A perspective on surrogate endpoints in controlled clinical trials

Area of Science:

• Biostatistics
• Clinical Trial Methodology
• Epidemiology

Background:

• Extensive research in surrogate marker and endpoint validation has occurred over the past two decades.
• Prentice's foundational work on single trial validation has been extensively discussed and extended.
• Recent advancements focus on hierarchical or meta-analytic frameworks for validating surrogates across multiple trials.

Purpose of the Study:

• To provide a comprehensive review of both single trial and hierarchical frameworks for surrogate endpoint validation.
• To consolidate and present various applications of these validation frameworks from existing literature.
• To outline the statistical challenges inherent in validating surrogate endpoints.

Main Methods:

• Review of existing literature on surrogate endpoint validation.
• Synthesis of single trial validation methods.
• Examination of hierarchical/meta-analytic approaches for multi-trial validation.

Main Results:

• The paper consolidates and reviews established and extended frameworks for surrogate endpoint validation.
• It highlights the statistical considerations crucial for validating surrogate endpoints.
• Applications from diverse studies are brought together to illustrate the concepts.

Conclusions:

• Statistical evidence is a critical component, but not the sole determinant, in surrogate endpoint validation.
• Validation processes must integrate statistical findings with clinical and biological considerations.
• The review emphasizes the evolution from single trial to multi-trial (hierarchical) validation approaches.