CDER Experience With Juvenile Animal Studies for CNS Drugs

Abstract

A survey was undertaken to evaluate juvenile animal studies conducted for drug applications reviewed by the Center for Drug Evaluation and Research between 2009 and 2014. Some conclusions about the nonclinical pediatric safety assessment based on studies performed in support of central nervous system–active compounds are presented here. A total of 44 completed studies from 32 New Drug Applications submitted to the Divisions of Psychiatry and Neurology Products were evaluated. Data on animal species and age range used, endpoints evaluated, and outcomes included in labeling were analyzed. Of the drugs evaluated, all but one had studies conducted in rats. In some cases, a second study in a nonrodent species (dog) was also conducted. Indices of growth and development and standard general toxicity parameters were included in all of the studies. Expanded neurohistopathology evaluations, bone mineral density measurements, and reproductive and neurobehavioral functional assessments were also generally carried out. A variety of neurological and neurobehavioral tests were employed. In the majority of rat studies, the potential for long-term cognitive impairment was evaluated using a complex water maze. Juvenile animal studies provided safety information considered relevant to drug use in children and that was included in labeling for 78% of the applications surveyed. The most commonly reported findings in labeling were for neurobehavioral effects, including changes in locomotor activity, auditory startle habituation, and learning and memory. Of the studies described in labeling with neurobehavioral effects, 54% found these effects to be persistent and to provide evidence of developmental neurotoxicity.

Evaluation of Juvenile Animal Studies for Pediatric CNS-Targeted Compounds: A Regulatory Perspective

“…The incidence of positive findings in our project is also roughly consistent with recently published data from a similar research project conducted by the FDA Divisions on Psychiatry and Neurology Drugs, 25 particularly the low incidence of positive findings for the FOB. Effects were observed during off-treatment for 5 of 14 drugs, that is, in 36% of the studies, compared to the 54% reported by FDA Divisions just mentioned.…”

Translating Neurobehavioral Toxicity Across Species From Zebrafish to Rats to Humans: Implications for Risk Assessment

“…In part this is why neurotoxicity assessments often rely on behavioral evidence along with neuropathological and/or neurochemical evidence (Bolon et al, 2011). Another reason behavioral assessment is used is because it represents the integrated output of the brain and is often a sensitive index of whether a significant effect on brain function has occurred (Piersma et al, 2012;Foster, 2014;Fisher et al, 2019). These factors, together with the fact that most of the human data are behavioral has led to behavior being a major component of developmental neurotoxicity testing (DNT) assessments.…”

Neuropathology Evaluation in Juvenile Toxicity Studies in Rodents: Comparison of Developmental Neurotoxicity Studies for Chemicals With Juvenile Animal Studies for Pediatric Pharmaceuticals

“…A juvenile toxicity study is likely warranted if damage is anticipated in one or many developing organs, 9,10,30 of which the nervous system is a principal target. 31 The CNS (and particularly the brain) of developing animals and humans is known to be targeted by certain small molecule classes including ethanol, 32,33 anesthetics (eg, isoflurane, ketamine, and other N-methyl-D-aspartate receptor antagonists), 11,34 antiepileptics (eg, phenytoin, sodium valproate, vigabatrin), 11,[35][36][37] antineoplastic chemotherapies, 38,39 retinoids, 36 and stimulants (eg, caffeine, methamphetamine) 36,40 as well as many environmental contaminants (chemicals and metals) [41][42][43] and various endogenous metabolites. 33 Neurodevelopmental effects of such agents depend on the developmental age of exposure.…”

“…Given that developmental processes associated with the immature CNS differentially affect the pharmacokinetics and pharmacodynamics of xenobiotics, [72][73][74][75] the neurotoxic potential of a pharmaceutical candidate is a major consideration in making such weight-of-evidence decisions. 5,31 Guidance for pharmaceutical development by regulatory agencies (eg, the US Food and Drug Administration [FDA] 8 ) or global consortia to standardize safety assessment methods for new medical products (eg, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals Image of a Multibrain preparation showing multiple young adult rat brains coembedded and simultaneously sectioned to produce highly homologous coronal brain sections to permit morphometric measurements on the hippocampus or on other neuroanatomic structures at this level of the brain. This anatomic orientation conforms to current STP "best practice" recommendations for the quantitative analysis portion of conventional developmental neurotoxicity studies (DNTS) in rats.…”

“…9,24 In most cases, JAS are performed in rats, although occasionally a second study in a nonrodent species (dog or rarely nonhuman primate) may be performed. 5,31 The preference for rats is founded in well-recognized methods for assessing and integrating anatomic and neurobehavioral data in this species as well as the robust historical control data for such endpoints in this species. 9,10 In a typical JAS in rats, test article exposure begins after birth by direct treatment of the offspring.…”