Optimizing randomized trial designs to distinguish which subpopulations benefit from treatment

M. Rosenblum, M. J. Van Der Laan

Research output: Contribution to journalArticlepeer-review

35 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)845-860
Number of pages16
Issue number4
StatePublished - Dec 2011


  • Adaptive design
  • Enrichment design
  • Group sequential design
  • Optimization
  • Patient-oriented research
  • Randomized trial
  • Subpopulation

ASJC Scopus subject areas

  • Statistics and Probability
  • Mathematics(all)
  • Agricultural and Biological Sciences (miscellaneous)
  • Agricultural and Biological Sciences(all)
  • Statistics, Probability and Uncertainty
  • Applied Mathematics


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