TY - JOUR
T1 - A framework for the definition and interpretation of the use of surrogate endpoints in interventional trials
AU - Ciani, Oriana
AU - Manyara, Anthony M
AU - Davies, Philippa
AU - Stewart, Derek
AU - Weir, Christopher J
AU - Young, Amber E
AU - Blazeby, Jane
AU - Butcher, Nancy J
AU - Bujkiewicz, Sylwia
AU - Chan, An-Wen
AU - Dawoud, Dalia
AU - Offringa, Martin
AU - Ouwens, Mario
AU - Hróbjartssson, Asbjørn
AU - Amstutz, Alain
AU - Bertolaccini, Luca
AU - Bruno, Vito Domenico
AU - Devane, Declan
AU - Faria, Christina D C M
AU - Gilbert, Peter B
AU - Harris, Ray
AU - Lassere, Marissa
AU - Marinelli, Lucio
AU - Markham, Sarah
AU - Powers, John H
AU - Rezaei, Yousef
AU - Richert, Laura
AU - Schwendicke, Falk
AU - Tereshchenko, Larisa G
AU - Thoma, Achilles
AU - Turan, Alparslan
AU - Worrall, Andrew
AU - Christensen, Robin
AU - Collins, Gary S
AU - Ross, Joseph S
AU - Taylor, Rod S
N1 - © 2023 The Author(s).
PY - 2023/11
Y1 - 2023/11
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85174067128&partnerID=8YFLogxK
U2 - 10.1016/j.eclinm.2023.102283
DO - 10.1016/j.eclinm.2023.102283
M3 - Journal article
C2 - 37877001
VL - 65
SP - 102283
JO - EClinicalMedicine
JF - EClinicalMedicine
SN - 2589-5370
M1 - 102283
ER -