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Responsible Conduct of Research Involving Animals

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					Responsible Conduct of Research
      Involving Animals




                 James Hicks
    Associate Vice Chancellor for Research
     University of California, Irvine
                  Outline
• Animal use definition and examples

• Ethical and humane use of animals

• Requirements before working with animals
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”
     Why Use Animals in Medicine, Biology and Biomedical
                           Research?
1.     Animals as spare parts

2.     Animals as factories

3.     Animals as models for human disease

4.     Animals as test subjects

5.     Animals to study basic physiological principles and integration of systems
                1. Evolutionary and comparative physiology
                      1. Novel solutions to complex problems
                2. Bioinformatics, comparative genomics, proteomics, metabolomics
                3. Systems biology


6.     Animals for the study of animals and the environment
                1. Conservation biology
                2. Ecological interactions and community structure
                3. Veterinary medicine

7.     Animals to study basic principles in biology
                1. Evolutionary biology
                      1. Experimental evolution
                2. Population genetics
                3. Population genomics
                4. Animal behavior

8.     Animals for the study of disease
                1. Virology and viral evolution
      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?
• 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.
From PlosBiology: http://biology.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pbio.0000058
            Benefits of Animal Research
•   Penicillin              •   Breast Cancer Treatments
        • Mice                      • Mice, Rats and Dogs



•   Blood Transfusions      •   Asthma Inhalers
        • Dogs                      • Guinea Pigs and Rabbits


•   Tuberculosis Medicine
        • Guinea pigs       •   Polio Vaccine
                                     • Mice


•   Meningitis Vaccine
       • Mice               •   Insulin for Diabetics
                                     • Dogs


•   Kidney Transplants
        • Dogs and Pigs     •   Deep Brain Stimulation for
                                Parkinson's Disease
                                    • Monkeys
•   Vaccine for Smallpox                 •   Modern Anaesthetics             Benefits Continued…
•   Vaccine for Anthrax                  •   Tetanus Vaccine
•   Rabies Vaccine                       •   Diphtheria Vaccine
•   Typhoid Vaccine                      •   Anticoagulants
•   Cholera Vaccine                      •   Streptomycin
•   Treatment for Beriberi               •   Kidney Dialysis
•   Treatment for Rickets                •   Whooping cough Vaccine
•   Corneal Transplants                  •   Heart Lung Machine
•   Local Anaesthetics                   •   Hip replacements
•   Discovery of Vitamin C               •   Cardiac Pacemakers
•   Canine Distemper Vaccine             •   High Blood Pressure Medicines
•   Coronary Bypass Operation            •   Replacements of Heart Valves
•   German Measles Vaccine               •   Chlorpromazine Psychiatric Medicine
•   MMR Vaccine                          •   MRI Scanning for improved Diagnosis
•   Antidepressants and Antipsychotic    •   Prenatal Corticosteroids for Premature Babies
•   CT Scanning for Improved Diagnosis   •   Treatment for River Blindness
•   Chemotherapy for Leukaemia           •   Life Support for premature Babies
•   Medicines to Treat Ulcers            •   Medicines to control Transplant Rejection
•   Inhaled Asthma Medication            •   Hepatitis B Vaccine
•   Combined Therapy for HIV infection   •   Leprosy Treatment
•   Medicines for Type 2 Diabetes        •   Oral and Inhaled Insulin for Type 1 Diabetes
•   Cervical Caner Antibodies            •   Angiogenesis Inhibitors for Cancer and
                                             Blindness
•   Bird Flu Vaccine
                                         •   Gene Therapy for Muscular Dystrophy
•   Malaria Vaccine
                                         •   Alzheimer’s Vaccine
            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
                                                          The Numbers…
                  2,500,000

                                   Number of Animals Used Annually for Research in the US (Species covered by the Animal
                                   Welfare Act)

                2,000,000
                                                                                                 Cats   Primates   Dogs   All Other Animals



                   1,500,000
Number of Animals Used




                  1,000,000




                         500,000




                              0




                                                                         Year
                                                       Numbers in Perspective
                             10000

                                                                                                                                                        9,031
                             9000


                             8000
Millions of animals killed




                             7000


                             6000


                             5000


                             4000


                             3000


                             2000


                              1000
                                                                                    365
                                                           26            150                        27                38              105
                                           1
                                0
                                     Research exc.    Research inc.    Hunting     Killed by   Ducks for food    cattle, sheep,   Pigs for food   Chickens for food
                                     Mice, rats and   Mice, rats and             Automobiles                    calves for food
                                         birds            birds
       Pain - The Percentages

“Some Pain, No                Some Pain,
                              Anaesthesia
Anesthesia”                      37%
                                                   No Pain,
                                                      No
This is only the case                             Anaesthesia
when anaesthesia (or                Some Pain,       56%
                                        No
other pain relief) would            Anaesthesia
have affected results e.g.,             7%
when testing another
pain relief drug
                       Veterinary advances
Vaccines developed to protect pets, farm animals, working animals and
animals in the wild
 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
        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
        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
1966
1966
1966
     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
       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
      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
                 Humane Standards
                    Milestones
1966              1985/1986                 1996
-Life Magazine    -HREA/PHS policy          - NASA Principles
-PPA/AWA          -Guide Revision           -Resurgence of 1959 3Rs

1960’s                                                        2000’s


           -1985 AWA                  -1993 AVMA
            amendment                  Euth Guidelines

                                     On the horizon-2006 Animal rights?
  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
           Humane Standards
              Milestones
1966             1985/1986                 1996
-Life Magazine   -HREA/PHS policy          - NASA Principles
-PPA/AWA         -Guide Revision           -Resurgence of 1959 3Rs

1960’s                                                       2000’s


           -1985 AWA                 -1993 AVMA
            amendment                 Euth Guidelines

                                    On the horizon-2006 Animal rights?
         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
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
     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
         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
 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
  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
            Refinement
• Better living conditions for animals


• Minimising pain
wherever possible


•Better training for animal technicians
                     Replacement
• In Vitro Testing            • MRI Scanning




                              • Micro dosing
• Computer Modelling
            Reduction
• Re-evaluating minimum numbers of animals
for statistical significance


                   • Methods allowing multiple
                   procedures on single animals


• Better designed experiments to reduce numbers
 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
          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
 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
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
   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
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)
 Animal Welfare Regulations,
    Policies & Guidelines
USDA AWRs-- Title 9 CFR, Chapter 1
USDA Animal Care Policies
OLAW PHS Policy (1986)
The Guide (NRC--5th Ed.)
2000 Report of AVMA Panel on Euthanasia
AAALAC, Intl. Accreditation Standards
     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
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
 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
       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
      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

				
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