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 research facilities, this includes live animals “used or intended for use in research, 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 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

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.

Defining ownership (Webster’s)

Legal right of possession

Lawful title to

Proprietorship (legal title or exclusive right to some property)

Defining Ownership

Shades of Grey

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

Animal Ownership≠

Intellectual Property

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

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

Responsibility & Accountability

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

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 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

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 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

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

Identify a legal gatekeeper

“Trade secret” information “Proprietary” animal models Contracts Animal ownership Assurance that the CRO will comply Reporting of adverse events

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

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

Evaluating CROs

Develop evaluation criteria for: animal care and use program research program

Evaluation criteria

Animal care and use program: regulatory status IACUC activity veterinary program animal husbandry

Evaluation criteria

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

Specifics

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

Specific surgical details Caging Bedding Water

Other considerations

Pilot or parallel studies Ethical information (3Rs) ABSL 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?

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

Contracting in Researchto 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 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

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, D.V.M., M.S., DACLAM

Professor

Medical University of South Carolina

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

Nonclinical studiesPart 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…..

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

Intended protocol focus

GLP Study Conduct

AWA Impact of Study on Animal Welfare

Critical Player for GLPsStudy 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 AWAAttending 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 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

Regulatory languageAWA 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 (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

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 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

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

AAALAC’s perspective Goal is avoid

/minimize distress and pain in concert with sound science

References AWA Does NOT reference

GLP’s

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.”

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

AAALAC’s perspectiveDEFFERED

PROBATION

INTENT TO REVOKE

REVOKE

Solution to challenge

TEAM APPROACH TO SAFETY STUDIES

COMMUNICATE Avoid GLP (us) versus AWA (them) debate

LEARN EACH OTHER’S BUSINESS

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.

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 Don’t create problems Not every laboratory has four walls and

HVAC What would “60 Minutes” ask me?

Names, locations, and species are changed to protect the

victims

International Research Contracts and Collaborations InvolvingLaboratory Animals

Dennis M. Stark, D.V.M., Ph.D., DACLAMExecutive Director Veterinary SciencesBristol-Myers SquibbPharmaceutical Research Institute

What are the issues?

Good Science

Appropriate Animal Care

Regulatory Compliance

Institutional Standing

Planned Oversight

Why the concern about standards?

Regulations

Cultures

Legal Codes

Ethical Codes

Language

Due diligence

IACUC Review

Legal Review

Site Visits – Pre/Ongoing

Written Agreement

What needs to be clear?

Study Design

Animal Care

Veterinary Care

Intellectual property

Roles

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

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

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 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.

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.

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

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) 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)

A sincere thanks to the following who helpedwith the preparation of this talk:

Contact AAALAC Internationalaccredit@aaalac.org

www.aaalac.org+301.231.5353