Special Series: Assessing Risks/Benefits

Risks and benefits must be evaluated separately

Risks and benefits are not parallel, experts point out

(Editor’s note: In this issue of IRB Advisor is the second part of a series on how IRBs can assess potential risks and benefits. Included are stories on the ASSERT statement, how to give potential benefits equal consideration, and past research mistakes involving an imbalance in risks and benefits.)

Rather than treat the risk of harm and potential for benefit as two weights on opposite sides of a scale, IRBs and researchers should fully explore and express the potentials of each, say research ethics experts. Too often, IRBs and researchers misunderstand a study’s goals with regard to benefits, and this can cause confusion on the part of subjects, as well as those involved with the research.

"Some IRBs may say that if an investigator does a lot of research with patient subjects, then benefiting subjects directly is a primary goal, and this is a misunderstanding," says Nancy M.P. King, JD, a professor of social medicine at the University of North Carolina-Chapel Hill. "But IRBs should look at societal benefit and make certain the risks have been minimized and the research is going somewhere that has value," she says.

For instance, suppose an IRB is presented with a proposed drug study that will treat a disorder that already has a dozen viable and approved drugs available. Suppose that the research protocol anticipates that the drug, if successful, will work as well as the other similar drugs on the market, King says. Some IRBs may not approve such a protocol, saying that the drug doesn’t provide enough of a societal benefit since there already is an adequate number of useful medication treatments on the market, she explains.

"They might say they don’t see the need to approve another compound that does the same thing as twelve other compounds," King says. "But other IRBs may say that another useful version of this drug is good because it gives patients more choices in the future." The bottom line is that it’s up to the IRB to make the call on societal benefit, and it’s permissible for different IRBs to have different opinions on this issue, she adds.

One of the obstacles to both investigators and IRBs adequately assessing potential benefits of a study is that those involved with the research and those reviewing the research may assume that good intentions equal good benefit outcomes. "One of the problems is that people think they’re going to do the right thing because they’re good people," says Dale Hammerschmidt, MD, FACP, associate professor of medicine at the University of Minnesota Medical School in Minneapolis. Hammerschmidt is an IRB member and has chaired IRBs.

The way to prevent assumptions from replacing a thorough and methodical examination of potential benefits is to define benefits in an organized way and assess each protocol according to one of the definitions below. King divides possible benefits into three types:1

  1. Direct benefit to subjects, which is when the volunteer subject receives a benefit that results from the intervention being studied.
  2. Collateral benefit to subjects, also called indirect benefit, is when a volunteer subject receives a benefit even when he or she did not receive the experimental intervention. This could include free medical care.
  3. Aspirational benefit, which is a benefit to society and future patients, resulting from the research.

Each proposed study needs to be evaluated according to these potential benefits, and each informed consent should discuss them in detail, rather than leave research volunteers with a vague idea that their participation may result in some benefits for themselves and/or others, the experts say. Taking the analysis a step further, investigators and IRBs should examine the probability and magnitude of each benefit, another concept that King and other researchers have promoted, says Paul B. Gold, PhD, an assistant professor of psychiatry at the Medical University of South Carolina in Charleston. Gold has conducted human subjects research and is an IRB member. For example, in a short-term, diabetes clinical trial that involves testing new drugs for treating diabetes Type II, what would be the probability and magnitude of the three types of benefits? Gold offers these simple assessments of each:

• Very low probability and magnitude of direct benefit: "If an IRB is reviewing a two-group study with a placebo-control group, and the study is a Phase I, II, or early Phase III study in which effective drug dosing has yet to be determined, then investigators need to be extremely conservative in conveying any impression of direct benefit to volunteers," Gold says. "This is because the placebo-group volunteers will not benefit, and most of the volunteers in the active group will not receive an effective dose of the drug."

• Low-to-moderate probability and magnitude of collateral benefit: There is a greater probability and magnitude associated with collateral benefit because the research participants will be given a blood sugar monitor that will allow them to check their own glucose levels at home, and they will receive education and frequent medical exams during the course of the study. For example, researchers will examine how the subject’s blood sugar levels fluctuate over the course of days while the person is enrolled in the study. "Not only does that generate information about the effectiveness of the drug, but people learn how to monitor their own blood sugar levels so they can take their own actions to prevent disease complications and to promote healthier behavior, even when the study is over," Gold explains. "They can learn how to keep their blood sugar levels from going too high or too low through diet control, taking medications at appropriate times, and monitoring their own blood sugar levels."

• Moderate-to-high probability and magnitude of societal or aspirational benefit: The probability and magnitude of a societal benefit likely would be the highest of the three benefits in this example because if the drug works as well as the study’s investigators expect then it would provide the large population of people with Type II diabetes with another effective treatment, Gold says.

In King’s research about benefits and clinical trials, she found examples of how little investigators and study participants discuss and understand potential benefits. "In our study, we interviewed investigators, study coordinators, and subjects involved in gene research," King says. There were two types of responses that appeared to be universal, she says. These were:

  1. For some diseases, such as genetic diseases that may affect the participant or the participant’s family, investigators will say people volunteered for the study for altruistic reasons, King explains.
  2. "The other response from investigators is to say that "no matter what we tell them, they’re always going to hope," she says.

"I think investigators believe this, and it seems to be true," King adds. "But the notion of being more explicit about potential benefits doesn’t devalue that at all." For study participants to hold out hope that they may receive a personal benefit from a particular trial in which the odds of that direct benefit are very low is similar to the hope people have each time they buy a lottery ticket, and it’s no less legitimate, she explains.

However, while investigators may believe that they have fairly and thoroughly communicated potential risks and benefits to participants and that despite what they’ve said that subjects will continue to hold out hope, the truth may be that they haven’t done as good a job communicating these as they think, King says. "It remains to be seen whether this belief in hope that subjects are said to have is irrational and flies in the face of evidence, or whether it comes from ambiguities in the way these issues have been discussed with them," King says.

Reference

1. King NMP. Defining and describing benefit appropriately in clinical trials. J Law Med Ethics 2000; 28:332-343.