Reporting of surrogate endpoints in randomised controlled trial protocols (SPIRIT-Surrogate): extension checklist with explanation and elaboration

Anthony Muchai Manyara^{1

2}, Philippa Davies³, Derek Stewart⁴, Christopher J Weir⁵, Amber E Young³, Jane Blazeby^{3

6

7}, Nancy J Butcher^{8

9}, Sylwia Bujkiewicz¹⁰, An-Wen Chan^{11

12}, Dalia Dawoud^{13

14}, Martin Offringa^{8

15}, Mario Ouwens¹⁶, Asbjørn Hróbjartsson^{17

18}, Alain Amstutz^{19

20

21}, Luca Bertolaccini²², Vito Domenico Bruno²³, Declan Devane^{24

25}, Christina D C M Faria²⁶, Peter B Gilbert²⁷, Ray Harris⁴, Marissa Lassere²⁸, Lucio Marinelli^{29

30}, Sarah Markham^{4

31}, John H Powers 3rd³², Yousef Rezaei^{33

34

35}, Laura Richert³⁶, Falk Schwendicke³⁷, Larisa G Tereshchenko³⁸, Achilles Thoma³⁹, Alparslan Turan⁴⁰, Andrew Worrall⁴, Robin Christensen⁴¹, Gary S Collins⁴², Joseph S Ross^{43

44}, Rod S Taylor^{1

45}, Oriana Ciani⁴⁶

Affiliations

¹ MRC/CSO Social and Public Health Sciences Unit, School of Health and Wellbeing, University of Glasgow, Glasgow, UK.
² Global Health and Ageing Research Unit, Bristol Medical School, University of Bristol, Bristol, UK.
³ Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
⁴ Patient author, UK.
⁵ Edinburgh Clinical Trials Unit, Usher Institute, University of Edinburgh, Edinburgh, UK.
⁶ Bristol NIHR Biomedical Research Centre, Bristol, UK.
⁷ University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK.
⁸ Child Health Evaluative Sciences, Hospital for Sick Children Research Institute, Toronto, ON, Canada.
⁹ Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
¹⁰ Biostatistics Research Group, Department of Population Health Sciences, University of Leicester, Leicester, UK.
¹¹ Women's College Research Institute, Toronto, ON, Canada.
¹² Department of Medicine, University of Toronto, Toronto, ON, Canada.
¹³ Science, Evidence, and Analytics Directorate, Science Policy and Research Programme, National Institute for Health and Care Excellence, London, UK.
¹⁴ Faculty of Pharmacy, Cairo University, Cairo, Egypt.
¹⁵ Department of Paediatrics, University of Toronto, Toronto, ON, Canada.
¹⁶ AstraZeneca, Mölndal, Sweden.
¹⁷ Centre for Evidence-Based Medicine Odense and Cochrane Denmark, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
¹⁸ Open Patient data Explorative Network, Odense University hospital, Odense, Denmark.
¹⁹ CLEAR Methods Centre, Division of Clinical Epidemiology, Department of Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland.
²⁰ Oslo Centre for Biostatistics and Epidemiology, Oslo University Hospital, Oslo, Norway.
²¹ Bristol Medical School, University of Bristol, Bristol, UK.
²² Department of Thoracic Surgery, IEO, European Institute of Oncology IRCCS, Milan, Italy.
²³ IRCCS Galeazzi-Sant'Ambrogio Hospital, Department of Minimally Invasive Cardiac Surgery, Milan, Italy.
²⁴ University of Galway, Galway, Ireland.
²⁵ Health Research Board-Trials Methodology Research Network, University of Galway, Galway, Ireland.
²⁶ Department of Physical Therapy, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
²⁷ Fred Hutchinson Cancer Centre, Seattle, WA, USA.
²⁸ St George Hospital and School of Population Health, University of New South Wales, Sydney, NSW, Australia.
²⁹ Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, Genoa, Italy.
³⁰ IRCCS Ospedale Policlinico San Martino, Genoa, Italy.
³¹ Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
³² George Washington University School of Medicine, Washington, DC, USA.
³³ Heart Valve Disease Research Centre, Rajaie Cardiovascular Medical and Research Centre, Iran University of Medical Sciences, Tehran, Iran.
³⁴ Ardabil University of Medical Sciences, Ardabil, Iran.
³⁵ Behyan Clinic, Pardis New Town, Tehran, Iran.
³⁶ University of Bordeaux, Centre d'Investigation Clinique-Epidémiologie Clinique 1401, Research in Clinical Epidemiology and in Public Health and European Clinical Trials Platform & Development/French Clinical Research Infrastructure Network, Institut National de la Santé et de la Recherche Médicale/Institut Bergonié/Centre Hospitalier Universitaire Bordeaux, Bordeaux, France.
³⁷ Charité Universitätsmedizin Berlin, Berlin, Germany.
³⁸ Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
³⁹ McMaster University, Hamilton, ON, Canada.
⁴⁰ Department of Outcomes Research, Anaesthesiology Institute, Cleveland Clinic, OH, USA.
⁴¹ Section for Biostatistics and Evidence-Based Research, the Parker Institute, Bispebjerg and Frederiksberg Hospital, Copenhagen and Research Unit of Rheumatology, Department of Clinical Research, University of Southern Denmark, Odense University Hospital, Odense, Denmark.
⁴² UK EQUATOR Centre, Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
⁴³ Department of Health Policy and Management, Yale School of Public Health, New Haven, CT, USA.
⁴⁴ Section of General Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
⁴⁵ Robertson Centre for Biostatistics, School of Health and Well Being, University of Glasgow, Glasgow, UK.
⁴⁶ Centre for Research on Health and Social Care Management, Bocconi University, Milan 20136, Italy oriana.ciani@unibocconi.it.

PMID: 38981624
PMCID: PMC11231880
DOI: 10.1136/bmj-2023-078525

Reporting of surrogate endpoints in randomised controlled trial protocols (SPIRIT-Surrogate): extension checklist with explanation and elaboration

Anthony Muchai Manyara et al. BMJ. 2024.

. 2024 Jul 9:386:e078525.

doi: 10.1136/bmj-2023-078525.

Authors

Affiliations

¹ MRC/CSO Social and Public Health Sciences Unit, School of Health and Wellbeing, University of Glasgow, Glasgow, UK.
² Global Health and Ageing Research Unit, Bristol Medical School, University of Bristol, Bristol, UK.
³ Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
⁴ Patient author, UK.
⁵ Edinburgh Clinical Trials Unit, Usher Institute, University of Edinburgh, Edinburgh, UK.
⁶ Bristol NIHR Biomedical Research Centre, Bristol, UK.
⁷ University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK.
⁸ Child Health Evaluative Sciences, Hospital for Sick Children Research Institute, Toronto, ON, Canada.
⁹ Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
¹⁰ Biostatistics Research Group, Department of Population Health Sciences, University of Leicester, Leicester, UK.
¹¹ Women's College Research Institute, Toronto, ON, Canada.
¹² Department of Medicine, University of Toronto, Toronto, ON, Canada.
¹³ Science, Evidence, and Analytics Directorate, Science Policy and Research Programme, National Institute for Health and Care Excellence, London, UK.
¹⁴ Faculty of Pharmacy, Cairo University, Cairo, Egypt.
¹⁵ Department of Paediatrics, University of Toronto, Toronto, ON, Canada.
¹⁶ AstraZeneca, Mölndal, Sweden.
¹⁷ Centre for Evidence-Based Medicine Odense and Cochrane Denmark, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
¹⁸ Open Patient data Explorative Network, Odense University hospital, Odense, Denmark.
¹⁹ CLEAR Methods Centre, Division of Clinical Epidemiology, Department of Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland.
²⁰ Oslo Centre for Biostatistics and Epidemiology, Oslo University Hospital, Oslo, Norway.
²¹ Bristol Medical School, University of Bristol, Bristol, UK.
²² Department of Thoracic Surgery, IEO, European Institute of Oncology IRCCS, Milan, Italy.
²³ IRCCS Galeazzi-Sant'Ambrogio Hospital, Department of Minimally Invasive Cardiac Surgery, Milan, Italy.
²⁴ University of Galway, Galway, Ireland.
²⁵ Health Research Board-Trials Methodology Research Network, University of Galway, Galway, Ireland.
²⁶ Department of Physical Therapy, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
²⁷ Fred Hutchinson Cancer Centre, Seattle, WA, USA.
²⁸ St George Hospital and School of Population Health, University of New South Wales, Sydney, NSW, Australia.
²⁹ Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, Genoa, Italy.
³⁰ IRCCS Ospedale Policlinico San Martino, Genoa, Italy.
³¹ Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
³² George Washington University School of Medicine, Washington, DC, USA.
³³ Heart Valve Disease Research Centre, Rajaie Cardiovascular Medical and Research Centre, Iran University of Medical Sciences, Tehran, Iran.
³⁴ Ardabil University of Medical Sciences, Ardabil, Iran.
³⁵ Behyan Clinic, Pardis New Town, Tehran, Iran.
³⁶ University of Bordeaux, Centre d'Investigation Clinique-Epidémiologie Clinique 1401, Research in Clinical Epidemiology and in Public Health and European Clinical Trials Platform & Development/French Clinical Research Infrastructure Network, Institut National de la Santé et de la Recherche Médicale/Institut Bergonié/Centre Hospitalier Universitaire Bordeaux, Bordeaux, France.
³⁷ Charité Universitätsmedizin Berlin, Berlin, Germany.
³⁸ Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
³⁹ McMaster University, Hamilton, ON, Canada.
⁴⁰ Department of Outcomes Research, Anaesthesiology Institute, Cleveland Clinic, OH, USA.
⁴¹ Section for Biostatistics and Evidence-Based Research, the Parker Institute, Bispebjerg and Frederiksberg Hospital, Copenhagen and Research Unit of Rheumatology, Department of Clinical Research, University of Southern Denmark, Odense University Hospital, Odense, Denmark.
⁴² UK EQUATOR Centre, Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
⁴³ Department of Health Policy and Management, Yale School of Public Health, New Haven, CT, USA.
⁴⁴ Section of General Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
⁴⁵ Robertson Centre for Biostatistics, School of Health and Well Being, University of Glasgow, Glasgow, UK.
⁴⁶ Centre for Research on Health and Social Care Management, Bocconi University, Milan 20136, Italy oriana.ciani@unibocconi.it.

PMID: 38981624
PMCID: PMC11231880
DOI: 10.1136/bmj-2023-078525

Abstract

Randomised controlled trials often use surrogate endpoints to substitute for a target outcome (an outcome of direct interest and relevance to trial participants, clinicians, and other stakeholders—eg, all cause mortality) to improve efficiency (through shortened duration of follow-up, reduced sample size, and lower research costs), and for ethical or practical reasons. However, their use has a fundamental limitation in terms of uncertainty of the intervention effect on the target outcome and limited information on potential intervention harms. There have been increasing calls for improved reporting of trial protocols that use surrogate endpoints. This report presents the SPIRIT-Surrogate, an extension of the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) checklist, a consensus driven reporting guideline designed for trial protocols using surrogate endpoints as the primary outcome(s). The SPIRIT-Surrogate extension includes nine items modified from the SPIRIT 2013 checklist. The guideline provides examples and explanations for each item. We recommend that all stakeholders (including trial investigators and sponsors, research ethics reviewers, funders, journal editors, and peer reviewers) use this extension in reporting trial protocols that use surrogate endpoints. Its use will allow for improved design of such trials, improved transparency, and interpretation of findings when trials are completed, and ultimately reduced research waste.

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Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from the UK Medical Research Council for the submitted work. SB is a member of the NICE Decision Support Unit and NICE Guidelines Technical Support Unit; has served as a paid consultant, providing methodological advice, to NICE, Roche, IQVIA, and RTI Health Solutions; received payments for educational events from Roche; and has received research funding from European Federation of Pharmaceutical Industries and Associations and Johnson & Johnson. MOu works for and has shares in AstraZeneca. JSR is a deputy editor at JAMA, was formerly an associate editor at The BMJ, and is co-founder (unpaid) of medRxiv; has received research support through Yale University from Johnson & Johnson to develop methods of clinical trial data sharing, from the Medical Device Innovation Consortium as part of the National Evaluation System for Health Technology, from the Food and Drug Administration for the Yale-Mayo Clinic Center for Excellence in Regulatory Science and Innovation programme (U01FD005938), from the Agency for Healthcare Research and Quality (R01HS022882), from the National Heart, Lung and Blood Institute of the National Institutes of Health (R01HS025164, R01HL144644), and from Arnold Ventures; was an expert witness at the request of Relator’s attorneys, the Greene Law Firm, in a qui tam suit alleging violations of the False Claims Act and Anti-Kickback Statute against Biogen that was settled in September 2022. NJB has received consulting fees from Nobias Therapeutics. AA and YR are associate editors at BMC Trials. OC is an associate editor for Value in Health and has received consulting fees from MSD and Janssen. RC is a founding member of the OMERACT Technical Advisory Group, which might be perceived as a possible conflict of interest. RH has shares in Johnson & Johnson. JHP has been a consultant for AdaptivePhage, Arrevus, Atheln, BavariaNordic, Cellularity, Eicos, Evofem, Eyecheck, Gilead, GSK, Mustang, OPKO, Otsuka, Resolve, Romark, SpineBioPPharma, and UTIlity,Vir. GSC is a statistics editor for The BMJ, and director of the UK EQUATOR Centre. CJW has undertaken consultancy for AB Science, for which his institution has received a fee. DD is an associate editor of Value in Health.

Comment in

Transparent and complete reporting of surrogate endpoints in trials: the SPIRIT-Surrogate and CONSORT-Surrogate extensions.
Manyara AM, Ciani O, Taylor RS; SPIRIT-Surrogate and CONSORT-Surrogate Project team and Consensus Group. Manyara AM, et al. Lancet. 2024 Jul 27;404(10450):322-324. doi: 10.1016/S0140-6736(24)01306-0. Epub 2024 Jul 11. Lancet. 2024. PMID: 39004089 No abstract available.

References

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Reporting of surrogate endpoints in randomised controlled trial protocols (SPIRIT-Surrogate): extension checklist with explanation and elaboration

Affiliations

Reporting of surrogate endpoints in randomised controlled trial protocols (SPIRIT-Surrogate): extension checklist with explanation and elaboration

Authors

Affiliations

Abstract

Conflict of interest statement

Comment in

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources