title: Blinded independent central review of progression in cancer clinical trials: results from a meta-analysis.
abstract: OBJECTIVE
  Progression free survival (PFS) is increasingly used as a primary end-point in oncology clinical trials. This paper provides observations and recommendations on the use of a blinded independent central review (BICR) for progression.
  
  
  METHODS
  The findings and recommendations are based on extensive simulations and a meta-analysis based on 27 previously conducted randomised phase III trials with BICR performed by the Pharmaceutical Research and Manufacturers Association (PhRMA) sponsored PFS Independent Review Working Group.
  
  
  RESULTS
  Results of the meta-analysis demonstrate a strong correlation between LE and BICR estimates of treatment effect (R=0.947). Further, differences between treatment groups in discordance rates predict the differences between LE and BICR estimates of treatment effect supporting the use of a sample-based BICR on a subgroup of patients.
  
  
  CONCLUSIONS
  The meta-analysis demonstrates that local evaluation (LE) provides a reliable estimate of the treatment effect with little evidence for systematic evaluation bias. Therefore, when a trial is blinded or a large effect on PFS is observed a BICR may not be warranted. When a BICR is warranted, a sample-based BICR may provide a reduction in operational complexity without compromising the credibility of trial results. While for large trials that are not adequately blinded a sample-based BICR may be recommended. A full BICR should be considered in the case of smaller trials or in situations in which there is a particular need to increase the confidence in the LE results.
authors.affiliation: GSK, Collegeville, PA 19426, USA. ohad.amit@gsk.com
authors.forename: O
authors.initials: O
authors.lastname: Amit
authors.forename: F
authors.initials: F
authors.lastname: Mannino
authors.forename: A M
authors.initials: AM
authors.lastname: Stone
authors.forename: W
authors.initials: W
authors.lastname: Bushnell
authors.forename: J
authors.initials: J
authors.lastname: Denne
authors.forename: J
authors.initials: J
authors.lastname: Helterbrand
authors.forename: H U
authors.initials: HU
authors.lastname: Burger
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015982:Bias; D017326:Clinical Trials, Phase III as Topic / Q000379:methods / Q000639:trends; D018450:Disease Progression; D018572:Disease-Free Survival; D006801:Humans; D008485:Medical Audit; D009369:Neoplasms / Q000188:drug therapy*; D016017:Odds Ratio; D016032:Randomized Controlled Trials as Topic / Q000379:methods / Q000639:trends; D012680:Sensitivity and Specificity; D016037:Single-Blind Method; D014481:United States
chemical_list: D000970:Antineoplastic Agents