Do No Harm Synthesis Report  A Why is the Safety of Medicines Important for Resilient Health Systems? Huihui Wang Patricio V Marquez Albert Figueras Kseniya Bieliaieva Korea–World Bank Partnership Facility China–World Bank Partnership Facility B Why Is the Safety of Medicines Important for Resilient Health Systems? © 2023 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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Table of Contents Reports in the Pharmacovigilance and Essential Public Health Services Series......................................................... iv Acknowledgements.. . . . . . . . . . . . . . . . . . . . ................................................................. v Abstract.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ................................................................ vi 1. Introduction.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .................................................................. 1 2. Why Drug Safety Matters?. . . . . . . . .................................................................. 2 2.1 Safety Is an Integral Part of Health Care Quality........................................... 2 2.2 The Burden of Adverse Drug Reactions...................................................... 2 3. What Is Pharma­covigilance?.. . . . ................................................................. 4 3.1 The Objective and Scope of PV.................................................................. 4 3.2 Core PV Activities. . . . . . . . . . . . . . . . . . . ................................................................. 6 3.3 Essential PV Pillars.. . . . . . . . . . . . . . . . ................................................................. 7 3.4 PV Methods. . . . . . . . . . . . . . . . . . . . . . . . . . . ................................................................. 7 3.5 Assessing PV Systems.. . . . . . . . . . . . ................................................................. 9 The Development of National Pharma­ 4.  covigilance Systems........................ 10 4.1 The Thalidomide Tragedy and Its Impact on the Development of PV.. ............ 10 4.2 Achievements.. . . . . . . . . . . . . . . . . . . . . . ................................................................ 10 4.3 Challenges.. . . . . . . . . . . . . . . . . . . . . . . . . . . ................................................................. 11 4.4 The Lessons of Successful PV Programs.. ................................................... 12 4.5 Key Lessons. . . . . . . . . . . . . . . . . . . . . . . . . . ................................................................ 14 5. The Contribution of PV to Building Health System Resilience. . ................... 19 6. Policy Considerations.. . . . . . . . . . . . . . ................................................................ 21 6.1 Considerations for Governments and National Stakeholders........................ 21 6.2 Considerations for Development Partners.................................................22 References.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............................................................... 23 Table of Contents iii Box Box 1. A Lesson of the COVID-19 Pandemic..................................................... 5 Tables Table 1. Activities, Actors, Mandates, and Incentives in Spontaneous ADR Reporting.. . . . . . ....................................................... 6 Table 2. PV Methods, Strengths and Weaknesses............................................. 8 Table 3. The Development of PV Systems, Selected Countries and Regions....... 13 Table 4. Areas of PV Intervention and Contribution in Health Systems............ 20 iv Why Is the Safety of Medicines Important for Resilient Health Systems? 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 led by Huihui Wang (Senior Health Economist, Health, Nutrition, and Population Global Unit), including Patricio V. Marquez (Consultant) and Albert Figueras (Consultant), and Kseniya Bieliaieva (Consultant). Input and support were provided by James K. Kumwenda (Consultant) and Stella Kim (Intern). The draft report was kindly reviewed by Zara Shubber (Senior Health Specialist, Health, Nutrition, and Population Global Practice, Global Engagement, World Bank Group), Delese Mimi Darko (CEO, Ghana Food and Drugs Authority), and Rian Marie Extavour (Program Manager, Caribbean Public Health Agency). Robert Zimmermann (Consultant, World Bank Group) 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, August 17, 2023 vi Why Is the Safety of Medicines Important for Resilient Health Systems? Abstract ■ This report discusses the importance of pharmacovigilance (PV) in contributing to building up resilient health systems. It is based on and summarizes the findings of a review of available literature on the topic and relevant case studies focusing on a set of country and regional experiences. ■ Although indispensable in improving health outcomes, the administration and use of medicines may produce adverse reactions, requiring continuous monitoring to ensure that the benefits outweigh the risks. PV, which involves the systematic detection, reporting, assessment, understanding, and prevention of adverse drug reactions (ADRs), is an essential public health function, but it is often overlooked. The goals of PV are to improve patient safety through the timely detection of previously unknown ADRs that are revealed to be associated with medicines during post marketing surveillance; promote the safe use of medication; enhance public health through the appropriate use of medication; contribute to the assessment of benefits, harm, effectiveness, and risks of medicines; and encourage the safe, rational, more effective, and cost-effective use of drugs. The recent Covid-19 pandemic has highlighted the value of PV in building resilient health systems that respond well during a public health crisis and in normal times. ■ The review suggests that successful PV programs are built on three essential pillars: statutory provisions that establish standards for PV centers and programs, well-trained health professionals and associated stakeholders, and engaged PV reporters using effective reporting systems. These pillars allow PV programs to be effective in three core activities: reporting adverse drug events (ADEs) and identifying signals, determining threats through a benefit-risk balance analysis, and taking appropriate actions. This is in addition to supporting various functions of a health system, such as national drug policy and regulation, the delivery of medical care, specific disease control programs, increasing the trust of the general public in the system, and promoting eco-PV. ■ Aided by emerging opportunities for development through automation and machine learning, PV programs show immense potential to enhance the monitoring of patient safety and improve the use of medicines. The report offers policy considerations for countries and international partners in building PV capacity as an essential public function of a health system. vii Why Is the Safety of Medicines Important for Resilient Health Systems? “是药三分毒” (shì yào sān fēn dú) “ “All medicines have three parts of poison” Chinese proverb Implies that every medicine, no matter how effective it may be, can also have harmful side effects if not used properly or if it is taken in excess. “Does a drug work? Does an intervention that everyone’s using already work? We can’t tell that without having some sort of systematically collected data. And I want to emphasize the ‘systematically’ part.” Eric Rubin, Perspective Intention to Treat, “Lessons for a Pandemic,” New England Journal of Medicine, June 1, 2023 1. Introduction 1 Clinical trials cannot reflect the experience in larger populations and in different geographical regions 1. Introduction medicines and vaccines, as a valuable opportunity to identify, describe, quantify, and, if necessary, reduce any adverse effects to the medications that might be revealed. In practice, this means establishing well-or- ganized PV or monitoring arrangements within a health system for the identification, reporting, and assessment of the risks associated with the use of medicines. These processes involve experienced personnel, policy makers, health care professionals, manufacturers, and citizens actively participate. This report is based on and summarizes the findings Medicines, vaccines, and other essential health of a review of available literature on the topic and technologies are among the main therapeutic tools relevant case studies focusing on a set of country used by health professionals for the prevention, and regional experiences. The goal of this report is detection, and treatment of diseases. Although indis- to provide a comprehensive picture of the role of PV pensable for improving health outcomes, medicine in health systems, discuss the building blocks of a and vaccine administration and usage can produce well-structured and functional PV system, and high- adverse effects, requiring continuous monitoring to light the value of drug safety monitoring in building ensure that the benefits outweigh the risks. resilience in health systems post-pandemic. The report concludes by presenting policy considerations Drug safety monitoring, also known as pharmacovig- for countries and international partners on building ilance (PV), takes advantage of the longer follow-up PV capacity as an essential public health service in an periods after the clinical trials and market approval, effective system. when patients with a wider range of characteristics and in different geographical locations are using the 2 Why Is the Safety of Medicines Important for Resilient Health Systems?  hy Drug Safety 2. W that are suspected to be related to or caused by the medicines. ADRs represent a significant challenge to Matters? health systems, particularly because of the increasing complexity of therapeutics, aging populations, and multiple comorbidities. Medication safety monitoring is an essential compo- nent of continuous quality improvement in health care, which involves a progressive, incremental improvement in processes, safety, and patient care (Marquez 2020). ADRs can occur in any setting, such as outpatient facilities, hospitals, nursing homes, and patient households. The underreporting of ADRs is a critical problem everywhere. 2.1 Safety Is an Integral Part of 2.2 The Burden of Adverse Health Care Quality Drug Reactions Although most ADRs are mild, serious ADRs The administration and use of medicines entail both sometimes lead to (a) clinical complications among benefits and risks. As explained by the US Food and patients who are already frail, (b) longer hospital Drug Administration, the benefits of medicines are stays or longer periods away from work to receive the helpful effects a person experiences in using additional treatments to manage the ADRs, (c) rising the medicines, such as lowering blood pressure, health care costs, and (d) the occasional death of curing infection, or relieving pain (FDA 2018). The the patient. The results of various studies suggest risks of medicines revolve around the chance that an that ADRs are common causes of hospital admission unwanted or unexpected reaction could occur to a and, in some cases, can be serious or fatal (Bénard- person who uses the medicine, such as the possibility Laribière et al. 2015; Brvar et al. 2009). of damage to body tissues or organ functions or a harmful interaction between the medicine and a food, A retrospective analysis of VigiBase, the World Health beverage, dietary supplement (including vitamins Organization (WHO) PV database, investigated and herbals), or other medicine. Any combination of fatal ADRs registered between January 1, 2010, and these products could increase the chances of adverse December 31, 2019, among adult men and women pharmacological interactions, the chance that the patients and reported by physicians (Montastruc et al. medicine may not work as expected, or the possibility 2021).1 It provided evidence on the extent of reported that the medicine may cause additional problems. fatal ADRs and the main drugs involved in these fatal ADRs. Because VigiBase is the largest PV database in Some of the risks of medicines are manifested as the world, it offers unique opportunities to cover the adverse drug events (ADEs), which are harms that global population, factoring in differences in medical may occur while patients are taking a medicine, practice and cultural characteristics to make com- irrespective of whether the medicine is suspected parisons and generalizing the results to the whole as the cause. However, some ADEs may be causally world and not only to a single part of the world or a related to medicines. These are referred to as adverse single country. A sample of 3,250,967 ADRs recorded drug reactions (ADRs). PV monitors ADEs and, by ana- in VigiBase were included in the study, according lyzing reports, identifies ADRs. ADRs are unwanted to the selection criteria. Among these, 43,685 (1.34 or harmful reactions that are experienced following the administration of a medicine or a combination of medicines under normal conditions of use and 1  See “About VigiBase,” Uppsala Monitoring Center, Uppsala, Sweden, https://who-umc.org/vigibase/. 2. Why Drug Safety Matters? 3 percent) were defined as fatal. More than 50 percent hospital stay of four days, which is similar to the of the reports concerned males, mostly patients ages conclusion of another study (Nobili et al. 2011). 45–64, from the Americas, followed by Europe. The The findings of a recent study in the Republic of Korea study found that the shares of fatal ADRs registered that compares health care costs six months before in VigiBase were stable (around 10 p ­ ercent–13 percent and after the ADRs show that (a) tertiary emergency each year) except in 2010, 2012, and 2013, when lower department visits associated with ADRs increased values were observed. The most frequent suspected the associated direct medical costs by 26.1 percent; pharmacological groups were antineoplastic/ (b) after emergency department visits for ADRs, the immunomodulating, neurological, and cardiovascular inpatient costs increased by 28.0 percent, and the drugs.2 A recent multiyear study in New Zealand copayments outpatient costs by 7.0 percent; and (c) ­ reported that opioids, antidepressants, antipsychot- for patients and noninsurance costs rose by 56.0 ics, and hypnotic-anxiolytics were the drugs causing percent and 41.3 percent, respectively (Lee et al. 2020). most fatalities (Fountain et al. 2020). The study also estimates that 16.6 percent of the The burden of ADRs on health systems has been ADR cases were preventable, which indicates that estimated using service utilization and health care preventing these ADRs would allow cost savings of ­ cost metrics. For example, the prevalence of hospital up to 19.9 percent of all ADR-induced costs. emergency department visits for ADRs in the United Another study provides estimates on the costs of States was estimated at 4 per 1,000 visits in 2013 and drug-symptom pairs for severe outpatient ADRs 2014; commonly used medicines, such as anticoag- that resulted in or contributed to hospitalizations in ulants, antibiotics, medications to treat type 1 and the United States (Aspinall et al. 2022). In the study, type 2 diabetes, and opioid analgesics, were the most the costs of ADRs by drug-ADR symptom–coded common drug classes implicated (Shehab et al. 2016). pairs using Medical Dictionary for Regulatory Recent work at the United States Centers for Disease Activities (MedDRA PT) terms were summarized, Control and Prevention has estimated that more than and the costs were adjusted to 2018 US dollars.4 1 million individuals are seen in hospital emergency The most frequently reported drug-symptom pairs departments for ADRs each year in the United States, were lisinopril-angioedema (7.9 percent of the and more than one-quarter of these patients must be reports), warfarin-hemorrhage (6.1 percent), and hospitalized for further treatment.3 warfarin–gastrointestinal hemorrhage (4.8 percent). Similarly, a European Commission report documented Hydrochlorothiazide/lisinopril-angioedema exhibited that 3 percent–10 percent of hospital admissions the lowest median cost during fiscal years 2014 between 2012 and 2014 were estimated to have been through 2018, at US$6,951 (interquartile range, associated with ADRs, totaling about €2.5 million–​ US$4,720–US$10,510). Enoxaparin-hemorrhage €8.4 million annually, and 2.1 percent–6.5 percent of exhibited the highest median cost, at US$29,535 hospitalized patients experienced an ADR, correspond- (interquartile range, US$21,231–US$44,236). The ing to €1.8 million–€5.5 million annually (EC 2016). In results of the study also illustrate the potential addition, at least one ADR onset during hospitalization cost avoidance of interventions to reduce ADRs was associated with a median prolongation in a (for instance, the use of a newly developed direct oral anticoagulants dashboard). 2  I n the anatomical therapeutic chemical classification system, active substances are divided into various groups according to the organ or system on which they act and their therapeutic, 4   edDRA is a rich and highly specific standardized medical M pharmacological, and chemical properties. For details, see ACT terminology developed to facilitate the sharing of regulatory (Anatomical Therapeutic Chemical Classification) (dashboard), information internationally on medical products used by World Health Organization Collaborating Center for Drug Statistics humans. It is used for registration, documentation, and the safety Methodology, Department of Drug Statistics, Norwegian Institute monitoring of medical products both before and after the products of Public Health, Oslo, https://www.who.int/tools/atc-ddd-toolkit/ have been authorized for sale. Products covered by MedDRA atc-classification. include pharmaceuticals, vaccines, and drug-device combination products. For details, see MedDRA (Medical Dictionary for 3  S  ee Medication Safety Program (dashboard), Centers for Regulatory Activities) (dashboard), International Council for Disease Control and Prevention, Atlanta, https://www.cdc.gov/ Harmonisation of Technical Requirements for Pharmaceuticals for medicationsafety/index.html. Human Use, Geneva, https://www.ich.org/page/meddra. 4 Why Is the Safety of Medicines Important for Resilient Health Systems? 3. What Is manufacturing and distribution of pharmaceutical products (Sardella et al. 2021; SPS 2009b). Pharma­covigilance? It has therefore been suggested that, to detect safety hazards associated with the use of newly approved medicines and to prevent the development of new complications that may arise because of the poor quality of older medicines, the manufacturing and pharmacovigilance quality systems be fully inte- grated in the medicine life cycle (Sardella et al. 2021). The aim of monitoring the quality of available pharmaceutical products is to identify products that are defective or deteriorated because of poor manufacturing practices (for instance, the inadequate control of quality defects in one or multiple batches or inadequate impact assessment of changes or 3.1 The Objective and Scope of PV variations in manufacturing or quality control The etymological roots of the word pharma- testing); inadequate storage and distribution pro- covigilance are as follows: pharmakon (Greek: cesses; inadequate control over distribution channels, φαρμακο-, φάρμακον) = medicinal substance, and including introducing in the supply chain counterfeit vigilia (Latin) = to keep watch. The WHO (2002, 7) or falsified products or medicines that have lost their defines PV as “the science and activities relating potency during storage at high temperatures. to the detection, assessment, understanding and Monitoring the drug safety hazards associated with prevention of adverse effects or any other possible medication errors is also critical in PV. Medication drug-related problems.” PV is thus a system to errors are defined as “any preventable event that monitor the safety and effectiveness of medicines may cause or lead to inappropriate medication and other pharmaceutical products and involving all use or patient harm while the medication is in the entities and resources that protect the public from control of the health care professional, patient, or ­ medicine-related harm, whether in personal health ­consumer.”5 They may result from faulty systems, care or in public health services (Shrestha et al. 2021). processes, or conditions that lead people to make Effective PV requires that the collection and assess- mistakes or fail to prevent mistakes. (For instance, ment of individual case safety reports be routinely problems can result from illegible handwriting, the undertaken for all medicinal products to identify use of faulty abbreviations, overlooked interactions previously known or unknown ADRs, especially with other medicines, oral miscommunication, and those that may be serious or fatal. sound-alike or look-alike products.) An ADR is a harmful response that may be fatal, life-threatening, Undertaking these activities is particularly important significantly disabling, or sometimes permanent in the first decade after marketing authorization of and that is caused by the medicine after it was a new drug, as they may help, for example, identify given to the patient in the recommended manner complications from drug administration and use that (dose, frequency, route, administration technique) were unknown before commercialization (Sardella (UMC 2000). et al. 2021). While there is general acceptance that the safety profile of older medicines, such as generic The overall goal of PV is to improve patient care and drugs, is already well established and unknown safety through the use of any kind of medication; adverse reactions are unlikely to occur, these medicines may generate new risks associated with 5  A  bout Medication Errors (dashboard), National Coordinating failures in control quality in the various phases of the Council for Medication Error Reporting and Prevention, United States Pharmacopeial Convention, Rockville, MD, https://www. nccmerp.org/about-medication-errors. 3. What Is Pharmacovigilance? 5 enhance public health and safety in the use of Building the capacity across countries and regions to medications; contribute to the assessment of the conduct thorough surveillance of the use of all me benefits, harm, effectiveness, and risks of medicines; dicines and vaccines is a critical public good invest- and encourage the safe, rational, more effective, and ment to ensure that these drugs work correctly and cost-effective use of drugs. This is accomplished that their health benefits outweigh the known risks. through the efficient and timely collection and The accumulated experience during the COVID-19 assessment of ADEs and the identification of ADRs pandemic clearly illustrates the important role among these events. The reporting of adverse reac- that PV can play in a health system not only tions after the use of a drug or vaccine contributes in normal times, but also during public health to (a) inform decision-making in a health system, crises (box 1). (b) update and supply guidance to health providers, (c) help address public safety concerns about new medicines and vaccines, and (d) stimulate prompt policy and regulatory actions. Box One A Lesson of the COVID-19 Pandemic The pandemic experience has shown that a EMA work also helped inform policy making robust PV system can play an important role in in countries outside Europe. For example, on two ways: (a) ensuring the detection, assessment, March 16, 2021, EMA stated that the benefits of understanding, and prevention of adverse effects the AstraZeneca vaccine continued to outweigh or any vaccine or medicine-related problem that the risks based on a review of all reports may only emerge after the approval of any new of thromboembolic events among 5 million people product and (b) informing governments and other receiving the vaccine. Subsequently, the WHO stakeholders about the safety of these products to issued a statement, on March 17, 2021, to reiterate guide policy making and regulatory action, and to the EMA position, and the African Centers for communicate risks properly and promote the take- Disease Control and Prevention, in a statement up of marketed vaccines and medicines. issued on March 19, 2021, recommended that African Union member states continue to roll While vaccination against COVID-19 provided clear out this vaccine as part of their vaccination public health benefits, it also carried potential risks. campaigns. For example, the European Medicines Agency (EMA), after reviewing safety signals associated with The work of the EMA has been crucial in informing the administration of the AstraZeneca COVID-19 not only governments, but also stakeholders on vaccine in some European Union (EU) countries the benefits and risks of marketed medicines. If not in early 2021, was able to advise governments to communicated well, reported adverse drug effects resume vaccination based on the results of its review have the potential to undermine public confidence and communicate to the population that the benefits in vaccines and other medicines and in government of the AstraZeneca vaccine in preventing COVID-19, actions in general. with the associated risk of hospitalization and death, outweighed the risks of reported adverse effects. Source: Wang, Marquez, and Figueras 2022. 6 Why Is the Safety of Medicines Important for Resilient Health Systems? 3.2 Core PV Activities balance between the benefits and risks of a given medicine, and (c) taking appropriate actions in a Different actors and mandates are involved in timely manner if necessary, for instance, improving monitoring and the responsibility for the safety safety labels, altering prescription practices and of medicines and vaccines across the three core guidelines, changing benefit packages, educating PV activities: (a) reporting on adverse events and service providers, communicating with patients and identifying ADRs, (b) detecting significant safety to the general public, and withdrawing a proven issues and identifying changes in achieving the harmful medicine from the market (table 1). Table 1  Activities, Actors, Mandates, and Incentives in Spontaneous ADR Reporting Activities Actors Mandates and incentives Reporting adverse Front-line health workers In general, reporting is not part of the mandatory events (physicians, nurses, pharmacists, responsibilities of health workers; often there is and others) little incentive for them to report. Underreporting is a common hurdle of safety monitoring programs. But other reporting systems are acceptable, such as the compulsory reporting of certain infectious diseases. Consumers (patients, family Empowerment: taking part in the decisions and members, patient associations) follow-up on health care issues Manufacturers (pharmaceutical Among manufacturers, there are often legal companies) requirements to report. A large number of reports are collected. Partial reports sometimes lack basic information. Detecting significant Public health professionals who Often full-time jobs or institutions with dedicated safety issues and code and analyze ADR reports, responsibilities and mandates for conducting identifying changes conduct research to amplify related activities; PV centers located at or in in the balance of signals, and, if needed, plan other close collaboration with university departments benefits and risks in comprehensive observational and public hospitals have an active role in this a given medicine studies research. Taking appropriate National and local health Policy changes and decision-making actions authorities, for example, ministries of health, local health councils Regulatory authorities with a role in Labeling modifications; changing the prescription translating meaningful PV findings status (over the counter or prescription only) into practical responses Those who finance health services Changing benefit packages, for instance, by and medicines (such as insurance excluding from public funding medicines with authorities) unfavorable risk-benefit ratios Training institutions to facilitate the This requires a closer relationship between PV adoption of new risk messages activities and results to improve teaching and updates on the selection, prescription, and rational use of medicines. Quality assurance agencies to Promotion of local drug utilization studies facilitate the enhancement (therapeutic audit studies), self-audit activities, and of behavior change in issuing comparisons with peers) prescriptions 3. What Is Pharmacovigilance? 7 3.3 Essential PV Pillars of cases by health care providers and patients, as well as by drug manufacturers, in accordance with There are three essential pillars or building blocks in mandatory regulatory requirements. A good example the successful completion of core PV activities. Their of this passive reporting system is the Yellow Card realization will ensure the path toward the maturity Scheme in the United Kingdom that is operated by of a national PV system. the Medicines and Healthcare Products Regulatory • First pillar: a statutory provision. The first pillar is Agency and the Commission on Human Medicines. the existence of a statutory PV provision (national The system is used to collect data on suspected ADRs policy or legislation), a requirement to define related to all licensed and unlicensed medicines and PV activities, a model of the PV program, the vaccines, including those issued by prescription or deployment of PV, the budget allocated to the PV purchased over the counter (Coleman and Pontefract program to support administrative, research, and 2016). information activities as part of the national health The major limitations of the system of spontaneous care system, the definition of the relationship with ADR reporting are well known: the poor quality of the manufacturers on safety issues, and international reports submitted; the significant underreporting; the participation, including membership in the WHO difficulty in calculating rates because of incomplete Program for International Drug Monitoring (WHO numerator data, along with unreliable consumption PIDM) (Peters et al. 2021).6 denominators; and the constraints on the ability to • Second pillar: a PV center. The second pillar is a establish cause and effect (Lexchin 2006). PV center run by well-trained health professionals who form a multidisciplinary team with clinic Active surveillance involves methodically searching and pharmacy backgrounds, training in phar- for ADRs at sentinel site facilities, in addition macoepidemiology, and skills in research and to following up with patients who have been communication with health professionals and the exposed to medicines of interest (SPS 2009b). The general public. design of this method facilitates the collection of • Third pillar: PV reporters and effective PV reporting more comprehensive ADR data relative to passive systems. Engaged reporters and good-quality surveillance by helping obtain a denominator on reports constitute the third pillar. Underreporting the persons exposed to medications of interest. is the Achilles heel of any national PV program This allows for the calculation of ADR rates, which based on spontaneous reporting. The reasons for can highlight medication safety among vulnerable underreporting have been largely explored, but populations, such as women of childbearing age. not addressed satisfactorily (Edwards 2001). Even Formal observational studies, such as case-control compulsory reporting by manufacturers is beset and cohort studies, identify and quantify the with problems, such as low-quality reporting strength of associations between a given medication (Plessis et al. 2017). exposure and adverse health outcome (see Dellicour et al. 2007; Ward et al. 2007; WHO and MMV 2009). Pharmaceutical manufacturers sometimes conduct 3.4 PV Methods post authorization studies, which, among other aims, may help identify significant risks. Table 2 summarizes the main characteristics of PV data collection methods. The most important, least Several methods that have proven successful in expensive, simplest, and most widely used method stimulating ADR reporting among the medical of detecting potential ADRs over the last half century community include educating doctors on the need has been the spontaneous and voluntary reporting to report; familiarizing doctors with the reporting system in general, along with the forms and guide- lines; and providing doctors with follow-up on the 6  W  HO PIDM (Programme for International Drug Monitoring), reports they have filed (Goldman 2004). World Health Organization, Geneva, https://www.who.int/ teams/regulation-prequalification/regulation-and-safety/ pharmacovigilance/health-professionals-info/pidm. 8 Why Is the Safety of Medicines Important for Resilient Health Systems? Table 2  PV Methods, Strengths and Weaknesses Type Characteristics/Structure Strengths Weaknesses Reactive Passive Spontaneous reporting by health Unspecific. Covers all Underreporting and care professionals received by the medicines and their adverse poor information PV center. effects. can be limiting Compulsory reporting by Covers the whole population. aspects. manufacturers. Inversed tree-like structure: Limited clinical Any adverse reaction. from patients to the national and laboratory PV program to the WHO information. Any product. PIDM. Requires an Adverse events do not necessarily indicate causality involving the Can detect rare and very rare individual causality suspected medicine. adverse events not identified assessment. in clinical trials. Some reports have The adverse reaction had already poor information; happened. Online reporting can increase the reporting rate. this hinders the causality Continuous in time. assessment. Active The PV center or researchers Designed to involve health It cannot be design a specific study to stimulate professionals managing maintained for a or reveal adverse reactions. specific patients or long time. Usually covers a specific adverse medicines. It requires reaction or a specific medicine or Helps strengthen signals additional human vaccine. detected by passive resources for each Usually for serious adverse reporting. intervention. reactions or new medicines. Helps identify and define It is useful only for Usually in controlled settings (for the characteristics of rare selected products. example, a hospital, an emergency adverse reactions. unit, or specialized external Electronic records can help consultation). in the identification of cases. The adverse reaction had already Short-time studies. happened. Proactive Preventive It involves all actions conducted Patients did not have the Its benefits can only to avoid or reduce the chance of chance to develop adverse be quantified by developing an adverse reaction. reactions. indirect measures. It may cover specific and unspecific Increases the efficiency of It requires the adverse reactions and medicines or treatments. development of a vaccines. Reduces some adverse preventive culture. Examples: taking actions to reactions. Some prescribers increase patient safety and avoid Electronic prescription tools can feel that their medication errors; checking for are useful. decisions are potential drug-drug interactions monitored. before prescribing; avoiding the Once a specific decision tree prescription of certain medicines or algorithm is established, for patients at risk; avoiding the it can be applied without prescription of low benefit–risk additional effort. medicines; patient counseling in pharmacies to reduce self- medication. The adverse reaction has not happened yet. 3. What Is 9 Computer technology, which allows multiple people, functions, and structures. Various indicators databases to be linked, is also helping in the are used to measure the existence and performance, investigation of drug safety issues. The widespread as well as the achievements, growth, or lack of use of electronic medical record databases has growth of PV systems. Two reports—Indicator-Based enhanced patient safety through the automation Pharmacovigilance Assessment Tool: Manual for of ADR signal detection, thereby improving health Conducting Assessments in Developing Countries care service delivery. Additionally, new tools that (SPS 2009a) and “WHO Pharmacovigilance aid decision-making in electronic prescriptions Indicators: A Practical Manual for the Assessment have demonstrated their value in preventing ADRs of Pharmacovigilance Systems” (WHO 2015)—each (Pons-Mesquida et al. 2021). include widely used and well-tested sets of indicators to measure the qualities of a system. The digitalization of prescriptions and medical records has huge potential to transform PV, especially The results of these assessments also allow countries in prevention and reporting. This area is quite new, to benchmark and compare the performance of and only a few studies from the PV perspective local PV systems with counterpart systems in other have been conducted. In practice, this point of nations and enable the quantification of the impact maturity has not yet been reached in many countries. of future policy and public health interventions to Moreover, in some countries where investments have ensure the safety of pharmaceutical products on the been made in these kinds of health technologies, market (Qato 2018). practical problems have arisen, such as a lack of Overall, the availability of these sets of PV indicators compatibility among systems and the inclusion of provides objective measures to describe the incomplete or inaccurate information in systems situation in a country (SPS 2009b). This helps PV ­ because of the human factor. accomplish the following: These electronic prescription tools are based on • Assess PV activities in health care facilities and alerting the prescriber, the pharmacist, or the nurse across regions and nationwide about potential problems, such as medication errors, • Assess the capacity of and for PV at these levels drug-drug interactions, duplicate treatments, or medi- • Provide tools for the supervision and monitoring of cines inappropriate for certain patients. However, PV activities these are only alerts; health care professionals must • Gauge progress and enable the prioritization of actively acknowledge them and act. In practice, some efforts based on the assessment of these alerts generate fatigue, and the professionals • Enable the comparison of PV activities across may not even read them. These types of tools have health facilities and geographical regions at a given proven useful, but realizing their potential will time and at different times require more development and dissemination. • Supply tools for measuring the impact of interventions • Provide information to enable governments and 3.5 Assessing PV Systems other stakeholders to take appropriate action in The assessment of the status of PV systems and the ensuring drug safety diagnosis of system strengths, weaknesses, and gaps • Maintain confidence by properly responding to are carried out using a PV assessment methodology. patients and to community concerns The assessment covers all aspects of the PV system: 10 Why Is the Safety of Medicines Important for Resilient Health Systems?  he Development 4. T arms and legs. The babies had been born to mothers exposed to thalidomide, a sedative marketed in of National 1957 that was later found to be effective at treating morning sickness. It was believed to be so safe that Pharma­covigilance it was available over the counter in several countries. However, it was withdrawn from most of the phar- Systems maceutical markets after the appearance of these congenital malformations between 1959 and 1962. The thalidomide tragedy raised concerns about the safety of medicines and the potential dangers to public health associated with unexpected adverse reactions to medicines. It highlighted the need for better safety and efficacy studies before market authorization of a new medicine, including the repurposed use of an existing medicine. It also raised concerns about the gaps in safety knowledge before a drug has been used in large populations and the need for accurate postmarket safety monitoring for the timely detection of any previously unknown 4.1 The Thalidomide Tragedy and ADRs, serious reactions, or unexpected clusters of side effects. Its Impact on the Development The short-term response in this context was the of PV adoption of resolution WHA 16.36 during the 16th PV was first implemented about 170 years ago, World Health Assembly in 1963, reaffirming the need although it was not known as pharmacovigilance for early action to promote the rapid dissemination at the time (Fornasier et al. 2018). Its importance of information on ADRs. This led to the creation of began to be realized as a result of deaths and alerts a WHO pilot research project with the participation raised by clinicians and the public about the safety of of nine countries to develop a system that could be anesthesia in England, which led the medical journal, implemented internationally for the detection of The Lancet, to form a commission to investigate previously unknown or poorly understood adverse the issue. The results were published in The Lancet effects of medicines. The initial activities of the pilot in 1893 (Lancet Commission on Anaesthetics 1893). project culminated in the establishment of the WHO The enactment of the US Federal Food and Drug Act PIDM, which is discussed below. on June 30, 1906, which prohibited the interstate transport of unlawful food and drugs under penalty of seizure of the questionable products and prosecu- 4.2 Achievements tion of the responsible parties, added momentum at The WHO PIDM has grown to become a global the international level to the development of PV as a network of national PV centers coordinated by the structured health activity to safeguard people’s safety Uppsala Monitoring Center (UMC).7 To improve (FDA 2019). The basis of the law, however, resided patient therapy and public health worldwide, in the regulation of product labeling rather than the the UMC collects, assesses, and communicates premarket assessment and approval of products. information from national PV programs on the harm, If one case was the real game changer in drug safety effectiveness, and risks of drugs and other substances monitoring, it was undoubtfully the well-known tragedy of thousands of babies with phocomelia, a 7  “  The WHO Programme for International Drug Monitoring (PIDM) condition that involves malformations of human and How to Join,” World Health Organization, Geneva, https:// whopvresources.org/who_pidm.php. 4. The Development of National Pharma­ covigilance Systems 11 used in medicine. The center also collaborates with health programs (44 percent), the Global Fund to countries in the development and practice of PV. Fight AIDS, Tuberculosis, and Malaria (36 percent), universities (26 percent), poison centers (21 percent), After the launch of the PIDM by nine pioneer the global nonprofit Management Sciences for Health countries in 1968, there was a wave of early percent), or the International Network for Rational (18 ­ adopters (21 countries by 1985), followed by an early Use of Drugs (15 percent). majority (104 countries by 2010) and a late majority (155 ­ countries by March 2023). At the WHO PIDM The commitments of countries and the technical annual meeting that was held in Rabat, Morocco, in support of the UMC, other agencies, and funding March 2023, the network included 155 full member stakeholders have contributed to the development countries and 22 associate members working together and strengthening of national PV systems. The to monitor the safety of medicines and vaccines support provided by regional organizations based on the spontaneous reporting of suspected has also been important for harmonization in ADRs under shared rules and a single database. The data collection, the training of personnel, and WHO PIDM had thus become a global, comprehensive the undertaking of regional analysis of specific network involving health professionals, patients, and safety signals. This is the case of the European manufacturers (Wang, Figueras, et al. 2023c). Union (EU) under the lead of the European Medicines Agency (EMA) or the common PV The growth over the past 55 years has paralleled approach adopted for small island countries in the significant progress in pharmacotherapy during Caribbean region coordinated by the Caribbean the golden age of chemical medicines or small Public Health Agency (CARPHA). ­ molecules. Later, there was the dawn and expansion of biological drugs, the consolidation of evidence-based medicine, the advances in ethics applied to medicine research, the increasing access 4.3 Challenges to information and electronic databases, and the Low- and middle-income countries face unique appearance of artificial intelligence as a tool to help challenges in establishing functional PV systems. in the early detection of signals and relevant clusters. The challenges include difficulties in conceptu- alizing the idea of a comprehensive PV system; The most comprehensive assessment of the making the necessary legislative changes to allow performance of national PV systems is a classical establishment, recognition, and operation; allocating survey conducted by Sten Olsson and his UMC team well-trained health professionals to run the system (Olsson et al. 2010). Although the landscape has and engage sufficient PV reporters to be able to changed significantly over the last decade, examining monitor ADEs in a country; interacting with the the study’s results is still useful. According to Olsson WHO PIDM network and other peer organizations and colleagues, almost half the PV centers were at the international level; and obtaining regular established during the 1990s, and the other half was funding for administrative, research, and dissemina- set up later. These PV centers were affiliated with tion activities. drug regulatory agencies (69 percent), ministries of health (20 percent), or universities or scientific Although national regulatory authorities have legal bodies (9 percent) in a high proportion of countries provisions on PV and postmarket surveillance at their (n = 42). Many PV centers were also involved in disposal, as in the case of countries in the Americas, other activities, such as providing drug information no clear approaches are being implemented to (63 percent), promoting patient safety (52 percent), support the performance of the required regulatory fostering the rational use of drugs (46 percent), or activities, and resources are often shifted rather disseminating information on poisons (15 percent). randomly among government entities (PAHO 2022). In addition, seven countries had sentinel sites A challenge that merits attention is the development to monitor HIV/AIDS patients and other special of PV as an integral element of the health system groups. Few countries (23 of 55) had any budget and the continuous enhancement of the capacity allocated for PV. Activities were sponsored by public 12 Why Is the Safety of Medicines Important for Resilient Health Systems? to monitor and assess the growing number and into assessments that inform and guide policy complexity of new drugs entering the market, in makers, program managers, and service providers, addition to the pharmaceutical products already help communicate drug safety concerns clearly to the being prescribed and used. For example, a study in general public, and, where appropriate, contribute to Africa indicates that PV activities are hindered by regulatory action. the scarcity of well-trained personnel, the lack of budgetary support by governments, high turnover among PV staff, whose training involves substantial 4.4 The Lessons of Successful resources, and the lack of awareness about PV among PV Programs health care workers, decision-makers, and consumers While there are accepted principles, functions, (Kiguba, Olsson, and Waitt 2023). and minimum standards at the international level PV systems are heavily reliant on voluntary reporting. for a functional PV system, there is no universal Partly caused by the spontaneous method used by all-fit method for developing a national or regional PV centers to collect information, underreporting PV system. The adoption and adaptation of the is a common problem in countries. Some staff do principles, functions, and minimum standards are not report ADRs because they may not be aware of influenced by contextual factors, such as organiza- the reporting procedure, do not have the time or tional arrangement, development priorities, policies, forget, are fearful of litigation or have doubts about legal and regulatory structures, institutional capacity, the diagnoses, or simply misdiagnose the event. and the available resources that are unique to each Staff training in PV centers therefore persists as an country or region. ongoing challenge in the effort to ensure that all Over the past six decades, some countries and ADRs are adequately reported and resolved. Low regions reviewed for this work, such as Brazil, Ghana, spontaneous reporting rates and the poor quality of Korea, Spain, the Caribbean Community, and the EU, reports also hinder robust signal detection analyses. have been successful in developing robust national Another challenge concerns the need to strengthen and regional PV systems that are well structured and coordination and collaboration with other programs rely on standardized data collection tools. Table 3 and institutions, particularly between public health summarizes some of the characteristics of these programs and national medicines regulatory PV systems. authorities, to enable the active engagement and support of all stakeholders in PV activities. This is needed to ensure that PV information is translated 4. The Development of National Pharma­ covigilance Systems 13 Table 3  The Development of PV Systems, Selected Countries and Regions Country, region Characteristics, (starting year) structure Specific game changers, strategies National approach to pharmacovigilance Brazil (2001) Decentralized: 27 state • A number of uncoordinated PV activities in various university centers coordinated by departments and among patient advocacy groups before the the Brazilian Health establishment of a federal agency to coordinate the initiatives. Surveillance Agency Early PV activities were carried out in certain states (for example, (ANVISA) Ceará, Rio de Janeiro, São Paulo). Funding: each state • Once ANVISA launched national activities, individual programs government, as part of were integrated into a harmonized PV system covering 26 states, the local center of health using a common reporting form and, since 2018, a common surveillance database (VigiMed). The consolidation of this effort in the states proceeded, however, at a varying pace that was determined by the availability of resources and trained health professionals. • A shared objective and dedicated human resources were crucial in the initial stage, given the size and the heterogeneity of the country. Ghana (2001) The country is among • Involving vertical public health programs that monitor the safety the pioneers of PV in the of the medicines administered represented a quick way to start Africa region. The National receiving reports and consolidating PV activities, but also to Pharmacovigilance Center increase the effectiveness of these programs by understanding was established in 2001 the adverse effects of the medicines used and increase patient under the Food and adherence. The latter helps reduce drug resistance to medicines Drugs Authority and was administered in tuberculosis, malaria, and HIV/AIDS programs. accepted into the WHO • Legislation exists to support PV activities; decentralized regionally PIDM. to ensure nationwide coverage. Since 2012, Ghana’s PV • Use of institutional contact persons in health care facilities as PV activity is coordinated by liaison persons. the Safety Monitoring and Clinical Trials Division of the authority. Korea, Rep. of Decentralized system with • Early creation of the KIDS: investing in strengthening one national (1992) a shared database and institution that covers various aspects of the use of medicines coordinated by the Korea (PV, drug utilization, drug selection, risk management, and Institute of Drug Safety and information) is a viable way to ensure patient safety, promote high- Risk Management (KIDS). quality research, and become a model in the region. • Built up following a systemic approach (legislation + institutional base + training) and taking advantage of new technologies (reporting system). Spain (1984) Decentralized: 17 regional • PV activities were undertaken within a small, but well-considered centers coordinated by the academic institution in Catalonia. In parallel, the center included Spanish Medicines Agency. clinical pharmacology in medical training, in addition to editing a Funding: under each local pocket-size medicine formulary and a monthly safety bulletin. The government PV effort was scaled up and evolved into a national program with the support of appropriate legislation, resources, and training. 14 Why Is the Safety of Medicines Important for Resilient Health Systems? Table 3  Continued Regional approach Caribbean Public CARPHA provides a • The 15 Caribbean Community countries are mainly small island Health Agency subregional mechanism countries. VigiCarib offers countries that have few available human (CARPHA 2017) that supports regulatory resources the possibility to participate in a regional PV approach, action to ensure access to although governments can report directly to the WHO PIDM if they safe medicines (VigiCarib). wish and have the capacity. • Focal points collect local reports, maintain local databases, and submit reports to VigiCarib. Technical officers receive, review, and follow up on reports, conduct searches for safety information on medicines and vaccines, and prepare aggregate reports. • A program manager runs VigiCarib network operations, identifies and communicates decision-making issues, reviews data and operational procedures, develops recommendations, and supports focal points. • Shares information on suspected ADRs and quality issues for member states to monitor locally European Decentralized. Each • The framework of the EU favors harmonization in various Medicines member state has its own initiatives among member states, including medicines approvals Agency (EMA PV program. and safety monitoring and evaluation. 2012) Coordination: EMA. • Various committees are involve, as follows: Each member state funds ° The Committee for Medicinal Products for Human Use (CHMP) its national PV program. is responsible for human medicines EMA can fund specific ° The Pharmacovigilance Risk Assessment Committee (PRAC) projects. is responsible for assessing and monitoring the safety of medicines • Each country provides experts for the committees. EMA provides support in harmonization and training. 4.5 Key Lessons 1960 and amended over the years, regulates the manufacture, import, sale, and advertising of The following experiences offer valuable lessons to drug products, sets the conditions for licensing, other countries or regions in the development of key establishing, and operating pharmacies, and aspects of functional PV systems. governs the operation of the PV system. The Korea 1. Legal and institutional aspects. The experiences Institute of Drug Safety and Risk Management of Korea and the EU demonstrate that building (KIDS), established in 2012 under the act, operates the capacity for a comprehensive PV system in as a dedicated agency of the Ministry of Food a country or region involves the development of and Drug Safety and supports evidence-based a robust legislative framework, a functional and decisions on drug safety. sustainable regulatory and organizational structure, At a regional level, the European drug regulatory and guidelines for PV and medicine safety system is based on a network of around 50 regula- monitoring. tory authorities in the 30 European Economic Area In the case of Korea, the national PV system has countries, including the European Commission and been the result of a continuous and sustained the EMA (Wang, Figueras, et al. 2023b). Established government effort, from small pilot projects to in 1995, the EMA operates at the heart of the a nationwide monitoring network, over the past network, coordinating and supporting interactions three decades (Wang, Marquez, et al. 2023a). among more than 50 national competent authori- The Pharmaceutical Affairs Act, adopted in ties in human and veterinary medicine and playing 4. The Development of National Pharma­ covigilance Systems 15 a major role in the harmonization of European and retailers, consumers, and media are critical for the international drug regulations. development of PV systems. 2. Levering disease-specific public health programs. The important role that stakeholders may play in Several countries have public health programs the development of a comprehensive PV system that are disease-specific and often operate is illustrated by the experience in Spain. The separately from the rest of the health system. Catalan Institute of Pharmacology, as part of the These programs, which are funded with the Autonomous University of Barcelona and the support of external donor organizations, operate associated teaching hospital, coordinated activities vertical treatment initiatives that depend on related to the safe use of medicines in the early good PV practices to monitor and assess ADRs, 1980s, a moment in which the concern about particularly if treatment is being scaled up, such the safety of medicines was low in the country as antiretroviral treatment for HIV/AIDS, or if the (Wang, Figueras, et al. 2023d). In addition to pilot standard treatment guidelines change, such as the PV activities in the region, the first pocket-size switch to artemisinin-based combination therapy therapeutic formulary book was published, and a for the treatment of nonsevere malaria caused by quarterly four-page bulletin was freely distributed Plasmodium vivax. This is also the case of immu- to all practitioners as a way to spread the seed of nization programs, particularly if new vaccines concern about medicines safety and the need for are introduced, for instance, for COVID-19. In some surveillance. This subnational academic initiative countries, the PV arrangements established under laid the groundwork for the development of the these public health programs provide a model national PV system, which consists of a national for the eventual establishment of a national PV coordinating center in the Spanish Medicines PV system. Agency and 17 regional centers located across the country. The experience shows that involving In Ghana, for example, the routine reporting of university groups as part of a PV system helps lever adverse events following immunization (AEFI) existing research capacity for data analysis and the began with the launch of the Expanded Program formulation of clinical guidelines and protocols. on Immunization in 1978 and, later, was continued by the Food and Drugs Authority beginning Likewise, in Ghana, the operation of the AEFI in 2001 upon establishment of the National surveillance system is a collaborative effort Pharmacovigilance Center. The surveillance between the Expanded Program on Immunization system was created with the overall aim of of the Ghana Health Service and the Food and promptly detecting and managing AEFI, real or Drugs Authority that involves the collection and perceived, and contributing to the credibility of collation of routine data using the health structures immunization programs by preventing inappro- of the Ghana Health Service (Laryea et al. 2022). priate responses to reports of AEFI that could Case reporting is passive, that is, caregivers and lead to crises or vaccine-hesitancy among the vaccinees report adverse events to health facilities, population in the absence of a surveillance system and the health facilities record reported events (Laryea et al. 2022). using a standard case reporting form to submit the report to the district health directorate, where 3. The active engagement and participation of the data forms are entered into the District Health various stakeholders. Functional, well-structured Information Management System II and transmit- PV systems result from collaborative efforts ted to the national level through an intervening among various stakeholders. Clearly defined regional focal point. Data are aggregated at the roles and responsibilities among expert advisory regional and national levels. Some notifications committees, public health programs, hospitals are sent directly from the community or the health and clinics, health care providers, professional facility to the Food and Drugs Authority through an associations, academic institutions, pharmaceu- electronic reporting system. tical manufacturers, importers, wholesalers and 16 Why Is the Safety of Medicines Important for Resilient Health Systems? 4. Resource allocation to support the operation of the the involvement of their staff members in EMA PV system. Assuring that infrastructure and staffing scientific committees, working groups, and other needs are filled and supported by predictable and activities. The national PV systems receive direct sustained budgetary allocations is a critical input funding from their governments. for a functional PV system. In particular, continuous Half the funding of CARPHA is provided by financial support for PV activities is essential to member states, and the other half by international ensuring that well-trained health professionals partners (Wang, Figueras, Extavour, et al. 2023). remain in the system and stay motivated to CARPHA offers a good practical example of improve their knowledge, enabling the system to South-South-North cooperation as Canada, France, evolve from a simple administrative committee Germany, the Netherlands, the United Kingdom, into a functional reference center for the continu- the United States, the EU, and Latin American ous monitoring of medicines safety. countries share intertwined interests in the In Korea, KIDS operates under funding from the Caribbean region (Hospedales 2019). Ministry of Food and Drug Safety, which provides 5. Capacity development. Increased awareness about 68 percent of the total KID revenue (Wang, among health care professionals of the importance Marquez, et al. 2023a). Additional funding comes of ADRs and of the development of skills and from contracting out research, evaluation, and competencies among PV personnel (for instance, services ordered by other government entities. surveillance methods) is crucial for the operation of In decentralized national health systems, such an effective PV system. as in Spain, each regional PV center depends on In Korea, for instance, KIDS exercises a critical func- the annual budget defined by regional health tion in education and promotion on PV and drug authorities (Wang, Figueras, et al. 2023d). In some safety (Wang, Marquez, et al. 2023a). KIDS provides cases, the PV centers are integrated into the health education on PV and drug safety among the public department or into a public hospital; in other cases, and among health care professionals and relevant the PV centers are run by university researchers organizations. The KIDS regional PV centers and professors. conduct related activities periodically, including the In the case of EMA, approximately 86 percent of production and distribution of newsletters, press its budget (€357.7 million in 2022) is expected to releases, and bulletin updates. come from fees for processing applications from 6. Drug safety monitoring, policy making, and companies that want to introduce a medicine on regulatory action. Pivotal functions of a PV system the EU market (Wang, Figueras, et al. 2023b). EMA are the monitoring, detection, reporting, evaluation, also charges fees for services related to marketing and documentation of drug safety data as well as medicines in the EU in areas such as scientific intervening, gathering information from, and pro- advice, inspections, and the establishment of viding educational feedback to prescribers, health maximum residue limits. The remaining 14 percent care workers, other health care professionals, and (€55.2 million in 2022) is expected from the EU consumers. contribution for public health issues, which mainly supports policies for orphan and pediatric The Korean PV system offers a good example of medicines, advanced therapies, and micro, small, how these functions are structured and operate in and medium enterprises. Some of these revenues practice (Wang, Marquez, et al. 2023a). KIDS fosters are redistributed to EU member countries because voluntary ADR reporting by health care providers, EMA coordinates the scientific evaluation of patients, and pharmaceutical companies, assesses applications and related work with the national drug safety information, performs causality assess- medicines regulatory authorities in EU members. ments, develops drug utilization review criteria, As part of this arrangement, EMA compensates disseminates drug safety information, and provides the national authorities for their related work and education to the general public. The Korean Adverse Event Reporting System, a computerized 4. The Development of National Pharma­ covigilance Systems 17 ADE reporting system developed by KIDS in 2012, Benefits of regional PV arrangements. The require- contains more than 1 million ADE reports from the ments behind the demand to institute and maintain various PV reporters, as well as reports based on a functioning PV system may be difficult to meet post marketing surveillance; observational studies, in countries that have institutional limitations such as pharmacoepidemiologic studies, to collect and resource constraints. This is the case of the safety information on drug products; and reports small countries and territories of the Caribbean from other drug adverse reaction surveillance Community. These economies have limited capacity programs. If new ADEs are detected after drug and face constraints in implementing core drug approval, the Ministry of Food and Drug Safety regulatory functions to ensure access to safe medi- takes action on the basis of guidance by KIDS to cines, including marketing authorization, PV and post inform the public, change a drug’s label, or remove marketing surveillance, legislation, and resources. a product from the market. CARPHA provides a dedicated subregional mecha- nism, the Caribbean Regulatory System, to support The experience of the Brazilian Health Surveillance pharmaceutical regulation. The system plays a critical Agency (Agência Nacional de Vigilância Sanitária, role in helping overcome individual country and terri- ANVISA), a regulatory body of the Brazilian tory limitations and constraints in ensuring access government that is independent of the Ministry to safe medicines among Caribbean Community of Health and that was established by Law 9782 of member states (Wang, Figueras, Extavour, et al. 2023). 1999, offers another good example (Wang, Figueras, It includes a subregional system for reporting ADEs et al. 2023a). ANVISA deals with various aspects of and substandard and falsified products (VigiCarib) health monitoring, including the authorization and and a regional post marketing drug quality testing safety of medicines. This has allowed the linking program through its Medicines Quality Control and of PV with other monitoring programs, such as Surveillance Department. CARPHA is a good example hemovigilance and the surveillance of medical of a subregional approach to facilitating well-­ supplies. To facilitate ADE reporting, ANVISA has functioning post marketing monitoring activities, provided all health professionals with access including PV. CARPHA is well established, integrates to the National System for Health Monitoring lessons from more experienced regulatory author- Reporting (Sistema Nacional de Notificações para ities, and supports small countries and territories a Vigilância Sanitária), a national web-based without specific PV programs, thus helping ensure computerized reporting system launched in 2006 the safety, quality, and effectiveness of the medicines to receive, register, and process reports of sus- and vaccines used in the region. A key lesson of the pected and confirmed cases of ADEs and technical experience of CARPHA is that regional initiatives and complaints, including reports of suspected ADRs, arrangements are complex and require clear objec- cases of therapeutic inefficacy, and medication tives, harmonization, respect for individual member errors causing ADRs. ANVISA has also had a countries and territories, and mutual trust. They also leading role in establishing a sentinel network require the development of policies, procedures, (rede sentinela) involving hundreds of hospitals communication mechanisms, staffing arrangements, across all the states of Brazil. The sentinel and engagement with member states, other partners, network includes the participation of health care and industry. professionals dedicated to monitoring the safety of medicines and other medical technologies. The In contrast, in a region with consolidated national PV state PV programs are being consolidated under systems, such as among EU countries, the region as the umbrella of the network, which thus acts as a whole may benefit from an expanded centralized a permanent observatory of various aspects of data and information repository. The repository may the safety of medicines and health technologies. be used to consolidate and assess the report submis- The network has thereby helped strengthen the sions of individual countries following a harmonized knowledge of health professionals about safety approach, such as the one adopted among the monitoring activities. EU member states and EMA in interpreting and 18 Why Is the Safety of Medicines Important for Resilient Health Systems? applying European Commission directives on the countries are enabled to further their professional demonstration of quality, safety, and efficacy. The development by taking part in the work of the EMA individual countries also benefit from participation scientific committees. EMA may also assist a country in the regional PV system. For example, the system in reaching policy decisions if the country does not facilitates access to reports from a range of countries have a strong PV capacity, and EMA may likewise on potential safety signals related to the use of serve as an impartial referee in cases of a safety new medications, and PV specialists in all member concern involving local manufacturers. 5. The Contribution of PV to Building Health System Resilience 19  he Contribution 5. T decrease the mortality and morbidity risks associated with ADEs. Building PV capacity should thus be of PV to Building understood as a critical public good investment by governments seeking to build resilience in a health Health System system (Chandler et al. 2020). Resilience PV can provide support for the performance of various functions in a health system, such as c ­ ollecting and assessing data on prescribed and dispensed medicines, as well as on the utilization of health services and the outcomes of treatment (Wang, Marquez, et al. 2023b) (table 4). Hence, a health system that includes PV can promote the safety of medications by minimizing the occurrence of ADRs; informing health care providers, regulators, manufacturers, and consumers to take remedial actions and adopt preventive measures to avoid ADRs in future patients; and improving how medicines are prescribed and used (FIP 2006). Risk reduction actions In a health system, resilience is the ability to prepare may be (a) regulatory, such as withdrawing marketing for, manage (absorb, adapt, and transform), and learn authorization or recalling a medication; (b) manage- from shocks (Sagan et al. 2022). These shocks are not rial, such as modifying coverage conditions in drug predictable and enduring stresses, but sudden and benefit plans or modifying prices as in countries of extreme changes, such as a pandemic, that affect the Organization for Economic Co-operation and a health system. Medicines, vaccines, and other Development (OECD 2019), revising formularies therapies are critical countermeasures both during in health facilities, or instituting drug distribution normal times and in a public health crisis. Although controls; or (c) educational, such as teaching prescrib- indispensable for improving health outcomes, ers about medicine-medicine interactions or proper medicines, vaccines, and their administration and product handling, thereby improving communication use may produce adverse effects. with patients and the general public on the evidence In post marketing medicine surveillance, PV is crucial derived from routinely collected data to confirm or to quantifying previously recognized adverse events counter suspected safety concerns. and identifying previously unrecognized adverse events to evaluate the effectiveness of medicines in real-world situations and, thanks to this knowledge, 20 Why Is the Safety of Medicines Important for Resilient Health Systems? Table 4  Areas of PV Intervention and Contribution in Health Systems Area of intervention PV action and result Drug policy and The provision of good-quality, safe, and effective medicines and their appropriate use are the regulation responsibility of national governments. PV contributes to the assessment of the value of the medicines in use in health care systems and, by helping ensure that risks in medicine use are anticipated and managed, provides information to policy makers and regulators on the amendment of recommendations on the use of the medicines and the adoption of regulatory action, as well as to program managers to inform decisions on the coverage conditions or prices for medicines. Medical care Monitoring the use of medicines in routine clinical practice helps identify the emergence services of unanticipated outcomes (rare or delayed adverse effects not detectable in clinical trials; variable clinical results) and reveals gaps between efficacy (benefits assessed in clinical trials) and effectiveness (benefits observed in clinical practice). The timely review of incoming data and real-time signal detection can provide important safety information and guide the work of health care providers, protecting the population from ADRs and ensuring that the use of pharmaceutical products contributes to good health outcomes. Evidence from routinely collected data is used to drive changes in clinical guidelines and care protocols. PV has the potential to strengthen current antimicrobial stewardship strategies because PV data can help identify antimicrobial resistance and prevent the inappropriate use of antibiotics (Habarugira, Härmark, and Figueras 2021). Public health Medicine safety monitoring is crucial to public health programs for disease control at programs the population level. For example, many tuberculosis programs have introduced and institutionalized active drug safety monitoring and management platforms for drug-resistant tuberculosis; the introduction of novel medicines and regimens for antiretroviral treatment for HIV/AIDS has also required comprehensive surveillance systems for ADRs; PV has been of great importance in malaria control programs given the increasing resistance to existing antimalarial medicines that has led countries to switch to combinations of various artemisinin derivatives as their first- and second-line treatments for malaria. Eco- Surveillance of the effects of drug residues in the environment, such as antibiotics, pharmacovigilance psychoactive drugs, and hormones, on human health and livestock. Biologically active compounds are specially designed to be effective even at low concentration levels. Pharmaceuticals in the environment may thus have adverse impacts on the health of human beings or other nontargeted organisms after long-term exposure (Wang et al. 2018). Strategic By providing evidence derived from routinely collected data to confirm or counter suspected communication medicine safety concerns, PV improves communication between health professionals with patients and the general public and educates health professionals in understanding the effectiveness or risk of medicines that they prescribe. The effective communication of the risks to the safety of drugs is a vital task to be carried out by governments and health care providers, as well as the pharmaceutical industry, to address the public perception of the hazards associated with medicines and build trust in the health system and other government actions. Adverse drug Manufacturing, selling, prescribing, or dispensing medicines may have serious consequences reaction relief that are the object of liability trial. PV can inform such trials and aid therapeutic decisions programs or causality analyses associated with adverse events, including medical and other scientific evidence of reported outcomes (Edwards and Body 2012). Some ADR relief services require criteria for compensation eligibility, including the proper use of the medication associated with the adverse event and any reasonably plausible association between the drug and the adverse event (Watanabe et al. 2019). Based on the results of causality assessments in ADRs, governments may offer compensation for victims who die, are injured, or are hospitalized because of unexpected ADRs despite proper care, using relief systems operated with financial assistance from pharmaceutical companies. For instance, see Adverse Drug Case (dashboard), Korea Institute of Drug Safety and Risk Management, Anyang, Gyeonggi, Republic of Korea, https://www.drugsafe.or.kr/iwt/ds/ko/report/WhatIsADR.do. 6. Policy Considerations 21 6. Policy robust medium- and long-term legal structures and institutional arrangements. Given the public goods Considerations nature of PV, governments should take responsibility for financing PV activities. Broad stakeholder participation. With the support of international partners, governments should also take charge of the mobilization and active involvement of various stakeholders in reviewing existing PV activities, identifying priorities for scaling-up efforts through a systems approach, and developing consensus on the role stakeholders might play in implementing a fully functioning PV system. Active data collection. While spontaneous or passive approaches to data collection on and the assessment The previous sections summarize the information of ADEs have been the most common in various available in scientific journals and reports and in countries globally, governments should consider country and regional case studies. This fact must adopting active surveillance methods, including the be highlighted because no experimental study has use of registries, sentinel sites, and follow-up among been conducted so far comparing the efficiency and patient cohorts, to overcome the underreporting effectiveness of various approaches to establishing and low-quality information associated with passive and developing a PV system. Nonetheless, the methods. This effort should also encompass atten- documented performance and results achieved tion to developments in information technology and through the PV systems in operation in more than advanced methodologies, including machine learning 150 countries have allowed us to formulate some techniques and the availability of large amounts of policy considerations for governments and other electronic health care data, that offer the opportunity national stakeholders, as well as for developments to leapfrog to the expansion of the PV capacity partners. These are presented below. to optimize drug benefit-risk profile evaluations in real-world settings (Trifirò and Crisafulli 2022). 6.1 Considerations for Systematic clinical data mining may accelerate the speed at which ADE signals can be detected, thereby Governments and National contributing to building health system resilience. Stakeholders Such an active drug safety surveillance system would The key to ensuring the development of comprehen- allow drugs to be monitored longitudinally over their sive PV systems involves highlighting the importance entire life cycle, providing regulatory authorities with of the systems and their sometimes overlooked timely access to new information with which to or poorly explored role beyond collecting reports, evaluate a drug’s risk profile and minimize the safety uploading the reports to a PV database, and preparing concerns associated with the increased volume and an annual activity summary. PV is an essential public complexity of new drugs and therapeutics regularly health function in a health system to help secure the becoming available on the market. safe and effective use of medicines. Strategic communication. The effective communica- Strategic planning and phased build-up. Accumulated tion of the risks to the safety of drugs is a vital task international experience suggests that countries that needs to be carried out by governments and can create such systems through careful strategic health care providers, as well as the pharmaceutical planning and a phased build-up. This requires polit- industry, to address the public perception of the ical commitment, coupled with dedicated technical hazards associated with medicines and build and financial support, to establish and sustain trust in the health system and other government 22 Why Is the Safety of Medicines Important for Resilient Health Systems? actions. Effective communication practices, the the Global Fund to Fight AIDS, Tuberculosis, and positive framing of mild side effects, and addressing Malaria, or bilateral organizations, support could misinformation related to vaccine adverse effects be included for developing and strengthening key can reduce the concerns about these adverse effects components of the PV system. (Motta et al. 2021; Rief 2021). Failure to communicate Promotion of stakeholder involvement. A critical effectively to health care professionals and the public area that may benefit from the technical assistance can lead to a loss of trust, the diminished reputation of development partners, such as the WHO, is the of regulators and other stakeholders, and the loss of provision of assistance to countries in mapping all lives (WHO 2020). stakeholder roles and responsibilities in the system and in bringing stakeholders together to address PV as a common issue (SPS 2009b). The development 6.2 Considerations for of a shared framework for establishing or strength- Development Partners ening a PV system can also facilitate coordination Support for system development. International among stakeholders. As part of a collaborative effort, experience suggests that building a functioning partners can identify gaps and areas of duplication, and effective PV system that is sustainable requires as well as successes and strengths to build on and a phased implementation process. This approach opportunities for streamlining and harmonizing roles is needed to deal with capacity and financial and responsibilities. constraints in low- and middle-income countries. A learning exchange among countries. Another area The sustained technical and financial assistance of that merits support by international partners is the development partners is of paramount importance in use of existing learning platforms or the develop- complementing and supporting country efforts. ment of new ones to foster the regular exchange of Technical assistance in specific areas. Based on experiences, knowledge, and skills among countries, their areas of interest and comparative advantages, thereby promoting more well harmonized PV development partners may choose to support specific approaches. PV activities, such as product quality monitoring; Overall, in supporting future endeavors to strengthen monitoring and reporting substandard and falsified PV capacity as part of building resilient health products; the development of capacity in country systems, international partners will be helping organizations, such as national PV monitoring countries realize a basic tenet associated with the centers; or a focus on a particular disease, program, or millennia-old Hippocratic oath, “First, do no harm,” group of pharmaceuticals, such as antiretrovirals, as which is at the core of public health and medical the cornerstone for the development of comprehen- practice, the monitoring of the risk-benefit ratio of sive PV programs in a health system. 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