1. Responsible Conduct in Research Animal Subjects Education Module Welcome to the WSU Animal Subjects Education Module Copyright©2002 Winona State University, P.O. Box 5838, Winona, Minnesota, 55987

2. Introduction –WSU encourages the review of this module by all WSU students, faculty and staff engaging in research, research training, experimentation, biological testing and related activities (including classroom demonstrations and exhibits) involving live, vertebrate animals on- or off-campus. –If you have any questions about the module’s contents, contact the Grants & Sponsored Projects (G&SP) Office at 5519 or npeterson@winona.edu for more information. npeterson@winona.edu Contents

3. –Rationale for the Education ModuleRationale for the Education Module –Institution-wide ApplicationInstitution-wide Application –Definitions -- Animals and Activities CoveredDefinitions -- Animals and Activities Covered –HistoryHistory Scientists’ Role Public Involvement Government Response U.S. Government Principles –Federal RegulationsFederal Regulations –Principle Investigator - General ResponsibilitiesPrinciple Investigator - General Responsibilities

4. Contents (Continued) –IACUCIACUC Authority Members General Responsibilities Purpose of the Protocol Review Protocol Form –AppealsAppeals –Animal Subjects - SummaryAnimal Subjects - Summary –Additional InformationAdditional Information

5. Rationale for the Education Module –Regulations on the care and use of animals in research and teaching are more complex than those covering human subjects. There is a single “common rule” on protecting human subjects, which is followed by 16 federal agencies. But for animal subjects, HHS and the U.S. Department of Agriculture (USDA) have extensive, at times, contradicting regulations. –The regulations also require adherence to non-government issued publications which undergo periodic revisions. Hence, the regulations on protection of animal subjects are in a constant state of flux. Contents

6. Rationale for the Education Module (Continued) –This Animal Subjects Education Module is designed to meet two goals: To assist researchers in complying with the complex and rapidly changing regulations on the care and use of animals. To provide evidence the institution has made information about the regulations publicly available. Contents

7. Institution-wide Application –WSU’s past practice has been to apply all federal research-related regulatory requirements to all research conducted under its auspices, regardless of source of financial support, if any. The HHS Office for the Protection of Research Risks has also gone on record as saying all species must be treated uniformly institution- wide regardless of whether or not they are “regulated.” “Only when an institution can document that the animal care and use program funded by a non-PHS source is entirely separate and distinct, physically and programmatically, from PHS-supported activities will OPRR consider its exclusion from the Institutional Assurance. Unless there is such total separation, OPRR cannot except the potential risks presented to animals involved in PHS-funded research.” Contents

8. Definitions - Animals and Activities Covered –The HHS Public Health Service (PHS) defines animal as “any live, vertebrate animal used or intended for use in research, research training, experimentation, or biological testing or for related purposes.” (Public Health Service Policy on Humane Care and Use of Laboratory Animals, III. A.) –The U.S. Department of Agriculture (USDA) 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.” It defines wild animal as “any animal which is now or historically has been found in the wild, or in the wild state….includes, but is not limited to, animals such as: deer, skunk, opossum, raccoon, mink, armadillo, coyote, squirrel, fox, wolf.” (Title 9, Chapter I, Part 1, Sec. 1.1) Contents

9. Definitions - Animals and Activities Covered (Continued) –The USDA regulations cover “research, testing, or teaching procedures that involve the care and use of animals” and “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.” (Title 9, Chapter I, Part 1, Sec. 1.1) –The USDA definition of animal excludes birds, rats, mice and farm animals. The HHS definition does not. It covers all vertebrates, including birds, rats, mice, fish, reptiles, amphibians, etc. The PHS Policy does not define wild animals, but refers to the Guide for the Care and Use of Laboratory Animals (the Guide), which states “the basic principles…apply to the use of animals living in natural conditions.”Guide for the Care and Use of Laboratory Animals Contents

10. Definitions - Animals and Activities Covered (Continued) –Most institutions across the country faced with contradictions in the regulations, adhere to the highest standards and the policy that ensures compliance with all the regulations. In doing so, the institution maintains its eligibility to apply for a variety of federal grants. –Hence, animals refers to all vertebrates, used on or off campus, including wildlife. Activities involving animals are covered when the animals are used in “research, research training, experimentation, or biological testing or for related purposes” (PHS) and/or “research, testing, or teaching procedures…in research, tests or experiments.” (USDA) –There are some exceptions. Contents

11. Definitions - Animals and Activities Covered (Continued) –Off campus, if a field study is strictly observational (USDA defined as “does not involve an invasive procedure, harm the animals under study, or materially alter the behavior of the animals under study”), it is not covered by the regulations. –Similarly, on campus, if an animal is simply on exhibit for observation, it is not covered. But if an animal is removed from its housing/exhibit for instructional uses or its environment is manipulated for research or teaching purposes, it is covered. –Students, faculty and staff are urged to seek guidance from the WSU IACUC (Institutional Animal Care and Use Committee described later) as to whether or not an activity is regulated. Contents

12. History - Scientists’ Role –Development of standards for the institutional care and use of animals was not a government-driven process. In 1946, five veterinarians at Chicago-area research institutions began meetings that would lead, in 1950, to the establishment of the Animal Care Panel (ACP). [The ACP eventually was renamed the American Association for Laboratory Animal Science (AALAS).]American Association for Laboratory Animal Science (AALAS) –In the early years of ACPs existence, there were no federal guidelines or regulations on the care and use of animals in research and teaching. Contents

13. History - Scientists’ Role (Continued) –In 1962, ACP applied for a National Institutes of Health (NIH) grant to develop national, professional standards, and in 1963, published the first Guide for Laboratory Animal Facilities and Care, forerunner of today’s Guide for the Care and Use of Laboratory Animals. Adherence to the Guide was voluntary.Guide for the Care and Use of Laboratory Animals –In 1963, ACP also appointed its first Animal Facilities Accreditation Board. That Board eventually became the Association of Assessment and Accreditation of Laboratory Care (AAALAC), the only accrediting agency for animal care programs currently recognized by HHS. Association of Assessment and Accreditation of Laboratory Care (AAALAC) Contents

14. History - Public Involvement –At the same time the Guide was being developed by scientists in ACP, Rachael Carson published Silent Spring (1962), a book credited with focusing the public’s attention on environmental issues and the welfare of animals in the wild.Guide –Four years later, a sensational article in the nationally-circulated Life magazine focused public attention on the welfare of animals used in research. The cover headline was “Concentration Camps for Dogs.” A sub-heading read “Your Dog is in Cruel Danger.” The article described conditions found at the site of a dealer who supplied animals to researchers with, the report claimed, “no questions asked.” It included a picture of a dog-owner re-united with his pet -- the identification tag of a research facility clearly visible on the dog’s collar. Contents

15. History -- Government Response –The public outcry over the Life magazine story spurred the U.S. Congress to pass the 1966 Laboratory Animal Welfare Act (now simply the Animal Welfare Act) and assigned the burden of its implementation to the USDA. The Act covers far more than research and teaching. It also contains licensing and regulatory requirements for breeders, dealers and exhibitors. –HHS’s National Institutes of Health (NIH) issued their first policy requiring institutional assurances of appropriate animal care and use in 1971, and PHS issued its Public Health Service Policy in 1973. The PHS Policy now applies to all departments and agencies within HHS. Contents

16. History -- Government Response (Continued) –In 1985, the Health Research Extension Act (Public Law 99-158) urged the USDA and PHS to coordinate further regulatory development, required institutions to establish Institutional Animal Care and Use Committees (IACUC) to oversee activities involving animals, and established national principles for the care and use of animals in research and teaching. –The U.S. Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research, and Training, established in the Act, apply to all federal agencies developing animal subject regulations and, in essence, represent a “common” federal regulatory policy. The nine principles are: – Contents

17. U.S. Government Principles –I. The transportation, care, and use of animals should be in accordance with the Animal Welfare Act (7 U.S.C. 2131 et. seq.) and other applicable Federal laws, guidelines, and policies. –II. Procedures involving animals should be designed and performed with due consideration of their relevance to human or animal health, the advancement of knowledge, or the good of society. –III. The animals selected for a procedure should be of an appropriate species and quality and the minimum number required to obtain valid results. Methods such as mathematical models, computer simulation, and in vitro biological systems should be considered. Contents

18. U.S. Government Principles (Continued) –IV. Proper use of animals, including the avoidance or minimization of discomfort, distress, and pain when consistent with sound scientific practices, is imperative. Unless the contrary is established, investigators should consider that procedures that cause pain or distress in human beings may cause pain or distress in other animals. –V. Procedures with animals that may cause more than momentary or slight pain or distress should be performed with appropriate sedation, analgesia, or anesthesia. Surgical or other painful procedures should not be performed on unanesthetized animals paralyzed by chemical agents. Contents

19. U.S. Government Principles (Continued) –VI. Animals that would otherwise suffer severe or chronic pain or distress that cannot be relieved should be painlessly killed at the end of the procedure or, if appropriate, during the procedure. –VII. The living conditions of animals should be appropriate for their species and contribute to their health and comfort. Normally, the housing, feeding, and care of all animals used for biomedical purposes must be directed by a veterinarian or other scientist trained and experienced in the proper care, handling, and use of the species being maintained or studied. In any case, veterinary care shall be provided as indicated. Contents

20. U.S. Government Principles (Continued) –VIII. Investigators and other personnel shall be appropriately qualified and experienced for conducting procedures on living animals. Adequate arrangements shall be made for their in-service training, including the proper and humane care and use of laboratory animals. –IX. Where exceptions are required in relation to the provisions of these Principles, the decisions should not rest with the investigators directly concerned but should be made, with due regard to Principle II, by an appropriate review group such as an institutional animal care and use committee. Such exceptions should not be made solely for the purposes of teaching or demonstration. Contents

21. U.S. Government Principles (Continued) –The first principle in the legislation includes a footnote indicating that for guidance in implementing the principles, the reader should refer to The Guide for the Care and Use of Laboratory Animals -- the Guide originally developed by the ACP. Today, both USDA and HHS refer the the Guide as an authoritative source for complying with their regulations. The latest edition (1996) was created by an ad hoc committee of scientists, veterinarians and nonscientists and produced by the Institute of Laboratory Animal Resources, National Research Council, National Academy of Sciences.The Guide for the Care and Use of Laboratory Animals –In summary, today’s federal regulations were created in response to public demand, but rely largely on self-imposed standards created by the scientists whose activities are regulated. Contents

22. Federal Regulations –The text of the federal regulations can be found at: U.S. Department of Health and Human Services - Office of Laboratory Animal Welfare (OLAW) - Public Health Service Policy on Humane Care & Use of Laboratory Animals (including the Health Research Extension Act (Public Law 99- 158 & US Government Principles) - http://grants.nih.gov/grants/olaw/references/phspol.htm#USGo vPrinciplesOffice of Laboratory Animal Welfare (OLAW) http://grants.nih.gov/grants/olaw/references/phspol.htm#USGo vPrinciples U.S. Department of Agriculture – Animal & Plant Health Inspection Service - Animal Welfare Act (Public Law 89-544, 1966, as amended, (P. L. 91-579, P.L. 94-279, P.L. 99-198) 7 U.S.C. 2131 et. seq.) published in the Code of Federal Regulations (CFR), Title 9, Chapter 1, Sub. A, Parts 1, 2 & 3) - htpp://www.aphis.usda.gov/animal_welfare/downloads/awr/aw r.pdfAnimal & Plant Health Inspection Service htpp://www.aphis.usda.gov/animal_welfare/downloads/awr/aw r.pdf Contents

23. Federal Regulations (Continued) –Both PHS and USDA also require adherence to: Guide for the Care and Use of Laboratory Animals - National Research Council - 1996 http://www.nap.edu/openbook.php?isbn=0309053773 http://www.nap.edu/openbook.php?isbn=0309053773 American Veterinary Medical Association (AVMA) Guidelines on Euthanasia – 2007 http://www.avma.org/resources/euthanasia.pdf http://www.avma.org/resources/euthanasia.pdf –Under the PHS Policy, institutions may be self-regulating and evaluated internally by their IACUCs or they may be evaluated and accredited by AAALAC (http://www.aaalac.org).http://www.aaalac.org Contents

24. Federal Regulations (Continued) –PHS Policy, the Animal Welfare Act and the Guide constantly cross-reference each other. All three refer to following the guidelines for euthanasia established in the most recent AVMA Panel report.Guide –Both PHS and USDA require filing of assurances; providing training for personnel; establishment of an IACUC with similar review, inspection, reporting and recommending responsibilities; and the authority to investigate concerns and suspend activities involving animals. –The Guide also calls for establishment of institutional policies, occupational health and safety programs (PHS also calls for such programs, but not USDA), and a disaster plan.Guide Contents

25. Principle Investigator (PI) - General Responsibilities –WSU faculty, students and staff engaged in research or teaching activities with vertebrates must adhere to the four primary regulations covering animal subjects care and use: Public Health Service Policy on Humane Care & Use of Laboratory Animals (Administered by HHS) Animal Welfare Act (Administered by the USDA) Guide for the Care and Use of Laboratory Animals American Veterinary Medical Association (AVMA) Panel on Euthanasia –Deviations are allowed, however, if PIs can produce written scientific justifications based on appropriate documentation, such as citations of standards set forth in publications by professional societies or articles in scientific journals. Contents

26. PI - General Responsibilities (Continued) PIs responsible for: Design and preparation of the research and/or teaching plan Submission of a Protocol for Animal Research and/or Teaching Activities to the IACUC prior to securing animals or initiating activities, including written justification for any deviation from regulations and standardsProtocol for Animal Research and/or Teaching Activities Oversight of the housing, feeding and non-medical care of the animals Appropriate euthanasia and disposal of the animals Training of students using animals in research and teaching Reporting to the IACUC any changes in activities and/or any data required by the IACUC for reporting purposes Contents

27. Institutional Animal Care & Use Committee (IACUC) - Authority –The Institutional Animal Care and Use Committee (IACUC) is an agent of the institution, authorized to act on its behalf. –It reports to a designated Institutional Official who is legally responsible for compliance with the federal regulations. –One IACUC member is a veterinarian who provides guidance on animal care and is responsible for directing a veterinary care program, as dictated by the species being used, as well as addressing possible problems in terms of animal health, behavior and well-being. Medical care for the animals at an institution must be available and provided by a qualified veterinarian. Contents

28. IACUC - Authority –Animals to be used in research or teaching may not be acquired and housed on campus, nor research and teaching activities involving animals initiated, prior to approval by the IACUC. –Animal may only be housed in facilities that have been inspected by the IACUC and must be housed under living conditions that meet regulatory requirements. –Reports of unauthorized animals housed on-campus or research or teaching being conducted without IACUC approval will be investigated. Unauthorized activities will be suspended until proper approval is secured. Contents

29. IACUC - Authority –The IACUC is also authorized to investigate any concerns raised by interested persons -- on or off-campus -- regarding the care and use of animals in research or teaching activities. If warranted, the IACUC may require previously approved research be discontinued. –Activities that have been reviewed and approved by an IACUC may be reviewed and disapproved by officials of the institution. However, those officials may not approve any project if it has been disapproved by the IACUC. Contents

30. IACUC - Members –Both the USDA and PHS require the Chief Executive Officer to appoint IACUC members with the experience and expertise needed to oversee the institution’s animal program and inspect its facilities and procedures. Hence, the overall membership must have both scientific and regulatory expertise. (Specific membership requirements appear on the next slide.) –An IACUC may invite individuals with competence in special scientific areas to assist them as needed. In recent years, institutions have also designated individuals to act as compliance facilitators for IACUCs (and other regulatory bodies) to provide authoritative advice when there are questions on regulatory requirements. Contents

31. IACUC - Members (Continued) –IACUCs, under PHS guidelines, must include: at least five members, including: one Doctor of Veterinary Medicine with program authority one practicing scientist experienced in research involving animals one member whose primary concerns are in a nonscientific area (for example, PHS suggests an ethicist, lawyer, clergy member, etc.) and one individual who is not associated with the institution in any way (nor may a member of his/her immediate family be so affiliated) Contents

32. IACUC - Members (Continued) –According to PHS, an IACUC member may meet more than one of the required categories, but the IACUC must still have at least 5 members. –The USDA regulations require only 3 members, including a chair, a veterinarian and an unaffiliated individual to represent community interests. –Most institutions follow the PHS five-member structure to assure compliance with both PHS and USDA requirements. Some also appoint alternates to ensure quorums are available on short notice. Contents

33. IACUC - General Responsibilities review the institution’s animal care program every six months inspect all animal facilities (all study/activity areas) every six months, reporting deficiencies to institutional officials and federal agencies as required prepare reports for the Institutional Official and federal offices and maintain written records of all meetings, proposals reviewed, decisions concerning reviews, and reports from investigators Contents

34. IACUC - General Responsibilities (Continued) make recommendations to institutional officials concerning any aspect of the animal care program review and investigate concerns involving the care and use of animals in research or teaching and suspend or terminate research that is not conducted in accord with federal requirements review animal use protocols and/or modifications to previously approved protocols, and approve, require modifications in or withhold approval of all proposed activities involving animals used in research or teaching, including the re-review of protocols every 3 years (PHS) or annually (USDA) Contents

35. IACUC - Purpose of the Protocol Review –The IACUC’s paramount responsibility is animal care. It reviews requests to use animals in research and teaching in that context. When in doubt, it relies on the U.S. Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research, and Training. –Reviews are conducted in accord with two general goals: Scientific reliance on live animals should be minimized. Pain, distress, and other harm to laboratory animals should be reduced to the minimum necessary to obtain valid scientific results. Contents

36. IACUC - Purpose of the Protocol Review (Continued) –The academic quality of proposed research or teaching activities is reviewed in the context of those two general goals. The research plan, design and methodology are reviewed as they are related to the protection of animal subjects -- that is, that the use of animals is justified, that any pain and distress is justifiable and that the animals will receive appropriate care. –There are nine general criteria that IACUCs consider when reviewing protocols: Contents

37. IACUC - Purpose of the Protocol Review (Continued) Selection and justification of species Living conditions of the animals Justification for the use of animals Application of the principles of replacement, reduction and refinement –Replacement - use of reasonably available alternative non- animal models (mathematical models, computer simulations, tissue cultures) if objectives can be achieved –Reduction - use of the minimal numbers of animals needed to produce scientifically valid results –Refinement - use of procedures that produce the least possible amount of pain, discomfort or distress Contents

38. IACUC - Purpose of the Protocol Review (Continued) Treatment of pain and discomfort Use of restraints Euthanasia methods Qualification of research personnel Occupational health and safety –A protocol may be reviewed by the Chair or a designated member of the IACUC. However if any member of the committee requests a full committee review, the IACUC must comply with the request. A quorum must be present at the review and a majority of those present must vote to approve or disapprove the protocol. Common practice at WSU is to conduct full reviews on all protocols. Contents

39. IACUC - Protocol Form –PHS and USDA require protocols include: a complete description of the proposed use of the animals a description of procedures that will be used to avoid or minimize discomfort, distress and pain, consistent with sound research design a description of procedures designed to assure that discomfort and pain or injury to animals will be limited to that which is unavoidable for the conduct of scientifically valuable research, and that analgesic, anesthetic and tranquilizing drugs will be used when appropriate to minimize discomfort and pain Contents

40. IACUC - Protocol Form (Continued) –The Guide summarizes the specific elements that should be included in a standard protocol form to facilitate IACUC review under both sets of regulations. Note, some elements may not be applicable to all protocols. The elements are:Guide Rationale and purpose of the proposed use of animals Justification of the species and number of animals requested. Whenever possible, the number of animals requested should be justified statistically Availability or appropriateness of the use of less-invasive procedures, other species, isolated organ preparation, cell or tissue culture, or computer simulation Contents

41. IACUC - Protocol Form (Continued) Adequacy of training and experience of personnel in the procedures used Unusual housing and husbandry requirements. Appropriate sedation, analgesia, and anesthesia Unnecessary duplication of experiments Conduct of multiple major operative procedures Criteria and process for timely intervention, removal of animals from a study, or euthanasia if painful or stressful outcomes are anticipated Postprocedure care Contents

42. IACUC - Protocol Form (Continued) Method of euthanasia or disposition of animal (must be consistent with the AVMA report unless a deviation is justified for scientific reasons in writing by the investigator) Safety of working environment for personnel –The WSU IACUC Protocol for Animal Research and/or Teaching Activities form is designed to include all the elements recommended in the Guide in order to provide the IACUC with enough information to conduct the review in accord with the two general goals and nine criteria.WSU IACUC Protocol for Animal Research and/or Teaching ActivitiesGuide Contents

43. IACUC - Appeals –An individual whose protocol request is disapproved by the IACUC may revise and resubmit the request and/or request a meeting with the IACUC to discuss the protocol and provide additional documentation in support of the protocol. (Note, the IACUC is required to have on file written scientific justifications for any deviations from the regulations.) –As noted earlier, activities disapproved by the IACUC cannot be approved by other institutional officials. However, those officials may disapprove activities approved by the IACUC. Contents

44. Animal Subjects - Summary –The regulations covering animal subjects are extensive and complicated. They specify animal facilities’ structural and physical requirements. For mammals, the regulations dictate what type and size of cage and what environmental conditions are required. When there are contradictions, the Guide defaults to the USDA and PHS regulations and PHS recommends following the USDA regulations.Guide –Specific care standards are not established for “cold-blooded” vertebrates, such as amphibians, snakes, fish, etc. Instead, PHS recommends defaulting to standards set by professional societies. Contents

45. Animal Subjects - Summary (Continued) –The PI is ultimately responsible for the well-being of the animals under his/her care, even if s/he delegates their day-to-day care to others. The IACUC is responsible for monitoring the care and use of animals on behalf of the institution. –The PI is also responsible for adhering to all regulatory requirements. As a monitoring body, the IACUC can assist the PI by providing regulatory guidance and acting as a liaison to federal agencies when questions arise. –The institution is ultimately responsible for the adequacy of its own “self-regulation” and accreditation. Contents

46. Additional Information –For additional information, students, faculty and staff are encouraged to review an online tutorial on the Office of Laboratory Animal Welfare (PHS) web site. http://grants.nih.gov/grants/olaw/tutorial/index.htm –PIs are also encouraged to contact the WSU IACUC any time they have any questions. Inquiries may be addressed to any member of the IACUC or to the G&SP Office, npeterson@winona.edu, ext. 5519.npeterson@winona.edu Contents