title: Optimizing randomized trial designs to distinguish which subpopulations benefit from treatment.
abstract: It is a challenge to evaluate experimental treatments where it is suspected that the treatment effect may only be strong for certain subpopulations, such as those having a high initial severity of disease, or those having a particular gene variant. Standard randomized controlled trials can have low power in such situations. They also are not optimized to distinguish which subpopulations benefit from a treatment. With the goal of overcoming these limitations, we consider randomized trial designs in which the criteria for patient enrollment may be changed, in a preplanned manner, based on interim analyses. Since such designs allow data-dependent changes to the population enrolled, care must be taken to ensure strong control of the familywise Type I error rate. Our main contribution is a general method for constructing randomized trial designs that allow changes to the population enrolled based on interim data using a prespecified decision rule, for which the asymptotic, familywise Type I error rate is strongly controlled at a specified level α. As a demonstration of our method, we prove new, sharp results for a simple, two-stage enrichment design. We then compare this design to fixed designs, focusing on each design's ability to determine the overall and subpopulation-specific treatment effects.
authors.affiliation: Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe St., Room E3616, Baltimore, Maryland 21205, U.S.A.
authors.forename: M
authors.initials: M
authors.lastname: Rosenblum
authors.forename: M J
authors.initials: MJ
authors.lastname: Van der Laan