Should IRB role include risk-benefit analysis?
Whole IRB mission might need change
As bioethicists and other experts in human subjects research protection take a closer look at the IRB's role, two interesting questions emerge: First, how can IRBs improve their risk-benefit analyses of trials, and, secondly, should IRBs even be in the business of making risk-benefit determinations?
IRBs operate under an impossible position, says Barry Bozeman, PhD, Ander Crenshaw professor of public policy and regents' professor of public policy at the University of Georgia in Athens, GA.
IRBs have no expertise in examining studies' research design, Bozeman says.
"But one of the exclusive requirements of IRBs is to weigh risk versus benefit, and it's utterly impossible to weigh risk versus benefit without making judgments about the research design," he explains.
A study that might appear to have potential benefit could have no benefit at all when its design is thoroughly analyzed, Bozeman adds.
The risk-benefit assessment is a routine requirement for research ethics committees that review and oversee biomedical research with human subjects, says Franklin G. Miller, PhD, senior faculty and bioethicist in the department of bioethics at the National Institutes of Health (NIH) in Bethesda, MD.
"Nevertheless, it remains unclear how to weigh and balance risks to research participants against the social benefits that flow from generating biomedical knowledge," Miller says.
Miller and co-researchers addressed the question of whether there are any reasonable criteria for defining the limit of permissible risks to individuals who provide informed consent for research participation in a recent paper published in the Journal of Medical Ethics.1
"We argue against any a priori limit to permissible research risks," Miller says. "However, attention to the uncertainty of potential social benefit that can be derived from any particular study warrants caution in exposing prospective research participants to a substantial likelihood of harm."
IRBs were given an important mission within a set of rules that are too general and too inconsistently interpreted, Bozeman says.
IRBs have national rules, but they execute the rules in a local context, he says.
"The people making up the IRBs are very different from one place to the next, and they're different in background and knowledge," he says.
This leads to inconsistency in how IRBs carry out their mission.
"There is no problem with what the IRB is trying to accomplish or the goals of individuals on IRBs," Bozeman explains. "The problem is in the nature of the institution."
One of the easiest ways to make IRBs quickly more efficient would be to narrow their focus, Bozeman says.
"A tremendous amount of time is spent by IRBs on reviewing conflicts where there is only the most diminished notion of vulnerability or threat," he adds.
One way IRBs could do risk-benefit analyses in a more consistent and meaningful way would be to take fewer cases for full review, Bozeman suggests.
Most protocols could be handled on an expedited basis, he says.
Then the remaining, difficult ones could be given more attention, Bozeman adds.
"There could be direct interaction and questions about exposure, instead of flying emails," he says. "People could show up and make assessments of risks and benefits."
Another challenge is determining when a potential risk is too much.
"There isn't any particular guidance in the U.S. federal regulations governing human subjects research on any limits to risk," Miller says. "The risks have to be reasonable to anticipated benefits."
There has been an ongoing debate in the research ethics field about this issue, he notes.
"There's a lack of any consensus on this question," Miller says. "Everyone expects IRBs to be risk averse, but there's no particular guidance which says how much risk they should allow."
If IRBs use the standard of balancing risks to subjects against benefits to society, then it would suggest that very high-risk research is justifiable if there also were expectations of high societal benefit, Miller says.
"Because it's an unsettled issue, we weighed in to see what we could contribute to the debate, and at the end of the day we don't have a definite answer," Miller says.
Miller's paper concludes that IRBs need to pay careful attention to eliminating unnecessary risks and avoid two types of errors: being under-protective of research subjects and foregoing social benefits from valuable research through overprotection.2
"For any particular study, it becomes a matter of context," Miller says. "What are the risks? How likely is it to yield important knowledge?"
Also, it's important to exercise caution in assuming actual benefit from any particular study, he adds.
"Science is tremendously beneficial as a system over time, but any particular study is only making a small contribution to the overall progress of science," Miller explains.
So IRBs need to keep this in mind when reviewing a study that has high risks and speculative benefits, he adds.
"Not only is the value of any given study in principle speculative, but it varies according to how it's going to turn out, and the answer to that is unknown," Miller says. "We put a lot of stress on the uncertainty factor as a reason to be cautious about the level of benefit, particularly if you have pretty good knowledge about the level of risk."
A great deal of uncertainty
In Miller's experience, IRBs typically are reluctant to approve studies that have a high level of risk of serious harm to participants' health.
"The kinds of studies that have gotten people most upset are where it turns out there was a lot more risk than was anticipated," Miller says.
When a participant dies during a research study it's usually a shock because people tend to believe the risk of death is minimal, he adds.
"There are always unknowns, and whenever IRBs are reviewing a study that involves something new and unexplored, there's a great deal of uncertainty," Miller says. "Our tolerance for risks has gotten somewhat lower, or there's more media attention paid to the research enterprise, and that creates a higher sense of caution."
Miller's advice to IRBs is to minimize risk by asking themselves and researchers these questions:
- What is the anticipated value of the knowledge the study will gain?
- What can really be learned, and how important is that knowledge?
- How good are the scientific methods so we can be confident when the experiment is run that it will be rigorous and have answers that could have an important impact?
- Have you carefully looked at the potential benefits, factoring in the great uncertainty of any benefit?
- If the anticipated benefit is realized, how good would that be?
- Are you confident in the methods used to obtain the results?
- What kind of monitoring plan is in place to detect problems early and to intervene when necessary?
- If you have to shut down a research study, will you be on top of the situation?
"By the end of the day, you're still making an intuitive judgment," Miller notes. "We do risk-benefit analyses in medicine all the time, but these look at the risks to an individual person and compare them to the benefits to the same person."
This type of risk-benefit analysis is considerably easier to do than the research form where you must weigh risks to individuals against benefits to society, Miller adds.
"That's the challenge IRBs have to make, but we don't have any rigorous methods available for making those judgments," Miller says.
References
- Bozeman B, Slade C, Hirsch P. Understanding bureaucracy in health science ethics: toward a better institutional review board. Am J Pub Health. 2009;99(9):1-9.
- Miller FG, Joffe S. Limits to research risks. J Med Ethics. 2009;35:445-449.
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