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Gatekeeping strategies for clinical trials that do not require all primary effects to be significant
Alexei Dmitrienko1, Walter W Offen, Peter H Westfall
1Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. dmitrienko_alex@lilly.com
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 (comprising the primary objectives) is treated as a 'gatekeeper', and the other family or families (comprising 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 the 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.
Insights
This study introduces gatekeeping strategies to manage multiplicity issues in clinical trials. These methods improve statistical power for testing multiple endpoints or dose levels, ensuring primary objectives are met efficiently.
Area of Science:
- Biostatistics
- Clinical Trial Design
- Statistical Methodology
Background:
- Clinical trials frequently involve multiple endpoints and dose levels, leading to multiplicity issues.
- Standard statistical methods can be underpowered when addressing these complex trial designs.
- Controlling for false positive rates is crucial for valid interpretation of trial results.
Purpose of the Study:
- To develop and present efficient gatekeeping strategies for handling multiplicity in clinical trials.
- To enhance the statistical power of hypothesis testing in trials with multiple objectives.
- To provide practical methods for constructing robust testing procedures.
Main Methods:
- Gatekeeping strategies are developed, designating a primary set of hypotheses as 'gatekeepers'.
- Secondary and tertiary hypotheses are tested conditionally upon rejection of gatekeeper hypotheses.
- Methods include weighted Bonferroni, weighted Simes, and weighted resampling tests within a closed testing framework.
Main Results:
- The proposed gatekeeping strategies were illustrated with examples from trials featuring co-primary endpoints and multiple endpoints in dose-finding studies.
- Power comparisons demonstrated that gatekeeping methods are more powerful than competing approaches when primary trial objectives must be satisfied.
- The developed procedures offer a statistically sound and efficient approach to multiplicity adjustment.
Conclusions:
- Gatekeeping strategies provide a powerful and flexible framework for addressing multiplicity in clinical trials.
- These methods are particularly beneficial for trials where meeting primary objectives is paramount.
- The study offers practical tools for statisticians and researchers designing and analyzing complex clinical trials.