Ethical concerns about adaptive randomization

In this issue, we recognize the passing of Marvin Zelen, a strong force in the creation of clinical trials coordinating centers, and an accomplished academic statistician who made many contributions to clinical trials methodology. He was at the forefront of trends that influenced the practice of clinical trials during the 1960s, 1970s, and beyond. One idea that he originated in 1969 was the ‘‘play-the-winner’’ rule. In Zelen’s original formulation of the play-the-winner rule, if a patient on a comparative clinical trial responded to treatment, the next patient would be assigned to this successful treatment. If not, the next patient would receive the alternate treatment. Zelen studied the mathematical properties of this design. This was, of course, the forerunner to adaptive randomization. Zelen motivated this work in part by an appeal to ethics, suggesting that ‘‘more patients tend to be assigned to the better treatment.’’ However, he also articulated the ‘‘ethical principle’’ of ‘‘not prolonging a trial longer than necessary,’’ a goal that is generally at variance with clinical trial designs that depart from conventional randomization to the two treatments with equal probability. I have always been very uneasy about the propriety of designs where the probability of being assigned to one treatment versus its comparator is dependent on emerging data. It is fine to tell patients during the consent process that their chances of being assigned to a promising treatment will be enhanced if the evidence supports it, but how do you explain the inevitable corollary that there will remain a significant chance that the patient will be assigned to a treatment you think is inferior? To me the notion that this enhances the ethical basis for clinical trials research is, quite simply, flawed. So, I have been pleased to see that at long last ethicists have started to take an active interest in this topic. In this context, our lead article in this issue, by Spencer Hey and Jonathan Kimmelman, addresses the use of adaptive randomization from an ethical perspective. Their analysis leads them to question its ethical basis. The article is the focus for lively debate in six commentaries and a rejoinder. As you can see, there is a wide divergence of opinions. While this debate will not resolve all the issues, it is an important one to conduct. Randomization is a pivotal methodological tool that has greatly enhanced the validity and quality of clinical research during the past half century and more. But this success is fragile. Many clinical trial participants do not understand it. Many clinical investigators support its use because of a perception that it represents mainstream thinking but would happily abandon it if the mainstream thinking were perceived to be up for debate. Asking patients with serious medical conditions to have their treatments determined by a chance mechanism is only supportable if there is genuine uncertainty about the relative efficacy of the treatments being compared in the trial, that is, if there exists clinical equipoise. Adaptive randomization challenges the whole notion of equipoise and as such challenges the entire basis for randomization. In short, in my view, it is an insidious threat to the most important tool in the clinical research armamentarium. Clearly, my views on this issue are not impartial! But I know they will not impede all of you from forming your own opinions after reading this lively series of commentaries, if your minds are not already made up!