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Validity of Surrogate Endpoints and Their Impact on Coverage Recommendations: A Retrospective Analysis across International Health Technology Assessment Agencies

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  • Oriana Ciani

    (Centre for Research on Health and Social Care Management, SDA Bocconi, Milan, Lombardia, Italy
    Evidence Synthesis & Modelling for Health Improvement, University of Exeter Medical School, Exeter, Devon, UK)

  • Bogdan Grigore

    (Evidence Synthesis & Modelling for Health Improvement, University of Exeter Medical School, Exeter, Devon, UK)

  • Hedwig Blommestein

    (Institute for Medical Technology Assessment, Erasmus School of Health Policy & Management, Erasmus University Rotterdam, Rotterdam, The Netherlands)

  • Saskia de Groot

    (Institute for Medical Technology Assessment, Erasmus School of Health Policy & Management, Erasmus University Rotterdam, Rotterdam, The Netherlands)

  • Meilin Möllenkamp

    (Hamburg Center for Health Economics, Universität Hamburg, Hamburg, Germany)

  • Stefan Rabbe

    (Hamburg Center for Health Economics, Universität Hamburg, Hamburg, Germany)

  • Rita Daubner-Bendes

    (Syreon Research Institute, Budapest, Hungary
    MRC/CSO Social and Public Health Sciences Unit & Robertson Centre for Biostatistics, Institute of Health and Well Being, University of Glasgow, Glasgow, Scotland, UK)

  • Rod S. Taylor

    (Evidence Synthesis & Modelling for Health Improvement, University of Exeter Medical School, Exeter, Devon, UK
    MRC/CSO Social and Public Health Sciences Unit & Robertson Centre for Biostatistics, Institute of Health and Well Being, University of Glasgow, Glasgow, Scotland, UK)

Abstract

Background Surrogate endpoints (i.e., intermediate endpoints intended to predict for patient-centered outcomes) are increasingly common. However, little is known about how surrogate evidence is handled in the context of health technology assessment (HTA). Objectives 1) To map methodologies for the validation of surrogate endpoints and 2) to determine their impact on acceptability of surrogates and coverage decisions made by HTA agencies. Methods We sought HTA reports where evaluation relied on a surrogate from 8 HTA agencies. We extracted data on the methods applied for surrogate validation. We assessed the level of agreement between agencies and fitted mixed-effects logistic regression models to test the impact of validation approaches on the agency’s acceptability of the surrogate endpoint and their coverage recommendation. Results Of the 124 included reports, 61 (49%) discussed the level of evidence to support the relationship between the surrogate and the patient-centered endpoint, 27 (22%) reported a correlation coefficient/association measure, and 40 (32%) quantified the expected effect on the patient-centered outcome. Overall, the surrogate endpoint was deemed acceptable in 49 (40%) reports ( k -coefficient 0.10, P = 0.004). Any consideration of the level of evidence was associated with accepting the surrogate endpoint as valid (odds ratio [OR], 4.60; 95% confidence interval [CI], 1.60–13.18, P = 0.005). However, we did not find strong evidence of an association between accepting the surrogate endpoint and agency coverage recommendation (OR, 0.71; 95% CI, 0.23–2.20; P = 0.55). Conclusions Handling of surrogate endpoint evidence in reports varied greatly across HTA agencies, with inconsistent consideration of the level of evidence and statistical validation. Our findings call for careful reconsideration of the issue of surrogacy and the need for harmonization of practices across international HTA agencies.

Suggested Citation

  • Oriana Ciani & Bogdan Grigore & Hedwig Blommestein & Saskia de Groot & Meilin Möllenkamp & Stefan Rabbe & Rita Daubner-Bendes & Rod S. Taylor, 2021. "Validity of Surrogate Endpoints and Their Impact on Coverage Recommendations: A Retrospective Analysis across International Health Technology Assessment Agencies," Medical Decision Making, , vol. 41(4), pages 439-452, May.
    • Handle: RePEc:sae:medema:v:41:y:2021:i:4:p:439-452
    DOI: 10.1177/0272989X21994553
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    References listed on IDEAS

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    1. Ruof, Jörg & Knoerzer, Dietrich & Dünne, Anja-Alexandra & Dintsios, Charalabos-Markos & Staab, Thomas & Schwartz, Friedrich Wilhelm, 2014. "Analysis of endpoints used in marketing authorisations versus value assessments of oncology medicines in Germany," Health Policy, Elsevier, vol. 118(2), pages 242-254.
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    1. Michael Drummond & Carlo Federici & Vivian Reckers‐Droog & Aleksandra Torbica & Carl Rudolf Blankart & Oriana Ciani & Zoltán Kaló & Sándor Kovács & Werner Brouwer, 2022. "Coverage with evidence development for medical devices in Europe: Can practice meet theory?," Health Economics, John Wiley & Sons, Ltd., vol. 31(S1), pages 179-194, September.
    2. Aleksandra Torbica & Rosanna Tarricone & Jonas Schreyögg & Mike Drummond, 2022. "Pushing the boundaries of evaluation, diffusion, and use of medical devices in Europe: Insights from the COMED project," Health Economics, John Wiley & Sons, Ltd., vol. 31(S1), pages 1-9, September.
    3. Oriana Ciani & Bogdan Grigore & Rod S. Taylor, 2022. "Development of a framework and decision tool for the evaluation of health technologies based on surrogate endpoint evidence," Health Economics, John Wiley & Sons, Ltd., vol. 31(S1), pages 44-72, September.

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