Oriana Ciani1, Sarah Davis2, Paul Tappenden2, Ruth Garside3, Ken Stein1, Anna Cantrell2, Everardo D Saad4, Marc Buyse5, Rod S Taylor1. 1. Peninsula Technology Assessment Group,University of Exeter Medical School,Veysey Building,Salmon Pool Lane,Exeter,EX2 4SG,UK. 2. Decision Support Unit,School of Health and Related Research,University of Sheffield,Regent Court,30 Regent Street,Sheffield,S1 4DA,UK. 3. European Centre for Environment and Human Health University of Exeter Medical School Knowledge Spa,Royal Cornwall Hospital,Truro,TR1 3HD,UK. 4. Dendrix Research,Rua Joaquim Floriano,72/24,04534-000,Sao Paulo,Brazil. 5. International Drug Development Institute,Avenue Provinciale,30,1340,Louvain-la-Neuve,Belgium.
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.
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.
Authors: Wanling Xie; Meredith M Regan; Marc Buyse; Susan Halabi; Philip W Kantoff; Oliver Sartor; Howard Soule; Donald Berry; Noel Clarke; Laurence Collette; Anthony D'Amico; Richard De Abreu Lourenco; James Dignam; Mario Eisenberger; Nicholas James; Karim Fizazi; Silke Gillessen; Yohann Loriot; Nicolas Mottet; Wendy Parulekar; Howard Sandler; Daniel E Spratt; Matthew R Sydes; Bertrand Tombal; Scott Williams; Christopher J Sweeney Journal: J Clin Oncol Date: 2020-06-18 Impact factor: 44.544
Authors: Alberto Martini; Rachel Jia; Bart S Ferket; Nikhil Waingankar; Elizabeth R Plimack; Simon J Crabb; Lauren C Harshman; Evan Y Yu; Thomas Powles; Jonathan E Rosenberg; Sumanta K Pal; Ulka N Vaishampayan; Andrea Necchi; N Peter Wiklund; Reza Mehrazin; Madhu Mazumdar; John P Sfakianos; Matthew D Galsky Journal: Cancer Date: 2019-05-31 Impact factor: 6.860
Authors: Oriana Ciani; Marc Buyse; Mike Drummond; Guido Rasi; Everardo D Saad; Rod S Taylor Journal: Nat Rev Drug Discov Date: 2016-06-03 Impact factor: 84.694
Authors: Oriana Ciani; Bogdan Grigore; Hedwig Blommestein; Saskia de Groot; Meilin Möllenkamp; Stefan Rabbe; Rita Daubner-Bendes; Rod S Taylor Journal: Med Decis Making Date: 2021-03-10 Impact factor: 2.583
Authors: Wanling Xie; Meredith M Regan; Marc Buyse; Susan Halabi; Philip W Kantoff; Oliver Sartor; Howard Soule; Noel W Clarke; Laurence Collette; James J Dignam; Karim Fizazi; Wendy R Paruleker; Howard M Sandler; Matthew R Sydes; Bertrand Tombal; Scott G Williams; Christopher J Sweeney Journal: J Clin Oncol Date: 2017-08-10 Impact factor: 44.544