The researchers, who claim this is the “first known empirical study of clinical trial experts’ views on ethical issues in adaptive clinical trials,” used surveys and mini-focus group questions to gather opinions of 53 clinical trial experts regarding the ethical advantages and disadvantages of ACT designs.
The respondents recognized potential ethical benefits of ACTs including a higher probability of trial participants receiving an effective intervention, optimizing resource utilization, and accelerating treatment discovery. Ethical challenges, however, included developing procedures so trial participants can make informed decisions about taking part in ACTs, and the potential risks of research personnel altering enrollment.
CROs (contract research organizations) seem to be slowly coming on board to the idea of adjusting parameters for ongoing clinical trials and in adopting more simple adaptive designs, such as early terminations of trials due to futility, according to a report from the Tufts Center for the Study of Drug Development.
Ethical Issues
The participant groups identified potential risks and ethical disadvantages of ACTs, for instance, if information about the results of interim analyses were leaked or inferred by clinicians involved in recruiting potential participants, bias could be introduced if the clinician then chose to enroll or not enroll patients on the basis of the information being leaked.
Consultant biostatisticians acknowledged that unblinding might be an issue, especially if “appropriate firewalls are not in place.” Clinician stakeholders also thought that ending a trial early could be a disadvantage if doing so led to a loss of funding as an ACT conducted with an early stopping rule could put an investigator at a financial disadvantage if grant funding ends earlier than anticipated.
Some academic biostatisticians also expressed concerns about informed consent, with one saying: “I think it will be a mess, the informed consents are long already but if you really want to inform your subjects, potential subjects, what the study is you’re going to have to explain all of that adaptations that you’re planning. So then to explain how your chances are going to change during the course of the study, it definitely could complicate.”
Advantages
From a societal perspective, the consultant biostatisticians all told researchers of the “definite ethical advantages” while responses from the academic clinicians and academic biostatisticians varied more.
“The adaptive approach, when properly done, pays more attention to individual ethics, in the sense that it ensures that the trial doesn’t continue when there isn’t a chance that either therapy is effective or that the therapy is more effective than the control. It can be designed to improve the outcomes of patients within the study,” according to one biostatistician.
But the researchers seemed to think that more work needs to be done to assess the ethical considerations of an ACT.
“As a starting point, these data suggest there may be substantive differences in the opinions of key stakeholder constituencies that need to work together to conduct ACTs. Thus, it would seem that data suggest further discussion about the ethics of ACTs is needed to facilitate the moral buy-in that achieves effective teamwork in ACT design and conduct, and ultimately accelerates movement of effective therapies from bench to bedside,” the researchers concluded.