[Federal Register Volume 67, Number 44 (Wednesday, March 6, 2002)]
[Proposed Rules]
[Pages 10115-10116]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 02-5247]
========================================================================
Proposed Rules
Federal Register
________________________________________________________________________
This section of the FEDERAL REGISTER contains notices to the public of
the proposed issuance of rules and regulations. The purpose of these
notices is to give interested persons an opportunity to participate in
the rule making prior to the adoption of the final rules.
========================================================================
Federal Register / Vol. 67, No. 44 / Wednesday, March 6, 2002 /
Proposed Rules
[[Page 10115]]
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 56
[Docket No. 01N-0322]
Institutional Review Boards: Requiring Sponsors and Investigators
to Inform IRBs of Any Prior IRB Reviews
AGENCY: Food and Drug Administration, HHS.
ACTION: Advance notice of proposed rulemaking.
-----------------------------------------------------------------------
SUMMARY: The Food and Drug Administration (FDA) is considering whether
to amend its institutional review board (IRB) regulations to require
sponsors and investigators to inform IRBs about any prior IRB review
decisions. These disclosures could help ensure that sponsors and
clinical investigators who submit protocols to more than one IRB will
not be able to ignore an unfavorable IRB review decision and that IRBs
reviewing a protocol will be aware of what other IRBs reviewing similar
protocols have concluded. FDA seeks information on IRB practices to
determine whether it should draft a regulation and, if a regulation is
to be drafted, to help determine the regulation's contents.
DATES: Submit written or electronic comments by June 4, 2002.
ADDRESSES: Submit written or electronic comments to the Dockets
Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers
Lane, rm. 1061, Rockville, MD 20852. Submit electronic comments to
http://www.fda.gov/dockets/ecomments.
FOR FURTHER INFORMATION CONTACT: Philip L. Chao, Office of Policy,
Planning, and Legislation (HF-23), Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857, 301-827-3380.
SUPPLEMENTARY INFORMATION:
I. Introduction
IRBs are boards, committees, or other groups formally designated by
an institution to review, approve the initiation of, and conduct
periodic review of biomedical research involving human subjects (see 21
CFR 56.102(g)). An IRB's primary purpose during such reviews is to
assure the protection of the rights and welfare of human subjects
(id.). FDA's IRB regulations are at 21 CFR part 56 and apply to
clinical investigations involving FDA-regulated products such as human
drugs, biological products, medical devices, and food additives. (While
section 520(g) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C.
360j(g)) refers to ``institutional review committees'' rather than
IRBs, FDA considers institutional review committees to be IRBs and to
be subject to the IRB regulations).
In 1998, the Department of Health and Human Services, Office of the
Inspector General (OIG) issued several reports on IRBs. The OIG sought
to identify the challenges facing IRBs and to make recommendations on
improving Federal oversight of IRBs. One recommendation was that
sponsors and clinical investigators be required to notify IRBs of any
prior review (see Office of the Inspector General, Department of Health
and Human Services, Institutional Review Boards: A Time for Reform, p.
14, June 1998). The OIG report stated that the OIG had:
* * * heard of a few situations where sponsors and/or research
investigators who were unhappy with one IRB's reviews switched to
another without the new IRB being aware of the other's prior
involvement. This kind of IRB shopping deprives the new IRB of
information that it should have and that can be important in
protecting human subjects. The ground rules should be changed so
that sponsors and investigators have the clear obligation to inform
an IRB of any prior reviews (footnote omitted). The obligation
should be applied to all those conducting research funded by HHS or
carried out on FDA-regulated products. It will have particular
importance for those sponsors and investigators working with
independent IRBs. Id.
It is important to note that the OIG never suggested that it was
inappropriate to challenge a negative decision or to seek another IRB's
review. What the OIG found troubling was the possibility that the
second IRB would be unaware of the first IRB's concerns and
reservations.
After reviewing the OIG's recommendation, FDA is considering
whether to revise its IRB regulations to require such disclosures and,
in this advance notice of proposed rulemaking (ANPRM), has identified
several issues on which it invites public comment. The public comments
will help FDA decide whether a regulation is needed and, if so, what
the regulation's requirements should be.
The issues, in no particular order, are as follows:
1. How significant is the problem of IRB shopping? The OIG report
refers to ``a few situations'' where IRB shopping supposedly occurred,
but does not offer any quantitative estimate. FDA seeks information on
how frequently IRB shopping occurs, the circumstances in which it
occurs, and the nature of the different conclusions reached by the
IRBs. For example, what number or percentage of sponsors and
investigators engage in IRB shopping? What issues lead to IRB shopping?
Is IRB shopping more prevalent where certain FDA-regulated products are
involved or more likely to occur in certain types of research or under
certain other situations? What sorts of differences in IRB conclusions
are observed? Are there particular areas of disagreement that suggest a
wider issue, such as review of certain trial practices or standards? Is
IRB shopping more prevalent when the protocol includes or excludes
certain populations (such as women and minorities)? Information on
specific occurrences of IRB shopping and disagreement would be useful
to help determine the seriousness of the problem.
2. Who should make these disclosures? The OIG report recommended
that sponsors and investigators inform IRBs about any prior reviews,
but FDA's experience suggests that there is some variation as to the
person who seeks IRB review. In some instances, a sponsor, rather than
an investigator, will seek IRB review, especially in the case of
devices. One way to deal with these variations could be to require the
person who sought the prior review, whether he or she is a sponsor,
investigator, or both a sponsor and investigator, to make the required
disclosures.
As FDA considered this issue further, questions arose as to whether
sponsors and investigators should have a duty to
[[Page 10116]]
inform IRBs about any prior reviews, even if the sponsor or
investigator had not sought the prior review, but somehow knew about
it. For example, if investigator X and investigator Y were using the
same protocol, and if investigator X knew that an IRB had disapproved
investigator Y's protocol, should investigator X inform his or her IRB
about that disapproval even though it involved a different
investigator? If the sponsor knew that an IRB had disapproved
investigator Y's protocol, should it notify investigator X so that he
or she could inform his or her IRB? FDA invites comment on these
issues.
3. Who should receive the disclosures? The OIG report states that
IRB's that are reviewing or are going to review a protocol should be
informed about prior IRB reviews. This assumes that the prior IRB's
decision is known at the time the second IRB is asked to review the
protocol. But what happens if the new IRB has already approved the
protocol at the time the prior IRB's decision becomes known? Would
information about prior IRB reviews still be helpful? One could argue
that sponsors and investigators should inform new IRBs about prior IRB
reviews, even if the new IRB has already approved the protocol, because
the prior reviews might be relevant to the new IRBs continuing review
of a protocol.
4. What information should be disclosed? The type of information to
be disclosed depends on the purpose of the disclosure. If the purpose
is solely to be certain that an IRB is aware of a prior adverse
conclusion, perhaps only unfavorable prior reviews would need to be
disclosed. If the purpose of the disclosure is to ensure that IRBs
receive all relevant information about a study, it might be appropriate
to disclose all prior IRB decisions, both positive and negative. Should
all prior IRB reviews, including approvals, be disclosed?
5. If a proposal would not require disclosure of all prior IRB
decisions, what information should be disclosed? Even if the purpose of
disclosure is solely to be sure an IRB is aware of an unfavorable IRB
review, there could be different degrees of disclosure. An unfavorable
IRB decision could encompass complete disapproval of a protocol, a
decision to approve a protocol with stipulations, and a request for
significant changes to a protocol. Even a decision to require
additional reviews by the IRB could be considered as an unfavorable
decision.
A requirement to disclose only prior unfavorable IRB reviews may
presume that an unfavorable review is more likely to be correct than a
favorable review. If one presumes that the earlier IRB correctly
disapproved, or requested modifications of, a protocol, then a new IRB
could, indeed, benefit from knowing about that decision. This could be
the case, for example, if the earlier IRB disapproved a protocol
because one of its scientific members recognized that the
investigational product would present a greater risk of harm to
research subjects than was acknowledged in the informed consent
document, based on that member's knowledge of certain animal studies.
This information would be helpful to a new IRB, particularly if its
scientific members did not possess the same expertise as the earlier
IRB. On the other hand, a favorable decision by a prior IRB with
superior expertise in a particular case could also be of value to a
subsequent IRB as well.
Conversely, in cases where an initial review, either favorable or
unfavorable, was not well-founded, information about the earlier IRB's
review decision may offer little or no value to a new IRB and might
lead to an ill-considered, ``defensive'' acceptance or rejection of a
satisfactory proposal. For example, if an IRB was associated with an
institution, and the institution was well-known or had a good
reputation, a subsequent IRB might be inclined to follow the first
IRB's decision even if the first IRB's decision was not well-founded.
6. To permit a subsequent IRB to assess the value of a prior IRB
decision, should information about the basis for the prior decision be
disclosed? Currently, IRBs are not generally required to document the
reasons for approving a study, so if a proposed rule would require all
IRB decisions to be disclosed, IRBs might have to explain their reasons
for approving a study. Should the disclosed information include
information about the composition and expertise of the prior IRB's
members? What would be the additional burden on IRBs if FDA required
the disclosure of the basis for all or even some IRB review decisions?
How would this affect the time needed to conduct an IRB review?
7. How should FDA enforce the requirement? The OIG report did not
suggest any method for enforcing a requirement that these disclosures
about prior IRB reviews occur. What would be an appropriate sanction to
impose on an investigator or sponsor for failure to comply with a
disclosure requirement?
FDA must learn about a violation before it can consider what
sanctions might be imposed. The OIG report did not recommend that
sponsors and investigators inform FDA about any prior IRB reviews; it
only recommended that sponsors and investigators inform IRBs. If FDA
has no knowledge about the prior IRB review, the agency might find it
difficult to detect noncompliance. FDA invites comment on how it might
enforce the requirement efficiently.
8. Are There Other Ways to Deal with IRB Shopping Other Than
Disclosure of Prior IRB Reviews? Although the OIG report recommended
requiring disclosure of prior IRB reviews, there may be other ways to
deal with IRB shopping. Therefore, if the problem of IRB shopping is
significant enough to warrant Federal regulatory action, are there
other requirements that could be employed to address the problem
besides mandating disclosure of prior IRB reviews?
II. Request for Comments
Interested persons may submit to the Dockets Management Branch
(address above) written or electronic comments regarding the issues
presented in this ANPRM by June 4, 2002. Two copies of any comments are
to be submitted, except that individuals may submit one copy. Comments
should be identified with the docket number found in brackets in the
heading of this document. Received comments may be seen at the Dockets
Management Branch between 9 a.m. and 4 p.m., Monday through Friday.
Dated: October 23, 2001.
Margaret M. Dotzel,
Associate Commissioner for Policy.
[FR Doc. 02-5247 Filed 3-5-02; 8:45 am]
BILLING CODE 4160-01-S