FDA validation of surrogate endpoints in oncology: 2005-2022

Abstract

Introduction: The number of oncologic drugs approved by the US Food and Drug Administration (FDA) on the basis of surrogate endpoints is rising. However, many surrogates have not demonstrated a correlation with clinically meaningful outcomes like overall survival. We sought to investigate surrogate validation studies conducted by the FDA over the past 17 years.

Methods: We reviewed analyses of surrogate outcomes published by the FDA from 2005 to 2022. Data extracted included the number of clinical trials included in each analysis, the associations of surrogate outcomes with OS or other surrogates, and the authors' interpretation of these associations.

Results: Of the 15 surrogate analyses conducted by the FDA, only one demonstrated a strong correlation between a surrogate outcome and overall survival. 87% only included clinical trials submitted to the FDA in their analysis, and all were published from 2014 onwards.

Discussion: The vast majority of FDA analyses of surrogate outcomes did not find strong correlations between surrogates and overall survival, raising concern about the use of such outcomes as endpoints in clinical trials. As most studies were based on limited data, further research is required to assess the true validity of surrogate outcomes.

Policy summary: Drugs approved on the basis of surrogates that are not associated with clinically meaningful outcomes can cause significant harm to patients. Until surrogate outcomes have been thoroughly and robustly validated, they should be used with caution in drug approval decisions.

Keywords: Cancer; Drug approval; Endpoint; FDA; Overall survival; Surrogate.