Adapted from Animal Care and Use Committees An American Perspective In: Animal Models of Infectious Disease, O. Zak and T. O'Reilly, eds., Basel, Switzerland: Academic Press, 1999, Chapter 1.
The views expressed by the authors do not necessarily represent positions or policies of the U.S. Department of Agriculture or any agency thereof and should not be interpreted as such.
The Animal Welfare Act (AWA) (1966) is the primary Federal law that governs the use of animals in research, testing, and teaching in the United States. Originally passed by Congress in 1966 and amended in 1970, 1976, 1985 and 1990, the AWA provides the basis for the regulatory authority given to the United States Department of Agriculture (USDA) to ensure the welfare of covered animals used in regulated activities. The Act includes all warm-blooded vertebrates, as defined by the Secretary of Agriculture, but specifically exempts all farm animals used in food or fiber research or production. Rats of the genus Rattus, mice of the genus Mus, and all birds are administratively exempted at this time by the Secretary of Agriculture. With the passage of the 1985 "Improved Standards for Laboratory Animals Act,'' sponsored by Senator Robert Dole and Representative George Brown, the provisions of the AWA were greatly expanded. The primary purpose of the new law was succinctly stated by Senator Dole in his remarks introducing the amendment. He said,
"Mr. President, the farm bill contains legislation dealing with the humane treatment of animals. The main thrust of the bill is to minimize pain and distress suffered by animals used for experiments and tests. In so doing, biomedical research will gain in accuracy and humanity. We owe much to laboratory animals and that debt can best be repaid by good treatment and keeping painful experiments to a minimum." (Congressional Record 1985)
The new law redefined humane care to include such factors as
sanitation, ventilation, and housing. The USDA was directed to
establish regulations to give dogs the opportunity for exercise
and to set standards relating to a physical environment adequate
to promote the psychological well- being of non-human primates.
Not unexpectedly, the regulations greatly expanded the powers
of the laboratory animal veterinarian and stressed the need to
minimize pain and distress through adequate veterinary care and
the proper use of anesthetics, analgesics, tranquilizers, and
euthanasia. The principle investigator was also obligated to consider
alternatives to any procedure likely to cause pain or distress.
USDA considers alternatives in the spirit of the 3R's of Russell
and Burch (1959)-- Reduction in the numbers of animals
used, Refinement of techniques to minimize pain or distress,
or Replacement with non-animal techniques. To ensure that
the new regulations were being followed, the law also called for
the establishment of Institutional Animal Care and Use Committees
(IACUC). The IACUC was given broad powers to oversee all aspects
of an institutions animal care and use program, including approval
or disapproval of animal use protocols, development of training
programs for animal care and use personnel, inspection of all
animal areas, review of the animal care program, and investigation
of any alleged problems. The development of the IACUC also allowed
USDA to begin "enforced self-regulation." Under this
concept, the institution is responsible for ensuring compliance
with the AWA regulations and reporting any problems to USDA. To
ensure that the IACUC is performing its duties, USDA inspects
all research facilities at least once each year. The new law also
established an information service (the Animal Welfare Information
Center) at USDA's National Agricultural Library to assist both
researchers and IACUCs in complying with provisions of the regulations.
Finally, the law provided for severe penalties for any IACUC member
that released proprietary information or other trade secrets garnered
in the course of IACUC activities.
Although the AWA regulations are the only Federal regulations governing the welfare of animals in research, the Guide for the Care and Use of Laboratory Animals (NRC, 1996) is a widely used reference on animal care and use. But, researchers receiving funding from the U.S. Public Health Service (PHS) are obligated to follow the animal care standards found in the Guide and must assure the PHS that they are doing so. Unlike the AWA, the Guide covers all species of animals used in biomedical research. By and large, the standards found in the Guide and the AWA regulations have been harmonized.
Because of the legal burden placed upon IACUCs, it is important to understand the organization and make-up of the committee, the regulations they are required to follow, the processes involved in review and inspection of the institution's policies and physical plant, the process of protocol review, common IACUC problems, and finally, a look at special issues in research.
Under the 1985 amendments, each institution must designate an Institutional Official (IO), who has the authority to legally commit on behalf of the research facility that the regulations of the AWA will be followed. The IACUC, which is appointed by the chief executive officer, reports directly to the Institutional Official. Although the IACUC is responsible for evaluating the animal care program, it is the IO who has ultimate legal responsibility for ensuring compliance with the regulations and proper functioning of the IACUC. Under both the AWA and the Guide, the IACUC has final authority to disapprove any activity involving the care and use of animals. However, activities approved by the IACUC may be subject to further scrutiny by the institution (USDA, 1995b; NRC, 1996).
The AWA provides that, at a minimum, each IACUC shall be composed of the chairman, a veterinarian, and an unaffiliated member. The unaffiliated member, as the name implies, has no affiliation with the institution and can receive only minimal compensation (e.g., travel expenses, meals, or modest monetary payments for participation) from the institution. If the committee is composed of more than three members, not more than three members can be from the same administrative unit.
By contrast, the Guide requires that an IACUC should include a practicing scientist experienced in research involving animals, a veterinarian experienced in laboratory animal science or medicine, and one must not be affiliated with the institution. The PHS Policy also discusses committee membership. A survey of 477 research facilities in 1995 found that most IACUC's consisted of 7 members with a range from 3 to 50 members (Borkowski, 1996).
The veterinarian must be trained and experienced in laboratory animal science and medicine, and must have direct or delegated responsibility for the animal care program and activities involving animals. The veterinarian should also help determine the institution's goals for its animal care program, develop training programs to ensure humane treatment of animals, and promote the use of alternatives to animals whenever possible (Van Hoosier, 1987; Schwindaman, 1994).
The Non-affiliated Member
The role of the non-affiliated member (NAM) has recently been the subject of much debate in the United States. The inclusion of NAM's on animal care committees was a hard fought victory for advocates of laboratory animals (Stevens, 1986). Under both the AWA and the Guide, the role of the NAM is to "provide representation for general community interests in the care and treatment of animals" (USDA, 1995b; NRC, 1996). Members of animal protection groups wanted the NAM to have a background in animal protection efforts and thought that the NAM would provide greater accountability from researchers. However, the NAM is appointed by the CEO with little input from the community and oftentimes has no background in animal welfare or animal protection. One of the reasons for this hesitancy to appoint animal protectionists is the underlying fear that s/he may be obstructive or damaging to the actions of the committee (Levin and Stephens, 1995). In the industrial sector, the whole issue of the nonaffiliated member is clouded by the possibility that trade secrets or other proprietary information could be made public. However, Congress recognized this possibility and provided for serious criminal penalties for release of trade secrets by anyone on the IACUC (USDA, 1995b).
Many observers agree that the NAM brings an unbiased view to the IACUC, and ensures that animal use is essential. By providing public accountability, the NAM serves as "the built-in integrity factor to counter negative public perception or prevent the real potential for conflict of interest" (Theran, 1997).
FEDERAL REQUIREMENTS FOR IACUC ACTIVITIES
The primary functions of an IACUC are to review and inspect all aspects of an institution's animal care and use program including all animal facilities and animal care records, review animal use protocols, review and investigate complaints about animal use, and make recommendations to the Institutional Official (USDA, 1995b; NRC, 1996). The purpose of these reviews and inspections is to provide a mechanism that ensures compliance with all regulations and policies and allows for interaction between the IACUC and institutional staff members. The IACUC becomes a group of individuals rather than a faceless in-house regulatory body, which serves to lessen the sometimes adversarial nature of the review process.
Review of the Animal Care Program
At least once every 6 months, the IACUC must conduct a thorough review of the institutions program for humane care and use of animals. It is useful to use the AWA regulations and the Guide as the basis. Evaluation of the program should concern itself with how these activities are administered, implemented, and documented. It will necessarily focus on record-keeping and review of written procedures and policies. The programs that should receive a thorough evaluation include all IACUC procedures and policies, methods for protection of personnel that report deficiencies in animal care or treatment, procedures for filing of semi-annual and annual reports to the Institutional Official and/or USDA, the facilities program of veterinary care, the occupational health program for animal care personnel, and finally, the facilities training program for all personnel involved in the use of animals (McLaughlin, 1993).
As with the program review, facility inspections must be completed once every 6 months by the IACUC. By observing the animals in their daily quarters, the IACUC can most readily determine if the institutional animal care policies are promoting the welfare of the animals. Another compelling reason is that the inspection ensures that the facility is complying with all Federal regulations and guidelines.
Members of the IACUC tour the facility's animal rooms, study rooms, feed and bedding preparation areas, necropsy rooms, cage wash areas, and any other rooms used in the animal program. If animals are routinely transported to laboratories or are maintained in satellite facilities, these areas must also be inspected. In addition to examining the animals, animal care personnel should be questioned about the daily and weekly animal husbandry routine. Facilities housing dogs and non-human primates have to meet special requirements concerning the well-being of these animals. It is imperative that the IACUC pay special attention to the implementation of these requirements for exercise in dogs and environmental enrichment for non-human primates. During the inspection process, the IACUC member should take detailed notes documenting, as needed, minor and significant deficiencies, or outstanding innovations that have improved animal welfare. These notes will be used in preparation of the report to the Institutional Official.
After the program review and facility inspection, a detailed report is generated noting any significant or minor deficiencies, the probable reason for the deficiency, and plans for corrective actions including a timetable for completion of these actions. The report should also note outstanding aspects of the program and facilities. Significant deficiencies, those that pose an immediate threat to the health or safety of the animals, must be corrected within a reasonable time frame. Any failure to adhere to the plan that results in a significant deficiency remaining uncorrected must be reported to the USDA and any Federal agency that has provided funding for a project. The final report must be approved by a majority of the IACUC and must include any dissenting viewpoints.
IACUC Review of Protocols
Both the AWA and the PHS Guide mandate the review of animal research protocols by the animal care and use committee before any research may begin. The AWA also requires the IACUC to review all approved protocols on an annual basis. The IACUC must review and approve, require modifications to a proposal in order to secure approval, or disapprove any protocol which it receives. The institution is given leeway in determining the most appropriate means of complying with these requirements (Dresser, 1989). The regulations and guidelines do not specify the frequency of meetings for IACUC's, leaving this to the needs of each institution. Animal care committees at large institutions may meet every week while smaller institutions may be able to function with bimonthly meetings.
The AWA mandates very specific criteria that must be met before an IACUC may grant approval to new proposals or changes in existing protocols (Schwindaman, 1994; USDA, 1995b). Those criteria include:
THE ANIMAL USE PROTOCOL REVIEW FORM
While Federal regulations give rather specific requirements for what an IACUC must consider for approval or disapproval of animal use protocols, the actual method for collecting that information has been left to the scientific community (Dresser, 1989). However, the protocol review form is the key to the entire process for it provides the IACUC members with the necessary information required for them to perform their jobs (Prentice et al., 1991). A successful review form should be regarded as a dynamic document that can change with the institutions experiences and evolving regulatory, professional and societal standards (Prentice et al, 1991). A well-designed review form challenges the scientist to examine and justify, both scientifically and ethically, all aspects of a procedure that affects the well-being of the animals (Russow, 1995).
To assist the scientist and the members of the IACUC, each institution should develop policies or standard operating procedures on common painful experimental procedures that carry a "high ethical cost," so that everyone involved in the review process has a common point of reference and consistent decisions are rendered. This also leads to a more efficient IACUC as time is not spent resolving the same conflicts time and again. Some of these procedures would include the use of complete Freund's adjuvant, death as an endpoint, tumor burdens, food and water deprivation, and LD50 studies for both toxicology and infectious disease studies (Dresser, 1987). Institutional guidelines may require that alternative methods be used for particularly painful procedures, may list criteria for euthanizing animals during a painful procedure, or may provide guidance as to monitoring animals for symptoms of pain or distress.
THE PROTOCOL REVIEW PROCESS
Contrary to public perception, the animal care and use committee is not an animal welfare committee. If IACUCs were required to approve protocols based solely on animal welfare issues most protocols would be rejected. The primary purpose of protocol review is to promote the welfare of animals without compromising valid scientific objectives that might benefit other animals and humankind. Protocol review is a moral and ethical evaluation that necessarily requires the evaluation of the science involved (Prentice et al., 1990; Prentice et al., 1992). Without addressing the validity of the proposed scientific objectives and methods, the IACUC can't decide if the ethical cost weighed against the potential benefits is morally justifiable (Prentice et al., 1992; Russow, 1995). It would appear that the Public Health Service Policy on Humane Care and Use of Laboratory Animals (PHS, 1996) provides the IACUC, as an appropriate institutional review board, with a legal basis for considering scientific merit of a proposed research activity. According to this document "procedures involving animals should be designed and performed with due consideration of their relevance to human or animal health, the advance of knowledge, or the good of society."(OPRR, 1991; Prentice et al., 1992)
The review process will be different at different institutions depending upon the needs of the facility. A committee may delegate review of protocols to a review team or may require all members of the IACUC to review the form. Regardless of the process used, the AWA and PHS Guide require that all members of the committee have full access to the protocol review form. Federal regulations and guidelines allow the designated reviewers to approve, require modifications to, or disapprove a protocol. But any member of the IACUC may request full committee review. Approval by the full committee requires that a quorum be present and a majority vote to approve (USDA, 1995b; NRC, 1996).
Because IACUCs are asked to review a broad range of activities, many of which may be outside the expertise of the committee, the use of consultants is allowed. However, the consultants do not have voting privileges unless they are members of the IACUC.
During the review process, the members of the IACUC should carefully assess the information provided by the scientist on the animal protocol form. If for any reason a reviewer is not satisfied with the information provided by the scientist, s/he may submit questions to the scientist asking for clarification or additional information. Typical reasons for a protocol being sent back to a scientist would include:
Consideration of Alternatives
Animal welfare regulations require that an investigator performing procedures that are painful or distressful to the animal provide assurance that no alternatives exist to the painful procedure. To provide this assurance, the investigator must provide, except in unique circumstances, a written narrative that describes the literature databases searched (e.g., Medline, EmBase, Biosis Previews, AGRICOLA, PREX), the keywords or strategy used to retrieve information, and a brief description of why alternatives are or are not available. In some circumstances, the IACUC may allow the investigator to provide other information describing the "methods and sources used to determine that no alternatives were available to the painful or distressful procedure" (DeHaven, 1999). The IACUC must satisfy itself that alternatives were adequately considered and must discuss the use of alternatives during meetings and note the discussion in its minutes. These must be made available to USDA inspectors, if requested. (USDA, 1989). Stokes and Jensen (1995) have developed guidelines to assist IACUCs in reviewing protocols for alternatives. Some institutions have developed animal alternatives committees (James et al., 1995; Holden, 1997) or appointed librarians familiar with this type of searching (Keefer and Westbrook, 1996) to help the IACUC with this aspect of protocol review. Smith (1994) has written a method paper on searching for alternatives that is an overview of this type of searching.
To assist both investigators and IACUCs, the 1985 amendment to the Animal Welfare Act established the Animal Welfare Information Center (AWIC) within USDA's National Agricultural Library. AWIC provides literature searching services and produces numerous publications and workshops on animal welfare and the use of alternatives in research, testing, and teaching.
As mentioned previously, the law provides for an annual review of protocols by the IACUC. The investigator should use this review as an opportunity to reexamine the literature for alternatives that may have been developed since the prior review.
Expedited Review of Animal Use Protocols
Under the Animal Welfare Act the principal investigator is required to provide the animal care and use committee with a written description of all activities that involve the care and use of animals that are covered by the regulations. If a full committee review is not apparently necessary or is not requested, then an expedited review of the protocol may be made. For an expedited review, the committee chairman designates at least one member of the IACUC who is qualified to conduct the review to review the protocol. This designated individual(s) is to review the protocol and has the authority to: (1) approve the protocol, (2) require modifications to the protocol, or (3) request a full committee review of the protocol. If a full committee review is requested, approval may be granted only after review, at a convened meeting of a quorum of the IACUC, and with approval vote of a majority of the quorum present. No member of the IACUC may participate in a protocol review or approval, or be part of a quorum, if that member has a conflicting interest in the protocol, except to provide requested information to the IACUC. The IACUC member making the expedited review does not have the authority to disapprove a protocol. Disapproval, or suspension, of a protocol may only be done by a majority vote of a quorum at a convened meeting of the IACUC.
Appropriate Animal Numbers
One of the primary responsibilities of the IACUC is to ensure that the fewest animals possible that will yield scientifically valid data are used in an experiment. Too many animals are an unethical waste of animals and an improper use of research funds. The same argument holds true for using too few animals. However, with proper planning and consultation with a biostatistician, calculating the proper number of animals can be attained. It should be noted, however, that other factors, such as ethical considerations, may also influence the number of animals in a sample size.
The scientist must provide adequate justification for the number of animals proposed for the protocol. The appropriate number of animals for a study will be determined by the variability of the parameter being studied and the statistical tests to be used in analyzing the experimental results (Festing, 1992). To successfully use statistical formulas for determining sample size, the scientist must have some idea of several parameters: the probability of accepting a false positive (alpha error) or a false negative (beta error), the smallest difference worth detecting (effect size), and the variability of experimental groups (Mann et al., 1991; Festing, 1995). Proper scrutiny of the relevant scientific literature may provide information on effect size and variability allowing the investigator to assign precise values to these variables for use in power analysis or other methods for estimating sample size.
Because of the profound effect of variability on the response of animals to an experimental challenge, it is necessary to understand this source of error if animal numbers are to be minimized (Festing, 1992). To minimize within group variability it is imperative that animals be free of clinical or sub-clinical disease and not subject to environmental or dietary stress (except as part of a protocol). The use of inbred strains of laboratory animals will further reduce variability and the number of animals needed because their high degree of uniformity increases the statistical power (the probability that a statistical test will detect a difference when the difference actually exists) (Festing, 1995).
Erb (1996) has provided an excellent review of the actual elements of the sample size calculations, issues that determine which sample size formula to use, and methods to decrease the needed sample size when the calculated sample size is impractical to use.
Minimizing Pain and Distress
U.S. animal welfare regulations define a painful procedure as one that "would reasonably be expected to cause more than slight or momentary pain or distress in a human being to which that procedure was applied, that is, pain in excess of that caused by injections or other minor procedures" (USDA, 1995b). Investigators are required to consult with a veterinarian to assure that pain or distress is minimized. Because many studies have the potential for causing pain in animals, the IACUC should establish guidelines for periodic monitoring of animals, set criteria for veterinary intervention to alleviate pain through use of analgesics or euthanasia, and require training for investigators and animal care personnel to ensure that all can recognize symptoms of pain and distress. Morton (1985) and other authors (Soma, 1987; NRC, 1992) provide comprehensive reviews on recognition of pain and distress in laboratory animals. The IACUC should make these available to animal use personnel.
Alternatives to Death as an Endpoint
Because certain studies may cause irreversible pain or distress before death ensues, the investigator should strive to incorporate earlier endpoints that will satisfy the requirements of the study and spare the animal a painful death (Siems and Allen, 1989; Olfert, 1995). Also, an earlier endpoint may result in better scientific data as the death of the animal may result in postmortem changes to tissue or body fluids (Amyx, 1987a; Siems and Allen, 1989). Because these earlier endpoints may be best addressed as part of the experimental design, IACUC review of the experimental design becomes very important, especially in infectious disease studies (Amyx, 1987b).
Hamm (1995) has proposed guidelines for IACUC acceptance of death as an endpoint. By establishing clear guidelines or criteria for early euthanasia of animal subjects, the IACUC can clearly minimize the pain or distress that the animal will experience. Numerous authors have outlined these criteria (Morton, 1985; Tomasovic, 1988; Hamm, 1995; Olfert, 1995). Frequently mentioned variables that should be observed include body weight, physical appearance, clinical signs such as temperature, heart rate, or bleeding, unprovoked behavior of the animal, and responses to external stimuli. In infectious disease studies, the investigator should use information available from the infectious disease literature on progression of symptoms, time course of the disease and other unique features of the disease being studied to establish earlier endpoints (Soothill et al., 1992). In some studies there may be a scientifically valid reason for allowing the progression to death. However, inconvenience to the investigator or cost of alternatives are not acceptable reasons (Tomasovic, 1988).
Alternatives in Antibody Production
This has emerged as a very controversial topic in the United States. In 1997, the U.S. Department of Agriculture and the National Institutes of Health were petitioned by the American Anti-Vivisection Society to ban the use of animals in the production of monoclonal antibodies (MAb) via the ascites method. Although several European countries have regulations limiting or prohibiting the use of animals for MAb production (McArdle, 1997), at this time USDA has no statutory authority to prohibit the use of animals for MAb production.
Production of antibodies in animals usually involves the use of an adjuvant or priming agent, such as Freund's complete or incomplete adjuvant or pristane, in conjunction with a selected antigen to stimulate the immune system of an animal to produce titres of antibodies. But it should be remembered that the purpose of the adjuvant is to induce antibodies not pain (Amyx, 1987b). Both types of Freund's adjuvants are known to produce serious inflammatory reactions that may result in abscesses, granuloma's or tissue necrosis. Consequently, IACUC's should always question the use of these adjuvants and should urge investigators to use alternative adjuvants such as Montanide ISA or Ribi's. These alternative adjuvants may provide immunopotentiation similar to Freund's but without the severe pain associated with the use of Freund's (Hanly, et al., 1997).
The production of MAb's via induction of ascites fluid has been an important tool in immunological and infectious disease research. However, unless the mouse or other animal is carefully monitored, the potential for severe pain is very real. In 1974 Kohler and Milstein showed that MAb's could be produced with in vitro methods. With Niels Jerne they won the 1984 Nobel Prize for their in vivo and in vitro work on MAb production (McArdle, 1997). Current in vitro methods widely used in Europe and the United States include modular bioreactors, static and agitated suspension cultures, and membrane-based and matrix-based culture systems (Marx et al., 1997; Petrie, 1997). Modular bioreactors used in the United States have been found to rival the efficiency of the ascites method (Petrie, 1997). The use of these in vitro methods, besides eliminating the use of animals, have the added advantage of being free of contaminating antibodies, cytokines and similar biologically active materials. Because the primary purpose of the IACUC is to minimize pain in animals, it should always encourage the use of alternative methods of MAb production at both the institutional and laboratory level. To assist IACUCs, a comprehensive bibliography on adjuvants and antibody production is available at http://www.nal.usda.gov/awic/pubs/antibody/ (Smith et al., 1997). Proceedings of a conference Alternatives in Monoclonal Antibody Production sponsored by NIH and The Johns Hopkins University Center for Alternatives to Animal Testing are available at http://altweb.jhsph.edu/meetings/mab/proceedings.htm
The 1985 amendments to the U.S. Animal Welfare Act have had a profound effect on the way that scientific research is conducted in the United States. With the establishment of institutional animal care and use committees, scientists wishing to conduct research using animals must receive approval from a committee composed of their peers and a representative of the general public. This accountability, for the privilege of using live animals in scientific endeavors, is enforced by periodic, unannounced inspections by veterinarians from the U.S. Department of Agriculture. Although no system of oversight is without problems, the animal care and use committee process in the United States seems to be doing its job of facilitating science while allowing for the welfare of those animals that must be used in research. However, with continuing societal concern over the use of animals in research, these committees should be advocates for alternative methods that implement the 3R's of Russell and Burch (1959) whenever possible.
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