Cash Rewards Not an Inherently Improper Influence on Study Participants

It was possible to use monetary incentives to increase clinical trial recruitment without having unethical effects on participants, a study suggested.

Rewards of up to $500 per participant improved enrollment in one randomized controlled trial on smoking cessation, but did not change enrollment in another trial evaluating ambulation, according to the study group led by Scott Halpern, MD, PhD, of the University of Pennsylvania in Philadelphia.

Notably, noninferiority analysis showed that such compensation did not impact patients’ perceptions of study risks, and therefore did not “unduly influence” them, according to the study group. Incentives also did not act as “unjust inducements” as they did not motivate participants at different income levels differently, the researchers reported in JAMA Internal Medicine.

Proponents for monetary incentives often argue that they allow for faster recruitment to socially beneficial clinical trials, a solution to problems of diversity and external validity in research participation, and appropriate compensation to participants for trial-related burdens.

Yet undue influence and unjust inducement are often cited as concerns by institutional review boards limiting the use or magnitude of such monetary incentives to boost research participation.

With their results, Halpern and colleagues argued that regulators “should relax restrictions on the use of incentives that are designed to improve enrollment in low-risk trials,” though they acknowledged that the effectiveness of these incentives “is likely to vary across trials.”

“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,” according to Winston Chiong, MD, PhD, of University of California San Francisco, and two colleagues in a corresponding editorial.

“[G]iven the potential benefits of monetary incentives for clinical research participation, those who would limit their application may owe us an applicable criterion for what makes an inducement undue or unjust. Presumably, exorbitant incentives or incentives specifically targeted at vulnerabilities for the most underserved could qualify, but it seems less likely for the $100 to $500 range of incentives considered in this trial,” they said.

The analysis by Halpern’s group was embedded in two clinical trials conducted from 2017 to 2019. Initially, the study included a third embedded clinical trial that compared forms of radiation therapy for lung cancer. However, the lung cancer clinical trial was suspended due to logistical barriers.

In the smoking cessation trial, 654 participants were recruited by phone and randomized to receive $0, $200, and $500. Enrollment rates tracked upward with increasing incentives: 21.8% with no reward, 35.9% with $200, and 47.1% with $500 (adjusted OR 1.70 for each increase in incentive, 95% CI 1.34-2.17). Half of participants in this trial were women, with the average age of all participants being 50.6 years.

In the ambulation trial, 642 patients were enrolled and randomized to receive $0, $100, and $300. This cohort had been recruited in-person at a hospital site. Unlike the smoking trial, participation did not correlate with compensation: 45.4% with no reward, 48.1% with $100, and 43.0% with $300 (adjusted OR 0.88, 95% CI 0.64-1.22). Over 56% of participants were women, and 46.7 years was the average age.

“The higher incentive sizes in the smoking trial are unlikely to explain the different results because the $300 incentive in the ambulation trial was ineffective, whereas the $200 incentive in the smoking trial increased enrollment,” the investigators wrote. “A more likely explanation is that the benefits of the ambulation trial relative to the risks were perceived to be high, yielding higher baseline consent rates and fewer patients whose decisions could be altered by incentives.”

They conceded that a limitation of their study is that they only looked at two clinical trials with different sets of risks, whereas higher-risk clinical trials may produce different results when incentives are used.

Chiong’s group raised the issue of the study’s reliance on noninferiority analysis and the choice of a small noninferiority margin not based on evidence. “To conclude that these results are not compatible with undue or unjust inducement depends on a particular threshold of how much inducement counts as undue or unjust, which is itself subject to ethical disagreement and argument,” the editorialists said.

“We chose noninferiority analyses rather than traditional superiority tests of these terms because concerns about undue and unjust inducement commonly limit the use of incentives in research, meaning that the burden of proof for practice to change requires establishing that such unintended consequences are unlikely to arise,” the investigators argued.

“Incentives for research participation have long been held to a higher burden of proof to justify their acceptability than the use of incentives in nearly all other walks of life. No single study can put all such concerns to rest; even the two studies with similar findings that we have published will not answer all questions,” Halpern wrote in an email to MedPage Today.

“However, these results do suggest that the burden of proof now lies with those who wish to limit the use of incentives, rather than with those who wish to broaden their use,” he said.