Historical use of research animals

1. Office for theResponsible Conduct of ResearchUse of live, vertebrateanimal subjects in researchB. Helen Jost, PhDIACUC DirectorIACUC Co-Chair

2. Historical use of research animals • Research animals have been used as human surrogates for well over a century • Without regulation • 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

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 • 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

4. The Animal Welfare Act • The Animal Welfare Act (AWA) was enacted in 1966 • 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) • Animals used for agriculture (cattle, pigs, sheep, goats, horses, llamas) • 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 • Non-compliant items (NCIs) are published on-line and may incur fines • 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 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

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 • There are no unannounced inspections • However, audits can occur, usually for cause • Serious and uncorrected violations can result in the loss of PHS funding • To individuals • To the institution as a whole

8. AAALAC accreditation • Association for the Assessment and Accreditation of Laboratory Animal Care • AAALAC is a voluntaryorganization that makes recommendations based on results of site visits • Standards are continually updatedto 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 • PHS assured • AAALAC accredited • The Institutional Official (IO) has ultimate responsibility for the animal care and use program • 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 • Veterinarians • Non-scientists • 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 • Unlike humans, animals can’t consent • The IACUC acts as their voice

11. IACUC responsibilities • Oversees the Animal Care and Use Program • Make recommendations to the IO for improvements • Inspects animal housing and research labs • Semi-annual inspections • Ensures protocol participants have training • To understand the laws and ethics of animal research • To conduct specific animal activities • To understand occupational health issues • Reviews and approves animal research and teaching • 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 • Teaching • Agriculture or field studies • 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 • Identification of humane endpoints • 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 • How will pain/distress be alleviated? • Why can’t pain/distress be alleviated?

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

15. The ethical balance • To humans • To animals • To science • To society Scientific value Ethical cost • Pain • Distress • Morbidity • 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 reduce the number of animals used and still achieve statistically significant data? • 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 • Development of drugs or therapies • When there are clear benefitsto society and the advancement of knowledge • Species ecology and conservation • Can a non-animal model be used? • In vitro assays, tissue culture • Computer models, simulations • Manikins, especially for training

18. Does the species need to be used? • Hierarchy of species • Non-human primates • Companion animals (dogs, cats) • Farm animals (cattle, pigs, sheep) • Rabbits, ferrets • Guinea pigs, hamsters, gerbils • Lab rats • Lab mice • Fish, frogs • Invertebrates • Ag and field studies do not follow this paradigm • 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 consistentwith generation of scientifically sound data • Justification can include use of: • A statistical method to ensure a pvalue • 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 • Identify appropriate scientific and humane endpoints • Remove animals from the study based on humane endpoints to minimize pain and suffering

21. The ethics of animal research • 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 • 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 • It is critical that everyone know what is approved • Submit amendments to modify animal activities before starting the work

22. The ethics of animal research • 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 • Most human studiesbeing conducted today rely directly or indirectly on data from animal studies • However, animal research should only be undertaken • After careful considerationof the scientific value obtained as compared to the ethical cost of using animals • With the utmost concern for animal welfare

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

24. Resources • USDA Animal Welfare Act • http://www.aphis.usda.gov/wps/portal/aphis/ourfocus/animalwelfare?1dmy&urile=wcm%3apath%3a%2Faphis_content_library%2Fsa_our_focus%2Fsa_animal_welfare%2Fsa_awa%2Fct_awa_program_information • PHS Policy • 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 • IACUC home page • http://orcr.arizona.edu/iacuc