Evaluation of Juvenile Animal Studies for Pediatric CNS-Targeted Compounds: A Regulatory Perspective

Central nervous system (CNS)-targeted products are an important category of pediatric pharmaceuticals. In view of the significant postnatal maturation of the CNS, juvenile animal studies (JAS) are performed to support pediatric development of these new medicines. In this project, the design and results of juvenile toxicity studies from 15 drug compounds for the treatment of neurologic or psychiatric conditions were analyzed. Studies were conducted mostly in rats; sometimes in addition in dogs and monkeys. The study design of the pivotal JAS was variable, even for compounds with a similar therapeutic indication. Age of the juvenile animals was not consistently related to the starting age of the intended patient population. Of 15 compounds analyzed, 6 JAS detected more severe toxicities and 6 JAS evidenced novel CNS effects compared to their adult counterparts. The effects of CNS on acoustic startle and learning and memory were observed at high dosages. Reversibility was tested in most cases and revealed some small effects that were retained or only uncovered after termination of treatment. The interpretation of the relevance of these findings was often hampered by the lack of matching end points in the adult studies or inappropriate study designs. Detailed clinical observation and motor activity measures were the most powerful end points to detect juvenile CNS effects. The need for more detailed behavioral examinations in JAS, for example, on learning and memory, should, therefore, be decided upon on a case-by-case basis, based on specific concerns in order to avoid overloading the studies.