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Some controversial multiple testing problems in regulatory applications.

H M James Hung1, Sue-Jane Wang

  • 1Division of Biometrics I, OB/OTS/CDER, FDA, Silver Spring, Maryland 20993-0002, USA. hsienming.hung@fda.hhs.gov

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Summary
This summary is machine-generated.

Navigating multiple testing in regulatory science requires careful hypothesis definition. Partitioning null hypotheses offers a flexible alternative to rigid gatekeeping strategies for complex clinical trial endpoints.

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Area of Science:

  • Biostatistics
  • Clinical Trial Design
  • Regulatory Science

Background:

  • Multiple testing poses significant challenges in regulatory applications, especially when dealing with multiple null hypotheses.
  • Existing sequential gatekeeping strategies can be overly restrictive for complex scenarios like multiple doses, endpoints, or composite endpoints.

Purpose of the Study:

  • To explore alternative strategies for managing multiple testing problems in clinical trials.
  • To address the limitations of traditional gatekeeping methods in regulatory settings.

Main Methods:

  • Proposes partitioning null hypotheses into clinically relevant orderings or sets as an alternative to closed testing.
  • Discusses the limitations of the intersection-union testing setting regarding alpha level stringency.
  • Suggests group-sequential designs with conservative sample size planning and alpha spending functions as a remedial approach.

Main Results:

  • Partitioning null hypotheses can resolve illogical restrictions imposed by gatekeeping strategies.
  • The intersection-union setting offers limited flexibility without substantial, often unjustifiable, parameter space restrictions.
  • Group-sequential designs can mitigate conservatism by allowing early conclusions.

Conclusions:

  • Reordering or partitioning null hypotheses based on clinical relevance offers a viable solution to complex multiple testing issues.
  • Group-sequential designs provide a practical approach to manage conservatism in regulatory trials with multiple endpoints.