Carleer Jacqueline, Karres Janina
Belgian Federal Agency for Medicines and Health Products, Brussels, Belgium.
Birth Defects Res B Dev Reprod Toxicol. 2011 Aug;92(4):254-60. doi: 10.1002/bdrb.20310. Epub 2011 Jun 2.
During the workshop organized by ILSI/HESI on May 5-6, 2010 on the value of juvenile animal toxicity studies, the implementation of the European Pediatric Regulation and in particular the review process of the nonclinical part of the Pediatric Investigation Plan (PIP) were described. A PIP is intended to outline the development of a medicinal product in the pediatric population (i.e. quality, safety, efficacy of the medicine and timing of studies); it is reviewed and agreed by the Pediatric Committee (PDCO) of the European Medicines Agency (EMA). The Nonclinical Working Group (NcWG) supports the PDCO in the review process of the nonclinical part of a PIP and is composed of members from the PDCO, the EMA Safety Working Party, additional experts from national competent authorities and the FDA. This article summarizes the NcWG review process and outcomes of 97 approved or ongoing PIPs, from the establishment of the NcWG in November 2008 to May 2010, as presented during the workshop. Juvenile animal studies were proposed by the applicant in 33% or required by the NcWG in 26% of the PIPs. The requirements were mainly motivated by concerns regarding potential developmental toxicities, in view of the young age of the pediatric population to be investigated, the lack of knowledge concerning the maturation of the pharmacological target, the lack of sufficient (non)clinical data, observed toxicities in the adult (non)clinical studies and the long duration of the intended treatments. Most juvenile animal studies were in the therapeutic areas of oncology, infectious diseases and endocrinology. In about 14% of the PIPs submitted, the NcWG requested either justifications of, or amendments to the study designs proposed by the applicants (e.g. justification of endpoints, study duration, species selection and timing with regards to clinical pediatric studies). Generally, only one species was selected or proposed for the juvenile studies, the rat being the most prevalent. The number of juvenile studies initially proposed by the applicant plus those requested by the NcWG was higher than the number of studies included in the "key binding elements" of the PIP opinions. This apparent discrepancy was mainly due to additional information or justifications submitted by the applicant during the clock stop. It was noted that the PIPs initially submitted often lacked information relevant to the nonclinical evaluation. Therefore, during the workshop, the need to provide scientifically based justifications when no juvenile animal studies are proposed in the initial PIP submission was stressed.
在国际生命科学研究所/健康与环境科学研究所于2010年5月5 - 6日举办的关于幼年动物毒性研究价值、欧洲儿科法规实施情况，特别是儿科研究计划（PIP）非临床部分审评程序的研讨会上，对上述内容进行了介绍。儿科研究计划旨在概述医药产品在儿科人群中的研发情况（即药品的质量、安全性、有效性及研究时间安排）；该计划需经欧洲药品管理局（EMA）的儿科委员会（PDCO）审评并批准。非临床工作组（NcWG）在儿科研究计划非临床部分的审评过程中为儿科委员会提供支持，其成员包括儿科委员会成员、EMA安全工作组人员、各国主管当局的其他专家以及美国食品药品监督管理局（FDA）的人员。本文总结了非临床工作组自2008年11月成立至2010年5月期间，对97项已批准或正在进行的儿科研究计划的审评过程及结果，这些内容在研讨会上进行了汇报。在33%的儿科研究计划中，申请人提出了幼年动物研究；在26%的儿科研究计划中，非临床工作组要求进行幼年动物研究。提出这些要求的主要原因在于，考虑到拟研究儿科人群的年龄较小、对药理学靶点成熟情况缺乏了解、缺乏足够的（非）临床数据、在成人（非）临床研究中观察到的毒性以及预期治疗的持续时间较长，担心存在潜在的发育毒性。大多数幼年动物研究涉及肿瘤学、传染病和内分泌学治疗领域。在提交的儿科研究计划中，约14%的计划，非临床工作组要求申请人对所提议的研究设计进行说明或修改（例如对研究终点、研究持续时间、物种选择以及与儿科临床研究时间安排相关的内容进行说明）。一般来说，幼年研究仅选择或提议使用一种物种，最常用的是大鼠。申请人最初提议的幼年研究数量加上非临床工作组要求的幼年研究数量，高于儿科研究计划意见“关键约束要素”中包含的研究数量。这种明显的差异主要是由于申请人在时间暂停期间提交了额外信息或说明。需要注意的是，最初提交的儿科研究计划往往缺乏与非临床评估相关的信息。因此，在研讨会上强调，在最初提交的儿科研究计划中未提议进行幼年动物研究时，需要提供基于科学的说明。
