2009 Investigator Technician Training Manual Module 1

2009 Investigator Technician Training Manual Module 1 Introduction Welcome to the training program of the Laboratory Animal Care and Use Program. This online training program gives you important information about the animal research program and what your responsibilities are in that program. For better or worse, the scrutiny of animal research is increasing, both by the federal government and by animal rights organizations. We have federal laws and policies with which we must comply and that compliance is everyone’s responsibility. Moreover, we want to provide you with information on how to conduct animal research with due regard for minimizing pain and distress. Animals that are provided good care produce better data than those subjected to pain and distress. Names and contacts for help in any area of the LAR are provided below. To print off a PDF copy of the table of contacts below, click HERE (Hyperlink). Questions about Contact Phone number Email Major program issues Pathology support Medical support See below

David M. Pinson DVM, PhD Director and Clinical Professor of Pathology

Office Phone 913-588-7351 Cell phone 913-568-7363

[email protected]

Program support Medical support Surgical support Disease control

Nathan Culley, DVM Associate Director

Office Phone 913-588-7352 Cell Phone 913-908-1369

[email protected]

Health problems, population health, surgical support, medical records

Clinical veterinarian Pending recruitment

Billing issues Yolande Cole, BS, CGFM, Asst Director

913-588-7016 [email protected]

Husbandry issues, repair requests, facility issues

Terri Brookshier BS, LATG Facility Manager


Husbandry issues and requests

Sarah Karina, BS Husbandry Manager


Caging needs Susan Anderson Cagewash Manager


Animal orders from vendors, institutions; material transfer agreements related to animal acquisitions

Laura Molinaro Senior Coordinator


Training Marcia Helwig, BS Senior Coordinator


IACUC and animal protocol issues

Latyona Luster Director, ARPP


Compliance Vacant Ed Phillips, Interim Associate Vice Chancellor for Compliance


Please note that you can submit online special requests from the LAR website at www.kumc.edu/lar. You can also submit animal orders online from the same website.

At this point, we would like to clarify acronyms that are frequently used in animal research and regulatory compliance. We provide these so you know what we are talking about should we fail to define them in the text. Abbreviation Meaning AAALAC Association for Assessment and Accreditation of Laboratory Animal Care AALAS American Association for Laboratory Animal Science ACLAM American College of Laboratory Animal Medicine ACUP Animal care and use proposal APHIS Animal and Plant Health Inspection Service, USDA ARPP Animal Research Protection Program of KUMC Division of Compliance AVMA Panel AVMA Guidelines on Euthanasia AWA Animal Welfare Act DEA Drug Enforcement Administration (controlled drugs/use/distribution/records) FDA Food and Drug Administration (gaining new drug approval for market) Guide Guide for Care and Use of Lab Animals, an NRC publication (all animals) LAR Laboratory Animal Resources NIH National Institutes of Health OLAW Office of Laboratory Animal Welfare, NIH (all animals) PHS Public Health Service PHS Policy PHS Policy on Humane Care and Use of Laboratory Animals REAC Regulatory Enforcement Animal Care, USDA USDA United States Department of Agriculture (regulated animals) RAC Research Advisory Committee of KUMC

Module 2 Laws and Policies The use of laboratory animals in biomedical research is a heavily regulated enterprise. There are two major laws and several other policies that provide the regulatory base on which we operate. We will provide a brief overview of these laws and policies. Internet links will take you to the actual documents. Both of the major laws require this training program for animal care and use staff. The Animal Welfare Act (AWA) was initially passed by Congress in 1966 and several revisions have occurred since that time (1970, 1976, 1985). In its current form, the act places many requirements on the research animal care and use program. The United State Department of Agriculture (USDA) enforces the Act and site visits the facility every year. We must register with the USDA as a research facility. The law requires the establishment of an Institutional Animal Care and Use Committee (IACUC) and provides details about how that committee is to function relative to review of the animal use program, facilities, proposed research, and considerations about pain and distress. The AWA also provides housing and care standards for each of the various species meeting the definition of animal, transportation standards, sanitation standards, the management of psychological well-being for primates, and exercise for dogs. The AWA requires the committee to accomplish semi-annual reviews of program and facilities where animals are housed or used (including investigator laboratories). The Act limits the definition of “animal” to live or dead dogs, cats, primates, hamsters, guinea pigs, rabbits, and farm animals used for basic science research, but it currently excludes rats of the genus Rattus, mice of the genus Mus, and birds. However, in all likelihood, these species will eventually come under regulation. Thus, it is prudent for us to treat all animals used in research according to these

standards. The act requires annual reporting to the USDA of how many animals are used in selected pain categories. These categories include the following: Category Description Category B Animals bred or held for research, but not used in studies. Category C Animals used in research involving no pain or distress. Category D Animals used in research involving pain or distress that is managed

by appropriate therapy such as analgesics and anesthetics. Category E Animals used in research involving pain or distress for which no

treatment is offered. These studies must be well-justified to the IACUC. Annual reports to the USDA must indicate what that justification was and how many animals were involved.

The USDA expects research facilities to accurately classify animals in these categories. Your research records must accurately reflect the number of animals used and the actual category in which they were used. If a regulated animal was not expected to suffer pain or distress (column C or D study), but research procedures actually caused pain or distress or death, then the animal must be classified as column E and a justification must be provided. Thus, it is important that accurate research records be maintained in case such studies are ever audited. An animal that dies of natural causes unrelated to the research need not be reported under category E studies. There is another complete set of documents called “The USDA AWA Policy Manual”. It is essentially statements and documents that describe how the USDA interprets its own regulations. The animal care and use program is designed to meet all of these requirements and keep adequate records that document that effort. We are reviewed at least once yearly by USDA officers. At this site visit, they scrutinize the facility, the animal housing, sanitation, and program and IACUC records. Many of the Standard Operating Procedures (SOPs) detailed below are designed to meet the requirements of this act. The second major law is the Health Research Extension Act of 1985. The law empowers the National Institutes of Health to mandate standards for animal care and use. These standards are advanced in a policy statement entitled the “The Public Health Service Policy on the Humane Care and Use of Laboratory Animals” (PHS Policy). This policy essentially endorses the Guide for the Care and Use of Laboratory Animals (Guide) and for all intents makes compliance with the Guide mandatory if an institution is going to use PHS funds to support research. The PHS Policy mandates that institutions using PHS funds for the conduct of animal research file an NIH Assurance. This is a negotiated document that describes the program for animal care and use and how it complies with the Guide. It is negotiated between the institution and the Office of Laboratory Animal Welfare, NIH (OLAW). Both the PHS Policy and the Guide require the establishment of the IACUC and mandate how this committee is to function. While the AWA only requires a committee of 3, the PHS Policy requires a committee of 5. At institutions like KUMC, committees must be much larger to deal with the workload. The PHS Policy requires review of animal care and use proposals before initiation of research, annually, and complete reviews tri-annually. The PHS Policy requires twice yearly reviews of both the program and any facilities where animals are housed or used (including investigator laboratories). We also have to file a report annually with the PHS to indicate any changes in the program, the IACUC, or important personnel. Here again, most of our SOPs are designed to address the requirements of the Guide.

A recent development is the NIH’s expectation that issues of noncompliance should be reported to the Office of Laboratory Animal Welfare. This has far reaching implications for both funded researchers and the institution. Whenever noncompliance with the Assurance or approved procedures or approved research is identified, we are required to file a formal report with the Office of Laboratory Animal Welfare (OLAW). OLAW has stated that it believes there is much more noncompliance than is reported. They begin to question any assured institution that never “fails”. At KUMC, we prefer to be up front and honest with the federal government and we will report to them when failures occur. Just so this is clear, noncompliance includes doing animal research procedures for which you are not approved (such as toe clipping, minor surgical procedures, use of drug treatments or anesthetics not listed on your approved protocol, not complying with housing policies, not using aseptic technique for surgery, employing people not listed on your approved protocol for animal related work, etc., etc.). KUMC has had to report several of these incidents over the last few years and you can be assured that such reporting is not fun for the compliance team or the investigator or for the investigator’s research staff. You do not want to come under such scrutiny. Thus, it is far better to know the standards and what you are approved to do with animals. If you do not know what you are approved for, you should ask your immediate supervisor for the approved protocols to review them. Finally, AAALAC has stated that it wants to know about any noncompliance reported to federal agencies. It is very important to know that the USDA and the OLAW have a memorandum of agreement. The memorandum denotes the sharing of information between these federal agencies. Thus, USDA findings are transmitted to OLAW and OLAW findings are transmitted to USDA. Historically, OLAW rarely visits institutions, but USDA does so regularly. We expect that any significant USDA findings will be promptly reported to OLAW. If findings by either agency are significant for noncompliance, the ramifications for research funding are substantial since OLAW can control PHS funding. In addition to the above documents (the AWA, the Guide, and the PHS Policy), we are required to comply with other federal and state regulations. Among these are standards for laboratory biosafety, Occupational Health and Safety regulations, radiation safety regulations, controlled drugs management (Drug Enforcement Administration), employment law, and hazardous waste and radioactivity regulations. Many of our SOPs are designed to address these issues, policies, and requirements. Controlled drugs (scheduled drugs with abuse potential) are a frequent area of interaction with the LAR. The Drug Enforcement Administration allows us (the LAR) to dispense narcotics and scheduled drugs under our license when they are used for the medical care of the animals. However, if you propose a research project designed to study the effects of these drugs on a biological system, the DEA would prefer that you (the principal investigator) obtain your own DEA license rather than using the LAR’s license. The reasoning behind this requirement is unclear, but the DEA is very clear on the issue of when an investigator needs to obtain his or her own license. SOP Prog 24 Controlled Drug Dispensing governs the distribution and use of these drugs. Abuse potential is what sets controlled drugs apart from other medications. The DEA requires accurate records of how controlled drugs are dispensed and used. The records must indicate to whom the drugs were dispensed, the date and dose of drug given to what specific animal or animals. The record of drug usage must remain with the bottle and the volume in the bottle should reflect what the record indicates as remaining. If requested by IACUC or any other inspector or federal agency, you should be able to produce the bottle and the record. The drugs that you have on hand in your laboratory must be consistent with your approved animal care and

use proposal. Finally the controlled drugs and records must be stored under lock and key together. Thus, DEA compliance is important to this aspect of research needs. Key Points

• Animal research is heavily regulated. • This training program is required by the applicable laws and policies. • Compliance is everyone’s responsibility. • We are subject to inspections by federal and state agencies. • Noncompliance that compromises animal welfare must be reported to federal agencies,

including who, what, and how the issue was remediated or resolved. • USDA and OLAW share information gleaned from their inspections. • The IACUC is a mandated committee responsible for the animal care and use program.

They monitor for and enforce the compliance structure of the University. • Your research records must be adequate to classify correctly the pain category for

animals used in your projects. See the section on medical records below. • Controlled drugs and records of use as governed by DEA regulations are an important

aspect of investigator compliance. Module 3 The Animal Care and Use Program The AWA, the PHS Policy, the Guide for the Care and Use of Laboratory Animals, and AAALAC indicate the need for the development of a comprehensive animal care and use program. The program of animal care and use covers much ground beyond simple animal husbandry. Programmatic requirements are included in all of the laws and policies and these requirements must be woven into the fabric of the program particularly in the areas of documenting compliance. The Animal Care and Use Program is built upon performance standards advanced in the Guide and the AWA. The working standards for KUMC are detailed in the manual of Standard Operating Procedures posted on the LAR website (www.kumc.edu/lar). These operating procedures are summarized in Module 7 below. The animal care and use program is incorporated into the University administration as noted in the following Organizational Chart.

In this organization, the financial issues of the department are under the Senior Associate Dean for Research of the School of Medicine and the compliance administration is under the Associate Vice Chancellor for Compliance. The Institutional Official responsible for the University’s compliance is the Associate Vice Chancellor for Compliance. At KUMC, this individual is the “go-to-jail” person if the University does not meet compliance expectations. Now jail seldom if ever happens, but our Associate Vice Chancellor for Compliance takes this responsibility very seriously. Compliance administration flows from the Associate Vice Chancellor via the Executive Team to the IACUC and to the Investigator. Noncompliance issues flow back through the IACUC to the Associate Vice Chancellor. Both the IACUC and the Associate Vice Chancellor have compliance enforcement authority and have exercised that authority in the past. The attending veterinarians have no enforcement authority other than being members of the IACUC and Executive Team. Laboratory Animal Resources (LAR) is the service department responsible for day-to-day management of the program and provision of general husbandry. We also provide medical care and research support. The organization of the LAR is shown in the chart below. The program is under the direction of David Pinson (DVM, PhD, Professor of Pathology). Dr. Pinson is board certified in both anatomic veterinary pathology and laboratory animal medicine. He is assisted by Dr. Nathan Culley (DVM), who provides extensive research support and basic medical care for the animals.

The core responsibilities by selected individuals and groups in the program are detailed in the following table. You should look at the responsibilities for your position in the program.

Associate Vice Chancellor for Compliance

1. Responsible for overall compliance program. 2. Responsible for enforcing faculty compliance with laws, policies and procedures. 3. Appoints the IACUC who monitors and enforces compliance and reviews research, facilities, and labs.

Senior Associate Dean for Research

1. Responsible for funding the LAR as governed by the School of Medicine. 2. Reviews and assigns budgets. 3. Assists in managing complicated programmatic issues (such as per diem rates, capital equipment, etc.).

Director of the LAR 1. Advises on management of compliance and establishment of standards of care. 2. Develops and establishes SOPs (with IACUC help). 3. Maintains AAALAC accreditation standards. 4. Maintains husbandry and veterinary care standards. 5. Maintains with Employee Health the Occupational Health Program. 6. Maintains the animal procurement program and reconciles animal orders to approved animal use protocols. 7. Provision of research support as needed. 8. Provides resources and expertise to achieve and maintain a high quality program. 9. Provision of high quality financial records for in depth cost analysis for per diem rate setting and financial status.

Program Requirements (all 3 of the above – essentially the institution’s responsibilities)

1. Administration of the animal care and use program. 2. Record keeping as required by laws and policies. 3. Annual reports to federal institutions and AAALAC. 4. Maintenance of the program and facilities. 5. Provision of adequate training for participants in the program.

Executive Team – Animal Research Protection Program

Includes chair and vice chair of IACUC, attending veterinarians, associate vice chancellor for compliance, and IACUC administrative team. This group runs the IACUC and gives direction to the compliance program.

IACUC See Module 4. This is the committee charged by law with oversight of the animal care and use program. The responsibilities of the committee are many, including, but not limited to protocol review and approval, review of ongoing animal research, facility and program reviews, responding to any concerns about the care and welfare of animals used in research. The committee holds the authority to suspend research and any suspensions handed down cannot be revoked by University administration.

Quality Assurance Protgram Personnel Post-Approval Compliance Monitor and LAR QA-QC Coordinator.

This program includes two individuals. They are the post-approval compliance monitor and the LAR QA-QC coordinator. The post approval monitor reviews investigators for compliance with approved protocols and standards and reports to IACUC. The LAR QA-QC Coordinator reviews activities of LAR staff for compliance with SOPs and reviews investigators working in the LAR for compliance with approved protocols. Both individuals work together, reporting to the executive team.

LAR Personnel 1. Provision of day-to-day husbandry. 2. Maintenance of room work records. 3. Provision of veterinary care. 4. Maintenance of facilities and equipment. 5. Sanitation 6. Provides for all animal procurement, transportation, receipt, etc. 7. Monitors and manages population health. 8. Provision of technical support for research as requested. 9. Participates in the occupational health program and works safely to prevent work related injuries or infections.

Principal Investigator 1. Conceives, designs, and submits for approval animal care and use proposals in support of grant based (peer reviewed) and non-peer reviewed research. 2. Responsible for assuring research staff completion of all training requirements. 3. Responsible for submitting addendums to animal use protocols as required, avoiding “protocol drift” (the gradual change in research procedures as projects progress). 4. Responsible for submission of all annual and tri-annual reviews as required by federal policies. 5. Responsible for animal colony breeding management either personally or via hired personnel. 6. Responsible for the compliance of his or her employees and understands that noncompliance and use of unapproved animals, procedures or drugs on their part has negative implications for them and for the institution via required reporting of noncompliance to federal agencies. 7. Responsible for assuring that his or her employees know what is approved in animal research protocols and the ramifications for doing procedures that are not approved in the protocol. 8. Responsible for assuring that accurate records of animal work, including medical records as indicated in SOPs, are extant. 9. Reports adverse events that occur in the process of animal research. Adverse events are any unexpected outcome that results in additional pain or distress or death of the animal(s). 10. Participates in the occupational health program and works safely to prevent work related injuries or infections. 11. Maintains animal use areas clean and in good repair. Maintains inventories of drugs specifically permitted in the animal care and use proposal. Disposes of expired drugs and food. Does not store food or drugs with potential contaminants.

Research Personnel (post docs, research technicians, senior scientists, etc.)

1. Conducts animal research in accordance with procedures specifically as approved in the animal care and use proposal. Thus, these people must know what is in the approved animal use protocol. 2. Maintains very accurate records of animal work, including procedures done, drugs used, doses, routes, and post-procedural care. These must be readily available on short notice since we do not know when regulators will want to review them. 3. Responsible for compliance with the programmatic SOPs. You should know what is in the SOPs that affect what you do in the animal use program. 4. Responsible for completing training as mandated by the program and by the PI. This includes LAR training and training in procedures specific to the research and approved in the protocols. 5. Knows that noncompliance and use of unapproved animals, procedures or drugs on their part has negative implications for them, for the PI, and for the institution via required reporting of noncompliance to federal agencies. These implications include remediation up to and including suspension of animal use privileges or termination of research programs. 6. Participates in the occupational health program and works safely to prevent work related injuries or infections. 7. Manages under PI direction rodent breeding programs to prevent overcrowding. 8. Maintains animal use areas clean and in good repair. Disposes of expired food and drugs.

LAR Advisory Committee This committee is distinct from the IACUC and is charged with providing advice to the LAR Director on sensitive user issues. This is the avenue where faculty and staff can raise concerns and issues about facility use policies that are not necessarily a mandate from federal laws and policies.

Key Points

• Animal users are an important part of the animal care and use program and have important responsibilities. Federal agencies and inspectors often review investigator laboratories for compliance in their responsibilities. Core personnel should know clearly their responsibilities.

• Compliance and records are key responsibilities in the program. Detailed records must be maintained.

• Research personnel do have a venue for expressing concerns about user issues via the LAR Advisory Committee, the IACUC, the program director, or the compliance division.

Module 4 The Institutional Animal Care and Use Committee

The chartering of the Institutional Animal Care and Use Committee is mandated by both the AWA and the PHS Policy. The committee is charged with several key responsibilities as outlined below. This committee is an important part of everything that you do in animal research.

• Reviews, evaluates, approves all new animal use proposals or requires modification of proposals to secure approval of new proposals

• Reviews annually all ongoing research programs involving animals. See paragraph below on the Post Approval Compliance Monitoring Program and the LAR QA-QC Program.

• Reviews any significant changes in ongoing research o Changes requiring amendments include: changes in experimental

procedures or design, surgical procedures, drugs, anesthetics, or treatments employed in the research, personnel changes, euthanasia methods, or changes in animal species or animal numbers. Note that changes in species must be reported to the NIH because they consider this a change in research scope. Overall, any change that potentially alters the pain or distress classification to a higher level or more painful/distressful encounter requires an amendment. It is important to recognize that any change involving pain or distress requires an amendment that includes a new literature search on that procedure causing the pain or distress and it requires a new consultation form with veterinarians on the managements of that pain or distress.

o Minor changes do not require amendments. These include modifications such as reduction in number of animals needed or elimination of painful procedures. This is very nebulous territory and we suggest you ask the IACUC administrators for a ruling on any changes. The long and short of the issue is that federal regulators expect you to conduct research exactly as you laid it out in the protocol.

• Semi-annual review of the animal care and use program and facilities, including investigator laboratories, using the Guide as standard. The committee files the report of this review with the Institutional Official

• Makes recommendations to the institution regarding any aspect of the animal care and use program

• Investigates any concerns or problems brought to the committee by any individual • Has authority to suspend activities not conducted in compliance with laws, the

Guide, and policies • Oversees training programs for all personnel involved with the care and use of

animals or maintenance of the facilities • Ensures faculty compliance with public law and policies, coordinating with the

Associate Vice Chancellor for Compliance who appoints the committee • Responsible for post-approval compliance monitoring. • Investigates and reports noncompliance to administration who is responsible for

reporting to federal and accrediting agencies. The primary mechanism for reviewing research is via the animal care and use proposal (ACUP). This is a document prepared by a faculty investigator that describes the proposed use of animals. This is not the grant application. The review is based on requirements set forth in several policies including the AWA, the Guide, the PHS Policy, and the US Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research, and Training

(http://grants.nih.gov/grants/olaw/references/phspol.htm#USGovPrinciples). The US Government Principles are for all intents a series of ethical policy statements. All of these laws and policies require certain information that is best clearly flagged in the ACUP so that inspectors and reviewers can determine easily that the review requirements are met. The procedures and criteria for review are detailed in SOP Program 1 IACUC. Prominent in the review criteria are the principles of reduction, refinement and replacement. Reduction means using as few animals as possible to achieve scientifically valid results. This usually means employing appropriate statistical methods and power analyses. Refinement means using appropriate experimental methods to reduce pain and distress such as anesthesia, analgesia, appropriate pre-defined endpoint criteria, etc. Replacement means using the least sentient animal model in place of higher more sentient species to accomplish the same experiment goals. (HYPERLINK TO SOP PROG 1). The IACUC is also charged with reviewing significant changes in approved protocols as indicated above. The review of addenda is designed to maintain currently approved protocols that are consistent with the work actually being done. The gradual deviation of research activities from the approved protocols is termed “protocol drift” and this is very common in active research institutions, including this one. Thus, the admonition is to be sure that your protocols are updated with addenda as your procedures need to change. The addenda and the approval process must precede the actual incorporation of changes in your research program. The post approval monitoring program is designed to detect unapproved changes. The indicated above under conditions requiring amendments warrants repetition. It is important to recognize that any change involving pain or distress requires an amendment that includes a new literature search on that procedure causing the pain or distress and it requires a new consultation form with veterinarians on the managements of that pain or distress. Other responsibilities of the committee are as indicated and details of how these are accomplished are provided in SOP Prog 1. The current form is designed to obtain organized information that meets requirements of the laws and policies. The form is frequently modified to adapt new information as indicated by regulatory agencies. Thus, we recommend that ACUP writers always download the latest form from the website. The IACUC’s review of this document is detailed. Thus, most new investigators have found that the committee will not accept just anything written down in the form. Information about completing the ACUP is provided in the next module, including areas of frequent difficulty. The medical center is engaging a post-approval compliance monitoring program that will involve two people. The first is the post-approval compliance monitor. This person will review periodically all projects involving animals with highest priority to regulated species. This person’s work process will involving reviewing laboratories for animal work, drugs, procedures, and sanitation and reconciling all findings to the approved animal care and use proposal and any amendments attached to it. These reviews will include evaluation of research records. The second person is the LAR QA-QC Coordinator. This person will review LAR facilities for compliance with SOPs, laws, regulations, and policies. Evaluation of research investigators working in the LAR is fair game for this individual who collaborates with the post-approval compliance monitor. Thus, information is freely shared between the monitors and all relevant findings are forwarded to the IACUC.

Key Points • The IACUC has specific responsibilities in the animal care and use program. • The animal care and use proposal (ACUP) is the key interface between the research lab

and the committee. • All research personnel involved in a project should know what is approved in the ACUP

and subsequently approved amendments. • Research programs will be monitored in depth by the post-approval compliance monitor

and the LAR QA-QC coordinator. Module 5 The Animal Care and Use Proposal You are taking this module because you indicated that you are expected to write animal care and use proposals. The animal care and use proposal form (ACUP) has evolved as laws and interpretation of laws have changed over the years. The form and submission paradigms will continue to be in flux as we move to an online submission system. Armed with that information, there are some key issues that frequently delay approval of the animal use protocol. We will provide information on those issues here. It is prudent that writers of animal use protocols be aware of the following.

• The committee is not in the rubber stamp mode. They review these documents in detail and look specifically for the information required by the laws and policies.

• Read the questions carefully. Based on some of the answers received on the form, it is clear that the question was not carefully considered and the answer provided had nothing to do with the question asked.

• Writers should use a simple and clear style. The primary and secondary reviewers are not always familiar with your research area. Thus, the writing style should be one for general scientists, not those unique to the proposed research area. Avoid acronyms and abbreviations. Simple and clear. If you are not fluent in English, help is available from the Writing Consult Center of the campus (http://www.kumc.edu/som/facdev/wrc.html).

• Communicate what will be done to the animals and the potential for pain or distress. Make this very clear. The background science and theory need only be brief. The best approach is by specific aims and specific experiments detailing what procedures will be done and the potential for pain and distress. If there is potential for pain and distress, you should indicate how this will be managed and minimized. If pain or distress cannot be managed or minimized, a sound justification for why should be included.

• The IACUC is required to review and approve the number of animals you are requesting and whether or not this is sufficient. The numbers in the experimental design section of the form MUST add up to the numbers in the USDA table (see section specific comments below). The approved number of each species is your cap and you cannot order more than this number without addendum approval. You need to include breeders and animals bred, but not used (animals with nontarget genotype, for example). While statistical justification is not always appropriate or needed, your justification for the requested number of animals should be sound and well-conceived. Why you may ask? Because the USDA looks at protocols at every site visit and the inspectors look for these justifications.

• If you write animal use proposals, you should review SOP program 1 to see how the committee reviews the document and how the committee functions. (Hyperlink).

The following information gives you some guidance on specific parts of the current form. If you are a writer of animal care and use proposals, we strongly recommend that you read this guidance. You can print off a current copy of the form at www.kumc.edu/lar. The following sections will not mean much without looking at the form. Form Section 1.0: This section just provides contact information and LAR training dates. Form Section 2.0: Indicate what type of proposal. Three-year de novos are rewrites of existing approved protocols. The NIH requires a 3 year approval and frowns upon extensions of protocols beyond 3 years. Thus protocols must expire at 36 months. If you have to write a de novo, we suggest you start early enough to get it through the committee before the existing protocol expires. Form Section 3.0: Indicate whether or not the research is peer reviewed and provide information about the grant support. If the research is not peer reviewed, we ask that you have your departmental chair or immediate superior review the work and sign off. Form section 4.0: We are asking for a brief (and we do mean brief) overview of your work and why you must involve animals. Be clear and lucid. These sections should be written so outside and nonscientist members can understand what you are doing. Abide by word limits. Form section 5.0: This is a laundry list of affirmations that deal with several sets of regulations and address specific required information. There are also affirmations that you essentially are agreeing to play by the rules established at this institution. Read carefully what you are signing. Be sure that you answer “yes” or “no” or “not applicable” where indicated. The committee certainly notices when you sign the affirmation for paralytics, but you have not proposed any use of them (implying that the question was not carefully read) and this happens all the time. Form section 6.0: This is where you tell us what you will be doing with the animals. The admonition here is to be clear and lucid. The faculty on this committee are busy people and want to spend only a reasonable amount of time reviewing your proposal. Poorly written documents take more than a reasonable amount of time. Read the suggestions. Use tables to define your animal numbers. An example is provided below. Specific Aim #1, Experiment A Animal Type Treatment Procedures USDA

Category Number Animals

TLRx+/+ Saline Control Liver, kidney harvest

B 6

TLRx+/+ Endotoxin 1 mg/kg IP

Liver, kidney harvest

D 6

TLRx-/- Saline Control Liver, kidney harvest

B 6

TLRx-/- Endotoxin 1 mg/kg IP

Liver, kidney harvest

D 6

Total Mice 24

Power analysis or provide a sound justification for the number of animals requested. In this section of the form, you only need mention surgical procedures as they fit in the context of your experimental design; you do not describe the actual procedures here. There is a surgery section. Form Section 6.2: This is a comprehensive summarizing table for your animal numbers. Be sure it agrees with your tables in the experimental design. Failure of agreement between your design section and this table is a very common contingency issue. If they do not agree, you will be asked to reconcile it. The data from this table are entered into the tracking software for ordering animals. The data are entered by species and pain category. Form Section 6.3: This is where you tell us how you will manage surgical procedures, what drugs you will use, and how you will manage post-operative care and pain. We give you the option of just checking any of several commonly used procedures and indicating what species and survival status. We have written standard operative procedures for these in SOP Vet 10. The committee expects that you will do these standardized procedures according to the SOP. For nonstandard procedures (those unique to your work), you will need to describe how you are going to do the surgery. Read the instructions. Form Section 6.3.6: The University, the IACUC, and the regulatory agencies expect that you will keep records of your procedures. We recommend that you keep good records. To that end, we have provided an online database that you can use to keep records of procedures. You can print these records off for your lab notebooks. Wherever you keep records, you need to be aware that they are University property. If you leave the institution, you must leave copies of the records. Form Section 6.4: This is where you tell us about nonsurgical procedures. Again, we give you some options to check off and the committee expects that these will be done according to the SOP. If your nonsurgical procedures are unique, you must describe them. Form Section 6.6: The committee wants to know about any and all compounds or drugs that you will be giving to the animals, particularly the potential for toxic reactions. Form Section 6.7: This is another series of compliance questions that deal with specific issues discussed in the Guide. You have to justify withholding food, water, or death as an endpoint. Form Section 6.8: Here you tell us how you will humanely kill animals. Be aware that failed euthanasia is reportable to the NIH OLAW and AAALAC. Thus, with injectable or gas anesthetics and carbon dioxide, you must provide a physical method of assuring death of the animal. This is primarily relevant to rodents and small mammals. We have had several incidents of mice awake in the morgue freezer and have had to report these to both OLAW and AAALAC. Know that we currently videotape the euthanasia room to document who has used it because of failed euthanasia. It is important. Form Section 6.9: We would like to know who will be doing what in this project and how were they trained to do this specific activity. We recommend that you NOT mark responsibility as “Research”. The University is moving in a direction of competency based training. The future is likely going to be one where trainees demonstrate their competency to the trainer. A sample table might look like the following:

Name Responsibilities Who Trained Them? When? Joe Study, PhD PI, experimental design, data

review, assign work Doctoral training 1986

Louella Iamagoodtech

Rodent ovariectomy Joe Study 2006

Sam Iamabadtech Feces collection Joe Study Initial 2004 Remediated 2005, 2006

Form Section 7.0: Tell us about the hazards involved in this project. These questions are self explanatory about recombinant DNA, human agents, and radioactivity. These relate to these hazards as they are used in research animals. Form Section 8.0: Rodents can be infected with any number of viruses and many of these can be transmitted in cell lines and rodents acquired from other institutions. The Hoglund Brain Imaging Center is considered a conventional facility that can receive animals from various places in the Kansas City area. Thus, anything could be there. We restrict animal cross traffic between this building and the other animal facilities. Form Section 9.0: Tell us about any special requirements such as different food, different light cycles, or other aspects that might affect daily husbandry activities. We are required by federal regulations to be certain that the housing and husbandry are appropriate for the species. Thus, we need to know when changes from standards are needed. Form Section 10.0: If you use animals in your laboratory, the IACUC has to inspect it. During these inspections, we look at what procedures you are doing, what drugs you are using, whether or not those drugs and supplies are in date, appropriate sterilized, labeled, etc. For users of regulated species, the USDA site visits have become very detailed for compliance issues. If you plan on maintaining animals in your laboratory for more than 12 hours, the lab then qualifies as a study area (according the USDA). It must then meet standard housing requirements for ventilation, sanitation, and light dark cycles. Form Section 11.0: The IACUC is receiving more requests for collaborative studies between institutions. If animals have to move back and forth between different assured and accredited institutions (KUMC and KU Lawrence for example), the requirements of a memorandum of agreement must be executed. If no memorandum of agreement exists, one must be negotiated and this takes time. KUMC and KU Lawrence already have a negotiated memorandum of agreement. Form Section 12.0: If an NIH style grant application supports this proposed work, we would like to see the Section F of this proposal. The regulatory agencies would like to see the committee reconcile the ACUP to the grant proposal at some level. As a result of recent USDA site visits, the IACUC will be requiring time line documents that indicate how the experiments will flow, how many procedures will be done in the work flow, and how monitoring will proceed. Adequate records of that workflow must be maintained.

A serious admonition for investigators and research personnel follows. Whether we like it or not, we must do research in the context of certain rules. One of the primary rules in animal research is that you obtain approval for what you want to do with animals and you do only what you are approved for. This is not intended to stifle creativity, but it does create some accountability issues. To this end, a post approval compliance monitoring program is being instituted. In this program, there will be visits to PIs and research staff to evaluate overall compliance with the approved animal care and use protocol. We strongly recommend that you keep the ACUP up to date with amendments for new procedures and do only what you are approved to do. Your research staff also needs to be up to date on what is approved. They need to understand the liability here. The IACUC will make every effort to get amendments to protocols approved as quickly as possible. Key Points

• Read the questions carefully and answer them thoughtfully. Write clearly. • The committee is not a “rubber stamp” committee. • All research personnel involved in a project must know what is approved. • Keep your protocol current with amendments. They are turned quickly by the

committee. Module 6 The Animal Care and Use Standard Operating Procedures The animal care and use program is based on the laws and policies described in Module 1. The implementation of those laws and policies at the University of Kansas Medical Center is through the LAR Standard Operating Procedures. All of these University polices and procedures are published on the LAR website at http://www.kumc.edu/lar/procedures.html. We will provide a brief summary of those SOPs below so you have the general content and know where to find the standards.

Procedure # Name Brief Description SOP Mngmt SOP Authority, Management, and Modification How SOPs are created and modified. SOP Prog 1 Institutional Animal Care and Use Committee How the IACUC functions. SOP Prog 2 Policies on Physical Restraint Defines prolonged restraint and

monitoring of same. SOP Prog 3 Policies on Multiple Major Surgical Procedures Defines policies on multiple survival

surgeries on the same animal. SOP Prog 4 Policies on Food and Fluid Restriction Defines policies on food or food

restriction and monitoring of animals maintained on such studies.

SOP Prog 5 Personnel Training How personnel are trained, including LAR technicians, research staff, and facility staff.

SOP Prog 6 Occupational Health and Safety Describes the occupational health program.

SOP Prog 7 Occupational Health Policies – primates Describes the occupational health program relative to users of primates.

SOP Prog 8 Promotion of Pychological Well-being Describes the program for environmental enrichment for animals to promote species typical behavior and psychological well-being.

SOP Prog 9 Animal Procurement and Receipt Describes how animals are purchased or obtained and what is required to bring them in house.

SOP Prog 10 Housing Standards and Policies Describes the housing standards and stocking densities for various species of animals. Portions of this SOP also deal with how we manage overcrowding.

SOP Prog 11 Tracking Repairs and Corrections This SOP defines how programmatic issues, repairs and corrections are monitored.

SOP Prog 12 Animal Identification Defines the standards for animal identification, a Guide requirement.

SOP Prog 13 Medical Records Defines the standards for medical records. SOP Prog 14 Rodent Genetics and Nomenclature Defines the standards for rodent naming

conventions. SOP Prog 15 Disaster Management Plan Describes the disaster management plan. SOP Prog 16 Office Procedures (for LAR staff) Describes LAR office procedures and

management. SOP Prog 17 Work Policies (for LAR staff) Describes work policies, vacation, sick

time, work start times, etc. This is primarily for LAR employees.

SOP Prog 18 Exercise for Dogs Defines the USDA requirement for exercise for dogs.

SOP Prog 19 Animal Census Describes how we conduct weekly census of animals. This affects how PIs are billed.

SOP Prog 20 Service/Supply Re-Bills Describes re-billing for services rendered to investigators and for supplies.

SOP Prog 21 Building Security Describes the building security program. SOP Prog 22 Mouse Ascites Antibody Production Defines the conditions surrounding and

monitoring required for production of monoclonal antibodies in ascites fluid.

SOP Prog 23 Polyclonal Antibody Production in Rabbits Defines the conditions surrounding and monitoring required for production of polyclonal antibodies in rabbits.

SOP Prog 24 Controlled Drug Dispensing Defines how control drugs are dispensed. SOP Prog 25 Departmental Record Keeping Defines departmental record keeping. SOP Prog 26 Compliance with Laws, Policies, and Operating

Procedures Describes the program for managing noncompliance in the animal care and use program.

SOP Prog 27 Employee Conduct (for LAR staff) Defines the general conduct for employees in the laboratory animal resources program.

SOP Prog 28 Management of Infectious Agents Research Defines how we manage selected infectious agents used in research.

SOP Prog 30 Primate MRI Sets conditions for movement of primates to and from the Hogland Brain Imaging Center

SOP Prog 31 Rodent MRI Sets the conditions for movements of rodents to and from the Hogland Brain Imaging Center.

SOP Prog 32 Management of lead acetate studies Defines the management and containment of studies involving lead.

SOP Prog 33 Management of virus positive colonies Defines the management of colonies diagnosed with viral infections.

SOP Prog 34 Policy on Embryonated Eggs Defines when pain management is an issue in embryonated eggs.

SOP Prog 35 Facility Access Defines procedures for entry and exit of the Kansas Life Sciences Innovation Center.

SOP Husb 1 Food, Water, and Bedding Management Defines how we manage food water and bedding, including stock rotation.

SOP Husb 2 Husbandry of Rats and Mice Defines the husbandry of rodents. SOP Husb 3 Husbandry of Rabbits Defines the husbandry of rabbits. SOP Husb 4 Husbandry of Dogs Defines the husbandry of dogs. SOP Husb 5 Husbandry of Cats Defines the husbandry of cats. SOP Husb 6 Husbandry of Primates Defines the husbandry of primates. SOP Husb 7 Husbandry of Guinea Pigs, Hamsters, Gerbils Defines the husbandry of guinea pigs,

hamsters, gerbils. SOP Husb 8 Husbandry of Chickens and Eggs Defines the husbandry of chickens and

eggs. SOP Husb 9 Husbandry of Sheep and Goats Defines the husbandry of sheep and goats. SOP Husb 10 Husbandry of Pigs Defines the husbandry of pigs. SOP Husb 11 Husbandry of Ferrets Defines the husbandry of ferrets. SOP Husb 12 Husbandry of Frogs Defines the husbandry of frogs. SOP Husb 13 Husbandry of Sea Urchins and Fish Defines the husbandry of sea urchin's and

fish. SOP Husb 14 Cage Wash Operations Defines how the cage wash operations are

managed. SOP Husb 15 General Facility Sanitation Set standards for general facility

sanitation. SOP Husb 16 Waste Disposal Set standards for waste disposal. SOP Husb 17 Pest Control Set standards for pest control. SOP Husb 18 Husbandry of Zebrafish Defines the husbandry of zebra fish. SOP Husb 19 Room check sheet maintenance Defines how animal room check sheets

are managed. SOP Vet 1 Preventative Medicine Describes the program for preventative

medicine. SOP Vet 2 Clinical Medicine Describes the program for clinical

medicine. SOP Vet 3 Anesthesia and Analgesia Provides details on the use and monitoring

of anesthetic agents and analgesics. SOP Vet 4 Survival Surgery of Rodents Defines the standards four survival

surgery in rodents. SOP Vet 5 Nonsurvival Surgery Defines the standards for non-survival

surgery. SOP Vet 6 Survival Surgery of Higher Species Defines the standards for surgical

procedures in higher species such as primates, dogs, pigs, sheep, goats, etc.

SOP Vet 7 Euthanasia Defines the standards for euthanasia. SOP Vet 8 Necropsy Procedures Defines the standards for necropsy

procedures in various species. SOP Vet 9 Virus Outbreak Management Defines the procedures for managing

outbreaks of infectious or parasitic diseases.

SOP Vet 10 Standardized Operative Procedures Defines the standards for common operative procedures and animals. This SOP includes methods and refers back to the animal care and use proposal form.

SOP Vet 11 Q Fever in Pregnant Goats Defines the program for monitoring Q-fever in pregnant goats.

Module 7 AAALAC Accreditation The Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC) is a nonprofit corporation that evaluates and accredits laboratory animal care programs. It is not a government agency and information provided to AAALAC is maintained

as private and confidential. AAALAC comes for site visits every three years to evaluate the program and facilities. They provide an exit interview to summarize findings and make suggestions for improvement. The primary benchmark for evaluation is the Guide for the Care and Use of Laboratory Animals, but other laws, policies, and standards are also used in the evaluation. Thus, in order to maintain accreditation, we demonstrate functional compliance with Guide. The University of Kansas Medical Center is fully accredited by AAALAC. This is not a trivial status. It is essential to the conduct of PHS funded research. Compliance with the Guide is mandatory in our NIH Assurance. In that assurance, we state that we are accredited and will maintain accreditation by AAALAC. Thus, this accreditation is part of our meeting of the PHS Policy on the Humane Care and Use of Laboratory Animals. It demonstrates a higher level of commitment to a quality program. Key Points

• AAALAC accreditation is voluntary. • The Guide is the primary benchmark for the AAALAC review. • Maintenance of accreditation is important in the NIH Assurance. • The three year site visits are big events in the program and require much preparatory

work. Module 8 Occupational Health Program The KU Medical Center has a comprehensive occupational health program that incorporates research personnel using animals. We emphasize prevention, but the program includes an exposure control program. Prevention includes appropriate training, yearly health questionnaires and tuberculosis screening. Primate and pregnant ruminant users are flagged for increased scrutiny and training since these species carry more risk than commonly used rodents. Details of the Occupational Health Program are provided in SOPs Program 6 (hyperlink), Program 7 (hyperlink), and Vet 11 (hyperlink). Research personnel do have responsibilities in the occupational health program. You need to be educated about what risks are present and how to protect yourself from those risks. You are expected to use correctly any safety equipment required for assigned tasks. You are expected to report spills and contaminations that may spread infections or cause problems and cleanup should be done using methods appropriate to the hazard. You are expected to use appropriate hygiene to prevent infection, including washing hands after degloving and removing gloves before handling doorknobs, elevator buttons and other common use equipment. You are expected to know where the Material Data Safety Sheets are for your work environment. There are risks to personnel working with animals. We summarize some of the more common risks below and provide some information on how to reduce risk. Risk Procedures to Reduce Risk Effectiveness Bite and Scratch Wounds (rodents, primates, dogs, etc., essentially anything with teeth and claws)

Take training on how to handle each species correctly. This is not a guarantee for prevention, but it does reduce risk.

Fair

Allergies (rodent urinary albumins, feline proteins, latex gloves, etc.)

Depends on the allergen. Procedures may include respiratory protection, use of nitrile or vinyl gloves, and prevention of contact.

Fair to good.

Chemicals (any number of hazardous chemicals in use)

Use of glove type appropriate for the chemical, lab coats, closed toe shoes (not sandals), possibly respiratory protection (fume absorbing canisters), use of fume hoods

Good

Radionuclides Use of gloves, lab coats, shielding appropriate for the nuclide, isolation of animals, proper carcass and waste disposal, proper decontamination, proper monitoring

Good

Noise pollution Hearing protection Good Primate B Virus, aka Cercopithecene Herpesvirus 1, a cause of fatal encephalitis in people

Protection of face/mucus membranes, use of gloves, lab coats, prevention of bite wounds, scratches, and splash incidents

Good

Primate Lentiviruses, blood borne pathogens, SIV, HIV, SHIV, similar to AIDS viruses in people

Protection of face/mucus membranes, use of gloves, lab coats, prevention of needle sticks, glass cuts, etc.

Good

Primate Fecal Borne Zoonoses (amebiasis, cryptosporidiosis, Salmonella, Shigella, Yersinia, etc.), causes of enteric infections

Prevent fecal oral contamination. Proper use of gloves and hygiene. No eating or drinking in primate areas.

Good

Pregnant ruminants (Q Fever risk), causes systemic infections in man with nondescript signs of illness such as fever, headache, myalgia, cough, night sweats, etc.

Proper monitoring of pregnant ruminants for agent. Acquisition of negative animals. Awareness.

Good

Zoonotic Bacteria, Select Agents, and the like

ABSL3 training. Conform to ABSL3 entry policies. Proper use of safety equipment.

Good

The exposure control plan is what transpires in the event of an accident or exposure. Essentially, any exposure, accident or injury should be reported to your immediate supervisor or principal investigator. This should be followed by a visit to the Employee Health Service if the incident occurs during normal working hours (8-4:45, M-F). If the incident occurs during other times, the employee should report to the Emergency Room at the KU Hospital. If the latter is elected, the employee should report to the Employee Health Service on the first working day after the work related incident. An incident report must be filed. You should know that workman’s compensation is not engaged until that incident report is filed by Occupational Health. All appropriate follow-up management will be handled by the Employee Health Service. Key Points

• An occupational health program is part of the animal care and use program. • An exposure control plan is in place. You need to know what to do in case of exposure. • Working with animals does involve hazards. We have summarized these for you. • You need to be educated about specific hazards with which you work. • You need to know and abide by clothing standards (provided lab coats, closed toe

shoes/not sandals, face and eye protection where required). • Workplace safety is everyone’s responsibility. • You need to be considerate of others by not operating common use equipment (doors,

elevator buttons) with contaminated latex gloves that may spread disease or chemical exposure.

Module 9 Standards for surgery, anesthesia, analgesia You are taking this module because you indicated that you would be doing animal surgery. We recognize that people taking this training have variable experience ranging from none to surgical residents to experienced surgeons. We still have to bridge that range of experience and provide

documentation of training. Animals vary in their response to anesthetic and analgesic drugs. Drug choice requires some knowledge about how animals respond and what procedures and research are being done. Thus, these choices are not trivial and human surgeons may not recognize all of the nuances of animal work. We provide information about anesthesia, analgesia and surgery in SOP Prog 3, SOP Vet 3-6, and SOP Vet 10. Since you are doing surgery, you are required to review these SOPs. LAR veterinarians are available to consult on anesthetic and analgesic choices and surgical methods. Links to these SOPs are provided below. The test questions that follow come from them. SOP Prog 3 SOP Vet 3 SOP Vet 4 SOP Vet 5 SOP Vet 6 SOP Vet 10 Current policies in the animal care and use program require that all drugs and surgical materials be in date. This means that any expiration date on the material should be in the future. The KUMC policy approved by the RAC supersedes the USDA Policy Manual suggestion that some nonsurvival procedures may employ expired sutures or other supplies. The ARPP considers such a policy permitting use of expired materials difficult or impossible to manage. All anesthetics and analgesics must be in date. This is accepted standard of care in veterinary medicine. Another important note about drug inventories should be advanced. The inventories of anesthetics and analgesics and other drugs in your animal research areas should be consistent with your approved protocol(s). In other words, you do not want to have drugs in your inventory that are not listed in the protocol. Inspectors have gone into laboratories and found such drugs and they have written up citations for these inconsistencies. Key points

• Choice of anesthetics, analgesics should be based on the species, the research goals, and the procedure. Veterinarians are available to help with these choices.

• Knowing how to monitor for depth of anesthesia and freedom from pain is fundamental for good surgical management. These are covered in the SOPs.

• You must understand the concepts of maintaining asepsis, use of sterile instruments, maintenance of sterile field, etc.

• Drugs and materials used in surgery must be in date. Regardless of the type of procedure, the anesthetics and analgesics must be effective at alleviating pain. Drug inventories in your lab must be consistent with your protocol. Unapproved drugs should not be present.

• For nonmedical/nonsurgical professionals, PIs or veterinary staff must provide training in the specific procedures that you will be doing so that you know how to do them correctly.

• Animals are subject to surgical infection, hypovolemic and septic shock. Animals are somewhat forgiving for sloppy technique, but they are subject to complications and these complications may alter research data or cause the death of the animal. Remember that adverse events must be reported to IACUC.

• Animals tend to hide pain. Expression of clinical pain reactions in animals indicates advanced or substantial pain. Pain management is required under almost all circumstances. Not providing pain management must well-justified and must be approved by the IACUC.

• Keeping good medical records of surgical procedures is an important part of surgical management.

Module 10 Euthanasia Euthanasia is defined as the humane termination of life. Ideal methods of euthanasia should include the following precepts. Any method of euthanasia should be rapid. The animal should be free of pain and distress both in preliminary handling and the actual procedure. The method should be simple and comfortable for the technician performing the procedure. While these precepts are wonderful, methods of euthanasia seldom meet all of them perfectly. Drugs and materials vary. Technician skill varies. Some methods such as decapitation are uncomfortable for the operator. Very few of the methods stop brain electrical activity quickly (usually seconds duration). Adequate performance of euthanasia requires some skill. As you learn to euthanize animals or do the procedures, keep these concepts in mind. Mentally put yourself in the animal’s place and try to understand how these creatures might perceive this. Such a mental exercise may give you an appreciation for the significance of what you are doing and how you are doing it. The foundation document for context is the AVMA Guidelines on Euthanasia (http://www.avma.org/issues/animal_welfare/euthanasia.pdf). This document provides information and evaluation on the accepted methods of euthanasia, including pros and cons of each. Generally, we adhere to the recommendations of this document. Any exceptions must be well-justified and approved by the IACUC. One of critical issues in euthanasia is confirming death. Several of the methods commonly used for euthanasia employ either anesthetics or carbon dioxide. In either scenario, if the dose is not sufficient, the animals may wake up potentially in severe pain or distress. Thus, we must not allow that to happen. Animals waking up after failed euthanasia is a serious issue and one for which reporting to federal agencies and AAALAC is mandated. We have had several instances of failed euthanasia at this institution and we have instituted remediation for that problem. Because you indicate that you are euthanizing animals, you must review SOP Vet 7 on euthanasia (www.kumc.edu/lar/sop/SOP_VET_7_Euthanasia.pdf). Key Points

• Euthanasia requires training and skill. • Methods of euthanasia must be those approved by the IACUC in the Animal Care and

Use Proposal document. • Death MUST be confirmed with any method that employs anesthetics or carbon

dioxide…any method from which an animal could wake up. • Failed euthanasias are reportable to federal agencies and AAALAC.

Module 11 Medical, Surgical, and Research Records Quality research is all about keeping good records. This is even more critical now because open records acts (freedom of information laws) make some or all of these records available to anyone by request. Thankfully, intellectual property and proprietary information put some restriction on this availability. Requested records are frequently redacted for personal contact information, proprietary information, or intellectual property. Regardless of these issues, we still receive yearly requests to turn over copies of records. You should keep good records of your animal experiments. These include study design, animals used, procedures done, and results obtained. Surgical and medical records are required on higher species such as dogs, cats, rabbits, monkeys, pigs, etc. It is prudent to keep good records on all procedures on any animal. SOP Prog 13 (http://www.kumc.edu/lar/sop/SOP%20PROG%2013%20Medical%20Records.pdf ) provides

programmatic details about medical records. We also provide an online data base that will keep track of your procedures and permit you to print off laboratory pages for your lab notebooks. This database is available on the LAR website (www.kumc.edu/lar). Knowing that outside organizations such as animal rights groups can and do request such records should prompt you to keep them very carefully. Inadequate or un-interpretable records will not reflect well on you. Another issue is ownership of your research records. The University owns your research records. If you leave the campus, you must leave copies of your research records. This is not voluntary. If this is not done, the University has legal right to demand them of you. The significance of these issues cannot be understated and events have occurred on this campus that have necessitated such demands. The Chair or Center Director over your research area is responsible for maintaining copies of your records. Your procedural records must include all types of data that your approved protocol indicates will be collected. If you say in the approved protocol that you monitor weight at weekly intervals, there must be records of the weight measurements. If you indicate you will monitor post-operative recovery at 30 minute intervals, there must be records of that monitoring. We are assigning the SOP on medical records for you to read. Research records of animal procedures must be detailed and complete and available for review by IACUC and outside inspectors. History indicates that USDA inspectors will ask for them. Key Points

• You need to keep good research and surgical records. • These records are the property of the University. • Some or all of them may be subject to Freedom of Information Acts. • Intellectual property rules do put some restrictions on the availability of records. • Research records must include all types of data that the approved protocol indicates will

be collected. If the protocol says you will do or monitor something, there needs to be a documenting record indicating that it was done, when, and by whom.

Module 12 Clothing and Activity Standards The animal care and use program does include clothing standards for working in the animal facilities. These standards depend on the species you are using. The Animal Transition Committee and the LAR Advisory Committee recently engaged new standards for entering any of the animal facilities. These new standards were established to help prevent fomite transmission of infectious agents. Fomites are inanimate objects that transmit infections (lab coats, equipment, wheels, etc.). The essentials of the clothing standard are outlined in the following key points. Details are provided in the attached SOP link. Key Points

• To enter any animal facility, you must don disposable lab coats, shoe covers, gloves, and head cover provided at the entry points to the animal facility.

• You may not use your linen lab coats in the animal facilities. • Carts entering the facility must have the wheels disinfected. • Working in primate areas requires additional protection from splash, including masks and

face shields. • Disposable materials are removed upon leaving the facilities. • Open toe sandals are not permitted.

Module 13 Rodent Use and Breeding Management Infectious disease is a significant concern in the use of rodents in research. Many subclinical infections in rodents can alter research results, particularly in such fields as cancer biology and immunology. We expend many thousands of program dollars annually to monitor the viral and parasitic status of animals used in research. You should be aware that your activities could transmit infections to rodents. For example, cell lines may carry rodent viruses. Injection of cells or products from cells could transmit those viruses to the rodent population at large. Feral rodents in old labs and buildings could contaminate carts, equipment, lab coats, and the like. Rolling or carrying this equipment into the facility for use with your rodent colonies could carry the infections (fomite transmission). We maintain a pest control contract that is monitored monthly to eliminate 99%+ of the feral rodents (escapees) in the animal facilities, but this does not extend beyond our building. Housing compliance in rodent breeding management is another big concern. Investigators frequently use intensive breeding schemes that include 2 or 3 females with one male in a cage. Needless to say, when 2 or 3 females get pregnant, they produce 15-25 pups. If these are allowed to progress to anywhere near weaning, overcrowding is an issue. Proper management requires separation of these animals, best done just prior to parturition (birthing) or to be very efficient about separation of the animals prior to weaning. The housing standards are published in the SOPs (Prog 10 Housing Standards). Mice (and rats) are efficient breeders, except for some transgenic strains. They can be bred on a post parturient heat cycle. Intensive breeding programs require intensive management. This is the responsibility of the research staff. For your convenience, we provide notices of noncompliance (see below) in housing and cage labeling. We recommend that you pay attention to the notices. If you fail to resolve the noncompliance, LAR staff members will fix the problem for you and bill you for it.

Another issue is proper animal identification. Cage cards are the primary method of identification and each animal in the facility has a bar coded cage card. You may not dispose of or replace that cage card. You can add cards that have your information on them, but the bar

NONCOMPLIANCE NOTICE TO INVESTIGATOR

This cage is in violation of KUMC housing standards. You have 48 hours to wean or split this cage into Guide-compliant housing (see

SOP 10: Housing Standards). Failure to do so will result in LAR staff weaning the animals. Your grant will be charged for this service at the overtime rate for actual work and record-keeping time. Continued noncompliance in this colony will be reported to the Research Compliance Division for

remediation. LAR staff shall not be held accountable for the integrity of your

genetic lines in this process. Principal Investigator_________________________________________ Room #___________Date Posted:______________ Time: __________

coded cards are to remain with the animal until it is euthanized. When the animal euthanized, its cage card is placed in black boxes throughout the facilities. These are collected daily and removed from the inventory. When removed from the inventory, there are no more per diems charged on that animal. When you wean animals, you must request new cage cards for those animals. The cage cards can be requested on line or in the LAR administration offices. Violations of cage card standards will result in another noncompliance notice similar to the one below. When you see this notice, you will need to request bar coded cage cards from the LAR.

Key Points

• Infectious disease in rodent colonies can be a significant problem. • We monitor extensively for these infections. • Be aware of the materials you use and the potential for fomite transmission of agents.

Any questions? Ask us. • Intensive breeding programs for rodents require intensive management to avoid

overcrowding. Daily checks are often required. • Pay attention to noncompliance notices posted on your cages. It will cost you research

and animal care money if you don’t. We would rather you spend those dollars for productive research.

Module 14 Thou Shalt Not….do these things.

• Overcrowd your animals. • Argue with site visitors, inspectors, or other regulators about compliance issues (it’s been

done!). • Allow euthanized animals to wake up. • Do procedures that are not approved in your working animal care and use protocol. • Use drugs that are not approved in your working animal care and use protocol. • Use out of date drugs or supplies. • Use personnel that are not approved in your animal care and use protocol.

NONCOMPLIANCE NOTICE TO INVESTIGATOR This cage is in violation of KUMC animal identification standards. You have 48 hours to correct this deficiency. Failure to do so will result in LAR staff reporting this noncompliance to the Research

Compliance Office for remediation.

Cage cards must contain the following information: Principal investigator, species, strain, charge account number, IACUC protocol number, and any critical PI-driven specific strain information. Principal Investigator__________________________________________ Room #__________ Date Posted:________________ Time: ________ LAR Action:_________________________________________________

A ti T k D t Ti

• Write over or otherwise obscure, efface, or destroy bar coded cage cards. • Operate elevator buttons and door knobs while wearing latex gloves. • Wear gloves and disposable smocks and protective gear in the LAR administration area. • Put live or dead animals in the cagewash preparation area.

Module 15 Some comments on the LAR finances and per diem rates. The Laboratory Animal Resources program is funded based on budgets in the school of medicine. We keep very accurate records of costs and charges. Our rates are set using the NIH Cost and Rate Setting Manual for Laboratory Animal Facilities. This manual provides the method for accumulating all facility costs and drilling them down to each species. These methods incorporate F&A costs, equipment, food, labor, and essentially all costs in caring for the animals. It might interest you to know that the current cost of caring for one mouse for one day is around $0.27-$0.28 (2008). Investigator costs are substantially reduced to the current per diem rate ($0.13 in 2008-2009) by University subsidization of the program. We do these cost analyses and projections once yearly and present this information to the University administration, who ultimately decides the level of subsidy. We operate the program as efficiently as possible and pull in as many revenue sources as possible. To this end, the LAR leadership writes grants, does service work, and participates in research, making every effort to reduce financial burden on the funds provided by the University. As of 2008, the leadership of the LAR has brought in $1.3 Million in NIH funding, approximately $300,000 in surgical pathology funds, $200,000+ in contracts and fee-for-service funds. We strive to bring in every source of outside funds we can muster. We take animal census one time each week to count the number of animals you have allotted to each account number that you (the PI or research personnel) have provided to us. We do not pick account numbers out of the air. You provide those numbers to us and we have records of when and how you provided them. This is why we require email communication of account number changes. We count the animals and enter these data into an accounting software program that calculates the number of care days for each species and account number based on the daily census information collected. Care days = # animals x #days. We factor in when you told us what day you permanently removed an animal from your inventory (euthanized it). The number of care days x the per diem rate gives the monthly charge for the care of your animals. In some cases, service charges apply where you have obtained drugs or requested that we do procedures for you. These are added to the billing. We generally have paperwork to support every line item on the bill. The financial records of the LAR are very detailed and we can show you exactly where and how charges were engaged and who engaged them. Hard copy invoices are mailed to the principal investigators each month, generally by the 9th or 10th business day. If you have questions about billing, please call us. We are happy to show you exactly where we got the numbers. Key Points

• The cost accounting of the LAR is very detailed. • Billing records are maintained to document where charges came from and where account

numbers came from. • We make every effort to operate as efficiently as possible to reduce costs. • We present cost analyses to University administration yearly. • Hard copy invoices are mailed to the investigator each month usually by the 9th or 10th

business day.

Module 16 Primates and Primate Use Issues Issues in Primate Work Primates are highly intelligent animals with fast reflexes and substantial strength. They can inflict severe injury quickly. They are highly regulated by the USDA for care, psychological well-being, and general healthcare. They can potentially carry and transmit a number of zoonotic diseases. Research at KU Medical Center includes work on immunodeficiency viruses. Thus, some of our primates at KUMC can also carry blood-borne pathogens. While not an issue of risk or danger, primates are very expensive, running from $3000-$7000 each for purchase, and usually followed by months to years of experimental investment. Thus, our care and use of this species should be well-conceived and managed. Two institutional committees review primate research proposals for safety issues. They are the Institutional Animal Care and Use Committee and the Institutional Research BioSafety Committee. Moreover, primate users are given additional scrutiny in the University’s Occupational Health program. The Occupational Health Program is detailed in SOP Prog 6 and SOP Prog 7, which you should have reviewed during the basic training session. Primate Zoonoses Infectious agents that can be carried by primates and transmitted to man include the following. This list is not complete, but includes more common and important agents. The list is most relevant to the macaque species, but some agents also infect new world monkeys. Agent Disease Significance for

Human Health Bacterial Diseases

Salmonella GI tract infection in monkeys, man Moderate Shigella GI tract infection in monkeys, man Moderate Yersinia GI tract infection in monkeys, man Moderate Mycobacteria Pulmonary, soft tissue in monkeys, man High Nocardia Soft tissue infection in monkeys, man Low

Protozoal Diseases Amebiasis GI tract infection in monkeys, man Moderate Cryptosporidiosis GI tract infection in monkeys, man High

Viral Diseases B virus Cold sore like lesion in monkeys; encephalitis in man High SIV Immunodeficiency in monkeys, uncertain in man Moderate SHIV Imunodeficiency in monkeys, uncertain in man High Poxviruses Systemic infection in monkeys, man Moderate Measles Systemic and pneumonia in monkeys. Moderate Filoviruses Fatal hemorrhagic disease in man Low, but serious The above listed diseases are important, but understanding how these diseases are transmitted to man is more critical. We are most concerned about bite wounds, splash incidents to the face and mucus membranes, scratch wounds, and hollow bore needle sticks, particularly with contaminated needles. These are the primary modes of transmission for B virus (herpesvirus) and immunodeficiency virus (lentivirus). Our goal in education is that you understand these

transmission routes and how to prevent them from happening. We also want you to understand what to do in the event of an accident or injury of any type. Standards for Working with Primates Understand the risks before you start. Avoid the common routes of exposure. Wear the required protective clothing appropriately, which includes head cover, shoe covers, lab coat, gloves, and face protection. Use a face shield if you expect to be producing water splash. Safety glasses are adequate for simple in-cage observation. Face protection means a nose/mouth mask. Surgeons mask is acceptable for routine work, but not for particle protection. Particle protection requires an N95 type filtering mask. Leather gloves are also available if you must handle awake primates, but we do not recommend it. Handling awake primates requires much skill. The protective clothing reduces risk of exposure to a tolerable level. This protective gear is not to be worn in public or administrative areas. Primate Handling We generally do not man-handle awake primates. Close examination or manipulation is generally done under sedation using ketamine 10 mg/kg IM or k ketamine 3 mg/kg IM + medatomidine 0.15 mg/kg. Some primates are collar and pole trained, but caution to avoid exposure routes is still important. Macaques can be trained for rack changes using transport cages. They quickly grow accustomed to this routine. Monkeys are housed in squeeze cages that can restrain them sufficient for injections. Smoking, eating, drinking and applying cosmetics in primate rooms or primate work areas is prohibited. Primates tend to hide clinical disease and can carry some infections without any visible signs. Common clinical problems to watch for in nonhuman primates include prolonged or bloody diarrhea, open draining wounds, cold sore like lesions on the lips, respiratory distress, red eyes. Everyone needs to recognize that B virus can be shed without any open sores or red eyes visible on the animal. Universal Precautions We believe the concepts of “universal precautions” are appropriate for most of the primate work we do. We generally study universal precautions in the context of blood-borne pathogens training. We would define the concept as a combination of mindsets and engineering controls designed to prevent transmission of infectious agents, including blood borne pathogens. They operate under the assumption that all blood, body fluids, and tissues are considered contaminated and they should be handled as such. The precautions apply to both human and animal blood, body fluids, and tissues. There are a collection of rules to follow. They include: • Wear protective clothing as indicated above. • Be careful handling solvents or fluids that may compromise the integrity of gloves. • Remove contaminated gloves carefully by pinching soiled gloves near palm and pulling one

glove off, followed by removal of the second glove by pulling a clean area of the glove cuff. Wash hands afterward.

• Do not turn doorknobs or operate elevator buttons with gloved hands. No one knows what you have been doing and whether or not the gloves are potentially contaminated. If you have

to wear gloves to protect yourself, why potentially expose everyone else by handling doorknobs and elevator buttons with contaminated gloves.

• Never recap needles. • Use appropriate disinfectants. Soap-and water and most common disinfectants will

inactivate AIDS viruses and herpesviruses. • Practice good personal hygiene. Wash hands often. Don’t eat food while wearing

contaminated clothing. • Clean up contaminated surfaces. • Transport contaminated fluids or tissues in sealed containers. • Work with cultures in laminar flow hoods. • Dispose of sharps in appropriate sharps containers. Never put sharps in bags or containers

through which they can penetrate. • Biohazardous waste should be placed in red biohazard bags. Dispose of full containers in a

timely fashion. • Biohazard work areas should be labeled with the hazards, personal protective gear required,

and emergency contact information. Necropsy procedures Primate necropsies should only be done by qualified individuals. Protective clothing listed above is required, including use of fluid-resistant Tyvek suits. Slice resistant gloves should be used in any conditions where potential for cut wounds exists. Necropsies on SHIV infected or exposed monkeys present the additional risk of known blood borne pathogens. Thus, only essential trained personnel should attend primate necropsies of this type. Preventative Medicine and Exposure Control Laboratory Animal Resources and the Employee Health Service operate a preventative medicine program for all LAR and research staff. The program includes yearly examinations, yearly TB surveillance, yearly flu shots, chest radiographs for BCG vaccinated individuals, maintenance of an exposure control plan (see below), and provision of training programs. The Exposure Control Plan provides details what you should do in the event of an injury or incident ON THE DAY OF THE INCIDENT, NOT 2-3 DAYS LATER. A PDF file of first aid instructions can be found by clicking HERE. For an accident during working hours, you should: • Immediately deglove by appropriate methods. • Wash the site for 3-5 minutes for penetrating injuries. • Wash mucus membranes with water for 3-5 minutes. • Report the incident to LAR administration, particularly what monkey was involved if known. • Report to the Employee Health Service to file an incident report. • If the monkey is known, veterinary staff will pull cultures and blood from that animal for B

virus surveillance. For an accident during weekends, evenings, or holidays, you should • Immediately deglove by appropriate methods. • Wash the site for 3-5 minutes for penetrating injuries. • Wash mucus membranes with water for 3-5 minutes.

• Report the incident to LAR administration via cell phone numbers posted all over the building.

• Report to the emergency room, taking memorandum of information with you (link to memorandum).

• On the first working day after the incident or injury, report to the Employee Health service to file the incident report.

Follow-up is important. Workman’s compensation is not engaged unless the incident report is filed by the Employee Health Service and this service will provide follow-up treatment and monitor progress, including any needed short, intermediate, and long-term care. Current evidence indicates that initiation of anti-herpesviral agents prior to the development of symptoms is effective at preventing disease development. Current evidence indicates that initiation of anti-retroviral therapy within a few hours of serious injury may prevent establishment of the infection. The key point is to obtain treatment early. Consideration of atypical medical problems You should consider seeking medical attention if you develop clinical problems that are not typical for you. Your physician should know that you work with primates. Be sure and give him or her that history. Potential problems worthy of medical consultation might include • Conjunctivitis (eye inflammation) that is not allergy related. • Prolonged diarrhea. • General malaise (just not feeling good) • Atypical or prolonged headaches. • Rashes. • Swollen lymph nodes. • Severe or painful sore throat. Physicians who evaluate such problems should know that you work with primates and should know something about the zoonoses that these animals carry. If you chose to be evaluated by an outside physician who may not know about these diseases, you should inform him or her about these infections that monkeys carry and transmit. Drs. Bill Barkman and Greg Bono are well-informed about these disease and can provide information. Drs. Pinson and Culley are also good sources of information. The latest death due to B virus occurred in 2001 or thereabouts. The victim was a 23 year old woman who was splashed from behind in a macaque corral. She was not wearing protective gear as we indicate you should here. Several days later she developed an eye inflammation and went to see her usual doctor. Apparently, she did not describe the incident, he did not know anything about monkeys and B virus, and he treated her symptomatically. She was dead of fatal encephalitis within 10-12 days. This is a true story. Go forth and do not do as she did. If you complete this training, you should be educated in the correct way to handle incidents. You have responsibilities as an employee working with macaques and other monkeys. • You must be trained in the hazards and prevention of exposure. • You must learn procedures and perform them correctly to prevent exposures. • You must report exposure incidents. • You should have atypical medical problems evaluated by knowledgeable physicians.

• You should ask questions about anything you do not understand or about anything you do not know how to do.

To complete this training, you must take the online examination for primate training as a tangible indication of your study here. Version History May 15, 2009

Documents

2009 Investigator Technician Training Manual Module 1