Who decides whether the risks to clinical trial participants are justified by the possible health benefits that they and other people might experience? According to modern ethical and legal norms, it is essential for each individual to make his or her own decisions after receiving accurate information about the study in question. "Informed consent" refers to the process through which investigators educate potential participants about a trial's risks, benefits and objectives. By formally providing informed consent, people attest to their understanding and acceptance of what they will be asked to do in the course of the trial.
Experience has suggested that informed consent by itself is not enough. Unless he or she happens to possess the relevant professional background, a person considering a clinical trial might find it challenging to rigorously evaluate the scientific underpinnings of the study protocol. And even someone with a sophisticated understanding of the protocol is still dependent on the study team to conduct itself with integrity. A study team that lacks the judgment or knowledge to work in an ethically sound manner can inflict physical or psychological harm on even the most educated study participant.
Formal systems for protecting research participants are relatively new in the history of medicine. The first widely recognized ethical document relating specifically to studies involving humans was a response to the atrocities committed by Germany's Nazi regime. Horrifying evidence of Nazi doctors' widespread experimentation on concentration camp prisoners gave rise to the 1947 Nuremberg Code. An American-led military tribunal formulated the Nuremberg Code in the course of issuing verdicts against 23 Germans implicated in the experiments.
The World Medical Association introduced a second influential ethical statement, the Declaration of Helsinki, in 1964. This document addresses important aspects of human subjects protections in more specific terms than the Nuremberg Code does.
The Nuremberg Code and the Declaration of Helsinki have done much to frame the discourse about how ethical principles should inform modern medical research. However, neither is actually a legally binding regulatory document. Medical researchers and research institutions in the United States and elsewhere were left to interpret and act upon the guidelines as they chose.
Research involving human subjects went on with minimal government oversight in the United States until the early 1970s, when news of the Tuskegee syphilis study marked a dramatic turning point. In 1972, a front-page New York Times article revealed that government researchers had intentionally withheld treatment from a large cohort of African-American men in a decades-long study of the effects of syphilis.
When the study began in Tuskegee, Alabama in the early 1930s, no treatment for this disease was known to be widely effective. In the years following World War II, penicillin became the standard treatment for syphilis. But the Tuskegee researchers, seeking to learn more about the natural progression of the disease, did not offer penicillin to study participants or inform them of its effectiveness.
Congressional hearings in the wake of this disclosure led to the passage of the 1974 National Research Act, which did much to define US regulatory structures and procedures. The legislation established the Office for Protection from Research Risks, as well as mandating IRB review of all research funded by the Department of Health, Education and Welfare.
An IRB is legally authorized to operate when OHRP has granted it permission to do so by issuing a "federal-wide assurance" (FWA). The FWA imposes a set of regulations that specify in great detail how the institution should carry out research activities that involve humans. For example, researchers must obtain informed consent from all study participants and must be able to document this consent.
The FWA serves as the primary enforcement mechanism in OHRP's oversight system. OHRP has the power to revoke the FWA of an institution that is found to not be in compliance with research regulations. If an FWA is revoked, then the institution must halt its research. The day-to-day work of conducting studies is actually brought to a standstill. Also, there is a freeze on funding from the many federal agencies that have adopted OHRP's standards. (These include the National Institutes of Health and the Centers for Disease Control and Prevention.)
While OHRP has never permanently revoked a major US research center's FWA, temporary revocations have compelled a number of institutions to overhaul their research procedures and practices. Johns Hopkins University, the University of California-Los Angeles, and Duke University Medical Center are among the institutions that have had their FWAs briefly suspended after OHRP identified major problems with how their IRBs were functioning.
IRBs have the enormous responsibility of considering proposed studies from an ethical standpoint, which means weighing potential benefits of new scientific knowledge against potential risks to subjects. There may be some clear benefits to subjects, e.g. medical care; financial compensation for their time; opportunities to try experimental regimens that possibly will be more efficacious than approved regimens. At the same time -- and also of concern to IRBs -- there is the potential for benefits such as those named to serve as undue inducements. That is, people might feel uneasy about a trial's drawbacks, but sign up anyway out of a sense of desperation.
As a check on the judgment of investigators, IRBs thus are at the nexus of the OHRP system. In the last several years, a number of widely publicized cases have shown that clinical trial participants' health -- and even their lives -- still can be put at risk, and that their rights still can be violated, in spite of IRB and OHRP oversight. These developments have raised questions about how strong the regulatory system is and whether individual IRBs are performing effectively.
One response to the latter issue has been the creation of new agencies to accredit IRB programs. The non-profit Association for the Accreditation of Human Research Protection Programs (AAHRPP) has emerged as the central player in the accreditation movement. Following intensive reviews, AAHRPP has accredited 35 institutions to date, including Johns Hopkins University, Stanford University and other research powerhouses. AAHRPP reports that another 365 organizations have begun the demanding accreditation process.
The US Food and Drug Administration (FDA) oversees research separately from OHRP. Any human study of an investigational new drug (IND) that might become a candidate for FDA approval should be implemented according to FDA regulations. Generally speaking, these regulations are similar to OHRP regulations (although from a legal perspective some of the differences might be considered significant). The FDA, like OHRP, calls for IRB oversight of all human research. (If a study of an IND takes place at an institution that has an FWA from OHRP, then the study falls under the jurisdiction of both OHRP and the FDA.)
In recent years, private independent IRBs have emerged as an alternative to IRBs convened by research institutions. A researcher affiliated with an OHRP-governed institution may have the option of hiring an independent IRB to review his or her protocol, providing that the IRB has an FWA from OHRP. Independent IRBs also review protocols for studies taking place in the private sector.
Some people have expressed skepticism about the adequacy of reviews by independent IRBs, which -- unlike university and hospital IRBs -- typically do not disclose the names of their board members. However, by and large, the most prominent independent IRBs seem to be winning the confidence of the biomedical and bioethical communities. At least two independent IRBs have been accredited by AAHRPP so far.
Throughout the 1980s and most of the 1990s, the workings of the IRB system elicited little public comment. Then in the late 1990s and early part of this decade, a series of episodes -- including the deaths of patients in three clinical trials -- called into question how well IRBs were meeting their responsibilities.
Medical journals and the mainstream media served as vehicles for calling attention to what a 2001 article in Annals of Internal Medicine called "a crisis in confidence" in the oversight system. OHRP underwent great scrutiny as it reviewed and restructured its role. In recent years, there have been fewer reports of ethical questions or lapses related to trials conducted in the United States. However, some highly important concerns remain to be addressed.
One of the most common themes to emerge from investigators' criticism of IRBs relates to the length and complexity of the review process. As IRBs have become more attentive to the details of applications -- in many cases asking for more information than in the past -- investigators have found themselves in what may seem like a maze of paperwork. Requirements for reporting "adverse events" -- health issues that develop for trial participants, and that might be related to the experimental regimens they are following -- add further to the workload.
Questions have been raised about whether IRBs are overburdened and insufficiently funded -- logical questions, since it appears as if backlogs at some IRBs have delayed the review and therefore the implementation of protocols. The nature of clinical research itself has changed in ways that affect this already-complicated situation. Far more multi-site trials are being conducted now than in the 1970s, when the IRB system took form. Some trials might be staged at two dozen sites or more. If one IRB requires revisions in the trial protocol, then the amended protocol might need to be re-approved by all of the other IRBs.
(Originally, multi-site trials required the review and approval of IRBs at all trial sites. OHRP and other federal institutions have made some progress in developing more efficient ways for multi-site trials to be approved. The National Cancer Institute, for example, is piloting a central review system that is designed to supplement the work of local IRBs. However, many multi-site trials still undergo full review at each participating institution.)
Another layer of complexity is added when US investigators want to implement protocols at sites in other countries. (The investigators are bound by the regulations of both the US government and the host country or countries.) Following the appropriate procedures and documenting the process to the appropriate degree can be particularly challenging in resource-limited countries, where a significant number of HIV clinical trial sites are now found.
Various stakeholders in the clinical research realm, including research institutions, their IRBs, and the federal agencies that oversee them, are working to streamline the administrative processes for clinical investigators. But the question of how to do this under the federal regulations inherited from the 1970s, without compromising the quality of the ethical review process, is a formidable one. (Some analyses have concluded that a new regulatory system is in order, but there has not been widespread consensus-building of the nature that would be required for Congress to create the necessary legislation.)
IRBs are charged with ensuring that both the ethical principles relating to research and the legal regulations intended to support those principles are honored. It could be argued that the US IRB system has stood the test of time in the sense that nothing on par with the Tuskegee scandal has been observed in the 30-plus years since then. However, there are various other ways in which IRBs might not be completely fulfilling their mandate.
The very nature of the IRB system, with internal ethical review of an organization's research protocols, creates the potential for conflicts of interest to undercut the protection of research participants. For example, an IRB member may feel reluctant to criticize a protocol from a colleague with whom he or she works closely.
Internal ethical review may also have the opposite effect. IRB members who are very concerned about protecting their institution's reputation may steer an overly cautious course and reject protocols that would impose an entirely reasonable level of risk on participants.
There is another type of conflict of interest that warrants scrutiny. In this era of major industry involvement in research, investigators may have strong financial incentives for enrolling people in clinical trials. In some cases, investigators may own stock in or be paid consultants to companies sponsoring research. In other cases, industry sponsors may offer payments to investigators who meet study enrollment goals. There may also be payments made to non-medical personnel to reward them for recruiting people for studies.
The presence of financial incentives is particularly troubling when the setting is the office of a physician whose patients expect him or her to use the best possible judgment in the course of providing medical care. Many people who are unaware of the existence of financial incentives will assume that their physicians and the physicians' staff are exclusively concerned with patient well-being. An invitation to join a clinical trial may erroneously be interpreted as a suggestion to pursue a better course of treatment than that which is currently available.
In clinical trials involving financial incentives, one can speculate that telling people about those financial incentives might affect their decisions about whether or not to enroll. Telling them might also affect their relationships with their physicians, raising questions in their minds about whether the physicians' clinical recommendations are colored by self-interest.
It is not known how effective IRBs are at mitigating the challenges that financial conflicts of interest may pose for clinical trial candidates. There is significant variation in the policies that individual IRBs have adopted in regard to whether or how investigators should acknowledge having financial stakes in trials.
Discrepant standards for the informed consent process constitute another major area of concern. There is relatively little empirical evidence to help investigators and IRBs identify best practices in regard to seeking informed consent from research participants. A three-page informed consent form describing a study's goals, risks and benefits might be considered too detailed by one IRB, but not detailed enough by another. The language in an informed consent form is supposed to be tailored to the literacy level of the intended audience, but deciding whether the form will succeed in conveying key information can be a subjective process.
From the research participant's standpoint, this means that enrolling in a study may involve receiving an informed consent form that is too complicated to understand. Alternately, the informed consent form may have been simplified to the point that it leaves out significant information. In either scenario, someone might be in danger of signing an informed consent form and undergoing an experimental treatment without fully understanding the risks.
In summation, there is more than one way to characterize the US regulatory system for protecting human subjects. Reasonable arguments could be made for the effectiveness of the system, especially as it compares to the regulation of clinical research in many other countries. On the other hand, the US regulatory system could also fairly be described as very much of a work-in-progress in some regards. There are shortcomings that urgently need to be addressed by both the biomedical field and those outside of the field who have taken on the charge of advocating for patients' interests.
It is important for the HIV/AIDS community to understand how IRBs are entrusted with safeguarding key components of the system, and to more broadly understand the roles of all major stakeholders in the ethical review process. Doing so will enable individuals to become more informed participants in HIV clinical trials. Just as importantly, it will ensure that the community as a whole has a voice in some of the most vital ethical issues of our era.
|What We Can Do: The Public's Role in Promoting Ethical HIV Clinical Trials|
Clinical investigators, institutional review boards and federal overseers are not the only parties responsible for ensuring that research participants' right and interests are protected. It is vitally important to recognize that we -- people living with HIV and their allies and advocates -- should also take an active role in the ethical dimension of the clinical research enterprise.
Before enrolling in a clinical study that is affiliated with an academic research center, consider this advice:
Some industry-sponsored trials are not affiliated with academic research centers, in which case the IRBs approving the trials may be operating under less scrutiny. In those situations, you may want to take the these measures:
-- Kelly Safreed-Harmon
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