A systematic approach to adaptive sequential design for clinical trials: using simulations to select a design with desired operating characteristics.

The failure rates of phase 3 trials are high. Incorrect sample size due to uncertainty of effect size could be a critical contributing factor. Adaptive sequential design (ASD), which may include one or more sample size re-estimations (SSR), has been a popular approach for dealing with such uncertainties. The operating characteristics (OCs) of ASD, including the unconditional power and mean sample size, can be substantially affected by many factors, including the planned sample size, the interim analysis schedule and choice of critical boundaries and rules for interim analysis. We propose a systematic, comprehensive strategy which uses iterative simulations to investigate the operating characteristics of adaptive designs and help achieve adequate unconditional power and cost-effective mean sample size if the effect size is in a pre-identified range.