|Policy & Guidance|
|Compliance & Oversight|
|Research Involving Human Subjects|
|Office of Laboratory Animal Welfare (OLAW)|
|Animals in Research|
|Peer Review Policies & Practices|
|Guidance for Reviewers|
|Intellectual Property Policy|
|Acknowledging NIH Funding|
|Invention Reporting (iEdison)|
|NIH Public Access|
|Lab Animal 35(2), 2006|
Dr. Harry Markowitz, an established cancer investigator at Great Eastern University, submitted a research grant to the National Institutes of Health (NIH). The NIH gave the grant a priority score of 130, which would probably result in the project being funded. Markowitz then submitted a protocol application to the IACUC. After deliberation the Committee requested a change in the number of animals to be approved, asking Markowitz to perform pilot studies to see if some of the proposed gene therapy experiments would actually be necessary. If the pilot studies showed any positive results he could then always amend his protocol to request more animals. Markowitz readily agreed to this condition. The Committee also requested some significant changes in the care of animals before and after the procedure in one of his planned experiments, to which Markowitz also agreed. Once all concerns were met, the IACUC approved the protocol.
Janis Hart was a graduate student in Markowitz’s laboratory. She and Markowitz never really ‘clicked’, and eventually Hart began to complain that Markowitz was harassing her. Perhaps there should have been a resolution to the problem at this point, but this did not happen, and eventually Hart contacted the Office of Laboratory Animal Welfare (OLAW) and the federal Office of Research Integrity (ORI), alleging scientific fraud (fabrication of data) and animal abuse. She provided what she considered to be adequate proof of both charges. Both federal organizations immediately contacted the appropriate officials at Great Eastern and requested an internal investigation. ORI and OLAW finally cleared Markowitz of the specific allegations, but secondary issues arose with OLAW. For example, according to Great Eastern’s own documentation, it was apparent that the IACUC’s letter of approval verification to OLAW did not include the IACUC’s approved changes to Markowitz’s protocol. Furthermore, the Great Eastern IACUC never compared the protocol application with the grant application, and there were animal studies in the grant that were not described in the IACUC protocol, and conversely, animal studies on the IACUC protocol that were not in the grant. OLAW asked for an explanation. Great Eastern responded that Markowitz decided not to perform some of the mouse studies described in the grant application, and thus he did not include them on the IACUC application. In their place he substituted related rat studies, which the IACUC reviewed in full. Neither Markowitz nor the IACUC considered these changes to be significant because of the inherent flexibility allowed under the NIH’s modular grant format. Furthermore, the IACUC was under the impression that so long as it approved the final version of the protocol, there was no need to document to NIH/OLAW any of the changes made as a consequence of the review process.
Was Great Eastern playing within the rules or just playing with the rules?
H. Edwin Kennah, PhD & Paul H. Bramson, DVM, MS
From the foregoing scenario it is impossible to determine if Great Eastern is playing with the rules or just ‘dropped the ball’ on this play. However, it appears that OLAW is correct in reprimanding Great Eastern for not conforming to the rules as stated in section IV.C of the Public Health Service Policy on Humane Care and Use of Laboratory Animals (PHS Policy). This policy requires the review and approval by the IACUC of all components of grant applications and contract proposals that relate to the care and use of animals. In addition, the signature of the authorized Institutional Official on the 398 grant application form certifies that the IACUC will or has reviewed and approved all animal-related activities in the grant application. It seems that the Great Eastern IACUC needs to develop a procedure for ensuring compliance with the requirements for review of a grant application’s animal care and use procedures. The IACUC only reviewed the protocol review form on which Markowitz provided information about his proposed use of animals. A procedure for the direct comparison of the information on the grant application form with the IACUC protocol review form may have kept Great Eastern out of the OLAW penalty box.
The second penalty called by OLAW was for failure to report changes made in the grant proposal. Markowitz decided to substitute some mouse studies described in the grant proposal with related studies on rats. The IACUC approved these changes as part of their review of Markowitz’s protocol review form, but did not understand the need to report them to NIH/OLAW. Because the IACUC’s review was performed after the grant application’s scientific review at NIH, PHS Policy IV.D.2 requires that any changes in the proposal be forwarded to the NIH as part of the delayed-approval notification process. Great Eastern’s contention that the changes are not significant will not stand up to review, because OLAW guidance1 states that a change in species is significant. Therefore, the Great Eastern challenge of the OLAW penalties should be denied, and the ruling called by OLAW will stand.
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(9), 24–26 (1995).
Kennah is IACUC Director and Associate Professor of Occupational and Environmental Medicine, University of Pittsburgh, Pittsburgh, PA. Bramson is Consultant to Research Conduct and Compliance Office, Animal Welfare Assurance, University of Pittsburgh, Pittsburgh, PA.
Michael D. Mann, PhD
According to Section IV.D.2 of the PHS Policy, “Applications or proposals (competing and non-competing) covered by this Policy from institutions which have an approved Assurance on file with OLAW shall include verification of approval (including the date of the most recent approval) by the IACUC of those components related to care and use of animals . . . . If verification of IACUC approval is submitted subsequent to the submission of the application or proposal, the verification shall state the modifications, if any, required by the IACUC.” Of this section, the only part modified in 2002 by the advent of “just-in-time” verification is the timing of the required submission. “The existing PHS Policy requirement that modifications required by the IACUC be submitted to the NIH with the verification of IACUC approval remains in effect, and it remains the responsibility of institutions to communicate any IACUC-imposed changes to NIH staff”1. Thus the nature of the submission is unchanged by this procedural alteration.
PHS Policy does not state how the IACUC is to review and approve the animal care and use components of the grant proposal—whether to review the grant proposal itself or compare it with an approved IACUC protocol. In a national IACUC meeting, Nelson Garnett, at that time the Director of OLAW, indicated that OLAW does not care whether an institution uses protocols or not. What OLAW wants to know is that the IACUC reviewed and approved the animal care and use aspects of the grant proposal. Clearly, Great Eastern had an obligation to either review the grant proposal or compare it with the IACUC protocol and to report to the NIH changes required in the protocol to obtain approval; in this scenario, the IACUC did neither.
The specific changes required by the IACUC in the protocol would probably not have caused a mismatch between the proposal and the protocol if a comparison had been made. NIH grant proposals often do not specify either the number of animals or the care before and after the proposed procedure. On the other hand, a thorough comparison should have detected procedures in the grant proposal not in the protocol. It is not unusual for a protocol to contain procedures that are not in the proposal, and this is normally not a cause for alarm. It is common in our institution for protocols to contain studies covered by more than one grant proposal. Such procedures could cause alarm if the investigator attempted to pay for them using money from this grant. However, if the investigator considered the change in species to be part of the grant proposal, then this may constitute a noncompliance. OLAW has made it clear that it considers a change in species to be a significant change2.
Many IACUCs neither review grant proposals nor compare them with IACUC protocols. Rather, they rely on the investigator’s statement that they correspond. Our experience is that nearly 25% of the time this would lead to a ‘false’ verification of the approval. Perhaps that is the error made by the IACUC. A recent survey indicates that Great Eastern is not alone in “playing with the rules.” In the survey 30% of respondents indicated that their institutions regularly act similarly (M.D.M. and E.D. Prentice, unpublished observations).
It is unclear what would have happened to the IACUC’s report had it made such a report. Although the PHS makes policy, it is the responsibility of the individual institutes to implement it. There does not seem to be a written policy what will happen if the IACUC demands changes in a project once it has been reviewed and just-in-time verification has been requested. Grants administrators at the NIH also seem uncertain about it.
1. NIH. NOT-OD-02-064. Laboratory animal welfare: change in PHS Policy on Humane Care and Use of Laboratory Animals. (8 August 2002).
2. 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(9), 24–26 (1995).
Mann is Professor, Cellular and Integrative Physiology and Executive Chair of the IACUC, University of Nebraska Medical Center, Omaha, NE.
Michele Cunneen, BA, LATg & Regina Correa-Murphy, RLATg, CIP
Great Eastern’s assertions that these changes did not need to be communicated to OLAW because of the inherent flexibility in the Modular Grant System may show a lack of knowledge about the system, or they may be trying to deflect the responsibility for an error in their reporting to OLAW. The intent of the modular system is to minimize rebudgeting, forecasting, and adjustments by providing noncategorical, total direct cost awards in modules of $25,000. These modules permit flexibility in how the money is spent, eliminating the need for line item rebudgeting. Therefore, under the modular grant system, Markowitz would not have had to rebudget the animal line item from mice to rats or to notify NIH of the change. This applies only to the finances. Nowhere in the modular grant process is there a modification or modularization of the reporting requirement with respect to “just-in-time” IACUC approval.
The other area in which Great Eastern appears not to understand reporting requirements is in the IACUC review process, in which the IACUC protocol must correspond to the grant submission. Although the OLAW does not require a direct review and matching, “PHS Policy (IV.D.) requires the institution to verify, before award, that the IACUC has reviewed and approved those components of grant applications and contract proposals related to the care and use of animals. This position is reiterated in NIH Grants Policy Statement under Part II, Terms and Conditions. Most institutions have developed an IACUC protocol form and require investigators to provide detailed information about the proposed use of the animals on this form.... Institutional submission of IACUC approval, subsequent to submission of the application/proposal, must represent approval of the information originally submitted in theapplication/proposal, or include notification of any significant changes required by the IACUC1”. It is clear that the University had a responsibility to review all aspects of the grant involving animal use and to notify OLAW of all required changes and modifications. In this case the choice of the investigator to switch species should have been covered in the letter to OLAW along with the IACUC’s required changes and strategy for the pilot studies and how the institution would proceed if the pilots were successful.
If neither the IACUC nor Markowitz believed that the changes to the grant proposal originally submitted were significant and thus reportable, this is a strong indication that more training is necessary for both the members of the IACUC and its investigators as to what constitutes a significant change and what is reportable to the sponsor(s) and regulatory agencies.
1. Wolff, A. et al. Frequently asked questions about the Public Health Service Policy on Humane Care and Use of Laboratory Animals. Lab Anim. (NY) 32(9), 33–36 (2003).
Cunneen is Principal, The AWEN Group Inc., Waltham, MA. Correa-Murphy is Administrative Officer R&D, Providence VA Medical Center, Providence, RI.
In response to the questions posed in this scenario, the Office of Laboratory Animal Welfare (OLAW) offers the following clarification and guidance:
The issues raised in this scenario are matters of institutional compliance with longstanding NIH Grants Policy and with the PHS Policy. The relevant requirements are as follows:
NIH Grants Policy Statement (GPS) states “NIH will not make an award for research involving live vertebrate animals unless the applicant organization…provide[s] verification that the IACUC has reviewed and approved those sections of the application that involve the use of vertebrate animals in accordance with the requirements of the [PHS] Policy…Verification of the IACUC review may be filed at any time before award unless required earlier…the IACUC should ensure that the research described in the application is consistent with any corresponding protocols reviewed and approved by the IACUC1.”
PHS 398 Application Instructions specify “Any modification of the Research Plan section of the application, required by the IACUC, must be submitted with the follow-up [IACUC] verification2.”
PHS Policy requires the IACUC to review “those components of PHS-conducted or supported activities related to the care and use of animals” and the institution to provide “verification of approval by the IACUC of those components related to the care and use of animals.” PHS Policy reiterates the 398 Instruction “If verification of IACUC approval is submitted subsequent to the submission of the application or proposal, the verification shall state the modifications, if any, required by the IACUC3.”
In this scenario, the IACUC requested several changes to the protocol and this information was not provided in the IACUC letter of verification to the NIH. If these changes constituted a modification of the Research Plan section of the application, then they are required to be submitted to the NIH as part of the verification.
Note verification of IACUC approval is submitted by the institution to the relevant Grants Management Officer (GMO) assigned responsibility for the grant application by the NIH Institute or Center, and not to OLAW.
The scenario further describes Great Eastern findings that there were animal studies in the grant that were not described in the protocol. This situation is an obvious violation of applicable requirements cited above. Apparently the investigator decided not to perform some of the studies, but substituted studies using a different animal model, which were approved by the IACUC. Since the PHS 398 requires identification of the species in the Research Plan, if the investigator decided to change species prior to receiving the grant award he or she should have notified the GMO. A change in animal model by the investigator post award is an action that, per the terms and conditions of the GPS, is considered a change in scope and therefore requires prior approval by the relevant GMO of the NIH awarding component (not OLAW). The 1995 OLAW guidance, referenced in two of the scenario responses, concerning criteria in determining what constitutes a “significant change” is in the context of whether IACUC review is required for changes that investigators might potentially make to approved protocols5.
NIH grantee institutions are collaborative partners with NIH; both parties have mutual obligations and responsibilities as stewards of Federal funds to ensure compliance with all Federal requirements. Institutions that rely upon statements by investigators that the grant application matches the IACUC protocol and have determined that this is an ineffective method of assuring compliance with Federal rules have a responsibility to develop and implement an appropriate system of policies and procedures to ensure compliance.
With regard to the NIH modular grant format, modular applications and awards employ a simplified process for developing and reviewing application budgets, documenting approved budgets, and making post-award budgetary changes. There are no changes regarding submission of information or policies concerning animal care and use under the Modular Grant procedures.
1. NIH Grants Policy Statement; Part II Terms and Conditions of NIH Grant Awards, Subpart A, Animal Welfare. (2003).
©2006 Lab Animal
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