Functions of the Institutional Animal Care and Use Committee. (IACUC) and GLP Regulated Studies GLP FORUM

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1 Functions of the Institutional Animal Care and Use Committee (IACUC) and GLP Regulated Studies ROBERT GEORGE YOUNG/GETTY IMAGES GLP Forum addresses topics of interest associated with good laboratory practices. We intend this column to be a useful resource for daily work applications. The key objective for the column: Useful information. Reader comments, questions, and suggestions are needed to help us fulfill our objective for this column. Please send your comments and suggestions to column coordinator Steven Kuwahara at stevekuwahara@yahoo.com or to journal coordinating editor Susan Haigney at shaigney@advanstar.com. KEY POINTS The following key points are discussed: Functions of the Institutional Animal Care and Use Committee (IACUC) in a good laboratory practice (GLP) animal testing facility are discussed. GLP regulations and United States Department of Agriculture regulations govern the handling of animals in research and testing. These apply to anyone employing animals in any kind of study in the United States. The Code of Federal Regulations definition of research facility encompasses any school, institution, organization, or person that uses or intends to use live animals in research, tests, or experiments. Specified functions of the IACUC including supporting regulations are discussed. The major responsibility of the IACUC is to ensure that studies are conducted in a manner that provides for the welfare of the animals while also making allowances for the needs of the research project. It is wise to provide for a fully functioning IACUC and to completely document their activities. 34 Journal of GXP Compliance

2 INTRODUCTION The Institutional Animal Care and Use Committee (IACUC) is a critical body in a good laboratory practice (GLP) animal testing facility. This discussion addresses the functions and responsibilities expected from the IACUC. Associated topics are also addressed. Pertinent GLP regulations are provided. GOVERNING REGULATIONS When conducting non-clinical laboratory studies on medicinal products, it is important to remember that the GLP regulations (1) are not the only rules pertaining to the use of animals in research and testing in the United States. The US Department of Agriculture (USDA) also has regulations related to the handling of animals in research and testing. While most USDA regulations are aimed at animals used for commercial purposes, some regulations apply to all animals, including those used in research and testing by pharmaceutical companies, university and hospital laboratories, or contract organizations. They apply to anyone employing animals in any kind of study in the United States. Some workers in pharmaceutical companies and university laboratories believe that USDA regulations do not apply to them because they believe their work is regulated only by the US Food and Drug Administration. The fact is that USDA regulations (2) are national regulations and apply to all appropriate activities conducted in the United States regardless of the nature of the industry. Scope of Regulations Another objection is the belief that the USDA regulations only apply to commercial or research establishments, not testing laboratories. However, the definition given in 9 CFR 1.1 states: Research facility means any school (except an elementary or secondary school), institution, organization, or person that uses or intends to use live animals in research, tests, or experiments, and that [1] purchases or transports live animals in commerce, or [2] receives funds under a grant, award, loan, or contract from a department, agency, or instrumentality of the United States for the purpose of carrying out research, tests, or experiments: Provided, That the Administrator may exempt, by regulation, any such school, institution, organization, or person that does not use or intend to use live dogs or cats, except those schools, institutions, organizations, or persons, which use substantial numbers (as determined by the Administrator) of live animals the principal function of which schools, institutions, organizations, or persons, is biomedical research or testing, when in the judgment of the Administrator, any such exemption does not vitiate the purpose of the Act. Note that this definition appears to contain an exemption for laboratories that conduct biomedical research or testing, but this exemption must be made by the USDA administrator. A laboratory that lacks such an exemption should consider itself to be regulated under the Animal Welfare Act (Title 9, Code of Federal Regulations, Subchapter A). Given the current social and political climate, it would be unusual for the USDA Administrator to be able to justify an exemption from the Act. IACUC Composition A discussion on the composition of the IACUC is found in a previous issue of the Journal of GXP Compliance (3). That article discusses how the IACUC is a critical component of compliance with the Animal Welfare Act. That paper also describes the need for training members of the IACUC, and the question that then arises is train to do what? The training should be in the functions expected of the IACUC. These functions will now be considered. FUNCTIONS OF IACUC The functions of the IACUC are clearly stated in the regulations. Reviews, Timing, and Reports Reviews, timing, and reports are discussed in 9 CFR 2.31(c) IACUC functions, as follows: With respect to activities involving animals, the IACUC, as an agent of the research facility, shall: [1] Review, at least once every six months, the research facility s program for humane care and use of animals, using title 9, chapter I, subchapter A Animal Welfare, as a basis for evaluation; Autumn 2010 Volume 14 Number 4 35

3 [2] Inspect, at least once every six months, all of the research facility s animal facilities, including animal study areas, using title 9, chapter I, subchapter A- Animal Welfare, as a basis for evaluation; provided, however, that animal areas containing free-living wild animals in their natural habitat need not be included in such inspection; [3] Prepare reports of its evaluations conducted as required by paragraphs (c)[1] and [2] of this section, and submit the reports to the Institutional Official of the research facility; Provided, however, That the IACUC may determine the best means of conducting evaluations of the research facility s programs and facilities; and Provided, further, That no Committee member wishing to participate in any evaluation conducted under this subpart may be excluded. The IA- CUC may use subcommittees composed of at least two Committee members and may invite ad hoc consultants to assist in conducting the evaluations, however, the IACUC remains responsible for the evaluations and reports as required by the Act and regulations. The reports shall be reviewed and signed by a majority of the IACUC members and must include any minority views. The reports shall be updated at least once every six months upon completion of the required semiannual evaluations and shall be maintained by the research facility and made available to APHIS and to officials of funding Federal agencies for inspection and copying upon request. The reports must contain a description of the nature and extent of the research facility s adherence to this subchapter, must identify specifically any departures from the provisions of title 9, chapter I, subchapter A Animal Welfare, and must state the reasons for each departure. The reports must distinguish significant deficiencies from minor deficiencies. A significant deficiency is one which, with reference to Subchapter A, and, in the judgment of the IACUC and the Institutional Official, is or may be a threat to the health or safety of the animals. If program or facility deficiencies are noted, the reports must contain a reasonable and specific plan and schedule with dates for correcting each deficiency. Any failure to adhere to the plan and schedule that results in a significant deficiency remaining uncorrected shall be reported in writing within 15 business days by the IACUC, through the Institutional Official, to APHIS and any Federal agency funding that activity The functions start with a requirement for a semiannual review and inspection of activities involving animals. These requirements make it clear that the IACUC must be an active unit that is involved with the operations of an animal testing facility. In performing these activities, the IACUC is considered to be acting on behalf of the management of the facility. As one would expect the timing of the semiannual reviews and inspections to begin on the date that a study is initiated, a facility with several studies being conducted will have several reviews and inspections being performed at the same time. Also, any study that lasts for more than six months should have at least one report from the IACUC included in the study files. The review of the animal welfare provisions and the inspection of the animal facilities have clearly defined requirements, except that for GLP studies, the inspection should also include the requirements found in 21 CFR 58. The resulting reports only need to be kept at the research facility s site, but must be available to Animal and Plant Health Inspection Service (APHIS) inspectors. One would also think that FDA investigators would also find them to be of interest. Responding to Public Complaints The handling of public complaints is addressed in 9 CFR 2.31(c)(4), which states: Review, and, if warranted, investigate concerns involving the care and use of animals at the research facility resulting from public complaints received and from reports of noncompliance received from laboratory or research facility personnel or employees The IACUC is assigned the task of responding to public concerns about violations of the Animal Welfare Act. This can become an important function because a facility that is seen as being non-responsive to concerns about its compliance with the Animal Welfare Act may find itself mired in public controversy with subsequent damage to its public image. Note that the IACUC must also respond to complaints received from within the company or facility. 36 Journal of GXP Compliance

4 In this work it would be best if it were to work together with the quality assurance unit (QAU) that is required by the GLP regulations. Changes to the Animal Program, Facilities, or Personnel Training Including Suspending Activities The recommendation, review, and approval of changes to the animal program, facilities, or personnel training are covered in 9 CFR 2.31(c), as follows: [5] Make recommendations to the Institutional Official regarding any aspect of the research facility s animal program, facilities, or personnel training [6] Review and approve, require modifications in (to secure approval), or withhold approval of those components of proposed activities related to the care and use of animals, as specified in paragraph (d) of this section [7] Review and approve, require modifications in (to secure approval), or withhold approval of proposed significant changes regarding the care and use of animals in ongoing activities [8] Be authorized to suspend an activity involving animals in accordance with the specifications set forth in paragraph (d)(6) of this section. The IACUC is also responsible for recommending changes and modifications to the program, facilities, and studies to ensure compliance with the Animal Welfare Act. The authorization to suspend activities should be specifically granted by upper management in a written document that assigns responsibilities and authority to the IACUC. Since the withholding of approval for the activities that relate to the handling of animals, and any requirements for modifying protocols, would be critical to the performance of an animal based nonclinical laboratory study, the IACUC should coordinate its activities with the study director who is responsible for the conduct of a nonclinical laboratory study under 21 CFR 58. Review of Activities Involving Animals The following sections describe the actions that the IACUC is expected to execute for the review of activities involving animals. As these activities are likely to have an impact on a nonclinical laboratory study, the IACUC should coordinate its activities with those of the study director and the QAU. It is clear that, while the study director is responsible for the overall conduct and scientific validity of the nonclinical laboratory study, the IACUC is responsible for conformance with the requirements of the Animal Welfare Act. In these sections, the USDA makes frequent references to the principal investigator of a study. In terms of the GLP requirements in 21 CFR 58, this would be the study director. Therefore, the GLP study directors should be familiar with the requirements of the Animal Welfare Act and the activities required of the IACUC. However, the study director should not be a member of the IACUC as this would create a conflict of interest. 9 CFR 2.31(d), states: [1] In order to approve proposed activities or proposed significant changes in ongoing activities, the IACUC shall conduct a review of those components of the activities related to the care and use of animals and determine that the proposed activities are in accordance with this subchapter unless acceptable justification for a departure is presented in writing; Provided, however, That field studies as defined in part 1 of this subchapter are exempt from this requirement. Further, the IACUC shall determine that the proposed activities or significant changes in ongoing activities meet the following requirements: (i) Procedures involving animals will avoid or minimize discomfort, distress, and pain to the animals; (ii) The principal investigator has considered alternatives to procedures that may cause more than momentary or slight pain or distress to the animals, and has provided a written narrative description of the methods and sources, e. g., the Animal Welfare Information Center, used to determine that alternatives were not available; (iii) The principal investigator has provided written assurance that the activities do not unnecessarily duplicate previous experiments; (iv) Procedures that may cause more than momentary or slight pain or distress to the animals will: (A) Be performed with appropriate sedatives, analgesics or anesthetics, unless withholding such Autumn 2010 Volume 14 Number 4 37

5 agents is justified for scientific reasons, in writing, by the principal investigator and will continue for only the necessary period of time; (B) Involve, in their planning, consultation with the attending veterinarian or his or her designee; (C) Not include the use of paralytics without anesthesia; (v) 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; (vi) The animals living conditions will be appropriate for their species in accordance with part 3 of this subchapter, and contribute to their health and comfort. The housing, feeding, and nonmedical care of the animals will be directed by the attending veterinarian or other scientist trained and experienced in the proper care, handling, and use of the species being maintained or studied; (vii) Medical care for animals will be available and provided as necessary by a qualified veterinarian; (viii) Personnel conducting procedures on the species being maintained or studied will be appropriately qualified and trained in those procedures; (ix) Activities that involve surgery include appropriate provision for pre-operative and post-operative care of the animals in accordance with established veterinary medical and nursing practices. All survival surgery will be performed using aseptic procedures, including surgical gloves, masks, sterile instruments, and aseptic techniques. Major operative procedures on nonrodents will be conducted only in facilities intended for that purpose which shall be operated and maintained under aseptic conditions. Non-major operative procedures and all surgery on rodents do not require a dedicated facility, but must be performed using aseptic procedures. Operative procedures conducted at field sites need not be performed in dedicated facilities, but must be performed using aseptic procedures; (x) No animal will be used in more than one major operative procedure from which it is allowed to recover, unless: (A) Justified for scientific reasons by the principal investigator, in writing; (B) Required as routine veterinary procedure or to protect the health or well-being of the animal as determined by the attending veterinarian; or (C) In other special circumstances as determined by the Administrator on an individual basis. Written requests and supporting data should be sent to the Animal and Plant Health Inspection Service, Animal Care, 4700 River Road, Unit 84, Riverdale, Maryland ; (xi) Methods of euthanasia used must be in accordance with the definition of the term set forth in 9 CFR part 1, 1.1 of this subchapter, unless a deviation is justified for scientific reasons, in writing, by the investigator. The requirements given here should be incorporated into the protocol for the GLP study, and the GLP study director and QAU should be sure to evaluate these points when reviewing the protocol. List of Activities to be Reviewed A list of activities to be reviewed is found in 9 CFR 2.31(d), which states: [2] Prior to IACUC review, each member of the Committee shall be provided with a list of proposed activities to be reviewed. Written descriptions of all proposed activities that involve the care and use of animals shall be available to all IACUC members, and any member of the IACUC may obtain, upon request, full Committee review of those activities. If full Committee review is not requested, at least one member of the IACUC, designated by the chairman and qualified to conduct the review, shall review those activities, and shall have the authority to approve, require modifications in (to secure approval), or request full Committee review of any of those activities. If full Committee review is requested for a proposed activity, approval of that activity may be granted only after review, at a convened meeting of a quorum of the IACUC, and with the approval vote of a majority of the quorum present. No member may participate in the IACUC review or approval of an activity in which that member has a conflicting interest (e.g., is personally involved in the activity), except to provide information requested by the IACUC, nor may a member who has a conflicting interest contribute to the constitution of a quorum; 38 Journal of GXP Compliance

6 [3] The IACUC may invite consultants to assist in the review of complex issues arising out of its review of proposed activities. Consultants may not approve or withhold approval of an activity, and may not vote with the IACUC unless they are also members of the IACUC; [4] The IACUC shall notify principal investigators and the research facility in writing of its decision to approve or withhold approval of those activities related to the care and use of animals, or of modifications required to secure IACUC approval. If the IACUC decides to withhold approval of an activity, it shall include in its written notification a statement of the reasons for its decision and give the principal investigator an opportunity to respond in person or in writing. The IACUC may reconsider its decision, with documentation in Committee minutes, in light of the information provided by the principal investigator... The following activities should be included as a part of the review and auditing activities of the GLP QAU. If they have been written into the protocol, it would be a simple matter of verifying that the activities required by the protocol are being conducted. As a matter of management it would be more efficient if the IACUC and the QAU coordinated their actions in this area. In any case, it is important that the members of the QAU should also be familiar with the requirements of the Animal Welfare Act. Continuing Reviews of Activities The review of activities is addressed in 9 CFR 2.31(d), which states: [5] The IACUC shall conduct continuing reviews of activities covered by this subchapter at appropriate intervals as determined by the IACUC, but not less than annually; [6] The IACUC may suspend an activity that it previously approved if it determines that the activity is not being conducted in accordance with the description of that activity provided by the principal investigator and approved by the Committee. The IACUC may suspend an activity only after review of the matter at a convened meeting of a quorum of the IACUC and with the suspension vote of a majority of the quorum present; [7] If the IACUC suspends an activity involving animals, the Institutional Official, in consultation with the IACUC, shall review the reasons for suspension, take appropriate corrective action, and report that action with a full explanation to APHIS and any Federal agency funding that activity; and [8] Proposed activities and proposed significant changes in ongoing activities that have been approved by the IACUC may be subject to further appropriate review and approval by officials of the research facility. However, those officials may not approve an activity involving the care and use of animals if it has not been approved by the IACUC. Note that [6] grants regulatory authority to the IACUC to suspend an activity if its review results in the conclusion that the protocol is not being followed with regard to the welfare of the animals that are being employed. Paragraph [8] creates a balance of responsibilities between the IACUC and test facility upper management. In addition, the activities of the QAU, study director, and the IACUC must be closely coordinated by the test facility management. Changes Regarding Use of Animals in Studies One of the major functions of the IACUC is to review proposals or changes to proposed activities regarding the use of animals in studies. Studies involving animals should not be allowed to proceed without the approval of the IACUC, and the proposals for these studies should include to following, as stated in 9 CFR 2.31(e): A proposal to conduct an activity involving animals, or to make a significant change in an ongoing activity involving animals, must contain the following: [1] Identification of the species and the approximate number of animals to be used; [2] A rationale for involving animals, and for the appropriateness of the species and numbers of animals to be used; [3] A complete description of the proposed use of the animals; [4] A description of procedures designed to assure that discomfort and pain to animals will be limited to that which is unavoidable for the conduct of scientifically valu- Autumn 2010 Volume 14 Number 4 39

7 able research, including provision for the use of analgesic, anesthetic, and tranquilizing drugs where indicated and appropriate to minimize discomfort and pain to animals; and [5] A description of any euthanasia method to be used. In a GLP-based nonclinical laboratory study, this proposal to conduct a study involving animals will probably come from the study director, and the IACUC approval of the study should be a required element before a test protocol may be executed. SUMMARY The major responsibility of the IACUC is to ensure that studies are conducted in a manner that provides for the welfare of the animals while also making allowances for the needs of the research project. It is important to have an effective IACUC when conducting nonclinical laboratory studies as the activities required by some nonclinical laboratory studies can easily be misinterpreted as disregarding animal welfare. In these instances it is important to show that an independent review was made of the activities and that full consideration was given to the welfare of the animals that were involved. Given the problems that can arise for a company that conducts studies while ignoring the welfare of the subject animals, it is wise to provide for a fully functioning IACUC and to completely document their activities. REFERENCES 1. FDA, Part 58 Good Laboratory Practice for Nonclinical Laboratory Studies, Code of Federal Regulations, Title 21, Volume I, Chapter I, Part 58, 21 CFR 58, Federal Register Volume 43, pp , December 22, 1973, and subsequent changes. 2. USDA, Title 9 Animals and Animal Products, Code of Federal Regulations, Title 9, Chapter I Animal and Plant Health Inspection Service, Department of Agriculture, Subchapter A Animal Welfare, Parts 1 & 2, 9 CFR 1 & 2, Federal Register Volume 54, pp & pp , August 31, 1989, and subsequent changes. 3. Kuwahara, S.S., Membership of the Institutional Animal Care and Use Committee (IACUC) and GLP Studies, Journal of GXP Compliance, Vol. 14, No. 3, Summer GXP ARTICLE ACRONYM LISTING APHIS Animal and Plant Health Inspection Service CFR Code of Federal Regulations FDA US Food and Drug Administration GLP Good Laboratory Practice IACUC Institutional Animal Care and Use Committee USDA US Department of Agriculture ABOUT THE AUTHOR, Ph.D., is principal consultant at GXP Bio- Technology LLC ( in Sunnyvale, CA. Steve has more than 30 years experience supervising quality control departments dealing with drugs, biologics, HCT/P, and nutraceuticals. He has supervised animal facilities and testing laboratories that operated under GLP rules and also those operating under GMP and ISO standards. He may be reached by at kuwahara@ gxpbiotech.org or stevekuwahara@yahoo.com and by phone at Journal of GXP Compliance