title: Important issues in the justification of a control treatment in paediatric drug trials.
abstract: OBJECTIVE
  The value of comparative effectiveness trials in informing clinical and policy decisions depends heavily on the choice of control arm (comparator). Our objective is to identify challenges in comparator reasoning and to determine justification criteria for selecting a control arm in paediatric clinical trials.
  
  
  METHODS
  A literature search was completed to identify existing sources of guidance on comparator selection. Subsequently, we reviewed a randomly selected sample of comparators selected for paediatric investigation plans (PIPs) adopted by the Paediatric Committee of the European Medicines Agency in 2013. We gathered descriptive information and evaluated their review process to identify challenges and compromises between regulators and sponsors with regard to the selection of the comparator. A tool to help investigators justify the selection of active controls and placebo arms was developed using the existing literature and empirical data.
  
  
  RESULTS
  Justifying comparator selection was a challenge in 28% of PIPs. The following challenging paediatric issues in the decision-making process were identified: use of off-label medications as comparators, ethical and safe use of placebo, duration of placebo use, an undefined optimal dosing strategy, lack of age-appropriate safety and efficacy data, and drug dosing not supported by extrapolation of safety/efficacy evidence from other populations.
  
  
  CONCLUSIONS
  In order to generate trials that will inform clinical decision-making and support marketing authorisations, researchers must systemically and transparently justify their selection of the comparator arm for their study. This report highlights key areas for justification in the choice of comparator in paediatric clinical trials.
authors.affiliation: Child Health and Evaluative Sciences, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Kelly
authors.affiliation: Enabling Research, London, UK.
authors.forename: Elin Haf
authors.initials: EH
authors.lastname: Davies
authors.affiliation: The European Medicines Agency, London, UK.
authors.forename: Agnes
authors.initials: A
authors.lastname: Saint-Raymond
authors.affiliation: The European Medicines Agency, London, UK.
authors.forename: Paolo
authors.initials: P
authors.lastname: Tomasi
authors.affiliation: Child Health and Evaluative Sciences, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Offringa
mesh_terms: D002648:Child; D002986:Clinical Trials as Topic / Q000379:methods*; D035061:Control Groups; D003657:Decision Making; D017277:Drug Approval / Q000379:methods*; D006801:Humans; D061214:Patient Safety
keywords: Clinical Trials; Comparators; Control Arm; Epidemiology; Paediatrics