Animal models of human disease: challenges in enabling translation

Biochem Pharmacol. 2014 Jan 1;87(1):162-71. doi: 10.1016/j.bcp.2013.08.006. Epub 2013 Aug 14.


Animal models have historically played a critical role in the exploration and characterization of disease pathophysiology, target identification, and in the in vivo evaluation of novel therapeutic agents and treatments. In the wake of numerous clinical trial failures of new chemical entities (NCEs) with promising preclinical profiles, animal models in all therapeutic areas have been increasingly criticized for their limited ability to predict NCE efficacy, safety and toxicity in humans. The present review discusses some of the challenges associated with the evaluation and predictive validation of animal models, as well as methodological flaws in both preclinical and clinical study designs that may contribute to the current translational failure rate. The testing of disease hypotheses and NCEs in multiple disease models necessitates evaluation of pharmacokinetic/pharmacodynamic (PK/PD) relationships and the earlier development of validated disease-associated biomarkers to assess target engagement and NCE efficacy. Additionally, the transparent integration of efficacy and safety data derived from animal models into the hierarchical data sets generated preclinically is essential in order to derive a level of predictive utility consistent with the degree of validation and inherent limitations of current animal models. The predictive value of an animal model is thus only as useful as the context in which it is interpreted. Finally, rather than dismissing animal models as not very useful in the drug discovery process, additional resources, like those successfully used in the preclinical PK assessment used for the selection of lead NCEs, must be focused on improving existing and developing new animal models.

Keywords: Animal models; Hierarchical data integration; Transgenic; Translational models; Validation.

Publication types

  • Review

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Disease Models, Animal*
  • Drug Discovery / methods
  • Drug Discovery / trends*
  • Humans
  • Translational Medical Research / methods*
  • Translational Medical Research / trends*