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Eur J Pharmacol. 2019 Sep 15;859:172524. doi: 10.1016/j.ejphar.2019.172524. Epub 2019 Jul 7.

Are some animal models more equal than others? A case study on the translational value of animal models of efficacy for Alzheimer's disease.

Author information

1
Utrecht Institute of Pharmaceutical Sciences, Department of Pharmaceutics, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, the Netherlands. Electronic address: d.h.veening-griffioen@uu.nl.
2
Utrecht Institute of Pharmaceutical Sciences, Department of Pharmaceutics, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, the Netherlands.
3
Utrecht Institute of Pharmaceutical Sciences, Department of Pharmaceutics, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, the Netherlands; Medicines Evaluation Board, Graadt van Roggenweg 500, 3531 AH, Utrecht, the Netherlands.
4
Copernicus Institute of Sustainable Development, Innovation Studies, Utrecht University, Princetonlaan 8a, 3584 CB, Utrecht, the Netherlands.
5
Medicines Evaluation Board, Graadt van Roggenweg 500, 3531 AH, Utrecht, the Netherlands.

Abstract

Clinical trial failures (>99%) in Alzheimer's disease are in stark contrast to positive efficacy data in animals. We evaluated the correlation between animal and clinical efficacy outcomes (cognition) in Alzheimer's disease using data from registered drugs as well as interventions tested in phase II or III clinical trials for Alzheimer's disease. We identified 20 interventions, which were tested in 208 animal studies in 63 different animal models. Clinical outcome was correlated with animal results in 58% of cases. But, individual animal models showed divergent results across interventions, individual interventions showed divergent results across animal models, and animal model outcomes were determined with 16 different methods. This result is unsurprising due to poor external validity (what do we model) of the animal models. Although the animal models all share Alzheimer's disease symptoms, none represents the whole syndrome. Investigators did not motivate why one model was chosen over another, and did not consider the ways the disease phenomena were generated (spontaneous, (experimentally) induced or by genetic modification), or the species characteristics, which determine the outcomes. The explanation for the lack of correlation between animal and human outcomes can be manifold: the pathogenesis of Alzheimer's disease is not reflected in the animal model or the outcomes are not comparable. Our conclusion is that currently no animal models exist which are predictive for the efficacy of interventions for Alzheimer's disease.

KEYWORDS:

Alzheimer's disease; Animal model; Drug development; Efficacy model; External validity; Translational research

PMID:
31291566
DOI:
10.1016/j.ejphar.2019.172524
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