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Human Research Protections
in Clinical Trials: A Public Perspective
Report to the Director, National Institutes of Health
From the NIH Council of Public Representatives
October 2001
Table of Contents
Council of Public Representatives:
- Michael D. Anderson, Ph.D.
- Ellen Grant Bishop, Ph.D., A.C.S.W.
- Evelyn J. Bromet, Ph.D.
- Luz Claudio, Ph.D.
- Melanie C. Dreher, Ph.D., R.N., F.A.A.N.
- Pam Fernandes
- Vicki Kalabokes
- Barbara B. Lackritz
- Joan H. Lancaster
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- Debra Lappin, J.D.
- Bob G. Martin, Ed.D.
- Roland McFarland
- Isaac D. Montoya, Ph.D.
- Rodrigo Munoz, M.D.
- Rosemary B. Quigley, J.D., M.P.H.
- Bob Roehr
- Leonard J. Tamura, Ph.D.
- Thomas Vaalburg
- Douglas Q. L. Yee
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Table of Contents
| Executive
Summary and Recommendations |
|
The Council of Public Representatives (COPR) presents this report
to the Director of the National Institutes of Health (NIH) as part of
its mandate to assist the NIH with enhancing public participation in
NIH activities. The American public plays various roles in biomedical
research: some elect to participate in clinical trials, many benefit
from discoveries related to that research, and all pay for it-both directly,
as a cost of medical services, and indirectly, through taxpayer-supported
research.
Over the course of the last year, the COPR Working Group on Human
Research Protections (HRP) has examined from a public perspective many
of the issues that are central to human clinical trials. Many of these
issues were raised in discussions that took place during the COPR meeting
held in spring 2001.
It has become clear to the HRP Working Group that the protection of
patients in clinical research derives from two critical, independent,
and complementary tracks. One is through creation of an institutional
system and culture that instills within all members of the research
community the highest ethical value for human life and demands that
their behavior reflects those values. The other, less apparent route
is through the ability of patients to protect themselves by virtue of
truly informed decision-making. This second, less recognized route of
protection leads to the following overarching premise:
Transformations in the systems of human research protections
must take place at all levels within and outside of the NIH in order
for the nation's vital clinical research enterprise to fulfill its
promises. As part of this transformation, the NIH must pave the way
to ensure that clinical research leads not only with the "high
tech" of cutting-edge science, but also with the high touch of
human interactions that values and empowers patients as active, informed,
and respected partners.
The COPR urges the NIH to adopt this premise as a guiding principle
in pursuing its intramural and extramural research agenda. The Council
recognizes that the NIH often has taken the lead in involving the public
in the research process, through its advisory councils and other bodies
and mechanisms. The NIH also has initiated many of the existing institutional
systems of human research protections, which are substantial improvements
over what had come before. It is this very history of leadership that
points to the NIH as the one to initiate these next steps in strengthening
the ethical basis and public support of biomedical research.
The Council believes that the issue of human research protections
requires immediate national attention from a number of different directions.
We speak as a voice of the public within the system of the NIH and our
comments are offered from this particular perspective. With this in
mind, the COPR has identified six key areas for discussion and action
in this report. These are: (1) informed consent, (2) availability and
transparency of information, (3) institutional review boards (IRBs),
(4) conflicts of interest, (5) confidentiality and privacy, and (6)
enhanced education and training of the public to better enable them
to play their role of partner in the research process.
These categories, and the recommendations within them, do not include
all of the issues examined by the working group, nor are they the only
avenues by which the NIH can strive to meld its research activities
with the overarching premise stated at the beginning of this summary.
Nonetheless, within the myriad and complex issues related to human research
protections, the COPR considers the recommendations elucidated here
to be the most important at this time. The Council urges the NIH to
implement these recommendations as an integral part of the federal research
programs that it administers.
Although the language of this report often is couched in terms of
clinical trials, the COPR recognizes both the similarities and the differences
that can apply to behavioral and social science research. The Council
further believes that the principles expressed in this document should
be applied to those venues of research, though at times modification
may need to be made in terms of their implementation.
The COPR will revisit this report and the recommendations contained
within it on a regular basis. During this process, the Council expects
to receive from the NIH a response to the recommendations contained
in this report, as well as to update and revise this report and its
recommendations as the environment of patient protections continues
to evolve.
- Establish the principle that informed consent is an ongoing, meaningful,
and educational process that is woven throughout the course of a research
study. Informed consent must not be viewed simply as an event that
occurs at the commencement of the study and concludes when the participant's
signature is obtained. Nor should it be seen merely as a step required
to satisfy specific regulations or to ensure legal protection of the
institution. These are all ancillary purposes. Rather, informed consent
is central to the process of the patient becoming a full, knowledgeable
partner in the research endeavor. Its purpose is to confirm and re-affirm,
through meaningful exchange, the willing and fully advised decision
of a participant to enter and remain in a clinical trial.
- Provide, at the clinical trial site, a list of "Frequently
Asked Questions" (FAQ) for those considering participation in
clinical trials. This FAQ should include the questions and other information
that would assist people in making informed decisions about participating
in trials. This list of points to consider should provide potential
participants with the means to formulate their own personal requests
for further information.
- Develop a multi-level approach to the informed consent process that
ensures easy access to all levels of information by all participants.
Beyond the basic and necessary "bedrock" level of information
that must be conveyed to all participants (the nature of the study,
risks and benefits, etc.), individual participants must also be able
to pursue and obtain increasingly complex information according to
their interests, needs, and sophistication. When an individual participant
wishes to seek additional information, the pathway to acquire such
information should be clear, easy to navigate, available without further
request, and accessible without going through the "gatekeeper"
of the investigator who treats the participant in the clinical trial.
- Encourage participants to seek additional relevant information
from a source other than the clinical trial staff and/or institutional
staff sponsoring the clinical trial. When considering entry into a
trial, participants should be provided contact information for independent
third parties who are knowledgeable in the field and who may be able
to counsel and advise potential participants. Written information
that offers a clear summary of the clinical trial should be provided
to all participants so that those who want to pursue additional information
from an outside source have a readily available resource to take with
them.
- Ensure that an adequate waiting period-between the time that trial
information is made available and when consent is requested-is built
into the consent process. Participants should be informed that, in
the absence of extenuating circumstances such as medical emergencies,
they are not required to give consent at the time of the request.
They should be encouraged to consult external sources of information
and advice before agreeing to participate in the research. This waiting
period would allow time for prospective participants to digest information
about the trial and to consult outside sources of information and
advice if they so choose.
- Make available to trial participants, in a timely manner, any new
or relevant information as it becomes available from other like trials,
particularly but not exclusively concerning adverse events. In the
spirit of informed consent as an ongoing process, the investigator
should consider obtaining an affirmation of the patient's willingness
to continue in the protocol after receiving and understanding such
additional information.
- Study the strengths and weaknesses of peer access, patient advocate,
and similar systems and mechanisms to determine whether these types
of interactions benefit the participants in clinical trials and, if
so, how such interactions can be better integrated into the informed
consent process.
| Availability and Transparency
of Information |
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- Provide research participants with basic information about the
protocol of the study. Moreover, because access to the protocol is
integral to the concept of the patient as a partner in the research
process, all participants should be informed that they have access
to the full protocol upon request. Limited exceptions to this recommendation
should be permitted by the IRB only when it can be demonstrated that
access to the protocol would in fact compromise the conduct and outcome
of the study.
- Support the implementation of a system ensuring the meaningful
and timely public reporting of adverse events and associated data
in a single trial, in multicenter sites of a large trial, and in similar
trials. This may include the reporting of adverse events in related
animal studies where the events were deemed serious. The NIH should
lead the way in developing this national system for reporting adverse
events, ensuring that it is widely publicized and easily accessible
to investigators, institutions, industry, IRBs, and in particular,
among those populations currently in trials and those most likely
to participate in those trials. This systemic change is a key component
of enhanced decision-making and patient protection in clinical research.
- The National Library of Medicine (NLM) should consider making available
on the Internet, through MEDLINE and its successors, relevant research
information published before 1966. Adding this information to MEDLINE-even
with only titles or keywords available for searching-would provide
researchers with access to older literature that could prove important
to their clinical work. Once researchers can identify these older
publications via the Internet, they could obtain print copies of these
articles through libraries.
- As a standard part of the research process, inform participants
about the outcome and results of the studies in which they take part.
Participants as partners in the research endeavor should be entitled
to learn of those outcomes before their publication.
| Institutional Review Boards
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- The NIH should lead or support, as appropriate, the study of the
ability of the IRB system as it is currently structured to meet the
needs of human research protections. The NIH should play a highly
visible public role in the growing national dialogue of those who
are examining and striving to correct deficiencies in the current
system.
- The NIH should lead or support, as appropriate, the study of individual
and institutional conflicts of interest within IRB decision-making
processes.
- The NIH should make every effort to encourage senior researchers
to serve on IRBs so that they can contribute their much-needed experience
and expertise to IRB determinations.
- Public members of IRBs are uniquely positioned to contribute to
an understanding of the needs of research participants and the balancing
of ethical issues involving research participation. The NIH should
take steps to ensure the appropriate participation and support of
public members on IRBs. This support should include, but not be limited
to, defining the roles and responsibilities of public members who
serve on IRBs and ensuring their appropriate education and training.
- All IRB members, but particularly public members, must have adequate
education and information to participate effectively in the local
review process. In addition to its own efforts concerning public education
and training, the NIH should encourage other appropriate agencies,
such as the Office of Human Research Protections (OHRP) and professional
and nonprofit organizations, to make recommendations regarding the
training, education, and expectations for all who serve on IRBs. Those
groups also should contribute to the preparation of IRB members for
those tasks.
- The NIH should lead or support, as appropriate, efforts to expand
non-institutional or independent representation on IRBs. Such efforts
may include the creation and/or support of independent, non-institutionally
affiliated IRBs as a means of enhancing the professionalism of these
bodies and reducing potential conflicts of interest in conducting
reviews.
- The financial ties of the investigator and/or institution conducting
the clinical trial should be disclosed to the study participants.
Through the informed consent process, participants in clinical research
should have clear and direct access to relevant information about
any financial ties that an investigator or institution has with the
particular research project or the industry sponsor of the trial.
- The NIH should develop an educational resource for participants
that will help them to identify relationships signaling a potential
conflict of interest, to understand why these relationships are important
in the context of the study, and to be guided as to their right and
ability to question and investigate such financial ties.
- The NIH should work toward a system that ensures that federal dollars
are directed to institutions that have in place a demonstrated, effective
system for disclosing and examining financial and other interests
that may, directly or indirectly, in fact or appearance, influence
the objectivity or outcome of research. This should include ensuring
that the grant application requires a summary demonstration of a grantee
institution's system for review of such interests and that inadequate
compliance with this requirement becomes a category to be identified
as a potential concern when grant applications are being considered.
| Confidentiality and Privacy |
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- The NIH should develop and widely disseminate educational information
on issues of privacy in clinical research, such as through the development
of a "Frequently Asked Questions" (FAQ) list. This information
should both inform the research community and provide investigators
with resources to pass along to trial participants.
- Participants must be informed about possible breaches of confidentiality
and the possible consequences of such lapses. For example, participants
should be warned that a breach of confidentiality can occur as a result
of identifying themselves as participants in such a trial, and that
such a disclosure could possibly affect their family members (e.g.,
in the case of genetic research) or their health insurance coverage.
- Privacy issues should be addressed through a process that begins
with the first interaction with the potential trial participant and
continues throughout the course of the trial, as well as with any
subsequent handling of data and published material on that trial.
| Enhanced Public Education and
Training |
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The NIH should develop model programs that establish new and tested
mechanisms for educating and training the public at large and, in particular,
trial participants to better equip them to become empowered and informed
partners in the research process. These programs and mechanisms necessarily
must address the related issue of how to instill a cultural sensitivity
among those conducting research that invites, welcomes, and respects
the public and the individual participant as an active partner in all
aspects of research. The COPR plans to make further recommendations
in this area.
| Additional Suggested Areas
of Research |
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The COPR urges the NIH to plan and fund research examining the role
of the participant at each phase of the clinical trial process. It is
especially important to examine the relationship between the investigator
and the participant and to explore ways to empower participants to become
active, respected partners in the process. Such research might focus
on the following:
- How effective are current approaches in the informed consent process?
For example, how do potential participants weigh the information provided
to them, and how do they behave as they experience this process?
- What are the best ways to communicate the risks and benefits of
a particular research project to a potential participant? How can
the effective exchange of information be enhanced within the informed
consent process?
- How can the informed consent process be strengthened to avoid the
occurrence of "therapeutic misconception," where an actual
or potential patient might mistakenly believe or be led to believe
that a clinical trial represents state of the art delivery of care,
with an expectation of benefit? This is especially an issue in Phase
I and II trials.
- How may biases or secondary motivations influence the behavior
of all the players in the research process in general and in informed
consent in particular?
- What types of follow-up would help potential participants decide
whether to participate in a clinical study? How can potential participants'
understanding of the study they are considering be enhanced through
the use of written material, interactive videos, or patient advocates?
- How do potential participants process the information presented
to them during an interview for a research study-for example, in terms
of timing, complexity, and quantity of information?
- Do concerns for individual or family privacy affect the decision-making
process?
- How do participants in clinical trials regard the reporting of
serious adverse events and the existence of conflicts of interest?
Still other research needs to take a broader look at ways to increase
public awareness and knowledge about the importance of clinical trials,
and how the public can become a more active partner in the research
process.
The main body of this report provides an in-depth discussion of the
questions and concerns that were explored by the COPR in its deliberations
and that served as the basis for its recommendations. The report is
not intended to describe or allude to all of the many NIH activities
and initiatives currently under way regarding the protection of human
participants in clinical research, but rather to identify areas needing
further emphasis and/or attention and to provide guidance for both existing
and new efforts in this area. The COPR will continue to examine the
areas addressed in this report and will offer more detailed recommendations
at a later date.
| Human Research Protections
in Clinical Trials: A Public Perspective |
If it is to fulfill its promises, clinical research must lead not
only with the high tech of cutting-edge science, but also with the high
touch of human interactions that value and empower patients as full
partners in the research process.
Protection of participants in clinical research derives from two critical,
independent, and complementary tracks. One is the creation of an institutional
system that instills within each member of the research community the
highest ethical value for human life, demands that all behaviors reflect
these values, and holds institutions accountable for the enforcement
of these standards. The other, less apparent strand of protection is
through the ability of participants to represent themselves effectively.
Participants in clinical research become equipped to protect their own
interests through informed decision-making that takes individual risk-benefit
analyses into account, through systems that work to empower the individual,
and through relationships based on equality and mutual respect among
researchers, medical providers, and patients themselves.
Today, there are few systems or resources devoted to, and few professional
careers tied to, strengthening and advancing this second aspect of human
research protection. Although considerable public debate and comment
today is focused on strengthening institutional protections for human
subjects, few consider these issues from a uniquely public perspective.
The Council of Public Representatives (COPR) at the National Institutes
of Health (NIH) has been charged with a broader mission to enhance public
participation in all aspects of biomedical research. This mission can
be accomplished through more widely available information that is presented
in a meaningful context, increased public transparency of the research
process and outcomes, and creation of an environment that elevates and
ensures a public voice in all discussions of the nation's research policy.
An increasingly informed public no longer considers clinical research
as research done to or for individuals, but rather as research done
with individuals. The paradigm for clinical research in the 21st century
is one of patients invited to participate as partners in the research
endeavor. This understanding of the roles of the clinical trial participant
and the public at large as active partners with the scientific community
must be brought forward in all discussions involving human research
protections. The elevation of this partnership is fundamental to ensuring
that science delivers on its promise to improve the health of the nation
and that society continues to maintain and grow its substantial commitment
of resources toward the advancement of the nation's scientific enterprise.
With this background in mind, the COPR has approached issues of human
research protections from the perspectives of the patients who participate
in clinical research and of the American public, who pays for and benefits
from such research.
Patients participate in clinical research for various reasons. Many
come forward because of an understanding that, because of their medical
circumstance, they have something truly unique and beneficial to offer
science. Through their altruism, society is given an extraordinary gift.
Some do so for purely pragmatic, economic reasons. They may have either
inadequate or no health insurance coverage, and a clinical trial may
represent their only access to care.
Some refuse to participate because of cultural and ethnic experiences
or distrust of the medical community as a whole. Others are simply too
frightened or unwell to deal with the idea of the unknown in clinical
trials. Still others have no knowledge of clinical research and fear
they will be used as "guinea pigs" in risky experiments.
Finally, there are those who have found no lasting relief from standard
care and who turn to research in desperation. Such desperation can leave
a participant vulnerable to false expectations and misinterpretations
of the "promise" of research. On the other hand, when all
avenues of standard care have been exhausted, a patient's only hope
for meaning and the glimmer of possible treatment may rest in participating
in a clinical trial. One danger of moving toward over-regulation or
over-correction in an attempt to redress previous errors may be to take
away this hope. This is an issue of public interest that cannot be overlooked.
We believe that the public viewpoint can be represented best, and
at times only, by members of the public sitting as equal partners at
the table where research policy decisions are being debated and decided.
All must come to understand that the empowerment and involvement of
research participants, together with the meaningful participation of
the public, will build trust, engender wider participation, and ultimately
enhance the quality of science and the efficient development of beneficial
therapies. All participants in this complex scheme-government, industry,
institutions, investigators, and the American public-must come together
and act with decisive moral authority to strengthen the nation's system
for protecting those who choose to participate in clinical research
and to ensure that their contributions are meaningful and beneficial
to the common good.
The discussion contained in this report relates primarily to the protection
of human subjects in clinical trials; however, much of the Working Group's
analysis presented here may apply to all aspects of research involving
human subjects, such as behavioral and social science research. When
this is the case, the Working Groups hopes that the principles expressed
in this document will be applied to those venues of research, though
at times modification may need to be made in terms of their implementation.
It is very easy to be wise (and critical) after the event; the problem
is to be wise (and ethical) before the event. – Sir Austin
Bradford Hill (Hill 1963)
The 40 years since this statement was made have witnessed dramatic
changes in the landscape of clinical research. Nonetheless, Hill’s simple
challenge remains as profoundly true today as when it was initially
made. Serious recent events—most notably the death in September 1999
of 18-year-old Jesse Gelsinger in a gene transfer clinical trial conducted
at the University of Pennsylvania and the death in June 2001 of Ellen
Roche, a healthy participant in an NIH-sponsored biomedical research
study at Johns Hopkins University—have been the catalysts for re-engaging
the nation in a dialogue surrounding protections afforded to human subjects
in clinical research. Across government, efforts continue on multiple
fronts to realign oversight responsibilities, reassess reporting guidelines,
and expand opportunities for public input, all in an effort to develop
wiser and more ethical policies that will serve to protect human subjects
in research before, during, and after the event.
Many of the concerns raised in this report are being actively identified
and discussed by others within government, industry, and academia:
- In September 2000, Donna Shalala, then Secretary of the Department
of Health and Human Services (DHHS), assumed a leading role when she
challenged “government, researchers, and research institutions to
come together with a state of urgency to reform the current system
of protections” (Shalala 2000).
- The Office of the Inspector General has issued several investigative
reports (OIG, April 2000, 2000a–2000c).
- Unprecedented numbers of people have taken advantage of enhanced
training opportunities provided by Public Responsibility in Medicine
and Research for members of Institutional Review Boards (IRBs).
- Agencies within the DHHS have stepped up enforcement of existing
rules, which in several cases has resulted in the temporary suspension
of trials at research institutions.
- In September 2001, the National Bioethics Advisory Commission (NBAC)
released an extensive report, “Ethical and Policy Issues in Research
Involving Human Subjects” (NBAC 2001), which recommends major changes
in the current system.
- The Institute of Medicine has agreed to conduct a two-part study
on human subjects protection. The first part, released in April 2001,
examines the accreditation for human subjects protection programs
and standards for IRBs. The second part, due in the fall of 2002,
will examine the complex framework for oversight of human research
protections.
- On November 30, 2000, the New England Journal of Medicine called
for all academic medical centers to adopt policies prohibiting equity
ownership by investigators in companies sponsoring clinical trials
(Drazen and Koski 2000).
- The American Association of Medical Colleges (AAMC) has established
a task force on institutional conflicts of interest.
- The National Advisory Council on Human Research Protections, appointed
through the Office of Human Research Protections (OHRP), promises
to play a leading role in future developments in this area.
These are but a few of the recent pronouncements and actions within
the public and private sectors that will enhance the protections afforded
by institutions engaged in clinical research across the nation. The
COPR is encouraged by this activity.
In 1998, the Director of the NIH, Harold Varmus, MD, formed the Council
of Public Representatives. His action was prompted in part by a report
issued earlier that year by the Institute of Medicine, “Committee on
the NIH Research Priority Setting Process, Scientific Opportunities
and Public Needs.” That report challenged the NIH to widen the scope
and opportunity for public input by offering the following:
The director of NIH should establish and appropriately staff a Director’s
Council of Public Representatives, chaired by the NIH director, to facilitate
interactions between NIH and the general public. (IOM 1998)
At the level of the Office of the Director, the COPR became an active
and chartered council of public representatives to advise the Director
of the NIH. The mission of the COPR is to “assist the NIH in enhancing
the participation of the public in NIH activities that have an impact
upon the public, in increasing public understanding of the NIH and its
programs, and in bringing important matters of public interest forward
for discussion in public settings” (COPR 1998). In the three formative
years since its inception, the inaugural COPR has continued to define
the nature and scope of its contributions and the processes by which
it will bring an active, public voice into the work of the NIH.
The COPR constitutes a diverse public group comprising patients, family
members of patients, health professionals, members of advocacy groups,
research scientists, students of science, and communicators in health
and medicine. Members agree to leave their specific disease interests
aside in service of the broader public interest and to provide input
on trans-NIH issues. The COPR is in a unique position to appreciate
both the importance of clinical research and the promise that it holds
for improving the health and well-being of all, as well as the imperative
to protect the individuals who participate in clinical studies as research
subjects.
| Forces Shaping Human Research
Protection |
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| Balancing Interests in Clinical
Research |
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The elusive question we face is how to establish a balance between
protection of individual human research participants and the advancement
of knowledge that promises to enhance the health and lives of greater
numbers of people. This balance is threatened by the introduction of
escalating costs associated with most clinical trials and the very real
economic pressures in industry trials to get a product to market quickly.
In this dynamic among individual rights and protections, communal
good, and commercial interests, ethical questions often present a very
close and difficult call. We recognize that people of goodwill may disagree.
We contend that when this occurs, the scale must be weighted ultimately
in favor of the protection of the individual in order for the participant,
society, industry, and the medical research enterprise to be served.
| Understanding Clinical Research |
|
The receipt of even basic medical care is not without risk. However,
clinical research, by its very nature, may change the standard of—and
increase the risk associated with—health care. The public, therefore,
must be better educated and informed about the inherent risks in research.
Moreover, while participation in research is supposed to be a voluntary
endeavor governed by informed consent, there is some evidence that individuals
enrolled in clinical research are not always aware of their status as
research subjects. The Subject Interview Study, conducted by the National
Advisory Committee on Human Radiation Experimentation (ACHRE 1995),
found that patients were very often confused about their past participation
in clinical research. Participants were not always aware that trials
generally involve unproven therapies that may or may not prove beneficial
to them. In fact, few research participants surveyed by the ACHRE were
able to distinguish between their “medical care” and their “research
participation.” Furthermore, when a serious medical condition was at
issue, and when other, demonstrated therapies had not worked, research
participants felt they had little choice about enrollment in research
(often a clinical trial) and were more likely to view the research as
“therapeutic.” These issues remain of considerable public concern today.
| Regulatory Framework for Clinical
Research |
|
The vast majority of protections for human participants in clinical
research are codified at 45 CFR Part 46 (Subpart A). The language in
this section governing the DHHS represents the Common Rule, the regulations
that have been adopted by 15 federal agencies and departments for human
subjects protections, including the Departments of Defense, Agriculture,
and Education. The regulations encompass all research on humans that
is “conducted, supported or otherwise subject to regulation by” the
federal government. A few federal agencies that are involved in human
subjects research have not subscribed to the Common Rule, including
the Department of Labor, the Nuclear Regulatory Commission, and the
National Endowment for the Humanities.
The Common Rule covers many aspects of the research enterprise, including
the composition of IRBs and the scope of their review. The regulations
also lay out criteria for IRB approval of research, including special
allowances for research involving less than minimal risk and research
scenarios necessitating waiver of consent. Perhaps most important is
the articulation of requirements for informed consent, including the
specifics of research participation, the potential risks and benefits
of participation, and confidentiality concerns. Other subparts of Part
46 discuss research involving special populations, including prisoners,
pregnant women, children, and fetuses.
| The Changing Nature of Clinical Research |
|
Enacted in December 12, 1980, the Bayh-Dole Act (Public Law 96-517)
encouraged the commercialization of discoveries arising from federally
funded biomedical research in the laboratories of government agencies
and grant recipients. This legislation helped to clear the way for companies
to patent therapeutic discoveries and bring them to market more rapidly
with a greater direct financial return. It also correlated with an explosive
increase in new therapeutic products and growth in the pharmaceutical
industry. The development of recombinant DNA technology, the recently
announced completion of the sequencing of the entire human genome, and
the potential envisioned for genomics and proteomics hold the promise
of continued, even more rapid innovation in biomedical research. These
rapid advances in science, however, have raised the specter of new risks:
the undue influence of conflicts of interest; new threats to individual
privacy and autonomy; the failure to discover, understand, and disclose
adverse events occurring in the accelerated course of research, often
in multicenter trials; and the inadequacy of the informed consent process,
to name but a few.
Recent years have witnessed an expansion of the sites of human clinical
trials beyond academic medical centers and into private clinical practice.
Large pharmaceutical and biotechnology companies, in addition to the
NIH, have become the major sponsors of clinical trials. As changing
market forces have moved increasing numbers of participants away from
university research facilities, industry has begun to offer significant
and creative financial incentives to clinicians in private practice
to recruit participants and to conduct clinical trials. In the past
two decades, these dynamic market forces have substantially transformed
the nation’s clinical research enterprise.
Substantial time and cost are required to bring a drug to market.
For example, new biological agents and therapies that may hold promise
for millions of Americans take years to develop, are very expensive,
and often come to market with a relatively short remaining patent life.
From the point of laboratory discovery, companies are pressured—and
in turn bring pressure to bear on the Food and Drug Administration (FDA)—to
bring any new drug to market as rapidly as possible so that maximum
financial return can be reaped before a generic form becomes available.
Current market incentives are for “blockbuster” drugs and procedures
that have the broadest possible application. But as the promise of understanding
the human genome unfolds, the practice of medicine may move away from
the "one size fits all" model of the blockbuster to the use
of certain therapeutic interventions—and the avoidance of others—tailored
to the genetic profile of each individual. Knowledge, especially the
reporting of adverse events in small numbers of patients, will become
increasingly crucial to the development and use of new biomedical interventions.
Not only will this knowledge save lives, it also will allow us to “rescue”
interventions that may be deadly to a small percentage of patients but
beneficial to others.
A more informed and educated public has come to demand rapid translation
of innovations discovered through research. The FDA has responded by
instituting its Fast Track Drug Development Program. This program is
designed to facilitate the development and expedite the review of new
drugs that demonstrate the potential for treating serious and life-threatening
conditions and for addressing unmet medical needs.
The accelerated translation of research, however, may present its
own unique risks. Many Phase III trials, it is argued, do not mirror
the actual, ultimate use by consumers, such as those with multiple disorders
or combining multiple therapies. It is reported that new drugs entering
the market are increasingly subject to relatively little Phase IV testing
or post-market surveillance. At the same time, the demand for participation
in clinical trials among certain informed populations is increasing,
encouraged in part by advocacy efforts focused on educating participants
about clinical trials and empowering them with openly available information.
The American Cancer Society, for example, estimating that only about
3% of adult cancer patients participate in clinical trials, reported
that it has established the goal of raising this number to 10% by fostering
participant awareness and opportunities.
Better standards of living, combined with advances in medical science
and technology, have created a society today in which people with chronic
health problems are living longer than ever before. Both adults and
children with illnesses that, until recently, were considered life threatening
are now enjoying relatively normal lives. This shift has generated a
public interest in research that focuses on the management of chronic
illnesses, their impact on families and community institutions such
as schools and workplaces, and means of prevention. Indeed, the concept
of what constitutes clinical research is expanding. Because research
studies do not always lend themselves to randomized clinical trials,
these studies may require special consideration regarding the confidentiality
of databases, blood banks, tissue repositories, and unintended impacts
on vulnerable groups and segmented populations.
| The Impact of the Information Age |
|
For their part, both the public and research participants are demanding
and gaining access to a new kind of information and are increasingly
able to use it to become directive and proactive, rather than merely
receptive, in their health care decisions. This rapidly evolving transformation
has been fueled in large part by the “Information Age.” The NIH Web
site ClinicalTrials.gov,
which is now posting more than 5,000 trials, helps prospective participants
navigate their own course toward participation in clinical trials (Landro
2000). This is but one example of the rapid exchange of information
that threatens to widen the gap between the changing needs and capabilities
of the trial participant and the perceptions and approach of the clinical
investigator.
| Areas of Institutional Concern
Regarding Human Research Protections |
|
The various components of the “institutional arm” of human research
protections is currently under intense and broad scrutiny within government,
academia, and industry. Recognizing this, the COPR has approached its
discussion of aspects of our system of institutional protections of
human subjects in clinical research from the distinct perspectives of
the NIH, the participant, and the American public.
Many IRBs and individual investigators are now embracing the concept
of informed consent as an ongoing process that is woven throughout the
course of the research effort. This perspective, however, must become
more fully integrated into the research culture. Thus, not only participants
but also investigators themselves must be equally prepared for their
role in research. The informed consent process must ensure that participants
fully comprehend the potential risks and benefits associated with their
participation. They must enter into and continue in the study on the
basis of truly informed, voluntary, and autonomous decisions. These
are the key ethical underpinnings of the informed consent process as
we understand it today.
To be effective, the informed consent process must take place within
the family, community, and cultural context of the participant. It is
important to inform and protect without patronizing, omitting key information,
or presenting the protocol in such simple terms that much is omitted.
On the other hand, it does no good to imply that informed consent has
been achieved if the patient is unable to understand the information
in the manner in which it has been presented.
A balance must be struck in a way that does not lose sight of the
participant’s need for education through the process of informed consent.
Participants have the right to take part in all medical decisions about
their care. Consent is “informed” only if it is predicated on both full
knowledge of the proposed research and an understanding of medical options
other than those available through participation in research, including
the option of no treatment at all. Participants have the right to be
informed of the entire scope of the protocol used in the clinical research,
to the extent that such knowledge on their part does not compromise
the validity of the results (e.g., as in a double-blind, randomized
trial). This information should include expectations for outcome; understanding
of potential problems, side effects, and late-effects; and ultimate
quality-of-life issues they may encounter. Achieving this objective
requires greater public transparency of information as well as systems
for delivering information on all relevant clinical research. Only in
this way can the prospective patient give truly informed consent to
enter into and continue participation in clinical research.
Many investigators tend to believe that the research participant will
be unable to understand the technical details of research. Although
it is true that different participants have different levels of interest
in the details of the studies in which they take part, it is the Working
Group’s contention that all participants are entitled to the amount
and kind of information that it is feasible to give the participants
in clinical trials and to have this information presented to them in
a way that they can understand.
| Availability and Transparency
of Information |
|
Greater transparency of information in all aspects of clinical research
will serve to sustain public trust in clinical research, undergird patient
recruitment efforts, and continue to build political and financial support.
The COPR realizes that greater openness and transparency can arguably
increase the risk that some trial participants will feel overwhelmed
or confused. Moreover, it is likely that only a portion, perhaps only
a small portion, of all participants in clinical research will be able
to take full and direct advantage of expanded sources of information.
However, these risks should not detract from a larger commitment to
enhance the transparency and meaningful reporting of information to
the American public.
One of the most contentious areas of discussion that arises when “transparency”
of information is being called for is the public reporting of adverse
events. In areas of novel research, the need for transparency of information
and timely reporting of adverse events is especially critical and is
currently the subject of public focus. The problems of who should receive
information, how it should be protected, and in what fashion it should
be disclosed and reported are confounded by the co-existing jurisdictions
of the NIH, the FDA, and the OHRP. Each has overlapping but differing
audiences, responsibilities, and information requirements. This fragmentation
of oversight has resulted in some confusion and duplication of activity.
Calls for consolidation and harmonization of reporting from all corners
are worthy of support.
However, in an effort to reach the goal of harmonization, we must
not lose sight of the public’s need for and entitlement to more comprehensive,
timely reporting of adverse events that occur during the course of the
trial. Harmonization should be in the direction of greater transparency
and greater availability of information, not less. If we are to err
with oversight of new, novel sciences, let it be in the direction of
protecting patients “too much.” Increased and timely public reporting
of adverse events and associated data is a key component of enhanced
decision-making and patient protection in clinical research and will
also lead to better decisions and better medicine. In the same spirit,
the results and outcomes of clinical trials should be made available
to those who have elected to participate in them. A proper role for
the NIH, in this regard, is to provide clinical and statistical expertise
to analyze relevant adverse events in a particular trial, in multicenter
sites of the subject trial, and in “like” trials; to assess trends;
and to make this information public in a timely and meaningful manner.
| Institutional Review Boards |
|
IRBs play a critical role in protecting the participants in clinical
research and serve as a critical link in a network of responsibility
among everyone involved in the research enterprise. IRBs, which operate
in accordance with and apply local community standards, are the ultimate
determinants of the extent of participant protections to be required
during a research study.
By all accounts, the IRB system today is under tremendous stress.
The burdens of service on an IRB are extensive for both the institution
and the individual. IRB members complain of the increase in caseloads,
the responsibility, and the burdens of service on their research careers.
Some question whether the system as it exists today is equipped to handle
the increasingly complex nature of clinical research and the rapidly
expanding demands for review and protection of human subjects. Concern
is particularly warranted over a growing tendency for IRB service to
be regarded as “dues” to be paid only by junior people. This attitude
can discourage service on IRBs by senior investigators, to the detriment
of the review process. The NIH should make efforts to counter this attitude
to motivate senior researchers to serve on IRBs.
The COPR is seriously concerned about conflicts of interest, whether
on the part of individual investigators or institutions, that directly
or indirectly, in fact or in appearance, influence the course, objectivity,
or outcome of research. Although the significant majority of researchers
have high standards of integrity, incidents of aberration are becoming
more apparent. All must be mindful of the corrosive effects of even
the appearance of impropriety on the nation’s continued faith in its
research enterprise.
The subject of conflicts of interest has grown increasingly complex
over the course of only the past few years. Today, the potential for
conflicts of interest exists on multiple levels: with the individual
investigator, with the institution, and among members of IRBs. Competitive
pressures to bring a new drug to market, the opportunity for an investigator
or the university to reap financial gain based on the conduct of scores
of trials or the confirmation of positive trial results, and significant
incentives reportedly paid for participant recruitment are but a sampling
of the emerging financial influences on the objective, unbiased conduct
of a clinical trial.
Financial relationships do not necessarily undermine the integrity
of an investigator or an institution, nor do they always equate with
bias or a lack of regard for the safety of participants. However, particularly
in industry-sponsored trials, financial relationships and ties have
been shown to affect the conduct and outcome of trials in terms of the
design of the study, the recruitment of participants, the selective
release of findings, and the control of trial data (Bodenheimer 2000).
Both the AAMC and the American Medical Association (AMA) have stepped
forward with important guidance for their respective constituencies.
The AAMC has placed primary responsibility on research institutions
for the oversight of conflicts of interest (AAMC 1990). In its guidance,
the AAMC considers not only conflicts that may compromise the integrity
of investigators, but also any associations that appear to compromise
professional judgment in conducting or reporting research. To preserve
the public trust in the research enterprise, it is essential to consider
these so-called “gray areas,” which involve matters of perception.
A DHHS Interim Guidance report issued in early 2001 indicated that
only about 25% of all IRBs ask investigators to disclose their financial
conflicts of interest. Even so, beyond required disclosure, it is not
clear what effect the knowledge of investigators’ financial interests
will have on participants in clinical trials. There have been no studies
on how this kind of information may or may not affect participants’
perceptions of the research in which they are engaged, the investigators
conducting it, and the institutions sponsoring it. Indeed, it is not
unreasonable to expect that trial participants will have different levels
of interest concerning how much they want to know about investigators’
financial relationships. At the very least, however, participants should
have the same amount and kind of information that institutions and investigators
are required to disclose publicly.
Some argue that trial participants, if they choose, should have access
to further information regarding the financial ties of the individuals
conducting the research, pointing to the fact that institutions have
various degrees of stringency in requiring or disallowing such relationships.
Not all IRBs, however, have the expertise to deal with issues concerning
conflicts of interest, and in any case, IRBs are only one element in
the complex web of entities governing disclosure. An entire spectrum
of mechanisms exists within institutions regarding requirements to disclose
financial conflicts of interest. Some institutions are very stringent,
having zero tolerance for any financial holdings relating to the research
in question. Others entrust ethics committees with the evaluation of
investigators’ financial relationships. The disclosure of equity ownership
in commercial sponsors of trials is one area in which disclosure could
well affect participants’ perceptions of and willingness to participate
in research. Currently there is a “closed loop”in which any type of
equity ownership must be divulged to the research sponsor; this information
is conveyed to the FDA, where it is kept confidential.
The COPR notes the recent actions of the American Society of Gene
Therapy stipulating that “all investigators and team members directly
responsible for participant selection, the informed consent process
and/or clinical management in a trial must not have equity, stock options
or comparable arrangement in companies sponsoring the trial” (IOM 1998).
In a recent editorial (Drazen and Koski 2000), the New England Journal
of Medicine has stated its support for this policy and suggested that
it be widely adopted.
| Confidentiality and Privacy |
|
The exciting pace and expansion of medical research has brought more
participants than ever before into clinical research, and this number
continues to grow. Unfortunately, this growth brings with it an opportunity
for the degradation of participant confidentiality, privacy, and autonomy.
This threat poses a real and present risk to the individual, the public,
and the research enterprise itself.
Breaches of confidentiality are of special concern among “vulnerable”
populations, such as those with socially stigmatizing health conditions
or, in the very near future, those with determined genetic predispositions
for certain conditions. These individuals may face devastating consequences
in obtaining or continuing health insurance, employment, housing, and
social relationships if their health conditions and/or genetic status
are revealed.
These reasons underscore the importance of educating participants
about issues of privacy when participating in clinical research. A new
DHHS privacy rule is currently under review and will be published in
the near future.
Healthy People 2010 has identified the elimination of health disparities
as one of only two sweeping public health goals to be accomplished within
this decade. In response, the NIH has developed a 5-year “Strategic
Research Plan to Reduce and Ultimately Eliminate Health Disparities.”
Each NIH Institute has produced its own mission-specific plan as well,
setting forth in greater detail ongoing and planned efforts to reduce
health disparities among minority populations. Many of these plans also
call for increased participation of minorities in clinical studies as
well as increasing the number of minority scientists.
As research continues to demonstrate glaring differences in the incidence,
prevalence, morbidity, mortality, and burden of diseases among underserved
and vulnerable groups, it is more important than ever that we improve
our understanding of what causes health disparities and work to address
them. The COPR believes that the NIH must play a major role in helping
the American public to reach that objective.
The issue of health disparities is not unrelated to the protection
of human subjects in clinical research. One of the contributing factors
to health disparities is a lack of adequate information about specific
medical issues relating to certain groups. The COPR can emphasize and
help to convey to the public the importance of inclusion and participation
of all populations in research, which will help to ensure that meaningful
results of clinical research can be applied to various populations.
By ensuring that clinical research populations include people of both
sexes; a range of ages; and a variety of ethnic groups, social classes,
and nationalities, the NIH can expand the scientific knowledge to all
people, thus helping to eliminate disparities.
At the same time, however, the goal of eliminating health disparities
is so complex, multifaceted, and extensive that the COPR has decided
to reserve its position and recommendations for a separate document
to be presented at a future COPR meeting. This deferral of the discussion
of health disparities should not be perceived as reflecting a diminished
importance of this topic but rather an endorsement of its significance.
| Social Science and Behavioral Clinical
Trials |
|
The amount of social science and behavioral research conducted at
the NIH is expanding. These studies, which will affect the understanding
of health disparities, lifestyle changes, and burden of illness measures,
are generally noninvasive and often involve less onerous reporting requirements.
On the other hand, such trials may present a risk of breach of confidentiality,
an invasion of privacy, or a threat to the dignity of not only individuals,
but also entire communities, tribes, or ethnic groups. Members of IRBs
who are skilled at examining biomedical research may not appreciate
these differences or the unique risks and may not be trained to monitor
these numerous studies appropriately.
The Social and Behavioral Science Working Group of the National Human
Research Protections Advisory Committee of OHRP is working to identify,
review, and address issues of human research protections that are unique
to the area of behavioral and social science research. Specifically,
this group has been charged with (1) developing guidelines to help IRBs
more effectively administer the human subjects protection system and
(2) to make specific recommendations regarding additions or changes
to the Common Rule with respect to the social and behavioral sciences.
The COPR will review the final report of the Social and Behavioral Science
Working Group when it is presented in March 2002 and provide public
comment at that time as appropriate.
As an advisory body to the NIH Director, the COPR is challenged to
survey the landscape of human research protections, to consider the
broad array of activities now under way within the public and private
sectors, and to decide how and in what manner to weigh in on behalf
of the public and those individuals who make the commitment to participate
in research. In all that it does, the COPR must be mindful of the expectations
for the Council’s role within the NIH and of its unique positioning
as representatives of the American public—the true owners and beneficiaries
of the nation’s exciting scientific enterprise. Always, the COPR will
be challenged to ask the right questions of the right people and to
obtain the right responses. In the area of human research protections,
the COPR hopes to do this through the blueprint for continued inquiry
and discussion set forth in this report.
Advisory Committee on Human Radiation Experimentation. Final Report
of the Advisory Committee on Human Radiation Experiments. 1995. Available
at: http://www.eh.doe.gov/ohre/roadmap/achre/report.html.
Accessed October 2001.
American Association of Medical Colleges. Guidelines for Dealing with
Faculty Conflicts of Commitment and Conflicts of Interest in Research.
February 22, 1990. Available at:
http://www.aamc.org/research/dbr/coi.htm. Accessed October 2001.
Bodenheimer T. Uneasy alliance: clinical investigators and the pharmaceutical
industry. N Engl J Med 342(20):1539–1544, 2000.
Charter of the Council of Public Representatives, 1998.
Department of Health and Human Services. Financial Conflicts of Interest
in Research Objectivity: Issues for Investigators and Institutional
Review Boards. June 5, 2000.
Drazen JM, Koski G. To protect those who serve. N Engl J Med 343:1643–1645,
2000.
Institute of Medicine. Scientific Opportunities and Public Needs.
Washington, DC: National Academy Press, 1998, p. 62.
Landro L. Web offers patients data on clinical trials but caution
is advised. WSJ 12/22/00.
National Bioethics Advisory Commission. “Ethical and Policy Issues
in Research Involving Human Subjects.” December 19, 2000.
Office of the Inspector General. Protecting Human Subjects—Status
of Recommendations. OEI-01-97-00197. April 2000.
Office of the Inspector General. FDA Oversight of Clinical Investigators.
OEI-05-99-00350. June 2000a.
Office of the Inspector General. Recruiting Human Subjects—Pressures
in Industry-Sponsored Clinical Research OEI-01-97-00195. June 2000b.
Office of the Inspector General. Recruiting Human Subjects—Sample
Guidelines for Practice. OEI-01-97-00196. June 2000c.
Shalala D. Protecting research subjects: what must be done. N Engl
J Med 343:808–810, 2000.
The COPR thanks the following individuals for the significant contributions
they made in preparing and refining this report:
Working Group on Human Research Protections:
Debra R. Lappin, J.D. (Chair)
Melanie Dreher, Ph.D.
Barbara B. Lackritz
Joan Lancaster
Roland McFarland
Isaac D. Montoya, Ph.D.
Rosemary Quigley, J.D., M.P.H.
Bob Roehr
Tom Vaalburg
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