CITI Module DraftWhat Investigators Need to Know About the Use of Animals in U.S. Public Health Service-Funded Research

Susan SilkCITI Developers MeetingKey West, FLMay 22, 2009

Introduction

This module is offered to help investigators understand their responsibilities when using live animals in PHS-funded research. Define target audience

Institutions that use animals in Public Health Service (PHS)-supported activities are required by the PHS to establish and maintain proper measures to ensure the appropriate care and use of these animals. This includes live vertebrate animals involved in research, research training, and biological testing activities. Define regulated community and regulator

National Institutes of Health (NIH), the Centers for Disease Control and Prevention (CDC) and the Food and Drug Administration (FDA) are the agencies of the PHS that fund animal activities. Define Public Health Service

Intro 1/2

Introduction

The PHS endorses the U.S. Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research, and Training (U.S. Government Principles). The PHS Policy on Humane Care and Use of Laboratory Animals (Policy) implements and supplements the U.S. Government Principles. The Policy requires that institutions base their programs of animal care and use on the Guide for the Care and Use of Laboratory Animals (Guide) and euthanasia protocols on the AVMA Guidelines on Euthanasia.

Provide links to reference documents.

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Why is the NIH Responsible for PHS Policy and Oversight of PHS-supported Animal Activities?

The primary goal of the PHS Policy is to ensure humane animal care and use and to contribute to the high quality of PHS-supported science. Emphasize relationship between Animal welfare and science The NIH, on behalf of the PHS, developed the Policy because the U.S. Congress, in the Health Research Extension Act of 1985 (HREA), directed the NIH Director to establish guidelines for the proper care of animals used for biomedical and behavioral research, teaching, and testing. Link ref document

Compliance with the Policy is required in all research either conducted by the NIH Intramural Program or funded extramurally by any of the PHS agencies. For NIH grantees, compliance with the PHS Policy is one of many terms and conditions of NIH Grants Policy. Compliance is required with PHS funds NIH 1/2

Why is the NIH Responsible for PHS Policy and Oversight of PHS-supported Animal Activities?

NIH policy is developed through an open, collaborative and transparent process. The NIH approaches policy development through interaction with stakeholders — scientists, research institutions, the public, and interest groups from many sectors — in order to fully understand variables, impact, and often, competing factors that must be carefully considered and balanced. Set up to understand development of Policy - maybe not needed??

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How the U.S. Oversight System Was Developed

The current PHS Policy evolved from a review process that began in 1983 when NIH conducted site visits to representative grantee institutions conducting research with animals. Policy was not arbitrary.

The subsequent 1984 report to the NIH Director concluded that the existing system was effective in fostering animal welfare but recommended that the system be expanded to be even more effective. Defensive? Eliminate?

The NIH published the report in conjunction with a proposed policy and invited public comment at hearings. Topics that received particular attention were the role of the veterinarian, animal care committee authority, the lack of qualified laboratory animal veterinarians, the role of the Guide, and potential financial and regulatory burdens. The same issues that are important today.

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How the U.S. Oversight System Was Developed

Following the public comment period, NIH established a 15-member PHS policy drafting committee of NIH staff and including representatives from other components of the PHS.

The committee was charged with considering the comments received in response to the solicitation and with drafting the final policy. The committee carefully considered multiple factors, including animal welfare issues, the nature of research investigations, societal concerns, ethics, budgetary realities, scientific standards, Congressional interest, and the mission and goals of the NIH.

The final Policy was published in June 1985. The 6th edition of the Guide was simultaneously incorporated by reference into the Policy. This could all be condensed or eliminated. History 2/6

How the U.S. Oversight System Was Developed

Also in 1985, the 90th U.S. Congress considered and approved amendments to the PHS Act to revise and extend the authorities of the NIH. The Health Research Extension Act of 1985 included Sec. 495 Animals in Research. Later the same year, Congress passed the 1985 amendments to the Animal Welfare Act (Act) that included significant provisions that were congruent with the PHS Policy. The Act directed the U.S. Department of Agriculture (USDA) to regulate many species of animals utilized in research. Found in the U.S. Code of Federal Regulations at Title 9, Chapter 1, Subchapter A, Parts 1-4, the rules rely on minimal engineering standards, inspections, and an administrative process of citations and fines. Further, the Act mandates that the Secretary of the USDA consult with the Secretary of Health and Human Services prior to the issuance of regulations. Adds links and information about regulatory overlap.

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How the U.S. Oversight System Was Developed

Whereas the HREA provided a legislative mandate for the PHS Policy and confirmed many of the provisions, it also required modification of the newly promulgated PHS Policy to accommodate the law. Of particular interest are provisions addressing refinement, reduction, and replacement (the 3Rs) including explicit requirements in the Policy that require the “concept, availability, and use of research or testing methods that limit the use of animals or limit animal distress”. Important to included 3Rs.

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How the U.S. Oversight System Was Developed

Also included was a mandate that institutional personnel receive training in the humane practice of animal maintenance and experimentation. Other provisions necessitating modification of the Policy included a requirement for Institutional Animal Care and Use Program (IACUC) program evaluation and reporting to the Institutional Official on a semiannual basis, inclusion of minority views in annual reports to the NIH, and IACUC responsibility for submitting reports to NIH through the Institutional Official.

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How the U.S. Oversight System Was Developed

Thus, the 1985 PHS Policy was modified and published in 1986.

Between 1986 and 2009, the only substantive change to the PHS Policy was promulgated after open opportunity for public comment and discussions with stakeholders. That change addressed the timing of IACUC approval relative to submission of grant applications to the NIH.

The 1986 Policy was embraced by the research community and has proved a dramatic success by effecting positive changes in virtually every animal care and use program in which PHS-supported research activities are conducted.

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What Does the PHS Policy Cover?

The Policy addresses institutional responsibility, animal care and use committee oversight, veterinary care, investigator training, minimization of pain and distress, selection of scientifically appropriate animal models and numbers, and humane euthanasia at appropriate endpoints. These factors affect animal welfare and also promote high quality science (i.e., research results that are both reliable and reproducible) and the use of alternatives, the 3Rs (refinement, replacement, and reduction), as well as responsibility and accountability.

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Administration of the PHS Policy

The NIH Office of Laboratory Animal Welfare (OLAW), located within the Office of the NIH Director, is responsible for the general administration of and compliance with the Policy, including education, Assurance and compliance oversight.

OLAW provides guidance and interpretation of the PHS Policy and supports programs that train and educate IACUC members, IACUC staff, and personnel involved in animal activities at PHS Assured institutions. Guidance is provided through Notices in the NIH Guide for Grants and Contracts, the OLAW website, targeted educational venues including online seminars, participation at meetings and workshops throughout the nation by OLAW professional staff, and in response to individual inquiries by telephone (301-496-7163), email (olaw@od.nih.gov) and mail (6705 Rockledge Blvd., Suite 360 Bethesda, MD 20892.

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Administration of the PHS Policy

OLAW ensures the quality of animal programs through the Assurance process. An Animal Welfare Assurance (Assurance) is a contract between OLAW and the institution. After it has been determined that an award will be funded, NIH grants personnel make a request that OLAW initiate the development of an Assurance, if the institution does not already have an Assurance in place. OLAW contacts the institution to initiate the negotiation of an Assurance. Using the sample Assurance document as a guide, the institution describes its animal program.

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Administration of the PHS Policy

OLAW Assurance Officers work closely with the institution to ensure that the Animal Program described meets the requirements of the PHS Policy. When OLAW Assurance officers approve the document, the Assurance then becomes the standard that the institution must meet to maintain compliance with the PHS Policy. Some institutions choose to exceed the requirements of the Policy. The institution is then obligated to meet that standard. Investigators and animal program personnel should become familiar with their institutional Assurance, as this is the standard that OLAW expects them to meet. (Decided against listing contact info as

PIs would not contact OLAW re Assurance.)

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Administration of the PHS Policy

PHS Policy oversight is based on a system of self-monitoring and self-reporting. When an institution experiences a reportable event or situation of noncompliance with the PHS Policy or the institutional Assurance, the institution is expected to promptly report the situation to OLAW. OLAW Compliance officers communicate with the institution to provide guidance on necessary corrective actions, assess the proposed corrective action and ensure that appropriate measures are put in place to prevent reoccurrence. (Decided not to list contact info, as PIs do not typically report noncompliance.)

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What is the Role of the IACUC?

The IACUC is a local institutional committee with federally mandated oversight responsibility. The Congressional Report that accompanied the HREA stated: “It is far preferable to place primary responsibility for assuring compliance with NIH guidelines on committees within institutions rather than relying on intrusive Federal inspections.” Thus the primary mechanism for animal program oversight in the U.S. is the Institutional Animal Care and Use Committees (IACUC). IACUCs, composed of individuals in the role of scientist, non scientist, veterinarian non affiliated member, and community representative, provide effective oversight of animal welfare while overseeing the unique requirements of robust biomedical research in the context of community standards.

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What are the Responsibilities of an IACUC?

The responsibilities of an IAUCUC include:

• Reviewing animal use protocols;

• Reviewing significant changes to protocols;• Evaluating institutional compliance with PHS Policy, USDA

Animal Welfare Regulations (AWR), and institutional policies;

• Monitoring institutional animal care and use programs, including inspecting animal facilities;

• Reviewing concerns about animal care and use; and • Through the IO, reporting noncompliance and

suspensions to OLAW.

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Who Must Comply With the PHS Policy?

The PHS Policy applies to all PHS-conducted or -supported activities involving live vertebrate animals, whether the activities are performed at a PHS agency, an awardee institution, or any other institution when conducted in the United States, the Commonwealth of Puerto Rico, or any territory or possession of the United States. Institutions in foreign countries receiving PHS support for activities involving animals comply with this Policy, or provide evidence to the PHS that acceptable standards for the humane care and use of the animals in PHS-conducted or -supported activities will be met.

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Who Must Comply With the PHS Policy?

Compliance with the International Guiding Principlals for Biomedical Research Involving Animals of the Council for

International Organizations of Medical Sciences (CIOMS) and compliance with local laws in effect in the country meet the meet this standard. No PHS support for an activity involving animals is provided unless the grantee is affiliated with or sponsored by an institution that can and does assume responsibility for compliance with PHS Policy.

The PHS Policy applies to extramural and intramural activities supported by any PHS agency, including NIH, FDA, and CDC. All funding mechanisms, including research and training grants, cooperative agreements, and contracts, conducted at domestic and foreign institutions, are covered by the Policy

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Which Regulations Have Priority?

It is an absolute requirement of the PHS that investigators and institutions using PHS funds to conduct animal activities comply with applicable regulations (9 CFR, Subchapter A) issued by the USDA under the Animal Welfare Act (AWA). Animal and Plant Health Inspection Service (APHIS) is the USDA unit that oversees animal health.

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Which Regulations Have Priority?

The AWA defines “animal” as “any live or dead dog, cat, nonhuman primate, guinea pig, hamster, rabbit, or any other warm-blooded animal, which is being used, or is intended for use for research, teaching, testing, experimentation, or exhibition purposes, or as a pet. This term excludes birds, rats of the genus Rattus, and mice of the genus Mus, bred for use in research.”

The PHS Policy defines “animal” as “Any live, vertebrate animal used or intended to for use in research, research training, experimentation, or biological testing or for related purposes.”

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Which Regulations Have Priority?

The PHS Policy does not override applicable state or local laws or institutional regulations that impose more stringent standards for the care and use of laboratory animals. PHS-funded institutions are also required to comply, as applicable, with the Animal Welfare Act, and other federal statutes and regulations relating to animals.

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Relationships Among Federal Regulators

Since the 1980s, the NIH, USDA, and FDA have worked cooperatively to ensure consistency and uniform standards where possible. The NIH, USDA APHIS, and the FDA have had a Memorandum of Understanding (MOU) Concerning Laboratory Animal Welfare in place since 1983 Although agency heads and liaison representatives have changed throughout the years, the MOU has changed very little and it has proved an effective tool for ensuring agency cooperation, the sharing of information, and for moderating the potential negative impact of overlapping federal jurisdictions.

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Relationships Among Federal Regulators

These agencies meet at least twice a year to discuss areas of concern and coordinate oversight responsibilities. The plethora of regulations and requirements reflect the differing missions and responsibilities of various agencies. Increased cooperation, communication, and joint review of proposed regulations and guidelines among the agencies reflect a commitment to reduce regulatory burden for biomedical researchers and research institutions.

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What are Institutional, Investigator and IACUC Responsibilities in PHS-supported

Animal Activities?

A collaborative relationship exists between the NIH and grantee institutions. PHS-funded research is a partnership among the grantee institution, the investigators, the IACUC, the NIH and OLAW. The partners share a mutual need to ensure compliance. Each partner has responsibilities and obligations as stewards of public funds.

PHS-funded investigators are responsible for animal welfare from the time that they begin planning the animal activities, applying for funding and through the duration of animal activities.

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Investigator Responsibilities

The proposed involvement of vertebrate animals is evaluated as part of the agency peer review process. In addition to providing IACUC approval status, applicants must address five points of the Vertebrate Animal Section in the Research Plan of the funding application. The five points are:

1. A detailed description of the proposed use of the animals, including species, strains, ages, sex, and numbers.

2. Justification of the use of animals, choice of species, and numbers to be used.

3. Information on the veterinary care of the animals.

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Investigator Responsibilities

4. A description of the procedures for ensuring humane treatment (i.e., minimization of discomfort, distress, pain, and injury).

5. The method of euthanasia, the reasons for its selection, and consistency with the AVMA Euthanasia Report.

Failure to adequately address these elements will result in the application being designated incomplete, and it is grounds for PHS to defer the application, or it may negatively affect the priority score.

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What Does OLAW Expect from Institutions and Investigators?

• Ensure congruence between animal activities described in the funding application and those described in the animal study protocol.

• Obtain IACUC approval prior to using animals and prior to implementing significant changes.

• Ensure research is conducted in accord with the IACUC-approved protocol.

• Compliance with institutional policies and procedures. • Address significant changes to the use of animals in

progress reports.• Address changes in the use of animals that may be a

potential change in scope.

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IACUC Review and Approval

IACUC approval is required prior to award except in rare circumstances (e.g., Just-in-Time awards). The IACUC will require the investigator to submit information about the care and use of animals on a protocol form. Most animal use protocols require a description of the following elements:

• Description of the research project;

• Rationale for animal use and consideration of alternatives;• Justification for the choice of species and number of animals;• Description of the research procedures involving animals;• Procedures to minimize pain and distress;• Animal living conditions and veterinary care;• Names and qualifications of personnel who will perform work

with animals;• Method of euthanasia; endpoint criteria.

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IACUC Review and Approval

The use of animals as described in the protocol approved by the IACUC must be congruent with the description in a competing grant application. Any modification required by the IACUC that affects the content of the application must be submitted to the funding agency along with the IACUC approval date.IACUC approval is required at least every 3 years by the PHS and annually if covered by USDA regulations. Significant changes in animal care and use are to be approved by the IACUC prior to implementation. Conducting research in the absence of a valid IACUC approval or implementing a significant change without IACUC approval constitutes noncompliance that must be reported to OLAW.

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IACUC Review and Approval

There is some overlap in the review of the funding proposal by the Scientific Review Group (SRG) and review of the animal study protocol by the IACUC. Both reviews are necessary and required. The SRG reviews the proposal to determine the scientific merit of the proposed research and whether the intended research is appropriate in the context of the nation’s research portfolio. The SRG must also consider the welfare of research animal subjects. The IACUC is primarily concerned with animal welfare but must also consider the value of the research to determine that use of animals is appropriate.

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Need Additional Clarification?

OLAW welcomes stakeholder questions by telephone (301-496-7163) or e-mail (olaw@od.nih.gov).

BibliographyDevelopment of Public Health Service Animal Welfare PolicyWhat Investigators Need to Know About the Use of Animals

Visit the following Web sites for additional information:NIH Office of Laboratory Animal Welfare1996 Guide for the Care and Use of Laboratory AnimalsNIH Grants Policy Statement (2003)PHS 398 Grant ApplicationSF424 (R&R) Application and Electronic Submission Information

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