Juvenile animal toxicity study designs to support pediatric drug development

Abstract

The objective of juvenile animal toxicity studies of pharmaceuticals is to obtain safety data, including information on the potential for adverse effects on postnatal growth and development. Studies in juvenile animals may assist in identifying postnatal developmental toxicities or other adverse effects that are not adequately assessed in the routine toxicity evaluations and that cannot be safely or adequately measured in pediatric clinical trials. Unlike the traditional reproductive and developmental toxicology studies that have been discussed in the accompanying reports, the design requirements for toxicity studies in juvenile animals are not explicitly defined in regulatory guidance. However, studies in juvenile animals can be useful in providing safety information necessary to enable pediatric clinical trials in pediatric patients or when there are special concerns for toxicities that cannot be safely or adequately measured in clinical trials. These juvenile animal toxicity studies are designed on a case-by-case basis. General design considerations and examples of study designs for assessment of juvenile animal toxicity are discussed.

Background Data for Hematological and Blood Chemical Examinations in Juvenile Beagles

“…With the progress in juvenile drug development in recent years, juvenile animal toxicity studies have come to receive much attention as a means of examining the potential for increased juvenile sensitivity to pharmaceuticals and for novel juvenile toxicities that are not detected in adults [2].…”

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

“…Organ systems examined included: central nervous, reproductive, pulmonary, renal, skeletal, cardiovascular, and immune systems (Baldrick, 2004). A series of articles reviewing the current knowledge on comparative postnatal function and physiologic development are discussed (Cappon et al, 2009) observing that in general the rat can be considered the appropriate specie, because most of the major organ systems maturation that occurs postnatally in humans also occurs during the postnatal period in rat. When the rat is not the relevant species mouse, minipig, dog and primate should be considered, comparative age categories are available for rats, minipigs, dogs, non human primates and humans based on CNS and reproductive development (Gad, 2001;Baldrik, 2004;Beck et al, 2006).…”

“…Until the last few years the majority of studies on juvenile animals are essentially the repetition of those conducted in the adult, and performed mainly in the environmental regulatory setting, particularly to investigated neurotoxicity (Atchison et al, 1982;Benke & Murphy, 1975;Brodeur & Dubois, 1963;Cappon et al, 1997;Rice, 1988;Rigdon et al, 1989), or to support investigations certain drug classes used in a paediatric population, e.g., antibiotic, anti-emetic, and anti-asthma drugs (Baldrick, 2004). Since the entry into force of the paediatric European and USA legislations, the interest of the regulators and pharmaceutical industry in non clinical juvenile toxicity studies has taken on characteristics of priority as also documented by recent publications on the subject (Baldrick, 2004;Cappon et al, 2009;Bailey & Mariën, 2009;Silva-Lima et al, 2010). To avoid production of unnecessary repetitive not interpretable data and to realize robust juvenile animal studies when they necessary, represent the main objectives requiring higher consideration than in the past.…”

“…A targeted approach for juvenile animal study design may be used to specifically address identified toxicity concerns, and " primary factors to consider when designing a targeted juvenile animal study are: (1) ensure that the organ system of concern is undergoing similar developmental processes during the postnatal period as in the intended paediatric population; (2) define the age of exposure in the experimental species to ensure that the organ systems of concern are at the same stage of development in the animal species as in the intended human paediatric population; and (3) ensure that the appropriate endpoints are included to enable an in-depth investigation of the organ system of concern" (Cappon et al, 2009) The same authors illustrate two examples, based on real paediatric drug development programs and accepted by regulatory agencies to support those products, of targeted study, one for central nervous system and reproductive development and the other focused on liver and reproductive development. This approach support the chance to use specific case by case study design to perform suitable, interpretable and not repetitive non clinical studies in juvenile animals to support risk assessment for paediatric population.…”

“…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).…”