Outcome-adaptive randomization in clinical trials: issues of participant welfare and autonomy

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.

Ethical Considerations in Conducting Clinical Trials

“…Accordingly, the results can be interpreted [9][10][11] because the researcher can re-evaluate them based on the parameters obtained during the study [12]. Also, in pragmatic clinical trial studies performed in real environments, it is crucial to design research questions and topics.…”

Randomised trials at the level of the individual

“…Given that these populations might have a varied understanding of research intent or conduct, RAR designs can raise complexities of obtaining consent from participants. 33…”

Non-static framework for understanding adaptive designs: an ethical justification in paediatric trials

“…18 Such information should, therefore, lead to an earlier identification of ineffective therapies compared with traditional clinical trials, thereby cutting down the overall participant burden and cost of a trial. 19 Regardless of these potential advantages, some scholars argue that ADs foster some degree of injustice, 13 may add to the burden borne by some of the participants enrolled in such trials, 20 complicate the process of consent 21 and may increase how patients fail to distinguish between being under clinical care and clinical research (therapeutic misconception). 22…”