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. Gilbert; Ray 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

doi:10.1016/j.eclinm.2023.102283

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

Research output: Contribution to journal › Article › peer-review

14 Scopus citations

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 language	English
Article number	102283
Journal	eClinicalMedicine
Volume	65
DOIs	https://doi.org/10.1016/j.eclinm.2023.102283
State	Published - Nov 2023
Externally published	Yes

Funding

The research was funded as part of development of SPIRIT and CONSORT extensions has been funded by the UK Medical Research Council (grant number MR/V038400/1). Gary Collins was supported by Cancer Research UK (programme grant: C49297/A27294). Jane Blazeby was supported by the NIHR Bristol Biomedical Research centre. Sylwia Bujkiewicz was supported by UK Medical Research Council (MR/T025166/1) and Leicester NIHR Biomedical Research Centre. Alain Amstutz receives his salary from the Research Fund Junior Researchers of the University of Basel. Robin Christensen wants to acknowledge that Section for Biostatistics and Evidence-Based Research, the Parker Institute, Bispebjerg and Frederiksberg Hospital is supported by a core grant. CDCMF receives research productivity fellowships from the Oak Foundation (OCAY-18-774-OFIL) national council for scientific and technological development (CNPq/Brazil–Grant: 08516/2021-4). The funders had no role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the review for publication.

Funders	Funder number
Universität Basel
Parker Institute for Cancer Immunotherapy
NIHR Bristol Biomedical Research Centre
Medical Research Council	MR/T025166/1, MR/V038400/1
Cancer Research UK	C49297/A27294
NIHR Leicester Biomedical Research Centre

Keywords

Intermediate outcomes
Surrogate endpoints
Target outcomes

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10.1016/j.eclinm.2023.102283

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Ciani, O., Manyara, A. M., Davies, P., Stewart, D., Weir, C. J., Young, A. E., Blazeby, J., Butcher, N. J., Bujkiewicz, S., Chan, A. W., Dawoud, D., Offringa, M., Ouwens, M., Hróbjartssson, A., Amstutz, A., Bertolaccini, L., Bruno, V. D., Devane, D., Faria, C. D. C. M., ... Taylor, R. S. (2023). A framework for the definition and interpretation of the use of surrogate endpoints in interventional trials. eClinicalMedicine, 65, Article 102283. https://doi.org/10.1016/j.eclinm.2023.102283

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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.",

keywords = "Intermediate outcomes, Surrogate endpoints, Target outcomes",

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

note = "Publisher Copyright: {\textcopyright} 2023 The Author(s)",

year = "2023",

month = nov,

doi = "10.1016/j.eclinm.2023.102283",

language = "English",

volume = "65",

journal = "eClinicalMedicine",

issn = "2589-5370",

publisher = "Elsevier",

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Ciani, O, Manyara, AM, Davies, P, Stewart, D, Weir, CJ, Young, AE, Blazeby, J, Butcher, NJ, Bujkiewicz, S, Chan, AW, Dawoud, D, Offringa, M, Ouwens, M, Hróbjartssson, A, Amstutz, A, Bertolaccini, L, Bruno, VD, Devane, D, Faria, CDCM, Gilbert, PB, Harris, R, Lassere, M, Marinelli, L, Markham, S, Powers, JH, Rezaei, Y, Richert, L, Schwendicke, F, Tereshchenko, LG, Thoma, A, Turan, A, Worrall, A, Christensen, R, Collins, GS, Ross, JS & Taylor, RS 2023, 'A framework for the definition and interpretation of the use of surrogate endpoints in interventional trials', eClinicalMedicine, vol. 65, 102283. https://doi.org/10.1016/j.eclinm.2023.102283

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.

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.

KW - Intermediate outcomes

KW - Surrogate endpoints

KW - Target outcomes

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U2 - 10.1016/j.eclinm.2023.102283

DO - 10.1016/j.eclinm.2023.102283

M3 - Article

AN - SCOPUS:85174067128

SN - 2589-5370

VL - 65

JO - eClinicalMedicine

JF - eClinicalMedicine

M1 - 102283

ER -

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

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