The European Partnership for Alternative Approaches to Animal Testing (EPAA) 10 th Anniversary Conference: A decade of support to the 3Rs

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1 The European Partnership for Alternative Approaches to Animal Testing (EPAA) 10 th Anniversary Conference: A decade of support to the 3Rs 1 Dec 2015, European Parliament, Brussels, Belgium Conference Report prepared by Ursula G. Sauer, Scientific Consultancy - Animal Welfare Established in 2005, the European Partnership for Alternative Approaches to Animal Testing (EPAA) is a public-private initiative between services of the European Commission (EC) and European industry stakeholders from seven sectors. Tied by the 3Rs Declaration, all EPAA activities serve the 3Rs principle to replace, reduce and refine animal testing (Russell and Burch, 1959). In celebrating its 10 th anniversary, EPAA organised the conference A decade of support to the 3Rs that took place on 1 December 2015 at the European Parliament (EP) in Brussels, Belgium. The event welcomed 75 participants from academia, civil society, industry, European and international institutions and regulatory authorities. This report summarizes the presentations and discussions from the conference. Session 1 : 10th anniversary of EPAA...2 Session 2 : 2015 at a glance for EPAA...4 Session 3 : Effectiveness and reliability of alternative methods used for regulatory purposes...7 1

2 Session 1: 10 th anniversary of EPAA (Chaired by MEP Giovanni La Via) 1. A decade of support to the 3Rs Antti Peltomäki, Deputy Director General, Directorate-General for Internal Market, Industry, Entrepreneurship and SMEs, European Commission (DG GROW, EC) Opening the conference, MEP G. La Via, Chair of the EP Committee on Environment, Public Health and Food Safety (ENVI), recollected how EPAA had been founded in 2005 by two European Commissioners Janez Potočnik and Günther Verheugen together with industry and a strong impetus from MEP Dagmar Roth-Behrendt who became the first chair of the EPAA Mirror Group. Just as citizens were highly concerned about the welfare of animals, this issue was of high priority for the EP. Accordingly, a specific EP Intergroup on the Welfare and Conservation of Animals addressed this topic. MEP G. La Via introduced the EPAA 10 th Anniversary Conference as an occasion to reflect on the EPAA s achievements and to discuss the future orientation of its work, which would focus on furthering regulatory acceptance of alternative methods. EPAA is considered a pioneer in 3Rs and underlined its outstanding role in supporting the EC in its commitment to the 3Rs principle. In the Treaty on the Functioning of the EU (TFEU, 2012), Article 13 requested paying full regard to the welfare requirements of animals in formulating and implementing EU policies. In this respect, alternative methods had the potential to improve the safety of humans and the environment. Directive 2010/63/EU on the protection of animals used for scientific purposes (EP and Council of the EU, 2010) firmly anchors the 3Rs principle. The Directive requires the use of alternative methods if available, setting the ultimate aim to phase out animal testing. In this context, the full marketing ban for cosmetic ingredients and products that were tested on animals came into force in 2013 (EP and Council of the EU, 2009). Addressing the civil society s ethical concerns, this ban was implemented even though alternative methods were not yet available for all toxicological endpoints. Yet, the marketing ban provided a strong incentive for non-eu countries (e.g. Israel, India) to follow the same path or to accept alternative methods (e.g. China). Promotion of alternatives has also been one of the objectives of the REACh legislation. Finally, A. Peltomäki confirmed the EC s openness to engage in a cross-sector dialogue on animal testing and alternative methods, e.g. with EU citizens or with legislators from non-eu countries. 2

3 2. European vision for the promotion of better predictive safety science Felix Wildschutz, Director of the Administration of Veterinary Services, Ministry of Agriculture, Viticulture and Rural Development, Grand Duchy of Luxembourg, Luxembourg Presidency of the Council F. Wildschutz emphasized that EU Member States contributed to supporting the 3Rs principles via their competent authorities responsible for the implementation of Directive 2010/63/EU. Nevertheless, the EC has been in charge of supervising this implementation, and by 10 November 2019 it was requested to prepare the respective report in accordance with Article 57 of the Directive. F. Wildschutz highlighted the leading role of the EPAA and praised it for bringing together relevant stakeholders thereby pooling knowledge from different sectors. 3. Milestones & Achievements: Ten years of EPAA & beyond Carlo Pettinelli, Director, Unit D: Consumer, Environmental and Health Technologies, DG GROW EC, EPAA European Commission Co-Chair As C. Pettinelli described, when EPAA was founded in 2005, the concept of a publicprivate initiative was very new, and it was considered a major success that different sectors cooperated in spite of prevailing differences. In the meantime, EPAA had grown to comprise a large number of companies 1, including global players in their respective sectors, which have been engaging in a continuous cross-sector dialogue with the EC to understand each others concerns. Thereby, EPAA has become a key player in promoting the regulatory acceptance of alternative methods. 4. 3Rs approaches for Regulatory Safety Testing: the contribution of EPAA Magda Chlebus, Director of Science Policy, European Federation of Pharmaceutical Industries and Associations (EFPIA) M. Chlebus indicated scientific and technological innovation, patient and consumer safety, and animal welfare as three equally important drivers of the EPAA s work. By contrast, major challenges that EPAA encountered in pursuing its goals included prevailing scientific and technological knowledge gaps, delays in the regulatory acceptance of available alternative methods, and a lack of international convergence on regulatory provisions. In the past decade, she assessed that EPAA has successfully contributed to meeting all of these challenges. 1 As of December 2015, EPAA brings together 5 Directorates-General of the European Commission, 36 companies and 7 industry federations. 3

4 M. Chlebus put the EPAA s work into a broader context highlighting how its activities serving to fill knowledge gaps were linked to the EU Framework Programme for Research and Innovation Horizon 2020 and industry-driven research initiatives. Flagship initiatives included the Cosmetics Europe research initiative: Safety Evaluation Ultimately Replacing Animal Testing (SEURAT-1 2 ); the EFPIA Innovative Medicines Initiative (IMI and IMI-2 3 ); the European Chemical Industry Council (Cefic) Long-Range Research Initiative (LRI 4 ); and the International Federation on Animal Health (IFAH) work towards deletion of the target animal batch safety test for veterinary vaccines. Also the EPAA s members, on their own, have been implementing new science and technology and massively invested in research and development. Similarly, while EPAA served as a driver to facilitate the regulatory acceptance of available alternative methods, the EU and national regulators were the ones responsible for granting this acceptance, as M. Chlebus explained. International convergence had to be accomplished on the global level, led by e.g. the International Conference on Harmonisation (ICH), the Organisation for Economic Co-operation and Development (OECD), the World Health Organisation (WHO). Session 2: 2015 at a glance for EPAA (Chaired by Carlo Pettinelli, EC EPAA Co- Chair) 1. EPAA Projects: 2015 developments Patrick Sinnett-Smith, Director, Animal Welfare and Compliance Europe, Pfizer, EPAA Industry Co-Chair The seven ongoing EPAA projects were related to science (development of new alternative methods) and regulation (regulatory acceptance of alternative methods), and they addressed the following topics: (1) Optimisation of testing strategies for skin sensitization; (2) Promotion of the vaccines consistency approach (VCA); (3) Waiving of the dermal route during acute toxicity testing; (4) Provision of a user-friendly in vitro/in vivo exposure predictor; (5) International convergence on the 3Rs principle in the quality control of biologicals; (6) Waiving of 2-year carcinogenicity studies in the pharmaceutical sector; (7) Fundamental research and communication on stem cells-based alternatives

5 In 2015, EPAA organised 4 scientific workshops; it published 5 peer reviewed articles and attended 3 international conferences. In association with the Institute for In Vitro Sciences 5, EPAA sponsored the development of a training video on the Bovine Corneal Opacity and Permeability (BCOP) assay, available online. 6 Eventually, the recently adopted Action Programme for was showcased. It will promote the EU-wide and international regulatory acceptance of alternative methods. The Action Programme also foresees the EPAA s continued assistance in shaping the EU research funding area by identifying priorities for 3Rs-relevant research. Last but not least, dissemination and communication in respect to 3Rs information are also emphasised. Finally, the EPAA s Action Programme included a special focus on the refinement of animal testing. 2. The EPAA 3Rs Laboratory Technician/Caretaker/ Animal Technologist Prize: Award Ceremony Horst Spielmann, Secretary General, European Society for Alternatives To Animal Testing (EUSAAT), EPAA Mirror Group Member, Prize Awardee The prize was awarded to Alexandra Lorenz, laboratory supervisor at TissUse GmbH for her work in developing and establishing a multi-organ chip for the co-culture of organ equivalents for long-term (up to 28 days) substance testing. Whereas animal models were not necessarily reliable predictors of human health effects and static human cell cultures were not systemic, the multi-organ chips used human cells, and they included a dynamic system, as A. Lorenz explained in her speech. An integrated micro-pump provides a stable pulsatile fluid flow enabling an almost physiological fluid-to-tissue ratio. The chip allowed flexible arrangements of 2-10 different organ equivalents and a connection to two different circuits reflecting the circulatory and excretory systems. 3. The Vaccines Consistency Approach Project: Achievements and way forward Catrina Stirling, Managing Director, Regulatory Affairs, Zoetis Quality Control (QC) testing is mandatory for vaccine batch release, and this QC testing includes in vivo potency testing of the final products (mostly for inactivated vaccines). For recently registered inactivated vaccines, the VCA has the potential to replace in vivo testing by integrating the quality assurance into the stage of vaccine development 5 IIVS; Gaithersburg MD, USA

6 instead of postponing it to the final stage of batch release testing. VCA ensures QC by strictly applying a quality system and by consistently producing batches identical to reference lots of known potency and safety. Since 2011, the EPAA VCA project provided a forum for communication and collaboration between all relevant stakeholders (the European Directorate for the Quality of Medicines & HealthCare (EDQM), the European Union Reference Laboratory for alternatives to animal testing (EURL-ECVAM), international vaccines producers). EPAA organised a series of workshops addressing four key areas: diphtheria, tetanus and polio vaccines; human rabies vaccines; veterinary rabies vaccines; and clostridial vaccines. By supporting specific collaborative studies and by promoting the VCA at scientific conferences and briefings within the EP, EPAA contributed to laying a scientific foundation for the VCA and to raising awareness on its applicability. Furthermore, the EPAA VCA project prepared the ground for the IMI-2 VCA project. Scheduled to begin in early 2016, the IMI-2 project would aim at developing and validating new methods that might ultimately replace in vivo vaccine batch release testing. Outcomes from the EPAA VCA project included global agreement on the way forward for human rabies vaccine testing; a proof-of-concept and the initiation of a validation study for process control methods for clostridial vaccines; and the establishment of an international dialogue on the global harmonisation of the VCA. 4. The EPAA Mirror Group views: an outer perspective on EPAA Horst Spielmann, Secretary General, European Society for Alternatives to Animal Testing (EUSAAT), EPAA Mirror Group Member The EPAA Mirror Group 7 consists of third-party (non EC, non industry) experts acting as an independent consultation forum in advising the EPAA Steering Committee, providing input from a broader societal perspective. H. Spielmann highlighted the extent of expenditure and time required to develop and validate alternative methods. To ensure that the final goal to achieve full replacement of procedures on live animals, as required in Directive 2010/63/EU, would eventually be reached, H. Spielmann called for a substantial increase in public funding serving the 3Rs principle

7 Session 3 : Effectiveness and reliability of alternative methods used for regulatory purposes (Chaired by MEP Julie Girling) The 3 rd and final session of the EPAA 10 th Anniversary Conference was conceived as panel discussion on the effectiveness and reliability of alternative methods used for regulatory purposes. Chaired by MEP and EPAA Mirror Group member Julie Girling, member of the European Parliament Committee on the Environment, Public Health and Food Safety (EP ENVI), the panel discussion participants were Maurice Whelan 8 (DG Joint Research Centre Institute for Health and Consumer Protection, European Commission, DG JRC-IHCP, EC, Italy); Sonja Beken 9 (European Medicines Agency, EMA, Belgium); Erwin Roggen 10 (Novozymes, Denmark); and Joop de Knecht 11, (Organisation for Economic Co-operation and Development, OECD, France). In the first round, MEP J. Girling invited all panellists to share their views on how research should be translated into effective and reliable alternative methods and to identify main drivers for change. M. Whelan highlighted three essential aspects: (1) there is a need to fund and engage researchers who are genuinely committed to the 3Rs and perform non-animal research that specifically addresses safety assessment. Researchers should ensure that their methods would be applicable for hazard and risk assessment and the classification and labelling of substances; (2) Research projects should be designed to ensure that they would deliver tangible methods applicable for regulatory purposes. Accordingly, they should include a focus on the translation and validation of the newly developed methods, and (3) finally, also risk assessors and risk managers should truly engage in formulating challenges and identifying needs. They could act as main drivers for change in the safety paradigm and open up to new methods and approaches. Frequently, alternative approaches deliver different and better information than animal tests they were intended to replace. S. Beken confirmed that regulators have played an important role in ensuring that research has yielded effective and reliable methods for safety testing, since they were in a position to specify the prerequisites for such methods. Highlighting the importance of a need-driven research, S. Beken advised involving regulators in constant dialogue and 8 Prof Maurice Whelan is Head of the Systems Toxicology Unit and Head of the European Union Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM) 9 Dr Sonja Beken is Head of the Non-Clinical Assessors of the Federal Agency for Medicines and Health Products (Belgium), and acts as chair of the Joint Expert Group on the Application of the 3Rs in Regulatory Testing of Medicinal Products (JEG 3Rs) at EMA. 10 Dr Erwin Roggen is the EPAA Industry Co-Chair of the Project Platform, as a representative for Novozymes. 11 Dr Joop de Knecht is principle administrator at the Environment, Health and Safety Programme. 7

8 early on in research projects to ensure that the resulting methods were truly relevant for safety testing. Often, regulators only played an advisory role, whereas the researchers in industry and academia were responsible for conducting the research work. From the perspective of a researcher developing non-animal testing approaches, E. Roggen deplored the difficulty in obtaining funding for applied research to develop and validate alternative methods that specifically meet the needs of industry or that are directly relevant for a given question. Highlighting the philosophy taken at the OECD, J. de Knecht explained that knowledge on the exact toxicity pathway leading to a specific toxic effect was required to develop alternative methods suitable to replace the corresponding in vivo tests. Accordingly, the OECD had established a programme to identify Adverse Outcome Pathways (AOPs). By evaluating the knowledge available on a specific AOP, it became possible to develop alternative methods that reflected its individual steps as the example of skin sensitisation testing revealed. Additionally, to facilitate the mutual acceptance of test methods and Integrated Approaches on Testing and Assessment (IATAs), the agreement was required on how, e.g., their applicability domain or degree of predictivity and level of uncertainty should be described and documented. Second, MEP J. Girling asked the panellists to explore how the effectiveness and liability of new methods might be demonstrated. M. Whelan responded that, generally, the effectiveness of a test method was reflected by its relevance and reliability. Currently, the biggest challenge for alternative methods was the demonstration of their relevance. As M. Whelan further elaborated, developers frequently struggled to explain the actual use of their test method for regulatory decisionmaking. Multiple types of methods with multiple types of outcomes had to be combined in a rational way to allow replacing a given animal test. Hence, the assessment of the results from alternative methods differed widely from the interpretation of any given animal study. To ensure applicability of an alternative method for a given purpose, it had to be developed and validated in view of the given regulatory context taking into account the available knowledge on toxicity mechanisms and pathways. In this respect, greater emphasis needed to be placed on bridging the gap between basic research and the necessities of routine toxicity testing. This included the need for well-defined test methods, the determination of relevant negative and positive controls, 8

9 and issues to be taken into consideration when implementing test methods in new laboratories. M. Whelan referred to the EU Network of Laboratories for the Validation of Alternative Methods (EU-NETVAL) that encompassed 26 laboratories of excellence. To make adequate use of this unprecedented network, it was necessary to identify and prioritise relevant test methods, to work with performance standards and to evaluate not only new but also existing methods, with more effective ways than conventional validation. There are opportunities of learning from the pharmaceutical sector which was considered as rich in human data and knowledge compared to the chemical sector. From the perspective of the pharmaceutical regulators, S. Beken pointed out to the ongoing development of the EMA guideline on regulatory acceptance of 3R testing approaches. Initially, this guideline was intended to cover only pre-clinical toxicity methods, but its scope was expanded to batch efficacy and safety testing. S. Beken highlighted that it was especially challenging to describe a method s toxicological mechanism and intended use (either on its own or as a part of an IATA) in sufficient scientific detail. In order to have co-ownership of the problem, the EMA was striving to engage the method developers, the users and the regulators, also on the ICH level, in discussions on the prerequisites for documenting individual methods. In respect to the requested reliability of a test method, E. Roggen remarked that this had to be determined for a given purpose. He welcomed that reliable in vitro test methods were in fact available, e.g. for skin sensitisation testing. Nevertheless, these methods would only yield reliable results if their applicability domain was respected. Oftentimes, test methods appeared ineffective because their applicability domain had not been explored in sufficient detail. Deploring the amount of time it usually took for an alternative method to gain regulatory acceptance, E. Roggen invited EPAA to engage in discussions with regulators on how this procedure may be accelerated. Referring to the applicability domain of a test method and its underlying toxicological mechanisms, J. de Knecht cautioned that the occurrence of false negative or false positive test results was not necessarily linked to the toxicological pathway addressed, but that it might also be caused by specific technological limitations of the test method in regard to certain chemicals. Nevertheless, researchers should strive to correlate occurring false negative and false positive test results to underlying toxicological mechanisms, as E. Roggen re-emphasized. 9

10 S. Beken pointed to the fact that, in the pharmaceutical sector, an abundance of alternative methods was being applied during drug discovery, whereas safety testing continued to be performed with traditional tests. Notwithstanding, mechanistic assays were demanded for safety testing. She advised exploring the possibility to transfer alternative methods that were being used during drug discovery to the stage of safety testing. For this purpose, the required performance standards for new methods would have to be determined. M. Whelan added that, for economic reasons in the chemicals sector, not all novel techniques and tools that are used for pre-screening in the pharma sector are available. Therefore, the suitability of alternative methods for risk assessment of chemicals is often assessed retrospectively. He highlighted that the initiative to waive 2-year carcinogenicity studies in the pharmaceutical sector might be applicable to other sectors as well, but that it was difficult to obtain relevant data to substantiate this expectation. This revealed the need for the various sectors to come together and establish an effective framework to generate human relevant data and learn from each other. Third, MEP J. Girling asked the panellists to identify further factors that were effective in promoting the regulatory acceptance of alternative methods assuming that their effectiveness and reliability had been demonstrated. To this, J. de Knecht explained that all test methods, be they in vitro or in vivo, might provide false negative and false positive results. This was also true for standardised methods that had been adopted as OECD test guidelines. Accordingly, the acceptable level of uncertainty had to be determined and agreed upon for each individual test method. This task would be facilitated if test methods reflected specific steps of a well-defined AOP, as was the case for skin sensitisation. In backing up this statement, E. Roggen underlined that it would take time to identify and describe the limitations of a given test method more so since validation studies inevitably only provided restricted information. E. Roggen advised establishing a framework to determine a test method s limitations and called for more flexible test guidelines that would enable companies to apply test methods more quickly. S. Beken emphasised the need to involve all key players in planned validation studies. The EURL ECVAM s Network for the Preliminary Assessment of Regulatory Relevance (PARERE) played an important role in ensuring that the necessary spectrum of substances was included in validation studies. However, even if a given method had 10

11 successfully passed a validation study, this did not necessarily imply that it was ready for regulatory acceptance. Therefore, the so-called safe harbour system was being applied in the pharmaceutical sector, for instance on the level of the ICH in assessing options to waive 2-year carcinogenicity studies. The safe harbour system allowed companies to use the new method alongside the traditional method. While the data from the new method were not used for product authorisation, this system ensured that eventually a sufficient number of compounds were submitted to both methods so that the acceptability of the new method could be determined. Finally, validated methods had to be taken up into the respective guidelines, and for this purpose the relevant decision-makers had to be aware of the new methods. M. Whelan cautioned that the decision-makers encompassed a very heterogeneous group and that it was oftentimes difficult to determine those truly responsible for making a decision in a given context. M. Whelan further welcomed that it was no longer considered necessary to only aim for alternative methods or approaches that enabled full replacement of animal testing for a given toxicological endpoint. Instead, also alternatives that provided only partial information were considered relevant. Nevertheless, the specific purpose of each alternative method had to be known, and the test substances selected for its assessment had to be justified accordingly. M. Whelan explained that the uncertainties of in vivo methods had been explored for many years to a point where they had become manageable and decision-makers felt confident in using information from these methods. Now, the same approach was required for alternative methods to specifically determine their variability, limitations and other aspects of uncertainty. Thereby, the likelihood of correctly using the outcome of an alternative method for decision-making could be established. While test method validation is essential to evaluate a method s effectiveness, it was not sufficient to gain its regulatory acceptance and use. Case studies provided a valuable tool in determining uncertainties and in building confidence in new methods. In backing up this statement, E. Roggen advised to start using the available in vitro methods thereby gaining confidence in them. Referring to the ongoing revision of the guideline for reproductive toxicity assessment that was taking place at ICH level, S. Beken lauded that the EU was frequently at the forefront of granting alternative methods regulatory acceptance. Nevertheless, the 11

12 international dialogue should not be neglected. Oftentimes, international convergence of regulatory provisions was a tedious and long-lasting process, but it was indispensable to ensure that companies producing for the global market would be in a position to apply the alternative methods. From the audience, C. Stirling (Zoetis) reflected that all deliberations came down to the applicability of alternative methods for risk assessment. However, between different sectors, different levels of risks in predictability were considered acceptable. As C. Stirling elaborated, this aspect required further consideration and EPAA could provide a platform for all sectors to think about risk as cross-sector learning. Additionally, companies required assurance that regulators would accept the submission of data from a new method; otherwise they would not be willing to take the economic risk to apply it. To this, M. Whelan added that the deployment of new alternative methods and approaches as well as the need to develop OECD reporting templates and to better describe the uncertainties were recognised and more and more efforts were being put into these tasks. MEP J. Girling invited all conference participants to bring the important reflections from the panel into their work in accelerating the development, validation and acceptance of alternative approaches to animal use in regulatory testing. In further concluding the conference, MEP J. Girling again congratulated EPAA for its outstanding role in facilitating the exchange of views and ideas for the 3Rs in regulatory testing. References EP and Council of the EU Regulation (EC) No 1907/2006 of the European Parliament and of the Council of 18 December 2006 concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH), establishing a European Chemicals Agency, amending Directive 1999/45/EC and repealing Council Regulation (EEC) No 793/93 and Commission Regulation (EC) No 1488/94 as well as Council Directive 76/769/EEC and Commission Directives 91/155/EEC, 93/67/EEC, 93/105/EC and 2000/21/EC. OJ L 396/1, 30 December EP and Council of the EU, Regulation (EC) No. 1223/2009 of the European Parliament and of the Council of 30 November 2009 in cosmetic products. O.J. L 342/59, 22 Dec EP and Council of the EU, 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. OJ L 276/33, 20 Oct Russell, W.M.S., Burch, R.L., The principles of humane experimental technique. London, UK. Methuen. Reprinted by UFAW, 1992: 8 Hamilton Close, South Mimms, Potters Bar, Herts EN6 3QD England, 238 pp. TFEU, Consolidated version of the Treaty on the Functioning of the European Union. OJ C 326, , p