Evaluation Methods for T-Association of a Surrogate Endpoint

Music City Center 

A surrogate endpoint is a biomarker or intermediate outcome used instead of a direct clinical endpoint to predict drug benefit. It serves as a substitute for a primary endpoint, offering advantages when measured earlier or more conveniently. Before its use in scientific conclusions, qualification is required. A valid surrogate must meet two associations: I-Association (linking the surrogate and true endpoints, e.g., disease response and overall survival) and T-Association (linking treatment effects on both, e.g., odds ratio and hazard ratio). While I-Association is commonly evaluated, T-Association is often overlooked. This study proposes methods to assess T-Association, assuming treatment effects on both endpoints follow a bivariate normal distribution. The key evaluation metric is the correlation coefficient, estimated via maximum likelihood, restricted maximum likelihood, and a Bayesian approach. Simulated and real-world data assess bias, standard error, and coverage probability. This method will support future FDA Accelerated Approval drugs.

Surrogate endpoint

Bivariate normal

maximum likelihood

restricted maximum likelihood

Bayesian 

Biopharmaceutical Section