3Who Owns the Animals? Kathryn Bayne, M.S., Ph.D., D.V.M., DACLAM Senior Director &Director of Pacific Rim ActivitiesAAALAC International
4Oversight authority OLAW USDA AAALAC International Follows the money trail“Covered” species on siteFollows animal ownership
5PHS Policy“This Policy is applicable to all PHS-conducted or supported activities involving animals, whether the activities are performed at a PHS agency, an awardee institution, or other institution and conducted in the United States, Commonwealth of Puerto Rico, or any territory or possession of the United States….”
6USDAThe Animal Welfare Act and accompanying Animal Welfare Regulations provide authority (as determined by the Secretary) for warm-blooded animalsIn research facilities, this includes live animals “used or intended for use in research, testing, or experiments”
8AAALAC InternationalAll animals used or to be used in research, teaching or testing at accreditable units are to be included and evaluated…. This includes traditional laboratory animals, farm animals, wildlife, and aquatic animals. Nontraditional animals, inclusive of invertebrate species, are also included where they are relevant to the unit's mission.
9What does AAALAC visit?If your accredited institution owns animals at another accredited institutionWe will not include those animals in your site visit; they will be addressed during the other institution’s visitIf your accredited institution owns animals at a non-accredited institutionYou will need to include those animals in your Program Description and we will include them in the site visit
10However, the accredited unit may have a more limited contract in which the accredited unit owns the animals. In this latter situation, AAALAC International considers those facilities to be an integral part of the institution's animal care program. The services and facilities provided by the contractual arrangement must be included in the application and annual reports, and the facilities will be visited as a part of the institution's original and periodic site visits to determine compliance with AAALAC International standards. Contractual agreements made by AAALAC International accredited institutions or applicants must provide for the inspection of the contracted facilities by AAALAC International site visit teams. If the contract facility is separately accredited by AAALAC International and is currently fully accredited, it will not be necessary to visit that facility during the site visit.
11What does AAALAC visit?If your accredited institution is involved in a collaboration or contract (regardless if the performance site is accredited or not), but does not own the animalsThis does not need to be described in the Program Description, nor declared as part of your accredited “unit”
12Institutions may have contractual arrangements for certain aspects of their animal care activities with other animal care agencies/facilities. In some situations, an accreditable unit may issue a comprehensive contract whereby the contractor provides most or all specified facilities, services, personnel, animals, etc., and the animals are owned by the contractor. In this situation, AAALAC International accreditation does not extend to the contracted facilities and their associated animal care programs.
17To define animal ownership: You may need to get the lawyers involved… …due to possibly varying state, municipal, and international laws regarding property ownership specific to your area
18How to avoid confusionDuring the development of a contractual relationship, establish who “owns” the animals (e.g., authority for final disposition of an animal)If your institution is providing monetary support in a collaborative project, use of that money to purchase animals should be addressed up front
20Animals at your institution that you don’t “own” but which may be reviewed by AAALAC Raptors in a rehab program owned by FWS, but used for teachingClient-owned animals in maintained in a vet school that are used in an IACUC approved protocol
21Animals at your institution that you don’t “own” but which may be reviewed by AAALAC Agricultural animals whose primary purpose is other than teaching or research, but which are also used for either of those purposesAnimal not owned by accredited unit, but housed in close proximity to those that are, and may impact well-being of the animalse.g., dairy cows used for milk and cheese production and sale, but also used for teachinge.g., one building (shared facility) houses animals for both accredited and non-accredited components of a university, such as a goat owned by a non-accredited component housed in a stall next to a goat owned by the accredited component of the university
23Contracting Out Research to CROs: What are the Issues? Wendy J. Underwood, D.V.M., M.S., DACVIMDirector, Veterinary ServicesEli Lilly and Company
24Introduction Pharmaceutical industry is under increasing pressure Increasing federal regulations and guidelinesIncreasing costs to deliver new molecular entitiesAs a result, research institutions are evaluating and utilizing contract research organizations (CROs)
25Issues Developing an outsourcing strategy Identifying and evaluating CROsDeveloping policies and procedures for oversight and approval of outsourced studiesIdentifying ongoing outsourced activitiesAssuring regulatory complianceIdentifying the level of institutional oversight necessary for contracted animal work
26Strategies and procedures Utilize only well-established CROs with proven records of success that are AAALAC accreditedUtilize only local CROs so that investigators can oversee studiesUtilize CROs with expertise in certain areasUtilize regional CROs with potential research and business synergies
27Who drives the process? Investigator driven Portfolio driven Management driven
28Each institution should develop its own strategy, understand its own strategy, and communicate that strategy prior to launching major outsourcing efforts.
29Initial stepsEstablish a centralized process for outsourced study approval and managementEstablish a process for veterinary and management approvalEnsure proper provision for research animalsEnsuring there is an alignment with business goals and objectives
30Identify key internal resources Routing of study protocolsInitial contact of potential CROsScheduling of appropriate internal meetingsCoordination of CRO communicationsDevelopment of Statements of Work, purchase orders, and legal contracts
31Identify a legal gatekeeper “Trade secret” information“Proprietary” animal modelsContractsAnimal ownershipAssurance that the CRO will complyReporting of adverse events
32Create a list of all on-going outsourced activities Centralized databaseIdentify approved CROsTrack ongoing outsourced activitiesIdentify CRO areas of expertiseDevelop agreed upon criteria for CROs
33Develop policies for outsourced studies CRO approval criteria and processExpectations for meeting all local, state, and national regulations and guidelinesExpectations for the level and extent of institutional oversight for contracted research including:Ensuring local IACUC review of animal use protocolsEnsuring that the 3 R’s have been addressedEnsuring that the use of alternatives have been addressedEnsuring that the minimum number of animals have been usedEnsuring that duplication of studies has not occurred.Ensuring appropriate removal from study and euthanasia
34Evaluating CROs Develop evaluation criteria for: animal care and use programresearch program
35Evaluation criteria Animal care and use program: regulatory status IACUC activityveterinary programanimal husbandry
36Evaluation criteria Research program: technical staff capabilities general capabilitiesdata collectionquality assurance programsrecords and record retention system
37Specifics Develop detailed study protocols Clearly state the purpose of the study and study objectivesDevelop sample handling and transport procedures
38HarmonizationDetermine if exact harmonization of veterinary care, surgical and animal husbandry procedures is needed between the CRO and the institution. This is critical for study success!
39Harmonization details Specific surgical detailsCagingBeddingWater
40Other considerations Pilot or parallel studies Ethical information (3Rs)ABSL 2 or 3
41Monitoring Who will do the monitoring? Who will report adverse events? Who will oversee:Data collection?Study reports?Final study package?Who has final study package approval?
42ConclusionsDon’t abdicate responsibility for the oversight of animal welfare!Establish company policies and/or guidelinesDevelop accepted CRO criteriaEvaluate CROsDevelop a list of approved CROsDevelop a veterinary and management approval processComplete thorough written contractsDetail study protocolsEstablish lines of communicationPerform and validate pilot studiesDevelop a process for study monitoring
43Contracting in Research to Universities: What are the Issues? Joseph N. Benoit, Ph.D.Dean, Graduate SchoolUniversity of North Dakota
44Contracts are partnerships An agreement between two or more parties to do or not do somethingContractee(University)Contractor(Industry)
45Understanding the partnership “The key to the successful partnership, however is the recognition on both sides that universities and industry have distinct missions. The mission of the university is the pursuit of knowledge for its own sake, the best-known strategy for innovation; and the mission of industries is to make money for their stockholders, the best known strategy for economic progress. In some contexts, these two missions can lead to aims that are antithetical. In other contexts, both aims can be fulfilled in pursuing a common goal, with corresponding benefit to society.”Zack W. Hall, Ph.D., The Academy and Industry: A View Across the Divide. In: Buying In or Selling Out? The Commercialization of the American University, D.G. Stein, Ed., Rutgers University Press, 2004
46Contractor expectations The party awarded the contract will be able to provide the services requested. The contractor assumes that the contractee has the expertise and infrastructure to perform the work.Contractor also expects to own the product of the work conducted by the contractee.
47Contractee viewsThe contractee understands that they will conduct the work.The contractee understands that they will be paid for the work that is done.The contractee may not fully recognize that their ability to to conduct curiosity based research may be curtailed by the contract.
48Universities are becoming more entrepreneurial Research generatesMoneyPrestigeIntellectual property
49The public’s perspective of the university mission has changed “In 1999, North Dakota leaders looked into the future and saw challenges and opportunities that required immediate action. They committed to taking the bold steps needed to improve the state’s economic and demographic picture. These leaders believed the North Dakota University System to be an integral part of expanding and diversifying the state’s economy and enhancing the quality of life for all North Dakotans. As a result, profound changes are taking place, many of which reflect the growing relationships between the NDUS and its many public and private partners.”North Dakota University System
50What are the issues associated with innovative university partnerships? OversightRegulatory ComplianceInfrastructureIntellectual PropertyCuriosity Driven Research vs. Contract Driven ResearchConflicts of Interest and Conflicts of Time
51Oversight of animal care & use Contractor or Contractee IACUC?Who owns the animals?Protocol reviewSearch for alternatives?Pain & Distress?Use of analgesia?Removal of animals from study?Who provides the veterinary care?Employee health and safety?Semiannual Review?
52Regulatory compliance USDAWhich organization is held accountable for deficiencies?Biohazardous AgentsWhich committee reviews and approves protocol?Pharmaceuticals with unknown properties?Infectious agents?Select agents?RadiationWho reviews?Who monitors?Who disposes?
53Infrastructure Adequacy of infrastructure to support the contract Does the contractor verify that the infrastructure exists?Economic benefit to the contractee?Does the contractee overextend their infrastructure for financial gain?
54Intellectual property Who owns the data?Where are the data stored and archived?Whose record retention policies govern data storage and archiving?What about tissue samples?Curiosity-driven research vs. contract-driven researchWho owns the idea?Who owns subsequent ideas?Who benefits when new discoveries are made?
55Academic integrity issues Conflict of interestConflict of time
56Successful contracts involve a complex balancing act
57Suggested readingBuying In or Selling Out? The Commercialization of the American Research University. Donald G. Stein, Ed., Rutgers University Press, 2004.The Creation of the Future: The Role of the American University. Frank H. T. Rhodes, Cornell University Press, 2001.Universities in the Marketplace: The Commercialization of Higher Education. Derek Bok, Princeton University Press, 2003.Science, Money and Politics: Political Triumph and Ethical Erosion. Daniel S. Greenberg, The University of Chicago Press, 2001.The Uses of the University. 5th Edition. Clark Kerr, Harvard University Press, 2001.
58Neutralizing Dual Regulations: AWRs vs. GLPs Kathy Laber, D.V.M., M.S., DACLAMProfessorMedical University of South Carolina
59Good Laboratory Practices 21 CFR Implemented in the late 70’sIn response to the FDA receiving research that was poorly conductedAssure quality and integrity of the safety data conducted in “nonclinical laboratory studies.”GLPs originated without animal impact as a specific focus/concern
60Nonclinical studies Part of FDA drug approval process Adequate pharmacology/ toxicology drug studies using laboratory animals or in vitroSupports that it’s reasonably safe to conduct clinical investigationsTypes of StudiesSingle/Repeat dose toxicity, Biocompatibility, Reproduction/Development, etc…..
61Animal Welfare Act CFR 7 Implemented in mid sixties AWRs originated with focus on random origin dogs & cats, facilities and sanitationImpact on was very limited in first 2 decadesImpact exploded with1985 amendmentsDefinition of the IACUCDefinition of AV /Adequate Veterinary Care
62Intended protocol focus GLPStudy ConductAWAImpact of Study on Animal Welfare
63Critical Player for GLPs Study director “study director has overall responsibility for the technical conduct of the study…..and represents the single point of study control”Does NOT MEAN they may disregard AWA, AV, IACUCFrom 21 CFR Part 58
64Critical player for AWA Attending veterinarian ‘has authority for activities involving animals …research facility shall assure that the attending veterinarian has appropriate authority to ensure the provision of veterinary care“..shall establish programs of adequate veterinary care that include:“daily observation of all animals to assess their health and well-being”From 9 CFR Part 2
65Regulatory language GLP’s “animals may be treated for disease or signs of disease provided that such treatment does not interfere with the study.”“diagnosis, authorization of treatment, description of treatment, and each date of treatment shall be documented…”“SOP’s written for : handling of animals found moribund or dead during study”From 21 CFR Part 58
66Regulatory language AWA Procedures that may cause more than momentary or slight pain or distress will:Involve in their planning, consultation with the Attending Veterinarian..”Animals that would otherwise experience severe or chronic pain or distress that cannot be relieved will be painlessly euthanized at the end of the procedure, or, if appropriate, during the procedureFrom 9 CFR Part 2
67Missing language from both CFRs Useful discussion of End PointsGLP driver- Evidence of Product SafetyAWA driver- Alleviation of pain/distressDefined Interface between Study Director (PI) and VeterinarianStudy Director (Tox Management) reports to FDA and hosts FDA auditsAttending veterinarian leads reporting of animal use (by pain category) to USDA and hosts USDA inspections
68Dueling CFRsToxicologists and Vets may resort to the use of “their” regulations as hammerType A personalities- difficult to resist the temptation to trump each other with higher authority for action/inaction
73Failure to address spirit of GLP’s Insufficient safety information to support clinical testingRepetition of studies and increased animal useIncreased time to make important therapies available to the publicIncreased cost that is forwarded to public
74Failure to address spirit of AWA Negative impact on animalUnrelieved animal care staff pain/distressReportable incident to regulatory agenciesUSDA citation/fineAdverse public relationships
75AAALAC’s perspectiveGoal is avoid /minimize distress and pain in concert with sound scienceReferences AWADoes NOT reference GLP’s
76AAALAC’s perspective“..Euthanasia occurred only after receiving permission from the study director—contrary to principles of Guide-MUST ensure AV has necessary authority to ensure prompt euthanasia.”
77AAALAC’s perspective“…study director determined whether or not veterinary assessment should occur. The study control by the study director does not supersede the requirement to assess animals by the veterinary staff…..attending veterinarian MUST..have the oversight authority for aspects of animal care and use
78AAALAC’s perspectiveDEFFEREDPROBATIONINTENT TO REVOKEREVOKE
80Solution to challenge TEAM APPROACH TO SAFETY STUDIES COMMUNICATE Avoid GLP (us) versus AWA (them) debateLEARN EACH OTHER’S BUSINESS
81Solution to challenge Pre-emptive strike critical to success: Protocol developmentSOP developmentStudy conductDiagnosis or treatment is permitted as long as it does not interfere with study objective. If the treatment interferes, the animal can be removed.
84Research Collaborations at Land Grant Institutions: What are the Issues? Joseph R. Haywood, Ph.D.Professor and ChairpersonDepartment Pharmacology & ToxicologyMichigan State University
85Land grant institutions represent a special challenge Agriculture- and animal science-based educationLarge numbers of undergraduate studentsOutreach efforts – 4H Clubs, toursWildlife and natural resourcesMany species of animalsDiversity of funding sources
86Institutional philosophy USDA: Intellectual and Property OwnershipAAALAC: ControlPHS: MoneyIssuesWhat are the standards of the institution?PHS assurance?
87Scenarios Taking the bull by the horns Shared ownership of animalsSnakes, Snakes, Snakes: What a zoo?No ownership, but faculty involvementFollow the shells: Where is the teaching animal?Informal or formal relationships with privately owned animalsProduction animals or teaching animals?
88Scenarios Out-of-site, Out-of-mind Trans-state-genics Off-site farms Large animal transgenics maintained on a private farmLarge animal antibody-production on a private farm
89Scenarios Lab for Rent: The mobile laboratory Swimming with the fishes Lab ownership, but not animalsSwimming with the fishesStudies with state-owned wildlife on campus and off campus
90Other known scenarios Spay-neuter clinic Veterinary clinical studies on client-owned animalsBlood donorsWildlife recovery ward
91The power of communication Memoranda of UnderstandingPlan for Adequate Veterinary CareProtocol ReviewOthersDisaster PlanOccupational Health concernsTraining issues
92Practical considerations Think logically and talk it throughDon’t create problemsNot every laboratory has four walls and HVACWhat would “60 Minutes” ask me?
93Names, locations, and species are changed to protect the victims
94International Research Contracts and Collaborations Involving Laboratory Animals Dennis M. Stark, D.V.M., Ph.D., DACLAMExecutive Director Veterinary SciencesBristol-Myers SquibbPharmaceutical Research Institute
95What are the issues? Good Science Appropriate Animal Care Regulatory ComplianceInstitutional StandingPlanned Oversight
96Why the concern about standards? RegulationsCulturesLegal CodesEthical CodesLanguage
97Due diligence IACUC Review Legal Review Site Visits – Pre/Ongoing Written Agreement
98What needs to be clear? Study Design Animal Care Veterinary Care Intellectual propertyRoles
99Contracts, agreements and memos of understanding Delineate who is responsible for whatRegulations covering laboratory animal useInspections/auditing defined/by whomReview of contract, institution program, and inspection reportsNotice of all changes in accreditation and regulatory standingProtocol reviewsOwnership of laboratory animalsAnimal and veterinary careProtect Intellectual PropertyConfidentiality provisionsSecurityData/Records/Samples
100What can we learn from granting agencies? Public Health ServiceThe National Institutes of HealthNational Science FoundationDepartment of DefenseNational Academies of ScienceU.S. Department of AgricultureOrganization for Economic Cooperation and Development
101NIH supported activities NIH will not make an award for research involving livevertebrate animals unless the applicant organization and all performance sites are operating in accordance with an approved Animal Welfare Assurance.Foreign organizations proposing activities involvingvertebrate animals are required to comply with the PHSPolicy or provide evidence that acceptable standards for the humane care and use of animals will be met.
102Statement of Compliance with Standards for Humane Care and Use of Laboratory Animals by Foreign InstitutionsIn reference to the Public Health Service Policy on Humane Care and Use of Laboratory Animals, it will comply with laws, regulations, and policies regarding humane care and use of laboratory animals of the jurisdiction in which the research will be conducted.This Institution is guided by the International Guiding Principles for Biomedical Research Involving Animals developed by the Council for International Organizations of Medical Sciences.This Institution acknowledges and accepts responsibility for the care and use of animals involved in activities covered by this Statement of Compliance.
103International Guiding Principles for Biomedical Research Involving Animals Basic Principles (XI)Special ProvisionsAcquisitionTransportationHousingEnvironmental ConditionsNutritionVeterinary CareRecordsMonitoringAlternatives
104Resources PHS Policy on Humane Care and Use of Laboratory Animals Animals.pdfNIH Grants Policy StatementInternational Guiding Principles for Biomedical Research Involving AnimalsApplication of the OECD Principles of GLP to the Organization and Management of Multi-Site Studies_ENV/JM/MONO(2002)9International Regulations
105Association For Assessment And Accreditation of Laboratory Animal Care International
106Thank you A sincere thanks to the following who helped with the preparation of this talk:Kathryn Bayne (AAALAC)Denis Doyle (NIH-OLAW)Terrance Hawk (GlaxoSmithKline)Michael Kastello (sanofi-aventis)Hilton Klein (Merck)Dale Martin (sanofi-aventis)Timothy Morris (GlaxoSmithKline)Edward Mundy (NSF)Mary Newman (BMS)Mary Pat Nowack (NAS)Gregory Reinhard (Merck)James Swearengen (AAALAC)Robert Trotta (BMS)Axel Wolff (NIH – OLAW)Joanne Zurlo (NAS-ILAR)
107Contact AAALAC International email@example.com www.aaalac.org +301.231.5353