- 4.0 Continuing Review: The Annual Review
- 4.1 The Third-Year Resubmission: de novo Review
- 4.2 Comparison of Protocols to Grants
- 4.3 Post-Approval Monitoring (PAM)
Animal Welfare Regulations require an annual review of protocols. PHS Policy requires the IACUC to conduct continuing review of each previously approved, ongoing activity covered by PHS Policy at appropriate intervals as determined by the IACUC, including a complete review in accordance with the PHS Policy IV.C.1-4 at least once every three years.
At The University of Texas at Austin, regardless of the species used, the IACUC requires an annual report on the status of each protocol. In doing so, the Investigator verifies that completed activities were conducted in accordance with the approved protocol, describes any proposed departures from the approved protocols, and solicits information about activities projected for the upcoming year. In addition, the number of animals used over the course of the previous protocol year needs to be provided.
When Annual Renewal Forms are submitted to the Office of Research Support prior to the protocol’s expiration date, the protocol is considered active and experiments can be conducted while the annual renewal is under review.
Sixty (60) days before the first and second anniversary of the protocol approval, the PI is sent a notification requesting the status of the protocol (active or inactive), requesting any proposed modifications to the protocol, and asking for the number of animals the PI has used in the previous 12 months. The PI must complete the Annual Renewal Form and return it to the Office of Research Support (ORS) by the first and second anniversary of the protocol approval. Review of the Annual Renewal Form is conducted as described in Section 3. If a PI fails to submit an Annual Renewal Form by the first and second anniversary of the protocol approval, the following action is taken:
- Depending on the species covered in the protocol:
- If the protocol covers species that are not regulated by the USDA, then the IACUC Chair (or in his/her absence, the Vice-Chair) will notify the PI, the Attending Veterinarian, and the Director of the Office of Sponsored Projects (if the project is externally funded), that all work under the animal protocol must cease until further notice. The Attending Veterinarian, in consultation with the IACUC Chair (or in his/her absence, the Vice-Chair), will determine if any threat to animal well-being is posed and if so will take the appropriate action.
- If the protocol includes species that are regulated by the USDA, then the action described in Section 4.1.1 will be followed.
- The PI must promptly provide, in writing, a statement that he or she will not use any animals under the protocol for teaching or research until the IACUC has reviewed and approved the annual renewal. If the PI fails to promptly provide such a verification statement and continues animal work, then the University may report such incident, as described in Section 8.5.
- When PI has successfully submitted and obtained approval of the annual renewal after an appropriate review method (as described in Section 3.6), animal work may continue.
- If the PI fails to successfully renew the protocol within 30 days of the protocol anniversary date, the protocol will be considered to be permanently expired and the PI will be required to resubmit a new protocol in order to restart work. Additionally, the IACUC may consider suspending (as described in Section 8.4.2) or terminating that PI’s animal use privileges.
If a protocol is allowed to lapse while the associated vertebrate animals are still being housed on campus, they must be turned over to the custody of the Animal Resource Center (an IACUC-approved holding protocol is present to cover such situations). The ARC Director will make a determination (after possible consultation with the IACUC Chair, the relevant Dean, and/or the Vice President for Research) on whether the animals can be safely and humanely maintained temporarily by the ARC staff, or if they should instead by transferred to another study, placed with an outside agency, or euthanized.
If the animals have been used primarily for teaching or demonstration and were originally privately-held animals that were not purchased with university funds, they may be able to be returned back to the original owners or another experienced individual. Requests for such transfers can be made to the ARC Director.
The purpose of continuing review is primarily threefold:
- To inform the IACUC of the current status of the project;
- To ensure continued compliance with PHS, USDA and institutional requirements; and
- To provide for re-evaluation of the animal activities at appropriate intervals.
Federal requirements, research ethics, and moral obligations of the scientific community to society demand that IACUC’s conduct appropriate and meaningful reviews of ongoing animal protocols in the same responsible manner that initial reviews are done. This means that the IACUC will not “rubber stamp” a previously approved protocol during continuing review just because it has undergone a thorough initial review. In a society where use of animals in research, testing and teaching is viewed with increasing concern, high standards of oversight must be maintained. Within the framework of federal regulations and policies, however, there is need for institutions to develop review procedures that are reasonable, meaningful and efficient, and that do not burden the IACUC or investigators with unnecessary requirements that do not contribute directly to the welfare of the animals or provide significant information relevant to the role of the IACUC.
Animal activities are most frequently justified from an ethical cost-benefit perspective. This means that any animal pain, morbidity and mortality must be outweighed or at least balanced, by the potential benefits of the project in terms of its relevance to human or animal health, advancement of knowledge or the good of society. Ethical cost-benefit assessment should be a major focus during initial and continuing review by the IACUC. This assessment should not, however, be misconstrued as the equivalent of an NIH study section review of scientific merit. Instead, it represents a threshold level of review that documents that the use of animals continues to be justified. Without such assessment, there is lack of accountability, which negates the purpose of continuing review, particularly for projects not funded by the PHS or other funding agencies with rigorous peer review.
The obvious question that arises is why an ethical cost-benefit relationship would change over time. After a protocol is initially approved by the IACUC it is possible that new information may have become available, which allows application of one of the “three R’s” (reduction, refinement, replacement). For example, new in vitro techniques or statistical methods may be discovered that could reduce the number of animals required. Or an investigator may find that a lesser degree of morbidity can be used as an experimental end point. Conversely, in some situations, it may be necessary for scientific reasons to increase the number of animals or to allow animals to reach a more advanced stage of morbidity than originally specified in the protocol. In either case, the ethical cost-benefit ratio will be altered and the IACUC should, therefore, re-evaluate this new relationship. Proposed changes in the protocol can be considered during continuing review and approved as warranted. Admittedly, there are considerations related to scientific continuity and grant requirements that may dictate whether changes in a protocol are possible. Nonetheless, it is incumbent on investigators and the IACUC alike to determine during continuing review whether the 3Rs can be applied further to the protocol.
The PHS Policy requires that a complete IACUC review of PHS-supported protocols be conducted at least once every three years. This triennial review is interpreted by OLAW as a requirement for de novo review, meaning that the criteria and procedures for review specified in IV.C. of the PHS Policy must be applied not less than once every three years.
The three-year period begins on the actual date of IACUC approval; the IACUC may not administratively extend approval beyond the three years. Since protocol approval period cannot be extended, investigators must be cognizant of the protocol approval period. To aid investigators, the Office of Research Support shall attempt to provide adequate warning of pending protocol expiration. Although a sophisticated protocol database exists, the automatic warning system is not fail-safe. It is the responsibility of the investigator to submit the third-year resubmission by the appropriate deadline date for a scheduled Full Committee Review (FCR) prior to protocol expiration. The IACUC requires a Third Year Resubmission be submitted as a new proposal, using the most recent version of the application.
Ninety (90) days prior to the three-year anniversary of the animal protocol approval date, the PI is sent a notification requesting a resubmission of the protocol. The PI must resubmit the entire protocol to the ORS. A de novo review of the third-year resubmission is conducted as Section 3.6. The third-year resubmission must be approved by the IACUC before the expiration date of the original protocol. If a PI fails to submit a third-year resubmission and receive approval by the expiration date of the protocol, the following action is taken:
- On the third anniversary of the protocol approval, the IACUC Chair (or in his/her absence, the Vice-Chair) will notify the PI, the PI’s dean (and/or department chair), the Attending Veterinarian, and the Director of the Office of Sponsored Projects (if the project is externally funded), that the animal protocol has expired. The PI will be notified in writing that all activities under the protocol must cease and any ongoing work under the expired protocol is a serious and reportable violation of PHS Policy.
- The Attending Veterinarian will be notified of the expired protocol and any remaining animals under that protocol will be transferred to a holding protocol. Per diems for animal care will continue to be charged. In the event that animal care charges are being charged to a sponsored project, an alternate account must be identified for such charges.
- When the PI has successfully obtained approval of the protocol animals will be transferred from the holding protocol to the new approved protocol.
- If the PI fails to successfully renew the protocol, the IACUC may consider suspension or recommending to the IO that the PI’s animal use privileges should be terminated.
4.2 Comparison of Protocols to Grants6
Public Health Service (PHS) agencies will not make an award for research involving live vertebrate animals unless the applicant organization and all performance sites are operating in accordance with an approved Animal Welfare Assurance and have provided verification that the IACUC has reviewed and approved those sections of the application that involve use of vertebrate animals, in accordance with the requirements of the Policy. Additionally, PHS agencies will not make an award for research involving live vertebrate animals to an individual unless that individual is affiliated with an organization that accepts responsibility for compliance with the Policy and has filed the necessary assurance with OLAW.
Regardless of when the review occurs, the investigator should ensure that the research described in the grant proposal application is consistent with any corresponding protocol(s) reviewed and approved by the IACUC. Therefore, a copy of the of the funded or unfunded grant proposal application may be requested by the IACUC and reviewed by designated member(s) to confirm that all research outlined in the grant is included in the approved IACUC protocol.
The extents of the verification of consistency between grant proposals and IACUC protocols will be a confirmation that the species and procedures relating to use of animals described in the proposal are included in the protocol. This will be a unidirectional comparison of the procedures described in the grants. In conducting the verification, the IACUC focuses on the following two (2) questions:
- Are the species used in the grant proposal included in the IACUC protocol?
- Are animal care and use procedures described in the grant proposal included in the IACUC protocol?
Verification of grant and protocol consistency concentrates on animal care and use and will not include a judgment of scientific merit.
The IACUC will compare the grant to the protocol during the review of the protocol. The verification will not add additional time to the review process. In addition, the IACUC will compare the grant to the protocol when a new funding source for a protocol is proposed, or when the Office of Sponsored Projects (OSP) requests verification.
There are two types of amendments to animal research protocols that have specific relevance to this policy—(1) a change in funding source and (2) a change in animal use procedures. Submission of an administrative amendment requesting a change in funding source will include a verification of consistency between the new grant and the current protocol to which it is being linked. The verification will include a confirmation that the species and procedures relating to use of animals described in the proposal are included in the protocol (see Section 4.2.1).
The IACUC understands that research projects evolve over time and therefore the specific direction of a protocol may change from the original description of animal use procedures. These changes should be submitted as a significant amendment to the protocol and should be consistent with the objectives, purpose, or aims stated in the original protocol. It is the Principal Investigator’s responsibility to explain how the changes relate to the original protocol. Because the determination of consistency between the grant and original protocol has already been established, there will generally be no need to “re-verify” grant-to-protocol consistency for amendments.
For PHS-supported grants (e.g., NIH, CDC, etc.) it is the responsibility of the Principal Investigator to indicate any significant changes in the use of vertebrate animals in the Progress Report Summary section of their Non-Competing Continuation Progress Report (PHS 2590).
The Attending Veterinarian usually conducts the grant to protocol comparison. The Principal Investigator, through the IACUC, will be consulted regarding any apparent inconsistency. As noted above, significant changes require that the PI notify the extramural Program Official. Verification of this request and subsequent approval must be shared with the IACUC.
Periodically, the IACUC will identify certain protocols or procedures that the IACUC determines that the laboratory could benefit from close veterinary oversight. The requirement of specific monitoring can be a provision of protocol approval and is communicated to the PI. Once a protocol action (e.g., new protocol, revision, etc.) is approved with a proviso for PAM, a specific notice to that effect will be sent to the PI. The notice will be sent separately rather than being combined with any other correspondence (such as approval notices or review queries). The Animal Resources Center (ARC) veterinary staff is notified of the need for monitoring and provided with the pertinent details. The veterinary group coordinates this monitoring and periodically, and as necessary, provides updates to the IACUC.
In addition, the veterinary group conducts random, but frequent, visits to high-use areas, including satellite facilities. The veterinary group has the philosophy that maintaining a friendly and collaborative presence in the research lab areas is a proactive way to ensure that minor issues are identified rapidly for quick and cordial correction, and that major issues are prevented.6. Sections 4.2, 4.2.1, 4.2.2, 4.2.3, and 4.2.4 contain content that was adapted from materials obtained from the University of Pennsylvania.