title: Validation of surrogate endpoints in advanced solid tumors: systematic review of statistical methods, results, and implications for policy makers.
abstract: OBJECTIVE
  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.affiliation: Peninsula Technology Assessment Group,University of Exeter Medical School,Veysey Building,Salmon Pool Lane,Exeter,EX2 4SG,UK.
authors.forename: Oriana
authors.initials: O
authors.lastname: Ciani
authors.affiliation: Decision Support Unit,School of Health and Related Research,University of Sheffield,Regent Court,30 Regent Street,Sheffield,S1 4DA,UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Davis
authors.affiliation: Decision Support Unit,School of Health and Related Research,University of Sheffield,Regent Court,30 Regent Street,Sheffield,S1 4DA,UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Tappenden
authors.affiliation: European Centre for Environment and Human Health University of Exeter Medical School Knowledge Spa,Royal Cornwall Hospital,Truro,TR1 3HD,UK.
authors.forename: Ruth
authors.initials: R
authors.lastname: Garside
authors.affiliation: Peninsula Technology Assessment Group,University of Exeter Medical School,Veysey Building,Salmon Pool Lane,Exeter,EX2 4SG,UK.
authors.forename: Ken
authors.initials: K
authors.lastname: Stein
authors.affiliation: Decision Support Unit,School of Health and Related Research,University of Sheffield,Regent Court,30 Regent Street,Sheffield,S1 4DA,UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Cantrell
authors.affiliation: Dendrix Research,Rua Joaquim Floriano,72/24,04534-000,Sao Paulo,Brazil.
authors.forename: Everardo D
authors.initials: ED
authors.lastname: Saad
authors.affiliation: International Drug Development Institute,Avenue Provinciale,30,1340,Louvain-la-Neuve,Belgium.
authors.forename: Marc
authors.initials: M
authors.lastname: Buyse
authors.affiliation: Peninsula Technology Assessment Group,University of Exeter Medical School,Veysey Building,Salmon Pool Lane,Exeter,EX2 4SG,UK.
authors.forename: Rod S
authors.initials: RS
authors.lastname: Taylor
mesh_terms: D018450:Disease Progression; D018572:Disease-Free Survival; D023381:Endpoint Determination; D019317:Evidence-Based Medicine; D006291:Health Policy; D006801:Humans; D009369:Neoplasms / Q000628:therapy*; D011050:Policy Making; D016032:Randomized Controlled Trials as Topic; D012107:Research Design; D013223:Statistics as Topic