Office for theOffice for theResponsible Conduct of ResearchResponsible Conduct of Research

Use of live, vertebrateUse of live, vertebrateanimal subjects in animal subjects in researchresearch

B. Helen Jost, PhDB. Helen Jost, PhDIACUC DirectorIACUC DirectorIACUC Co-ChairIACUC Co-Chair

Historical use of Historical use of research animalsresearch animals Research animals have been used as Research animals have been used as

human surrogateshuman surrogates for well over a century for well over a centuryWithout regulationWithout regulationOften without concern for animal welfareOften without concern for animal welfare

During that time, there were a number of During that time, there were a number of animal cruelty laws animal cruelty laws in several states across in several states across the countrythe countryHowever, there were However, there were no laws no laws that specifically that specifically

addressed the addressed the procurement procurement andand use use of animals in of animals in researchresearch

Genesis of animal research Genesis of animal research regulationregulation Several affiliated research groups formulated Several affiliated research groups formulated

and used and used standards of care standards of care for rodentsfor rodentsStandardized conditions were important to Standardized conditions were important to

experimental reproducibilityexperimental reproducibilityAnimal welfare was also considered (3 R’s)Animal welfare was also considered (3 R’s)

Dognapping of “strays” to Dognapping of “strays” to sell to research labs sell to research labs was a realitywas a realityIn 1965, a story in In 1965, a story in TimeTime about Pepper the about Pepper the

Dalmatian sparked a strong desire across the Dalmatian sparked a strong desire across the country to halt this practicecountry to halt this practice

The Animal Welfare ActThe Animal Welfare Act The Animal Welfare Act (AWA) was enacted in The Animal Welfare Act (AWA) was enacted in

19661966Only included Only included dogs dogs andand cats cats

The AWA covers animals used in commerce, The AWA covers animals used in commerce, exhibition, teaching, testing, and exhibition, teaching, testing, and researchresearch

The AWA excludes:The AWA excludes:Cold-bloodedCold-blooded animals (reptiles, fish, frogs) animals (reptiles, fish, frogs)Animals used for Animals used for agricultureagriculture (cattle, pigs, sheep, goats, (cattle, pigs, sheep, goats,

horses, llamas)horses, llamas)MiceMice, , ratsrats and and birdsbirds purposely bred for use in research purposely bred for use in research

■ 90% animal research uses lab mice and rats90% animal research uses lab mice and rats

AWA oversightAWA oversight UnannouncedUnannounced inspections by a USDA inspections by a USDA

Veterinary Medical Officer (Veterinary Medical Officer (VMOVMO)) The VMO is charged with The VMO is charged with identifying identifying

non-compliance non-compliance with the AWA and its regulationswith the AWA and its regulationsVisits facilities, inspects animals, reviews recordsVisits facilities, inspects animals, reviews records

Non-compliant items (NCIs) are Non-compliant items (NCIs) are publishedpublished on-line on-line and and may incur finesmay incur finesIdentification and correction Identification and correction priorprior to inspection is to inspection is

not cited as an NCInot cited as an NCI

Public Health Service Public Health Service AssuranceAssurance Institutions receiving PHS funds Institutions receiving PHS funds for animal for animal

research must research must assureassure that research will be that research will be conducted as described in the PHS Policy on conducted as described in the PHS Policy on the Humane Care and Use of Laboratory the Humane Care and Use of Laboratory AnimalsAnimalsMust follow Must follow all applicable lawsall applicable lawsMust follow the Must follow the GuideGuide to the Care and Use of to the Care and Use of

Laboratory AnimalsLaboratory Animals The The AssuranceAssurance is renewed every 5 years, with is renewed every 5 years, with

reports submitted annuallyreports submitted annuallyWithout this Assurance there is no NIH/NCI funding Without this Assurance there is no NIH/NCI funding

for research involving animalsfor research involving animals

OLAW oversightOLAW oversight The Office of Lab Animal Welfare The Office of Lab Animal Welfare

monitors compliancemonitors compliance with the PHS Policy with the PHS Policy OLAW uses a mechanism of OLAW uses a mechanism of self-policingself-policing and and self-self-

reportingreportingThe institution identifies The institution identifies non-compliancenon-compliance and and reportsreports to to

OLAW with corrective actionsOLAW with corrective actions

There are no unannounced inspectionsThere are no unannounced inspectionsHowever, However, audits can occuraudits can occur, usually for cause, usually for cause

SeriousSerious and and uncorrecteduncorrected violations can result in the violations can result in the loss of PHS fundingloss of PHS fundingTo individualsTo individualsTo the institution as a wholeTo the institution as a whole

AAALAC accreditationAAALAC accreditation Association for the Assessment and Association for the Assessment and

Accreditation of Laboratory Animal CareAccreditation of Laboratory Animal CareAAALAC is a AAALAC is a voluntaryvoluntary organization that organization that

makes recommendations based on results of makes recommendations based on results of site visitssite visits

Standards are continually Standards are continually updatedupdated to reflect to reflect current knowledgecurrent knowledge in laboratory animal science in laboratory animal science

OLAW OLAW acceptsaccepts AAALAC accreditation AAALAC accreditation in lieu in lieu of additional OLAW oversightof additional OLAW oversight

Regulatory authority at Regulatory authority at UAUA The University of Arizona is:The University of Arizona is:

Registered with the Registered with the USDAUSDA as a research institution as a research institution

PHSPHS assured assured

AAALACAAALAC accredited accredited

The Institutional Official (The Institutional Official (IOIO) has ultimate ) has ultimate responsibility for the animal care and use programresponsibility for the animal care and use programVice President for ResearchVice President for Research

The Institutional Animal Care and Use Committee The Institutional Animal Care and Use Committee ((IACUCIACUC) administers the animal care and use ) administers the animal care and use programprogram

The IACUCThe IACUC IACUC membership must include:IACUC membership must include:

ScientistsScientistsVeterinariansVeterinariansNon-scientistsNon-scientistsNon-affiliated “community” membersNon-affiliated “community” members

Due to the diversity of the Committee, the Due to the diversity of the Committee, the rationale for the use of animals must be written rationale for the use of animals must be written in in easy to understand easy to understand languagelanguageThe “lay” descriptionThe “lay” description

Unlike humans, animals can’t Unlike humans, animals can’t consentconsentThe IACUC acts as their The IACUC acts as their voicevoice

IACUC responsibilitiesIACUC responsibilities OverseesOversees the Animal Care and Use Program the Animal Care and Use Program

Make Make recommendationsrecommendations to the IO for improvements to the IO for improvements

InspectsInspects animal housing and research labs animal housing and research labsSemi-annual inspectionsSemi-annual inspections

Ensures protocol participants have Ensures protocol participants have trainingtrainingTo understand the To understand the laws and ethics laws and ethics of animal researchof animal researchTo conduct To conduct specificspecific animal animal activitiesactivitiesTo understand To understand occupational health occupational health issuesissues

ReviewsReviews and and approvesapproves animal research and animal research and teachingteachingProtocols and amendmentsProtocols and amendments

IACUC review of animal IACUC review of animal studiesstudies IACUC review and approval is required for IACUC review and approval is required for

all activities involving warm and cold all activities involving warm and cold blooded vertebrate animals, including:blooded vertebrate animals, including:ResearchResearchTeachingTeachingAgriculture or field studiesAgriculture or field studiesUse of UA-funded animals at other institutionsUse of UA-funded animals at other institutions

Approval must be obtained Approval must be obtained beforebefore the the work beginswork begins

Description of animal Description of animal activitiesactivities A brief description of the A brief description of the aimaim/purpose/purpose A narrative description of all A narrative description of all animal activitiesanimal activities, in , in

the order they will occurthe order they will occur Identification of the Identification of the scientific endpointsscientific endpoints

The point at which the The point at which the experimentalexperimental aims are met aims are met

Identification of Identification of humane endpointshumane endpoints The point at which animals The point at which animals must be removed must be removed from the from the

study, even if the experimental aims are not metstudy, even if the experimental aims are not met

Identification of Identification of painpain and and distressdistress Clinical signsClinical 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?

Any changes in your research with animals Any changes in your research with animals must be approved must be approved beforebefore the work starts the work startsAdditional animals or speciesAdditional animals or speciesAddition of new strains or breedingAddition of new strains or breedingNew or modified procedures or time pointsNew or modified procedures or time pointsAdditional of surgeryAdditional of surgeryAdditional drugs/compoundsAdditional drugs/compoundsChanges in dosages/administration routeChanges in dosages/administration routeChanges in euthanasia methodsChanges in euthanasia methods

Modifications to approved Modifications to approved activitiesactivities

The ethical The ethical balancebalance

ScientificScientificvaluevalue

EthicalEthicalcostcost

To humansTo humansTo animalsTo animalsTo scienceTo scienceTo societyTo society

PainPainDistressDistressMorbidityMorbidityMortalityMortality

The 3 R’s (Russell and The 3 R’s (Russell and Birch, 1959)Birch, 1959)

The The 3 R’s 3 R’s are one tool that the IACUC uses are one tool that the IACUC uses to balance the scalesto balance the scales

Can we Can we replacereplace the use of animals with non- the use of animals with non-animal models or lower species?animal models or lower species?

Can we Can we reducereduce the number of animals used and the number of animals used and still achieve statistically significant data?still achieve statistically significant data?

Can we Can we refinerefine the procedures to minimize or the procedures to minimize or eliminate pain and distress?eliminate pain and distress?

Do animals need to be Do animals need to be used?used?

Does the Does the benefit outweigh the harm benefit outweigh the harm to the animal?to the animal?The data can be The data can be translatedtranslated into future human or animal into future human or animal

clinical studiesclinical studies■ Development of Development of drugsdrugs or therapies or therapies

When there are clear When there are clear benefitsbenefits to society and the to society and the advancement of knowledgeadvancement of knowledge■ Species Species ecologyecology and and conservationconservation

Can a Can a non-animalnon-animal model be used? model be used?In vitro assays, tissue cultureIn vitro assays, tissue culture

Computer models, simulationsComputer models, simulations

Manikins, especially for trainingManikins, especially for training

Does the species need to Does the species need to be used?be used?

Hierarchy of speciesHierarchy of species Non-human primatesNon-human primates

Companion animals (dogs, cats)Companion animals (dogs, cats)

Farm animals (cattle, pigs, sheep)Farm animals (cattle, pigs, sheep)

Rabbits, ferretsRabbits, ferrets

Guinea pigs, hamsters, gerbilsGuinea pigs, hamsters, gerbils

Lab ratsLab rats

Lab miceLab mice

Fish, frogsFish, frogs

InvertebratesInvertebrates

Ag and field studies do not follow this paradigmAg and field studies do not follow this paradigmNot animal Not animal modelsmodels

USDA

regulat

ed

Are the fewest animals Are the fewest animals used?used?

The The numbernumber of animals requested must be of animals requested must be justifiedjustified

The number of animals per experimental The number of animals per experimental group should be group should be consistentconsistent with generation with generation of of scientifically sound datascientifically sound data

Justification can include use of:Justification can include use of:A statistical method to ensure a A statistical method to ensure a pp value valuePreviously documented experience (PI or Previously documented experience (PI or

literature)literature)

The most important R – The most important R – refine?refine? Review current scientific literature to identify Review current scientific literature to identify

modified techniques that modified techniques that reduce pain or distressreduce pain or distress Use Use appropriateappropriate sedation, sedation, analgesiaanalgesia and/or and/or

anesthesiaanesthesia for painful or distressful procedures for painful or distressful procedures LimitLimit the number of procedures experienced by any the number of procedures experienced by any

individual animal individual animal Ensure adequate Ensure adequate post-procedural carepost-procedural care

Know Know the signs of pain and distressthe signs of pain and distress

Identify appropriate scientific and Identify appropriate scientific and humane endpointshumane endpoints RemoveRemove animals from the study based on humane animals from the study based on humane

endpoints to endpoints to minimizeminimize pain and suffering pain and suffering

Animal research is affected by the same ethical Animal research is affected by the same ethical issues as other kinds of researchissues as other kinds of research Data fabrication or falsification; researcher bias; Data fabrication or falsification; researcher bias;

conflict of interest; intellectual property issues; conflict of interest; intellectual property issues; misuse of fundsmisuse of funds

However, there is also protocol However, there is also protocol non-compliancenon-compliance, , that is performing animal activities that have not that is performing animal activities that have not been reviewed and approved by the IACUCbeen reviewed and approved by the IACUC Non-compliance may be Non-compliance may be reportablereportable to the USDA or to the USDA or

OLAWOLAW It is critical that everyone know what is approvedIt is critical that everyone know what is approved

Submit Submit amendmentsamendments to modify animal activities to modify animal activities before before startingstarting the work the work

The ethics of animal The ethics of animal researchresearch

The ethics of animal The ethics of animal researchresearch As scientists, we should be As scientists, we should be awareaware of the of the impact impact

that animal research has on our accumulated that animal research has on our accumulated knowledgeknowledgeMuch of what we know about the biological sciences Much of what we know about the biological sciences

had its starthad its start with animal research with animal researchMost Most human studieshuman studies being conducted today rely directly being conducted today rely directly

or indirectly on data from animal studiesor indirectly on data from animal studies

However, animal research should only be However, animal research should only be undertakenundertakenAfter After careful considerationcareful consideration of the scientific value of the scientific value

obtained as compared to the ethical cost of using obtained as compared to the ethical cost of using animalsanimals

With the utmost concern for With the utmost concern for animal welfareanimal welfare

IACUC ContactsIACUC Contacts Sean Limesand, PhDSean Limesand, PhD, IACUC Chair , IACUC Chair

Phone: 626-8903Phone: 626-8903Email: Email: limesand@email.arizona.edu

David Besselsen, DVM, PhDDavid Besselsen, DVM, PhD, Attending Veterinarian, Attending VeterinarianPhone: 626-1066 or 621-1564Phone: 626-1066 or 621-1564

Email: Email: besselsd@email.arizona.edu Helen Jost, PhDHelen Jost, PhD, IACUC Director and IACUC co-Chair, IACUC Director and IACUC co-Chair

Phone: 626-5304 Phone: 626-5304

Email: Email: jost@email.arizona.edu

Or email: Or email: ORCR-iacuc@email.arizona.edu

ResourcesResources USDA Animal Welfare ActUSDA Animal Welfare Act

http://www.aphis.usda.gov/wps/portal/aphis/ourfocus/http://www.aphis.usda.gov/wps/portal/aphis/ourfocus/animalwelfare?1dmy&urile=wcm%3apath%3aanimalwelfare?1dmy&urile=wcm%3apath%3a%2Faphis_content_library%2Fsa_our_focus%2Faphis_content_library%2Fsa_our_focus%2Fsa_animal_welfare%2Fsa_awa%2Fsa_animal_welfare%2Fsa_awa%2Fct_awa_program_information%2Fct_awa_program_information

PHS PolicyPHS Policyhttp://grants.nih.gov/grants/olaw/references/phspol.htmhttp://grants.nih.gov/grants/olaw/references/phspol.htm

The The GuideGuidehttp://grants.nih.gov/grants/olaw/Guide-for-the-Care-http://grants.nih.gov/grants/olaw/Guide-for-the-Care-

and-Use-of-Laboratory-Animals.pdfand-Use-of-Laboratory-Animals.pdf

IACUC home pageIACUC home pagehttp://orcr.arizona.edu/iacuchttp://orcr.arizona.edu/iacuc