Clinical Trials That Pay Participants Are Not Unethical: Study

Paying people to participate in clinical trials remains controversial. But to date, most reservations are based on hypothetical scenarios or expert opinion with little real-world data to support them.

Research released this week could change that.

Investigators offered nearly 1300 participants in two clinical trials either no payment or incentives up to $500 to partake in a smoking cessation study or an analysis of a behavioral intervention to increase ambulation in hospitalized patients.

More cash was associated with greater agreement to participate in the smoking cessation study but not the ambulation trial.

But the bigger news may be that offering payment did not appear to get people to accept more risks or skew participation to lower-income individuals, as some ethicists have warned.

Dr Scott D. Halpern

“With the publication of our study, investigators finally have data that they can cite to put to rest any lingering concerns about offering moderate incentives in low-risk trials,” lead author Scott D. Halpern, MD, PhD, the John M. Eisenberg professor of medicine, epidemiology, and medical ethics & health policy at the University of Pennsylvania Perelman School of Medicine in Philadelphia, told Medscape Medical News.

This initial real-world data centers on low-risk interventions and more research is needed to analyze the ethics and effectiveness of paying people to join clinical trials with more inherent risk, the researchers note.

The study was published online September 20 in JAMA Internal Medicine.

A Good First Step?

Dr Ana S. Iltis

“Payments to research participants are notoriously controversial. Many people oppose payments altogether or insist on minimal payments out of concern that people might be unduly influenced to participate,” Ana S. Iltis, PhD, told Medscape Medical News when asked for comment. “Others worry that incentives will disproportionately motivate the less well-off to participate.” 

“This is an important study that begins to assess whether these concerns are justified in a real-world context,” added Iltis, director of the Center for Bioethics, Health and Society and professor of philosophy at Wake Forest University in Winston-Salem, North Carolina.

In an accompanying invited commentary, Sang Ngo, Anthony S. Kim, MD, and Winston Chiong, MD, PhD, write: “This work is welcome, as it presents experimental data to a bioethical debate that so far has been largely driven by conjecture and competing suppositions.”

The commentary authors, however, question the conclusiveness of the findings. “Interpreting the authors’ findings is complex and illustrates some of the challenges inherent to applying empirical data to ethical problems,” they write.

Recruitment Realities

When asked his advice for researchers considering financial incentives, Halpern said: “All researchers would happily include incentives in their trial budgets if not for concerns that the sponsor or institutional review board might not approve of them.”

“By far the biggest threat to a trial’s success is the inability to enroll enough participants,” he added.

Iltis agreed, framing the need to boost enrollment in ethical terms. “There is another important ethical issue that often gets ignored, and that is the issue of studies that fail to enroll enough participants and are never completed or are underpowered,” she said.

“These studies end up exposing people to research risks and burdens without a compensating social benefit.”

“If incentives help to increase enrollment and do not necessarily result in undue influence or unfair participant selection, then there might be ethical reasons to offer incentives,” Iltis added.

Building on previous work assessing financial incentives in hypothetical clinical trials, Halpern and colleagues studied 654 participants with major depressive disorder in a smoking cessation trial. They also studied another 642 participants in a study that compared a ‘gamification’ strategy to usual care for encouraging hospitalized patients to get out of bed and walk.

Halpern and colleagues randomly assigned people in the smoking cessation study to receive no financial compensation, $200, or $500. In the ambulation trial, participants were randomly allocated to receive no compensation, $100, or $300.

Key Findings

A total of 22% of those offered no incentive enrolled in the smoking cessation study. In contrast, 36% offered $200 agreed, as did 47% of those offered $500, which the investigators say support offering cash incentives to boost enrollment. The differences were significant (P < .001).

In contrast, the amount offered did not significantly incentivize more people to participate in the ambulation trial (P = .62). Rates were 45% with no compensation, 48% with $100 payment, and 43% with $300 payment.

In an analysis that adjusted for demographic differences, financial well-being, and Research Attitudes Questionnaire (RAQ-7) scores, each increase in cash incentive increased the odds of enrollment in the smoking cessation trial by 70% (adjusted OR [aOR], 1.70; 95% CI, 1.34 – 2.17).

The same effect was not seen in the ambulation trial, where each higher cash incentive did not make a significant difference (aOR, 0.88; 95% CI, 0.64 – 1.22).

“The ambulation trial was a lower-risk trial in which patients’ willingness to participate was higher in general. So there were likely fewer people whose participation decisions could be influenced by offers of money,” Halpern said.

Inducement vs Coercion

The incentives in the study “did not function as unjust inducements, as they were not preferentially motivating across groups with different income levels or financial well-being in either trial,” the researchers note.

Halpern and colleagues also checked for any perceptions of coercion. More than 70% of participants in each smoking cessation trial group perceived no coercion, as did more than 93% of participants in each ambulation trial group, according to scores on a modified Perceived Coercion Scale of the MacArthur Admission Experience Survey. 

Furthermore, perception of risks did not significantly alter the association between cash incentives and enrollment in either trial.

After collecting the findings, Halpern and colleagues informed participants about their participation in RETAIN and explained the rationale for using different cash incentives. They also let all participants know they would ultimately receive the maximum incentive — either $500 or $300, depending on the trial.

Research Implications

A study limitation was reliance on participant risk perception, as was an inability to measure perceived coercion among people who chose not to participant in the trials. Another potential limitation is that “neither of these parent trials posed particularly high risks. Future tests of incentives of different sizes, and in the context of higher-risk parent trials, including trials that test treatments of serious illnesses, are warranted,” the researchers note.

“While there are many more questions to ask and contexts in which to study the effects of incentives, this study calls on opponents of incentivizing research participants with money to be more humble,” Iltis said. “Incentives might not have the effects they assume they have and which they have long held make such incentives unethical.”

“I encourage researchers who are offering incentives to consider working with people doing ethics research to assess the effects of incentives in their studies,” Halpern said. “Real-world, as opposed to hypothetical studies that can improve our understanding of the impact of incentives can improve the ethical conduct of research over time.”

Responding to Criticism

The authors of the invited commentary questioned the definitions Halpern and colleagues used for undue or unjust inducement. “Among bioethicists, there is no consensus about what counts as undue inducement or an unjust distribution of research burdens. In this article, the authors have operationalized these constructs based on their own interpretations of undue and unjust inducement, which may not capture all the concerns that scholars have raised about inducement.”

Asked to respond to this and other criticisms raised in the commentary, Halpern said: “Did our study answer all possible questions about incentives? Absolutely not. But when it comes to incentives for research participation, an ounce of data is worth a pound of conjecture.”

There was agreement, however, that the findings could now put the onus on opponents of financial incentives for trial participants.

“I agree with the commentary’s authors that our study essentially shifts the burden of proof, such that, as they say, ‘those who would limit [incentives’] application may owe us an applicable criterion,'” Halpern said.  

The authors of the invited commentary also criticized use of the study’s noninferiority design to rule out undue or unjust inducement. They note this design “may be unfamiliar to many bioethicists and can place substantial evaluative demands on readers.”

“As for the authors’ claim that noninferiority designs are difficult to interpret and unfamiliar to most clinicians and ethicists, I certainly agree,” Halpern said. “But that is hardly a reason to not employ the most rigorous methods possible to answer important questions.”

The study was supported by funding from the National Cancer Institute.

JAMA Intern Med. Published online September 20, 2021. Study, Commentary

Damian McNamara is a staff journalist based in Miami. He covers a wide range of medical specialties, including infectious diseases, gastroenterology, and critical care. Follow Damian on Twitter: @MedReporter.

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