Presentation (CTI)

OBJECTIVES: Use and validation of surrogate endpoints for clinically meaningful outcomes can support accelerated regulatory approvals and health technology assessments (HTAs) of novel treatments. With precedent guidance from the EU Member State Coordination Group, Institute for Quality and Efficiency in Health Care (IQWiG), and the National Institute for Health and Care Excellence (NICE), a newly formed working group of other HTAs, including the Institute of Clinical and Economic Review (ICER) and Canada’s Drug Agency (CDA-AMC), recently published recommendations on best practice use of surrogate endpoints. As ICER and CDA-AMC largely represent North American HTA activities, this study aimed to characterize their applications of surrogate endpoints.
METHODS: All 2015-2025 publicly available ICER assessments and CDA-AMC reimbursement reviews were scanned for terms “surrogate” or “surrogacy”. Extraction data included submission date, intervention, indication, surrogate endpoint with final clinical outcome, surrogacy evidence citations, sponsor-conducted surrogacy methods, reviewer critique of surrogacy evidence, and reimbursement recommendations. Robustness of surrogacy methods was assessed against precedented Level 1 (study-level), Level 2 (patient-level) and Level 3 (biological plausibility) validation criteria.
RESULTS: A total of 90 ICER assessments and 617 CDA-AMC reviews were identified. Key themes included reviewer critiques that the surrogacy evidence provided lacked population-specific relevance, even when Food and Drug Administration (FDA) accelerated approvals were cited. More recent submissions (2020-2025) demonstrated greater adoption of EU and UK HTA surrogacy validation criteria, aligning with those disseminations. Another identified theme was that longer-term trial data was crucial to establish clinically meaningful benefits. Even when surrogacy analyses estimated strong to moderate correlations, uncertainty was still cited due to immature final outcome data.
CONCLUSIONS: This thematic and temporal analysis of ICER and CDA-AMC reviews conveys the uptake of surrogacy methods adhering to international HTA guidelines. However, uncertainty in surrogate endpoint validity persisted alongside limitations from the clinical trial evidence.