Real life juvenile toxicity case studies: The good, the bad and the ugly

Juvenile animal studies in the development of pediatric medicines: experience from European medicines and pediatric investigation plans

“…The JAS main objective is to determine whether there are toxicities that might be unique to immature animals, what stage of postnatal development might be more sensitive and whether there are any resulting consequences in the adult, to pediatric administration (De Schaepdrijver et al, 2008). However, toxicity studies in juvenile animals also play a role in defining the risk for pediatric patients especially in cases where the potential toxicity cannot be safely or ethically monitored in patients (Cappon et al, 2009).…”

Juvenile Animal Toxicity Studies: Regulatory Expectations, Decision Strategies and Role in Paediatric Drug Development

“…Alternatively, should they be viewed as general screening studies designed to evaluate all possible outcomes and to avoid missing any unique toxicity? In the first case, they serve as valuable adjunct studies to address specific concerns or fill a data gap whereas, in the second case, they rarely yield meaningful data for the assessment of paediatric safety (Baldrick, 2004;Brent, 2004;Beck et al, 2006;De Schaepdrijver et al, 2008. A scientific strategic approach, taking into account all clinical and nonclinical data and future development plans, is key.…”

Changes in Research and Development of Medicinal Products since the Paediatric Regulation

“…When a pre-and postnatal study is also being used to address a specific aspect of juvenile toxicity, such a study should be extended to include appropriate developmental endpoints: if specific developmental endpoints cannot be assessed within the context of pre-and postnatal studies, additional juvenile animal studies will be required. In the combined pre-and postnatal development toxicity study design (De Schaepdrijver & Bailey, 2009, Cappon et al, 2009) the maternal animal is dosed from implantation through post natal dose day 5. Dosing is then suspended for maternal animals and the offsprings are directly dosed until maturity ( about 9 weeks).…”

“…Dosing is then suspended for maternal animals and the offsprings are directly dosed until maturity ( about 9 weeks). A clear advantage of this study is the reduced number of animals to be used, but it is not always suitable to investigated potentially additional end points related to target organs of concern, and excessive toxicity in the directly dosed pups can be observed (Cappon et., 2009, De Schaepdrijver et al, 2008, De Schaepdrijver & Bailey, 2009). The guideline CHMP/SWP/169215/2005 is not rigid about the timing for performing juvenile animal studies, if these studies are considered necessary, they should preferably be available before the starting of clinical studies in paediatric populations, and pharmacokinetic data from humans and animals (including juvenile animals if available) should also be evaluated before the proposed paediatric clinical trial(s).…”