protocol review Jerald Silverman, DVM, Column Coordinator
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© 2014 Nature America, Inc. All rights reserved.
Remote monitoring is high-tech, but is it humane? Dr. John Hodges believed he had the ultimate animal monitoring system for his research. Using a commercially available blood glucose sensor that was surgically implanted into a rat’s artery, he was able to monitor and record the rat’s blood g lucose concentration, a ctivity and body t emperature via telemetry for three weeks. The rat was placed on a platform that acted as electrocardiogram (ECG) electrodes so that he could measure the animal’s heart rate and ECG. A remotely controlled i nfusion pump allowed him to provide specific amounts of subcutaneously administered insulin, and a small camera took a picture of the rat every 60 seconds. Although the s ystem was already quite sophisticated, Hodges took his methodology to an even higher level by adapting the entire system to interface with his smart phone, allowing him to monitor and infuse his animals from home or any other location. Hodges knew that his system worked because he had developed and tested it at
Response Reconsider, communicate, collaborate Lois Zitzow, MS, DVM, DACLAM & George Langan, DVM, DACLAM
According to the Guide for the Care and Use of Laboratory Animals, the IACUC should carefully consider two types of endpoints during protocol review: the e xperimental endpoint, which occurs when the scientific aims and objectives have been reached, and the humane endpoint, which occurs when pain or distress in an e xperimental a nimal is prevented, t erminated or relieved 1 . In this scenario, Hodges has developed and v alidated a sophisticated m onitoring system for his research study that will allow him to monitor and track changes in a number of physiologic parameters remotely. LAB ANIMAL
his former institution with IACUC approval and an in-house grant. Now, at Great Eastern University, his goal was to m onitor rats’ blood glucose, activity, food intake and ECG response to dietary manipulations and new drugs being developed to treat type 2 diabetes. The Great Eastern IACUC was supportive of the study’s scientific goals but questioned aspects of the methods to be used. Hodges’ protocol clearly stated how critical it was to have close and f requent monitoring of his animals during the first 48 hours of their treatment with a new antidiabetic drug. After regular work hours, Hodges p roposed to continue to m onitor the animals once an hour from home. From there, he could provide insulin in the event that a rat e xperienced h yperglycemia (high blood sugar). However, the IACUC was equally concerned about h ypoglycemia (low blood sugar) and other acute problems such as rapid or slow heart rate, cardiac a rrhythmia or very high or low body
t emperature that might occur during the first 48 hours. Hodges responded that any animal that developed arrhythmia, severe hypoglycemia or an excessively high or low body temperature would be excluded from the study. This response did not satisfy the IACUC as it appeared to the committee that exclusion from the study, as proposed by Hodges, was not a humane endpoint and could result in unnecessary animal suffering until Hodges euthanized or p rovided treatment to the affected rats. Hodges ran a one-man operation; he was a young assistant professor with no laboratory support staff and very limited funds. Should the IACUC reconsider its position and allow Hodges to continue his study, or should it hold its ground? Should Hodges simply forget his elaborate at-home monitoring mechanism and remain with his animals, making observations every hour, for 48 hours? Is there a reasonable way to resolve this problem?
Most of this monitoring appears to have been designed to assure that his animals can reach the e xperimental e ndpoint. However, the monitoring plan described in his protocol does not take advantage of data that could be used to determine early euthanasia criteria, such as the rats’ appearance in the images he is collecting. In addition, by indicating that animals with severe hypoglycemia or excessively high or low body temperature would simply be excluded from the study rather than treated or humanely euthanized, Hodges has failed to identify humane endpoints. The IACUC seems to be asking Hodges to define humane endpoints on the basis of abnormalities in the physiologic data, even if some of these abnormalities do not always indicate pain or distress. For e xample, bradycardia, tachycardia and cardiac arrhythmia can be benign or clinically insignificant, and mild or moderate hypoglycemia is often subclinical. Taken by themselves, these
parameters might not be indicators that an animal requires treatment or has reached a humane endpoint. The IACUC should reconsider this study. Hodges does not seem to understand the difference between humane and e xperimental endpoints, why they are important and how they relate to the study. The IACUC should take this opportunity to educate him about these concepts. In addition, the IACUC, the v eterinarians and Hodges should work together to assess the types of data being collected, determine which data are clinically relevant and d evelop better humane endpoints. The IACUC should also encourage the use of the remote monitoring system because it will enable more aggressive monitoring, thus addressing the animal welfare concerns, while allowing the i nvestigator to conduct this work with limited staff and funds. This is especially important in today’s funding climate. Furthermore, the
Volume 43, No. 11 | november 2014 391
protocol review
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© 2014 Nature America, Inc. All rights reserved.
IACUC should consider asking Hodges to carry out a pilot study, with veterinary oversight, to test the monitoring system and to allow the IACUC to review how he is addressing any welfare issues. The review of the pilot study data by the team (IACUC, v eterinarians and researcher) should allow for the d evelopment of a m onitoring s trategy that allows the e xperiment to be carried out while ensuring that the rats’ welfare is protected. Once the study is approved, periodic monitoring of the research records by the IACUC will provide continued assurance that the welfare needs of the animals are being addressed. 1. Institute for Laboratory Animal Research. Guide for the Care and Use of Laboratory Animals 8th edn. (National Academies Press, Washington, DC, 2011). Zitzow is Veterinarian, Animal Resources Center, and Associate Professor, Department of Surgery, and Langan is Attending Veterinarian and Director, Animal Resources Center, and Associate Professor, Department of Surgery at The University of Chicago, Chicago, IL.
Response Clarity for humane intervention points Michael W. Brunt, MSc, RMLAT, CMAR
Efficient and clear communication is of p articular importance when p rincipal i nvestigators, attending v eterinarians (AVs) and IACUCs are d etermining humane intervention points and adequate m onitoring procedures for animals p articipating in research protocols. Hodges’ elaborate remote monitoring and drug-delivery mechanism was shown to be effective through v alidation at his previous institution. But an action plan for u nexpected events that might occur during the monitoring period has not been adequately defined. The AV would be the ideal person to develop this action plan in c ollaboration with Hodges. The Guide for the Care and Use of Laboratory Animals1 states, “The p rimary focus of the veterinarian is to oversee the well-being and clinical care of animals used in research, testing, teaching, and production. This responsibility extends 392 Volume 43, No. 11 | november 2014
to monitoring and promoting animal well-being at all times during animal use and during all phases of the animal’s life.” In this situation, d efinition of humane intervention points will be critical. Once specific clinical risks are identified (e.g., high or low blood glucose concentrations, high or low heart rate, etc.), limits must be set to determine when e uthanasia will be required. If Hodges plans to use remote monitoring systems, then he should be expected to return to the facility i mmediately to treat or e uthanize any a nimals reaching these humane i ntervention points. Hodges’ “one-man operation” may not be appropriate for extended m onitoring periods. The IACUC, the AV and Hodges should identify the adverse events that are most likely to be seen, the experimental time points at which they are likely to be seen and the level of pain or distress expected to result from these. This information may be available from p revious studies, enabling Hodges to carry out a risk assessment to determine an a ppropriate monitoring interval that will allow early detection and prompt resolution of the majority of adverse events. If the information is unknown, then Hodges should carry out a pilot study to identify the most critical time period for animal monitoring, as well as the incidence and severity of adverse events. Once a plan has been approved by the IACUC, postapproval monitoring should be i mplemented in the early stages of study execution, and the observations of this monitoring should be used to determine whether adjustments should be made to the monitoring protocol to ensure that a nimals are not experiencing unnecessary pain or distress. This should be a c ollaborative effort between the IACUC, the AV and the investigator. Although Hodges’ monitoring device represents a refinement to one aspect of postsurgical monitoring, the IACUC’s concerns surrounding humane i ntervention points are also valid. This scenario represents on opportunity for Hodges and the IACUC to work together to improve animal wellbeing and build trust within the Great Eastern University community. A collegial, cooperative and consultative approach is needed in this situation to exploit the benefits of Hodges’ monitoring procedures and alleviate the concerns of the IACUC.
1. Institute for Laboratory Animal Research. Guide for the Care and Use of Laboratory Animals 8th edn. (National Academies Press, Washington, DC, 2011). Brunt is a Campus Animal Facilities Project Manager, University of Guelph, ON, Canada.
Response Proceed, but cautiously Jo Ann Henry, LATG, CPIA, Gordon Roble, DVM, DACLAM & Jaclyn Steinbach, BVetMed (Hons) MRCVS
Members of an IACUC are generally f amiliar with reviewing protocols that test new technologies such as surgical i nstruments and implants. For s tudies involving untested devices, IACUCs will typically require intensive m onitoring and early endpoints to minimize any potential pain or distress experienced by the a nimals used. Novel monitoring equipment and technologies used to assess at-risk a nimals warrant additional caution during IACUC review. Hodges is on a t echnological cutting edge by proposing use of i ndwelling c annulas, electrodes and a camera to monitor and infuse his d iabetic rats remotely using a smart phone. Although this is a laudable goal, the study design does not address certain factors that need to be considered by the IACUC. The Guide for the Care and Use of Laboratory Animals1 states that the IACUC should evaluate the criteria and process for timely intervention during the protocol review process. Monitoring procedures and humane endpoints should be based on the specific parameters of the individual p rotocol. If Hodges or other appropriate personnel, such as animal care staff or other technical staff, can respond to adverse events or other developments within a reasonable time-frame, then off-site monitoring may be f easible. But without the ability to intervene as necessary, monitoring alone will accomplish nothing. Removing animals from the study does not adequately resolve welfare concerns. If Hodges means removal from the study to include euthanasia, then the capability for remotely initiating appropriate euthanasia should be considered. www.labanimal.com
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© 2014 Nature America, Inc. All rights reserved.
Remote monitoring is high-tech, but is it humane? Dr. John Hodges believed he had the ultimate animal monitoring system for his research. Using a commercially available blood glucose sensor that was surgically implanted into a rat’s artery, he was able to monitor and record the rat’s blood g lucose concentration, a ctivity and body t emperature via telemetry for three weeks. The rat was placed on a platform that acted as electrocardiogram (ECG) electrodes so that he could measure the animal’s heart rate and ECG. A remotely controlled i nfusion pump allowed him to provide specific amounts of subcutaneously administered insulin, and a small camera took a picture of the rat every 60 seconds. Although the s ystem was already quite sophisticated, Hodges took his methodology to an even higher level by adapting the entire system to interface with his smart phone, allowing him to monitor and infuse his animals from home or any other location. Hodges knew that his system worked because he had developed and tested it at
Response Reconsider, communicate, collaborate Lois Zitzow, MS, DVM, DACLAM & George Langan, DVM, DACLAM
According to the Guide for the Care and Use of Laboratory Animals, the IACUC should carefully consider two types of endpoints during protocol review: the e xperimental endpoint, which occurs when the scientific aims and objectives have been reached, and the humane endpoint, which occurs when pain or distress in an e xperimental a nimal is prevented, t erminated or relieved 1 . In this scenario, Hodges has developed and v alidated a sophisticated m onitoring system for his research study that will allow him to monitor and track changes in a number of physiologic parameters remotely. LAB ANIMAL
his former institution with IACUC approval and an in-house grant. Now, at Great Eastern University, his goal was to m onitor rats’ blood glucose, activity, food intake and ECG response to dietary manipulations and new drugs being developed to treat type 2 diabetes. The Great Eastern IACUC was supportive of the study’s scientific goals but questioned aspects of the methods to be used. Hodges’ protocol clearly stated how critical it was to have close and f requent monitoring of his animals during the first 48 hours of their treatment with a new antidiabetic drug. After regular work hours, Hodges p roposed to continue to m onitor the animals once an hour from home. From there, he could provide insulin in the event that a rat e xperienced h yperglycemia (high blood sugar). However, the IACUC was equally concerned about h ypoglycemia (low blood sugar) and other acute problems such as rapid or slow heart rate, cardiac a rrhythmia or very high or low body
t emperature that might occur during the first 48 hours. Hodges responded that any animal that developed arrhythmia, severe hypoglycemia or an excessively high or low body temperature would be excluded from the study. This response did not satisfy the IACUC as it appeared to the committee that exclusion from the study, as proposed by Hodges, was not a humane endpoint and could result in unnecessary animal suffering until Hodges euthanized or p rovided treatment to the affected rats. Hodges ran a one-man operation; he was a young assistant professor with no laboratory support staff and very limited funds. Should the IACUC reconsider its position and allow Hodges to continue his study, or should it hold its ground? Should Hodges simply forget his elaborate at-home monitoring mechanism and remain with his animals, making observations every hour, for 48 hours? Is there a reasonable way to resolve this problem?
Most of this monitoring appears to have been designed to assure that his animals can reach the e xperimental e ndpoint. However, the monitoring plan described in his protocol does not take advantage of data that could be used to determine early euthanasia criteria, such as the rats’ appearance in the images he is collecting. In addition, by indicating that animals with severe hypoglycemia or excessively high or low body temperature would simply be excluded from the study rather than treated or humanely euthanized, Hodges has failed to identify humane endpoints. The IACUC seems to be asking Hodges to define humane endpoints on the basis of abnormalities in the physiologic data, even if some of these abnormalities do not always indicate pain or distress. For e xample, bradycardia, tachycardia and cardiac arrhythmia can be benign or clinically insignificant, and mild or moderate hypoglycemia is often subclinical. Taken by themselves, these
parameters might not be indicators that an animal requires treatment or has reached a humane endpoint. The IACUC should reconsider this study. Hodges does not seem to understand the difference between humane and e xperimental endpoints, why they are important and how they relate to the study. The IACUC should take this opportunity to educate him about these concepts. In addition, the IACUC, the v eterinarians and Hodges should work together to assess the types of data being collected, determine which data are clinically relevant and d evelop better humane endpoints. The IACUC should also encourage the use of the remote monitoring system because it will enable more aggressive monitoring, thus addressing the animal welfare concerns, while allowing the i nvestigator to conduct this work with limited staff and funds. This is especially important in today’s funding climate. Furthermore, the
Volume 43, No. 11 | november 2014 391
protocol review
npg
© 2014 Nature America, Inc. All rights reserved.
IACUC should consider asking Hodges to carry out a pilot study, with veterinary oversight, to test the monitoring system and to allow the IACUC to review how he is addressing any welfare issues. The review of the pilot study data by the team (IACUC, v eterinarians and researcher) should allow for the d evelopment of a m onitoring s trategy that allows the e xperiment to be carried out while ensuring that the rats’ welfare is protected. Once the study is approved, periodic monitoring of the research records by the IACUC will provide continued assurance that the welfare needs of the animals are being addressed. 1. Institute for Laboratory Animal Research. Guide for the Care and Use of Laboratory Animals 8th edn. (National Academies Press, Washington, DC, 2011). Zitzow is Veterinarian, Animal Resources Center, and Associate Professor, Department of Surgery, and Langan is Attending Veterinarian and Director, Animal Resources Center, and Associate Professor, Department of Surgery at The University of Chicago, Chicago, IL.
Response Clarity for humane intervention points Michael W. Brunt, MSc, RMLAT, CMAR
Efficient and clear communication is of p articular importance when p rincipal i nvestigators, attending v eterinarians (AVs) and IACUCs are d etermining humane intervention points and adequate m onitoring procedures for animals p articipating in research protocols. Hodges’ elaborate remote monitoring and drug-delivery mechanism was shown to be effective through v alidation at his previous institution. But an action plan for u nexpected events that might occur during the monitoring period has not been adequately defined. The AV would be the ideal person to develop this action plan in c ollaboration with Hodges. The Guide for the Care and Use of Laboratory Animals1 states, “The p rimary focus of the veterinarian is to oversee the well-being and clinical care of animals used in research, testing, teaching, and production. This responsibility extends 392 Volume 43, No. 11 | november 2014
to monitoring and promoting animal well-being at all times during animal use and during all phases of the animal’s life.” In this situation, d efinition of humane intervention points will be critical. Once specific clinical risks are identified (e.g., high or low blood glucose concentrations, high or low heart rate, etc.), limits must be set to determine when e uthanasia will be required. If Hodges plans to use remote monitoring systems, then he should be expected to return to the facility i mmediately to treat or e uthanize any a nimals reaching these humane i ntervention points. Hodges’ “one-man operation” may not be appropriate for extended m onitoring periods. The IACUC, the AV and Hodges should identify the adverse events that are most likely to be seen, the experimental time points at which they are likely to be seen and the level of pain or distress expected to result from these. This information may be available from p revious studies, enabling Hodges to carry out a risk assessment to determine an a ppropriate monitoring interval that will allow early detection and prompt resolution of the majority of adverse events. If the information is unknown, then Hodges should carry out a pilot study to identify the most critical time period for animal monitoring, as well as the incidence and severity of adverse events. Once a plan has been approved by the IACUC, postapproval monitoring should be i mplemented in the early stages of study execution, and the observations of this monitoring should be used to determine whether adjustments should be made to the monitoring protocol to ensure that a nimals are not experiencing unnecessary pain or distress. This should be a c ollaborative effort between the IACUC, the AV and the investigator. Although Hodges’ monitoring device represents a refinement to one aspect of postsurgical monitoring, the IACUC’s concerns surrounding humane i ntervention points are also valid. This scenario represents on opportunity for Hodges and the IACUC to work together to improve animal wellbeing and build trust within the Great Eastern University community. A collegial, cooperative and consultative approach is needed in this situation to exploit the benefits of Hodges’ monitoring procedures and alleviate the concerns of the IACUC.
1. Institute for Laboratory Animal Research. Guide for the Care and Use of Laboratory Animals 8th edn. (National Academies Press, Washington, DC, 2011). Brunt is a Campus Animal Facilities Project Manager, University of Guelph, ON, Canada.
Response Proceed, but cautiously Jo Ann Henry, LATG, CPIA, Gordon Roble, DVM, DACLAM & Jaclyn Steinbach, BVetMed (Hons) MRCVS
Members of an IACUC are generally f amiliar with reviewing protocols that test new technologies such as surgical i nstruments and implants. For s tudies involving untested devices, IACUCs will typically require intensive m onitoring and early endpoints to minimize any potential pain or distress experienced by the a nimals used. Novel monitoring equipment and technologies used to assess at-risk a nimals warrant additional caution during IACUC review. Hodges is on a t echnological cutting edge by proposing use of i ndwelling c annulas, electrodes and a camera to monitor and infuse his d iabetic rats remotely using a smart phone. Although this is a laudable goal, the study design does not address certain factors that need to be considered by the IACUC. The Guide for the Care and Use of Laboratory Animals1 states that the IACUC should evaluate the criteria and process for timely intervention during the protocol review process. Monitoring procedures and humane endpoints should be based on the specific parameters of the individual p rotocol. If Hodges or other appropriate personnel, such as animal care staff or other technical staff, can respond to adverse events or other developments within a reasonable time-frame, then off-site monitoring may be f easible. But without the ability to intervene as necessary, monitoring alone will accomplish nothing. Removing animals from the study does not adequately resolve welfare concerns. If Hodges means removal from the study to include euthanasia, then the capability for remotely initiating appropriate euthanasia should be considered. www.labanimal.com
