Regulatory acceptance of animal models of disease to support clinical trials of medicines and advanced therapy medicinal products

Regulatory Forum Opinion Piece*: Use and Utility of Animal Models of Disease for Nonclinical Safety Assessment: A Pharmaceutical Industry Survey

“…Recommendations for the use of AMDs in nonclinical safety testing have been outlined previously (Morgan et al 2013; Cavagnaro and Silva Lima 2015). Salient features to consider when utilizing an AMD in such investigations include robust characterization of the disease model with subsequent evaluation of a specific hypothesis-driven question and focusing on hazard identification/understanding rather than on establishing a safety margin (although there are circumstances where approximations or rank ordering of safety margins from AMDs can be useful).…”

Preclinical Development of Cell-Based Products: a European Regulatory Science Perspective

“…typically such studies are done in research facilities where the animals, sometimes with specific genetic abnormalities, happen to be, and these are not facilities able to conduct GLP studies. In circumstances where the generation of preclinical safety data in compliance with GLP is not possible, or where there are existing non-GLP data, such that conducting additional testing would not result in further preclinical safety data of relevance to human use of the product, a claim for a waiver of the expectation for GLP compliance may be accepted by regulatory reviewers [ 43 , 44 ]. The reason(s) for lack of GLP compliance need to be explained but where there is a justification presented that available and relevant data are considered reliable, lack of compliance with GLP may be acceptable.…”

Biotherapeutics: Challenges and Opportunities for Predictive Toxicology of Monoclonal Antibodies

“…This includes advances in: in silico predictions [ 25 , 26 , 27 , 28 , 29 , 30 , 31 , 66 ] and different mAb structure and/or functional designs [ 27 , 32 , 33 , 67 ]. In vitro assays are fully functional [ 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 ]; however, the obvious variability that occurs (tissue-to-tissue, assay formats, and accuracy standards) has to be considered, particularly when using an in vitro endpoint in an in vitro/in vivo extrapolation (IVIV) such as in a pharmacokinetic/pharmacodynamic (PK/PD) modeling and analysis. The key components moving forward are the variability in outcome based on patient characteristics, disease status, and concomitant drug therapy.…”

“…Data from studies in Points (C) and (D) would theoretically provide an understanding of expected human immune related pharmacological and potential toxicological effects of a mAb and whether this is likely to be predicted by toxicology species. Several other assays have been developed [ 40 , 41 , 42 , 43 ]; however, as described in several reviews, many of the more serious adverse events observed in humans when administered mAbs are classified as rare events such as cancer, serious infections, and progressive multifocal leukoencephalopathy. Therefore, these serious events are unlikely to be derisked from a mAb by nonclinical in vitro and in vivo studies [ 11 ].…”