Are you developing an investigational advanced therapy medicinal product (ATMPs)? Selecting appropriate non-clinical models is critical to generate translational, regulatory-acceptable evidence. Key considerations include:
- The most pharmacologically relevant models available (in vitro, in vivo, in silico) should be used, integrating the 3Rs (replacement, reduction, refinement) principles. Advanced systems like 3D cultures, organoids, and microfluidic organs-on-chips can be valuable for elucidating mechanism of action and may reduce animal studies.
- Models that closely mimic the patient’s disease (age, stage, pathology) should be chosen. Proof-of-concept models may be spontaneous or induced disease models, transgenic/knock-in strains, humanized animals or homologous systems; however, the chosen model should reproduce the target pathology relevant to the intended clinical population. For safety assessment, use of disease models may be warranted when healthy-animal studies do not capture clinically relevant risks.
- When necessary, small animals (e.g., rodents) should be used as a starting point, however, anatomical or procedural limitations (delivery route, device compatibility, surgical technique) can necessitate large-animal models. Whenever possible, use the same species for both biodistribution and toxicity studies to correlate exposure with safety signals.
- If human-derived products trigger rejection or rapid elimination in animals, immunodeficient hosts or homologous models (species-matched cells/vectors or orthologous genes) should be used. Moreover, the surrogate/species-matched homologous test article should closely resemble the human clinical product, and any manufacturing differences should be justified in terms of their impact on data relevance.
- All model choices should be justified by scientific rationale and regulatory alignment. Complex ATMPs may require multiple complementary models: if one model or species cannot address all relevant critical questions, additional species or systems should be employed and scientifically justified.
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