Note: The original document was converted from pdf to HTML format.
PURPOSE
To summarize the challenges facing institutional review
boards and to make recommendations for Federal oversight.
BACKGROUND
Role of Institutional Review Boards
Institutional review boards (IRE3s) play vital roles in
protecting human research subjects. They review initial research plans to
make certain that the plans provide subjects with adequate opportunity to
provide informed consent and do not expose subjects to unreasonable risks.
They also conduct continuing review of approved research to ensure that
human-subject protections remain in force. They carry out their initial
and continuing review functions in accord with Federal regulations first
established in the 1970s and applicable to all research funded by the U.S.
Department of Health and Human Services or carried out on products
regulated by the Food and Drug Administration.
This Summary Report
This is a synthesis report. It draws on our broad
inquiry of 1-s and on findings we presented in three parallel reports. Its
overarching conclusion is that the long-established system for protecting
human research subjects has vulnerabilities that threaten its
effectiveness. In the report we highlight the major elements leading to
this conclusion and offer recommendations for improvement. The
recommendations are especially important in view of current Federal plans
to increase significantly the numbers of human subjects participating in
clinical trials, and proposals to give IRE& increased responsibility
in the areas of genetics and confidentiality.
With this report, we offer a warning signal and a
framework for a concerted response to it. We do not document, nor do we
suggest that widespread harm is being done to human subjects. We recognize
the strengths of the current system and seek to build on them to enhance
human-subject protections.
Methodology
Given our focus on the overall system of protections, we
did not carry out audits of IRBs or investigations of particular cases. To
help us understand the big picture, we conducted an extensive review of
Federal records and pertinent literature; held interviews and group
discussions with many Federal officials and with representatives of about
75 IRBs; visited IRE3s at 6 academic health centers where extensive
clinical research is taking place; attended IRE3 meetings; and accompanied
FDA inspectors on IRB site visits.
IRBS: A Time For
Reform.
FINDINGS
The Effectiveness of IRBs Is in Jeopardy.
They Face Major Changes in the Research Environment. The current framework of IRB practices was shaped in the 1970s in an
environment where research typically was carried out by a single
investigator working under government funding with a small cohort of human
subjects in a university teaching hospital. In recent years, that
environment has been changing dramatically as a result of the expansion of
managed care, the increased commercialization of research, the
proliferation of multi-site trials, new types of research, the increased
number of research proposals, and the rise of patient consumerism. Each of
these developments has presented major disruptions and challenges for
IRBs. "Never before," concluded one recent review, "has
such a pressure-cooker atmosphere prevailed within the IRB system."
They Review Too Much, Too Quickly, with Too Little Expertise. This is
especially apparent in many of the larger institutions. Expanded
workloads, resource constraints, and extensive Federal mandates contribute
to a rushed atmosphere where sufficient deliberation often is not
possible. At the same time, the IRBs frequently are hard pressed to gain
access to the scientific expertise they need to reach informed judgments
about the research taking place under their jurisdiction.
They Conduct Minimal Continuing Review of Approved
Research. In the environment described above, continuing review often
loses out. Even where there is the will, there often is not the time to go
beyond the perfunctory obligations. A lack of feedback from other entities
that oversee multi-site trials contributes to the problem. The result is
that IRBs have all too little information about how the informed consent
process really works and about how well the interests of subjects are
being protected during the course of research.
They Face Conflicts That Threaten Their Independence. Clinical research provides revenue and prestige to the institutions to
which many IRBs belong. The institutions expect IRBs to support these
interests at the same time that they protect human subjects. The resulting
tension can lessen the IRBs’ focus on their basic mission. The minimal
"outside" representation that typically exists on IRBs deprives
them of an important counterbalance to the institutional interests. For
independent IRBs, the dependence on revenue from industry sponsors exerts
similar possibilities for conflict.
They Provide Little Training for Investigators and
Board Members. The RI3 system depends heavily on research
investigators’ commitment to uphold human-subject protections. But as
that system now operates, it offers little educational outreach to
investigators to help them become informed and sensitized about these
protections.
Similarly, it provides minimal orientation and
continuing education for IRB members--a-w deficiency that is especially
detrimental to nonscientific and noninstitutional members.
OEI-Ol-97-00193 IRBS: A Time For
Reform.
Neither IRBs Nor HHS Devote Much
Attention to Evaluating IRB Effectiveness. IRBs
rarely conduct inquiries to determine how well they are accomplishing
their mission; their judgments of effectiveness rely mainly on the number
of protection lapses or complaints that are brought to their attention.
The HHS agencies conducting oversight seldom go any further. The Offrce
for Protection from Research Risks, in the National 1 Institutes of
Health, focuses almost entirely on upfront assurances. The Food and Drug
Administration relies on compliance-focused inspections.
RECOMMENDATIONS
With the above findings, we do not claim that there are
widespread abuses of human research subjects. The current system of
protections is supported by many conscientious research investigators
committed to protecting human subjects and by many dedicated IRB members
and staff doing their best under trying circumstances. A reviewer of this
system can not help but be impressed by the contributions of these
individuals, and the important function that IRBs have fulfilled over the
past quarter of a century.
But our findings present an important warning signal.
The capacity of IRBs to accomplish all that is expected of them is
strained. In the years ahead, this difficult situation could become even
worse in view of Federal plans to increase significantly the numbers of
subjects in clinical trials and various proposals to give IRBs added
responsibility in the areas of genetics and confidentiality. It is time,
we believe, for reform.
Our recommendations offer a framework for such a
response. We direct them jointly to the two HHS agencies responsible for
IRB oversight: the Office of Protection from Research Risks (OPRR), which
is located within the National Institutes of Health (NIH), and the Food
and Drug Administration (FDA). These agencies oversee IRBs with different
jurisdictions and operational approaches. It is essential, therefore, for
them to collaborate closely if HHS as a whole is to respond effectively to
the serious concerns that emerge from our inquiry. Below we present our
general recommendations for the two agencies. In the text, we offer more
explicit elaborations directed, as appropriate, to the particular
agencies.
Recast Federal IRB Requirements So That They Grant
IRBs Greater Flexibility and Hold Them More Accountable for Results.
Eliminate or lessen some of the procedural
requirements directed to IRBs.
Require that IRBs undergo regular
performance-focused evaluations.
Strengthen Continuing Protections for Human
Subjects-Participating in Research.
Require Data Safety Monitoring Boards
for some multi-site
trials
. . . .
IRBS: A Time For Reform.
Provide IRESs with feedback on
developments concerning multi-site trials.
Routinely provide IRE&s with feedback about
FDA actions against investigators.
Require sponsors and investigators to notify IRBs of
prior reviews of research plans.
Call for increased IRE3 awareness of on-site research
practices.
Enact Federal Requirements That Help Ensure That
Investigators and IRB Members Are Adequately Educated About and Sensitized
to Human-Subject Protections.
Require that research institutions have a program for
educating its investigators on human-subject protections.
Require that investigators provide a written
attestation of their familiarity with and commitment to human-subject
protections.
Require that IRBs have an educational program for
board members.
Help Insulate IRBs from Conflicts That Can Compromise
Their Mission in Protecting Human Subjects.
Require more representation on Irks of nonscientific
and noninstitutional members.
Reinforce to IRE3 institutions the importance of IRBs
having sufficient independence.
Prohibit IRE! equity owners from participating in the
IRE3 review process.
Recognize the Seriousness of the Workload Pressures
That Many IRBs Face and Take Actions That Aim to Moderate Them.
Require that IREJs have access to adequate resources.
Reengineer the Federal Oversight Process.
Revamp the NIWOPRR assurance process.
Revamp the FDA on-site inspection process.
Require the registration of 1-s.
iv 031-01-97-00193 IRRS: A
Time For Reform.
COMMENTS ON THE DRAFT REPORTS
Within the Department of Health and Human Services (HHS),
we received comments on our four draft reports from the National
Institutes of Health (NIH), the Food and Drug Administration (FDA), and
jointly from the Assistant Secretary for Planning and Evaluation (ASPE)
and the Assistant Secretary for Health (ASH). We also solicited and
received comments from the following external organizations: the Applied
Research Ethics National Association (ARENA), the American Association of
Medical Colleges (AAMC), the Consortium of Independent Review Boards (CIRB),
and Public Citizen’s Health Research Group. We include the detailed text
of their comments and our responses to them in appendix D. Below we
summarize the major thrust of both their comments and our responses. We
made a number of changes in the final reports. Most were technical in
nature. Their comments sought to clarify certain findings and a few
involved clarifications and elaborations concerning the recommendations.
NIH, FDA, and ASPE/ASH Comments
The HHS parties viewed the reports as raising important
issues and recommendations warranting widespread discussion. They
suggested various ways this could be accomplished. The NIH expressed
particular support for our recommendation calling for the assurance
process to be revamped so that it rests essentially on an institutional
attestation to conform to IRB requirements and thereby enables OPRR to
focus more on performance assessment and education. The FDA expressed
reservations about refocusing its compliance-oriented inspection process,
which it regards as having "great value," to one that is more
performance-oriented. The FDA also raised concerns about the resource
implications of some of our recommendations.
We will support efforts to engage broadly-based
dialogue on our findings and recommendations. At the same time, we
underscore the importance ofpractical near-term actions that can be taken
to address the vulnerabilities we point out. We particularly
urge that FDA and NIH incorporate into their oversight spectfic lines of
inquiry to determine how well IRBs are actually protecting human subjects.
This would call for examining such matters as how the processes of
recruiting, selecting, and gaining informed consent@om human subj*ects
actually work. It would also call for addressing vertftcation efforts to
make sure that protocols are in fact submitted for review and that
approved protocols do not stray offcourse. On the matter of resources, we
agree that this is an important issue warranting serious attention in the
research and policy communities, particularly in view of added
responsibilities IRBs may well face in the years
ahead.
External Organizations’ Comments
While the external parties supported many of our
findings and recommendations, they also raised some strong concerns.
Basically, these involved differences of substance and objections to the
use of certain terms and language. In regard to the former, Public
V OEI-Ol-97-00193 IRBS: A Time For Reform.
Citizen, in expressing considerable
alarm over our findings, felt that we should have gone further with our
investigations and recommendations. On the other hand, ARENA and AAMC had
reservations about our call for performance-focused evaluations and for
more outside representation on IRBs. They were also concerned that a more
active IRB role in conducting continuing review could undermine the trust
that has existed between IRBs and the research community. With respect to
the language we used, ARENA, AAMC, and CIRE3 called for a more precise use
of a number of terms. The ARENA indicated that our use of the term
"IRE3 oversight" was particularly misleading. The ARENA and AAMC
both indicated that some of our wording was unduly alarmist and more
encompassing than our methodology warranted.
To facilitate a serious examination of
the matters of substance we raise, we changed some of the language we used
in the draft reports. Most notably, instead of referring to "IRB
oversight, " we focused on IRB responsibilities and authorities to
conduct "continuing review, " as spectfied in Federal
regulations. But, this and various other such textual modifications we
made in no way lessen our assessment that the effectiveness of the IRB
system is in jeopardy. Our wide ranging and in-depth inquiry offers us
ample basis to sound that warning. With respect to concerns raised that
focus more strictly on matters of substance, we must underscore that if
IRBs are to meet the significant challenges they face in the years ahead
they must become more fully accountable to the public. Trust in the
investigators performing research is vitally important, but in itself is
insuf$cient. The IRBs and Federal oversight agencies mustfind more
effective and open ways of verifying that the consumer protection mission
of IRBs is in fact being accomplished.
This is especially important as the research environment in which IRBs
function becomes increasingly commercialized.