Pediatric Developmental Drug Toxicity: Description of Juvenile Animal Studies in US FDA Prescribing Information and Assessing the Need for New Approach Methodologies

Abstract Currently juvenile animal studies (JAS) are the standardized way for pediatric preclinical developmental safety assessments. With advancement of new approach methodologies (NAMs) and reduced animal testing that can add to JAS findings, the assessment of the prior outcome of JAS in pediatric drug development is essential. The objectives of this study were to (a) identify, extract, and analyze JAS studies from the prescribing information (PIs) of approved pediatric products, and (b) assess the results which were obtained through those JAS studies in relation to the latest guidance. This study identified 74 approved pediatric drug products with JAS described on the PIs. For JAS, 83.8% included one species with rats being the most common. The weight of evidence approach, outlined in the S11 Nonclinical Safety Testing in Support of Development of Pediatric Pharmaceuticals Guidance, considers two objective criteria that can be easily assessed from PIs: youngest intended pediatric age and the clinical treatment duration. More than half of the products (64.9%) were intended for children and adolescents, and about half of the products (51.4%) were intended for acute or single use. JAS produced a warning added in the pediatric use section of the PIs in only 8.1% (6/74) of approved pediatric products. NAMs are being developed in areas such as secondary targets, developmental genetics, microphysiologic systems, and quantitative systems pharmacology modeling, all of which can compliment JAS for developmental safety assessments. So while JAS can contribute to pediatric preclinical safety assessment, the development of NAMs should be further explored.