OBJECTIVES : Surrogate endpoints are adopted in clinical trials when final clinical endpoints are difficult or costly to be measured within the timeframe of clinical studies. The suggestion to establish the correlation between surrogate and final endpoints was proposed in 1996 and a conceptual approach based on the recommendation was published. In 2008, the US FDA set up Biomarker Qualification Program to validate surrogate endpoints. Health technology assessment bodies also released principles on surrogate endpoint evaluation. However, there are very few surrogate endpoints that are validated. This research aims to explore the challenges associate with surrogate endpoint validation.

METHODS : A literature search was conducted on electronic databases including PubMed, EMBase, Web of Science, and Medline. Published articles and grey literature after 2010, together with official guidance on surrogate endpoints validation in the US and UK were also reviewed. In addition, three interviews with experts from regulator and health technology assessment bodies were held to enrich the discussion with expert opinions.

RESULTS : Fifteen articles were included, 11 adopted the regulatory perspective and 4 the pharmaceutical industry perspective. No specific guide on essential evidence for surrogate endpoint evaluation was found in official technical guidance. The main challenges in surrogate endpoint validation are limited knowledge of diseases, lack of incentives and harmonized criteria, costly and time-consuming from stakeholders’ point of view. Expert opinions aligned with the literature findings. Resolutions on establishing a harmonized framework, collaborative work between stakeholders, and data sharing to accelerate surrogate endpoint validation were discussed.

CONCLUSIONS : There are 5 categories of challenges associated with surrogate endpoint validation: 1. Lack of physiopathology knowledge; 2. Lack of harmonized criteria for validation; 3. Lack of incentives; 4.Cost and time barriers; 5. Lack of collaboration between stakeholders.