Accounting for variation in the required sample size in the design of group-sequential trials.

ABSTRACT

INTRODUCTION: Most literature on optimal group-sequential designs focuses on minimising the expected sample size. We highlight other factors for consideration. METHODS: We discuss several quantities less-often considered in adaptive design: the median and standard deviation of the random required sample size, and the probability of committing an interim error. We consider how the optimal timing of interim analyses changes when these quantities are accounted for. RESULTS: Incorporating the standard deviation of the required sample size into an optimality framework, we demonstrate how and when this quantity means using a group-sequential approach is not optimal. The optimal timing of an interim analysis is shown to be highly dependent on the pre-specified preference for minimising the expected sample size relative to its standard deviation. CONCLUSIONS: Examining multiple factors, which measure the advantages and disadvantages of group-sequential designs, helps determine the best design for a specific trial.