1. Office for the Responsible Conduct of Research Use of live, vertebrate animal subjects in research B. Helen Jost, PhD IACUC Director IACUC Co-Chair

2. Historical use of research animals  Research animals have been used as human surrogates for well over a century Without regulation Without regulation Often without concern for animal welfare Often without concern for animal welfare  During that time, there were a number of animal cruelty laws in several states across the country However, there were no laws that specifically addressed the procurement and use of animals in research However, there were no laws that specifically addressed the procurement and use of animals in research

3. Genesis of animal research regulation  Several affiliated research groups formulated and used standards of care for rodents Standardized conditions were important to experimental reproducibility Standardized conditions were important to experimental reproducibility Animal welfare was also considered (3 R’s) Animal welfare was also considered (3 R’s)  Dognapping of “strays” to sell to research labs was a reality In 1965, a story in Time about Pepper the Dalmatian sparked a strong desire across the country to halt this practice In 1965, a story in Time about Pepper the Dalmatian sparked a strong desire across the country to halt this practice

4. The Animal Welfare Act  The Animal Welfare Act (AWA) was enacted in 1966 Only included dogs and cats Only included dogs and cats  The AWA covers animals used in commerce, exhibition, teaching, testing, and research  The AWA excludes: Cold-blooded animals (reptiles, fish, frogs) Cold-blooded animals (reptiles, fish, frogs) Animals used for agriculture (cattle, pigs, sheep, goats, horses, llamas) Animals used for agriculture (cattle, pigs, sheep, goats, horses, llamas) Mice, rats and birds purposely bred for use in research Mice, rats and birds purposely bred for use in research ■ 90% animal research uses lab mice and rats

5. AWA oversight  Unannounced inspections by a USDA Veterinary Medical Officer (VMO)  The VMO is charged with identifying non-compliance with the AWA and its regulations Visits facilities, inspects animals, reviews records Visits facilities, inspects animals, reviews records  Non-compliant items (NCIs) are published on-line and may incur fines Identification and correction prior to inspection is not cited as an NCI Identification and correction prior to inspection is not cited as an NCI

6. Public Health Service Assurance  Institutions receiving PHS funds for animal research must assure that research will be conducted as described in the PHS Policy on the Humane Care and Use of Laboratory Animals Must follow all applicable laws Must follow all applicable laws Must follow the Guide to the Care and Use of Laboratory Animals Must follow the Guide to the Care and Use of Laboratory Animals  The Assurance is renewed every 5 years, with reports submitted annually Without this Assurance there is no NIH/NCI funding for research involving animals Without this Assurance there is no NIH/NCI funding for research involving animals

7. OLAW oversight  The Office of Lab Animal Welfare monitors compliance with the PHS Policy  OLAW uses a mechanism of self-policing and self-reporting The institution identifies non-compliance and reports to OLAW with corrective actions The institution identifies non-compliance and reports to OLAW with corrective actions  There are no unannounced inspections However, audits can occur, usually for cause However, audits can occur, usually for cause  Serious and uncorrected violations can result in the loss of PHS funding To individuals To individuals To the institution as a whole To the institution as a whole

8. AAALAC accreditation  Association for the Assessment and Accreditation of Laboratory Animal Care AAALAC is a voluntary organization that makes recommendations based on results of site visits AAALAC is a voluntary organization that makes recommendations based on results of site visits Standards are continually updated to reflect current knowledge in laboratory animal science Standards are continually updated to reflect current knowledge in laboratory animal science  OLAW accepts AAALAC accreditation in lieu of additional OLAW oversight

9. Regulatory authority at UA  The University of Arizona is: Registered with the USDA as a research institution Registered with the USDA as a research institution PHS assured PHS assured AAALAC accredited AAALAC accredited  The Institutional Official (IO) has ultimate responsibility for the animal care and use program Vice President for Research Vice President for Research  The Institutional Animal Care and Use Committee (IACUC) administers the animal care and use program

10. The IACUC  IACUC membership must include: Scientists Scientists Veterinarians Veterinarians Non-scientists Non-scientists Non-affiliated “community” members Non-affiliated “community” members  Due to the diversity of the Committee, the rationale for the use of animals must be written in easy to understand language The “lay” description The “lay” description  Unlike humans, animals can’t consent The IACUC acts as their voice The IACUC acts as their voice

11. IACUC responsibilities  Oversees the Animal Care and Use Program Make recommendations to the IO for improvements Make recommendations to the IO for improvements  Inspects animal housing and research labs Semi-annual inspections Semi-annual inspections  Ensures protocol participants have training To understand the laws and ethics of animal research To understand the laws and ethics of animal research To conduct specific animal activities To conduct specific animal activities To understand occupational health issues To understand occupational health issues  Reviews and approves animal research and teaching Protocols and amendments Protocols and amendments

12. IACUC review of animal studies  IACUC review and approval is required for all activities involving warm and cold blooded vertebrate animals, including: Research Research Teaching Teaching Agriculture or field studies Agriculture or field studies Use of UA-funded animals at other institutions Use of UA-funded animals at other institutions  Approval must be obtained before the work begins

13. Description of animal activities  A brief description of the aim/purpose  A narrative description of all animal activities, in the order they will occur  Identification of the scientific endpoints The point at which the experimental aims are met The point at which the experimental aims are met  Identification of humane endpoints The point at which animals must be removed from the study, even if the experimental aims are not met The point at which animals must be removed from the study, even if the experimental aims are not met  Identification of pain and distress Clinical signs Clinical signs How will pain/distress be alleviated? How will pain/distress be alleviated? Why can’t pain/distress be alleviated? Why can’t pain/distress be alleviated?

14.  Any changes in your research with animals must be approved before the work starts Additional animals or species Additional animals or species Addition of new strains or breeding Addition of new strains or breeding New or modified procedures or time points New or modified procedures or time points Additional of surgery Additional of surgery Additional drugs/compounds Additional drugs/compounds Changes in dosages/administration route Changes in dosages/administration route Changes in euthanasia methods Changes in euthanasia methods Modifications to approved activities

15. The ethical balance ScientificvalueEthicalcost To humans To humans To animals To animals To science To science To society To society Pain Pain Distress Distress Morbidity Morbidity Mortality Mortality

16. The 3 R’s (Russell and Birch, 1959)  The 3 R’s are one tool that the IACUC uses to balance the scales Can we replace the use of animals with non- animal models or lower species? Can we replace the use of animals with non- animal models or lower species? Can we reduce the number of animals used and still achieve statistically significant data? Can we reduce the number of animals used and still achieve statistically significant data? Can we refine the procedures to minimize or eliminate pain and distress? Can we refine the procedures to minimize or eliminate pain and distress?

17. Do animals need to be used?  Does the benefit outweigh the harm to the animal? The data can be translated into future human or animal clinical studies The data can be translated into future human or animal clinical studies ■ Development of drugs or therapies When there are clear benefits to society and the advancement of knowledge When there are clear benefits to society and the advancement of knowledge ■ Species ecology and conservation  Can a non-animal model be used? In vitro assays, tissue culture In vitro assays, tissue culture Computer models, simulations Computer models, simulations Manikins, especially for training Manikins, especially for training

18. Does the species need to be used?  Hierarchy of species Non-human primates Non-human primates Companion animals (dogs, cats) Companion animals (dogs, cats) Farm animals (cattle, pigs, sheep) Farm animals (cattle, pigs, sheep) Rabbits, ferrets Rabbits, ferrets Guinea pigs, hamsters, gerbils Guinea pigs, hamsters, gerbils Lab rats Lab rats Lab mice Lab mice Fish, frogs Fish, frogs Invertebrates Invertebrates  Ag and field studies do not follow this paradigm Not animal models Not animal models USDA regulated

19. Are the fewest animals used?  The number of animals requested must be justified  The number of animals per experimental group should be consistent with generation of scientifically sound data  Justification can include use of: A statistical method to ensure a p value A statistical method to ensure a p value Previously documented experience (PI or literature) Previously documented experience (PI or literature)

20. The most important R – refine?  Review current scientific literature to identify modified techniques that reduce pain or distress  Use appropriate sedation, analgesia and/or anesthesia for painful or distressful procedures  Limit the number of procedures experienced by any individual animal  Ensure adequate post-procedural care Know the signs of pain and distress Know the signs of pain and distress  Identify appropriate scientific and humane endpoints Remove animals from the study based on humane endpoints to minimize pain and suffering Remove animals from the study based on humane endpoints to minimize pain and suffering

21.  Animal research is affected by the same ethical issues as other kinds of research Data fabrication or falsification; researcher bias; conflict of interest; intellectual property issues; misuse of funds Data fabrication or falsification; researcher bias; conflict of interest; intellectual property issues; misuse of funds  However, there is also protocol non-compliance, that is performing animal activities that have not been reviewed and approved by the IACUC Non-compliance may be reportable to the USDA or OLAW Non-compliance may be reportable to the USDA or OLAW  It is critical that everyone know what is approved Submit amendments to modify animal activities before starting the work Submit amendments to modify animal activities before starting the work The ethics of animal research

22.  As scientists, we should be aware of the impact that animal research has on our accumulated knowledge Much of what we know about the biological sciences had its start with animal research Much of what we know about the biological sciences had its start with animal research Most human studies being conducted today rely directly or indirectly on data from animal studies Most human studies being conducted today rely directly or indirectly on data from animal studies  However, animal research should only be undertaken After careful consideration of the scientific value obtained as compared to the ethical cost of using animals After careful consideration of the scientific value obtained as compared to the ethical cost of using animals With the utmost concern for animal welfare With the utmost concern for animal welfare

23. IACUC Contacts  Sean Limesand, PhD, IACUC Chair Phone: 626-8903 Email: limesand@email.arizona.edu limesand@email.arizona.edu  David Besselsen, DVM, PhD, Attending Veterinarian Phone: 626-1066 or 621-1564 Email: besselsd@email.arizona.edu besselsd@email.arizona.edu  Helen Jost, PhD, IACUC Director and IACUC co-Chair Phone: 626-5304 Email: jost@email.arizona.edu jost@email.arizona.edu Or email: ORCR-iacuc@email.arizona.edu ORCR-iacuc@email.arizona.edu

24. Resources  USDA Animal Welfare Act http://www.aphis.usda.gov/wps/portal/aphis/ourfocus/an imalwelfare?1dmy&urile=wcm%3apath%3a%2Faphis_ content_library%2Fsa_our_focus%2Fsa_animal_welfar e%2Fsa_awa%2Fct_awa_program_information http://www.aphis.usda.gov/wps/portal/aphis/ourfocus/an imalwelfare?1dmy&urile=wcm%3apath%3a%2Faphis_ content_library%2Fsa_our_focus%2Fsa_animal_welfar e%2Fsa_awa%2Fct_awa_program_information  PHS Policy http://grants.nih.gov/grants/olaw/references/phspol.htm http://grants.nih.gov/grants/olaw/references/phspol.htm  The Guide http://grants.nih.gov/grants/olaw/Guide-for-the-Care- and-Use-of-Laboratory-Animals.pdf http://grants.nih.gov/grants/olaw/Guide-for-the-Care- and-Use-of-Laboratory-Animals.pdf  IACUC home page http://orcr.arizona.edu/iacuc http://orcr.arizona.edu/iacuc