Abstract
Outcome-adaptive randomization (OAR) has been proposed as a corrective to certain ethical difficulties inherent in the traditional randomized clinical trial (RCT) using fixed-ratio randomization. In particular, it has been suggested that OAR redresses the balance between individual and collective ethics in favour of the former. In this paper, I examine issues of welfare and autonomy arising in relation to OAR. A central issue in discussions of welfare in OAR is equipoise, and the moral status of OAR is crucially influenced by the way in which this concept is construed. If OAR is based on a model of equipoise that demands strict indifference between competing interventions throughout the trial, such equipoise is disturbed by accruing data favouring one treatment over another; OAR seeks to redress this by weighting randomization to the seemingly superior treatment. However, this is a partial response, as patients continue to be allocated to the inferior therapy. Moreover, it rests upon considerations of aggregate harms and benefits, and does not therefore uphold individual ethics. Issues of fairness also arise, as early and late enrollees are randomized on a different basis. Fixed-ratio randomization represents a fuller and more consistent response to a loss of equipoise, as so construed. With regard to consent, the complexity of OAR poses challenges to adequate disclosure and comprehension. Additionally, OAR does not offer a remedy to the therapeutic misconception—participants’ tendency to attribute treatment allocation in an RCT to individual clinical judgments, rather than to scientific considerations—and, if anything, accentuates rather than alleviates this misconception. In relation to these issues, OAR fails to offer ethical advantages over fixed-ratio randomization. More broadly, the ethical basis of OAR can be seen to lie more in collective than in individual ethics, and overall it fares worse in this territory than fixed-ratio randomization.
Highlights
Recent advances in randomized clinical trials (RCTs) include the use of adaptive designs
Allocation of participants in traditional RCTs is independent of any accruing data, in contrast to the dynamic method of randomization used within Outcome-adaptive randomization (OAR)
OAR gives rise to several ethical issues related to welfare and autonomy, and these issues are largely connected to the way in which OAR responds to changing information during the trial (Fig. 1)
Summary
Recent advances in randomized clinical trials (RCTs) include the use of adaptive designs. In. A final ethical difficulty facing OAR is that of demonstrating why an accumulation of evidence that, within E1, is considered sufficient to disturb equipoise, and to justify weighting randomization against one intervention on the grounds of its perceived inferiority, is not a reason to stop the trial altogether, as would likely occur during a planned interim analysis in a trial using FRR. In some circumstances, more participants in total may be allocated to the inferior treatment than to the superior treatment, given the conclusion reached at the end of the study Even if this situation does not characterize the trial as a whole, it may hold at a particular time within the trial’s duration—that is, at one or more points in the trial, OAR may favour the treatment shown to be inferior, even though randomization across the whole trial may prove to be weighted towards the superior treatment. An additional possibility is switching—those aware that they are receiving the less desirable intervention may try to obtain the better alternative
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