A framework for the definition and interpretation of the use of surrogate endpoints in interventional trials

Oriana Ciani, Anthony M Manyara, Philippa Davies, Derek Stewart, Christopher J Weir, Amber E Young, Jane Blazeby, Nancy J Butcher, Sylwia Bujkiewicz, An-Wen Chan, Dalia Dawoud, Martin Offringa, Mario Ouwens, Asbjørn Hróbjartssson, Alain Amstutz, Luca Bertolaccini, Vito Domenico Bruno, Declan Devane, Christina D C M Faria, Peter B GilbertRay Harris, Marissa Lassere, Lucio Marinelli, Sarah Markham, John H Powers, Yousef Rezaei, Laura Richert, Falk Schwendicke, Larisa G Tereshchenko, Achilles Thoma, Alparslan Turan, Andrew Worrall, Robin Christensen, Gary S Collins, Joseph S Ross, Rod S Taylor

Abstract

BACKGROUND: Interventional trials that evaluate treatment effects using surrogate endpoints have become increasingly common. This paper describes four linked empirical studies and the development of a framework for defining, interpreting and reporting surrogate endpoints in trials.

METHODS: As part of developing the CONSORT (Consolidated Standards of Reporting Trials) and SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) extensions for randomised trials reporting surrogate endpoints, we undertook a scoping review, e-Delphi study, consensus meeting, and a web survey to examine current definitions and stakeholder (including clinicians, trial investigators, patients and public partners, journal editors, and health technology experts) interpretations of surrogate endpoints as primary outcome measures in trials.

FINDINGS: Current surrogate endpoint definitional frameworks are inconsistent and unclear. Surrogate endpoints are used in trials as a substitute of the treatment effects of an intervention on the target outcome(s) of ultimate interest, events measuring how patients feel, function, or survive. Traditionally the consideration of surrogate endpoints in trials has focused on biomarkers (e.g., HDL cholesterol, blood pressure, tumour response), especially in the medical product regulatory setting. Nevertheless, the concept of surrogacy in trials is potentially broader. Intermediate outcomes that include a measure of function or symptoms (e.g., angina frequency, exercise tolerance) can also be used as substitute for target outcomes (e.g., all-cause mortality)-thereby acting as surrogate endpoints. However, we found a lack of consensus among stakeholders on accepting and interpreting intermediate outcomes in trials as surrogate endpoints or target outcomes. In our assessment, patients and health technology assessment experts appeared more likely to consider intermediate outcomes to be surrogate endpoints than clinicians and regulators.

INTERPRETATION: There is an urgent need for better understanding and reporting on the use of surrogate endpoints, especially in the setting of interventional trials. We provide a framework for the definition of surrogate endpoints (biomarkers and intermediate outcomes) and target outcomes in trials to improve future reporting and aid stakeholders' interpretation and use of trial surrogate endpoint evidence.

FUNDING: SPIRIT-SURROGATE/CONSORT-SURROGATE project is Medical Research Council Better Research Better Health (MR/V038400/1) funded.

Original languageEnglish
Article number102283
JournalEClinicalMedicine
Volume65
Pages (from-to)102283
ISSN2589-5370
DOIs
Publication statusPublished - Nov 2023

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