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2 The Evolving Regulatory Environment Judy MacArthur Clark, chief inspector of the Animals Scientific Pro- cedures Inspectorate at the UK Home Office and session chair, described regulatory balance as the overlap of scientific quality, animal welfare, and public confidence. MacArthur Clark observed that regulations should pro- mote high-quality science and ensure that animal suffering is minimized without developing bureaucratic systems that are obstructive. Extensive evi- dence demonstrates that the quality of science is impacted by the welfare of the animals. The public wants to benefit from scientific advances, but also wants to be reassured research does not impose unnecessary suffering on animals, said MacArthur Clark. The nature of this balance can vary among countries due to differences in culture, economy, religion, and social factors. To explore similarities and differences across countries and regions, four invited speakers from Europe, North America, Asia, and South America described current regulations in their regions and emerging issues surrounding animal research. EUROPE: EUROPEAN UNION Karin Blumer, of Novartis, Switzerland, described pan-European leg- islation, that is, legislation that applies to all 27 member states of the European Union (EU), but not necessarily to all countries of the European continent. 7

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8 INTERNATIONAL ANIMAL RESEARCH REGULATIONS History of European Animal Welfare Legislation Historically, animal research regulations across Europe have been frag- mented. In the early 1800s, the first animal welfare legislation was intro- duced in Great Britain, followed by Saxony and Germany; however, these laws were not specific to laboratory use of animals. The first law specifically governing the use of animals in laboratories was not enacted until the late 1800s in Great Britain. In the twentieth century, significant differences remained in animal welfare awareness and legal protection across Europe. Many countries en- acted laboratory animal welfare legislation during the mid- to late 1980s. In 1986, Europe, as a political union (then the European Economic Commu- nity), approved Directive 86/609, which very specifically governed the use of laboratory animals (European Communities and Office for Official Pub- lications, 1986). Blumer noted that this legislation set minimum standards across member states while allowing for stricter national-level legislation. However, in 2000, national animal welfare legislation still varied widely across the European Union. Given the significant advances in biomedical technology, the addition of new member states whose animal welfare legislation was rudimentary or nonexistent, and increased public sensitivities, stakeholders concluded that revisions to EU Directive 86/609 were needed. One of the criticisms of EU Directive 86/609 was that it did not include strong guidance on housing and care, or provisions for genetic modifications of animals. Revision of the law began in 2002, and in 2010, EU Directive 2010/63 was adopted, updating and replacing Directive 86/609 (European Union, 2010). The deadline for adoption and transposition of the directive is January 2013. EU Directive 2010/63 The new directive is a complex document, Blumer said, structured as an introduction with 56 “recitals” explaining the rationale and objectives of the law, followed by 6 chapters defining provisions, procedures, and authorizations, and 8 annexes providing additional detail (Box 2-1). The main areas of focus are • harmonization among EU member states; • expansion of the legislative scope (e.g., more species, earlier stages); • a push for the implementation of the 3Rs (replacement, refinement, and reduction); • authorization of projects; • limits on individual animal exposure (including upper pain limits and limitations on the reuse of animals);

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9 THE EVOLVING REGULATORY ENVIRONMENT BOX 2-1 Key Features of European Union Directive 2010/63 Chapter I (General Provisions) • idened scope: Specific invertebrates and fetuses in last trimester of develop- W ment; animals in basic research, education, and training (Art. 2). • ormal introduction of 3Rs (reduction, refinement, and replacement) as guiding F principles (Art. 4). • imitation of acceptable methods of sacrifice (Art. 6, Annex IV). L Chapter II (Provisions for Certain Animals) • estricted use of endangered species (Art. 7). R • estricted use of non-human primates, ban on use of Great Apes (Art. 8). R • urpose-bred requirement for most commonly used lab species; F2 require- P ment for non-human primates (Art. 10, Annex I). Chapter III (Procedures) • andatory use of alternatives, reduction, and refinement (Art. 13). M • everity classification system, ban on severe studies (Art. 15). S • euse limitations (Art. 16). R Chapter IV (Authorization) • ompetence of personnel, institutional animal welfare person, designated C veterinarian, and animal welfare body (Art. 23, 24, 25, 27). • asks of animal welfare body (Art. 27). T • reeding strategy for non-human primates (Art. 28). B • are and accommodation (Art. 33). C • nspections, controls of member states inspections (Art. 34, 35). I • roject authorization, application, evaluation (including ethical considerations), P retrospective assessment, granting of authorization, simplified administration procedure (Art. 36). • on-technical project summaries (Art. 43). N Chapter V (Avoidance of Duplication and Alternatives) • utual data acceptance of member states (Art. 46). M • nion Reference Laboratory (Art. 48). U • ational committees for laboratory animal protection (Art. 49). N Chapter VI (Final Provisions) • eporting obligations for member states (Art. 54). R • afeguard clauses (Art. 55)—Great Apes, most severe studies. S • ommission report to the European Parliament and the Council—every 5 C years after 2019 (Art. 57). • ive-year reviews (2017) with special focus on advancements of alternatives— F specifically for non-human primates (Art. 58). SOURCE: Blumer presentation.

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10 INTERNATIONAL ANIMAL RESEARCH REGULATIONS • highly specific regulations for certain species including Great Apes and non-human primates; • increased transparency within institutions and to the public; and • continuous review of laws and regulations. One of the biggest advancements for animal welfare, Blumer said, is that fundamental principles of care and accommodation will now be har- monized on a pan-European level, which means that all member states will be required to use the same housing and care standards. Emerging Trends Blumer noted that an emerging trend in the European Union over the past 10 years is the increased involvement of the lay public in issues re- garding animal research regulation. The societal call for special status or “rights” for select animals such as Great Apes or companion animals is increasingly reflected in the legislative process. Blumer also noted a growing recognition that policy makers no longer recognize or understand the essen- tial nature of science and research because science is so complex and great “breakthroughs” have been so limited. A related trend is that many policy makers fail to appreciate the essential importance of basic science to applied research and innovation. Finally, Blumer pointed out an emerging reduction- ist approach to the 3Rs, with the primary focus often only on replacement. NORTH AMERICA: UNITED STATES Taylor Bennett, senior scientific advisor for the National Association for Biomedical Research (NABR), referred participants to the Guide for the Care and Use of Laboratory Animals which summarizes the U.S. animal regulatory environment. The guide says, “The use of laboratory animals is governed by an interrelated, dynamic system of regulations, policies, guide- lines, and procedures” (NRC, 2010). This oversight system is composed of both activities mandated by law or required as a condition of funding and activities that an individual or institution voluntarily adhere to as part of their overall commitment to research and academic excellence (Box 2-2). Animal Welfare Act The Animal Welfare Act1 passed in 1966 and has been amended six times, most recently in 2008. The Act empowers the U.S. Depart- 1 See http://awic.nal.usda.gov/nal_display/index.php?info_center=3&tax_level=3&tax_ subject=182&topic_id=1118&level3_id=6735&level4_id=0&level5_id=0&placement_default=0.

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11 THE EVOLVING REGULATORY ENVIRONMENT BOX 2-2 Components of the U.S. Animal Research Oversight System Mandatory • nimal Welfare Act, enforced by U.S. Department of Agriculture (USDA). A • ublic Health Service (PHS) Policy on Humane Care and Use of Laboratory P Animals, administered by the Office of Laboratory Animal Welfare (OLAW) of the National Institutes of Health (NIH). • ood Laboratory Practices (GLPs) regulations of the U.S. Food and Drug G Administration (FDA). • equirements set by private funding agencies. R Voluntary • ccreditation: A o ssociation for the Assessment and Accreditation of Laboratory Animal A Care International (AAALAC). • tandards set and maintained by individual users. S SOURCE: Bennett presentation. ment of Agriculture (USDA) to develop definitions, regulations, and stan- dards for the care and use of animals, including laboratory animals. The USDA licenses animal dealers, registers research institutions (~1,100 in the United States), requires certain recordkeeping, and enforces the law through unannounced inspections. The Act defines “animal” as a warm-blooded mammal (excluding birds, mice, and rats) raised for research and farm animals used for agricultural purposes. Animal welfare regulations can be modified through amendments to the Act itself. In addition, the Secretary of Agriculture may propose additions or changes to the existing regulations by publication of a Proposed Rule in the Federal Register. Bennett explained that the Act prohibits the promulgation of rules, regulations, or orders that would interfere with the conduct of actual re- search. Determination of what constitutes actual research is left to the dis- cretion of the research facility. Rules, regulations, or orders may be added as they relate to areas covered by the program of adequate veterinary care and areas that ensure that professionally acceptable standards governing the care, treatment, and use of animals are followed by the research facility during actual research or experimentation. Animal welfare regulations establish certain institutional responsibili- ties, including the appointment of an onsite Institutional Animal Care and Use Committee (IACUC) and a program of adequate veterinary care. The

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12 INTERNATIONAL ANIMAL RESEARCH REGULATIONS regulations also cover the training of qualified personnel, recordkeeping, and annual reports. Institutional Animal Care and Use Committee A key function of the IACUC is the semi-annual inspection and review of animal facilities, investigators’ laboratories, and overall management practices (the “Animal Care and Use Program”). Reports of these investi- gations are provided to responsible institutional officials who oversee the program and, if necessary, include a specified time frame for correcting any deficiencies. Failure to correct deficiencies are noted and reported to the appropriate regulatory agency. The IACUC also reviews concerns raised by both internal and external groups and has the authority to make recom- mendations to institutional officials on any aspect of the Animal Care and Use Program. The majority of the IACUC time is dedicated to reviewing and approv- ing or requiring modification of research protocols involving the use of animals. Part of that review is to ensure that personnel are properly trained and that the investigator adheres to the principles of the 3Rs in terms of justification of alternative methodology and assurance of unnecessary dupli- cation. The IACUC has the authority to suspend research activity and must report any such suspensions to regulatory and funding agencies. Attending Veterinarian and Adequate Veterinary Care Program Institutions conducting research involving animals are required to em- ploy an attending veterinarian with the authority to ensure the provision of adequate veterinary care and to oversee the adequacy of other aspects of the animal care and use program. The veterinarian also is a voting member of the IACUC. Each research facility is required to provide the attending veterinarian with the necessary resources to manage an effective program of veterinary care, including facilities, personnel, equipment, and services. The veteri- narian needs to be able to implement appropriate methods and systems to prevent, control, diagnose, and treat diseases and injuries through daily observation of all the animals as well as through emergency care. Finally, the veterinarian must be provided with the necessary resources to be able to provide guidance to investigators and other personnel regard- ing handling, immobilization, anesthesia, analgesia, tranquilization, and euthanasia, and ensuring adequate pre- and postprocedural care in accor- dance with current established veterinary medical and nursing procedures.

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13 THE EVOLVING REGULATORY ENVIRONMENT Public Health Service (PHS) Policy The PHS Policy on Humane Care and Use of Laboratory Animals2 is intended to implement and supplement the U.S. Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research, and Training.3 The PHS requires the institutions it funds to follow the Guide for the Care and Use of Laboratory Animals. While the USDA regulations exclude rats, mice, and birds raised for research, the PHS Policy covers all vertebrate animals. The PHS process is self-regulatory, the IACUC composition is slightly different, and the PHS has an Animal Welfare Assurance process, whereas the USDA has a reg- istration process. Another difference between the two agencies is that the USDA conducts unannounced inspections while PHS only does inspections for cause. Together, however, the USDA regulations and standards and the PHS policy provide broad oversight of key animal care and use issues. Emerging Trends Bennett highlighted four emerging trends in U.S. regulation of the use of animals in research. First, institutional “downstreaming” due to decreas- ing budgets at many research institutions is increasing the administrative burden of animal regulation. Bennett indicated that there is anecdotal evidence that departments and individual investigators are spending more time on administrative issues associated with the use of animals. Another trend is the USDA shift away from an education focus to an enforcement focus, leading to increased citations, fines, and animal-use stipulations. The increasing use of Freedom of Information requests is leading to a growing administrative burden to fulfill requests and increasing visibility of individ- ual investigators as identities are disclosed.4 Finally, as financial resources decline, the cost of assuring regulatory compliance is being passed on to the investigators in the form of increased per diems and service charges, reduc- ing the resources available for research itself, Bennett asserted. ASIA: CHINA Jianfei Wang, director of laboratory animal science at GlaxoSmithKline Research and Development Center, China, provided a high-level summary of laboratory animal regulation in Asia (Box 2-3), followed by specific ex- 2 See http://grants.nih.gov/grants/olaw/references/phspol.htm. 3 The U.S. Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research, and Training are discussed further by Brown in Chapter 7 of this document. 4 Discussed further in Chapter 3.

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14 INTERNATIONAL ANIMAL RESEARCH REGULATIONS BOX 2-3 Laboratory Animal Welfare Regulations in Asia Japan • uideline for Proper Conduct of Animal Experiments passed in 2000, revised G in 2006. • nstitutional Animal Care and Use Committee (IACUC) responsibility for over- I sight and incorporation of 3Rs (reduction, refinement, and replacement). • ee http://www.scj.go.jp/ja/info/kohyo/pdf/kohyo-20-k16-2e.pdf. S Korea • nimal protection law passed in 2007. A • thical review committee along with consideration of alternative models. E • ee http://www.koreananimals.org/animals/apl/2007apl.htm. S Singapore • n extensive set of guidelines released in 2004. A • ased on the principles of the 3Rs, IACUC responsibility for oversight. B • ee http://www.ava.gov.sg/AnimalsPetSector/CareAndUseAnimalsForScientific S Purp/#naclar. India • revention of Cruelty to Animals (PCA) issued in 1960. P • ommittee for the Purpose of Control and Supervision of Experiments on C Animals (CPCSEA), Institutional Animal Ethics Committee (IAEC). • ee http://www.aaalac.org/resources/CPCSEA_Conference_IAEC_SOP.pdf. S China • uideline on Administration of Laboratory Animals released in 1988. G • umane treatment of laboratory animals and IACUC review. H • ee http://www.lascn.net/policy/Index.html. S SOURCE: Wang presentation. amples from China. Asia is very diverse, he noted, and there is no pan-Asian union comparable to the Euroepan Union. Laboratory Animal Science and Regulations in China Thirty years ago, Wang said, there was essentially no concept of labo- ratory animal science in China. However, this has changed in recent years. Under the direction of the Ministry of Science and Technology (MOST), the Provincial Department of Science and Technology (PDST) handles organizational licensing and inspections through Provincial Administrative

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15 THE EVOLVING REGULATORY ENVIRONMENT Offices. The National Monitoring Center oversees the quality of animal programs and facilities through Provincial Monitoring Units. Additionally, the Chinese Association for Laboratory Animal Science (CALAS) promotes laboratory animal science education and training. Wang noted that the Chinese government has issued more than 100 regulatory standards for topics such as microorganism control, environ- ment and housing facilities, genetic quality control, and diet and nutrition. The purpose of these national standards is to ensure both the quality of laboratory animals and the scientific knowledge derived from these animals. To promote laboratory science in China, the government established eight laboratory animal resource centers. There also are graduate and under- graduate programs in laboratory animal science at universities and medical, veterinary, pharmacy, and biotechnology schools. Wang mentioned three legal milestones governing laboratory animal science in China: the 1988 Statute of Laboratory Animal Administration, the 2001 Regulation on the Management of Laboratory Animal License System, and the 2006 Guideline on Humane Treatment of Laboratory Animals. Guideline on Humane Treatment of Laboratory Animals The Guideline on Humane Treatment of Laboratory Animals is the country’s first broad animal welfare regulation and is aligned with practices in countries/regions such as the United States and the European Union. The notion of animal welfare is well accepted by Chinese scientists and the government, Wang noted. The guideline covers animal welfare from procurement through completion of a research project. IACUC review is required and the principles of 3Rs must be incorporated into the experi- mental design. A proper animal environment, husbandry, and care must be provided, as well as adequate veterinary care. Pain and distress are a particular focus of the guidelines, so humane endpoints must be established and animals must be properly euthanized. Factors Influencing Quality of Animal Care and Use in China Scientists in China have come to realize that good animal welfare is necessary for good science, Wang observed. Regulatory practice has been influenced by an increasing number of Chinese scientists trained overseas who have returned to China with an understanding of the practices and protocols of other countries. Additional factors causing change in China’s regulatory practices include increased international academic collaboration and participation in international conferences where scientists share animal welfare information.

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16 INTERNATIONAL ANIMAL RESEARCH REGULATIONS The Chinese culture of embracing traditional virtues such as compas- sion for living things, Wang explained, also influences animal care because cruelty to animals creates a very negative public image. Another positive influence on quality of animal care and use in China is the presence of multinational pharmaceutical and contract research organizations. While there are diverse animal study requirements to satisfy the needs of drug discovery, development, and safety assessment, animal welfare needs ap- pear to be the same. The number of institutions in the Pacific Rim that are accredited by the Association for the Assessment and Accreditation of Laboratory Animal Care International (AAALAC) is increasing, including several institutions in China. Economic concerns also influence animal care and use. China is one of the largest agricultural countries in the world, yet it faces severe restraints on trade in animal products due to concerns over quality standards and animal protection. Wang noted that the Chinese government is beginning to realize that animal welfare is linked to economic development. Animal resources in China, however, are not as abundant as in the United States and veterinarian training is inadequate, said Wang. The primary focus of current legislation is on quality of animal production and supply, not on animal welfare. Emerging Trends Although enormous progress has been made, laboratory animal science across Asia, including China, is uneven and rudimentary. Factors influenc- ing the quality of animal care and use include globalization, international exchange, economic development, and increased AAALAC-accredited in- stitutions. Wang suggested that the most notable emerging trend in China is the shift toward alternatives to animal testing, which could lead to an overhaul of existing research paradigms in China. While the government is considering legislation that would eliminate animal testing of cosmetics, there appears to be no concerted effort to replace animal testing in other fields such as pharmaceutical, agrochemical, and chemical research. SOUTH AMERICA: BRAZIL Brazil is a diverse country with economic, religious, cultural, and social differences in addition to varied geographical areas with major cities and regions of the Amazon accessible only by boat or plane. Ekaterina Rivera, professor at the Biological Sciences Institute of the University of Goias in Brazil, said these differences lead to different approaches to animal research and animal regulations. The southeastern part of Brazil has the largest cities and several estab- lished centers of excellence. In developing areas of Brazil, universities are

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17 THE EVOLVING REGULATORY ENVIRONMENT new and just beginning to build laboratories and animal facilities. These universities and centers are working to catch up with the other regions. Rivera mentioned, for example, the National Institute of Research of the Amazon, which is mainly focused on nutrition studies using regional fruits. This institute has a very modern, specific pathogen-free animal house and is pursuing AAALAC accreditation. Laws and Regulations In 1985, a group of veterinarians and others created the National Col- lege on Animal Experiments (Colégio Brasileiro de Experimentação Animal [COBEA]) and issued the COBEA Ethical Principles based on the Council for International Organizations of Medical Sciences (CIOMS) principles. This was the starting point of laboratory animal science in Brazil. In 1986, COBEA became a member of the International Council for Laboratory Animal Science (ICLAS) and in 2009 its name was changed to the Brazilian Society of Laboratory Animal Science (SBCAL) to reflect its broader mem- bership. SBCAL has been central to the promulgation of animal regulations in Brazil and has served as a model for other Latin American countries pursuing similar interests. Until recently, Brazil had no regulations regarding the implementation of ethical committees; universities and institutions had nowhere to seek guidance or ask questions, Rivera said. Currently the primary Brazilian research body, the National Counsel of Technological and Scientific Devel- opment (CNPq), prohibits grants to be awarded to projects that have not passed an ethical review. This, Rivera said, was a critical step toward better science and animal care in Brazil as it caused a significant change in the approach scientists have toward laboratory animals. The Arouca Law In 1995, Sergio Arouca, a physician and a federal congressman, led a group of scientists in developing the first draft law governing the use of ani- mals in research. Approved 13 years after it was drafted, the Arouca Law (Law nº11.794-October 8, 2008) regulates the use of vertebrate animals in research, teaching, and testing. The law also created the National Council for the Control of Animal Experimentation (CONCEA), which registers institutions, regulates experiments, and requires institutions to establish an ethics committee for the review of projects using animals. This law is similar to U.S. and EU laws in that it includes mention of the 3Rs, specifi- cally the use of alternatives to animals and the avoidance of additional pain and distress. Rivera noted, however, that there is more emphasis on ethical committees in Brazil than elsewhere. The Arouca Law was subsequently

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18 INTERNATIONAL ANIMAL RESEARCH REGULATIONS regulated by Presidential Decree (nº6899/2009), providing the framework for CONCEA and its governing rules and functions. Emerging Trends Although relatively new, Rivera offered several comments on the effects of the laws and regulations over the past 10 years. Ethical committees have led to a “culture of care,” changing the minds of those conducting research using animals. Brazil now has better animal houses, better trained person- nel, and ultimately, better animals. In addition, veterinarians have a much larger role than before. There is a focus on alternatives to the use of animals and interdisciplinary meetings to advance animal science. In essence, the law helped set Brazil on the same path as its peers in other countries. Some issues still need to be resolved, Rivera noted. For example, dis- tance presents a significant challenge in a country the size of Brazil, affect- ing proper transportation of animals and access to supplies. The size of the country also affects the ability to inspect all of the laboratory animal houses. Rivera also noted that like any new law in Brazil, implementing the new animal law involves a good deal of bureaucracy. Like Asia, the countries in South and Central America are diverse and at different stages in the development of their animal research regulations. The Brazilian law stimulated discussions across Latin America, and has served as a starting point for countries that still have no regulations. Cur- rently, Brazil, Mexico, and Uruguay have specific laws on the use of animals in research. Argentina, Chile, Colombia, and Costa Rica have animal wel- fare laws with at least one provision relevant to laboratory animal science. SUMMARY Following the presentations, panelists and participants discussed the similarities and differences across countries and regions. Several speakers and participants noted there is a need to reduce bureaucracy that could hamper the progress of science, the value of increasing public confidence about the role of animals in research and the regulatory system, and the potential usefulness of developing appropriate metrics of success in balanc- ing scientific quality, animal welfare, and public confidence (summarized in Box 2-4).

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19 THE EVOLVING REGULATORY ENVIRONMENT BOX 2-4 Summary of Session Points Science Within the Regulatory Environment • primary role of research support services is to facilitate research by making A compliance as seamless as possible for the investigator, while still assuring institutional compliance. • he cost of regulation can be both a fiscal as well as a time cost for regulators T and scientists (i.e., administrative burden). • ureaucracy is inevitable and may have a greater impact on animal research B regulation enforcement in some countries more than others. Animal Welfare and Scientific Quality • uggestions for improving both animal welfare and scientific quality: S o inimize non-experimental (e.g., environmental) confounding variables. M o mprove the environment in which the animals are maintained to reduce I experimental variability. o educe unnecessary duplication of studies. R o nhance the productivity of current animal models. E Public Confidence • ublic confidence in the regulatory process may increase if the scientific com- P munity helps to educate the public and politicians about o he nature of fundamental research, t o ow animal research contributes to science, and h o nimal research regulatory laws, policies, and requirements. a • ngagement by the scientific community in the regulatory and legislative pro- E cess may result in more scientifically-based animal research regulations. • cience might benefit from fostering relationships with alliance partners (e.g., S patient groups, industry, animal welfare organizations) to bring a shared mes- sage to legislators. • echanisms are in place for scientific organizations to comment on proposed M regulations. • cientists in regions such as Asia and South America with less developed S animal research regulations may have greater opportunities to participate in the process and educate lawmakers. SOURCE: Individual panelists and participants.

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