Ethics and practice: alternative designs for phase III randomized clinical trials.

For decades, biostatisticians have developed and refined the methodology for clinical trials with the intent of giving trial participants a better representation than traditional, equal-allocation, fixed sample-size designs. Despite these methodologic advances and ethical advantages, alternative or data-dependent designs for phase III clinical trials, including sequential designs, Bayesian methods, and adaptive designs, have not been widely adopted in practice. We attempt to characterize situations under which these designs are feasible and desirable from ethical and logistical standpoints. In particular, we describe the role of individual and collective ethics in designing clinical trials and argue that greater attention should be paid to the former. We give examples of those alternative designs that have been used in practice, including discussion of their strengths and shortcomings. We conclude that alternative designs are applicable in limited classes of trials and that investigators should consider them more often when planning clinical trials.