European Surveillance of Veterinary Antimicrobial Consumption (ESVAC):

4 Focus Veterinary medicines European Surveillance of Veterinary Antimicrobial Consumption (ESVAC): Establishment of the project and key outputs Authors Kari Grave, ESVAC National Expert; David Mackay, Head of Veterinary Medicines Division; Arno Muller, ESVAC Data Analyst; Jordi Torren-Edo, ESVAC Scientific Administrator, European Medicines Agency, London, UK. Keywords European Medicines Agency (EMA); Antimicrobial agents; Harmonisation; Sales data; Antimicrobial resistance (AMR); National competent authority (NCA); National contact point (NC); Data manager; Population Correction Unit (PCU). Abstract The ESVAC project was launched by the European Medicines Agency (EMA) in September 2009. At that time it was identified that eight EU/EEA countries had surveillance systems in place on the sales of veterinary antimicrobial agents; however, the data were not fully harmonised. For 2010, harmonised sales data detailed at package level was collected for the first time according to an agreed protocol and by application of a template from 19 EU/EEA countries, and for 2011, a total of 25 EU/EEA countries provided sales data. Through fostering cooperation, collaboration and communication, the ESVAC project has been successful in a remarkably short period of time in publishing harmonised data on sales of veterinary antimicrobial agents within the EU. The ESVAC project has been fortunate to benefit from strong institutional support as well as a clear consensus that the collection and publication of data on sales of veterinary antimicrobial agents is an essential component of ensuring their rational use in veterinary medicines. Introduction The Council of the European Union ( the Council ) Conclusions on Antimicrobial Resistance of 2008 1 states: [The Council] Calls upon the Member States to strengthen surveillance systems and improve data quality on antimicrobial resistance (AMR) and use of antimicrobial agents from both human health and veterinary sector, and healthcare associated infections. With this statement, the EU member states (MS) provided their commitment to collect data on consumption and this was further supported in another Council conclusion in 2012. 2 The European Surveillance of Veterinary Antimicrobial Consumption (ESVAC) project was launched in September 2009, following a request from the European Commission to develop an approach for the harmonised collection and reporting of data on the use of antimicrobial agents in animals in the MS. Through the terms of reference from the Commission, the Agency, among other activities, was requested to: l Identify the existing data/surveillance systems established for collection of sales and use of antibacterial drugs in the MS l Develop a harmonised approach for the collection and reporting of data based on national sales figures, combined with estimates of usage in at least major groups of species (poultry, pigs, veal calves, other ruminants, pets and fish) l Collect the data from MS and manage the database l Draft and publish a summary annual report with the data from MS. With regard to the data collection, the Agency was advised to facilitate comparability with the sale/use of antimicrobials in humans should be ensured. Following the mandate given to the EMA, the Commission, through its Action Plan on Antimicrobial Resistance, has continued to promote the ESVAC project, 3 committing the Commission to the promotion and extension of the European Surveillance of Veterinary Antimicrobial Consumption (ESVAC) with the collaboration of EMA to obtain harmonised data on the usage per animal species and production categories as well as for different indications from all Member States. Currently, the ESVAC project collects sales data on veterinary antimicrobial agents at package level from the EU MS and EEA countries. The collection of consumption data by species is in preparation; a draft reflection paper was published for consultation on 18 December 2012 and a system for collection of data on the consumption by species will be rolled out in 2015. Organisation of the ESVAC project Involvement of MS with ongoing surveillance programmes. One of the first steps of the ESVAC project was the establishment of a Technical Consultancy Group (TCG) consisting of experts from the eight MS that had operated ongoing surveillance programmes on the sales veterinary antimicrobial agents for more than five years. This group provided its expertise to the Agency for the creation of an EU-wide surveillance of sales of veterinary antimicrobial agents, including the development of the standardised ESVAC protocol and data collection form (template). The group also participated in a pilot project to test the system that was developed. The fostering of ownership in the project and its outcomes was also considered important, because the surveillance systems established in these MS were not harmonised and they therefore had to change the system they had operated for several years in order to supply harmonised and comparable data. The ESVAC network. The core of the ESVAC project is the ESVAC network of main national contact points ( ESVAC main NCs ) and data managers nominated by the national competent Regulatory Rapporteur Vol 11, No 9, September 2014 www.topra.org

Focus Veterinary medicines 5 authorities (NCAs) in the participating EU and EEA countries. For the collection of data by species, a network of ESVAC by Species NCs is currently under development. A kick-off meeting was held with this network in 2009, where the terms of reference from the Commission were presented and the harmonised approach suggested by the EMA, including the involvement of TCG, was presented and discussed. Since then, annual ESVAC network meetings have been convened annually to ensure face-to-face communication. The tasks of the ESVAC main NCs/data managers are to provide data on sales at package level to the ESVAC team at the EMA following annual data calls; to revise the data in terms of quality and validity following requests from the ESVAC team; to validate the data applied to calculate the population correction unit; and to provide comments on the annual ESVAC report. The ESVAC project on sales data is supported by an ad hoc expert group (ESVAC EG) that comprises representatives from the ESVAC network. There are also observers from the Commission, the European Centre for Disease Prevention and Control (ECDC) and the European Food Safety Authority (EFSA). The task of the ESVAC EG is to provide technical advice on surveillance of overall sales data of antimicrobial agents, including collection and analysis of data and preparation of the annual report. The organisation of the ESVAC project is detailed in Figure 1. Communication on the ESVAC project. The success of the project has been built on extensive cooperation between the various national authorities involved in the project to promote effective communication and cooperation. To achieve quick success and to secure continued development of the project over time, it has been important to ensure the objectives of the data collection are understood and agreed from the outset. In this case, the need at European level to understand how antimicrobial agents are used is seen by all parties as an essential component for the development of rational policies to minimise the risk to animal and human health that may arise from the use of antimicrobial agents in animals. It was also important to engage at an early stage with the pharmaceutical industry and wholesalers that ultimately supply the data on sales to the ESVAC NCs. This engagement is considered key in gaining confidence and buy-in to the objectives and outcomes of the project. To facilitate effective and ongoing communication, yearly meetings are held with the stakeholders that also involve the participation of the ESVAC network. The engagement and involvement of experts with recognised expertise and experience has been essential in gaining confidence in the project s operation, and ESVAC was fortunate to obtain the services of both a Project Coordinator and Data Manager fitting the criteria. The project has also involved experts in surveillance of consumption of antimicrobial agents from Food and Agriculture Organisation of the United Nations (FAO), World Organisation for Animal Health (OIE) and World Health Organisation (WHO) and their input and peer review has been very helpful in ensuring alignment of the project with best practice at a global level and with similar surveillance on antimicrobial use in human medicines. Figure 1: ESVAC project organisation 2014. EURL-AMR FDA WHO OIE FAO WHO Collaborating Centre for Drug Statistics Methodology National Contact Points ESVAC Main National Contact Points (NCs)/Alternates ESVAC Species NCs Data Managers European Surveillance of Veterinary Antimicrobial Consumption (ESVAC) at European Medicines Agency (EMA) National Networks overall sales data and consumption by species European Commission CVMP Other stakeholders: IFAH, EGGVP, FVE ESVAC project team Project sponsor Coordinators Data managers Ad hoc ESVAC Expert Group ESVAC NRs, ECDC and EFSA Ad hoc working groups www.topra.org Regulatory Rapporteur Vol 11, No 9, September 2014

6 Focus Veterinary medicines Technical support and building confidence in the MS. The major factors for success in obtaining harmonised data from so many countries in such a short time are believed to be: l Continuously acknowledging the effort of the MS for their commitment to the project l Acknowledging that the data are owned by the MS and originally supplied by a range of stakeholders, including wholesalers and the pharmaceutical industry l Endorsement of the ESVAC reports by the MS prior to their publication l A quick response time on any questions from MS on the interpretation of the ESVAC protocol and on how to fill in the ESVAC template l Providing technical support to the MS in a bilateral manner but also through training courses l Defining a clear policy on the use of data and ensuring appropriate levels of confidentiality to ensure commercially confidential data are not released. The technical support provided by the ESVAC team to each MS has consisted of a quality check of the data provided in terms of harmonisation/standardisation, both by application of a data programme developed by the EMA and also manually. In each case, feedback has been delivered to the MS consisting of detailed explanations for the corrections made by the ESVAC data manager and thorough descriptions of the changes to be made by the MS, if applicable. In the first year of data gathering by the MS in accordance with the ESVAC protocol and template, the ESVAC team spent considerable resources on this task, varying from one to six days for each country. However, since standardised/harmonised and valid registers of veterinary antimicrobial products have now been established for most of the MS, the current resources used on completing the ESVAC template by the MS, as well as the quality check of the data, have been significantly minimised. Key outputs of the ESVAC project Initially, the ESVAC project collected and published already existing data for the period of 2005 2009 from eight EU/EEA countries and Switzerland in a harmonised manner, including a harmonised denominator (Population Correction Unit PCU). 4,5 Harmonised sales data detailed at package level were collected for the first time for 2010 according to an agreed protocol 6 and by application of a template 7 from 19 EU/EEA countries. 5 For 2011, 25 EU/EEA countries provided sales data. 8 Among others the amount of veterinary antimicrobial agents sold in the different countries is linked to the animal demographics in each country. In ESVAC, the annual sales figures in each country were divided by the estimated weight at treatment of livestock and of slaughtered animals in the corresponding year, taking into account the import and export of animals for fattening or slaughter in another MS. The PCU is used as the term for the estimated weight. The PCU is purely a technical unit of measurement, used only to estimate sales corrected by the animal population in individual countries and across countries. Basically, 1 PCU = 1 kg of different categories of livestock and slaughtered animals. The data sources used and the methodology for the Figure 2: Numbers and types of data providers in the 25 EU/EEA countries in 2011. 180 160 140 120 100 80 60 40 20 MAHs* Wholesalers Feed mills Others** *MAHs Marketing authorisation holders. **Others Data from pharmacies, veterinarians and/or importers of medicated feed and/or PSUR data for premix and/ or data collected from wholesalers from other countries. 0 Austria Belgium Bulgaria Cyprus Czech Republic Denmark Estonia Finland France Germany Hungary Iceland Ireland Italy Latvia Lithuania Netherlands Norway Poland Portugal Slovakia Slovenia Spain Sweden UK Regulatory Rapporteur Vol 11, No 9, September 2014 www.topra.org

Focus Veterinary medicines 7 calculation of PCU are comprehensively described in Appendix 2 of the Agency s report, Trends in the sales of veterinary antimicrobial agents in nine European countries: 2005-2009. 5 Animal categories included in the calculation of the PCU and the weights used are described in Annex 3. For 2011, the data type for 22 countries were sales data (sales to farmers, veterinarians, feed mills, retailers and/or pharmacies) from wholesalers or marketing authorisation holders (MAHs); in Denmark and Sweden the data were based on prescription data, while Slovakia provided purchase data (purchased by wholesalers). Some countries obtained purchase data of premixes from feed mills (see Figure 2). In 21 of the 25 countries, a legal basis existed for the NCA to request data on sales or prescription of veterinary antimicrobial agents from the distributors of such products, while in four countries (Ireland, France, the Netherlands and Spain) data were provided to the NCA voluntarily. The data from 2011 shows there are substantial differences in the sales reported as mg active ingredient per PCU between the least- and most-selling countries and also in the sales patterns of different classes of antimicrobial agents (see Figure 3). 8 This is likely to be due to differences in the composition of the animal population in the various countries (eg, more pigs than cattle, or a high proportion of veal calves within the cattle population). There may also be considerable variation in terms of daily dose used for the various antimicrobial agents, length of treatment period, or formulations used; this may also in part explain some of the differences between the countries. However, these factors can only partly explain the differences in the sales observed between the 25 countries; other factors also need to be considered. For all 25 countries, the sales of tetracyclines, penicillins and sulfonamides, in mg/pcu, accounted for more than 71% of the total sales (range 53% 88%) in 2011 (see Figure 4). The proportions accounted for by premixes and oral powders varied considerably between the countries (see Figure 5), which could be attributed to whether the country uses medicated feeding stuff prepared by a feed mill by use of premixes or whether group treatment is performed by application of oral powder as top-dressing or on the feed or in wet-feed at the farm. It could also be influenced by the distribution of the animal species, as mass medication is mostly used in poultry and pigs, and less in calves and other animals, therefore countries like Norway and Iceland with significantly smaller populations of pigs and poultry are exceptions. Also, the assortment of products available and of national policies for mass medication can have had an influence. Aggregated by the 25 countries, in 2011 the sales of the various pharmaceutical forms of veterinary antimicrobial agents for food-producing animals (including horses) in mg/pcu of premixes accounted for 36% of the overall sales, while 48% were for oral powder, 8% for oral solution and 7% for injectable preparations. Figure 3: Sales for food-producing species, including horses, in mg/pcu, of the various veterinary antimicrobial classes, by country, for 2011 (1 PCU= 1 kg). 450 mg/pcu 400 350 300 250 200 150 100 Pleuromutilins Polymyxins Aminoglycosides Fluoroquinolones Lincosamides Macrolides Trimethoprim Sulfonamides Penicillins Tetracyclines Others* 50 0 Austria Belgium Bulgaria Cyprus Czech Republic Denmark Estonia Finland France Germany Hungary Iceland Ireland Italy Latvia Lithuania Netherlands Norway Poland Portugal Slovakia Slovenia Spain Sweden UK *Amphenicols, cephalosporins, other quinolones and other antibacterials (classified as such in the ATCvet system). www.topra.org Regulatory Rapporteur Vol 11, No 9, September 2014

8 Focus Veterinary medicines Figure 4: Sales of the antimicrobial agents by antimicrobial class as percentage of the total sales for food-producing species (including horses), in mg/pcu, aggregated by the 25 countries, for 2011. 2.5% 4.2% 7.0% 2.0% 1.6% 2.9% 37% Tetracyclines Fluoroquinolones Penicillins Aminoglycosides 8.0% Sulfonamides Polymyxins 1.6% Trimethoprim Macrolides Pleuromutilins Others* 11% Lincosamides *Amphenicols, cephalosporins and other quinolones. 23% Figure 5: Country by country distribution of sales of veterinary antimicrobial agents for food-producing animals (including horses), in mg/pcu, by pharmaceutical form, for 2011. 100% 90% 80% 70% 60% 50% 40% Intrauterine prep Intramammary Bolus Oral paste Injection Oral solution Oral powder Premix 30% 20% 10% 0% Austria Belgium Bulgaria Cyprus Czech Republic Denmark Estonia Finland France Germany Hungary Iceland Ireland Italy Latvia Lithuania Netherlands Norway Poland Portugal Slovakia Slovenia Spain Sweden UK Regulatory Rapporteur Vol 11, No 9, September 2014 www.topra.org

Focus Veterinary medicines 9 Summary Overall, the major proportion of sales of veterinary antimicrobial agents in the 25 countries was for herd or group treatment, but considerable variations between countries are seen. A large difference in sales, expressed as the indicator mg/pcu, was observed between the most- and least-selling countries. The prescribing patterns of the various antimicrobial classes, expressed as mg/pcu, varied substantially between the countries. Acknowledgements Kristine Ignate is gratefully acknowledged for editing this manuscript. Our Global Regulatory Expertise Disclaimer The views expressed in this article are the personal views of the authors and may not be understood or quoted as being made on behalf of or reflecting the position of the European Medicines Agency or any of its committees or working parties. References 1 Council of the European Union. Council Conclusions on Antimicrobial Resistance (AMR), 2008. http://register.consilium. europa.eu/pdf/en/08/st09/st09637.en08.pdf (accessed 6 March 2014). 2 Council of the European Union. Council conclusions on the impact of antimicrobial resistance in the human health sector and in the veterinary sector a One Health perspective, 2012. http://www. consilium.europa.eu/uedocs/cms_data/docs/pressdata/en/ lsa/131126.pdf (accessed 6 March 2014). 3 European Commission. Communication from the Commission to the European Parliament and the Council: Action plan against the rising threats from antimicrobial resistance (2011). http:// ec.europa.eu/dgs/health_consumer/docs/communication_ amr_2011_748_en.pdf (accessed 6 March 2014). 4 K Grave, C Greko, M K Kvaale et al. Sales of veterinary antibacterial agents in nine European countries during 2005 09: trends and patterns, The Journal of Antimicrobial Chemotherapy, 2012. 5 EMA/ESVAC. European Medicines Agency, European Surveillance of Veterinary Antimicrobial Consumption. Trends in the sales of veterinary antimicrobial agents in nine European countries, reporting period: 2005 2009. 6 EMA/ESVAC. European Medicines Agency. European Surveillance of Veterinary Antimicrobial Consumption (ESVAC). Data Collection Protocol (version 3). http://www.ema.europa.eu/docs/en_gb/ document_library/other/2010/04/wc500089584.pdf: EMA, 2013; 1 18 (accessed 3 March 2014). 7 EMA/ESVAC. European Medicines Agency. European Surveillance of Veterinary Antimicrobial Consumption (ESVAC) data collection form (template). http://www.ema.europa.eu/ema/index. jsp?curl=pages/regulation/document_listing/document_ listing_000302.jsp&mid=wc0b01ac0580153a00: EMA, 2013 (accessed 3 March 2014). 8 EMA. European Surveillance of Veterinary Antimicrobial Consumption. Sales of veterinary antimicrobial agents in 25 EU/ EEA countries in 2011. Third ESVAC report. http://www.ema. europa.eu/docs/en_gb/document_library/report/2013/10/ WC500152311.pdf: European Medicines Agency, 2013; 1 115 (accessed 3 March 2014). From farm production to family pets, veterinary medicines are key to maintaining the health, productivity and welfare of our animals. At Cyton Biosciences, we have in depth regulatory expertise covering all therapeutic classes, target animal species, product types and delivery routes. We offer regulatory support from early product development, through product approval procedures, up to and including post-approval life cycle maintenance. Cyton Biosciences experts have acquired knowledge and experience from almost two decades of regulatory activity working alongside global corporations and SMEs. Because we understand the importance of local expertise, we work closely with our offices in Europe, USA, China and Thailand. Take advantage of our expertise and expand your regulatory capability. For further information visit our website or contact us by e-mail or phone. Cyton Biosciences Ltd. Tel +44 117 973 9036 United Kingdom enquiries@cyton.com www.cyton.com www.topra.org Regulatory Rapporteur Vol 11, No 9, September 2014