Brazil Case Study  A Pharmacovigilance in Brazil Creating an Effective System in a Diverse Country Huihui Wang Albert Figueras Patricio V. Marquez Kseniya Bieliaieva With contribution from Luana Araujo Korea-World Bank Partnership Trust Fund (KWPF) B Pharmacovigilance in Brazil: Creating and Effective System in a Diverse Country © 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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Pharmacovigilance in Brazil Creating an Effective System in a Diverse Country ii Pharmacovigilance in Brazil: Creating and Effective System in a Diverse Country Table of Contents Reports in the Pharmacovigilance and Essential Public Health Services Series............................................................................ iv Acknowledgements............................................................................................................... v Acronyms.................................................................................................................................. vi 1. Introduction...........................................................................................................................2 The Beginning: Initial Steps in Pharmacovigilance in Brazil....................................3 2.  Pharmacovigilance in São Paulo.................................................................................... 4 3.  The creation and consolidation of ANVISA................................................................ 6 4.  ANVISA’s establishment and  coordinating bodies.....................................................................................................................................6 ANVISA’s mandate........................................................................................................................................6 A new standardized database............................................................................................................... 11 The new structure of ANVISA.............................................................................................................. 12 AEFI Vigilance............................................................................................................................................... 13 Strengthening PV and reducing underreporting..................................................... 14 5.  The Sentinel Network (Rede Sentinela) – An example of active PV .............................. 14 Reporting pharmacies – joining efforts to increase reporting rates................................15 Conclusions and take-home messages....................................................................... 17 6.  Take-home messages................................................................................................................................17 Table of Contents iii Figures Figure 1.  Pharmacovigilance Activities in Different Brazilian States before National Consolidation within the Brazilian Medicines Agency (ANVISA).. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ....................................................... 5 Figure 2.  ANVISA Organigram.. . . . . . . . . . . . . . . . ....................................................... 7 Figure 3.  Origin of the Reports of Suspected Adverse Effects of Medicines Uploaded in VigiMed. . . . . . . . . . . . . . ...................................................... 12 Table Table 1.  Key Laws and Regulations Related to Pharmacovigilance in the National Pharmacovigilance System in Brazil (1976–2021)....................... 8 iv Pharmacovigilance in Brazil: Creating and Effective System in a Diverse Country 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). Luana Araujo (Brazilian Public Health Specialist) provided valuable input and guidance. The draft report was kindly reviewed by Roberto F. Iunes (Senior Health Economist, HHNGE, WBG), and Courtney Price Ivins, (Health Specialist, HLCHN, 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 Pharmacovigilance in Brazil: Creating and Effective System in a Diverse Country Acronyms ADE Adverse drug event AEFI Adverse effect following immunization ANVISA Agência Nacional de Vigilância Sanitária CNMM Centro Nacional de Monitorização de Medicamentos CVS-SP Centro de Vigilância Sanitária (São Paulo) GFARM Gerência de Farmacovigilância GPUIM Group for the Prevention of Improper Use of Pharmaceuticals ICH Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use MedDRA Medical Dictionary for Regulatory Activities NOTIVISA Sistema Nacional de Notificações para a Vigilância Sanitária PERI Programa Estadual de controle de Iatrogenias PMID Program for International Drug Monitoring (WHO) PV Pharmacovigilance Sinitox Sistema Nacional de Informações Tóxico – Farmacológicas SNVS Sistema Nacional de Vigilância Sanitária VIGIPOS Sistema de Notificação e Investigação em Vigilância Sanitária WHO World Health Organization 1 Pharmacovigilance in Brazil: Creating and Effective System in a Diverse Country Overview Starting and developing an effective pharmacovigilance (PV) system based on reporting adverse effects of medicines and vaccines is a well-recognized way to improve patients safety. Notwithstanding this, the size and complexity of Brazil has presented particular challenges in developing and consolidating an effective pharmacovigilance (PV) system, with lessons and experiences that may be of particular interest. It has 212 million inhabitants,1 ranking as the sixth most populated country and its population is very diverse. Geographically, it is the largest country in Latin America and fifth in the world, after Russia, Canada, the United States, and China. Furthermore, Brazil is a federative republic organized in 26 states and is classified as an upper-middle-income country. According to the 1988 Federal Constitution and several Laws (Leis 8.080/90 and 8.142/90), Brazilian healthcare management and policies depend on a decentralized but integrated system involving the central government, the states and the municipalities. In practice, this means that the responsibilities of the healthcare sector are distributed between the three government levels. In August 2001, Brazil became the 62nd country admitted to the World Health Organization Program for International Drug Monitoring (PMID). But, as in many other countries, pioneering work to monitor the safety of medical treatments actually started long before. Once the Brazilian Health Surveillance Agency (Portuguese: Agência Nacional de Vigilância Sanitária, ANVISA) was created and deployed, PV in Brazil became a harmonized program covering all 26 states, using a common reporting form and, since 2018, a common database (VigiMed). As of February 2022, VigiMed contained more than 98,000 reports of suspected adverse drug reactions collected since 2018. The leading state in reporting volume is São Paulo (accounting for 20 percent of all Brazilian reports).2 1   orld Bank, “Brazil Country Report,” from online database, available at https://databank.worldbank.org/views/reports/ W reportwidget.aspx?Report_Name=CountryProfile&Id=b450fd57&tbar=y&dd=y&inf=n&zm=n&country=BRA. 2   NVISA, “Notificações de farmacovigilância,” webpage, https://www.gov.br/anvisa/pt-br/acessoainformacao/ A dadosabertos/informacoes-analiticas/notificacoes-de-farmacovigilancia. 1. Introduction 2 Pharmacovigilance plays a vital role in ensuring that patients receive appropriate vaccines and medicines that are safe and effective. 1. Introduction While this may seem obvious, the process of building the necessary capacity and even recognition of the importance of this work has taken decades. A key starting point occurred in 1968, with the creation of the World Health Organization (WHO) Program for International Drug Monitoring (PIDM). Since then, attention to these issues including surveillance of The ability to oversee and monitor the use of all adverse drug effects (ADEs) caused by new vaccines newly authorized drugs and vaccines, both brand- and medicines gradually spread and has now become name and generic, is critical to ensure that they work a matter of global interest. correctly and that their health benefits outweigh their Brazil is a particularly notable example because it known risks when used in daily clinical practice. This ranks in the top five amongst the largest and the process, known as pharmacovigilance, plays a vital most populated countries—two characteristics that role in ensuring that patients receive appropriate difficult the deployment and consolidation of a vaccines and medicines that are safe and effective. pharmacovigilance system. This report reviews this experience. 3 Pharmacovigilance in Brazil: Creating and Effective System in a Diverse Country 2. The Beginning: centers and conducted pharmacovigilance activities.6 GPUIM started its activities in 1990, but it was officially Initial Steps in recognized by the end of 1995. One of its first research projects that had an international impact involved the Pharmacovigilance detection of off-label, over-the-counter use of miso- prostol (a medicine prescribed for gastric disorders) in Brazil for abortion.7 In 1990, abortion was illegal in Brazil and “day after” pills were not yet marketed. As a result, misoprostol started to be used for its abortifacient effect. However, to be effective, misoprostol should be used appropriately and under careful healthcare In Brazil, the passage of Law 6360 (Sept. 23, 1976) supervision, which was not the case when it was was an important milestone: establishing that med- being used for abortions. This led to continued ications, drugs, pharmaceutical supplies, healthcare pregnancies and exposure of the fetuses to a medicine products, cosmetics, and sanitizers are subject to which causes severe congenital malformations. health surveillance.3 Publications of this problem appeared in The Lancet, Turning the law into actual surveillance was the next and were used as a reference by the U.S. Food and step. In that regard, an important advance was the Drug Administration in deciding to include a warning establishment in 1980 of the National System for Toxico- on the label of that product.8 Pharmacological Information (Portuguese: Sistema Additionally, in 1997, consumer advocacy groups and Nacional de Informações Tóxico – Farmacológicas pharmacy societies led by SOBRAVIME (the Brazilian (Sinitox)), a pioneering surveillance activity that Society for Medicines Surveillance; Portuguese: created a continuous flow of information concerning Sociedade Brasileira de Vigilância de Medicamentos) the available medicines. Although Sinitox was not organized the SOBRAVIME IV International Congress formally considered a pharmacovigilance (PV) system, focusing on PV in the southern state of Paraná. it did collect information on cases of intoxication and This event helped to bring together Brazilian health poisoning from 31 regional centers, with a total of professionals interested in PV and share discussions 386,861 cases reported as of 1995.4 Among these cases of with experts working in the field in other countries. intoxication, there were a few ADEs—a reporting area that lies at the heart of effective PV work.5 So, during this period, ideas from participants in the global pharmacovigilance movement sparked Similarly to other countries, the first PV-specific discussions in Brazil concerning nationwide systems; activities in Brazil started in universities, drug infor- and the ideas from the global level complemented the mation centers, and health professionals’ associations national pharmacovigilance initiatives and regulations during the 1990s. For example, in the northeast state of in Brazil.9,10 Ceará, the Group for the Prevention of Improper Use of Pharmaceuticals (Portuguese: Grupo para a Prevenção do Uso Inapropriado de Medicamentos) GPUIM), based 6  H.L. Coêlho, P.S. Dourado Arrais, and A. Parente Gomes, “Sistema de Farmacovigilância do Ceará: um ano de experiencia,” Cadernos de in hospital pharmacies, served as drug information Saúde Pública (September, 1999) 15(3):631–40, https://doi.org/10.1590/ S0102-311X1999000300021. 7  H.I. Coelho, C. Misago, W.V. da Fonseca, D.S. Sousa, and J.M. de 3  L  aw no. 6,360 of September 23, 1976, DISPÕE SOBRE A VIGILÂNCIA Araujo. “Selling Abortifacients Over the Counter in Pharmacies SANITÁRIA A QUE FICAM SUJEITOS OS MEDICAMENTOS, AS DROGAS, in Fortaleza, Brazil,” The Lancet (1991) 338(8761):247, https://doi. OS INSUMOS FARMACÊUTICOS E CORRELATOS, COSMÉTICOS, org/10.1016/0140-6736(91)90379-4,. SANEANTES E OUTROS PRODUTOS, E DÁ OUTRAS PROVIDÊNCIAS, (English translation) https://www.emergobyul.cn/sites/default/files/ 8  HL Coelho, “Misoprostol – A solucão não é tao simples,” Rev. Saúde file/lei_6.360_1976_health_surveillance_standards.pdf. Pública (1998) 32(4), https://doi.org/10.1590/S0034-89101998000400013. 4   . Rozenfeld, “Farmacovigilância: elementos para a discussão e S 9  K.G. Palma Rigo and P. Nichiyama, “A evolução da farmacovigilância perspectivas,” Cadernos de Saúde Pública (April 1998) 14(2):237–63, no Brasil,” Acta Scientiarum. Health Sciences (2005) 27(2):131–35, https://doi.org/10.1590/S0102-311X1998000200002. http://www.redalyc.org/pdf/3072/307223952005.pdf. 5  T  he “term adverse drug event” (ADE) refers to any medical 10  K. Moscou, J.C. Kohler, and A. MaGahan, “Governance and occurrence that may appear during treatment with a pharmaceutical Pharmacovigilance in Brazil: A Scoping Review,” Journal of product, but which does not necessarily have a causal relationship Pharmacological Policy and Practice (2016) 9(3), https://doi. with the treatment. org/10.1186/s40545-016-0053-y. 3. Pharmacovigilance in São Paulo 4 3. Pharmacovigilance In parallel, a commission made up of members from relevant state universities and hospitals provided in São Paulo counsel and guidance to the CVS-SP. The initial PV team consisted of a couple of medical and pharmaceu- tical professionals, interns, and one national and one international medical consultant. This team started working with the routine analysis of the reports they were receiving, mostly from manufacturers, public and private hospitals, and a few health professionals São Paulo is the wealthiest state in Brazil (it accounts working in primary health care. for 30 percent of Brazil’s gross domestic product), and it To increase reporting by health professionals, the earned the nickname “locomotive of Brazil.” The capital CVS-SP conducted many dissemination activities city of the same name, with a population of over 12 in different fora (e.g., articles in journals published million, is the most populous city in the Americas by the local medical council and attending national and the fourth largest globally. This prosperous and medical and pharmaceutical meetings in São Paulo). industrialized state has many renowned universities, In addition, the CVS-SP published a bulletin called research centers, and tertiary-level public and private Alertas terapêuticos (Therapeutic Alerts) to share hospitals. It should also be noted that the Brazilian information on newly reported severe or previously medicines market (US$17.04 billion in 2017, US$21 unknown ADEs, mostly associated with recently billion in 2020) ranked 10th among the top national marketed medicines. pharmaceutical markets worldwide; and within Brazil, São Paulo is the center of the pharmaceutical industry. A major advance was the enactment of a new regula- With more than half of the national and international tion (Portaria CVS no. 10, de 22/11/2000) in 2000, which companies operating in the country based in the state, made ADE reporting compulsory for all manufacturers it is not surprising that São Paulo was among the first with headquarters in São Paulo state. This initiative, states in Brazil to start PV activities. which reflected common practice for international manufacturers, was designed to increase the engage- Efforts in the state began in the 1990s, and in 1998, the ment of local manufacturers in the safety of medicines. Health Surveillance Centre in São Paulo (Portuguese: Nine years later, a federal law extended this measure to Centro de Vigilância Sanitária, CVS-SP) established a the entire country. set of programs to: From its inception until its replacement in 2018 by the • Set up the inspection of pharmaceutical industries to ANVISA database described later in this chapter, the PV ensure the production quality; program in São Paulo continued growing and strength- • Build up an information system related to ening, with a specific database (PERIWEB) including the registry of medicines and the listing of all the received reports information. A few previously existing manufacturers; unknown ADEs were described, and the traditional • Establish health inspections at different levels; and PV activities based on spontaneous reporting were • Promote the rational use of medicines. complemented by some specific active PV programs, The São Paulo authorities also established the state especially in selected hospitals. For example, the program for the iatrogenic control (Portuguese: CVS-SP created a network involving 11 hospitals which Programa Estadual de controle de Iatrogenias, PERI)11 regularly reported to the PERIWEB. During a search for to: (1) promote epidemiological research on ADEs; (2) potential signals, 33 cases of chemical conjunctivitis operationalize the flow of reports; and (3) facilitate in newborn babies were found. (In certain countries, training staff to conduct these activities. instilling eye drops of silver nitrate just after delivery was a common practice to prevent eye infections.) That cluster of cases led to different activities to 11  “Iatrogenic” is any condition, illness, or symptoms induced as identify additional cases and to try to strengthen that the result of a physician’s actions or the healthcare environment. association. One year later, six hospitals had identified Usually, we call “iatrogenic” any consequence of taking a medicine prescribed by the physician. and reported 622 cases. Despite being an already 5 Pharmacovigilance in Brazil: Creating and Effective System in a Diverse Country Pharmacovigilance Activities in Different Brazilian States before Figure 1   National Consolidation within the Brazilian Medicines Agency (ANVISA) Ceará–1996 First PV activites ANVISA–2001 Brazilian Universidade Federal Universidade Federaldo doCeará Ceará Medicines Agency establishes GPUIM Drug Information Center the National PV Centre Mato Grosso do Sul–1997 Drug Information Centre Rio de Janeiro–1985-2005 Fiocruz SINITOX São Paulo– Centro Vigilancia 1998 Centro Vigilancia Sanitária Sanitária–Organized PV activities at the state level 2000 Compulsory reporting Paraná–1997 Drug for manufacturers Information Centre 2002–First PV database (PERIWEB) Rio Grande do Sul– 2005–Reporting Pharmacy 1985-2005 SINITOX project Source: For the map itself: map.comsersis.com (https://map.comersis.com/carte-Vector-map-of-Brazil-states--cm03t21c436. html),and source for the annotations: author’s work. Note: GPUIM = Group for the Prevention of Improper Use of Pharmaceuticals (Portuguese: Grupo para a Prevenção do Uso Inapropriado de Medicamentos); SINITOX = National System of Toxico-Pharmacological Information (Portuguese: Sistema Nacional de Informações Tóxico – Farmacológicas). known and mild adverse effect of these eye drops, determined by the available resources and trained the reaction scared the new parents. In response, the health professionals. Additionally, there was no PV team led group discussions with the hospitals and common PV database. Figure 1 highlights some of povidone-iodine was recommended as a substitute the PV activities conducted before 2005. As a result for silver nitrate.12 of these factors, harmonization of these state-based efforts became necessary. Notwithstanding this, although some Brazilian states such as São Paulo started to consolidate a functional PV program which obtained some results, most Brazilian states did not follow that course. The problem was that each state moved at its own pace, 12  B.M. Napchan, R.P. Morales, M.L. Carvalho, K.V. Cunha, and A. Figueras, “From Suspicion to Action: The Chemical Conjunctivitis and Silver Nitrate Connexion Example in Brazilian Hospitals,” Pharmacoepidemiology and Drug Safety (2005) 14: 555–59, https:// doi.org/10.1002/pds.1050. 4. The creation and consolidation of ANVISA 6 The creation and 4.  Hospital Infections; (ii) monitoring the prices of medicines and medical devices; (iii) overseeing consolidation of the regulation, control, and inspection of smoking products; and (iv) providing relevant technical ANVISA support for the granting of patents by the National Institute of Industrial Property. In the area of sanitary control, ANVISA is responsible for protecting the population’s health by exercising sanitary control over the production and marketing of products and services subject to sanitary surveil- ANVISA’s establishment and  lance. This includes premises and manufacturing coordinating bodies. processes and the full range of relevant inputs and In 1990, the Federal Law (Lei 8080/90, Sept. 19, 1990) technologies. In addition, ANVISA exercises control made provisions for creating commissions and over ports, airports, and borders, and also liaises defining policies and programs for the surveillance with the Brazilian Ministry of Foreign Affairs and of medicines.13 It took sometime, however, before a foreign institutions on international aspects of federal agency was established to carry out this func- sanitary surveillance. tion in the health system nationwide. The Brazilian Overall, ANVISA regulates medicinal products for Health Surveillance Agency (Agência Nacional de human use, medical devices, food, cosmetics, and Vigilância Sanitária, ANVISA) was established by Law sanitizers. The total number of staff at ANVISA is 9782, of January 26, 1999.14 approximately 1,600, including 200 reviewers of ANVISA is a self-governed body linked to the Ministry marketing authorization/product licenses, who are of Health, with administrative independence, stabil- primarily pharmacists. The total annual budget of ity of its directors and financial autonomy. It is part about US$840 million is 40 percent government of the Unified Health System (SUS) as the coordinator funded and 60 percent fee based.16 of the National Health Surveillance System (SNVS), ANVISA’s 5th Diretoria formulates guidance to and is active throughout the Brazilian territory (see establish strategies to monitor the quality and safety https://www.gov.br/anvisa/pt-br).15 of products and services related to health surveil- Its structure is complex (Figure 2); the different lance. This includes: managing units (Gerências) belong to any of the five • Monitoring the population’s health at ports, Directorates (Diretorias). Pharmacovigilance activities airports, and borders are part of the 5th Diretoria. • Monitoring activities concerning the import and export of products related to health surveillance ANVISA’s mandate. • Pharmacovigilance ANVISA is responsible for regulating and approving • Risk management of products related to pharmaceutical products, establishing and enforcing health surveillance sanitary standards, and regulating the food industry. Essentially, ANVISA’s 5th Diretoria is responsible It is also responsible for: (i) coordination of the for surveillance to ensure that premarketing safety National Health Surveillance System (Sistema conditions are maintained during the post marketing Nacional de Vigilância Sanitária, SNVS), the National stages. These activities constitute the analytic intel- Program of Blood and Blood Products, and the ligence of the national system of health monitoring. National Program of Prevention and Control of The monitored products include medicines, vaccines, 13  Lei Federal no. 8080/90 (Sept. 19, 1990), https://www.saude.mg.gov. br/index.php?option=com_gmg&controller=document&id=7576. 14  Lei no. 9782 (Jan. 26, 1999). https://www.planalto.gov.br/ccivil_03/ 16  P  atel P, Cerqueira DM, Santos GML, de Lima Soares R, Sousa VD, leis/l9782.htm Liberti L, McAuslane N. 2020. "A Baseline Analysis of Regulatory Review Timelines for ANVISA: 2013-2016". Ther Innov Regul Sci. 15  Moscou et al., “Governance and Pharmacovigilance in Brazil: A 54(6):1428-1435. doi: 10.1007/s43441-020-00169-5. Epub 2020 Jun 9. Scoping Review.” PMID: 32519282; PMCID: PMC7704494. 4. The creation and consolidation of ANVISA 7 ANVISA Organigram Figure 2   Dicol–Collegiate Directorship Levels of Governance Support Specific Units • Consultive Board • OUVID–Support Centre • CEAnvisa–Anvisa's Ethical Commission • PROCR–Procuracy • CGE–Strategy, Risks and Institutional • AUDIT–Internal Audit Innovation Managing Committee • COGER–Review Board • CGD–Digital Governance Committee Second Directorship Third Directorship Director–President Fourth Directorship Fifth Directorship GADIP–Director-President Office Dir 2 Subordinated Units Dir 3 Subordinated Units GADIP Subordinated Units Dir.–Pres. Governance Dir 4 Subordinated Units Dir 5 Subordinated Units Supporting Units GGALI–Food Gen. Mger. GGTOX–Toxicology Gen. Aspar–Parliamentary GGMON–Health Consultancy SGCOL–Collegiate Director- GGFIS–Health Mger. Products Surveil- GGMED–Drugs Gen. ship General Secretariat Inspection Gen. Mger. Aplan–Planning Consult. lance and Monitor- Mger. GGTPS–Health Products GGGAF–Financing and Gelas–Public Health ing Gen. Mger. Technology Gen. Mger. Aainte–International Affairs GGBIO–Biol Products, Administrative Administration Laboratories Manager Consult. GFARM–Pharma- Radiodrugs, Blood, Tissues, GGTAB–Smoking Gen. Mger. Cajis–Health covigilance Cells, Organs and Products Inspection Gen. ASNVS–National Health GGPES–Human Resources Infraction Management Advanced Ther. Gen. Mger. Mger. Surveillance System Gen. Mger. Consult. Hearing Coordination GGPAF–Borders, COPER–Drugs and GHCOS–Hygiene, GGTIN–Information technolo- and Analyses Customs, Ports and Biological products Clinical Perfumes, Cosmetics and GGREC–Resources Gen. gy Gen. Mger. Airports Gen. Mger. Research Coordination Health products Gen. Mger. Mger. GGCIP–Knowledge, Innova- SCMED–Drug Market tion and Research Gen. Mger. GGTES–Health Services Regulatory House Executive technology Gen. Mger. Secretariat Source: ANVISA, https://www.gov.br/anvisa/pt-br/acessoainformacao/institucional/arquivos/organograma.pdf/view. 8 Pharmacovigilance in Brazil: Creating and Effective System in a Diverse Country food, hygienic products, cosmetics and perfumes, the creation of ANVISA. Following this, the National blood, cells, and human tissues and organs.17 Center for Medicines Monitoring (Centro Nacional de Monitorização de Medicamentos, CNMM), hosted The Gerência de Farmacovigilância by GFARM, was created in 2001 after Directive 696 (Pharmacovigilance Managing Body, GFARM) belongs (May 2001) to strengthen PV actions and contribute to the 5th Diretoria and was established just after to the rational use of medicines. It was established 17  ANVISA, “Atribuições,” available at https://www.gov.br/anvisa/pt- in 2001, months before Brazil joined the WHO-PMID br/composicao/quinta-diretoria/atribuicoes. (see Table 1). Key Laws and Regulations Related to Pharmacovigilance in the Table 1   National Pharmacovigilance System in Brazil (1976–2021) Law/Regulation Topic / Key sentence Law no. 6.360 (Sept. 23, 1976) Article 79 “...all the reports about accidents or noxious reactions produced by medicines will be sent to the health authority…” Directive no. 577 (Dec. 20, Recommended that the Câmara Técnica de Medicamentos (Medicines 1978) Technical Board) of the Conselho Nacional de Saúde (National health Council) “...adopt necessary measures to implement a national system of pharmacological surveillance, with the aim of reporting, registering and assessment of the adverse reactions to the medicines registered by the Ministry of Health…” Directive MS/SVS no. 40 Introducing a commission to propose the National System (May 9, 1995) of Pharmacoepidemiology. Directive no. 3.916 (Oct. 30, Approving a National Medicines Policy that had two directives: (i) the 1998) sanitary regulation of medicines; and (ii) the guarantee of the safety, efficacy, and quality of medicines. Directive no. 6 (Jan. 29, 1999) Article 89: “...the local Health Authority must establish mechanisms to conduct the pharmacovigilance of medicines based on the substances listed in Portaria SVS/MS no. 344/98 and its updates when they are considered of increased risk for individual and collective health…” Law no. 9.782 (Jan. 26, 1999) Creating the Agência Nacional de Vigilância Sanitária (Brazilian Health Surveillance Agency, ANVISA) to establish, coordinate, and monitor the toxicological and pharmacological vigilance systems. Directive MS no. 696 (May 7, Creating the Centro Nacional de Monitorização de Medicamentos 2001) (Brazilian Medicines Monitoring Centre, CNMM), located in ANVISA’s Unidade de Farmacovigilância (Pharmacovigilance Unit). Resolution RDC no. 136 (May Requiring that the marketing authorization holders present 29, 2003) pharmacovigilance data according to the structure of the Periodic Safety Update Report/International Conference on Harmonization to renew medicines’ registries by ANVISA. Directive ANVISA no. 354 Approving and promulgating ANVISA’s internal rules. (Aug. 11, 2006) Resolution RDC no. 04 (Feb. Establishing the pharmacovigilance rules for marketing 19, 2009) authorization holders. Directive n° 1.660 (July 22, Putting in place the Sistema de Notificação e Investigação em 2009) Vigilância Sanitária (Health Monitoring System for Reporting and Research, Vigipós) in ANVISA. 4. The creation and consolidation of ANVISA 9 Key Laws and Regulations Related to Pharmacovigilance in Table 1 (CONT)   the National Pharmacovigilance System in Brazil (1976–2021) Law/Regulation Topic / Key sentence Regulatory Instruction IN Approving pharmacovigilance guidance. no. 14 Oct. 27, 2009) Resolution RDC no. 55 Setting out the registry of new biological products. (Dec.16, 2010) Resolution RDC no. 36 (July Instituting compulsory reporting of adverse events by the Patient 25, 2013) Safety Nucleus of each Health Service. Resolution RDC no. 51 (Sept. Setting the Rede Sentinela (Sentinel Network) for the National System 29, 2014) of Health Surveillance which was created in 2002 Directive no. 1.856 (Nov. 7, Establishing the Câmara Técnica de Farmacovigilância 2017) (Pharmacovigilance Technical Board) Resolution RDC no. 200 Updating the registry and renovation of new medicines authorization (Dec. 26, 2017) Resolution RDC no. 406 Enumerating the Good Pharmacovigilance Practices for Marketing (July 22, 2020) Authorization Holders for human use Regulatory Instructions IN Setting out the Periodic Benefit-Risk Evaluation Report (PBRER) to be no. 63 (July 29, 2020) submitted to ANVISA by marketing authorization holders Resolution RDC No. 585 (Dec. Approving and promulgating ANVISA’s updated internal rules. 10, 2021) Sources: V.L.E. Pepe and H.M.D. Novaes, “National Pharmacovigilance Systems in Brazil and Portugal: Similarities, Differences, and Challenges,” Cad. Saúde Pública (2020) 36 (7), https://doi.org/10.1590/0102-311X00043019; and ANVISA, RDC no. 406/2020 e IN no. 63/2020, https://www.gov.br/anvisa/pt-br/assuntos/fiscalizacao-e-monitoramento/farmacovigilancia/ rdc-no-406-2020-e-in-no-63-2020. CNMM is located in ANVISA, and represents Brazil to receive, register, and process reports of suspected in the WHO PIDM. Its activities include: collecting and confirmed cases of ADEs and technical and evaluating reports; developing the database and complaints. ADE reports include suspected adverse periodic analyses to assess the rational and safe use drug reactions, cases of therapeutic inefficacy, and of medicines; disseminating information to health medication errors causing ADEs. It is important to professionals and the general population; proposing highlight that this includes interactions between regulatory measures to protect the health of medi- medicines causing unwanted outcomes, problems cines’ users; and sending reports to the WHO -PIDM.18 associated with the off-label use, and abuse of medicines. Technical complaints comprise suspected Monitoring ADEs is a key component of ANVISA’s alterations or irregularities associated with products work at the national level. To facilitate ADE reporting, and manufacturers. ANVISA provided all health professionals with access to the Sistema Nacional de Notificações para The ANVISA ADE reporting process also uses a Vigilância Sanitária (National System for Health additional guidance. As a full member of the Monitoring Reporting, NOTIVISA), a national, web- International Council for Harmonization of Technical based computerized reporting system started in 2006 Requirements for Pharmaceuticals for Human Use (ICH), ANVISA adopted the Medical Dictionary for 18   ssociação Brasileira das Empresas do Setor Fitoterápico, A Regulatory Activities (MedDRA), a comprehensive Suplemento Alimentar e de Promoção da Saúde (ABIFISA), “Centro terminology developed by ICH to standardize medical de Monitorização de Medicamentos completa 20 anos,” news release (July 5, 2021), available at https://abifisa.org.br/centro-de- monitorizacao-de-medicamentos-completa-20-anos/. 10 Pharmacovigilance in Brazil: Creating and Effective System in a Diverse Country terms including medicines and ADEs in several acceptability, representativeness, completeness, and languages, including Portuguese.19 validity, consistency, and positive predictive error and timeliness.22 During the study period, 63,512 reports In 2009, the law RDC no. 04/09 detailed the PV regula- were identified in the database; most of them were tions specifically addressed to all manufacturers severe (60.5 percent). The performance of NOTIVISA with a medicinal product authorized in the country was considered satisfactory regarding two of the for human use.20 The law also states that all phar- eight attributes (validity and positive predictive maceutical companies operating in Brazil must have error) and deficient in the six remaining attributes a PV department and details certain requirements (simplicity, acceptability, representativeness, com- concerning the composition of those departments pleteness, consistency, and timeliness). As a result of and their reporting obligations. Previous laws already these findings, the authors concluded that the system regulated different aspects of PV. However, prior to needed to be improved. the 2009 law, reporting by manufacturers was not compulsory at the national level; it was mandatory only in a few states such as São Paulo. Also in 2009, the Health Monitoring System for Report and Research (Sistema de Notificação e Investigação em Vigilância Sanitária, VIGIPOS) was established to strengthen post-marketing surveillance of medical products. Operating within the framework of the SNVS as a part of the unified health system (Sistema Único de Saúde, SUS), VIGIPOS was specif- ically mandated to monitor, analyze, and research ADEs and technical complaints related to services or products under the sanitary surveillance umbrella.21 VIGIPOS activities are designed to (1) measure the impact of the use of products as well as services adopting or not good practices; and (2) recommend preventive and corrective measures to avoid adverse events caused by not following the established processes. To share relevant information, VIGIPOS generates alerts addressed to hospitals, institutions, clinical wards, and health professionals describing these events. To assess the performance of the medication module of NOTIVISA, a health evaluation study was conducted between 2008 and 2013 using eight attributes established by international guidelines to assess public health surveillance systems: simplicity, 19  International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), Understanding MedDRA: The Medical Dictionary for Regulatory Activities (2013), https://admin.meddra.org/sites/default/ files/main_page_slideshow/meddra2013_0.pdf. 22  D.M. Mota, Á. Vigo, R.S. Kuchenbecker, “Avaliação do desempenho 20  Resolution RDC no. 04 (Feb. 10, 2009), https://bvsms.saude.gov.br/ do Sistema Nacional de Notificações para a Vigilância bvs/saudelegis/anvisa/2009/res0004_10_02_2009.html. Sanitária: uma ferramenta do sistema de farmacovigilância no Brasil” [Evaluation of the Performance of the Brazilian 21   Centro de Vigilância Sanitária, PORTARIA MS Nº 1.660, DE Notification System for Health Surveillance: A Tool in Brazil’s 22 DE JULHO DE 2009, https://cvs.saude.sp.gov.br/zip/U_PT- Pharmacovigilance System], Cien Saúde Coletiva (2020) MS-1660_220709.pdf. 25(5):1955–66, https://doi.org/10.1590/1413-81232020255.19522018. 4. The creation and consolidation of ANVISA 11 A new standardized database In 2018, GFARM, jointly with the Uppsala Monitoring Centre (UMC, and coordinator of the WHO PIDM network), replaced NOTIVISA with a new reporting system known as VigiMed (Figure 3). While it is based on the WHO PIDM database VigiFlow, VigiMed is tailored specifically for Brazil. This approach allows VigiMed to ensure the harmonization of the national PV program with international standards. It also benefits from different outputs, such as specific modules for health professionals and citizens (known as eReporting). As a result, citizens can report any suspected event associated with any medicine or vaccine. In addition, VigiMed is an open database, and any citizen can search reported adverse events to different products at the following link: https://www.gov.br/anvisa/pt-br/acessoain- formacao/dadosabertos/informacoes-analiticas/ notificacoes-de-farmacovigilancia. The searchable VigiMed database includes all reports received since January 2018. However, reports submit- ted directly to some states before the national inte- gration of the Brazilian PV system in 2018 and reports in the NOTIVISA database have not yet been added to VigiMed. As of February 2022, VigiMed contained more than 98,000 reports collected. The leading state in terms of reporting volume is São Paulo (accounting for 20 percent of all Brazilian reports).23 23  ANVISA, “Notificações de farmacovigilância,” https://www.gov. br/anvisa/pt-br/acessoainformacao/dadosabertos/informacoes- analiticas/notificacoes-de-farmacovigilancia. 12 Pharmacovigilance in Brazil: Creating and Effective System in a Diverse Country Origin of the Reports of Suspected Adverse Effects of Medicines Figure 3   Uploaded in VigiMed Global WHO PIDM Database VigiMed (National PV Database) Other Programs, Citizens Resources, etc. (voluntary reporting) Manufacterers Health Professionals (compulsory reporting) (voluntary reporting) Reporting Pharmacies Sentinel Network Program (finished) (active PV in hospitals) Note: PV = pharmacovigilance; WHO PIDM = World Health Organization Program for International Drug Monitoring. The new structure of ANVISA was constituted25 with the aim of proposing improve- In December 2021, a new resolution (RDC 585/2021) ments to Brazilian PV informed by best international was approved. This resolution established a new best practices and integrating working groups to structure for ANVISA, which affects PV, among other contribute developing specialized topics. activities. As a result, GFARM was dissociated from Additionally, with the goal of strengthening and the managing body of products subject to health modernizing PV teaching and research in Brazil, monitoring and became a direct part of the ANVISA’s ANVISA asked for letters of expression of interest General Management (Fifth Directorate, Quinta from universities, teaching hospitals, and research Direitoria). This movement aims to strengthen all institutions with the aim of selecting the best actions related to the monitoring of medicines proposals and funding them with grants.26 and vaccines.24 Also, on April 8, 2022, an international PV technical advisory board (Câmata Técnica de Farmacoviglância) 25   Ministério da Saúde/Agência Nacional de Vigilância Sanitária/5ª Diretoria, “Portaria N° 222, de 8 de Abril de 2022,” publicado em: 13/04/2022 | Edição: 71 | Seção: 2 | Página: 52, gov.br (online), https://www.in.gov.br/web/dou/-/portaria-n-222-de-8-de-abril- de-2022-392944816. 26  ANVISA, Solicitação de Manifestação de Interesse No 01/2022 (Incentivo ao Ensino, à Pesquisa e ao desenvolvimento de ações 24  ANVISA, “Publicado novo Regimento Interno da Anvisa,” online de Farmacovigilância no Brasil) (May 5, 2022), https://www.gov. article (December 17, 2021), https://www.gov.br/anvisa/pt-br/ br/anvisa/pt-br/assuntos/noticias-anvisa/2022/anvisa-investe- assuntos/noticias-anvisa/2021/publicado-novo-regimento-interno- no-fortalecimento-e-na-modernizacao-da-farmacovigilancia/ da-anvisa. manifestacao-de-interesse.pdf. 4. The creation and consolidation of ANVISA 13 AEFI Vigilance. That separation of identification, reporting, and During the COVID-19 pandemic and the emergency assessment systems for ADEs and AEFIs is not new approval of vaccines, the monitoring of safety and and, additionally, is common in many countries. It the appearance of AEFIs (adverse effects following even was reflected in the structure of WHO until immunization) become a challenge for PV systems. In 2021, when medicines and vaccines safety teams many countries this was a challenge for the pre-ex- that had been separate until that time were merged isting PV teams. This was also the case in Brazil, into one team dealing with pharmacovigilance and where the national immunization program had had the safety of medicinal products in the Regulation a small PV team since its creation, even before the and Prequalification (RPQ) department.27 Hopefully, consolidation of ANVISA. As a result, ADEs and AEFIs countries will mirror this merger soon. were collected and assessed by different teams; although, in the end, all the reports were uploaded to the Global WHO PIDM database. In the case of ANVISA, some AEFI reports are received through VigiMed and are analyzed by the PV team. These reports are sent from citizens, the network of sentinel hospitals, and some health professionals. On the other hand, the immunization program has a spe- cific reporting system that uses the Sistema Unico de Saúde (Unified Health System, SUS) database, which received AEFI originated in the vaccination wards. Soon after the onset of ANVISA activities, the Institutional Committee of Pharmacovigilance was created; the GFARM participates in it. Both teams have access to both reporting systems and they are working to make the systems compatible with the Global WHO-PDIM database. 27  WHO, “2021 ACSoMP Recommendations,” October 26–28, 20201, https://www.who.int/publications/m/item/2021-acsomp- recommendations. 14 Pharmacovigilance in Brazil: Creating and Effective System in a Diverse Country 5. Strengthening outputs of medicines and vaccines needed for such safety surveillance and regulatory decisions. PV and reducing Many factors lie behind the scarcity of good quality underreporting data, including underreporting by health profes- sionals, which is common in Brazil (as it is in other countries) for a variety of reasons. To overcome this reality, ANVISA created Rede Sentinela (the Sentinel Network), an interesting and quite unique solution based on active surveillance conducted by a sample set of hospitals dispersed across Brazil’s 26 states. It is well-known that one of the most important Rede Sentinela’s pilot phase (2002–04), included problems undermining PV activities is under- a strong focus on training for medical doctors, reporting; this is a common challenge in many nurses, pharmacists, and engineers (because of their countries. To tackle the challenge in Brazil, ANVISA, responsibility for maintenance at some installations). in collaboration with the state-level CVSs across In each selected hospital, a Health and Hospital the country, launched two initiatives to increase Risk Management Team (Gerencia de Risco, GR) reporting capacity. was designed, and all participants were trained and continuously updated. Around 2,000 health professionals were trained in risk detection and basic The Sentinel Network (Rede Sentinela) – epidemiology during this period. An example of active PV Participating hospitals were selected through a As explained earlier, ANVISA is responsible for Brazil’s process conducted by ANVISA with support from health surveillance at the national level and also the ministries of health and education (reflecting the municipal and state health surveillance centers. the fact that these facilities were training facilities). ANVISA decides which products receive marketing Invitations to participate in Rede Sentinela were authorization in Brazil. It also has the legal authority sent to a limited number of large and medium-sized and obligation to withdraw marketing authorization training hospitals that conduct clinical procedures if a product’s use in clinical practice shows any involving varied and complex medical technologies. problems related to its safety or efficacy. Marketing The number of invited hospitals per state also authorization is granted after an evaluation process reflected the proportion of medical residency that collects and reviews the available evidence positions offered in each state. for each new candidate product (usually from the results of clinical trials). This pre-marketing evidence Ninety-six hospitals were involved in the pilot is generated based on the experiences of a limited phase, and 91 successfully established a GR. They number of exposed individuals; so, this evaluation all delivered the requested products according to to grant the marketing of a new medical product their terms of reference signed with ANVISA. The does not necessarily ensure safety for all. In fact, financial resources were used to acquire computers safety issues are typically detected during large-scale and material for the GR office, payment of pro-labore exposure to new products, so some adverse effects activities, and dissemination material. Adherence to may not be discovered until after marketing autho- the networks is voluntary, it depends on the hospital rization is granted—a major reason post-marketing decision and does not entail any transference of surveillance is essential. PV is the most common money from ANVISA. method of post-marketing authorization surveillance. In most cases, the GR coordinators were already But to effectively analyze post-marketing safety and hospital staff; so, their work responsibilities were efficacy, it is crucial to have data. Unfortunately, in modified to cover the sentinel activities, including daily practice in Brazil, it is quite difficult to obtain maintaining integrated information systems for complete and high-quality data describing the technovigilance, hemovigilance, pharmacovigilance, 5. Strengthening PV and reducing underreporting 15 and technical complaints. Up to 60 percent of the institution, and it does not entail direct transference participant hospitals reported online to one or more of financial resources from ANVISA.31 of the four information systems. From 2002 to 2003, The sentinel network is an interesting strategy to the four systems received a total of 2,158 reports, promote pharmacovigilance within a wider health including 230 documenting ADEs. In the following surveillance framework. As it involves hospital years, the number of ADE reports kept growing: with facilities, the monitoring activities focus on more 798 in 2004 and 969 in 2005.28, 29 severe patients than those usually attending primary The good results of the pilot phase led to a five-year healthcare centers. It is a low-cost strategy to dissem- grant (ANVISA/PNUD04/010) that lasted until 2009. inate healthcare surveillance concepts and to enable The aim was to ensure an improvement of the ADE identification through either spontaneous quality of the health products and a better quality of reporting or active surveillance of specific suspicions the provided healthcare. During this second phase, or signals. The deployment of such a complex the Sentinel Network admitted interested centers. It network is necessarily slow; it requires time to involved 221 accredited institutions, corresponding spread the word, engage health professionals, reduce to 3 percent of Brazilian hospitals and covering 24 of underreporting, and to be able to conduct quick Brazil’s 27 federative units: of which 56 percent were surveys as required by ANVISA. Notwithstanding large hospitals and 24 percent were medium-sized this, the activities conducted to date certainly have hospitals, with small hospitals accounting for the influenced the reporting rate to VigiMed. rest. Among the 50 federal university hospitals involved, 23 joined the Sentinel Network, from Reporting pharmacies – joining efforts which 19 were administered by the Brazilian Hospital to increase reporting rates Services Company (EBSERH). Within the network, In 2005, ANVISA and the CVS of São Paulo state there were 161 general hospitals and 60 specialized established the pilot project Farmácias Notificadoras institutions. It is noteworthy that 126 institutions (Reporting Pharmacies) in coordination with the of the Sentinel Network were certified as teaching state association of pharmacists. The aim of the hospitals, representing 64 percent of hospitals program is to:32 certified by the Ministry of Education.30 • Widen the sources reporting suspected ADE and After 2009, ANVISA started taking steps to enhance quality complaints (i.e., lack of efficacy, use of the continuity and sustainability of the network and medicines for non-authorized indications, intoxica- to expand it. In 2011, ANVISA published criteria for tion, drug-drug interactions, drug-food interactions) the recognition of a GR. And in 2014, two regulations • Contribute to the early identification of signals were promulgated that provide an additional legal and public health risks suggested by previously framework for the network’s activities and the unknown adverse reactions commitment of the health professionals involved. • Improve the quality and number of reports by It is important to highlight that joining the Sentinel community pharmacists Network is a voluntary decision by the health Initially, 43 pharmacies (out of a total of 14,000) aimed to increase the number of qualified spontaneous 28  ANVISA, “Rede Sentinela,” archived webpage, https://www.anvisa. gov.br/servicosaude/hsentinela/historico.htm. 29  ANVISA, “Rede Sentinela,” gov.br (October 13, 2020), https://www. gov.br/anvisa/pt-br/assuntos/fiscalizacao-e-monitoramento/rede- sentinela/rede-sentinela-1. 30  Renata Soares de Macedo and Elena Bohomol, “Análise da 31  ANVISA, “Rede Sentinela,” gov.br (October 13, 2020). estrutura organizacional do Núcleo de Segurança do Paciente dos hospitais da Rede Sentinela,” Revista Gaúcha de Enfermagem 32  Conselho Regional de Farmácia do Estado de São Paulo, webpage, (2019) 40 (spe.), e20180264, https://doi.org/10.1590/1983- http://www.crfsp.org.br/67-farmacias-notificadoras/farmacias- 1447.2019.20180264. notificadoras/276-farmacias-notificadoras.html. 16 Pharmacovigilance in Brazil: Creating and Effective System in a Diverse Country reports of ADEs and quality deviations in medica- In addition, ANVISA reported that 7,000 pharmacists tions.33 Additionally, for public and private pharma- had been trained to identify and report suspected cies, belonging to this network is an added value, ADEs.36 The program continues, and it is expected which entails going beyond commercial activity and that the reports collected through these pharmacies getting involved in patient care and public health. will contribute to the new VigiMed database. To become part of the reporting pharmacies network The incentives to participate are the public acknowl- and obtain the badge that accredited pharmacies edgement of their involvement in the network, as receive as such, there are a few requisites and well as training in medicines safety issues. pharmacies must accede to the requirements of ANVISA and the Pharmacists Association. Examples of requisites include attending training activities and the requirement that at least one pharmacist must remain in the establishment while it is open.34 This project was later expanded to other states of Brazil, but with at least three changes: (i) the project’s name was changed to Reporting by Pharmacies Program; (ii) an advisory committee was created to support ANVISA in the project’s development; and (iii) covering promotion of safe and rational drug use in the Community Pharmacy context.35 In 2015, 3,000 pharmacies adhered to the program in 16 states and 800 cities. International experience in PV has already shown that the number and quality of the collected reports depend on the knowledge that potential reporters have about the PV program and how it works, as well as periodic stimulation of the reporting obligation and actively sharing feedback about medicines safety and identified signals. As a result, the wider the reporting pharmacies network and the more pharmacists involved, the better the efficiency of the program. 33  Daniel Marques Mota, Álvaro Vigo, and Ricardo de Souza Kuchenbecker, “Evolução e elementos-chave do sistema de farmacovigilância do Brasil: uma revisão de escopo a partir da criação da Agência Nacional de Vigilância Sanitária,” Cadernos de Saúde Pública (2018) 34(10), https://doi.org/10.1590/0102- 311X00000218. 34  ANVISA, “Anvisa estabelece novas diretrizes para o Programa Farmácias Notificadoras,” web posting (June 25, 2015), https:// www.gov.br/anvisa/pt-br/assuntos/noticias-anvisa/anos- anteriores/anvisa-estabelece-novas-diretrizes-para-o-programa- farmacias-notificadoras. 35  D.M. Mota, Á Vigo, and R.S. Kuchenbecker, “Evolution and Key Elements of the Brazilian Pharmacovigilance System: A Scoping Review Beginning with the Creation of the Brazilian Health Regulatory Agency,” Cad. Saúde Pública (2018) 11:34(10):e00000218. 36  Portalfarma, “Anvisa estabelece novas diretrizes para o English, Portuguese, https://doi.org/10.1590/0102-311x00000218; Programa Farmácias Notificadoras,” web posting (June 25, 2015), erratum in: Cad. Saúde Pública (2018) 20:34(12):eER000218, PMID: https://pfarma.com.br/noticia-setor-farmaceutico/eventos- 30328994, https://doi.org/10.1590/0102-311XER000218. farmaceutico/425-diretrizes-programa-farmacia-notificadora.html. 6. Conclusions and take-home messages 17 6. Conclusions overwhelming the system with mild and unimport- ant reports). This network balances the reports sent and take-home by the manufacturers and those sent by consumers, which always contain fewer clinical details and lack messages the necessary context for the appropriate assessment of the reports. Almost two decades after the admission of Brazil has a full member of the WHO PV program, the country has a PV database fully compatible with the WHO requisites and binding together the activities of the health surveillance centers of all the states. To roll out a national pharmacovigilance program, Health professionals, manufacturers, and consumers it is essential to have political will, a regulatory contribute to the PV Program, and the database is framework, a well-trained team of experts in fully accessible. medicines safety, and also the active involvement of health professionals, manufacturers, and citizens, to report suspected adverse events. In addition to Take-home messages. these elements, which are common to any country, • The PV program in Brazil has been shaped by deploying PV in a very large and middle-income the geographic and demographic magnitude of country such as Brazil with a federative structure, the country as well as its federal administrative more than 200 million inhabitants, and strong structure, which is organized in 26 states and the differences between the states, requires additional Distrito Federal (Federal District). efforts and a few imaginative proposals. • Before the regulatory creation of the Brazilian Medicines Agency (ANVISA) in 1999, university Brazil was admitted as a full member of the WHO departments, societies of health professionals, and PIDM program in 2004. But PV had started at least citizen movements were already advocating to one decade before, as un-networked activities mostly promote health surveillance and the appropriate linked to academia and state health surveillance and safe use of medicines. centers. This basal work is essential to start raising • During ANVISA’s consolidation period (2000–09), awareness about the safety of medicines and to train different PV initiatives were pioneered at the state the local experts who will inspire the program once level, especially in São Paulo. For example, the PV the regulatory aspects allow national dissemination. team working in the Health Surveillance Centre of A particularity in Brazil was the creation and São Paulo was the first to build a PV database and consolidation of a national health surveillance regulate important aspects such as compulsive agency structurally and politically independent from reporting for the manufacturers. the ministry of health. ANVISA deals with different • The Sentinel Network (Rede Sentinela) is an aspects of health monitoring, including the autho- active PV initiative started by ANVISA, involving rization and safety of medicines. This allowed the hundreds of hospitals across the country that act linking of PV with other monitoring programs such as as permanent observatories of different aspects hemovigilance and surveillance of medical supplies. related to the safety of medicines and health Among other initiatives, the Sentinel Hospital technologies. The Reporting Pharmacies Network Network is especially relevant. Because of the also contributed to this development. This network dimensions of the country, it was decided to has helped consolidate PV across the country, prioritize surveillance focusing on a group of strengthening health professionals’ knowledge of hospitals across the country, which act as observers safety monitoring activities. of what is happening. Focusing on hospitals means observing conditions that are serious (thus avoiding 18 Pharmacovigilance in Brazil: Creating and Effective System in a Diverse Country