Overview
The area of animal research presents a myriad of regulatory and ethical issues. Currently, clinical trials in animals are required as a condition to approval of new drugs by the U.S. Food and Drug Administration (FDA),[2] and thus, animal research plays an important role in pharmaceutical innovation. Accordingly, research compliance officers should be familiar with the regulatory requirements governing animal research. This chapter will provide an overview of the regulatory structure that governs animal research and includes a discussion of the following topics:
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Primary principles, laws and regulatory agencies governing animal research
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Major players in animal research programs and their roles and responsibilities
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Additional compliance considerations unique to animal research
Within each of these areas, focus areas for effective compliance programs are identified.
Primary Principles, Laws and Regulatory Agencies Governing Animal Research
The overarching set of ethical principles that govern animal research conducted or regulated by the federal government is the U.S. Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research and Training (the “Principles.”)[3] The principles set forth the premises that should be followed in designing and conducting animal research, and they form the basis of all other laws regulating animal research.
The principles are based on the “3 Rs” of animal research: Reduce the number of animals used in research; Refine experiments to minimize pain and discomfort to animals; and Replace animal experiments with alternatives when feasible. Research compliance programs should ensure that personnel who staff animal care and use programs are familiar with the principles’ main tenets:
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Avoid using animals needlessly. Design and perform research procedures in a way that ensures the research is relevant to advancing human/animal health or important knowledge.
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Use an appropriate animal species and the minimum number of animals necessary to obtain valid research results.
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Research should be designed to prevent or minimize discomfort, pain, and distress in animals. If a procedure would hurt a human, it should be assumed to hurt an animal, unless specific knowledge to the contrary has been established.
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Research that causes more than momentary or slight pain or distress in an animal should incorporate the use of anesthetics, analgesics or tranquilizers (“AAT Drugs”).
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Animals that suffer severe or chronic pain or distress that cannot be relieved should be euthanized.
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Research animals must have appropriate living conditions and receive care that is directed by a qualified veterinarian.
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Research must be conducted by qualified investigators who are trained in the use of research animals.
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Animal research must be conducted in accordance with all applicable federal regulations, and any exceptions to the regulations must be pre-approved by an Institutional Animal Care and Use Committee (IACUC).
The principles’ influence is readily apparent in the two main sets of federal laws that govern animal research in the United States: (a) the Public Health Service Policy on Humane Care and Use of Laboratory Animals,[4] and (b) the Animal Welfare Act[5] and its implementing Animal Welfare Regulations,[6] referred to collectively as the “AWA.” Each of these laws is discussed more fully below. As with any area in which multiple laws and regulations apply, the strictest of the applicable laws or regulations should always be followed.
Public Health Service Policy and the Office of Laboratory Animal Welfare
The Public Health Service Policy on Humane Care and Use of Laboratory Animals (“PHS Policy”) applies to live, vertebrate animals of all types (whether warm or cold blooded) that are used in research, research training or experimentation that is supported by funding from the United States Public Health Service (PHS) or one of its components (e.g., National Institutes of Health [NIH], FDA, Centers for Disease Control and Prevention, etc.). The PHS Policy covers PHS-funded activities that take place both inside or outside of the United States, and it applies to both traditional lab-based research and field work in the animals’ natural setting.
The PHS Policy is administered and enforced by the federal Office for Laboratory Animal Welfare (OLAW). The PHS Policy requires that individuals who receive PHS-funding for animal research be affiliated with an institution that assumes responsibility for complying with the PHS Policy. The PHS Policy requires that the institution comply with the Guide for the Care and Use of Laboratory Animals (the “Guide”)[7] and that euthanasia methods conform to the American Veterinary Medical Association Guidelines for the Euthanasia of Animals.[8] Additionally, the PHS Policy requires inclusion of the following information in PHS grant applications for animal research: rationale for use of animals; appropriateness of species to be used; number of animals to be used; description of proposed use; description of methods used to minimize pain and discomfort; and euthanasia methods.
Prior to the receipt of any PHS funds for animal research, and every four years thereafter, institutions must file an Animal Welfare Assurance (“assurance”) with OLAW.[9] The assurance mandates, among other things, that institutions adhere to the following requirements:
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Compliance with the Principles, AWA, PHS Policy and the Guide.
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Establishment of an institutional animal care and use program with appropriate lines of responsibility and participation by qualified veterinarians.
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Establishment of an IACUC.
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Maintenance of specific assurance, IACUC and animal care and use program records.
The assurance document must provide an accurate description of the research institution’s animal care and use program, and the research compliance officer should be very familiar with the assurance’s contents. If the institution makes any changes to its animal care and use program that affect the assurance, an amended assurance must be filed with OLAW at the time of the change.
The assurance must include a description of all of the institution’s facilities in which animals and used or housed, and include the species and number of animals that are used. The assurance requires designation of an institutional official who has top-level authority within the organization for oversight of the animal care and use program. A description of the program’s specific lines of authority and approval also is required. The assurance must describe the membership of the IACUC and its procedures, including those for reporting and reviewing concerns about the care and use of animals at the institution. Finally, the assurance must describe the training required for animal users and caretakers, as well as the occupational health program in place for all persons who work with animals at the institution. Research compliance officers should ensure that appropriate institutional health and safety officials are involved in the development and implementation of the occupational health program to ensure compliance with any workers compensation and/or state or federal occupational health and safety requirements.
In addition to filing the assurance, each research institution also must file an annual report with OLAW. This annual report must describe any changes in the animal care and use program, including any change in an institution’s accreditation status if accredited by AAALAC (see accreditation discussion below). The report also must include an assurance that all IACUC inspections and program evaluations have been conducted, as well as any minority view voiced by an IACUC member who disagreed with the IACUC’s conclusions regarding facility or program reviews.
The Guide for the Care and Use of Laboratory Animals
As noted above, the PHS Policy and Assurance require that institutions performing PHS-funded animal research follow the requirements of the Guide for the Care and Use of Laboratory Animals, or the “Guide.” The Guide sets forth very detailed standards for the administration and operation of animal care and use programs, including IACUC operations; engineering standards for animal environment, housing and management; veterinary care; physical plant; and emergency and disaster planning. Research compliance programs should undertake a detailed review of the Guide and determine its specific application to their institutions’ facilities and programs. Working with the IACUC, the compliance officer should develop appropriate checklists to ensure that Guide requirements are being addressed.
Animal Welfare Act and the U.S. Department of Agriculture
The Animal Welfare Act and its implementing regulations (referred to collectively as the “AWA”) governs live or dead warm-blooded animals that are intended for use in research, teaching, testing, experimentation, exhibition or as pets. The AWA is enforced by the U.S Department of Agriculture (USDA) through its Animal and Plant Health Inspection Service (APHIS). The AWA applies to research using all species of live or dead warm-blooded animals (“covered species”) with a very important exception: research with mice, rats and birds is not covered.
Under the AWA, organizations or individuals must register with the USDA as “research facilities” if they plan to use a covered species in research and the research is federally-funded, or the animals were purchased in commerce. A new registration must be filed with the USDA every three years, and each registration or renewal requires the facility to certify that it is in full compliance with the AWA. Research compliance officers should be aware that their facilities additionally will need to apply to the USDA for an animal dealer’s license if they also sell or trade some of their research animals to other research facilities.
Each registered research facility will be annually inspected by a USDA inspector. The inspector generally arrives at the facility unannounced and visually inspects all facilities in which covered species are used, housed or transported. In addition, the USDA inspector will review program records, as well as records maintained by the IACUC. Deficiencies noted during inspections must be corrected within the timeframe specified by the USDA, and serious or uncorrected deficiencies may result in citations and fines.
In addition to registration, each research facility must file an annual report that the USDA posts on its website. The annual report lists the number and type of each covered species held by the research facility, along with the USDA pain and distress class to which the animal has been assigned. The pain and distress classes are as follows:
Class B: The animal is being held but has not yet been used for research.
Class C: The animal is used in research that does not involve any pain or distress and does not use any analgesics, anesthetics or tranquilizers (collectively referred to as “AAT Drugs”)
Class D: The animal is used in research that causes pain and/or distress but AAT Drugs are used.
Class E: The animal is used in research that causes pain and/or distress and AAT Drugs are not used because their use would have an adverse impact on the research. For animal used in Class E research, the annual report must include a description of the procedures that the animals undergo and the scientific justification for withholding AAT Drugs.
The annual report is a very important document because it is posted on the USDA website to permit public scrutiny of the number of animals being held in various pain and distress classes, with particular attention being paid to animals used in Class E research. Research compliance officers should work closely with their animal care and use programs to ensure that there are solid processes in place for maintaining accurate animal counts and that rigorous scientific justification is required for any animals being used in Class E research.
Other Pertinent Laws and Regulations
Although the PHS Policy, Guide and the AWA form the backbone of animal research regulation in the United States, other federal laws and state and local laws also must be considered. For example, if the research involves capturing animals in their natural setting, state or local laws may require that certain capture permits be obtained. Similarly, if the research requires the collection and/or transport of certain animal specimens, U.S. Fish and Wildlife regulations may apply and/or certain USDA permits may need to be obtained. Attention also must be paid to the species of animals involved, in order to determine if there are any species-specific regulatory research requirements or prohibitions. For instance, research involving species of animals protected by the U.S. Endangered Species Act, the Convention on International Trade in Endangered Species of Wild Flora and Fauna (CITES), or other similar laws may require special permits, or in some cases, be prohibited altogether. Accordingly, in all cases involving the collection, transport or use of wild animals or animal specimens, the research compliance officer should consult with counsel’s office for assistance in identifying all applicable legal and regulatory requirements.
Major Players in Animal Research Programs and Their Roles and Responsibilities
A team of highly skilled individuals is required to properly administer and operate an animal research facility. These persons may act individually, such as by serving as the attending veterinarian, or they may act as members of the IACUC, the institutional committee charged with primary responsibility for animal research oversight. Set forth below is a description of the roles and responsibilities of each of the major players in a research facility’s animal care and use program. Research compliance officers should identify the persons within their organizations who serve in these roles and be familiar with their various responsibilities.
Institutional Official
The institutional official is the individual at a research facility who has administrative and operational authority over the animal care and use program. The institutional official must be a top-level administrative who has the authority within the institution to ensure compliance with the AWA, PHS Policy and PHS Assurance. This authority must include the ability to commit institutional resources to support the institution’s animal care and use program. In this regard, the institutional official must ensure that the program is properly resourced with staff, facilities, materials and funding because lack of resources can never serve as an excuse or mitigating factor for non-compliance with the AWA, PHS Policy or the Guide.
The institutional official is named on and signs the PHS Assurance on behalf of the research institution. He/she is responsible for reporting to USDA and/or OLAW any IACUC suspensions of protocols or instances of serious or continuing non-compliance or serious deviations from the requirements of the Guide. Although, the institutional official may halt animal research, only the IACUC can officially suspend a research protocol. Further, if the IACUC disapproves an animal research protocol, the institutional official cannot overrule the IACUC’s disapproval.
Attending Veterinarian
The attending veterinarian is the veterinarian at the research facility who is in charge of seeing that all research animal receive adequate veterinary care. The attending veterinarian must have appropriate training and experience in the veterinary oversight of animal research programs, and he/she must have extensive knowledge of the requirements of the AWA, PHS Policy, and most especially, the Guide. Like the institutional official, the attending veterinarian must have appropriate lines of authority within the institution to ensure that the health and welfare of research animals is always protected. As a part of this authority, the attending veterinarian must have the power within the institution to prevent or end an animal’s participation in a research protocol and/or to euthanize the animal if necessary, even if the principal investigator in charge of the protocol disagrees. The attending veterinarian is required to be a voting member of the IACUC, and will ensure that veterinary review and oversight is provided for research protocols.
Institutional Animal Care and Use Committee (IACUC)
Membership: A research facility’s establishment of an IACUC is required by the AWA and the PHS Policy, but the two laws have different requirements for the IACUC’s composition. These requirements are summarized in the table below, and for IACUCs subject to both the AWA and the PHS Policy, the stricter of the two requirements apply.
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AWA IAUC Requirements | PHS Policy IACUC Requirements |
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| Minimum of 3 members. | Minimum of 5 members. |
| Members appointed by institution’s CEO or his/her designee. | Members appointed by institution’s CEO or his/her designee. |
| Membership must include at least one veterinarian with training/experience in lab animal care and program responsibility (i.e., the attending veterinarian). | Membership must include at least one veterinarian with training/experience in lab animal care and program responsibility (i.e., the attending veterinarian). |
| One member must not be affiliated with the research facility. If the IACUC has more than 3 members, then no more than 3 members may be from the same administrative unit in the facility. |
One or more persons with the following qualifications must be members, however, a single person may fulfill more than one qualification, provided there are 5 members:
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| Quorum consists of 50% of the IACUC membership +1. Individuals with specific qualifications are not necessary to constitute quorum, but if these individuals do not regularly attend IACUC meetings, the IACUC will not be considered properly constituted. | Quorum consists of 50% of the IACUC membership +1. Individuals with specific qualifications are not necessary to constitute quorum, but if these individuals do not regularly attend IACUC meetings, the IACUC will not be considered properly constituted. |
Meetings and Protocol Review: The IACUC must have regular convened meetings at which quorum is present in order to carry out its’ responsibilities. Detailed minutes must be kept of each IACUC meeting, including a record of each vote taken.
One of the IACUC’s primary responsibilities is to perform initial and continuing review of animal research protocols that are conducted at the research facility. The IACUC must initially approve a protocol before it can be conducted, and this approval is required before any federal funds can be expended for the research. Significant modifications to a protocol also require IACUC approval. The IACUC must conduct continuing review of research protocols involving AWA covered species at least annually, while continuing review of research that is regulated by PHS must be conducted at least every three years. Members who have conflicts of interest that prevent them from being able to participate in a particular protocol’s review (e.g., they are part of the research team conducting the protocol) must recuse themselves from the IACUC meeting while the protocol is discussed, and review cannot continue if their absence causes the IACUC to lose quorum.
Research compliance officers frequently attend IACUC meetings as “ex officio” members, and they need to have a thorough knowledge of the IACUC protocol review requirements and the types of IACUC review that may be used. IACUCs may review research protocols by one of two methods: review by the full IACUC committee (“full committee review” or “FCR”); or review by or by one or more designated members of the IACUC appointed by the IACUC chair (“designated member review” or “DMR”). IACUCs may have procedures that require FCR for certain types of research, e.g., research involving animals in the pain and distress Class E, or research involving non-human primates. Further, before DMR can be used, the IACUC must have fulfilled the following conditions:
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All members of the IACUC must be provided an opportunity to request FCR for each individual protocol or pursuant to a written procedure in place to which all IACUC members previously have agreed.
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If no member requests FCR, then the protocol may be reviewed by DMR.
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If DMR is performed by more than one designated reviewer, the reviewers must be unanimous in their decisions regarding the protocol, including any decisions regarding required modifications.
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DMR may not be used to withhold approval from a protocol. Disapproval may only be carried out the full IACUC.
DMR also may be used to review protocols that previously have been reviewed by FCR but require additional modifications to secure approval. In order to use DMR in this manner, the IACUC must fulfill the following conditions:
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If all members of the IACUC are present at the convened meeting, then the IACUC may vote to require modifications to the protocol to secure approval and to have the revised protocol reviewed and approved by DMR, as opposed to returning to the IACUC for FCR.
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If all members of the IACUC are not present, then in order for DMR to be used to approve a protocol that FCR has determined requires modifications for approval: (a) the use of DMR for this purpose must be included in the institution’s Assurance; (b) all IACUC members must have agreed in advance in writing that a quorum of member present at a convened meeting may decide by unanimous vote to use DMR to review a protocol that requires modifications for approval; and (c) any member of the IACUC may, at any time, request to see the revised protocol and/or require FCR.[10]
Approval Criteria: In order to approve a research protocol, the IACUC must determine that specific criteria have been met. First, the investigator must have provided evidence that he/she has considered alternatives to the use of animal research and that his/her research does not unnecessarily duplicate prior experiments. Second, the research procedures that are used must minimize pain, discomfort and distress and either utilize appropriate AAT drugs, or provide rigorous scientific justification as to why such drugs must be withheld to conduct the research. In addition, the research may not involve the use of paralyzing agents without the concurrent use of anesthesia, and when appropriate, animals must be euthanized with appropriate agents. Third, the protocol must have been reviewed by a veterinarian who will oversee the animals’ living conditions, housing, feeding and veterinary care. Fourth, all personnel involved in the research must be appropriately trained, and medical care must be provided by a qualified veterinarian. Fifth, with the exception of rodents, if surgery is involved, it must use sterile techniques and include appropriate pre- and post-operative care. Finally, in general, no animal may be used in more than one major operative procedure from which it is permitted to recover. IACUC minutes should reflect that approval criteria have been met.
Facility Inspections: In addition to protocol reviews, IACUCs must perform semiannual inspections of the research institution’s animal care and use program (i.e., its policies and procedures) and of all physical facilities in which animals are used or held. For covered species, facilities must be inspected by the IACUC if animals are kept there for longer than 12 hours. For non-covered species that are regulated under the PHS Policy, inspection is required if the animals are kept there for more than 24 hours.
Facility inspections are conducted by groups of IACUC members who report back to the full IACUC with their findings. Any member of the IACUC who requests to attend an inspection must be permitted to participate. IACUC or institution policy generally permits participation by the research compliance officer as well, and participation is a facility inspection is an excellent way for the compliance officer to gauge the status of an animal care and use program. A compliance officer who wants to participate in a facility inspection, however, should be mindful of any animal safety or occupational health and safety requirements that must be met to gain access to animal facilities. For example, training in the use of appropriate personal protective equipment and/or a negative skin test for tuberculosis may be required in order to visit certain animal facilities.
The IACUC inspection team reviews the program and the facility with respect to its compliance with the requirements of the AWA, PHS Policy and the Guide. Physical facilities, personnel training, animal transport mechanisms, surgical suites, animal feed and pharmaceuticals are all subject to inspection. Results of inspections are recorded in reports that are provided first to the IACUC for acceptance, and then to the institutional official. The reports must distinguish between significant deficiencies—deficiencies that are or may be a threat to the health or safety of animals—and minor deficiencies. When deficiencies are noted, they must be accompanied by a plan for their correction within a prescribed time. Failure to correct a significant deficiency affecting a covered species in accordance with the schedule must be reported within 15 business days to the USDA by the institutional official.
Post-Approval Monitoring: In addition to program and facility inspections, many IACUCs have programs in which they monitor the conduct of specific research protocols. Under these post-approval monitoring programs, IACUC employees or members will visit the sites at which the research is conducted and observe the research to verify that the protocol and all applicable laws and IACUC policies are being followed. Post-approval monitoring is an excellent tool for ensuring compliance in the animal care and use program.
Protocols Involving Field Work: Both the AWA and the PHS Policy can apply to animal research that is conducted in an animal’s natural setting, but the criteria for application of the AWA and PHS Policy differs. . Under the AWA, a field study is a study conducted on “free-living animals in their natural habitat.” The AWA does not require IACUC review or site inspection for true “field studies,” but if the study involves an invasive procedure or harms or materially alters the behavior of a study animal, then IACUC review, but not site inspection, is required. Under the PHS Policy, however, the IACUC always has oversight over PHS-funded field studies involving vertebrate animals. This oversight requires that the IACUC be aware of the field study’s location, as well as the nature of the procedures involved and their impact on the animals. The IACUC, however, is not required to conduct a protocol review unless under the PHS Policy unless the field study research alter or influence the animals’ activities (i.e., capture and release of the animals). Similar to the AWA, the PHS Policy does not require IACUC inspection of field sites of free-living wild animals.
Other IACUC Responsibilities: In addition to protocol review and inspections, the IACUC is also responsible for carrying out the following responsibilities:
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Suspension of animal research protocols. Only the IACUC can vote to suspend a protocol at a full committee meeting, although the institutional official can halt research activity until the IACUC can meet and vote on suspension.
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Investigation of concerns and complaints regarding non-compliance with applicable IACUC policies, laws and regulations. In this regard, the AWA specifically prohibits retaliation against persons who report possible violations of the AWA.
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Report to the USDA and/or OLAW via the institutional official any of the following occurrences: serious or continuing non-compliance with the AWA, PHS Policy, or the Guide; serious deviation from the Guide; failure to correct a program or facility deficiency in accordance with a prescribed plan; or suspension of a research protocol.
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Make any other recommendations to the institutional official regarding the animal care and use program.
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Prepare the annual reports for the USDA and OLAW that are transmitted by the institutional official. The reports must include any minority views expressed by a member of the IACUC who did not agree with the IACUC’s conclusions regarding program or facility compliance.
Accrediting Agencies
In addition to the governmental agencies that regulate animal research, research facilities also may voluntarily apply for accreditation by the AAALAC International. Accreditation by AAALAC requires adherence to AAALAC standards, which for facilities within the United States are based primarily on the Guide. Documentation of a site’s adherence to AAALAC standards must be set forth in a detailed program description. AAALAC inspectors visit the site and perform a detailed inspection prior to initial accreditation and every three years thereafter. The USDA and OLAW recognize AAALAC accreditation.
Additional Compliance Considerations
The world of animal research is one in which policies and regulations are subject to constant change. Some of this change has been brought about through ethical challenges to animal research and concerns about animal care and use championed by organizations such as the Humane Society of the United States, People for the Ethical Treatment of Animals (PETA) and similar groups.
Organizations advocating against the use of animals in research may use lawful processes to facilitate their activities such as requesting information about government-funded animal research through state open-records and federal Freedom of Information Act requests. Compliance officials should contact their counsel’s office for advice about how to respond to any request for records that is received.
In addition, to promoting lawful changes in laws and regulations, some anti-animal research groups may resort to illegal actions to promote their agenda, such as breaking into research facilities to remove animals or threatening animal research personnel. Accordingly, compliance personnel must be cognizant of these potential security threats, and incorporate processes and procedures to respond to these possible emergency situations.
Conclusion
Animal research is a complex area of compliance that is subject to many varied laws and regulations. The research compliance officer working in the area must have a solid understanding of these regulations, and in particular the AWA, PHS Policy and the Guide. In addition, the research compliance officer must know and work closely with personnel in the institution who have primary oversight for animal research programs such as the Institutional Official and the Attending Veterinarian. Finally, and perhaps foremost, the research compliance officer also must be prepared to work closely with the institution’s IACUC in its efforts to ensure full regulatory compliance and protection of all research animals’ health, safety and welfare.