Animal use in drug development

1. Animal use in drug development Pediatric Oncology Subcommittee Meetingof the Oncologic Drugs Advisory Committee October 21, 2005 Sadhana Dhruvakumar Director, Medical Testing Issues People for the Ethical Treatment of Animals (PETA) SadhanaD@peta.org (617) 276-3650

2. People for the Ethical Treatment of Animals (PETA) • Founded in 1980, PETA is a 501(c)(3) non-profit that has grown to 850,000 members worldwide, with a budget of ~$30 million and over 300 staff in offices in Norfolk VA (headquarters), Washington DC, New York, San Francisco, Los Angeles, UK, Germany, India, and Asia-Pacific • Areas of concern: animals used for experimentation, animals raised for food, animals raised for their skins, animals used for entertainment • We work through: partnerships with industry and government,public education, cruelty investigations and whistleblowers, animal rescue

3. Animal experimentation • Decades-old tests that could not be validated today • Not reliably predictive of human responses, esp. for different patient populations • Species variation and extrapolation • Poor disease models • Confounding effects of laboratory confinement, stress, environment, food, and so on • Reliability/reproducibility • Expensive, time-consuming, and not amenable to high throughput • Attempting to translate research from animals to humans not as efficient as studying humans directly

4. Species differences in predictions of chemically induced birth defects1 1 Evidence of harmful effects (+), no evidence of harmful effects (–), or equivocal evidence (±) Source: Schardein JL. Chemically Induced Birth Defects, 3rd Ed. Rev, 1109 pp. New York: Marcel Dekker (2000).

5. The costs of animal research to human health Missed opportunities • "How fortunate we didn't have these animal tests in the 1940s, for penicillin would probably never have been granted a license, and possibly the whole field of antibiotics might never have been realized.” – Sir Alexander Fleming Missed problems • COX-2 inhibitors(e.g., Vioxx)were found in animal studies to have a protective effect on cardiovascular health

6. Human-based development of medical products • Target discovery • Genomics/proteomics profiles of human tissues (e.g., diseased vs. normal) • Epidemiology with genetic analysis • Safety and efficacy testing • In vitro technologies (tissue cultures, physicochemical) • Genomics/proteomics/imaging biomarkers in experimental medicine trials • Predictive toxicology based on human molecular biology & chemical databases, QSARS, computer modeling and simulation

7. Advantages of modern human-based in vitro technologies • Faster results • Less expensive • Greater repeatability/reproducibility • Able to be automated/labor-saving • Amenable to high throughput • Species-relevant and thus more predictive (if developed correctly) • Possibility of predicting human pharmacogenetics • Enable earlier incorporation of safety testing, and thus better portfolio management • Less paperwork/doesn’t require animal care and use committee approval • Less exposure of personnel to animals and diseases • More humane/less controversial

8. ICCVAM Authorization Act, 2000 “Each Federal agency shall promote and encourage the development and use of alternatives to animal tests, including batteries of tests and test screens, where appropriate, for the purpose of complying with Federal regulations, guidelines, or recommendations, in each instance, and for each chemical class, for which such tests are found to be effective for generating data at least equivalent for hazard identification or dose--response assessment purposes to the method established under the current regulatory scheme.”

9. Animals in the FDA’s “critical path” • 92% of drugs that pass preclinical testing, currently almost all in vivo animal-based, now fail in clinical trials. • “We must modernize the critical development path that leads from scientific discovery to the patient” - Critical Path report, 3/04 • Assessing Safety • Animal toxicology is “laborious, time-consuming, requires large quantities of product, and may fail to predict the specific safety problem that ultimately halts development.” (Critical Path report, 3/04) • ADMET problems responsible for 60-90% of drug failures • Demonstrating Medical Utility (efficacy) • “Currently available animal models… have limited predictive value in many disease states.” (Critical Path report, 3/04) • Attempting to improve poor animal models is a relative waste of resources.

10. Problems with Animal Testing for Cancer Therapies • Animal tumors are inherently different from human tumors • Generally grow much more quickly and also regress spontaneously • Natural animal tumors are generally of different types than human ones - e.g., mice suffer from much higher rates of bone and muscle tumors than humans • Species-specific mechanisms abound, e.g., example of saccharine • Metabolism is significantly divergent between species, impacting both response to cancer-causing chemicals as well as chemotherapeutic drugs • Induction of cancer in experimental animals is highly unnatural (e.g., chemical or radiation poisoning, tumor transplantation, mutation) and irrelevant to the real environmental and genetic risks in humans, which are not well-enough understood • In 1992 several research teams reported the development of Rb-defective mice, but none of animals showed any signs of retinoblastoma. • The tobacco industry was able to delay widespread acceptance of the link between cancer and smokingfor more than a decade, largely because in study after study, animals forced to inhale smoke and exposed to tobacco derivatives did not develop cancer.A similar situation was true for asbestos, coal tar, and other hazards.

11. Track Record of Animal Cancer Research • “In [NCI‘s 25-yr screening program] 40,000 plant species were tested for anti-tumor activity. Several of the plants proved effective and safe enough in the chosen animal model to justify clinical trials in humans. In the end, none of these drugs was found useful for therapy because of too high toxicity or ineffectivity in humans. This means despite 25 years of intensive research and positive results in animal models, not a single antitumor drug emerged from this work. As a consequence, the NCI now uses human cancer cell lines for the screening of cytotoxics.”Handbook of Laboratory Animal Science, Volume II, Animal Models, Svendensen and Hau (Eds.) CRC Press 1994 p4  • “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.” • - Dr. Richard Klausner, former Director of National Cancer Institute, The Press, 8 May 1998 p 5

12. Non-Animal Methods in Cancer Research • Basic Research • Clinical Research, e.g., using gene expression profiling to help dissect mechanisms as well as make prognoses • Cell/tissue culture models • Testing Drug Candidates: • Biochips: microcircuits lined with human cells • One version of “The Hurel” biochip incorporates human uterine or colon tumor cells as well as healthy cells from various organs, testing for drugs that selectively kill the tumor cells • Biochips based on a patient’s cells will enable personalized medicine • In silico prediction • Companies like Entelos and Physiomics predict the responses patients will have to drugs; Physiomics focuses on cancer drugs • Early exploratory studies in humans/microdosing • E.g., PET scans can detect glucose uptake (necessary for tumor growth), a much earlier surrogate endpoint than tumor shrinkage

13. Targeted Therapies: Gleevec • Research • 1960: “Philadelphia chromosome” discovered through microscopic examination of DNA of patients with chronic myeloid leukemia (CML) • Only a subset of CML patients have the Bcr-Abl translocation • Research in an animal model of CML would not have resulted in this understanding • Discovery • Late-90’s: Brian J. Druker of Oregon Health & Sciences University tested imatinib meslyate on cancer cells in culture and found that it was potent in suppressing growth while having no effect on normal blood cells • Testing • Novartis almost did not pursue imatinib mesylate partly because it was toxic to dogs at high doses • Microdosing studies using PET scans showed that glucose uptake by tumor stopped as early as one day after first dose

14. PETA’s priorities for FDA change • Replace requirements for animal tests with internationally validated alternatives • PETA’s “Give the Animals 5” campaign highlighting pyrogenicity, phototoxicity, skin absorption, skin irritation, skin corrosion • Validate and accept other alternatives • In vitro ADME tests/microdosing • Develop tests for longer-term endpoints • Non-genotoxic carcinogenicity (needed for in vitro battery to replace 2 year rodent cancer bioassay) • Reproductive and other organ toxicities • Delete unnecessary requirements • Acute toxicity

15. Carcinogenicity • 2-yr cancer bioassay in rodents widely acknowledged to be highly problematic • Irrelevantly high doses and assumption of linearity • Test classifies > 50% of chemicals are carcinogens • Transgenic mouse variation has been rejected by scientists, including SACATM • Increasing questioning of 2-yr rodent cancer bioassay • Tox Forum 1/05 – cancer risk of coffee and PPARs • Papers: Gaylor 3/05, current British Medical Journal (10/15/05) & many others • American Council on Science & Health’s 1/05 book “America’s War on Carcinogens” and 8/05 petition to EPA • Society of Toxicology 3/05: “The Great Debate”: The 2-yr Rodent Carcinogenesis Bioassay: Relevant or Relic? • NTP 6/05 workshop: “Strains & Stocks - Should We Switch?” • 9/05 ECVAM Invalidation Workshop • Efforts to develop in vitro alternatives have not resulted in replacement • In vitro genotoxicity tests widely used in addition to rodent bioassay • Cell transformation assays (1999 ECVAM workshop & report) • Can a battery of in vitro tests replace the rodent bioassay?

16. Barriers to change • FDA has no established structures or channels for keeping up to date on evolving preclinical research technologies, for evaluating and accepting new non-animal alternatives, or for incorporating them into regulations. • Regulators commonly measure performance of non-animal tests against the wrong standards (unvalidated animal tests as the “gold standard”)  need to compile reference databases of human results • Regulators commonly spend vast amounts of time validating non-animal tests and hold them to unreasonably high standards (especially considering corresponding animal test being used in meanwhile has usually not been validated). • This does not appear to be the case for novel animal tests (e.g., FDA accepts the 25% of rodent cancer bioassays currently submitted in transgenics, even though transgenic mouse assay failed validation)  legally, this double standard is not allowed • Inertia, knee-jerk conservatism, fear of change, lack of urgency, lack of interest, vicious circle of waiting for others to start

17. Next steps Guidances and regulations • Incorporate validated non-animal technologies and delete corresponding animal tests New alternatives • Devote more FDA research and funding to validating and developing modern non-animal technologies (and/or work with NIH to direct funding) Meetings • Organize FDA workshops on animal testing alternatives including all stakeholders (gov’t, industry, academia, animal protection organizations) • Better familiarize FDA reviewers/researchers with new technologies Enlist animal protection community • Place animal protection organization staff scientists and alternatives experts on FACA committees • Help establish ICH participation for animal protection coalition