Phase I studies of new drugs tend to be the riskiest for human subjects since they are the first trials that involve people. Thus, these investigations usually are conducted with healthy volunteers who receive only a single dose of the drug.
“The problem in cancer is that a lot of the drugs are pretty toxic. The thought is: ‘It’s not ethical, it is too risky to give those to healthy volunteers,’ particularly when you are talking about minors,” says David Wendler, MA, PhD, head of the section of research ethics at NIH Clinical Center.
Instead, researchers give the drug to pediatric patients with the cancer in question, or maybe a broad range of cancers, if the researchers believe the drug may be safe and effective for other cancers. Typically, studies limit enrollment to children who either have not performed well on other treatments, or for whom there are no other available standard treatments. The idea is study participants are not forgoing any treatment that is known to be effective. “The challenge is, those trials are extremely important for developing new treatments for pediatric cancers. At the same time, over the years there has been a lot of ethical consternation expressed about them,” Wendler says.
Additionally, trials can be risky. It is unclear whether there is any benefit for participants, and the children who are enrolled are critically ill. “While parents do enroll their children, and children do assent to the extent they’re able, there’s a lot of worry that maybe they don’t really understand how risky these trials are,” Wendler observes.
It is ethically concerning if parents believe there is a greater chance for benefit than there really is. “It’s been a long-running ethical debate. In the past, people have tried to address the ethical issues in different ways,” Wendler explains.
For example, some researchers argue an important factor is whether the goal and intent of the trial is to benefit the individual patients. “That provides a kind of assessment or proxy for whether or not there is potential benefit to being in these trials. I’ve always been skeptical of those approaches. It seems to me that what people are really worried about is the risk/benefit ratio,” Wendler argues.
Researchers struggled with the lack of good data on the risks and benefits of phase I trials in general, let alone pediatrics. In 2018, researchers published the results of a meta-analysis of the risks and benefits of phase I pediatric trials.1 “That seemed to give us an opportunity for really assessing whether or not the potential benefits justify the risks,” Wendler says.
Previously, all researchers could do was ask people what they thought of the risks and potential benefits of phase I pediatric oncology trials based on their overall impressions. “But that study allowed us, in our survey, to estimate the risks and potential benefits of average trials — the percentage of death, the percentage chance of tumor shrinkage,” Wendler says.
Rather than simply compiling a vague, overall impression, these researchers found a way to specify the risks and potential benefits. They asked if people thought the potential benefits outweigh the risks, if the risks outweigh the potential benefits, or if they are about equal.
Building on that 2018 paper, Wendler and colleagues surveyed U.S. adults on whether they thought the potential medical benefits of phase I pediatric oncology trials justified the risks.2 A total of 58.5% of respondents thought the potential medical benefits were equal to or greater than the risks. In a subsequent study, Wendler and the same colleagues asked IRB members the same question. Of 80 IRB members, 18% said the potential benefits did outweigh the risks, 32.5% said the potential benefits and risks are about equal, and 48.5% said the risks outweighed the potential benefits.3
Notably, there was disagreement within each group. Some members of the public thought the trials were justified, and others did not. The same was true of IRB members. “That helps explain why these trials remain ethically controversial. People just see them in different ways,” Wendler notes.
IRB members were more likely than the public to think the risks outweighed the potential medical benefits. Wendler suggests this reflects the different roles and perspectives of the two groups. Parents and adults think about the possibility of caring for a child with severe cancer and no treatment alternatives. “If you’re a parent in that situation, you’ll be focused on accessing any possible treatments that might help the child, and more inclined to think the potential benefits do justify the risks,” Wendler says.
IRBs play a different role — to ensure trials are ethical and that pediatric subjects are not exposed to excessive risk. That colors the IRB’s decision-making process, possibly leading members to conclude the risks of a given treatment exceed the potential benefits. In light of this, one way to interpret the study’s findings is IRBs understand phase I trials better than parents, who might hold an overly optimistic opinion. Another possible conclusion is IRBs are worrying too much about protecting participants at the expense of access to treatments. “One way to think about the ethics of research is to think about protecting subjects from the risk. But, recently, there is an emphasis on the potential benefits to be gained by participating in clinical trials,” Wendler says.
The truth lies somewhere in the middle. Researchers have to weigh these competing factors when designing study protocols. Ideally, this process includes the perspective of parents. An IRB member could provide this perspective, or a parent from the community could be invited to serve as an ad hoc member of the IRB. “The IRB is already represented when reviewing study protocols,” says Wendler. “It might be valuable to figure out ways to get the parental perspective represented as well.”
REFERENCES
1. Waligora M, Bala MM, Koperny M, et al. Risk and surrogate benefit for pediatric phase I trials in oncology: A systematic review with meta-analysis. PLoS Med 2018;15:e1002505.
2. Schupmann W, Li X, Wendler D. Do the potential medical benefits of phase 1 pediatric oncology trials justify the risks? Views of the United States public. J Pediatr 2021;238:249-258.e3.
3. Wendler D, Schupmann W, Li X. Views of IRB members regarding phase 1 pediatric oncology trials. Pediatr Hematol Oncol 2022 May 3;1-12.
IRB members are more likely than the public to think the risks outweigh the potential medical benefits. Parents think about the possibility of caring for a child with severe cancer and no treatment alternatives. IRBs ensure trials are ethical and that pediatric subjects are not exposed to excessive risk.
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