Changes are still needed on multiple co-primary endpoints

Area of Science:

• Clinical Trials Methodology
• Biostatistics
• Regulatory Science

Background:

• The US Food and Drug Administration (FDA) issued draft guidance on Multiple Endpoints in Clinical Trials in January 2017.
• The guidance addresses technical implementation but raises questions regarding its application to safety-focused studies.
• Multiple co-primary endpoints are often required by regulators for certain disorders.

Purpose of the Study:

• To question the application of the FDA's draft guidance on multiple endpoints in clinical trials for safety studies.
• To address the issue of power loss associated with the standard 'min test' for multiple co-primary endpoints.
• To propose a new approach to enhance statistical power and reflect product effectiveness across multiple, unrelated endpoints.

Main Methods:

• Review of existing approaches to mitigate power loss in clinical trials with multiple co-primary endpoints.
• Analysis of the 'min test' and its limitations when applied to more than two co-primary endpoints.
• Proposal of a novel methodology for assessing drugs with multiple, equally important, and unrelated endpoints.

Main Results:

• The standard 'min test' for multiple co-primary endpoints leads to significant power loss when the number of endpoints exceeds two.
• Existing methods to address power loss are reviewed.
• A new approach is proposed to improve the assessment of drugs with multiple co-primary endpoints.

Conclusions:

• The current draft guidance's principles may not be optimally applied to safety-focused clinical trials.
• There is a need for methodological advancements to overcome power limitations in trials with multiple co-primary endpoints.
• A path forward is urged that utilizes differentiated claims to accurately represent product efficacy across diverse endpoints.