3. Who Owns the Animals? Kathryn Bayne, M.S., Ph.D., D.V.M., DACLAM
Senior Director &
Director of Pacific Rim Activities
AAALAC International

4. Oversight authority OLAW USDA AAALAC International
Follows the money trail
“Covered” species on site
Follows animal ownership

5. 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….”

6. USDA
The Animal Welfare Act and accompanying Animal Welfare Regulations provide authority (as determined by the Secretary) for warm-blooded animals
In research facilities, this includes live animals “used or intended for use in research, testing, or experiments”

8. 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.

9. 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 institution’s 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

10. 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.

11. 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”

12. 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.

15. Defining ownership (Webster’s)
Legal right of possession
Lawful title to
Proprietorship (legal title or exclusive right to some property)

16. Defining Ownership
Shades of Grey

17. 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

18. 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

19. Animal Ownership ≠ Intellectual Property

20. Animals 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 teaching
Client-owned animals in maintained in a vet school that are used in an IACUC approved protocol

21. Animals 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 purposes
Animal not owned by accredited unit, but housed in close proximity to those that are, and may impact well-being of the animals
e.g., dairy cows used for milk and cheese production and sale, but also used for teaching
e.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

22. Responsibility & Accountability

23. Contracting Out Research to CROs: What are the Issues?
Wendy J. Underwood, D.V.M., M.S., DACVIM
Director, Veterinary Services
Eli Lilly and Company

24. 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)

25. Issues Developing an outsourcing strategy
Identifying and evaluating 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

26. 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

27. Who drives the process? Investigator driven Portfolio driven
Management driven

28. Each institution should develop its own strategy, understand its own strategy, and communicate that strategy prior to launching major outsourcing efforts.

29. Initial steps
Establish a centralized process for outsourced study approval and management
Establish a process for veterinary and management approval
Ensure proper provision for research animals
Ensuring there is an alignment with business goals and objectives

30. Identify key internal resources
Routing of study protocols
Initial contact of potential CROs
Scheduling of appropriate internal meetings
Coordination of CRO communications
Development of Statements of Work, purchase orders, and legal contracts

31. Identify a legal gatekeeper
“Trade secret” information
“Proprietary” animal models
Contracts
Animal ownership
Assurance that the CRO will comply
Reporting of adverse events

32. Create a list of all on-going outsourced activities
Centralized database
Identify approved CROs
Track ongoing outsourced activities
Identify CRO areas of expertise
Develop agreed upon criteria for CROs

33. Develop policies for outsourced studies
CRO approval criteria and process
Expectations for meeting all local, state, and national regulations and guidelines
Expectations for the level and extent of institutional oversight for contracted research including:
Ensuring local IACUC review of animal use protocols
Ensuring that the 3 R’s 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

34. Evaluating CROs Develop evaluation criteria for:
animal care and use program
research program

35. Evaluation criteria Animal care and use program: regulatory status
IACUC activity
veterinary program
animal husbandry

36. Evaluation criteria Research program: technical staff capabilities
general capabilities
data collection
quality assurance programs
records and record retention system

37. Specifics Develop detailed study protocols
Clearly state the purpose of the study and study objectives
Develop sample handling and transport procedures

38. 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!

39. Harmonization details
Specific surgical details
Caging
Bedding
Water

40. Other considerations Pilot or parallel studies
Ethical information (3Rs)
ABSL 2 or 3

41. 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?

42. Conclusions
Don’t abdicate responsibility for the oversight of animal welfare!
Establish company policies and/or guidelines
Develop accepted CRO criteria
Evaluate CROs
Develop a list of approved CROs
Develop a veterinary and management approval process
Complete thorough written contracts
Detail study protocols
Establish lines of communication
Perform and validate pilot studies
Develop a process for study monitoring

43. Contracting in Research to Universities: What are the Issues?
Joseph N. Benoit, Ph.D.
Dean, Graduate School
University of North Dakota

44. Contracts are partnerships
An agreement between two or more parties to do or not do something
Contractee
(University)
Contractor
(Industry)

45. 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

46. 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.

47. 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.

48. Universities are becoming more entrepreneurial
Research generates
Money
Prestige
Intellectual property

49. The 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

50. 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

51. 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?

52. 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?

53. 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?

54. 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?

55. Academic integrity issues
Conflict of interest
Conflict of time

56. Successful contracts involve a complex balancing act

57. 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.

58. Neutralizing Dual Regulations: AWRs vs. GLPs
Kathy Laber, D.V.M., M.S., DACLAM
Professor
Medical University of South Carolina

59. Good Laboratory Practices 21 CFR
Implemented in the late 70’s
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

60. Nonclinical studies Part of FDA drug approval process
Adequate pharmacology/ toxicology drug studies using laboratory animals or in vitro
Supports that it’s reasonably safe to conduct clinical investigations
Types of Studies
Single/Repeat dose toxicity, Biocompatibility, Reproduction/Development, etc…..

61. Animal Welfare Act CFR 7 Implemented in mid sixties
AWRs originated with focus on random origin dogs & cats, facilities and sanitation
Impact on was very limited in first 2 decades
Impact exploded with1985 amendments
Definition of the IACUC
Definition of AV /Adequate Veterinary Care

62. Intended protocol focus
GLP
Study Conduct
AWA
Impact of Study on Animal Welfare

63. 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

64. 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

65. Regulatory 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

66. 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

67. 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 (PI) 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

68. 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

73. Failure to address spirit of GLP’s
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

74. 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

75. AAALAC’s perspective
Goal is avoid /minimize distress and pain in concert with sound science
References AWA
Does NOT reference GLP’s

76. AAALAC’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.”

77. AAALAC’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

78. AAALAC’s perspective
DEFFERED
PROBATION
INTENT TO REVOKE
REVOKE

80. Solution to challenge TEAM APPROACH TO SAFETY STUDIES COMMUNICATE
Avoid GLP (us) versus AWA (them) debate
LEARN EACH OTHER’S BUSINESS

81. Solution to challenge Pre-emptive strike critical to success:
Protocol development
SOP development
Study conduct
Diagnosis or treatment is permitted as long as it does not interfere with study objective. If the treatment interferes, the animal can be removed.

84. Research Collaborations at Land Grant Institutions: What are the Issues?
Joseph R. Haywood, Ph.D.
Professor and Chairperson
Department Pharmacology & Toxicology
Michigan State University

85. 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

86. Institutional philosophy
USDA: Intellectual and Property Ownership
AAALAC: Control
PHS: Money
Issues
What are the standards of the institution?
PHS assurance?

87. 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?

88. Scenarios Out-of-site, Out-of-mind Trans-state-genics Off-site farms
Large animal transgenics maintained on a private farm
Large animal antibody-production on a private farm

89. Scenarios Lab for Rent: The mobile laboratory Swimming with the fishes
Lab ownership, but not animals
Swimming with the fishes
Studies with state-owned wildlife on campus and off campus

90. Other known scenarios Spay-neuter clinic
Veterinary clinical studies on client-owned animals
Blood donors
Wildlife recovery ward

91. The power of communication
Memoranda of Understanding
Plan for Adequate Veterinary Care
Protocol Review
Others
Disaster Plan
Occupational Health concerns
Training issues

92. Practical considerations
Think logically and talk it through
Don’t create problems
Not every laboratory has four walls and HVAC
What would “60 Minutes” ask me?

93. Names, locations, and species are changed to protect the victims

94. 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

95. What are the issues? Good Science Appropriate Animal Care
Regulatory Compliance
Institutional Standing
Planned Oversight

96. Why the concern about standards?
Regulations
Cultures
Legal Codes
Ethical Codes
Language

97. Due diligence IACUC Review Legal Review Site Visits – Pre/Ongoing
Written Agreement

98. What needs to be clear? Study Design Animal Care Veterinary Care
Intellectual property
Roles

99. Contracts, agreements and memos of understanding
Delineate who is responsible for what
Regulations covering laboratory animal use
Inspections/auditing defined/by whom
Review of contract, institution program, and inspection reports
Notice of all 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

100. What can we learn from granting agencies?
Public Health Service
The National Institutes of Health
National Science Foundation
Department of Defense
National Academies of Science
U.S. Department of Agriculture
Organization for Economic Cooperation and Development

101. 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.

102. 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 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.

103. International Guiding Principles for Biomedical Research Involving Animals
Basic Principles (XI)
Special Provisions
Acquisition
Transportation
Housing
Environmental Conditions
Nutrition
Veterinary Care
Records
Monitoring
Alternatives

104. Resources PHS Policy on Humane Care and Use of Laboratory Animals
Animals.pdf
NIH Grants Policy Statement
International Guiding Principles for Biomedical Research Involving Animals
Application of the OECD Principles of GLP to the Organization and Management of Multi-Site Studies_ENV/JM/MONO(2002)9
International Regulations

105. Association For Assessment And Accreditation of Laboratory Animal Care International

106. Thank 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)

107. Contact AAALAC International accredit@aaalac.org www.aaalac.org +301.231.5353