From: Contemporary Topics 35(5):53-56, 1996
GWENN S.F. OKI, MPH (1), ERNEST D. PRENTICE, PHD (2), NELSON L. GARNETT, DVM (3), DALE F. SCHWINDAMAN, DVM (4), and CAROL Y. WIGGLESWORTH (5)
(1) Director, Research Subjects Protection, Research Administration, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010-3000; (2) Associate Dean for Research, University of Nebraska Medical Center, 600 South 42nd Street, Omaha, NE 68198-6810; (3) Director, Division of Animal Welfare, Office for Protection from Research Risks, 6100 Executive Boulevard, Suite 3B01, MSC 7507, Rockville, MD 20892; (4) Deputy Administrator, United States Department of Agriculture, Animal and Plant Health Inspection Service, Regulatory Enforcement and Animal Care, 4700 River Road, Unit 97, Riverdale, MD 20737-1234; (5) Senior Policy Analyst, Division of Animal Welfare, Office for Protection from Research Risks, 6100 Executive Boulevard, Suite 3B01, MSC 7507, Rockville, MD 20892. [The Animal Welfare Division of OPRR was renamed Office of Laboratory Animal Welfare (OLAW) in 2000.]
Abstract: Although institutional animal care and use committee (IACUC) continuing review of ongoing animal related activities is a requirement imposed by the Public Health Service Policy (PHS Policy) and United States Department of Agriculture (USDA) animal welfare regulations, there is lack of uniform understanding and application of these federal requirements. This paper endeavors to clarify the purpose and substance of continuing review through exploration of the requirements of the PHS Policy and the USDA regulations. It proposes a model that incorporates a practical, meaningful, and reasonable method of performing continuing review which institutions can adopt or modify to suit their individual needs.
The PHS Policy at IV.C.5. states "the IACUC shall conduct continuing review of activities covered by this policy at appropriate intervals as determined by the IACUC but not less than once every three years (3)". The USDA regulations 9 CFR 2.31(a)(5) (4) use similar language, except that continuing review must be performed not less than annually.
The OPRR has interpreted the PHS Policy provision for continuing review as a requirement for a "de novo" review (5-7). In this context, "de novo" means that the criteria and procedures for review of projects specified in IV.C. of the PHS Policy must be applied not less than once every three years. The IACUC must make the determination that the project conforms with the criteria at IV.C.1.a-g. of the PHS Policy. These criteria address such factors as pain and distress, pain relief, animal husbandry, veterinary care, personnel qualifications and methods of euthanasia. In addition to confirmation that projects are in compliance with the PHS Policy, the IACUC must also determine that the project is being conducted in a manner consistent with the "Guide for the Care and Use of Laboratory Animals" (Guide), unless departure is justified.
The preamble to the USDA regulations provides guidance on the USDA requirement for annual continuing review as follows: "We are adding a provision to the Final Rule to require that the Committee conduct continuing review of activities covered by the Animal Welfare Regulations at appropriate intervals, and at least annually [Final Rule 2.31(d)(5)]. This review...is intended to provide current information to the Research Facility regarding all ongoing activities so it can remain in compliance" (8).
The USDA interprets the role and purpose of the annual continuing review as one form of monitoring the use of animals. Monitoring can be accomplished by the use of a standard form containing basic protocol information to be provided by the investigator (status of the project, assurance that activities are being conducted in accordance with the approved protocol, and proposed departures from the protocol in the upcoming year). It should be noted that the USDA regulations [9 CFR Part 2, Subpart C, 2.31(c)(7); 2.31(d)] and the PHS Policy [IV.C.1] require that proposed significant changes to the currently approved protocol be reviewed and approved by the IACUC prior to implementation.
THE PURPOSE AND SUBSTANCE OF CONTINUING REVIEW
On the basis of the aforementioned regulatory requirements and our collective interpretation, the purpose of continuing review appears to be 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 IACUCs conduct appropriate and meaningful reviews of ongoing animal protocols in the same responsible manner that initial reviews are effected. This means that IACUCs should 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 (9), 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 IACUCs 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 IACUCs.
Current status of the project: Information concerning the current status of the project should be provided by the investigator to the IACUC. Logically, this information would include funding status, number of animals used, and proposed amendments. In addition, some IACUCs may choose to ask the investigator to submit a brief report that will update the Committee on the progress being made on achieving the specific aims of the protocol. In general, however, progress reports or updates should not be used in the context of an assessment or evaluation unless there is an indication that the animal use is not consistent with good science.
Compliance with PHS, USDA and institutional requirements: The investigator should provide assurance that the animal activity has not deviated from the current IACUC approved protocol. Although it may generally be assumed that the initial review constituted a thorough and in depth assessment of the protocol for compliance with the requirements in place at the time, changes may have occurred in IACUC policies and procedures, the "state of the art", as well as in the PHS Policy and the USDA regulations. Therefore, protocols should be updated and reviewed, as necessary, to comply with the current standards.
Ethical cost-benefit analysis: 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 (10). Ethical cost-benefit assessment should be a major focus during initial and continuing review by the IACUC (10,11). 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 which 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 which 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 Rs" (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 IACUCs alike to determine during continuing review whether the 3Rs can be applied further to the protocol.
ONE METHOD FOR PERFORMING CONTINUING REVIEW
Combining PHS and USDA review procedures: Many institutions have sought to simplify their continuing review process by combining the requirements of both the PHS Policy and the USDA regulations. At some institutions, this can be accomplished most easily by satisfying the admittedly more stringent PHS Policy continuing review requirements, on an annual basis rather than triennially, thereby eliminating the dual tracking system for the one- and three-year cycles. However, comprehensive annual reviews may not be administratively feasible at large institutions, although, it should be remembered that both the PHS Policy and the USDA regulations also specify that continuing review be performed "at appropriate intervals...". Thus, it is possible that an IACUC may decide that a project should be reviewed more often than annually.
To satisfy the requirements of the PHS Policy, the method of performing continuing review must conform to one of the two procedures described in the PHS Policy [IV.C.2.], that is: review by the "full committee" or use of the "designated reviewer" process. The OPRR accepts the review as being "de novo" if it includes, in accordance with IV.C. of the PHS Policy, a review of complete, current information about the animal activity and follows one of the two procedures described previously. Accordingly, if nothing has changed in the original protocol, review and approval of the continuing review form and the original protocol at appropriate intervals, following the prescribed procedures, also satisfies the PHS Policy requirement for triennial "de novo" continuing review as well as the USDA annual review requirements.
The IACUC continuing review form: To conduct practical, reasonable, and meaningful continuing review of animal activities, which would satisfy both USDA regulatory and PHS Policy requirements, two of the authors (GSFO, EDP) propose the use of the following form (which has been labeled with section and item numbers, and corresponding explanations).
IACUC#:______________________ DATE OF INITIAL APPROVAL:______________
PRINCIPAL INVESTIGATOR: _____________________________________________
CAMPUS ADDRESS:______________________________ PHONE: _______________
- RECORD OF ANIMAL USAGE
Species Total # Approved # Used to Date ____________________________ ____________________ ____________________ ____________________________ ____________________ ____________________ ____________________________ ____________________ ____________________
- NATURE OF THE PROTOCOL/STUDY. (Check [ X ] all applicable items.)
[ ] Survival (Chronic) Study [ ] Prolonged Restraint [ ] Inducement of a Disease State [ ] Terminal (Acute) Study [ ] Neuromuscular Blockers [ ] Inducement of Behavioral Stress [ ] Multiple Surgeries [ ] Antibody Production [ ] Blood/Tissue Collection [ ] Transgenic Breeding
- [USDA] PROJECT (Pain) CATEGORY [ X ]: [ ] C [ ] D [ ] E
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
- PROTOCOL STATUS. Please indicate ( X ) the status of this project.
Request Protocol Continuance
- A. Active - project ongoing.
- B. Currently inactive - project was initiated but is presently inactive.
- C. Inactive - project never initiated but anticipated start date is ________________.
Request Protocol Termination
- D. Inactive - project never initiated.
- E. Currently inactive - project initiated but project has not/will not be completed.
- F. Completed - no further activities with animals will be done.
- FUNDING SOURCE: Specify the funding source.
- PROJECT PERSONNEL.
[ ] Yes: Have there been any personnel/staff changes since the last IACUC approval was granted? [ ] No: If yes, please complete the following sections (Additions/Deletions). For additions, please submit a completed Personnel Qualification Statement with this Continuing Review Form and make arrangements with the Animal Resources Center staff for inservice training on the proper care and handling of laboratory animals.
Additions: Name/Role/Responsibility for Project
- PROGRESS REPORT. If the status of this project is 4.A. (active; project ongoing) or 4.B. (project was initiated, but is presently inactive), provide a brief update on the progress made in achieving the specific aims of the protocol.
- PROBLEMS/ADVERSE EVENTS. If the status of this project is 4.A. (active; project ongoing) or 4.B. (project was initiated, but is presently inactive), describe any unanticipated adverse events, morbidity or mortality, the cause(s), if known, and how these problems were resolved. If NONE, this should be indicated.
- ALTERNATIVES TO ANIMAL USE. Alternatives to the use of animals should be considered and used when possible. Since the last IACUC approval, have alternatives to the use of animals become available that could be substituted to achieve your specific project aims?
- ALTERNATIVES TO POTENTIALLY PAINFUL PROCEDURES. (Address the following if your project involves USDA Category D or Category E.) Procedures that cause the least amount of pain or distress to the animals should be considered and used when possible. Since the last IACUC approval, have alternatives which are potentially less painful or distressful become available that could be used to achieve your specific project aims?
- DUPLICATION. Activities involving animals must not unnecessarily duplicate previous experiments. Provide written assurance that the activities of this project remain in compliance with the requirement that there must be no unnecessary duplication.
- FUTURE PLANS.
- No changes are planned and the project will continue as previously approved by the IACUC.
- Changes are planned. Provide a full description and justification for the proposed changes. (A copy of the IACUC Protocol Amendment Form has been included for this purpose.)
[Please note that if the modifications are significant, you may be required to complete a new application. If you have questions or require assistance in making this determination, please contact the IACUC Office and/or the Attending Veterinarian.]
- Other. Provide a brief explanation.
- No changes are planned and the project will continue as previously approved by the IACUC.
CERTIFICATION OF THE PRINCIPAL INVESTIGATOR. Signature certifies that the Principal Investigator understands the requirements of the PHS Policy on Humane Care and Use of Laboratory Animals, applicable USDA regulations and the Institution's policies governing the use of vertebrate animals for research, testing, teaching or demonstration purposes. Signature further certifies that the investigator will continue to conduct the project in full compliance with the aforementioned requirements.
|Signature of the Principal Investigator||Date|
Section 1 would be completed by the IACUC Office via database generation of the report form. The information captured in this section is considered to be basic protocol-identifying data, which may be helpful to any designated reviewer, as well as to the Committee, in their assessment. In addition, certain items, such as the pain category and nature of the protocol may prompt the IACUC to look more closely at the continuing review update.
Item 4--Protocol Status; 5--Funding Status; and 6--Project Personnel. The status of the protocol, funding source, and changes in project personnel are fairly standard questions to which the investigator is expected to provide responses.
Item 7--Progress Report. The progress in achieving the specific aims of the protocol should be described. The information in this section should be provided as an update to help the IACUC document the continued approvability of the research. For example, if 50 dogs were used and the investigator had no progress to report, in light of the specific aims of the protocol, it would be reasonable for the IACUC to request clarification. It should, however, be recognized that scientific inquiry may involve "blind alleys", and failed experiments, thus resulting in little progress in the short- versus long-term.
Item 8--Problems/Adverse Events. Any unanticipated problems or adverse events that have occurred should be reported, as well as an explanation of how these events/problems were resolved. Depending on the information provided here, this response may also need to be factored into the IACUC's assessment of the ethical cost-benefit justification.
Item 9--Alternatives to Animal Use. This section raises the question of whether any viable alternatives to use of live animals have become available since the last IACUC review.
Item 10--Alternatives to Potentially Painful Procedures. This section asks whether there are any alternatives to USDA Category D or E procedures that are potentially less painful and could be used to achieve any of the specific aims of the research. The USDA Category D and E procedures are defined as follows. Animal activities in Category D involve "procedures that may cause more than momentary or slight pain or distress" for which appropriate sedatives, analgesics, or anesthetics will be administered (12,13). Category E is similarly defined, with the exception that sedatives, analgesics, or anesthetics cannot/will not be administered due to scientific considerations/requirements (13).
Item 11--Duplication. This section requests assurance that the animal activities do not unnecessarily duplicate previous experiments, as required by USDA regulations.
Item 12--Future Plans. The investigator is asked to indicate future plans for continuation of his/her project. This would include an indication as to whether the research would continue as originally approved; or conversely, if changes are planned, an outline, description, and brief justification of the proposed changes should be provided.
Finally, the investigator is asked to sign the Continuing Review Form, which contains a certification of his/her understanding and responsibility for conduct of animal activities in accordance with the PHS Policy, USDA regulations and the institution's (IACUC) policies. Signature here also attests to the accuracy of the investigator's responses. Requiring completion of this form, at least annually, indicates to the investigator the seriousness of the IACUC's review and the importance of investigator accountability for his/her research activity; for reporting it accurately; and for justifying continuance of the research project for another year. Accordingly, the IACUC, through its designated reviewer mechanism, is also held accountable for appropriate and responsible review of the IACUC protocol file, and for continuation approval of ongoing animal research, if it is still justified.
Method of IACUC continuing review. All IACUC members would be provided a copy of the completed Continuing Review Form, and would have access to the corresponding IACUC protocol file on request. Any IACUC member could ask for a full committee review of the Continuing Review Form and the protocol. Utilizing the "designated reviewer" process, if none of the IACUC members requests full committee review, the IACUC Chair would then designate at least one qualified member (i.e., designated reviewer) to conduct an in-depth review of the current protocol in conjunction with the Continuing Review Form. This review would include consideration of the previously described continuing review criteria in accordance with PHS Policy IV.C. The designated reviewer would then review and be authorized to approve, require modifications in order to approve, or require full committee review of the protocol in question. By conducting such a comprehensive "de novo" review on an annual basis, using this model, there is no further PHS Policy requirement for continuing review at three-year intervals.
The way in which an institution chooses to implement the PHS Policy and USDA regulations is subject to change over time. Changes in IACUC membership may result in different perceptions and judgements regarding animal use issues. These changes may affect the outcome of continuing review, as will the evolutionary changes in protocol review forms, new regulations and guidelines, and precedents set by ongoing regulatory compliance activities, internal and external to the institution. Oki and Prentice, therefore, recommend that, in addition to the procedures outlined previously, a complete new IACUC protocol review form (i.e., new IACUC application form) be submitted if a project will extend beyond six years. There is, however, no federal requirement for resubmission of a new application for IACUC review within any time frame.
In summary, the review process and report form described in this section meet the requirements of the PHS Policy and the USDA regulations for continuing review. Use of this model for performing IACUC continuing review would rely upon yearly comprehensive "de novo" reviews for institutions desiring to comply with both sets of requirements (PHS Policy and USDA regulations).
The PHS Policy and USDA regulations were intentionally written to avoid a great deal of specificity with regard to institutional procedures. This has provided institutions with a needed degree of flexibility in designing, implementing and adjusting their own individual systems of ensuring compliance with the PHS Policy and the USDA regulations. Many provisions of the PHS Policy and USDA regulations are, therefore, open to variable methods of implementation. Over the last decade, academicians, administrators and federal regulators have struggled with the imperative to interpret and apply the PHS Policy and USDA regulations in a practical, meaningful and reasonable way to ensure the highest possible standards of laboratory animal welfare while facilitating valuable research for the benefit of humans and/or animals. As a result, our understanding of what constitutes appropriate animal welfare in a research context has grown tremendously. Today, the IACUC is a far more sophisticated and effective review body than it was in 1985 when the PHS Policy was first promulgated.
It is not surprising that there has not always been agreement between the academic/research community and federal regulators. Some have publicly criticized the OPRR and the USDA for failing to provide "black and white" guidance on exactly how the PHS Policy and USDA regulations should be interpreted and implemented. In response, however, it is our contention that laboratory animal welfare is best promoted by engaging in a partnership of communication and problem solving between the federal regulators of animal welfare, the IACUCs, and the investigators who use animals in research and other activities. In addition, the philosophy and message of animal welfare groups who oppose animal-based research should be given thoughtful consideration as we struggle to achieve the appropriate balance between the needs of science and fulfillment of our moral and ethical responsibility to animals and society. Our joint and mutually accepted understanding of the meaning of the "letter" and the "spirit" of the PHS Policy and USDA regulations has evolved and continues to do so in the interest of promoting animal welfare and facilitating valuable research.
The model for continuing review presented in this paper represents a comprehensive approach and should not be confused with a minimalist's approach to the task (i.e., compliance with only the "letter of the law" without attempting to address "the spirit of the law"). To achieve the highest possible standards of laboratory animal welfare, institutions should view the PHS Policy and USDA regulations as establishing standards that serve as a platform on which to build as our understanding of science, animal welfare and research ethics increases. We think the institution's animal care and use program should be dynamic and evolving in nature as we identify ways in which laboratory animal welfare can be improved. It is important to note that although the model described herein by Oki and Prentice was designed principally to meet PHS requirements for triennial review, it also complies with and, indeed, exceeds the USDA requirements for annual review. Finally, we point out that institutions may adopt other models for performing continuing review that may be equally acceptable from regulatory and ethical viewpoints.
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