1. Responsible Conduct of Research Involving Animals
James Hicks
Associate Vice Chancellor for Research
University of California, Irvine

2. Outline Animal use definition and examples
History of animal welfare regulations
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. Benefits of Animal Research
Penicillin
Mice
Blood Transfusions
Dogs
Tuberculosis Medicine
Guinea pigs
Meningitis Vaccine
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

6. Benefits Continued… Modern Anaesthetics Tetanus Vaccine
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

7. 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

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

9. The Numbers…

10. Numbers in Perspective

11. 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

12. 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
comparative and evolutionary studies

13. Animal Rights vs. Animal Welfare
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
People’s attitudes fall somewhere along a continuum – at the far end on one side is Animal Rights

14. Animal Rights vs. 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

15. Humane Standards Milestones
Public perception requires the research community to strive for excellence in humane care and use of animals.
This is perfect segway into the NASA ethical principles and the resurgence of the 3Rs concept

16. In 1966, LIFE magazine published an article titled, “Your Dog is in Cruel Danger.” The article was about pets being stolen for use in research
1966

17. 1966
Concentration camp for dogs --article depicted under nourished, unhappy dogs and poor living conditions in a Baltimore, MD animal dealer facility

18. 1966
Public outrage and worry about their animals. Public trust in research was at an all time low.

19. 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

20. 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
Public outcry led to first federal law governing animal welfare
Specifically addressed animals most often considered pets – cats and dogs.

21. 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
PPA = Groundbreaking law – for research, breeders, many other uses of animals (breeders were unregulated, leading to problems with pet health)
Set the stage for other laws and regulations that followed, many as amendments of the original act

22. 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
Several amendments through the years – name changed to Animal Welfare Act to reflect its broadening focus
Most important amendment for research institutions – provisions were added that directly applied to the use of animals by research institutions...
UCLA early 80’s – no IACUC

23. Humane Standards Milestones
Public perception requires the research community to strive for excellence in humane care and use of animals.
This is perfect segway into the NASA ethical principles and the resurgence of the 3Rs concept

24. 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
Specific to research institutions –
Much overlap with Public Health Service policy
Rats, mice of the genus Mus, and all birds: USDA does not currently cover them
Why: lack of manpower, high costs, etc. Not a high political priority (HSUS notwithstanding) Most rodents are considered (a) snake food or (b) VERMIN. Ongoing talk about expanding the AWA to cover these species, particularly pet-trade birds (like parrots)

25. 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
Also in 1985, Congress enacted Health Research Extension Act: Public Health Service in the animal-regulating business
Public Health Service Policy on Humane Care and Use of Laboratory Animals (hold up booklet).
PHS policy: Only research, testing and teaching activities funded by PHS money (taxpayer funds)
Cover all vertebrate animals: rats, mice, birds, and anything else with a spine, like goldfish, snakes, and frogs.
All PHS funded institutions must have an Assurance of Compliance with PHS Policy – a negotiated agreement
HANDOUT #3 (FIRST ORANGE) – UCI’s OLAW Assurance, detailed description of our animal program.

26. 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
Main difference between the USDA regulations and PHS Policy:
USDA’s focus is broader as far as use of the animals is concerned, but oversight is limited to warm blooded animals
PHS policy narrows the focus to animals used in research, testing and teaching, and broadens the species covered to include all live vertebrate animals. Key elements are essentially the same

27. 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
Two documents that provide the guiding principles for ethical treatment of animals in research.
Unlike the regulations, these principles aren’t mandated by law, but rather they are the guidelines voluntarily followed by all ethical animal care and use programs.

28. 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
NASA Principles is based on three basic ethical principles.
All life is precious and deserving of respect
Societal benefit – we talked about that as being basic to the whole issue of research in animals – some return for the animal’s sacrifice
Do no harm, or rather as little harm as possible.

29. 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
The other guiding principle for animal use is a book written in 1959 (quite a while before the first federal law came into being) - introduced the concept of “the three Rs”
Replacement – use of computer models, commercially available or existing tissue or cell lines, in vitro or work with non-vertebrates (worms, fruit flies, etc.)
Refinement – examples include use of anesthesia, post surgical pain relievers, techniques performed by experienced personnel (example, blood draw by inexperienced technician)
Reduction – justify every animal’s life, make the best use each one
Balance: minimizing numbers without unduly increasing the pain and distress (such as multiple survival surgery) or sacrificing scientific rigor (not enough animals to prove the point)

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

31. Replacement MRI Scanning Micro dosing In Vitro Testing
Computer Modelling
MRI Scanning
Micro dosing

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

33. 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
IACUC reviews all research, testing and teaching projects on campus or elsewhere if supported by UCI-managed funds.
Fed regs dictate who must be on the committee – incl. non scientist and representative from community (unaffiliated)
Not all faculty members serving on the IACUC currently use animals – clinicians who work with human patients bring a valuable perspective to the committee, since they know what’s painful, what the disease process looks like, etc.

34. 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
Program review – semi-annual tune up of the program, try to troubleshoot what’s ahead.
Facility inspection – physical walkthrough of all facilities, including laboratory areas if live animals are used there.
Review concerns (whistleblower complaints) /investigate non-compliance – committee (chair) has the authority to suspend activities if necessary
Now I’ll hand the clicker back to Dr. Mulder and he’ll talk about ULAR’s role in UCI’s animal program.

35. 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
To understand the process, let’s look at what the protocol is…

36. What Activities Require Review?
Definition:
“Any live, vertebrate animal used or intended for use in research, research training, experimentation, or biological testing or for related purposes.”
-PHS Policy
This is a definition from the Public Health Service policy. An animal care and use committee approval is required for all research involving…(read the definition). The words in red are the key terms

37. 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
DOCUMENTATION
Why animals are necessary
How procedures will be conducted – in detail
Unnecessary duplication – that’s specifically listed in the regulations (USDA policy 12). Researchers must keep abreast of what’s being done in their field, and avoid repeating experiments unnecessarily.
Analgesics, anesthesia and adequate training = all refinements

38. 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)

39. Animal Welfare Regulations, Policies & Guidelines
USDA AWRs-- Title 9 CFR, Chapter 1
USDA Animal Care Policies
OLAW PHS Policy (1986)
The Guide (NRC--8th Ed.)
2000 Report of AVMA Panel on Euthanasia
AAALAC, Intl. Accreditation Standards
These regulations establish the committee review procedures and information that needs to be contained in the protocol.
They also set the requirement that all individuals working with animals be trained to handle the animals and perform the experiments.

40. 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

41. 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

42. 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

43. 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

44. 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

45. Despite medical advancements associated with animal use and ethical arguments for animal experimentation prior to human experimentation there are those who believe animal have rights, the same as human beings.