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VALIDATION OF SURROGATE ENDPOINTS IN ADVANCED SOLID TUMORS: SYSTEMATIC REVIEW OF STATISTICAL METHODS, RESULTS, AND IMPLICATIONS FOR POLICY MAKERS

Published online by Cambridge University Press:  02 September 2014

Oriana Ciani
Affiliation:
Peninsula Technology Assessment Group, University of Exeter Medical School, Veysey Building, Salmon Pool Lane, Exeter, EX2 4SG, UK CERGAS - Università Commerciale L. Bocconi, via Roentgen, 1 20136 Milan, ITo.ciani@exeter.ac.uk
Sarah Davis
Affiliation:
Decision Support Unit, School of Health and Related Research, University of Sheffield, Regent Court, 30 Regent Street, Sheffield, S1 4DA, UK
Paul Tappenden
Affiliation:
Decision Support Unit, School of Health and Related Research, University of Sheffield, Regent Court, 30 Regent Street, Sheffield, S1 4DA, UK
Ruth Garside
Affiliation:
European Centre for Environment and Human Health University of Exeter Medical School Knowledge Spa, Royal Cornwall Hospital, Truro, TR1 3HD, UK
Ken Stein
Affiliation:
Peninsula Technology Assessment Group, University of Exeter Medical School, Veysey Building, Salmon Pool Lane, Exeter, EX2 4SG, UK
Anna Cantrell
Affiliation:
Decision Support Unit, School of Health and Related Research, University of Sheffield, Regent Court, 30 Regent Street, Sheffield, S1 4DA, UK
Everardo D. Saad
Affiliation:
Dendrix Research, Rua Joaquim Floriano, 72/24, 04534-000, Sao Paulo, Brazil
Marc Buyse
Affiliation:
International Drug Development Institute, Avenue Provinciale, 30, 1340, Louvain-la-Neuve, Belgium
Rod S. Taylor
Affiliation:
Peninsula Technology Assessment Group, University of Exeter Medical School, Veysey Building, Salmon Pool Lane, Exeter, EX2 4SG, UK

Abstract

Objectives: Licensing of, and coverage decisions on, new therapies should rely on evidence from patient-relevant endpoints such as overall survival (OS). Nevertheless, evidence from surrogate endpoints may also be useful, as it may not only expedite the regulatory approval of new therapies but also inform coverage decisions. It is, therefore, essential that candidate surrogate endpoints be properly validated. However, there is no consensus on statistical methods for such validation and on how the evidence thus derived should be applied by policy makers.

Methods: We review current statistical approaches to surrogate-endpoint validation based on meta-analysis in various advanced-tumor settings. We assessed the suitability of two surrogates (progression-free survival [PFS] and time-to-progression [TTP]) using three current validation frameworks: Elston and Taylor's framework, the German Institute of Quality and Efficiency in Health Care's (IQWiG) framework and the Biomarker-Surrogacy Evaluation Schema (BSES3).

Results: A wide variety of statistical methods have been used to assess surrogacy. The strength of the association between the two surrogates and OS was generally low. The level of evidence (observation-level versus treatment-level) available varied considerably by cancer type, by evaluation tools and was not always consistent even within one specific cancer type.

Conclusions: Not in all solid tumors the treatment-level association between PFS or TTP and OS has been investigated. According to IQWiG's framework, only PFS achieved acceptable evidence of surrogacy in metastatic colorectal and ovarian cancer treated with cytotoxic agents. Our study emphasizes the challenges of surrogate-endpoint validation and the importance of building consensus on the development of evaluation frameworks.

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Copyright © Cambridge University Press 2014 

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