Optimizing randomized trial designs to distinguish which subpopulations benefit from treatment

• 成果类型: Article
• 署名作者: Rosenblum, M.; van der Laan, M. J.
• 署名单位: Johns Hopkins University; Johns Hopkins Bloomberg School of Public Health; University of California System; University of California Berkeley
• 刊物名称: BIOMETRIKA
• ISSN/ISSBN: 0006-3444
• DOI: 10.1093/biomet/asr055
• 发表日期: 2011
• 页码: 845860
• 关键词: adaptive interim analyses; clinical-trials; treatment selection; sequential designs; hypotheses

摘要

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 alpha. 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.