A gated group sequential design for seamless Phase II/III trial with subpopulation selection

Background: Due to the high cost and high failure rate of Phase III trials, seamless Phase II/III designs are more and more popular to trial efficiency. A potential attraction of Phase II/III design is to allow a randomized proof-of-concept stage prior to committing to the full cost of the Phase III trial. Population selection during the trial allows a trial to adapt and focus investment where it is most likely to provide patient benefit. Methods: : Motivated by a clinical trial to find the population that potential benefits with dual-primary endpoints progression free survival (PFS) and overall survival (OS), we propose a gated group sequential design for a seamless Phase II/III trial design with population selection. Results: : The investigated design controls the familywise error rate and allows multiple interim analyses to enable early stopping for efficacy or futility. Simulations and an illustrative example suggest that the proposed gated group sequential design can have more power than the commonly used classical group sequential design, and reduces the patient’s exposure to less effective treatment if the complementary sub-group has less significant treatment effect. Conclusions: : The proposed gated group sequential design controls the familywise error rate and allows multiple interim analyses to enable early stopping for efficacy or futility. It has the potential to save drug development cost and more quickly fulfill unmet medical needs.