1 Division of Neurology Products, Center for Drug Evaluation and Research (CDER), Office of New Drugs (OND), US Food and Drug Administration (FDA), Silver Spring, MD, USA.
2 Division of Psychiatry Products, Center for Drug Evaluation and Research (CDER), Office of New Drugs (OND), US Food and Drug Administration (FDA), Silver Spring, MD, USA.
Int J Toxicol. 2019 Mar/Apr;38(2):88-95. doi: 10.1177/1091581818824313. Epub 2019 Feb 10.
A survey was undertaken to evaluate juvenile animal studies conducted for drug applications reviewed by the Center for Drug Evaluation and Research between 2009 and 2014. Some conclusions about the nonclinical pediatric safety assessment based on studies performed in support of central nervous system-active compounds are presented here. A total of 44 completed studies from 32 New Drug Applications submitted to the Divisions of Psychiatry and Neurology Products were evaluated. Data on animal species and age range used, endpoints evaluated, and outcomes included in labeling were analyzed. Of the drugs evaluated, all but one had studies conducted in rats. In some cases, a second study in a nonrodent species (dog) was also conducted. Indices of growth and development and standard general toxicity parameters were included in all of the studies. Expanded neurohistopathology evaluations, bone mineral density measurements, and reproductive and neurobehavioral functional assessments were also generally carried out. A variety of neurological and neurobehavioral tests were employed. In the majority of rat studies, the potential for long-term cognitive impairment was evaluated using a complex water maze. Juvenile animal studies provided safety information considered relevant to drug use in children and that was included in labeling for 78% of the applications surveyed. The most commonly reported findings in labeling were for neurobehavioral effects, including changes in locomotor activity, auditory startle habituation, and learning and memory. Of the studies described in labeling with neurobehavioral effects, 54% found these effects to be persistent and to provide evidence of developmental neurotoxicity.
本研究旨在评估中心药物评价与研究中心（CDER）在 2009 年至 2014 年期间审查的药物申请中的幼年动物研究。这里提出了一些基于支持中枢神经系统活性化合物进行的研究的非临床儿科安全性评估的结论。共评估了提交给精神病学和神经病学产品分部的 32 份新药申请中的 44 项已完成研究。分析了所使用的动物物种和年龄范围、评估终点以及标签中包含的结果。在所评估的药物中，除了一种之外，其余均在大鼠中进行了研究。在某些情况下，还在非啮齿动物（狗）中进行了第二项研究。所有研究均包括生长和发育指数以及标准的一般毒性参数。还通常进行了扩展的神经组织病理学评估、骨矿物质密度测量以及生殖和神经行为功能评估。采用了各种神经和神经行为测试。在大多数大鼠研究中，使用复杂的水迷宫评估了长期认知障碍的潜力。幼年动物研究提供了被认为与儿童用药相关的安全性信息，并包含在 78%接受调查的申请的标签中。标签中最常报告的发现是神经行为影响，包括运动活动、听觉惊跳习惯化和学习记忆的变化。在标签中描述的具有神经行为影响的研究中，有 54%发现这些影响是持久的，并提供了发育神经毒性的证据。
