Optimal adaptive group sequential design with flexible timing of sample size determination.

Flexible sample size designs, including group sequential and sample size re-estimation designs, have been used as alternatives to fixed sample size designs to achieve more robust statistical power and better trial efficiency. In this work, a new representation of sample size re-estimation design suggested by Cui et al. [5,6] is introduced as an adaptive group sequential design with flexible timing of sample size determination. This generalized adaptive group sequential design allows one time sample size determination either before the start of or in the mid-course of a clinical study. The new approach leads to possible design optimization on an expanded space of design parameters. Its equivalence to sample size re-estimation design proposed by Cui et al. provides further insight on re-estimation design and helps to address common confusions and misunderstanding. Issues in designing flexible sample size trial, including design objective, performance evaluation and implementation are touched upon with an example to illustrate.