Do No Harm Overview Report  1 The Value of Pharmacovigilance in Building Resilient Health Systems Post-COVID Huihui Wang Patricio V. Marquez Albert Figueras Kseniya Bieliaieva Korea–World Bank Partnership Facility (KWPF) China-World Bank Partnership Trust Fund (CWPF) 2 The Value of Pharmacovigilance in Building Resilient Health Systems Post-COVID © 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. The World Bank does not guarantee the accuracy, completeness, or currency of the data included in this work and does not assume responsibility for any errors, omissions, or discrepancies in the information, or liability with respect to the use of or failure to use the information, methods, processes, or conclusions set forth. The boundaries, colors, denominations, and other information shown on any map in this work do not imply any judgment on the part of The World Bank concerning the legal status of any territory or the endorsement or acceptance of such boundaries. Nothing herein shall constitute or be construed or considered to be a limitation upon or waiver of the privileges and immunities of The World Bank, all of which are specifically reserved. Rights and Permissions The material in this work is subject to copyright. Because The World Bank encourages dissemination of its knowledge, this work may be reproduced, in whole or in part, for noncommercial purposes as long as full attribution to this work is given. Any queries on rights and licenses, including subsidiary rights, should be addressed to World Bank Publications, The World Bank Group, 1818 H Street NW, Washington, DC 20433, USA; fax: 202-522-2625; e-mail: pubrights@worldbank.org. Cover photo: © World Bank / Henitsoa Rafalia i The Value of Pharmacovigilance in Building Resilient Health Systems Post-COVID ii The Value of Pharmacovigilance in Building Resilient Health Systems Post-COVID Table of Contents Reports in the Pharmacovigilance and Essential Public Health Services Series.................................................................... iv Acknowledgements...................................................................................................... vi Introduction: A general background on drug safety 1.  monitoring and the associated response to COVID-19............................. 1 The challenge of emerging diseases......................................................... 3 Pharmacological countermeasures in general context and during the COVID-19 pandemic.. . . ............................................................ 4 Drug safety risks in trials and the practice of monitoring.. ........................... 6 The value of pharmacovigilance illustrated by the COVID-19 experience....... 8  rug safety monitoring and the health system: general 2. D considerations. . . . . . . . . . . . . . . . . . . . . . . . . . .......................................................... 12 The impact of ADRs on service utilization and health outcomes................. 13 Impact of ADRs on health care costs....................................................... 15 ADEs, ADRs, and the key building blocks of pharmacovigilance 3.  and national and regional systems...................................................... 16 Building knowledge on the safety of medicines........................................ 17 The objectives and scope of pharmacovigilance....................................... 18 Organizational and operational arrangements. . ........................................ 19 Challenges in system development in low- and middle- income countries. . . . . . . . . . . . . . . . . . . . . . . . .......................................................... 25 4. Using pharmacovigilance to foster resilient health systems................ 27 What is health system resilience?. . .........................................................28 Support for national drug policy and medicine regulation......................... 30 Support for the delivery of clinical services to patients.............................. 31 Data to identify antimicrobial resistance and inappropriate use of antibiotics.. . . . . . . . . . . . . . . . . . . . . . ........................................................... 32 Support for the implementation of Eco-Pharmacovigilance. . ...................... 33 Support for public health programs on disease control.............................. 34 Support for building trust in the health system......................................... 35 Support to achieve health impacts..........................................................36 5. Final Considerations. . . . . . . . . . . . . . . . . .......................................................... 37 Guiding questions for strengthening national pharmacovigilance systems within the wider health system resilience effort. . ......................... 38 Building PV capacity in a health system. . ................................................. 39 Table of Contents iii Tables Table 1  Serious Viral Outbreaks over the Past 100 Years.............................. 3 COVID-19 Vaccines with WHO Emergency Use Listing, by Table 2  Date of Listing. . . . . . . . . . . . . . . . . . . . . . . . . . . . ................................................. 4 Table 3  Summary of WHO Recommendations on Drugs for COVID-19......... 5 Figures Figure 1  Adverse Drug Events and Adverse Drug Reactions. . ....................... 7 Figure 2  The Drug Life Cycle.. . . . . . . . . . . . . . . . . . ................................................ 18 The Flow of Information through the European Figure 3  Medicines Agency.. . . . . . . . . . . . . . . . . . . . ................................................ 21 Figure 4  Illustration of the Drug Safety Monitoring Process. . .................... 22 Figure 5  Key Capacities: Reforms to Improve Resilience. . ......................... 29 Box Selected Serious Adverse Events of Interest Following COVID-19 Box 1.  Vaccination as Reported by the United States Vaccine Adverse Event Reporting System.. . . . . . . . . . . . . . . . ................................................ 10  he Work of the European Medicines Agency in Monitoring and Box 2. T Assessing Safety Signals Associated with the Administration of the AstraZeneca COVID-19 Vaccine in European Union Countries in 2021.. . . . . . . . . . . . . . . . . . . . . . . . . . ................................................. 11 iv The Value of Pharmacovigilance in Building Resilient Health Systems Post-COVID 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 37 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), including Patricio V. Marquez (Consultant, Albert Figueras (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 1 1 1. A general background on drug safety monitoring and the associated response to COVID-19 1 A general background on drug safety monitoring and the associated response to COVID-19 1. A general background on drug safety monitoring and the associated response to COVID-19 2 Monitoring medicine and vaccine safety serves as an early warning system that helps identify adverse events that occur after use postmarketed Although indispensable for improving health outcomes, medicines and vaccines or their adminis- tration and use can produce adverse effects, requiring continuous vigilance to ensure that the benefits outweigh the risks. Monitoring the safety of the use of marketed medicines and vaccines, also known as pharmacovigilance, should therefore become much more explicit in efforts to strengthen health systems Medicines, vaccines, and other essential health and prepare for pandemics because the world is technologies are among the main therapeutic tools determined to build back better after the COVID-19 used by health professionals for the prevention, pandemic (Barış et al. 2022; Rentschler et al. 2021). detection, and treatment of diseases, including The objective of this report is to examine the impor- rehabilitation and palliative care. The COVID-19 pan- tance of pharmacovigilance in a health system both demic has clearly shown that the effective control during a health crisis and in normal times, describe of public health crises also requires pharmaceutical the function, structure, and processes of a functional interventions, including the introduction of new pharmacovigilance system, and explain the value vaccines and therapies, as well as the repurposing of drug safety monitoring in building resilience in of existing medicines. health systems post-COVID-19 pandemic. 3 The Value of Pharmacovigilance in Building Resilient Health Systems Post-COVID Table 1  Serious Viral Outbreaks over the Past 100 Years Popular name Virus type Year detected Global deaths Spanish flu Orthomyxovirus 1918 50,000,000 Asian flu (H2N2) Orthomyxovirus 1957 1,100,000 Hong Kong flu (H3N2) Orthomyxovirus 1968 1,000,000 HIV Retrovirus 1981 32,700,000 SARS-CoV-1 Coronavirus 2002 774 Influenza (H1N1) Orthomyxovirus 2009 284,000 MERS Coronavirus 2012 875 Ebola Filovirus 2014 11,310 Zika Filovirus 2015 — Ebola Filovirus 2018 2,300 SARS-CoV-2 Coronavirus 2019 6,492,894a Sources: Adapted from White House 2021; data on SARS-CoV-2: Coronavirus (COVID-19) Deaths (dashboard), Our World in Data, Global Change Data Lab, University of Oxford, Oxford, UK, https://ourworldindata.org/covid-deaths. Note: — = not available. a. As of September 2, 2022. This section investigates the importance of pharma- that span five virus families (table 1). Two of these ceutical products, both vaccines and other medicines, outbreaks have caused more deaths than COVID-19: as countermeasures during a public health crisis. It the Spanish flu, which appeared in two deadly waves, elaborates on the important role that postmarket in 1918 and 1919, after the devastating consequences pharmacovigilance—drug safety monitoring—plays of World War I, and the HIV pandemic, which has in a health system by helping identify adverse events been around for more than 40 years. In addition, that occur after vaccination or the administration many other new viruses have been emerging in of other medicines, thereby providing valuable recent decades, including severe acute respiratory information for assessing possible safety concerns, syndrome (SARS), the Avian influenza in humans, preventing serious risks, and, ultimately, ensuring Ebola, Marburg hemorrhagic fever, Nipah virus, patient safety. and the current COVID-19 pandemic. In the case of COVID-19, its full impact has extended well beyond the number of deaths reported. While the cumulative The challenge of number of confirmed deaths since the beginning of emerging diseases the pandemic stands at 6.3 million, estimates put at 18.2 million the number of people who have died The COVID-19 pandemic is a stark reminder of the worldwide because of the pandemic, as measured ongoing and future challenge of newly emerging by excess mortality over the period (Checchi diseases, those that have never been recognized and Roberts 2005; COVID-19 Excess Mortality before, and reemerging or resurging infectious Collaborators 2022).2 Overall, these public health diseases, those that have been around for decades or crises have triggered major international concern, centuries, but have come back in a different form or a raised new scientific challenges, led to major human different location (Fauci 2005). Cholera, yellow fever, suffering, and imposed enormous economic damage. and epidemic meningococcal diseases, for example, made a comeback in the last quarter of the twentieth century (WHO 2007). 2  E  xcess mortality is a term used in epidemiology and public health Serious viral outbreaks have occurred periodically to refer to the number of deaths from all causes during a crisis that since the early 1900s, caused by pandemic pathogens is above and beyond the number that would have been expected under normal conditions. 1. A general background on drug safety monitoring and the associated response to COVID-19 4 COVID-19 Vaccines with WHO Emergency Use Listing, Table 2   by Date of Listing Vaccine Date listed Pfizer/BioNTech Comirnaty December 31, 2020 SII/COVISHIELD and AstraZeneca/AZD1222 February 16, 2021 Janssen/Ad26.COV 2.S developed by Johnson & Johnson March 12, 2021 Moderna COVID-19 (mRNA 1273) April 30, 2021 Sinopharm COVID-19 May 7, 2021 Sinovac-CoronaVac June 1, 2021 Bharat Biotech BBV152 COVAXIN November 3. 2021 COVAX (NVX-CoV2373) December 17, 2021 Nuvaxovid (NVX-CoV2373) December 20, 2021 Source: WHO 2022a. Dealing effectively with these public health crises products or unapproved uses of approved products to has required the capacity to conduct constant disease address public health emergencies.3 surveillance, prompt diagnosis and case confirma- tion, and robust research to understand the basic No vaccines in history have been developed and biology of new organisms and the human suscepti- authorized as quickly as the COVID-19 vaccines. bilities to them, as well as to develop effective and About 23 different vaccines against SARS-CoV-2 have safe countermeasures to control them (Fauci 2005). already been authorized for use around the world, and hundreds more are in development (Mallapaty et al. 2021). The emergence of virus variants, such as the Omicron variant and its subvariant BA.2, Pharmacological countermeasures have reaffirmed the importance of vaccination in general context and during the (CDC 2022a). COVID-19 pandemic Unprecedented scaled-up efforts have also been The importance of pharmaceutical products, mounted in health systems across the world to both vaccines and other medicines, during a public health crisis was made evident during the COVID-19 pandemic. 3  C  OVID-19 vaccines have only received an EUA and not formal approval. Formal approval by WHO or a national or regional stringent regulatory authority, such as the FDA, requires a laborious Vaccines and vaccination. One countermeasure process of data verification and assessment, and, in the case of has been the development of new vaccines, which an emergency situation, an authorization is granted while the former is completed. While an EUA is time limited, approval is have been at the center of the global response, open-ended. For example, in the case of emergency medical under accelerated delivery timelines. Multiple supplies and medications that have not been approved for use, the FDA allows the use of these products for the diagnosis, vaccines of different types have been developed and treatment, and prevention of life-threatening medical conditions received emergency use listing by the World Health and disease if the products meet certain criteria. The FDA requires safety and effectiveness data to review an EUA. The FDA reviews Organization (WHO) and emergency use authoriza- medical records, records on site visits to manufacturing facilities, tion (EUA) by stringent regulatory authorities, such previous compliance history, and data on compliance with good as the US Food and Drug Administration (FDA) and manufacturing practices to ensure safety post-EUA. The FDA looks at the risk versus the benefit of waiting for all the evidence needed for the European Medicines Agency (EMA) (table 2). full approval and does not allow the use of a test, medical supply, or Emergency use listing and EUA against COVID-19 medication if they are not found to be safe. After approval, the FDA allows a drug company to market a drug or vaccine for approved are expedited authorizations of unapproved medical indications. 5 The Value of Pharmacovigilance in Building Resilient Health Systems Post-COVID Table 3  Summary of WHO Recommendations on Drugs for COVID-19 Population, recommendations Disease Severity Nonsevere Severe Critical Patients w/ Absence of signs of severe Oxygen saturation <90 Requires life confirmed or critical disease percent on room air sustaining treatment COVID-19 Signs of pneumonia Acute respiratory Signs of severe distress syndrome respiratory distress Sepsis Septic shock Interventions Strong • Corticosteroids Depending on availability recommendations • IL-6 receptor blockers as well as clinical and in favor • Baricitinib contextual factors Immune modulators that help activate, boost, or suppress the immune function. In the case of COVID-19 infection, the immune system can become hyperactive which may result in worsening of disease Weak or conditional • Sotrovimab Evidence of limited For those with recommendations • Molnupiravir efficacy against Omicron seronegative status for in favor (for those • Casirivimab BA1 variant SARS-CoV-2 antibodies and Imdevimab For those with with highest risk of seronegative status for Monoclonal Antibodies: hospital admission laboratory-produced SARS-CoV-2 antibodies antibodies that can help the immune system's attack on SARS-COV-2) For those with highest risk of hospital admission Weak or conditional • Corticosteroids • Ruxolitinib and recommendations • Remdesivir Tofacitinib against • Ivermectin Should be considered only if neither baricitinib nor IL-6 receptor blockers are available • Convalescent • Plasma Should be considered only in the context of a clinical trial) Strong • Convalescent plasma recommendations • Hydroxychloroquine against • Lopinavir-ritonavir Source: Agarwal et al. 2020. 1. A general background on drug safety monitoring and the associated response to COVID-19 6 support the administration of vaccines, requiring Adverse events after the administration of a drug the strengthening of key core activity areas, from are common, yet often mild and preventable. planning and management, supply and distribution, However, in some cases they cause disability and and program delivery to systems and infrastructure, even death. Besides the intrinsic dangers associated including the establishment of mass vaccination sites with the drugs themselves, individual patients may (Marquez et al. 2020). The vaccination effort has also exhibit particular and unpredictable sensitivities to required building public confidence through public certain medicines, and, if more than one medicine education campaigns, community mobilization and is prescribed, there is always a risk of negative involvement, and on-the-ground, grassroots outreach interactions. efforts (Marquez, Eyman, and Hanan 2021). Monitoring drug safety serves as an early warning system that helps identify adverse events that COVID-19 therapies. Additionally, a collection occur after vaccination or the administration of of therapies for consideration in the treatment of other medicines, providing valuable information coronavirus infections has been recommended to assess possible safety concerns. These systems by WHO (2022b) (table 3). The WHO Guideline are especially useful for detecting unusual or Development Group, consisting of an expert panel unexpected patterns of adverse events that might of global experts, frontline providers, and patient indicate a possible safety problem with a vaccine partners, develops and updates COVID-19 clinical or a medicine. practice guidelines on the basis of a review of evidence summaries from international clinical Under EUA provisions, a stringent regulatory trials for the use of therapeutics to treat patients authority expects vaccine manufacturers to with COVID-19 at any level of disease severity. The include in their EUA requests a plan for active rapid adaptation and implementation of these peer follow-up for safety, including deaths, hospital- reviewed WHO-recommended therapeutics into izations, and other serious or clinically significant COVID-19 clinical care pathways are essential at the adverse events, among individuals who receive the local and national levels to affect patient outcomes vaccine under an EUA, to inform ongoing benefit-­ and reduce the pandemic’s toll in the societies and risk determinations to support the continuation the economies of countries. of the EUA. The regulatory authority also expects manufacturers that receive an EUA to continue their clinical trials to obtain additional safety and Drug safety risks in trials effectiveness information and pursue licensure and the practice of monitoring (approval) (FDA 2020a). Overall, medicines are generally safe if they are used as prescribed or as directed on the label. Differences among side effects, adverse Despite all their benefits, however, there are risks drug effects, and adverse drug reactions in taking any medicine. Once a drug has received Although side effects and adverse effects are similar an EUA or been approved for marketing and use by terms often used in medicine, they are distinctly potentially thousands of patients, the type, rate, and different. A side effect is an effect of a drug, severity of adverse events caused by the drug may chemical, or other medicine that is in addition to the be much different than those observed during the intended effect, while an adverse effect is a harmful, drug’s development. In some cases, the regulatory undesirable effect that results from a medication authorities or drug manufacturers have removed or other intervention such as surgery (Pediaa 2015). from the market drugs that have been shown to A side effect may be either harmful or beneficial; an have unacceptable health risks once they were in adverse effect is typically harmful and undesirable. In widespread use. addition, adverse effects tend to be more severe and life-threatening than side effects. 7 The Value of Pharmacovigilance in Building Resilient Health Systems Post-COVID Figure 1  Adverse Drug Events and Adverse Drug Reactions Causal Relationship Adverse Drug not established Events (ADEs) Causal Relationship is suspected/established Adverse Drug Reactions (ADRs) The term adverse drug events (ADEs) refers to any muscle ache, chills, diarrhea, and pain or redness medical occurrence that may appear during treat- at the injection site (WHO 2021). Not everyone will ment with a pharmaceutical product, but that does experience side effects. These side effects may not necessarily have a causal relationship with the influence the ability to carry out daily activities, but treatment (figure 1). Adverse drug reactions (ADRs) they often disappear in a few days on their own. are unintended, harmful events attributed to the use Serious adverse events are rare, but do occur. Box of medicines (Coleman and Pontefract 2016; Montané 1 describes serious, but rare adverse events of and Santesmases 2020). interest post–COVID-19 vaccination as reported by the Centers for Disease Control and Prevention ADEs after COVID-19 vaccination (CDC) and the FDA that have hindered vaccination efforts or caused vaccine hesitancies in the United Billions of people around the world have been safely States (the example associated with the EMA is vaccinated against COVID-19. Similar to all vaccines, presented in Box 2). Two of these, thrombosis the approved COVID-19 vaccines have been carefully with thrombocytopenia syndrome (TTS), a rare tested through a rigorous, multistage testing process, syndrome characterized by venous or arterial including large clinical trials that involve tens of thrombosis and thrombocytopenia, and Guillain- thousands of people (Marquez and Hanan 2020). Barré syndrome (GBS), a rare autoimmune neuro- Although these trials are specifically designed to logic disorder characterized by ascending weakness identify any safety concerns, they may nonetheless and paralysis, have been reported after Janssen not detect adverse effects that occur in the popula- COVID-19 vaccination. One (myocarditis, cardiac tion after the vaccines receive market authorization. inflammation) has been reported after mRNA As with any vaccine, some people have experienced COVID-19 vaccination (Pfizer-BioNTech COVID-19 and reported mild to moderate side effects after vaccination or Moderna COVID-19 vaccination), being vaccinated against COVID-19. This is an particularly after the second dose. expected sign of an immunological response to In the United States, the FDA’s Advisory Committee the inoculated antigens or proteins. Side effects to on Immunization Practices reviewed the data COVID-19 vaccines include fever, fatigue, headache, 1. A general background on drug safety monitoring and the associated response to COVID-19 8 associated with the reports of serious adverse events the FDA’s EUA mechanism, which is not the same and comprehensively assessed the benefits and risks as approval (FDA 2020b). associated with receipt of these vaccines. The com- Other drugs used as adjunctive or supportive mittee concluded that the benefits outweigh the risks ­ treatments for COVID-19 include antiviral, anti-­ for rare serious adverse events after COVID-19 vacci- inflammatory, and antimalaria drugs and other nation and that the information about rare adverse traditional or nontraditional treatments (Ho et al. events should be disseminated to providers, vaccine 2021). However, it has been reported that the use of recipients, and the public (Rosenblum et al. 2021). these drugs may have negative effects and comor- The findings of these types of assessments based on bidities. Moreover, as suggested in a recent study, real-life observations and reporting have contributed the current data indicate that the risk of drug-drug to addressing safety concerns about some of the interactions may also be high in polypharmacy cases, authorized vaccines among the population and especially among the elderly, in some comorbidity supported the roll-out of the vaccination effort. Many situations, and among intensive care unit patients other vaccines have been authorized and used in (Ağagündüz et al. 2021). The study also notes that it countries outside the United States. Each vaccine has is highly possible that these situations may increase a specific safety profile; this is why monitoring safety the risk of drug-drug interactions, but also raise the at the local level is important. risk of food and nutrition-drug interactions and affect nutritional status. ADEs of therapies for COVID-19 COVID-19 is a chronic inflammatory disease. The value of pharmacovigilance Although the exact mechanisms of COVID-19 have not yet been established, some drugs have been illustrated by the COVID-19 found to be helpful in treatment based on immune experience basic and antiviral properties of the disease. Because The pandemic has highlighted the relevance of the deterioration of the COVID-19 condition is pharmacovigilance during a public health emergency. associated with a weaker immune system, most of The fast-tracked or accelerated approval of drugs the identified therapies act on the immune system and vaccines to tackle COVID-19 did not allow the and immune cells. more comprehensive preauthorization studies that WHO has issued a conditional recommendation are usually conducted with medicines. Instead, it for the use of these therapies because the reviewed emphasized the need to expedite the generation of evidence on the benefits and risks of intervention safety data in postmarketing settings by identifying are less certain. Hence, only supportive care has and preventing serious risks and ultimately ensuring been approved by WHO for now. For example, patient safety (Trifirò and Crisafulli 2022). WHO issued a conditional recommendation against Indeed, during the postvaccination period, a constant the use of remdesivir, meaning that there is not watch over the deployment and application of enough evidence to support the use of remdesivir. pharmacovigilance is critical to identifying previously In contrast, stringent regulatory authorities, such unknown serious adverse events. Monitoring vaccine as the FDA, recognizing that patients affected by safety is also much more than merely looking COVID-19 are in great need of medicines to treat the at the vaccine alone. Vaccines can interact with disease, approved remdesivir, as the first drug to treat concomitant medications taken by individuals. How COVID-19, for use among adults and pediatric patients individuals respond can be affected by concurrent ages 12 and older, weighing at least 40 kilograms preexisting conditions (chronic, such as hypertension (about 88 pounds), and requiring hospitalization. or diabetes, or acute, such as other infections). The This approval does not include the entire population safety of the vaccination process is equally important. that had been authorized to use remdesivir under 9 The Value of Pharmacovigilance in Building Resilient Health Systems Post-COVID The main interest of monitoring activities is the generation of knowledge about the safety of the individuals receiving a COVID-19 vaccine, taking into account the different actions, actors, and situations involved in immunization campaigns covering various population groups, geographical regions, and diverse health care systems. Indeed, adverse events following immunization can occur because of vaccination risks, such as underdosing, replacing one vaccine brand with another that is deemed less desirable by a specific population, replacing a vaccine with a nonvaccine product, revaccination with different COVID-19 vaccines if the product supply chain is interrupted, the cold chain is broken, or the quality of the inoculated vaccine is low, and vaccinating using expired vaccines or inappropriate inoculation techniques and safety protocols at the facility level. The above considerations illustrate the importance of monitoring not only the safety and effectiveness of vaccines, but also the tracking of vaccination safety (Wang, Figueras, and Marquez 2021). By doing this, policy makers and program managers are able to gain a wider knowledge of the impact of adverse events associated with vaccines, such as COVID-19 vaccines, but also with their administration. Inappropriate vaccination processes may thus increase the chance that adverse events from vaccination may appear. This knowledge could be the basis for the early identification of problems and the design of specific interventions to avoid preventable adverse outcomes that could harm the population and undermine the trust in the vaccination effort, further delaying the economic and social recovery of countries. 1. A general background on drug safety monitoring and the associated response to COVID-19 10 Box One Selected Serious Adverse Events of Interest Following COVID-19 Vaccination as Reported by the United States Vaccine Adverse Event Reporting System Anaphylaxis after COVID-19 vaccination is rare. Guillain-Barré syndrome (GBS) in people who It has occurred among approximately five people have received the J&J/Janssen COVID-19 vaccine per million vaccinated in the United States. is rare. GBS is a rare disorder whereby the body’s Anaphylaxis, a severe type of allergic reaction, immune system damages nerve cells, causing can occur after any kind of vaccination. If it muscle weakness and sometimes paralysis. Most happens, health care providers can effectively people fully recover from GBS, but some have and immediately treat the reaction. permanent nerve damage. After more than 18.6 million J&J/Janssen COVID-19 vaccine doses Thrombosis with thrombocytopenia syndrome had been administered, there were around 313 (TTS) after Johnson & Johnson’s Janssen (J&J/ preliminary reports of GBS identified in VAERS Janssen) COVID-19 vaccination is rare. TTS as of April 7, 2022. These cases have largely is a serious adverse event that causes blood been reported about two weeks after vaccination clots in large blood vessels and low platelets and mostly among men, many in the 50 and (blood cells that help form clots). As of April older age-group. Based on the data, the rate of 7, 2022, more than 18.6 million doses of the GBS within the first 21 days of vaccination was J&J/Janssen COVID-19 vaccine had been found to be 21 times higher following the J&J/ administered in the United States. The Centers Janssen COVID-19 vaccination than after the for Disease Control and Prevention (CDC) and Pfizer-BioNTech or Moderna vaccination (mRNA the Food and Drug Administration (FDA) have COVID-19 vaccines). After the first 42 days, the identified 60 confirmed reports of people who rate of GBS was 11 times higher following the J&J/ received the J&J/Janssen COVID-19 vaccine Janssen COVID-19 vaccination. Analysis found and later developed TTS. The CDC has also no increased risk of GBS after Pfizer-BioNTech or identified nine deaths that have been caused Moderna (mRNA COVID-19 vaccines). by or were directly attributed to TTS following J&J/Janssen COVID-19 vaccination. Women Myocarditis and pericarditis after COVID-19 ages 30–49, especially, should be aware of the vaccination are rare. Myocarditis is inflammation increased risk of this rare adverse event. There of the heart muscle, and pericarditis is are other COVID-19 vaccine options available inflammation of the outer lining of the heart. for which this risk has not been seen. To date, Most patients with myocarditis or pericarditis four confirmed cases of TTS following mRNA after COVID-19 vaccination responded well to COVID-19 vaccination (three after Moderna; one medicine and rest and felt better quickly. As after Pfizer-BioNTech) have been reported to the of April 7, 2022, VAERS had received 2,341 Vaccine Adverse Event Reporting System (VAERS) preliminary reports of myocarditis or pericarditis after more than 544 million doses of the mRNA among people ages 30 or younger who had COVID-19 vaccines had been administered in received COVID-19 vaccines. Most cases were the United States.a Based on the available data, reported after receiving Pfizer-BioNTech or there is not an increased risk of TTS after mRNA Moderna (mRNA COVID-19 vaccines), especially COVID-19 vaccination. among male adolescents and young adults. Source: CDC 2022c. Note: The information in the box is valid as of April 12, 2022. VAERS is an early warning system used to monitor adverse events that occur after vaccination. VAERS is co-sponsored by a.  the Centers for Disease Control and Prevention (CDC), and the Food and Drug Administration (FDA), agencies of the U.S. Department of Health and Human Services (HHS) (https://vaers.hhs.gov/about.html). 11 The Value of Pharmacovigilance in Building Resilient Health Systems Post-COVID Box Two The Work of the European Medicines Agency in Monitoring and Assessing Safety Signals Associated with the Administration of the AstraZeneca COVID-19 Vaccine in European Union Countries in 2021 A robust pharmacovigilance system can play EMA’s scientific committees and related groups an important role in two ways: (a) ensuring conduct the scientific work of the Agency. For the detection, assessment, understanding and example, the Pharmacovigilance Risk Assessment prevention of adverse effects or any other Committee (PRAC) is responsible for the safety vaccine/medicine related problem that may of medicines, and recommends changes in their only emerge after approval; (b) informing marketing authorization, including its suspension governments and other stakeholders on or withdrawal from the market if necessary, the safety of these products to properly if modifications or variations to an existing communicate risks and promote the uptake marketing authorization are identified. of marketed vaccines/medicines. Risk communication in pharmacovigilance is The work of agencies such as EMA demonstrates important. For example, EMA, after reviewing the value of a regional harmonized approach early in 2021 safety signals associated with the in monitoring the safety of vaccines and other administration of the AstraZeneca COVID-19 medicines. Its experience can be relevant for vaccine in some EU countries, was able countries/regions that are seeking to establish/ to advise national governments to resume strengthen their own pharamcovigilance system vaccination based on the results of its review and/or benefit from a more harmonized approach and to communicate to the population that across countries. the benefits of the AstraZeneca vaccine in preventing COVID-19, with its associated risk of EudraVigilance, the European Union (EU) hospitalization and death, outweighed the risks database for adverse reactions (AR) reports, of reported adverse effects. is the tool that EMA and National Competent Authorities (NCAs) use in monitoring the safety EMA work also helped inform policy making of all authorized vaccines/other medicines in the in countries outside Europe. For example, on 31 countries of the European Economic Area as March 16, 2021, EMA stated that AstraZeneca well as those being studied in clinical trials. Since vaccine’s benefits continued to outweigh the 2017, the electronic reporting of suspected ARs risks based on PRAC’s review of all reports of related to vaccines/other medicines by NCAs and thromboembolic events among 5 million people marketing authorization bodies to EudraVigilance vaccinated with the vaccine. Subsequently, WHO is mandatory. Its database holds over 18 issued a statement on March 17, 2021 to reiterate million safety reports and is one of the largest the EMA position, and the African Centers for pharmacovigilance databases in the world. Disease Control and Prevention recommended that African Union Member States continue to roll-out this vaccine as part of their vaccination campaigns in a statement issued on March 19. Source: Wang, Marquez, and Figueras 2022 12 2. Drug safety monitoring and the health system: general considerations 2 Drug safety monitoring and the health system: general considerations 2. Drug safety monitoring and the health system: general considerations 13 ADRs, especially those that are serious or life-threatening, represent a global public health problem that should be routinely addressed by health systems The impact of ADRs on service utilization and health outcomes ADRs are a significant challenge within a health system, particularly because of the increasing complexity of therapeutics, an aging population, and multiple comorbidities. Although most ADRs are mild, In this section, a detailed discussion is presented on serious ADRs sometimes lead to (1) clinical complica- the impact of ADRs in the health system and how tions among patients who are already frail, (2) longer pharmacovigilance contributes to building health hospital stays or longer work leaves for additional system resilience by strengthening system capacities treatments to manage the ADRs, (3) rising health care and helping achieve positive outcomes. costs, and (4) the occasional death of the patient. ADRs, especially those that are serious or life- The burden of ADRs on health systems may be more threatening, represent a global public health problem. well appreciated by a look at the related metrics. They result in high mortality and morbidity. Various For example, the prevalence of hospital emergency trends in ADR-related hospitalizations have been department visits for ADRs in the United States studied in many countries, providing evidence that, was estimated at 4 per 1,000 visits in 2013 and 2014, without proper monitoring, analysis, and investigation, and anticoagulants, antibiotics, diabetes agents, these unintended events can impose extra burdens and opioid analgesics were the most common on a health system (additional disease burden and drug classes implicated (Shehab et al. 2016). Recent deaths, deprivation of resources, and so on), slowing work at the CDC has estimated that more than the world’s progress toward universal health care. 14 The Value of Pharmacovigilance in Building Resilient Health Systems Post-COVID 1 million individuals are seen in hospital emergency with a median prolongation in the hospital stay of departments for ADRs each year in the United four days, which is similar to the findings of another States; more than one-quarter of these patients must study (Nobili et al. 2011). be hospitalized for further treatment.4 Similarly, Another study using a census of hospital admission according to a European Commission report, data from New South Wales, Australia, between percent–10 percent of hospital admissions between 3 ­ July 2000 and June 2012 assessed the changes 2012 and 2014 were estimated to have been associ- in incidence and their impact on length of stay, ated with ADRs, totaling about 2.5 million–8.4 million readmission, and in-hospital mortality (Walter annually, and 2.1 percent–6.5 percent of hospitalized et al. 2017). The authors conclude that the relative patients experienced an ADR, corresponding to incidence of serious ADRs, at best, did not decrease million–5.5 million annually (EC 2016). 1.8 ­ between 2000 and 2012 and, in some cases, Although there are no recent country studies substantially increased. Additionally, serious available, previous studies have suggested that, in ADRs were associated with a considerably longer some countries, ADRs rank among the leading causes hospital stay and a significant increase in the risk of hospitalization and death. For example, between of readmission or in-hospital mortality for certain 44,000 and 98,000 deaths in the United States occur types of ADR. annually from medical errors, and, of this total, an In terms of COVID-19 vaccines, and observed estimated 7,000 deaths occur because of ADRs (Kohn, adverse reactions among different population Corrigan, and Donaldson 2000). Other studies among groups, a study that assessed data from the hospitalized patients provide higher estimates on European Database of Suspected Adverse Drug the overall incidence of serious ADRs. They estimate Reaction (EudraVigilance) and the United States that 6.7 percent of hospitalized patients have serious Vaccine Adverse Events Reporting System (VAERS) ADRs, with a fatality rate of 0.32 percent (Lazarou, from 2020 to October 2021, including more than Pomeranz, and Corey 1998). These findings, then, 7.8 million adverse reactions of about 1.6 million suggest that there are more than 2,216,000 serious persons, showed a higher risk of reporting serious ADRs among hospitalized patients that cause over adverse reactions for the COVID-19 vaccines 106,000 deaths annually and that rank ADRs as the in comparison with the influenza vaccines fourth leading cause of death in the United States (Montano 2022). Individuals ages 65 and older (Gurwitz et al. 2000). These statistics, however, do not were associated with a higher frequency of death, include the number of ADRs that occur in ambulatory hospitalizations, and life-threatening reactions settings. It is estimated that over 350,000 ADRs occur than younger individuals (relative risk estimates in US nursing homes each year (Kohn, Corrigan, and between 1.49 and 8.61). Outcome onset of serious Donaldson 2000). adverse reactions occurred within the first seven A more recent study in Italy estimated the in-­hospital days after vaccination in about 77.6 percent–89.1 incidence rate of ADRs at 3.2 per 100 patients percent of cases. The largest absolute risks were admitted, compared with findings of several observed for allergic, constitutional reactions, previous studies that reported a range of 1.7 percent dermatological, gastrointestinal, neurological to 50.9 percent, depending on differences in data reactions, and localized and nonlocalized pain. collection methods, definitions of ADRs, the popula- The largest relative risks between COVID-19 and tions studied, and the settings in which the studies influenza vaccines were observed for allergic were performed (Giardina et al. 2018). The onset of at reactions, arrhythmia, general cardiovascular least one ADR during hospitalization was associated events, coagulation, hemorrhages, gastrointestinal, ocular, sexual organs reactions, and thrombosis. 4  S  ee Medication Safety Program (dashboard), Centers for Disease Control and Prevention, Atlanta, https://www.cdc.gov/ medicationsafety/index.html. 2. Drug safety monitoring and the health system: general considerations 15 Impact of ADRs on health care costs Besides the clinical consequences of ADRs for the individual, ADRs are expensive. ADRs raise health care resource utilization, including for emergency department visits. Likewise, ADR-related hospitalization is a significant factor in rising direct medical costs. Indeed, the findings of a recent study in the Republic of Korea suggest that drug-related emergency department visits increase the burden on health insurance systems and the out-of-pocket costs to patients, mostly because of higher hospitalization costs (Lee et al. 2020). The findings of the study show that the mean cost per ADR rose by 26.1 percent during the six-month follow-up compared with the cost during the six months before the emergency department visit and that preventable ADRs accounted for approxi- mately 19.9 percent of the cost increase among all ADR cases. 16 3. ADEs, ADRs, and the key building blocks of pharmacovigilance and national and regional systems 3 ADEs, ADRs, and the key building blocks of pharmacovigilance and national and regional systems 3. ADEs, ADRs, and the key building blocks of pharmacovigilance and national and regional systems 17 Knowledge on the effectiveness and safety of new and already approved treatments under real-life conditions is essential women, and individuals with comorbid conditions. Hence, clinical trials cannot reflect the experience in larger populations and across geographical regions that may differ from one another with respect to genetics, food habits, life style, and clinical practices. For this reason, gathering knowledge to determine the effectiveness and safety of new and already approved treatments under real-life conditions Building knowledge on the  once they receive market authorization is essential. safety of medicines More information is often needed about the safety and effectiveness of drug use in specific population Knowledge about the safety of medicines is typically groups, notably, children, pregnant women and the generated during the processes involved in the clini- elderly, and about the efficacy and safety of chronic cal development of medicines as illustrated in figure use, especially in combination with other medicines. 2. During clinical trials, most medicines are only Experience has shown that many adverse effects, tested for short-term safety and efficacy. Normally, interactions with foods or other medicines, and risk clinical trials cover a relatively limited number of factors come to light only during the years after the individuals who are selected according to strict release and use of a medicine among the general inclusion criteria. The criteria often exclude special population (WHO 2002). patient groups, such as children, the elderly, pregnant 18 The Value of Pharmacovigilance in Building Resilient Health Systems Post-COVID Figure 2  The Drug Life Cycle Drug Life Cycle Drug development and life-cycle timeline Submission of Pre-human • Compound selection investigational Research • Lab and animal studies new drug (IND) application to FDA • First human studies Phase 1 • Dose-ranging pharmacokinetics tolerability • Exploratory studies of efficacy and safety Phase 2 • Refining dose • Confirmatory studies of efficacy and safety Submit Phase 3 • Define efficacy and safety for approval application for approval FDA Review Approval • Monitoring adverse event reports • As needed: epidemiological studies of safety • Clinical trials of safety Post approval • Risk management efforts & Phase 4 • Clinical trials of new indications Source: Dal Plan 2015. Note: This figure illustrates the principal activities that occur during the life cycle of a drug, from prehuman studies through postmarketing surveillance. The duration of each phase varies from drug to drug and is not reflected in the figure. FDA= US Food and Drug Administration A review of ADEs carried out in the context of a The objectives and scope safety signal, which is information on a new or incompletely documented adverse event that is of pharmacovigilance potentially caused by a medicine and that warrants Pharmacovigilance is “the science and activities relat- further investigation under an accelerated timetable, ing to the detection, assessment, understanding, and is critically important to inform decision-making in a prevention of adverse effects or any other possible health system and to protect the population. drug-related problems” (WHO 2002, 7). This definition Drug safety monitoring through pharmacovigilance focuses on monitoring and evaluating the safety activities, including mining spontaneous reporting of the use of drugs, key components in effective and carrying out observational prospective cohort drug regulation systems. In practice, this signifies or retrospective database studies, allows longer establish-ing a well-organized pharmacovigilance follow-up periods among patients with a much wider system to identify, describe and occasionally prevent range of characteristics, thereby providing valuable the risks associated with the use of medicines. means to gain knowledge on the detection, descrip- tion, quantification, and, where possible, reduction of ADRs. 3. ADEs, ADRs, and the key building blocks of pharmacovigilance and national and regional systems 19 The principal aims of a pharmacovigilance system are individual patients, and national medicine policies as follows: and treatment guidelines • To develop and maintain drug utilization • Improve patient care and safety in the use of information medicines and all medical and paramedical • To identify issues associated with the unregulated interventions by increasing the knowledge on the prescription and dispensing of medicines risks associated with the use of these medicines in real-life conditions • Improve public health and safety in the use of Minimum requirements for a medicines functional pharmacovigilance system • Contribute to the assessment of the benefits, The following are the minimum requirements that harms, effectiveness, and risks of medicines to WHO and partners agree should be met in any encourage safe, rational, and more effective use, national pharmacovigilance system (WHO and including cost-effective use GFATM 2010): • Promote understanding, education, and clinical • A national pharmacovigilance center that has training in pharmacovigilance and effective designated staff (at least one full time), stable communication about pharmacovigilance among basic funding, clear mandates, and well-defined health professionals and the public structures and roles and that collaborates with the WHO Program for International Drug Monitoring The functions of national • A national spontaneous reporting system—a pharmacovigilance systems passive surveillance system that relies on health The functions include the following (WHO 2015): care professionals to detect and report on ADRs— with a national individual case safety report form, • To promote pharmacovigilance in the country, an ADR reporting form notably, to collect and manage ADR reports and • A national database or system for collating and reports on medication errors and on suspected managing ADR reports counterfeit or substandard drugs • A national ADR or pharmacovigilance advisory • To collaborate and harmonize with existing ADR committee able to provide technical assistance report collection activities within the country (for on causality assessment, risk assessment, risk example, national disease control programs and management, case investigation, and, where the ministry of health) as well as international necessary, crisis management, including crisis studies on ADR monitoring among defined patients communication or populations (cohorts) • A clear communication strategy for routine • To identify signals, that is, unknown or poorly communication and communication during crises identified adverse events in relation to a medicine or a combination of medicines and their use • To undertake assessments of risks and options for Organizational and risk management operational arrangements • To identify quality issues in medicines that result in ADRs and, more generally, to support the identifica- Institutional arrangements and processes have been tion of quality issues in medicines established at the national, regional, and global levels • To provide effective communication on aspects to conduct pharmacovigilance. Detailed examples are related to the safety of medicines, including presented below. dispelling unfounded rumors of toxicity attributed United States. The FDA is responsible for conducting to medicines and vaccines pharmacovigilance activities to identify new safety • To apply information resulting from pharmacovig- concerns that may be related to a marketed product, ilance for the benefit of public health programs, evaluating a manufacturer’s compliance with 20 The Value of Pharmacovigilance in Building Resilient Health Systems Post-COVID reporting regulations, and responding to outside The reports of RPVCs provide data and information requests for information (FDA 2018). The collected for the early detection of new, rare, and serious ADEs. ADE reports are reevaluated by clinical reviewers at The paradigm of pharmacovigilance in Korea is the Center for Drug Evaluation and Research and the expected eventually to undergo development to over- Center for Biologics Evaluation and Research who come some of the limitations in passive surveillance, monitor the safety of products after they have been which relies on voluntary ADE reporting and which is approved by the FDA. If a potential safety concern is plagued by underreporting. This would occur through identified, further evaluation is performed, including the establishment of an active surveillance system conducting studies using other large databases, such for postmarket drugs, for example, the application as those available in the Sentinel System. Based on of detection algorithms for drug-induced liver injury an evaluation of the potential safety concern, the based on electronic health records and data on FDA may take regulatory action to improve product claims at the National Health Insurance Institute. safety and protect public health, such as updating a product’s labeling information, restricting the use of European Union. The European drug regulatory the drug, communicating new safety information to system is based on a network of around 50 regulatory the public, or, in rare cases, removing a product from authorities in the 30 European Economic Area coun- the market. tries, the European Commission, and the EMA (Wang, Marquez, and Figueras 2022). The EMA, established Republic of Korea. Korea has a decentralized drug in 1995, operates at the heart of the network, coor- safety monitoring system (Wang, Marquez, and dinating and supporting interactions among more Figueras 2021). The Korea Institute of Drug Safety and than 50 national competent authorities in human Risk Management was established in 2012 by Article and veterinary medicine. The EMA has also become 68-3 of the Pharmaceutical Affairs Act as a dedicated a major player in the harmonization of European agency under the Ministry of Food and Drug Safety. and international drug regulations. The EMA Its purpose is to support evidence-based decisions on scientific committees and related groups conduct drug safety by fostering voluntary ADE reporting by the scientific work of the agency. For example, the health care providers, patients, and pharmaceutical Pharmacovigilance Risk Assessment Committee is companies, assessing drug safety information, responsible for the safety of medicines and recom- performing causality assessments, developing drug mends changes in the marketing authorization of utilization review criteria, disseminating safety infor- medicines, including suspension or withdrawal from mation, and providing education to the public. The the market if necessary modifications or variations in institute acts as a center for a nationwide monitoring an existing marketing authorization are identified. network comprised of 28 regional pharmacovigilance centers (RPVCs). Among the RPVCs, 26 are local Figure 3 illustrates the integrated steps and processes teaching hospitals; one, the Korea Pharmaceutical followed in pharmacovigilance, the role played by Association, is linked with pharmacies throughout countries within the regional system of the European the country; and one is the RPVC for Korean Herbal Union, and the flow of information within the Medicines. The RPVCs monitor ADEs, including ADEs system. The safety signal report, which contains reported by local clinics and pharmacies. They also information on a new or incompletely documented undertake the intensive monitoring of the drugs adverse event that is potentially caused by a used among special populations (such as pediatric medicine and that warrants investigation under an or geriatric drugs) or of special medicinal products accelerated timetable, originates at the country level. designated by the Ministry of Food and Drug Safety. The pharmacovigilance programs in the countries The ministry is the chief governmental body that are responsible for encouraging reporting, ensuring regulates food, pharmaceuticals, biologics, and that reports reach the relevant pharmacovigilance medical products and is responsible for overseeing center, including the minimum information to be the registration, manufacture, and distribution of considered, are appropriately assessed, and are these products and for postmarketing surveillance. shared with the regional pharmacovigilance program. 3. ADEs, ADRs, and the key building blocks of pharmacovigilance and national and regional systems 21 Figure 3  The Flow of Information through the European Medicines Agency EMA EudraVigilance Signals WHO US FDA Pharmacovigilance Risk Assessment Committee (PRAC) Countries/ Country Country Country Safety National A B C Information Authorities 1 2 Local PV 3 (optional) Reports Reports Reports Country Country Country Public Information, Reporters A B C Social media, etc. PV Model: centralized decentralized Source: World Bank elaboration. National pharmacovigilance programs can either development by taking part in the work of the EMA raise a signal or make a signal more robust by adding scientific committees. The EMA can assist countries reports. Additionally, national pharmacovigilance in policy decisions if a given country does not have programs use safety information originating at the a strong pharmacovigilance capacity, or it can serve EMA level and ensure that local differences at the as an impartial referee in cases of safety concern country level are studied. involving a local manufacturer. Individual countries can also benefit by being part of Postmarketing safety surveillance a regional pharmacovigilance system. For example, such a system facilitates access to reports from As with any medical treatment, the only way to various countries on potential safety signals related observe extremely rare risks is to continue to gather to the use of new medications. Also, specialists from data once the drugs are in use among the general all member countries can further their professional population. The monitoring of medicine safety 22 The Value of Pharmacovigilance in Building Resilient Health Systems Post-COVID includes several processes throughout the product Select postmarketing data sources life cycle, as follows: The most important, least expensive, simplest, and • The collection and management of data, most widely used method of detecting potential ­ information, and documents on product safety ADRs over the last half century has been the sponta- • The review and assessment of data, information, neous and voluntary reporting of cases by patients, and documents on product safety consumers, and health care professionals, as well as • Action on the basis of coordinated decision- by drug manufacturers in accordance with manda- making through technical committees and a tory regulatory requirements. Reporting systems, such coordination group as the Yellow Card Scheme in the United Kingdom • Coordination of safety communications operated by the Medicines and Healthcare Products • Monitoring the implementation and impact Regulatory Agency and the Commission on Human of regulatory actions Medicines, collect data on suspected ADRs related to all licensed and unlicensed medicines and vaccines, Figure 4 illustrates the process of the monitoring of including those issued by prescription or purchased medicine safety after the administration of a drug to over the counter (Coleman and Pontefract 2016). a patient. Figure 4  Illustration of the Drug Safety Monitoring Process Patient experiencing Someone suspects Reporting to an event an adverse event the PV Centre New Knowledge Feedback ADVERSE REACTION Signal Local • Intrinsic Investigating causes. detection database • Inappropriate use Causality assessment • Error PV Network COINCIDENTAL - database NOT RELATED EVENT Source: World Bank elaboration. 3. ADEs, ADRs, and the key building blocks of pharmacovigilance and national and regional systems 23 The spontaneous and voluntary reporting of to new information with which to evaluate a drug’s suspected ADRs generates signals about rare, delayed, risk profile. and unexpected drug reactions that are undetected in the initial phases of drug development. Pharmacovigilance databases The major limitations of the system of sponta- Computerized databases of spontaneous reports neous reporting of ADRs are well known: the have been established at the country, regional, and poor quality of the reports submitted; significant global levels to support postmarketing drug safety underreporting of adverse reactions; difficulty in monitoring. In the United States, for example, the calculating rates because of incomplete numerator FDA Adverse Event Reporting System (FAERS) is data, along with unreliable denominators; and a database that supports the FDA’s postmarketing the limited ability to establish cause and effect safety surveillance program aimed at all marketed (Lexchin 2006). drug and therapeutic biologic products (FDA 2017). It functions as follows: A number of methods that have proven successful in stimulating ADR reporting in the medical • The structure of the FAERS database adheres ­ community include educating doctors on the to the international safety reporting guidance issued by the International Conference on need to report, familiarizing doctors with the Harmonization.5 reporting system in general and the forms and • Adverse events and medication errors are coded guidelines in particular, and providing doctors to terms in the Medical Dictionary for Regulatory with follow-up on the reports they have filed Activities terminology.6 (Goldman 2004). • Reporting on adverse events and medication Computer technology, which allows multiple errors by health care professionals and consum- databases to be linked, is also helping in investi- ers is voluntary in the United States. The FDA gating drug safety issues. The widespread use of receives some adverse event and medication electronic medical record databases has enhanced error reports directly from health care profes- patient safety through the automation of signal sionals (such as physicians, pharmacists, and detections for ADRs, thereby improving health care nurses) and consumers (such as patients, family service delivery. members, and lawyers). Health care professionals and consumers may also report adverse events Voluntary or required postmarketing studies, such or medication errors to product manufacturers. If as observational studies (including automated a manufacturer receives an adverse event report, health care and databases) and randomized it is required to send the report to the FDA as clinical trials, also provide drug safety data specified by regulations. The reports received and information. directly and the reports from manufacturers are In the future, the development of advanced entered into FAERS. methodologies, including machine learning Another example is the Korea Adverse Event techniques and the availability of large amounts of Reporting System, which is a computerized ADE electronic health care data, offers the opportunity reporting system developed by the Korea Institute to optimize drug benefit–risk profile evaluations of Drug Safety and Risk Management in 2012 (Wang, in real world settings (see Trifirò and Crisafulli 2022). Indeed, systematic clinical data mining can accelerate the speed at which ADE signals 5  S  ee E2B(R3) Individual Case Safety Report (ICSR) Specification and can be detected, thereby contributing to building Related Files (dashboard), International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, resilience in health systems. Such an active drug Geneva, https://www.ich.org/page/e2br3-individual-case-safety- safety surveillance system would allow drugs to be report-icsr-specification-and-related-files. 6  S  ee MedDRA (Medical Dictionary for Regulatory Activities), monitored longitudinally over their entire life cycle, International Council for Harmonisation of Technical Requirements providing regulatory authorities with timely access for Pharmaceuticals for Human Use, Geneva, https://www.meddra.org/. 24 The Value of Pharmacovigilance in Building Resilient Health Systems Post-COVID Marquez, and Figueras 2021). The associated database The purpose of EudraVigilance is as follows: contains more than one million ADE reports from • Electronic exchange of individual case safety health care professionals, consumers, RPVCs, and reports based on the international safety reporting pharmaceutical companies, as well as reports based guidance issued by the International Conference on postmarketing surveillance, observational studies, on Harmonization (see above) such as pharmacoepidemiologic studies to collect • Electronic exchange of suspected ADR reports safety information on drug products, and studies of among the EMA, national authorities, marketing other drug adverse reaction surveillance programs. authorization holders, and sponsors of clinical The Indian Pharmacopoeia Commission trials in the European Economic Area acts as the national coordination center for the • Early detection of possible safety signals associated Pharmacovigilance Program of India (Kalaiselvan et with medicinal products for human use al. 2015). In various medical institutions and hospitals • The continuous monitoring and evaluation of across India, 150 ADR monitoring centers have been potential safety issues in relation to reported established to monitor and collect ADR reports for adverse reactions the program. The program encourages all types of • A decision-making process based on a broader reporting on suspected ADRs, whether they are known understanding of the adverse reaction profile of or unknown, serious or nonserious, or frequent or medicinal products, especially in the framework rare, regardless of any established causal relationship of risk management between a drug and the reaction. All health care Since 2017, the electronic reporting of suspected ADRs professionals, patients, and consumers can report related to vaccines or other medicines by the national ADRs to the Indian Pharmacopoeia Commission or competent authorities of the European Union the ADR monitoring centers. The pharmaceutical member states to EudraVigilance is mandatory. The companies can also send individual case safety EudraVigilance database holds over 18 million safety reports on their product to the commission. Suspected reports and is one of the largest pharmacovigilance ADR reporting forms for health care professionals databases in the world. and consumers are available on the website of the commission. To remove language barriers in ADR At the global level, the Uppsala Monitoring reporting, the consumer reporting form is available in Center, located in Uppsala, Sweden, is the WHO 10 vernacular languages (Assamese, Bengali, Gujarati, Collaborating Center for International Drug Hindi, Kannada, Malayalam, Marathi, Oriya, Tamil, Monitoring.7 Since 1978, the management of the and Telugu). ADRs may also be reported through the WHO Program for International Drug Monitoring helpline number of the Pharmacovigilance Program of and the coordination of the relevant activities of the India on weekdays from 9 am to 5:30 pm. The mobile program’s more than 100 country participants have Android application for ADR reporting has also been been the responsibility of the center. To improve made available to the public. patient therapy and public health worldwide, the center collects, assesses, and communicates informa- At the regional level, a good example of an ADR tion from national pharmacovigilance programs on reporting system is the European Union Drug the benefits, harm, effectiveness, and risks of drugs Regulating Authorities Pharmacovigilance and other substances used in medicine. The center (EudraVigilance), a data processing network and also collaborates with countries in the development management system for reporting and evaluating and practice of the science of pharmacovigilance. suspected ADRs during the development stage and following the marketing authorization of medic- VigiBase is the WHO global database of individ- inal products in the 30 countries of the European ual case safety reports managed by the Uppsala Economic Area (Wang, Marquez, and Figueras 2022). 7   MC (Uppsala Monitoring Centre) (website), Uppsala, Sweden, U https://who-umc.org/. 3. ADEs, ADRs, and the key building blocks of pharmacovigilance and national and regional systems 25 Monitoring Center.8 National and regional agencies Challenges in system contribute internationally to the database by sending regular reports on ADRs. VigiBase is the largest development in low- and database of its kind in the world, with over 30 million middle-income countries reports of suspected adverse effects of medicines, The findings of recent studies are presented below submitted, since 1968, by WHO member countries to highlight the unique challenges facing low- and and regional agencies. It is continuously updated middle-income countries in establishing functional with incoming reports. National centers are asked to pharmacovigilance systems. send reports at least quarterly. VigiBase is a computerized pharmacovigilance Africa system in which information is recorded in a A study focusing on the situation in Africa found structured, hierarchical form to allow for easy and that a major challenge is the limited integration and flexible retrieval and analysis of the data. Alongside reliability of pharmacovigilance systems despite data management and quality assurance tools, recent efforts to harmonize rules and regulations the VigiBase system is linked to medical and drug (Kiguba, Olsson, and Waitt 2021). There are particular classifications such as MedDRA, WHO-ART, WHODrug challenges relating to the need to translate reporting Global, and WHO ICD.9 These classifications enable tools into numerous local languages and the low structured data entry, retrieval, and analysis at number of health care providers relative to the various levels of precision and aggregation, which number of patients, which leads to short consulta- are vital in enabling effective and accurate analysis. tions. Additional factors found in the study include Typical methods of managing ADRs include altering the high take-up of herbal and traditional medicines, a dosage regimen or withdrawing a medicine mostly through self-medication; disruptive political suspected of causing an ADR. For instance, under conflicts that jeopardize fragile systems; and little European Union legislation, the approval of all new or no access to drug utilization data, which makes medicines on the market must now be accompanied the reliable estimation of the true risks of using the by a robust risk management plan from the mar- medicines difficult. keting authorization holder, which may involve the The study also indicates that pharmacovigilance development of specific treatments for managing activities are hindered by the scarcity of well-trained specific ADRs, as well as ongoing safety trials personnel and the lack of budgetary support by gov- (Coleman and Pontefract 2016). ernments; high turnover among pharmacovigilance staff, whose training involves substantial resources; and the lack of awareness about pharmacovigilance among health care workers, decision-makers, and consumers. Furthermore, little collaboration was found between public health programs and national medicine regulatory authorities, coupled with limited investment in pharmacovigilance activities, 8  “ About VigiBase,” Uppsala Monitoring Centre, Uppsala, Sweden, https://who-umc.org/vigibase/. especially during the mass administration of drugs 9  S  ee, respectively, MedDRA (Medical Dictionary for Regulatory against neglected tropical diseases. Mass vaccina- Activities), International Council for Harmonisation of Technical tions often produce major challenges if a culture of Requirements for Pharmaceuticals for Human Use, Geneva, https:// www.meddra.org/; WHO-ART (WHO Adverse Reaction Terminology) systematically embedding pharmacovigilance has (website), Uppsala Monitoring Centre, Uppsala, Sweden, https:// not been established. Low spontaneous reporting who-umc.org/vigibase/vigibase-services/who-art/; WHODrug Global (WHO Drug Dictionary) (dashboard), Uppsala Monitoring Centre, rates and the poor quality of reports also hinder Uppsala, Sweden, https://who-umc.org/whodrug/whodrug-global/; robust signal detection analyses. WHO ICD (International Statistical Classification of Diseases and Related Health Problems) (dashboard), World Health Organization, Although the implementation of pharmacovigi- Geneva, https://www.who.int/standards/classifications/ classification-of-diseases. lance systems in resource-limited countries is a 26 The Value of Pharmacovigilance in Building Resilient Health Systems Post-COVID complicated endeavor, there are good experiences. legal provisions for pharmacovigilance and Despite country- and continent-specific challenges, postmarket surveillance at their disposal, no clear the government and stakeholders in the Democratic approaches have been implemented to support Republic of Congo have been able to develop one the performance of the regulatory activities of the most active pharmacovigilance systems in required, and resources are often shifted rather Sub-Saharan Africa. The experience to set up a randomly among government entities. The national pharmacovigilance system for antimalarial drug regulatory authorities in the region also report ADRs safety monitoring has been assessed by WHO as a to global monitoring systems at lower rates than best practice that needed to be documented to help other international reference authorities, although improve the country’s pharmacovigilance system they have made substantial progress in reporting and scale it up in other African countries (Nzolo cases of substandard and falsified medicines. The et al. 2019). Lessons learned from the experience of assessment concluded that, while there is room for the Democratic Republic of Congo show that it is improvement, some national regulatory authorities possible to implement pharmacovigilance systems are using targeted or active pharmacovigilance to to promote patient safety in resource-limited gain efficiencies in the detection and evaluation Sub-Saharan African countries with no guaranteed of medicine adverse reaction information, and funding. The ability of national pharmacovigilance their capacity to translate pharmacovigilance data centers to collaborate with public health stakehold- into regulatory action is also increasing. However, ers, including public health authorities at all levels the rise in illegal online sales of medicines and and public health programs, and to use existing the limited enforcement of a ­ dvertising rules pose health information systems is considered the key particular challenges in tackling substandard and to success and may substantially reduce the cost falsified products. of pharmacovigilance activities. Takeaways Southeast Asia The accumulated experience on p ­ harmacovigilance Similar positive experiences have been documented in low- and middle-income countries clearly shows among countries in the Association of Southeast that there are systemic aspects that merit particular Asian Nations. Thus, among countries that responded attention. These include the need to ensure budget- to a survey (Cambodia, Indonesia, the Lao People’s ary predictability and the appropriate allocation of Democratic Republic, Malaysia, the Philippines, resources (such as funding, staff, and training) to Singapore, Thailand, and Vietnam), the pharmacovig- support pharmacovigilance as an integral element ilance systems in four countries (Indonesia, Malaysia, of the health system to enhance the capacity of Singapore, and Thailand) achieved all aspects of countries to address in a timely manner the growing the WHO minimum requirements for a functional number and complexity of drugs entering the market. national pharmacovigilance system, including Strengthening coordination with other programs capacity, functionality, and legislative framework and institutions is also needed to enable the active (Suwankesawong et al. 2016). The remaining coun- support and engagement of all stakeholders in tries were deemed to have unclear communication pharmacovigilance activities and to improve ADR strategies or no official advisory committee. management and assessment, including global reporting, so that pharmacovigilance information is Americas translated into assessments that inform and guide An assessment conducted by the Pan American policy makers, program managers, and service Health Organization (PAHO 2022) finds that, providers and, where appropriate, contribute to although all national regulatory authorities have regulatory action. 27 4. Using pharmacovigilance to foster resilient health systems 4 Using pharmacovigilance to foster resilient health systems 4. Using pharmacovigilance to foster resilient health systems 28 Providing support for pharmacovigilance and evidence gathering on medicine and vaccine safety and effectiveness helps enhance health systems health technologies is one of the essential public health functions (EPHFs) that are part of the core capacities of a resilient health system (PAHO 2020) (figure 5; also see section 5).10 10   PHFs are defined according to four stages of an integrated E What is health system resilience? approach whereby each function has equal relevance and cannot be isolated from the others, as follows: (a) Assessment: EPHF 1: monitoring and evaluation of health and well-being, equity, In a health system, resilience is the ability to prepare social determinants of health, and health system performance for, manage (absorb, adapt, and transform), and and impact; EPHF 2: public health surveillance; control and management of health risks and emergencies; EPHF 3: promotion learn from shocks (Sagan et al. 2022).The shocks are and management of health research and knowledge. (b) Policy often sudden and extreme natural, financial, or other development: EPHF 4: development and implementation of health policies and the promotion of legislation that protects the health of acute disturbances, such as a pandemic. The shock the population; EPHF 5: social participation and social mobilization, experience and shock management provide valuable inclusion of strategic actors, and transparency. (c) Allocation of resources: EPHF 6: development of human resources for health; information not only for improving the current EPHF 7: ensuring access to and the rational use of good-quality, safe, system, but also for handling a subsequent shock and effective essential medicines and other health technologies; EPHF 8: efficient and equitable health financing. (d) Access: EPHF more effectively in the future. 9: equitable access to comprehensive good-quality health services; EPHF 10: equitable access to interventions that seek to promote health, reduce risk factors, and promote healthy behaviors; EPHF Ensuring access to and the rational use of good-­ 11: management and promotion of interventions on the social quality, safe, and effective medicines and other determinants of health. 29 The Value of Pharmacovigilance in Building Resilient Health Systems Post-COVID Figure 5  Key Capacities: Reforms to Improve Resilience Governance, Coordination and Partnerships, Policy 1 Public health functions Innovation and 2 Service delivery including primary care Technology Financing 3 Supply chain 4 Response readiness and emergency operations 5 Community engagement and risk communications Human Resources Source: Adapted from World Bank 2022. This function addresses three key dimensions: (1) the to newly authorized drugs, is a critical public regulation and monitoring of the safety, quality, and good investment to ensure that these drugs work efficacy of medicines and other health technologies; correctly and that their health benefits outweigh ­ (2) the selection, evaluation, incorporation, and their known risks. rational use of essential medicines and health The reporting of adverse effects and reactions after technologies; and (3) the promotion, provision, the use of a drug is a critical tool to (1) informing and financing of medicines and other essential decision-making in a health system, (2) educating health technologies. and offering guidance to health providers, (3) helping Pharmacovigilance, which relates to the systematic address public safety concerns about new medicines detection, reporting, assessment, understanding, and vaccines, and (4) stimulating prompt policy and and prevention of adverse events and reactions, regulatory actions. is an essential aspect of the first dimension under While in-depth reviews of reports on serious ADE and this essential public health function (Shrestha et al. safety signals are conducted, there is also a need to 2021). The overall goal in undertaking this work is undertake drug utilization reviews to analyze patterns to improve patient care and safety through the use of drug usage in the health system against predeter- of any kind of medication; enhance public health mined standards (Wang, Marquez, and Figueras 2021). and safety in the use of medication; contribute to These reviews play a key role in improving the quality the assessment of benefits, harm, effectiveness, and of pharmaceutical care by supplying prescribers and risks of medicines; and encourage safe, rational, pharmacists with feedback on their performance and more effective, and cost-effective use of drugs among prescribing behaviors to prevent inappropriate drug countries (WHO 2002). use. Drug utilization reviews can effectively reduce Building the capacity in countries and at the regional the incidence of preventable ADEs. level to conduct thorough surveillance of the use of all medicines and vaccines, with particular attention 4. Using pharmacovigilance to foster resilient health systems 30 Support for national drug policy forthcoming, the issue of safety is less certain. There is a possibility that rare yet serious adverse events and medicine regulation will not be detected during the preregistration The use of medicine and vaccines has become an development of the drug leading to the need for the integral aspect of life. Drug expenditure is an import- constant postmarketing monitoring of drug safety ant component of total health expenditure, amount- risks (WHO 2004). ing to about 15 percent of total health spending, a The undertaking of this work involves a multidis- relatively steady share across the 11 major markets ciplinary collaboration that includes various health in the world over time (the United States, Japan, system stakeholders, from departments in ministries Germany, France, Italy, Spain, the United Kingdom, of health, the pharmaceutical industry, and universi- Brazil, Canada, Korea, and Australia) (IQVIA 2021). ties to professional associations. Reports of suspected The provision of good quality, safe and effective ADEs associated with these products are submitted medicines and their appropriate use is the responsibil- to VigiBase, the global database of individual case ity of national governments. For all medicines, there safety reports, which is managed by the Uppsala is a trade-off between the benefits and the potential Monitoring Center, a WHO-collaborating center, to for harm (Jeetu and Anusha 2010). Pharmacovigilance inform on global public health recommendations plays a specialized and critical role in ensuring ongoing and guide programs. safety of medicinal products. In particular, postmarket- In the case of the COVID-19 vaccines, these vaccines ing safety drug monitoring, includes detection of rare have undergone and will continue to undergo the ADRs not detected in clinical trials, drug interactions most intensive safety monitoring ever implemented and other effects caused by the use of medicines in in the European Union and the United States, as well everyday care, assessing the contribution of excipients as in other countries. For example, to make sure that and preservatives to the safety profile, systems for COVID-19 vaccines are safe, the CDC expanded and comparing safety profiles of similar medicines, and strengthened the ability of stakeholders to monitor measuring the environmental burden of medicines vaccine safety by developing new ways to gather through the surveillance of the effects of drug residues more information about the safety of COVID-19 vac- such as antibiotics, psychoactive drugs and hormones cines, including web-based platforms that give CDC on human health and livestock (Wilkinson et al. 2022). scientists information about the safety of COVID-19 The COVID-19 pandemic has highlighted the import- vaccines in real time (CDC 2022b). Vaccine safety ant role that pharmacovigilance plays in national experts can thus monitor and detect issues that may drug policy and medicine regulation by supporting not have been observed during COVID-19 vaccine the provision of good quality, safe, and effective clinical trials. If any vaccine adverse events are medicines and the appropriate use of medicines. reported, CDC scientists can quickly study them and The global emergency response to the pandemic has determine if there is a safety concern with a particu- required the introduction of various types of vaccines, lar vaccine. Because of this vaccine safety monitoring the repurposing of several existing drugs, and the effort, evidence from the billions of vaccines admin- adoption of new antiviral therapies. istered globally has been gathered, demonstrating that the vaccines are safe and ­ effective (CDC The work of national and regional medicine regu- 2021). Most of the accumulated evidence, however, latory agencies and their designated centers for the originates from the United States and European study of ADRs is crucial to the achievement of this Union pharmacovigilance systems, mostly covering function. To obtain the approval of drug regulatory medicines and vaccines used in these places. For this authorities, sufficient evidence is necessary to reason, strengthening pharmacovigilance in other demonstrate that the new drug is a good-quality, countries across the world is a priority in determining efficacious, and safe product. While the first two criteria must be met before market approval is 31 The Value of Pharmacovigilance in Building Resilient Health Systems Post-COVID the safety of medicines as administered to different The pandemic has once more highlighted the populations living in other realities. importance of affiliating pharmacovigilance within health care systems to allow clinicians, faced with A health system that includes pharmacovigilance treatment decisions during public health crises and promotes the safety of medications by minimizing in the absence of data from randomized controlled the occurrence of ADRs and provides a warning trials, to use real-life observational data on treatment network of various health care providers, regulators, benefits and harms. manufacturers and consumers to take remedial actions in a timely and orderly manner, and preven- During the first waves of the pandemic, the absence tive measures to avoid ADRs in future patients by of vaccines and drugs for the treatment and improving how medicines are prescribed and used prevention of COVID-19 led to a rush to repurpose (Jose et al. 2021). drugs already approved for other indications (Trifirò and Crisafulli 2022). For example, remdesivir, As shown by the experience of OECD countries, hydroxychloroquine, ivermectin, and azithromycin regulatory agencies have use evidence derived have been used off-label—that is, the unapproved from routinely collected data to confirm or counter use of an approved drug—for the treatment of suspected safety concerns, and depending on the COVID-19 patients, even if the underlying scientific results, such evidence has led to market withdrawal, evidence on benefits was low in quality and mostly safety notifications and labelling changes, modified based on in vitro studies. After some adverse effects indications, or confirmation of the initial terms of from the administration of these drugs were reported marketing authorization (OECD 2019). among COVID-19 patients, regulatory agencies Retrospective observational studies, using appro- issued warnings against their use to prevent serious priate analytical methods, can therefore help in problems among patients. This was the case of assessing the value of medicines in use in health azithromycin, an antibiotic that has been widely used care systems. In countries such as Australia, Estonia, for the treatment of COVID-19 patients, but of which Finland, and France, observational studies based on the known proarrhythmogenic activity (producing or routinely collected data have influenced decisions tending to produce cardiac arrhythmia) may be exac- on coverage conditions or prices (OECD 2019). erbated if the drug is used in combination with other drugs proposed for COVID-19 treatment, for example, hydroxychloroquine (Crisafulli et al. 2021; Sultana, Support for the delivery of Crisafulli, et al. 2020; Sultana, Cutroneo, et al. 2020; clinical services to patients Thomet et al. 2021). Or the case of kidney damage associated with the use of remdesivir reported to the The safety monitoring of newly approved medicines U.S. Food and Drug Administration Adverse Event and medicines in widespread use should be an Reporting System (FAERS) (Silva et al. 2021). integral part of clinical practice because it can have a large impact on the quality of health care. A regular A systematic review of the urgent clinical manage- exchange of information on safety in the use of ment of patients using drugs currently administered medicines through national pharmacovigilance for other diseases has shown that some of these programs help identify gaps in the understanding of drugs have proved to be not only ineffective, but adverse reactions caused by medicines and prevent also harmful because of adverse events associated risks to patients. Effective patient care is enhanced by with drug-drug interactions (Conti et al. 2022). These education and training among health professionals findings suggest that the use of drug interaction on drug safety, the exchange of information among checkers may have identified several ADRs associated national pharmacovigilance centers, the coordination with drug-drug interactions, including severe and of such exchanges, and the linking of clinical experi- life-threatening events. Hence, the interactions ence in drug safety with research and health policy. among the drugs used to treat COVID-19 and between 4. Using pharmacovigilance to foster resilient health systems 32 the COVID-19 drugs and those already used by was similar or lower than the corresponding share patients should be evaluated. after the administration of the second vaccine dose documented in several previous studies. A recent study published by JAMA Cardiology, based on nationwide immunization and hospitalization reg- The integration of pharmacovigilance with clinical ister data in Denmark, Finland, Norway, and Sweden, practice and the further development and strength- evaluates the relative incidence of myocarditis and ening of pharmacovigilance are vital as a contribu- pericarditis after immunization against SARS-CoV-2 tion to building resilience in health systems. The (Karlstad et al. 2022). Using data on more than 23 timely review of incoming data and real-time signal million individuals, the study demonstrates what has detection can provide important safety information been shown previously: the risk of vaccine-associ- and guide the work of health care providers during ated myocarditis is not homogeneous; in fact, young health emergencies as well as in normal times in pro- men and adolescent boys appear to be at the highest tecting the population from ADEs and ensuring that risk. Nor is the risk consistent across vaccines. the use of pharmaceutical products helps generate To date, the risk appears to be much higher after good health outcomes. administration of mRNA-1273 (Moderna) than after Evidence from routinely collected data has been used the administration of BNT162b2 (Pfizer-BioNTech). to drive changes in clinical guidelines, for example At the individual level, immunization prevents not on medicines used in the management of attention only COVID-19–related myocarditis, but also severe deficit hyperactivity disorder (ADHD) in Australia, disease, hospitalization, long-term complications given the concern that the practice of given children after COVID-19 infection, and death. For example, aged 5 years and younger antipsychotics for behavior older adults, who are at the highest risk of COVID-19 modification was inappropriate, on statin use in pre- complications, appear to be at extremely low risk of vention of cardiac events in patients with ischemic vaccine-associated myocarditis. Given the high rates heart disease in Israel, and in the United Kingdom, of morbidity and mortality from COVID-19 infection where evidence on the safety of pertussis vaccine among older adults and the efficacy of the vaccine in in pregnant women supported the continuation of preventing severe infection and death, the benefits of the vaccination program (OECD 2019). Or, conversely, immunization among individuals ages more than 40 the detection of poor adherence to guidelines for clearly outweigh the risks. the management of diabetes because some patients Another recent study assesses the occurrence of showed an increase in ADR in Cameroon (Elangwe et adverse events among adults ages 60 or more who al. 2020). have received a booster dose and illustrates the important part played by pharmacovigilance in informing the rollout of vaccination campaigns Data to identify antimicrobial (Auster et al. 2022). To address concerns about resistance and inappropriate waning immunity after Pfizer-BioNTech BNT162B2 use of antibiotics mRNA vaccination, the Israeli Ministry of Health started a campaign to administer booster (third) The inappropriate use of antimicrobials poses a doses to individuals who had received their second particularly difficult challenge to health systems dose at least five months previously. The booster was globally. Antimicrobial overuse, underuse, or use for initially approved for individuals ages 60 or more. inappropriate infections contribute to the increase The results of the survey conducted for the study in antimicrobial resistance, which is associated with indicated that adverse events after the BNT162b2 a number of clinical complications, unnecessary mRNA vaccine booster dose were generally mild and prolongation of hospital stays, and, in some cases, usually did not require medical care and that the the deaths of patients. This represents a high expen- share of self-reported adverse events that occurred diture in the health system, and the problem will 33 The Value of Pharmacovigilance in Building Resilient Health Systems Post-COVID worsen in the future if it is not addressed effectively monitoring strategies, pharmacovigilance databases (World Bank 2017). can serve as sources of data on suspected resistance and inappropriate use. Specifically, the authors posit, A review of antimicrobial resistance estimated that these pharmacovigilance data can signal issues that 700,000 deaths each year globally may be caused may help provide a bigger picture to prescribers who by drug-resistant bacterial infections, including have a choice to make during each consultation. They multidrug-resistant and extensively drug-resistant also report that information on off-label use or drug tuberculosis (Review on Antimicrobial Resistance use in contraindicated treatments can be communi- 2016). This poses a major public health threat because cated to entities responsible for national policies on routine surgeries and minor infections could become antimicrobials to affect the decision-making process life-threatening once again, and the inroads made in a timely manner. The pharmacovigilance data in controlling infectious diseases in the last 50 years can also facilitate the identification of reports on could be jeopardized. antibiotics on the Reserve and Watch list, which is This problem was also evident during the pandemic. of special interest from an antimicrobial resistance As with other viral diseases, the effect of COVID-19 perspective. Analysis of such reports may lead to disease on the immune response of the host information on how and why antibiotics on the facilitates concurrent bacterial infections. In the case Watch and Reserve list may be overused or used of patients with severe COVID-19 disease, there is off-label, depending on the indications and available an added risk of coinfection by multidrug-resistant formulations. Moreover, the authors make the case bacteria and fungus because of prolonged stays that tackling antimicrobial resistance issues based in intensive care units and the use of mechanical on existing pharmacovigilance methods represents ventilators. This may have been aggravated by the an opportunity for pharmacovigilance to evolve fact that, during the first months of the pandemic, as a field and allow countries to see more value in when general knowledge about the virus was null or investing in pharmacovigilance systems. limited, many antibiotics, such as azithromycin, used to treat many different types of infections caused by bacteria, such as respiratory infections, were Support for the implementation widely prescribed to COVID patients as a precaution of Eco-Pharmacovigilance or to test if there was any response (Marquez and The occurrence of pharmaceuticals in the natural Figueras 2021a). The unexpectedly high rate of environment has been frequently reported around antibiotic prescription during the early months the world. As noted in a recent article, as biologically of the COVID-19 pandemic (April–August 2020) in active compounds specially designed to be effective the United Kingdom, for example, has also been even at very low concentration levels, pharmaceuti- attributed to the increase in remote consultations, cals in the environment could have adverse impact which might have led clinicians to take greater on the health or other non-targeted organisms due to precautions in cases of possible infection given the long-term exposures (Wang et al. 2018). To minimize greater diagnostic uncertainty that results from an the pharmaceutical pollution is has been proposed inability during telephone appointments to examine that drawing on the experience of PV, EPV could patients and perform investigations (Armitage and be developed. More specifically, it is suggested that Nellums 2021). common methods and activities used in PV including spontaneous reporting, intensive monitoring, Antimicrobial resistance requires urgent multidis- database studies, and their potential applicability to ciplinary solutions, and pharmacovigilance has the environment, could be adapted and applied to the potential to strengthen current antimicrobial support the future development of EPV stewardship strategies. Indeed, as Habarugira, Härmark, and Figueras (2021) argue in a recent study, in addition to existing antimicrobial resistance 4. Using pharmacovigilance to foster resilient health systems 34 Support for public health If adverse effects and toxicity do appear, especially if they have not been observed previously, it is essential programs on disease control that these events be reported and analyzed and that Monitoring medicine safety is important for public their significance be communicated effectively to the health programs on disease control within countries. policy makers, program managers, and regulators This is especially the case in the use of new medi- who must interpret and act upon the information cines, such as COVID-19 vaccines, that are developed, provided, as well as to the population, to reduce assessed, and receive market authorization on safety concerns. accelerated schedules and that are administered For all medicines, there is a trade-off between the following abbreviated clinical trials. benefits and the potential for harm. For instance, the Most vaccines take years to develop, but scientists risk of myocarditis following COVID-19 immunization created multiple vaccines against SARS-COV-2 is real, but low, and this risk must be considered in within a single year (Marquez and Hanan 2020). For the context of the overall benefit of the vaccine. At example, it took years of research to understand the the population level, immunization helps decrease complexities of the influenza virus before the first community spread and the chances of new variants vaccine was approved for use in the United States in emerging, protects people who are immunocompro- 1945. And then, two years later, in 1947, researchers mised, and ensures that the health care system can concluded that seasonal changes in the composition continue to serve communities (Navar and Bonow of the virus rendered existing vaccines ineffective. 2022). There are two main types of influenza virus that The potential harm can be minimized by ensuring cause seasonal epidemic infections nearly every year, that medicines of good quality, safety, and efficacy influenza A and influenza B, along with multiple new are used rationally and that the expectations and strains of the virus. Because of this, scientists have concerns of patients are taken into account when had to adjust the influenza vaccine every year. therapeutic decisions are made. Pharmacovigilance Clinical trials for new drugs generally involve a can also help ensure that risks in drug use are antici- limited number of patients based on strict inclusion pated and managed under public health programs on criteria, often excluding special patient groups, such disease control, that related information is conveyed as individuals with comorbid conditions, children, to regulators to amend the recommendations on the elderly, and pregnant women. Hence, they do the use of the medicines, and that communication not reflect the experience in larger populations and is guided among public health officials, service across different geographical regions during the providers, and the population. marked phase of drugs, which may differ from one Likewise, monitoring medicine safety is important to another with respect to genetics, nutritional habits, public health programs for disease control at the pop- lifestyle, health conditions, and public health and ulation level. Many TB programs have introduced and clinical practices. institutionalized active drug safety monitoring and Postvaccine or other medicine surveillance can thus management platforms for drug-resistant TB (Stevens play a critical role in informing the rollout of public et al. 2022). In Vietnam, as the management of mul- health programs on disease control given the risk tidrug-resistant tuberculosis (MDR-TB) is a significant of possible clinically important adverse effects from public health challenge due to the complexity and the administration and use of these pharmaceutical long duration of the MDR-TB treatment, active TB products in real-world situations involving large drug-safety monitoring among patients has shown populations and other variables that cannot be to be useful to understand the safety of MDR-TB controlled, unlike the situation in clinical trials, for treatment and explore the risk factors for toxicity, instance, the ways a vaccine is transported and helping reduce the inconvenience, discomfort, and stored or how patients are vaccinated. toxicity of such regimens, and, importantly, increase 35 The Value of Pharmacovigilance in Building Resilient Health Systems Post-COVID adherence and likelihood of successful treatment risks that is propagated through social media and completion (Ngoc et al. 2021). other communication channels. The introduction of novel medicines and regimens The effective communication of the risks in the for antiretroviral (ARV) treatment for HIV/AIDS also safety of drugs is a vital task carried out by gov- requires comprehensive surveillance systems for ernments and health care providers, as well as the adverse events and adverse drug reactions. Because pharmaceutical industry, to address the public per- HIV programs must develop active ARV toxicity ception of the hazards associated with medicines monitoring systems to ensure safe global scale-up of and to build trust in the health system and other newer regimens, such as tenofovir-lamivudine-do- gov-ernment actions. Effective communication lutegravir, building on existing drug monitoring practices, the positive framing of mild side effects, infrastructure has been proposed to actively monitor and address-ing misinformation related to vaccine ARV regimens as a synergistic TB/HIV collaborative adverse effects can reduce the concerns about these activity and to narrow active toxicity monitoring gaps adverse effects (Motta et al. 2021; Rief 2021). Failure (Stevens et al. 2022). to communicate to health care professionals and the public effectively can lead to a loss of trust, Pharmacovigilance has also been of great importance the diminished reputation of regulators and other for malaria control programs in view of the increas- stakeholders, and the loss of lives (WHO 2020). ing resistance to existing antimalarial medicines that led countries to switch to using combinations During the pandemic, for example, robust monitoring of various artemisinin derivatives as their first- and and the assessment of adverse events have been vital second-line treatments for malaria (Hemingway et in informing the public communication activities al. 2016). that are needed to build vaccine confidence, roll out vaccination programs, and promote take-up as shown by the experience of the EMA in the European Support for building trust Union (Wang, Marquez, and Figueras 2021). For in the health system instance, in early 2021, the EMA, after receiving safety Besides communicating the outcomes of pharma- signals associated with the administration of the covigilance on the evidence for the safety of given AstraZeneca COVID-19 vaccine that had led some drugs to policy makers, regulators, and service countries of the European Union, including France, providers, equally important is sharing the outcomes Germany and Italy, to suspend the administration in communications with patients and the general of this vaccine temporarily, reviewed all reports public (Marquez, Eyman, and Hanan 2021). of thromboembolic events among the five million people vaccinated with the AstraZeneca jab (Henley During the pandemic, for example, the rapid 2021). On March 18, 2021, the EMA, on the basis of development of COVID-19 vaccines raised concerns its review, advised national governments to resume about the safety of vaccines, contributing to vaccine vaccination and communicate to the population that hesitancy among large groups of the population the benefits of the AstraZeneca vaccine in preventing (Ullah et al. 2021). These groups included health care COVID-19, with its associated risk of hospitalization workers, many of whom expressed concerns about and death, outweighed the risks of reported adverse vaccine safety, efficacy, and potential side effects effects (EMA 2021). The EMA work also helped inform as the main reasons for COVID-19 vaccination policy making in countries outside Europe (Africa hesitancy (Biswas et al. 2021). A major challenge CDC 2021). The rollout of the AstraZeneca vaccine that hampered country emergency responses continued as part of vaccination campaigns in has revolved around the ways to address vaccine Europe and elsewhere to control the pandemic and hesitancy effectively to clear up concerns over the support the rapid reactivation of economic activity. safety of the COVID-19 vaccines, which has often been influenced by misinformation about vaccine 4. Using pharmacovigilance to foster resilient health systems 36 As illustrated by the experience of the COVID-19 Overall, large-scale vaccine safety monitoring vaccination in the countries of the European Union, reports have supported the rollout of the vaccination ADEs raised alarm because governments, as in programs globally by finding, on the basis of evi- other spheres of public policy, have to consider not dence, that, at a population level, the benefits of the only the evidence on the safety and effectiveness protection provided by the vaccine far outweigh any of vaccines or other medications once they begin potential risks of either systemic or cardiovascular to be administered to the general population, but side effects associated with the vaccine. It has been also the impact of potential adverse effects that estimated that more than eight billion doses for are reported during a vaccination campaign on an SARS-COV-2, mostly of eight front-runner vaccines, already vaccine-hesitant population. If not handled have now been administered around the world, the well, these events could further undermine public vast majority in 2021 (Mallapaty et al. 2021). confidence in COVID-19 vaccines and in government The global vaccination campaign has helped achieve action in general because, in a large number of key health system outcomes by significantly curbing countries, governments are simply not trusted by the virus’s spread and death toll in 2021, saving the population in the handling of such concerns thousands of lives and averting hospitalizations (Marquez and Figueras 2021b). because of severe disease. For example, it is esti- mated that the rapid development and deployment of these vaccines have saved at least 750,000 lives Support to achieve in the United States and Europe alone and probably many more globally. An estimated 470,000 deaths health impacts were averted across 33 European countries among The postmarket monitoring of the safety of the use of individuals ages 60 or more (Meslé et al. 2021). drugs contributes to the establishment of drug safety Another modeling study estimates that 279,000 lives profiles, including information on the administration had been saved by June 2021 by the vaccination and take-up by the population in need of therapy, drive in the United States (Galvani, Moghadas, and thereby helping prevent disease and death. Schneider 2021). In the case of the COVID-19 pandemic, the emergence of SARS-CoV-2 was followed by the rapid develop- ment, licensure, and rollout of several vaccines from late 2020 onward, initially targeting select groups, including those at higher risk of severe disease, particularly older adults. By the end of 2021, the vaccines had been administered to more than four billion people worldwide, and the safety profiles of the vaccines had become well established in clinical trials and postmarketing safety monitoring. In general, the adverse risk profiles have been found to be mild, and adverse side effects, such as lymph node enlargement and elevations and temperatures, have been identified (Vaduganathan 2021). Certain cardiovascular side effects have also been identified and assessed, but found to be typical compared with other types of myocarditis. The risks, on average, are low on an absolute level, estimated at about 10–20 per million persons who have been vaccinated, and both the illness severity and the illness duration are short in most cases. 37 5. Summary: the way forward 5 Final Considerations • 5. Summary: the way forward 38 Strengthening pharmacovigilance fosters the realization of a basic tenet associated with the millennia-old Hippocratic oath, “First, do no harm” medicines and vaccines plays in building resilient health systems (Chandler et al. 2020). The following are some considerations for guiding efforts to strengthen the PV capacity in a health system: • How can the capacity of the health system be supported in collecting data and reports on the benefits, harms, effectiveness, and risks medicines Guiding questions for and health technologies? • How can it be improved in gathering data and strengthening national reports on adverse reactions and other reactions to pharmacovigilance systems the use of medicines after marketing? within the wider health • How can it be enabled to assess accurately any system resilience effort issues involving the safety, quality, and effective- ness of medicines and other health technologies COVID-19 has made evident the importance of that are revealed in the data and reports collected? medicines and vaccine safety on normal times and • How can it be supported in regulating the safety, when dealing with a public health crisis, highlighting quality, and effectiveness of medicines and other the critical function that monitoring the safety of health technologies? 39 The Value of Pharmacovigilance in Building Resilient Health Systems Post-COVID • How can it be empowered in delivering the most care workers, other health care professionals, and efficient and effective patient care especially in consumers. light of adverse reactions to the use of new drugs? The realization of these functions requires that, once • How can it be enhanced in conducting public information on an adverse event has been collected, information campaigns on the proper use of evaluators undertake analysis to determine the severity, medicines and other health technologies? probable causality, and preventability of the event. • How can it be reinforced in determining and managing the most effective responses to a to a Also, significant data must be communicated public health crisis? effectively to a structure or entity that has the • How can it be strengthened in anticipating appro- authority to take appropriate action (such as at the priate responses to future public health crises? facility, national, or even international level). The risk reduction action may be regulatory (withdrawing marketing authorization or recalling a medication), Building PV capacity in a managerial (revising a hospital formulary or institut- health system ing distribution controls), or educational (teaching prescribers about medicine–medicine interactions or As explored in the previous sections of this report, proper product handling). key building blocks for effective pharmacovigilance in a health system include (SPS 2009): To encourage continued participation in the process, interventions should be shared with the data • A functional and sustainable regulatory and reporters as part of a feedback loop. organizational structure, operational plan, and guidelines for monitoring the safety in the use of In conclusion, it should be clear that efforts to medicines. support the strengthening of the pharmacovigilance • Clearly defined roles and responsibilities of expert capacity as part of efforts to build strong and resilient advisory committees, public health programs, health systems, stakeholders and other actors will health care providers, professional associations, help realize a basic tenet associated with the millen- academic institutions, pharmaceutical manu- nia-old Hippocratic oath, “First, do no harm,” which is facturers, importers, wholesalers and retailers, at the core of public health and medical practice. consumers, and media. • Assuring that infrastructure and staffing needs are fulfilled, starting with the national pharmacovigi- lance center. • Increasing awareness among health care profes- sionals of the importance of ADR and helping pharmacovigilance personnel build new skills and competencies (for example, clinical pharmacy and active surveillance methods). • Institutionalizing appropriate tools (such as standard operating procedures, reporting and com- munication forms, job aids) to support improved data collection, analysis, and reporting. Key pharmacovigilance functions that need to be developed include monitoring, detection, reporting, evaluation, and documentation of drug safety data as well as gathering information from and providing educational feedback to prescribers, health References 40 References Africa CDC (Africa Centres for Disease Control and CDC (Centers for Disease Control and Prevention). 2022b. Prevention). 2021. “Statement to African Union “Pfizer-BioNTech COVID-19 Vaccine (Also Known as Member States on the Deployment of the AstraZeneca COMIRNATY): Overview and Safety.” May 25, CDC, COVID-19 Vaccine to the Continent and Concerns Atlanta. https://www.cdc.gov/coronavirus/2019-ncov/ about Adverse Event Reports Coming from Europe.” vaccines/different-vaccines/Pfizer-BioNTech.html. Statement, March 19, 2021, Africa CDC, African Union CDC (Centers for Disease Control and Prevention). 2022c. Commission, Addis Ababa, Ethiopia. https://africacdc. “Selected Adverse Events Reported after COVID-19 org/news-item/­statement-to-african-union-member- Vaccination.” May 31, CDC, Atlanta. https://www.cdc.gov/ states-on-the-deployment-of-the-astrazeneca-covid-19- coronavirus/2019-ncov/vaccines/safety/adverse-events. vaccine-to-the-continent-and-concerns-about-adverse- html. event-reports-coming-from-europe/. Chandler, Rebecca E., Deirdre McCarthy, Jean-Christophe Ağagündüz, Duygu, Menşure Nur Çelik, Merve Esra Çıtar Delumeau, and Mira Harrison-Woolrych. 2020. “The Dazıroğlu, and Raffaele Capasso. 2021. “Emergent Drug Role of Pharmacovigilance and ISoP during the Global and Nutrition Interactions in COVID-19: A Comprehensive COVID-19 Pandemic.” Drug Safety 43 (6): 511–12. Narrative Review.” Nutrients 13 (5): 1550. Checchi, Francesco, and Les Roberts. 2005. “Interpreting and Agarwal, Arnav, Bram Rochwerg, François Lamontagne, Using Mortality Data in Humanitarian Emergencies: Reed Ac Siemieniuk, Thomas Agoritsas, Lisa Askie, A Primer for Non-epidemiologists.” HPN Network Paper 52 Lyubov Lytvyn, et al. 2020. “A Living WHO Guideline (September), Humanitarian Practice Network, Overseas on Drugs for COVID-19.” BMJ: British Medical Journal Development Institute, London. 370 (September 4): m3379. Coleman Jamie J., and Sarah K. Pontefract. 2016. “Adverse Drug Armitage, Richard, and Laura B. Nellums. 2021. “Antibiotic Reactions.” Clinical Medicine 16 (5): 481–85. Prescribing in General Practice during COVID-19.” Lancet Infectious Diseases 21 (6), E144. Conti, Valeria, Carmine Sellitto, Martina Torsiello, Valentina Manzo, Emanuela De Bellis, Berenice Stefanelli, Nicola Auster, Oren, Uriah Finkel, Noa Dagan, Noam Barda, Alon Bertini, et al. 2022. “Identification of Drug Interaction Laufer, Ran D. Balicer, and Shay Ben-Shachar. 2022. Adverse Events in Patients with COVID-19: A Systematic “Short-Term Adverse Events after the Third Dose of the Review.” JAMA Network Open 5 (4), e227970. BNT162b2 mRNA COVID-19 Vaccine in Adults 60 Years or Older.” JAMA Network Open 5 (4), e227657. COVID-19 Excess Mortality Collaborators. 2022. “Estimating Excess Mortality Due to the COVID-19 Pandemic: Barış, Enis, Rachel Silverman, Huihui Wang, Feng Zhao, A Systematic Analysis of COVID-19–Related Mortality, and Muhammad Ali Pate. 2022. Walking the Talk: 2020–21.” Lancet 399 (10334): 1513–36. Reimagining Primary Health Care after COVID-19. Washington, DC: World Bank. https://openknowledge. Crisafulli, Salvatore, Valentina Ientile, Luca L’Abbate, Andrea worldbank.org/handle/10986/35842. Fontana, Claudio Linguiti, Sonia Manna, Mariangela Mercaldo, et al. 2021. “COVID-19 Patient Management Biswas, Nirbachita, Toheeb Mustapha, Jagdish Khubchandani, in Outpatient Setting: A Population-Based Study from and James H Price. 2021. “The Nature and Extent of Southern Italy.” Journal of Clinical Medicine 11 (1), 51. COVID-19 Vaccination Hesitancy in Healthcare Workers.” Journal of Community Health 46 (6): 1244–51. Dal Plan, Gerald J. 2015. “The US Food and Drug Administration, Neurologists, and Drug Development CDC (Centers for Disease Control and Prevention). 2021. and Regulation.” Neurology: Clinical Practice 5 (4): “Ensuring COVID-19 Vaccine Safety in the US.” September 338–43. 28, CDC, Atlanta. https://www.cdc.gov/coronavirus/​ 2019-ncov/vaccines/safety.html. EC (European Commission). 2016. “Pharmacovigilance Related Activities of Member States and the CDC (Centers for Disease Control and Prevention). European Medicines Agency Concerning 2022a. “Omicron Variant: What You Need to Know.” Medicinal Products for Human Use (2012–2014).” March 29, CDC, Atlanta. https://www.cdc.gov/ Commission Staff Working Document SWD (2016) coronavirus/2019-ncov/variants/omicron-variant.​ 284 (August 8), EC, Brussels. https://ec.europa.eu/ html?s_cid=11735:omicron%20variant%20 health//sites/health/files/files/pharmacovigilance/ symptoms:sem.b:p:RG:GM:gen:PTN:FY22. pharmacovigilance-report-2012-2014_annex_en.pdf. 41 The Value of Pharmacovigilance in Building Resilient Health Systems Post-COVID Elangwe, A., Katte, JC., Tchapmi, D. et al. 2020. Adverse drug Gurwitz, Jerry H., Terry S. Field, Jerry Avorn, Danny reactions to anti-diabetic drugs are commonest in McCormick, Shailavi Jain, Marie Eckler, Marcia Benser, patients whose treatment do not adhere to diabetes Amy C. Edmondson, and David W. Bates. 2000. “Incidence management clinical guidelines: cross-sectional study and Preventability of Adverse Drug Events in Nursing in a tertiary care service in sub-Saharan Africa. Eur J Homes.” American Journal of Medicine 109 (2): 87–94. Clin Pharmacol 76, 1601–1605. https://doi.org/10.1007/ Habarugira, Jean Marie Vianney, Linda Härmark, and Albert s00228-020-02949-2 Figueras. 2021. “Pharmacovigilance Data as a Trigger to EMA (European Medicines Agency). 2021. “COVID-19 Vaccine Identify Antimicrobial Resistance and Inappropriate AstraZeneca: Benefits Still Outweigh the Risks Despite Use of Antibiotics: A Study Using Reports from the Possible Link to Rare Blood Clots with Low Blood Netherlands Pharmacovigilance Centre.” Antibiotics Platelets.” March 18, EMA, Amsterdam. https://www. 10 (12), 1512. ema.europa.eu/en/news/covid-19-vaccine-astrazeneca-​ Hemingway J, Shretta R, Wells TNC, Bell D, Djimdé AA, et benefits-still-outweigh-risks-despite-possible-link-rare- al. 2016. “Tools and Strategies for Malaria Control and blood-clots. Elimination: What Do We Need to Achieve a Grand Fauci, Anthony S. 2005. “Emerging and Reemerging Infectious Convergence in Malaria?”. PLOS Biology 14(3): e1002380. Diseases: The Perpetual Challenge.” Academic Medicine https://doi.org/10.1371/journal.pbio.1002380 80 (12): 1079–85. Henley, Jon. 2021. “France Seeks Swift Safety Verdict on FDA (Food and Drug Administration, United States). 2017. AstraZeneca Vaccine.” Coronavirus (blog), March 16, “FDA Adverse Event Reporting System (FAERS).” 2021. https://www.theguardian.com/world/2021/mar/16/ June 9, FDA, Silver Spring, MD. https://www. oxford-vaccine-to-be-reviewed-by-who-after-countries- fda.gov/drugs/drug-approvals-and-databases/ suspend-jab. fda-adverse-event-reporting-system-faers. Ho, Ping, Jing-Quan Zheng, Chia-Chao Wu, Yi-Chou Hou, FDA (Food and Drug Administration, United States). 2018. Wen-Chih Liu, Chien-Lin Lu, Cai-Mei Zheng, Kuo-Cheng “Questions and Answers on FDA’s Adverse Event Lu, and You-Chen Chao. 2021. “Perspective Adjunctive Reporting System (FAERS).” June 4, FDA, Silver Spring, Therapies for COVID-19: Beyond Antiviral Therapy.” MD. https://www.fda.gov/drugs/surveillance/questions- International Journal of Medical Sciences 18 (2): 314–24. and-answers-fdas-adverse-event-reporting-system-faers. IQVIA. 2021. “Drug Expenditure Dynamics 1995–2020: FDA (Food and Drug Administration, United States). Understanding Medicine Spending in Context.” October, 2020a. “Emergency Use Authorization for Vaccines IQVIA Institute for Human Data Science, Parsippany, NJ. Explained.” November 20, FDA, Silver Spring, MD. https://www.fda.gov/vaccines-blood-biologics/vaccines/ Jeetu G, Anusha G. 2010. “Pharmacovigilance: a worldwide emergency-use-authorization-vaccines-explained. master key for drug safety monitoring”. J Young Pharm. 2010 Jul;2(3):315-20. doi: 10.4103/0975-1483.66802. PMID: FDA (Food and Drug Administration, United States). 2020b. 21042493; PMCID: PMC2964775. “FDA’s Approval of Veklury (remdesivir) for the Treatment of COVID-19: The Science of Safety and Effectiveness.” Jose J, Al Rubaie MH, Al Ramimmy H, Varughese SS. 2021. October 22, FDA, Silver Spring, MD. https://www.fda.​ “Pharmacovigilance: Basic concepts and an overview of gov/drugs/news-events-human-drugs/fdas-approval- the system in Oman”. 2021. Sultan Qaboos Univ Med J. veklury-remdesivir-treatment-covid-19-science-safety-​ May;21(2):e161-e163. doi: 10.18295/squmj.2021.21.02.001. Epub and-effectiveness. 2021 Jun 21. PMID: 34221460; PMCID: PMC8219341. Galvani, Alison, Seyed M. Moghadas, and Eric C. Schneider. Kalaiselvan, Vivekanandan, Pranay Kumar, Prabhakar Mishra, 2021. “Deaths and Hospitalizations Averted by Rapid U.S. and Gyanendra Nath Singh. 2015. “System of Adverse Vaccination Rollout.” Issue Brief, July 7, Commonwealth Drug Reactions Reporting: What, Where, How, and Whom Fund, New York. https://www.commonwealthfund. to Report?” Indian Journal of Critical Care Medicine org/publications/issue-briefs/2021/jul/deaths-and-​ 19 (9): 564–66. hospitalizations-averted-rapid-us-vaccination-rollout. Karlstad, Øystein, Petteri Hovi, Anders Husby, Tommi Giardina, Claudia, Paola M. Cutroneo, Eleonora Mocciaro, Härkänen, Randi Marie Selmer, Nicklas Pihlström, Jørgen Giuseppina T. Russo, Giuseppe Mandraffino, Giorgio Vinsløv Hansen, et al. 2022. “SARS-CoV-2 Vaccination Basile, Franco Rapisarda, Rosarita Ferrara, Edoardo Spina, and Myocarditis in a Nordic Cohort Study of 23 Million and Vincenzo Arcoraci. 2018. “Adverse Drug Reactions Residents.” JAMA Cardiology April 20. https://jamanet- in Hospitalized Patients: Results of the FORWARD work.com/journals/jamacardiology/fullarticle/2791253. (Facilitation of Reporting in Hospital Ward) Study.” Kiguba, Ronald, Sten Olsson, and Catriona Waitt. 2021. Frontiers in Pharmacology 1 (9), 350. “Pharmacovigilance in Low- and Middle-Income Goldman, Stephen A. 2004. “Communication of Medical Countries: A Review with Particular Focus on Africa.” Product Risk: How Effective Is Effective Enough?” Drug British Journal of Clinical Pharmacology. Published Safety 27 (8): 519–34. ahead of print, December 22, 2021. https://bpspubs. onlinelibrary.wiley.com/doi/10.1111/bcp.15193. References 42 Kohn, Linda T., Janet M. Corrigan, and Molla S. Donaldson, eds. doi: 10.3389/fpubh.2021.756633. PMID: 35186864; PMCID: 2000. To Err Is Human: Building a Safer Health System. PMC8850379. Washington, DC: National Academy Press. Motta, Matthew, Steven M. Sylvester, Timothy Callaghan, and Lazarou, Jason, Bruce H. Pomeranz, and Paul N. Corey. 1998. Kristin Lunz Trujillo. 2021. “Encouraging COVID-19 Vaccine “Incidence of Adverse Drug Reactions in Hospitalized Uptake through Effective Health Communication.” Patients: A Meta-analysis of Prospective Studies.” JAMA, Frontiers in Political Science 3 (January 28): 1. https://doi. Journal of the American Medical Association 279 (15): org/10.3389/fpos.2021.630133. 1200–05. Navar, Ann Marie, and Robert O. Bonow. 2022. Lee, Min-Sun, Ju-Yeun Lee, Min-Gyu Kang, Jae-Woo Jung, “Communicating the Benefits of Vaccination in Light Hye-Kyung Park, Hye-Kyung Park, Sang-Heon Kim, and of Potential Risks.” JAMA Cardiology April 20, 2022. Eui-Kyung Lee. 2020. “Cost Implications of Adverse doi:10.1001/jamacardio.2022.059. Drug Event-Related Emergency Department Visits: Ngoc, NB, Dinh, HV , Thuy, NT, et al. 2021. “Active surveillance A Multicenter Study in South Korea.” Expert Review of for adverse events in patients on longer treatment regi- Pharmacoeconomics and Outcomes Research 20 (1): mens for multidrug-resistant tuberculosis in Viet Nam”. 139–46. PLOS ONE 16(9): e0255357. https://doi.org/10.1371/journal. Lexchin, Joel. 2006. “Is There Still a Role for Spontaneous pone.0255357 Reporting of Adverse Drug Reactions?” CMAJ, Canadian Nobili, Alessandro, Giuseppe Licata, Francesco Salerno, Luca Medical Association Journal 174 (2): 191–92. Pasina, Mauro Tettamanti, Carlotta Franchi, Luigi De Mallapaty, Smriti, Ewen Callaway, Max Kozlov, Heidi Ledford, Vittorio, et al. 2011. “Polypharmacy, Length of Hospital John Pickrell, and Richard Van Noorden. 2021. “How Stay, and In-Hospital Mortality among Elderly Patients in COVID Vaccines Shaped 2021 in Eight Powerful Charts.” Internal Medicine Wards: The REPOSI Study.” European Nature 600 (7890): 580–83. Journal of Clinical Pharmacology 67 (5): 507–19. Marquez, Patricio V., Sarah Eyman, and Betty Hanan. 2021. “To Nzolo, Didier, Andrea Kuemmerle, Yves Lula, Nsengi Vaccinate or Not to Vaccinate? The COVID-19 Vaccination Ntamabyaliro, Aline Engo, Bibiche Mvete, Jerry Liwono, Dilemma.” (blog), June 22, 2021. http://www.pvmarquez. et al. 2019. “Development of a Pharmacovigilance System com/vaccinehesitancy. in a Resource-Limited Country: The Experience of the Democratic Republic of Congo.” Therapeutic Advances in Marquez, Patricio V., and Albert Figueras. 2021a. “The Deadly Drug Safety 10 (July 16). https://journals.sagepub.com/doi/ Risk of Hospital-Acquired Infections and Antimicrobial full/10.1177/2042098619864853. Resistance for COVID-19 Patients.” (blog), February 13, 2021. http://www.pvmarquez.com/amrcovid19. OECD (Organization of Economic Cooperation and Development). 2019. “Using Routinely Collected Data Marquez, Patricio V., and Albert Figueras. 2021b. “A Perspective to Inform Pharmaceutical Policies Analytical Report for on the AstraZeneca COVID-19 Vaccine Uncertainty.” OECD and EU Countries.” OECD, Paris. https://www.oecd. (blog), March 16, 2021. http://www.pvmarquez.com/ org/els/health-systems/routinely-collected-data-to-in- vacunacovid-19dilema. form-pharmaceutical-policies.htm Marquez, Patricio V., and Betty Hanan. 2020. “What We Know PAHO (Pan American Health Organization). 2020. The Essential about the New COVID-19 Vaccines: Are We There Yet?” Public Health Functions in the Americas, A Renewal for (blog), November 24, 2020. http://www.pvmarquez.com/ the 21st Century: Conceptual Framework and Description. covid19vaccine. Universal Health Series. Washington, DC: PAHO. Marquez, Patricio V., Betty Hanan, Sheila Dutta, and Mary PAHO (Pan American Health Organization). 2022. Regulatory Mulusa. 2020. “How to Strengthen Health Care Systems System Strengthening in the Americas: Lessons Learned to Support COVID 19-Vaccination?” (blog), November 16, from the National Regulatory Authorities of Regional 2020. http://www.pvmarquez.com/covid-19vaccination. Reference. Washington, DC: PAHO. Meslé, Margaux M. I., Jeremy Brown, Piers Mook, José Hagan, Pediaa. 2015. “Difference between Side Effect Roberta Pastore, Nick Bundle, Gianfranco Spiteri, et al. and Adverse Effect.” Medical Terms (blog), 2021. “Estimated Number of Deaths Directly Averted October 21, 2015. https://pediaa.com/ in People 60 Years and Older as a Result of COVID-19 difference-between-side-effect-and-adverse-effect/. Vaccination in the WHO European Region, December 2020 to November 2021.” Eurosurveillance 26 (47), Rentschler, Jun Erik Maruyama, Christoph Klaiber, Mersedeh pii=2101021. Tariverdi, Chloé Desjonquères, and Jared Mercadante. 2021. “Frontline: Preparing Healthcare Systems for Montané, Eva, and Javier Santesmases. 2020. “Adverse Drug Shocks, from Disasters to Pandemics.” World Bank, Reactions.” Medicina Clínica 154 (5): 178–84. Washington, DC. Montano D. 2021. "Frequency and Associations of Adverse Reactions of COVID-19 Vaccines Reported to Review on Antimicrobial Resistance. 2016. “Tackling Pharmacovigilance Systems in the European Union Drug-Resistant Infections Globally: Final Report and and the United States". Front Public Health 3;9:756633. Recommendations.” May, Wellcome Trust and UK Government, London. 43 The Value of Pharmacovigilance in Building Resilient Health Systems Post-COVID Rief, Winfried. 2021. “Fear of Adverse Effects and COVID-19 “Pharmacovigilance Activities in ASEAN Countries.” PDS, Vaccine Hesitancy: Recommendations of the Treatment Pharmacoepidemiology and Drug Safety 25 (9): 1061–69. Expectation Expert Group.” JAMA Health Forum 2 (4), Thomet, Urs, Bogdan Amuzescu, Thomas Knott, Stefan 210804. A. Mann, Kanigula Mubagwa, and Beatrice Mihaela Rosenblum, Hannah G., Stephen C. Hadler, Danielle Moulia, Radu. 2021. “Assessment of Proarrhythmogenic Risk Tom T. Shimabukuro, John R. Su, Naomi K. Tepper, Kevin for Chloroquine and Hydroxychloroquine Using the C. Ess, et al. 2021. “Use of COVID-19 Vaccines after Reports CiPA Concept.” European Journal of Pharmacology of Adverse Events among Adult Recipients of Janssen 913 (December 15), 174632. (Johnson & Johnson) and mRNA COVID-19 Vaccines Trifirò, Gianluca, and Salvatore Crisafulli. 2022. “A New (Pfizer-BioNTech and Moderna): Update from the Era of Pharmacovigilance: Future Challenges and Advisory Committee on Immunization Practices, United Opportunities.” Frontiers in Drug Safety and Regulation 2 States, July 2021.” Morbidity and Mortality Weekly Report (February 25). https://www.frontiersin.org/articles/10.3389/ 70 (32): 1094–99. fdsfr.2022.866898/full. Sagan, Anna, Scott L. Greer, Erin Webb, Martin McKee, Ullah, Irfan, Kiran Shafiq Khan, Muhammad Junaid Tahir, Natasha Azzopardi Muscat, Suszy Lessof, Isabel de la Ali Ahmed, and Harapan Harapan. 2021. “Myths and Mata, and Josep Figueras. 2022. “Strengthening Health Conspiracy Theories on Vaccines and COVID-19: Potential System Resilience in the COVID-19 Era.” Eurohealth Effect on Global Vaccine Refusals.” Vacunas 22 (2): 93–97. 28 (1): 4–8. Vaduganathan, Muthiah. 2021. “Cardiac Concerns and Shehab, Nadine, Maribeth C. Lovegrove, Andrew I. Geller, the COVID-19 Vaccines: What We Know So Far.” Kathleen O. Rose, Nina J. Weidle, and Daniel S. Budnitz. COVID-19: On the Frontlines (podcast), October 29, 2016. “US Emergency Department Visits for Outpatient 2021. https://tunein.com/podcasts/Science-Podcasts/ Adverse Drug Events, 2013–2014.” JAMA, Journal of the COVID-19-On-The-Frontlines-p1312405/?topicId=167409674. American Medical Association 316 (20): 2115–25. Walter, Scott R., Richard O. Day, Blanca Gallego, and Shrestha, Sunil, Januka Khatri, Sujyoti Shakya, Krisha Johanna I. Westbrook. 2017. “The Impact of Serious Danekhu, Asmita Priyadarshini Khatiwada, Ranjit Adverse Drug Reactions: A Population-Based Study of Sah, Bhuvan KC, Vibhu Paudyal, Saval Khanal, and a Decade of Hospital Admissions in New South Wales, Alfonso J. Rodriguez-Morales. 2021. “Adverse Events Australia.” British Journal of Clinical Pharmacology Related to COVID-19 Vaccines: The Need to Strengthen 83 (2): 416–26. Pharmacovigilance Monitoring Systems.” Drugs and Therapy Perspectives 37 (8): 376–82. Wang J, Zhang M, Li S, He B. 2018. “Adapting and applying common methods used in pharmacovigilance to the Silva NAO, Zara ALSA, Figueras A, Melo DO. 2021. “Potential environment: A possible starting point for the imple- kidney damage associated with the use of remdesivir for mentation  of eco-pharmacovigilance”. Environ Toxicol COVID-19: analysis of a pharmacovigilance database”. Cad Pharmacol. Jul;61:67-70. doi: 10.1016/j.etap.2018.05.020. Saude Publica. Nov 12;37(10):e00077721. doi: 10.1590/0102- Epub 2018 May 24. PMID: 29852371. 311X00077721. PMID: 34787281. Wang, Huihui, Albert Figueras, and Patricio V. Marquez. 2021. SPS (Strengthening Pharmaceutical Systems). 2009. “Monitoring the Safety and Effectiveness of COVID-19 “Supporting Pharmacovigilance in Developing Countries: Vaccines and Vaccination.” Investing in Health (blog), The Systems Perspective.” September, SPS, Management June 9, 2021. https://blogs.worldbank.org/health/ Sciences for Health, Arlington, VA. monitoring-safety-effectiveness-covid-19-vaccines-and- vaccination. Stevens, L, Perry, KE, Moide, I, Kaemala, F. et al. 2022 “Leveraging Experience From Active TB Drug-Safety Wang, Huihui, Patricio V. Marquez, and Albert Figueras. 2021. Monitoring and Management for Monitoring Active “Learning from Korea’s Experience Monitoring Drug and Antiretroviral Toxicity”. Global Health: Science Vaccine Safety.” Investing in Health (blog), December and Practice 10(2):e2100595; https://doi.org/10.9745/ 17, 2021. https://blogs.worldbank.org/health/learning-​ GHSP-D-21-00595 koreas-experience-monitoring-drug-and-vaccine-safety. Sultana, Janet, Salvatore Crisafulli, Flic Gabbay, Elizabeth Wang, Huihui, Patricio V. Marquez, and Albert Figueras. 2022. “The Lynn, Saad Shakir, and Gianluca Trifirò. 2020. “Challenges Value of a Regional Harmonized Approach in Monitoring the for Drug Repurposing in the COVID-19 Pandemic Era.” Safety of Vaccines and Other Medicines.” Investing in Health Frontiers in Pharmacology 11 (November 6), 588654. (blog), February 8, 2022. https://blogs.worldbank.org/health/ value-regional-harmonized-approach-monitoring-safety-​ Sultana, Janet, Paola Maria Cutroneo, Salvatore Crisafulli, vaccines-and-other-medicines. Gabriele Puglisi, Gaetano Caramori, and Gianluca Trifirò. 2020. “Azithromycin in COVID-19 Patients: White House. 2021. “American Pandemic Preparedness: Pharmacological Mechanism, Clinical Evidence, and Transforming Our Capabilities.” September 2, White House, Prescribing Guidelines.” Drug Safety 43 (8): 691–98. Washington, DC. https://www.whitehouse.gov/wp-content/​ uploads/2021/09/American-Pandemic-Preparedness- Suwankesawong, Wimon, Teerapon Dhippayom, Wei- Transforming-Our-Capabilities-Final-For-Web.pdf. Chuen Tan-Koi, and Chuenjid Kongkaew. 2016. References 44 WHO (World Health Organization). 2002. “The Importance of Pharmacovigilance: Safety Monitoring of Medicinal Products.” WHO, Geneva. WHO (World Health Organization). 2004. “Pharmacovigilance: Ensuring the Safe Use of Medicines.” WHO Policy Perspectives on Medicines 9 (October), WHO, Geneva. WHO (World Health Organization). 2007. “The World Health Report 2007, A Safer Future: Global Public Health Security in the 21st Century.” WHO, Geneva. WHO (World Health Organization). 2015. “WHO Pharmacovigilance Indicators: A Practical Manual for the Assessment of Pharmacovigilance Systems.” WHO, Geneva. WHO (World Health Organization). 2020. “Risk Communication and Community Engagement Readiness and Response to Coronavirus Disease (COVID-19).” Interim Guidance (March 19), WHO/2019-nCoV/ RCCE/2020.2, WHO, Geneva. WHO (World Health Organization). 2021. “Side Effects of COVID-19 Vaccines.” March 31, WHO, Geneva. https:// www.who.int/news-room/feature-stories/detail/ side-effects-of-covid-19-vaccines. WHO (World Health Organization). 2022a. “Coronavirus Disease (COVID-19): Vaccines.” Questions and Answers (May 17), WHO, Geneva. https://www. who.int/news-room/questions-and-answers/item/ coronavirus-disease-(covid-19)-vaccines. WHO (World Health Organization). 2022b. Therapeutics and COVID-19: Living Guideline, 22 April 2022. Geneva: WHO. WHO (World Health Organization) and GFATM (Global Fund to Fight AIDS, Tuberculosis, and Malaria). 2010. “Minimum Requirements for a Functional Pharmacovigilance System.” WHO, Geneva. https://who-umc.org/media/1483/ pv_minimum_requirements_2010_2.pdf. Wilkinson, J. L., A. B. A. Boxall, D. W. Kolpin, K. M. Y. Leung, R. W. S. Lai, C. Galbàn-Malagón, A. D. Aell, et al. 2022. "Pharmaceutical Pollution of the World's Rivers." Proceedings of the National Academy of Sciences 119 (8): e2113947119. World Bank. 2017. Drug-Resistant Infections: A Threat to Our Economic Future, Final Report. March. Washington, DC: World Bank. World Bank. 2022. "Change Cannot Wait : Building Resilient Health Systems in the Shadow of COVID-19 - Investing in Health System Resilience for the Anthropocene". World Bank Group: Washington, DC. https://documentsinternal. worldbank.org/search/33965765