Comment Letter on Ethical
and Policy Issues in Research Involving Human Participants
January 26, 2001
Eric M. Meslin, Ph.D.
Executive Director
National Bioethics Advisory Commission
6705 Rockledge Drive, Suite 700
MSC 7979
Bethesda, MD 20892-7979
Dear Dr. Meslin:
On behalf of the Association of American Medical Colleges
(AAMC), an organization representing all 125 allopathic medical
schools, over 400 major teaching hospitals and 91 academic
societies, I am responding to your invitation to provide comments
on the draft report, "Ethical and Policy Issues in Research
Involving Human Participants." As you know, the AAMC
has been deeply involved in efforts to strengthen the ethical
conduct of research involving human participants in a variety
of ways. For example, we have jointly sponsored educational
programs with the organization, Public Responsibility in Medicine
and Research (PRIM&R), for Institutional Review Board
(IRB) members, staff, and institutional officials responsible
for clinical research oversight at our member institutions,
and we have created a web site to highlight and make accessible
the most impressive initiatives developed by our members to
address the education and credentialing of clinical investigators.
Like the National Bioethics Advisory Commission (NBAC), the
AAMC and its members believe that the protection of human
participants in clinical research is of the utmost importance,
and that protection is most effective in settings that place
a high priority on, and give strong attention to, clinical
research ethics and compliance with the regulatory process.
At the outset, the AAMC congratulates you and your colleagues
for preparing a document that is extremely thorough and balanced
in tone, and that seeks to address virtually all of the ethical
and policy issues involved in research on human participants.
The Association especially welcomes your objective historical
review of ethical issues in clinical research, and we strongly
endorse your appreciation of the need for balanced solutions
aimed at identifiable problems. We completely agree with your
view that the future of clinical research depends upon public
trust, and that a vibrant program of clinical research is
essential if we are to translate advances in science and technology
into improved treatments and prevention efforts that can advance
human health.
The first chapter of the report highlights some perceived
gaps and regulatory conflicts in our present system of human
subjects protection. You have sought to define these at three
levels: structural, regulatory and local. At the structural
level, you note inconsistencies in the ways that different
federal agencies interpret the Common Rule, and that these
discrepancies can produce confusion and frustration among
investigators and IRBs. You further note inconsistencies in
the ways that different agencies deal with special protections
for vulnerable populations. You observe that an undefined
volume of privately funded research that falls outside the
purview of the Food and Drug Administration (FDA) lies beyond
the reach of federal regulation and may be conducted without
regard to regulatory requirements. You argue that the Common
Rule has not been adaptable enough to accommodate emerging
ethical issues or new scientific developments, and finally
with respect to structural issues, that lines of enforcement
authority are awkward, the repertory of sanctions designed
to address the range of possible violations, extremely limited,
and the process of oversight and investigation, uneven.
The AAMC agrees with many of your observations about inconsistencies
in the application of the Common Rule across federal agencies.
Like NBAC, the Association believes that the different interpretations
that individual agencies put on the Common Rule can create
conflicts and confusion for IRBs, investigators and institutions.
We believe that this issue can and should be addressed under
the guidance of the Office of Science and Technology Policy
(OSTP) and the Committee on Science of the National Science
and Technology Council (NSTC), bodies that have been able
to develop solutions to other important conflicts in research
regulatory policy among agencies.
In regard to problems with the regulatory process, you note
that the regulatory emphasis has been too focused on procedural
requirements rather than ethical principles. We agree with
your concerns. We strongly support your observation that the
repertory of sanctions needs to be tailored to respond proportionately
to a range of violations, and that enforcement bodies should
have powerful options short of shutting down all clinical
research to deal with the range of problems encountered. We
are especially supportive of your position that the Common
Rule should apply to all research involving human participants
and we strongly endorse your observation that compensation
for research-related injuries is not being adequately addressed.
This is an area of special significance if we as a nation
wish seriously to acknowledge the substantial contributions
to the public good being made each day by human volunteers
in clinical research studies.
At the local level, you correctly cite the numerous regulations
and growing workloads facing IRBs, and the administrative
burdens associated with the preparation and modification of
Multiple Project Assurances (MPA). You note, as have others,
the particular burdens imposed on IRBs in evaluating and monitoring
multisite clinical trials. You observe that "IRBs may
be squandering precious resources having dozens or hundreds
of IRBs review all aspects of a single multisite protocol
when the design and methods cannot be changed…," and
that local IRBs may be poorly situated to evaluate such research
or to provide continuing oversight of adverse events and other
issues in multisite trials. The AAMC agrees that these issues
need to be addressed, and that IRB members and investigators
need to be educated and supported in the application of ethical
principles to clinical research. We applaud your recommendation
(5.1) that the oversight system must have adequate resources
and that institutions should be permitted to request from
federal or private sponsors direct funding for IRBs and other
oversight activities. The Association also endorses your observation
that local IRBs are not in a conflict of interest de facto
by virtue of their location in an institution that is being
funded to conduct a research project.
Following your cogent analysis of the issues, you propose
a more problematic major re-organization of the federal oversight
role in clinical research oversight. While the AAMC endorses
your view that Congress should pass legislation mandating
that all research involving human participants be covered
by federal regulations, regardless of funding source, we
believe that it would be undesirable and unwise at this time
to establish a new, independent, single federal office to
lead and coordinate the oversight system for all human research.
You propose to give this agency broad authority for policy
development, including rule making and interpretation, education,
research review, monitoring, enforcement and accountability,
but you would, at the same time, retain the human research
oversight activities that exist at the departmental or agency
level, such as Office for Human Research Protections (OHRP)
in the Department of Health and Human Services (HHS), and
the regulatory authorities of the FDA.
We are unconvinced that the proposed new single federal agency
(the National Office of Human Research Oversight--NOHRO) would
be well positioned to address the problems that you have identified
in Chapter 1. We fear that your proposal will lead to confusion
of hegemony and administrative responsibility with respect
to implementation of federal regulations and could actually
undermine the very protections of human research subjects
that you are trying to enhance. Moreover, we observe that
the new OPHR has been in existence for only a very short period
of time and has barely begun to establish its identity and
authority. We believe that the creation of the proposed new
agency will create additional uncertainties at the federal
level about the authority and actions of OHRP at a time when
its role and responsibilities should be unambiguous. As you
know, a new accrediting mechanism for IRBs and institutional
oversight of human subjects protection is about to be launched.
These independent, but complementary, efforts (OHRP and the
Association for the Accreditation of Human Research Protection
Programs--AAHRPP), need to be given the opportunity to work
before deciding to create a new super-agency to oversee the
protection of human participants in clinical research.
The AAMC believes that the Executive Branch has sufficient
authority to address problems of inconsistency in interpreting
and applying the Common Rule, and that the Office of Science
and Technology Policy and the Committee on Science of the
NSTC should be directed to bring the representatives of the
17 federal agencies together to resolve these matters as expeditiously
as possible.
In contrast to our serious disagreement with your proposal
to create NOHRO, AAMC endorses your definition of research
and of human research participants. Because your definition
of human research participants does not include deceased individuals,
embryos, fetal tissues, the analysis of non-identifiable data
from human beings, and information revealed by a research
subject about others, it should help to define a framework
for the requirements of informed consent which is sensitive
to the protection of patient privacy, while not discouraging
important research in such areas as population health and
stem cell transplantation.
In Chapter 3, you take on the complex subject of risk/benefit
ratios. While the definitions of risk and benefit are clear
in your analysis, you suggest a departure from current standards
that is certain to have unintended negative consequences.
Because of your concern that the promise of an effective treatment
might serve as an inducement for an IRB to approve a protocol
that included a riskier non-treatment-related research component,
you propose that IRBs should disarticulate therapeutic and
non-therapeutic aspects of each research project that they
review, and then determine separately the risk/benefit ratio
of each component. You then go on to define minimal risk on
the basis of minimal risk as experienced by normal, healthy
individuals. You employ an example from pediatrics when you
argue that a relative standard of minimal risk as applied
to diseased populations would "violate the ethical principle
of justice." However, this position is at variance with
current ethical standards, as well as with federal regulations
that require IRBs to classify risk involving children into
one of four categories that may merit approval:
-
Research not involving risk
-
Research involving greater than minimal risk, but presenting
the prospect of direct benefit to an individual subject
-
Research involving greater than minimal risk with no
prospect of direct benefit to individual subjects, but
likely to yield generalizable knowledge about the subject's
disorder or condition. Research in this category is
approvable provided: (a) the risk represents a minor increase
over minimal risk; (b) the intervention or procedure presents
experiences to subjects that are reasonably commensurate
with those inherent in their actual or expected medical,
dental, psychological, social, or educational settings;
and (c) the intervention…is likely to yield generalizable
knowledge about the …disorder or condition….
-
Research that is not otherwise approvable, but which
presents an opportunity to understand, prevent, or alleviate
a serious problem affecting the health or welfare of children"
may be conducted or funded by DHHS "provided that
the IRB and the Secretary, after consultation with a panel
of experts" conclude that the research is ethically
and scientifically justified."
The AAMC believes that your proposal is extremely ill advised,
and would, if implemented, virtually eliminate patient oriented
research in pediatrics. Indeed, if your proposal were extended
to all vulnerable populations, it would effectively eliminate
much patient oriented research in psychiatry, neurology, and
other fields of adult medicine and surgery. In the first place,
it is not clear that the therapeutic and non-therapeutic aspects
of a research project can be cleanly separated. Second, by
prohibiting a relative standard of risk based upon what an
ill person normally experiences (compared to a normal person),
you force risk assessment to be conducted within a framework
of unreality in which virtually all procedures must necessarily
be deemed to be of "more than minimal risk" because
they are not typically experienced by normal, healthy individuals.
Third, by separating the therapeutic and non-therapeutic aspects
of a project, and not offering a de facto third category of
risk ("minor increase over minimal risk"), you would
make it extremely difficult for sick children or other vulnerable
populations to participate in those components of a research
project deemed "non-therapeutic" (e.g., exposure
to a functional MRI scan). The AAMC believes that recommendations
3.1 and 3.2 are dangerous in their present form and need to
be substantially modified to conform your proposal to the
contours of current ethical practice.
In contrast to your recommendations on assessing risk/benefit
ratios, the AAMC is very impressed with your recommendations
on informed consent. The discussion of the issues around these
recommendations is thoughtful and well-informed. We completely
agree that "the process of ensuring informed consent"
is much more important than "the form of its documentation."
We were especially pleased by your recommendations on vulnerable
populations. Rather than cast an entire class of individuals
(e.g.: the "mentally ill") as vulnerable on the
basis of "impaired capacity", you propose an analytic
approach that describes different types of vulnerabilities
and a range of appropriate safeguards. This analysis is very
sophisticated and consistent with current research on informed
consent. The AAMC supports your notion that an IRB should
be able to offer an administrative review for all research
that is no more than minimal risk, even if it involves vulnerable
subjects.
While the Association is not comfortable with your proposal
to create a new agency to oversee all research involving human
participants, we do support your proposal to provide some
centrally coordinated mechanism to review research involving
vulnerable individuals who cannot give informed consent, where
the local IRB is unable to act on the proposal. Your recommendation
(3.12) to convene interested parties in discussions about
ethical issues and the challenges facing the research community
might help to establish the right tone and venue for all interested
stakeholders to confront these dilemmas in a collaborative
way.
In Chapter 4, you lay out an educational agenda for IRBs,
investigators and educators of the next generation of clinical
researchers. The AAMC strongly endorses these recommendations
(4.1-4.4). As you know, the AAMC has been centrally involved
in creating a new organizational structure (AAHRPP) to accredit
human subjects protections programs. Our strategy is fully
consistent with your view that the education of investigators
and IRB members is an institutional responsibility. We also
agree with recommendations 4.5 and 4.6 that issuances of assurance
should be non-duplicative (i.e., simplified), and that institutions
should develop internal mechanisms to ensure IRB and investigator
compliance with regulations, guidance and institutional procedures.
Institutions must ensure that conflicts of interest will not
subject research participants to any harm.
While your analysis of the importance of local IRB review
and continuing monitoring of clinical research was exemplary,
the AAMC has serious questions about the workability of your
proposal that at least 50% of the membership of an IRB should
not be affiliated with the institution, and that at least
50% should be non-scientists. For one thing, having a critical
mass of professional knowledge on an IRB, familiar with the
science, the institutional milieu, and the capability of the
investigators, is fundamental to the concept of the local
IRB and to the responsible discharge of the IRB's mandate.
Second, service on an IRB is burdensome and requires dedication
on the part of its members. As you have noted in your analysis,
it is very difficult for institutions to secure such dependable
dedication from outside of the institution. Rather than mandate
50% membership from outside the institution and from non-scientists,
it would seem more reasonable to recommend that the institution
should ensure that a credible number of non-scientists and
unaffiliated individuals serve on the IRB.
In addition, the institution must ensure that members of
the IRB have no conflict of interest in their review of proposals.
We note that there is one error on Page 31 of Chapter 4. You
state that "Phases 4 and 5 are not research". In
fact, Phase 4 (post-marketing) studies often involve controlled
clinical trials comparing different approved treatments. These
studies are definitely "research" and must be reviewed
by local IRBs. Moreover, the FDA has an interest in ensuring
that data from Phase 4 studies are credible and not inappropriately
driven by marketing considerations.
Finally, your concluding chapter well reflects the helpful
tone that you sought to present throughout your analysis.
Your advocacy of "guidance" and "education"
over regulations can only be applauded. Your recognition that
a credible system of oversight of research involving human
participants will require new funding at the federal and local
levels should be noted by all who are concerned about clinical
research and the protection of participants in that research.
The AAMC stands with NBAC in its efforts to buttress public
trust in clinical research and believes that after further
deliberation and modification as we have suggested, the document
can stand as a commendable roadmap for clinical research oversight
in the United States.
The AAMC is grateful for the opportunity to comment on the
draft report and look forward to the next iteration of this
important piece of work. Let me also express my appreciation
of the efforts you have made to encourage interaction between
NBAC and AAMC staff in framing the issues and developing your
conclusions about these very complicated and challenging areas
of biomedical research ethics and oversight.
Sincerely,
Jordan J. Cohen, M.D.
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