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Peer-reviewedCC BYBMJ (Clinical research ed.)

Recommendations for Evaluating A Single Surrogate Endpoint (REASSurE): Consensus-based surrogate evaluation framework with explanation and elaboration

  • Wang Pok Lo1,2
  • Stuart G Baker3
  • Luca Bertolaccini4,5
  • Sylwia Bujkiewicz6
  • Catey Bunce7
  • Marc Buyse8
  • Oriana Ciani9
  • Robin Christensen10,11
  • Jane Daniels12
  • Sara Gandini13
  • Tamer A Gheita14
  • Peter B Gilbert15
12 more authors
  • Laura Jaeger16
  • Dorcas Kareithi17,18
  • Marissa Lassere19
  • Nicholas T Longford20,21
  • Anthony M Manyara22
  • Koji Oba23
  • Emily K Roberts24
  • Rod S Taylor25
  • Carlos J Toro-Huamanchumo26,27
  • Steff Lewis28
  • Hannah Ensor28
  • Christopher J Weir28
28 affiliations
  1. 1Centre for Population Health Sciences, Usher Institute, School of Population Health Sciences, University of Edinburgh, Edinburgh, UK
  2. 2School of Medicine and Biomedical Sciences, Green Templeton College, University of Oxford, Oxford, UK
  3. 3Independent researcher, Columbia, MD, USA
  4. 4Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
  5. 5Department of Thoracic Surgery, IEO, European Institute of Oncology IRCCS, Milan, Italy
  6. 6Biostatistics Research Group, Division of Public Health and Epidemiology, School of Medical Sciences, University of Leicester, Leicester, UK
  7. 7International Centre for Eye Health (ICEH), London School of Hygiene and Tropical Medicine, UK
  8. 8International Drug Development Institute, Louvain-La-Neuve, Belgium
  9. 9Centre for Research on Health and Social Care Management, SDA Bocconi, Milan 20136, Italy
  10. 10Section for Biostatistics and Evidence-Based Research, the Parker Institute, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark
  11. 11Research Unit of Rheumatology, Department of Clinical Research, University of Southern Denmark, Odense University Hospital, Denmark
  12. 12Nottingham Clinical Trials Unit, University of Nottingham, Nottingham, UK
  13. 13Department of Experimental Oncology, IRCCS European Institute of Oncology, Milan, Italy
  14. 14Rheumatology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
  15. 15Fred Hutchinson Cancer Center, Seattle, WA, USA
  16. 16Office of New Drugs, Center for Drug Evaluation and Research, United States Food and Drug Administration, Silver Spring, MD, USA
  17. 17Biostatistics Research Group, Newcastle University, UK
  18. 18Jasiri Cancer Research Foundation, Embu, Kenya
  19. 19St George Hospital and School of Population Health, University of New South Wales, Sydney, NSW, Australia
  20. 20SNTL Statistics Research and Consulting, London, UK
  21. 21Institute of Econometrics, Warsaw School of Economics (SGH), Warsaw, Poland
  22. 22Global Health and Ageing Research Unit, Bristol Medical School, University of Bristol, Bristol, UK
  23. 23Interfaculty Initiative in Information Studies, The University of Tokyo, Tokyo, Japan
  24. 24Department of Biostatistics, University of Iowa, Iowa City, Iowa, USA
  25. 25Robertson Centre for Biostatistics & Primary Care and General Practice, School of Health and Wellbeing, University of Glasgow, Glasgow, UK
  26. 26Unidad de Investigación para la Generación y Síntesis de Evidencias en Salud, Universidad San Ignacio de Loyola, Lima, Peru
  27. 27OBEMET Center for Obesity and Metabolic Health, Lima, Peru
  28. 28Edinburgh Clinical Trials Unit, Usher Institute, School of Population Health Sciences, University of Edinburgh, Edinburgh, UK
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Abstract

The use of a surrogate endpoint to replace a primary outcome relevant to patients in a clinical trial may allow faster approval of a novel treatment, but at the cost of increased uncertainty about treatment benefit. This risk may be amplified if the surrogate endpoint was inadequately or inappropriately evaluated against the patient relevant outcome. Many components of this evaluation currently lack consensus, including the most important non-statistical factors, the choice of statistical method, and whether numerical thresholds should be used. This paper presents a consensus based, multi-stakeholder framework (REASSurE: Recommendations for Evaluating A Single Surrogate Endpoint) containing a list of mandatory and recommended items for surrogate endpoint evaluation, with guidance on how to assess each item. Statisticians, trials methodologists, regulators, health technology assessment agencies, payers, and clinicians could use the REASSurE framework to achieve a holistic evaluation of a candidate surrogate endpoint, which is vital to ensure that the use of the surrogate endpoint is an appropriate decision.

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Cite

BibTeXRIS
BibTeX
@article{lo2026recommendations,
  title = {{Recommendations for Evaluating A Single Surrogate Endpoint (REASSurE): Consensus-based surrogate evaluation framework with explanation and elaboration}},
  author = {Wang Pok Lo and Stuart G Baker and Luca Bertolaccini and Sylwia Bujkiewicz and Catey Bunce and Marc Buyse and Oriana Ciani and Robin Christensen and Jane Daniels and Sara Gandini and Tamer A Gheita and Peter B Gilbert and Laura Jaeger and Dorcas Kareithi and Marissa Lassere and Nicholas T Longford and Anthony M Manyara and Koji Oba and Emily K Roberts and Rod S Taylor and Carlos J Toro-Huamanchumo and Steff Lewis and Hannah Ensor and Christopher J Weir},
  journal = {BMJ (Clinical research ed.)},
  year = {2026},
  month = sep,
  doi = {10.1136/bmj-2026-100618},
  url = {https://doi.org/10.1136/bmj-2026-100618},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Recommendations for Evaluating A Single Surrogate Endpoint (REASSurE): Consensus-based surrogate evaluation framework with explanation and elaboration
AU  - Wang Pok Lo
AU  - Stuart G Baker
AU  - Luca Bertolaccini
AU  - Sylwia Bujkiewicz
AU  - Catey Bunce
AU  - Marc Buyse
AU  - Oriana Ciani
AU  - Robin Christensen
AU  - Jane Daniels
AU  - Sara Gandini
AU  - Tamer A Gheita
AU  - Peter B Gilbert
AU  - Laura Jaeger
AU  - Dorcas Kareithi
AU  - Marissa Lassere
AU  - Nicholas T Longford
AU  - Anthony M Manyara
AU  - Koji Oba
AU  - Emily K Roberts
AU  - Rod S Taylor
AU  - Carlos J Toro-Huamanchumo
AU  - Steff Lewis
AU  - Hannah Ensor
AU  - Christopher J Weir
PY  - 2026
DA  - 2026/09/29
JO  - BMJ (Clinical research ed.)
DO  - 10.1136/bmj-2026-100618
UR  - https://doi.org/10.1136/bmj-2026-100618
AB  - The use of a surrogate endpoint to replace a primary outcome relevant to patients in a clinical trial may allow faster approval of a novel treatment, but at the cost of increased uncertainty about treatment benefit. This risk may be amplified if the surrogate endpoint was inadequately or inappropriately evaluated against the patient relevant outcome. Many components of this evaluation currently lack consensus, including the most important non-statistical factors, the choice of statistical method, and whether numerical thresholds should be used. This paper presents a consensus based, multi-stakeholder framework (REASSurE: Recommendations for Evaluating A Single Surrogate Endpoint) containing a list of mandatory and recommended items for surrogate endpoint evaluation, with guidance on how to assess each item. Statisticians, trials methodologists, regulators, health technology assessment agencies, payers, and clinicians could use the REASSurE framework to achieve a holistic evaluation of a candidate surrogate endpoint, which is vital to ensure that the use of the surrogate endpoint is an appropriate decision.
SN  - 0959-8138
SN  - 1756-1833
ER  -