Do No Harm Situation Analysis  A Safety Monitoring of Medicines and Vaccines Huihui Wang Albert Figueras Patricio V Marquez Kseniya Bieliaieva Korea–World Bank Partnership Facility (KWPF) China-World Bank Partnership Trust Fund (CWPF) © 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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Safety Monitoring of Medicines and Vaccines A Situation Analysis ii Safety Monitoring of Medicines and Vaccines: A Situation Analysis Table of Contents Reports in the Pharmacovigilance and Essential Public Health Services Series............................................................................ iv Acknowledgements............................................................................................................... v Acronyms.................................................................................................................................. vi Abstract. . ............................................................................................................... 1 Introduction. . ....................................................................................................... 2  he PIDM: A Global System.............................................................................. 3 1. T 1.1. Rationale for Action....................................................................................... 3 1.2. The Uppsala Monitoring Center..................................................................... 5 1.3. Building up the network................................................................................ 6 1.4. VigiBase: the global PV database.................................................................... 7  harmacovigilance systems in practice.......................................................... 9 2. P 2.1. Evaluation of country pharmacovigilance systems......................................... 9 2.2. Overview: pharmacovigilance in 55 countries............................................... 17 2.3. Regional networks: a strategic support......................................................... 19 Take-Home Messages..................................................................................... 29 3.  3.1. The need for and advantages of a national PV system. . ................................. 29 3.2. The difficulties in consolidating national PV systems. . ................................. 29 3.3. Wide collaboration to harmonize actions, share costs, and raise awareness..... 29 References. . ........................................................................................................ 30 Table of Contents iii Boxes Box 1.  Pharmacovigilance: A Working Definition. . ................................................... 5 Box 2.  Requirements to Become a Full Member of the WHO-PIDM Network.......... 7 Box 3.  Summary Survey Findings: Four East African Countries............................. 10 Box 4.  Common Features of PV Development in Limited-Resource Economies.... 16 Box 5.  The Steady Growth in African PIDM Members Since 2000.. ........................ 19 Box 6.  What Had African Countries Reported to VigiBase by 2016?...................... 20 Box 7.  National Regulatory Authorities of Regional Reference in the Americas. . ... 25 Figures Figure 1.  Mechanics of Global Pharmacovigilance: Reporting Suspected ADRs ...... 4 Figure 2.  Structure of the Pharmacovigilance System, Vietnam............................ 13 Figure 3.  Regional Distribution of VigiBase Reports. . .............................................. 8 Figure 4.  Additional Problems Reported through Pharmacovigilance Centers...... 18 Figure 5.  PV Survey Results, Arab and Eastern Mediterranean Region, 2015.......... 24 Figure 6.  The Distribution of the Reports Included in the WHO-PIDM VigiBase.... 26 Figure 7.  Annual PV Reports, Brazilian Health Regulatory Agency......................... 27 Tables Table 1.  PV Systems and Coordination, Ethiopia, Kenya, Rwanda, and Tanzania.... 11 Table 2.  Signal Detection and Data Management in East Africa............................. 11 Table 3.  Analysis of WHO Core Pharmacovigilance Structural Indicators, Iran. . .... 15 Table 4  Regulatory Actions Based on PV Activities, 2007........................................ 17 iv Safety Monitoring of Medicines and Vaccines: A Situation Analysis 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 The report was prepared by a team at the World Bank Group (WBG) led by Huihui Wang (Senior Health Economist, Health, Nutrition, and Population Global Unit) and including Albert Figueras (Consultant), Patricio V. Marquez (Consultant), and Kseniya Bieliaieva (Consultant). The draft report was kindly reviewed by Volkan Cetinkaya (Senior Health Economist, HMNHN, WBG), and Severin Rakic (Extended Term Consultant, HMNHN, WBG). Robert Zimmermann (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 has been carried out with the support of the Korea– World Bank Partnership Facility (KWPF) and the China–World Bank Partnership Facility (CWPF). Washington, DC, July 23, 2023 vi Acronyms ADR adverse drug reaction AMRH African Medicines Regulatory Harmonization ASEAN Association of Southeast Asian Nations PANDRH Pan American Network for Drug Regulatory Harmonization NRA national regulatory agency NRAr national regulatory authority of regional reference PIDM Program for International Drug Monitoring PV pharmacovigilance UMC Uppsala Monitoring Center WHO World Health Organization 1 Safety Monitoring of Medicines and Vaccines: A Situation Analysis Abstract Medicines, vaccines, medical devices, and blood are commonly used to treat disease. Medicines deserve a special focus because almost any medical visit ends with at least one prescription. So, monitoring the safety and effectiveness of therapeutic treatments and procedures is crucial at both the individual and community levels. In the case of medicines and vaccines, this surveillance activity is known as pharmacovigilance. Various methods are used to monitor the adverse and unwanted effects of medicinal products after they have received authorization for marketing, but reporting adverse reactions is the most widespread. The network of the Program for International Drug Monitoring (PIDM), which is supported by the World Health Organization (WHO), involves more than 170 countries. Its activities were initiated in 1968. The WHO-PIDM is the world’s most comprehensive network involving health professionals, patients, and manufacturers. This situation analysis describes relevant aspects of the PIDM, including achievements and weak points. The analysis is the product of a systematic revision of studies that focus on the WHO-PIDM activities and related findings published in different medical journals and listed in PubMed. Available information was selected and organized according to different topics and summarized and presented in the different sections of the report. As information for some countries and regions is lacking in the available literature, the report is not a comprehensive review of the pharmacovigilance across countries. The report, therefore, shows what is in place and highlight some of the difficulties faced by many countries, particularly low-and-middle income countries . It offers an overview of the (1) common points and failures; (2) the advantages of a national PV system; (3) the difficulties in scaling up and consolidating these systems; and (4) the advantages of regional collaboration. This report is part of a series of companion reports on pharmacovigilance, that provide a detailed overview and discussion on technical aspects and country and regional experiences. Introduction 2 Involving more than 170 countries, The Program for International Drug Monitoring is the most comprehensive network of health professionals, patients, and health product manufacturers in the world. Introduction report is a product of a revision of previously published papers and does not include primary data collected for its preparation. The review is structured into two parts and popu- lated them with specific experiences reported by the countries. The aim of this Situation Analysis of Pharmacovigilance The first part describes the WHO-PIDM network; how (PV) and PV activities is to review the existing literature was it created; the coordinating role of the UMC, and that describe how the WHO PIDM has been developed, the evolution of the PV program that cover 170 coun- as well as achievements and difficulties experienced by tries; how national PV systems are evaluated; and the some of the 170 countries that are part of that network. importance of VigiBase, the global PV database which To our knowledge, no previously published report facilitates the identification of harms of medicines describes the practical aspects of implementing PV and vaccines. systems at the national level and the difficulties faced The second part describes the difficulties and results of in establishing them from a global perspective. The PV from the national and regional perspectives, focus- most comprehensive analysis was published in 2010 ing on (but not limiting to) low-and middle-income and included information from 55 countries. economies. PV activities in high-income countries, such The Analysis is the result of a review of the publications as the European Union countries, are the object of a containing keywords such as “pharmacovigilance”, separate case study. “surveillance”, “monitoring”, and/or “medicines” This report is part of a series of companion reports on included in PubMed until March 2023. Additionally, this pharmacovigilance, that together provide a detailed information has been complemented by reports and overview and discussion on technical aspects and articles published by the Uppsala Monitoring Centre country and regional experiences. (UMC), that coordinates the WHO-PIDM. Hence, this 3 Safety Monitoring of Medicines and Vaccines: A Situation Analysis  he PIDM: 1. T hundred patients can easily detect and characterize these frequent ADRs. A Global Fortunately, serious or fatal ADRs are much less frequent. A side effect of medicines that is catego- System rized as very rare appears in fewer than 1 case among 10,000 individuals exposed to the causal drug. An example is severe gastrointestinal bleeding after taking aspirin, which could occur in approximately two patients out of 10,000 users of that anti-inflam- matory. The drawback is that, because they are such rare events, they cannot be detected if the sample Thalidomide was the cause of an epidemic that size of a relevant study is small. This explains why affected at least 10,000 children and possibly as many these rare but serious ADRs are only detected after as 100,000 children worldwide. The children were thousands of patients have been exposed to the born with limb deformities to mothers who had used medicine. Because it would be extremely difficult to the medicine to relieve morning sickness during follow cohorts of 100,000+ patients, the best method pregnancy (Vargesson and Stephens 2021). This was for identifying patients presenting these ADRs not the first disaster associated with drugs. Still, consists of collaborating with multiple observers who because of the relevance of the congenital malfor- are available to report identified cases to a centralized mations, the number of victims, and the worldwide surveillance unit (figure 1). To improve the knowledge impact, this episode prompted a global response of the safety of medicines, a network of voluntary to minimize the chances of similar disasters in the reporters is the most effective method, and this is future. One of these responses was the adoption the method that has been selected for the global during the 16th World Health Assembly in 1963 of a pharmacovigilance (PV) surveillance network. resolution (WHA 16.36) that reaffirmed the need for The first practical international cooperation in drug early action regarding the rapid dissemination of monitoring was initiated in 1968 to ensure that evi- information on adverse drug reactions (ADRs). This dence about harm to patients was collected from as led to the creation of a World Health Organization many sources as possible. The initial activities of the (WHO) pilot research project with the participation pilot project culminated in the current WHO Program of 10 countries to develop a system that could be for International Drug Monitoring (PIDM), which implemented internationally to detect the previously has grown to become a global network of national unknown or poorly understood adverse effects PV centers around the world.1 This network enables of medicines. individual countries to be alerted to patterns of harm that have emerged worldwide, but that might not be evident from only the local data of a country. 1.1. Rationale for Action Members of the program work nationally and ADRs, especially those that are serious and fatal, are collaborate internationally to monitor and identify quite rare and cannot be identified in experimental the harm caused by medicines, reduce the risks to premarketing studies such as clinical trials. For patients, and establish worldwide PV standards and example, a mild case of skin rash or nausea after systems (see figure 1). Pharmacovigilance is the safety taking the painkiller ibuprofen is a well-known monitoring of medicines (box 1). adverse effect considered common or very common. It may appear in 1 percent–10 percent of individuals taking ibuprofen. So, even relatively small studies such as clinical trials involving dozens to a few 1  S  ee “The WHO Programme for International Drug Monitoring (PIDM) and How to Join,” World Health Organization, Geneva, https://whopvresources.org/who_pidm.php. 1. The PIDM: A Global System 4 Figure 1  Mechanics of Global Pharmacovigilance: Reporting Suspected ADRs a. Health professional interactions with patients 1 3 Health Professional 2 4 Patient treated without adverse events Patient developing an adverse event b. PV center inactions with the PV database Note: Panel a: Each health professional follows many patients treated with one or more medicines without presenting any ADR. But, if one patient develops an ADR., then the health professional who detects it reports the case to the local PV center. Panel b: Periodically, each local PV center uploads all the received ADR reports to the global PV database, maintained by the Uppsala Monitoring Center (UMC). 5 Safety Monitoring of Medicines and Vaccines: A Situation Analysis Box 1 Pharmacovigilance: A Working Definition The WHO defines pharmacovigilance as “the science and activities relating to the detection, assessment, understanding, and prevention of adverse effects or any other possible drug- related problems” (WHO 2002, 7). This description is an umbrella for multiple elements relating to the safety of medications, including the reporting of substandard and falsified medicines, medication errors, drug abuse and misuse, exposure to medicines during pregnancy and breastfeeding, therapeutic ineffectiveness, occupational exposure, off-label use, ecopharmacovigilance (environmental pollution), medical devices and diagnostics, overdose, and the suspected transmission of infectious agents via medicines (Peters et al. 2021; Viana et al. 2021). It can even be useful in identifying therapeutic failure and antimicrobial resistance (Habarugira and Figueras 2021). 1.2. The Uppsala 1.2.1. Mission Monitoring Center The UMC has the mission to promote rational medicines therapy through the following ­ To increase the effectiveness of the search for (Olsson 1998): previously unknown ADRs, all the monitoring activities conducted in health centers and research • Collecting and analyzing information about drug units worldwide must be somewhat coordinated. safety at the international level The Uppsala Monitoring Center (UMC) has been • Collecting, classifying, and disseminating responsible for the technical and operational information about national activities ­ aspects of the WHO-PIDM since 1978. As an inde- ­ concerning drug safety pendent, nonprofit foundation, the UMC works with • Developing professional and scientific expertise the WHO and engages stakeholders who share the to improve the analysis of international same vision of advancing the safety of medicines, ­ questions concerning drug safety and developing together with the global pharmacovigilance methods for use in work within drug safety and community.2 neighboring fields • Supporting the development of standards The UMC is independent and self-funded; the center for the assessment of risk and beneficial use finances its operations by selling pharmacovigilance of drug therapy products and services to external bodies, most • Contributing to the improvement of notably the WHO Drug Global portfolio of products. communication and education among relevant Funding its own operations ensures intellectual and interest groups concerning the risks and scientific independence, sustainability, and freedom advantages of drug treatment to pursue UMC’s vision (UMC 2022c). • Contributing, on request, to the development of methods for international application within fields closely linked to drug safety 2   ee “Get to Know UMC,” Uppsala Monitoring Center, Uppsala, S Sweden, https://who-umc.org/about-uppsala-monitoring-centre/. 1. The PIDM: A Global System 6 1.2.2. Activities the Drug Information Association, and the Within the framework of PV, UMC activities can be Council for International Organizations of summarized as follows: Medical Sciences), and actively taking part in conferences organized by these parties • Collection of ADR reports worldwide and main- tenance and use of an international database: the UMC maintains and periodically analyzes VigiBase, 1.3. Building up the network the global PV database. The rationale for setting up the WHO-PIDM was to • Dissemination of information: in addition to many make it possible to identify rare ADRs that cannot research articles published in medical journals, be found in the clinical trials conducted during the quarterly journal Uppsala Reports publishes the preauthorization process for the marketing of national information and updates submitted by medicines. In addition, the WHO network represents WHO-PIDM members (UMC 2021a). the wealth of competence and experience that • Education and advice: One of the UMC pillars is at the disposal of countries wishing to join the consists of developing training to ensure the international pharmacovigilance community (Olsson knowledge and expertise of the health profession- 1998). This results from collaborative work involving als involved in PV. This includes online and live many countries, an extraordinary number of health training initiatives covering various topics, from PV professionals, and even citizens. But to reach this basics to the analysis of signals (UMC 2022b). point of maturity has taken more than five decades. • Research and development: The periodical analysis The 10 founding members of the WHO-PIDM in 1968 of the database to identify safety signals is one of were Australia, Canada, Czechoslovakia, the Federal the most important objectives of PV. Some of these Republic of Germany, Ireland, the Netherlands, New research activities lead to publications in scientific Zealand, Sweden, the United Kingdom, and the journals; most of which are collected in the UMC United States. As of June 2022, the WHO-PIDM is a PV library.3 Global Collaboration Patient Safety Network consti- • International harmonization: The role of interna- tuted by 152 full member economies and 21 associated tional harmonization in pharmacovigilance is highly members; this means that PIDM is an initiative relevant because the WHO program c ­ ontributes to covering about 99 percent of the world’s population.4 the development of common standards and meth- The full and associate members belonging to the odologies in the area of medicines safety monitoring WHO-PIDM can be conferred in the WHO webpage.5 chiefly through the following (Olsson 1998): Some overseas territories may be covered by another – Developing definitions of words commonly used full member or benefit from the consolidated PV in pharmacovigilance system of a neighboring country. For example, in the – Organizing annual meetings of representatives case of Gibraltar, reports are received and analyzed of national centers in collaboration with WHO by the UK’s Medicines and Healthcare products headquarters, Geneva Regulatory Agency.6 In the case of Liechtenstein, that – Maintaining tools commonly used in drug safety country has an agreement with the Swiss PV system activities (for instance, the WHOART and the (VigiServe Foundation 2020). Box 2 presents the WHO Drug Dictionary, tools for the recording of requirements for joining the network. drug safety information) – Closely collaborating with other organizations involved in pharmacovigilance (such as the 4   ee the website of the WHO Programme for International Drug S International Society of Pharmacoepidemiology, Monitoring, at https://who-umc.org/about-the-who-programme- for-international-drug-monitoring/. the International Society of Pharmacovigilance, 5   ee https://www.who.int/teams/regulation-prequalification/ S regulation-and-safety/pharmacovigilance/health-professionals- info/pidm. 3  S  ee “Discover Scientific Publications on Pharmacovigilance,” 6  S  ee the website of the UK Medicines and Healthcare products Uppsala Monitoring Center, Uppsala, Sweden, https://who-umc. Regulatory Agency, at https://www.gov.uk/government/organisations/ org/publications-library/research/. medicines-and-healthcare-products-regulatory-agency. 7 Safety Monitoring of Medicines and Vaccines: A Situation Analysis Box 2 Requirements to Become a Full Member of the WHO-PIDM Network Participation in the WHO-PIDM network is voluntary and depends on the choice of each country. But, once it has decided to become involved in the international safety surveillance network, a government must officially express its interest and apply to the UMC. The ministries of health of member countries are required to establish a pharmacovigilance center responsible for the safety of medicines and maintain contact with the WHO in this specific field. Additionally, to ensure that the international data are as up-to-date as possible, member countries are asked to send reports of suspected adverse reactions to the UMC at least every quarter, preferably more frequently. The reports must be submitted in a specific, compatible format, with attention to both the quality and completeness of the data (UMC 2021b). Once countries show that they are ready to fulfill these requirements, they can become full WHO-PIDM members. If a given country is interested in developing PV activities, it may be named an associate member until it is ready to become a full member. Each country participating in the WHO program appoints a national center. This center is responsible for collecting spontaneously reported suspicions of ADRs. These case reports originate mostly from health professionals; in some countries, citizens may also contribute reports. Additionally, marketing authorization holders must report any suspected adverse event associated with their products and occurring in their country. Then, the national centers regularly transform these case reports into a specific WHO format and periodically submit them to the UMC. At the UMC, reports are checked for technical accuracy and entered into the WHO database (Olsson 1998). The WHO supports countries in promoting 1.4. VigiBase: sustainable monitoring systems under the PIDM. The WHO’s regional offices support program the global PV database implementing in low- and middle-income countries Collecting all the information delivered by more than to respond to the needs of these economies, while 150 countries requires a robust database. So, in 1978, considering intended state-of-the-art pharmacovig- an initial database at WHO headquarters in Geneva ilance initiatives (Olsson et al. 2010). Issues related was moved to the UMC. This became VigiBase. to drug use and adverse event profiles can vary VigiBase is the largest database of its kind globally. It from one country to another because of differences contains records submitted by member countries of across manufacturing processes, local therapeutic the WHO-PIDM dating back to 1968 on the reported practices, and the population’s genetic factors. Every potential side effects of medicinal products. Until country should therefore develop its own national about a decade ago, the expansion of VigiBase was pharmacovigilance system (Khalili et al. 2020; relatively slow. But an increasing awareness of the Pirmohamed et al. 2007). importance of global pharmacovigilance—reflected in changes to national and regional laws, regulations, and practice—has led to much higher levels of 1. The PIDM: A Global System 8 Figure 3  Regional Distribution of VigiBase Reports European Union 24% Asia 20% Oceania 3% Latin America 2% Africa 1% United States 50% Source: Based on the analysis of Watson et al. 2019. reporting and sharing data. In September 2021, the According to a September 2021 report (UMC 2021c), number of reports in VigiBase passed 28 million the contributions to VigiBase were dominated by (UMC 2021c). reports from the United States (which accounted for 45 percent of the data). The European Union con- An analysis of the more than three million ADR tributed another 20 percent. However, the share of reports from 96 countries added to VigiBase from reports from Asia rose appreciably: China, India, and 2000 to 2009 shows that approximately 85 percent the Republic of Korea showed larger shares among were provided by high-income countries, primarily the total and in annual contributions. and Australia, Canada, France, Germany, the United Kingdom, and the United States. Reports from Other sections of this report describe various case upper-middle-income and lower-middle-income studies covering PV in the Caribbean, the European countries constituted 7 percent and 8 percent, Union, Brazil, Ghana, India, Korea, Spain, and the respectively, of all reports, and fewer than 1 percent United States. So, this situation analysis is a descrip- of the reports were supplied by low-income countries tive review focusing on the development and current (Aagaard et al. 2012). status of PV in lower-middle-income economies and various regions: Africa, Asia, Latin America, and the An analysis of the ADRs on men and women Middle East. collected within VigiBase up to January 2018 included more than 15 million reports from the 131 member countries of the WHO-PIDM at that time (Watson et al. 2019). Figure 3 shows the regional distribution of these reports. 9 Safety Monitoring of Medicines and Vaccines: A Situation Analysis Pharmacovigilance 2.  reports, leading to more rigorous decision-making in pharmacovigilance. In addition, various indicators systems in practice are used to assess the performance and maturity of country PV programs. Utilizing such measurement tools allows countries to benchmark and compare their performance with counterpart nations and enables quantification of the impact of future public health interventions through policy enhancements to ensure the safety of pharmaceutical products on the market (Qato 2018). Two commonly used and well-tested indicators were Globally, over 150 countries have a fully operational included in the document “WHO Pharmacovigilance PV system. The history, characteristics, challenges, Indicators: A Practical Manual for the Assessment and outcomes of each of these systems are different. of Pharmacovigilance Systems.” (WHO 2015) and The first part of this section (2.1) explains how we the document “Indicator-Based Pharmacovigilance can evaluate a PV system and what we have learned Assessment Tool: Manual for Conducting from establishing PV systems. Section 2.2 then Assessments in Developing Countries” (SPS 2009). summarizes the findings of a published overview of PV in 55 countries and describes different regional networks to improve the surveillance of medicines 2.1.1. Maturity of the WHO-PIDM network safety. Despite the differences among national PV PV in countries is dynamic, evolves, and improves systems and the variations in the time elapsed since with time. The results obtained by a PV center thus the incorporation of the systems into the WHO-PIDM, not only depend on the actual number of reports high-income countries generally have more mature received, but also on the reporting rate per million PV systems because of the resources allocated by inhabitants, the amount of time the local PV system and the commitment of governments, the related is operating, the number of specialized health supranational structures that support the PV work professionals working in it, the turnover of the staff, in these countries, and a long history of monitoring and the available funding to deploy the PV program. medicine safety. This is the case of most European The year each country undertook PV activities serves countries, where the European Medicines Agency is as an indication of the maturity of the local system. harmonizing and supporting the efforts of country Examples demonstrate this heterogeneity and the members. Additionally, their results and achieve- associated contributing factors. ments are well known and their safety decisions have been highly publicized. The analysis of the situation in lower-middle-income countries offers a The example of East Africa: Ethiopia, Kenya, marked contrast that requires additional local and Rwanda, and Tanzania international support to build the PV capacity as an Abbie Barry and her team conducted a survey to integrated component of a health system. assess the functionality and identify the strengths and limitations of the national pharmacovigilance systems in Ethiopia, Kenya, Rwanda, and Tanzania 2.1. Evaluation of country (Barry et al. 2021). pharmacovigilance systems Ethiopia, Kenya, Rwanda, and Tanzania are all Evaluating a PV system facilitates actions to members of the PIDM. Tanzania (Tanzania Medicines overcome the deficiencies that have been identified and Medical Devices Authority) was the first to join and improve the quantity and quality of ADR the program, in 1993, followed by Ethiopia (Ethiopian 2. Pharmacovigilance systems in practice 10 Box 3 Summary Survey Findings: Four East African Countries • The national pharmacovigilance programs of Ethiopia, Kenya, Rwanda, and Tanzania were well supported by legal instruments and guidelines. • New regulations or guidelines aiming to converge with international pharmacovigilance standards are currently being introduced in all four countries. • Although the local PV institutions enjoy legal support and have established pharmacovigilance systems and structures, limited stakeholder involvement and engagement in the pharmacovigilance systems are manifested in low reporting rates. • In all four countries, procedures for data collection and management, signal analysis, and decision-making have been instituted or are being introduced. However, at the time of the assessment, the pharmacovigilance systems did not have sufficient capacity systematically to identify new problems among pharmaceutical products occurring in local health care delivery systems. Source: Barry et al. 2021. Food and Drugs Authority) in 2008. Kenya (Pharmacy Thus, despite the differences in the duration of and Poisons Board) and Rwanda (Ministry of Health) operations (since 1993 in Tanzania and since 2008 or joined in 2010 and 2013, respectively. later among the others), Barry et all (2021) still find that these PV systems are not yet at full capacity. The survey was based on the East African Community Harmonized Pharmacovigilance Indicators tool, As a useful recap, tables 1 and 2 describe the national which is derived from the WHO p ­ harmacovigilance systems, structures, stakeholder coordination, signal indicators and the Indicator-Based Pharmacovigilance generation, and data management in the four East Assessment Tool (SPS 2009). The main results are African countries included in the surveillance. summarized in box 3. 11 Safety Monitoring of Medicines and Vaccines: A Situation Analysis Table 1  PV Systems and Coordination, Ethiopia, Kenya, Rwanda, and Tanzania Existence of a Communication source of data plan to on consumption disseminate Defined annual and/or Web- pharma- budget for prescription of Pre-service In- service based covigilance Toll- free Country pharmacovigilance medicines training training training information number Website Ethiopia         Kenya      a   Rwanda         Tanzania          present,  missing/not available, NMRA National Medicines Regulatory Authority, PPB Pharmacy and Poisons Board a No specific plan for pharmacovigilance; communication plan available for the NMRA (PPB), but not specific to pharmacovigilance Source: Barry et al. 2021. Table 2  Signal Detection and Data Management in East Africa Existence of a Existence of Existence of standard Existence of national database for standard adverse adverse event electronic adverse Process for collection, pharmacovigilance event reporting reporting form for the event reporting recording, and analysis Country information form public system of ADR reports Ethiopia      Kenya      Rwanda a     Tanzania       present,  missing/not available, ADR adverse drug reaction a Database was not in use Source: Barry et al. 2021. Vietnam: ups and downs before International Development Cooperation Agency. system consolidation In 1999, Vietnam became the 98th member of the Nguyen et al. (2018) have published an overview WHO-PIDM. of the development and consolidation of PV in This is what happened soon after that milestone: Vietnam. The experience of Vietnam offers an example of the ups and downs in the dynamics • Unexpectedly, in 2004, soon after the Swedish of some national PV centers and also of one way support ended, PV activities decreased significantly, maturity can be reached. and all ADR reports were forwarded to the Drug Administration of Vietnam. • From 2004 to 2009, although the drug administra- First steps tion strived to maintain basic PV activities, ADR In 1994, the country launched its first ADR monitoring reporting resulted in no connection or feedback to center, an experimental center under the National reporters or health care units, and the drug admin- Institute for Drug Quality Control undertaken with istration faced many difficulties in database control financial and technical support from the Swedish 2. Pharmacovigilance systems in practice 12 and management, especially when the number of in reporting ADRs. An interactive two-way mech- reports increased. anism between the center and health care units • In March 2009, the Ministry of Health launched has been created to enhance the quality of the the university-based National Drug Information pharmacovigilance process, from signal detection and Adverse Drug Reaction Monitoring Center to risk management. in a significant step toward catching up with international trends (Ministry of Health decision Initial achievements 991/QDBYT). The center is under the management The analysis supporting this review has quantified of Hanoi University of Pharmacy and under the some achievements in Vietnam that may promote direction of the Ministry of Health. an understanding of what may be expected from an • The center began operations six months later as an appropriate investment in PV. important milestone, creating new opportunities to develop drug safety surveillance. In addition, the • Within seven years of the establishment of the decentralization of pharmacovigilance activities national information and monitoring center, was approved, and the creation of three regional the quality and the quantity of ADR reporting in pharmacovigilance centers was planned in the Vietnam had increased considerably. From 2010 north, middle, and south of the country (see Prime to 2016, the center officially received 40,031 ADR Minister 2006). reports from various sources (health care units, • However, by March 2011, only one regional center public health care programs, and marketing had been established (at Cho Ray hospital, Ho Chi authorization holders). Minh City). By 2017, only two centers had collected • The number of reports has risen rapidly. drug safety information across the entire country particular, reports received between 2014 and In ­ and assisted the drug administration in drug 2017 account for more than 70 percent of the total regulation activities. reports received since 2009. This can be explained • The Pharmacy Act (2005), which supported by the positive attitudes, knowledge, and accep- PV activities, was strengthened by the revised tance of pharmacovigilance among health care Pharmacy Act (April 2016), which addressed the professionals. In terms of quality, the completeness specific responsibilities of the various stakeholders score for reports from health care professionals in in the PV system. 2010–14 was relatively better than the international average score. The National Drug Information and Adverse Drug • Between 2010 and 2015, the Ministry of Health Reaction Monitoring Center is an independent issued several legal documents related to center that has benefited from the well-educated pharmacovigilance: the National Guideline human resources and research capacities of Hanoi on Pharmacovigilance, specific guidance on University of Pharmacy and from close coordination reporting ADRs in health care facilities, and a with the drug regulatory authority in managing series of technical guidelines on ADR (Trâ `n 2017). all PV activities. The center receives national and Figure 2 depicts the structure resulting from international support from the Global Fund to Fight these actions. AIDS, Tuberculosis, and Malaria and benefits from increased participation from clinical pharmacists 13 Safety Monitoring of Medicines and Vaccines: A Situation Analysis Figure 2  Structure of the Pharmacovigilance System, Vietnam International WHO-UMC Centre Ministry of Health Risk management Vietnamese Drug Administration Risk communication National Assessment Risk evaluation National DI&ADR Centre Signal detection Regulatory activities Database management Centralizing Regional Regional DI& regional database Reporting ADR Centre management Reporting Healthcare Manufacturers Drug safety notification Units PHP MAH Quality defect Adverse Drug Event Communities Medication Error Patients FEEDBACK REPORT Source: Nguyen et al. 2018. Note: DI&ADR = drug information and adverse drug reaction monitoring. PHP = public health care programs. MAH = marketing authorization holder. WHO-UMC = World Health Organization–Uppsala Monitoring Center. Challenges burden of work in health care centers and differ- Identifying challenges helps in planning improve- ences in knowledge, attitude, and practice had ments. The main obstacle faced by the Vietnamese led to underreporting. Pharmacovigilance might PV system is the remarkable variation in the quality still be unfamiliar to most health care workers and quantity of reports across regions, hospitals, despite the official National Pharmacovigilance and subgroups of health care professionals (that is, Guideline promulgated in June 2015. physicians, pharmacists, nurses). • Reporting activities were considered routine practice in HIV/AIDS, tuberculosis, and • Until 2016, only 805 of 13,617 health establish- malaria programs. Still, this integration was ments (fewer than 6 percent) had participated in difficult to maintain because of a lack of direct reporting activities. The imbalance was worse in government support and clear institutional remote areas because of a lack of highly quali- instructions. fied health care professionals. Furthermore, the 2. Pharmacovigilance systems in practice 14 • The Drug Administration of Vietnam registers and fear of punishment and criticism (Afifi et al. 2014; vaccines and herbal medicines, but the super- Mirbaha et al. 2015). The system’s current status and vision of vaccines in the community is mainly efficiency are unknown, and there is little adequate performed through the Department of Preventive systematic data on the effectiveness and functional- Medicine (an administrative unit in the Ministry ity of the center. of Health), while the control of herbal medicines Khalili et al. (2020) analyze the WHO indicators on is under the Traditional Medicine Administration the country. They find that, despite the existence (also an administrative unit in the Ministry of a functioning PV structure and resource, policy, of Health). Lack of effective communication and regulatory framework, the performance and between these units has sometimes proven to achievements of the Iranian PV program require be a barrier to pharmacovigilance. Safety issues suitable and sustained improvement. However, related to vaccines may lead to rumors, possibly “the state of completeness and causality assessment damaging overall confidence in vaccination and of the reports was satisfactory, and the PVC [the dramatically affecting immunization coverage center] of Iran had appropriately utilized statistical and disease incidence. methods to help detect signals from the ADR reports” • Drug safety is the responsibility of the PV centers, (Khalili et al. 2020, 5). the Ministry of Health, and the community. Reporting by private pharmacies and patients • The status of structural indicators on Iran’s PV should be considered appropriate parts of the program demonstrated a relatively satisfactory pharmacovigilance system. Support and a clear commitment to improving medication safety strategy exercised by the national authority are and providing direction to enhance the needed to deal with this issue. system. • This program had a statutory budget and limited PV in Iran: the issue of underreporting human resources to function. • The absence of PV in the training curriculum Underreporting and low-quality reporting are major among health care professionals in Iran suggests limitations of PV systems because the method’s their lack of preparedness for career challenges in effectiveness requires trying to capture as many ADRs medicine safety issues. as possible by observers in primary care and hospital facilities. Underreporting is an issue in almost all Limited budgets and the lack of trained personnel PV systems, and this example in Iran highlights are two reasons for low performance in PV programs. the causes. However, it is a quite common problem, shown by The Pharmacovigilance Center of Iran launched Qato (2018), in the region that is also highlighted by activities under the supervision of the Iran Food Olsson and his colleagues in their classical analysis and Drug Administration in 1991. It then became a of PV in 55 lower-middle-income countries (Olsson full member of the WHO-PIDM in 1998. In the first 10 et al. 2010). Table 3 shows an example of the analysis years of center activity, the underreporting of ADRs of structural indicators to identify weak points in was a common drawback (Shalviri, Valadkhani, and a system. Dinarvand 2009). The center is supported by a national policy, trained staff, and a statutory budget. In 2017, the number of ADR reports was 15 per 100,000 population, and 262 signals were detected during the preceding five years (Khalili et al. 2020). The main causes of underreporting in Iran are lack of awareness of the existence of the national center and its functions, inadequate knowledge about reporting, 15 Safety Monitoring of Medicines and Vaccines: A Situation Analysis Table 3  Analysis of WHO Core Pharmacovigilance Structural Indicators, Iran Assessment Indicators Answers Description 1. Existence of a pharmacovigilance center, Yes Center for the registration and reporting of health department, or unit with a standard products’ safety and adverse effect, with non-standard accommodation accommodation (a small office space, the shortage in some basic office equipment and facilities required to receive, analyze and transmit ADR reports). 2. Existence of a statutory provision Yes • Guidelines for registration of ADR and medication (national policy, legislation) for errors reporting with the signature of the Minister of pharmacovigilance Health (available at: https://www.fda.gov.ir/en): as a mandatory policy in the Iranian FDA. • Legal commission vote on manufacturing and import of medicines in 2005. 3. Existence of a medicines regulatory authority or Yes Department of Assessment and Control on Prescribing agency and Use of Medicines and Health-related Products. 4. Existence of any regular financial provision Yes The annual budget for interventions and activities (eg, statutory budget) for the pharmacovigilance such as education about ADR reporting and center pharmacovigilance, holding workshops and training courses, implementing related projects, and empowering regional pharmacovigilance centers. 5. Existence of human resources to carry out its Yes There was a shortage of human resources functions properly for the pharmacovigilance (only 5 pharmacists and physicians). center 6. Existence of a standard ADR reporting form in Yes Yellow ADR form and online system for ADR and the setting medication error reporting: https://adr.ttac.ir 6a. The standard reporting form provides for No Only the Yellow ADR form is available, and all drug- reporting: suspected medication errors, suspected related problems are reported by this form. Moreover, counterfeit/ substandard medicines, therapeutic the general population could report ADR via website: ineffectiveness, suspected misuse, abuse of and/or https://adr.ttac.ir dependence on medicines, ADRs by the general public 7. Existence of a process in place for collection, Yes Reports of suspected ADRs submitted voluntarily to a recording, and analysis of ADR reports regional center or the national regulatory authority by healthcare professionals or patients via completing the yellow card, e-mail, telephone, fax, or online website. Finally, all reports are assessed and analyzed by the staff of PVC. 8. Incorporation of pharmacovigilance into the No Pharmacovigilance has not been incorporated into national curriculum of the various healthcare the national curriculum of the various healthcare professions (medical doctors, dentists, professions. pharmacists, nurses or midwives, and others) 9. Existence of a newsletter, information bulletin Yes Dissemination of information via and/or website as a tool for dissemination of https://www.fda.gov.ir/en information on pharmacovigilance 10. Existence of a national ADR or Yes Predominantly physicians and pharmacists serving as pharmacovigilance advisory committee or an members of this committee and have 5 main members. expert committee in the setting capable of They hold their meetings occasionally. providing advice on medicine safety Source: Khalili et al. 2020. Abbreviations: WHO, World Health Organization; ADR, adverse drug reaction; MoH, Ministry of Health; PVC, Pharmacovigilance Center. 2. Pharmacovigilance systems in practice 16 The key messages of their analysis of the PV program including participation in educational events and in Iran include a few ideas that seem to be quite scientific meetings. common in various lower-middle-income countries (Khalili et al. 2020): 2.1.2. Establishing PV systems: • Usually, PV programs need suitable and sustained what we have learned improvement despite a basic PV structure, resource, Sten Olsson and his team from the UMC published policy, and regulatory framework. a review on PV in economies with limited resources • In the example of Iran, the system requires countries after five years of activity (Olsson, Pal, and the higher prioritization of PV in public health Dodoo 2015) (box 4). One key message is that “every programs and a greater allocation of resources country is unique, and there is no general recipe on to bolster the system and achieve the country’s how to establish a PV system in a country” (Olsson, objectives in safety monitoring. Pal, and Dodoo 2015, 450). Nonetheless, the review • The suitable and sustained promotion of a highlights common features of the development of PV program can be facilitated by improved PV that are important in planning actions for the ­ collaboration with professional organizations, establishment or strengthening of programs. Box 4 Common Features of PV Development in Limited-Resource Economies • PV is often initiated by a few dedicated health care professionals who observe treatment- related harm in patients. They take it upon themselves to introduce a reporting and learning system in their environment to minimize the recurrence of such harms in the future. Such individuals may be based in clinical or academic settings and can often convince decision-makers to organize the systematic collection of observations of suspected medicine-related harm. • PV activities invariably start with the spontaneous reporting of individual case safety reports because this is the least resource-demanding method that may be initiated without major investment. • Country authorities often apply for formal training in the PV methodology during the early implementation phase, such as the training offered by the WHO-PIDM through network collaborating centers, professional associations such as the International Society of Pharmacovigilance, or a limited number of academic institutions. An alternative way of learning PV basics is through internships in well-established PV centers. • Some country authorities only start PV as part of a regional or subregional initiative involving economic communities, such as the Economic Community of West African States or the East African Community. In these settings, one or two country actors take the lead in establishing PV centers, which are often used by the others for contacts, learning, and capacity building. Source: Olsson, Pal, and Dodoo 2015. 17 Safety Monitoring of Medicines and Vaccines: A Situation Analysis Olsson Pal, and Dodoo (2015) also reflect on bud- the use of medicines and vaccines, thereby preventing getary aspects and the difficulties of rendering the or reducing ADRs among others. principal PV activities sustainable. Although country The next sections of the Situation Analysis detail how authorities may benefit from regulatory provisions in PV is evolving at the regional level. establishing PV systems, only when these provisions are matched with a regular and sustainable budget can real action and long-term planning be achieved. 2.2. Overview: pharmacovigilance Good examples exist in countries such as China and in 55 countries India. In India, initiatives have been taken by various academic and research institutions and the regula- Perhaps the most comprehensive assessment of the tory authority to establish PV in the country since performance of national PV systems was a classical the mid-1980s. However, only when the government study conducted by Sten Olsson and his UMC team created a budgeted staff position for PV in 2010 was (Olsson et al. 2010). Although the panorama has the PV system effectively established in the whole changed a lot in the last decade, examining the country (Biswas 2013; also, see below). In China, the results of the study is useful. government invested heavily in PV training in the The aims of the survey were as follows: provinces, leading to a rapid increase in the submis- sion of individual case safety reports to the National • Assess current and planned pharmacovigilance Coordinating Center (Zhang et al. 2014). activities • Identify gaps and the most urgent PV priorities at In summary, the WHO, through UMC activities, has the national and international levels and define a major role in harmonizing the safety monitoring the elements of a sustainable global pharmacovigi- programs of the 152 full members, defining standards, lance strategy training and updating the network of health professionals, taking advantage of the information Fifty-five countries completed the questionnaire; almost uploaded to the common database, contributing to half the PV centers were established during the 1990s, the signal detection process, and making collabora- and the other half were set up later. These PV centers tors aware of new safety concerns. were affiliated with their Drug Regulatory Agency (69 percent), with the Ministry of Health (20 percent), Despite this harmonizing role, the WHO-PIDM is the or with a university or scientific body (9 percent) in a fruit of the contributions of 152 countries with different high proportion of these countries (n = 42). characteristics, heterogeneous human and financial capacity, and diverse experiences, backgrounds and Table 4 illustrates the consequences of PV activities interests in (1) detecting and reporting suspected ADRs, in these countries, measured as the number of (2) analyzing the received reports to contribute identi- regulatory actions that are the consequence of the fying signals, and (3) using the country PV activities to safety monitoring results. disseminate information on safety issues and improve Table 4  Regulatory Actions Based on PV Activities, 2007 No. of times action taken No. of countries once or three or Action taken taking action twice more times not stated Safety warnings 24 13 9 2 Changes of product information 21 8 7 6 Suspension/withdrawal of drug product licence 20 7 7 6 None of the above 15 Source: Olsson et al. 2010. 2. Pharmacovigilance systems in practice 18 Figure 4  Additional Problems Reported through Pharmacovigilance Centers 50 40 # of Countries 30 20 10 0 Unexpected lack Quality Medication Dependence/ Drug of efficacy defects errors abuse poisoning Source: Olsson et al. 2010. Many PV centers were also involved in other The results of that survey, conducted with the activities, such as drug information (63 percent), participation of the UMC, helped identify strengths promoting patient safety (52 percent), fostering the and weaknesses and plan future actions. rational use of drugs (46 percent), and disseminat- “A pharmacovigilance strategy for low- and mid- ing poison ­ information (15 percent). In addition, dle-income countries needs to ensure reasonable seven countries had sentinel sites to monitor HIV/ economies of scope, that is, it needs to help build AIDS patients and other special groups. Figure 4 a system that can serve the purpose of multiple illustrates how some of these PV centers contribute health conditions using some criteria to prioritize to detecting other medication-­ related problems questions that meet a country’s specific needs. beyond the side effects of treatments, especially “It needs to identify and implement feasible lack of efficacy, quality defects, or medication errors. systems, governance, infrastructures, human Few countries (23 of 55) have any budget allocated for resource, training and capacity building, pharmacovigilance. sustainable methodologies, and innovations; a key component will be the dissemination of PV activities were sponsored by public health medicines safety information to policy makers programs (44 percent), the Global Fund to Fight and regulators and knowledge sharing through AIDS, Tuberculosis, and Malaria (36 percent), high-quality informatics and learning tools. In its universities (26 percent), poison centers (21 percent), narrower objective, a pharmacovigilance strategy Management Sciences for Health (18 percent), and should enable better use of adverse events the rational use of drugs networks (15 percent). data, thereby promoting a more evidence-based Lack of training and funding were mentioned as approach to policy making and treatment guide- major challenges to pharmacovigilance in many lines. Capturing comprehensive data as a source countries. of learning and the basis for preventive action is a cornerstone of improving patient safety. “While all but seven of the responding countries indicated the presence of a designated pharmacovigi- “Thus, in its broader remit, the pharmacovigilance lance program, considerable variations and gaps exist strategy needs to contribute to the coordination in the pharmacovigilance infrastructure, resources, of an extended role for population-based phar- and methodologies.” macovigilance in improving patient care through —Olsson et al. 2010 actionable learning.” —Olsson et al. 2010. 19 Safety Monitoring of Medicines and Vaccines: A Situation Analysis 2.3. Regional networks: Middle East. It also details the involvement of the African Medicines Regulatory Harmonization (AMRH) a strategic support Initiative and Pan American Network for Drug The commitments of countries and the support of Regulatory Harmonization (PANDRH) initiatives. the WHO UMC, other agencies, and funding stake- holders contribute to the strengthening of national 2.3.1. African economies PV systems. But another factor has an important role: The involvement of African countries in PV was the regional support by supranational organizations. first analyzed extensively in 2016. The first factor Regional involvement has various characteristics to be considered is the duration of the PIDM and is driven by different organizations, although the engagement of countries. Following the start of aims are similar: harmonization, training support, the WHO-PIDM by 10 member countries in 1968, and regional analysis of specific signals. it took another 24 years for the first two African This section reviews PV activities in Africa, the countries to join, in 1992, by which time the number Association of Southeast Asian Nations (ASEAN), of member ­ countries in the PIDM had grown to 33 Latin America and the Caribbean, and the (Ampadu et al. 2016) (box 5). Box 5 The Steady Growth in African PIDM Members Since 2000 With increased access to medicines, the need to monitor medicines safety has become obvious. • The Global Fund to Fight AIDS, Tuberculosis, and Malaria, for instance, insisted on the safety monitoring of all its products as a key requirement for grant recipients as early as 2002; however, this was only partially adhered to. As a result, the fund included a mandatory field relating to PV on all grant application forms in 2010. • WHO headquarters, the UMC, and the WHO Collaborating Center for PV in Rabat, Morocco, undertook a focused approach to building PV capacity in Africa. As a result, UMC alone trained 100 Africans in its annual PV course beginning in 1993. • The United States Agency for International Development, working especially with Management Sciences for Health, also supported PV activities in Africa. • However, the most direct impact on countries joining the PIDM was the establishment of an African hub to lead PV development on the continent. In June 2009, the UMC established an African office (UMC–Africa) with dedicated funding, while the WHO designated the University of Ghana (October 2009) as a WHO Collaborating Center for Advocacy and Training in Pharmacovigilance, working hand-in-hand with UMC–Africa. The African hub—the WHO collaborating center and UMC–Africa—undertook advocacy, country visits, and training and capacity building in several countries, culminating in most of them becoming full PIDM members. The rapid increase in the number of African countries joining the PIDM beginning in 2009 was due mainly to this focused continental effort. Source: Ampadu et al. 2016. 2. Pharmacovigilance systems in practice 20 PV was not a priority in Africa before 2000 for several capacity. Furthermore, only 4 countries among these reasons, including poor legislation on medicines 46 countries (9 percent) had pharmacovigilance regulation, lack of access to medicines and health systems with the capacity to detect, evaluate, and commodities, weak and uncoordinated supply prevent safety issues, indicating the limited capaci- chains for medical products, lack of knowledge and ties of these countries to monitor medicines safety ­ awareness of PV, and lack of financial, human, and (Barry et al. 2021). technical resources for PV. But the panorama changed The situation started improving with the support a bit, together with a concerted effort to increase of the UMC and other stakeholders. An indicator access to medicines in Africa to manage priority of this change is the reports originating in communicable diseases, such as HIV/AIDS, malaria, the new African member states that started and tuberculosis. In addition, the emerging middle to be regularly uploaded to VigiBase. All these class can pay out of pocket for medical care, espe- reports were uploaded to VigiBase and started cially for noncommunicable disease. Both changes contributing to the global database. Though the shifted the national development agenda toward report submission rate was lower in Africa than the safe and cost-effective use of these products and in other regions, the findings showed that the the establishment of surveillance systems for safety, reports mirrored the reality of the population, the effectiveness, and quality (Ampadu et al. 2016). epidemiology, the interests of the various donors In 2011, of the 46 countries in Sub-Saharan Africa, and stakeholders, and the characteristics of the 25 (54 percent) had minimal or no pharmacovigilance health care system (box 6). Box 6 What Had African Countries Reported to VigiBase by 2016? • The number of African countries in the PIDM was 35. • The cumulative number of reports submitted to VigiBase by these countries was 103,499 (0.88 percent of global reports). • The main class of suspected medicines in these reports were medicines used in the treatment of HIV infections (28.6 percent), the combinations of antibiotics sulfonamides + trimethoprim (almost 3.0 percent), and angiotensin-converting enzyme inhibitors used in hypertension (2.4 percent). These medicines were completely different from the main product classes implicated in the reports received from the rest of the world. • The 18–44 age-group dominated in the reports from Africa, while the 45–64 age-group dominated in the rest of the world. Source: Ampadu et al. 2016. 21 Safety Monitoring of Medicines and Vaccines: A Situation Analysis Harmonization of pharmacovigilance One of the five key tenets of this legislative frame- systems in Africa work is the harmonization of the requirements Since 2009, the AMRH initiative has served as a foun- and processes for ensuring safe medicines in Africa dation for the African Medicines Agency. “The AMRH (AUDA-NEPAD and PATH 2016b).7 This model law initiative was established to strengthen medicines was developed and promoted by the Africa Union regulation in Africa by promoting the effectiveness, Development Agency–New Partnership for Africa’s efficiency, transparency, and collaboration of regula- Development (Mwangi 2016). tory mechanisms in these settings” (Kiguba, Olsson, • In 2019, the African Union Assembly adopted the and Waitt 2021). African Medicines Agency treaty, which each member state is expected to sign and then enact In 2009, Ghana began to host the WHO a corresponding national law to implement the Collaborating Center for Advocacy and Training in treaty. Rwanda was the first African Union member Pharmacovigilance, promoting PV uptake by minis- state to sign the treaty, in 2019, and 16 other tries of health and other stakeholders across Africa member states subsequently signed (Ncube, Dube, (Isah et al. 2012). This had a major impact on the and Ward 2021). development of PV in Africa. The training was pro- • Only five member states had ratified the vided in English by people with a local perspective, African Medicines Agency treaty as of mid-2020 but it excluded francophone countries in Africa. In (AMRH 2020). 2011, Morocco began hosting the WHO Collaborating Center for Strengthening Pharmacovigilance Capacity in the Eastern Mediterranean, Francophone, and Arab 2.3.2. Asia and ASEAN countries States. This has enabled numerous patient safe- The ASEAN members are Brunei Darussalam, ty-related research and training activities, including Cambodia, Indonesia, Lao People’s Democratic the PV of medication errors, herbal medicines, and Republic, Malaysia, Myanmar, the Philippines, vaccines (Kiguba, Olsson, and Waitt 2021). Singapore, Thailand, and Vietnam. ASEAN covers a geographical area with more than The current panorama 600 million inhabitants. The comprehensive review conducted by Kibuga There is no integrated action in the region to and his team was published in 2021; so it depicts the harmonize and support the strengthening of present panorama (Kiguba, Olsson, and Waitt 2021). national PV systems. However, initial steps on • In Africa, 54 of the 55 countries have established pharmaceutical harmonization have already been national medicines regulatory authorities or taken, together with ASEAN health care integration administrative units that perform all or some of and the activities of the Pharmaceutical Product the relevant functions, albeit with differing growth, Working Group. According to some experts, expertise, and maturity levels. Of these authorities, ­ pharmacovigilance systems equivalent to the system 87 percent lack functional pharmacovigilance of the European Medicines Agency will emerge in systems (Ndomondo-Sigonda et al. 2017). Asia in coming years if there is strong leadership • None of the African authorities has reached from ­stakeholders, including governments and WHO Global Benchmarking Tool maturity level 4. ­pharmaceutical companies.8 In Sub-Saharan Africa, only the national medicines regulatory authorities in Ghana and Tanzania are at maturity level 3, which identifies stable and 7  A  lso see “AU Model Law on Medical Products Regulation,” New well-functioning systems (WHO 2022). Partnership for Africa’s Development, Midrand, Johannesburg, • In 2016, the African Union Model Law on Medical South Africa, https://www.nepad.org/publication/au-model-law- medical-products-regulation. Products Regulation was endorsed to promote 8  “ ASEAN Countries Will Lead Asian Pharmacovigilance medicines regulatory harmonization and collab- Harmonisation,” interview with Suzette H. Lazo, Pharma IQ, https:// oration in Africa (AUDA-NEPAD and PATH 2016a). www.pharma-iq.com/regulatorylegal/interviews/asean-countries- will-lead-asian-pharmacovigilance. 2. Pharmacovigilance systems in practice 22 A survey was conducted to review PV development facing the challenge of receiving a huge quantity and the status of signal detection tools in the ASEAN of ADR reports beyond evaluator capabilities in countries. It also compared the findings in these individual review (Lundin 2016). countries against findings among more established Pharmacovigilance in Asian countries includes agencies in Australia, Canada, Japan, Korea, success stories. Other chapters describe in detail the Switzerland, the United Kingdom, and the United case studies of India and Korea. States (Chan, Ang, and Li 2017). Nine of the 10 ASEAN countries have conducted 2.3.3. The Middle East PV studies. Myanmar had not launched PV when Some initiatives, such as the Gulf Health Council or the study was conducted, and it was not included. the Gulf Central Committee for Drug Registration, However, all countries had a PV framework that can be the starting point for pharmaceutical shared broad similarities in general structure. As a ­ harmonization in the Middle East and coordinated result, the following results were found: actions in PV. • Regarding official structure, 15 countries, except Lao The situation of PV in the region can be analyzed PDR, had a designated center, department, or unit through a few descriptive studies. specifically dedicated to PV activities. While Lao PDR does not have a dedicated center, PV activities are subsumed as part of drug regulatory activities. PV in the Middle East • Most countries (except Cambodia and Lao PDR) The UMC Assessment of Country Pharmacovigilance mandated ADR reporting by companies. Reporting Situation questionnaire was adapted, translated into by health care professionals has been mandated Arabic, and administered to the heads of relevant only by some countries in Asia and elsewhere, centers responsible for medication safety in 13 Arabic- namely, Indonesia, Japan, Korea, Malaysia, the speaking Middle Eastern countries (Wilbur 2013). Philippines, Switzerland, and Vietnam. Doctors The main results are as follows: and pharmacists are required to report ADRs in • Six countries had implemented formal national Switzerland, for comparison. pharmacovigilance programs (the Arab Republic • As a basic framework, all countries monitored of Egypt, Iraq, Jordan, Oman, Saudi Arabia, and the the safety profile of pharmaceuticals, including United Arab Emirates). Five (Bahrain, Kuwait, Qatar, biologics and vaccines. In addition, most extended West Bank and Gaza, and Yemen) reported no the safety monitoring to other health products, active program or designated center. such as cosmetics, health supplements, traditional • Most were funded by the government, but claimed and herbal medicines, and medical devices. This that staff resources were constrained, ranging from indicates that all countries are fully aware of the 2 to 10 people. gatekeeper role of ADR monitoring in public health. • Among the programs, 67 percent facilitated the • Concerning the volume of ADR reporting, the submission of spontaneous ADRs to the center median of 47 ADR reports per year per million by email, but none directly through a web-based population in the nine ASEAN countries was lower platform. than the non-ASEAN countries and the rest of the • All used the information for drug regulatory countries in the WHO database. purposes, and five reported dissemination of safety • Regarding the capacity to analyze ADR data information to the public. effectively, all nine ASEAN countries and seven non-ASEAN countries had a system for handling Oman’s program is the oldest in the region, with over ADR reports. 15 years of experience in conducting postmarketing • However, some countries experienced constraints surveillance activities. The center in Saudi Arabia in human resources; so it was difficult to handle started operations in 2013 under the Saudi Food and a large number of signals. This was especially Drug Authority. It was the largest such body in the relevant in a country such as Singapore, which was region. Its formal mission included responsibility 23 Safety Monitoring of Medicines and Vaccines: A Situation Analysis to ensure the safety, quality, and efficacy of drugs provider awareness, and assist in the development by developing and enforcing an appropriate of pharmacovigilance systems still in their nascent ­regulatory system. stage” (Qato 2018, 210). It has been suggested that these two PV centers In most cases, countries that performed well in could serve as important resources for neighboring one domain performed well in other domains. governments and stakeholders wishing to establish This suggests the need to holistically address national systems, especially given that the human each country’s policy and programmatic gaps resources devoted to this task were relatively small based on available resources and infrastructure. in most countries. Additionally, the Gulf Central “Furthermore, while Egypt and Morocco performed Committee for Drug Registration was established very strongly in the survey, with Egypt achieving the with a stated mission to unify efforts through various maximum possible pharmacovigilance performance health initiatives, including providing safe and score, there is still much room for improvement” effective medications at reasonable prices in the Gulf (Qato 2018, 215). For example, the underreporting states (Wilbur 2013). of ADRs should be addressed. The results can be summarized as follows The Arab and Eastern Mediterranean region (Qato 2018): In 2015, Arab and Eastern Mediterranean countries contributed only 0.6 percent of the 2.1 million • More than three-quarters (17) of the 22 countries suspected case reports to VigiBase, reflecting general reported that a formal PV program or policy had conditions of low participation in the reporting of been instituted. However, of these 17 countries, only adverse drug events. about a third had a budget specifically earmarked for activities related to pharmacovigilance, A study describing the current state of PV systems and 75 percent had a workplace specifically in Arab and Eastern Mediterranean countries dedicated to pharmacovigilance activities and was conducted between May and September at least one full-time staff member involved in 2015 (Qato 2018). The study survey included more ­pharmacovigilance activities. countries than those previously analyzed, namely, • Only six countries (30 percent of the sample) had Mediterranean countries (Algeria, Lebanon, Libya, met the minimum requirements for a functional Morocco, and Tunisia), predominantly Islamic national pharmacovigilance system: Egypt, Jordan, countries in South Asia (Afghanistan and Pakistan, Morocco, Saudi Arabia, Sudan, and Tunisia. “Given as well as the Islamic Republic of Iran), and the the infrastructure required for pharmacovigilance African region (the Comoros, Djibouti, and Sudan) activities and the budget constraints within which (Wilbur 2013). Qato justifies the selection of these (most) countries in the sample operate, especially countries because, “although the Arab and EM concerning public health programming, this [Eastern Mediterranean] region is heterogeneous, and low performance on pharmacovigilance is not each country has a unique set of social, economic, surprising” (Qato 2018, 217). development, and geopolitical characteristics, there • In more than 70 percent of the countries with full- are shared linguistic, historical, and cultural traits time staff devoted to pharmacovigilance activities, that make a holistic account of the state of pharma- total staff members were fewer than seven. “This covigilance in the region a useful endeavor to inform situation reflects the triple challenges of lack of targeted future interventions” (Qato 2018, 211). human capital capacity, inadequate resources The findings suggested that there were “wide dis- devoted to drug safety efforts at the national level, parities in pharmacovigilance systems in the region, as well as the low prioritization of PV within the underscoring the need for a multistakeholder effort public health agenda of some countries in the in bolstering program development and the necessity Arab and EM [Eastern Mediterranean] region” to build collaboration regionally and internationally (Qato 2018, 218). to enhance capacity, improve public and health care 2. Pharmacovigilance systems in practice 24 • · Countries that have made considerable progress Alshammari et al. (2019) describe the situation of over the years and have comparatively more PV systems in Arab countries. The main message is human resources, such as Egypt, Saudi Arabia, that Arab countries in Asia have some advantages and Tunisia, have established PV centers dating over those in Africa because 50 percent of the former back to 1984 (Tunisia). They have made substantial are part of the Gulf Cooperation Council, indicating investments at the national level. In Saudi that most of them can utilize similar approaches in Arabia, this investment has included significant the majority of activities related to the health care ­ financial ­ backing from the Ministry of Health system, including pharmacovigilance. Participation (Aljadhey et al. 2015). in the Gulf Cooperation Council thus enables closer • Central to developing a robust PV system is the connections among these countries. However, one of presence of trained health professionals and the the strengths in Africa is that Morocco is partnering capacity to employ them. In several countries in with the WHO through the WHO Collaborating the region, there is a shortage of highly qualified Center to enhance and strengthen pharmacovigi- PV professionals. lance across the Eastern Mediterranean and among francophone and Arab countries. Figure 5  PV Survey Results, Arab and Eastern Mediterranean Region, 2015 50 45 42.7 12 11 40 Total Pharmacovigilance Score 12 9 35 11 7 7 30 8 7 9 5 17 17 5 14 25 12 11 13 9 6 14 20 10 11 7 11 7 4 11 7 15.1 15 4 8 12 10 19 19 19 19 19 19 17 15 15 15 14 14 13 5 5 12 10 1 7 2 5 5 4 2 0 AV co ud dan Su a Tu n sia an Pa an n n ia Le ya AV en n C tine os gh Iraq ar Jo D Pa SD or t Ye it E yp bi da ta Ira no a r +S UA b at or oc ist ge m m ni w ra kis - Eg Li s r ba Q G O om Ku an le G iA Al M Af Sa Structural Process Impact Source: Qato 2018. Note: The figure shows the total survey score on pharmacovigilance structural, process, and impact performance. n = 20 countries. 25 Safety Monitoring of Medicines and Vaccines: A Situation Analysis 2.3.4. Latin America and the Caribbean In Latin America, NRAs have substantially advanced The Pan American Health Organization (PAHO) the development of PV and postmarketing surveil- has published a comprehensive document on the lance systems in the past decade through PANDRH. regulatory system in the Americas (PAHO 2022). This Between 2008 and 2010, for example, the PANDRH document includes an overview of the development pharmacovigilance working group developed a set of and achievements of PV in the region. In addition, good PV practices for the Americas (PAHO 2011). the progression of many national PV systems in Since 2017, one of PANDRH's core activities has been the region toward maturity can be explained by the the establishment of two networks of focal points activities of the PANDRH. throughout the Americas to exchange PV and substan- dard and falsified information and conduct collabo- The role of the PANDRH in PV and rative projects. For example, NRAs in Brazil, Canada, postmarketing surveillance in the Americas Chile, Colombia, Costa Rica, Cuba, Mexico, Paraguay, Strengthening the regulatory system has been a and Peru have participated in joint evaluations of PV priority since the establishment of the PANDRH in documents, such as risk management plans and peri- 1998. PAHO member states work together to support odic safety update reports. These evaluations prioritize regulatory harmonization and convergence. They strategic products with gaps in their safety profiles and agreed in 2006 to the development of a qualification biologicals and molecules with specific critical risks. system coordinated by PAHO to help establish Postmarketing surveillance activities facilitated by the mechanisms for cooperation and recognition across PANDRH focal points include the rapid dissemination national regulatory agencies (NRAs) (PAHO 2020). of product safety alerts and investigations into clusters of cases in the region. Box 7 National Regulatory Authorities of Regional Reference in the Americas In the Americas, NRAr refers to national regulatory agencies (NRAs) that have been assessed by PAHO and found to be competent and efficient in the performance of the health regulation functions needed to guarantee the safety, efficacy, and quality of medicines. This grouping meets regularly in person or virtually to share strategic updates on challenges and important initiatives. PAHO recognizes eight NRArs in the Americas: • The National Administration of Drugs, Foods, and Medical Devices, Argentina • The Brazilian Health Regulatory Agency, Brazil • Health Canada, Canada • The Public Health Institute of Chile • The Colombia National Food and Drug Surveillance Institute, Colombia • The Center for State Control of Drugs and Medical Devices, Cuba • The Federal Commission for the Protection against Sanitary Risks, Mexico • The Food and Drug Administration, United States Together, these NRArs cover 82 percent of the population of the Americas. Source: PAHO 2022. 2. Pharmacovigilance systems in practice 26 Legal provisions surveillance. In addition, some NRArs have Legal provisions for PV of medicines, including vac- established programs to monitor specific medicines cines, exist in all Latin American national regulatory on which there are safety concerns (for instance, authorities of regional reference (NRAr) countries. clozapine and isotretinoin). NRArs also have proce- dures for systematically collecting and evaluating • NRArs are legally required to establish a reporting safety information reports through collaborative and monitoring system to collect adverse drug projects with public health programs for vaccines, event data in standardized terminology and to use tuberculosis, and malaria. this information to take regulatory action where appropriate. Between 2015 and 2017, the National Administration • In the case of serious adverse effects associated of Drugs, Foods, and Medical Devices (Argentina), the with vaccines, all NRAr countries have established Public Health Institute of Chile, and the Colombia procedures or norms for coordinating their National Food and Drug Surveillance Institute took investigation and subsequent action with national part in a proof-of-concept project as part of a global immunization programs, which is often perceived protocol that used sentinel hospitals to confirm the as a challenge in non-NRAr countries throughout magnitude of the associations between measles, the Americas (PAHO 2022). mumps, and rubella vaccines and idiopathic • All Latin American NRArs are based on legal thrombocytopenic purpura and aseptic meningitis provisions requiring marketing authorization (Bravo-Alcántara et al. 2018). holders to have a PV system to monitor product safety and report results to the NRAs. In all cases, National ADR reporting the NRAs have the authority to inspect the market- One take-home concept is that the Americas region is ing authorization holder. responsible for half the reports included in the WHO- Latin American NRArs use different approaches PIDM VigiBase. Still, the reports from Latin American to PV, including advanced strategies for gathering NRArs represent only a small share (under 2 percent) and assessing ADRs, such as targeted and active (figure 6). Figure 6  The Distribution of the Reports Included in the WHO-PIDM VigiBase USA/CANADA 49.30% Latin America NRAr 1.62% Americas 51.50% Rest of NRA in Americas 0.58% Rest of the world 48.50% Source: PAHO 2022. 27 Safety Monitoring of Medicines and Vaccines: A Situation Analysis Despite this small share: data to VigiFlow, the case report management system developed by UMC to ensure that data are stored, • All NRAr countries exceed the standard population-​ processed, and shared in a standard format. For based reporting ratio of 200. example, in 2018, the Brazilian Health Regulatory • On average, 20 percent of all ADR reports to NRArs Agency introduced a new software, VigiMed, that were serious, although important variations across is fully compatible with VigiBase. As a result, it has individual NRArs have been observed. strengthened its capacity for global ADR reporting, ADR reporting to the NRAs is generally regarded as and the total number of ADR reports shared with an indicator of a PV system’s development. Higher UMC rose from 1,752 in 2017 to more than 25,000 in reporting rates are thought to reflect significantly 2019 (figure 7). higher awareness and participation by all stake- There is, however, no substitute for PV and postmar- holders in a system, including patients, health care keting surveillance in one's market, as there may providers, marketing authorization holders, and be unique PV interactions in a local population that government bodies. cannot be found elsewhere or there may be product Nonetheless, some NRArs did not submit any reports failures of locally manufactured products that are not in 2019, which indicates that many NRArs have sold in other markets. no mechanism to ensure continued reporting to So, all NRAs must monitor their markets. The PAHO VigiBase (PAHO 2022). An important reason behind recommends that even the smallest authorities (such the differences in reporting is a lack of compatibility as those in the Caribbean and in Central America, between national software and VigiBase. The only where PV systems are the most limited) prioritize PV way to upload the reports is by manually entering Figure 7  Annual PV Reports, Brazilian Health Regulatory Agency 70,000 6,229 60,000 50,000 20,434 40,000 # of Countries 30,000 13,939 20,000 15,998 24,458 6,039 10,000 2,893 4,516 4,368 2,734 5,851 0 2018 2019 2020 2021 2022 Pharmaceutical Companies Patients and Health Professionals Health Services Vaccination Services Source: Anvisa 2021. 2. Pharmacovigilance systems in practice 28 and postmarketing surveillance and use tools and – Analyzing and processing reports initiatives, such as the PIDM and the WHO Global – Sharing and searching regional, global, or other Surveillance and Monitoring System, to bolster their relevant databases approaches (Preston et al. 2020). – Conducting specialized assessments to consider the need for regulatory action – Communicating relevant findings to the public Recommendations for action As a result of this experience, the PAHO report • Strengthen efforts to tackle illegal online sales by includes the following set of recommendations for addressing existing gaps in regulation, by training, action (Preston et al. 2020): and by dedicating regulatory staff permanently to monitor high-risk websites and social media, • Increase stability and allocate appropriate establish links with law enforcement authorities, resources (for example, funding, staff, training) to and create awareness among users. PV and postmarketing surveillance to ensure that • Establish national track and trace systems in NRArs NRAs respond on time to the growing number to contribute to international monitoring systems and complexity of products entering their health and support drug safety–related actions concerning systems. substandard and falsified quality reports. • Improve ADR and substandard and falsified case • Boost efficiencies in conducting PV and postmar- management, global reporting, and information keting surveillance. This can be done by enhancing for regulatory action. These efforts should include information sharing with other NRAs, adopting facilitating and improving reporting to the NRA risk-based postmarketing surveillance strategies, through public, provider, industry, and other and the ongoing, well-structured monitoring of stakeholder networks. It is also important to trusted PV and postmarketing surveillance infor- maintain dedicated staff who can be assigned to mation sources. the following: 29 Safety Monitoring of Medicines and Vaccines: A Situation Analysis 3. Take-Home 3.2. The difficulties in consolidating national Messages PV systems • As discussed in the previous sections of this report, most situation analyses of national PV systems concur in highlighting the lack of continuity in financial support as the commonest problem PV systems face. The discontinuity of funding increases the risk of a high turnover among trained and experienced staff in PV centers, undermining 3.1. The need for and advantages the safety monitoring activities and hindering the of a national PV system development and consolidation of the PV systems. • Underreporting is a global problem in PV systems. • A well organized and structured safety surveil- The dissemination of the activities of the PV lance system for medicines and vaccines at the system, the advantages of reporting, and how to do national level is an asset in helping ensure the it could therefore help improve the work perfor- quality of health care through the identification of mance of the national PV centers. Specific training safety alerts and by contributing to the prevention focused on signal detection and the dissemination of well-known risks associated with the use of of PV results to health care professionals and the therapeutic procedures and products. population contribute to the development of the PV • Genetic, epidemiological, and environmental system. differences contribute to the heterogeneous response to the medicines and vaccines across the world originating safety problems . It is therefore 3.3. Wide collaboration to important that pharmacovigilance systems be developed in all countries and, if possible, cover harmonize actions, share costs, all geographic areas within countries. and raise awareness • The safety of any single medicine is never com- • A mature PV system is based on three main pillars: pletely known while the medicine continues to be appropriate regulation, well-trained, experienced prescribed and used. A strong, wide, and collabo- staff, and reports sent by mindful and informed rative PV network is the best way to identify new health professionals and citizens. Wide collab- risks and more accurately describe and monitor oration to harmonize actions, share costs, and issues that have already been identified. raise awareness can help address the limitations • PV systems contribute to build resilience in health faced by different countries, particularly low-and systems by (1) helping prevent serious adverse middle-income countries, in these areas. reactions to common medicines, (2) reducing • Indeed, intercountry and regional collaboration the need for additional treatments or prolonged can help meet some of the identified needs in hospitalization or medical leaves, (3) contributing countries, for example, training and technical to improving how medicines are used, and (4) support from neighboring countries, sharing detecting substandard products and unexpected expertise in the evaluation of reports, and shortages in efficacy. intensifying locally detected signals. 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