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Research ethics for emerging trial designs: does equipoise need to adapt?

BMJ 2018; 360 doi: https://doi.org/10.1136/bmj.k226 (Published 25 January 2018) Cite this as: BMJ 2018;360:k226
  1. Spencer Phillips Hey, research scientist12,
  2. Charles Weijer, professor3,
  3. Monica Taljaard, senior scientist4,
  4. Aaron S Kesselheim, associate professor12
  1. 1Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital, Boston, USA
  2. 2Center for Bioethics, Harvard Medical School, Boston, USA
  3. 3Rotman Institute of Philosophy, Western University, London, Canada
  4. 4Clinical Epidemiology Program, Ottawa Hospital Research Institute, University of Ottawa, Canada
  1. Correspondence to: S P Hey shey{at}bwh.harvard.edu

New trial designs present challenges for applying equipoise and discussing risks with patients and participants, say Spencer Hey and colleagues

Key messages

  • The research environment has changed since clinical equipoise was first proposed 30 years ago

  • New trial designs—such as umbrella and basket trials, adaptive platform trials, and cluster randomised trials—raise new ethical challenges for evaluating the state of scientific uncertainty and communicating about risks with patients and participants

  • Clinical equipoise needs to evolve

  • We propose the design of specific guidelines to provide ethics committees and trialists with instructions for how to evaluate equipoise in the context of new designs and biomarkers and how to optimise communication with participants

Clinical trials are conducted to resolve uncertainties. Benjamin Freedman’s concept of clinical equipoise, introduced 30 years ago, famously captured the link between uncertainty and ethics. He said that, for a trial to be ethical, the expert community must be uncertain about the relative merits of each trial arm, and the trials must be designed to resolve uncertainty and bring consensus.1

Freedman’s concept has become foundational for research ethics. It can help to identify important research questions and the appropriate methods to answer them. It is useful for members of research ethics committees, who must decide whether risks in a trial are reasonable in relation to the anticipated benefits.2 For patients and their physicians, it promotes trust in the research enterprise and informs discussion of whether trial participation is in the patient’s best interests.3

But 30 years ago most trials randomly assigned people into two (or more) parallel treatment arms. Many new trial designs have emerged or become more common since then, including umbrella and basket trials,4 adaptive platform trials,5 and cluster randomised trials (box 1).6 We describe how the uncertainties and ethics in these trial types may …

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