Who Owns the Animals? Kathryn Bayne, M.S., Ph.D., D.V.M., DACLAM Senior Director & Director of Pacific Rim Activities AAALAC International
Oversight authority OLAW USDA AAALAC International Follows the money trail Covered species on site Follows animal ownership
PHS 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….
USDA The Animal Welfare Act and accompanying Animal Welfare Regulations provide authority (as determined by the Secretary) for warm- blooded animals In laboratory animal programs, this includes live animals used or intended for use in research, teaching, testing, or experiments
AAALAC International All 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.
What does AAALAC visit? If your accredited institution owns animals at another accredited institution We will not include those animals in your site visit; they will be addressed during the other institutions visit If your accredited institution owns animals at a non-accredited institution You will need to include those animals in your Program Description and we will include them in the site visit
However, 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.
What 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 animals This does not need to be described in the Program Description, nor declared as part of your accredited unit
Institutions 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.
To 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
How to avoid confusion During 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
Animals at your institution that you dont own but which may be reviewed by AAALAC Raptors in a rehab program owned by FWS, but used for teaching Client-owned animals in maintained in a vet school that are used in an IACUC approved protocol
Animals at your institution that you dont 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 purposes Animal not owned by accredited unit, but housed in close proximity to those that are, and may impact well-being of the animals
Contracting Out: What are the Issues? Wendy J. Underwood, DVM, MS, DACVIM Director, Veterinary Resources Eli Lilly and Company
Introduction Pharmaceutical industry is under increasing pressure Increasing federal regulations and guidelines Increasing costs to deliver new molecular entities As a result, research institutions are evaluating and utilizing contract research organizations (CROs)
Issues Developing an outsourcing strategy Identifying, evaluating and approving CROs Developing policies and procedures for oversight and approval of outsourced studies Identifying ongoing outsourced activities Assuring regulatory compliance Identifying the level of institutional oversight necessary for contracted animal work
Strategies and procedures Utilize only well-established CROs with proven records of success that are AAALAC accredited Utilize only local CROs so that investigators can oversee studies Utilize CROs with expertise in certain areas Utilize regional CROs with potential research and business synergies
Who drives the process? Investigator driven Portfolio driven Management driven
Each institution should develop its own strategy, understand its own strategy, and communicate that strategy prior to launching major outsourcing efforts.
Initial steps Establish a centralized process for outsourced study approval and administrative management Establish a process for veterinary and management approval Ensure proper provision for research animals Ensure alignment with business goals and objectives
Identify key internal resources Routing of study protocols and contracts Initial contact of potential CROs Scheduling of appropriate internal meetings Coordination of CRO communications Development of Statements of Work, Purchase Orders, and legal contracts
Identify a legal gatekeeper Trade secret information Proprietary animal models Contracts should be detailed Ownership of animals Assurance that the CRO will comply Reporting of adverse events
Centralized database List approved CROs Identify CRO areas of expertise List all outsourced activities Track ongoing outsourced activities
The institution should develop policies for outsourced studies! CRO approval criteria Expectations for meeting all local, state, and national regulations and guidelines Expectations for the level and extent of institutional oversight including: Ensuring IACUC review of animal use protocols Ensuring that the 3 Rs have been addressed Ensuring that the use of alternatives have been addressed Ensuring that the minimum number of animals have been used Ensuring that duplication of studies has not occurred. Ensuring appropriate removal from study and euthanasia
Evaluating CROs Develop evaluation criteria for: animal care and use program research program
Evaluation criteria Animal care and use program: regulatory status veterinary program animal husbandry physical plant security
Evaluation criteria Research program: organizational structure technical staff capabilities general research capabilities data collection methods and capabilities quality assurance programs records and record retention systems
CRO specialties Surgical models surgeon qualifications number and location of surgical sites surgeon turnover and training Breeding programs genetic integrity record keeping and animal tracking biosecurity and veterinary care security and transportation
Many issues arise, but can be addressed! Develop detailed study protocols Clearly state the purpose of the study and study objectives Develop sample handling and transport procedures
Harmonization Determine 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!
Harmonization details Health status Veterinary program Specific surgical details Husbandry Caging Bedding Water
Other considerations Pilot or parallel studies Ethical information (3Rs) Biosafety: ABSL level 2 or 3?
Monitoring 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?
An informal survey was done for benchmarking purposes Went to COMPMED, Council, colleagues 32 responses
Question #1: What type of contracting organization 14 private 11 pharma (6-disc; 4-disc/tox; 1-ASR) 3 biotech 18 public 4 were vet schools 12 were universities 1 was a hospital 3 mixed
Q#2: Asked if profit, nonprofit, AAALAC, USDA, etc. 24/32 were AAALAC Accredited 28/32 were USDA registered 20/32 were PHS Assured 30/32 had an IACUC Indicates general compliance Contractors can use this information
Q#3: Is the process official? 14/32 had an official process 13/32 had an unofficial process 5/32 had no process
Q#4: What did the formal approval process include? 2/32 said a thorough process was created and required a site visit, but 7/32 said the process could be better Other: 4-AAALAC, 5-PHS; 7-USDA 6-9: policy/guideline based Tox units required official visits and AAALAC Accreditation
Q#5: What did the informal process include? 6/32 req AAALAC; 18 prefer, 3 dont 16/32 req USDA; 3 prefer, 3 dont 11/32 req PHS; 4 prefer; 4 dont 7/32 req GLP; 6 prefer; 7 dont Private sector puts more emphasis on USDA and GLP, while public sector puts more emphasis on USDA and PHS.
Q#6: What official paperwork is required? 6/32 said none 10/32 said official IACUC approval letters by both institutions! [9/32 were from Private sector!) So, institutions do require some paperwork, and the public sector usually requires IACUC documentation.
Q#7: If concerned about differing standards for ACU. 13/14 for-profit said Yes 8/18 not-for-profit said Yes Implies general concern for differing standards for animal care and use.
Q#8: Who coordinates contracted studies? 27/32 had an over sight program 9/32 said Lab Animal Management 8/32 said Research Management 10/32 said other, IACUC So, a variety of organizational units administrate contracted studies.
Q#9: Is the unit moving toward a more official process? 18/32 said Yes! 12/14 for-profit private institutions said Yes 6/18 not-for-profit public said Yes Interesting! For-profit units also indicated (Q#7) concern about differing standards.
Q#10: Does lab animal management know the total number of studies contracted? 14/32 said Yes 9/18 not-for-profit said Yes 5/14 for-profit said Yes
Q# 11: Does the IACUC know the number and type of studies outsourced? 15/32 said Yes 3/14 of for-profit said Yes 12/18 of not-for-profit said Yes Interesting contrast!
Conclusions Dont abdicate responsibility for the oversight of animal welfare! Establish company policies and/or guidelines Develop database of approved CROs Establish an institutional approval process for outsourced studies
Conclusions (contd) Develop thorough written contracts Create detailed study protocols Perform and validate pilot studies Establish lines of communication Develop a process for study monitoring
Contracting in Research to Universities: What are the Issues? Joseph N. Benoit, Ph.D. Dean, Graduate School University of North Dakota
Contracts are partnerships An agreement between two or more parties to do or not do something Contractor (Industry) Contractee (University)
Understanding 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
Contractor 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.
Contractee views The 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.
Universities are becoming more entrepreneurial Research generates Money Prestige Intellectual property
The publics 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 states economic and demographic picture. These leaders believed the North Dakota University System to be an integral part of expanding and diversifying the states 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
What are the issues associated with innovative university partnerships? Oversight Regulatory compliance Infrastructure Intellectual property Curiosity driven research vs. contract driven research Conflicts of Interest and Conflicts of Time
Oversight of animal care & use Contractor or Contractee IACUC? Who owns the animals? Protocol review Search for alternatives? Pain & Distress? Use of analgesia? Removal of animals from study? Who provides the veterinary care? Employee health and safety? Semiannual Review?
Regulatory compliance USDA Which organization is held accountable for deficiencies? Biohazardous Agents Which committee reviews and approves protocol? Pharmaceuticals with unknown properties? Infectious agents? Select agents? Radiation Who reviews? Who monitors? Who disposes?
Infrastructure 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?
Intellectual 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 research Who owns the idea? Who owns subsequent ideas? Who benefits when new discoveries are made?
Academic integrity issues Conflict of interest Conflict of time
Successful contracts involve a complex balancing act
Suggested reading Buying 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.
Neutralizing Dual Regulations: AWRs vs. GLPs Kathy Laber, DVM, MS, DACLAM Professor Medical University South Carolina
Good Laboratory Practices 21 CFR Implemented in the late 70s In response to the FDA receiving research that was poorly conducted Assure quality and integrity of the safety data conducted in nonclinical laboratory studies. GLPs originated without animal impact as a specific focus/concern
Nonclinical studies Part of FDA drug approval process adequate pharmacology/ toxicology drug studies using laboratory animals or in vitro supports that its reasonably safe to conduct clinical investigations Types of Studies Single/Repeat dose toxicity, Biocompatibility, Reproduction/Development, etc…..
Animal Welfare Act CFR 7 Implemented in mid sixties AWRs originated with focus on random origin dogs & cats, facilities and sanitation Impact was very limited in first 2 decades Impact exploded with1985 amendments Definition of the IACUC Definition of AV /Adequate Veterinary Care
Intended protocol focus GLP Study Conduct AWA Impact of Study on Animal Welfare
Critical 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, IACUC From 21 CFR Part 58
Critical 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
Regulatory language GLPs 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… SOPs written for : handling of animals found moribund or dead during study From 21 CFR Part 58
Regulatory 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 procedure From 9 CFR Part 2
Missing language from both CFRs Useful discussion of End Points GLP driver- Evidence of Product Safety AWA driver- Alleviation of pain/distress Defined Interface between Study Director and Veterinarian Study Director (Tox Management) reports to FDA and hosts FDA audits Attending veterinarian leads reporting of animal use (by pain category) to USDA and hosts USDA inspections
Dueling CFRs Toxicologists and Vets may resort to the use of their regulations as hammer Type A personalities- difficult to resist the temptation to trump each other with higher authority for action/inaction
Failure to address spirit of GLPs Insufficient safety information to support clinical testing Repetition of studies and increased animal use Increased time to make important therapies available to the public Increased cost that is forwarded to public
Failure to address spirit of AWA Negative impact on animal Unrelieved animal care staff pain/distress Reportable incident to regulatory agencies USDA citation/fine Adverse public relationships
AAALACs perspective Goal is avoid /minimize distress and pain in concert with sound science References AWA Does NOT reference GLPs
AAALACs 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.
AAALACs 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 …
AAALACs perspective DEFFERED PROBATION INTENT TO REVOKE REVOKE
Solution to challenge TEAM APPROACH TO SAFETY STUDIES COMMUNICATE Avoid GLP (us) versus AWA (them) debate LEARN EACH OTHERS BUSINESS
Solution to challenge Pre-emptive strike critical to success: Protocol development: Diagnosis or treatment is permitted as long as it does not interfere with study objective. If the treatment interferes, the animal can be removed SOP development: Study conduct i.e. define nursing care
Solution to challenge Define endpoints Minimize mortality, opt for human euthanasia Rapid weight loss (15-20%) Extended period of weight loss>emaciation Prolonged lethargy Debilitating/prolonged diarrhea Condition that interferes with animals ability to eat/drink i.e. ataxia/weakness Bleeding, marked icterus, anemia
Research Collaborations at Land Grant Institutions: What are the Issues? Joseph R. Haywood, Ph.D. Professor and Chairperson Department Pharmacology & Toxicology Michigan State University
Land grant institutions represent a special challenge Agriculture- and animal science-based education Large numbers of undergraduate students Outreach efforts – 4H Clubs, tours Wildlife and natural resources Many species of animals Diversity of funding sources
Institutional philosophy USDA: intellectual and property ownership AAALAC: control PHS: money Issues What are the standards of the institution? PHS assurance?
Scenarios Taking the bull by the horns Shared ownership of animals Snakes, snakes, snakes: What a zoo? No ownership, but faculty involvement Follow the shells: Where is the teaching animal? Informal or formal relationships with privately owned animals Production animals or teaching animals?
Scenarios Out-of-site, out-of-mind Off-site farms Trans-state-genics Large animal transgenics maintained on a private farm Large animal antibody-production on a private farm
Scenarios Lab for rent: the mobile laboratory Lab ownership, but not animals Swimming with the fishes Studies with state-owned wildlife on campus and off campus
Other known scenarios Spay-neuter clinic Veterinary clinical studies on client-owned animals Blood donors Wildlife recovery ward
The power of communication Memoranda of Understanding Plan for Adequate Veterinary Care Protocol Review Others Disaster Plan Occupational Health concerns Training issues
Practical considerations Think logically and talk it through Dont create problems Not every laboratory has four walls and HVAC What would 60 Minutes ask me?
Names, locations, and species were changed to protect the victims
International Research Contracts and Collaborations Involving Laboratory Animals Dennis M. Stark, D.V.M., Ph.D., DACLAM Executive Director Veterinary Sciences Bristol-Myers Squibb Pharmaceutical Research Institute
What are the issues? Good science Appropriate animal care Regulatory compliance Institutional standing Planned oversight
Why the concern about standards? Legal codes Regulations Ethical codes Cultures Language
Due diligence Site visits – pre/ongoing Written agreement Legal review IACUC review
What needs to be clear? Study design Animal care Veterinary care Roles Intellectual property
Contracts, agreements and memos of understanding Delineate who is responsible for what Regulations covering laboratory animal use Inspections/auditing defined Periodic contract, program, and inspection report review Notice of changes in accreditation and regulatory standing Protocol reviews Ownership of laboratory animals Animal and veterinary care Protect Intellectual Property Confidentiality provisions Security Data/Records/Samples
What can we learn from public agencies? Public Health Service The National Institutes of Health National Science Foundation Department of Defense National Academies of Science US Department of Agriculture Organization for Economic Cooperation and Development
NIH supported activities NIH will not make an award for research involving live vertebrate animals unless the applicant organization and all performance sites are operating in accordance with an approved Animal Welfare Assurance. Foreign organizations proposing activities involving vertebrate animals are required to comply with the PHS Policy or provide evidence that acceptable standards for the humane care and use of animals will be met.
Statement of Compliance with Standards for Humane Care and Use of Laboratory Animals by Foreign Institutions In 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 acknowledges and accepts responsibility for the care and use of animals involved in activities covered by this Statement of Compliance. This Institution is guided by the International Guiding Principles for Biomedical Research Involving Animals developed by the Council for International Organizations of Medical Sciences.
International Guiding Principles for Biomedical Research Involving Animals Basic Principles (XI) Special Provisions Acquisition Transportation Housing Environmental conditions Nutrition Veterinary care Records Monitoring Alternatives
Resources PHS Policy on Humane Care and Use of Laboratory Animals http://grants2.nih.gov/grants/olaw/references/PHSPolicyLab Animals.pdf NIH Grants Policy Statement http://grants1.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part5.htm#_Toc54600087 http://grants1.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part5.htm#_Toc54600087 International Guiding Principles for Biomedical Research Involving Animals http://www.cioms.ch/1985_texts_of_guidelines.htm Application of the OECD Principles of GLP to the Organization and Management of Multi-Site Studies - ENV/JM/MONO(2002)9 www.oecd.org/ehs/ International Regulations http://www.aaalac.org/resources/internationalregs.cfm
Association For Assessment And Accreditation of Laboratory Animal Care International
Thank you Kathryn Bayne (AAALAC) Denis Doyle (NIH-OLAW) Betty Goldentyer (USDA) 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 Wolf (NIH – OLAW) Joanne Zurlo (NAS-ILAR) A sincere thanks to the following who helped with the research for this talk:
Contact AAALAC International email@example.com www.aaalac.org +301.231.5353