Variation in Ethical Justification of Randomized Clinical Trials
July 1, 2022 3 minutes read
To ethically justify a randomized clinical trial, IRBs often use the term “equipoise” to indicate there is uncertainty on which treatment would benefit the participant most. “But they are not defining ‘equipoise’ consistently,” says Brian Dewar, clinical research coordinator at The Ottawa Hospital Research Institute.
For Dewar and colleagues, this observation led to a broader question: What ethical justifications were offered for randomization? “We tried to capture which justifications were offered in the medical literature,” Dewar says.
Dewar and colleagues conducted a literature review of 273 articles with arguments expressing reasons for justifying the ethical permissibility of randomized clinical trials.1 They identified 10 types of reasons used to justify randomization. Half these reasons were linked to equipoise (i.e., the uncertainty of the medical community, an individual doctor’s uncertainty, the patient’s uncertainty, or uncertainty in another context). The other types of reasons were not linked to equipoise (i.e., the patient’s best interest, risk-benefit tradeoffs, methodological rigor, social value, and informed consent alone as sufficient). The study findings suggest there are conceptual differences in how randomized clinical trials are ethically justified. “We hope these results will encourage researchers to explicitly state which ethical standards a given trial meets and how it meets them,” Dewar says.
Researchers are using the term “equipoise” to mean somewhat different things. Also, IRBs are concluding a trial is ethically justified without clearly stating which ethical standard the trial meets. “Opportunities for misunderstandings arise,” Dewar says.
Ideally, when a researcher presents a randomized clinical trial to an ethics board (and to study participants), the term “equipoise” is defined explicitly. This ensures both the study investigator and the IRB mean the same thing when they say the randomization of patients is ethically justified. “Potential participants can make more informed choices about whether to participate in the trial because they know how the trial has been ethically assessed,” Dewar says.
Randomized clinical trials provide the highest-quality evidence for definitively establishing the effects of therapies. “Major declines in rates of cardiovascular events in recent years were possible because of randomized trials that demonstrated benefits of statin medications and blood pressure control on improved cardiovascular outcomes,” notes Mary McGrae McDermott, MD, professor of preventive medicine at Northwestern University.
Concurrently, randomized trials have provided critical information on potential therapies that were ineffective and should not be prescribed. “Benefits of novel cancer therapies cannot be definitively established, relative to their risks and other available therapies, without randomized trials,” McDermott notes.
However, randomized trials must be conducted in a way that minimizes risk to potential participants and ensures established, beneficial, guideline-recommended therapies are not withheld from participants. McDermott says IRBs should be asking specific questions when reviewing study protocols: Is there adequate evidence to support the therapy under investigation? If the therapy was evaluated, is additional evidence in a randomized trial needed? “Data safety monitoring boards can monitor the safety of a trial,” McDermott says.
Investigators should ensure a therapy has been adequately studied in Phase I or II trials before many people are exposed to the therapy in Phase III trials. “It is important for clinical trials to have adequate statistical power so that the results can optimally inform care,” McDermott says.
Is the comparator the correct one to best advance science (e.g., using placebo vs. another established therapy)? Is the study design the most appropriate to advance clinical science (e.g., a superiority trial vs. a non-inferiority trial)? “The comparator group and the trial design should be carefully selected to ensure the best science while minimizing participant risk,” McDermott says.
REFERENCE
- Fedyk M, Dewar B, Jurkovic L, et al. How are randomized clinical trials ethically justified? A systematic scoping review and thematic analysis of reasons that ethically justify randomized clinical trials. J Clin Epidemiol 2022;147:160-167.
Ideally, when a researcher presents a randomized clinical trial to an ethics board (and to study participants), the term “equipoise” is defined explicitly. This ensures both the study investigator and the IRB mean the same thing when they say the randomization of patients is ethically justified.
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