Comparative organ system development: An update.

Abstract

In 1998, the Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER) developed regulations requiring the assessment of pharmaceuticals for use in pediatric populations (U.S. Food and Drug Administration [FDA], 1998). In 2003, the Pediatric Research Equity Act (PREA) was enacted to amend the Federal Food, Drug, and Cosmetic Act to authorize the FDA to require certain research into drugs used in pediatric patients (Pediatric Research Equity Act of 2003). PREA was reauthorized under FDAAA (Food and Drug Administration Amendments Act, 2007) when the Pediatric Review Committee (PeRC) was established and made permanent under FDASIA (Food and Drug Administration Safety and Innovation Act, 2012). The result is that, in the United States, pharmaceutical development for pediatric use requires a pediatric study plan (PSP) to be submitted to the agency and for pediatric clinical trials to be conducted before submission of a New Drug Application (NDA). A similar process exists in Europe following issuance of the Paediatric Regulation (Pediatric Regulation, Regulation (EC) No 1901/2006) requiring that a Paediatric Investigation Plan (PIP) be submitted to the European Medicines Agency (EMA) before the conduct of pediatric clinical trials and before submission of a Marketing Authorization Application (MAA). Regulatory guidance regarding the need and conduct of nonclinical studies in juvenile animals is currently provided by the FDA Guidance for Industry, Nonclinical Safety Evaluation of Pediatric Drug Products (CDER, 2006), the EMEA Guideline On The Need For Non-Clinical Testing In Juvenile Animals On Human Pharmaceuticals For Pediatric Indications (EMEA/CHMP/SWP/169215/2005), and the Japanese Guideline on the Nonclinical Safety Study in Juvenile animals for Pediatric Drugs (Japan, 2012). Work is currently ongoing to harmonize these guidelines under the auspices of the International Conference on Harmonization (ICH S11). Any need for nonclinical testing in juvenile animals should be made based on the intended pediatric clinical plan and the weight-of-evidence of all available data, including animal data and human safety data. Critical to the design of juvenile animal studies is the selection of species and age relative to the age of the human pediatric population and the target organs of concern. A strong understanding of comparative organ system development between humans and laboratory animals is essential. Current nonclinical regulatory guidance focuses on “late developing organ systems” such as the central nervous system, skeletal growth, immune, reproductive, pulmonary, renal, gastrointestinal, and hepatobiliary systems. However, with the emergence of rare disease targets that impact children from birth (including those considered “premature”) there has been an increased focus in recent years on pediatric-only indications and treatment of children under the age of 2 years where all organ systems are undergoing structural and/or functional development and where juvenile animal studies may provide the primary nonclinical support. The following series of papers on development of the lung and kidney, gastrointestinal, and reproductive systems provide updates to the corresponding International Life Sciences Institute–Health and Environmental Sciences Institute publications in 2003 (Beckman and Feuston, 2003; Hew and Keller, 2003; Marty, Chapin, Parks, & Thorsrud 2003; Zoetis & Hurtt, 2003a, 2003b) and 2005 (Walthall, Cappon, Hurtt, & Zoetis, 2005). In addition, two new reviews are included addressing development of the ear and eye. Each review provides a tabulated summary of development comparing human with common laboratory animals. Jim Ridings GlaxoSmithKline, Ware, United Kingdom