title: Modelling of the outcome of non-inferiority trials by integration of historical data.
abstract: The approval and differentiation of new compounds in clinical development often demands non-inferiority trials, in which the test drug is compared against a reference treatment. However, non-inferiority trials impose major operational burden with serious ethical and scientific implications for the development of new medicines. Traditional approaches make limited use of historical information on placebo and neglect inter-trial variability, relying on the constancy assumption that the control-to-placebo effect size is maintained across trials. We propose a model-based approach that overcomes such limitations and may be used as a tool to explore differentiation during clinical development. Parameter distributions are introduced which reflect the heterogeneity of trials. The method is illustrated using data from impetigo trials. Based on simulation scenarios, this Bayesian technique yields a definitive, consistent increase in the statistical power over two accepted statistical methods, allowing lower sample size requirements for the assessment of non-inferiority.
authors.affiliation: Department of Computer Engineering and Systems Science, University of Pavia, Pavia, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Russu
authors.forename: Erik
authors.initials: E
authors.lastname: van Zwet
authors.forename: Giuseppe
authors.initials: G
authors.lastname: De Nicolao
authors.forename: Oscar
authors.initials: O
authors.lastname: Della Pasqua
mesh_terms: D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001499:Bayes Theorem; D002986:Clinical Trials as Topic; D017326:Clinical Trials, Phase III as Topic; D016208:Databases, Factual; D004311:Double-Blind Method; D005672:Fusidic Acid / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D007169:Impetigo / Q000188:drug therapy*; D010919:Placebos; D012107:Research Design; D018401:Sample Size; D012984:Software; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents; D010919:Placebos; D005672:Fusidic Acid