2nd Edition 2002 arena/olaw institutional Animal Care and Use Committee Guidebook

Review of Changes to Approved Protocols

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Review of Changes to Approved Protocols

Significant changes to an IACUC-approved protocol must be reviewed and approved by the IACUC before they occur (PHS Policy IV.C.1., and AWR §2.31[d][1]). It is prudent for an IACUC to develop a policy on the kinds of changes that are considered significant in order to avoid ambiguity. OLAW has identified the following kinds of significant changes that may serve as examples to guide the IACUC in its determinations:

  • change in objectives of a study;

  • proposals to switch from nonsurvival to survival surgery;

  • change in degree of invasiveness of a procedure or discomfort to an animal;

  • change in species or in the approximate number of animals used;

  • change in personnel involved in animal procedures;

  • change in anesthetic agent(s) or in the use or withholding of analgesics;

  • change in methods of euthanasia, or

  • change in duration, frequency, or number of procedures performed on an animal.

Review of significant changes may be conducted using either the full com-ittee review or the designated member review method described above.

Frequency of Review of Approved Protocols
The PHS Policy requires that a complete IACUC review of PHS supported protocols be conducted at least once every three years. This triennial review is interpreted by OLAW as a requirement for de novo review, mean-ing that the criteria and procedures for review specified in IV.C. of the PHS Policy must be applied not less than once every three years. The three-year period begins on the actual date of IACUC approval; IACUCs may not administratively extend approval beyond the three years. The triennial review may be conducted using either the full committee review or the designated member review method described above.
AWRs require an annual review, which may be a monitoring mechanism whereby the IACUC requires the investigator to annually report on the status of the protocol, verify that completed activities were conducted in accordance with the approved protocol, describe any proposed departures from the approved protocols, and solicit information about activities pro-jected for the upcoming year. (Proposed significant changes would require IACUC review prior to initiation.) This kind of a monitoring system will satisfy the AWR requirement for annual review, but would not be sufficient for the complete IACUC review required on a triennial basis.
Garnett, N.L. and W.R. DeHaven. Commentary: Protocol Review - Playing By the Rules. Lab Animal, 27(8):18. 1998.
Potkay, S., et al. Frequently Asked Questions about the Public Health Service Policy on Humane Care and Use of Laboratory Animals. Lab Animal, 24(9):24-26. 1995.
OPRR Staff. The Public Health Service Responds to Commonly Asked Questions. ILAR News, 33(4):68-70, Fall, 1991
OPRR Staff. Frequently Asked Questions about the Public Health Service Policy on Humane Care and Use of Laboratory Animals. ILAR News, 35(3-4):47-49, Summer/Fall, 1993.
Oki, G.S.F., et al. Model for Performing Institutional Animal Care and Use Committee Continuing Review of Animal Research. Contemporary Topics, 35(5):53-56, September 1996.

Reduction_and_Refinement'>C.2. Protocol Review Criteria

C.2.a. Alternatives – Replacement, Reduction and Refinement
There is significant interest in the application of alternatives to animals used in research, education and testing. The PHS Policy and the AWRs require research institutions to ensure that investigators have appropriately considered alternatives to procedures that can cause more than slight or momentary pain or distress in animals, consistent with sound research design. Through US Government Principle III (Appendix F), the PHS Policy further requires that the minimum number of animals be used and that non-animal methods be considered.
The “3 Rs”
Alternatives are framed within the context of the “3 Rs” articulated originally by Russell and Burch in 1959; they include:

  1. Replacement, or utilizing non-animal models;

  1. Reduction of numbers of animals used; and

  1. Refinement, or elimination or reduction of unnecessary pain and distress in animals.

Replacement alternatives utilize:

  • living systems,

  • non-living systems, or

  • computer simulations.

Living systems include in vitro methods that utilize organ, tissue or cell culture techniques. Invertebrate animals, such as the fruit fly, have long been used in research and represent another type of living alternative to vertebrate animals. Finally, microorganisms and plants represent living alternatives for some types of research and testing. If no invertebrate model is appropriate, use of species lower on the phylogenetic scale may be considered a replacement alternative.
Nonliving systems include physical or mechanical systems and chemical techniques. Mechanical models may be used in the training of specific techniques (cardiopulmonary resuscitation, for example) and have replaced living animals in some cases. Chemical techniques are the most widely used nonliving systems and include such useful systems as the enzyme linked immunosorbent assay (ELISA). Techniques that identify the presence of chemical reactions and enzymes, or simply analyze chemical structure, can all be useful in the prediction of toxicity without the use of animals.
Computer simulations may replace some animal use and can be particularly useful when a question is well defined and there is existing data.
Although opportunities for replacement are numerous in product safety testing and education, they appear more limited in research. If it is demon-strated that there is no in vitro alternative to the use of animals, it is impor-tant for the IACUC members to focus on the other alternative approaches, reduction and refinement.
Reduction of numbers of animals may be accomplished by a variety of methods described in Table A:
C.2.a. Table A. Methods for Reduction of Numbers of Animals Used



Rational selection of group size

  • Pilot studies to estimate variability and evaluate procedures and effects

  • Power analysis

Careful experimental design

Maximizing use of animals

  • Performing several terminal procedures per animal

  • Animals euthanized by one investigator used for tissue needed by another

Correct choice of model

  • Use of healthy, genetically similar animals decreases variability

Minimizing loss of animals

Statistical analysis

  • Appropriate use of statistical software can generate maximum information from minimum number of animals

Refinement of technique to reduce or eliminate unnecessary pain and distress in study animals is the most commonly practiced of the 3 Rs, although it is not always recognized as one of the applications.
Investigators are required to consider alternatives to painful procedures, and to avoid or minimize discomfort, distress and pain, consistent with sound scientific practice and the goals of the research. This requires an understanding of the potential of pain or distress in the animals (see Section C.2.d.)
When there is no consensus among IACUC members as to whether a cer-tain procedure actually causes pain or distress in the affected animals, U.S. Government Principle IV should be applied. This Principle states, “Unless the contrary is established, investigators should consider that procedures that cause pain or distress in human beings may cause pain or distress in other animals.”

To assist in this deliberation, the IACUC may need to utilize one or more of the following:

  • pilot studies,

  • evaluations of clinical signs,

  • clinical pathology,

  • gross and histological necropsy studies,

  • review of comparable literature, and

  • consultation with experts.

If there remains any doubt about the presence of pain or distress, the IACUC should err on the side of protecting the animals against the potential of unnecessary pain or distress.

Some refinement opportunities include:

  • pain-relieving drugs,

  • non-pharmacologic techniques,

  • new diagnostic and therapeutic techniques,

  • environmental enrichment programs, and

  • establishment of more humane endpoints.

Pain-relieving drugs: While it is preferable to design a protocol that prevents pain and distress, when this is not possible the AWRs require that the AV (or designee) be consulted to develop an appropriate plan for the use of anesthetics, analgesics, or other measures, such as anti-inflammatory agents, antibiotics, or sedatives.

New diagnostic and therapeutic techniques: In addition to the use of pain relieving drugs, new diagnostic and therapeutic techniques may have the capability to dramatically reduce the invasiveness of data collection and thereby refine animal research. These include:

  • use of sophisticated imaging equipment to replace invasive proce-dures, and

  • blood and tissue sampling techniques that allow for easier collection and the processing of smaller sample sizes.

Environment: The IACUC should consider that environmental factors, such as noises, odors, infrequent or inexperienced handling, or boredom from lack of environmental stimulation can cause unnecessary distress, and that US Government Principle IV should be applied to this area as well. Aside from the AWR requirement to provide environment enhancement for non-human primates, many institutions have implemented environmental modi-fications for other species with a view to reducing unnecessary distress.
Humane endpoints: The establishment of the earliest possible humane endpoint consistent with the research design may provide an additional opportunity to significantly reduce pain and distress, thereby refining the experiment. For any study that defines death of the experimental animal as the endpoint, the IACUC should ask if there is an earlier point in the study when the necessary data have been collected and the animal could be euthanized without proceeding through more severe illness and death. Or, alternatively, if death is a necessary endpoint, the IACUC could ask for careful ongoing assessment of the animal, so that, when it is determined that death is inevitable, the animal can be euthanized. The Canadian Council on Animal Care Guidelines on Choosing an Appropriate Endpoint in Experiments Using Animals for Research, Teaching and Testing (1998) is a good resource for IACUCs. (See also Section C.2.c. Humane Endpoints.)
USDA Requirements for Consideration of Alternatives
USDA AWRs require that investigators consider alternatives to procedures that may cause more than momentary or slight pain or distress and provide a written narrative of the methods used and sources consulted to determine availability of alternatives. Animal Care Policy 12 provides guidance on the requirements for the written narrative, which should include adequate information for the IACUC to assess that a reasonable and good faith effort was made to determine the availability of alternatives or alternative methods. Resources in the area of alternatives include the USDA Animal Welfare Information Center (AWIC); ALTWEB, a Web site maintained under the auspices of the Johns Hopkins University Center for Alternatives to Animal Testing; and the University of California Center for Animal Alternatives (see Appendix A).
C.2.b. Euthanasia
“Euthanasia means the humane destruction of an animal accomplished by a method that produces rapid unconsciousness and subsequent death without evidence of pain or distress, or a method that utilizes anesthesia produced by an agent that causes painless loss of consciousness and subsequent death” (AWR). The choice of a method depends on species, age, availability of restraint, skill of the individuals performing euthanasia and other considerations. In a research setting, the method of euthanasia must be consistent with the research goals.
The PHS Policy and the AWRs require that an IACUC review and approve methods of euthanasia. The PHS Policy specifically states that methods of euthanasia must be consistent with the recommendations of the American Veterinary Medical Association (AVMA) Panel on Euthanasia, unless scien-tific justifications for alternative methods are presented in writing by the investigator and approved by the IACUC. The most recent Panel convened in 2000, and published its Report in March 2001.
The criteria used as the basis for the Panel’s recommendations include:
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