Niall Shanks and I, in our book Animal Models in Light of Evolution discuss, among other things, evolution, genetics, complex systems, and empirical evidence. We conclude that animal models cannot predict human response to drugs and disease. Needless to say, if you are reader of this blog, our position has come under fire from people whose livelihoods depend upon animal models. There are two reasons for this.
Number 1, if you use animals as predictive models for drug and disease response our position directly challenges you to prove us wrong. (Actually, our position challenges the person claiming that animal models are predictive to prove the claim, as that is where the burden of proof in science lies.)
Number 2, basic researchers that use animals also rely on the claim that animals can predict human response to drugs and disease. They will dance around this fact but if you can pin them down, the claim will quickly come to the forefront.
Nevertheless, every month more empirical evidence reveals that our position is correct and more scientists acknowledge that animal models of X or Y are not predictive. For example, an editorial in Nature Reviews Drug Discovery:
The search for disease-modifying drugs for Alzheimer's disease has been beset with expensive setbacks, such as the recent failure of a Phase III trial of dimebon, a compound for which Pfizer paid Medivation a US$225 million upfront fee for global marketing rights in 2008. This field is challenging to work in for several reasons, which include poorly predictive animal models of Alzheimer's disease and a lack of qualified biomarkers that can predict disease progression and drug response in clinical trials . . . (Editorial 2010)
In the same issue of Nature Reviews Drug Discovery, Hampel et al.:
There is a growing need for biomarkers of Alzheimer's disease pathology to improve drug development related to the disorder. Animal models of Alzheimer's disease have low predictive power for determining the efficacy of treatments in patients with sporadic Alzheimer's disease (Blennow, de Leon, and Zetterberg 2006). (Hampel et al. 2010)
Alzheimer’s is not unique.
Two reviews addressed those drug cases where the clinical toxicity was so severe as to lead to withdrawal from marketing in the approximate period 1960-1990. In one, 4 of 24 cases correlated with animal data and in the other report, only 6 of 114 clinical toxicities had animal correlates. (Heywood 1990) (Spriet-Pourra, Auriche, and (Eds) 1994)
Fletcher reported on drug safety tests and subsequent clinical experience with 45 major new drugs. Some effects were seen only in animals, while others were observed only in man. The survey established that 25% of toxic effects observed in animals might be expected to occur as adverse reactions in man. (Fletcher 1978)
In one small series in which the toxicity in clinical trials led to the termination of drug development, it was found that in 16/24 (67%) cases the toxicity was not predicted in animals. (Lumley 1990)
Lindl et al. 2005:
According to the German Animal Welfare Act, scientists in Germany must provide an ethical and scientific justification for their application to the licensing authority prior to undertaking an animal experiment. Such justifications commonly include lack of knowledge on the development of human diseases or the need for better or new therapies for humans. The present literature research is based on applications to perform animal experiments from biomedical study groups of three universities in Bavaria (Germany) between 1991 and 1993. These applications were classified as successful in the animal model in the respective publications. We investigated the frequency of citations, the course of citations, and in which type of research the primary publications were cited: subsequent animal-based studies, in vitro studies, review articles or clinical studies. The criterion we applied was whether the scientists succeeded in reaching the goal they postulated in their applications, i.e. to contribute to new therapies or to gain results with direct clinical impact. The outcome was unambiguous: even though 97 clinically orientated publications containing citations of the above-mentioned publications were found (8% of all citations), only 4 publications evidenced a direct correlation between the results from animal experiments and observations in humans (0.3%). However, even in these 4 cases the hypotheses that had been verified successfully in the animal experiment failed in every respect. The implications of our findings may lead to demands concerning improvement of the licensing practice in Germany. (Lindl, Voelkel, and Kolar 2005)
Blennow, K., M. J. de Leon, and H. Zetterberg. 2006. Alzheimer's disease. Lancet 368 (9533):387-403.
Editorial. 2010. Learning from failure. Nat Rev Drug Discov 9 (7):499-499.
Fletcher, A. P. 1978. Drug safety tests and subsequent clinical experience. J R Soc Med 71 (9):693-6.
Hampel, Harald, Richard Frank, Karl Broich, Stefan J. Teipel, Russell G. Katz, John Hardy, Karl Herholz, Arun L. W. Bokde, Frank Jessen, Yvonne C. Hoessler, Wendy R. Sanhai, Henrik Zetterberg, Janet Woodcock, and Kaj Blennow. 2010. Biomarkers for Alzheimer's disease: academic, industry and regulatory perspectives. Nat Rev Drug Discov 9 (7):560-574.
Heywood, R. 1990. Clinical Toxicity--Could it have been predicted? Post-marketing experience. In Animal Toxicity Studies: Their Relevance for Man, edited by CE Lumley and S. Walker. Lancaster: Quay.
Lindl, T., M. Voelkel, and R. Kolar. 2005. [Animal experiments in biomedical research. An evaluation of the clinical relevance of approved animal experimental projects]. ALTEX 22 (3):143-51.
Lumley, C. 1990. Clinical toxicity: could it have been predicted? Premarketing experience. In Animal Toxicity Studies: Their Relevance for Man, edited by C. Lumley and S. Walker: Quay.
Spriet-Pourra, C, M Auriche, and (Eds). 1994. SCRIP Reports: PJB.