Sample size re-estimation designs in confirmatory clinical trials: Current state, statistical considerations and practical guidance

摘要

Confirmatory clinical trials that are a critical milestone in a drug development program. In these trials, sample size determination is observed as an important activity for the choice of subjects for tests. While any trial is in progress, there are occasions where a re-sample is required. In this article, it is proposed to discuss various sample size re-estimation designs (SSRs) for confirmatory clinical trials taking into account the current state, statistical considerations, and practical guidance. It is pointed out that SSR design is a flexible, adaptive design with the primary purpose of allowing sample size of a study to be reassessed in the mid-course of the study to ensure adequate power. In this regard, an overview of statistical methods related to the designs of unblinded SSR or blinded SSR clinical trials are provided. Methods for handling multiplicity encountered in studies using SSR are then identified. Group sequential design methods are discussed in brief followed by which the points to be considered when selecting one of these design options for a confirmatory study are elaborated. Real world examples and simulations are considered to provide practical guidance for the implementation of SSR designs. The paper concludes with a detailed discussion on the findings. (44 refs.)