Grants and Funding
Office of Laboratory Animal Welfare
Protocol Review
Jerald Silverman, DVM, Column Coordinator

Lab Animal 32(9), 2003

A Mouse Isn't a Rat, But What's the Big Deal?

Suspending an IACUC-approved animal use activity is about the last thing a research institution wants to do. Consider the predicament that the Great Eastern University IACUC faced when Dr. Janet Jenkins, the Attending Veterinarian (AV), suspended all animal use activity on an approved protocol of Dr. Roy Maslo.

Jenkins had the IACUC's authority to suspend a protocol temporarily, subject to review by a quorum of the full Committee. She alleged that Maslo used mice from his breeding colony, not purchased rats, to begin a new study. Jenkins saw Maslo's technicians bringing mouse cages to a procedure room and preparing for a minor survival surgery. She asked them to wait until she clarified things, because she felt confident that the protocol called for rats. She called Maslo and asked him if the study had been approved for mice, to which he responded affirmatively. Still not feeling quite assured, she went to her office, reviewed the protocol, and found only rat studies described. She also called the IACUC office to see if there were any approved amendments that she may not have received, and was told that there were none. By the time she returned, one procedure had been completed. Understandably upset, she informed the technicians and Maslo that any further activity on the protocol was suspended until the issue was resolved. Jenkins informed the IACUC Chair, who in turned called an emergency meeting of the Committee.

When Maslo addressed the Committee, he readily admitted that an error had been made, but said he truly thought that mice were the approved species. In fact, he pointed out that he had initially written on his protocol that either mice or rats would be used, but the Committee requested that he choose the most appropriate species. He chose rats because he thought the surgery might be slightly easier to perform on a larger animal. However, when the time came to begin, he simply forgot about the rats and told his technicians to work with the mice because most of his other research involved mice and his technicians were skilled in mouse surgery. After he left the room, the Committee deliberated and determined that, overall, no significant harm had been done. The research was still valid, the surgery went well, all the correct drugs and surgical procedures were used, and Maslo had apologized for the oversight. The Committee voted to rescind Jenkins's temporary suspension and allow Maslo's study to continue. He was told to submit an amendment immediately, changing the species of animal to be used, and otherwise to modify the protocol to accommodate the use of mice. Because timing was not critical for the research, Maslo agreed to all conditions and demands.

Dr. Lawrence Schiller, the Institutional Official (IO) and Vice President for Research, was informed of the IACUC's decision. It was not clear whether he was unhappy with the decision, Maslo, or both, but he informed the IACUC that there were too many loose ends and he was taking it upon himself to uphold the suspension until it was made clear to him why Maslo's technicians were apparently unaware of the information in the approved protocol, why Maslo did not check the protocol himself after Jenkins raised a warning flag, and why the procedure had progressed contrary to the instructions of Jenkins. The IACUC Chair was in a quandary. First, he was not sure whether Schiller had the authority to overrule the Committee's vote. Next, if Maslo was now suspended, did he have to notify OLAW, because none of the suspensions emanated from an approved action of the IACUC? Finally, the IACUC, unlike Schiller, did not consider this a major infraction worthy of reporting to OLAW, independent of the suspension question.

Could Schiller suspend Maslo's study when the IACUC had voted otherwise? Did the IACUC have to inform OLAW?


Lighten Up!

Craig W. Stevens, PhD

It sounds as if Maslo made an honest mistake and forgot which common rodent species he was actually approved to use. He clearly wanted the protocol to give him the flexibility to use both rats and mice, but for some reason, perhaps involving an overzealous IACUC or an ultraconservative Chair, the IACUC did not want two species approved for the same protocol. Perhaps Maslo needed to save some research dollars and thus used mice that were freely available from the breeding colony instead of high-priced designer rats ordered from commercial suppliers. Whatever the reason, a rat is not a mouse, but it is not as if he mistook a monkey for a guinea pig. No harm, no foul.

The scenario shows that the tracking of animal use at Great Eastern functioned extremely well. Jenkins should be commended for her perspicuity and attention to detail. As usual, she is always in the right place at the right time. The technicians may be expected to know what they are doing but are usually directed by the Principal Investigator (PI) and may not be aware of the details of the approved protocol. Any acts of ignorance by a research technician are ultimately the PI's responsibility. In this case, the IACUC felt that Maslo was sincere and made an honest mistake, acknowledging his responsibility and exonerating the technicians at the same time. The real problem lies with Schiller. As is often the case with administrators far from the reaches of reality, Schiller makes much ado about nothing. He clearly has no clue about the rigors of biomedical research using animals and does not appear particularly supportive of Maslo's efforts. The Public Health Service Policy on Humane Care and Use of Laboratory Animals (PHS Policy ) states, “The IACUC, through the Institutional Official, shall promptly provide OLAW with a full explanation of the circumstances and actions taken with respect to: (a) any serious or continuing noncompliance with this Policy ; (b) any serious deviation from the provisions of the Guide or (c) any suspension of an activity by the IACUC 1.” This wording makes clear that any reporting of suspended activity begins with the IACUC and that the IACUC must initiate the suspension. At Great Eastern, the IACUC did not suspend the activity, so there is no mandate to report to the OLAW. Schiller should lighten up and let the research proceed.

REFERENCE

1. Public Health Service. Policy on Humane Care and Use of Laboratory Animals IV.F.3 (US Department of Health and Human Services, Washington, DC, 1986).

Stevens is Professor of Pharmacology, OSU-Center for Health Sciences, College of Osteopathic Medicine, Tulsa, OK.


Inappropriate IO Action

James Cox, BS, MLAS, RLATG and Lisa Portnoy, DVM, DACLAM

The situation that Jenkins and the Great Eastern IACUC confronted about Maslo's protocol is not all that uncommon. Many of us can recall a time when the lab technicians and even the PIs don't remember or don't even know what is exactly on each protocol. Nevertheless, it is important for the IACUC and the AV to ensure that the research is conducted according to the protocol as submitted.

Jenkins was justified in temporarily suspending the protocol. She had the IACUC's authority, and the technicians did not heed her request to wait until she verified the species listed in the protocol. The IACUC was also justified in rescinding the temporary suspension in light of the facts presented at the emergency meeting. Maslo admitted to the error, the procedure was done correctly, animals did not suffer and were not wasted, and the research was still valid. As long as an amendment would be submitted to add mice to the protocol, the suspension should be rescinded. The IACUC should have also instructed Maslo that his technicians should be aware of the protocols on which they are working and listen to instructions given by the AV about the use of laboratory animals. Since the suspension was not enforced by the IACUC, they are not required to inform OLAW, at this point.

The larger problem with this scenario comes from the decision made by the IO. It is not appropriate for the IO to overturn a decision by the IACUC. The IO, through the authority of the CEO, has appointed the members of the IACUC to serve as an agent of the institution 1. The reason for the Committee's existence is to provide a group of knowledgeable individuals, not a single person, who can make the appropriate decisions about the use of laboratory animals in research for the institution. If the IO was not happy with Maslo and the ignorance of his technicians, then he should have addressed it with Maslo and his department chair.

The only scenario in which it would have been appropriate for the IO to override the decision of the IACUC would be if this had not been Maslo's first offense. If Maslo had committed similar offenses and the IACUC failed to take action, then the IO would be correct in overriding the IACUC, but he would also need to address the IACUC on how they handle investigators who are consistent violators of policies covering the use of animals in research.

For this scenario though, the IO should not have upheld the suspension after the IACUC had made their decision. The IACUC is not responsible for informing OLAW, because the suspension was not instituted or enforced by the IACUC. In the future, the IACUC should place an assurance statement on the protocol form indicating that all individuals listed on the protocol have read and understand the procedures described for each species.

REFERENCE

1. Public Health Service. Policy on Humane Care and Use of Laboratory Animals IV.F.3 (US Department of Health and Human Services, Washington, DC, 1986).

Cox is Assistant Director, Division of Comparative Medicine and Portnoy is Interim Co-Director and Chief of Veterinary Medical Services, Division of Comparative Medicine, Georgetown University, Washington, DC.


A Question of Authority

Earl W. Morgan, DVM, DACVPM, DABT

This situation raises a number of issues regarding authority. Clearly Jenkins, as the AV, has the authority to suspend research projects for animal welfare reasons, and we are told that the Great Eastern IACUC has granted her the authority to suspend a protocol pending review by a quorum of the full Committee.

However, did Schiller have the authority to suspend the research after the IACUC had approved continued research pending the prompt submission of an amendment changing the species from rats to mice? The PHS Policy states, “Applications and proposals that have been approved by the IACUC may be subjected to further appropriate review and approval by officials of the institution. However, those officials may not approve an activity involving the care and use of animals if it has not been approved by the IACUC 1”, whereas the Animal Welfare Act Regulations (AWAR) state that the IO “may subject protocols that have been approved by the IACUC to further review and approval, but may not approve an activity that has not been approved by the IACUC 2 .” Thus in both his roles, as Great Eastern's Vice President for Research and as the IO, Schiller has authority to review and approve or withhold approval, in this case suspend, research projects. He could not overrule the IACUC and approve a protocol that they had rejected, but he can, as he has in this case, suspend a project for further review of the issues raised.

Although I can certainly agree with the Committee's desire to work with the investigator to resolve problems and allow the investigator to continue research, I agree with the IO that there are many unresolved issues in this case. Because the meeting involved the potential suspension of a protocol, I would have invited the IO to attend the meeting. This probably would have eliminated the problem of Schiller countering the IACUC. Jenkins had full authority to suspend the research temporarily. The technicians should not have continued with the surgery until after the meeting resolved the issue. The technicians were not aware of what rodent species was on the protocol. This makes me wonder how many other protocol issues on this and other projects escaped the awareness of the technicians. Additionally, it would appear that Maslo is directing the technicians without following the protocol.

The US Government Principles for the Utilization and Care of Vertebrate Animals requires that animals be of the appropriate species 3, and the Guide for the Care and Use of Laboratory Animals lists the key items of a protocol to include justification of the species 4. The PHS Policy and AWAR require that IACUCs review and approve protocols, and that significant changes be reviewed and approved before being implemented.

Maslo had selected rats as the most appropriate species at the time that the protocol was approved. To use mice would require submitting an amendment request with justification to the IACUC. When Jenkins raised the issue of mice versus rats, the technicians should have stopped the procedure and Maslo should have reviewed his protocol. This was a fairly innocent error on the part of the investigator, in that he felt that either rats or mice were valid animal models for his work. That they were not using the approved species, even though Maslo was able to defend the research as still valid with mice, was a major infraction. Furthermore, that Maslo and his technicians continued the project without checking the protocol should also be considered a major infraction.

Finally, the IACUC Chair does not notify OLAW. PHS Policy requires the IO in consultation with the IACUC to review the reasons for suspension, take appropriate corrective action, and report that action with a full explanation to OLAW 5. I would consider the use of an unapproved species, compounded by continuing the work on that species after the temporary suspension by the AV, to be a major infraction and thus reportable.

REFERENCES

1. Public Health Service. Policy on Humane Care and Use of Laboratory Animals IV.C.8 (US Department of Health and Human Services, Washington, DC, 1986).
2. Animal Welfare Act Regulations, 9 CRF Ch. 1, Subchapter A. 2.31, d.8.
3. Interagency Research Animal Committee. U.S. Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research, and Training III (Office of Science and Technology Policy, Washington, DC, 1985).
4. Institute of Laboratory Animal Resources, National Research Council. Guide for the Care and Use of Laboratory Animals 10 (National Academy Press, Washington, DC, 1996).
5. Public Health Service. Policy on Humane Care and Use of Laboratory Animals IV.C.7 (US Department of Health and Human Services, Washington, DC, 1986).

Morgan is Chair, Institutional Animal Care and Use Committee, Pacific Northwest National Laboratory, Richland, WA.


A Word From OLAW and USDA

Although this scenario involves rats and mice only, this commentary was coordinated between the Office of Laboratory Animal Welfare (OLAW) and the United States Department of Agriculture, Animal and Plant Health Inspection Service, Animal Care (USDA/APHIS/AC) because some of the basic IACUC and IO authority comments would apply to both agencies if the scenario had involved a USDA-covered species. This commentary assumes that the research project in question was PHS-supported. Readers are cautioned that the issues involved in this analysis are highly context-specific and should not be overly generalized.

This scenario poses two central questions: does the IO have the authority to stop an activity that the IACUC has approved, and must the infraction be reported promptly to OLAW (and/or APHIS for USDA-covered species)?

In both cases, the answer is an unequivocal “yes”.

As pointed out by one of the reviewers, PHS Policy at IV,C,8 is explicit in recognizing the authority of officials at the institution to conduct further appropriate review of proposals that have been approved by the IACUC. 9 CFR Section 2.31(d)(8) containsalmost identical language for Animal Welfare Act enforcement purposes.

For PHS Policy purposes, it may be a matter of semantics as to the correctness of describing the IACUC or IO actions as suspensions if the activity in question was never approved in the first place. Some may view this as an unauthorized “significant change” from a previously approved protocol, while others may simply call it a new activity conducted without a protocol. Regardless of whether the action is labeled a suspension, the unapproved animal activity still constitutes serious noncompliance with the PHS Policy (IV.F.3) and, as such, requires prompt reporting to OLAW.

For APHIS purposes, 9 CFR Section 2.31(d)(7) requires the IO to report to APHIS any suspension of an animal activity initiated by the IACUC. Even though the suspension in this case was not conducted strictly according to regulatory requirements (which state that this can only be done at a convened meeting of a quorum of the IACUC), it apparently was done in accordance with the institution's decision to allow the AV to temporarily suspend a protocol, and therefore would have to be promptly reported to USDA and any Federal agency funding that activity.

OLAW has issued guidance that identifies a change of species as an example of a “significant change” requiring prior IACUC approval1,2. This is also consistent with the NIH Grants Policy Statement (Rev.03/01) that identifies the substitution of one animal model for another as an example of “change of scope” likely requiring prior NIH (Grants Management Officer) approval. The signature block on the face page of the PHS form 398 grant application requires the institution to declare that it meets and will maintain compliance with all applicable terms and conditions of award. Knowingly submitting false information in a federal grant application subjects the signers to civil or criminal penalties.

Notwithstanding the fact that the IACUC could have approved the use of more than one species in the original protocol, there is no question about the IACUC's intent regarding the limitation of its approval to rats. The PI acknowledged this limitation when he revised the protocol to exclude mice, and cannot subsequently claim a misunderstanding. The technicians' disregard for the veterinarian's instructions to wait for clarification may also indicate a culture of noncompliance within the lab. No amount of rationalization about lack of harm done can erase the fact that the PI knowingly violated the protocol. The IACUC's willingness to accept such behavior is shocking, given the potential consequences for the institution that include violations of PHS Policy , NIH Grants Policy (including possible disallowance of charges against the grant), and the federal False Claims Act (31 U.S.C. §§ 3729-3730).

Another matter for consideration is the publication of articles in scientific journals. Most scientific journals have editorial policies or require statements attesting to full compliance with applicable federal animal welfare laws and policies. The investigator in this scenario would not be able to make such a statement truthfully. To act dishonestly in this regard would risk public embarrassment to the PI and his institution, and could harm the integrity of the biomedical research enterprise.

REFERENCES

1. Potkay, S., Garnett, N.L., Miller, J.G., Pond, C.L. & Doyle, D.J. Frequently asked questions about the Public Health Service Policy on Humane Care and Use of Laboratory Animals. Lab Anim. (NY) 24 , 24-26 (1995).
2. USDA/APHIS/AC. Research Manual Part 18. http://www.aphis.usda.gov/ac/researchmanual/18-4PROC.PDF.

Nelson L. Garnett, DVM
Director, OLAW
National Institutes of Health

Chester A. Gipson, DVM
Deputy Administrator
USDA/APHIS/AC