INSTITUTIONAL ANIMAL CARE AND USE COMMITTEE

PROTOCOL INFORMATION

1. Protocol Preparation.  The IACUC Protocol Form is available on-line, and is a detailed description of the use of animals in a research or training program. The attending veterinarians are available for consultation when completing a protocol, and other tools are available on this website through the protocol form.

The protocol form is designed to elicit information that is required by the agencies regulating the care and use of animals.  Completed protocols are part of the IACUC records that may be inspected and reviewed at any time by various accrediting, governmental, and granting agencies.

The protocol must be signed by the principal investigator, all personnel named on the protocol, and the department chairperson.  Principal investigators must also include required radiation, pathogen, and chemical substance safety forms, as well as the Facility Access, Occupational Health and Training form.

Protocol Submission and Review.  The protocol form is to be submitted electronically to the IACUC Office email iacuc@case.edu. Please bring signature pages to the School of Medicine room WG-77 and 78.  Upon receipt, the protocol is reviewed for completeness, and the necessary attachments.  Principal investigator information is reviewed to ensure that s/he has completed the required training.

The protocol is then evaluated to determine if it needs a full or designated review.  Protocols falling into specific categories require a discussion at a convened meeting of the IACUC.

All protocols are distributed to all members of the IACUC, but one member is appointed as the primary reviewer.  One of the attending veterinarians is the secondary reviewer for each protocol.  Reviewers’ questions about the protocol are forwarded to the principal investigator. 

2. The IACUC Protocol Form. is modular in design. The Core portion of the form must be completed fully by all investigators. Attachments may need to be completed depending on the responses to the checklist in Section V of the Core.

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3. Protocol Review/Meeting Schedule. The Case-IACUC meets regularly on the third Tuesday of each month with ad hoc meetings convened as needed.  The schedule of meetings and protocol submission dates are below.  Protocols should be submitted by the posted dates if it is critical that they be reviewed at a specific meeting.

Submission dates are the last Friday of the previous month. Meeting dates are the third Tuesday of the month.

1. As of  March 1, 2006, the IACUC Office will no longer accept paper copies of protocols.
 
2. Submit protocol electronically as a word document to the IACUC using the following email address IACUC@case.edu.  Our new website address is http://casemed.case.edu/ora/Iacuc/.

3.  Follow-up with signed hard copies of signature pages:  Section III – Investigator Assurances, page 3; Section IV – Departmental Chair, page 4; and Section V– Personnel, page 4.  Form Date: 07/2008

4.  The Facility Access and Occupational Health (F.A.O.H.) form for established personnel is no longer required; however, all new personnel will need to complete this form.  http://casemed.case.edu/ora/iacuc/forms/index.cfm

5.  Any changes to the protocol form must be done electronically as an updated version of the original submission.  These changes must be clearly indicated…ex:  highlighted.

Contact the IACUC Office:

Diana Zyzanski, Coordinator
216-368-3815
djp@case.edu

Theresa Bridges, Assistant Coordinator
216-368-6979
tdb3@case.edu                                   

The IACUC office performs a review of the protocol before sending the protocol to the primary reviewer and veterinarian reviewer. The IACUC office allows five business days for the reviewers to send comments to the IACUC office. The IACUC office then combines the comments from both the primary reviewer and veterinarian reviewer and sends them to the principal investigator for their response. Once the principal investigator responds to IACUC the responses are sent to the primary reviewer and veterinarian reviewer for their authorization. If the protocol is a full review protocol it would then go to the next scheduled meeting of the IACUC for final review and approval. If the protocol is a designated review the protocol will then go to the IACUC chair for approval.

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4. Protocol Review Criteria

Full Review
 
Unrelieved pain
Multiple survival surgery
Use of surgical muscle relaxant drugs without adequate anesthesia
Unusual or questionable methods of euthanasia
Use of Freund’s adjuvant in any manner likely to cause pain or discomfort, e.g.
involving injection of footpads or multiple injections of complete Freund’s
Use of nonhuman primates
Unusual, potentially stressful or prolonged forms of animal restraint
Any form of survival surgery for which no precedent exists
Severe post procedural handicap
Death as an endpoint without the option of interventional euthanasia
Tumor growth exceeding 10% of the animal’s weight
Unusual biohazards or other elements potentially hazardous to ARC staff

Designated Review

Breeding
Tissue collection
Genetic mapping
Nutritional studies
Aging
Exercise physiology
Behavioral tests
Antibody production
Terminal (acute) study

Investigators based at the Louis Stokes Cleveland Department of Veterans Affairs Medical Center (LSCDVAMC.)  Case and the LSCDVAMC have established procedures for the review and approval of animal study protocols that involve faculty with appointments at the VA.  Protocols for work that is being conducted at the LSCDVAMC should be submitted and reviewed by the LSCDVAMC Subcommittee on Animal Studies (SAS.) If this animal work is supported by a grant that is administered by Case, the Case IACUC will review the approved VA protocol, and once approved, it will be maintained in the Case IACUC office.  If the work is to be conducted at Case, with funding administered by the LSCDVAMC (e.g., VA merit review), the same process will be followed.  However, if the animal work is to be done at Case, with Case-administered funding, the Principal Investigator must submit a Case protocol for review and approval.

Investigators based at the Cleveland Clinic Lerner College of Medicine (CCLCM.)  Case and CCLCM have established procedures for the review and approval of animal study protocols that involve faculty based at the CCLCM.  Animal work being performed at the CCLCM and funded through NIH grants should be reviewed and approved by the Cleveland Clinic IACUC.  The face page of the grant application, however, should bear the Case Animal Welfare Assurance number.

If animal studies will be conducted at Case, the Case IACUC should review and approve the protocol even if the PI is based at CCLCM.

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5. Justify the Number of Animals Requested

A formal sample size justification should contain the following elements:

1. Statement of the primary objective:

e.g., to determine whether histological and/electrophysiological properties of the mouse brain are correlated with behavior, as measured by the rotorad test.

1. Statement of the primary outcome measures

e.g., the rotarod test results are measures of the stopping RPM, length of test (in units), and distance traveled (in units).
The outcome of the Purkinje cell experiments is the percent of cells counted in each animal that exhibit abnormal morphology

1. Statement of the appropriate statistical test

e.g., a Spearman’s rank correlation coefficient will be used to measure the relationship between each of the rotarod results and the Purkinje cell results.

1. Statement of the size of the difference (correlation, etc) which is scientifically meaningful in your work

e.g., for the purposes of our work, a correlation of >=0.85 will be considered meaningful.  Anything smaller would be ambivalent.

1. Any other assumptions on which your calculations are based (normal values, amount of variability you expect to observe, etc.) where relevant
2. The results of the sample size estimation using software for this purpose, or citing other work where similar formal analyses have been done.

e.g., When the sample size is 6, the study will have 80% power (p = 0.05, two-sided) to detect a correlation coefficient of 0.85 (provide a reference, either the software used, or a citation where an appropriate estimation has been done).

The following link has an extensive listing of interactive statistical sites, including many for sample size calculations for all kinds of tests (they are at the bottom of the page).  As a rule of thumb, any information that you are required to enter for the software to perform the calculation, should be reported along with the result.  The reasoning is the same as when you give detailed instructions on a lab procedure – so that anyone can reproduce your analysis if he/she felt it was warranted.

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6. Alternative Searches. Why Searches for Alternatives must be performed: The Animal Welfare Act requires that you justify the use of animals and the procedures to be performed on them, and that documentation of searches of databases or other relevant sources and/or documentation of consultations be provided in your justification.

You must address the following three points ("the three R's" from "The Principles of Humane Experimental Technique" by W.M.S. Russell and R.L. Burch).

• Replacement: Justify why vertebrate animals must be used. Why are other methods, e.g. in vitro or in silico methods, or invertebrate animal models, unsuitable?
• Refinement: Justify the pain or distress that animals may experience as a result of the proposed work. A search must be performed for alternative or more refined procedures which would cause less pain or distress or would result in better animal welfare. If the procedures performed on animals are not the most refined procedures available (producing the least pain or distress or resulting in better animal welfare), a scientific justification for using the proposed procedures must be provided.
• Reduction: Justify why the number(s) of animals cannot be reduced from those requested. A search showing that the proposed work does not unnecessarily duplicate previous work must be performed. Indicate if the animals can be reused for other purposes.

How to Document Searches and Consultations. The Animal Welfare Act requires that you document your justifications with data from two or more sources. One source must be a set of searches of a relevant database: name the database searched, the terms searched, when it was searched and the frequency of searches. The second source can be a set of searches of a second relevant database, or consultation with a laboratory animal science veterinarian, or courses/meetings/consultations with qualified personnel. A consultation with a qualified laboratory science veterinarian must be performed if the animals are expected to experience pain or distress. Sufficient documentation, such as the consultant's name and qualifications and the date and content of the consult, should be provided to the IACUC to demonstrate the expert's knowledge of the availability of alternatives in the specific field of study. With the prepared search strategies for different species (links above), you can easily fulfill the requirements for searches of two databases.

How to Perform Searches. Use the following questions to guide your search for replacement and reduction alternatives:

• Are there in vitro techniques that may reduce or replace the number of animals used (e.g., chorioallantoic membrane assay, use of primary cultured cells, etc.)?
• Are there alternative animal models (e.g., invertebrates, fish, microbes, etc.)?
• Have computer models or simulations been developed that relate to the study?
• Have statistical methods been developed which could reduce sample size?

Use the following questions to guide your search for refinement alternatives:

• Are there surgical approaches which are less invasive?
• Are there anesthetics or analgesics which are more effective?
• Are there experimental endpoints which are earlier than those proposed or other ways to shorten time post-procedure?
• Are there other means to lessen the pain or distress of the procedure or improve the welfare of the animal?

Performing a meaningful search for replacement, refinement and reduction is not the same as searching for recent advances in your field of science or medicine. Special search strategies are required to find meaningful results.

Pub Med: Pub Med uses a specialized vocabulary to structure information, the "Medical Subject Headings" (MeSH Terms). To make a search for alternatives effective, it is essential that you use this tool. Links to searches, detailed examples, and a link to the MeSH Term Browser are below (including searches of databases other than Pub Med):

Mice | Rats | Dogs | Cats | Rabbits | Frogs | Ferrets | Goats | Pigs | Fish | Primates

Additional assistance with the design and use of electronic database searches can be had by contacting Mike McGraw 368-3218 mpm3@case.edu  

Additional search information and databases can be found here.

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7. How to add personnel to a protocol Personnel may be added to existing protocols by completing and submitting the Facility Access and Occupational Health Form F.A.O.H..

If you are a new employee to Case you must complete the Facility Access and Occupational Health Form F.A.O.H.

Standardized hands on training and on line training is provided by ARC and is required for Animal Facility access. Protocol specific training is also required.

You will find all the on line training modules on the ARC web site http://labanimals.cwru.edu/training.htm.

Contact Tami McCourt at txm9@case.edu for your specific facility and protocol training requirements.

You may contact the following personnel directly for training appointments.

Ramona Boyd(General Training: facility tours, microisolator technique and basic rodent handling):  368-2819 or Ramona.Boyd@Case.edu
Pam Steele (Athymic Facility Orientation):  368-0074 or pas@case.edu
Jean Holbert (Special technique training and species specific training):  368-0504 or jal27@case.edu
Veterinarian Technique Training: 368-3490

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8. Guidelines for Training and Demonstration Protocols   The use of animals for surgical training and demonstration and for the development of new surgical procedures may be necessary in those circumstances where it can be demonstrated that a suitable alternative is not available. Failure to properly train surgeons in new procedures can have serious implications for patient care. Nevertheless, the Institutional Animal Care and Use Committee (IACUC) must ensure that such use is justified, according to the following conditions which are based on the Guide, Animal Welfare Act and Public Health Service Policy on Humane Care and Use of Laboratory Animals (PHS) for scientific purposes.

The Guidelines for Training and Demonstration Protocols was developed as guidance when considering applications for the use of animals to train surgeons or other individuals in new techniques on how to use new technology.

The Teaching and Demonstration Attendance form s hould be used by the Principal Investigator and/or the Primary Investigator who is responsible for the teaching & demonstration laboratory, in order to ensure the identity of all attendants. The attendance list should be completed and submitted to the IACUC Office at least 24 hours before the laboratory is held (except for the signature of each attendant). The Animal Resource Center may require ARC personnel to be present for all or part of the laboratory session. Please contact the ARC for details. At the beginning of the laboratory, each attendant should sign verify all information and sign the attendance form. The Primary Investigator who is responsible for the teaching & demonstration laboratory must verify the identity of each attendant.

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9. How to deal with animal experiments that involve infectious agents, biohazards, or recombinant DNA?   Such experiments require approval from other Case safety committees.  Go to the links listed below for applications and instructions for the specific approval process. Your animal protocol will not receive final approval of the IACUC until the safety committee approval is received.

Carcinogen form
Radioisotope Form
Pathogen Safety Form
Recombinant DNA Form

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10. Non-Affiliated Scientific Merit Review.
It is the policy of Case Western Reserve University (Case) to have the department chair of each investigator affiliated with Case review or have a qualified person or committee review the protocol for scientific merit following the guidelines below. If the protocol is from a non-affiliated investigator the scientific merit review must be completed by a faculty member of Case not affiliated with the protocol. (Forms for scientific merit review in Microsoft Word format are available for download).

A reviewer of scientific merit should evaluate the science of the project, not the procedures performed on animals or the protocol. The project should be evaluated for quality of the science and the impact it may have on its field.

The review should address the following issues with regard to the project:

• Does this study address an important problem or scientific question? Does the project employ novel concepts, approaches or methods in addressing the question?
• Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Are the aims of the project clear and reasonable in the context of the project?
• What new information is likely to result from this study?
• Is the investigator appropriately trained and well suited to carry out this work?
• What is the basis for your knowledge of the study: grant proposal, published material, discussions, etc.?
• Do you have a conflict of interest which would prevent you from making an unbiased evaluation?
• Please include the name of the principal investigator in your review. This will insure that the IACUC Office can match scientific review letters with the correct animal protocols.

Please submit the completed scientific merit review form to the IACUC Office, School of Medicine, WG-77, 10900 Euclid Avenue, Cleveland, Ohio 44106-4919. If you have any questions please call the IACUC office at 368-3815. Thank you.

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11. How to coordinate protocol review with a grant submission  Many sponsors no longer require that animal protocols be approved at the time that you submit an application. However, funds will not be awarded unless there is an approved protocol, so it is important to have the protocol reviewed and approved sometime during the time the application is under review. There is not sufficient time for protocol review and approval once the sponsor notifies you that this information is needed for possible funding.

Information needed in grant applications. Along with specific information about the experiments that you propose, you may include a statement about the institutional capacity for animal research and information about the accreditation. An example of such a statement is below.

The animals described in this study will be housed in the AAALAC accredited facilities of the CWRU School of Medicine (SOM) or the Veterans Affairs Medical Center (VAMC). Standard Operating Procedures and reference materials are available from the IACUC Office for animal use. The animal health program for all Case owned laboratory animals is directed by the Case Animal Resource Center Director, W. John Durfee, DVM, Diplomate ACLAM, and provided by two full-time veterinarians. Animals in each room are observed daily for signs of illness by the animal technician responsible for providing husbandry. Medical records and documentation of experimental use are maintained individually for non-rodents and individually or by cage group for rodents. Veterinary technicians under the direction of the attending veterinarian provide routine veterinary medical care to all animals. Animal care and use is additionally monitored for training and compliance issues by the Training and Compliance Manager. The Case Assurance number is A-3145-01, valid until 04/30/11.

• Aaalac Full Accreditation date - November 23, 2005
• USDA Registration - 31-R-0028 valid until August 23, 2011
• OLAW Assurance - A3145-01 valid until April 30, 2011

Additional information is available at How to Write an Application Involving Research Animals at the NIAID website, Animal Welfare Act of 1966 (P.L. 89-544) inclusive of amendments; 1970 (P.L. 91-579; 1976 (P.L. 94-279); 1985 (P.L. 99-198).