title: Steps toward harmonization for clinical development of medicines in pediatric ulcerative colitis-a global scientific discussion, part 2: data extrapolation, trial design, and pharmacokinetics.
abstract: OBJECTIVE
  To facilitate global drug development, the International Pediatric Inflammatory Bowel Disease Working Group (i-IBD Working Group) discussed data extrapolation, trial design, and pharmacokinetic (PK) considerations for drugs intended to treat pediatric ulcerative colitis (UC), and considered possible approaches toward harmonized drug development.
  
  
  METHODS
  Representatives from the US Food and Drug Administration, European Medicines Agency, Health Canada, and the Pharmaceuticals and Medical Devices Agency of Japan convened monthly to explore existing regulatory approaches, reviewed the results of a literature search, and provided perspectives on pediatric UC drug development based on the available medical literature.
  
  
  RESULTS
  Although pediatric UC, when compared with UC in adults, has a similar disease progression and response to intervention, the similarity of the exposure-response relation has not been adequately established. Consequently, clinical endpoints should be selected to optimally assess efficacy in children. The inclusion of a placebo control in pediatric trials to assure assay sensitivity may be appropriate under limited circumstances. In clinical studies, although the drug under investigation could provide possible direct benefit, placebo treatment should present no more than a minor increase over minimal risk to children with UC.
  
  
  CONCLUSIONS
  Partial extrapolation of efficacy from informative adult studies may be appropriate. Placebo-controlled efficacy trials are scientifically and ethically appropriate for pediatric UC given appropriate patient selection and the use of early escape. Clinical studies in pediatric UC may include initial dose-finding studies and exposure-response modeling followed by an efficacy and safety study to further explore the exposure-response relation.
authors.affiliation: *US Food and Drug Administration, Silver Spring, MD †European Medicines Agency, London, UK ‡Health Canada, Ottawa, Ontario, Canada §Pharmaceuticals and Medical Devices Agency, Tokyo, Japan.
authors.forename: Haihao
authors.initials: H
authors.lastname: Sun
authors.forename: Richard
authors.initials: R
authors.lastname: Vesely
authors.forename: Robert M
authors.initials: RM
authors.lastname: Nelson
authors.forename: Jan
authors.initials: J
authors.lastname: Taminiau
authors.forename: Peter
authors.initials: P
authors.lastname: Szitanyi
authors.forename: Maria
authors.initials: M
authors.lastname: Isaac
authors.forename: Agnes
authors.initials: A
authors.lastname: Klein
authors.forename: Shinobu
authors.initials: S
authors.lastname: Uzu
authors.forename: Donna
authors.initials: D
authors.lastname: Griebel
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Mulberg
mesh_terms: D002170:Canada; D002648:Child; D002986:Clinical Trials as Topic; D003093:Colitis, Ulcerative / Q000188:drug therapy*; D003299:Cooperative Behavior; D004305:Dose-Response Relationship, Drug; D005060:Europe; D006801:Humans; D007564:Japan; D017063:Outcome Assessment, Health Care; D010599:Pharmacokinetics; D015990:Placebo Effect; D012107:Research Design; D014481:United States