Michael Kaeding Julia Schmälter · Christoph Klika Pharmacovigilance in the European Union Practical Implementation across Member States Pharmacovigilance in the European Union Michael Kaeding · Julia Schmälter Christoph Klika Pharmacovigilance in the European Union Practical Implementation across Member States Prof. Dr. Michael Kaeding Julia Schmälter Christoph Klika Universität Duisburg-Essen Duisburg, Deutschland ISBN 978-3-658-17275-6 ISBN 978-3-658-17276-3 (eBook) DOI 10.1007/978-3-658-17276-3 Library of Congress Control Number: 2017932440 © The Editor(s) (if applicable) and The Author(s) 2017. This book is published open access. 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Lektorat: Jan Treibel Printed on acid-free paper This Springer imprint is published by Springer Nature The registered company is Springer Fachmedien Wiesbaden GmbH The registered company address is: Abraham-Lincoln-Str. 46, 65189 Wiesbaden, Germany Contents Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IX List of Tables, Figures and Boxes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . XI Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . XIII 1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1 .1 Background and Terms of Reference . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1 .2 Methodology: Selection of Countries . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 1 .3 Methodology: Research Strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 1 .4 Summary of Evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 1 .5 Implementation Assessment Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 2 Pharmacovigilance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 2 .1 Fundamentals of Pharmacovigilance . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 2 .2 Importance of Pharmacovigilance for Biologicals . . . . . . . . . . . . . . . . 13 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 3 The EU Pharmacovigilance System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 3 .1 EU Institutions and Pharmacovigilance Actors . . . . . . . . . . . . . . . . . . 21 3 .2 Legislative Developments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 3 .3 The Pharmacovigilance Reform: Directive 2010/84/EU and Article 102 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 V VI Contents 4 Timely and Correct Transposition of Pharmacovigilance across Member States . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 4 .1 Timely Transposition of Directive 2010/84/EU across Member States . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 4 .2 Correct Transposition of Directive 2010/84/EU across Member States . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 4 .2 .1 Correct Transposition – Processes and Actors . . . . . . . . . . . . . 37 4 .2 .2 Correct Transposition – Quality and Content . . . . . . . . . . . . . . 40 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 5 Practical Implementation in Six Member States . . . . . . . . . . . . . . . . . . . . . 45 5 .1 ADR Reporting in the United Kingdom . . . . . . . . . . . . . . . . . . . . . . . . . 45 5 .1 .1 The System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 5 .1 .2 Perceived Challenges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 5 .1 .3 Perceived Best Practices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53 5 .2 ADR Reporting in Finland . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57 5 .2 .1 The System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57 5 .2 .2 Perceived Challenges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62 5 .2 .3 Perceived Best Practices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 5 .3 ADR Reporting in Poland . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 5 .3 .1 The System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 5 .3 .2 Perceived Challenges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 5 .3 .3 Perceived Best Practices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71 5 .4 ADR Reporting in France . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73 5 .4 .1 The System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73 5 .4 .2 Perceived Challenges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76 5 .4 .3 Perceived Best Practices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79 5 .5 ADR Reporting in Portugal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81 5 .5 .1 The System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81 5 .5 .2 Perceived Challenges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85 5 .5 .3 Perceived Best Practices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88 5 .6 ADR Reporting in Germany . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90 5 .6 .1 The System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90 5 .6 .2 Perceived Challenges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94 5 .6 .3 Perceived Best Practices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 Contents VII 6 Challenges and Best Practices in Perspective . . . . . . . . . . . . . . . . . . . . . . . 103 6 .1 Pharmacovigilance Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104 6 .2 Major Challenges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107 6 .3 Comparison of Factors Contributing to Underreporting . . . . . . . . . 109 6 .3 .1 Lack of Awareness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109 6 .3 .2 Complexity of ADR Reporting . . . . . . . . . . . . . . . . . . . . . . . . . . 110 6 .3 .3 Lack of Cooperation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111 6 .3 .4 Interconnectivity Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113 7 Conclusions and Recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115 7 .1 Specific Recommendations in Relation to Article 102 . . . . . . . . . . . . 116 7 .2 General Recommendations: National Healthcare Systems and Policy Options for Pharmacovigilance . . . . . . . . . . . . . . . . . . . . . . . . . 120 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 7 Abbreviations ÄAAS Ärzteausschuss Arzneimittelsicherheit (Germany) ADR Adverse Drug Reaction AFSSAPS Agence Française de Sécurité Sanitaire des Produits de Santé (France) AGRIFISH Agriculture and Fisheries (Council)) AkdÄ Arzneimittelkommission der Deutschen Ärzteschaft (Germany) AMK Arzneimittelkommission der Deutschen Apotheker (Germany) ANSM Agence Nationale de Securité du Medicament et des Produits de Santé (France) BfArM Bundesinstitut für Arzneimittel und Medizinprodukte (Germany) CHMP Committee for Medicinal Products for Human Use CMPh Co-ordination Group for Mutual Recognition and Decentralised procedures – Human CRPV Centre Régionaux de Pharmacovigilance (France) DG Directorate General (European Commission) EBGM Empirical Bayes Geometric Mean (Method) EMA European Medicines Agency ENVI Environment, Public Health and Food Safety (European Parliament) EP European Parliament EPSCO Employment, Social Policy, Health and Consumer Affairs (Council) EU European Union FPD French Pharmacovigilance Database Fimea Lääkealan Turvallisuus- Ja Kehittämiskeskus (Finland) GDP Good Distribution Practice GIS Główny Inspektorat Sanitarny (Poland) GMP Good Manufacturing Practice GROWTH Directorate General Internal Market, Industry, Entrepreneurship and SMEs (European Commission) GVP Good Pharmacovigilance Practice IX X Abbreviations HCP Healthcare Professional ICSR Individual Case Safety Report IMCO Internal market and Consumer Protection (European Parlaiment) INFARMED Autoridade Nacional do Medicamento e Produtos de Saúde (Portugal) IT Information Technology ITRE Industry, research and Energy (European Parliament) MAH Marketing Authorisation Holder MDSO Medical Device Safety Officer MHRA Medicines and Healthcare Products Regulatory Agency (United Kingdom) MSO Medical Safety Officer NCA National Competent Authority NHS National Health Service (United Kingdom) NIM National Implementing Measure PASS Post-Authorisation Safety Study PEI Paul-Ehrlich-Institut (Germany) PHAGRO Bundesverband des Pharmazeutischen Großhandels (Germany) PRAC Pharmacovigilance Risk Assessment Committee SANTE Directorate General Health and Food Safety (European Commission) SCOPE Strengthening Collaboration for Operating Pharmacovigilance in Europe THL Terveyden-Ja Hyvinvoinnin Laitos (National Institute for Health and Welfare, Finland) URF Unidade Regional de Farmacovigiláncia (Portugal) URPL Urząd Rejestracji Produktów Leczniczych, Wyrobów Medycznych i Produktów Biobójczych (Poland) WHO World Health Organisation WIS Wojewodzki Inspektorat Sanitarny (Poland) YCC Yellow Card Centre (United Kingdom) List of Tables, Figures and Boxes 3 The EU Pharmacovigilance System Fig . 3 .1 The pharmacovigilance network on the European level . . . . . . . 18 Tab . 3 .1 Development of Article 102 of Directive 2010/84/EU . . . . . . . . . 29 4 Timely and Correct Transposition of Pharmacovigilance across Member States Fig . 4 .1 Timely transposition of Directive 2010/84/EU across EU Member States (provided by the European Commission) . . 36 Tab . 4 .1 Correct transposition of Directive 2010/84/EU across EU Member States – processes and actors . . . . . . . . . . . . . . . . . . . 38 Tab . 4 .2 Correct transposition of Directive 2010/84/EU across EU Member States – quality and content . . . . . . . . . . . . . . . . . . . 41 5 Practical Implementation in Six Member States 5.1 United Kingdom Fig . 5 .1 ADR reporting in the United Kingdom . . . . . . . . . . . . . . . . . . . . . 46 Fig . 5 .2 ADR reporting by actors (2005-2014) . . . . . . . . . . . . . . . . . . . . . . 48 Box 5 .1 Best Practice: The Yellow Card App . . . . . . . . . . . . . . . . . . . . . . . . 54 Box 5 .2 Best Practice: Yellow Card Hospital Champion Scheme Wales . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55 5.2 Finland Fig . 5 .3 ADR reporting in Finland . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 Fig . 5 .4 ADR reporting by actors in 2015 . . . . . . . . . . . . . . . . . . . . . . . . . . . 60 Tab . 5 .1 How vaccines are identified . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 XI