Multiple Comparisons Procedures for Analyses of Joint Primary Endpoints and Secondary Endpoints.

Area of Science:

• Biostatistics
• Clinical Trial Design
• Drug Development

Background:

• Selecting primary endpoints for rare disease drug development is complex due to varying sensitivity and sample size constraints.
• Supporting regulatory claims for multiple endpoints and doses introduces multiplicity issues, further complicating study design.

Purpose of the Study:

• To introduce a robust two-stage gatekeeping framework for testing hierarchically ordered hypotheses in rare disease drug development.
• To address challenges in managing multiplicity and sample size when using Joint Primary Endpoints (JPEs) for regulatory claims.

Main Methods:

• A novel truncated closed testing procedure is employed in the first stage for flexible primary endpoint evaluation.
• A two-stage framework controls the global family-wise Type I error rate, propagating a fraction of the error rate to the second stage for secondary endpoints.

Main Results:

• The proposed framework demonstrates efficiency and adaptability in evaluating multiple endpoints and dose regimens.
• Numerical simulations and real-world applications confirm the approach's practical utility in rare disease drug development.

Conclusions:

• The two-stage gatekeeping framework effectively manages multiplicity and sample size issues in rare disease drug development.
• This approach facilitates meeting stringent regulatory requirements for drug approval, particularly with Joint Primary Endpoints (JPEs).