EMA Case Study  A Realizing a Regional Approach to Pharmacovigilance A Review of the European Union Approach Huihui Wang Albert Figueras Patricio V. Marquez Kseniya Bieliaieva Korea-World Bank Partnership Trust Fund (KWPF) B Realizing a Regional Approach to Pharmacovigilance: A Review of the European Union Approach © 2022 International Bank for Reconstruction and Development / The World Bank 1818 H Street NW Washington DC 20433 Telephone: 202-473-1000 Internet: www.worldbank.org This work is a product of the staff of The World Bank with external contributions. The findings, interpretations, and conclusions expressed in this work do not necessarily reflect the views of The World Bank, its Board of Executive Directors, or the governments they represent. 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Realizing a Regional Approach to Pharmacovigilance: A Review of the European Union Approach ii Realizing a Regional Approach to Pharmacovigilance: A Review of the European Union Approach Table of Contents Reports in the Pharmacovigilance and Essential Public Health Services Series......................................................... iv Acronyms.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ................................................................. v Acknowledgements.. . . . . . . . . . . . . . . . . . . ................................................................. vi Key Messages. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ................................................................. v Introduction.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .................................................................. 1 The European Medicines Agency: Assessing Medicines’ Quality, Safety, and Efficiency.. . . . . . . . . . . . . . . . . . ................................................................. 2 Mission and tasks.. . . . . . . . . . . . . . . . . . . . . .................................................................. 2 How EMA works: committees and working groups.. ......................................... 4 Funding.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ................................................................. 6 The European Pharmacovigilance Model....................................................... 7 Governance and institutional arrangements................................................... 7 The system in action: The PV plan of the EU Medicines Regulatory Network for COVID-19 vaccines.. . . ................................................................. 8 Takeaways: Lessons from the EU on Using a Regional PV Architecture. . ......... 13 Roles for and advantages of regional PV programs.......................................... 13 Roles of country PV programs within a regional PV program............................ 13 Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ................................................................ 14 Table of Contents iii Box Box 1.  Actions and Tasks Not Conducted by the European Medicines Agency..... 3 Figures Figure 1.  EMA Committee Structure.. . . . . . . . ....................................................... 5 EMA’s Pharmacovigilance Process and Safety Information Figure 2.  Feedback Mechanism.. . . . . . . . . . . . . . ....................................................... 8 Table Main COVID-19 vaccines pharmacovigilance findings timeline Table 1.  (Jan. – July 2021).. . . . . . . . . . . . . . . . . . . . . . . ...................................................... 10 iv Realizing a Regional Approach to Pharmacovigilance: A Review of the European Union Approach Reports in the Pharmacovigilance and Essential Public Health Services Series Global Synthesis Report on Pharmacovigilance: Why is the Safety of Medicines Important for Resilient Health Systems? Positioning Report on Pharmacovigilance: The Value of Pharmacovigilance in Building Resilient Health Systems Post-COVID Pharmacovigilance Situation Analysis Report: Safety Monitoring of Medicines and Vaccines Regional Realizing a Regional Approach to Pharmacovigilance: A Review of the European Union Approach The Caribbean Regulatory System: A Subregional Approach for Efficient Medicine Registration and Vigilance Financing of Essential Public Health Services in the Caribbean Region Country Scope Learning from the Republic of Korea: Building Health System Resilience Learning from Best Practices: An Overview of the Republic of Korea Pharmacovigilance System Pharmacovigilance in Brazil: Creating an Effective System in a Diverse Country Starting and Strengthening a National Pharmacovigilance System: The Case of Catalan Regional Activities that Propelled the Spanish Pharmacovigilance System Ghana’s Pharmacovigilance Experience: From Vertical Program Activity to Nationwide System Acknowledgements v Acknowledgements This report was prepared by a team led by Huihui Wang (Senior Health Economist, World Bank Group (WBG), including Albert Figueras (Consultant, WBG), Patricio V Marquez (Consultant, WBG), and Kseniya Bieliaieva (Consultant, WBG). The draft report was kindly reviewed Elvira Anadolu (Senior Health Specialist, HECHN, WBG). Katherine Theresa Elizabeth Ward (Consultant, WBG) kindly reviewed and edited the draft report. Juan Pablo Uribe, Global Director of the WBG’s Health, Nutrition and Population | Director, Global Financing Facility (GFF), and Monique Vledder, Practice Manager, HHNGE, WBG, provided strategic guidance during the preparation of the reports on pharmacovigilance and essential public health services that form this collection. Design and layout for the report was created by Spaeth Hill. The preparation of this report was carried out under the support provided by the Korea-World Bank Partnership Trust Fund (KWPF). Washington, D.C. July 18, 2023 vi Realizing a Regional Approach to Pharmacovigilance: A Review of the European Union Approach Acronyms ADR Adverse drug reaction CHMP Committee for Medicinal Products for Human Use ECPDC European Centre for Disease Prevention and Control EMA European Medicines Agency EU European Union MAH Marketing authorization holder PRAC Pharmacovigilance Risk Assessment Committee PV Pharmacovigilance US FDA United States Food and Drug Administration VAZ Vaccine AstraZeneca VJ&J COVID-19 Vaccine Janssen WHO World Health Organization vii Realizing a Regional Approach to Pharmacovigilance: A Review of the European Union Approach Key Messages ■ The European Medicines Agency (EMA) coordinates the European Union (EU) pharmacovigilance system and operates services and processes to support the region’s pharmacovigilance. EMA is also responsible for developing and maintaining EudraVigilance, a system for managing and analyzing information on suspected adverse reactions to medicines authorized in the European Economic Area. ■ EudraVigilance is a single repository for reports of suspected adverse reactions (ADRs) seen in healthcare practice and clinical trials. It is used by EU Member States, EMA, and industry. ■ Studying the PV process for specific COVID-19 vaccines at the EU level, demonstrates the structure, requirements, and aims of the regional system in action. ■ Identifying neighboring countries to establish close collaboration, harmonize processes, and share knowledge and expertise can be an efficient way to strengthen national PV activities. Introduction 1 Communication should be a priority in pharmacovigilance. It is especially relevant for COVID-19 vaccines due to the importance of vaccination and the need to reduce vaccine hesitancy Introduction Before turning to the role of EMA, it is important to note the overall approach of the EU system. The EU “complements national health policies by supporting local EU governments to achieve common objectives, pool resources, and overcome shared challenges. In addition to formulating EU-wide laws and standards for health products and services, it also provides In the integrated network of the European Union funding for health projects across the EU.”1 There are where issues of medicine and safety transcend two EU agencies supporting national governments borders, decision-makers in country capitals and on health issues: beyond are increasingly focused on cross-border • the European Centre for Disease Prevention and collaboration as a key component of efforts to ensure Control (ECPDC), which assesses and monitors pharmacovigilance (PV)—the quality, safety, and effi- emerging disease threats to coordinate responses, cacy of medicines—to improve health care for their and citizens. This report reviews the pharmacovigilance • EMA, which manages the scientific assessment of system of the European Union (EU) mapping out its all EU medicines’ quality, safety, and efficiency. structure and processes with any eye to features that may be of particular interest to decision makers in Within this structure, the ECDPC collaborates other regions as they weigh options related to cre- with other EU agencies in closely related fields by ating a regional pharmacovigilance architecture for exchanging information and cooperating on matters themselves. It begins with a review of the European of mutual interest; EMA is one of these agencies. Medicines Agency (EMA), which plays a central role in the EU system, followed by an overview of the EU PV assessment and monitoring process and an example of the system in action regarding COVID-19 vaccines. It concludes with a summary several key 1  E  uropean Union, “Supporting Public Health in Europe,” webpage, insights of particular relevance for decision makers. https://europa.eu/european-union/topics/health_en. 2 Realizing a Regional Approach to Pharmacovigilance: A Review of the European Union Approach The European underpin important decisions about medicines marketed in Europe. As part of the evaluation Medicines Agency: workstream, EMA coordinates inspections in connection with the assessment of marketing Assessing Medicines’ authorization applications. (3) Monitoring the safety of medicines across Quality, Safety, and their lifecycle through the EudraVigilance system and the work of specific safety Efficiency committees (described below). (4) Providing clear and impartial information about medicines and their approved uses to healthcare professionals and patients. Interestingly, in the EU, herbal medicines are authorized by medicines regulatory authorities in the EU Member States. However, EMA helps in To understand the EU system, it is important to begin preparing scientific opinions on the quality, safety, with the European Medicines Agency, which plays and efficacy of herbal medicines in order to better a central role in the regional pharmacovigilance harmonize this information across the EU. These system. This section summarizes how EMA operates opinions, known as Community Herbal Monographs, and focuses on safety surveillance using the are prepared by the Committee on Herbal Medicinal EudraVigilance system. Products (HMPC).3 It is important to highlight that EMA cannot Mission and tasks sponsor medicines or fund research studies for EMA’s mission is to foster scientific excellence in specific medicines or force companies to research the evaluation and supervision of medicines for the particular medicines or treatments for a particular benefit of public and animal health in the EU.2 condition. But EMA can and does publicize areas where there is a need for new medicines—for EMA protects human and animal health through example, new a ­ ntibiotics—to encourage interested four activities: parties to research them.4 Box 1 lists aspects of (1) Facilitating the development of and access medicine ­ regulation in the EU that do not fall to medicines. This is done by enabling timely under EMA’s remit. patient access to new medicines and playing a central role in supporting medicine development for the benefit of patients. (2) Evaluating applications for marketing authorization. EMA evaluations of marketing authorization applications, which are submitted through a centralized procedure, provide the basis for authorizing medicines in Europe. These assessments are conducted by EMA’s scientific committees, which base their independent recommendations on a comprehensive, scientific evaluation of data. These evaluations also 3   MA, “Frequently Asked Questions,” webpage, https://www.ema. E europa.eu/en/about-us/frequently-asked-questions#questions- about-the-agency-section. 2   MA, “About Us: What We Do,” webpage, https://www.ema.europa. E eu/en/about-us/what-we-do. 4  EMA, “About Us: What We Do,” webpage.  The European Medicines Agency: Assessing Medicines’ Quality, Safety, and Efficiency 3 Box 1 Actions and Tasks Not Conducted by the European Medicines Agency  5 • Evaluate the initial marketing authorization application of all medicines in the EU. Most medicines available in the EU are authorized at the national level. • Evaluate applications for the authorization of clinical trials. These applications are evaluated at the national level. However, EMA does play an important role in ensuring standards of good clinical practice are applied. EMA also manages a database of clinical trials carried out in the EU. • Evaluate medical devices. They are regulated by national authorities. • Evaluate food supplements and cosmetics. They are evaluated at the national level. • Carry out research or develop medicines. This is done by pharmaceutical companies or other medicines developers. • Take decisions or have information on the price or availability of medicines. Decisions concerning price and reimbursement are made by EU Member States in the context of their national health systems. • Control the advertising of non-prescription medicines. It is primarily conducted on a self- regulatory basis by industry bodies, supported by national regulatory authorities pursuant to their statutory roles. • Control or have information on pharmaceutical patents. In most EU countries, patents can be obtained either nationally, via national patent offices, or through a centralized process at the European Patent Office. • Develop treatment guidelines. National governments or their health authorities develop guidelines for decisions concerning diagnosis, management, and treatment in specific areas of health care. • Provide medical advice. Providing such advice is considered the task of health care professionals. • Develop laws concerning medicines. The European Commission develops EU legislation concerning medicines, and the European Parliament and the Council of the European Union adopt it. The European Commission also develops EU policies in the field of human or veterinary medicines and public health. • Issue marketing authorizations. The legal decision to grant, suspend, or revoke a marketing authorization for any medicine is part of the remit of the European Commission for centrally authorized products and the relevant national authorities for nationally authorized products. Source: EMA, “About Us: What We Do,” webpage, https://www.ema.europa.eu/en/about-us/what-we-do. 5  EMA, “About Us: What We Do,” webpage.  4 Realizing a Regional Approach to Pharmacovigilance: A Review of the European Union Approach How EMA works: committees Note that the European Commission uses the outcome of the evaluation by EMA to decide whether and working groups a medicine can be authorized for marketing in the The Management Board is EMA’s integral EU; a company that produces a medicine can only governance body. The board has a supervisory role ­ market it once it has received marketing authoriza- with responsibility for budgetary and planning tion from the European Commission.8 matters, appointing the executive director, and monitoring EMA’s performance. The Pharmacovigilance Risk Assessment Its members are appointed based on their expertise Committee (PRAC) in management and, if appropriate, experience EMA has established a specific committee responsi- in human or veterinary medicines. The selection ble for assessing and monitoring the safety of human process is designed to guarantee the highest levels medicines: the Pharmacovigilance Risk Assessment of specialist qualifications, a broad range of relevant Committee (PRAC).9 expertise, and the broadest possible geographical The objectives of PRAC include the evaluation of spread within the EU. The Management Board safety signals10 from EudraVigilance (discussed includes one representative of each EU Member below), and the committee may recommend regula- State, two representatives for the European tory actions as a result. To conduct its assessments, Commission, two representatives for European EMA also supports PRAC with data from clinical Parliament, two for patients’ organisations, one practice available in electronic health records or representative of doctors’ organizations, and one prescription databases. representative for veterinarians’ organizations.6 PRAC is composed of experts in medicines safety EMA has seven scientific committees and several from regulatory authorities in the EU Member States working parties, and related groups that conduct and scientific experts and representatives of patients its scientific work (Figure 1).7 The most important and health care professionals nominated by the tasks of the EMA committees in this process are European Commission. (i) evaluating marketing authorization applications that are submitted through the centralized procedure PRAC meets periodically to evaluate new signals and and (ii) contributing to the development of medicines the evolution of active signals and make recommen- and medicine regulation. Two EMA committees dations that are always reported in public documents of particular importance in this regard—the with messages addressed to health authorities, Pharmacovigilance Risk Assessment Committee health professionals, and the public. (PRAC) and Committee for Medicinal Products for Human Use (CHMP)—are discussed in more detail below. The EMA committees, working parties, and related groups are composed of European experts made 8   MA, “FAQs,” webpage, https://www.ema.europa.eu/en/about-us/ E available by competent national authorities frequently-asked-questions#questions-about-the-agency-section. of the EU and member states of the European 9  E  MA, “Pharmacovigilance Risk Assessment Committee,” webpage, Economic Area. https://www.ema.europa.eu/en/committees/pharmacovigilance- risk-assessment-committee-prac. 10   he main purpose of PV is to detect previously unknown adverse T reactions associated to specific medicines. When a few reports (for example, 3–10) describing similar previously unknown adverse drug reactions are received, that possible association must be studied in detail, including the strength of the causal relationship 6  E  MA, “Management Board,” webpage, https://www.ema.europa.eu/ and its clinical plausibility. That initial signal is disseminated with en/about-us/who-we-are/management-board. the purpose of collecting additional reports to amplify or make a signal more robust, in order to reach a conclusion. One example, 7  E  MA, “How Committees Work,” https://www.ema.europa.eu/en/ discussed below, is the initial cases of clots associated with the committees/how-committees-work. Astra Zeneca vaccine. The European Medicines Agency: Assessing Medicines’ Quality, Safety, and Efficiency 5 Figure 1  EMA Committee Structure Management Board Supervisory role with general responsibility for budgetary and planning matters, the appointment of the executive director and the monitoring of EMA performance Pharmacovigilance Risk Assessment Committee (PRAC) Committee for Medicinal Committee for Medicinal Assesses and monitors the safety of human medicines. Products for Human Use Products for Veterinary (CHMP) Use (CVMP) Committee for Advanced Authorisation of medicines in Authorisation of veterinary Therapies (CAT) the EU (centralised procedure) medicines in the EU Prepares a draft opinion on each AT application submitted to EMA, before the Committee for Coordination Group for Mutual Coordination Group for Mutual Medicinal Products for Human Use (CHMP) adopts a final opinion Recognition and Decentralised Recognition and Decentralised on its marketing authorisation Procedures - Human (CMDh) Procedures - Veterinary (CMDv) Examines questions relating to Examines questions relating to the Committee for Orphan the marketing authorisation of marketing authorisation of human medicines in two or more veterinary medicines in two or Medicinal Products (COMP) EU countries more EU countries Evaluates applications for orphan designation. Committee on Herbal Medicinal Products (HMPC) Paediatric Committee (PDCO) Compiles and assesses scientific data on herbal substances to Assesses the paediatric support the harmonisation of the investigation plans (PIPs). EU market. Note: Arrows represent lines of interaction; EMA = European Medicines Agency. The Committee for Medicinal Products recommendations on the safety of marketed med- for Human Use icines, and when necessary, making to recommen- The Committee for Medicinal Products for Human dations to the European Commission changes to a Use (CHMP) is the EMA committee responsible medicine’s marketing authorization, or its suspension for human medicines. CHMP plays a vital role in or withdrawal.11 the authorization of medicines in the EU. Within that centralized procedure, CHMP is responsible for: (i) conducting the initial assessments of EU-wide marketing authorization applications; (ii) assessing modifications or extensions to existing 11   MA, “The Committee for Medicinal Products for Human Use,” E webpage, https://www.ema.europa.eu/en/committees/committee- marketing authorizations; and (iii) considering PRAC medicinal-products-human-use-chmp. 6 Realizing a Regional Approach to Pharmacovigilance: A Review of the European Union Approach Funding Some of these revenues are redistributed to the countries because EMA coordinates the scientific The annual budget, revenues, and expenditures of evaluation of applications and related work with the EMA are published in detail each year. For 2022, the national medicines regulatory authorities in the EU total EMA budget is €417.5 million. Member States. As part of this arrangement, EMA • Approximately 86 percent of the EMA budget compensates the national authorities for their related (€357.7 million in 2022) is expected to come from work and the involvement of their staff members fees for processing applications from companies in EMA scientific committees, working groups, and that want to bring a medicine to the market. EMA other activities.13 also charges fees for services related to marketing medicines in the EU in areas such as scientific advice, inspections, and the establishment of maximum residue limits. All of these fees are public and transparent. • Approximately 13 percent (€55.2 million in 2022) is expected from the EU contribution for public-health issues, which mainly supports poli- ­ cies for orphan and pediatric medicines, advanced therapies, and micro, small, and medium-sized enterprises.12 12   MA, “Funding,” webpage, https://www.ema.europa.eu/en/about- E us/how-we-work/governance-documents/funding. 13  EMA, “Funding,” webpage.  The European Pharmacovigilance Model 7 The European public information, and communication before decision making and publication Pharmacovigilance • The World Health Organization (WHO), com- municating measures taken regarding centrally Model authorized medicines that may have a bearing on public health protection in countries outside the EU Figure 2 provides a visual summary of the compo- nents of the EU PV process and safety information feedback mechanism. While EMA plays a central role in the EU’s regional pharmacovigilance (PV) architecture, it is also EudraVigilance – A common and important to understand that broader structure. This powerful database section maps out that system and uses a case study All reports of suspected adverse drug reactions of COVID-19 vaccine decisions as an example of how (ADRs) collected by the different countries are the EU PV model works. uploaded to EudraVigilance.15 According to the last report (2021),16 the database holds over 22.3 million individual case safety reports and is one of the largest Governance and institutional pharmacovigilance databases in the world. In 2021, arrangements 14 3.5 million reports of suspected ADRs occurring in EU legislation requires each marketing authorization the post-authorization phase were collected and holder (MAH), the competent national authority, and managed in EudraVigilance. It is interesting to note EMA to operate a pharmacovigilance system. So, the that in 2021, European patients and consumers overall EU pharmacovigilance system operates via directly submitted 781,632 reports (680,272 concerning cooperation amongst EU Member States, EMA, and COVID-19 vaccines and 101,360 on other products). the European Commission. The system builds on Support includes training materials, guidance, tools, previous harmonization efforts designed to ensure: and templates to strengthen national pharmacovig- (1) the legal feasibility of this system; and (2) that all ilance systems and support EU Member States in parties agree to use similar language and minimal implementing best practices. These materials are common requirements. publicly available and useful for marketing authori- At the same time, this harmonization preserves zation holders, healthcare professionals, patient and some characteristics particular to each country. consumer organizations, and academia. For example, in some EU Member States, the PV Additionally, EMA maintains a publicly available oper- system is structured using regional PV centers; in ational plan describing EudraVigilance key activities, that case, while the system uses those regional developments, and milestones. The plan, which is centers, for EU collaboration, a national coordinating periodically defined, evaluated, and updated, helps to center representing the competent national harmonize the pace of all the country PV programs. authority would serve as the sole country focal point (see Figure 2). EMA works closely with different partners, including: 15  E  MA, “EudraVigilance,” webpage. https://www.ema.europa.eu/en/ human-regulatory/research-development/pharmacovigilance/ • The United States Food and Drug Administration eudravigilance#annual-reports-section. EudraVigilance database (U.S. FDA), sharing information on drug safety is publicly-accessible: https://www.adrreports.eu/en/search_subst. html issues as well as anticipated regulatory action, 16  EMA, 2021 Annual Report on EudraVigilance for the European Parliament, the Council and the Commission, Amsterdam: EMA, 14  E  MA, “Pharmacovigilance Overview,” webpage, https://www.ema. available at https://www.ema.europa.eu/en/human-regulatory/ europa.eu/en/human-regulatory/overview/pharmacovigilance- research-development/pharmacovigilance/eudravigilance#annual- overview. reports-section. 8 Realizing a Regional Approach to Pharmacovigilance: A Review of the European Union Approach EMA’s Pharmacovigilance Process and Safety Information Figure 2   Feedback Mechanism EMA EudraVigilance Signals WHO US FDA Pharmacovigilance Risk Assessment Committee (PRAC) Countries/ Country Country Country Safety National A B C Information Authorities 1 2 Local PV 3 (optional) Reports Reports Reports Country Country Country Public Information, Reporters A B C Social media, etc. PV Model: centralized decentralized Note: CHMP = Committee for Medicinal Products for Human Use; EMA = European Medicines Agency; PV = pharmacovigilance; US FDA = United States Food and Drug Administration; WHO = World Health Organization. The system in action: The PV plan EMA operates at the heart of the network, coordinating and supporting interactions between ­ of the EU Medicines Regulatory over 50 national competent authorities for both Network for COVID-19 vaccines human and veterinary medicines.17 One of the cornerstones of the European system’s The COVID-19 pandemic is a good example of the work is the structure that brings together its activities of the network. closely coordinated regulatory network of national competent authorities in the member states of the European Economic Area (EEA) working in concert with EMA and the European Commission. This 17  E  MA, “European Medicines Regulatory Network,” webpage, is called the EU Medicines Regulatory Network. https://www.ema.europa.eu/en/about-us/how-we-work/european- medicines-regulatory-network. The European Pharmacovigilance Model 9 In parallel with the marketing authorization of This case is illustrative because the first serious COVID-19 vaccines, EMA published the pharmacovig- adverse effect was described only one month after ilance plan for COVID-19 vaccines (“COVID-19 plan”).18 starting mass vaccination campaigns. It was followed The plan describes how EMA and the competent by intense media coverage surrounding uncertainty national authorities in the EU Member States during the initial days, thus leading to an increase promptly identify and evaluate any new information in vaccine hesitancy and individual decisions by that arises, including any safety signals relevant for different national medicines agencies, until the the risk-benefit analysis of these vaccines. adverse effect was completely understood and EMA released its recommendations. Table 1 provides a The plan focuses on the active collection of data on timeline of key events in this process. potential risks attributed to COVID-19 vaccines; the rapid identification and assessment of emerging A few weeks later, blood clotting problems were safety information; and ensuring the prompt also described for the vaccine marketed by Janssen. evaluation of the impact of detected safety issues on This vaccine uses a manufacturing process similar the risk-benefit analysis of the vaccines, taking into to the AstraZeneca one, thus showing that the blood account exposure and effectiveness data, among clotting problem was not limited to one brand, but other information. perhaps a class effect. The COVID-19 plan also describes the roles and In the end, PV and appropriate risk communication responsibilities of MAHs, competent national activities proved important in understanding the authorities, and EMA and its scientific committees risk-benefit relationship and showed that the benefits (PRAC and CHMP). of getting the vaccine greatly outweigh the risks. In addition, PV studies also helped define high-risk Communication should be a priority in PV, and it is populations and thus supported the development of especially relevant for COVID-19 vaccines because adaptations to vaccination campaigns to minimize of the importance of vaccination and the need to those risks as much as possible. reduce vaccine hesitancy. So, in addition to ensuring the production and dissemination of separate press releases for each vaccine, with explanations addressed to health care professionals and patients, the COVID-19 plan also covers the publication and dissemination of “info-cards” on why, what, and how to report.19 The safety of the COVID-19 vaccine Soon after COVID-19 vaccination campaigns started in Europe, the alarms were raised after reports of some cases of severe and fatal coagulation disorders associated with one of the COVID-19 vaccines manufactured by AstraZeneca, later called Vaxzevria. 18  E  MA, Pharmacovigilance Plan of the EU Regulatory Network for COVID-19 Vaccines, (2020) EMA/333964/2020, available at https:// www.ema.europa.eu/en/news/ema-publishes-safety-monitoring- plan-guidance-risk-management-planning-covid-19-vaccines. 19   MA, “Reporting Suspected Side Effects of Medicines in Patients E with COVID-19,” press release (April 24,2020), https://www.ema. europa.eu/en/news/reporting-suspected-side-effects-medicines- patients-covid-19. 10 Realizing a Regional Approach to Pharmacovigilance: A Review of the European Union Approach Table 1  Main COVID-19 Vaccines Pharmacovigilance Findings Timeline (Jan. – July 2021) Date (2021) Event January 29 EMA recommends granting a conditional marketing authorization for COVID-19 Vaccine AstraZeneca (VAZ) to prevent COVID-19 in people from 18 years of age. This decision came after an evaluation suggesting its efficacy and safety.20 February 27 FDA issues an emergency use authorization for COVID-19 Vaccine Janssen (VJ&J) for the prevention of COVID-19 for use in individuals 18 years of age and older.21 March 7 The Austrian Federal Office for Safety in Health Care (BASG) states it has received two reports in a temporal connection with vaccination from the same batch (ABV 5300) of the VAZ in the district of Zwettl: a woman (49 yrs.) died as a result of severe coagulation disorders; another woman (35 yrs.) who developed a pulmonary embolism is on the way to recovery.22 March 10 Specific data reported: 30 thromboembolic events reported as of March 10, 2021, among close to 5 million people vaccinated with VAZ in the European Economic Area.23 March 11 The Danish Health Authority pauses its vaccination campaign with VAZ as a precautionary measure. At the same time, a full investigation is ongoing into reports of blood clots in people who received the vaccine, including one case in Denmark where a person died.24 March 15 A dozen European countries also pause their vaccination campaigns in a cascade response, including Germany, France, Italy, and Spain. In addition, different mass media and social networks replicate this news and focus on coagulation disorders reports and deaths suspected to be associated with VAZ.25 March 15 EMA publishes a note saying: “There is currently no indication that vaccination has caused these conditions, which are not listed as side effects with this vaccine. Therefore, the position of EMA’s safety committee PRAC is that the vaccine’s benefits continue to outweigh its risks, and the vaccine can continue to be administered. At the same time, investigation of cases of thromboembolic events is ongoing.”26 March 17 WHO issues a statement noting that, “At this time, WHO considers that the VAZ benefits outweigh its risks and recommends that vaccinations continue.”27 20   MA, “EMA Recommends COVID-19 Vaccine AstraZeneca for Authorisation in the EU,” news release (Jan. 29, 2021), https://www.ema.europa. E eu/en/news/ema-recommends-covid-19-vaccine-astrazeneca-authorisation-eu. 21   nited States Food and Drug Administration, “Janssen COVID-19 Vaccine,” webpage, https://www.fda.gov/emergency-preparedness-and- U response/coronavirus-disease-2019-covid-19/janssen-covid-19-vaccine. 22   ASG (Austrian Federal Office for Safety in Health Care), “Incidents After Vaccination with AstraZeneca’s COVID-19 Vaccine,” messages in B brief (July 3, 2021), https://www.basg.gv.at/en/market-surveillance/official-announcements/detail/zwischenfaelle-nach-impfung-mit-covid-19- impfstoff-von-astrazeneca. 23   MA, “COVID-19 Vaccine AstraZeneca: PRAC Investigating Cases of Thromboembolic Events - Vaccine’s Benefits Currently Still Outweigh E Risks – Update,” news release (Mar. 11, 2021), https://www.ema.europa.eu/en/news/covid-19-vaccine-astrazeneca-prac-investigating-cases- thromboembolic-events-vaccines-benefits. 24  EMA, “COVID-19 Vaccine AstraZeneca: PRAC Investigating Cases of Thromboembolic Events.”  25   Which Countries Have Stopped Using AstraZeneca’s COVID Vaccine?” Al-Jazeera (March 15, 2021), https://www.aljazeera.com/news/2021/3/15/ “ which-countries-have-halted-use-of-astrazenecas-covid-vaccine. 26  E  MA, “Investigation of COVID-19 Vaccine AstraZeneca and Thromboembolic Events Continues,” news release (March 16, 2021), https://www.ema.europa.eu/en/news/investigation-covid-19-vaccine-astrazeneca-thromboembolic-events-continues. 27   orld Health Organization, “WHO Statement on AstraZeneca COVID-19 Vaccine Safety Signals,” statement (March 17, 2021), W https://www.who.int/news/item/17-03-2021-who-statement-on-astrazeneca-covid-19-vaccine-safety-signals. The European Pharmacovigilance Model 11 Table 1 (CONT)  Main COVID-19 Vaccines Pharmacovigilance Findings Timeline (Jan. – July 2021) Date (2021) Event March 29 Canada urges a halt in the use of VAZ in people under 55. Germany has also made the same recommendation.28 March 30 Research published as a pre-print by German and Austrian researchers describing nine cases (four fatal) showed that all four patients tested strongly positive for anti-PF4/heparin antibodies.29 The researchers suggest that these events resemble a known disorder – heparin- induced thrombocytopenia (HIT) – which is treatable if identified promptly. March 30 COVID-19 vaccine Astra Zeneca changes its name (from now on, Vaxzevria (VAZ)).30 April 9 Announcement that EMA’s safety committee (PRAC) has concluded that unusual blood clots with low blood platelets should be listed as very rare side effects of VAZ.31 April 9 Announcement PRAC has started reviewing a safety signal to assess reports of thromboembolic events (formation of blood clots, resulting in the obstruction of a vessel) in people who received VJ&J. 32 April 13 Announcement the U.S. FDA will review that VJ&J signal and that until that process is complete, it recommends a pause in using this vaccine out of an abundance of caution.33 April 16 Blood Clot Risk from COVID-19 Higher than After Vaccines: Study (but all vaccines seem to be associated with this risk).34 (VAZ and those using messenger RNA [mRNA]) April 20 COVID-19 Vaccine Janssen (VJ&J): EMA finds a possible link to very rare cases of unusual blood clots with low blood platelets.35 May 7 Announcement that PRAC has started reviewing myocarditis and pericarditis after vaccination with Comirnaty (PFZR) vaccine reported in Israel. Most of these cases were mild and resolved within a few days.36 28  Paul Vieira and Kim Mackrael, “Canada Urges Halt in Use of AstraZeneca COVID-19 Vaccine in People Under 55” The Wall Street Journal  (as updated March 29, 2021), https://www.wsj.com/articles/canada-to-recommend-halt-in-use-of-astrazeneca-covid-19-vaccine-in-people- under-55-11617046072. 29   . Greinacher, T. Thiele, T.E. Warkentin, K. Weisser P. Kyrie, and S. Eichinger, “A Prothrombotic Thrombocytopenic Disorder Resembling A Heparin-Induced Thrombocytopenia Following Coronavirus-19 Vaccination” March 28, 2021, preprint available at Research Square (https://doi.org/10.21203/rs.3.rs-362354/v1). 30   MA, “Vaxzevria (previously COVID-19 Vaccine AstraZeneca),” webpage, https://www.ema.europa.eu/en/medicines/human/EPAR/vaxzevria- E previously-covid-19-vaccine-astrazeneca. 31   MA, “Meeting Highlights from the Pharmacovigilance Risk Assessment Committee (PRAC) 6-9 April 2021,” news release (April 9, 2021), E https://www.ema.europa.eu/en/news/meeting-highlights-pharmacovigilance-risk-assessment-committee-prac-6-9-april-2021. 32  EMA, “Meeting Highlights from the Pharmacovigilance Risk Assessment Committee (PRAC) 6-9 April 2021.”  33  “ Joint CDC and FDA Statement on Johnson & Johnson COVID-19 Vaccine,” FDA statement attributable to Dr. Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research and Dr. Anne Schuchat, Principal Deputy Director of the CDC (April 13, 2020), https://www.fda. gov/news-events/press-announcements/joint-cdc-and-fda-statement-johnson-johnson-covid-19-vaccine. 34   . Williams, “Blood Clot Risk from COVID-19 Higher than After Vaccines: Study” The Scientist (April 16, 2021), https://www.the-scientist.com/ S news-opinion/blood-clot-risk-from-covid-19-higher-than-after-vaccines-study-68675. 35  E  MA, “COVID-19 Vaccine Janssen: EMA Finds Possible Link to Very Rare Cases of Unusual Blood Clots with Low Blood Platelets,” news release (April 20, 2021), https://www.ema.europa.eu/en/news/covid-19-vaccine-janssen-ema-finds-possible-link-very-rare-cases-unusual-blood-clots- low-blood. 36   MA, “Meeting Highlights from the Pharmacovigilance Risk Assessment Committee (PRAC) 3-6 May 2021,” news release (May 7, 2021), E https://www.ema.europa.eu/en/news/meeting-highlights-pharmacovigilance-risk-assessment-committee-prac-3-6-may-2021. 12 Realizing a Regional Approach to Pharmacovigilance: A Review of the European Union Approach Table 1 (CONT)  Main COVID-19 Vaccines Pharmacovigilance Findings Timeline (Jan. – July 2021) Date (2021) Event May 21 CHMP recommends that health care professionals: • Must not give VAZ to anyone who has had blood clots with low blood platelets (thrombosis with thrombocytopenia syndrome, TTS) after receiving the vaccine. Should check for signs of blood clots in any person who has low blood platelets within three weeks of vaccination. • Should check for signs of low blood platelets in any person who has blood clots within three weeks of vaccination. • Should ensure that patients who have blood clots with low blood platelets after vaccination receive specialist care37 June 11 PRAC confirms a new ADR: the risk of capillary leak syndrome. Recommendation addressed to health professionals to avoid vaccination with VAZ. Information added to the product information as a new side effect of the vaccine.38 June 11 Announcement PRAC is continuing its assessment of reports of myocarditis and pericarditis in a small number of people following vaccination with PFZR detected in April. The report mainly concerns males under 30, with symptoms mostly starting within several days of vaccination with the second dose.39 July 9 Announcement PRAC has found a possible link to very rare cases of myocarditis and pericarditis with mRNA COVID-19 vaccines (PFZR and mRNA).40 EMA advises against use of COVID-19 Vaccine VJ&J in people with history of capillary leak syndrome. VAZ: warning for Guillain-Barre syndrome (GBS).41 (On July 13, the U.S. FDA publishes a press release describing cases of GBS associated with VJ&J.) Safety monitoring is a never-ending task. It must new COVID-19 vaccines, to show the suspicion, the continue while the medicine or vaccine is on the initial doubts, and the eventual confirmation of some market. Obviously, the most relevant period is serious adverse events within the framework of the the initial months after receiving the marketing uncertainty and the difficulty to communicate risks authorization. So, this table only collects the activities when misinformation and hesitancy could adversely of the PRAC during the first six months of life of the affect the vaccination campaigns. 37   MA, “Vaxzevria: Further Advice on Blood Clots and Low Blood Platelets,” news release (May 21, 2021), https://www.ema.europa.eu/en/news/ E vaxzevria-further-advice-blood-clots-low-blood-platelets. 38  E  MA, “Vaxzevria: EMA Advises Against Use in People with History of Capillary Leak Syndrome,” news release (June 11, 2021), https://www.ema. europa.eu/en/news/vaxzevria-ema-advises-against-use-people-history-capillary-leak-syndrome. 39   MA, “COVID-19 Vaccines: Update on Ongoing Evaluation of Myocarditis and Pericarditis,” news release (June 11, 2021), https://www.ema. E europa.eu/en/news/covid-19-vaccines-update-ongoing-evaluation-myocarditis-pericarditis. 40  E  MA, “Comirnaty and Spikevax: Possible Link to Very Rare Cases of Myocarditis and Pericarditis,” news release (July 9, 2021), https://www. ema.europa.eu/en/news/comirnaty-spikevax-possible-link-very-rare-cases-myocarditis-pericarditis. 41   MA, “EMA Advises Against Use of COVID-19 Vaccine Janssen in People with History of Capillary Leak Syndrome,” news release (July 9, 2021), E https://www.ema.europa.eu/en/news/ema-advises-against-use-covid-19-vaccine-janssen-people-history-capillary-leak-syndrome. Takeaways: Lessons from the EU on Using a Regional PV Architecture 13 Takeaways: Roles of country PV programs Lessons from the EU within a regional PV program Within the framework of a regional PV program, on Using a Regional individual countries continue to have an essential role that should not be overlooked, as explained PV Architecture below: • The “safety signal” reports, which is information on a new or incompletely documented adverse event that is potentially caused by a medicine and that warrants further investigation under an accelerated The EU experience offers several insights that may timetable, originates at the country level. help decision makers in other regions as they weigh • The PV programs in the countries are responsible options related to creating a regional PV architecture for encouraging reporting, ensuring that reports get for themselves. These fall broadly into two categories: to the PV center, including the minimum informa- (i) roles for a regional program; and (ii) roles for tion to be considered, and appropriately assessing country PV programs operating in the framework of and sharing with the regional PV program. a regional PV system. • National PV programs can either raise a safety signal or make it more robust by adding its reports. Roles for and advantages • Additionally, national PV programs use safety of regional PV programs information originated at the EMA level and ensure that local differences at the country level are Within the regional framework, the regional PV studied. coordinating center can have different advantages for • The country PV program helps to reassure the the PV at the country level. Among others: citizens that their country is appropriately • By collecting the reports from different countries, conducting surveillance of medicines and vaccines it contributes to increase the number of reports of in accordance with regional and global standards. interest and identifies potential signals before a In the case of COVID-19 vaccines, for example, PV single country obtains that number of significant has contributed to reduce vaccine hesitancy by reports. It makes easier, more possible, and robust increasing trust. the analysis of rare events. • The country PV program can encourage reporters • It helps to harmonize PV at the regional level, and the public to report additional cases to help can help with technical assistance, and organize better define the clinical characteristics of patients, peer-learning within the region. populations at risk, and other key attributes. • A recognized regional safety committee with • The country PV program can ensure that the equitable representation and with clear governing available information from the regional PV program rules: (1) ensures the representation of the whole reaches the population of interest with messaging region in relevant safety decisions; (2) helps in appropriate to that population’s background difficult decision-making processes when a given delivered in the relevant language(s). country does not have a strong PV capacity yet, and • The country PV program can study local differences (3) can be an impartial referee in cases of safety at the country level (e.g., differences due to ethnic concern involving a local manufacturer. or genetic characteristics and variations in vaccina- • It can be a valid spokesperson in front of the big tion policies or campaigns). PV counterparts (e.g., U.S. FDA and the WHO) and • The country PV program can support local health can share relevant information with them, to authorities in future decision-making and assessing ensure that geographical or ethnical characteristics implications of information received from the influencing medicines and their adverse reactions regional PV system. are also considered in Global decisions. 14 Realizing a Regional Approach to Pharmacovigilance: A Review of the European Union Approach Conclusions Proximity is one of the keys to the success of pharmacovigilance because it is based partly on confidence and trust between health professionals, citizens, and health care authorities. Notwithstanding this, individual countries’ PV also benefits from a supranational or regional approach, which helps to harmonize regulations and procedures; contributes to data sharing and signal strengthening; and facilitates the dialogue with other agencies, regional PV centers and transnational manufacturers.