title: Phase IV non-inferiority trials and additional claims of benefit.
abstract: BACKGROUND
  Non-inferiority (NI) trials in drug research are used to demonstrate that a new treatment is not less effective than an active comparator. Since phase IV trials typically aim at informing a clinical decision, the value of a phase IV non-inferiority trial hinges also on its clinical relevance. In such trials, clinical relevance would refer to the added benefit claims of a specific drug, apart from efficacy, relative to its comparator drug in the trial.
  
  
  METHODS
  In this study, we reviewed 41 phase IV trials and extracted information on whether the authors mentioned any additional benefit beyond the NI (efficacy) claim of the drug and whether the additional benefit was proven in the trial. We checked whether the additional claim was based on descriptions only or on formal statistical analyses.
  
  
  RESULTS
  Our results showed that 22 out of the 41 NI trials mentioned additional benefit of the test drug and most of these claims were related to the safety profile. Of all the post-authorization NI trials that claimed additional benefit, 10 out of 22 NI trials used formal statistical analyses to show additional benefit, and only one included a sample size calculation for the additional benefit prior to the trial.
  
  
  CONCLUSIONS
  We conclude that there is room for improvement in terms of designing phase IV NI trials with added benefit claims and in proving these additional claims.
authors.affiliation: Julius Center for Health Sciences and Primary Care, Utrecht University Medical Center, Utrecht, The Netherlands. R.Bernabe@umcutrecht.nl
authors.forename: Rosemarie D L C
authors.initials: RD
authors.lastname: Bernabe
authors.forename: Grace
authors.initials: G
authors.lastname: Wangge
authors.forename: Mirjam J
authors.initials: MJ
authors.lastname: Knol
authors.forename: Olaf H
authors.initials: OH
authors.lastname: Klungel
authors.forename: Johannes J M
authors.initials: JJ
authors.lastname: van Delden
authors.forename: Anthonius
authors.initials: A
authors.lastname: de Boer
authors.forename: Arno W
authors.initials: AW
authors.lastname: Hoes
authors.forename: Jan A M
authors.initials: JA
authors.lastname: Raaijmakers
authors.forename: Ghislaine J M W
authors.initials: GJ
authors.lastname: van Thiel
mesh_terms: D017327:Clinical Trials, Phase IV as Topic / Q000592:standards*; D005260:Female; D006801:Humans; D008297:Male; D004364:Pharmaceutical Preparations; D018570:Risk Assessment; D012449:Safety
chemical_list: D004364:Pharmaceutical Preparations