Use of surrogate endpoints in health technology assessment: A review of company submissions for cancer drugs in Singapore.

Abstract

e23147 Background: Surrogate endpoints are increasingly used to accelerate clinical trials and regulatory approval of new cancer drugs. However, their use poses challenges for health technology assessment (HTA), which focuses on long-term clinical outcomes and cost-effectiveness. In Singapore, the Agency for Care Effectiveness (ACE) conducts HTA to inform funding decisions by the Ministry of Health Drug Advisory Committee. Since 2023, companies have provided evidence submissions to ACE for cancer drugs to be evaluated for funding via the company-led submission process. This review examines the extent to which surrogate endpoints are used, and how they are validated, in cancer drug submissions to ACE. Methods: We reviewed all cancer drug submissions to ACE between 2023 and 2025. Data were extracted on the use of surrogate endpoints, including their purpose, evidence base and methods used to validate the surrogate-final outcome relationship. Results: Of 31 submissions, 24 (77%) were for solid tumours and the remaining 7 (23%) for blood cancers. Surrogate endpoints were used as key evidence in 17 submissions (55%) to support clinical or cost-effectiveness analyses. In most of these submissions (82%), overall survival data were immature at the time of evaluation. Eight different surrogate endpoints were considered across the 17 submissions. Progression-free survival was the most commonly used (59%), followed by disease-free survival (18%) and event-free survival (12%). The strength of evidence supporting the validity of the surrogate relationship varied considerably. Five submissions (29%) provided no supporting evidence for the surrogate relationship. Ten submissions (59%) cited randomised controlled trials; however, these were often conducted in populations or settings not fully aligned with the submission context. Two submissions (12%) relied on assessments from overseas HTA agencies. Quantitative measures of surrogate validity were infrequently reported: correlation coefficients were provided in six submissions (35%), and surrogate threshold effects estimating the expected treatment effect on the final clinical outcome in only one submission (6%). Conclusions: Most cancer drug submissions for funding consideration in Singapore rely on surrogate endpoints, often without adequate validation. While surrogate endpoints may support accelerated regulatory approval, inadequate validation introduces significant uncertainty into HTA assessments of clinical benefit and cost-effectiveness. Strengthening evidence for surrogate validation in company submissions could support more robust HTA evaluations and help reduce uncertainty in decision-making.