IRB activities (21 CFR
56.115(a)). IRBs are also
required to follow written procedures for the conduct of initial and
continuing review of clinical research and for reporting their
findings and actions to the investigator and the institution (21 CFR
section 56.108(a), 56.115(a)(6)). The following recommendations
should help IRBs fulfill these requirements.
If an institution, its IRB, and a central IRB
agree (under 21 CFR 56.114) to participate in a centralized IRB
review process, they should document that action in an agreement
signed by the parties. IRBs should report this action to the
investigator and the institution, for example, by providing copies
of the agreement to the investigator, and the institution.
If the agreement apportions IRB review responsibilities between a
central IRB and the institution's IRB, the agreement should
delineate the specific responsibilities of the central IRB and the
institution's IRB for the initial and continuing review of the
study.
When an
institution and an institution's IRB rely on review by a central IRB,
both IRBs must have written procedures in place to implement the
centralized IRB review process (21 CFR 56.108, 56.114). For example,
procedures should address the following:
·
How the
institution's IRB determines that the central IRB is qualified to
review research conducted at the institution
·
How the central
IRB intends to communicate with relevant institutions, the
institutions’ IRBs, and investigators regarding its review
·
How the central
IRB ensures that it provides meaningful consideration of relevant
local factors for communities from which research subjects will be
drawn (see Section IV)
·
How the central
IRB assesses the ability of a geographically remote site to
participate in a study (e.g., whether the site has medical services
appropriate to the complexity of the study)
When an
institution, an institution's IRB, and a central IRB
agree to apportion IRB review responsibilities between the two IRBs,
each IRB must have written procedures describing how it implements
its responsibilities under the agreement (21 CFR 56.108,
56.115(a)(6)).
VI. Using A Central IRB at
unaffiliated sites
At clinical
sites that are not already affiliated with an IRB, investigators and
sponsors typically rely on the review and oversight of a central IRB.
In this situation, the central IRB should document in meeting
minutes or other records how it considered relevant local factors
for the various communities from which research subjects are to be
drawn (see Section IV). The central IRB must also document its
action in agreeing to conduct IRB review for the site (21 CFR
56.115) and must have written procedures in place that describe how
it will perform its initial and continuing review responsibilities
at remote sites (21 CFR 56.108, 56.115(a)(6))
(see Section
V).
There are a
variety of mechanisms that have been used to distribute IRB review
responsibilities between an institution’s IRB and a central IRB.
This guidance is not intended to endorse any particular mechanism.
These examples are provided only to illustrate possible mechanisms.
The primary model contemplated by this guidance
is a centralized IRB review process used for a single multicenter
trial performed by a commercial or publicly funded sponsor. Under
21 CFR 56.114, IRBs affiliated with the study sites could enter into
agreements with a central IRB to rely on all or some of the review
findings of the central IRB, or could decline to participate in a
centralized IRB review (i.e., do their own complete review). Study
sites not already affiliated with an IRB would rely on a central IRB
for all IRB review responsibilities.
B. Central IRB Formed to Review
Multicenter Trials in a Therapeutic Category
A central IRB can be formed to review
multicenter trials in a therapeutic category. For example, the
National Cancer Institute (NCI) has created a freestanding central
IRB (NCI central IRB) to provide the option for centralized IRB
review for the many multicenter cancer trials conducted by NCI.
This NCI central IRB is a standing body with subject matter
expertise that reviews all NCI-sponsored phase 3 trials in adults
with cancer. The IRBs affiliated with the study sites have the
option of accepting the review of the NCI central IRB, or doing
their own complete review of the protocol and informed consent.
IRBs at some academic medical centers have
entered into ongoing cooperative agreements in which their IRBs have
the option of accepting reviews by IRBs at other centers when both
centers are participating in a multicenter trial.
The Agency hopes that sponsors, institutions,
institutional review boards (IRBs), and clinical investigators
involved in multicenter clinical research will consider the use of
a single central IRB (centralized IRB review process), especially if
using centralized review could improve the efficiency of IRB
review.
Federal Register, Vol. 46, pp. 8958, 8970, January 27, 1981.
Federal Register, Vol. 46, p. 8966, January 27, 1981
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Date created: March 15, 2006 |