A Practical Perspective: Application of the Generalized Approach for Adaptive Design.

Abstract

Adaptive design methodology has been well studied for continuous, binary, and survival outcomes for decades. However, for complicated endpoints such as recurrent hospitalization in the joint frailty setting and composite endpoint in the win-ratio setting, adaptive design is not intuitive because of sophistication in existing methods to perform sample size re-estimation. The objective of this paper is to propose a practical generalized approach to implement the above activities at the interim stage through approximation so that sample size re-estimation becomes easily understood and readily amenable. Through simulations on representative complex situations, the proposed method can maintain the planned statistical power by sample size re-estimation while controlling the type I error. The proposed adaptive approach is easy to implement in general sample size re-estimation situations. Its validity can be verified through simulation under varying scenarios. In summary, this approach offers a transparent communication channel with regulatory agencies to facilitate clinical trial development regardless of the complexity of the underlying situations.