protocol review Jerald Silverman, DVM, Column Coordinator
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© 2014 Nature America, Inc. All rights reserved.
Changing a protocol form to list animal number by strain At Great Eastern University, investigators using animals were required to list on the IACUC protocol form the number of animals, by species, being requested. Although this requirement was well-established at Great Eastern and many other institutions, it was questioned by the school’s IACUC administrator, who believed it would be more appropriate to list on the IACUC protocol form the number of animals requested by strain and species, rather than by species alone. Her rationale was simple: many research protocols at Great Eastern required one or more specific strains of mice, and she felt that failure to list the number of animals needed for each strain could lead to the acquisition of more animals than needed, animals that could be potentially unusable. For example, she said, “If 100 mice were required for a study, and 50 of them had to be C57Bl/6, how would the IACUC know whether the investigator used only the approved 50 rather than 100 C57Bl/6 mice, if only the species was i ndicated on rotocol? And, if 100 C57BL/6 were the p obtained, what were the extra 50 used for?”
Response Right info, wrong place Holly McEntee, MA, CPIA
The purpose of the protocol form is to collect the i nformation required by law to enable the IACUC to make an informed decision about the p roposed use of animals, b alancing p otential benefits of the proposed use against the potential and real pain and distress experienced by the animals. Two pieces of information the IACUC needs to make this decision are the identification of the species and the LAB ANIMAL
Of course, not everybody agreed with that reasoning, particularly the r esearchers on the committee. They presented four points of view against h aving to list s pecific strains on the protocol form. First, researchers would never spend their precious research grant dollars purchasing animals they did not need. Second, the Animal Welfare Act regulations1 and the Public Health Service Policy on Humane Care and Use of Laboratory Animals 2 indicate a need to justify the approximate number of animals required by species, not by any additional descriptions. Third, research needs change and researchers would not want to waste time submitting p rotocol amendments to change the number of a nimals of a p articular strain requested. And fourth, n oncompliance is n oncompliance, no m atter which species, strain or stock is being used. Nevertheless, some other m embers of the IACUC took up the a dministrator’s cause, r eminding the i nvestigators that when multiple strains were to be used in a p rotocol, the i nformation about
the strains was already included in the descriptive parts of the protocol form in order for the reviewers to understand the c omponent parts of the planned study. They also noted that when animals were eeded strain had eventually ordered, the n to be i ndicated. Therefore, they wanted to know why it would be a problem to list strain information on the protocol form where the species and total number of animals r equested was shown. That way, they claimed, there would be less chance for ordering errors and less chance for noncompliance. What is your opinion? Do you think Great Eastern University should change the protocol form along the lines suggested by the IACUC a dministrator or leave it as it is, as favored by the researchers?
approximate number of animals to be used (section 2.31 (e)(1) of the Animal Welfare Act regulations) 1 . Because the Public Health Service Policy on Humane Care and Use of Laboratory Animals2 requires compliance with the Animal Welfare Act regulations, investigators must identify for the IACUC all vertebrate species to be used in the protocol—not only those species covered by the Animal Welfare Act—and the approximate n umber of each species to be used. For the purposes of IACUC oversight and e valuation of p roposed and ongoing animal use, n either r egulatory d ocument requires the p rovision of information beyond species identification.
I would not advocate for listing specific strains and numbers of animals requested by strain on the IACUC animal protocol form. In my opinion, too often institutions try to use the IACUC animal care and use protocol application to fulfill institutional responsibilities beyond that of informing the IACUC’s decisions. A well-coordinated institutional animal program should have systems and processes that proactively prevent the ordering of more animals than is approved by the IACUC or that i dentify noncompliance if more animals were ordered than were approved by the IACUC. The approved IACUC protocol can be a source document to inform those systems
Volume 43, No. 1 | JANUARY 2014 13
1. Animal Welfare Act and Regulations. 9 CFR, Chapter 1, Subchapter A. 2. Public Health Service. Policy on Humane Care and Use of Laboratory Animals (US Department of Health and Human Services (US Department of Health and Human Services, Washington, DC, 1986; amended 2002).
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and processes, but it alone should not be relied upon to serve this need. Appropriate strain choice is as important as appropriate species choice from the s tandpoint of scientific integrity and ethics: one must always match the model to the s cientific question being posed. Determination of appropriate strain choice to best fit the science is most effectively left to the investigator and the veterinary consultant involved in the preparation of a protocol for the IACUC’s review ( section 2.31 (d)(1)(B)) 1 . The development of specialized strains of research animals into more refined disease models has had effects on animal welfare, some predicted and some unintended. Investigators, research animal veterinarians and animal care technicians have had to increase their knowledge of strain-specific c linical effects in order to optimally monitor the health status of the animals and to intervene in order to prevent unnecessary pain and distress. Strengthening this aspect of the pre-submission veterinary consultation would be a more efficient use of institutional programmatic resources. The IACUC in turn must be p rovided rotocol sufficient information in the animal p about the known and possible health effects of an investigator’s p referred mouse strain, and the endpoints for which staff must monitor, to fulfill its role in a ssessing whether animal pain and distress will be minimized and appropriately mitigated. The IACUC also can provide an objective opinion when the v eterinarian and the investigator cannot agree upon a specific strain during the review of the p rotocol itself. Protocols as documents serve a specific purpose, as different from monthly billing invoices and weekly animal censuses as they are different from grant applications. I would caution institutional management personnel to think carefully about r elying too heavily on the IACUC protocol as the sole document upon which the entire animal program pivots. 1. Animal Welfare Act and Regulations. 9 CFR, Chapter 1, Subchapter A. 2. Public Health Service. Policy on Humane Care and Use of Laboratory Animals (US Department of Health and Human Services (US Department of Health and Human Services, Washington, DC, 1986; amended 2002). McEntee is IACUC Administrator, University of Wisconsin-Madison, Madison, WI.
14 Volume 43, No. 1 | JANUARY 2014
Response Change to ensure compliance Thea McCready, BA
I agree with the statement that “noncompliance is n oncompliance,” which is why I feel that Great Eastern University’s IACUC should change the protocol form to list animal strains instead of species alone. Noncompliance is a serious offense and should be avoided at all costs. Although the change may be perceived as extraneous work by the researchers now, it could help to ensure that investigators maintain protocol oncompliance may compliance. Protocol n still occur, but it is within the IACUC’s purview to put in place a method to safeguard investigators by minimizing the potential for noncompliance. By s pecifying animal strains and strain numbers, researchers will give the IACUC the i nformation it needs to conduct a thorough review of proposed activities. The provision of this information also allows less opportunity for errors in procurement and animal use, thus lessening the chances for inadvertent noncompliance. The Animal Welfare Act regulations 1 (AWARs, §2.31.e.1; §2.31.e.2), the Public Health Service Policy on Humane Care and Use of Laboratory Animals2 (IV.D.1.b) and the Guide for the Care and Use of Laboratory Animals3 (the Guide) state that IACUC proposals should include a r ationale for involving animals, i dentification of the a nimal species involved and its appropriateness for the proposed use and the approximate number of animals to be used. Additionally, §2.31.e.3 of the AWARs1 requires that IACUC proposals include “a complete description of the proposed use of the animals.” Although the regulations do not specifically state that the IACUC must review and approve the use of a p articular strain, these provisions implicitly require investigators to fully address their animal construct as it relates to the proposed experimental design. The Guide 3 states that “while the responsibility for scientific merit review n ormally lies outside the IACUC, the c ommittee members should e valuate scientific elements of the protocol as they
relate to the welfare and use of the animals.” Phenotypic assessment is n ecessar y because it directly relates to the research o utcomes and must be s cientifically justified. Particularly, strain variances can pose the potential for genetically based developmental problems or leave an animal more susceptible to disease. Use of strains with these sorts of characteristics requires an outlined plan for addressing the potential pain and distress that might result from the phenotypic features. Researchers should consult the l iterature available for assistance in selecting the a ppropriate animal species and strain, as well as the appropriate c ontrol animals. Initial s election of an incorrect strain for the desired research can result in the unnecessary or inappropriate use of animals; therefore, it is critical for the IACUC to assess the proposed phenotype. Inclusion of the animal strain is a requirement for Department of Defense p roposals, as outlined in its Standard Animal Use Protocol Format 4 , and its p resence as part of the protocol form positively contributes to the concept of best practices within an animal care and use program. IACUCs that strive to be proactive rather than reactive should s eriously consider the potential benefits of including strain and number specifications as part of the protocol form. 1. Animal Welfare Act and Regulations. 9 CFR, Chapter 1, Subchapter A. 2. Public Health Service. Policy on Humane Care and Use of Laboratory Animals (US Department of Health and Human Services, Washington, DC, 1986; amended 2002). 3. Institute for Laboratory Animal Research. Guide for the Care and Use of Laboratory Animals 8th edn. (National Academies Press, Washington, DC, 2011). 4. Department of Defense. Instruction 3216.01. Use of Animals in DoD Programs. (Department of Defense, Washington, DC, 2010). McCready is IACUC Administrator, Armed Forces Radiobiology Research Institute, Bethesda, MD.
Response When strain matters Bill Moseley, MA, CPIA & Elaine Kim, BS
Great Eastern’s IACUC administrator is clearly a professional interested in assisting the IACUC in fulfilling its regulatory www.labanimal.com
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© 2014 Nature America, Inc. All rights reserved.
Changing a protocol form to list animal number by strain At Great Eastern University, investigators using animals were required to list on the IACUC protocol form the number of animals, by species, being requested. Although this requirement was well-established at Great Eastern and many other institutions, it was questioned by the school’s IACUC administrator, who believed it would be more appropriate to list on the IACUC protocol form the number of animals requested by strain and species, rather than by species alone. Her rationale was simple: many research protocols at Great Eastern required one or more specific strains of mice, and she felt that failure to list the number of animals needed for each strain could lead to the acquisition of more animals than needed, animals that could be potentially unusable. For example, she said, “If 100 mice were required for a study, and 50 of them had to be C57Bl/6, how would the IACUC know whether the investigator used only the approved 50 rather than 100 C57Bl/6 mice, if only the species was i ndicated on rotocol? And, if 100 C57BL/6 were the p obtained, what were the extra 50 used for?”
Response Right info, wrong place Holly McEntee, MA, CPIA
The purpose of the protocol form is to collect the i nformation required by law to enable the IACUC to make an informed decision about the p roposed use of animals, b alancing p otential benefits of the proposed use against the potential and real pain and distress experienced by the animals. Two pieces of information the IACUC needs to make this decision are the identification of the species and the LAB ANIMAL
Of course, not everybody agreed with that reasoning, particularly the r esearchers on the committee. They presented four points of view against h aving to list s pecific strains on the protocol form. First, researchers would never spend their precious research grant dollars purchasing animals they did not need. Second, the Animal Welfare Act regulations1 and the Public Health Service Policy on Humane Care and Use of Laboratory Animals 2 indicate a need to justify the approximate number of animals required by species, not by any additional descriptions. Third, research needs change and researchers would not want to waste time submitting p rotocol amendments to change the number of a nimals of a p articular strain requested. And fourth, n oncompliance is n oncompliance, no m atter which species, strain or stock is being used. Nevertheless, some other m embers of the IACUC took up the a dministrator’s cause, r eminding the i nvestigators that when multiple strains were to be used in a p rotocol, the i nformation about
the strains was already included in the descriptive parts of the protocol form in order for the reviewers to understand the c omponent parts of the planned study. They also noted that when animals were eeded strain had eventually ordered, the n to be i ndicated. Therefore, they wanted to know why it would be a problem to list strain information on the protocol form where the species and total number of animals r equested was shown. That way, they claimed, there would be less chance for ordering errors and less chance for noncompliance. What is your opinion? Do you think Great Eastern University should change the protocol form along the lines suggested by the IACUC a dministrator or leave it as it is, as favored by the researchers?
approximate number of animals to be used (section 2.31 (e)(1) of the Animal Welfare Act regulations) 1 . Because the Public Health Service Policy on Humane Care and Use of Laboratory Animals2 requires compliance with the Animal Welfare Act regulations, investigators must identify for the IACUC all vertebrate species to be used in the protocol—not only those species covered by the Animal Welfare Act—and the approximate n umber of each species to be used. For the purposes of IACUC oversight and e valuation of p roposed and ongoing animal use, n either r egulatory d ocument requires the p rovision of information beyond species identification.
I would not advocate for listing specific strains and numbers of animals requested by strain on the IACUC animal protocol form. In my opinion, too often institutions try to use the IACUC animal care and use protocol application to fulfill institutional responsibilities beyond that of informing the IACUC’s decisions. A well-coordinated institutional animal program should have systems and processes that proactively prevent the ordering of more animals than is approved by the IACUC or that i dentify noncompliance if more animals were ordered than were approved by the IACUC. The approved IACUC protocol can be a source document to inform those systems
Volume 43, No. 1 | JANUARY 2014 13
1. Animal Welfare Act and Regulations. 9 CFR, Chapter 1, Subchapter A. 2. Public Health Service. Policy on Humane Care and Use of Laboratory Animals (US Department of Health and Human Services (US Department of Health and Human Services, Washington, DC, 1986; amended 2002).
npg
© 2014 Nature America, Inc. All rights reserved.
protocol review
and processes, but it alone should not be relied upon to serve this need. Appropriate strain choice is as important as appropriate species choice from the s tandpoint of scientific integrity and ethics: one must always match the model to the s cientific question being posed. Determination of appropriate strain choice to best fit the science is most effectively left to the investigator and the veterinary consultant involved in the preparation of a protocol for the IACUC’s review ( section 2.31 (d)(1)(B)) 1 . The development of specialized strains of research animals into more refined disease models has had effects on animal welfare, some predicted and some unintended. Investigators, research animal veterinarians and animal care technicians have had to increase their knowledge of strain-specific c linical effects in order to optimally monitor the health status of the animals and to intervene in order to prevent unnecessary pain and distress. Strengthening this aspect of the pre-submission veterinary consultation would be a more efficient use of institutional programmatic resources. The IACUC in turn must be p rovided rotocol sufficient information in the animal p about the known and possible health effects of an investigator’s p referred mouse strain, and the endpoints for which staff must monitor, to fulfill its role in a ssessing whether animal pain and distress will be minimized and appropriately mitigated. The IACUC also can provide an objective opinion when the v eterinarian and the investigator cannot agree upon a specific strain during the review of the p rotocol itself. Protocols as documents serve a specific purpose, as different from monthly billing invoices and weekly animal censuses as they are different from grant applications. I would caution institutional management personnel to think carefully about r elying too heavily on the IACUC protocol as the sole document upon which the entire animal program pivots. 1. Animal Welfare Act and Regulations. 9 CFR, Chapter 1, Subchapter A. 2. Public Health Service. Policy on Humane Care and Use of Laboratory Animals (US Department of Health and Human Services (US Department of Health and Human Services, Washington, DC, 1986; amended 2002). McEntee is IACUC Administrator, University of Wisconsin-Madison, Madison, WI.
14 Volume 43, No. 1 | JANUARY 2014
Response Change to ensure compliance Thea McCready, BA
I agree with the statement that “noncompliance is n oncompliance,” which is why I feel that Great Eastern University’s IACUC should change the protocol form to list animal strains instead of species alone. Noncompliance is a serious offense and should be avoided at all costs. Although the change may be perceived as extraneous work by the researchers now, it could help to ensure that investigators maintain protocol oncompliance may compliance. Protocol n still occur, but it is within the IACUC’s purview to put in place a method to safeguard investigators by minimizing the potential for noncompliance. By s pecifying animal strains and strain numbers, researchers will give the IACUC the i nformation it needs to conduct a thorough review of proposed activities. The provision of this information also allows less opportunity for errors in procurement and animal use, thus lessening the chances for inadvertent noncompliance. The Animal Welfare Act regulations 1 (AWARs, §2.31.e.1; §2.31.e.2), the Public Health Service Policy on Humane Care and Use of Laboratory Animals2 (IV.D.1.b) and the Guide for the Care and Use of Laboratory Animals3 (the Guide) state that IACUC proposals should include a r ationale for involving animals, i dentification of the a nimal species involved and its appropriateness for the proposed use and the approximate number of animals to be used. Additionally, §2.31.e.3 of the AWARs1 requires that IACUC proposals include “a complete description of the proposed use of the animals.” Although the regulations do not specifically state that the IACUC must review and approve the use of a p articular strain, these provisions implicitly require investigators to fully address their animal construct as it relates to the proposed experimental design. The Guide 3 states that “while the responsibility for scientific merit review n ormally lies outside the IACUC, the c ommittee members should e valuate scientific elements of the protocol as they
relate to the welfare and use of the animals.” Phenotypic assessment is n ecessar y because it directly relates to the research o utcomes and must be s cientifically justified. Particularly, strain variances can pose the potential for genetically based developmental problems or leave an animal more susceptible to disease. Use of strains with these sorts of characteristics requires an outlined plan for addressing the potential pain and distress that might result from the phenotypic features. Researchers should consult the l iterature available for assistance in selecting the a ppropriate animal species and strain, as well as the appropriate c ontrol animals. Initial s election of an incorrect strain for the desired research can result in the unnecessary or inappropriate use of animals; therefore, it is critical for the IACUC to assess the proposed phenotype. Inclusion of the animal strain is a requirement for Department of Defense p roposals, as outlined in its Standard Animal Use Protocol Format 4 , and its p resence as part of the protocol form positively contributes to the concept of best practices within an animal care and use program. IACUCs that strive to be proactive rather than reactive should s eriously consider the potential benefits of including strain and number specifications as part of the protocol form. 1. Animal Welfare Act and Regulations. 9 CFR, Chapter 1, Subchapter A. 2. Public Health Service. Policy on Humane Care and Use of Laboratory Animals (US Department of Health and Human Services, Washington, DC, 1986; amended 2002). 3. Institute for Laboratory Animal Research. Guide for the Care and Use of Laboratory Animals 8th edn. (National Academies Press, Washington, DC, 2011). 4. Department of Defense. Instruction 3216.01. Use of Animals in DoD Programs. (Department of Defense, Washington, DC, 2010). McCready is IACUC Administrator, Armed Forces Radiobiology Research Institute, Bethesda, MD.
Response When strain matters Bill Moseley, MA, CPIA & Elaine Kim, BS
Great Eastern’s IACUC administrator is clearly a professional interested in assisting the IACUC in fulfilling its regulatory www.labanimal.com
