Outcome-adaptive randomization: some ethical issues Julius Sim Keele Clinical Trials Unit Research Institute for Primary Care and Health Sciences Keele University, UK

Outline of talk Conventional versus outcome-adaptive randomization The moral case for outcome-adaptive randomization Some problematic ethical issues equipoise consent methodology

Adaptive clinical trials Adjustments are made to the trial while it is in progress, regarding: The number of arms Number and timing of interim analyses Case definition Allocation ratio

Conventional vs outcome-adaptive randomization Conventional approach to randomization Outcome-adaptive randomization Fixed (usually 1:1) allocation ratio at outset Allocation remains fixed Initial allocation adjusted in the light of accruing data, to favour the superior treatment Judgment on relative benefit is suspended until end of trial (or planned interim analysis) Judgment on relative benefit is continually re-appraised

The moral case for adaptive randomization A distinction can be made here between collective and individual ethics: Collective – doing what is best for the population of future patients Individual – doing what is best for individual patients in the trial Adaptive randomization is often considered to affirm individual ethics (Pullman & Wang, 2001; Legocki et l, 2015)

Equipoise

The principle of equipoise A trial is ethical in as much as the researcher (or the clinical community) is genuinely uncertain of the relative aggregate effectiveness of the treatments being tested. (Fried, 1974; Freedman, 1987) Hence, at the outset of the trial, no patient is knowingly disadvantaged by being randomized

Equipoise In conventional randomization, equipoise is not re-evaluated during the trial (except at any interim analyses) – judgment is suspended In adaptive randomization, equipoise is continually re-evaluated – and the allocation ratio adjusted accordingly

Equipoise and adaptive randomization – 1 Patients are still allocated to the inferior treatment, although at a lower rate This compensates for a loss of equipoise, but does not restore it Some patients are therefore knowingly disadvantaged

Equipoise and adaptive randomization – 2 The principle of ‘individual ethics’ is undermined Need to be confident that not only the proportion but also the number of patients allocated to the inferior treatment is smaller than in conventional randomization

Informed consent

Informed consent and adaptive randomization – 1 Moral force of consent depends upon: An understanding of what the study involves An ability to give – or withhold – consent freely and autonomously

Informed consent and adaptive randomization – 2 Problems in terms of understanding: Complexity of adaptive randomization may be hard to convey (Saxman, 2015) The therapeutic misconception may be reinforced – participants may believe that allocation is personalized rather than random (Appelbaum et al, 1987)

Informed consent and adaptive randomization – 3 Problems in terms of information: If equipoise is continuously revised, the information on which consent is based must be updated accordingly: for new participants, and for those already in the trial If this cannot be achieved, consent is not adequately informed and loses moral force

Methodological issues

Methodological implications of adaptive randomization – 1 To be morally sound, a study must be methodologically sound (Emanuel et al, 2000) Adaptive randomization may face challenges of: confounding (population drift, alongside changing allocation ratio) loss of blinding (repeated monitoring of outcome) outcomes (hard to use long-term outcomes) sample size (may require larger numbers)

Methodological implications of adaptive randomization – 2 If, overall, designs using adaptive randomization are methodologically less robust than those using conventional randomization… …they lose some of their ethical authority on that basis.

Conclusion Outcome-adaptive randomization has the merit of seeking to maximize benefit for patients in the trial, but it also raises other ethical issues that are potentially problematic

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References Appelbaum PS et al (1987) False hopes and best data: consent to research and the therapeutic misconception. Hastings Center Report 17: 20–24 Emanuel EJ et al (2000) What makes clinical research ethical? JAMA 283: 2701–2711. Freedman B (1987) Equipoise and the ethics of clinical research. New England Journal of Medicine 317: 141–145. Fried C (1974) Medical Experimentation: Personal Integrity and Social Policy. Amsterdam: North-Holland. Legocki LJ et al (2015) Clinical trialist perspectives on the ethics of adaptive clinical trials. BMC Medical Ethics 16: 27 Pullman D, Wang X (2001) Adaptive designs, informed consent, and the ethics of research. Controlled Clinical Trials 22: 203–210. Saxman SB (2015) Ethical considerations for outcome-adaptive trial designs. Bioethics 29: 59–65.