title: Analyzing overall survival in randomized controlled trials with crossover and implications for economic evaluation.
abstract: BACKGROUND
  Offering patients in oncology trials the opportunity to cross over to active treatment at disease progression is a common strategy to address ethical issues associated with placebo controls but may lead to statistical challenges in the analysis of overall survival and cost-effectiveness because crossover leads to information loss and dilution of comparative clinical efficacy.
  
  
  OBJECTIVE
  We provide an overview of how to address crossover, implications for risk-effect estimates of survival (hazard ratios) and cost-effectiveness, and how this influences decisions of reimbursement agencies. Two case studies using data from two phase III sunitinib oncology trials are used as illustration.
  
  
  METHODS
  We reviewed the literature on statistical methods for adjusting for crossover and recent health technology assessment decisions in oncology.
  
  
  RESULTS
  We show that for a trial with a high proportion of crossover from the control arm to the investigational arm, the choice of the statistical method greatly affects treatment-effect estimates and cost-effectiveness because the range of relative mortality risk for active treatment versus control is broad. With relatively frequent crossover, one should consider either the inverse probability of censoring weighting or the rank-preserving structural failure time model to minimize potential bias, with choice dependent on crossover characteristics, trial size, and available data. A large proportion of crossover favors the rank-preserving structural failure time model, while large sample size and abundant information about confounding factors favors the inverse probability of censoring weighting model. When crossover is very infrequent, methods yield similar results.
  
  
  CONCLUSIONS
  Failure to correct for crossover may lead to suboptimal decisions by pricing and reimbursement authorities, thereby limiting an effective drug's potential.
authors.affiliation: OptumInsight AB, Klarabergsviadukten, Stockholm, Sweden. Electronic address: linus.jonsson@ki.se.
authors.forename: Linus
authors.initials: L
authors.lastname: Jönsson
authors.affiliation: Global Health Economics and Outcomes Research, Pfizer Oncology, Sollentuna, Sweden.
authors.forename: Rickard
authors.initials: R
authors.lastname: Sandin
authors.affiliation: OptumInsight AB, Klarabergsviadukten, Stockholm, Sweden.
authors.forename: Mattias
authors.initials: M
authors.lastname: Ekman
authors.affiliation: OptumInsight AB, Klarabergsviadukten, Stockholm, Sweden.
authors.forename: Joakim
authors.initials: J
authors.lastname: Ramsberg
authors.affiliation: Global Outcomes Research, Specialty Care BU, Pfizer, Paris, France.
authors.forename: Claudie
authors.initials: C
authors.lastname: Charbonneau
authors.affiliation: Oncology Clinical Development, San Diego, CA, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Huang
authors.affiliation: Stockholm School of Economics, Stockholm, Sweden.
authors.forename: Bengt
authors.initials: B
authors.lastname: Jönsson
authors.affiliation: Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA; OptumInsight, Medford, MA, USA.
authors.forename: Milton C
authors.initials: MC
authors.lastname: Weinstein
authors.affiliation: Centre for Health Economics, University of York, York, North Yorkshire, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Drummond
mesh_terms: D000970:Antineoplastic Agents / Q000191:economics / Q000627:therapeutic use; D017326:Clinical Trials, Phase III as Topic / Q000191:economics* / Q000401:mortality*; D003362:Cost-Benefit Analysis; D018592:Cross-Over Studies; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000191:economics / Q000401:mortality; D016032:Randomized Controlled Trials as Topic / Q000191:economics* / Q000401:mortality*; D015996:Survival Rate / Q000639:trends
chemical_list: D000970:Antineoplastic Agents
keywords: cost effectiveness; crossover; oncology; sunitinib; surviva