Some practical considerations in three-arm non-inferiority trial design

Non-inferiority trials aim to demonstrate whether an experimental therapy is not unacceptably worse than an active reference therapy already in use. When applicable, a three-arm non-inferiority trial, including an experiment therapy, an active reference therapy, and a placebo, is often recommended to assess assay sensitivity and internal validity of a trial. In this paper, we share some practical considerations based on our experience from a phase III three-arm non-inferiority trial. First, we discuss the determination of the total sample size and its optimal allocation based on the overall power of the non-inferiority testing procedure and provide ready-to-use R code for implementation. Second, we consider the non-inferiority goal of 'capturing all possibilities' and show that it naturally corresponds to a simple two-step testing procedure. Finally, using this two-step non-inferiority testing procedure as an example, we compare extensively commonly used frequentist p -value methods with the Bayesian posterior probability approach. Copyright © 2016 John Wiley & Sons, Ltd.