Date of Award

January 2026

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Joseph Ross

Abstract

The U.S. Food and Drug Administration (FDA) has traditionally required the use of clinical outcome measures as clinical trial endpoints to support the approval of new drugs. However, clinical outcome trials are typically large, lengthy, and expensive. To expedite this process, Congress has enacted several regulatory programs to facilitate FDA approval of new drugs on the basis of surrogate markers, endpoints that are reasonably likely to predict clinical benefit, as trial endpoints. However, the evidence demonstrating the validity and reliability is mixed, creating uncertainty for patients and physicians about the true clinical benefits of new drugs approved on the basis of surrogate markers. Accordingly, to better understand the extent to which surrogate markers are being used and the evidence supporting their use, we performed an umbrella review of the association between surrogate markers and clinical outcomes.

The aim of this study is to identify, evaluate, and summarize the accumulated evidence on the strength of association between surrogate markers that form the basis of FDA’s therapeutic approval and clinical outcomes for nononcologic chronic disease indications.

To accomplish this, we performed an umbrella review focused on identifying trial-level systematic reviews, meta-analyses, or pooled analyses evaluating the strength of association between surrogate markers and clinical outcomes for disease listed in the FDA’s Adult Surrogate Endpoint Table. Of the 124 surrogate markers included in the table, our evaluation focused on 37 surrogate markers used for chronic disease indications.

Final analysis included 37 surrogate markers listed in the FDA’s table and used as primary endpoints in clinical trials across 32 unique nononcologic chronic diseases. For 22 (59%) surrogate markers across 21 chronic diseases, no eligible meta-analyses were identified. For 15 (41%) surrogate markers across 14 chronic diseases, at least 1 meta-analysis was identified with a total of 54 meta-analyses. The 54 meta-analyses reported 109 unique surrogate marker-clinical outcome pairs. 59 (54%) reported at least 1 r or R2, 10 (17%) of which reported at least 1 classified as high strength, whereas 50 (46%) reported slopes, effect estimates, or results of meta-regression analyses only, 26 (52%) of which reported at least 1 statistically significant result.

We hope that our work will provide a clearer understanding of the extent and validity of surrogate endpoint use and ultimately help inform policy decisions that may allow for a more consistent and thorough validation of surrogate endpoints prior to their use as pivotal trial endpoints such that physicians and patients may make informed decisions about treatment.

Comments

This is an Open Access Thesis.

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