Research with Humans and Research with Humans and Animals:Animals:IRB and IACUC BasicsIRB and IACUC Basics

Suzanne M. Rivera, Ph.D.Suzanne M. Rivera, Ph.D.Associate Vice PresidentAssociate Vice President

UT Southwestern Medical CenterUT Southwestern Medical Center

Research is RegulatedResearch is Regulated

Use of human subjects and animals in Use of human subjects and animals in research is a privilegeresearch is a privilege

Numerous regulatory bodies authorize, Numerous regulatory bodies authorize, monitor, and have authority to halt human monitor, and have authority to halt human and animal researchand animal research

Effective oversight supports the research Effective oversight supports the research enterprise (no compliance= no money)enterprise (no compliance= no money)

Ethical PrinciplesEthical Principles

BELMONT (Human)BELMONT (Human)

Respect for PersonsRespect for PersonsBeneficenceBeneficenceJusticeJustice

SUNDOWNER (Animal)SUNDOWNER (Animal)

Respect for LifeRespect for LifeNonNon--MaleficenceMaleficenceSocietal BenefitSocietal Benefit

Use of AnimalsUse of Animals

What is Animal Care and Use?What is Animal Care and Use?For purposes of this session, the word For purposes of this session, the word ““animalsanimals””means live, vertebrate animals used in research, means live, vertebrate animals used in research, testing, teaching, health surveillance, or for related testing, teaching, health surveillance, or for related purposes. purposes.

For purposes of this session, the phrase For purposes of this session, the phrase ““care and usecare and use”” means procurement, housing, means procurement, housing, transport, husbandry, health maintenance, transport, husbandry, health maintenance, experimentation, treatment and humane euthanasia. experimentation, treatment and humane euthanasia.

Animal Rights v. Animal WelfareAnimal Rights v. Animal Welfare

Current U.S. RegulationsCurrent U.S. RegulationsAnimal Welfare Act, 1966 [USC Title 7, Sections 2131 to 2156] asAnimal Welfare Act, 1966 [USC Title 7, Sections 2131 to 2156] as amended in 1970, amended in 1970, 1976, 1985 and 1990. 1976, 1985 and 1990.

Animal Welfare Regulations [Title 9 CFR, Subchapter A, Animal WeAnimal Welfare Regulations [Title 9 CFR, Subchapter A, Animal Welfare, Parts 1, 2 and lfare, Parts 1, 2 and 3]3]

Health Research Extension Act, 1985 [Health Research Extension Act, 1985 [Public Law 99Public Law 99--158, November 20, 1985, Section 158, November 20, 1985, Section 495] 495]

US Government Principles for the Utilization and Care of VertebrUS Government Principles for the Utilization and Care of Vertebrate Animals Used in ate Animals Used in Testing, Research, and Training, 1985Testing, Research, and Training, 1985

PHS Policy on Humane Care and Use of Laboratory Animals, 1986 PHS Policy on Humane Care and Use of Laboratory Animals, 1986

2000 2000 Report of the AVMA Panel on EuthanasiaReport of the AVMA Panel on Euthanasia [JAVMA, Vol. 218, No. 5, March 1, [JAVMA, Vol. 218, No. 5, March 1, 2001]2001]

Guide for the Care and Use of Laboratory Animals (Guide for the Care and Use of Laboratory Animals (GuideGuide) [NRC, 5th Ed., 1996] ) [NRC, 5th Ed., 1996]

NIH Grants Policy Statement (03/01), Part II: Terms and ConditioNIH Grants Policy Statement (03/01), Part II: Terms and Conditions of NIH Grant ns of NIH Grant Awards Subpart A: General Awards Subpart A: General ---- Part 2 of 7Part 2 of 7

EnforcementEnforcement

USDA (regulations)USDA (regulations)OLAW (regulations)OLAW (regulations)AAALAC, Int. (voluntary accreditation standards)AAALAC, Int. (voluntary accreditation standards)States (statutes)States (statutes)Local Municipalities (laws)Local Municipalities (laws)Institutions (policies)Institutions (policies)Attending Veterinarian/Institutional Animal Care Attending Veterinarian/Institutional Animal Care PersonnelPersonnelLocal Local IACUCsIACUCs (policies, procedures)(policies, procedures)

IACUC (What is it?)IACUC (What is it?)The IACUC is the institutional body with responsibility for The IACUC is the institutional body with responsibility for review and oversight of the institutionreview and oversight of the institution’’s program for the s program for the humane care and use of animals. humane care and use of animals.

The IACUC supports, facilitates, and promotes ethical and The IACUC supports, facilitates, and promotes ethical and humane use of animals by upholding the standards set forth in humane use of animals by upholding the standards set forth in all applicable laws, policies & guidance.all applicable laws, policies & guidance.

Per PHS Policy, must consist of no fewer than five members, Per PHS Policy, must consist of no fewer than five members, including a Veterinarian, one practicing scientist experienced including a Veterinarian, one practicing scientist experienced in research involving animals, one member whose primary in research involving animals, one member whose primary vocation is in a nonvocation is in a non--scientific area, and one member scientific area, and one member unaffiliated with the institution. unaffiliated with the institution.

IACUC AuthoritiesIACUC AuthoritiesReview institutionReview institution’’s animal care and use program 2x/yr.s animal care and use program 2x/yr.

Inspect institutionInspect institution’’s animal facilities, laboratories, and other s animal facilities, laboratories, and other areas where animals are used 2x/yr.areas where animals are used 2x/yr.

Provide IACUC program evaluations and facility inspections to Provide IACUC program evaluations and facility inspections to the IO. the IO.

Review and approve, require modifications in (to secure Review and approve, require modifications in (to secure approval) or withhold approval of proposed and continuing approval) or withhold approval of proposed and continuing animal activities.animal activities.

Review and approve, require modifications in (to secure Review and approve, require modifications in (to secure approval) or withhold approval of all proposed changes approval) or withhold approval of all proposed changes (modifications) to approved protocols.(modifications) to approved protocols.

IACUC Authorities, cont.IACUC Authorities, cont.Notify investigators in writing of its decision to approve, requNotify investigators in writing of its decision to approve, require ire modifications in (to secure approval) or withhold approval of modifications in (to secure approval) or withhold approval of proposed animal activities.proposed animal activities.

Investigate concerns involving the care and use of animals.Investigate concerns involving the care and use of animals.

Suspend animal activities that are not being conducted in Suspend animal activities that are not being conducted in accordance with applicable requirements.accordance with applicable requirements.

Make written recommendations to the IO regarding any aspect Make written recommendations to the IO regarding any aspect of the institutionof the institution’’s animal care and use program.s animal care and use program.

IACUC ReviewIACUC ReviewImportance of research question justifies use of animals?Importance of research question justifies use of animals?

Study personnel have training in species/techniques?Study personnel have training in species/techniques?

RRefineefine-- consider alternatives to any procedure that causes more consider alternatives to any procedure that causes more than momentary pain or distressthan momentary pain or distress

RReduceeduce-- the number of animals used should be the minimum that the number of animals used should be the minimum that is consistent with the aims of the experiment is consistent with the aims of the experiment

RReplaceeplace-- use nonuse non--animal models when possible (e.g., animal models when possible (e.g., in vitroin vitromethods)methods)

ModificationsModifications

Any change in an ongoing study must be Any change in an ongoing study must be approved prior to implementation*approved prior to implementation*

Most common changes: personnel, procedures, Most common changes: personnel, procedures, animal numbersanimal numbers

Significant changes reviewed by Full CommitteeSignificant changes reviewed by Full Committee

*except to avoid an immediate apparent hazard*except to avoid an immediate apparent hazard

Continuing ReviewContinuing Review

OLAW covered species are reviewed OLAW covered species are reviewed de novode novo every three yearsevery three years

USDA covered species are reviewed at least annuallyUSDA covered species are reviewed at least annually

Most universities look at all protocols annually, with more inMost universities look at all protocols annually, with more in--depth (or depth (or ““from scratchfrom scratch””) review every three years) review every three years

InvestigatorInvestigator’’s responsibility to request continuing review s responsibility to request continuing review sufficiently prior to expiration of approval to avoid a lapsesufficiently prior to expiration of approval to avoid a lapse

Animal CareAnimal Care

Attending VeterinarianAttending Veterinarian

Animal Care Staff: vet techs, husbandry techs, Animal Care Staff: vet techs, husbandry techs, procurement staff, transport staff, procurement staff, transport staff, cagewashcagewashpersonnel, etc.personnel, etc.

Compliance/postCompliance/post--approval monitoringapproval monitoring(may reside with IACUC)(may reside with IACUC)

Animal Care DutiesAnimal Care Duties

HousingHousingDaily Health ChecksDaily Health ChecksPathogen ControlPathogen ControlFeed, BeddingFeed, BeddingTransportTransportMonitoring of Surgery/Other ProceduresMonitoring of Surgery/Other ProceduresNecropsyNecropsyPhysical Plant UpkeepPhysical Plant UpkeepEquipment MaintenanceEquipment MaintenanceScientific/Clinical Input on IACUC ReviewScientific/Clinical Input on IACUC ReviewIACUCIACUC’’ss ““eyes and earseyes and ears”” in the Fieldin the Field

Training Is RequiredTraining Is RequiredFederal law mandates that all individuals who work Federal law mandates that all individuals who work with animals in biomedical research be appropriately with animals in biomedical research be appropriately qualified and trained.qualified and trained.

Training program should be available to all Training program should be available to all investigators, fellows, students, and technicians who investigators, fellows, students, and technicians who work with research animals.work with research animals.

Various media can be used: webVarious media can be used: web--based, inbased, in--person, person, brochure, handsbrochure, hands--on, classroom style, etc.on, classroom style, etc.

Compliance ActivitiesCompliance Activities

Lab Inspections at least twice annuallyLab Inspections at least twice annually

PostPost--approval Monitoring (not for cause)approval Monitoring (not for cause)

Investigations (for cause)Investigations (for cause)

SemiSemi--annual Program Evaluationsannual Program Evaluations

Report to OLAW (and UDSA, if covered) serious/continuing Report to OLAW (and UDSA, if covered) serious/continuing problems in a timely fashion; summarize for AAALAC annual problems in a timely fashion; summarize for AAALAC annual reportreport

Keep Good Records!!Keep Good Records!!

What is AAALAC?What is AAALAC?

AAALAC, International is a private, nonprofit AAALAC, International is a private, nonprofit organization that promotes the humane treatment of organization that promotes the humane treatment of animals in science through a voluntary accreditation animals in science through a voluntary accreditation program. program.

Formal site visits are conducted at threeFormal site visits are conducted at three--year intervals year intervals and are a method of ensuring that animal care and use and are a method of ensuring that animal care and use programs maintain high standards. programs maintain high standards.

What Does AAALAC Do?What Does AAALAC Do?AAALAC site visitors evaluate all aspects of an AAALAC site visitors evaluate all aspects of an animal care and use program, including conformance animal care and use program, including conformance with established procedures and overall performance with established procedures and overall performance in the area of animal care and use in research, in the area of animal care and use in research, education, testing or breeding. education, testing or breeding.

The basic components of a program that are evaluated The basic components of a program that are evaluated include (but are not limited to) institutional/IACUC include (but are not limited to) institutional/IACUC policies, animal husbandry, veterinary care, and the policies, animal husbandry, veterinary care, and the physical plant. physical plant.

Worker Protection & Worker Protection & OccOcc. Health. Health

Risks for Animal UsersRisks for Animal Users

Allergies Allergies AsthmaAsthmaSkin RashesSkin RashesBurns, cuts, needle sticksBurns, cuts, needle sticksChemical exposuresChemical exposuresInfectious agentsInfectious agentsRepetitive stress, overexertionRepetitive stress, overexertion

Worker Protection ProgramWorker Protection Program

Employee Health ClinicEmployee Health ClinicBrochureBrochureHealth History Questionnaire Health History Questionnaire Tutorial on risks for animal users and bystandersTutorial on risks for animal users and bystandersAccess to hazards limited pending Access to hazards limited pending assessment/tutorialassessment/tutorialConsultation and referral to specialistConsultation and referral to specialistCase management for WorkerCase management for Worker’’s Compensation s Compensation claimsclaims

Use of Human SubjectsUse of Human Subjects

What is Human Research?What is Human Research?

““any any systematicsystematic investigation that is investigation that is designed designed to to develop or contribute to generalizeable develop or contribute to generalizeable knowledgeknowledge, and which , and which uses living humansuses living humans or or identifiable informationidentifiable information about living humansabout living humans””

-- 45CFR Part 46 (45CFR Part 46 (““The Common RuleThe Common Rule””))

ExamplesExamplesanalyses of existing biological specimensanalyses of existing biological specimenschart reviewschart reviewsclinical trialsclinical trialscognitive and perceptual experimentscognitive and perceptual experimentsevaluations of social or educational programsevaluations of social or educational programsinterviews and focus groupsinterviews and focus groupssurveys and questionnairessurveys and questionnairestreatment outcome studies treatment outcome studies

Current RequirementsCurrent Requirements

45 CFR Part 46 (PHS)45 CFR Part 46 (PHS)21 CFR Part 56 (FDA)21 CFR Part 56 (FDA)45 CFR Parts 160 & 164 (HIPAA)45 CFR Parts 160 & 164 (HIPAA)State statutesState statutesLocal ordinancesLocal ordinancesInstitution/Campus policies and proceduresInstitution/Campus policies and proceduresCommunity standardsCommunity standards

45 CFR Part 4645 CFR Part 46

““The Common RuleThe Common Rule””: Federal Policy for the : Federal Policy for the Protection of Human Subjects Protection of Human Subjects

DHHS subpartsDHHS subpartsSubpart B: Pregnant women, Fetuses and Subpart B: Pregnant women, Fetuses and

NeonatesNeonatesSubpart C: PrisonersSubpart C: PrisonersSubpart D: MinorsSubpart D: Minors

21 CFR Parts 50 and 56 (FDA) 21 CFR Parts 50 and 56 (FDA)

IDEsIDEs-- New DevicesNew Devices

INDsINDs-- New Drugs/ BiologicsNew Drugs/ Biologics

Emergency Use of Test Article Emergency Use of Test Article

45 CFR Parts 160 & 164 (45 CFR Parts 160 & 164 (HIPAA)HIPAA)

Privacy BoardPrivacy Board

AuthorizationAuthorization

Waiver of AuthorizationWaiver of Authorization

DeDe--identified Data Setidentified Data Set

EnforcementEnforcement

DHHSDHHS-- OHRPOHRPDHHSDHHS-- FDAFDAAHRPP (voluntary accreditation)AHRPP (voluntary accreditation)State and Local GovernmentsState and Local GovernmentsInstitutions (e.g., universities, hospitals)Institutions (e.g., universities, hospitals)Local Local IRBsIRBs

IRB (What is it?)IRB (What is it?)

An IRB is an institutional body with responsibility for An IRB is an institutional body with responsibility for review and oversight of the human subject protection review and oversight of the human subject protection program.program.

The IRB supports, facilitates, and promotes ethical use of The IRB supports, facilitates, and promotes ethical use of human subjects by upholding the standards set forth in all human subjects by upholding the standards set forth in all applicable laws, policies & guidance.applicable laws, policies & guidance.

Per federal Policy, must consist of no fewer than five Per federal Policy, must consist of no fewer than five members, including one practicing scientist, one member members, including one practicing scientist, one member whose primary vocation is in a nonwhose primary vocation is in a non--scientific area, and one scientific area, and one member unaffiliated with the institution. member unaffiliated with the institution.

IRB AuthoritiesIRB AuthoritiesReview and approve, require modifications in (to secure Review and approve, require modifications in (to secure approval), or disapprove all research activities covered by approval), or disapprove all research activities covered by the regulations;the regulations;

Require that information given to subjects as part of Require that information given to subjects as part of informed consent is in accordance with the regulations;informed consent is in accordance with the regulations;

Require documentation of informed consent or may waive Require documentation of informed consent or may waive documentation in accordance with the regulations;documentation in accordance with the regulations;

Notify investigators and the institution in writing of its Notify investigators and the institution in writing of its decision to approve or disapprove proposed research or of decision to approve or disapprove proposed research or of modifications required to secure IRB approval of the modifications required to secure IRB approval of the research activity; research activity;

IRB Authorities, cont.IRB Authorities, cont.Conduct continuing review of research covered by the Conduct continuing review of research covered by the regulations at intervals appropriate to the degree of risk, but regulations at intervals appropriate to the degree of risk, but not less than once per year; not less than once per year;

May observe or have a third party observe the consent May observe or have a third party observe the consent process and the research; andprocess and the research; and

May suspend or terminate approval of research that is not May suspend or terminate approval of research that is not being conducted in accordance with the being conducted in accordance with the IRB'sIRB's requirements requirements or that has been associated with unexpected serious harm to or that has been associated with unexpected serious harm to subjects.subjects.

IRB ReviewIRB Review

Risks justified and reduced to fullest extent?Risks justified and reduced to fullest extent?

Benefits maximized to fullest extent?Benefits maximized to fullest extent?

Importance of research question justifies risks in Importance of research question justifies risks in light of anticipated benefits?light of anticipated benefits?

Selection of subjects is equitable?Selection of subjects is equitable?

IRB Review, cont.IRB Review, cont.

Proposed subject population not unduly harmed?Proposed subject population not unduly harmed?

Method, content, and documentation of consent appropriate?Method, content, and documentation of consent appropriate?

Provision for monitoring the data collected to ensure the Provision for monitoring the data collected to ensure the safety of subjects?safety of subjects?

Provisions to protect subjectsProvisions to protect subjects’’ privacy and maintain privacy and maintain confidentiality of data?confidentiality of data?

Informed Consent Must Be: Informed Consent Must Be:

consistent with regulations re: required elements;consistent with regulations re: required elements;

obtained from subject or legallyobtained from subject or legally--authorized representative;authorized representative;

presented in language understandable to the subject/ rep.;presented in language understandable to the subject/ rep.;

in writing (unless IRB approved verbal or waiver); andin writing (unless IRB approved verbal or waiver); and

obtained in circumstances that offer the subject/rep. sufficienobtained in circumstances that offer the subject/rep. sufficient t opportunity to consider whether to participate.opportunity to consider whether to participate.

ModificationsModifications

Any change in an ongoing study must be Any change in an ongoing study must be approved prior to implementation*approved prior to implementation*

Most common changes: personnel, procedures, Most common changes: personnel, procedures, subject populations, recruitment methodssubject populations, recruitment methods

ModsMods that affect risk/benefit ratio or increase that affect risk/benefit ratio or increase subject safety reviewed by Full Boardsubject safety reviewed by Full Board

*except to avoid an immediate apparent hazard*except to avoid an immediate apparent hazard

Adverse Events/Safety DataAdverse Events/Safety Data

All AEs must be reported to the IRB within 10 days. All All AEs must be reported to the IRB within 10 days. All deaths and hospitalizations also must be reported by phone, fax deaths and hospitalizations also must be reported by phone, fax or eor e--mail within 48 hoursmail within 48 hours

IRB Chairs review serious local IRB Chairs review serious local AEsAEs between meetingsbetween meetings

IRB AE data reports provided to members at time of CRIRB AE data reports provided to members at time of CR

PIs asked to submit copies of DSMB reports at time of CRPIs asked to submit copies of DSMB reports at time of CR

Continuing ReviewContinuing Review

Expedited and Full Committee studies are reviewed at least Expedited and Full Committee studies are reviewed at least annuallyannually

Opportunity to reevaluate importance of research question, Opportunity to reevaluate importance of research question, appropriateness of risksappropriateness of risks

Opportunity to review Opportunity to review AEsAEs and request modifications to and request modifications to protocol and/or consentprotocol and/or consent

InvestigatorInvestigator’’s responsibility to request continuing review s responsibility to request continuing review sufficiently prior to expiration of approval to avoid a lapsesufficiently prior to expiration of approval to avoid a lapse

ComplianceCompliance

Policy for Regulatory NoncompliancePolicy for Regulatory Noncompliance

Staff conduct Administrative AuditsStaff conduct Administrative Audits

IRBs (or subcommittees) perform reviewsIRBs (or subcommittees) perform reviews

Efforts made to resolve informally whenever possibleEfforts made to resolve informally whenever possible

IRBs empowered to impose corrective actionsIRBs empowered to impose corrective actions

Report to OHRP (and FDA, if covered) serious/continuing Report to OHRP (and FDA, if covered) serious/continuing problems in a timely fashionproblems in a timely fashion

What is AAHRPP?What is AAHRPP?

AAHRPP is a private, nonprofit organization that AAHRPP is a private, nonprofit organization that promotes the protection of human subjects through a promotes the protection of human subjects through a voluntary accreditation program. voluntary accreditation program.

Formal site visits are conducted at threeFormal site visits are conducted at three--year intervals year intervals and are a method of ensuring that human subjects and are a method of ensuring that human subjects protection programs maintain high standards. protection programs maintain high standards.

What Does AAHRPP Do?What Does AAHRPP Do?AAHRPP site visitors evaluate all aspects of a human AAHRPP site visitors evaluate all aspects of a human subjects protection program, including conformance subjects protection program, including conformance with established procedures and overall performance.with established procedures and overall performance.

The five domains that are evaluated include:The five domains that are evaluated include:OrganizationOrganizationResearch Review UnitResearch Review Unit (including (including IRBsIRBs))InvestigatorInvestigatorSponsored ResearchSponsored ResearchParticipant OutreachParticipant Outreach

Effective ComplianceEffective Compliance

Have a policy and procedures for monitoring and Have a policy and procedures for monitoring and enforcement (avoid S.L.A.G.I.A.T. method)enforcement (avoid S.L.A.G.I.A.T. method)

Honor due process, document actionsHonor due process, document actions

Keep the Institutional Official informedKeep the Institutional Official informed

Emphasize training over punishment (an ounce of Emphasize training over punishment (an ounce of preventionprevention……))

Questions?Questions?