By: Narasimha Midde, PhD
The regulatory framework set forth by legislation in the US and Europe describe the expectations for evaluation of drug products for the pediatric population. As of August 2017, 703 drug products were updated with new pediatric labeling information at the FDA and this list continues to expand.
The inherent maturational differences between infants, children, adolescent and adults present added considerations for pediatric drug development. Information from adult safety testing, both in humans and animals, may not be sufficient to predict potential toxicities in young patients. Additional animal studies in juvenile animals are often needed to address gaps in data. These data provide information to alert the clinician to age-related and drug-induced postnatal development toxicities in pediatric drug development programs.
The regulatory guidelines suggest that the conduct of juvenile studies should be considered on case-by-case basis For example, drugs intended to treat children at an age when an organ system is undergoing maturation, that have a known target organ toxicity for that system, are candidates for the addition of juvenile animal studies. However, it does not mean that these studies need to be performed routinely to support clinical investigations in pediatric patients. Review of data from the adult animal studies, prior experience in adult human studies and information across a drug class for example, may provide adequate assurance to proceed with the pediatric trials. In such a case, a summary justification and rationale can be provided to support the planned clinical trial. Drugs that are specifically designed for pediatric populations, utilize juvenile animal studies in lieu of repeat-dose adult animal toxicity studies. Planned nonclinical safety studies must be discussed and approved by regulatory agencies. There is no standard template to design and conduct juvenile toxicology studies. In fact, these studies are more complicated than adult reproductive toxicology studies considering the dynamic anatomy and physiology, statistics, and difficulty of measuring direct and/or indirect end points etc. The usual study design considerations are type of species, age of animals at the start of treatment, route of administration, formulation, duration and dosing levels, and sampling strategy for toxicokinetic evaluation. Additionally, neurobehavioral examination, immunotoxicity assessment, specialized growth measurements, reproductive development, and sensory and motor developmental milestones are also needs to be considered.
Juvenile toxicology studies can be a key part of the pediatric drug development program. Early interaction with regulatory agencies to discuss planned studies, clear understanding of available adult safety data, exploiting modeling and simulations for dose selection and to improve study design, and developing focused juvenile study design that include both standard and developmental related endpoints in relation to the pediatric age groups are essential to speed up the approval process.