The Scientific Case Against Animal Use in Medical Research

1. The Scientific Case Against Animal Use in Medical Research John J. Pippin, MD, FACC Director of Academic Affairs Physicians Committee for Responsible Medicine jpippin@pcrm.org

2. Animals in Research: HIV-AIDS HIV-AIDS vaccine research began in 1983 About 90 HIV-AIDS vaccines have been successful in animal tests (mostly nonhuman primates) All of more than 200 human trials of these vaccines have failed to prevent or suppress HIV infection NHP research for HIV-AIDS vaccines and treatments is now widely discredited, yet it continues

3. Animals in Research: HIV-AIDS Merck’s much-hyped HIV vaccine (V520) failed spectacularly in 2007 V520 not only failed to protect, but was associated with greater HIV risk An urgent HIV-AIDS summit was held at NIH in March 2008, led by Dr. Anthony Fauci, Director of NIAID

4. Animals in Research: HIV-AIDS "Despite hundreds and hundreds of millions of dollars, the reality in 2008 is that an HIV vaccine clearly remains beyond our grasp." Warner C. Greene, MD, UCSF Co-chair, HIV-AIDS Summit March 2008, Bethesda, MD

5. Animals in Research: HIV-AIDS “No ideal model exists that can imitate the natural history and pathogenesis of HIV infection and AIDS in the human body, as HIV virus exclusively infects and causes disease in humans.” “Further, there is not one documented case of anyone being truly cured of HIV infection.” NIAID website (http://www.niaid.nih.gov/topics/hivaids/Pages/Default.aspx)

6. Animals in Research: Stroke More than 700 successful stroke therapies have been demonstrated in animal tests (mostly rodents) More than 150 of these have been tested in humans All stroke treatments have failed to improve survival After more than five decades of animal research we still do not have treatments to improve stroke survival

7. Animals in Research: Stroke “The repeated failures of laboratory-proven stroke therapies in humans can be due only to the inapplicability of animal models to human cerebral vascular disease.” Neff S. Stroke 1989;20:699-700

8. Animals in Research: Cancer • Cancer research is the highest-cost and lowest-yield category of animal experimentation for the study and treatment of human diseases • At least 95% of cancer drugs safe and effective in animal tests fail in human trials, due to inefficacy or toxicity • New approved cancer drugs have modest benefits, usually measured in extra weeks or months of life in an average of only 25-30% of patients; cures are virtually nonexistent

9. The War on CancerWhere Are We Now? • Since 1971, more than $100 billion in federal research funds has been spent on cancer research (mostly on animal research) • Since 1971, more than $100 billion from pharma, NGOs, and other sources has been spent on cancer research • Death rates have declined for some cancer types, due to lifestyle changes and earlier detection, but notdue to treatments • Overall U.S. cancer death rates have not declined appreciably since the 1970s (SEER Cancer Statistics) • The natural history of cancer has been redefined but not significantly improved by animal research in the last four decades

10. Animals in Research: Cancer “The history of cancer research has been a history of curing cancer in the mouse. We have cured mice of cancer for decades, and it simply didn’t work in humans.” Richard Klausner, M.D., Director, National Cancer Institute (1995-2001) (L.A. Times, May 6, 1998)

11. Animals in Research: Cancer “Unfortunately our track record shows that far less than 1 percent of our promising approaches actually make the grade in patients.” Bert Vogelstein, MD, Director of the Ludwig Center for Cancer Genetics and Therapeutics at Johns Hopkins University School of Medicine, and Howard Hughes Medical Institute researcher New York Times, June 29, 2009

12. Animals in Research: Correlations Between Human and Rodent Cancers • 38 chemicals that cause pancreatic cancer in rodents; 39 chemicals that cause colorectal cancer in rodents • Review of all these chemicals as human carcinogens • Results: None of these chemicals is known to cause pancreatic or colorectal cancers in humans. • Conclusion: “Rodent pancreatic and colorectal tumors are not predictive of human responses.” Card JW, et al. Regulatory Toxicology & Pharmacology 2012;64(3):442-458.

13. Animals in Research: Diabetes At least two dozen diabetes cures have been demonstrated in animal studies All have failed in human clinical trials The traditional mouse diabetes model has been discredited (Cabrera 2006; Vassilopoulos 2009), and decades of diabetes research is compromised

14. Animals in Research: SCI (Paralysis) More than 20 treatments have cured or ameliorated acute SCI in animal studies (mostly rodents) Every one of 10 RPCTs and many other trials in humans have shown no benefits for any SCI treatments Standard rodent models of SCI are widely discredited There are still no effective treatments for SCI

15. Animals in Research: Poor Translation • 101 “highly promising” basic science research results in six leading journals from 1979-1983 • Outcomes tracked through 2002 • Only 27 were approved for clinical trials • Only five resulted in approved treatments • Only one was in routine use (ACE inhibitor) Contopoulos, et al. AJM 2003;114(6):477-84

16. CONCLUSION: “Even the most promising findings of basic research take a long time to translate into clinical experimentation, and adoption in clinical practice is rare.” Contopoulos, et al. AJM 2003;114(4):477-84

17. Summary: Animal Research Compared to Human Results for Some Major Diseases Research areaAR successHuman success HIV-AIDS vaccine 90+ agents 0/200 clinical trials Stroke treatments 700+ agents 0/150 clinical trials* Diabetes treatments 24+ cures No cures SCI treatments 20+ cures No cures Cancer treatments ubiquitous Rare, especially cures ____________________________________________________ * rtPA may improve symptoms, but does not improve mortality

18. Animals in Research Pharmaceutical Development and Drug Testing

19. Pharmaceutical Research in Animals:Differences in Drug Metabolism Aspirin plasma half-life is: 15-20 minutes for humans 8 minutes for rats 1 hour for horses 8 hours for dogs 40 hours for cats

20. Aspirin and Birth Defects In animal studies, aspirin produces birth defects in mice, rats, guinea pigs, rabbits, cats, dogs, sheep, and monkeys Yet aspirin is safe during all stages of human pregnancy

21. Pharmaceutical Research in Animals:Differences in Drug Metabolism Diazepam metabolism is species-dependent Single low doses can cause fatal liver failure in cats Very high doses (2-3 mg/kg) may be required to control seizures in dogs, due to rapid hepatic metabolism This dosage would be rapidly lethal if given to humans

22. Animals in Drug Testing: Vioxx 8 preclinical Vioxx studies in 6 species showed no cardiovascular toxicities; some showed benefits Post-marketing study in African green monkeys showed no cardiovascular thrombogenic effects 60,000 Americans and 140,000 worldwide died of MI, stroke, and heart failure Vioxx was withdrawn by Merck in September 2004

23. Human and Animal Drug Availability: The Interspecies Scattergram

24. Failure Rate of Animal Research for Drug Development 96% of drugs safe and effective in animal tests later fail in human clinical trials (increased from 86% in 1985 and 92% in 2003) Of the 4% approved, half are recalled or relabeled for lethal or severe toxicities not detected in animal tests Other drugs lose FDA indications when later shown to be ineffective (e.g., Avastin, Mylotarg, Iressa, Zetia) [Data updated 2013 based on reports of stage-specific clinical trial failure rates: Phase I = 56%; Phase II = 82%; Phase III = 50%. Cumulative failure rate = 96%]

25. Failure Rate of Animal Research for Drug Development • It takes at least 100 successful animal-tested drugs to produce one unique, effective, safe drug for patients • > 90% of FDA-approved drugs work for fewer than half of patients; on average, only 25-30% of patients respond favorably to cancer and neurology drugs

26. Failure Rate of Animal Research for Drug Development • Only 1 in 9 FDA-approved drugs since 1960 provides any measureable therapeutic advantage over previously available drugs • A new drug that passes animal safety and efficacy testing is much more likely to harm than to benefit patients Light DW. The Risks of Prescription Drugs (2010)

27. Criticisms of Drug and Chemical Safety Testing in the U.S. National Cancer Institute (1980s) Institute of Medicine (January 2007) National Research Council (July 2007) Science Board of the FDA (November 2007) Institute of Medicine (April 2008) NIH, EPA, FDA memorandum (2008 – Tox21) All have adopted or recommended in vitro and human-based drug and chemical testing methods to replace animal research

28. Reliability of Mouse Research for Major Category of Human Disease: Inflammation • Comprehensive review for burns, trauma, and sepsis • Mouse models long thought to be mechanistically reliable, but clinical translation was almost nil • Seok et al. compared 4,918 inflammation response genes in humans and mouse models for all three inflammatory diseases Seok, et al. PNAS 2013; 110(9):3507-3512.

29. Reliability of Mouse Research for Major Category of Human Disease: Inflammation • Correlation of gene responses in humans and mice was “virtually absent” • Conclusions: (1) “Responses in mice cannot predict human responses”; (2) “There is no reason to believe that the correlation would be better in any other field”; (3) “Focus on the more complex human conditions rather than relying on mouse models.” Seok, et al. PNAS 2013; 110(9):3507-3512.