Two-stage designs for dose-finding trials with a biologic endpoint using stepwise tests

Mei Yin Polley, Ying Kuen Cheung

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


We deal with the design problem of early phase dose-finding clinical trials with monotone biologic endpoints, such as biological measurements, laboratory values of serum level, and gene expression. A specific objective of this type of trial is to identify the minimum dose that exhibits adequate drug activity and shifts the mean of the endpoint from a zero dose to the so-called minimum effective dose. Stepwise test procedures for dose finding have been well studied in the context of nonhuman studies where the sampling plan is done in one stage. In this article, we extend the notion of stepwise testing to a two-stage enrollment plan in an attempt to reduce the potential sample size requirement by shutting down unpromising doses in a futility interim. In particular, we examine four two-stage designs and apply them to design a statin trial with four doses and a placebo in patients with Hodgkin's disease. We discuss the calibration of the design parameters and the implementation of these proposed methods. In the context of the statin trial, a calibrated two-stage design can reduce the average total sample size up to 38% (from 125 to 78) from a one-stage step-down test, while maintaining comparable error rates and probability of correct selection. The price for the reduction in the average sample size is the slight increase in the maximum total sample size from 125 to 130.

Original languageEnglish (US)
Pages (from-to)232-241
Number of pages10
Issue number1
StatePublished - Mar 2008


  • Familywise error rate
  • Futility interim
  • Minimum effective dose
  • Monotonicity
  • Multiple comparison
  • Probability of correct selection

ASJC Scopus subject areas

  • Statistics and Probability
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Agricultural and Biological Sciences(all)
  • Applied Mathematics


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