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Dmitrienko Offen Westfall 2003

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Dmitrienko, A., Offen, W., Westfall, P.H. (2003). Gatekeeping strategies for clinical trials that do not require all primary effects to be significant. Statistics in Medicine. 22, 2387-2400.

Abstract

In this paper we describe methods for addressing multiplicity issues arising in the analysis of clinical trials with multiple endpoints and/or multiple dose levels. Efficient "gatekeeping strategies" for multiplicity problems of this kind are developed. One family of hypotheses (comprised of the primary objectives) is treated as a "gatekeeper" and the other family or families (comprised of secondary and tertiary objectives) are tested only if one or more gatekeeper hypotheses have been rejected. We discuss methods for constructing gatekeeping testing procedures using weighted Bonferroni tests, weighted Simes tests, and weighted resampling-based tests, all within a closed testing framework. The new strategies are illustrated using an example from a clinical trial with co-primary endpoints, and using an example from a dose-finding study with multiple endpoints. Power comparisons with competing methods show the gatekeeping methods are more powerful when the primary objective of the trial must be met.

Paper

Download Dmitrienko Offen Westfall 2003. Note that there are two minor typos in the published paper (Table 2, Decision matrix for the parallel Bonferroni gatekeeping procedure). These typos have been corrected in this PDF file.

Extensions

The methodology developed in this paper has been extended in multiple directions:

  • Multistage parallel gatekeeping procedures based on a broad family of separable tests, including Holm-type, Hochberg-type, fallback-type and Dunnett-type tests, see Dmitrienko Tamhane Wiens 2008.

Review papers and chapters

For more information on gatekeeping procedures in clinical trials, see

Software implementation

Bonferroni-based parallel gatekeeping procedures can be implemented using the Gatekeeper macro described in Analysis of Clinical Trials Using SAS (Chapter 2) by Alex Dmitrienko, Geert Molenberghs, Christy Chuang-Stein and Walt Offen.

The Gatekeeper macro can be downloaded from Implementation of Gatekeeping Procedures.

Other papers

For information on other publications on gatekeeping procedures in clinical trials, see Gatekeeping Papers.