title: [Strategic considerations on the design and choice of animal models for non-clinical investigations of cell-based medicinal products].
abstract: For the development of medicinal products animal models are still indispensable to demonstrate efficacy and safety prior to first use in humans. Advanced therapy medicinal products (ATMP), which include cell-based medicinal products (CBMP), differ in their pharmacology and toxicology compared to conventional pharmaceuticals, and thus, require an adapted regime for non-clinical development. Developers are, therefore, challenged to develop particular individual concepts and to reconcile these with regulatory agencies. Guidelines issued by the European Medicines Agency (EMA), the U.S. Food and Drug Administration (FDA) and other sources can provide direction.The published approaches for non-clinical testing of efficacy document that homologous animal models where the therapeutic effect is investigated in a disease-relevant animal model utilizing cells derived from the same species are commonly used. The challenge is that the selected model should reflect the human disease in all critical features and that the cells should be comparable to the investigated human medicinal product in terms of quality and biological activity. This is not achievable in all cases. In these cases, alternative methods may provide supplemental information. To demonstrate the scientific proof-of-concept (PoC), small animal models such as mice or rats are preferred. During the subsequent product development phase, large animal models (i.e. sheep, minipigs, dogs) must be considered, as they may better reflect the anatomical or physiological situation in humans. In addition to efficacy, those models may also be suitable to prove some safety aspects of ATMP (e.g. regarding dose finding, local tolerance, or undesired interactions and effects of the administered cells in the target tissue). In contrast, for evaluation of the two prominent endpoints for characterizing the safety of ATMP (i.e. biodistribution, tumorigenicity) heterologous small animal models, especially immunodeficient mouse strains, are favourable due to their tolerance to the human cell therapy product. The execution of non-clinical studies under the principles of good laboratory practice (GLP) increases the acceptance of the results by authorities and the scientific community.
authors.affiliation: Fraunhofer-Institut für Zelltherapie und Immunologie (IZI), Perlickstraße 1, 04103, Leipzig, Deutschland. joerg.lehmann@izi.fraunhofer.de.
authors.forename: Jörg
authors.initials: J
authors.lastname: Lehmann
authors.affiliation: Fraunhofer-Institut für Zelltherapie und Immunologie (IZI), Perlickstraße 1, 04103, Leipzig, Deutschland.|Translationszentrum für Regenerative Medizin (TRM), Universität Leipzig, Philipp-Rosenthal-Straße 55, 04103, Leipzig, Deutschland.|Biotechnologisch-Biomedizinisches Zentrum (BBZ), Universität Leipzig, Deutscher Platz 5, 04103, Leipzig, Deutschland.
authors.forename: Ronny M
authors.initials: RM
authors.lastname: Schulz
authors.affiliation: Paul-Ehrlich-Institut, Paul-Ehrlich-Straße 51-59, 63225, Langen, Deutschland. Ralf.Sanzenbacher@pei.de.
authors.forename: Ralf
authors.initials: R
authors.lastname: Sanzenbacher
mesh_terms: D000047:Academies and Institutes; D023401:Animal Use Alternatives / Q000331:legislation & jurisprudence / Q000379:methods; D000818:Animals; D001688:Biological Products / Q000009:adverse effects* / Q000494:pharmacology*; D064987:Cell- and Tissue-Based Therapy / Q000009:adverse effects* / Q000379:methods*; D055808:Drug Discovery / Q000379:methods; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005858:Germany; D006801:Humans; D023421:Models, Animal
chemical_list: D001688:Biological Products
keywords: ATMP; Animal models; CBMP; Non-clinical trials; Somatic cell therapy medicinal products