Points to Consider in Designing and Conducting Juvenile Toxicology Studies

Abstract

In support of a clinical trial in the pediatric population, available nonclinical and clinical data provide input on the study design and safety monitoring considerations. When the existing data are lacking to support the safety of the planned pediatric clinical trial, a juvenile animal toxicity study is likely required. Usually a single relevant species, preferably a rodent, is chosen as the species of choice, while a nonrodent species can be appropriate when scientifically justified. Juvenile toxicology studies, in general, are complicated both conceptually and logistically. Development in young animals is a continuous process with different organs maturing at different rates and time. Structural and functional maturational differences have been shown to affect drug safety. Key points to consider in conducting a juvenile toxicology study include a comparative development of the organ systems, differences in the pharmacokinetics/absorption, distribution, metabolism, excretion (PK/ADME) profiles of the drug between young animal and child, and logistical requirement in the juvenile study design. The purpose of this publication is to note pertinent points to consider when designing and conducting juvenile toxicology studies and to aid in future modifications and enhancements of these studies to enable a superior predictability of safety of medicines in the pediatric population.

CDER Experience With Juvenile Animal Studies for CNS Drugs

“…Recommendations for nonclinical testing strategies that employ a JAS in order to better assess the potential for drug toxicity in pediatric patients have been the subject of numerous literature articles as well as regulatory guidance documents. [5][6][7][8][9] A new ICH (S11) guideline intended to provide guidance on the nonclinical safety studies needed to support a pediatric drug development program is currently in the draft stage. 10 The United States Food and Drug Administration (FDA)/ Center for Drug Evaluation and Research (CDER) guidance on nonclinical studies performed to detect potential adverse effects of drug use in pediatric populations describes a caseby-case approach that relies upon selection of an appropriate, scientifically justified study design.…”

“…Recommendations for nonclinical testing strategies that employ a JAS in order to better assess the potential for drug toxicity in pediatric patients have been the subject of numerous literature articles as well as regulatory guidance documents. 5 -9 A new ICH (S11) guideline intended to provide guidance on the nonclinical safety studies needed to support a pediatric drug development program is currently in the draft stage. 10…”

Nimodipine treatment does not benefit juvenile ferrets with kaolin-induced hydrocephalus

“…DMSO is generally considered to be safe [ 16 ]. However, chronic ocular toxicity is greater in dogs than in rats [ 17 ] and it is likely that metabolism of DMSO differs between very young ferrets and adults [ 18 ].…”

Challenges and New Frontiers in the Paediatric Drug Discovery and Development

“…As also underlined by Anderson et al, it is important to conduct the preclinical experiments in the most appropriate species at the most relevant age on the basis of comparability of the specific organ system development in question [47]. And many issues have to be considered in juvenile toxicology studies: difficulties in the dose administration due to the small size of the animals, in blood and tissue sample collection, and in distinguishing direct versus latent effects [48].…”