Protocol Review - Lab Animal 28(7), 1999

Lab Animal 28(7), 1999

Who's to Blame?

Dr. Rozalind Becker, an established researcher at Great Eastern University, finished her grant proposal (for a study that used rabbits) just before the PHS deadline. Nevertheless, she still had 60 days to get her IACUC application reviewed and approved, and to have the approval letter reach the PHS. She quickly wrote the IACUC protocol and, indeed, the entire IACUC review and approval process was completed in time, including a modification eliminating the need for several redundant control groups.

All was well until, during a routine look at IACUC-approved protocols, the USDA inspector noticed that while Becker’s study was approved for one surgery, what the inspector had just seen in the animal facility clearly indicated Becker had performed a second surgery. The inspector questioned the Attending Veterinarian, who said that with so many protocols in use at the same time, his staff would probably not know if the IACUC had approved one or two survival surgical procedures. The inspector then asked to meet with Becker, who readily admitted to performing the second surgery.

Becker said that her grant stated clearly that a small subgroup would undergo a second surgery, but in her rush to complete the IACUC form, she had unintentionally omitted this information. She apologized, and promised to correct the oversight immediately. She also mentioned that, as per the standard committee procedure, she had attached her PHS application to the IACUC protocol form, and, had the IACUC chosen to examine it, they would have found the second surgery described and justified fully.

When Steve Crane, IACUC Chair, learned of the situation, he implied that the blame should fall on Becker, not the IACUC. The IACUC, he said, had done what it was supposed to with the information Becker provided. But, the USDA inspector replied that the IACUC could not shed its responsibility, since Becker had attached written documentation of a second major surgical procedure. Crane became a little concerned, and then worried when the inspector casually asked if Great Eastern remembered to notify the PHS about the approved modification to the protocol. Crane knew that it was not Great Eastern’s policy to do so—he had not realized that it was necessary, and did not know of any university that did. Still, he wondered if he and Great Eastern were in trouble.

Should Great Eastern have compared the grant application to Becker’s IACUC protocol? Is there any regulatory requirement to do so? When Great Eastern approved Becker’s IACUC protocol, should the university have informed the PHS of the modification? How would you approach the issues raised in this case study?

Fear and Trembling at Great Eastern University

Brent Swenson, DVM

It is, perhaps, significant and representative of contemporary priorities that the preeminent emphasis of this case study comprises paranoia rather than problem-solving. Kierkegaard would say, “I told you so.” Where else but in America-the-Hyperregulated would an apparent oversight generate such an impenetrable cincture of finger-pointing and denial of individual responsibility?

What really happened here? The investigator had inadvertently omitted a description of a second survival surgical procedure—apparently performed with adequate technique and post-operative care—from the document summarizing the study’s animal use procedures.

Who screwed up? Pretty much everybody and nobody. The PI was typically late providing the IACUC with documents to review, but she was otherwise unusually cooperative. The Attending Veterinarian was less than familiar with animal use activities in his facility. The IACUC relied excessively on the protocol form for its review of the proposed animal use procedures. The USDA inspector was doing what USDA inspectors do best: locating and magnifying technical deviations from the letter of regulations, irrespective of performance consequences.

In practice, there was no evidence that the incident was intentional or negligent, nor that animal welfare suffered, nor that the outcome would have differed if the protocol omission had not occurred.

But if mere technical compliance is to be our emphasis, it is necessary to note several points. The PI had provided all necessary information to the IACUC, and was in technical regulatory compliance (though probably not with institutional policy). The AV was technically responsible for ensuring adequate surgical and post-surgical care, not policing investigators. Since the investigator had provided the grant application to the IACUC along with the protocol form, it is arguable that the IACUC technically had approved the second surgical procedure, albeit unintentionally. Moreover, the IACUC had no responsibility to report protocol modifications to OPRR. Technically, the USDA inspector was accountable for identifying instances of noncompliance with regulations, not for evaluating their animal welfare consequences or prevalence. But do those sentiments represent regulatory intent? I doubt it.

Irrespective of technical correctness, all parties should be able to use the episode as an occasion to review their practices candidly. The veterinary and animal care staffs are “in the trenches,” and should be the first to notice potential problems. The PI is responsible for providing the IACUC with the information it needs to review animal use procedures in a form that is complete, concise, and understandable. The IACUC’s duty is to provide oversight of animal care and use procedures, whether or not information is easily accessible. The public intent of AWA regulations is to identify and correct preventable animal welfare concerns, not to catalogue technical violations.

USDA inspectors should be able to provide editorial commentary on the relevance of their findings, rather than simply inventorying them in a dispassionate manner. Of course, they would have to understand the relevance of their findings, which often requires a dialogue with institutional personnel. Dialogues don’t occur in an atmosphere of fear. Except when problems are clearly intentional, negligent, or persistent, the system ought to function to fix the problem, not the blame.

Swenson is affiliated with Veterinary Consulting and Clinical Services, Lilburn, GA.

Quit Pointing Fingers

Guy B. Mulder, DVM, MS and Clifford R. Roberts, DVM, Dipl. ACLAM

In the above scenario, both the IACUC and the investigator must share the blame for noncompliance. The inspector is correct in her assessment that the institution must ultimately bear responsibility, but the IACUC should have been aware of the subset of animals undergoing multiple surgeries, since it did have access to the grant proposal. Yet, while the IACUC should have reviewed the proposal for agreement with the animal use protocol in accordance with PHS Policy, it is not bound by actual regulation to compare the application with the IACUC protocol. Further, the PI has a responsibility to describe fully all animal procedures in an animal use protocol, and animals to undergo multiple survival surgeries particularly require full description and additional justification.

Great Eastern did have an obligation to notify PHS of any changes or modifications that would affect the grant application. Even changes made in compliance with the 3Rs—e.g., eliminating a “redundant control group”—should prompt notification of PHS. It’s possible that a scientific study section may not agree that the groups were redundant.

In the instructions for preparing a PHS grant application (PHS 398), Section 1(C) describes requirements for work involving vertebrate animals. The directions state clearly that “any modifications of the Research Plan section of the application, required by the IACUC, must be submitted with the follow-up verification.”

The directions are less clear, however, in delineating whose responsibility it is to notify the PHS of modifications. The directions go on to state that it is the responsibility of the principal investigator or the program director and the applicant organization to submit follow-up verification. In general, we suggest that the PI should notify the PHS of IACUC-required modifications when she notifies the agency of IACUC approval. In addition, the IACUC should have noticed the discrepancy between the grant application and the protocol, and should have reminded the PI that modifications to the protocol should be communicated to the funding agency.

Mulder is Senior Veterinarian, and Roberts the Director, of ULAR, University of California, Irvine.


A Word From OPRR and USDA

The problems outlined in the above scenario are not trivial from the standpoint of the federal overseers of animal welfare, nor according to NIH grants policy. Although the IACUC has missed several opportunities to prevent noncompliance, the institution is ultimately accountable for correcting, preventing, and reporting, as applicable.

One significant noncompliance issue is the fact that multiple major survival surgeries were conducted without the requisite IACUC approval. Both the AWA Regulations and the PHS Policy (by reference to the Guide for the Care and Use of Laboratory Animals) allow multiple major survival surgery only under special circumstances and with scientific justification.

A number of other PHS Policy and NIH grants policy issues are involved. The NIH scientific review group would have assumed, based on the verification of IACUC approval, that the IACUC had approved a specific scientific justification for the multiple surgeries. Also, because the IACUC approval was submitted after the grant application, the scientific review group would have assumed that any changes in the proposal (altered control groups) would have been forwarded to them as part of the delayed approval notification, as required by PHS Policy (IV, D, 2).

The 398 grant application form certifies, among other things, that the IACUC has (or will have within 60 days of the application) reviewed and approved all animal-related activities associated with that grant application. The signature of an authorized institutional official on the 398 indicates the organization’s intent to comply with the laws, regulations, and policies to which a grant is subject, including applicable public policy requirements. That official is also attesting to the fact that the information contained in the application is true and complete, and conforms with federal requirements and the organization’s own policies and requirements. The signature blocks for both the PI and the responsible institutional representative also make it very clear that there are potential civil and criminal penalties for submitting false statements or claims. However inadvertent, it is clear that the certification in this case was not true. Because the information was used as the basis for seeking a federal award, there are also more broad federal statutes that may apply to knowingly making “false claims” to the government.

Policy (IV, D, 1) also requires that all applications and proposals contain the “five points” described. Institutions are free to devise different mechanisms to accomplish these ends. One excellent way to prevent problems of inconsistency between the two, and to ensure that the “five points” are included, is to implement a procedure for direct comparison of the grant application with the protocol. In this scenario, such an institutional policy appears to have been in place but was not applied effectively.

Having recognized the problems, the institution has several obligations. The immediate priority is to avoid any further violations by ceasing the conduct of any additional multiple surgeries without prior IACUC approval and by instituting an effective mechanism to ensure that IACUC protocols are consistent with PHS applications. Further, the institution is required to notify OPRR promptly of any serious or continuing noncompliance with the PHS Policy, or any serious deviation from the provisions of the Guide. Any IACUC-suspended activity must be reported to both OPRR and USDA.

A thorough review of IACUC procedures and institutional sponsored projects office policies should take place. Reports to both the NIH program and grants administrators for the grant in question, as well as to OPRR, appear to be in order. Typically, such reports would include an identification of the noncompliance, the corrective actions taken, and any measures implemented to prevent recurrence.

Nelson Garnett, DVM, Director, Division of Animal Welfare, OPRR, NIH.
W. Ron DeHaven, DVM, acting deputy administrator, Animal Care, USDA/APHIS


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