Institutional Animal Care and Use Committee Postapproval Monitoring Programs: A Proposed Comprehensive Classification Scheme

Abstract

Introduced over 20 y ago, IACUCs undertaking postapproval monitoring (PAM) of animal research procedures as a means to ensure researcher compliance is now widely used as an oversight tool in laboratory animal research. Through a literature review evaluating the history of PAM in the United States, discussions of controversy surrounding PAM activities, and reflections on how PAM activities are described within the IACUC community, we present an up-to-date and comprehensive classification system for PAM program methodologies that could serve to standardize how such activities are characterized in IACUC policies, communicated to research staff, used in training programs, implemented for the desired impact by individuals involved in animal research oversight, and referenced by regulatory agencies.

Numerous peer-reviewed manuscripts and book chapters describe the logistical components involved in supporting an IACUC's postapproval monitoring (PAM) program, although the creation and maintenance of such programs is not expressly found in federal animal research regulations and guidelines. Early references to PAM appeared in the late 1990s.⁸ Two foundational references to the “monitoring of approved protocols” come from the 2002 publication Institutional Animal Care and Use Committee Guidebook and a report on research integrity from the National Academies of Science.^3,8,12 The term ‘post-approval monitoring,’ specific to protocols, was the focus of a 2003 manuscript published in Contemporary Topics in Laboratory Animal Science, now called the Journal of the American Association of Laboratory Animal Science (that is, JAALAS), and appears to be the earliest mention of the PAM terminology within the peer-reviewed literature.¹⁹

In 2008, the Institute for Laboratory Animal Resources (ILAR) Journal published a series of articles focused on postapproval monitoring in volume 49. That issue, issue 2, was titled “Animal Use and Oversight: Balancing Risk Management with Burden.” To this day, that issue remains the source of 2 pivotal and widely cited papers on PAM programs and regulatory burden.^5,11 The descriptions of PAM in that issue were subsequent to a 2007 book chapter on the same topic.⁴

Since the 2008 ILAR Journal issue, very few peer-reviewed manuscripts have provided more appropriately detailed and robust discussions of PAM, including how outcomes and successes should be evaluated.^17,20 At the same time, a growing community of IACUC administrators and members has developed additional descriptors for various PAM activities that do not appear in the peer-reviewed literature. Through this overview, we seek to update, illustrate, define, and classify various types of PAM activities as they are now undertaken by IACUCs and to discuss how providing such precise descriptions can benefit animal care and use programs and animal research oversight at-large.

Defining Postapproval Monitoring

Perhaps the most fundamental definition of PAM, as conducted by an IACUC, is found in one author's contribution to the aforementioned 2008 ILAR Journal issue.⁶ His definition is: “PAM can be briefly defined as any effort focused on determining what happens to animals after IACUC approval has been granted for their use in research, teaching, or testing.”

In short, PAM is a mechanism for assuring that animal activities are conducted in a manner consistent with the IACUC-approved protocol. Such a simple—and admittedly brief—definition allows an IACUC to craft their own PAM programs. This accommodation is especially crucial given that implementing and maintaining a compliance program with the use of the term “postapproval monitoring” is not directly included in the most commonly referenced regulations and guidelines that outline IACUC responsibilities.^6,7 For example, the Animal Welfare Regulations state that after approval of proposed activities, IACUC facility inspections must be conducted “at least once every 6 months” and continuing reviews be conducted “not less than annually.”² A new section entitled “Postapproval Monitoring” was included in the 2011 edition of the Guide for the Care and Use of Laboratory Animals.¹⁰ Multiple IACUC activities, such as continuing protocol review, laboratory inspection, veterinary observations, and others, were included as possible mechanisms for postapproval monitoring, although the Guide's authors recognized that “The level of formality and intensity of PAM should be tailored to institutional size and complexity… .”¹⁰ Federal laws, regulations, and policies are referenced as requiring continuing IACUC oversight of animal activities, but no explicit obligation is provided.¹⁰ The PHS Policy on Humane Care and Use of Laboratory Animals does not contain the phrase ‘postapproval monitoring’ but mentions the necessity for “…continuing review of each previously approved, ongoing activity….at appropriate intervals as determined by the IACUC, including a complete review…at least once every 3 years¹⁴.”

PAM programs emerged 2 decades ago as a common method to fulfill various IACUC requirements and expectations, as appropriate to institutional programmatic oversight, as well as protocol review activities.⁶ Therefore, an IACUC must understand that PAM programs are entirely dependent on how the institution defines and conducts that program. Although PAM reference sources provide some best practices for IACUCs as they develop PAM programs—including recommendations regarding logistics, tracking and metrics, resourcing, and reporting—PAM is a very institutionally specific activity due to the lack of exacting requirements.

Classifying Postapproval Monitoring Program Methodologies

Given the opportunity to institutionally define PAM programs, including features of PAM methodology, goals, allocated resources, and compliance focus, the IACUC community has created many classifications and descriptors for PAM. Some commonly used descriptors of PAM program methodology have their origin in the early literature, whereas many of the newer descriptors, which are a result of the maturation of PAM programs and discourse at IACUC-focused conferences and meetings, have not yet been documented in the peer-reviewed literature.

PAM program methodology descriptors are generally presented as choices between 2 options, a distinction which developed early in the PAM literature. Selecting between the options is not necessarily mutually exclusive, given that multiple PAM activities and options can be used concurrently within the same animal care and use program. Because of the ubiquity of this compare-and-contrast ideology for PAM program methodologies, we adopt this binary scheme for our classifications discussed here. We do not include descriptors that are specific to the types of research procedures being monitored, such as surgical PAM, which have previously been described, as well as descriptors of a PAM program's goals, such as “compliance” and “collaboration.”^4,5,8 The intent of our updated descriptors and proposed classification scheme is to allow for PAM activities to be identified independently from the types of research being monitored, such that any type of PAM activity as defined in our classification scheme can be applied to any type of research or animal procedure being monitored.

The proposed classifications are presented in a binary fashion and start with those already described in the literature, in the order of their appearance in the literature. After those classifications, we then define newer descriptions that are not yet included in the literature.

Protocol or administrative review compared with procedural observations.

As previously noted, early discussions of PAM referred to the activity as “monitoring” and, in particular, the monitoring of protocols.^18,19 Protocol and administrative monitoring, or reviews, has generally been described as conducted through a meeting between principal investigators or animal research staff and IACUC representatives, without direct observation of animal procedures.⁷

Procedural observations include direct observation of an animal procedure by a trained person authorized (or otherwise delegated) by the IACUC to determine adherence to approved protocols, IACUC policies, and other applicable guidelines as established by the IACUC.⁷ Several authors present these 2 PAM activities as a sequence: first, there is a meeting between the IACUC designee and researchers to discuss procedures and other requirements, and then second, there is the observation of the previously discussed procedure.^7,18 One can infer that these activities could occur either during the same visit or be separated by a period of time.

Some institutions with limited resources or insufficient qualified personnel to conduct procedural observations as part of their PAM program have restricted their PAM activities to protocol and administrative reviews only. In doing so, they may use a detailed checklist (an example of which can be found in reference 18) and a standard set of questions during their meetings, to ensure that they are gathering the intended information. Limitations of using this approach as the sole mechanism for monitoring are self-evident and include the inability to match procedure descriptions included in the protocol with actual procedure conduct, receipt of incomplete or incorrect check-lists due to nonunderstanding of the questions or meeting context, inability of the PAM monitor to effectively solicit the correct information, and meeting with research staff who are not knowledgeable about the protocol or procedure conduct. Because of these limitations, many authors exhibit a clear preference for performing procedural observations as the main component of the PAM process.^4,5

Formal compared with informal (or active compared with passive) PAM.

After solid descriptions of PAM activities were published, including the protocol or administrative and procedural observations categories, debate started regarding what exactly constitutes PAM. The 2008 description of PAM in the ILAR Journal contains no indication that PAM has to be an entirely separate program conducted by the IACUC or other institutional entity (for example, attending veterinarian, institutional official, compliance officer) compared with one that is packaged within an already existing IACUC activity.^7,15

Other authors, in their contribution to the 2008 ILAR Journal issue, argued that “…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.”¹⁵ Essentially, these authors contended that if the prescribed IACUC review mechanisms already operate with appropriate quality and effectiveness, the need for a formal PAM outside of these prescribed activities diminishes. Already existing mechanisms that they identified as contributing to informal PAM activities included training, establishing IACUC-approved policies and procedures, conducting protocol and amendment review, conducting semiannual program reviews and inspections, and reviewing unanticipated outcomes and animal program concerns. Others have identified ongoing observations of animals by the animal care and veterinary staff as another mechanism of informal PAM.¹³

Opposition to the idea that PAM can be accomplished without formal or active monitoring stems from ideological differences regarding the intent of mandated activities for IACUCs. Required IACUC program reviews and inspections serve as high-level overviews of an animal care and use program's overall compliance, thus contrasting with the intent of active protocol review or procedure observations that serve to document protocol congruency and making PAM “complementary” to activities required by regulations and guidelines.⁴ Descriptions of possible PAM methods, as previously noted, depicted in the Guide do not appear to promote formal programs as compared with informal programs, leaving that decision to the IACUC despite general encouragement for IACUCs to incorporate PAM into their programs.¹⁰ Because the Animal Welfare Regulations² do not require PAM, no description of any PAM program needs to be submitted to the enforcing agency (that is, the USDA). PAM is not a required element in the OLAW Assurance document submitted every 4 y by institutions receiving NIH funds, although providing a description a formal PAM program can be used when writing about an institution's methods of continuing review as required by PHS Policy.¹⁴ AAALAC asks about “…ongoing protocol assessment and compliance…” in its program description document, and the use of PAM could be recognized as a superior method of ensuring compliance.¹

IACUC staff, IACUC members, veterinarians, and others debate this issue within their institutions, at conferences, and with regulators on a continual basis. Descriptors of ‘informal’ and ‘formal’ PAM have developed to identify postapproval activities conducted within the confines of what IACUCs are required to do (informal) as compared with the undertaking specific activities outside of those required with the sole purpose of identifying compliance to IACUC-approved procedures (formal). By extension, one could then label the informal approach as passive PAM (that is, occurring passively through ongoing IACUC actions) and the formal approach as active PAM (that is, engaging in additional, nonmandated activities). The reason for the continued debate between these two PAM approaches is multifaceted and includes the strong desire to not create self-imposed regulatory burden, understanding that small programs should concentrate on conducting required activities as effectively as possible and should not be made to feel as though their program is somehow deficient in the absence of formal PAM activities, recognizing that extra activities identified as PAM should not supplant IACUC-required activities, and acknowledging that PAM activities are not required by federal laws, regulations, and guidelines.^6,13,16

Unlike protocol or administrative review, procedural observations, and other PAM options included in this manuscript, informal PAM is already in existence within the animal care and use program without any label being ascribed to it. Programs maintain informal or passive PAM, regardless of the effectiveness of such monitoring, through continuing activities until if or when they implement designated monitoring in addition to the ongoing required IACUC activities. At that time, the IACUC has instituted a formal PAM program.

While the debate continues, the persistent use of the acronym PAM in IACUC vernacular has become synonymous with formal or active PAM, most likely as a result of the need to distinguish required monitoring activities from nonrequired activities as well as the acknowledged growth in the number of IACUC staff whose conduct of formal PAM work constitutes either a portion or the entirety of their position. An example of this application can be found in a recent publication evaluating postapproval monitoring practices at biomedical research facilities with NIH funding.⁸ Even though informal PAM activities were surveyed and reported on, when a “PAM program” was referenced, the phrase was taken to mean a formal or active program according to the program methodology classification scheme provided in this manuscript.

Announced compared with unannounced (or scheduled compared with unscheduled) monitoring.

Distinguishing between announced and unannounced PAM is explicit. IACUCs who conduct formal PAM should determine whether they will use unannounced PAM visits if they conduct formal PAM activities. Given the previous assessment of protocol or administrative reviews and procedural observations, the default for such PAM would be to request a meeting time with the identified researcher and to announce the nature and focus of the monitoring activity prior to any meeting or animal procedure observation.

One author has suggested that unannounced PAM visits should preferably be a component of “high-risk” reviews of specific laboratories.⁵ In this case, researchers would have little to no time to prepare, allowing for a baseline evaluation. In addition, unannounced PAM can serve as an opportunity to substantiate (or not) allegations of impropriety.⁵ A more robust discussion about whether advance notice should be given to investigators should include whether facilities or locations—rather than researchers or procedures—should be identified as areas where unannounced PAM occur with increased frequency, in light of the nature of the animal research conducted in that area.

Random compared with targeted or selected review.

Little has been discussed in the literature regarding random or targeted researcher selection for PAM visits. With this classification scheme, formal PAM activities could be administrative or observational and then announced or unannounced. The gist is that with random PAM visits, there is no particular reason that a researcher has been identified to undergo PAM monitoring other than a chance selection by monitoring staff. However, the larger group of researchers from which recipients of random PAM are selected should purposefully be organized.

For example, IACUC policies and procedures could categorize approved procedures by risk to the animals, the researcher's competency and compliance history, the species, and other factors.⁸ Once risk has been established—usually categorized as low, medium, or high or some derivation thereof—then a certain number of researchers or procedures can be selected at random from that larger group for PAM visits. For example, an institution could state that each year, 10% of all high-risk procedures but 5% of all medium- and low-risk procedures will be selected randomly and observed under a formal PAM program. From year to year, researchers could be moved in or out of the larger selection group, according to previous PAM outcomes or other predetermined criteria.

Much information has been written about risk in animal care and use programs, including the previously cited references from the 2008 ILAR Journal issue. In 2002, the then USDA APHIS Administrator indicated that USDA pain classification (B, C, D, or E) could also serve as a risk classification method, and many institutions have since adopted this viewpoint, resulting in increased scrutiny and detailed review of proposed IACUC protocols that include procedures that are classified as category E.⁹ Closer evaluation reveals, however, that the pain classifications (or columns, given that they refer to columns of the currently formatted USDA Annual Report form [APHIS Form 7023]) do not directly correspond to risk. Pain category definitions do not include risk, instead focusing on whether animals are used in research and whether they undergo painful and distressful procedures with or without alleviation of the pain or distress.² It is conceivable that one animal can undergo a very transient, noninvasive yet painful or distressful procedure without alleviation of the pain and distress, be placed in column E, and then noted as “high risk,” whereas another animal may undergo multiple major survival surgeries with significant medical risk, be placed in column D due to alleviation of pain and distress through analgesics and other methods, and be considered at reduced risk, due to the incongruity between pain category definitions and procedure risk. Institutions should, therefore, give careful consideration to what they consider risk for purposes of establishing PAM frequency and include in their deliberations not just pain columns, but the invasiveness of procedure, competency of the researchers, species being used, compliance history, appropriateness of facilities and support equipment, newness to the institution, as well as the history of procedural outcomes.

Targeted or selected PAM programs assign the receipt of formal PAM activities on the basis of the aforementioned risk analysis as well as other criteria established by the institution. With the adoption of these criteria, a PAM visit would be explicit and conducted with specific intent. During the PAM visits, the monitor can ask to view specific procedures or ask targeted questions to gather the information needed to evaluate ongoing risk.

Regularly scheduled compared with heightened monitoring.

All of the above classifications for PAM assume a level of regularity in an institution's PAM visit schedule. Established PAM schedules can provide assurance that monitoring is occurring within the frequency prescribed by the IACUC and provide assurance to researchers that they will not receive monitoring at a rate that could interfere with their research.

Heightened PAM, which has not yet been fully described in the peer-reviewed literature, therefore infers that there exists an increased frequency of PAM activities for a researcher in light of previous PAM outcomes or recent incidents of noncompliance, either of which can indicate that the researcher needs additional assistance with animal procedures to meet IACUC and regulatory expectations. With more frequent monitoring, PAM staff are available for the researchers as they ask questions or need immediate assistance to achieve compliance. In addition, the fulfillment of any required corrective actions can be ascertained quickly.

When researchers have been identified for heightened PAM, they should be told so and given a reason why, so that they do not inadvertently interpret the IACUC's actions as “harassment.”⁴ In addition, investigators should be informed regarding whether visits will be announced or unannounced and for how long they will be subject to this increased monitoring. Periods of heightened PAM can extend for a specific time (for example, 3 mo), a specific number of visits (for example 3 additional visits during a year), until a preidentified goal is reached (for example, 3 experimental surgeries conducted with no complications), or other predetermined objective. In our experience, requiring heightened PAM for a researcher can serve as the corrective action to address situations of noncompliance.

Conclusion

IACUCs should describe their PAM program methodologies, regardless of their intent to implement a formal PAM program. Ideally, this description should be found in a dedicated PAM policy or in policies for required IACUC activities during which postapproval monitoring occurs (for example, facility inspections). Armed with good policies describing monitoring endeavors, IACUCs can readily explain their philosophy and actions to regulators, accreditors, researchers, administrators, and others. To emphasize an IACUC's choice in the type of PAM used, principal investigators and their research staff should be told what kind of PAM they underwent when they receive a report (for example, where they randomly selected? Or were they specifically selected owing to a high-risk procedure?).

Both authors teach intensive IACUC training programs across the United States where audience members are composed of IACUC members, administrators, veterinarians, and institutional officials. Presenting the PAM program methodologies within a framework of binary classifications has proven to be an effective training technique. Trainees quickly learn not only how to label PAM activities but also how to describe how and when they can best be integrated into existing IACUC functions, or how formal PAM programs can be created anew. Thus, classifying PAM program methodologies becomes an effective training tool.

The classification scheme of PAM program methodologies that we furnish herein can give IACUCs the ability to describe their formal PAM activities and write policies in a consistent and standardized manner; again, this consistency can help with regulatory inspections, accreditation visits, and training. The ability to explain a PAM program as “formal, focused on procedural observations, with both random and targeted visits” conveys a lot of information to a new researcher or visitor assessing a laboratory animal program. Adopting this classification scheme can standardize the way with which the animal research community discusses PAM, aid IACUC training, and create the ability of IACUC administrators to consistently benchmark PAM programs and outcomes across institutions, perhaps fostering PAM-centered research and more inclusion within the peer-reviewed literature.