title: Improvement of Pediatric Drug Development: Regulatory and Practical Frameworks.
abstract: OBJECTIVE
  A dearth in pediatric drug development often leaves pediatricians with no alternative but to prescribe unlicensed or off-label drugs with a resultant increased risk of adverse events. We present the current status of pediatric drug development and, based on our data analysis, clarify the problems in this area. Further action is proposed to improve the drug development that has pediatric therapeutic orphan status.
  
  
  METHODS
  We analyzed all Phase II/III and Phase III trials in ClinicalTrials.gov that only included pediatric participants (<18 years old) between 2006 and 2014. Performance index, an indicator of pediatric drug development, was calculated by dividing the annual number of pediatric clinical trials by million pediatric populations acquired from Census.gov. Effects of the 2 Japanese premiums introduced in 2010, for the enhancement of pediatric drug development, were analyzed by comparing mean performance index prepremiums (2006-2009) and postpremiums (2010-2014) among Japan, the European Union, and the United States. The European Union Clinical Trials Register and published reports from the European Medicines Agency were also surveyed to investigate the Paediatric Committee effect on pediatric clinical trials in the European Union.
  
  
  RESULTS
  Mean difference of the performance index in prepremiums and postpremiums between Japan and the European Union were 0.296 (P < 0.001) and 0.066 (P = 0.498), respectively. Those between Japan and the United States were 0.560 (P < 0.001) and 0.281 (P = 0.002), indicating that pediatric drug development in Japan was more active after the introduction of these premiums, even reaching the level of the European Union. The Pediatric Regulation and the Paediatric Committee promoted pediatric drug development in the European Union. The registered number of clinical trials that includes at least 1 participants <18 years old in the European Union Clinical Trials Register increased by 247 trials (from 672) in the 1000 days after regulation. The ratio of pediatric clinical trials with an approved Paediatric Investigation Plan increased to >15% after 2008.
  
  
  CONCLUSIONS
  Recruitment and ethical obstacles make conducting pediatric clinical trials challenging. An improved operational framework for conducting clinical trials should mirror the ever-improving regulatory framework that incentivizes investment in pediatric clinical trials. Technological approaches, enhancements in electronic medical record systems, and community approaches that actively incorporate input from physicians, researchers, and patients could offer a sustainable solution to recruitment of pediatric study participants. The key therefore is to improve pediatric pharmacotherapy collaboration among industry, government, academia, and community. Expanding the regulatory steps taken in the European Union, United States, and Japan and using innovative clinical trial tools can move pediatric pharmacotherapy out of its current therapeutic orphan state.
authors: Global Regulatory Science, Gifu Pharmaceutical University, Gifu, Japan. Electronic address: tsukamoto@gifu-pu.ac.jp.
authors: Katusra
authors: K
authors: Tsukamoto
authors: Clinical and Translational Research Program, Stanley Manne Children's Research Institute, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.
authors: Kelly A
authors: KA
authors: Carroll
authors: Global Regulatory Science, Gifu Pharmaceutical University, Gifu, Japan.
authors: Taku
authors: T
authors: Onishi
authors: Global Regulatory Science, Gifu Pharmaceutical University, Gifu, Japan.
authors: Naoki
authors: N
authors: Matsumaru
authors: Université libre de Bruxelles, Brussels, Belgium.
authors: Daniel
authors: D
authors: Brasseur
authors: Clinical Research and Development, National Research Institute for Child Health and Development, Tokyo, Japan.
authors: Hidefumi
authors: H
authors: Nakamura
mesh_terms: D002648:Child; D015195:Drug Design; D004348:Drug Labeling; D005062:European Union; D006801:Humans; D007564:Japan; D056687:Off-Label Use; D010372:Pediatrics; D014481:United States
keywords: European Medicines Agency; Japan Ministry of Health; Labour, and Welfare; US Food and Drug Administration; clinical operation; pediatric drug development; regulatory framework