Tsukamoto Katusra, Carroll Kelly A, Onishi Taku, Matsumaru Naoki, Brasseur Daniel, Nakamura Hidefumi
Global Regulatory Science, Gifu Pharmaceutical University, Gifu, Japan.
Clinical and Translational Research Program, Stanley Manne Children's Research Institute, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.
Clin Ther. 2016 Mar;38(3):574-81. doi: 10.1016/j.clinthera.2016.01.012. Epub 2016 Feb 8.
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.
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.
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.
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.
儿科药物研发的匮乏常常使儿科医生别无选择，只能开具未获许可或未按批准说明书使用的药物，从而增加了不良事件的风险。我们介绍了儿科药物研发的现状，并基于数据分析阐明了该领域存在的问题。我们还提出了进一步的行动建议，以改善具有儿科治疗孤儿药地位的药物研发。
我们分析了ClinicalTrials.gov中2006年至2014年间仅纳入儿科参与者（<18岁）的所有II/III期和III期试验。通过将儿科临床试验的年度数量除以从美国人口普查局获取的每百万儿科人口数来计算儿科药物研发的绩效指标。通过比较日本、欧盟和美国在引入两项旨在促进儿科药物研发的日本激励措施之前（2006 - 2009年）和之后（2010 - 2014年）的平均绩效指标，分析了这两项激励措施的效果。我们还查阅了欧盟临床试验注册库以及欧洲药品管理局发布的报告，以调查儿科委员会对欧盟儿科临床试验的影响。
日本与欧盟在引入激励措施前后绩效指标的平均差异分别为0.296（P < 0.001）和0.066（P = 0.498）。日本与美国在引入激励措施前后绩效指标的平均差异分别为0.560（P < 0.001）和0.281（P = 0.002），这表明在引入这些激励措施后，日本的儿科药物研发更加活跃，甚至达到了欧盟的水平。《儿科法规》和儿科委员会推动了欧盟的儿科药物研发。在法规实施后的1000天内，欧盟临床试验注册库中至少纳入1名<18岁参与者的临床试验注册数量增加了247项（从672项增加）。2008年后，具有获批儿科研究计划的儿科临床试验比例增至>15%。
招募和伦理障碍使得开展儿科临床试验具有挑战性。一个改进的临床试验操作框架应与不断完善的监管框架相匹配，该监管框架激励对儿科临床试验的投资。技术手段、电子病历系统的改进以及积极纳入医生、研究人员和患者意见的社区方法，可为招募儿科研究参与者提供可持续的解决方案。因此，关键在于改善行业、政府、学术界和社区之间的儿科药物治疗合作。扩大欧盟、美国和日本所采取的监管措施，并使用创新的临床试验工具，可以使儿科药物治疗摆脱目前的治疗孤儿药状态。
