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

Oriana Ciani, Centre for Research on Health and Social Care Management, SDA Bocconi School of Management, Milan, Italy.
Anthony M. Manyara, MRC/CSO Social and Public Health Sciences Unit, School of Health and Wellbeing, University of Glasgow, Glasgow, UK.
Philippa Davies, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
Derek Stewart, Patient and Public Involvement Partner, UK.
Christopher J. Weir, Edinburgh Clinical Trials Unit, Usher Institute, University of Edinburgh, Edinburgh, UK.
Amber E. Young, Bristol NIHR Biomedical Research Centre, Bristol, UK.
Jane Blazeby, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
Nancy J. Butcher, Child Health Evaluative Sciences, The Hospital for Sick Children Research Institute, Toronto, Canada.
Sylwia Bujkiewicz, Biostatistics Research Group, Department of Population Health Sciences, University of Leicester, Leicester, UK.
An-Wen Chan, Women's College Research Institute, Toronto, Canada.
Dalia Dawoud, Science, Evidence and Analytics Directorate, Science Policy and Research Programme, National Institute for Health and Care Excellence, London, UK.
Martin Offringa, Child Health Evaluative Sciences, The Hospital for Sick Children Research Institute, Toronto, Canada.
Mario Ouwens, AstraZeneca, Mölndal, Sweden.
Asbjørn Hróbjartssson, Centre for Evidence-Based Medicine Odense (CEBMO) and Cochrane Denmark, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
Alain Amstutz, CLEAR Methods Center, Division of Clinical Epidemiology, Department of Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland.
Luca Bertolaccini, Department of Thoracic Surgery, IEO, European Institute of Oncology IRCCS, Milan, Italy.
Vito Domenico Bruno, Department of Minimally Invasive Cardiac Surgery, IRCCS Galeazzi - Sant'Ambrogio Hospital, Milan, Italy.
Declan Devane, University of Galway, Galway, Ireland.
Christina D. Faria, Department of Physical Therapy, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
Peter B. Gilbert, Fred Hutchinson Cancer Centre, Seattle, USA.
Ray Harris, Patient and Public Involvement Partner, UK.
Marissa Lassere, St George Hospital and School of Population Health, The University of New South Wales, Sydney, Australia.
Lucio Marinelli, Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, Genoa, Italy.
Sarah Markham, Department of Biostatistics, King's College London, London, UK.
John H. Powers, George Washington University School of Medicine, Washington, USA.
Yousef Rezaei, Heart Valve Disease Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran.
Laura Richert, University Bordeaux, INSERM, Institut Bergonié, CHU Bordeaux, BPH U1219, CIC-EC 1401, RECaP and Euclid/F-CRIN, Bordeaux, France.
Falk Schwendicke, Charité Universitätsmedizin Berlin, Berlin, Germany.
Larisa G. Tereshchenko, Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
Achilles Thoma, McMaster University, Hamilton, Ontario, Canada.
Alparslan Turan, Department of Outcomes Research, Anesthesiology Institute, Cleveland Clinic, OH, USA.
Andrew Worrall, Patient and Public Involvement Partner, UK.

Document Type

Journal Article

Publication Date

11-1-2023

Journal

EClinicalMedicine

Volume

65

DOI

10.1016/j.eclinm.2023.102283

Keywords

Intermediate outcomes; Surrogate endpoints; Target outcomes

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.

Department

Medicine

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