title: Pediatric analgesic clinical trial designs, measures, and extrapolation: report of an FDA scientific workshop.
abstract: Analgesic trials pose unique scientific, ethical, and practical challenges in pediatrics. Participants in a scientific workshop sponsored by the US Food and Drug Administration developed consensus on aspects of pediatric analgesic clinical trial design. The standard parallel-placebo analgesic trial design commonly used for adults has ethical and practical difficulties in pediatrics, due to the likelihood of subjects experiencing pain for extended periods of time. Immediate-rescue designs using opioid-sparing, rather than pain scores, as a primary outcome measure have been successfully used in pediatric analgesic efficacy trials. These designs maintain some of the scientific benefits of blinding, with some ethical and practical advantages over traditional designs. Preferred outcome measures were recommended for each age group. Acute pain trials are feasible for children undergoing surgery. Pharmacodynamic responses to opioids, local anesthetics, acetaminophen, and nonsteroidal antiinflammatory drugs appear substantially mature by age 2 years. There is currently no clear evidence for analgesic efficacy of acetaminophen or nonsteroidal antiinflammatory drugs in neonates or infants younger than 3 months of age. Small sample designs, including cross-over trials and N of 1 trials, for particular pediatric chronic pain conditions and for studies of pain and irritability in pediatric palliative care should be considered. Pediatric analgesic trials can be improved by using innovative study designs and outcome measures specific for children. Multicenter consortia will help to facilitate adequately powered pediatric analgesic trials.
authors.affiliation: Division of Pain Medicine, Department of Anesthesiology, Perioperative and Pain Medicine, Children's Hospital, Boston, Boston, MA 02115, USA. charles.berde@childrens.harvard.edu
authors.forename: Charles B
authors.initials: CB
authors.lastname: Berde
authors.forename: Gary A
authors.initials: GA
authors.lastname: Walco
authors.forename: Elliot J
authors.initials: EJ
authors.lastname: Krane
authors.forename: K J S
authors.initials: KJ
authors.lastname: Anand
authors.forename: Jacob V
authors.initials: JV
authors.lastname: Aranda
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Craig
authors.forename: Carlton D
authors.initials: CD
authors.lastname: Dampier
authors.forename: Julia C
authors.initials: JC
authors.lastname: Finkel
authors.forename: Martin
authors.initials: M
authors.lastname: Grabois
authors.forename: Celeste
authors.initials: C
authors.lastname: Johnston
authors.forename: John
authors.initials: J
authors.lastname: Lantos
authors.forename: Alyssa
authors.initials: A
authors.lastname: Lebel
authors.forename: Lynne G
authors.initials: LG
authors.lastname: Maxwell
authors.forename: Patrick
authors.initials: P
authors.lastname: McGrath
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Oberlander
authors.forename: Laura E
authors.initials: LE
authors.lastname: Schanberg
authors.forename: Bonnie
authors.initials: B
authors.lastname: Stevens
authors.forename: Anna
authors.initials: A
authors.lastname: Taddio
authors.forename: Carl L
authors.initials: CL
authors.lastname: von Baeyer
authors.forename: Myron
authors.initials: M
authors.lastname: Yaster
authors.forename: William T
authors.initials: WT
authors.lastname: Zempsky
mesh_terms: D000328:Adult; D000367:Age Factors; D000700:Analgesics / Q000009:adverse effects / Q000145:classification / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D059350:Chronic Pain / Q000188:drug therapy*; D002986:Clinical Trials as Topic / Q000941:ethics / Q000379:methods*; D004493:Education / Q000941:ethics; D004992:Ethics, Medical; D005240:Feasibility Studies; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D012107:Research Design; D016896:Treatment Outcome; D014481:United States; D014486:United States Food and Drug Administration / Q000941:ethics
chemical_list: D000700:Analgesics