Abstract

Introduction

A pharmacovigilance system is an essential part of drug regulatory policies ¹1. Maigetter K, Pollock AM, Kadam A, Ward K, Weiss MG. Pharmacovigilance in India, Uganda and South Africa with reference to WHO's minimum requirements. Int J Health Policy Manag 2015; 4:295-305. and pharmacogovernance, defined as government structures, policy instruments, regulations, standards, and institutional authority, administered in such a way as to safeguard society’s interests in relation to patient safety, and to protect against adverse drug events (ADEs) ²2. Moscou K, Kohler JC, MaGahan A. Governance and pharmacovigilance in Brazil: a scoping review. J Pharm Policy Pract 2016; 9:3.. The purpose is to identify, evaluate, analyze, and prevent ADEs ³3. World Health Organization. Glossary of terms used in pharmacovigilance. http://www.who-umc.org/graphics/27400.pdf (acessado em 15/Nov/2015).
http://www.who-umc.org/graphics/27400.pd... , which are relevant causes of morbidity and mortality ⁴4. Mota DM, Melo JRR, Freitas DRC, Machado M. Perfil da mortalidade por intoxicação com medicamentos no Brasil, 1996-2005: retrato de uma década. Ciênc Saúde Coletiva 2012; 17:61-70.^,55. Souza TT, Godoy RR, Rotta I, Pontarolo R, Fernandez-Llimos F, Correr CJ. Morbidade e mortalidade relacionadas a medicamentos no Brasil: revisão sistemática de estudos observacionais. Rev Ciênc Farm Básica Apl 2014; 35:519-32.^,66. Kongkaew C, Noyce P, Ashcroft D. Hospital admissions associated with adverse drug reactions: a systematic review of prospective observational studies. Ann Pharmacother 2008; 42:1017-25..

The World Health Organization (WHO) has encouraged the implementation of sustainable national pharmacovigilance systems ¹1. Maigetter K, Pollock AM, Kadam A, Ward K, Weiss MG. Pharmacovigilance in India, Uganda and South Africa with reference to WHO's minimum requirements. Int J Health Policy Manag 2015; 4:295-305.^,77. Lalvani P, Milstein J. Access to new health products in low income countries and the challenge of pharmacovigilance. https://www.empowerschoolofhealth.org/download.php?filename=1489064872_Pharmacovigilance%20Discussion%20Paper_new.pdf (acessado em 15/Mar/2016).
https://www.empowerschoolofhealth.org/do... , especially since the “thalidomide epidemic” in 1961-1962. Different approaches have characterized the studies analyzing public health surveillance systems ⁸8. German RR, Lee LM, Horan JM, Milstein RL, Pertowski CA, Waller MN, et al. Updated guidelines for evaluating public health surveillance systems: recommendations from the guidelines working group. MMWR Recomm Rep 2001; 50(RR-13):1-35.^,99. European Centre for Disease Prevention and Control. Data quality monitoring and surveillance system evaluation. Stockholm: European Centre for Disease Prevention and Control; 2014.^,1010. Calba C, Goutard FL, Hoinville L, Hendrikx P, Lindberg A, Saegerman C, et al. Surveillance systems evaluation: a systematic review of the existing approaches. BMC Public Health 2015; 15:448., particularly pharmacovigilance systems ¹1. Maigetter K, Pollock AM, Kadam A, Ward K, Weiss MG. Pharmacovigilance in India, Uganda and South Africa with reference to WHO's minimum requirements. Int J Health Policy Manag 2015; 4:295-305.^,1111. Nwokike J, Ludeman E, Thumm M. Pharmacovigilance systems in five Asian countries: comparative analysis of pharmacovigilance systems in five Asian countries. Arlington: Systems for Improved Access to Pharmaceuticals and Services; 2013.^,1212. Olsson S, Pal SN, Stergachis A, Couper M. Pharmacovigilance activities in 55 low- and middle-income countries. Drug Saf 2010; 33:689-703.. In 2010, the WHO issued recommendations for minimum requirements and attributions of the national pharmacovigilance systems ¹³13. World Health Organization. Minimum requirements for a functional pharmacovigilance system. October 2010. http://www.who.int/medicines/areas/quality_safety/safety_efficacy/PV_Minimum_Requirements_2010_2.pdf (acessado em 15/Nov/2015).
http://www.who.int/medicines/areas/quali... .

Brazil has a reasonably comprehensive legal framework for the country’s pharmacovigilance activities. However, there is a persistent lack of studies evaluating pharmacovigilance activities, especially from the perspective of reporting systems and processing and analysis of the information and feedback to the reporting sources through effective actions that expand the rational use of medications and patient safety. The aim of this study was to describe and characterize Brazil’s drug safety system, called the National Pharmacovigilance System (SINAF) ¹⁴14. Agência Nacional de Vigilância Sanitária. Farmacovigilância no Brasil. http://portal.anvisa.gov.br/wps/content/Anvisa+Portal/Anvisa/Pos+-+Comercializacao+-+Pos+-+Uso/Farmacovigilancia (acessado em 25/Abr/2016).
http://portal.anvisa.gov.br/wps/content/... ^,1515. Agência Nacional de Vigilância Sanitária. Diretrizes para o gerenciamento do risco em farmacovigilância. http://portal.anvisa.gov.br/wps/wcm/connect/4140a10047cd94dc9845fed498087ae1/Diretrizes_para_o_GRFV.pdf?MOD=AJPERES (acessado em 25/Abr/2016).
http://portal.anvisa.gov.br/wps/wcm/conn... , emphasizing the activities by the Brazilian Health Regulatory Agency (Anvisa) and verifying compliance with the minimum national requirements for pharmacovigilance proposed by the WHO ¹³13. World Health Organization. Minimum requirements for a functional pharmacovigilance system. October 2010. http://www.who.int/medicines/areas/quality_safety/safety_efficacy/PV_Minimum_Requirements_2010_2.pdf (acessado em 15/Nov/2015).
http://www.who.int/medicines/areas/quali... .

Method

The scoping review was conducted in April and May 2016. It describes the evolution of the SINAF and its key elements, based on a non-exhaustive list from the European Centre for Disease Prevention and Control ⁹9. European Centre for Disease Prevention and Control. Data quality monitoring and surveillance system evaluation. Stockholm: European Centre for Disease Prevention and Control; 2014.. The results of the review of the documental evidence were used to verify the extent to which SINAF meets the minimum requirements suggested by the WHO for characterization of a “functional” pharmacovigilance system”, including: (1) a national pharmacovigilance center; (2) a national spontaneous reporting system; (3) a national database or information system for data collection and storage; (4) a pharmacovigilance advisory committee; and (5) a communication strategy for pharmacovigilance activities ¹³13. World Health Organization. Minimum requirements for a functional pharmacovigilance system. October 2010. http://www.who.int/medicines/areas/quality_safety/safety_efficacy/PV_Minimum_Requirements_2010_2.pdf (acessado em 15/Nov/2015).
http://www.who.int/medicines/areas/quali... . For the current study’s purposes, the term “minimum” and “functional” were interpreted as: what should be done, at least, to ensure the existence of a national pharmacovigilance system, capable of providing some guarantee of user safety ¹³13. World Health Organization. Minimum requirements for a functional pharmacovigilance system. October 2010. http://www.who.int/medicines/areas/quality_safety/safety_efficacy/PV_Minimum_Requirements_2010_2.pdf (acessado em 15/Nov/2015).
http://www.who.int/medicines/areas/quali... .

The scoping review aimed to identify information in the so-called “gray” scientific, technical, and legal literature and summarize it as a narrative describing the evolution of the SINAF and its key elements. The review provides for six phases ¹⁶16. Arskey H, O'Malley L. Scoping studies: towards a methodological framework. Int J Soc Res Methodol 2005; 8:19-32.^,1717. Levac D, Colquhoun H, O'Brien KK. Scoping studies: advancing the methodology. Implement Sci 2010; 5:69., described next. Divergences and doubts were resolved by consensus among the authors.

Phase 1: identification of the research question

The review addressed the following research question: “What were the characteristics, at the federal level, of the SINAF and its key elements, from January 1, 1999, to March 31, 2016?”. This period was chosen because the authors felt that it represents a time of key changes in pharmacovigilance practices influenced by the creation of the Anvisa, concluding in 2016 at the end of the study’s search strategy and document analysis. SINAF was defined as a set of activities coordinated by Anvisa, capable of: detecting and reporting ADEs, case investigation, data collection, analysis, and interpretation, including the identification and monitoring of safety signals, feedback, and dissemination of results and answers through prevention and control activities.

Phase 2: identification of publications

The literature search strategy for identification of publications followed STARLITE recommendations (Standards for Reporting Literature Searches) ¹⁸18. Booth A. "Brimful of STARLITE": toward standards for reporting literature searches. J Med Libr Assoc 2006; 94:421-9, e205. (Box 1).

The searches were conducted in April 2016 with 15 search terms, in keeping with each data source, and the different combinations were defined by “trial-and-error” until reaching the desired final arrangement.

The search in MEDLINE/PubMed (https://www.ncbi.nlm.nih.gov/pubmed/) used 11 search terms in English, covering 21 combinations plus the expression “not animal”. In the Brazilian National Press (http://portal.imprensanacional.gov.br), two terms were used: pharmacovigilance and technical chamber on medications. This data source, where each search result was done annually, was characterized as a document, while in the selection phase a document that may have yielded more than one result was included as one publication. In Google (https://www.google.com), the search used a single combination of terms in quotations marks (“pharmacovigilance” AND “Brazil”) and only the first 100 results (classified according to relevance by Google) were verified, and the resulting documents were included in the study’s set of publications.

In the Anvisa website (http://portal.anvisa.gov.br/), publications were identified without using search terms, given the limitation of the agency’s search system, focusing on documents contained on two webpages: (i) the pharmacovigilance technical area (http://portal.anvisa.gov.br/farmacovigilancia) and (ii) the National Reporting System for Health Surveillance (Notivisa; http://portal.anvisa.gov.br/notivisa).

Phase 3: selection of publications

Based on the retrieved publications, one of the authors (D.M.M.) proceeded to the identification of those that were potentially eligible (Figure 1) according to the inclusion and exclusion criteria, indicating analysis of the full texts when necessary to confirm their relevance to the research question. The order in the choice of publications when the same topic appeared in different documents was: (i) first document published on the topic (primary document), in cases other than publication of scientific articles and (ii) scientific articles taking priority over congress proceedings, newsletters, bulletins, and others, in the absence of more current data. It was not possible to blind the reviewer in relation to any part of the publications.

Phases 4, 5, and 6: data extraction, analysis, and synthesis of publications and key informant’s participation

Extraction of the qualitative evidence from the publications was based on a selective and iterative process, i.e., the authors alternated between reading the primary documents, extraction of the information, analysis, synthesis, and interpretation in various cycles based on the key themes ¹⁹19. Noyes J, Lewin S. Extracting qualitative evidence. In: Noyes J, Booth A, Hannes K, Harden A, Harris J, Lewin S, et al., editors. Supplementary guidance for inclusion of qualitative research in Cochrane Systematic Reviews of Interventions. Version 1. Cochrane Collaboration Qualitative Methods Group; 2010. http://cqrmg.cochrane.org/supplemental-handbook-guidance.
http://cqrmg.cochrane.org/supplemental-h... . A standardized summary spreadsheet was used for the data extraction, including the principal author, year, title, and/or other part of the content, type of document (scientific article, legislation, technical document, etc.) and data source.

The study also drew on the first author’s empirical knowledge, having worked in the pharmacovigilance area of Anvisa from 2005 to 2010. The information from the staff expert referred to as the key informant is identified with the initials KI in the final text.

The study was approved by the Ethics Research Committee of Hospital de Clínicas de Porto Alegre, under case review n. 950.737/2015.

Results

Data from the scoping review

The search identified 1,068 publications, predominantly those characterized as “gray literature” in the identification (n = 783; 73.3%), selection 1 (n = 102; 77.8%), and final inclusion (n = 37; 78.7%) stages (Figure 1). The most frequent publications were, in the following order: legal provisions (n = 14; 29.8%), technical documents (n = 13; 27.6%), and scientific articles (n = 10; 21.3%). The main reasons for the rejection of 1,021 publications were: failure to meet inclusion criterion (n = 880; 86.2%) and duplicate publication (n = 139; 13.6%). In relation to the rejection of 128 scientific articles from the first round, the main reasons were: (i) studies on ADEs (n = 31; 24.2%); (ii) studies on vaccines (n = 21; 16.4%); and (iii) studies on drug treatment (n = 15; 11.7%).

Evolution of the configuration of the SINAF

Pharmacovigilance regulatory activities were effectively organized in Brazil beginning with the creation of Anvisa (Law n. 9,782²⁰20. Brasil. Lei nº 9.782, de 26 de janeiro de 1999. Define o Sistema Nacional de Vigilância Sanitária, cria a Agência Nacional de Vigilância Sanitária, e dá outras providências. Diário Oficial da União 1999; 27 jan., January 26, 1999), with the attributions, among others, of “establishing and coordinating the toxicological and pharmacological surveillance systems”. The year 1999 witnessed the creation of the first federal-level pharmacovigilance technical unit in the country, called the Pharmacovigilance Administration (GFARM), part of the General Drug Administration of the Directorate for Drugs and Products ²¹21. Agência Nacional de Vigilância Sanitária. Resolução nº 1, de 26 de abril de 1999. Aprova o Regimento Interno e Quadro de Distribuição de Cargos em Comissão e Funções Comissionadas de Vigilância Sanitária. Diário Oficial da União 1999; 27 abr..

According to the documents, the proceedings for the creation of the SINAF began in October 1999, with the compilation of the necessary documents for the National Pharmacovigilance Center, aimed at Brazil’s adherence to the WHO Program for International Drug Monitoring ²²22. Dias MF. A Agência Nacional de Vigilância e o Sistema Nacional de Farmacovigilância. BEPA Bol Epidemiol Paul 2005; (16). http://www.cve.saude.sp.gov.br/agencia/bepa16_msfarmaco.htm.
http://www.cve.saude.sp.gov.br/agencia/b... .

The method for spontaneous reporting for nationwide monitoring of ADEs was implemented for first time in 2000, through the reporting form on the Anvisa website ²²22. Dias MF. A Agência Nacional de Vigilância e o Sistema Nacional de Farmacovigilância. BEPA Bol Epidemiol Paul 2005; (16). http://www.cve.saude.sp.gov.br/agencia/bepa16_msfarmaco.htm.
http://www.cve.saude.sp.gov.br/agencia/b... , basically covering adverse reactions and quality deviations in medications leading to patient harm, assessed and stored manually in a databank (“Bdfarm”) ²³23. Balbino EE, Dias MF. Farmacovigilância: um passo em direção ao uso racional de plantas medicinais e fitoterápicos. Rev Bras Farmacogn 2010; 20:992-1000.. That year, GFARM was renamed the Pharmacovigilance Unit (UFARM) (Ruling n. 593²⁴24. Agência Nacional de Vigilância Sanitária. Portaria nº 593, de 25 de agosto de 2000. Diário Oficial da União 2000; 22 dez., August 25, 2000).

Some authors defended the participation of drug information centers or services (CIM/SIM) distributed across Brazilian states in the implementation of a National Pharmacovigilance System ²⁵25. Arrais PSD, Vidotti CCF, Heleodoro NM, Martins R, Castilha SR. Sistema nacional de farmacovigilância: propostas de contribuição do Sistema Brasileiro de Informação sobre Medicamentos (Sismed). Saúde Debate 2002; 26:210-8.. Participation by UFARM representatives in the CIM/SIM Meeting in October 1999 and November 2000 produced cooperative proposals, aimed at the dissemination of the spontaneous reporting methods in health services ²⁵25. Arrais PSD, Vidotti CCF, Heleodoro NM, Martins R, Castilha SR. Sistema nacional de farmacovigilância: propostas de contribuição do Sistema Brasileiro de Informação sobre Medicamentos (Sismed). Saúde Debate 2002; 26:210-8., among other measures, as a way of publicizing the pharmacovigilance activities that were beginning under the coordination of Anvisa.

The year 2001 saw the creation of the National Drug Monitoring Center (CNMM), housed in the UFARM (Ruling n. 696²⁶26. Ministério da Saúde. Portaria nº 696, de 7 de maio de 2001. Diário Oficial da União 2001; 8 mai., May 7, 2001), with the following responsibilities: (i) decentralize the collection and analysis of reports, training and supporting the state-level drug safety units for this purpose; (ii) develop a database and periodic analyses to assess rational and safe drug use and to generate signals and hypotheses; (iii) refer the ADE reports to the Uppsala Monitoring Centre (Uppsala, Sweden) on the WHO form; and (iv) disseminate the information to health professionals with alerts, bulletins, and reports, improving the clinical decision-making process and reporting ²⁶26. Ministério da Saúde. Portaria nº 696, de 7 de maio de 2001. Diário Oficial da União 2001; 8 mai..

The Technical Chamber on Medications (CATEME), created in 2001, established a roster of ad hoc consultants on medications ²⁷27. Agência Nacional de Vigilância Sanitária. Resolução nº 89, de 8 de maio de 2001. Diário Oficial da União 2001; 14 mai.^,2828. Agência Nacional de Vigilância Sanitária. Resolução nº 90, de 8 de maio de 2001. Diário Oficial da União 2001; 4 jun. with the following responsibility, among others: “report on issues related to pharmacovigilance of medications...” ²⁸28. Agência Nacional de Vigilância Sanitária. Resolução nº 90, de 8 de maio de 2001. Diário Oficial da União 2001; 4 jun.. Also in 2001, Brazil became the 62nd member of the WHO Program for International Drug Monitoring, coordinated by the Uppsala Monitoring Centre ²²22. Dias MF. A Agência Nacional de Vigilância e o Sistema Nacional de Farmacovigilância. BEPA Bol Epidemiol Paul 2005; (16). http://www.cve.saude.sp.gov.br/agencia/bepa16_msfarmaco.htm.
http://www.cve.saude.sp.gov.br/agencia/b... ^,2929. Uppsala Monitoring Centre. Members of the WHO Programme. https://www.who-umc.org/global-pharmacovigilance/members/2016 (acessado em 16/Mar/2016).
https://www.who-umc.org/global-pharmacov... , reaffirming the first pharmacovigilance activities by Anvisa. UFARM took charge of the implementation and coordination of SINAF, with provision for participation by Regional Pharmacovigilance Centers, “Sentinel Hospitals”, and “Sentinel Physicians” ¹⁴14. Agência Nacional de Vigilância Sanitária. Farmacovigilância no Brasil. http://portal.anvisa.gov.br/wps/content/Anvisa+Portal/Anvisa/Pos+-+Comercializacao+-+Pos+-+Uso/Farmacovigilancia (acessado em 25/Abr/2016).
http://portal.anvisa.gov.br/wps/content/... ^,3030. Arrais PSD. O uso irracional de medicamentos e a farmacovigilância no Brasil. Cad Saúde Pública 2002; 18:1478-9..

Some state-level health surveillance agencies have State Pharmacovigilance Centers, notably the states of São Paulo, Rio de Janeiro, Paraná, Santa Catarina, and Bahia ²2. Moscou K, Kohler JC, MaGahan A. Governance and pharmacovigilance in Brazil: a scoping review. J Pharm Policy Pract 2016; 9:3.^,3131. Agência Nacional de Vigilância Sanitária. Centros de farmacovigilância. http://portal.anvisa.gov.br/wps/content/Anvisa+Portal/Anvisa/Pos+-+Comercializacao+-+Pos+-+Uso/Farmacovigilancia (acessado em 24/Abr/2016).
http://portal.anvisa.gov.br/wps/content/... . Several other states, like Ceará, implemented the Pharmacovigilance Center housed in Universidade Federal do Ceará since 1996, one of the most active in pharmacovigilance work in Brasil ³²32. Coêlho HL, Arrais PSD, Gomes AP. Sistema de Farmacovigilância do Ceará: um ano de experiência. Cad Saúde Pública 1999; 15:631-40..

The creation of the Sentinel Hospitals Project (currently called the Sentinel Network) by Anvisa in 2002 strengthened the organization of the SINAF. This was the first initiative by Anvisa to obtain information on the safety of drugs and other products, reaching a peak of 180 Brazilian hospitals ³³33. Petramale CA. Projeto Hospitais Sentinela: uma estratégia de vigilância para a pós-comercialização de produtos de saúde. http://repositorio.enap.gov.br/bitstream/handle/1/483/Projeto_Hospitais_Sentinelas.pdf?sequence=1 (acessado em 02/Abr/2016).
http://repositorio.enap.gov.br/bitstream... .

The review identified a provision, which was soon revoked, proposing “sentinel physicians” to monitor and report clinical or laboratory events, treatment failures, or adverse drug reactions (ADRs) ³⁴34. Agência Nacional de Vigilância Sanitária. Resolução nº 278, de 24 de outubro de 2002. Diário Oficial da União 2002; 25 out.. The provision ³⁴34. Agência Nacional de Vigilância Sanitária. Resolução nº 278, de 24 de outubro de 2002. Diário Oficial da União 2002; 25 out. defined a “sentinel physician” as a “medical professional from a given specialty of interest to Anvisa who voluntarily agreed to the terms of the Sentinel Physicians project, contributing periodically with information on adverse reactions (safety), drug treatment results (effectiveness), and data on the use of health products selected for surveillance”.

Brazil’s pharmacovigilance activities resulted in a 4,517% increase in spontaneous reports of suspected cases of ADRs analyzed by CNMM/UFARM from 2000 to 2004, or from 76 to 3,585 events, most of which from sentinel hospitals ²²22. Dias MF. A Agência Nacional de Vigilância e o Sistema Nacional de Farmacovigilância. BEPA Bol Epidemiol Paul 2005; (16). http://www.cve.saude.sp.gov.br/agencia/bepa16_msfarmaco.htm.
http://www.cve.saude.sp.gov.br/agencia/b... .

In 2005, the spontaneous reporting method incorporated two forms of data collection in addition to the ADE reporting forms targeted to health professionals, namely: (i) reporting of adverse events by users of medications (Sisfarmaco) ²³23. Balbino EE, Dias MF. Farmacovigilância: um passo em direção ao uso racional de plantas medicinais e fitoterápicos. Rev Bras Farmacogn 2010; 20:992-1000.; and (ii) Reporting System for Adverse Events and Technical Complaints Related to Health Products (SINEPS), for sentinel hospitals ²²22. Dias MF. A Agência Nacional de Vigilância e o Sistema Nacional de Farmacovigilância. BEPA Bol Epidemiol Paul 2005; (16). http://www.cve.saude.sp.gov.br/agencia/bepa16_msfarmaco.htm.
http://www.cve.saude.sp.gov.br/agencia/b... . That same year, Anvisa established the pilot project entitled Reporting by Pharmacies in the state of São Paulo, with initial participation by 43 pharmacies (out of a total of 14,000), aimed at increasing the number of qualified spontaneous reports of adverse events and quality deviations in medications ²2. Moscou K, Kohler JC, MaGahan A. Governance and pharmacovigilance in Brazil: a scoping review. J Pharm Policy Pract 2016; 9:3.^,2222. Dias MF. A Agência Nacional de Vigilância e o Sistema Nacional de Farmacovigilância. BEPA Bol Epidemiol Paul 2005; (16). http://www.cve.saude.sp.gov.br/agencia/bepa16_msfarmaco.htm.
http://www.cve.saude.sp.gov.br/agencia/b... . This was later expanded to other states of Brazil, 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 Program’s development; and (iii) promotion of safe and rational drug use in the Community Pharmacy context ³⁵35. Agência Nacional de Vigilância Sanitária. Resolução RDC nº 40, de 8 de março de 2006. Diário Oficial da União 2006; 9 mar..

In 2008, Anvisa created the Notivisa, providing for a standardized online form for data collection on drugs involved in health harms to patients (Notivisa-medicamento) ²2. Moscou K, Kohler JC, MaGahan A. Governance and pharmacovigilance in Brazil: a scoping review. J Pharm Policy Pract 2016; 9:3.^,2323. Balbino EE, Dias MF. Farmacovigilância: um passo em direção ao uso racional de plantas medicinais e fitoterápicos. Rev Bras Farmacogn 2010; 20:992-1000.^,3636. Agência Nacional de Vigilância Sanitária. Apresentação do Notivisa. http://www.anvisa.gov.br/hotsite/notivisa/apresenta.htm (acessado em 25/Abr/2016).
http://www.anvisa.gov.br/hotsite/notivis... . The system replaced the SINEPS and became the most wide-reaching alternative for reporting ADEs. Drug poisoning has a specific reporting form in Notivisa and its access focuses on centers for toxicological information and care (CIATs) ³⁷37. Agência Nacional de Vigilância Sanitária. Relatório de notificações de eventos adversos, intoxicações e queixas técnicas por Produto Motivo. http://www.anvisa.gov.br/hotsite/notivisa/relatorios/relatorio_notificacoes.html (acessado em 25/Abr/2016).
http://www.anvisa.gov.br/hotsite/notivis... . Although Notivisa-medicamento is Brazil’s main data repository on ADEs, there are still numerous reports from the state of São Paulo that are not integrated into the system. For these reports, Anvisa provides access via online spreadsheets (KI).

The document published by Anvisa in March 2008 entitled Guidelines for Risk Management in Pharmacovigilance describes SINAF as part of the National System for Reporting and Investigation (VIGIPOS), as a subsystem of the Brazilian Health Regulatory System (SNVS) ¹⁵15. Agência Nacional de Vigilância Sanitária. Diretrizes para o gerenciamento do risco em farmacovigilância. http://portal.anvisa.gov.br/wps/wcm/connect/4140a10047cd94dc9845fed498087ae1/Diretrizes_para_o_GRFV.pdf?MOD=AJPERES (acessado em 25/Abr/2016).
http://portal.anvisa.gov.br/wps/wcm/conn... . The document harmonized definitions and work processes on risk management in pharmacovigilance with the SNVS, which involves Anvisa and state, municipal, and Federal District health surveillance agencies ¹⁵15. Agência Nacional de Vigilância Sanitária. Diretrizes para o gerenciamento do risco em farmacovigilância. http://portal.anvisa.gov.br/wps/wcm/connect/4140a10047cd94dc9845fed498087ae1/Diretrizes_para_o_GRFV.pdf?MOD=AJPERES (acessado em 25/Abr/2016).
http://portal.anvisa.gov.br/wps/wcm/conn... .

Two legal provisions filled an important gap in the legal framework for consolidating the SINAF. Resolution n. 4³⁸38. Agência Nacional de Vigilância Sanitária. Resolução nº 4, de 10 de fevereiro de 2009. Diário Oficial da União 2009; 11 fev. of February 10, 2009, ruled on pharmacovigilance activities by drug registration holders (DRM), such as mandatory reporting of adverse events, the creation of a minimum pharmacovigilance structure in the pharmaceutical laboratories, definition of adverse events to be reported to the SNVS, and health inspections of the pharmacovigilance activities conducted by the drug registration holders ³⁸38. Agência Nacional de Vigilância Sanitária. Resolução nº 4, de 10 de fevereiro de 2009. Diário Oficial da União 2009; 11 fev.. Resolution n. 36³⁹39. Agência Nacional de Vigilância Sanitária. Resolução nº 36, de 25 de julho de 2013. Diário Oficial da União 2013; 26 jul. of July 25, 2013, determined patient safety measures in health services, requiring that such services report adverse events leading to death within 72 hours of the event. The improvements in SINAF contributed to a mean ADE reporting rate in Notivisa-medicamento from 2008 to 2013 of 25 per million inhabitants, ranging from 15 (2008) to 36 (2013) ⁴⁰40. Agência Nacional de Vigilância Sanitária. Relatórios de notificações de 2006 a 2013. http://www.anvisa.gov.br/hotsite/notivisa/relatorios/index.htm (acessado em 25/Abr/2016).
http://www.anvisa.gov.br/hotsite/notivis... .

Description of key elements in the SINAF

Purpose and objectives

The review failed to identify any document explicitly characterizing the purpose and objectives of SINAF. However, some of its important components, such as Notivisa-medicamento and CNMM, mention ends and objectives that can be attributed to the SINAF, aimed at orienting pharmacovigilance activities by the country’s health surveillance authorities. The objectives of Notivisa-medicamento are: (i) to support SNVS in identification of adverse reactions or unwanted effects; (ii) to improve knowledge on the effects of products, and when indicated, alter the recommendations on their use and safety precautions; and (iii) to promote measures to protect the public health through regulation of products marketed in the country ⁴¹41. Agência Nacional de Vigilância Sanitária. Notivisa - Sistema de Notificação em Vigilância Sanitária. http://www.anvisa.gov.br/hotsite/notivisa/apresenta.htm (acessado em 25/Abr/2016).
http://www.anvisa.gov.br/hotsite/notivis... . The principal objective of the CNMM is “the early identification of a new adverse reaction or an increase in the knowledge of an adverse reaction with limited accumulated information and that may bear a causal relationship to the marketed drugs” ²⁶26. Ministério da Saúde. Portaria nº 696, de 7 de maio de 2001. Diário Oficial da União 2001; 8 mai..

List of adverse events for reporting

The list of ADEs was identified in ruling on holders of drug registrations, which could be extended to other reporting sources. The complete list includes: (i) suspected adverse drug reactions; (ii) adverse events due to deviations in drug quality; (iii) adverse events resulting from unapproved use of medications; (iv) drug-drug interactions; (v) total or partial therapeutic ineffectiveness; (vi) drug-related poisoning; (vii) abusive use of medications; and (viii) potential and actual medication errors ⁴²42. Agência Nacional de Vigilância Sanitária. Guias de farmacovigilância para detentores de registro de medicamentos. 2010. http://portal.anvisa.gov.br/wps/wcm/connect/e687bc0047457e328a38de3fbc4c6735/Guias+de+Farmacovigilância+Detentores+Registro+Medicamento.pdf?MOD=AJPERES (acessado em 20/Abr/2016).
http://portal.anvisa.gov.br/wps/wcm/conn... ^,4343. Gerência Geral de Monitoramento de Produtos Sujeitos à Vigilância Sanitária; Gerência Geral de Tecnologia em Serviços de Saúde, Agência Nacional de Vigilância Sanitária. Nota técnica conjunta nº 02/2015. Brasília: Agência Nacional de Vigilância Sanitária; 2015.. At the start of pharmacovigilance activities in Brazil, only ADRs and deviations in drug quality involving patient harms were reported to Anvisa.

Case definition

No standard case definition for adverse events subject to surveillance was found in the search, according to health surveillance standards, which includes clinical manifestations, laboratory results, epidemiological information, and/or specific behaviors, as well as levels of case certainty, such as confirmed/defined, probable, possible, or suspected ⁴⁴44. Mota DM. Investigação em farmacoepidemiologia de campo?: uma proposta para as ações de farmacovigilância no Brasil. Rev Bras Epidemiol 2011; 14:565-79.. Various Anvisa documents orient the reporting of “suspected” ADRs. The other levels of certainty are only used in the evaluation of causality for each adverse drug reaction ¹⁵15. Agência Nacional de Vigilância Sanitária. Diretrizes para o gerenciamento do risco em farmacovigilância. http://portal.anvisa.gov.br/wps/wcm/connect/4140a10047cd94dc9845fed498087ae1/Diretrizes_para_o_GRFV.pdf?MOD=AJPERES (acessado em 25/Abr/2016).
http://portal.anvisa.gov.br/wps/wcm/conn... . Here, the categories of causality defined by the WHO and used by SINAF are the following: (i) defined; (ii) probable; (iii) possible; (iv) improbable; (v) conditional/not classified; and (vi) not accessible /not classifiable ¹⁵15. Agência Nacional de Vigilância Sanitária. Diretrizes para o gerenciamento do risco em farmacovigilância. http://portal.anvisa.gov.br/wps/wcm/connect/4140a10047cd94dc9845fed498087ae1/Diretrizes_para_o_GRFV.pdf?MOD=AJPERES (acessado em 25/Abr/2016).
http://portal.anvisa.gov.br/wps/wcm/conn... ^,4545. Penido CS, Silva LAM, França LFS, Calado GS. Brazilian National Pharmacovigilance Center: an overview of case safety reports assessment. In: 34th Annual Meeting of Representatives of the National Centres participating in the WHO Programme for International Drug Monitoring. Dubrovnik: World Health Organization; 2011. p. 1..

In the document Guidelines for Risk Management in Pharmacovigilance, Anvisa mentions the need to “reassess causality and revise case definition based on new data” in investigation in pharmacovigilance ¹⁵15. Agência Nacional de Vigilância Sanitária. Diretrizes para o gerenciamento do risco em farmacovigilância. http://portal.anvisa.gov.br/wps/wcm/connect/4140a10047cd94dc9845fed498087ae1/Diretrizes_para_o_GRFV.pdf?MOD=AJPERES (acessado em 25/Abr/2016).
http://portal.anvisa.gov.br/wps/wcm/conn... .

Reporting sources

It is possible for various reporting sources to record ADEs in different ways, especially in the Notivisa-medicamento system. These sources include independent health professionals such as physicians, pharmacists, and nurses, health surveillance professionals and/or staff affiliated with the Sentinel Network hospitals or Patient Safety Center (NSP), and other hospitals, sentinel physicians, reporting pharmacies, DRM, CIATs, universities, and individual citizens, patients, or family members (laypersons) ³⁴34. Agência Nacional de Vigilância Sanitária. Resolução nº 278, de 24 de outubro de 2002. Diário Oficial da União 2002; 25 out.^,3636. Agência Nacional de Vigilância Sanitária. Apresentação do Notivisa. http://www.anvisa.gov.br/hotsite/notivisa/apresenta.htm (acessado em 25/Abr/2016).
http://www.anvisa.gov.br/hotsite/notivis... ^,4646. Carmo EH. Monitoramento e gestão de risco sanitário: os desafios do SNVS para o usuário que é sujeito, cidadão e cliente. In: 15º Encontro da Rede Sentinela - Fórum Internacional de Gestão do Risco Sanitário. Ipojuca: Agência Nacional de Vigilância Sanitária; 2015.^,4747. Agência Nacional de Vigilância Sanitária. Resolução RDC nº 44, de 17 de agosto de 2009. Diário Oficial da União 2009; 18 ago.. The latter can report events on a specific form, not integrated electronically into the Notivisa-medicamento system and available on the Anvisa website ³⁶36. Agência Nacional de Vigilância Sanitária. Apresentação do Notivisa. http://www.anvisa.gov.br/hotsite/notivisa/apresenta.htm (acessado em 25/Abr/2016).
http://www.anvisa.gov.br/hotsite/notivis... .

This diversity of reporting sources notwithstanding, four sources merit special attention in the following order, due to the volume of reports recorded in the Notivisa-medicamento system from 2008 to 2014: (i) professionals from the Sentinel Network/NSP; (ii) independent health professionals; (iii) professionals from other hospitals/NSP; and (iv) health surveillance professionals ⁴⁶46. Carmo EH. Monitoramento e gestão de risco sanitário: os desafios do SNVS para o usuário que é sujeito, cidadão e cliente. In: 15º Encontro da Rede Sentinela - Fórum Internacional de Gestão do Risco Sanitário. Ipojuca: Agência Nacional de Vigilância Sanitária; 2015.. During this same period, no reports came from either the Reporting by Pharmacies Program or the Sentinel Physicians ⁴⁶46. Carmo EH. Monitoramento e gestão de risco sanitário: os desafios do SNVS para o usuário que é sujeito, cidadão e cliente. In: 15º Encontro da Rede Sentinela - Fórum Internacional de Gestão do Risco Sanitário. Ipojuca: Agência Nacional de Vigilância Sanitária; 2015..

Data and information flow

Figure 2 shows an attempt at mapping the data flow for ADEs reported to SINAF. Given the different reporting sources, the flow shows at least three routes that converge in Anvisa, with some relevant cases of ADRs forwarded to the WHO Uppsala Monitoring Centre ²⁶26. Ministério da Saúde. Portaria nº 696, de 7 de maio de 2001. Diário Oficial da União 2001; 8 mai..

As for the route that involves reporting to Notivisa-medicamento, each registered reporting source can monitor the set of its reports recorded in the system, the data of which are forwarded to Anvisa in real time. The capacity to manage and analyze the data with municipal, state, and national repercussions and the publication of information are the responsibility of the respective health authorities at their various management levels (KI). Information on ADEs reported by individual citizens, patients, and family members also reach Anvisa through the agency’s hotline and its Ombudsman’s Office (Figure 2) ⁴⁸48. Penido CS, Bittencourt MO, Cruz FCS, Silva LAM. Experiences from consumer reports in Brazil. In: 12th Annual Meeting of International Society of Pharmacovigilance. Cancun: International Society of Pharmacovigilance; 2012. p. 1..

Surveillance networks

The networks for ADE surveillance consist of all the actors participating in the reporting process to Anvisa (KI), such as state, regional, municipal, and Federal District health surveillance agencies and the Sentinel Network. According to the purposes and objectives of SINAF, the pharmacovigilance technical area of Anvisa induced the establishment of surveillance networks within Brazil and abroad ⁴⁹49. Agência Nacional de Vigilância Sanitária. Portaria nº 406, de 14 de outubro de 2005. Diário Oficial da União 2005; 17 out.^,5050. Agência Nacional de Vigilância Sanitária. Resolução nº 61, de 3 de fevereiro de 2016. Diário Oficial da União 2016; 5 fev., allowing an increase in the detection of adverse events, communication of alerts, and staff training ¹⁴14. Agência Nacional de Vigilância Sanitária. Farmacovigilância no Brasil. http://portal.anvisa.gov.br/wps/content/Anvisa+Portal/Anvisa/Pos+-+Comercializacao+-+Pos+-+Uso/Farmacovigilancia (acessado em 25/Abr/2016).
http://portal.anvisa.gov.br/wps/content/... . The initiatives for integration of SINAF with public health programs from other systems, like the National TB Control Program ⁵¹51. Rocha JL, Silva CHL, Cyriaco CSS, Cury MEC, Oliveira MG, Gasparotto FS, et al. Farmacovigilância em tuberculose: relato de uma experiência no Brasil. Vigil Sanit Debate 2015; 3:131-5. and the National Program for the Prevention and Control of Viral Hepatitides ⁵²52. Ministério da Saúde. Guia de notificação de reações adversas no tratamento da hepatite C. Brasília: Ministério da Saúde; s.d. are examples of networks that have promoted ADE reporting in Brazil.

Population under surveillance and geographic coverage

The target population basically includes residents of Brazil that have suffered health harms purportedly caused by medications licensed in the country (KI). Except for pregnant women, the review did not identify surveillance priorities as to vulnerable populations such as under-five children, elderly, and patients with multiple comorbidities ³⁸38. Agência Nacional de Vigilância Sanitária. Resolução nº 4, de 10 de fevereiro de 2009. Diário Oficial da União 2009; 11 fev.^,4949. Agência Nacional de Vigilância Sanitária. Portaria nº 406, de 14 de outubro de 2005. Diário Oficial da União 2005; 17 out.^,5050. Agência Nacional de Vigilância Sanitária. Resolução nº 61, de 3 de fevereiro de 2016. Diário Oficial da União 2016; 5 fev.. The drugs under surveillance include phytomedicines, pharmacy-manipulated products, homeopathic preparations, specific products such as parenteral solutions and vitamins, over-the-counter drugs, and drugs prescribed by qualified health professionals ⁵³53. Agência Nacional de Vigilância Sanitária. Manual do usuário. Notivisa - Sistema Nacional de Notificações para a Vigilância Sanitária - Módulo de notificação. Anexo 3 (Profissional da Saúde). Brasília: Ministério da Saúde; s.d.. Drug registration holders are required to send periodic safety reports to Anvisa on new drugs marketed in the country ³⁸38. Agência Nacional de Vigilância Sanitária. Resolução nº 4, de 10 de fevereiro de 2009. Diário Oficial da União 2009; 11 fev..

There is mention of so-called “special-interest” adverse events such as agranulocytosis, anaphylaxis, aplastic anemia, blindness, malignant hyperthermia, toxic epidermal necrolysis, rhabdomyolysis, and Stevens-Johnson syndrome ¹⁵15. Agência Nacional de Vigilância Sanitária. Diretrizes para o gerenciamento do risco em farmacovigilância. http://portal.anvisa.gov.br/wps/wcm/connect/4140a10047cd94dc9845fed498087ae1/Diretrizes_para_o_GRFV.pdf?MOD=AJPERES (acessado em 25/Abr/2016).
http://portal.anvisa.gov.br/wps/wcm/conn... . However, it is not clear whether they are prioritized in the reporting flows.

The geographic coverage of SINAF includes the entire country, although some network strategies thus far do not cover all 27 states, like the State Pharmacovigilance Centers ³¹31. Agência Nacional de Vigilância Sanitária. Centros de farmacovigilância. http://portal.anvisa.gov.br/wps/content/Anvisa+Portal/Anvisa/Pos+-+Comercializacao+-+Pos+-+Uso/Farmacovigilancia (acessado em 24/Abr/2016).
http://portal.anvisa.gov.br/wps/content/... and the Reporting by Pharmacies ⁵⁴54. Agência Nacional de Vigilância Sanitária. Farmácias participantes. http://portal.anvisa.gov.br/wps/content/Anvisa+Portal/Anvisa/Pos+-+Comercializacao+-+Pos+-+Uso/Farmacovigilancia/Assunto+de+Interesse/Farmacias+Notificadoras (acessado em 25/Abr/2016).
http://portal.anvisa.gov.br/wps/content/... . Others have not even been implemented at all, like the Sentinel Physicians program (KI).

Types of surveillance

SINAF is characterized as a passive surveillance system in which spontaneous reporting is the main method for monitoring ADEs (KI). Active surveillance has largely occurred to meet specific demands, as in the case of the abusive use of benzydamine, in which consultations are made with reporting pharmacies and CIATs as an alternative used by authors to explore this type of ADE ⁵⁵55. Mota DM, Costa AA, Teixeira CDS, Bastos AA, Dias MF. Uso abusivo de benzidamina no Brasil: uma abordagem em farmacovigilância. Ciênc Saúde Coletiva 2010; 15:717-24..

The other types of surveillance are: (i) mandatory - DRM and health services are required to report ADEs that have come to their attention and (ii) comprehensive - various documents published by Anvisa state that all deaths and other serious drug-related events must be reported, as well as all adverse reactions not listed on the product’s package insert ³⁹39. Agência Nacional de Vigilância Sanitária. Resolução nº 36, de 25 de julho de 2013. Diário Oficial da União 2013; 26 jul.^,4141. Agência Nacional de Vigilância Sanitária. Notivisa - Sistema de Notificação em Vigilância Sanitária. http://www.anvisa.gov.br/hotsite/notivisa/apresenta.htm (acessado em 25/Abr/2016).
http://www.anvisa.gov.br/hotsite/notivis... ^,5656. Agência Nacional de Vigilância Sanitária. Boletim de Farmacovigilância 2012; 1(1)..

Reporting format and data specification

SINAF maintains and encourages the use of only online formats for the ADE reporting forms (citizens/patients/families and Notivisa-medicamento) ³⁶36. Agência Nacional de Vigilância Sanitária. Apresentação do Notivisa. http://www.anvisa.gov.br/hotsite/notivisa/apresenta.htm (acessado em 25/Abr/2016).
http://www.anvisa.gov.br/hotsite/notivis... . Such forms record individual information related to ADEs, such as name, age, sex, medical diagnosis, description of the adverse event, date of onset and end of the event, currently used medications, time using the product, relevant complementary data, and reporting source, etc. ⁵³53. Agência Nacional de Vigilância Sanitária. Manual do usuário. Notivisa - Sistema Nacional de Notificações para a Vigilância Sanitária - Módulo de notificação. Anexo 3 (Profissional da Saúde). Brasília: Ministério da Saúde; s.d.^,5757. Agência Nacional de Vigilância Sanitária. Formulário para notificação do cidadão. http://www.anvisa.gov.br/hotsite/notivisa/formularios.htm (acessado em 24/Abr/2016).
http://www.anvisa.gov.br/hotsite/notivis... . The Notivisa-medicamento form for health professionals assessed in November 27, 2015, has at least 92 variables, covering four domains (KI): event, drugs/company, patient or user, and other information ⁵³53. Agência Nacional de Vigilância Sanitária. Manual do usuário. Notivisa - Sistema Nacional de Notificações para a Vigilância Sanitária - Módulo de notificação. Anexo 3 (Profissional da Saúde). Brasília: Ministério da Saúde; s.d.. The content of the information on the individuals’ identity is confidential.

Reporting rate

The reporting rate was defined for holders of drug registrations and health services according to health standards. In the first case, every serious adverse event involving death or risk of death must be reported to Anvisa within seven days from receiving the information. The deadline is extended to 15 days for other serious adverse events ³⁸38. Agência Nacional de Vigilância Sanitária. Resolução nº 4, de 10 de fevereiro de 2009. Diário Oficial da União 2009; 11 fev.. As for health services, the reports are to be sent monthly to Anvisa, and as mentioned previously, adverse events evolving to death must be reported within 72 hours of the event ³⁹39. Agência Nacional de Vigilância Sanitária. Resolução nº 36, de 25 de julho de 2013. Diário Oficial da União 2013; 26 jul..

Data entry

Data entry in Notivisa-medicamento requires using the user registration system, which allows different levels of access according to the user profile ⁵³53. Agência Nacional de Vigilância Sanitária. Manual do usuário. Notivisa - Sistema Nacional de Notificações para a Vigilância Sanitária - Módulo de notificação. Anexo 3 (Profissional da Saúde). Brasília: Ministério da Saúde; s.d.. Registered health surveillance professionals have access to the Notivisa-medicamento features that are not available to users registered as independent health professionals. The system validates the registered user’s data before starting a new report. Information on ADEs are keyed manually into a data entry mask on the webpage, through a form containing open and closed fields, where the data may possibly not be record uniquely or regularly (KI).

Production and dissemination of information

No mention was found of the amount and periodicity of publication of information from Notivisa-medicamento or from other data repositories belonging to the SINAF, as a form of feedback to the reporting sources and society ⁴¹41. Agência Nacional de Vigilância Sanitária. Notivisa - Sistema de Notificação em Vigilância Sanitária. http://www.anvisa.gov.br/hotsite/notivisa/apresenta.htm (acessado em 25/Abr/2016).
http://www.anvisa.gov.br/hotsite/notivis... ^,5353. Agência Nacional de Vigilância Sanitária. Manual do usuário. Notivisa - Sistema Nacional de Notificações para a Vigilância Sanitária - Módulo de notificação. Anexo 3 (Profissional da Saúde). Brasília: Ministério da Saúde; s.d.^,5858. Agência Nacional de Vigilância Sanitária. Manual do usuário. Notivisa - Sistema Nacional de Notificações para a Vigilância Sanitária - Módulo de notificação. Anexo 3 (Indústria). Brasília: Ministério da Saúde; s.d..

The Anvisa website yielded four editions (two in 2012, one in 2013, and another in 2014) of a Pharmacovigilance Bulletin targeted to actors in the National Pharmacovigilance System aimed at “disseminating knowledge and orientation on the topic for health professionals, the Sentinel Network, and the state, municipal, and Federal District health surveillance agencies” ⁵⁶56. Agência Nacional de Vigilância Sanitária. Boletim de Farmacovigilância 2012; 1(1).. No space on the Anvisa website was dedicated to the publication of plans to minimize drug risks - a new pharmacovigilance strategy for risk-benefit assessment of new drugs and biologicals, in order to orient action by different sectors of society ⁵⁹59. Botelho SF, Reis AMM. Planos de minimização de riscos em farmacovigilância: uma ação de saúde pública para promoção da segurança de medicamentos. Ciênc Saúde Coletiva 2015; 20:3897-905..

The pharmacovigilance area of Anvisa has published reports and safety alerts to disseminate information primarily to health professionals. From 2001 to 2015, 84 reports were published (average 5.6/year) that addressed drug safety issues ⁶⁰60. Agência Nacional de Vigilância Sanitária. Informes. http://portal.anvisa.gov.br/wps/content/Anvisa+Portal/Anvisa/Pos+-+Comercializacao+-+Pos+-+Uso/Farmacovigilancia (acessado em 25/Abr/2016).
http://portal.anvisa.gov.br/wps/content/... . From 2000 to 2009, 67 alerts were published, of which 48 (72%) referred to ADRs ⁶¹61. Mariz LCV, Menezes FG. Estudo descritivo e comparativo de procedimentos em farmacovigilância no Brasil. Rev Eletrônica Farm 2012; IX:43-58..

No publication addressed to common citizens was found that encouraged them to report ADEs or containing information on the possibility that any medication can increase health risks if not properly oriented and used correctly ⁶⁰60. Agência Nacional de Vigilância Sanitária. Informes. http://portal.anvisa.gov.br/wps/content/Anvisa+Portal/Anvisa/Pos+-+Comercializacao+-+Pos+-+Uso/Farmacovigilancia (acessado em 25/Abr/2016).
http://portal.anvisa.gov.br/wps/content/... . In addition, the review did not yield any type of activity in detection, assessment, and monitoring of safety signals indicative of follow-up for medications suspected of causing adverse events.

Minimum requirements for a functional pharmacovigilance system

Box 2 summarizes part of the findings in the evolution of SINAF and its key elements, besides mentioning other information from the scoping review, e.g., the Anvisa Activities Report ⁶²62. Agência Nacional de Vigilância Sanitária. Relatório de atividades 2014. Brasília: Agência Nacional de Vigilância Sanitária; 2015., aimed at using the set of information to verify compliance with the minimum requirements proposed by the WHO.

Discussion

This study described and characterized the evolution and key elements of the SINAF, based on initiatives, especially by Anvisa, in addition to a comparative analysis of the minimum requirements for a functional pharmacovigilance system proposed by the WHO ¹³13. World Health Organization. Minimum requirements for a functional pharmacovigilance system. October 2010. http://www.who.int/medicines/areas/quality_safety/safety_efficacy/PV_Minimum_Requirements_2010_2.pdf (acessado em 15/Nov/2015).
http://www.who.int/medicines/areas/quali... . Although this was a descriptive study, the analysis represents a potential benefit for activities in the evaluation of SINAF and identification of its limitations ¹, since questions related to its performance can be identified in this phase ⁸8. German RR, Lee LM, Horan JM, Milstein RL, Pertowski CA, Waller MN, et al. Updated guidelines for evaluating public health surveillance systems: recommendations from the guidelines working group. MMWR Recomm Rep 2001; 50(RR-13):1-35.^,99. European Centre for Disease Prevention and Control. Data quality monitoring and surveillance system evaluation. Stockholm: European Centre for Disease Prevention and Control; 2014..

The characterization of pharmacogovernance further allows understanding a pharmacovigilance system like SINAF as a key structure not only for processing and analyzing ADEs, but also in the relations between the different stakeholders (users, health professionals, regulatory agents) in shaping the practices the lend a material basis to public drug safety policies. Although the CNMM meets the formal WHO requirements for a functional pharmacovigilance system, no documents and studies were identified that demonstrate its intentions and contributions to the consolidation of a national system, whether due to the characteristics of marked decentralization of actions in an inter-federative health system like the Brazilian one, or due to the absence of mechanisms for integration between the actions by CNMM and other activities in the country’s pharmacogovernance structure.

The review also revealed some difficulties in clearly defining the organizational, functional, and budget structure of CNMM and GFARM and the key actors in the country’s pharmacogovernance ²2. Moscou K, Kohler JC, MaGahan A. Governance and pharmacovigilance in Brazil: a scoping review. J Pharm Policy Pract 2016; 9:3.. No documents or studies were found that specified the budget allocations for programmatic pharmacovigilance activities in Brazil. Insufficient budgeting for pharmacovigilance activities has been described in some countries, like India, Uganda, and South Africa ¹1. Maigetter K, Pollock AM, Kadam A, Ward K, Weiss MG. Pharmacovigilance in India, Uganda and South Africa with reference to WHO's minimum requirements. Int J Health Policy Manag 2015; 4:295-305.. As in other low and medium-income countries, the financing of GFARM/Anvisa activities is part of the overall budget for regulatory activities in Brazil, not specifically earmarked for pharmacovigilance ¹²12. Olsson S, Pal SN, Stergachis A, Couper M. Pharmacovigilance activities in 55 low- and middle-income countries. Drug Saf 2010; 33:689-703. or to the CNMM. The literature also suggests a lack of equitable distribution of funds for monitoring and assessing drug safety in Brazil ²2. Moscou K, Kohler JC, MaGahan A. Governance and pharmacovigilance in Brazil: a scoping review. J Pharm Policy Pract 2016; 9:3..

The creation of a technical area for pharmacovigilance at Anvisa and the definition of its attributions in 1999 were an undeniable step forward in the development of regulatory activities and in the shaping of SINAF itself. However, the scoping review found no legislation that formally instituted the SINAF, although discussions since 1995 point to the establishment of a national pharmacovigilance system ⁶³63. Arrais PSD. Farmacovigilância no Brasil. O papel da comissão instituída pela portaria da Secretaria de Vigilância Sanitária do Ministério da Saúde (SVS/MS) nº 40 de 9/5/95. Cad Saúde Pública 1999; 15:205-6.. Documents produced by the technical area of Anvisa ¹⁵15. Agência Nacional de Vigilância Sanitária. Diretrizes para o gerenciamento do risco em farmacovigilância. http://portal.anvisa.gov.br/wps/wcm/connect/4140a10047cd94dc9845fed498087ae1/Diretrizes_para_o_GRFV.pdf?MOD=AJPERES (acessado em 25/Abr/2016).
http://portal.anvisa.gov.br/wps/wcm/conn... ^,6464. Agência Nacional de Vigilância Sanitária. Farmacovigilância no Brasil. Unidade de Farmacovigilância. Brasília: Agência Nacional de Vigilância Sanitária; s.d., scientific studies ²2. Moscou K, Kohler JC, MaGahan A. Governance and pharmacovigilance in Brazil: a scoping review. J Pharm Policy Pract 2016; 9:3.^,2222. Dias MF. A Agência Nacional de Vigilância e o Sistema Nacional de Farmacovigilância. BEPA Bol Epidemiol Paul 2005; (16). http://www.cve.saude.sp.gov.br/agencia/bepa16_msfarmaco.htm.
http://www.cve.saude.sp.gov.br/agencia/b... ^,3030. Arrais PSD. O uso irracional de medicamentos e a farmacovigilância no Brasil. Cad Saúde Pública 2002; 18:1478-9.^,6565. Yadav S. Status of adverse drug reaction monitoring and pharmacovigilance in selected countries. Indian J Pharmacol 2008; 40 Suppl 1:S4-9., and national policy legislation ⁶⁶66. Ministério da Saúde. Portaria nº 971, de 3 de maio de 2006. Aprova a Política Nacional de Práticas Integrativas e Complementares (PNPIC) no Sistema Único de Saúde. Diário Oficial da União 2006; 6 mai. have referred to this system, even questioning this formal gap ³⁰30. Arrais PSD. O uso irracional de medicamentos e a farmacovigilância no Brasil. Cad Saúde Pública 2002; 18:1478-9. and justifying the need for its formal existence and functioning ²⁵25. Arrais PSD, Vidotti CCF, Heleodoro NM, Martins R, Castilha SR. Sistema nacional de farmacovigilância: propostas de contribuição do Sistema Brasileiro de Informação sobre Medicamentos (Sismed). Saúde Debate 2002; 26:210-8..

No studies were identified that evaluated strategies to encourage ADE reporting, although this is clearly a limiting factor for pharmacovigilance activities. Likewise, no documents were found that pointed to the need for prioritizing active reporting and recording methods for ADEs ¹1. Maigetter K, Pollock AM, Kadam A, Ward K, Weiss MG. Pharmacovigilance in India, Uganda and South Africa with reference to WHO's minimum requirements. Int J Health Policy Manag 2015; 4:295-305.. Studies have shown that passive surveillance systems only capture 1% to 10% of adverse reactions ⁶⁷67. Wiktorowicz M, Lexchin J, Moscou K, Silversides A, Eggertson L. Keeping an eye on prescription drugs, keeping Canadians safe. Toronto: Health Council of Canada; 2010., highlighting the importance of active surveillance methods in the identification of ADEs ¹1. Maigetter K, Pollock AM, Kadam A, Ward K, Weiss MG. Pharmacovigilance in India, Uganda and South Africa with reference to WHO's minimum requirements. Int J Health Policy Manag 2015; 4:295-305.. The legal requirement of mandatory reporting by holders of drug registrations and health services can help reduce underreporting in Brazil. In addition, the Reporting by Pharmacies and Sentinel Physicians programs have the potential to expand ADE reporting and recording, although their participation thus far has been virtually nonexistent ²2. Moscou K, Kohler JC, MaGahan A. Governance and pharmacovigilance in Brazil: a scoping review. J Pharm Policy Pract 2016; 9:3.^,4646. Carmo EH. Monitoramento e gestão de risco sanitário: os desafios do SNVS para o usuário que é sujeito, cidadão e cliente. In: 15º Encontro da Rede Sentinela - Fórum Internacional de Gestão do Risco Sanitário. Ipojuca: Agência Nacional de Vigilância Sanitária; 2015..

Although the staff size for pharmacovigilance activities at the federal level meets the minimum requirements from WHO (at least in terms of fulltime staff), the needs are broader for monitoring adverse events in a decentralized health system and in a country with continental dimensions like Brazil. Staff shortage was identified as an important challenge in pharmacovigilance systems in low and medium-income countries ¹²12. Olsson S, Pal SN, Stergachis A, Couper M. Pharmacovigilance activities in 55 low- and middle-income countries. Drug Saf 2010; 33:689-703. like India, Uganda, and South Africa ¹1. Maigetter K, Pollock AM, Kadam A, Ward K, Weiss MG. Pharmacovigilance in India, Uganda and South Africa with reference to WHO's minimum requirements. Int J Health Policy Manag 2015; 4:295-305., among others.

During the period analyzed here, no legal instrument was identified that established an advisory committee in pharmacovigilance to provide technical consultation to SINAF, particularly in terms of the activities developed by the CNMM, thus compromising full compliance with the minimum requirements for a functional pharmacovigilance system proposed by WHO ¹³13. World Health Organization. Minimum requirements for a functional pharmacovigilance system. October 2010. http://www.who.int/medicines/areas/quality_safety/safety_efficacy/PV_Minimum_Requirements_2010_2.pdf (acessado em 15/Nov/2015).
http://www.who.int/medicines/areas/quali... . However, on November 7, 2017, under Ruling n. 1,857⁶⁸68. Agência Nacional de Vigilância Sanitária. Portaria nº 1.857, de 7 de novembro de 2017. Diário Oficial da União 2017; 9 nov., Anvisa established a Technical Chamber on Pharmacovigilance to respond to the need for this committee. Since this committee only began to function more recently, it was not possible to conduct a more in-depth analysis of its influence on SINAF.

The ADE reporting rate in Brazil in 2011 (29/million inhabitants) was substantially lower than that in South Africa (77/million), higher than in India (15/million) ¹1. Maigetter K, Pollock AM, Kadam A, Ward K, Weiss MG. Pharmacovigilance in India, Uganda and South Africa with reference to WHO's minimum requirements. Int J Health Policy Manag 2015; 4:295-305. and far short of the target proposed in the international literature, suggesting 300 reports per million inhabitants ⁶⁹69. Meyboom RH, Egberts AC, Gribnau FW, Hekster YA. Pharmacovigilance in perspective. Drug Saf 1999; 21:429-47.. Some reasons for the low reporting rate include health professionals’ perception that the task of reporting ADEs means even more work in an already busy schedule, besides reporting of other health problems, lack of specific training for physicians and pharmacists, and rare government initiatives to encourage reporting of ADRs ¹1. Maigetter K, Pollock AM, Kadam A, Ward K, Weiss MG. Pharmacovigilance in India, Uganda and South Africa with reference to WHO's minimum requirements. Int J Health Policy Manag 2015; 4:295-305.. The effective implementation of strategies like Sentinel Physicians and Reporting by Pharmacies and emphasis on training of health professionals at the graduate level may contribute to increasing ADE reporting rates in Brazil. The low reporting rates, plus reporting by patient/families/common citizens and the state of São Paulo outside the Notivisa-medicamento system hinder the detection and monitoring of safety signals, risk assessment, and adoption of the necessary regulatory measures to protect patients ¹1. Maigetter K, Pollock AM, Kadam A, Ward K, Weiss MG. Pharmacovigilance in India, Uganda and South Africa with reference to WHO's minimum requirements. Int J Health Policy Manag 2015; 4:295-305..

The scoping review indicates inequalities in the current forms of risk reporting by identifying drug safety problems ²2. Moscou K, Kohler JC, MaGahan A. Governance and pharmacovigilance in Brazil: a scoping review. J Pharm Policy Pract 2016; 9:3.. GFARM publishes various documents targeted mainly to health professionals. However, effective communication targeted to laypeople is still a challenge. In order for any pharmacovigilance system to be effective, it needs to define communication strategies with laypeople/patients and health professionals and between these two groups and society ⁷⁰70. Bahri P. Public pharmacovigilance communication: a process calling for evidence-based, objective-driven strategies. Drug Saf 2010; 33:1065-79.. Failure to publicize drug risk mitigation plans was another gap identified by the review. Health professionals should be familiar with the main information contained in these documents in order to better guide their clinical practice and thus minimize patients’ health risks ⁵⁹59. Botelho SF, Reis AMM. Planos de minimização de riscos em farmacovigilância: uma ação de saúde pública para promoção da segurança de medicamentos. Ciênc Saúde Coletiva 2015; 20:3897-905..

The study’s limitations can be attributed to the characteristics of a scoping review, including the process of identification, selection, and analysis of the publications and the document analysis conducted from the authors’ perspective, whether as a function of their understanding of pharmacovigilance activities or because document analysis may not suffice to identify all the elements in pharmacovigilance policies. Scoping reviews usually pose research questions that are broader than in systematic reviews, in addition to the more qualitative methods in summarizing the results, aimed at identifying parameters and gaps in specific themes ⁷¹71. Armstrong R, Hall BJ, Doyle J, Waters E. "Scoping the scope" of a cochrane review. J Public Health (Bangkok) 2011; 33:147-50..

Some other sources of international data were not included, such as Embase, International Pharmaceuticals Abstracts (IPA), Web of Science, and Scopus, so that some relevant studies may not have been identified. A study on the scientific research on health surveillance of medications in Brazil, and which searched the above-mentioned databases, found 16 studies related to “pharmacovigilance” from 1999 and 2011 ⁷²72. Izidoro A. Aspectos da produção científica da vigilância sanitária de medicamentos [Dissertação de Mestrado]. São Paulo: Faculdade de Saúde Pública, Universidade de São Paulo; 2013.. Of these, only five studies were aligned with our research question, and all of them had been identified in phase 1 of the scoping review, which aims to explore patterns and thus is not intended to produce an exhaustive literature search ⁷³73. Gough D, Thomas J, Oliver S. Clarifying differences between review designs and methods. Syst Rev 2012; 1:28..

The authors’ personal perception may have influenced the identification and selection of publications in Google, the Brazilian National Press, and especially in the Anvisa website, considering the inherent limitations in the latter’s search system. The search in Google may have missed some publications, due to the predefined cutoff after the first 100 results. In addition, no specialist was contacted to suggest additional relevant publications that may not have been included in the scoping review. The difficulties in retrieving the gray literature may also have influenced the results. Another limitation relates to the review’s objective, i.e. to describe and characterize the SINAF from the perspective of activities developed by Anvisa, without focusing on the state, municipal, and Federal District health surveillance agencies and other relevant actors in Brazil’s pharmacogovernance. The study’s findings may thus reflect only part of the SINAF.

Although this review had not originally planned to assess the publications’ methodological quality, particularly that of the scientific studies, two studies were excluded from the full text analysis stage, since they presented important quality problems, based on the researchers’ experience. The need to assess the studies’ quality should address the challenges with assessment of the types and amount of publications and the study models that can be included in the review, which may or may not exclude the study itself ⁷⁴74. Pham MT, Rajic A, Greig JD, Sargeant JM, Papadopoulos A, McEwen SA. A scoping review of scoping reviews: advancing the approach and enhancing the consistency. Res Synth Methods 2014; 5:371-85.. In our review, most of the publications were technical and legal document that proved at least as important as the scientific articles and were essentially sufficient to help characterize the SINAF.

Drug safety and effectiveness require regulatory and pharmacogovernance systems ²2. Moscou K, Kohler JC, MaGahan A. Governance and pharmacovigilance in Brazil: a scoping review. J Pharm Policy Pract 2016; 9:3. and particularly a functional pharmacovigilance system, since the safety profile of many drugs studied in developed countries may not necessarily be generalizable to developing countries, where the incidence, usage pattern, individual risk behaviors, and severity of adverse reactions may differ considerably because of the environment and genetic factors ⁷⁵75. Pirmohamed M, Atuah KN, Dodoo ANO, Winstanley P. Pharmacovigilance in developing countries. BMJ 2007; 335:462.. However, there are real concerns that impact the capacity of SINAF to monitor and effectively control the pharmaceuticals market in Brazil, one of the world’s largest and with a growing demand ⁷⁶76. Vashisth S, Singh G, Nanda A. A comparative study of regulatory trends of pharmaceuticals in Brazil, Russia, India and China (BRIC) countries. J Generic Med 2012; 9:128-43.. For example, the mean reporting rate per million inhabitants according to this study suggests lack of sufficient size to significantly detect safety signals. Given the key role of pharmacovigilance systems in establishing pharmacogovernance practices and infrastructure in the country, the analysis of the characteristics and limitations of the SINAF represents a potential contribution to both the improvement of the system itself and strengthening of public drug safety policies in Brazil.

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