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Journal Vol 49 (4)

Program Oversight Enhancements (POE): The Big PAM

Aaron Plante and Mary Lou James

Aaron Plante, MLAS, MJ, is an IACUC Compliance Specialist at Wyeth Research in Collegeville, Pennsylvania. Mary Lou James, BA, LATG, is a consultant in regulatory compliance and research animal welfare in St. Louis, Missouri.

Address correspondence and reprint requests to Mr. Aaron Plante, IACUC Compliance Specialist, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426 or email plantea@wyeth.com.

Abstract

Federal animal welfare regulations and policies require compliance during animal research. But the methods used to oversee, assess, and ascertain compliance are left in the hands of the research institution and its institutional animal care and use committee (IACUC). Differences in institutional cultures, research goals, individuals responsible for animal care and use activities and oversight, and availability of financial and personnel resources have given rise to a variety of institution-specific mechanisms for ensuring compliance with the federal requirements and specifically with IACUC-approved animal research activities. In recent years one such mechanism, postapproval monitoring (PAM), has risen in popularity. An often cited topic in animal welfare–related conferences and periodicals, it is well on its way to becoming a compliance standard. However, it is but one mechanism for ensuring postapproval compliance and is not required by the federal animal welfare regulations. In this article we describe alternative mechanisms for ensuring compliance with IACUC-approved animal research through the use of program oversight enhancements (POE) in the context of an institution's animal care and use program. We present these enhancements in a way that allows readers to pick and choose those of interest. While these methods may not be feasible at all institutions, adopting even a few should improve a program's ability to ensure compliance with approved animal research and reduce the need for an aggressive and formal postapproval monitoring process.

Key Words: compliance; institutional animal care and use committee (IACUC); institutional official; postapproval compliance; program oversight enhancements; postapproval monitoring (PAM)

PAM Alternatives

Although PAM has grown in popularity in the regulated biomedical research community, the process is not federally mandated. Compliance with IACUC-approved activities, however, is required. It is therefore important to consider other mechanisms for ensuring compliance in institutions with robust animal care and use programs, as well as sufficient, if not substantial, resources to support a strong program at all levels. As the quality and effectiveness of these mechanisms improve, the need for PAM diminishes.

Institutions should strive to ensure a compliant and humane animal care and use program while balancing the allocation of fiscal and human resources. The responsible and logical approach is to allocate funds toward ensuring the effectiveness of required program components on the front end.

While PAM can be valuable in assessing the health of program components that contribute to compliance, it is not an essential ingredient for a compliant animal care and use program. Whether or not PAM is a value-added activity depends on a number of factors including (but not limited to) current level of compliance, institutional support, team dedication, program size and structure (e.g., centralized or decentralized), program dynamics (e.g., employee turnover, research complexity, growth rate), financial and personnel resources, and the effectiveness of other mechanisms for ensuring compliance.

Program Oversight Enhancements

Monitoring postapproval compliance is integral to ensuring and sustaining an institution's commitment to humane animal care and use in biomedical research. Such monitoring can be accomplished through program oversight enhancements (POE) with a myriad of processes, procedures, and personnel that are integral to a persuasive and sustainable culture of responsibility and dedication to compliance.

There are two categories of POE: those that employ institutional and IACUC oversight mechanisms and those that do not rely directly on the IACUC (e.g., animal support staff, facility operations and security personnel). Because we focus here on the most critical oversight practices, we acknowledge but do not address other oversight mechanisms (e.g., the guidelines of the Food and Drug Administration's Good Laboratory Practices, the Occupational Health and Safety Administration, and the National Research Council) and scientific integrity requirements that may also contribute to program compliance.

Institutional and IACUC Oversight Mechanisms

Federally Mandated Mechanisms

Many institutional animal care and use program components have been established in response to regulatory requirements. Although they are spelled out in section and paragraph enumerations in the regulations, it is important to reflect on the importance of each component and to describe useful strategies to ensure compliance. Collectively, these required program components should accomplish postapproval compliance without a formal PAM process.

The institutional official. Postapproval compliance is possible only through strong and visible institutional support starting with the institutional official (IO¹). As a member of senior management, this individual has both the authority and the responsibility to ensure the alignment of the institution's goals with the ethical and legal responsibilities of animal research. Strong institutional support starts from the top and promotes active participation in IACUCs, an understanding and respect for the charge of the IACUC, and a commitment to compliance.

Active IACUC recognition from the institutional official plays an important role in ensuring IACUC commitment and investigator compliance. It is prudent for the IO to champion support for the IACUC, actively and visibly endorse the importance of IACUC activities, and foster the institutional expectation that all animal users take seriously their responsibility for ensuring compliance. Such an atmosphere depends on open acknowledgment at institutional events, the development of an institutional policy on the care and use of animals in research, and periodic written correspondence to investigators and IACUC members.

Equally important is the IO's recognition of each IACUC member and the IACUC committee as a whole for their contributions to humane animal care and use, ensuring institutional compliance and safeguarding the privilege to use animals in research. Options for such recognition include periodic appearances and introductory remarks at IACUC meetings, an annual gathering to personally thank members, and acknowledgment and support by upper management (i.e., department heads, attending veterinarians, other managers) of IACUC participation.

The IACUC. The membership of the IACUC plays strongly into ensuring compliance. Selecting the right mix of individuals is a sound investment of time and effort. Members should be appointed based on their willingness to take their IACUC responsibilities seriously and on their ability to, collectively, bring the necessary expertise and perspectives to fulfill the IACUC charges. In addition, appointees must have sufficient time to participate effectively. Providing metrics to senior management and department heads so they are aware of the amount of time and effort necessary to serve on the IACUC will help them to identify and recommend individuals who are available to fully commit to the IACUC.

Newly appointed IACUC members should be briefed about both the committee's and their individual charges based on their IACUC position (e.g., chair, community member, scientific member, attending veterinarian, OHSP representative). Describing the committee charges and member roles in the appointment letter—and providing a copy to the individual's immediate supervisor—is an effective way to make clear for all the scope of the tasks involved (Greene et al. 2007; Haywood et al. 2005; James 2002).

The appointment of at least one representative from each major area of animal research offers several advantages. Research area representatives can provide the IACUC with information about proposed research activities and help the other members better understand an application's research objectives and proposed approaches. An IACUC is more likely to make fair and balanced decisions with input from individuals with relevant scientific expertise, helping to ensure that approved activities are reasonable and justified from both scientific and animal welfare perspectives. Research area representatives are also well positioned to disseminate information gleaned from their participation on the IACUC to members of their departments, thereby facilitating and enhancing animal users' understanding of and compliance with IACUC policies, operating procedures, and institutional expectations.

Training programs. IACUC members and animal care and use personnel need training and/or experience to fulfill their roles. The provision of relevant training programs and educational resources is an institutional responsibility and as such must be fully supported at the highest levels of the institution. The most effective training draws on a variety of mechanisms such as relevant publications, web-based tutorials, IACUC-sponsored information sessions, and internal and external training forums.

At a minimum, and certainly for US Department of Agriculture (USDA)–regulated institutions, programs for prospective animal care and use personnel must address the specific topics defined in the USDA Animal Welfare Regulations (CFR 2005 § 2.32(c) 1-5). These are often best addressed in an orientation session that is prerequisite to the submission of an animal use proposal. This orientation should also cover institutional and IACUC-specific policies and procedures, common animal use techniques, occupational health and safety in the research animal environment, the process for applying to use animals in research, and the necessary steps for a required modification to an approved animal activity.

IACUC policies and procedures. Compliance is more likely to be achieved if expectations are clearly defined and disseminated. The IACUC can promote compliance only as well as it can communicate to researchers and other animal care and use personnel. For example, all animal research-related policies and procedures should be readily accessible on the institution's intranet or through other technology-based methods. Depending on the size and scope of the research program, several kinds of information should be accessible to different personnel:

Global information: Institutionwide information applicable at all sites/satellite facilities.

Institutional IACUC policies, procedures, and guidelines (e.g., protocol submission guidelines, dosing guidelines)
IACUC training/education components (e.g., resource information, tutorials)
Animal care office information (e.g., contact information, organizational charts)

IACUC internal information: Secure information accessible only to IACUCs and their administration.

Institutional official information (e.g., internal memoranda, institutional correspondence)
Multisite IACUC internal templates for standardized policies, procedures, guidelines, and forms (e.g., document distribution guidelines, appointment letter templates, report templates)

Site-specific information: Multisite institutions typically have different policies and procedures customized to their unique programs that must be communicated to researchers.

Internal IACUC site-specific information (e.g., committee meeting dates/deadlines, access forms, protocol submission guidelines, species-specific information)
Animal care office, site-specific information (e.g., vivarium access, wet laboratory training schedules, contact information)

Several technology-based strategies effective for disseminating information are shown in Table 1. However, the IACUC should also engage in face-to-face interactions to ensure that the committee is not a faceless, mechanized review and approval apparatus.

Enhancing Mandated IACUC Oversight Standards

With no shortage of regulations, policies, or standards in animal research, efforts to go beyond the minimum requirements may at first seem unproductive and inefficient. But strengthening existing standards and enhancing oversight can promote compliance without increasing burden or decreasing efficiency. The following methods build on mandated IACUC functions.

Protocol review. Both the USDA Animal Welfare Regulations and the US Public Health Service (PHS¹) Policy for the Humane Care and Use of Laboratory Animals obligate IACUCs to review and approve all animal use activities and significant modifications before initiation. After approval, in keeping with USDA requirements, IACUCs must review the animal research at least annually (CFR 2005 § 2.31(c) 1.d.5); and in keeping with PHS Policy requirements, they must conduct a de novo review of ongoing animal research at least every 3 years (NIH 2002, IV.C.5).

These initial and ongoing reviews and approvals are an important step for ensuring that animal activities are conducted as approved. The annual review reminds, and even encourages, investigators to consider, propose, and justify modifications (e.g., increases in animal numbers, addition of new personnel, changes in surgical approaches) that may be necessary to ensure that the research meets its objectives. The annual review thus ensures that the approved protocol reflects the actual animal activities. The 3-year de novo review gives both the investigator and the IACUC the opportunity to reconsider the research design in terms of its relevance and value, advances in alternatives, the appropriateness of the animal model and animal numbers, personnel training and qualifications, and research program progress.

Although required only every 3 years, more frequent de novo review of animal research applications enhances the IACUC's familiarity with active protocols and improves the quality of the written application. Resubmission and rereview are especially important at the first- and second-year marks when the need for significant modifications is most likely. More frequent reviews are more time-consuming than the "continuing" (annual) review of an abridged protocol application (i.e., a "short form" that typically focuses on research status, progress, and proposed modifications), but this burden can be reduced through the use of quality protocol management software and a clear understanding of the information that must be presented in a protocol application. Resubmission of the entire protocol at more frequent intervals helps to minimize "protocol drift" and maximize postapproval compliance by reminding investigators of what has been approved and encouraging them to carefully consider the need for significant modifications. In addition, with each subsequent review and fine-tuning of the protocol application, the efficiency of IACUC review increases. Annual de novo review improves the IACUC's familiarity with the protocol and thus enables the committee to evaluate the renewal submission and identify modifications required for approval more efficiently and effectively. As a result, both the review time and the number of required modifications decrease, streamlining the review process.

Amendment review. As mentioned, the IACUC must review and approve any significant changes to previously approved activities before their implementation. To help ensure compliance as well as to effectively manage IACUC burden, it behooves IACUCs to develop broad, flexible, and clear definitions of significant and minor modifications and to ensure that investigators clearly understand those definitions and the steps required before a change can be implemented. Modifications deemed significant can be brought to the attention of all IACUC members with an opportunity to request full-committee review; those deemed minor can be administratively entered by IACUC personnel into the protocol application without committee notification.

It is beneficial, however, to require that all changes, whether minor or significant, be brought to the attention of the IACUC administration. This approach ensures that investigators do not err in defining a significant change as minor and inadvertently initiate a procedure that should have had IACUC review and approval. If minor in nature and entered administratively in the application, this practice not only reduces the administrative burden on the IACUC but also ensures that all protocols accurately reflect all ongoing activities.

Semiannual program review and facility inspections. Both the USDA Animal Welfare Regulations (CFR 2005 § 2.31(c) 1 and 2) and the PHS Policy (NIH 2002, IV.B.1 and 2) obligate IACUCs to review the institutional animal care and use program and inspect animal facilities at least every 6 months. Together, these two activities are the IACUC's best opportunity to assess both the effectiveness of the program and institutional compliance and to make recommendations for enhancing the program as necessary. An effective means of conducting program review is to assign one or more of the program components to pairs of voting members (for USDA-regulated programs only) for close evaluation before the program review and then for presentation at a meeting where the committee can consider and assess the quality of the component. Such an approach necessitates the provision of related documents to the various teams so they can familiarize themselves with the process, review changes implemented over the previous 6 months, and prepare their recommendations for improvement if needed.

For example, 4 weeks before the scheduled program review, the IACUC chair assigns the investigator training program to the community member and the attending veterinarian. IACUC staff provide the team with a written description of the training component of the animal care and use program, frequency of delivery, documentation of participation, and training and qualification records. With this information the team ensures, at a minimum, that topics include those mandated by the USDA Animal Welfare Regulations (CFR 2005 § 2.32(c) 1-5), new animal users are enrolled in a timely manner, participation is documented, and specialized training (e.g., wet labs) and/or proficiency assessments are in place as needed. At the IACUC's semiannual program review meeting, the team presents an overview of the training program, changes implemented since the previous review, the effectiveness of identifying and enrolling new users, training documentation, and any incidents that may indicate lapses in training. With all of this information IACUC members will be sufficiently knowledgeable to assess whether the institutional training program permits the IACUC to fulfill its charge of ensuring that users are appropriately trained and qualified.

The physical inspection of animal facilities and support areas presents another opportunity for the IACUC to assess compliance. Teams of at least two voting members (USDA-regulated areas only) should be assigned to each required inspection area including those outside the centralized animal facilities (e.g., laboratories). These teams should receive previous inspection reports to alert them to areas that may need greater scrutiny. Augmenting the team with an escort such as the responsible veterinarian or animal care supervisor well versed in the ongoing animal care and use activities also makes the inspection process much more effective. Providing copies of relatively controversial or invasive animal research protocols in their inspection areas also prepares the team to look for and recognize unapproved activities and unexpected outcomes. Once the teams have inspected all areas, they should reconvene and present their findings to the IACUC for consideration and action as needed.

Unexpected outcomes. Investigative staff and veterinary and animal care personnel should clearly understand their obligation to recognize unexpected study outcomes (i.e., unanticipated or unpredicted adverse events such as mortality, morbidity, or increases in pain and distress) and to alert the IACUC if they occur. All members of the team (not just investigative staff) must therefore have access to and be familiar with the approved procedures and anticipated outcomes. If there are deviations, these individuals must notify all key personnel including the IACUC. Unexpected outcomes may necessitate rereview of the approved protocol, significant modifications to the research design, consultation with the attending veterinarian, and/or consideration or reconsideration of alternatives to painful/distressful procedures. Ensuring that all team members understand their responsibility will help ensure that ongoing activities are in keeping with the approved procedures and, if a modification is necessary to minimize or thwart future unexpected outcomes, that it is appropriate and approved before the research continues.

Creating and maintaining this culture of self-auditing can be challenging. In order for it to succeed, the philosophy must be supported by senior management and practiced at every level. Because unexpected outcomes may be perceived as a consequence of noncompliance, investigators may be reluctant to report adverse events and may become defensive when such events are brought to their attention, which can set the stage for antagonism before any formal investigative measures are taken. It is therefore important to use a collegial and nonconfrontational approach, which will encourage investigators to report unexpected study outcomes. Keeping discussions informal, scheduling meetings in neutral or comfortable locations, reinforcing the necessity of the process, and reviewing information collaboratively will go a long way toward creating a positive and open environment for the investigation. Moreover, with a clear understanding of what occurred, the researcher, in concert with animal support staff and the IACUC, will likely develop methods to prevent or minimize future occurrences.

Mechanism for reporting animal welfare concerns. Functional, transparent, and trusted mechanisms for voicing animal welfare concerns and apparent noncompliance contribute to postapproval compliance. This is especially true if individuals understand that it is indeed their obligation to report animal welfare concerns and that their reporting will not have negative repercussions for them.

Unfortunately, even though mechanisms for voicing animal welfare concerns must protect whistleblowers, individuals may be reluctant to report concerns because of the perceived challenges of maintaining anonymity. In addition, complainants must be willing to provide enough information for the IACUC to consider and, if warranted, investigate the concern, including the names of individuals associated with the incident, information that may point to the identity of the individual voicing the concern.

Large institutions may help reduce anonymity concerns through the use of an institutional ethics hotline. In some institutions, hotlines are already in place to address other mandated whistleblower requirements and are staffed by people specially trained to deal with internal affairs. With additional training, hotline personnel can receive and route IACUC-related concerns and act as an intercessor for the individual. In smaller institutions, individuals can be directed to someone outside the day-to-day research arena such as a member of the occupational health and safety office, who in turn can inform the IACUC. In either case, these relatively independent parties can bring a comfort level to the process, making it a "safe," functional, and valuable tool for helping to ensure compliance.

Non-IACUC Oversight Standards

Several non-IACUC oversight enhancements can help to ensure compliance. These practices draw on other departments such as laboratory animal resources, facility operations, security, and environmental health and safety for methods of overseeing components of animal care and welfare.

Clearly Defined Organizational Chart

The intertwining of regulatory lines of authority among various offices and departments can complicate an institution's research oversight structure. Responsibilities and lines of authority should therefore be clearly defined in an accessible and widely distributed organizational chart, which maps the hierarchy and can expedite the resolution of noncompliance issues by clearly indicating whom to notify.

Research Personnel

All animal research staff should have access to and be familiar with both their assigned responsibilities and approved animal use protocols. Such knowledge relies on an institutional culture that fosters collaboration and communication not only between scientists but also between support departments (e.g., laboratory animal resources, facilities operations, environmental health and safety). Only when all team members are fully knowledgeable about animal use activities can compliance be ensured.

Animal Support Staff Personnel

A vigorous, diverse, and well-trained animal support staff (i.e., animal care and veterinary personnel) is one of the most vital components of the animal care and use program. These individuals serve as the animals' "first line of defense" and are often the first responders for care and welfare issues. Additionally, they typically provide direct or indirect support by working closely with research staff. It is therefore critical to provide animal support staff with appropriate training and education not only about animal husbandry and basic veterinary care but also about the research being conducted and the approved animal activities in their areas of care. Such training will enable them to predict and prevent potential problems and better recognize animal health issues related to the research.

A well-engaged animal support staff member can serve informally as a PAM auditor. There are several advantages to this scenario:

The number of animal support personnel typically exceeds that of the individuals dedicated to a formal postapproval monitoring program. In addition, and unlike compliance officers charged with PAM, because animal support personnel are in the animal facility and interacting with animals on a daily basis, they can "audit" compliance at all times, which increases the likelihood of preventing or identifying noncompliant activities.
Animal support personnel who are familiar with the protocol, research staff, and animals are well positioned to recognize protocol drift and/or unexpected outcomes.
Because they work in close proximity to each other, animal support personnel and research staff often develop mutual respect and trust, thereby minimizing potential antagonism and encouraging collaborative approaches.
Daily observation of animals helps to identify deviations from normal behavior, whether unanticipated or expected as a consequence of the research.

Animal support staff that manage animal procurement, animal census, and veterinary service requests can use this information as well to help ensure protocol compliance. In an institution where most animal use activities are conducted by animal support staff, compliance can be ensured by cross referencing service requests with the approved animal use protocol. When service requests differ from what was approved by the IACUC, these individuals can point out the discrepancies and work with the investigator and IACUC to ensure that an amendment is approved before the start of the activity. This proactive relationship reduces the likelihood of noncompliance.

In all these ways, animal support staff serve as the "first line of defense" not only for the animals but also for the IACUC in helping to ensure protocol compliance.

Inherent Safeguards

Animal use personnel must have a sound understanding of the IACUC approval process and must be proficient in the techniques they are approved to perform. Animal use proficiency and a sound understanding of animal use requirements will help to prevent unapproved activities and minimize animal use mishaps.

Centralized Animal Ordering/Census

Animal procurement and census management software should be used to track animal usage back to the approved protocol. Such software also provides a central data storage repository and method of procuring animals under animal support personnel control. The use of third-party or in-house-developed software makes the management of this information much easier. In addition, safeguards (e.g., warning PIs of their protocol's pending expiration and/or the percent of animals already used) and limits (e.g., preventing PIs from requesting animal orders past the protocol expiration date, establishing blackout order dates) build in compliance. Through the use of software controls (e.g., blackout dates, approval expiration alerts, and cross checks with approved protocols), strong centralized animal ordering procedures virtually eliminate the risk of using more animals than are approved and prevent the ordering of animals or species not approved for use. Integrated census software can remove many of the difficulties associated with manual census taking and serves as a backup to the animal ordering data, ensuring that the numbers ordered correspond with the actual number in the facility.

Medical Records Maintenance and Review

The proper documentation and monitoring of medical records relating to dosing; pre-, peri-, and postoperative care; and scoring systems are important to ensure compliance with the approved protocol. Any deviations from the protocol (other than veterinary emergencies) should prompt the submission and review of an amendment as necessary. The development, maintenance, and storage of medical records should be managed by animal support staff. Veterinary staff should routinely review these records as part of their veterinary care program.

Centralized Drug Dispensing

The centralization of drug acquisition and dispensing enables the proper monitoring of their use and allows the dispensary to stock, distribute, and monitor only those drugs that have been approved for animal use, safeguarding against the use of unapproved drugs.

Restricted Access to Animal Facilities

Access to vivariums and other animal facilities should be restricted to approved animal users and should be contingent on the completion of prerequisite training as well as an approved protocol. Animal care managers or supervisors should escort new animal users through the facility, describe entry procedures and personal protective equipment, and reinforce the importance of enrolling in the occupational health and safety program and adhering to IACUC policies and procedures. Vivarium management systems can support many of these tasks (e.g., create/limit access, track personnel in the facility).

Centralized Facilities

Limiting the use of laboratories and areas outside of the centralized animal facilities will facilitate frequent daily monitoring of the animals and activities by animal support staff. This approach not only minimizes the amount of necessary oversight resources but also helps to ensure compliance.

Conclusions

A formal PAM process is not a regulatory requirement, but it can be a valuable tool for assessing overall program health as well as ensuring compliance with IACUC-approved activities, which is clearly mandated. While useful on a case-by-case basis, however, PAM is not actually necessary to achieve a healthy and sustainable animal care and use program. And implementing a formal PAM process for the sole purpose of identifying protocol deviations—without a subsequent reassessment of the adequacy of the program component(s) that should have prevented noncompliance in the first place—creates just another time-consuming and expensive process that falls short of its full potential and funnels monetary and personnel resources away from other program components that could benefit from them.

Alternatives exist for institutions willing to invest the resources to develop a comprehensive animal care and use program. In particular, the enhancement of certain mandated program components to improve oversight can help minimize or prevent noncompliance. Ensuring postapproval compliance using such program oversight enhancements (POE) can strengthen the animal care and use program and decrease its dependency on a formal postapproval monitoring process, as well as supplement and in many cases prevent the need for a formal PAM process.

A properly functioning program identifies and corrects its own deficiencies through aggressive training and monitoring at all levels, along with a culture dedicated to collaboration, teamwork, and self-regulation, without the need for regulatory enforcement. Whatever approaches are used to ensure compliance, they should be adapted to the nature and frequency of compliance issues at the institution, and they should strive to foster partnerships that meet the needs of the research program while ensuring compliant animal care and use.

Abbreviations used in this article: IACUC, institutional animal care and use committee; IO, institutional official; PAM, postapproval monitoring; PHS, US Public Health Service

References

CFR [Code of Federal Regulations]. 2005. Regulations Title 9, Volume 1, rev. January 1, 2005. Washington: Government Printing Office. Available online (http://www.aphis.usda.gov/animal_welfare/downloads/awr/9cfr2.31.txt), accessed June 11, 2008.

Greene M, Pitts M, James ML. 2007. Training strategies for institutional animal care and use committee (IACUC) members and the institutional official (IO). ILAR J 48:131-142.

Haywood J, Greene M, James ML, Bayne K. 2005. Engaging the IACUC through comprehensive training. Lab Anim 34:33-37.

James ML. 2002. IACUC training: From new-member orientation to continuing education. Lab Anim 31:26-31.

NIH [National Institutes of Health]. 2002. Public Health Service Policy on Humane Care and Use of Laboratory Animals. Bethesda: NIH Office of Laboratory Animal Welfare (OLAW). Available online (grants.nih.gov/grants/olaw/references/phspol.htm), accessed June 11, 2008.