Post Approval Monitoring (PAM) Program Fostering progressive science while ensuring animal welfare

PAM Program Function Post Approval Liaisons (PALs) Jeanna Crookshanks Jamie Lewis The PAM Program’s function is to facilitate and monitor animal care and use at UTMB in a collegial and educational manner.

Regulatory Background

Why does UTMB need the PAM program? As part of the oversight requirement of the Institutional Care and Use Committee (IACUC) as set forth in the United States Department of Agriculture (USDA) Animal Welfare Regulations 9CFR 2.31, and Public Health Service (PHS) Policy on Humane Care and Use of Laboratory Animals PL , Section IV.B.2. To aid in maintaining AAALAC accreditation. Since 99 of the top 100 NIH funded institutions are AAALAC accredited, there is clearly importance to upholding our accreditation. To guarantee to regulatory agencies, sponsors, legislative bodies, and the public that our animal research program has sufficient integrity This is NOT new ground or new regulations; UTMB is choosing to fulfill its post approval monitoring in a collegial and educational manner.

One bad apple can spoil the whole barrel If a regulatory agency identifies a non- compliant situation, research privileges for the entire campus could be revoked. If PAM identifies a non-compliant situation, the situation can be corrected internally. It is better for the non-compliant lab to bear the consequences, than the entire research community.

AAALAC = Association for Assessment and Accreditation of Laboratory Animal Care ARC = Animal Resource Center AWA = Animal Welfare Act AWR = Animal Welfare Regulations FDA = Food and Drug Administration GLP = Good Laboratory Practices IACUC = Institutional Animal Care and use Committee ILAR = Institute for Laboratory Animal Research NIH = National Institutes of Health NRC = National Research Council OLAW = Office of Laboratory Animal Welfare PAM = Post Approval Monitoring PHS = Public Health Service USDA = United States Department of Agriculture USDA UTMB Animal Care and Use Program Research Labs IACUC ARC PAM Institutional Official: Bill New FDA NIH PHS OLAW AAALAC Animal Welfare Assurance Statement and Annual Report State and local laws Institutional policies ILAR NRC USDA Registration: Yearly animal Inventory and “E” Pain Level statements The Guide for the Care and Use of Laboratory Animals Unannounced site inspections Accreditation not Regulation GLP Regulations Animal Research Compliance Diagram AWA PHS Policy on Humane Care and Use of Animals AWR

What are the Regulations? Animal Welfare Act and Animal Welfare Regulations (Federal law) Enforced by the United States Department of Agriculture - sets minimal standards for animal care AWA was passed by Congress in 1966 because of concern that stolen pets were being used in research. It was known as the Pet Theft Act. This act authorized the USDA to develop regulations (AWR) for the care and use of animals in research, testing and training, or as pets. AWR regulates the use of all warm-blooded animals except birds, purpose bred rats and mice, and farm animals used for food or fiber. The Act covers all wild mammals. UTMB is a registered USDA facility and must undergo yearly, unannounced site inspections, submit an annual animal inventory, and all “E” level pain statements from protocols involving registered species. AWR state that the Guide * should be followed ( * see future slide) Therefore, the USDA does not regulate the use of mice and rats unless they are “wild caught”. However PHS Policy does cover mice and rats. See next slide. USDA AWA AWR

What are the Regulations? PHS Policy on Humane Care and Use of Laboratory Animals Public Health Service, parent organization of the National Institutes of Health Enforced by the Office of Laboratory Animal Welfare PHS Policy covers all vertebrate animal activities at institutions supported by PHS agencies Conforms with the Guide * (see future slide), the Animal Welfare Regulations and the American Veterinary Medical Association’s Guidelines on Euthanasia Inclusive of the U.S. Government Principles of Vertebrate Animals (See next slide) UTMB submits an Animal Welfare Assurance Statement to PHS describing our animal care and use program and our compliance plan. In it we state we will follow Animal Welfare Regulations for all species of animals, including purpose bred mice, rats and birds PHS OLAW NIH

What are other Principles? U.S. Government Principles for the Utilization and Care of Vertebrate Animals used in Testing, Research and Training: Transportation, care and use in accordance with Animal Welfare Act Animal experiments should be designed with consideration to the relevance to human and animal health, the advancement of knowledge and the good of society Animals selected should be appropriate species and minimum number for valid results; mathematical models, computer simulations and in vitro systems should be used instead when possible - Continued -

Other Principles continued. U.S. Government Principles for the Utilization and Care of Vertebrate Animals used in Testing, Research and Training: -Continued – Avoid or minimize pain, discomfort and distress Use sedation, analgesia and anesthesia in procedures Use euthanasia used when chronic pain or distress is an outcome Appropriate living conditions and veterinary care should be provided Personnel should be qualified, experienced and trained Exceptions should be made by a review group, not the investigator

What are the Regulations? * Guide for the Care and Use of Laboratory Animals (the Guide) The Guide covers all aspects of animal care and use: Institution Policies and Responsibilities Monitoring the care and use of animals, personnel qualifications and training, occupational health and safety of personnel Animal Environment, Housing and Management Physical environment, behavioral management, husbandry population management Veterinary Medical Care Procurement and transportation, preventative medicine, surgery, pain, analgesia, anesthesia, euthanasia Physical Plant Functional areas, construction guidelines, surgery facilities ILAR NRC

What is our Accreditation? Covers all animals Symbolizes quality – high standards for animal care Promotes scientific validity – better research practices and outcomes Recruiting tool – helps attract top researchers Demonstrates accountability – and willingness to go above and beyond Provides a confidential peer-review – as well as requires self evaluation Impresses funding sources – Private organizations highly recommend; Government sources regard it as evidence of a commitment to excellence Shows a commitment to humane animal care Uses the Guide as a standard AAALAC Association for Assessment and Accreditation of Laboratory Animal Care, International

What are other associated regulations? System of management controls to ensure the quality and integrity of data in preclinical trials on animals prior to clinical research in humans Generate data by which the hazards and risks of the tested substance can be assessed Helps assure regulatory authorities that the data submitted are a true reflection of the results obtained during the study and can therefore be relied upon when making risk/safety assessments Should not be confused with standards for laboratory safety FDA Food and Drug Administration Good Laboratory Practice (GLP) Regulations

Other associated regulations cont. Historically used by business and industry Since the September 11 th attack, the US government has turned to academia for the development of treatments for select agent exposure UTMB has the expertise to conduct studies for prevention, treatment and diagnosis of life threatening diseases caused by select agents, thus GLP group formed at UTMB: FDA Food and Drug Administration Good Laboratory Practice (GLP) Regulations

What are the IACUC’s Functions? USDA and PHS define IACUC functions as: Review and approve animal protocols Review and approve amendments to animal protocols Inspect all animal use facilities every 6 months (known at UTMB as the “semi-annuals”) Review institution’s animal program every 6 months Investigate concerns of animal care and use Authorized to suspend animal activities – report to OLAW Prepare reports of evaluations Make recommendations to Institutional Official PHS USDA

Principals in Animal Care and Use The 3 R’s of Russell and Birch Replacement of animals by cell or tissue culture or by mathematical models where possible Refinement of procedures to minimize stress or pain to animals by using personnel trained in procedures, use of anesthetics, analgesics and euthanasia. Use of the least sentient species possible Reduction to the minimum number of animals that will serve a useful purpose, yield statistically sound data and produce scientific benefit. Employ techniques which use an animal for more than one time point

Ethical Cost-Benefit of Animal Research Scientific Value Ethical Cost humans animals science society pain discomfort distress morbidity mortality The scientific value must out weigh the ethical cost

PAM Program Structure within UTMB

Reporting Structure of the PAM Program liaison Research Services IACUC Regulatory Affairs Animal Resource Center Research Subject Protection PAM Research Labs liaison

UTMB areas involved in the PAM Program Institutional Animal Care and Use Committee (IACUC) Animal Resource Center (ARC) Research Laboratories

Institutional Animal Care and Use Committee IACUC Staff Allan Silva – IACUC Manager Cathy Simmons – IACUC Coordinator The Committee is comprised of volunteers which serve a one year term: Scientists Veterinarians Non scientist Lay persons, not associated with the institution Research Subject Protection

Animal Resource Center Veterinary Team Bill Masters, DVM - ARC Director Karen Vargas, DVM - Associate Director Monica Fann, DVM - Clinical Veterinarian Cheryl Bobbitt, BAGS, RVT, RLATG - Vet Tech Supervisor Animal Husbandry Leaders Mary MacCallum, LATG – Manager, Operations Seth Linde, LATG - Manager, ABSL 3 & ABSL 4 Ofelia Ramirez-Herrera, LAT - Supervisor – Satellites Sofia Gomez, ALAT - Team Leader – ARC Judy Barnett, RLATG – Supervisor - ABSL2 Phillip Bordelon, RLATG - Supervisor – MRB Ben Thompson, RLATG -Supervisor – Building 17 Karolyn Niven, LATG - Supervisor - Bldg 21 Tim Fleming, LATG – Supervisor – GNL Cage Processing Animal Resource Center

Background of Animal Welfare Regulations

W W II Experiments on Humans Principle #3 of the Nuremberg Code of The (human) experiment should be so designed and based on the results of animal experimentation and a knowledge of the natural history of the disease or other problem under study, that the anticipated results will justify the performance of the experiment.

Public Opinion Public opinion about animals used in research took a turn for the worse when this article made the cover of Life magazine in 1966

Pets stolen from homes This article claimed pets were being stolen for use in research. This increased public awareness of animal welfare issues.

Public Awareness The article suggested a need for animal research regulation and enforcement, especially for dogs and cats

Animal Welfare Act passed by Congress The Animal Welfare Act was passed by Congress in This established federal legal standards for laboratory animal care and use in the United States for the first time. The United States Department of Agriculture (USDA) was named the enforcement agency and developed the Animal Welfare Regulations. Animal Welfare Act and Regulations Animal Welfare Information Center Animal Welfare Information Center United States Department of Agriculture

Animal Research Compliance Timeline st edition of the Guide for the Care and Use of Laboratory Animals aka (Guide) 1966 Laboratory Animal Welfare Act passed by Congress, USDA named the responsible agency Regulated use of all warm-blooded animals except birds and purpose bred rats and mice, & farm animals used for food or fiber. The Act covers all wild mammals Institutions using animals must register with the USDA Regulations for housing, handling, feeding, watering, sanitation, ventilation, transportation, species separation and veterinary care. Submit yearly inventory form describing acquisition and disposal of animals 1965 Incorporation of American Association for the Accreditation of Laboratory Animal Care (AAALAC) st Public Health Service (PHS) Policy on Humane Care and Use of Laboratory Animals replaced NIH Policy 1979 PHS policy requires a PHS Assurance statement from institutions receiving PHS funding and expanded its definition of animal to include all vertebrates; Policy enforced by Office for Protection from Research Risks (OPRR) 1985 Animal Welfare Act Amendments passed by Congress Establish IACUCEnrichment for primates Personnel trainingUse of analgesia/anesthesia Exercise for dogsOne major surgery Assign responsibility to IOConsider alternatives to animals Facility Inspection by IACUC 1990 Office for Protection from Research Risks (OPRR) established a Division of Animal Welfare 1996 AAALAC became Association for the Assessment and Accreditation of Laboratory Animal Care International th edition of the Guide 2000 Division of Animal Welfare separated from OPRR, became the Office of Laboratory Animal Welfare (OLAW) 1971 National Institutes of Health Policy on Care and treatment of Laboratory Animals, required institutional oversight committee for animal care and use

Animal use is a Privilege not a Right Scientists accept the responsibilities associated with animals: Plan and conduct research in the context of quality animal care Know and adhere to policies and procedures regarding animal acquisition and use Ensure that the protocol is approved and followed Ensure personnel are appropriately trained Ensure that personnel working on the protocol are listed on the protocol Society demands that animal use be both justified and humane The PI, ARC, IACUC, PAM, USDA, OLAW, and AAALAC are all members of the same team

UTMB’s PAM Program

What are the goals of the PAM Program? Ensure animal well being Serve as a resource to the research community Confirm that husbandry procedures are being performed in accordance with regulations Confirm that animal procedures are being performed in accordance with approved protocols Encourage self regulation/reporting within the research community

How will the PAM Program achieve this? With Post Approval Liaisons (PALs) who will Be liaisons between IACUC, ARC and laboratories Assist in protocol and amendment submission Educate research community on regulatory issues Encourage a culture of compliance and self regulation Ensure animal program integrity PALs are unbiased observers and do not have independent enforcement authority

Who will be interacting with the PALs? Principal Investigators Laboratory staff Animal husbandry technicians Veterinary staff IACUC members Research Services

Is participation in the PAM Program required? Yes, the PAM Program is the way which UTMB has chosen to fulfill its obligation of post approval monitoring. PHS Policy on Humane Care and Use of Laboratory Animals - Frequently Asked Questions Monitoring of animal care and use is required, though neither the PHS Policy nor the Guide explicitly address or require specific or separate post approval monitoring (PAM) procedures to compare the practices described in approved protocols and SOPs against the manner in which they are actually conducted.

Attitude is Everything Perfection is not expected, in fact it would be unusual if there were nothing wrong When protocol drift occurs, labs should add an amendment or return to the original protocol procedures If an animal is harmed, labs are expected to report the event, along with steps taken to prevent it from occurring again Self regulation and reporting is part of the process We should be good animal stewards, not just because the regulations require it but because it is the right thing to do

Why is this program important? Provides investigators with verification of good performance in their laboratories Detects compliance issues early and enables laboratories to resolve them while they are still minor concerns Assures proper and consistent animal care Proper and consistent animal care = Reliable scientific data

Animal related factors can affect data Data Genetic Disease Biological determinants Biological cycles and rhythms Metabolic functions Bedding Materials Water quality Temperature Food composition Humidity Air composition Microbial flora and fauna Light cycles and quality Population density Personnel attitudes Local policiesLegal requirements Husbandry practices Experimental manipulations Conflicting experimental procedures Pollution, transportation and supply problems Veterinary Care

Why is the husbandry staff important? They are the first ones to see the animals arrive at UTMB Prepare and transport the animals within the facility Know which animals belong to which PI Maintain a sound program of animal husbandry Report any abnormal behavior, illness or dead animals Monitor and maintain a clean, stable environment Report physical plant malfunctions to authorities Process caging for cleaning and sanitizing Assist with breeding programs Maintain records of animals and environmental observations Stock supplies and dispose waste Receive ongoing training

What are veterinary staff responsibilities? Oversees surveillance, diagnosis, treatment, and control of disease, including zoonosis control Consults on surgery and proper anesthetic, analgesic and euthanasia methods Assures that pre-procedural and post-procedural care is in accordance with established veterinary medical and nursing procedures Assessment of animal well-being - including psychological well being of primates and environmental enrichment program Ensures compliance with appropriate regulations Ensures proper record keeping of animal populations. (Medical records, USDA paperwork, etc.) Provide pre-review service for protocols Are the final decision on disposition of animals Ensure adherence to AVMA Guidelines on Euthanasia

The PAL visit

How will protocols be selected for review? All approved protocols will be reviewed - either randomly or by request of IACUC, ARC or the Quality Assurance division of Research Services

What is the protocol review process? PI contacted by PALs Protocol discussion with PI and lab staff Observation of protocol procedures Debriefing

What will we be discussing? Discussions will include but are not limited to: PAM Program introduction Discussion of protocol procedures Self regulation/reporting Tools for animal researchers Record keeping Humane endpoints and euthanasia Recognizing pain and distress in animals

What will we be observing? Observations will include but are not limited to: Protocol activity Anesthesia/analgesia/euthanasia Aseptic technique Staff training Record keeping – controlled substances Safety issues Experimental agents within expiration

What is the most important way to prepare for a PAL visit? The latest approved protocol and all associated forms and amendments should be in the laboratory All personnel working on the protocol are listed on the protocol All personnel have read and understood the protocol

Does the Principal Investigator need to be present for the entire process? Initial contact from the PAM program will be with the PI, the protocol discussion will be with the PI and their lab staff, however laboratory staff can work with the PALs during the procedure observations if so desired.

Why do PALs ask so many questions? ???????????????? Questions do not mean that there is a problem – we are simply working to collect as much information as possible. PALs want to understand all aspects of your protocol. This allows us to be your advocate. ????????????????

Will this replace the IACUC semi-annual lab visit? NO! The PAL visits do not replace the IACUC’s semi-annual animal program and facilities review, but please think of us as a dress rehearsal for those visits! We are here to help.

What the PAM program is not! Animal police Replacement for the IACUC Required by sponsors Required by USDA or PHS A funded mandate New ground or a new regulation

In Conclusion A proactive community of investigators at UTMB who meet obligations for the proper care and use of laboratory animals will help UTMB to meet its scientific goals while maintaining regulatory compliance

Contact Information Jamie Lewis PAL Jeanna Crookshanks PAL Research Services Monitoring & Quality Assurance Research Services – PAM Program 4th floor Rebecca Sealy East (3 right turns from the east elevators)

Animal Welfare Act and Regulations Guide for the Care and Use of Laboratory Animals the “Guide” (ILAR and NRC) Public Health Service Policy On Humane Care and Use Of Laboratory Animals USDA Policy Manual NIH Animal Research Advisory Council (ARAC Guidelines) Office of Laboratory Animal Welfare Association for Assessment and Accreditation of Laboratory Animal Care Regulations, Guidelines and Policies Regarding the Care and Use of Animals