Matthew R. Bailey

Love Animals? Support Animal Research

is working to reduce, refine, and replace the use of animals when and wherever it is feasible. Positive language resonated with focus group participants, while defensive posturing raised red flags. In a follow up national poll4, participants offered a serviceable answer to the question of how to change public opinion: a clear majority—57%—would support the use of animals in scientific and medical studies for “the development of medications prescribed by veterinarians for animals.” It’s important for people to understand how medications and treatments developed with animal research have included drugs to prevent heartworm infection, vaccines against rabies, and even better nutrition for pets. And in the future, companion animals stand to benefit from discoveries that will result from scientific and medical studies with animals. After all, an estimated 12 million cats and dogs are diagnosed with cancer each year in the United States5. If, as FBR’s polling results suggest, the public is likelier to view animal research more favorably when they consider how their pets are direct beneficiaries, efforts to change hearts and minds should focus on the relationship between scientific studies with animals and advancements in veterinary medicine. Messages should also emphasize how medical research benefits both humans and animals simultaneously. In an educational outreach campaign that launched in late 2017, FBR is using this approach to promote broader public understanding of, and subsequent support for, animal research.

Two opportunities to address regulatory burden

all existing regulations, policies, guidance documents, FAQs, and interpretive rules. There was also a recommendation that the NIH and USDA establish a risk-based process for review of animal research protocols similar to that for human subject research where defined procedures can be managed as either exempt from review or undergo an expedited review process without concurrence by the full IACUC. There was a separate set of recommendations for the NIH including streamlining the assurance process to include proof of accreditation in lieu of the detailed program description, revising the guidelines on prompt reporting to include only those incidents that jeopardized the health or well-being of animals, and eliminating the requirement for verification of protocol and grant congruency. There was also a recommendation that because the Guide recognizes the need for alternative strategies to “should” statements, such alternative strategies should not be considered departures or deviations from the recommendations in the guide. Final ly there were recommendations to the USDA calling for a revision to §2.31(d)(5) of the AWA Regulations (AWR) so that the current requirement for annual review would be changed to at least once every three years. There were two recommendations requesting changes to USDA Animal Care Policy #14 and #12 to reflect the existing language in the AWA and AWR placing the final authority for approving multiple major operative procedures and the written narrative description concerning alternatives to potentially painful or distress procedures in the hands of the IACUC. The USDA’s Federal Register notice requests comments from the public about the regulatory burden they have experienced and ideas for regulatory reform at the department. Specifically, USDA is looking On October 24th, the Association of American Medical Colleges (AAMC), the Federation of American Societies for Experimental Biology (FASEB), the Council on Governmental Relations (COGR), and NABR released a report (http://www.faseb.org/Portals/2/PDFs/ opa/2017/FASEB-Animal-RegulatoryReport-October2017.pdf) on regulatory burden in response to the language in the 21st Century Cures Act. The report grew out of an April 2017 workshop convened by these organizations. The workshop participants sought to identify federal requirements that demand significant administrative effort but do not enhance animal welfare. “The goal of the workshop was to develop recommendations for promoting regulatory efficiency, animal welfare, and sound science.” These recommendations were to be directed to federal agencies involved in the oversight of federally funded animal research, in particular the NIH and USDA. These recommendations propose changes to federal regulations, policies, and guidelines governing the use of animals in research. The proposed changes would ensure that standards of care in animal research are maintained and would have the practical effect of promoting efficiency among researchers. There were recommendations directed to the Executive Office of the President and Congress addressing issues such as consolidating animal research oversight under a single Federal entity, requiring a 60 day comment period for policies, guidance documents, frequently asked questions (FAQs), or interpretive rules, and amending the statutory language for annual inspection of research facilities and semi-annual inspections and reviews by IACUCs. There were recommendations directed at both NIH and USDA including appointing an external advisory group of experts to assist with the review mandated by the Currently there are two opportunities for the biomedical research community to address the issue of regulatory/administrative burden. One involves the language contained in the 21st Century Cures Act (https://www.congress.gov/114/bills/hr34/ BILLS-114hr34enr.pdf) and the other the United States Department of Agriculture’s (USDA) Request for Information (RFI) published in the July 17th Federal Register entitled “Identifying Regulatory Reform Initiatives” (https://www.regulations.gov/ document?D=USDA-2017-0002-0001). This piece will review these opportunities. The 21st Century Cures Act was signed into law December 13, 2016. The Act contains several features important to the biomedical research community, including measures intended to advance research and expedite approval for lifesaving cures. It also provides for the review of regulations and policies affecting researchers using animal models, with an emphasis on reducing administrative and regulatory burden. The key language appears on page 69 in Section 2034 of the Act entitled “Reducing the Administrative Burden for Researchers.” That language requires the Director of the National Institutes of Health (NIH) to collaborate with the USDA and Food and Drugs Administration (FDA) in a review of policies and regulations for the care and use of laboratory animals and where appropriate. It also requires the agencies to revise and reduce burden placed on investigators, while protecting research animals and maintaining the integrity and credibility of research findings. A report on these efforts is due within two years of the enactment of the law. The language in the Act specifies that the input of experts should be sought in this process and identifies three specific areas that the collaborating parties should address. Two opportunities to address regulatory burden

Addressing administrative burden: a primer for submitting comments to the USDA and OLAW

In the February issue of Lab Animal, we provided an overview of two opportunities for the research community to address regulatory burden. One of those was issued by the USDA, titled “Pursuant to Executive Order 13777—Enforcing the Regulatory Reform Agenda,” and the final date for comment is July 17, 2018. The second opportunity was the result of language in Section 2034 of the 21st Century Cures Act, which requires that “the Director of National Institutes of Health, in collaboration with the Secretary of Agriculture and the Commissioner of Food and Drugs, shall complete a review of applicable regulations and policies for the care and use of laboratory animals and make revisions, as appropriate, to reduce administrative burden on investigators while maintaining the integrity and credibility of research findings and protection of research animal.” The NIH released a notice requesting comments in the Federal Register (Vol. 83, No. 50 / Wednesday, March 14, 2018, p 11221) and posted Notice Number NOT-18-152 on its website. Comments are due by June 12, 2018. In this commentary we will review the two different processes for submitting comments because, as stated previously, this is a unique opportunity for the regulated community to provide input on changes to regulations, guidelines and policies that could reduce regulatory burden on investigators, which should in turn increase the time available for them to carry out their research. It should be noted that the current Animal Welfare Regulations and Public Health Service Policy have not been substantially changed since their development following the 1985 amendments to the Animal Welfare Act and the passage of the 1985 Health Research Extension Act. While the regulations and policy have not substantially changed, the responsible agencies have issued guidelines and policies that have affected the regulated community and resulted in administrative burden impacting individual investigators. Comments submitted in response to the USDA’s Request for Information (RFI) can be submitted by mail to the address contained in the Federal Register notice or electronically through the Regulations. gov website (https://www.regulations. gov/document?D= USDA-2017-00020001). The RFI includes four questions the USDA would like commenters to consider, but one is not required to address them individually or at all, and there is no limit to the length of comments. Comments can be written in the online form, or previously developed comments can be uploaded. Some commenters will choose to upload the comments of professional organizations in their entirety while others will simply endorse the comments of a particular organization. Commenters are free to make whatever comments they so choose. All previously submitted comments are available for review in the “Docket Folder.” To submit comments in response to the NIH’s request, the simplest way is to go to NOT-OD-18-152 Request for Information (RFI): Animal Care and Use in Research ((https://grants.nih.gov/grants/guide/noticefiles/NOT-OD-18-152.html). The Notice provides the Purpose of the RFI, some Background Information, the Information Requested and How to Submit a Response, which links to the response portal. Unlike the aforementioned Regulations.gov portal, this portal asks commenters for input on specific proposed actions and restricts users to a 1000 word limit for each comment box. There is also a comment box for other approaches not mentioned. OLAW is also asking for feedback on whether five identified tools/resources are or would be helpful in reducing burden on investigators. Unlike the Regulations.gov portal, the NIH portal will not provide access to the comments that have been previously submitted. The regulatory process in the United States is a participatory process that allows the regulated community to provide their expertise as regulations are being developed, and it has been over thirty years since the current regulations and policies that govern how animal care and use programs operate were proposed. The Final Rule to implement Parts 1 & 2 of the Animal Welfare Regulations subsequent to the 1985 amendments to the AWA received 7,857 comments (https://www.nal.usda.gov/awic/ final-rules-animal-welfare-9-cfr-parts-12-and-3), while the more recent USDA RFI published January 26, 2016 entitled “Identifying and Reducing Regulatory Burdens” (https://www.regulations.gov/ docket?D= USDA-2016-0001) received 73 comments, of which only 19 came from the biomedical research community. The current NIH notice lists five reports or surveys which address the issue and/or impact of regulatory/administrative burden on investigators. Reducing that burden would not only allow the investigators to be more productive but allow those responsible for the oversight of the animal care and use program to devote more time and resources to activities that have direct impact on animal welfare. In this commentary we have described the steps necessary to participate in the regulatory process by making comments on two RFIs which are requesting information on ways to reduce the regulatory/ administrative burden on investigators. In the recent past the research community has failed to take full advantage of this participatory process at the level it did in the late 1980’s. That needs to change. It is important that federal agencies requesting this information hear from the regulated community so they fully understand which regulations, guidelines and policies could be revised to reduce administrative burden on investigators “while maintaining the integrity and credibility of research findings and protection of research animals.” ❐

Updates on Animal Care guidance documents

A recap from the latest “Q&A with the USDA” webinar addressing the USDA Tech Note on Incentives and updates to the Animal Welfare Inspection Guide.

Policy watch: revisions to the Animal Welfare Inspection Guide

that had serious or severe animal welfare consequences and there are ongoing risks for the same serious or severe adverse effects at the time of the inspection should be marked as a Direct.” An example of this would be equipment that resulted in a prior serious injury or death to an animal that was still malfunctioning with a high potential to cause additional serious injury or death in the future. There are three areas addressing delivery of the inspection report. On pages 2–12 the requirement for an in-person exit interview has been strengthened and the language on pages 2–13 requiring an explanation for the refusal of a facility representative to sign an inspection report has been expanded to include specifics regarding “who said what to whom, when, where, and how.” On pages 3–20 (Completing the Inspection Report) is the requirement that inspection reports with Direct NCIs must be completed and delivered to the licensee/registrant immediately after the inspection. The new section on the review of inspection and teachable moment reports on pages 2–22 requires the supervisor or their designee to review the inspection report in a timely manner and refers to checklists in Appendix A, pages A-28 and A-34, which should be reviewed by those managing ACUPs. Finally, on pages 3–6, reference is made to an Environmental Enrichment Plan Checklist in Appendix A on page A-24. The checklist is not considered to be allinclusive, and is not retained in the facilities official AC file. Thus, it is not available under FOIA, but should be reviewed by those housing nonhuman primates. While we consider the above sections to be some of the most relevant changes to AWIG, we encourage readers to do their own review of these chapters. “Critical” NCI Identified (a new section on pages 2–9) contains examples of issues classified as “Critical”. Of particular interest to research facilities are issues that involve “a prior adverse event that had serious or severe animal welfare consequences to one or more animals, but poses no current risks to the animals.” The majority of the critical citations reviewed appear to be based on information contained in the facility’s records, specifically the IACUC minutes. Some of the examples of adverse events raised questions that we asked the USDA to clarify during the July 18 webinar. One involved a handling violation resulting in death or serious injury. This raised the question of whether a facility would be cited for incidents where a death or serious injury occurred as a result of another animal’s actions. It would depend upon the history of the facility as it relates to monitoring animal interactions and making necessary changes when issues arise. The USDA recognizes that death and serious injury can result from another animal’s actions with no previous history of aggression between animals, and where no other issues or citations exist, this would not be cited. Another example pertains to conducting procedures involving pain and distress without approval of the IACUC, which states “without appropriate response from the IACUC,” implying if such activity was identified and handled correctly by the IACUC, there would be no citation. There are two scenarios where a facility could be cited: (1) if there was actual serious or severe animal welfare consequences, such as unrelieved pain or distress, regardless of the action taken by the IACUC; (2) where the IACUC had not taken any action regardless of whether the pain and distress was appropriately managed. On pages 2–10 (“Direct” NCI Identified) is a statement we believed needed additional clarification involving “A prior adverse On June 23, 2017, the USDA APHIS Animal Care (AC) released a Stakeholder’s announcement pertaining to revisions to Chapters Two and Three of the Animal Welfare Inspect ion Guide (AWIG) (ID:APHISUSDA/Animal Welfare/ Animal-Care-Inspection-Guide) which addressed the issue of increasing consistency in four specific areas of the inspection process and the types of inspections carried out by the AC inspectors. The issue of increased consistency involved guidance on “teachable moments,” identification of critical Non-Compliant Items (NCIs) to assure correct frequency of follow up inspections, guidance on the review of inspection and teachable moments reports, and documenting the requirements for documenting indoor/sheltered/outdoor housing facilities. Here, we summarize several of the changes in AWIG of interest to those managing animal care and use programs (ACUPs) at registered research facilities. In the process of conducting our review, several questions arose which were addressed by representatives of the USDA who participated in NABR’s July 18, 2017 webinar Q&A with the USDA. On pages 2–5 of AWIG is a list of all of the criteria that must be met in order for a teachable moment to be issued. Within that list, the phrase “Other Critical” appears. Critical NCIs include Direct NCIs while all other examples, found on pages 2–9, are referred to as “Other Critical.” The section entitled Recurring/Chronic NCI on pages 2–8 was moved from Chapter 3 with minor editorial changes. Inspection reports will not designate a Recurring/Chronic NCI, as is the case with Direct, Repeat and Critical NCIs. Policy watch: revisions to the Animal Welfare Inspection Guide

Policy watch: adapting to change in the animal care and use oversight environment

ments submitted is important to provide the requesting agency with a basis for making decisions, the importance of the number of comments cannot be over stated and the lack of input on the part of the research community to this RFI does not bode well for realizing any changes to the Animal Welfare Regulations that could reduce the current regulatory requirements. There were only a total of 29 comments for the proposed De Minimis rule of which merely four appeared to be from the research community. Two were from advocacy organizations and two from individuals. This was not surprising when one considers the proposed rule had little, if any, impact on the research community. However, it did include a technical issue related to the justification of a proposed change that was factually inaccurate; a point that both advocacy groups stressed and which 2 comments from the public highlighted. Adapting to change in the dynamic oversight process in the U.S. is an important element of managing an ACUP, and a key factor in being successful is staying informed and participating in that process when the opportunity presents itself. Staying informed is relatively easy because of the availability of representatives from the regulatory, funding and accrediting organizations at a variety of meetings and with information regularly included in Lab Animal. Participating in the process is also relatively easy because of advocacy groups like NABR which monitor the oversight process and provide their members with necessary information to do so.

USDA inspection data: what a difference a decade makes

for the past four fiscal years are depicted in Table 1. To compare the number of citations for FY 2006 and 2016, a spreadsheet was created using the data from the 2006 Violations Summary (ID: APHISUSDA/animal welfare/violations/2006 violations) for those sections of data contained in Subpart C of the Animal Welfare Regulations ( I D : U S DA A P H I S / A C / B l u e B o o k / AWA/508comp). Subpart C contains those sections unique to research facilities. In FY 2006 there were 2,017 citations in Subpart C compared to 347 in FY 2016 (Fig. 1 depicts the comparison for those citations covered in Subpart C). The total number of citations issued to research facilities under Subpart C has decreased by 87%. For IACUC issues that resulted in no citations. There were a total of 470 citations of which 421 were listed as non-critical, 45 as critical and four as direct noncompliant items (NCIs). Of this total, 44 of the citations were also listed as repeat NCIs. There were 253 facilities which received citations. Of those 160 (63%) only had one citation, the majority of which were records based and did not impact animal welfare. The number of non-critical NCIs, formerly called indirect NCIs, dropped from FY 2015 and this is likely the result of the use of “Teachable Moments.” The number of inspection reports with no citations also went up and is now approaching 80%, an impressive number when you consider a fair number of the citations are based on information contained in a facility’s own records. These data document that the vast majority of the research facilities are doing an excellent job managing compliant programs. A key part of the review and analysis of the inspection data is examining the top ten most frequently cited NCIs and noting the changes over the years in four major areas: IACUC, Veterinary Care, Miscellaneous The National Association for Biomedical Research (NABR) advocates for sound public policy in support of ethical and essential laboratory animal research. One of the essential elements for effective advocacy is being able present facts to those who establish public policy, and often those facts rely on data that are readily available on governmental agency websites. On February 3, 2017, the Animal Plant Health Inspection Service (APHIS) announced that it was removing inspection reports, regulatory correspondence, research facility annual reports, and enforcement records that have not received final adjudication from its website. At the same time the Animal Care Information Service database was deactivated, which NABR uses to conduct an annual review and analysis of the inspection process for its membership. This information is presented in webinars, the most recent of which was entitled “The 2016 USDA Inspection Data: What a Difference a Decade Makes,” where we compared the research facility specific compliance data from FY 2016 with that reported by the USDA for FY 2006. This comparison would have not been possible without access to the deactivated search tool which was used to develop a spreadsheet of the citations for FY 2016. In this News we will highlight the data for FY 2016 and compare it to data from a decade ago. The data demonstrate that the research community has made significant progress in terms of compliance over the last ten years. The spreadsheet generated for the FY 2016 inspections includes 1,339 inspections reports of which 281 included one or more citations; 79% of all inspections USDA inspection data: what a difference a decade makes

Policy Watch: putting the new terms on USDA inspection reports into perspective

animals and half of those involved nonhuman primates. There were eight critical citations involving sections within Part 3 of the regulations and four of those involved nonhuman primates, two of which involved escapes due to alleged cage design issues as opposed to improper handling. There were six critical citations for §2.31 IACUC issues with three involving IACUC functions, two reviews of proposed activities and one involving makeup of the committee. There were three citations for noncompliance with §2.32 Personnel Qualifications and all these involved adverse outcomes following experimental procedures. Data available for the past three fiscal years for research facilities at the time of this commentary was prepared includes 4,102 inspection reports of which 114 included a total of 145 critical citations, which represent approximately 10% of the total citations. During that same period, direct citations accounted for less than 2% of the total citations. The changes that have taken place in how inspections and citations are identified on the inspection reports and entered into the ACIS database should not impact the overall enforcement process for individual facilities. The critical NCI designation has been used for years, included in the database and considered in the overall enforcement process. The fact that this information is now easily accessible in the database along with the inspections that are focused on a specific issue will make that information readily available to those interested in obtaining it, and institutions should be aware and prepared to respond when confronted with such information. adverse impact on animal welfare. Such an event could be one that was noted by the inspector in medical records, in IACUC minutes, or self-reported to the USDA or other federal agencies that operate under an MOU with the USDA. The announcement also indicates that “Direct, repeat and critical NCIs may result in more frequent USDA inspections.” This statement is consistent with the January 31, 2011 Animal Care Enforcement Actions (EA) Guidance for Inspection Reports that appeared in previous editions of the Animal Care Inspection Guide. A search of the ACIS database for FY 2016 indicated that there were 4 direct, 44 repeat and 46 critical NCIs. A review of the actual inspection reports containing critical NCIs reveals that, with one exception, the term “Critical” only appeared on the actual reports generated after September 2016, but a review of all the reports provides examples of what types of events are being so classified. Of the critical citations on inspection reports, two could have been cited as direct noncompliant items because they were observed during the actual inspection process. The most frequently cited noncompliant item involved §2.33 Attending Veterinarian and Adequate Veterinary Care (ID: USDAAPHIS/AC/ BlueBook/AWA/508comp) which was cited 16 times. Three of those citations involved lack of appropriate documentation of the program of veterinary care; four involved the use of appropriate methods for the diagnosis and treatment of medical problems and four for the observation of medical problems and communicating those problems to the attending veterinarian. There were 12 critical citations under A USDA Stakeholder Announcement released on September 22, 2016 (ID: USDAAPHIS/bulletins/16620a4) explained that two new terms will appear on USDA inspection reports: focused inspections and critical noncompliant items. These terms now appear on inspection reports and in the Animal Care Inspection Service (ACIS) database, allowing interested parties the ability to identify facilities that have undergone a focused inspection or been cited for a critical noncompliant item. These changes have raised some questions and concerns within the regulated community. This commentary will attempt to put those changes into perspective. According to the announcement, “A focused inspection is an unannounced inspection that, for a variety of reasons, does not cover the entire facility.” A search of the ACIS database for “focused inspections” done in preparing this commentary found a total of 18, with the first one so designated in the database dated August 17, 2016. Also defined in the announcement is a direct noncompliant item (NCI), as one that at the time of the inspection is “having a serious or severe adverse effect on the welfare of an animal or has the high potential to have that effect in the immediate future”. A critical noncompliant item is not defined but examples are provided. One example which should be of interest to the research community is, “all direct NCIs – as well as other NCIs that resulted in serious, adverse impacts on the welfare of an animal (including NCIs that occurred outside of the USDA inspection process).” So a critical noncompliant item is an event which occurred prior to an inspection and had an Policy Watch: putting the new terms on USDA inspection reports into perspective

USDA's removal of information from their website

Russia, 2Research Institute of Marine Drugs and Nutrition, Guangdong Ocean University, Zhanjiang, China, 3ZENEREI Institute and the International Zebrafish Neuroscience Research Consortium (ZNRC), Slidell, Louisiana, USA, 4Institute of Chemical Technologies, Ural Federal University, Yekaterinburg, Russia, 5Laboratory of Biological Psychiatry, St. Petersburg State University, St. Petersburg, Russia. Correspondence should be addressed to A.V.K. (avkalueff@gmail.com) 10. Cousin, M.A. et al. PLoS ONE 9, e90467 (2014). 11. Anonymous. Zebrafish make a splash in FDA research. http://www.fda. gov/ForConsumers/ConsumerUpdates/ucm343940.htm (U.S. Food & Drug Administration, April, 2013).