Chapter 11 - Juvenile Toxicity Testing to Support Clinical Trials in Pediatric Population

Abstract

There are profound anatomical, physiological, and developmental differences between immature and mature systems leading to differences in the metabolism, renal clearance, drug–drug interactions, and overall response to medications. US FDA and European (EMA) regulations have significantly changed the pediatric drug development process. Pharmaceutical companies are now encouraged to start considering their pediatric assessments and appropriate study plan early in development. The increased interest and/or need to perform pediatric clinical trials for marketing and safe use of a wider range of drugs in children have raised the necessity for juvenile animal studies. Guidance documents have been issued for the nonclinical safety testing of juvenile animals in the United States, Europe, and Japan. The juvenile toxicity study design is approached case-by-case based on scientific rationale and should mimic the pediatric clinical trial. Critical points relevant to juvenile animal studies include the need to design studies focused on addressing specific questions pertinent to children, rather than adapting standard toxicology designs to juvenile studies. Activities aimed at harmonizing these guidelines and conforming to the current state of science have already started. ICH S11 on nonclinical safety studies to support a pediatric development program is expected to be completed in 2016 and implemented in 2018. This chapters covers regulatory aspects of pediatric development, nonclinical safety guidelines, study design considerations, technical and logistical limitations of conducting neonatal/juvenile toxicity studies as well as the use of juvenile animal data in risk assessments.