Stepwise two‐stage sample size adaptation

Abstract

Several adaptive design methods have been proposed to reestimate sample size using the observed treatment effect after an initial stage of a clinical trial while preserving the overall type I error at the time of the final analysis. One unfortunate property of the algorithms used in some methods is that they can be inverted to reveal the exact treatment effect at the interim analysis. We propose using a step function with an inverted U-shape of observed treatment difference for sample size reestimation to lessen the information on treatment effect revealed. This will be referred to as stepwise two-stage sample size adaptation. This method applies calculation methods used for group sequential designs. We minimize expected sample size among a class of these designs and compare efficiency with the fully optimized two-stage design, optimal two-stage group sequential design, and designs based on promising conditional power. The trade-off between efficiency versus the improved blinding of the interim treatment effect will be discussed.