Flaws With Animal Research a Deep-Rooted Problem
By Aysha Akhtar, M.D., M.P.H., and Jarrod Bailey, Ph.D.

This letter was published on Feb. 9, 2007, in the online British Medical Journal.

Editor(s):

Kudos to you for encouraging discussion and debate regarding animal experimentation.(1) We agree with Hackam’s editorial that methodological flaws constitute a prevalent problem among animal studies, but believe there is a more inherent and confounding problem: inter-species differences in physiology.

The more we study the relevance of animal tests, the more apparent their shortcomings become. Even subtle physiological differences between humans and animals can manifest as profound differences in disease physiology and treatment effectiveness and safety. For example, numerous differences in spinal cord physiology and reaction to injury exist between species and even strains within a species.(2-4) These differences likely contribute to the repeated failure of spinal cord treatments that have tested safe and effective in animals to translate into human benefit.

Here are just a few of the myriad examples: numerous beneficial agents for stroke, cancer, and AIDS in animals have failed to translate into effective clinical therapies; tests in rodents for predicting human carcinogenicity with a false negative rate approaching two-thirds,(5) potentially causing widespread human exposure to carcinogens;(6) teratology studies in animals that concur with human studies at best half of the time;(7) and the Vioxx (killing over 140,000 people (8-10)) and TGN1412 disasters (severely injuring six clinical trial patients), both of which failed to show adverse reactions in animal tests.

A major shift in our research paradigm is long overdue. The move away from animal experiments toward more accurate methods of studying disease and intervention is scientifically superior and more ethical for humanity, as well as for animals.

References
1. Hackam DG: Translating animal research into clinical benefit. BMJ 2007; 334: 163-164.
2. Ma M, Wei P, Wei T, Ransohoff RM, Jakeman LB: Enhanced axonal growth into a spinal cord contusion injury site in a strain of mouse (129X1/SvJ) with a diminished inflammatory response. J Comp Neurol 2004; 474:469-486.
3. Popovich PG, Wei P, Stokes BT: Cellular inflammatory response after spinal cord injury in Sprague-Dawley and Lewis rats. J Comp Neurol 1997; 377:443-464.
4. Schmitt C, Miranpuri GS, Dhodda VK, Isaacson J, Vemuganti R, Resnick DK: Changes in spinal cord injury-induced gene expression in rat are strain-dependent. The Spine Journal 2006; 6:113-119.
5. Lave LB, Ennever FK, Rosenkranz HS, Omenn GS: Information value of the rodent bioassay. Nature 1988; 336:631-633.
6. Ennever FK, Lave LB: Implications of the lack of accuracy of the lifetime rodent bioassay for predicting human carcinogenicity. Regulatory Toxicology and Pharmacology 2003; 38:52-57.
7. Bailey J, Knight A, Balcombe J: The future of teratology research is in vitro. Biogenic Amines 2005; 19:97-145
8. Topol EJ: Failing the public health – rofecoxib, Merck, and the FDA. NEJM 2004;351:1707-9.
9. Graham DJ, Campen D, Hui R, Spence M, Cheetham C, Levy G, Shoor S, Ray WA: Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study. Lancet 2005;365:475-81.
10. Bresalier RS, Sandler RS, Quan H, Bolognese JA, Oxenius B, Horgan K, Lines C, Riddell R, Morton D, Lanas A, Konstam M, Baron JA, for the Adenomatous Polyp Prevention on Vioxx (APPROVe) Trial Investigators: Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. NEJM 2005;352:1092-1102.

Competing interests: Senior Research Advisor and Consultant for Physicians Committee for Responsible Medicine, a non-profit organization dedicated to the promotion of alternatives to animal research.

Aysha Z Akhtar, M.D., M.P.H., is a senior medical advisor and Jarrod Bailey, Ph.D., is a senior research consultant for the Physicians Committee for Responsible Medicine.

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