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For Institutional Review Boards, Decisions Can Be Subjective

Tom Reynolds

When evaluating a clinical trial protocol, institutional review boards (IRBs) must determine whether the likely benefits to patients outweigh the risks. How do IRBs sort through the complexity of medical, scientific, and ethical considerations to reach these decisions?

In a new study, researchers in the Netherlands interviewed 53 IRB members from six research hospitals and cancer centers to find out how they make risk/benefit assessments for phase II cancer clinical trials. The results suggest that they use a range of approaches but rarely employ a formal, systematic analysis. In an article published in the Aug. 1 Annals of Oncology, Heleen van Luijn, Ph.D., of the Institute for Ethics, Vrije Universiteit, Amsterdam, and colleagues describe findings from the first phase of a four-part study in which they use different techniques to examine risk/benefit decisions.

"Most of the decision strategies followed do not reflect a process of weighing risks and benefits against each other in a systematic way," said senior author Neil Aaronson, Ph.D., head of the Division of Psychosocial Research and Epidemiology at The Netherlands Cancer Institute in Amsterdam, "but rather involve gaining an overall impression (20% of members), considering what alternative treatments are available (15%), or considering whether one would be willing to undergo the trial-based treatment oneself or would advise a family member to do so (10%)." Twelve percent of IRB members said weighing risks and benefits was a task for the committee as a whole rather than for individual members.

When asked about the decisive factors in assessing the risk/benefit ratio, benefit to medical science was named most frequently (21%), followed by risks, burdens, and inconvenience to patients (18%), and reasonable expectation of benefit to patients (18%). Thirty-four percent said they did not make a risk/benefit calculation.

The question of whether the risk/benefit ratio is acceptable may not be raised explicitly in the IRB’s discussion of a protocol, Aaronson said. "Often I think it’s implicit in the board’s discussion of toxicities and other issues."

Many of the IRB members surveyed felt information was lacking in the protocol to adequately evaluate specific questions such as the likelihood, duration, and seriousness of risks. Several members rated it difficult or very difficult to assess the benefits to participating patients (34%), benefits to future patients (34%), and burden, inconvenience, and risks to participants (30%). Not surprisingly, oncologists—the technical experts in the group—generally reported greater competence in these judgments compared with other IRB members.

Aaronson said these findings are not as troubling as they might appear because an IRB works as a group, and medical experts and nonmedical IRB members have complementary expertise and perspectives.

"Undoubtedly the whole is more than the sum of its parts," Aaronson said. "The fact that some individual members feel less than fully competent to evaluate the risk/benefit of trials doesn’t mean the IRB considers itself incompetent. People take up the slack for one another."

Eric Meslin, Ph.D., director of the Indiana University Center for Bioethics and former executive director of the Clinton-era National Bioethics Advisory Commission, has written extensively about the work of IRBs in the United States and Canada.



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Dr. Eric Meslin

 
"What the Dutch researchers found really matches with the experience of many North American IRBs and research ethics boards," said Meslin. "They showed empirically what a lot of people have been saying for some time. Despite U.S. federal regulations specifying that IRBs are to make a systematic assessment of risks and benefits, this turns out to be a very difficult thing to do."

One way to better understand how IRBs make risk/benefit decisions, he said, would be to increase the transparency of the IRB decision-making process: "to have individual members make clear what their own personal assessments of acceptable risk of harm would be."

In the July-August 1994 issue of the journal IRB, Meslin and colleagues examined the criteria that research ethics board members at the University of Toronto used to decide on the ethical merit of trials. A surprising finding was that scientific merit of the trial was mentioned as a criterion by about as many board members (both clinicians and nonclinicians) as were informed consent and risk/benefit considerations—despite the fact that scientific value is not explicitly within the purview of ethics boards.

As a bioethicist, Meslin has wrestled with what he calls "the incommensurability of risk and benefit," which he said is at the crux of the difficulty in balancing them. Although the commonly used term "risk/benefit ratio" suggests a precise calculation, these complex considerations do not easily yield to quantitative analysis, he noted. Also, a large proportion of a trial’s benefits are likely to apply not to the patients in the trial but to future patients and medical science at large.

The authors of The Netherlands study note "an intriguing asymmetry" between the benefits listed by IRB members in their study and those identified by patients in previous research. Only 24% of IRB members cited "possible treatment effect" as a benefit to participants, while the vast majority of cancer patients cite hope of therapeutic benefit as a reason for enrolling. IRB members were more likely to mention psychological benefit (68%) and increase in quality of life (37%) as potential patient benefits.

Aaronson said this discrepancy points to the need for greater attention to how information is presented to patients about the aims of trials and the likelihood of treatment benefit.

"It is natural for patients to hold onto even the most remote hope from an experimental treatment, regardless of what they are told," he said.

In their article, the authors describe as "somewhat disconcerting" the finding that 17% of IRB members said they leave risk/benefit evaluations to patients. But in an interview, Aaronson explained this may not mean they are abdicating their responsibility.

"I think what those respondents meant is that, if we approve a protocol, patients are going to receive information before consenting," he said. The important thing, he said, "is that patients have accurate and understandable information allowing them to make the decision."

Meslin said studies need to be done comparing the judgments of IRB members to those of cancer patients, and he suggested that perhaps the role of IRBs should be reformulated to give greater leeway to patients in deciding what risks they will take.

"What a physician–investigator might consider to be an acceptable risk, or balance of risks and benefits, may be very different from what a patient or subject may think," he said. For one thing, he believes many patients would willingly enter trials that today’s IRBs would reject.

"A number of studies have found that desperately ill people, for example with cancer, are prepared to enroll in a chemotherapy trial with a very toxic drug for the outside possibility they might benefit," he said. "But protocols like that are never presented to patients," because IRBs judge them to carry unacceptable risk. "This shows just how difficult a job IRBs have."

But Thomas Stair, M.D., of Brigham and Women’s Hospital and Harvard Medical School, Boston, countered that because patients often misjudge the risks and the prospects for benefit, their protection demands oversight from the more dispassionate perspective of the IRB.

"Not all patients are skilled at making risk/benefit judgments," said Stair, who conducted a study comparing decisions across IRBs in a multicenter trial (see sidebar, p. 1519). "And I’ve seen studies in which 80% of cancer patients thought they were in the treatment group when in fact 50% were in the control group. If the patients are being unrealistic, they might actually benefit from another point of view that’s a little more interested in their safety ... and that’s the role of the IRB."


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