Journal of the American Association for Laboratory Animal Science Copyright 2015 by the American Association for Laboratory Animal Science
Vol 54, No 2 March 2015 Pages 192–197
Making Progress and Gaining Momentum in Global 3Rs Efforts: How the European Pharmaceutical Industry Is Contributing Gill Fleetwood,4 Magda Chlebus,1,* Joachim Coenen,2 Nicolas Dudoignon,3 Catherine Lecerf,1 Catherine Maisonneuve,5 and Sally Robinson6 Animal research together with other investigational methods (computer modeling, in vitro tests, etc) remains an indispensable part of the pharmaceutical research and development process. The European pharmaceutical industry recognizes the responsibilities inherent in animal research and is committed to applying and enhancing 3Rs principles. New nonsentient, ex vivo, and in vitro methods are developed every day and contribute to reducing and, in some instances, replacing in vivo studies. Their utility is however limited by the extent of our current knowledge and understanding of complex biological systems. Until validated alternative ways to model these complex interactions become available, animals remain indispensable in research and safety testing. In the interim, scientists continue to look for ways to reduce the number of animals needed to obtain valid results, refine experimental techniques to enhance animal welfare, and replace animals with other research methods whenever feasible. As research goals foster increasing cross-sector and international collaboration, momentum is growing to enhance and coordinate scientific innovation globally—beyond a single company, stakeholder group, sector, region, or country. The implementation of 3Rs strategies can be viewed as an integral part of this continuously evolving science, demonstrating the link between science and welfare, benefiting both the development of new medicines and animal welfare. This goal is one of the key objectives of the Research and Animal Welfare working group of the European Federation of Pharmaceutical Industries and Associations. Abbreviations: EFPIA, European Federation of Pharmaceutical Industries and Associations; EPAA, European Partnership for Alternative Approaches to Animal Testing; EU, European Union; IMI, Innovative Medicines Initiative; NC3Rs, National Centre for the 3Rs; RAW, Research and Animal Welfare.
Research and Animal Welfare Strategies Integral to the Science Policy Objectives of the European Federation of Pharmaceutical Industries and Associations (EFPIA)
The EFPIA represents the pharmaceutical industry operating in Europe. Through its direct membership of 33 national associations and 40 leading pharmaceutical companies, EFPIA is the voice on the European Union (EU) scene of 1900 companies committed to researching, developing, and bringing to patients innovative and effective medicines. These are designed to fight diseases in a variety of areas (for example, cardiovascular, CNS, gastrointestinal, pain control and anesthesia, respiratory, inflammation, infection, and cancer). Millions of people worldwide suffer from diseases in these areas and would benefit from such research. The European pharmaceutical industry’s commitment to the 3Rs and animal welfare is not new. The EFPIA Research and Animal Welfare (RAW) working group was established in the late 1980s, concomitantly with the first discussion regarding, Received: 17 Feb 2014. Revision requested: 26 Mar 2014. Accepted: 08 May 2014. 1Science Policy Platform, Animal Welfare, European Federation of Pharmaceutical Industries and Associations (EFPIA), Belgium; 2Corporate Animal Science & Welfare (EQ-A) Merck KGaA, Germany; 3Disposition, Safety and Animal Research, Animal Research and Welfare, Sanofi, France, 4Office of Animal Welfare, Ethics and Strategy, GlaxoSmithKline, United Kingdom; 5Animal Health and Welfare, Drug Safety, Servier, France; 6Drug Safety and Metabolism, AstraZeneca, United Kingdom. *Corresponding author. Email: [email protected]
and the subsequent adoption of, the EU Directive 86/609 on the protection of animal used for scientific purposes.7 This unique industry structure contributes to shaping the political, legal, and regulatory environment surrounding animal research and testing. It detects and addresses threats to, and seeks opportunities to enhance feasibility of, research, industry practices, and reputation. It works to reconcile research needs with animal welfare imperatives and promotes development and uptake of 3Rs approaches in research and testing, both within the pharmaceutical industry and beyond. The membership of the RAW group consists of veterinarians, toxicologists, pharmacologists, ethicists, lawyers, public affairs and communication specialists, and animal welfare officers, as well as observers from research defense organizations, academia, and authorities (where appropriate). The group supports or complements the activities of other committees taking care of research collaboration and science policy, as well as of preclinical research in particular. All these expert groups have the common objective of improving the efficiency of research and development processes to provide safer and better medicines to patients more quickly and to address unmet medical needs. EFPIA and its member companies recognize the ethical dilemma surrounding the use of animals in research. To put animal welfare principles into action, member companies only use animals where no alternative exists, use the minimum numbers to achieve the scientific objective, and ensure that the animals experience the least possible pain and distress at all steps—from their breeding to their use in research environment.
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EFPIA member companies also continues to work to better understand mechanisms of disease and to improve the scientific robustness of the preclinical models (animal and nonanimal) to enhance our ability to deliver new effective and safe treatments. The research-based pharmaceutical industry not only complies fully with the regulations that exist to ensure high standards for laboratory animal care and use, it goes beyond compliance, promoting higher animal welfare standards and the 3Rs by leading by example. A prime illustration of this practice is EFPIA’s support for the inclusion of explicit 3Rs requirements into the 2010 revision of the EU Directive on the protection of animals used for scientific purposes (Directive 2010/63/EU).13 The following sections provide illustrations of some of EFPIA’s recent activities in support of 3Rs principles and animal welfare. These activities fall into 3 main categories: contributing to discussions regarding animal research with policy makers and regulators, engaging with other organizations and sectors involved with animal research to share and promote 3Rs activities, and working to ensure that high standards of animal welfare and the outputs from our 3Rs initiatives are communicated to the wider scientific community.
Contributing to Global Discussion on the 3Rs and Animal Welfare
Every new piece of legislation on the use and protection of animals is a source of inspiration for authorities around the world. During the 7-y legislative process, many countries very carefully watched the discussion regarding and adoption of Directive 2010/63 on the protection of animals used for scientific purposes. Therefore, even though the directive applies in the EU, it is already part of the global policy discussion regarding live animals and 3Rs in research and development. This new legislation updated and ensured common high standards regarding animal welfare across the whole of Europe. It imposed mandatory ethical review based on benefit risk assessment, the authorization of studies involving animals, and the application of and promotion of the 3Rs methodologies as soon as they become available and have been scientifically validated. This directive brings a new evaluation scale, which categorizes procedures by the degree of pain, suffering, distress, or lasting harm expected to be experienced by an individual animal during the course of the procedure. Last but not least, the legislation harmonized new education and training standards for personnel dealing with live animals and provided requirements for inspections that will strengthen the enforcement of consistent high standards for laboratory animal care and use. Pharmaceutical industry experts played a leading role in the consultations and working groups that provided input into the drafting and legislative process of the Directive. The result—a compromise text—was aimed at delivering improvements in animal welfare but also supports continuation of scientifically and ethically justified animal research and active implementation of the 3Rs. Implementation of these provisions is not always straightforward and might sometimes result in bureaucracy without any added value for welfare of animals. Now that the new Directive 2010/63 is in place, EFPIA and its member companies continue to play a leading role in guiding its implementation at EU level and within member states. These expert discussions address some of the ‘gray zones’ left in the text when the political compromise was set. Many of these unclear points are directly relevant to the implementation, promotion, and enforcement of 3Rs and welfare principles and increased transparency. These
areas address statistical reporting, genotyping, education and training, inspections, project evaluation and retrospective assessment, lay summaries, and so forth. Because of the international impact of the animal protection legislation, EFPIA is also part of a wider scientific European coalition including animal science experts (Federation of Laboratory Animal Science Associations), academia and charities (European Science Foundation/Science Europe), veterinarians (European College of Laboratory Animal Medicine and European Society of Laboratory Animal Veterinarians) and breeders (Federation of European Laboratory Animal Breeder Associations), which provide input into EU-level discussions. The collaborative effort ensures that the legislation is implemented in day-to-day research activities, taking account of specificities of each sector while considering the ‘highest common denominator’ approach. Questions that the coalition discussed included, for example, the interpretation of what is a project or a procedure and how the delegation of powers from a centralized point to the local level for conducting ethical evaluation or delivering authorizations might work in practice. Where differences of operational and scientific focus appeared, the coalition sought alignment for increased influence on research and welfare. All partners in this coalition worked toward the EU objective of securing a level ‘playing field’ and avoiding possible ‘welfare dumping,’ that is, the potential of research being moved to places with lower standards of animal welfare. The other global 3Rs dimension of Directive 2010/63 relates to the source of nonhuman primates. The EU policy-makers decided that nonhuman primates used in research in Europe should be sourced from second-generation (F2) born-incaptivity animals. EFPIA invited experts from the public and private sectors and professional organizations to define how to assess feasibility as well as the health and welfare effects of this requirement. The group recommended looking into the positive or negative effects of moving toward F2 colonies according to behavior and socialization, the total number of animals to be maintained in captivity, and the management of surplus animals during transitional period. The result of this reflection process was published in the French Review of Primatology.9 The directive requires conducting such feasibility and welfare impact assessment by 2017. Encouraging new standards requires the communication and dissemination of information. EFPIA organized webinars for the constituent members of the scientific coalition and participated in various laboratory animal science events to promote the Directive and explain its new provisions. In 2010 and 2011, EFPIA presented the new requirements of the directive at Eurotox, Charles River Associates short courses, the European Parliament, and national laboratory animal science events across Europe. The Directive imposed new standards for housing and caging for improving welfare and enhancing refinement. Instituting this change requires both financial and human resources. Although industry was largely compliant with the new standards (which were included as guidelines in Appendix A of the ETS 123 Convention of the Council of Europe in 20066), upgrading facilities in public research institutions proved to be a financial challenge. EFPIA partnered with the Federation of Laboratory Animal Science Associations and animal welfare organizations to call upon national authorities to provide the necessary resources to maintain high quality research in Europe. This multistakeholder public–private initiative highlights the intertwined relationship between fundamental and applied research and the common endeavor to enhance welfare of animals used in research. 193
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The work regarding Directive 2010/63 is an example of a global effort that crosses the boundaries between companies, sectors, countries, and stakeholder groups whose objectives sometimes contradict each other initially. It offers robust foundations on which to build future dialogue and collaborative initiatives.
Measuring 3Rs Progress
Limited information is available in the public domain against which to measure 3Rs progress. The statistics on animal procedures on living animals cannot be used as benchmark because a range of legal, scientific, business, and strategic factors independent of 3Rs influences the numbers of animals reported in annual statistics. For example, numbers reported in a given period often depend on the start and end of large-scale long-term projects relative to the reporting date and the therapeutic area being studied; changes in regulatory requirements or legislation; historically individual countries have differing criteria for what constitutes a scientific procedure. In 2011, the RAW group conducted a survey of its members and, based on the responses, developed the first-ever series of key performance indicators8 to help in assessing the effect of investments in 3Rs within individual companies. After a review of more than 15 potential metrics, 5 key performance indicators were prioritized as: • examples in the reduction of severity, • evidence of senior executive ownership of 3Rs, • existence of internal 3Rs structures, • number, subject, and impact of internal 3Rs awards, and • involvement in external 3Rs initiatives. This core list comprising a set of quantitative and qualitative key performance indicators helps not only to assess the effectiveness of 3Rs but also to communicate about the 3Rs efforts through Corporate Social Responsibility reports by individual companies and, at an aggregate level, by their trade organizations. The core list can be complemented with others identified during the survey.8 Examples of implementation of these key performance indicators can be found in the section titled “Examples of 3Rs activities from EFPIA member companies” of this article and in the EFPIA reports “Putting Animal Welfare Principles and 3Rs into Action.”10,12
Transport: Global 3Rs Opportunities and Risks
For many years, EFPIA and its members have been involved in the global discussion on transport and countering the moratoria that transporters implement under pressure from animal rights groups. Certain species cannot easily be bred close to the research sites where they are required, and the need to access a variety of animals (particularly transgenic strains) calls for access to high quality and efficient transport. Moratoria on transport by scheduled service and experienced airlines force researchers to turn to alternative routes with the risk of negative effects on animal welfare. Longer transport durations, more transit stops with increased handling and inadequate connections increase the risk of delays to shipments, thus potentially jeopardizing animal health and welfare. Even the switch from passenger to cargo planes to transport animals can lead to unexpected travel delays. Indeed, passenger planes always have precedence over cargos when there is any reason to prioritize flights (for example, weather conditions, strikes). Consequently cargo plane schedules can be highly unpredictable. Additional delays can be caused by customs procedures. Their length is related, to a certain degree, to lack of a harmonized information package and documentation accompanying the animals;
the development of such documentation is recommended by the World Organisation for Animal Health. Although internationally recognized codes and guidelines on how to safeguard animal welfare during transport exist,5,19,24 they need to be reviewed and updated regularly. The EFPIA RAW group and its member companies contribute to discussions about such regulations and processes to further improve the quality of animal transportation to ensure the delivery of healthy, unstressed, well-maintained, acclimated animals. There is a continued need to engage in an international multistakeholder dialogue with representatives of all those involved in the research network, including breeders, transporters, users and competent authorities at international (World Organisation for Animal Health), European (Commission), and national levels (veterinary inspections) to find solutions that will combine continuity of supply and animal welfare and will prevent wellintended policy decisions from having unintended negative effects on animal welfare and scientific progress.
The Era of Global Communication
Promoting good science and good welfare and increasing understanding of how the two are intertwined for the benefit of patients is an essential part of promoting and facilitating high-quality research. The RAW group is driving several initiatives that complement companies’ internal and external communication. The report “The 3Rs and Welfare: Putting Animal Welfare and 3Rs Principles into Action.” In 2012, the EFPIA published its first report illustrating industry’s efforts and commitment to the 3Rs principles.10 The report is structured around 3 themes—compliance, leading by example, and open communication—and is based on examples of actual activities by either EFPIA or member companies in the area of the 3Rs. These examples are related to regulations, training programs, sharing and encouraging best practices, global animal welfare standards, assessment of animal welfare, and contribution to open and constructive dialogue on animal welfare. The second edition of this report was published in January 2014.12 “Animal Testing Perspectives” blog. Animal research and testing is a controversial topic that has generated a great deal of passion in the industry, the public, and the scientific community. As a result, having a rational and open debate on the issues often has proven to be difficult. To facilitate this discussion, EFPIA now offers a social media platform titled “Animal Testing Perspectives.” The main purpose of this initiative is to engage in a constructive discussion with key stakeholders, including opponents of animal research and testing, to demonstrate the genuine efforts of the industry to implement 3Rs and improvements in animal welfare and to shift the discussion away from being a purely ideological and emotional one to a factual one.2 “Animal Research for Life” website. The “Animal Research For Life” website was created in the context of the revision of the legislative work on Directive 2010/63 on the protection of animals used for scientific purposes. This educational tool gives basic and simple information regarding the use made of animals in the pharmaceutical industry, the value and limitations of alternative approaches, and the legal framework for the use and protection of animals used in research.1
Global Research: From Science to the 3Rs
Today’s scientific and healthcare challenges are so complex that no single stakeholder alone will be able to address them successfully. Cross-sector, multistakeholder, and international
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collaborations are the only way forward. Solutions that are developed through this collaborative effort will benefit the entire scientific community irrespective of where they are located. The search for better tools to address safety and efficacy challenges often has driven more rational use of live animals and alternatives in biomedical research. Examples of such initiatives follow. The Innovative Medicines Initiative (IMI). The IMI17 is a public–private partnership between the European Commission and the members of EFPIA. IMI’s key mission is to enhance the competitiveness of the pharmaceutical sector in Europe, for the benefit of patients and scientists, by supporting open innovation and precompetitive research in pharmaceutical research and development. IMI was launched in 2008 by the EU and EFPIA, with a total budget of €2 billion to be spent over a 10-y period; IMI is the largest public–private partnership in the life sciences.16 Although the focus of IMI projects is finding breakthrough medicines, the implementation of 3Rs practices is integral to this process. Several IMI projects are at the forefront of novel approaches to replacing and reducing animal research. The eTox project integrates bioinformatics and chemo-informatics approaches for the development of expert systems allowing the in silico prediction of toxicities. The SAFE-T project is developing improved tools for the prediction, detection, and monitoring of drug-induced injuries to the kidney, liver, and vascular system, by using markers in patients’ blood or urine. The project Mechanism-Based Integrated Systems for the Prediction of Drug-Induced Liver Injury (MIP-DILI) seeks to improve the tools used to test liver toxicity during drug development. This project will use induced pluripotent stem cells, hepatic cell culture, and custom computer models to unravel the complex mechanisms behind drug-induced liver injury. This novel approach will contribute to the replacement of tests on animals during drug development. To build on the success of IMI, the pharmaceutical industry and European Commission decided to continue this public– private collaboration until 2024 under the banner of IMI2. The strategic research agenda of IMI211 focuses on personalized prevention and treatment and outlines 3Rs opportunities that new sciences and knowledge can bring. The advances in studies of the human genome, breakthroughs in high-speed information processing, and the promise of nanotechnology are highlighted in the agenda as offering the prospect for developing new or improved medicines with decreased dependence on animal models. As knowledge accumulates and because of concentrated efforts to improve our understanding of the underlying causes of human disease and other research activities outlined in the strategic research agenda, the number of opportunities to either replace existing animal models with nonanimal alternatives or to adjust the animal model so that it becomes more predictive of clinical outcomes, requires fewer animals to evaluate, or uses a more humane endpoint (for example, a biomarker rather than the development of clinical disease) will increase. The European Partnership for Alternative Approaches to Animal Testing (EPAA). The EPAA is an unprecedented collaboration among European Commission services, trade federations, and major companies from 7 industry sectors.14 The partners have committed to pooling knowledge, research, and resources to accelerate the development, validation, and acceptance of alternative approaches to safety testing. EFPIA is one of the founding members of EPAA. In addition, many EFPIA companies are direct members of this public–private partnership. Participation in EPAA projects enables all members to pool knowledge, research, and resources within a more general context. This collaboration helps to accelerate the develop-
ment, validation, and acceptance of alternative approaches for regulatory use. Together with the European Commission, participants from academia, nongovernmental organizations, individual pharmaceutical companies, and EFPIA collaborated on the following EPAA projects. 1) The European pharmaceutical industry was able to share its experience and learning across pharmaceutical companies from its review of acute toxicity testing in the development of new medicines. The information sharing was led by AstraZeneca and facilitated by the United Kingdom’s National Centre for the 3Rs (NC3Rs), and led to the removal of the regulatory requirement for acute toxicity tests in the pharmaceutical industry. This work was the impetus for a cross-sector review through EPAA23 2) Through the cross-sector review, EPAA was able to provide evidence to regulators that only one testing route was necessary to show the toxicity of a substance; that is, there is little or no value in performing an acute dermal study when oral data are already available. Accordingly, a significant opportunity exists to reduce the number of animals used for this purpose. 3) Another project looked at integrated testing strategies, making the case that this methodology provides more data than do current existing methods, with the agreement that “industry, academia, and regulators need to educate each other, and integrated testing strategies [are] among the most efficient solutions to address the 3Rs.” Other EPAA projects that European pharmaceutical companies have supported include the potential for using stem cells to replace single-organ animal testing and for enhancing integrated testing strategies. Although EPAA is a European initiative, the partners realized that real change would come from international application of the new approaches, supported by international regulatory acceptance. Supported by the Commission, international dialogue, and regulatory collaboration tools, EPAA engaged several international regulators. Additional information about EPAA and the 3Rs can be found in the article “The European Partnership for Alternative Approaches to Animal Testing (EPAA): Promoting Alternative Methods in Europe and Beyond” in the current issue.14 Examples of 3Rs activities from EFPIA member companies. In addition to working together under the umbrella of EFPIA, many of the member companies also work together as part of other initiatives that have 3Rs effects. For example, many EFPIA companies directly contribute to NC3Rs activities. For example for acute toxicity studies, several EFPIA companies, facilitated by NC3Rs, provided a novel, evidence-based challenge to the regulatory requirement for acute toxicity studies where lethality was an endpoint. Appropriate preclinical and clinical data were shared, and the analysis of this information demonstrated that acute toxicity studies have limited value for assessing human safety and, as such, their continued requirement by regulators could not be justified.22 As a direct consequence of this initiative and the subsequent engagement of collaborators and regulators, the revision of guideline M320 from the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use incorporated the recommendations of this team. Other cross-company initiatives facilitated by NC3Rs include the joint project of the Medicines and Healthcare Products Regulatory Agency and NC3Rs to assess the need for recovery animals in toxicology and the CRACK-IT initiative.21 Another recent cross-company project reviewed approaches to microsampling (that is, obtaining small volumes of blood by using a refined method). Microsampling can increase the amount of nonclinical safety information available, can improve its validity by linking toxic effects to drug exposure in individual 195
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animals, and represents the most significant short-term opportunity to reduce and refine animal use in toxicology studies.3 Representatives from several companies in France have developed, together with their public research counterparts, a training program for project evaluators and ethics committee members to try and harmonize the ethical review process throughout the different committees across the country. Courses were based on the National Charter on the ethics of animal experimentation published by the Comité National de Réflexion Ethique sur l’Expérimentation Animale,4 and the Guide for the Ethical Evaluation of Experiments using Laboratory Animals15 that was approved by the French authorities. In addition, several companies across Europe worked with the European Center for the Validation of Alternative Methods to validate a cytotoxicity test to identify nontoxic chemicals. This test has been implemented for the testing of chemical substances, and the information is included in safety testing requirements.18 The validated test replaces most of the previously required in vivo experiments. Animal welfare principles in globalized research. The same rationale of aligning on scientifically driven animal welfare standards motivated EFPIA and the RAW group to start to establish links and form partnerships and collaboration with other organizations active in the United States and globally. For example, EFPIA joined the AAALAC Board of Trustees. In the future, the EFPIA RAW group will continue to reinforce these interactions to help improve animal welfare standards worldwide. In this context, dialogue with the International Consortium on Innovation and Quality in Pharmaceutical Development in the United States is greatly appreciated as an important initiative to promote the sharing and integration of high-quality scientific practices to advance the 3Rs.
Conclusions
The science underlying the research and development of new medicines faces global challenges because medicines are developed and used globally. The scientific community has a unique opportunity to join forces and advance initiatives in science policy, research and development, and 3Rs principles and practices that will enhance the quality of medicines for patients and the understanding of research imperatives. This goal can only be achieved through global collaboration at all levels— across companies, sectors, stakeholder group, and countries. The initiatives we have described herein can be used as starting points for further progress in reconciling research, health, and 3Rs agendas. Securing the time and resources necessary for such collaborations would be worthwhile investments for the future. EFPIA and its RAW group stand ready to engage and to explore new grounds for collaboration with all interested parties.
References
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fr/file/Encadrement_des_pratiques_de_recherche/58/1/ Charte_nationale_portant_sur_l_ethique_de_l_experimentation_animale-version_anglaise_243581.pdf 5. Committee on Guidelines for the Humane Transportation of Laboratory Animals, Institute for Laboratory Animal Research. 2001. Guidelines for the humane transportation of research animals. Washington (DC): National Academies Press. 6. Council of Europe. [Internet] 2007. Appendix A to the European Convention for the Protection of Vertebrate Animals Used for Experimental and Other Scientific Purposes. Guidelines for accommodation and care of animals. [Cited 22 April 2014 ]. Available at: http://conventions.coe.int/Treaty/en/Treaties/Html/123-A.htm 7. Council of the European Communities. [Internet] 1986. European Council Directive of 24 November 1986 on the approximation of laws, regulations, and administrative provisions of the Member States regarding the protection of animals used for experimental and other scientific purposes (86/609/EEC). [Cited 22 April 2014]. Available at: http://ec.europa.eu/food/fs/aw/aw_legislation/ scientific/86-609-eec_en.pdf 8. Decelle T, Chlebus M, Robinson S. 2011. Defining metrics to measure and communicate progress of 3Rs investments and activities—European Federation of Pharmaceutical Industries and Associations (EFPIA). ALTEX 28:242. 9. Decelle T, Mikkelsen LF, Smith D, Chlebus M. [Internet]. 2011. Criteria for feasibility, health and welfare assessment of requirement to use second and subsequent generations of nonhuman primates or animals from self-sustaining colonies in research. Extract from an expert group report endorsed by EFPIA, FELASA, ESLAV, and ECLAM, 2010. [Cited 22 April 2014]. Available at: www.primatologie.revues.org/853 10. European Federation of Pharmaceutical Industries and Associations. [Internet]. 2012. Putting animal welfare principles and 3Rs into action—2011 report. [Cited 22 April 2014]. Available at: www.efpia. eu/documents/14/61/Putting-animal-welfare-principles-and3Rs-into-action-European-Pharmaceutical-Industry-2011-Report 11. European Federation of Pharmaceutical Industries and Associations. [Internet]. 2013. Vaccines Europe, EBE 2013, IMI2 Strategic Research Agenda: the right prevention and treatment to the right patient at the right time. [Cited 22 April 2014]. Available at: www. efpia.eu/documents/48/63/SRA-PUBLIC-CONSULTATION 12. European Federation of Pharmaceutical Industries and Associations. [Internet]. 2014. Putting animal welfare principles and 3Rs into action: European pharmaceutical industry 2012 report update. [Cited 22 April 2014]. Available at: www.efpia.eu/mediaroom/139/44/ Putting-animal-welfare-principles-and-3Rs-into-action-EuropeanPharmaceutical-Industry-2012-Report-Update 13. European Parliament and Council. [Internet] 2010. Directive 2010/63/EU of the European Parliament and of the Council of 22 September 2010 on the protection of animals used for scientific purposes. [Cited 22 April 2014]. Available at: http://eur-lex. europa.eu/legal-content/EN/TXT/HTML/?uri=CELEX:32010 L0063&from=EN 14. European Partnership for Alternatives Approaches to Animal Testing. [Internet] 2015. The European Partnership for Alternative Approaches to Animal Testing (EPAA). [Cited 5 March 2015] Available at: http://ec.europa.eu/enterprise/epaa/about/ index_en.htm 15. GIRCOR. [Internet]. 2009. Guide for the ethical evaluation of experiments using laboratory animals. [Cited 22 April 2014]. Available at: www.recherche-animale.org/sites/default/files/ guide_for_the_ethical_evaluation_of_experiments_using_laboratory_ animals.pdf 16. Gunn M, Vaudano E, Goldman M. 2012. The rational use of animals in drug development: contribution of the Innovative Medicines Initiative. Altern Lab Anim 40:307–312. 17. Innovative Medicines Initiative. [Internet] 2014. Innovative Medicines Initiative [Cited 22 April 2014]. Available at: www.imi. europa.eu 18. Institute for Health and Consumer Protection. [Internet]. 2013. EURL ECVAM Recommendation on the 3T3 NRU assay for supporting the identification of substances not requiring classification for acute oral toxicity. [Cited 22 April 2014]. Available
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Making Progress and Gaining Momentum in Global 3Rs Efforts: How the European Pharmaceutical Industry Is Contributing Gill Fleetwood,4 Magda Chlebus,1,* Joachim Coenen,2 Nicolas Dudoignon,3 Catherine Lecerf,1 Catherine Maisonneuve,5 and Sally Robinson6 Animal research together with other investigational methods (computer modeling, in vitro tests, etc) remains an indispensable part of the pharmaceutical research and development process. The European pharmaceutical industry recognizes the responsibilities inherent in animal research and is committed to applying and enhancing 3Rs principles. New nonsentient, ex vivo, and in vitro methods are developed every day and contribute to reducing and, in some instances, replacing in vivo studies. Their utility is however limited by the extent of our current knowledge and understanding of complex biological systems. Until validated alternative ways to model these complex interactions become available, animals remain indispensable in research and safety testing. In the interim, scientists continue to look for ways to reduce the number of animals needed to obtain valid results, refine experimental techniques to enhance animal welfare, and replace animals with other research methods whenever feasible. As research goals foster increasing cross-sector and international collaboration, momentum is growing to enhance and coordinate scientific innovation globally—beyond a single company, stakeholder group, sector, region, or country. The implementation of 3Rs strategies can be viewed as an integral part of this continuously evolving science, demonstrating the link between science and welfare, benefiting both the development of new medicines and animal welfare. This goal is one of the key objectives of the Research and Animal Welfare working group of the European Federation of Pharmaceutical Industries and Associations. Abbreviations: EFPIA, European Federation of Pharmaceutical Industries and Associations; EPAA, European Partnership for Alternative Approaches to Animal Testing; EU, European Union; IMI, Innovative Medicines Initiative; NC3Rs, National Centre for the 3Rs; RAW, Research and Animal Welfare.
Research and Animal Welfare Strategies Integral to the Science Policy Objectives of the European Federation of Pharmaceutical Industries and Associations (EFPIA)
The EFPIA represents the pharmaceutical industry operating in Europe. Through its direct membership of 33 national associations and 40 leading pharmaceutical companies, EFPIA is the voice on the European Union (EU) scene of 1900 companies committed to researching, developing, and bringing to patients innovative and effective medicines. These are designed to fight diseases in a variety of areas (for example, cardiovascular, CNS, gastrointestinal, pain control and anesthesia, respiratory, inflammation, infection, and cancer). Millions of people worldwide suffer from diseases in these areas and would benefit from such research. The European pharmaceutical industry’s commitment to the 3Rs and animal welfare is not new. The EFPIA Research and Animal Welfare (RAW) working group was established in the late 1980s, concomitantly with the first discussion regarding, Received: 17 Feb 2014. Revision requested: 26 Mar 2014. Accepted: 08 May 2014. 1Science Policy Platform, Animal Welfare, European Federation of Pharmaceutical Industries and Associations (EFPIA), Belgium; 2Corporate Animal Science & Welfare (EQ-A) Merck KGaA, Germany; 3Disposition, Safety and Animal Research, Animal Research and Welfare, Sanofi, France, 4Office of Animal Welfare, Ethics and Strategy, GlaxoSmithKline, United Kingdom; 5Animal Health and Welfare, Drug Safety, Servier, France; 6Drug Safety and Metabolism, AstraZeneca, United Kingdom. *Corresponding author. Email: [email protected]
and the subsequent adoption of, the EU Directive 86/609 on the protection of animal used for scientific purposes.7 This unique industry structure contributes to shaping the political, legal, and regulatory environment surrounding animal research and testing. It detects and addresses threats to, and seeks opportunities to enhance feasibility of, research, industry practices, and reputation. It works to reconcile research needs with animal welfare imperatives and promotes development and uptake of 3Rs approaches in research and testing, both within the pharmaceutical industry and beyond. The membership of the RAW group consists of veterinarians, toxicologists, pharmacologists, ethicists, lawyers, public affairs and communication specialists, and animal welfare officers, as well as observers from research defense organizations, academia, and authorities (where appropriate). The group supports or complements the activities of other committees taking care of research collaboration and science policy, as well as of preclinical research in particular. All these expert groups have the common objective of improving the efficiency of research and development processes to provide safer and better medicines to patients more quickly and to address unmet medical needs. EFPIA and its member companies recognize the ethical dilemma surrounding the use of animals in research. To put animal welfare principles into action, member companies only use animals where no alternative exists, use the minimum numbers to achieve the scientific objective, and ensure that the animals experience the least possible pain and distress at all steps—from their breeding to their use in research environment.
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EFPIA member companies also continues to work to better understand mechanisms of disease and to improve the scientific robustness of the preclinical models (animal and nonanimal) to enhance our ability to deliver new effective and safe treatments. The research-based pharmaceutical industry not only complies fully with the regulations that exist to ensure high standards for laboratory animal care and use, it goes beyond compliance, promoting higher animal welfare standards and the 3Rs by leading by example. A prime illustration of this practice is EFPIA’s support for the inclusion of explicit 3Rs requirements into the 2010 revision of the EU Directive on the protection of animals used for scientific purposes (Directive 2010/63/EU).13 The following sections provide illustrations of some of EFPIA’s recent activities in support of 3Rs principles and animal welfare. These activities fall into 3 main categories: contributing to discussions regarding animal research with policy makers and regulators, engaging with other organizations and sectors involved with animal research to share and promote 3Rs activities, and working to ensure that high standards of animal welfare and the outputs from our 3Rs initiatives are communicated to the wider scientific community.
Contributing to Global Discussion on the 3Rs and Animal Welfare
Every new piece of legislation on the use and protection of animals is a source of inspiration for authorities around the world. During the 7-y legislative process, many countries very carefully watched the discussion regarding and adoption of Directive 2010/63 on the protection of animals used for scientific purposes. Therefore, even though the directive applies in the EU, it is already part of the global policy discussion regarding live animals and 3Rs in research and development. This new legislation updated and ensured common high standards regarding animal welfare across the whole of Europe. It imposed mandatory ethical review based on benefit risk assessment, the authorization of studies involving animals, and the application of and promotion of the 3Rs methodologies as soon as they become available and have been scientifically validated. This directive brings a new evaluation scale, which categorizes procedures by the degree of pain, suffering, distress, or lasting harm expected to be experienced by an individual animal during the course of the procedure. Last but not least, the legislation harmonized new education and training standards for personnel dealing with live animals and provided requirements for inspections that will strengthen the enforcement of consistent high standards for laboratory animal care and use. Pharmaceutical industry experts played a leading role in the consultations and working groups that provided input into the drafting and legislative process of the Directive. The result—a compromise text—was aimed at delivering improvements in animal welfare but also supports continuation of scientifically and ethically justified animal research and active implementation of the 3Rs. Implementation of these provisions is not always straightforward and might sometimes result in bureaucracy without any added value for welfare of animals. Now that the new Directive 2010/63 is in place, EFPIA and its member companies continue to play a leading role in guiding its implementation at EU level and within member states. These expert discussions address some of the ‘gray zones’ left in the text when the political compromise was set. Many of these unclear points are directly relevant to the implementation, promotion, and enforcement of 3Rs and welfare principles and increased transparency. These
areas address statistical reporting, genotyping, education and training, inspections, project evaluation and retrospective assessment, lay summaries, and so forth. Because of the international impact of the animal protection legislation, EFPIA is also part of a wider scientific European coalition including animal science experts (Federation of Laboratory Animal Science Associations), academia and charities (European Science Foundation/Science Europe), veterinarians (European College of Laboratory Animal Medicine and European Society of Laboratory Animal Veterinarians) and breeders (Federation of European Laboratory Animal Breeder Associations), which provide input into EU-level discussions. The collaborative effort ensures that the legislation is implemented in day-to-day research activities, taking account of specificities of each sector while considering the ‘highest common denominator’ approach. Questions that the coalition discussed included, for example, the interpretation of what is a project or a procedure and how the delegation of powers from a centralized point to the local level for conducting ethical evaluation or delivering authorizations might work in practice. Where differences of operational and scientific focus appeared, the coalition sought alignment for increased influence on research and welfare. All partners in this coalition worked toward the EU objective of securing a level ‘playing field’ and avoiding possible ‘welfare dumping,’ that is, the potential of research being moved to places with lower standards of animal welfare. The other global 3Rs dimension of Directive 2010/63 relates to the source of nonhuman primates. The EU policy-makers decided that nonhuman primates used in research in Europe should be sourced from second-generation (F2) born-incaptivity animals. EFPIA invited experts from the public and private sectors and professional organizations to define how to assess feasibility as well as the health and welfare effects of this requirement. The group recommended looking into the positive or negative effects of moving toward F2 colonies according to behavior and socialization, the total number of animals to be maintained in captivity, and the management of surplus animals during transitional period. The result of this reflection process was published in the French Review of Primatology.9 The directive requires conducting such feasibility and welfare impact assessment by 2017. Encouraging new standards requires the communication and dissemination of information. EFPIA organized webinars for the constituent members of the scientific coalition and participated in various laboratory animal science events to promote the Directive and explain its new provisions. In 2010 and 2011, EFPIA presented the new requirements of the directive at Eurotox, Charles River Associates short courses, the European Parliament, and national laboratory animal science events across Europe. The Directive imposed new standards for housing and caging for improving welfare and enhancing refinement. Instituting this change requires both financial and human resources. Although industry was largely compliant with the new standards (which were included as guidelines in Appendix A of the ETS 123 Convention of the Council of Europe in 20066), upgrading facilities in public research institutions proved to be a financial challenge. EFPIA partnered with the Federation of Laboratory Animal Science Associations and animal welfare organizations to call upon national authorities to provide the necessary resources to maintain high quality research in Europe. This multistakeholder public–private initiative highlights the intertwined relationship between fundamental and applied research and the common endeavor to enhance welfare of animals used in research. 193
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The work regarding Directive 2010/63 is an example of a global effort that crosses the boundaries between companies, sectors, countries, and stakeholder groups whose objectives sometimes contradict each other initially. It offers robust foundations on which to build future dialogue and collaborative initiatives.
Measuring 3Rs Progress
Limited information is available in the public domain against which to measure 3Rs progress. The statistics on animal procedures on living animals cannot be used as benchmark because a range of legal, scientific, business, and strategic factors independent of 3Rs influences the numbers of animals reported in annual statistics. For example, numbers reported in a given period often depend on the start and end of large-scale long-term projects relative to the reporting date and the therapeutic area being studied; changes in regulatory requirements or legislation; historically individual countries have differing criteria for what constitutes a scientific procedure. In 2011, the RAW group conducted a survey of its members and, based on the responses, developed the first-ever series of key performance indicators8 to help in assessing the effect of investments in 3Rs within individual companies. After a review of more than 15 potential metrics, 5 key performance indicators were prioritized as: • examples in the reduction of severity, • evidence of senior executive ownership of 3Rs, • existence of internal 3Rs structures, • number, subject, and impact of internal 3Rs awards, and • involvement in external 3Rs initiatives. This core list comprising a set of quantitative and qualitative key performance indicators helps not only to assess the effectiveness of 3Rs but also to communicate about the 3Rs efforts through Corporate Social Responsibility reports by individual companies and, at an aggregate level, by their trade organizations. The core list can be complemented with others identified during the survey.8 Examples of implementation of these key performance indicators can be found in the section titled “Examples of 3Rs activities from EFPIA member companies” of this article and in the EFPIA reports “Putting Animal Welfare Principles and 3Rs into Action.”10,12
Transport: Global 3Rs Opportunities and Risks
For many years, EFPIA and its members have been involved in the global discussion on transport and countering the moratoria that transporters implement under pressure from animal rights groups. Certain species cannot easily be bred close to the research sites where they are required, and the need to access a variety of animals (particularly transgenic strains) calls for access to high quality and efficient transport. Moratoria on transport by scheduled service and experienced airlines force researchers to turn to alternative routes with the risk of negative effects on animal welfare. Longer transport durations, more transit stops with increased handling and inadequate connections increase the risk of delays to shipments, thus potentially jeopardizing animal health and welfare. Even the switch from passenger to cargo planes to transport animals can lead to unexpected travel delays. Indeed, passenger planes always have precedence over cargos when there is any reason to prioritize flights (for example, weather conditions, strikes). Consequently cargo plane schedules can be highly unpredictable. Additional delays can be caused by customs procedures. Their length is related, to a certain degree, to lack of a harmonized information package and documentation accompanying the animals;
the development of such documentation is recommended by the World Organisation for Animal Health. Although internationally recognized codes and guidelines on how to safeguard animal welfare during transport exist,5,19,24 they need to be reviewed and updated regularly. The EFPIA RAW group and its member companies contribute to discussions about such regulations and processes to further improve the quality of animal transportation to ensure the delivery of healthy, unstressed, well-maintained, acclimated animals. There is a continued need to engage in an international multistakeholder dialogue with representatives of all those involved in the research network, including breeders, transporters, users and competent authorities at international (World Organisation for Animal Health), European (Commission), and national levels (veterinary inspections) to find solutions that will combine continuity of supply and animal welfare and will prevent wellintended policy decisions from having unintended negative effects on animal welfare and scientific progress.
The Era of Global Communication
Promoting good science and good welfare and increasing understanding of how the two are intertwined for the benefit of patients is an essential part of promoting and facilitating high-quality research. The RAW group is driving several initiatives that complement companies’ internal and external communication. The report “The 3Rs and Welfare: Putting Animal Welfare and 3Rs Principles into Action.” In 2012, the EFPIA published its first report illustrating industry’s efforts and commitment to the 3Rs principles.10 The report is structured around 3 themes—compliance, leading by example, and open communication—and is based on examples of actual activities by either EFPIA or member companies in the area of the 3Rs. These examples are related to regulations, training programs, sharing and encouraging best practices, global animal welfare standards, assessment of animal welfare, and contribution to open and constructive dialogue on animal welfare. The second edition of this report was published in January 2014.12 “Animal Testing Perspectives” blog. Animal research and testing is a controversial topic that has generated a great deal of passion in the industry, the public, and the scientific community. As a result, having a rational and open debate on the issues often has proven to be difficult. To facilitate this discussion, EFPIA now offers a social media platform titled “Animal Testing Perspectives.” The main purpose of this initiative is to engage in a constructive discussion with key stakeholders, including opponents of animal research and testing, to demonstrate the genuine efforts of the industry to implement 3Rs and improvements in animal welfare and to shift the discussion away from being a purely ideological and emotional one to a factual one.2 “Animal Research for Life” website. The “Animal Research For Life” website was created in the context of the revision of the legislative work on Directive 2010/63 on the protection of animals used for scientific purposes. This educational tool gives basic and simple information regarding the use made of animals in the pharmaceutical industry, the value and limitations of alternative approaches, and the legal framework for the use and protection of animals used in research.1
Global Research: From Science to the 3Rs
Today’s scientific and healthcare challenges are so complex that no single stakeholder alone will be able to address them successfully. Cross-sector, multistakeholder, and international
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collaborations are the only way forward. Solutions that are developed through this collaborative effort will benefit the entire scientific community irrespective of where they are located. The search for better tools to address safety and efficacy challenges often has driven more rational use of live animals and alternatives in biomedical research. Examples of such initiatives follow. The Innovative Medicines Initiative (IMI). The IMI17 is a public–private partnership between the European Commission and the members of EFPIA. IMI’s key mission is to enhance the competitiveness of the pharmaceutical sector in Europe, for the benefit of patients and scientists, by supporting open innovation and precompetitive research in pharmaceutical research and development. IMI was launched in 2008 by the EU and EFPIA, with a total budget of €2 billion to be spent over a 10-y period; IMI is the largest public–private partnership in the life sciences.16 Although the focus of IMI projects is finding breakthrough medicines, the implementation of 3Rs practices is integral to this process. Several IMI projects are at the forefront of novel approaches to replacing and reducing animal research. The eTox project integrates bioinformatics and chemo-informatics approaches for the development of expert systems allowing the in silico prediction of toxicities. The SAFE-T project is developing improved tools for the prediction, detection, and monitoring of drug-induced injuries to the kidney, liver, and vascular system, by using markers in patients’ blood or urine. The project Mechanism-Based Integrated Systems for the Prediction of Drug-Induced Liver Injury (MIP-DILI) seeks to improve the tools used to test liver toxicity during drug development. This project will use induced pluripotent stem cells, hepatic cell culture, and custom computer models to unravel the complex mechanisms behind drug-induced liver injury. This novel approach will contribute to the replacement of tests on animals during drug development. To build on the success of IMI, the pharmaceutical industry and European Commission decided to continue this public– private collaboration until 2024 under the banner of IMI2. The strategic research agenda of IMI211 focuses on personalized prevention and treatment and outlines 3Rs opportunities that new sciences and knowledge can bring. The advances in studies of the human genome, breakthroughs in high-speed information processing, and the promise of nanotechnology are highlighted in the agenda as offering the prospect for developing new or improved medicines with decreased dependence on animal models. As knowledge accumulates and because of concentrated efforts to improve our understanding of the underlying causes of human disease and other research activities outlined in the strategic research agenda, the number of opportunities to either replace existing animal models with nonanimal alternatives or to adjust the animal model so that it becomes more predictive of clinical outcomes, requires fewer animals to evaluate, or uses a more humane endpoint (for example, a biomarker rather than the development of clinical disease) will increase. The European Partnership for Alternative Approaches to Animal Testing (EPAA). The EPAA is an unprecedented collaboration among European Commission services, trade federations, and major companies from 7 industry sectors.14 The partners have committed to pooling knowledge, research, and resources to accelerate the development, validation, and acceptance of alternative approaches to safety testing. EFPIA is one of the founding members of EPAA. In addition, many EFPIA companies are direct members of this public–private partnership. Participation in EPAA projects enables all members to pool knowledge, research, and resources within a more general context. This collaboration helps to accelerate the develop-
ment, validation, and acceptance of alternative approaches for regulatory use. Together with the European Commission, participants from academia, nongovernmental organizations, individual pharmaceutical companies, and EFPIA collaborated on the following EPAA projects. 1) The European pharmaceutical industry was able to share its experience and learning across pharmaceutical companies from its review of acute toxicity testing in the development of new medicines. The information sharing was led by AstraZeneca and facilitated by the United Kingdom’s National Centre for the 3Rs (NC3Rs), and led to the removal of the regulatory requirement for acute toxicity tests in the pharmaceutical industry. This work was the impetus for a cross-sector review through EPAA23 2) Through the cross-sector review, EPAA was able to provide evidence to regulators that only one testing route was necessary to show the toxicity of a substance; that is, there is little or no value in performing an acute dermal study when oral data are already available. Accordingly, a significant opportunity exists to reduce the number of animals used for this purpose. 3) Another project looked at integrated testing strategies, making the case that this methodology provides more data than do current existing methods, with the agreement that “industry, academia, and regulators need to educate each other, and integrated testing strategies [are] among the most efficient solutions to address the 3Rs.” Other EPAA projects that European pharmaceutical companies have supported include the potential for using stem cells to replace single-organ animal testing and for enhancing integrated testing strategies. Although EPAA is a European initiative, the partners realized that real change would come from international application of the new approaches, supported by international regulatory acceptance. Supported by the Commission, international dialogue, and regulatory collaboration tools, EPAA engaged several international regulators. Additional information about EPAA and the 3Rs can be found in the article “The European Partnership for Alternative Approaches to Animal Testing (EPAA): Promoting Alternative Methods in Europe and Beyond” in the current issue.14 Examples of 3Rs activities from EFPIA member companies. In addition to working together under the umbrella of EFPIA, many of the member companies also work together as part of other initiatives that have 3Rs effects. For example, many EFPIA companies directly contribute to NC3Rs activities. For example for acute toxicity studies, several EFPIA companies, facilitated by NC3Rs, provided a novel, evidence-based challenge to the regulatory requirement for acute toxicity studies where lethality was an endpoint. Appropriate preclinical and clinical data were shared, and the analysis of this information demonstrated that acute toxicity studies have limited value for assessing human safety and, as such, their continued requirement by regulators could not be justified.22 As a direct consequence of this initiative and the subsequent engagement of collaborators and regulators, the revision of guideline M320 from the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use incorporated the recommendations of this team. Other cross-company initiatives facilitated by NC3Rs include the joint project of the Medicines and Healthcare Products Regulatory Agency and NC3Rs to assess the need for recovery animals in toxicology and the CRACK-IT initiative.21 Another recent cross-company project reviewed approaches to microsampling (that is, obtaining small volumes of blood by using a refined method). Microsampling can increase the amount of nonclinical safety information available, can improve its validity by linking toxic effects to drug exposure in individual 195
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animals, and represents the most significant short-term opportunity to reduce and refine animal use in toxicology studies.3 Representatives from several companies in France have developed, together with their public research counterparts, a training program for project evaluators and ethics committee members to try and harmonize the ethical review process throughout the different committees across the country. Courses were based on the National Charter on the ethics of animal experimentation published by the Comité National de Réflexion Ethique sur l’Expérimentation Animale,4 and the Guide for the Ethical Evaluation of Experiments using Laboratory Animals15 that was approved by the French authorities. In addition, several companies across Europe worked with the European Center for the Validation of Alternative Methods to validate a cytotoxicity test to identify nontoxic chemicals. This test has been implemented for the testing of chemical substances, and the information is included in safety testing requirements.18 The validated test replaces most of the previously required in vivo experiments. Animal welfare principles in globalized research. The same rationale of aligning on scientifically driven animal welfare standards motivated EFPIA and the RAW group to start to establish links and form partnerships and collaboration with other organizations active in the United States and globally. For example, EFPIA joined the AAALAC Board of Trustees. In the future, the EFPIA RAW group will continue to reinforce these interactions to help improve animal welfare standards worldwide. In this context, dialogue with the International Consortium on Innovation and Quality in Pharmaceutical Development in the United States is greatly appreciated as an important initiative to promote the sharing and integration of high-quality scientific practices to advance the 3Rs.
Conclusions
The science underlying the research and development of new medicines faces global challenges because medicines are developed and used globally. The scientific community has a unique opportunity to join forces and advance initiatives in science policy, research and development, and 3Rs principles and practices that will enhance the quality of medicines for patients and the understanding of research imperatives. This goal can only be achieved through global collaboration at all levels— across companies, sectors, stakeholder group, and countries. The initiatives we have described herein can be used as starting points for further progress in reconciling research, health, and 3Rs agendas. Securing the time and resources necessary for such collaborations would be worthwhile investments for the future. EFPIA and its RAW group stand ready to engage and to explore new grounds for collaboration with all interested parties.
References
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