HISTORICAL PERSPECTIVE AND EVOLVING CONCERNS FOR HUMAN RESEARCH
Bernard Lo, MD and Nesrin Garan
Program in Medical Ethics, Department of Medicine, Universio of California Sun Francisco Sun Francisco, California, USA
1. INTRODUCTION
Clinical trials have identified effective new cancer therapies and screening strategies. Additional clinical trials are needed for further progress in cancer prevention, screening, and treatment. However, clinical trials raise ethical concerns because volunteers take on risk for the primary goal of advancing scientific knowledge and helping future patients. Moreover, the risks and benefits of interventions studied in clinical trials are not yet fully known. If a research question has already been answered and the efficacy and safety of the intervention have already been established, there would be no point in carrying out the study. Indeed, it would be unethical to assign participants in a clinical trial to an intervention that was known to be less effective or less safe than the intervention in another arm of the trial.
Furthermore, in several historical and recent cases, participants in clinical research suffered serious harm due to ethical lapses in research conduct. In response to such tragic cases, government regulations have been enacted.
However, the current regulatory system is flawed: it is burdensome on
researchers and institutions, yet does not cover all clinical research and may
not be effective in achieving its goals.
HISTORICAL BACKGROUND
Research studies that involved serious ethical lapses have led to federal regulations and professional guidelines regarding the ethical conduct of research with human participants. During World War
11,Nazi
"experiments" intentionally inflicted serious harms on prisoners who gave no consent. In response to these atrocities, the Declaration of Helsinki of 1964 required consent from research subjects and established the need to balance the risks and benefits of the study.' In 1972, news reports revealed egregious misconduct in the Tuskegee study, which was conducted by the U.S. government. Researchers deceived impoverished, poorly educated, African-American men into believing they were receiving treatment for syphilis and later withheld antibiotics after they became a ~ a i l a b l e . ~ Revelations about the Tuskegee study led to the promulgation of federal regulations on the ethical conduct of human subjects research, the requirement of informed consent from subjects, and the creation of Institutional Review Boards (IRBs) to review federally sponsored human research. These federal regulations form the basis for oversight of clinical trials today.
More recently, 18-year-old Jesse Gelsinger died in 1999 from liver failure during a gene transfer trial at the University of ~ e n n s ~ l v a n i a . ~ . ~ In retrospect, investigators did not pay sufficient heed to animal data indicating the possibility of adenovirus-induced liver failure and overlooked abnormalities in Gelsinger's liver function tests. The principal investigator was also the founder of the biotechnology company that produced that adenovirus vector used in the study and thus had a significant financial interest in the success of the clinical trial. The researchers in this study also failed to use the consent form approved by the IRB and failed to report as adverse events instances of mild liver toxicity in previous participants. The tragic outcome in this highly publicized case led to additional federal regulations regarding conflicts of interest, training investigators in human participant's protection, and reporting adverse events.
Public outrage at such egregious cases is understandable. All clinical research raises ethical concerns. In clinical care, patients who accept the risk of treatments are the same individuals who will benefit from the treatments.
In research, however, participants assume risk primarily for the benefit of
future patients and for the advancement of scientific knowledge. The
effectiveness of interventions in clinical trials is not known until the study is
completed. Also, the risks of new therapies are identified only after data
from the clinical trial are analyzed. Participants in research do not have as
much knowledge about the risks and potential benefits of a clinical trial as
do investigators, peer reviewers, and IRBs. Participants depend on them to
assure that the risks of the study are reasonable and minimal. Thus, if there is excessive risk or misrepresentation during the consent process, participants, as well as the public, feel betrayed. This sense of betrayal and mistrust is particularly strong when research is publicly sponsored.
Taxpayers may feel complicit
ifparticipants in federally funded research are seriously harmed. One response to egregious cases is a demand for greater oversight, which usually means greater government regulation.
The Gelsinger case and other recent cases in which research volunteers died or suffered grave harm indicate serious problems with the current system of human subjects protection.2.4 IRBs have come under strong criticism because they are underfunded and under~taffed.~.~ In some highly publicized cases, IRBs failed to follow federal regulations and keep adequate records. In these incidents, IRBs reviewed protocols when no member with relevant clinical expertise was present, or when the university official charged with promoting research in the institution was present.5 Hence research volunteers may not be adequately protected by the current system.
However, stricter enforcement of existing regulations or promulgation of additional regulations may not be beneficial. Many IRBs and researchers complain that administrative burdens of compliance with federal regulations are increasing, while doing little to protect research participants.
Changes in the organization of clinical trials raise additional concerns.
Traditionally, the bulk of clinical research was funded by the federal government and carried out at academic health centers. However, the majority of clinical research is now funded privately or carried out at contract research organizations (CROs). Federally sponsored research undergoes rigorous peer review and must comply with federal regulations for the protection of human subjects. Most academic health centers agree to apply these regulations to all research at their institution. In contrast, research funded by for-profit sponsors may not receive external peer review.
Moreover, federal regulations apply to privately funded research only if the study will be submitted to the Food and Drug Administration (FDA) as part of a new drug application or if the research is carried out in an institution that has agreed to apply the federal human subjects regulations to all research. Many private sponsors follow the Guideline for Good Clinical Practice of the International Conference of Harmonization, which require informed consent and review by an IRB. However, these international guidelines have no provisions regarding conflicts of interest or on training investigators in human subjects protection.
In response to these problems, several broad suggestions have been made
to improve human participant's protection. First, accreditation of IRBs may
be a less burdensome and more effective and flexible alternative to increased
government regulation.' Moreover, it may provide more assurance that
appropriate guidelines and procedures to protect research participants are actually being followed at the institution. Second, a quality improvement approach would focus attention on improving outcomes of the oversight system rather than on compliance with regulations for its own sake.2 The challenge is to devise outcomes measures that capture the goal of human subjects protection and that can be readily measured. Third, greater representation of nonscientists and community members on IRBs may help assure that the perspective and concerns of research participants and vulnerable communities are appropriately ~onsidered.~ Lay and noninstitutional IRB members may identify unappreciated risks in the study and problems with the consent process, as well as suggest how to ameliorate them.
EVOLVING ETHICAL C0NCERNS:OVERSIGHT OF MULTICENTER CLINICAL TRIALS
Conducting research at multiple institutions is desirable because it results in shorter and more efficient trials and more generalizable findings.
Also if pivotal trials are conducted in several countries simultaneously, the sponsor can apply for licensing a new drug in those countries at the same time. However, multicenter trials also present many challenges in oversight.
Local IRBs differ widely on their assessment of risk and benefit in clinical re~earch.~ Inconsistent reviews by IRBs at different sites lead to delays in finalizing a common protocol.7 Moreover, full review by multiple local IRBs requires considerable duplication of effort for busy IRBs, leads to few substantive changes, and places unnecessary burden on sites that enroll few participants.8
The National Cancer Institute (NCI) is currently experimenting with a
centralized review process for Phase
3multicenter clinical trials,' with the
goal of improving the quality and efficiency of IRB review. A national IRB
whose members have appropriate ethical, legal, and scientific expertise
carries out in-depth review. The local IRBs maintain a role in determining
whether local context requires restrictions or minor changes in the protocol
or consent form and in assuring that the local researchers are qualified to
carry out the research and receive adequate training in human subjects
protection. The local IRB may choose to make the central IRB responsible
for annual reviews and reviews of adverse events. This central NCI review
board will need to work out how it interacts with the NCI scientific review
committees and data and safety monitoring boards. In addition, the national
IRB needs to determine the extent to which its review of the ethical aspects
of a protocol also requires consideration of the scientific aspects of the study.
A similar centralized IRB system introduced in the U.K. faced procedural difficulties, mostly because local research ethics committees were unwilling to defer to a centralized authority.9
3.1 Conflicts of interest
Industry sponsorship of clinical research has increased dramatically, now exceeding federal support for clinical research. Federal policies promote technology transfer to the private sector, in order to better translate publicly funded discoveries into clinical therapies. These policies have resulted in universities' and their researchers' developing close relationships with for- profit companies, through founding companies, holding stock and options, and forming long-term consulting arrangements.10 These closer ties between industry and academic institutions, while having the promise of bringing discoveries to the bedside more efficiently, raise concerns about conflicts of interest. University-based researchers play an important public role as impartial and independent agents, distinct from the role of partisan employees of for-profit companies who are manufacturing a drug." This distinction may be particularly important in clinical trials, whose results will influence clinical care of patients.
Studies show that industry-sponsored clinical trials and studies conducted by investigators with ties to industry are more likely to report positive findings for the investigational inter~ention.'~"~ While this may represent more careful selection of drugs under study, it may also be due to an unwillingness to report negative findings or bias in the design of trials and interpretation of findings.14-'8 In several cases, sponsors refused to allow
investigators to publish negative findings about the study d r ~ ~ , ~ ~ - ~ ~ even though such publication is essential to establish a rigorous evidence base for
clinical practice and ultimately to provide the best care to patients.
Moreover, typical contracts between academic researchers and industry sponsors do not provide access to data and freedom to publish all findings.22 To address concerns about academic freedom to publish findings, many leading medical journals now require investigators in clinical trials to disclose conflicts of interest when they submit manuscripts for publication and to certify that they had full access to data, had responsibility for data analysis and interpretation, and controlled the decision to publish.23
Under the current system, researchers at an institution receiving federal
funding must disclose financial conflicts of interest to the institution, which
then has considerable discretion in managing conflicts and implementing
conflict of interest policies.10 Federal regulations do not require researchers
to disclose conflicts of interest to the IRB or to research participants.
However, such disclosure should be carried out as a matter of sound ethical practice. Recent voluntary guidelines establish a presumption that academic researchers in a clinical trial should not hold stock or stock options in the manufacturer of the therapies under study, nor be officers in the company.24 Instead, researchers should be compensated only for their time, effort, and expenses; their remuneration should not increase if the trial shows that the investigational therapy is effective and safe.
3.2 Informed consent
Informed consent from research participants is essential for the ethical conduct of clinical trials. However, it is difficult to achieve. The so-called
"therapeutic misconception" is common2' among research participants, indicating a fundamental misunderstanding about clinical trials. Many participants believe that clinical trials provide individualized treatment and direct benefit to subjects, whereas research by definition has the goal of generalized knowledge and involves unproven interventions. The popular press reinforces this misconception by portraying research too optimistically.
A recent study assessed the quality of informed consent in cancer therapy trials. Researchers found that 48% of subjects believed that all treatments and procedures in the clinical trial were standard therapy for their type of cancer.26 Thirty-eight percent believed that the clinical trial did not carry any additional risks or discomforts compared with standard treatments, while 29% believed that the treatment being studied was proven to be the best treatment for their type of cancer.26 In fact, clinical trials generally involve nonstandard treatment, potentially increased risks, and unproven benefits.
Moreover, cancer researchers frequently have misunderstandings about the purpose of clinical trials. One study found that 43% of medical oncologists enrolled patients in clinical trials to assure they got the most state-of-the-art treatment, while 41
%enrolled them to improve the treatment of future cancer patients.27 However, there is no rigorous evidence that patients who enroll in clinical trials have better outcomes than comparable patients who do not participate in clinical trials.28 Thus the claim that "the best cancer care is in a clinical trial" is not substantiated by convincing evidence.
Researchers often fail to distinguish between different types of benefit that participants may experience in clinical trials. Direct benefits result from the intervention being studied, which may turn out to be more effective or safer than standard care. However, at the onset of a clinical trial it is unknown which arm is superior. Thus it is more accurate to speak about the
"prospect" of direct benefit. Several dimensions of direct benefit need to be
distinguished. Cancer clinical trials commonly evaluate whether the size of the tumor decreased - a so-called "objective response." An objective response may be partial or complete, long-lasting or short-lived. A short- term partial response in a Phase
1clinical trial may be sufficient evidence to justify further studies. However, a temporary decrease in the size of the tumor is unlikely to lead to any clinically meaningful outcome.
Collateral benefits of participating in a clinical trial might include closer follow-up, more personal attention, or greater attention to the timing and dosage of therapies, which in turn might lead to improved outcomes, even if the intervention being studied is no more effective than standard care.25729 Finally, a clinical trial may provide hope, particularly to patients for whom no effective therapy is available. Hope is always desirable, but unrealistic hope can lead to uninformed decisions to participate in clinical trials. A participant may realize that the probability of a meaningful response to an experimental intervention is low, yet still hope, despite long odds, that he will gain such a response. Such hope is completely consistent with informed consent.
Recent empirical studies highlight the difficulties in attaining informed consent. For example, cancer patients commonly decide to enter a clinical trial before they meet the researchers and hear about the potential benefits and risks. Despite researchers' efforts to explain the experimental nature of clinical trials, there may be difficulties in effectively communicating this information to patients. A recent study found that 50% of parents who enrolled their children in clinical leukemia trials did not understand the concept of randomization, a key factor distinguishing these trials from standard treatment in which the choice of therapy is an individualized decision based on what is best for the patient.30 In addition, some consent forms may reinforce the therapeutic misconception. Vague wording, such as
"you may or may not benefit" or "we cannot guarantee that you will
benefit," may imply that benefit is in fact likely.31 Another study found that
in NCI-sponsored clinical trials, consent forms are generally clear in
explaining potential risks, harms, and benefits to subjects in Phase I trials.32
Hence improving consent forms per se is unlikely to solve all problems with
informed consent. Other studies found that innovative means of providing
information, such as videotapes or CDs, did not consistently enhance
participants' understanding of key features of clinical trials.33 Taken
together, these studies underscore that informed consent must be viewed as a
process or an ongoing dialogue between researcher and participant, rather
than a lengthy legal form that patients must sign before they enroll in clinical
research.34
CONCLUSION
Historically, scandals that shook public trust in research have led to new government regulations. These regulations, however, may be burdensome yet ineffective in protecting research participants. In a systems approach to research oversight, multiple parties have responsibility for protecting participants - sponsors, research institutions, IRBs, and investigators.34 Investigators have particular responsibilities because they have power over what happens to research subjects and because their decisions and actions during the course of a project cannot be effectively monitored. Thus the ethical integrity and judgment of the investigators are crucial protections for research participants, particularly in situations where the regulations are silent, ambiguous, or controversial. It is essential that researchers fulfill their ethical obligations when designing and carrying out clinical trials. Failure to do so might lead to additional government regulations, thus further complicating the current system rather than facilitating further progress in cancer research.
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