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Related Experiment Videos

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

Mei-Yin Polley1, Ying Kuen Cheung

  • 1US Clinical Development Biostatistics, Amgen Inc., 1120 Veterans Blvd, Mailstop ASF21-2, South San Francisco, CA 94080, USA. meic@amgen.com

Biometrics
|June 19, 2007
PubMed
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This study introduces two-stage designs for early phase dose-finding clinical trials, optimizing sample size for monotone biologic endpoints. These designs reduce average sample size by up to 38% while maintaining statistical accuracy.

Area of Science:

  • Clinical Trials
  • Biostatistics
  • Pharmacology

Background:

  • Early phase dose-finding trials aim to identify the minimum effective dose (MED) for drugs.
  • Traditional stepwise testing procedures are often single-stage, potentially leading to larger sample sizes.
  • Monotone biologic endpoints, such as serum levels or gene expression, are common in these trials.

Purpose of the Study:

  • To extend stepwise testing to a two-stage enrollment plan for dose-finding trials.
  • To reduce sample size requirements through early stopping of unpromising doses (futility interim).
  • To evaluate the performance of four proposed two-stage designs.

Main Methods:

  • Development and examination of four novel two-stage dose-finding trial designs.
  • Application of these designs to a hypothetical statin trial with four doses and a placebo.

Related Experiment Videos

  • Calibration of design parameters and discussion of implementation strategies.

    • Main Results:

    • A calibrated two-stage design reduced the average total sample size by 38% (from 125 to 78) compared to a one-stage test.
    • Error rates and probability of correct selection were maintained comparably.
    • The maximum total sample size slightly increased from 125 to 130.

    Conclusions:

    • Two-stage designs offer significant average sample size reductions in early phase dose-finding trials.
    • These designs provide an efficient alternative to traditional one-stage methods for monotone biologic endpoints.
    • The trade-off for reduced average sample size is a marginal increase in the maximum sample size.