In response to the letter from Archibald et al. (Archibald, Coleman, and Foster 2011) (I blogged about this letter here), Balkwill et al. wrote the following:
Animal research and testing is essential for understanding normal and disease processes. In the preclinical development of new treatment candidates, animals are crucial for understanding their pharmacokinetics and pharmacodynamics, and for detecting unforeseen toxic effects. The identification of developmental and carcinogenic hazards is particularly reliant on continued animal testing, since such effects would not become evident in patients for many years. (Balkwill et al. 2011)
Lets compare the above with comments from scientists about pharmacodynamic (PD), pharmacokinetics (PK), toxicity, and cancer.
Editors Nature Reviews Drug Discovery 2011: “Unpredicted drug toxicities remain a leading cause of attrition in clinical trials and are a major complication of drug therapy.” (Editors 2011)
Sarkar, Director, Clinical Imaging, Medicines Development within Oncology R&D at GlaxoSmithKline:
High attrition rates, particularly at the late stage of drug development, is a major challenge faced by the entire pharmaceutical community. The average success rate from first in man to registration for all therapeutic areas combined is 11% (Kola and Landis 2004). For oncology, this is even lower at 5%. Approximately 59% of all oncology compounds that enter in Phase III of development undergo attrition (Kola and Landis 2004). In fact, the estimated cost of bringing a potential drug to the market has increased significantly and at the current cost growth rate the projected cost for a new drug approval (assuming the R&D was initiated in 2001) is $1.9 billion in 2013 (DiMasi, Hansen, and Grabowski 2003). (Sarkar 2009)
Chabner and Roberts:
Fewer than 10% of new drugs entering clinical trials in the period from 1970 to 1990 achieved FDA approval for marketing, and animal models seemed unreliable in predicting clinical success. (Chabner and Roberts 2005)
Björquist et al. Drug Discovery World 2007:
Furthermore, the compound attrition rate is negatively affected by the inability to predict toxicity and efficacy in humans. These shortcomings are in turn caused by the use of experimental pre-clinical model systems that have a limited human clinical relevance. (Björquist and Sartipy 2007)
January 12, 2006, then U.S. Secretary of Health and Human Services Mike Leavitt:
Currently, nine out of ten experimental drugs fail in clinical studies because we cannot accurately predict how they will behave in people based on laboratory and animal studies. (FDA 2006)
These examples could be easily multiplied and they are based on scientific studies that I have cited elsewhere. Balkwill et al are simply wrong. Animal models do not predict human PD/PK or toxicity. What about cancer?
David Salsburg of Pfizer writes:
If we restrict attention to long term feeding studies with mice or rats, only seven of the 19 human non-inhalation carcinogens (36.8%) have been shown to cause cancer. If we consider long term feeding or inhalation studies and examine all 26, only 12 (46.2%) have been shown to cause cancer in rats or mice after chronic exposure by feeding or inhalation. Thus the lifetime feeding study in mice and rats appears to have less than a 50% probability of finding known human carcinogens. On the basis of probability theory, we would have been better off to toss a coin. (Salsburg 1983)
Abelson: “The standard carcinogen tests that use rodents are an obsolescent relic of the ignorance of past decades.” (Abelson 1990)
Professor Andre McLean, Department of Clinical Pharmacology, University College MCM, London, speaking at a conference reported in Animals and Alternatives in Toxicology 1991.
Yes, I think it is very clear to all of us who are engaged in the business of assessing toxicity data that, when volumes of data are proudly presented to us after a carcinogenicity study, showing that there was a tumour in this organ or that, we look at it and we scratch our heads, and we wonder what on earth we can make of it. This is especially true when huge doses are given, with nothing to suggest what would be expected at low doses. I think very often the carcinogenicity studies are a waste of everybody's time and a fearful waste of animals. They are conducted partly because we are not sure what to do instead, and partly because they are a political gesture and a very miserable one at that. (McLean 1991)
Habeck in Drug Discovery Today:
A new study points towards distinct differences in the process by which mouse and human cells are transformed into cancer cells, emphasizing a need for caution when applying to humans what has been learned about disease pathways in mice. (Habeck 2002)
These examples could also be easily multiplied and they are based on scientific studies, many of which I have cited elsewhere. And let’s not forget that animal models misled scientists into thinking smoking and asbestos were not carcinogens. Once again Balkwill et al. are simply wrong.
The authors of this letter come from places with a clear vested interest in the animal experimentation industry:
Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK
Understanding Animal Research, London, UK
Association of the British Pharmaceutical Industry, London, UK
Association of Medical Research Charities, London, UK
BioIndustry Association, London, UK
Genetic Alliance UK, London, UK
Animal Science Group, Society of Biology, London, UK
Institute of Animal Technology, Oxford, UK
School of Biomedical Sciences, King's College London, London, UK
UCL Institute of Neurology, University College London, London, UK
British Neuroscience Association, Cambridge, UK
Sadly, the position of Balkwill et al. is not unique. In the same issue Banerjee wrote:
The limitations of animal studies are well known, and their main use for small molecules is early prediction of harms, such as teratogenicity and mutagenicity, as well as allowing some prediction of human pharmacokinetics. (Banerjee 2011)
As I have said, animals cannot predict human response to drugs and disease unless by predict one means a correct rate that one normally associates with astrology and fortunetellers. (See Animal Models in Light of Evolution and or FAQs About the Use of Animals in Science: A handbook for the scientifically perplexed.)
The prediction argument is the heart of the scientific aspect of the controversy surrounding the use of animals in research and testing. Scientists that use animals clearly make the prediction claim and society accepts vivisection as a necessary evil on that basis. If the vested interest groups lose on prediction, they realize the ramifications will cascade all the way down to dissection in high school biology classes. Animal use in research, testing, and education depends on prediction. (See Is the use of sentient animals in basic research justifiable? for more.)
But I think the thing I liked best about the Balkwill et al. letter was at the bottom where they said: “We declare that we have no conflicts of interest.” Riiiiggght! Look at those organizations. Of course they don’t.
Abelson, P. H. 1990. Testing for carcinogens with rodents. Science 249 (4975):1357.
Archibald, Kathy, Robert Coleman, and Christopher Foster. 2011. Open letter to UK Prime Minister David Cameron and Health Secretary Andrew Lansley on safety of medicines. The Lancet 377 (9781):1915.
Balkwill, Frances, Stephen Whitehead, Phil Willis, Nigel Gaymond, Alastair Kent, Clive Page, Robin Lovell-Badge, Roger Morris, Roger Lemon, and Duncan Banks. 2011. Safety of medicines and the use of animals in research. The Lancet 378 (9786):127-128.
Banerjee, Anjan. 2011. Safety of medicines and the use of animals in research. The Lancet 378 (9786):128.
Björquist, Petter, and Peter Sartipy. 2007. Raimund Strehl and Johan Hyllner. Human ES cell derived functional cells as tools in drug discovery. Drug Discovery World (Winter):17-24.
Chabner, B. A., and T. G. Roberts, Jr. 2005. Timeline: Chemotherapy and the war on cancer. Nat Rev Cancer 5 (1):65-72.
DiMasi, J. A., R. W. Hansen, and H. G. Grabowski. 2003. The price of innovation: new estimates of drug development costs. J Health Econ 22 (2):151-85.
Editors. 2011. In this issue. Nat Rev Drug Discov 10 (4):239-239.
FDA. 2010. FDA Issues Advice to Make Earliest Stages Of Clinical Drug Development More Efficient. FDA, June 18, 2009 2006 [cited March 7 2010]. Available from http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2006/ucm108576.htm.
Habeck, Martina. 2002. Of Mice and men, and cancer research. Drug Discovery Today 7 (19):981-2.
Kola, I., and J. Landis. 2004. Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov 3 (8):711-5.
McLean, A. 1991. Concluding Remarks. In Animals and Alternatives in Toxicology: Present Status and Future Prospects edited by M. Balls, J. Bridges and J. Southee: Wiley-VCH.
Salsburg, D. 1983. The lifetime feeding study in mice and rats--an examination of its validity as a bioassay for human carcinogens. Fundam Appl Toxicol 3 (1):63-7.
Sarkar, Susanta K. 2009. Molecular imaging approaches. Drug Discovery World (Fall):33-38.