Response-adaptive decision-theoretic trial design: operating characteristics and ethics.

Adaptive randomization is used in clinical trials to increase statistical efficiency. In addition, some clinicians and researchers believe that using adaptive randomization leads necessarily to more ethical treatment of subjects in a trial. We develop Bayesian, decision-theoretic, clinical trial designs with response-adaptive randomization and a primary goal of estimating treatment effect and then contrast these designs with designs that also include in their loss function a cost for poor subject outcome. When the loss function did not incorporate a cost for poor subject outcome, the gains in efficiency from response-adaptive randomization were accompanied by ethically concerning subject allocations. Conversely, including a cost for poor subject outcome demonstrated a more acceptable balance between the competing needs in the trial. A subsequent, parallel set of trials designed to control explicitly types I and II error rates showed that much of the improvement achieved through modification of the loss function was essentially negated. Therefore, gains in efficiency from the use of a decision-theoretic, response-adaptive design using adaptive randomization may only be assumed to apply to those goals that are explicitly included in the loss function. Trial goals, including ethical ones, which do not appear in the loss function, are ignored and may even be compromised; it is thus inappropriate to assume that all adaptive trials are necessarily more ethical. Controlling types I and II error rates largely negates the benefit of including competing needs in favor of the goal of parameter estimation.