title: Statistical controversies in clinical research: requiem for the 3 + 3 design for phase I trials.
abstract: BACKGROUND
  More than 95% of published phase I trials have used the 3 + 3 design to identify the dose to be recommended for phase II trials. However, the statistical community agrees on the limitations of the 3 + 3 design compared with model-based approaches. Moreover, the mechanisms of action of targeted agents strongly challenge the hypothesis that the maximum tolerated dose constitutes the optimal dose, and more outcomes including clinical and biological activity increasingly need to be taken into account to identify the optimal dose.
  
  
  METHODS
  We review key elements from clinical publications and from the statistical literature to show that the 3 + 3 design lacks the necessary flexibility to address the challenges of targeted agents.
  
  
  RESULTS
  The design issues raised by expansion cohorts, new definitions of dose-limiting toxicity and trials of combinations are not easily addressed by the 3 + 3 design or its extensions.
  
  
  CONCLUSIONS
  Alternative statistical proposals have been developed to make a better use of the complex data generated by phase I trials. Their applications require a close collaboration between all actors of early phase clinical trials.
authors.affiliation: Biostatistics and Epidemiology Department, Gustave Roussy, Villejuif; INSERM U1018, CESP, Paris-Sud University, Villejuif. Electronic address: xavier.paoletti@gustaveroussy.fr.
authors.forename: X
authors.initials: X
authors.lastname: Paoletti
authors.affiliation: INSERM/Institut Curie/Mines ParisTech U900, Paris.
authors.forename: M
authors.initials: M
authors.lastname: Ezzalfani
authors.affiliation: INSERM/Institut Curie/Mines ParisTech U900, Paris; Department of Medical Oncology, Clinical Trial Unit, Institut Curie, Paris & Saint-Cloud, France.
authors.forename: C
authors.initials: C
authors.lastname: Le Tourneau
mesh_terms: D000465:Algorithms; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D054316:Biomarkers, Pharmacological; D035843:Biomedical Research / Q000379:methods*; D017321:Clinical Trials, Phase I as Topic / Q000379:methods*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020714:Maximum Tolerated Dose; D008962:Models, Theoretical; D012107:Research Design
chemical_list: D054316:Biomarkers, Pharmacological
keywords: continual reassessment method; dose finding; efficiency; targeted agents