Adaptive enrichment designs involve preplanned rules for modifying enrollment criteria based on accruing data in a randomized trial. We focus on designs where the overall population is partitioned into two predefined subpopulations, e.g., based on a biomarker or risk score measured at baseline. The goal is to learn which populations benefit from an experimental treatment. Two critical components of adaptive enrichment designs are the decision rule for modifying enrollment, and the multiple testing procedure. We provide a general method for simultaneously optimizing these components for two stage, adaptive enrichment designs. We minimize the expected sample size under constraints on power and the familywise Type I error rate. It is computationally infeasible to directly solve this optimization problem due to its nonconvexity. The key to our approach is a novel, discrete representation of this optimization problem as a sparse linear program, which is large but computationally feasible to solve using modern optimization techniques. Applications of our approach produce new, approximately optimal designs.



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