Spain Case Study  A Starting and Strengthening a National Pharmacovigilance System The Case of Catalan Regional Activities that Propelled the Spanish Pharmacovigilance System Huihui Wang Albert Figueras Patricio V. Marquez Kseniya Bieliaieva Korea-World Bank Partnership Trust Fund (KWPF) B The Case of Catalan Regional Activities that Propelled the Spanish Pharmacovigilance System © 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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Starting and Strengthening a National Pharmacovigilance System: The Case of Catalan Regional Activities that Propelled the Spanish Pharmacovigilance System ii The Case of Catalan Regional Activities that Propelled the Spanish Pharmacovigilance System Table of Contents Acknowledgements.. . . . . . . . . . . . . . . . . . . ................................................................. iii Reports in the Pharmacovigilance and Essential Public Health Services Series......................................................... iv Acronyms.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ................................................................. v Introduction.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ................................................................. 2 Understanding the System: Origins and Key Features. . ................................... 3 Key features and financing arrangements for pharmacovigilance. . ..................... 3 The System in Action: Examples from Gangliosides and COVID-19 Vaccines. . . . . . . . . . . . . . . . .................................................................. 7 Takeaways: Lessons on Using a Subnational Initiative to Build a PV Architecture. . . . . . . . . . . .................................................................. 9 References.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ................................................................ 10 Boxes Box 1.  Overview of the Spanish System of Pharmacovigilance. . ........................ 4 Box 2.  Basis of the adverse drugs reactions reporting system........................... 5 Acknowledgements iii 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 by 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 iv The Case of Catalan Regional Activities that Propelled the Spanish Pharmacovigilance System 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 Acronyms v Acronyms ADR Adverse drug reaction AstraZenca AZ DPh-AUB Department of Pharmacology, Autonomous University of Barcelona European Medicines Agency EMA Guillain-Barré syndrome GBS Ministry of Health MoH Program for International Drug Surveillance (WHO) PIDM Pharmacovigilance PV Spanish System of Pharmacovigilance SSPV World Health Organization WHO 1 The Case of Catalan Regional Activities that Propelled the Spanish Pharmacovigilance System Key Messages ■ Pharmacovigilance (PV) in Spain demonstrates the power of a subnational, academic initiative to lay the groundwork for a national PV program. PV in Spain started as a research project designed by a university department in Catalonia in 1982 and has grown to consist of a Coordinating Center in the Spanish Medicines Agency and 17 regional centers. ■ Involving university groups as part of the pharmacovigilance system helps to incorporate research and methodological thinking, which is very helpful in data analysis and in a clinical approach. ■ Appropriate legislation is a necessary step but is not enough. A mature PV system also depends on the quality of the reports and the technical background of the professionals working in it. These two elements define the success of the safety monitoring activities and the time required to reach maturity. ■ Providing feedback to the reporters is crucial because it engages them, shows the program's achievements, and updates the reporters on critical safety problems. ■ Continuous financial support to the PV program is essential to ensure well-trained health professionals remain on the job and motivated. ■ To strengthen and enhance a PV program in any country requires time. However, results will come once professionals acquire the desired expertise level and reporters know and trust the program. Introduction 2 Pharmacovigilance in Spain demonstrates the power of a subnational, academic initiative to lay the groundwork for a national PV program Introduction Of particular interest to others considering various options for developing pharmacovigilance systems is the fact that this case study highlights an example that built from the ground up and actually started in academia: the SSPV began as a research project in a university institution in Catalonia that was later adopted by the Ministry of Health. From these origins, The Spanish System of Pharmacovigilance (SSPV) a regulatory framework gradually allowed this ini- started its activities almost 40 years ago, in 1985. tiative to expand to the whole country. In 1990, after Although pharmacovigilance (PV) is a broad term technical training for the professional staff involved, including wide variety activities aimed at the identi- responsibility for coordinating the system was fication, study, and prevention of adverse reactions transferred to a specially created coordinating center associated with the use of medicines and vaccines, for the SSPV located in the Spanish the initial activities of the SSPV focused on a single Medicines Agency. PV method: the spontaneous reporting system, also This report reviews the origins of the system and its known as the “Yellow Card” scheme. key features, followed by two examples of the system in action and closing comments on aspects and lessons that may be of particular value to others developing pharmacovigilance systems elsewhere. 3 The Case of Catalan Regional Activities that Propelled the Spanish Pharmacovigilance System Understanding national Ministry of Health had started to become interested in this initiative. the System: Origins Several factors help to explain the success of the and Key Features initial project, including the following: 1. The DPh-AUB was the first faculty in Spain to include a clinical pharmacology course during the last semester of medical school; the other medical school in Catalonia subsequently adopted the same practice. During the years leading up to the start of PV work, this special situation helped to spread among a few cohorts of recently trained medical doctors the idea of the importance of taking into Key features and financing account the toxicity of medicines. arrangements for 2. In 1980, the DPh-AUB began publishing a popular pocket-book to help primary health doctors pharmacovigilance select medicines. This annotated formulary was updated every two years and freely distributed to The origins: a pilot research project, well- all practicing medical doctors. Thus, these health timed, well-supported, and well-developed professionals were already sensitized to the Following the tragedy of the thalidomide (which beneficial and adverse effects of medicines, as well was linked to severe birth defects in thousands of as the lack of efficacy of some marketed products. children) and the related cases of phocomelia in the 3. In addition to the DPh-AUB, the local Ministry early 1960s, growing concern led to the creation of of Health in Catalonia and the Medical Sciences the World Health Organization (WHO) Program for Academy also supported the project, thus ensuring International Drug Surveillance (PIDM) in Uppsala, its dissemination and the building of trust in Sweden in 1968. Worried about the need for deeper the project. and earlier knowledge of the safety profile of medi- As a result, PV was not an isolated initiative by a cines, many countries started joining the PIDM and university department, but instead became a new developing local PV activities. and exciting proposal that complemented the There was no functioning PV program in Spain during worry in the broader community about the safety of that time, but a step forward occurred in Catalonia patients treated with medicines that had arisen in in 1982. A team of clinical pharmacologists of the previous years. Department of Pharmacology at the Autonomous University of Barcelona (DPh-AUB) designed a pilot Regulations supporting PV study to determine the feasibility of implementing a With the new democratic constitution in place, PV program in the region. Following that assessment, Spain had also started a decentralization process in they joined forces with the local Ministry of Health 17 autonomous administrative regions. The recently and the Medical Academy of Catalonia to submit elected Ministry of Health understood the need to the project in response to a public call for research develop a PV program. The network of autonomous proposals by the Ministry of Health. regions facilitated the design of a program with a Two years later, an analysis of the results showed new PV coordinating center located in the future that: (1) ADRs were identified and reported by doctors; Spanish Medicines Agency and 17 peripheral PV (2) some serious ADRs had been reported; and (3) the centers (one in each administrative region). But, in Understanding the System: Origins and Key Features 4 1984, this was just an idea still waiting to be fully Meanwhile, the SSPV continued on its consolidation developed in the years that followed. path. In 1985, the Ministry of Health constituted the National Pharmacovigilance Commission, a After defining the structure, the Catalan center consultive organ to assess the safety of medicines was chosen to serve temporarily as the national and vaccines. One of its functions was to guide efforts coordinating center, and Spain formally requested to reduce risks associated with medicinal products. to become part of the WHO PIDM. Additionally, the Catalan center started training health professionals One year later (1986), the General Health Law estab- from other regions at its headquarters in Barcelona. lished that any professional working in the health- During the next 10 years, the SSPV grew gradually. care system or the public technological research and Then, in 1990, the coordination role was transferred development areas had the right to participate and to the Spanish Medicines Agency. New and modern the duty to collaborate in evaluating and controlling regulation of medicines, research on medicines, medicinal products by reporting all observed serious and pharmacovigilance were approved in the adverse reactions. This obligation was also extended following years. to manufacturers and importers. Box 1 Overview of the Spanish System of Pharmacovigilance While Spain did see the enactment in 1973 of a regulation defining medicines safety monitoring, it received less than 100 reports in a decade and it is generally acknowledged that pharmacovigilance in Spain really started as a research project designed by a university department in Catalonia in 1982. The good results and adequate support by health regulatory authorities allowed the progressive implementation over time of the Spanish System of Pharmacovigilance (SSPV), building on the success of the Catalonia project. The SSPV consists of a Coordinating Center in the Spanish Medicines Agency and 17 regional centers, following the administrative structure of Spain. In 2019, the SSPV received more than 37,000 reports (32 percent from health professionals, 6 percent from citizens, and 62 percent from registration holders). In 2021, it received 81,447 reports, but 68 percent were reports describing adverse events after receiving a COVID-19 vaccine. Over the years, many signals have been identified and have led to a variety of actions ranging from the modification of the product leaflet and communicating new risks to the health professionals, to, in the most extreme case, the withdrawal of the medicine from the market due to the risks associated with it. 5 The Case of Catalan Regional Activities that Propelled the Spanish Pharmacovigilance System Box 2 Basis of the adverse drugs reactions reporting system The Catalonian team proposed a model based on schemes already working in other countries and the PIDM: the “Yellow Card” system. At that time, all medical doctors received the reporting forms (Yellow Cards) at home. Those reporting forms contained the minimal information required to assess suspected adverse drug reactions (ADRs) and establish a causal relationship with the suspected medicine. Once filled out by the reporter, the Yellow Card was sent to the PV center by postal mail free of charge. The yellow color was chosen to differentiate them from other letters and postcards handled by the postal services. This same scheme has been the starting point in many countries including Australia, Canada, France, the United Kingdom, and the United States. This initial regulatory framework reached an Institutional and administrative arrange- important milestone in 1990 with the establishment ments: financing and accountability of the Medicines Law, which included a whole Due to the decentralized structure of health care in chapter defining the regulation of PV in Spain, which Spain, each PV center depends on the annual budget was half deployed at that time. Then, in 1993, a new defined by its local Ministry of Health. In some decree regulated the authorization and registry of cases, the PV centers are integrated into the health medicines and also harmonized all aspects related to department or into a public hospital; in other cases, medicines and vaccines for human use, including PV, the PV centers are run by university researchers with the relevant European Union (EU) regulations. and professors. The Spanish Medicines Agency (Agencia Española de Medicamentos y Productos Sanitarios, AEMPS) was In any case, the annual budget depends on individual created in 2011; and in 2013, an additional decree was negotiations with each local Ministry of Health. The published that further aligned the Spanish PV system common database (Farmacovigilancia Española Datos with the EU regulatory framework. de las sospechas de las Reacciones Adversas, FEDRA), shared by all centers, was developed by the national While regulations establish the necessary framework coordinating center, which controls its maintenance to develop PV activities, another key pillar of a fully and updating. operational monitoring system consists of reports and reporters. A close look at what happened in Spain Each regional PV center has at least one clinical between 1982 and 1992 illustrates how it is possible pharmacologist or pharmacist in charge; the centers to boost reporting and increase health professionals’ in more populated regions have more staff since they trust in the safety monitoring system. generate more reports. At present, the PV staff in each regional center is hired directly by each local Ministry of Health. Understanding the System: Origins and Key Features 6 Communications strategy The example of the center in Catalonia is a case in Soon after the program started, the Technical point. The system leveraged three strategies from Committee of Pharmacovigilance was established. the beginning: To bolster timely communications, the committee • Once the PV center receives a report, it sends an included representatives not only from the individualized letter to the reporter to acknowledge Coordinating Center and the Ministry of Health receipt and to express appreciation for the report- (MoH), but also at least one member from each er’s contribution to the PV program. regional PV center. Monthly meetings helped to: • The PV center publishes a free, four-page bulletin • Harmonize and coordinate practices between the (Butlletí Groc and, later renamed as Butlletí de centers, Farmacovigilància de Catalunya2) for health profes- • Define the objectives and planning, and sionals. That bulletin includes an overview of the • Discuss interesting reports and potential signals.1 program’s work and updates on therapeutic aspects (news on the appropriate selection of medicines Another important aspect of communication is and their toxicity with a focus on these issues in the feedback given to those who fill and send the context of primary health care). The bulletin reports (reporters). This is quite time-consuming, is widely distributed to all health professionals but essential—in part because effective feedback actively working for the public and private sectors creates a positive, reinforcing loop that encourages in the region. reporters to continue to report. The feedback loop • The DPh-AUB3 also works to disseminate messages is also an important tool for ongoing education of about medicine safety in the local mass media health professionals. whenever possible. 2   vailable online: https://medicaments.gencat.cat/ca/professionals/ A 1   Signal” is the term used in PV to designate two or more similar “ butlletins/butlleti-de-farmacovigilancia-de-catalunya/. reports suggesting a relation between a medicine and a condition which deserves a careful investigation by trying to gather 3  I n June 2022, the Catalan PV center was transferred from the DPh- additional similar reports. AUB to the Catalan Health Department. 7 The Case of Catalan Regional Activities that Propelled the Spanish Pharmacovigilance System The System in A complete description was published in the British Medical Journal. Action: Examples The Spanish Medicines Agency discussed this signal from Gangliosides in two of its regular meetings in 1991 and 1992. The cases were presented to the committee of clinical and COVID-19 pharmacologists and medical specialists, including neurologists. The registration holder (i.e., the entity Vaccines authorized to market these gangliosides) was also invited to share its evidence and present its specialists. In the end, following consideration of the information shared, the agency recommended the withdrawal of this preparation from the market. Some months later, the registration holder, which was based in Italy, decided to stop manufacturing Consideration of two examples of the system in bovine gangliosides. The Committee for Proprietary action (responding to side effects from gangliosides Medicinal Products (CPMP) of the European and addressing COVID-19 vaccine hesitancy) helps Commission recommended in September 1994 that to elucidate how it operates when confronted with the marketing authorizations for the most popular real-life challenges. mixture of gangliosides for treating peripheral neuropathies should be withdrawn. In recent years, purified gangliosides (GM1) have been studied to be Gangliosides and repurposed in different neurological conditions. Guillain-Barré syndrome Bovine gangliosides were injectable preparations The power of two weeks: key steps using marketed for the treatment of different types of pain. coordination and communication to Gangliosides were popular in Spain and Italy, among quickly reduce vaccine hesitancy other countries, during the 1980s. The Catalan PV center is part of the Spanish System The Catalan PV center received two reports describing of PV which, in turn, is part of the European PV cases of Guillain-Barré syndrome (GBS), a serious but System (including the EudraVigilance database of the rare neurological disease. The patients had received European Medicines Agency (EMA)). gangliosides a few weeks before they presented with symptoms of GBS and no alternative cause was In March 2021, only a few weeks after the start of the found. It was determined that these two reports could COVID-19 vaccination campaign using Vaxzervria be an initial safety signal. (the COVID-19 vaccine manufactured by AstraZeneca (AZ)), reports describing severe coagulation disorders The suspicion of a link in these cases between the were received in Austria. In the following days, new use of gangliosides and the subsequent appearance cases were reported to the PV systems of other of GBS was shared with the other SSPV regional European Union (EU) countries. centers and explained in the local bulletins. This helped to spread awareness of the suspicion through- The vaccination rollout was stopped or withheld in out the network. The safety signal was also amplified; a number of locations across the EU while the signal 17 reports (three fatal) were received in Catalonia and was studied by the EMA, and newspapers and social other PV centers during the following weeks. media started disseminating news, misinformation, The System in Action: Examples from Gangliosides and COVID-19 Vaccines 8 or fake news.4 Even at that time, some studies had March 19, 2021: The Spanish MoH explains that AZ already shown that negative tweets about vaccines vaccination will resume on March 23, but that only attract higher engagement on social media. So it individuals 60 years old and above will receive this was imperative to develop an effective campaign vaccine because the PV studies had shown that the that would boost public confidence and addresses risk of bleeding complications is lowest in this popu- hesitancy about the COVID-19 vaccine. The following lation. In the press release, the MoH also explains the chronology maps out key steps taken over a two- role of PV as a safeguard concerning problems related week period in March to meet these needs in Spain. to COVID-19 vaccines. March 10, 2021: The Spanish Medicines Agency These quick measures continued to produce results disseminates a note explaining that one AZ vaccine in following weeks and month. One example was the batch has been kept off the market in Austria. The situation as reflected in the April 30, 2021 edition of agency also explains that it has checked and con- the PV Bulletin of Catalonia. It included an update on firmed that no case had been reported in Spain. the reports received by the Catalan PV Program as of April 25th: 7,561 reports describing suspected adverse March 15, 2021: The Catalan MoH explains that events to all three vaccines (Pfizer, AstraZeneca, and 127,000 doses of the AZ vaccine will be withheld Moderna), while the total number of vaccine doses while EMA studies the signal detected in different EU delivered by that point stood at 2.35 million. countries. It also notes that Spain has suspended vac- cinations with AZ. One case of coagulation disorder had been reported in Spain. None in Catalonia. March 16, 2021: As a way to reassure the population about the safety of the vaccination process, the head of PV in Catalonia and the Catalonia Public Health Director use a press conference to explain the reasons for withholding the vaccination and to describe the important role of PV in analyzing any potential signal. Withholding the vaccination rollout with this vaccine is presented as the result of a fully working PV system caring for individuals. March 18, 2021: The EMA safety committee (Pharmacovigilance Risk Assessment Committee) announces its initial conclusion that AZ vaccine has far greater benefits than risks. It states that at that moment, no clear relationship between the vaccine and the bleeding episodes could be established. This spreads a message of confidence and highlights the difference between the big denominator (approxi- mately 29 million people exposed) and the very low numerator (less than 100 cases amongst those 29 million individuals). 4   preprint by D. Jemielniak and Y. Krempovych, posted on April A 16, 2021, describes the analysis of 50,000 tweets about AstraZeneca during the first trimester of 2021. The authors found the commonly retweeted tweets to be filled with misinformation and sourced from well-established disinformation outlets. D. Jemielniak and Y. Krempovych, “AstraZenca Disinformation on Twitter,” preprint posted online April 16, 2021 (now published in Public Health), https://www.medrxiv.org/content/10.1101/2021.04.08.21255107v1.full. 9 The Case of Catalan Regional Activities that Propelled the Spanish Pharmacovigilance System Takeaways: for the safety of medicines at the country level and internationally. Lessons on Using a • To strengthen and enhance a pharmacovigilance program in any country requires time. However, Subnational Initiative results will come once professionals acquire the desired expertise level and reporters know and to Build a PV trust the program. Once those milestones are reached, momentum builds as key actors become Architecture increasingly involved as active reporters identifying possible adverse events and alerting the national surveillance program by sending accurate reports. • Appropriate legislation to ensure PV activities in the country is a necessary step to implement PV activities. However, legislation alone is not enough to ensure a mature PV system. • There are different methods for developing a • A mature PV system depends on the quality of pharmacovigilance system. Determining which one the reports and the technical background of the to use depends on the administrative model of the professionals working in it. When a country starts country and its geographical complexity. In the case its PV activities, these two elements define the of Spain, with its autonomous regions, a decentral- success of the safety monitoring activities and the ized model worked better than a centralized model. time required to reach maturity. • Involving university groups as part of the pharma- • A good option is to involve as many professionals covigilance system helps to incorporate research as possible, including those with an existing PV or and methodological thinking—which is very useful research background. These professionals can be in data analysis, clinical thinking. Including active found in university departments, hospital wards, pharmacovigilance studies can also be very useful and hospital pharmacy services. (for example, in the case of new vaccines). In some cases, as happened in Catalonia, a university group can serve as the starter engine for a national PV program. • Providing feedback to the reporters is crucial to for several reasons: it engages the reporters; it shows the program’s achievements continuously; and it updates the reporters on critical safety problems. In Catalonia, one particularly useful form of feedback has been a free, quarterly, four-page bulletin, widely distributed to all health professionals actively working for the public and private sectors in the region. • Continuous financial support to the pharma- covigilance program is essential to ensure that well-trained health professionals remain in their duty stations and stay motivated to improve their knowledge. This provides the critical spark that enables the system to evolve from a simple administrative committee into a real reference References 10 References Agencia Española de Medicamentos y Productos Sanitarios (AEMPS). Resumen de actividad del Sistema Español de Farmacovigilancia de Medicamentos de Uso Huma- no (SEFV-H) del año 2021. https://www.aemps.gob.es/ informa/notasinformativas/medicamentosusohuma- no-3/seguridad-1/2022/resumen-de-actividad-del-siste- ma-espanol-de-farmacovigilancia-de-medicamen- tos-de-uso-humano-sefv-h-del-ano-2021/?lang=en. Aronson JK. Meyler’s Side Effects of Drugs: The Internation- al Encyclopedia of Adverse Drug Reactions and Interac- tions. Amsterdam: Elsevier, 2016. Capella D, Laporte JR. La notificación espontánea de reac- ciones adversas a medicamentos. In J.R. Laporte and G. Tognoni: La epidemiología del medicamento. Barcelo- na: Salvat, 1992. Figueras A, Morales-Olivas FJ, Capellà D, Palop V, Laporte JR. 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