Adaptation Will Not Solve The Problem with Equipoise
We agree with Hey et al. (1) that emergent clinical trial designs may present new variations on the foundational questions of clinical trial ethics. However, we doubt their assumption that the modern response needs to be based on the concept of equipoise. For, as Hey et al. identify, we still do not have a standardized way of determining when equipoise is fulfilled. As they write, "systematic evidence reviews, formal surveys, and peer critique of a trial's protocol" may all point towards equipoise, but these are not equivalent things.
If equipoise just means uncertainty then yes - on a very superficial level - it should factor into the ethical evaluation of both traditional and novel RCTs. But clearly this is too low a bar to meet: there is always uncertainty, at least with regards to how any one patient will respond to a given treatment (2). And if equipoise specifically means disagreement within a community, then a series of as yet unanswered questions need to be resolved: whose uncertainty, how much, established how, and upon what basis? Without answers to these questions, it becomes too easy to use equipoise to justify almost any design: because of how flexible and multi-varied scientific uncertainty can be, clinical equipoise is unable to objectively discriminate between permissible and impermissible clinical research.
Therefore, we have suggested a series of questions that may more thoroughly ensure that a given trial is ethically sound (3,4).
1. Does the trial have a clear question and a precise hypothesis?
2. Is the trial non-redundant - ie. has the question not already been answered?
3. Is that non-redundancy established through a systematic review of the literature?
4. Are all of the treatment strategies being compared scientifically plausible and reasonable in clinical practice - ie. are patients enrolled in the trial not deprived of accepted treatments?
5. Does the trial have the sufficient methodological rigour (sample size, recruitment strategy, formalized outcome measures) to be likely to produce a meaningful result?
We hope to bring these questions to the broader research community with the intention of ensuring that any RCTs seeking to enroll patients - be they of traditional or emergent design - are scientifically necessary and ethically justified.
(1) Hey SP, Weijer C, Taljaard M, Kesselheim AS. Research ethics for emerging trial designs: does equipoise need to adapt? BMJ 2018;360:k226.
(2) Shamy M, Stahnisch FW, Hill MD. Fallibility: a new perspective on the ethics of clinical trial enrollment. Int J Stroke 2015;10:2-6.
(3) Shamy M, Fedyk M. Why the ethical justification of randomized clinical trials is a scientific question. J Clin Epi 2018; https://doi.org/10.1016/j.clinepi.2017.12.026
(4) De Meulemeester J, Fedyk M, Lurkovic L, et al. Many randomized clinical trials may not be justified: a cross-sectional analysis of the ethics and science of randomized clinical trials. J Clin Epi 2018; https://doi.org/10.1016/j.clin.epi.2017.12.027
Competing interests: No competing interests