title: Complete cytogenetic response and major molecular response as surrogate outcomes for overall survival in first-line treatment of chronic myelogenous leukemia: a case study for technology appraisal on the basis of surrogate outcomes evidence.
abstract: OBJECTIVE
  In 2012, the National Institute for Health and Care Excellence assessed dasatinib, nilotinib, and standard-dose imatinib as first-line treatment of chronic phase chronic myelogenous leukemia (CML). Licensing of these alternative treatments was based on randomized controlled trials assessing complete cytogenetic response (CCyR) and major molecular response (MMR) at 12 months as primary end points. We use this case study to illustrate the validation of CCyR and MMR as surrogate outcomes for overall survival in CML and how this evidence was used to inform National Institute for Health and Care Excellence's recommendation on the public funding of these first-line treatments for CML.
  
  
  METHODS
  We undertook a systematic review and meta-analysis to quantify the association between CCyR and MMR at 12 months and overall survival in patients with chronic phase CML. We estimated life expectancy by extrapolating long-term survival from the weighted overall survival stratified according to the achievement of CCyR and MMR.
  
  
  RESULTS
  Five studies provided data on the observational association between CCyR or MMR and overall survival. Based on the pooled association between CCyR and MMR and overall survival, our modeling showed comparable predicted mean duration of survival (21-23 years) following first-line treatment with imatinib, dasatinib, or nilotinib.
  
  
  CONCLUSIONS
  This case study illustrates the consideration of surrogate outcome evidence in health technology assessment. Although it is often recommended that the acceptance of surrogate outcomes be based on randomized controlled trial data demonstrating an association between the treatment effect on both the surrogate outcome and the final outcome, this case study shows that policymakers may be willing to accept a lower level of evidence (i.e., observational association).
authors.affiliation: PenTAG, Institute of Health Services Research, University of Exeter Medical School, Exeter, UK. Electronic address: oriana.ciani@pcmd.ac.uk.
authors.forename: Ciani
authors.initials: C
authors.lastname: Oriana
authors.forename: Hoyle
authors.initials: H
authors.lastname: Martin
authors.forename: Pavey
authors.initials: P
authors.lastname: Toby
authors.forename: Cooper
authors.initials: C
authors.lastname: Chris
authors.forename: Garside
authors.initials: G
authors.lastname: Ruth
authors.forename: Rudin
authors.initials: R
authors.lastname: Claudius
authors.forename: Taylor
authors.initials: T
authors.lastname: Rod
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers; D020732:Cytogenetic Analysis; D005260:Female; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D019982:Organizational Case Studies; D017063:Outcome Assessment, Health Care / Q000379:methods*; D016019:Survival Analysis; D013673:Technology Assessment, Biomedical; D055815:Young Adult
chemical_list: D015415:Biomarkers
keywords: HTA; chronic myeloid leukemia; complete cytogenetic response; dasatinib; health technology assessment; imatinib; intermediate outcomes; major molecular response; nilotinib; surrogate end points; systematic review; technology appraisal