Responsible Conduct of Research Involving Animals

1. Responsible Conduct of Research Involving Animals James Hicks Chair-IACUC University of California, Irvine

2. Outline • Animal use definition and examples • Ethical and humane use of animals • Requirements before working with animals

3. Definition of Animal Use • “Any live, vertebrate animal used or intended for use in research, research training, experimentation, or biological testing or for related purposes”

4. Why Use Animals in Medicine, Biology and Biomedical Research? • Animals as spare parts • Animals as factories • Animals as models for human disease • Animals as test subjects • Animals to study basic physiological principles and integration of systems • Evolutionary and comparative physiology • Novel solutions to complex problems • Bioinformatics, comparative genomics, proteomics, metabolomics • Systems biology • Animals for the study of animals and the environment • Conservation biology • Ecological interactions and community structure • Veterinary medicine • Animals to study basic principles in biology • Evolutionary biology • Experimental evolution • Population genetics • Population genomics • Animal behavior • Animals for the study of disease • Virology and viral evolution

5. The level of the question and heuristic models • Phylogenetic differences can provide patterns—discovery of novel genes and regulatory networks • As the questions becomes more specific, the model needs to approach isomorphic characters—but does it have to achieve “pure” isomorphism?

6. Heuristic is the art and science of discovery and invention. The word comes from the same Greek root as "eureka": which means "I find". A heuristic is a way of directing your attention fruitfully.

7. From PlosBiology: http://biology.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pbio.0000058

8. Benefits of Animal Research • Penicillin • Mice • Blood Transfusions • Dogs • Tuberculosis Medicine • Guinea pigs • Meningitis Vaccine • Mice • Kidney Transplants • Dogs and Pigs • Breast Cancer Treatments • Mice, Rats and Dogs • Asthma Inhalers • Guinea Pigs and Rabbits • Polio Vaccine • Mice • Insulin for Diabetics • Dogs • Deep Brain Stimulation for Parkinson's Disease • Monkeys

9. Benefits Continued… • Vaccine for Smallpox • Vaccine for Anthrax • Rabies Vaccine • Typhoid Vaccine • Cholera Vaccine • Treatment for Beriberi • Treatment for Rickets • Corneal Transplants • Local Anaesthetics • Discovery of Vitamin C • Canine Distemper Vaccine • Coronary Bypass Operation • German Measles Vaccine • MMR Vaccine • Antidepressants and Antipsychotic • CT Scanning for Improved Diagnosis • Chemotherapy for Leukaemia • Medicines to Treat Ulcers • Inhaled Asthma Medication • Combined Therapy for HIV infection • Medicines for Type 2 Diabetes • Cervical Caner Antibodies • Bird Flu Vaccine • Malaria Vaccine • Modern Anaesthetics • Tetanus Vaccine • Diphtheria Vaccine • Anticoagulants • Streptomycin • Kidney Dialysis • Whooping cough Vaccine • Heart Lung Machine • Hip replacements • Cardiac Pacemakers • High Blood Pressure Medicines • Replacements of Heart Valves • Chlorpromazine Psychiatric Medicine • MRI Scanning for improved Diagnosis • Prenatal Corticosteroids for Premature Babies • Treatment for River Blindness • Life Support for premature Babies • Medicines to control Transplant Rejection • Hepatitis B Vaccine • Leprosy Treatment • Oral and Inhaled Insulin for Type 1 Diabetes • Angiogenesis Inhibitors for Cancer and Blindness • Gene Therapy for Muscular Dystrophy • Alzheimer’s Vaccine

10. US Yearly Benefits of Animal Research 450,000 Prescriptions for anabolic (growth) hormones1 520,000 Heart bypass operations2 1,500,000 Prescribed for Erythropoietin (for Anaemia)3 34,000,000 Anticoagulants dispensed4 95,000,000 Prescriptions for asthma5 150,000,000 Prescriptions for antibiotics6 1. Source: IMS Health, IMS National Prescription Audit TM, 2/2008 2. Source: IMS Health, ClinicalPlus 3. Source: IMS Health, IMS National Sales Perspectives TM, 2/2008 4. Source: IMS Health, IMS National Prescription Audit TM, 2/2008 5. Source: IMS Health, IMS National Prescription Audit TM, 2/2008 6. US Center for Disease Control and Prevention

11. The Numbers…

12. Numbers in Perspective

13. Pain - The Percentages “Some Pain, No Anesthesia” This is only the case when anaesthesia (or other pain relief) would have affected results e.g., when testing another pain relief drug

14. Veterinary advances Vaccines developed to protect pets, farm animals, working animals and animals in the wild

15. Examples of Animal Use at UCI • development of new therapies for humans and animals • pre-clinical drug/device trials • classes to teach surgical and other medical techniques • behavioral studies • tissue harvest for in-vitro studies

16. Animal Rights vs. Animal Welfare • Animal Rights • Animals and man share equal rights-- “personhood” for animals • All sentient beings deserve equal moral consideration • Animal-based research is never justified, nor is pet ownership, food or fiber production, etc. • “A rat is a pig is a dog is a boy. They’re all animals.”Ingrid Newkirk, PETA

17. Animal Rights vs. Animal Welfare • Animal Welfare • Animals and man are not equal, animals do not have the same rights as people • Stewardship: Man has an obligation to protect the welfare of animals (ie: provide food and shelter, limit pain and suffering, treat when injured, etc.) • Foundation of contemporary animal welfare regulations and guidelines

18. 1966

19. 1966

20. 1966

21. Life Magazine--1966 • Raid of a Baltimore, MD animal dealer by Humane Society of the United States (HSUS) • 29 charges of animal cruelty brought against Lester Brown • Congress put forth eight bills to outlaw inhumane treatment of animals

22. Pet Protection Act • 1966: Congress enacted the Pet Protection Act • Precursor to today’s Animal Welfare Act • Protected against theft of pets by research dealers • Gave authority to USDA to enforce and administer the Act • Provided protection to dogs, cats, rabbits, monkeys, guinea pigs and hamsters

23. Pet Protection Act (cont’d) • Established humane standards for treatment of animals • Set licensing requirements for animal dealers • Required annual USDA inspections of dealers and research institutions

24. Humane Standards Milestones

25. 1985 Animal Welfare Act Amendment • Establishment of an Institutional Animal Care and Use Committee (IACUC) • Requirements for veterinary consult and oversight • Requirements for canine exercise and non-human primate psychological enrichment • Requirements for consideration of alternatives to animal use and painful procedures and avoidance of unnecessary duplication of already-conducted studies

26. Humane Standards Milestones

27. USDA Regulations • Set requirements for committee (IACUC) composition and function • Provide performance standards for: • veterinary care • animal husbandry • animal transportation • Covers all warm-blooded animals • excludes rats, mice and birds

28. NIH Office of Laboratory Animal Welfare • Health Research Extension Act is the legislative mandate for Public Health Service (PHS) policy • Covers all vertebrate animals • NIH funded institutions must adhere to the PHS Policy • Office of Laboratory Animal Welfare is responsible for assuring compliance with PHS policy

29. Key Elements of the Federal Regulations • Justify why animals are necessary • Minimize pain and distress • Personnel must be qualified to perform their duties • Provide appropriate husbandry and care • Use of appropriate euthanasia methods

30. Ethical Guidance • 1996 NASA Principles for Ethical Care & Use of Animals: “Sundowner Report” • Principles of Humane Experimental Technique by W. M. Russell and R. L. Burch, 1959

31. NASA Principles - “Sundowner Report” • Respect for Life • All living creatures deserve respect • Societal Benefit • Some valuable return in exchange for the sacrifice of the animal’s life • Non-maleficience • “Do no harm” • Pain, distress and discomfort to the animals must be minimized

32. Principles of Humane Experimental Technique The 3 Rs • Replacement • Use of live animals as the research model should be replaced if possible • Refinement • Procedures should be refined to minimize pain, distress and discomfort • Reduction • Number of animals should be reduced to the minimum necessary to achieve scientific significance without increasing pain and distress

33. Refinement • Better living conditions for animals • Minimising pain wherever possible • Better training for animal technicians

34. Replacement • MRI Scanning • Micro dosing • In Vitro Testing • Computer Modelling

35. Reduction • Re-evaluating minimum numbers of animals for statistical significance • Methods allowing multiple procedures on single animals • Better designed experiments to reduce numbers

36. Institutional Animal Care and Use Committee • Campus committee charged with oversight of UCI’s animal program • Member Composition: • Faculty with animal expertise • Attending Veterinarian • Non-scientific member • Unaffiliated member • Biosafety officer

37. The IACUC’s Role • Review and approve activities involving animals at UCI (protocol review) • Review the animal program and inspect all facilities every 6 months • Review concerns involving animal use • Investigate issues of non-compliance • Report to regulatory agencies

38. Why Do We Review Protocols? The protocol is… • The written documentation of all procedures to be performed on live animals • The means by which adherence to the federal animal welfare regulations is assessed • The document that confirms the ethical treatment of animals used in the research

39. What Activities Require Review? “Any live, vertebrateanimal used or intended for use in research, research training, experimentation, or biological testing or for related purposes.” -PHS Policy Definition:

40. IACUC Protocol Review • Rationale for the use of animals • Justification of the species and number of animals • Conduct of experiments • Unnecessary duplication of experiments • Appropriate sedation, analgesia, anesthesia • Adequate training of personnel

41. The Ethical Bottom Line • The use of animals is a privilege, not a right • Society grants permission to use animals with the expectation that health benefits may be derived • the benefits to society outweigh the adverse effects imposed on individual animals (discovery and new knowledge)

42. Animal Welfare Regulations, Policies & Guidelines • USDA AWRs-- Title 9 CFR, Chapter 1 • USDA Animal Care Policies • OLAW PHS Policy (1986) • TheGuide (NRC--5th Ed.) • 2000 Report of AVMA Panel on Euthanasia • AAALAC, Intl. Accreditation Standards

43. Requirements before Working with Animals • Be sure the IACUC approves you to work with animals • The Lead Researcher must submit a modification request to add students to their protocols • Complete the animal tutorial • Complete a Qualifications of Personnel • Complete a Work Health History form for EH&S’ Occupational Health Program

44. Requirements (cont’d) • Read the approved protocol • Ensure the procedures you will perform are approved by the IACUC • New procedures? • LR should file a modification request and wait for IACUC approval

45. RGS On-Line Tutorial • Fulfills a federal investigator education requirement • Is required for all personnel working with animals • Requires log-in with a UCINetID and password • Covers core concepts of animal use • Not sure if you taken the animal tutorial? • Check the tutorial verification database

46. Lead Researcher Responsibilities • Obtain all required approvals prior to commencing the research; follow IACUC approved procedures • Ensure all personnel are trained to handle animals and perform procedures • Make no changes to the approved protocol without first having submitted those changes for review and approval by the IACUC

47. Responsibilities (continued) • Acquire or procure all animals thorough ULAR • Obtain annual renewals and 3-year renewal in order to continue working with animals • when protocols expire, all animal work must stop • faculty & staff can access IACUC protocol information via the web • Promptly report adverse events or problems to a ULAR Vet and the IACUC