Sample size re-estimation for pivotal clinical trials

Abstract

It is well known that if the hypothesis test is left unchanged, the Type I error rate may be inflated for sample size re-estimation (SSR) designs. To address this issue, three main approaches have been proposed in the literature: combination test, conditional error and conventional test with sample size increase in the allowable region (AR) only. These three seemingly different approaches are in fact connected. For each combination test, there is a corresponding conditional error function and AR. Designing adaptation rules in this AR with conventional test guarantees the Type I error rate control but at the same time always leads to smaller power comparing to the corresponding combination test (or conditional error) approach. In cases where conventional test is still preferable, step-wise type adaptation rules that do not fully reside in the AR can be alternatively considered. We believe controversies in the statistical community on the efficiency comparisons between group sequential (GS) and SSR design stem partially from the misalignment of performance metrics and conditional versus unconditional evaluations. We advocate summary metrics, such as median, variance or tail probabilities of the sample size in addition to expectation and personalizing efficiency definition for each trial sponsor. Conditional metrics by favorable, promising and unfavorable zones of the interim results provide additional insights and should always be incorporated into the decision-making process.