From Adaptive Design to Modern Protocol Design for Drug Development: Part II. Success Probabilities and Effect Estimates for Phase 3 Development Programs

Abstract

In this article we investigate success probabilities and effect estimates for several standard phase 3 programs consisting of two pivotal studies, each with placebo and either one or two doses. We investigate the probability of success for the entire phase 3 program as well as the resulting bias and mean square error of the effect estimates. We also investigate an alternative development strategy, where the first of the two pivotal trials uses an adaptive trial design with treatment selection at interim. The dose selection at the interim analysis of that adaptive trial triggers a second confirmatory, nonadaptive trial comparing the selected dose(s) with placebo and otherwise following the same protocol as the adaptive trial. After describing key considerations, we report the main results of extensive simulation studies.