Ethical function of human subjects review boards: a US perspective

erupted led to the formation of the National Bioethics Commission and the elaboration of what became known as the Belmont Report.

The Belmont Report elaborated three basic principles: autonomy, beneficence, and justice, which remain the ethical underpinnings of American human research protections.³ This was soon followed by federal regulations that created a standard for evaluation, review and consenting for humans participating in research subjects. The role of Institutional Review Boards (IRBs) was carefully described “The IRB shall be sufficiently qualified through the experience and expertise of its members and the diversity of the members, including consideration of race, gender, and cultural backgrounds and sensitivity to such issues as community attitudes, to promote respect for its advice and counsel in safeguarding the rights and welfare of human subjects…the IRB shall be able to ascertain the acceptability of proposed research in terms of institutional commitments and regulations, applicable law, and standards of professional conduct…The IRB shall therefore include persons knowledgeable in these areas.”⁴

Of note, there are two separate, related, but distinct sets of regulations in the USs. Most research undertaken at medical schools with funding from the NIH are governed by the Department of Health and Human Services Protection of Human Subjects found at 45 CFR 46 (CFR = Code of Federal Regulations). However, there is a separate, similar, but not identical set of regulations that govern the Food and Drug Administration. Anyone proposing to submit a drug for FDA approval must follow those regulations.⁵ In many cases, both sets of regulations apply simultaneously.

Even with this set of regulations in place, IRBs remained somewhat sleepy backwaters of compliance in major medical schools. Following another series of scandals, federal authorities removed the authorization to use federal monies for research from a number of major educational institutions in the late 1980s and early 1990s. This resulted in a major overhaul and significant augmentation of the human subjects protections programs in all major schools and the rapid evolution of independent institutional review boards. Since that time, there has been an appreciation that human subjects protections is a profession, which has evolved it’s own certification process for individuals (CIP – certified IRB professional) and an accreditation process for programs (AAHRPP – Association for the Accreditation of Human Research Protection Programs).

IRBs have frequently been referred to as ethics boards and indeed the charge includes the assessment of the ethics of a proposed study. However, in practice modern IRBs are responsible for assuring that investigators are in compliance with the regulations regarding human subjects research. Thus, the content of informed consent documents, which is delineated in US federal regulations and compliance with specific protections afforded to special groups of potential participants are required activities that IRBs must document. This compliance function frequently appears to take precedence over the pure ethics of a clinical trial. Whether this type of review is more or less beneficial to the goal of protecting human subjects is an interesting ethical question in its own right, but one beyond the scope of this chapter.

In the index case presented above, both the IRB and the investigator apparently failed to properly identify a specific risk. This failure could be described as a failure of the principle of beneficence, and nonmaleficenc (the principle to do no harm). It can also be seen as having severely limited the autonomy of the participants, whom, in the absence of a potentially critical piece of information, might not have been able to make an informed decision regarding their participation. Appropriate actions following the identification of such risks should include the notification of participants.

Determination of risk, risk/benefit ratio, and risk management

One of the principal obligations of IRBs is the determination of the level of risk posed to a participant and assuring that the risks are both acceptable and minimized by appropriate research design risk. This idea is frequently couched in the phrase risk/benefit ratio, which makes this determination sound like a calculation with a definable answer. Risk involves the expected value and likelihood of one or more future events. Unfortunately, the concept of risk is not defined in federal regulations and remains a particularly difficult concept to apply in the setting of human experimentation. Bioethicists, such a Ezekiel Emmanuel from the National Institutes of Health have argued for an actuarial definition of risk, based on the statistical likelihood of a an untoward occurrence. In this construct, human research is, for the most part, much safer than many daily human activities such a driving a car or participating in a contact sport such as football. On a practical basis, IRBs find themselves considering risk in a relation to a relative level of tolerance or acceptability. So, while the risk of driving a car is well understood, it is also generally acceptable in that very few individuals would consider not using an automobile based on the risk of death or injury, while a much lower absolute likelihood of injury or death in a biomedical research is not so well accepted.

The index case provides an interesting example. The cancer warning for the drug was established based on animal experiments of a related drug. There was no indication that the related drug actually did produce cancer in any humans and the actual drug in use was never tested for chronic use in animals, so the actual drug proposed for the study had never been reported to cause cancer. The warning was based on very little information and could arguably be dismissed from a scientific basis; however, failing to note the warning was clearly an error on the part of both the investigator and the review board. Any risk of cancer, no matter how small or theoretical, might be legitimately considered to be significant.

What is the IRB’s role in scientific review?

A frequent complaint leveled against current IRBs is the tendency to review the scientific design of a research proposal. Investigators argue, with some justification that scientific review occurs at other venues. Particularly for major grants, such as those funded by the National Institutes of Health, extensive review by panels of experts have critiqued the scientific content of the proposal. One could legitimately argue that IRBs, even with some direct expertise, are not as well equipped and provide little added value to previous professional scientific review. Even in the absence of this highly sophisticated professional review process, many institutions have internal scientific review bodies that can provide high quality review of the science underlying a proposal. These groups should be at least as good at evaluating the current standard of care and determining whether an experiment is justified and well designed.

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