In May, I travelled to Brussels to testify before the European Commission (EC) regarding a European Citizen’s Initiative (ECI). The ECI asked the EC “to abrogate Directive 2010/63/EU1 on the protection of animals used for scientific purposes and put forward a new proposal aimed at phasing out the practice of animal experimentation, making compulsory the use - in biomedical and toxicological research - of data directly relevant for the human species.”

The EC made public its decision regarding the Initiative earlier this week and in essence they rejected it outright. This was anticipated. What I found interesting was why they rejected it. Note that the ECI was about science not animal welfare, but from reading the decision it immediately became clear that from the perspective of the EC, this was only about animal welfare. This is called dodging the question and is very disingenuous, albeit common, in government, as politicians want to keep the status quo as it favors their donors and potential employers.

When the EC did address the science they used the usual tropes against abandoning animal modeling. In their Communication from the Commission on the European Citizens' Initiative "Stop Vivisection" the EC states:

Animal studies have historically been key to developing ways to prevent and reduce human and animal diseases. They have contributed to improved health and quality of life as well as longer life expectancy. Today, there are effective treatments for many infectious diseases, some forms of cancer, and several chronic diseases such as diabetes. These advancements would have been impossible without the insights gained in animal studies. Such studies are required by legislation to authorise human clinical trials, and to protect health and the environment. The same holds true for the prediction of medicine efficacy. In such cases, after generating as much information as possible from alternative methods, animal studies are used to fill the knowledge gaps to safeguard human, animal and environmental health. Furthermore, animal studies have provided invaluable insight into basic biological processes that underpin health and disease of humans and animals. Animal models11 have also been used for their predictive value for pharmacology and toxicology12.

Reference 12 is to the entire July 15 issue of European Journal of Pharmacology, which was devoted to translational research and the predictive value of animal models. The issue begins with an editorial from Groenink, Folkerts, and Schuurman.

The predictive value of animal models for a given clinical condition is getting increasing attention.

I wonder why? 

Models in both large and small animal species have value for pharmacology and toxicology, including the first evaluation of adverse side effects and pharmacological efficacy of innovative disease intervention strategies, as well as the selection in a given therapeutic discovery program. Also, such models are helpful in elucidating pathways in physiological or pathological processes.[1]

They continue: 

Evidently, preclinical animal studies are performed with the understanding that animal modeling is required or indicated to enhance the knowledge database about clinical (disease) conditions, and to facilitate the clinical implementation of new medical entities. Obviously, for this purpose it is of extreme importance to know whether a given animal model has predictive value for the situation in men. Such insights prevent any unnecessary use of animals and prompt innovations in modeling to improve their translational value.

The entire issue is about the predictive value of animal models. I skimmed it and it appeared most of the articles simultaneously say animal models have good predictive value except for when they don’t. This too is pretty much standard for such articles and the issue as a whole confirms something I have said for years. But before I get to that, lets examine the paragraph from the EC decision quoted above.

Animal studies have historically been key to developing ways to prevent and reduce human and animal diseases.

One would expect studies on animals to yield information about diseases and drugs in the species being studied so that part of the sentence is a tautology. Likewise if one wants to understand a disease that is transmitted from animals to humans then learning about the pathogen in the animal could be informative (for example, malaria and the mosquito). But to say the same about animal studies of human diseases and drugs is not self-evident, contradicts current science, and the EC offer no evidence to support their claims. This is standard for the animal modeling industry. The document continues:

They have contributed to improved health and quality of life as well as longer life expectancy. Today, there are effective treatments for many infectious diseases, some forms of cancer, and several chronic diseases such as diabetes. These advancements would have been impossible without the insights gained in animal studies.

Again, these are claims not supported by evidence.

Such studies are required by legislation to authorise human clinical trials, and to protect health and the environment.

That part is important because it directly states animal models have predictive value and, as I have shown many times, they don’t. This myth however, is why society believes animal-based research, or animal experimentation, or vivisection is a necessary evil.

The same holds true for the prediction of medicine efficacy. In such cases, after generating as much information as possible from alternative methods, animal studies are used to fill the knowledge gaps to safeguard human, animal and environmental health.

Animal models have no predictive value for efficacy or safety in humans. The pharmaceutical industry acknowledges this as do most scientists that address the issue.[2-41]

Furthermore, animal studies have provided invaluable insight into basic biological processes that underpin health and disease of humans and animals.

No, they haven’t. That’s why drugs fail when the target was identified in animals. At the level of disease and drug action, animal models have failed miserably and they certainly have no predictive value. At the level of gross morphology, yes they did a great job in the 1800s of informing us of what functions various organs perform.

Animal models11 have also been used for their predictive value for pharmacology and toxicology12.

Yes, they have but they have failed miserably in performing this function. See above references or about anything I have published in the peer-reviewed literature in the past 7 years.

The EC also used financial arguments that were about as viable as the scientific arguments.

However, a premature ban of research using animals in the EU would likely export the biomedical research and testing outside the EU to countries where welfare standards may be lower and more animals may be needed to achieve the same scientific result. 

First, if the EU banned vivisection on scientific grounds most nations would follow as they would be forced to accept that animal modeling is not financially viable and hence would not want to continue to fund it. Second, most countries fund most of the animal-based research that is performed in that particular country. So the taxpayers and charity-donors are the ones that fund most animal-based research. If they stopped funding it, that research would not go elsewhere. Third, even if the research did go elsewhere the taxpayers of the EU would still be in for a net gain as the research and testing methods that would replace animal modeling would give a much greater return on the investment.

Finally, there is animal-based research that is performed in country and is paid for by the pharmaceutical industry. That’s the research and testing that has been analyzed the most and shown to have no predictive value. Stoping that research and testing would cost a very few people their jobs but it would also open up a greater number of new jobs that actually advanced medical care. Last time I checked, no one thought industry should provide a welfare program for people whose jobs are now obsolete. I don’t think that Toyota sends checks every month to blacksmiths who were forced into retirement when the automobile was invented. Furthermore, the jobs we are discussing here are the ones that are supposed to protect the health of people. Animal modeling harms patients. It should be abandoned for that reason alone.

The document continues: “The regulatory framework for inter alia health products (pharmaceuticals), chemicals (including pesticides, biocides), and food and feed requires testing of products prior to marketing them to prove that they are safe for humans, animals or the environment.” Again, this is a straightforward claim that animal models have predictive value and is demonstrably false. Of course, being false does not mean such statements will not be taken at face value by politicians. That is what happened in Brussels: the EC was untouched by education but heavily swayed by the vested interest groups that gain from the status quo. Animal modeling is not going to end by appealing to those that profit from it nor by appealing to those who are controlled by those who profit from it.

But what the EC states indirectly, and what this issue of European Journal of Pharmacology confirms directly and what I have been accusing the animal model industry of claiming, is that is that all animal-based research and testing, in the form of both basic and applied research, has predictive value. Moreover, this is how they have been selling their product for decades. What happens in a monkey or mouse, regardless of what type of research it was, should be expected to happen in a human. I have been honest in my criticisms of vivisection and attacked applied research for lacking predictive value [29, 42] but confined my criticism of basic research to the cost:benefit ratio and I have not criticized it for lacking predictive value (unless someone specifically claimed it did). By definition basic research should not have predictive value (see[43, 44]). But with the formal endorsement of this claim, I can now attack the predictive value of basic research.

This is not the first time the animal model community has claimed predictive value for animal models used in basic research. On March 25, 2011, the following from Andrew B. Rudczynski, Yale University’s associate vice president for research administration, was published in the New Haven Register: “Contrary to claims in a letter to the editor, the basic research model used by Yale University and its peer institutions is scientifically valid and predictive of human diseas

Freeman and St Johnston write:

Many scientists who work on model organisms, including both of us, have been known to contrive a connection to human disease to boost a grant or paper. It’s fair: after all, the parallels are genuine, but the connection is often rather indirect. DMM is about something quite different. This new journal is aimed at people who set out with an explicit goal to investigate human disease using model organisms.[45]

Such claims are also common in grant applications [42] and other articles [46-51].

By including all animal animal-based research and testing in the predictive value category, the animal modelers have shot themselves in the head. This argument is ludicrous from a scientific perspective. Good from a PR perspective for now, but eventually this nonsense will catch up with them. The research that has attempted to quantify the predictive value or translational rate of basic research reveals that it translates to something of value to humans about 0.004% of the time.[52, 53] And this study only examined top tier journals. If one included all journals the translation rate would be much lower and positive predictive value would probably be around 1 in a million or lower. If one analyzed only basic research that used animals, I think the value would be about the same as, based on the figures available, most basic biomedical research uses animals. Regardless of the exact figures, the range of possible values for the positive predictive value for basic research that uses animals does not approach any value that could be considered flattering to animal modelers or that could seriously be considered to be scientifically viable.

So, a big THANK YOU to the EC and the European Journal of Pharmacologyfor making my job easier. The ECI went down in defeat but the cost will eventually be more than the animal model community can pay.

References

1.         Groenink, L., G. Folkerts, and H.J. Schuurman, European Journal of Pharmacology, Special issue on translational value of animal models: Introduction. Eur J Pharmacol, 2015. 759: p. 1-2. http://ac.els-cdn.com/S0014299915002678/1-s2.0-S0014299915002678-main.pdf?_tid=fe9087ee-0b1c-11e5-869a-00000aab0f02&acdnat=1433465666_f6ea7752b2ddf3fe8ea79fefc008a5ce

2.         Abate-Shen, C., A new generation of mouse models of cancer for translational research. Clin Cancer Res, 2006. 12(18): p. 5274-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17000659

3.         Abbott, A., Animal testing: more than a cosmetic change. Nature, 2005. 438(7065): p. 144-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16281001

4.         Alini, M., et al., Are animal models useful for studying human disc disorders/degeneration? Eur Spine J, 2008. 17(1): p. 2-19. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17632738

5.         Arrowsmith, J., Trial watch: Phase III and submission failures: 2008-2010. Nat Rev Drug Discov, 2011. 10(2): p. 87-87. http://dx.doi.org/10.1038/nrd3375

6.         Arrowsmith, J., Trial watch: Phase II failures: 2008-2010. Nat Rev Drug Discov, 2011. 10(5): p. 328-329. http://dx.doi.org/10.1038/nrd3439

7.         Björquist, P., et al., Human ES cell derived functional cells as tools in drug discovery. Drug Discovery World, 2007(Winter): p. 17-24.

8.         Calabrese, E.J., Principles of Animal Extrapolation. 1991, Boca Raton: CRC Press.

9.         Collins, F.S., Reengineering Translational Science: The Time Is Right. Science Translational Medicine, 2011. 3(90): p. 90cm17. http://stm.sciencemag.org/content/3/90/90cm17.abstract

10.       Connors, T., Anticancer Drug Development: The Way Forward. Oncologist, 1996. 1(3): p. 180-181. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10387985

11.       Dennis, C., Cancer: off by a whisker. Nature, 2006. 442(7104): p. 739-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16915261

12.       Dixit, R. and U. Boelsterli, Healthy animals and animal models of human disease(s) in safety assessment of human pharmaceuticals, including therapeutic antibodies. Drug Discovery Today, 2007. 12(7-8): p. 336-42.

13.       Duyk, G., Attrition and translation. Science, 2003. 302(5645): p. 603-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14576424

14.       Eason, C.T., F.W. Bonner, and D.V. Parke, The importance of pharmacokinetic and receptor studies in drug safety evaluation. Regul Toxicol Pharmacol, 1990. 11(3): p. 288-307. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=2196638

15.       Editorial, The time is now. Nat Rev Drug Discov, 2005. 4(8): p. 613. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16106580

16.       Editorial, Learning from failure. Nat Rev Drug Discov, 2010. 9(7): p. 499-499. http://dx.doi.org/10.1038/nrd3222

17.       FDA. Innovation or Stagnation? Challenge and Opportunity on the Critical Path to New Medical Products. 2004 2004 [cited 2013 November 25]; Available from: http://www.fda.gov/downloads/ScienceResearch/SpecialTopics/CriticalPathInitiative/CriticalPAthOpportunitiesReports/ucm113411.pdf.

18.       FDA. FDA Issues Advice to Make Earliest Stages Of Clinical Drug Development More Efficient. 2006 June 18, 2009 [cited 2010 March 7]; FDA News Release]. Available from: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2006/ucm108576.htm.

19.       Geerts, H., Of mice and men: bridging the translational disconnect in CNS drug discovery. CNS drugs, 2009. 23(11): p. 915-26. http://www.ncbi.nlm.nih.gov/pubmed/19845413

20.       Kola, I. and J. Landis, Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov, 2004. 3(8): p. 711-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15286737

21.       Lin, J.H., Species similarities and differences in pharmacokinetics. Drug Metab Dispos, 1995. 23(10): p. 1008-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8654187

22.       Littman, B.H. and S.A. Williams, The ultimate model organism: progress in experimental medicine. Nat Rev Drug Discov, 2005. 4(8): p. 631-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16056389

23.       Mahmood, I., Can absolute oral bioavailability in humans be predicted from animals? A comparison of allometry and different indirect methods. Drug Metabol Drug Interact, 2000. 16(2): p. 143-55. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10962646

24.       McGee, P., Breeding Better Animal Models. Drug Discovery & Development, 2006(April): p. 18-23.

25.       O'Collins, V.E., et al., 1,026 experimental treatments in acute stroke. Ann Neurol, 2006. 59(3): p. 467-77. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16453316

26.       PhRMA. 2011 Profile. 2011 2011 [cited 2015 February 22]; Available from: http://report.nih.gov/investigators_and_trainees/acd_bwf/pdf/Phrma_Industry_Profile_2011.pdf.

27.       Rice, J., Animal models: Not close enough. Nature, 2012. 484(7393): p. S9-S9. http://dx.doi.org/10.1038/nature11102

28.       Seok, J., et al., Genomic responses in mouse models poorly mimic human inflammatory diseases. Proceedings of the National Academy of Sciences of the United States of America, 2013. http://www.ncbi.nlm.nih.gov/pubmed/23401516

29.       Shanks, N., R. Greek, and J. Greek, Are animal models predictive for humans? Philos Ethics Humanit Med, 2009. 4(1): p. 2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19146696

30.       Suter, K., What can be learned from case studies? The company approach., in Animal Toxicity Studies: Their Relevance for Man, C. Lumley and S. Walker, Editors. 1990, Quay: Lancaster. p. 71-8.

31.       Young, M., Prediction v Attrition Drug Discovery World, 2008(Fall): p. 9-12.

32.       Zielinska, E., Building a better mouse. The Scientist, 2010. 24(4): p. 34-38.

33.       Ennever, F.K., T.J. Noonan, and H.S. Rosenkranz, The predictivity of animal bioassays and short-term genotoxicity tests for carcinogenicity and non-carcinogenicity to humans. Mutagenesis, 1987. 2(2): p. 73-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=3331705

34.       Fletcher, A.P., Drug safety tests and subsequent clinical experience. J R Soc Med, 1978. 71(9): p. 693-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=712750

35.       Grass, G.M. and P.J. Sinko, Physiologically-based pharmacokinetic simulation modelling. Adv Drug Deliv Rev, 2002. 54(3): p. 433-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11922957

36.       Igarashi, T., S. Nakane, and T. Kitagawa, Predictability of clinical adverse reactions of drugs by general pharmacology studies. J Toxicol Sci, 1995. 20(2): p. 77-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=7473897

37.       Igarashi, T., T. Yabe, and K. Noda, Study design and statistical analysis of toxicokinetics: a report of JPMA investigation of case studies. J Toxicol Sci, 1996. 21(5): p. 497-504. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9035061

38.       Lesko, L.J. and J. Woodcock, Translation of pharmacogenomics and pharmacogenetics: a regulatory perspective. Nat Rev Drug Discov, 2004. 3(9): p. 763-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15340386

39.       Litchfield, J.T., Jr., Symposium on clinical drug evaluation and human pharmacology. XVI. Evaluation of the safety of new drugs by means of tests in animals. Clin Pharmacol Ther, 1962. 3: p. 665-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14465857

40.       Lumley, C., Clinical toxicity: could it have been predicted? Premarketing experience, in Animal Toxicity Studies: Their Relevance for Man, C. Lumley and S. Walker, Editors. 1990, Quay: London. p. 49-56.

41.       van Meer, P.J.K., et al., The ability of animal studies to detect serious post marketing adverse events is limited. Regulatory Toxicology and Pharmacology, 2012. 64(3): p. 345-349. http://www.sciencedirect.com/science/article/pii/S027323001200181X

42.       Shanks, N. and R. Greek, Animal Models in Light of Evolution. 2009, Boca Raton: Brown Walker.

43.       Greek, R. and N. Shanks, FAQs About the Use of Animals in Science: A handbook for the scientifically perplexed. 2009, Lanham: University Press of America.

44.       Greek, R. and J. Greek, Is the use of sentient animals in basic research justifiable? Philos Ethics Humanit Med, 2010. 5: p. 14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20825676

45.       Freeman, M. and D. St Johnston, Wherefore DMM? Disease Models & Mechanisms, 2008. 1(1): p. 6-7. http://dmm.biologists.org/content/1/1/6.short

46.       Mohun, T., et al., Deciphering the Mechanisms of Developmental Disorders (DMDD): a new programme for phenotyping embryonic lethal mice. Disease Models & Mechanisms, 2013. 6(3): p. 562-566. http://dmm.biologists.org/content/6/3/562.abstract

http://dmm.biologists.org/content/6/3/562.full.pdf

47.       't Hart, B.A., et al., The marmoset monkey: a multi-purpose preclinical and translational model of human biology and disease. Drug Discovery Today, 2012. 17(21-22): p. 1160-5. http://www.ncbi.nlm.nih.gov/pubmed/22728226

48.       Fishman, M., Mark Fishman. Interview by Asher Mullard. Nature reviews. Drug discovery, 2012. 11(1): p. 14-5. http://www.ncbi.nlm.nih.gov/pubmed/22212670

49.       Devoy, A., et al., Genomically humanized mice: technologies and promises. Nat Rev Genet, 2012. 13(1): p. 14-20. http://dx.doi.org/10.1038/nrg3116

50.       National Science Foundation. Press release: Of Mice and Men. 2011 September 14 [cited 2011 October 6]; Available from: http://www.nsf.gov/news/news_summ.jsp?cntn_id=121653&org=NSF&from=news.

51.       Fomchenko, E.I. and E.C. Holland, Mouse models of brain tumors and their applications in preclinical trials. Clin Cancer Res, 2006. 12(18): p. 5288-97. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17000661

52.       Contopoulos-Ioannidis, D.G., E. Ntzani, and J.P. Ioannidis, Translation of highly promising basic science research into clinical applications. Am J Med, 2003. 114(6): p. 477-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12731504

53.       Crowley, W.F., Jr., Translation of basic research into useful treatments: how often does it occur? Am J Med, 2003. 114(6): p. 503-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12727585