Editorial
February 20, 2023
The Ethics of Clinical Research: Managing Persistent Uncertainty
Alex John London, Christopher W. Seymour
JAMA. Published online February 20, 2023. doi:10.1001/jama.2023.1675
In the face of novel pathogens, incomplete knowledge, and disagreement about the merits of medical treatments, translating the duty to care into concrete benefits for patients depends on our ability to quickly act on the duty to learn.1 Learning is a dynamic process whose goal, in medical research, is to generate the evidence needed to reduce uncertainty and shift care toward safer, more effective, and efficient practice. It is also a social process that requires the cooperation of multiple stakeholders, including funders, researchers, health care professionals, health systems, regulatory bodies, and patients. The interests of these stakeholders can conflict, and the requirement of clinical equipoise is seen as a way to ensure that research promotes medical progress without compromising the interests of study participants. The equipoise requirement holds that (1) research that addresses uncertainty or conflicting medical judgments of conscientious and informed experts is likely to have social value and (2) allocating individuals to interventions that are subject to such conflict or uncertainty is consistent with respect for their rights or welfare.2 But when does clinical equipoise no longer hold?
The importance of this question is illustrated by the report from Naggie et al published in JAMA.3 The authors report results from the Accelerating Covid-19 Therapeutic Interventions and Vaccines 6 (ACTIV-6) platform randomized clinical trial, in which 1206 participants with mild to moderate COVID-19 were randomized to receive a maximum targeted dose of 600 μg/kg of ivermectin daily for 6 days compared with placebo. This trial investigated both a higher dose and longer duration of ivermectin than prior studies. Most participants (84%) received at least 2 COVID-19 vaccine doses and 60% received the study drug within 5 days of symptom onset. The median time to recovery was 11 days in the ivermectin group compared with 11 days in the placebo group, and there was no significant benefit from ivermectin for any secondary outcomes or in subgroup analyses.
These findings are consistent with previous research, including 3 other randomized trials of different doses and duration of ivermectin. However, there are currently more than 10 trials of ivermectin recruiting participants on ClinicalTrials.gov. After considering factors that can influence the persistence of clinical equipoise, we argue that decisions about what investigations to undertake must be responsive to the relative social value of continuing to reduce uncertainty around one intervention, and stakeholders must consider whether scarce time, resources, and participant effort could be better invested examining other questions.
What Is Clinical Equipoise?
Clinical equipoise holds that it is ethically permissible to randomize study participants to receive an alternative from a set of interventions for a given indication if there is uncertainty or conflict regarding the therapeutic, prophylactic, or diagnostic merits of the interventions in that set and there is not consensus that participant interests would be better advanced by receiving an alternative intervention. Explicit in this requirement is the idea that it is impermissible to randomize participants to receive forms of medical treatment that are known to be worse than an available alternative. The requirement of conflicting medical judgments or uncertainty about the relative merits of interventions promotes respect for participant well-being.
In medical practice and research, there is often a wider range of uncertainty or professional disagreement than capacity to run clinical trials. Uncertainty alone is not sufficient to ensure that studies bridge a knowledge gap critical to advancing the ability of clinicians and health systems to promote the interests of patients effectively and equitably. That requires efforts to ensure that the evidence a trial is designed to generate relates to a priority need for patients or the health systems that serve them. The understanding of when equipoise no longer exists is complicated by many factors, including the uptake of new knowledge, the complexity of medical treatment, and changes in the context in which interventions are evaluated.
Examples of Factors Affecting Equipoise During COVID-19
The pandemic uncovered numerous failures in the production and synthesis of evidence in medicine and public health and many examples of factors that influence the existence of clinical equipoise.4
Early in the pandemic, small, low-quality studies promoted interest in a handful of repurposed treatments.5 Most of these treatments would subsequently be shown to lack clinical value in larger, more rigorous studies. As fully informed and conscientious experts updated their judgments considering the new evidence, their recommendations sometimes differed from common practice or patient preferences. This type of uncertainty or disagreement that reflects incomplete engagement with the full range of available medical evidence does not constitute clinical equipoise.
In other cases, even informed and conscientious experts remained enthusiastic about interventions whose merits were not vindicated in well-designed trials. Trials do not test all uses of a drug, only a specific “treatment ensemble” (ie, a specific dose, duration, population, and purpose).6 When one such ensemble fails, some proponents might conclude that studying a different dose, duration, or population will produce the desired results for the same use case. For example, the study by Naggie et al3 increased the dose and duration of ivermectin while evaluating similar patients and end points as previous trials. In other cases, interest may shift to a different use case, for example, from treatment for the severely ill to reducing disease course or to prevention.
Perhaps counterintuitively, changes in clinical context can also alter the relevance of previously discarded interventions. For example, an intervention may fail to demonstrate a large treatment effect early in a pandemic, but after changes in population immunity and the successful development of alternative treatments, experts might consider whether the intervention has a smaller treatment effect in patients receiving an improved standard of care.
These and other factors can lead to the persistence of informed uncertainty or disagreement about whether a drug is likely to feature in an effective treatment ensemble. But, the relative social value of performing research to address these uncertainties may not persist across these scenarios.
Managing Persistent Uncertainty
Studies that meet the requirements of clinical equipoise for study participants can lack social value if the knowledge gaps they investigate are of more marginal value compared with alternative questions. Although institutional review boards are tasked with ensuring that protocols do not knowingly disadvantage study participants and violate the duty to care, the system for aligning the duty to learn with priority knowledge gaps requires strengthening.
To ensure that uncertainty or conflict reflect an impartial engagement with all relevant evidence, stakeholders should promote the production of comprehensive evidence synthesis through living and systematic reviews. Despite repeated calls for such reforms, a 2022 random sample of research protocols found that “none contained statements suggesting a systematic search for relevant clinical evidence.”7 Funding agencies and institutional review boards should require that claims relating to clinical equipoise and the importance of the knowledge gaps investigated are justified against the background of such reviews, especially for cases in which the same drug is the focus of repeated clinical investigation for similar indications.
Disagreement among stakeholders reflecting different values and social commitments is the norm, not the exception. However, critical to the integrity of medical research is our collective ability to mount studies that target priority health questions using sufficiently rigorous methods that their findings are likely to shift expert judgment and practice. Reasonable uncertainty may persist, but as evidence matures, stakeholders must ensure that scarce time, resources, and patient effort are aligned with knowledge gaps most likely to advance fundamental interests of patients.
