Schmitt, Georg, Ridings, James, De Schaepdrijver, Luc, van Dosesum-Wolters, Ciska, Cappon, G and Hartmann, Andreas (2016) Non-clinical safety considerations for development of medicines targeted primarily at pediatric use: An industry view. Regulatory Toxicology .

Abstract

This paper provides considerations on approaches to the development of medicines targeted primarily for pediatric use. Drugs initially developed for pediatric use, i.e. ‘pediatric-first’ or ‘pediatric-only’ drugs, indicate pediatric drugs with no adult indication and may use first-in-human studies in adult or pediatric populations. These terms should not be confused with the definition ‘first-in-pediatrics’, i.e. when a drug is given first time to a pediatric population, irrespective of whether the drug has an adult indication in addition to a pediatric indication.
The most common development approach to pediatric-first drugs involves a first in human (FIH) clinical trial with healthy adult volunteers to assess safety and tolerability in accordance with relevant regulatory guidelines (add ref). This approach generally requires traditional non-clinical repeat-dose studies in adult rodent and non-rodent species (reference to ICH M3(R2) ?). Safety pharmacology and genetic toxicology studies in adult animals are also performed for small molecule drugs. Additional studies in juvenile (i.e. immature) animals may be required prior to clinical trials in pediatric patients, on a case-by-case basis guided by knowledge of the pharmacological target, existing data in adult animals and humans, and risk-benefit considerations. In this paradigm the starting dose for pediatric patients is primarily driven by modeling from the adult PK assessment and pharmacology data.
A second development approach is where the FIH clinical trial is conducted in pediatric patients (e.g. when involving healthy adult volunteers would be ethically unacceptable), with the option of a deferral for the younger age categories. This approach is generally supported by repeat-dose studies in juvenile rodent and non-rodent species, with the onset of dosing at ages that developmentally correlate to the age of the pediatric patients. The safety pharmacology and in vivo genetic toxicology studies are still, however, generally performed in adult animals for small molecule drugs. To define a safe yet minimally efficacious starting dose for pediatric patients, various complementing approaches can be used, including human equivalent dose, minimal anticipated biological effect level, and physiologically based pharmacokinetic modeling.
Similar considerations apply to the development of biopharmaceuticals, with the caveat that often non-human primates are the only relevant species, in which case safety pharmacology endpoints are often included in the repeat-dose studies and genetic toxicology are usually not required.
Because the non-clinical development strategy is driven by the clinical requirements, timely interactions with regulatory authorities are recommended to address key clinical questions early on, such as age groups, dosing regimen, and currently available therapies. Case examples for pediatric-first drug candidates show how both drug development approaches, i.e. entry into human first in adults or directly in pediatric populations are used in the pharmaceutical industry.

Item Type:	Article
Date Deposited:	26 Apr 2016 23:45
Last Modified:	26 Apr 2016 23:45
URI:	https://oak.novartis.com/id/eprint/27725