期刊
BIOMETRIKA
卷 98, 期 4, 页码 845-860出版社
OXFORD UNIV PRESS
DOI: 10.1093/biomet/asr055
关键词
Adaptive design; Enrichment design; Group sequential design; Optimization; Patient-oriented research; Randomized trial; Subpopulation
资金
- National Institutes of Health, U.S.A.
- U.S. Food and Drug Administration
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.
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