Korea Case Study  A Learning from Best Practices Overview of the Republic of Korea Pharmacovigilance System Huihui Wang Patricio V. Marquez Albert Figueras Kseniya Bieliaieva Korea-World Bank Partnership Trust Fund (KWPF) B Overview of the Republic of Korea Pharmacovigilance System © 2022 International Bank for Reconstruction and Development / The World Bank 1818 H Street NW Washington DC 20433 Telephone: 202-473-1000 Internet: www.worldbank.org This work is a product of the staff of The World Bank with external contributions. The findings, interpretations, and conclusions expressed in this work do not necessarily reflect the views of The World Bank, its Board of Executive Directors, or the governments they represent. 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Introduction.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .................................................................. 1 2. Drug Regulation in Korea.. . . . . . . . . .................................................................. 2 Legislation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .................................................................. 2 Regulatory bodies.. . . . . . . . . . . . . . . . . . . . . .................................................................. 3 Funding for medicines.. . . . . . . . . . . . . . . .................................................................. 3 3. Monitoring the Safety of Drugs and Medicines in Korea. . ............................ 4 Overview of the National Pharmacovigilance System....................................... 4 The role of the MFDS.. . . . . . . . . . . . . . . . . ................................................................. 4 Pharmacovigilance System.. . . . . . . . . ................................................................. 5 Korea Institute of Drug Safety and Risk Management....................................... 6 Pharmacovigilance Network in Korea. . ........................................................... 6 The Korea Adverse Event Reporting System.. ................................................... 9 Establishment of integrated ‘Comprehensive Drug Information System (NeDrug)’. . . . . . . . . . . . . . . . . . . . . . . . ................................................................ 10 Completeness in Adverse Event Reports generated by Hospitals/Clinics, Pharmacies, Consumers, and Pharmaceutical Companies in Korea.................... 11 Characteristics and Trends of Spontaneous Reporting of Therapeutic Ineffectiveness in Korea.. . . . . . . . . . . . . ................................................................ 12 Pharmacoepidemiology. . . . . . . . . . . . . . . ................................................................ 13 Drug Utilization Review (DUR) Program in Korea............................................ 14 Influence of Drug Utilization Reviews. . .......................................................... 15 4. Safety Measures Based on Pharmaceutical Safety Information Reports...... 16 Safety Measures Based on Domestic Pharmaceutical Safety Information Reports. . . . . . . . . . . . . . . . . . . . ................................................................ 16 Safety Measures Based on Information on Pharmaceutical Safety from Abroad.. . . . . . . . . . . . . . . . . . . . ................................................................ 16 Setup of a Ground to Safely Use Vaccines over the Entire Lifecycle and Provide Technical Support for the WHO’s Pre-Qualification (PQ)....................... 16 Table of Contents iii 5. Adverse Drug Reaction (ADR) Relief System. . ............................................. 17 Product Liability Act. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...................................................... 17 Product Liability Claims.. . . . . . . . . . . . . . . . . . . . . . . . ...................................................... 18 Challenges and Future I 6.  ­ mprovements in Korea’s Pharmacovigilance System. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...................................................... 19 Takeaways: Lessons from Korea’s Experience Monitoring the 7.  Safety of Medicines.. . . . . . . . . . . . . . . . . . . . . . . . . . . . ..................................................... 20 8. Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...................................................... 21 Tables Milestones in the Development of the Pharmacovigilance Table 1.  System in Korea.. . . . . . . . . . . . . . . . . . . . . . . . ....................................................... 5 Table 2.  Funding for KIDS, 2016-2021.. . . . . . . ....................................................... 6 Figures Figure 1.  National Pharmacovigilance System in Korea.................................... 4 Figure 2.  Regional Pharmacovigilance Center in Korea.................................... 7 Figure 3.  Operating System of RPVCs. . . . . . . ....................................................... 8 Figure 4.  Reports from RPVCs, per year.. . . ....................................................... 9 Figure 5.  Korea’s Adverse Drug Reporting System........................................... 10 Figure 6.  Reported Individual Case Safety Reports (ICSRs), by year................... 11 Figure 7.  Pharmacoepidemiology Activities in Korea. . ..................................... 13 Figure 8.  DUR as Part of the COVID-19 Response. . ........................................... 14 Figure 9.  Adverse Drug Reaction Relief System Flow Chart. . ............................ 18 Figure 10.  Types of Relief Benefits. . . . . . . . . . . . ...................................................... 18 iv Overview of the Republic of Korea Pharmacovigilance System Reports in the Pharmacovigilance and Essential Public Health Services Series Global Synthesis Report on Pharmacovigilance: Why is the Safety of Medicines Important for Resilient Health Systems? Positioning Report on Pharmacovigilance: The Value of Pharmacovigilance in Building Resilient Health Systems Post-COVID Pharmacovigilance Situation Analysis Report: Safety Monitoring of Medicines and Vaccines Regional Realizing a Regional Approach to Pharmacovigilance: A Review of the European Union Approach The Caribbean Regulatory System: A Subregional Approach for Efficient Medicine Registration and Vigilance Financing of Essential Public Health Services in the Caribbean Region Country Scope Learning from the Republic of Korea: Building Health System Resilience Learning from Best Practices: An Overview of the Republic of Korea Pharmacovigilance System Pharmacovigilance in Brazil: Creating an Effective System in a Diverse Country Starting and Strengthening a National Pharmacovigilance System: The Case of Catalan Regional Activities that Propelled the Spanish Pharmacovigilance System Ghana’s Pharmacovigilance Experience: From Vertical Program Activity to Nationwide System Acknowledgements v Acknowledgements This report was prepared by a team led by Huihui Wang (Senior Health Economist, World Bank Group (WBG), including Patricio V Marquez (Consultant, WBG), Albert Figueras (Consultant, WBG), and Kseniya Bieliaieva (Consultant, WBG). Seng Eun Choi (Senior Researcher, Korea Institute of Government Expenditure) provided valuable inputs and guidance on the funding of the pharmacovigilance program in Korea. The draft report was kindly reviewed by Rocio Schmunis (Senior Health Specialist, HHNGE, WBG), Inuk Hwang (Assistant Professor, Seoul University, Rep. of Korea), and Rian Marie Extavour (Program Manager, Caribbean Public Health Agency (CARPHA), and Kevin Yunil Kim (Operations Analyst, WBG Korea Office). 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 was carried out under the support provided by the Korea-World Bank Partnership Trust Fund (KWPF). Washington, DC, July 23, 2023 vi Overview of the Republic of Korea Pharmacovigilance System Acronyms ADE Adverse drug event ADR Adverse drug reaction AE Adverse event ATC Anatomical Therapeutic Chemical (classification system, WHO) CI Confidence interval DUR Drug utilization review FDA Food and Drug Administration (United States) HIRA Health Insurance Review & Assessment Service (Korea) ICSR Individual Case Safety Report KAERS Korea Adverse Event Reporting System KFDA Korea Food and Drug Administration KIDS Korea Institute of Drug Safety & Risk Management KRW Korean wan MAH Marketing authorization holder MFDS Ministry of Food and Drug Safety MoHW Ministry of Health and Welfare NHI National Health Insurance pADR Preventable adverse drug reaction PV Pharmacovigilance RPVC Regional Pharmacovigilance Center UMC Uppsala Monitoring Center (WHO) USD United States dollar WHO World Health Organization vii Overview of the Republic of Korea Pharmacovigilance System Key Messages ■ Building capacity in countries to conduct thorough surveillance of the use of all newly authorized drugs and vaccines, both brand- name and generic, is a critical “public good” investment to ensure that drugs work correctly and that their health benefits outweigh their known risks.  ■ Korea’s pharmacovigilance system (PVS) is an international best practice. It is the result of a continuous and sustained government effort over the past three decades—from small pilot projects to a nationwide monitoring network—and offers valuable lessons to other countries on the vital role that such a system can play in ensuring the safety of drugs post-marketing. ■ Key functions of the Korea Institute of Drug Safety & Risk Management (KIDS), that operates as National PV Center, include: ■ Collection, analysis, and provision of drug safety information ■ Conduct pharmacoepidemiological investigation and research ■ Operate the adverse drug reactions relief program ■ Develop drug utilization review information ■ Establish and manage narcotics information system ■ Operate pharmaceutical integrated intelligence system ■ Provide pharmacovigilance education and training ■ Manage regional pharmacovigilance centers ■ Operate regulatory science center for advance biopharmaceuticals ■ The Korean experience is an example of PV systems contributing to strengthening the health system, particularly for countries where there is a single ministry of health, and the PV function may get lost. The example of having a dedicated entity for drug regulation and safety monitoring is an effective approach. Hence, countries that are developing their systems may start with establishing a dedicated division for pharmacovigilance. 1. Introduction 1 Clinical trials cannot reflect the experience in larger populations and in different geographical regions 1. Introduction co-morbid conditions, children, the elderly, and pregnant women. Hence, clinical trials cannot reflect the experience in larger populations and in different geographical regions, which may differ from one another with respect to genetics, food habits, lifestyle, or clinical practices. This makes it obligatory to conduct thorough surveillance of the use of all newly authorized medicinal products.2 Health professionals or patients Pharmacovigilance, the monitoring of safety in the report adverse events (AE) after the administration and use of medicines after they have been licensed for use of a medicine; the PV team assesses each report use—plays a vital role in ensuring that patients are and investigates the causality; if there is a suspicion of administered and use appropriate medical products causality, then the events are categorized as suspected that are safe and effective. Pharmacovigilance adverse drug reactions (ADR). PV centers periodically involves the collection, detection, assessment, review all the received reports describing events, to be monitoring, and prevention of adverse effects with able to identify some adverse reaction candidates to be pharmaceutical products. As such, it is a critical tool considered "signals" (which is information on a new or to inform decision making in health systems. This is incompletely documented adverse event that is poten- because before a new medicinal product is marketed, tially caused by drugs and vaccines and that warrants its safety and efficacy exposure are limited to its use further investigation on an accelerated timetable). in clinical trials. PV also helps to monitor serious This report provides an overview of the Korean adverse effects of any medicine or vaccine, new or old. pharmacovigilance system, describing its main In fact, “old” medicines, those that theoretically are structural and operational elements, to monitor the well-known, continue to be the cause of thousands safety and effectiveness of medicines. It draws from of emergency room admissions (Budnitz et al 2017).1 a review of available literature in journal articles, as Generally, clinical trials cover limited number well as from the websites and reports of Korean of patients with strict inclusion criteria, often institutions. excluding special patient groups like those with 2   ontrary to the normal belief, the terms “drugs” and “medicines” C are not synonymous; they are actually quite different. A drug is any chemical substance which when acting on the living body alter the 1   udnitz DS, Shehab N, Lovegrove MC, Geller AI, Lind JN, Pollock B physiological process and is used for prevention, diagnosis, control, DA. 2021. “US Emergency Department Visits Attributed to and/or treatment of disease. Medicine is the formulated form of Medication Harms, 2017-2019”. JAMA. 326(13):1299–1309. doi: 10.1001/ the drug having definite dose and dosages form, which is used for jama.2021.13844. PMID: 34609453; PMCID: PMC8493432. prevention, diagnosis, control, and/or treatment of disease. 2 Overview of the Republic of Korea Pharmacovigilance System 2. Drug Regulation The Pharmaceutical Affairs Act categorizes pharmaceutical products as either drugs or herbal in Korea medication. Drugs are defined as articles: • Listed in the Korean Pharmacopoeia, other than quasi-drugs. • Used for the purposes of diagnosis, medical care, alleviation, treatment, or prevention of diseases of human beings or animals, other than appliances, machinery, or equipment. • Used for the purpose of exerting p­ harmacological effects upon the structure or functions of Drug regulation refers to process of testing, human beings or animals, other than appliances, developing and marketing of medicines that has machinery, or equipment. to be regulated to protect the public. The two main Biological medicines are also deemed to be “drug components of drug regulation are legislation and products” under the Pharmaceutical Affairs Act, regulatory bodies. standards but they are subject to different set of ­ In this section, an overview of the legal and from pharmaceutical products in terms of safety, regulatory elements that govern drug regulation efficacy, manufacturing standards, and testing in Korea is presented. They encompass various methods. The submission materials required to functions such as licensing new medicines, ensuring obtain market authorization are also different compliances in various legal and regulatory aspects between biological and pharmaceutical medicines. of a drug, enforcing rules and regulations and issuing In 2019, the Act on the Safety and Support of guidelines to regulate drug development process, ­ Innovative Regenerative Therapies and Innovative licensing, registration, manufacturing, marketing and Biologic Drugs (Regenerative Bio Act) came into labeling of pharmaceutical products. force. The Regenerative Bio Act takes precedence over the Pharmaceutical Affairs Act with respect to the manufacture, import and sales, and safety Legislation management of biological medicines, cell therapies, Pharmaceutical Affairs Act. Pharmaceutical and gene therapies. products in the Republic of Korea are regulated by Under the Pharmaceutical Affairs Act, pharmaceu- the Pharmaceutical Affairs Act adopted in 1960,3 as tical products can only be distributed and sold by amended in July 2002, to align laws more closely licensed manufacturers, importers, wholesalers, or with those in Australia, Canada, the European Union, pharmacists and registered sellers of emergency and the United States, and recently in April 2020.4 medicinal products. It includes: (i) comprehensive provisions relating Post-marketing surveillance refers primarily to to the manufacture, import, sale, and advertising of safety; in some cases it can help to analyze the pharmaceutical products; and (ii) the conditions for effectiveness (efficacy in a real clinical context) of a licensing, establishing, and operating pharmacies. new medicinal product. For example, the following are subject to post-marketing surveillance during the 3  See: https://elaw.klri.re.kr/eng_service/lawView. following re-evaluation periods, starting from the do?hseq=40196&lang=ENG. date of the product license approval: 4  A  mendments to the Pharmaceutical Affairs Act to Strengthen Administrative & Criminal Sanctions for Data Manipulation • New drugs: 6 years Related to Applications for Regulatory Approvals. Accessed at: • Pre-approved prescription drugs with a new https://www.legal500.com/developments/thought-leadership/ amendments-to-the-pharmaceutical-affairs-act-to-strengthen- indication (that is, a new application for an existing administrative-criminal-sanctions-for-data-manipulation-related- approved drug): 4 years to-applications-for-regulatory-approvals/. 2. Drug Regulation in Korea 3 • Orphan drugs (a pharmaceutical that remains kickback practices), enforcing drug pricing rules and commercially undeveloped owing to limited regulations, and overseeing matters relating to health potential for profitability): 10 years care institutions. The number of patient subjects for the post-­ marketing surveillance is determined on a product-​ by-product basis by taking into consideration the Funding for medicines characteristics of the relevant indication. The National Health Insurance Act of 1999 includes items on benefit package, reimbursement, contribu- Violation by marketing authorization holders of tion, the National Health Insurance Services (NHIS), post-marketing surveillance requirements can result the Health Insurance Review & Assessment Service in a sales suspension, and repeated violations can (HIRA) but does not oversee Medical Aid Program result in a revocation of the marketing authorization. (which operates under separate Medical Aid Program Act and covers approximately 2.8% of the population) Regulatory bodies and the Long-term care insurance (LTCI) introduced The main administrative authorities overseeing in 2008, which also operates under the Long-term pharmaceuticals in Korea are the Ministry of Food Care Act first introduced in 2007.6 and Drug Safety (MFDS)5 and Ministry of Health and The National Health Insurance (NHI) scheme, a Welfare (MoHW). single-payer system, covers the entire population, Ministry of Food and Drug Safety. The Ministry of and all citizens earning an income in Korea must Food and Drug Safety (MFDS) was formerly known contribute a percentage of their monthly salary. as the Korea Food and Drug Administration (KFDA). Employers are also responsible for matching It was established in April 1996 as the KFDA, and later employee contributions. The contributions paid by elevated to become a ministry in March 2013. The one working citizen cover health insurance for his or MFDS is the chief governmental body that regulates her entire family. food, food additives, pharmaceuticals, biologics As of 2019, 97.2 percent of the Korean population (including vaccines, blood products, cell/gene were enrolled in the NHI; for those not enrolled, therapeutics, and biosimilars), cosmetics, and the government provides subsidies in the form quasi-pharmaceuticals (such as masks, hand sanitiz- of medical benefits payments.7 The NHI is mostly ers, and medical devices, including diagnostic testing funded by insurance premiums paid by enrollees, kits). It is responsible for overseeing medical device and government subsidies (14 percent of total). Health and pharmaceutical registration, manufacturing, promotion funds generated through tobacco taxes and distribution in Korea. The MFDS is composed of (6 percent) cover the balance.8 1,946 staff members and in 2020 it had an operating In Korea, a “positive drug list” applies where only budget of US$460 million (540 billion Korea won). those products proved to be of clinical usefulness and The vision of MFDS is “Safe Food and Drugs, Healthy cost-effective may be reimbursed under the NHI in People” and it has three major goals: accordance to negotiated maximum prices between • Food safety that makes consumers healthier companies and the NHI. • Medicine and medical devices quality assurance for patients 6   ee National Health Insurance Act (No. 5854 of 1999), as amended, S International Labor Organization: https://www.ilo.org/dyn/natlex/ centered”) • A “People-centered” (rather than “product-­ natlex4.detail?p_isn=66766. approach to food and drug safety policy 7  G  lobal Legal Insights: https://www.globallegalinsights.com/ Ministry of Health and Welfare. The MoHW is practice-areas/pricing-and-reimbursement-laws-and-regulations/ korea mainly focused on maintaining order in pharmaceu- 8   .E. Choi and P.V. Marquez, Reducing Tobacco Use through S tical sales practice (for example, regulation of illegal Taxation: The Experience of the Republic of Korea (Washington, DC: World Bank Group, 2018), https://documents1.worldbank. org/curated/en/150681529071812689/pdf/127248-WP-PUBLIC-ADD- 5   Site of the MFDS: https://www.mfds.go.kr/eng/wpge/m_17/denofile.do. SERIES-WBGTobaccoKoreaFinalweb.pdf. 4 Overview of the Republic of Korea Pharmacovigilance System 3. Monitoring the A detailed discussion of the different parts of the system follows. Safety of Drugs The role of the MFDS and Medicines The provisions for the reporting, evaluation, in Korea distribution, and control of safety related information during handling and using of Pharmaceuticals and Quasi-Drugs (“Medicinal Products etc.”) are included in MFDS Notification No. 2014-97, of February 20, 2014, Partial Amendment, in accordance with respective Articles of the Pharmaceutical Affairs Act (Amended on May 29, 2016)9 and the Articles of the Regulation on Safety of Medicinal Products. The MFDS is tasked with establishing standards and specifications for medical products, monitoring pre- and post-management procedures, ensuring Good Manufacturing Practices, reinforcing the Overview of the National safety control system, and improving the industrial Pharmacovigilance System competitiveness of medical products. Under the Figure 1 provides a comprehensive overview of the MFDS, the Pharmaceutical Safety Bureau, the organizational arrangement, actors involved and their Medical Device Safety Bureau, the Medical Device interaction, and functions of the Korean PV system. Information and Technology Assistance Center, Figure 1  National Pharmacovigilance System in Korea Media, Online International Foreign Regulatory Ministry of Embassy Information Organization Agency Foreign Affairs WHO-UMC Foreign Communication Communication Press corps Healthcare professionals AE/ADR Reporting Korea Institute of Drug Ministry of Food Patients, Safety and Risk Management and Drug Safety Consumer Sharing Information Regional Provide AE data Center PV centers Safety reporting Pharmaceutical Affairs council KDCA Industry Regulatory Action Safety alerts/ Label Withdrawal/ Forbid or letters change Recall restrict sale Source: Adopted from the presentation “Korea Institute of Drug Safety & Risk Management (KIDS) and Pharmacovigilance in Korea”, delivered by Dr. Hyun-Joo Jung, Korea Institute of Drug Safety & Risk Management(KIDS), at a dedicated session organized by the World Bank on June 29, 2023. during 3rd World NCD Congress, Toronto, Canada that was held on June 25–30, 2023. 9  https://www.mfds.go.kr/eng/brd/m_18/view.do?seq=71344  3. Monitoring the Safety of Drugs and Medicines in Korea 5 and the National Institute of Food and Drug Safety Pharmacovigilance System Evaluation hold primary responsibility over the review, approval, and regulation of medical device As shown in Table 1, Korea has been making and pharmaceutical products. continuous efforts in the field of pharmacovigilance for the last 3 decades.10 The adverse drug reactions The MFDS also collects reports on adverse drug (ADR) reporting system was launched in 1988 by reactions from consumers, hospitals/clinics, the Korea MFDS and spontaneous ADR reports have pharmacies, pharmaceutical manufacturers been collected from health care professionals and (importers), and regional drug safety centers to the general public. The country joined the World manage pharmaceutical safety more efficiently. Health Organization Program for International Data thus gathered are ultimately developed into Drug Monitoring in 1992, and the activities of new safety information after they are subjected to Pharmacovigilance Research Network, Korean statistical analysis, literature review, examination Society for Pharmacoepidemiology and Risk of permits issued abroad, and consultation with Management, and Regional Pharmacovigilance experts. This leads to appropriate safety processes Center (RPVC) have contributed to the develop- such as change of licenses, directions for research ment. The Korea Institute of Drug Safety & Risk investigation, suspension of sales, recall and Management, under the MFDS, is in charge of disposal; and related information is provided operating the decentralized national to medical institutions, doctors/pharmacists, pharmacovigilance system. and consumers. Milestones in the Development of the Pharmacovigilance System Table 1   in Korea 1988 Established a voluntary ADR reporting system Designated 376 ADR monitoring institutions 1990 Expanded ADR monitoring institutions nationwide to 920 simplified case report format 1992 Joined the World Health Organization (WHO) Program for International Drug Monitoring 1996 ADR monitoring institutions reached 44,034 1998 Expanded ADR monitoring institutions to entire clinics, hospitals, and pharmacies Introduced ADR reporting through the internet 1999 Launched the pilot project to organize the ADR reporting system 2004 Mandatory ADR reporting of pharmaceutical companies and pharmacies 2006 RPVC started in 3 university hospitals 2007 RPVC extended to 6 university hospitals Founded the Korean Society for Pharmacoepidemiology and Risk Management 2008 RPVC extended to 9, organized RPVC council 2009 Launched the Pharmacovigilance Research Network 2011 RPVC extended to 20 university hospitals 2012 Established the Korea Institute of Drug Safety & Risk Management (KIDS) 2013 Authorized KIDS to manage the national pharmacovigilance system 2016 RPVC extended to 27 university hospitals Source: D.Y. Kang, K.M. Ahn, H.R. Kang, and S.H. Cho, “Past, Present, and Future of Pharmacovigilance in Korea,” Asia Pacific Allergy (July, 2017) 7(3):173–78, https://doi.org/10.5415/apallergy.2017.7.3.173. Note: ADR = adverse drug reaction; RPVC = Regional Pharmacovigilance Center; WHO = World Health Organization. 10  D  .Y. Kang, K.M. Ahn, H.R. Kang, and S.H. Cho, “Past, Present, and Future of Pharmacovigilance in Korea,” Asia Pacific Allergy (July, 2017) 7(3):173–78, https://doi.org/10.5415/apallergy.2017.7.3.173. 6 Overview of the Republic of Korea Pharmacovigilance System Korea Institute of Drug Safety More specifically, as a public institution managing drug safety, KIDS supports evidence-based decisions and Risk Management in drug safety by promoting adverse drug event (ADE) The MFDS established the Korea Institute of Drug report, assessing drug safety information, performing Safety Risk Management (KIDS)11 in 2012 as a causality assessments, developing drug utilization ­ dedicated entity responsible for the collection, review (DUR) criteria, disseminating safety informa- ­ analysis, and management of safety information, tion, and providing education to the public. including side effects of medicines, and also Funding. KIDS operates under the funding from increased the Regional Pharmacovigilance Centers. the MFDS, which provides about 68 percent of total The goal of KIDS is to “achieve excellence with revenue. Additional funding comes from contracting creativity to proactively collect, analyze, assess, out research, evaluation, and services ordered by the and manage drug safety information. With the government (Table 2). drug safety information, it aims to serve and devote to the safety of Korean citizens through public education and training programs.” KIDS Pharmacovigilance aspires to be a global leading institute in Network in Korea pharmacovigilance and risk management. In Korea, the pharmacovigilance system is KIDS’s role is to help enhance national health care operated on a decentralized basis. In this system, quality through prevention and recognition of a central center functions as the coordinator for drug-related issues in accordance with the regulation regional centers and collects data from each regional of Article 68-3 of Pharmaceutical Affairs Act to center. These regional centers are called Regional collect, manage, analyze, evaluate, and provide Pharmacovigilance Centers (RPVCs). Starting from various information related to drug safety such as three RPVCs designated in 2006, the number of adverse drug events and drug labeling information. centers gradually increased to six in 2007 and to nine Table 2  Funding for KIDS, 2016-2021     2016 2017 2018 2019 2020 2021 Revenues Government Contribution 8,900 8,345 9,158 10,799 11,528 11,747 from Subsidy 1,955 710 0 0 0 0 Government Secondary Revenue 0 0 0 3 2 0 (Korean Won, million) Business Revenue 43 50 51 52 34 45 Contracting out Revenue 510 600 4,241 3,538 5,364 5,446 SUBTOTAL 11,408 9,705 13,450 14,392 16,928 17,238 Non- Other business Revenue 478 495 78 0 0 0 Government Secondary Revenue 0 0 1 0 0 0 Revenue Others 0 280 376 858 1,338 0 (Korean Won, million)   TOTAL 11,886 10,480 13,905 15,250 18,266 17,238 KRW (approx. US$ 14,516 million*) Source: Personal Communication with Seng Eun Choi, Senior Research Fellow, Korea Institute of Public Finance (KIPF). 11  KIDS website: https://www.drugsafe.or.kr/iwt/ds/ko/report/ WhatIsADR.do. Note: * Exchange rate: 1.00 KRW = 0.000836 USD (KRW = Korean wan; USD = United States dollar). 3. Monitoring the Safety of Drugs and Medicines in Korea 7 in 2008. By 2011, it increased to 20 centers through a global database managed by the WHO Program Pharmacovigilance Research Network (PVNet). Since for International Drug Monitoring. KIDS contributes 2012, KIDS plays the central role in managing all the to effective, comprehensive data management on RPVCs: 22 RPVCs in 2013, 27 RPVCs in 2019, and in adverse side effects of drug intake through regular 2020, with the addition of the new RPVC for Korean reports made with Uppsala Monitoring Center Herbal Medicines, a total of 28 RPVCs (Figure 2). (UMC) under WHO. The RPVCs are staffed with competent PV teams. MFDS requires swift reporting upon any drug-related KIDS focuses on raising awareness of drug safety irregularities, based on which necessary measures issues, supporting evidence-based decisions on drug follow, including changes to drugs’ earlier approval safety, and providing accurate drug information to for sale, recalls or market withdrawals as well as increase public safety. KIDS gathers data form the investigations or inspections into the determination RPVCs, the analyses of which provides the MFDS of causes. The collected information is made with statistics, safety information, and reports of available to doctors, pharmacists, consumers and all adverse effects The data feeds into VigiBase, relevant organizations. Figure 2  Regional Pharmacovigilance Center in Korea Seoul (8) Gangwon (1) Pharmacy Network (1) • Asan Medical Center • Hallym Chuncheon Sacred • Korea Pharmaceutical • Chung-Ang Univ. Hospital Heart Hospital Association • Hanyang Univ. Hospital • Korea University Guro Hospital The Center of Public • Samsung Medical Center Healthcare (1) • Seoul National Univ. Hospital • National Medical Center • Seoul St. Mary’s Hospital • Severance Hospital RPVC for Herbal Medicines (1) • Dongguk Univ. Ilsan Inchun, Gyeonggi (5) Oriential Hospital • Ajou Univ. Hospital • Dongguk Univ. Ilsan Hospital • Hallym Univ. Dongtan Sacred Daegu, Hyungpook (2) Heart Hospital • Inha Univ. Hospital • Kyungpook National Univ. • Seoul National Univ. Bundang Hospital Hospital • Keimyung Univ. Daegu Dongsan Hospital Daejeon, Sejong, Pusan, Ulsan, Kyungnam (4) Chungcheong (3) • Dong-A Univ. Hospital • Chungbuk National Univ. • Inje Univ. Pusan Paik Hospital Hospital • Inje Univ. Haeundae Paik Hospital • Chungnam National Univ. • Pusan National Univ. Hospital Hospital • Dankook Univ. Hospital Gwangju, Jeolla, Jeju (2) • Chosun Univ. Hospital • Chunnam Univ. Hospital Source: Adopted from KIDS, Regional PV Center/Korea Institute of Drug Safety & Risk Management, https://www.drugsafe.or.kr/ iwt/ds/en/community/EgovHistoryPvCenter.do. 8 Overview of the Republic of Korea Pharmacovigilance System Figure 3  Operating System of RPVCs Academic Clinics Regional Members PV Centers Public Health Pharmacies Organizations AE Intensive AE Education & Monitoring Monitoring Consultation Promotion • Monitor AE reports • Monitor special • Consult consumer • Train in-center within the center populations (Geria- AEs personnel • Perform causality trics/ Pediatrics) • Consult reporter • Train healthcare assessments • Monitor designated questions professionals • Report collected drugs from MFDS • Offer education data to the • Collect data and programs for central center perform causality medical/pharmacy • DUR contraindi- assessments students cated medicines Source: Adopted from: KIDS. https://www.drugsafe.or.kr/iwt/ds/ko/report/WhatIsADR.do. Note: PV = pharmacovigilance. Functions of the Regional Pharmacovigilance Collection, analysis, and evaluation of ADR in Centers (RPVCs). Figure 3 describes the operating Korea. The focus of the work of KIDS12 is to generate system of RPVCs in Korea. Each RPVC monitors AE drug safety information from various sources related reports within the center and also outside reports to pharmacovigilance (PV) activities, including ADE from local clinics and pharmacies. It performs and ADR. To do this, KIDS collects reports from an intensive monitoring on special populations consumers, health care professionals, consumers, (e.g., pediatrics, geriatrics) or special medicinal RPVCs, and pharmaceutical companies. products designated by the MFDS and offers In addition, signal detection13 is performed using consultations to reporters and consumers as well. ­ data mining methods. Potential signals detected Finally, it emphasizes education and ­ promotional campaigns to stimulate the pharmacovigilance activities. 12   .Y. Shin, S.Y. Jung, S.H. Ahn, S.H. Lee, S.J. Kim, J.M. Seong, J S.Y. Chung, and B.J. Park, “New initiatives for Pharmacovigilance in South Korea: Introducing the Korea Institute of Drug Safety and Risk Management (KIDS),” Pharmacoepidemiology and Drug Safety (2014) 23:11: 1115–22. https://doi.org/10.1002/pds.3715 13  A  s defined by WHO, this term refers to reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented previously. It is a possible association considered important enough to investigate further. 3. Monitoring the Safety of Drugs and Medicines in Korea 9 Figure 4  Reports from RPVCs, per year 539,441 600,000 550,000 500,000 400,000 315,867 350,000 262,983 259,089 257,438 252,611 228,939 300,000 198,037 190,474 250,000 183,554 175,257 184,861 181,273 171,608 171,748 163,676 137,602 200,000 118,544 150,000 100,000 50,000 0 2014 2015 2016 2017 2018 2019 2020 2021 2022 reports from RPVCs reports in Korea Source: Korea Institute of Drug Safety & Risk Management (KIDS), https://www.drugsafe.or.kr/iwt/ds/en/community/ EgovCurrentActivitiesPvCenter.do. from the ADR database raise hypothesis, which KIDS AE reports, which stood at approximately 1,000 will investigate further. If the signal is relevant and reports in 2005, significantly increased with the significant, safety information produced as the result initiation of RPVC in late 2006. As shown in Figure 4, of it may be applied to specific regulatory decisions the significant increase in the number of voluntary such as label updates. AE reports (more than 3,000 reports per year) within a short period of time shows the importance of RPVCs KIDS also proactively monitors drug safety issues in stimulating AE monitoring. and adverse events of interest, broadening the scope of signal detection from using spontaneous Education and promotion on pharmacovigilance ADR reports to using the national medical claims and drug safety. KIDS provides education regarding database. As a PV center, KIDS lists drugs of interest PV and drug safety for the public, as well as health that require intensive monitoring. These drugs are care professionals and related organizations. In the followed up carefully by RPVCs, which continuously RPVCs, education and promotional campaigns conduct intensive monitoring in special medicines regarding the importance of pharmacovigilance (e.g., oral contraceptives) and special populations are done periodically, including production and (e.g., pediatrics and geriatrics). The lists of drugs are ­ distribution of newsletters, press-releases, and updated periodically upon outbreaks of safety issues updates in the bulletin. or requests from health care professionals. The Korea Adverse Event The RPVCs have individual electronic AE reporting systems. Each center builds collaborative relation- Reporting System ships with local health care providers to stimulate As illustrated in Figure 5 below, the Korea Adverse voluntary AE reporting.  The number of voluntary Event Reporting System (KAERS) is a system 10 Overview of the Republic of Korea Pharmacovigilance System Figure 5  Korea’s Adverse Drug Reporting System A A. Consumer Anyone who experiences an AE can report via KAERS. Health Care B Professionals (HCPs) F Ministry of Food and Drug Safety (MFDS) HCPs can report AEs or request KIDS periodically provides MFDS causality assessment to RPVCs via KAERS. A with AE report statistics and safety information generated from signal analysis. B F KAERS Regional C C E Uppsala monitoring Pharmacovigilance E Centre (UMC) Centers (RPVCS) D RPVCs evaluate causal KIDS periodically submit ICSR relationships of cumulated AE reports to the WHO-UMC. information in the region and Pharmaceutical report via KAERS. D Company Pharmaceutical companies report AEs via KAERS, especially the reports which are required mandatory based on the pharmaceutical regulation. Source: Adopted from KIDS, https://www.drugsafe.or.kr/iwt/ds/ko/report/WhatIsADR.do. developed by KIDS to facilitate reporting and Establishment of integrated management of AE reports. All reports of AE have been accumulated in KAERS since 2012. Suspected ‘Comprehensive Drug drug and AE information are reported to KIDS in a Information System (NeDrug)’ form named Individual Case Safety Reports (ICSRs). ICSRs are important because they provide a Suspected ADR can also be reported via an ADR different perspective than adverse event reports, call center and other routes such as fax and e-mail. which can be collected from multiple patients. ICSR, However, all information received is stored within as an individual case safety report, includes data KAERS as an ICSR. on individuals who have had experience with the KIDS detects and evaluates signals from accumu- medical treatments or products we want to know lated data to generate and provide drug safety about (https://www.idmp1.com/wiki/icsr-in-pharma- information. The KAERS database is compatible covigilance/). These types of cases may not always with the i ­nternational standards, and the WHO-UMC represent the same information as other studies. (Uppsala Monitoring Centre) international drug The MFDS joined the International Council for monitoring program. Harmonization of Technical Requirements for The minimum criteria for an adverse event report to Pharmaceuticals for Human Use (ICH), as a full be valid are AE information, drug information, and regulatory member in 2016. Since joining ICH, MFDS patient and reporter information. KIDS periodically adopted an application system for the use of an provides the MFDS with AE report statistics and international standard form E2B (R3) for adverse safety information generated. drug event reporting, and has been operating in 3. Monitoring the Safety of Drugs and Medicines in Korea 11 Figure 6  Reported Individual Case Safety Reports (ICSRs), by year 300,000 257,438 262,983 259,089 252,611 250,000 228,939 200,000 150,000 100,000 50,000 0 2016 2017 2018 2019 2020 Source: KIDS https://www.drugsafe.or.kr/iwt/ds/ko/report/WhatIsADR.do. parallel the Korea Adverse Event Reporting System Submission of foreign ICSRs has been made (KAERS) and the Integrated Drug Information System mandatory since August 2014 for MAHs, as an effort (NeDrug), which was developed in 2019 to provide to manage safety information comprehensively. drug-related information, including about clinical The KAERS database includes the data collected trials, patents, and drug safety. through spontaneous reports, reports from studies (re-examination, post-marketing studies, individual As announced on March 7, 2023, KAERS was case studies, etc.), and literature information. Figure 6 integrated into the NeDrug system to function as an above provides data on the number of ICSRs reported integrated ‘Comprehensive Drug Information System’ by year between 2016 and 2020. (NEDrug). No changes to the reporting system itself have been announced.14 Who reports to KAERS? Anyone who experiences Completeness in Adverse Event AE can report to KIDS using KAERS: consumers, Reports generated by Hospitals/ health care professionals, RPVCs, and marketing Clinics, Pharmacies, Consumers, authorization holders (MAHs), which are mostly pharmaceutical companies. and Pharmaceutical Companies The RPVCs evaluate causal relationships of AE reports in Korea submitted to their center within the region and report A recent study evaluated the differential pattern and them to KIDS via KAERS. Pharmaceutical companies characteristics of completeness in AE reports gener- report AE via KAERS as well, especially the mandatory ated by hospitals/clinics, pharmacies, consumers, and reports required by the pharmaceutical regulations. pharmaceutical companies in Korea.15 It identified the characteristics of complete AE reports, compared What kinds of reports are submitted to KAERS? with those of incomplete AE reports, using a KIDS collects domestic and foreign ICSRs and manages the quality of the reports via KAERS. ­ 15  I .S. Oh, Y.H. Baek, H.J. Kim, M. Lee, and J.Y. Shin, “Differential Completeness of Spontaneous Adverse Event Reports among Hospitals/Clinics, Pharmacies, Consumers, and Pharmaceutical 14  M  edi:Gate News.  Accessed at: https://medigatenews.com/ Companies in South Korea,” PLoS One (February 14, 2019) 14(2): news/1503204759 (Accessed on May 12, 2023). e0212336, https://doi.org/10.1371/journal.pone.0212336. 12 Overview of the Republic of Korea Pharmacovigilance System completeness score and data from Korea Institute of Given that health care professionals and manufac- Drug Safety and Risk Management-Korea Adverse turers are equally important stakeholders of AE, the Event Reporting System Database (KIDS-KD) study findings point out to the need for systematic between January 1, 2016 and December 31, 2016. The training programs (e.g., on standardized coding completeness score was determined out of a total guidelines for the preparation of adverse reports) to of 100 points, based on the presence of information enhance report completeness. Implementation of on temporal relationships, age and sex of patients, strategies to engage health care professionals will be AE progress, name of reported medication, reporting critical for enhancing completeness in spontaneous group by profession, causality assessment, and infor- reports and early signal detection. mational text. AE reports were organized into four groups based on affiliation: hospitals/clinics, phar- Characteristics and Trends macies, consumers, and pharmaceutical companies. Affiliations that had median completeness scores of Spontaneous Reporting of greater than 80 points were classified as “well-doc- Therapeutic Ineffectiveness umented” and these reports were further analyzed in Korea by logistic regression to estimate the adjusted odds Therapeutic ineffectiveness involves drug-related ratios and 95 percent confidence intervals (CIs). therapeutic failure, inefficacy, or resistance. A recent Findings indicate that the median values of the study evaluated reporting trends in therapeutic completeness scores were the highest for hospitals/ ineffectiveness by year and described factors affect- clinics (95 points), followed by those for consumers ing therapeutic ineffectiveness using the KAERS in (85), pharmacies (75), and manufacturers (72). Korea.19 Proportion of therapeutic ineffectiveness Reports with causality assessment of “certain”, reports was based on total submitted reports “probable”, or “possible” were more likely to be between 2000 and 2016. The study found that during “well-documented” than reports that had causality this period, the proportion of therapeutic ineffective- assessments of “unlikely”. Serious reports of AE ness adverse drug reactions reporting ranged from were positively associated with “well-documented” 0.0 ­percent to 3.7 percent. Of 228,939 reports, 2,797 reports and negatively associated with hospitals/ (1.2 percent) were submitted in 2016. Consumers clinics. The low completeness score of manufacturer accounted for 6.92 percent of reports and doctors reports ­corroborates a study16 of reports from the accounted for 45.49 percent, in which, consumers U.S. Food and Drug Administration (FDA) that were more likely to report therapeutic ineffective- also observed poor completeness of reports by ness than doctors (adjusted ROR 3.98; 95 percent pharmaceutical companies for serious adverse drug CI, 2.92 to 5.41). According to the Anatomical events. Similar conclusions were reached in studies Therapeutic Chemical (ATC) classification system,20 conducted in other countries (e.g., Brazil, Spain).17,18 19  H.J. Kim, H.E. Jeong, J.H. Bae, Y.H. Baek, and J.Y. Shin, “Characteristics  and Trends of Spontaneous Reporting of Therapeutic Ineffectiveness in South Korea from 2000 to 2016,” PLoS One (February 28, 2019) 16   .J. Moore, C.D. Furberg, D.R. Mattison, and M.R. Cohen, T 14(2):e0212905, doi: 10.1371/journal.pone.0212905. PMID: 30817781; “Completeness of Serious Adverse Drug Event Reports PMCID: PMC6395031, https://pubmed.ncbi.nlm.nih.gov/30817781/. Received by the US Food and Drug Administration in 2014,” 20  I n the WHO Anatomical Therapeutic Chemical (ATC) classification Pharmacoepidemiology Drug Safety (February 10, 2016) 25 (6):​ system, the active substances are divided into different groups 713–18, Epub 2016/02/11, https://doi.org/10.1002/pds.3979. according to the organ or system on which they act and their 17  R  ibeiro, A, et al. 2017. “Filling quality of the reports of adverse therapeutic, pharmacological, and chemical properties. Drugs drug reactions received at the Pharmacovigilance Centre of are classified in groups at five different levels: ATC 1st level (the São Paulo (Brazil): missing information hinders the analysis of system has 14 main anatomical or pharmacological groups (1st suspected associations”. Expert Opin Drug Saf. 16(12):1329–1334. level); ATC 2nd level pharmacological or therapeutic subgroup; doi: 10.1080/14740338.2017.1369525. Epub 2017 Aug 23. PMID: 28817316. ATC 3rd & 4th levels chemical, pharmacological, or therapeutic subgroup; and ATC 5th level chemical substance. The 2nd, 3rd, and 18   lessis, L, et al. 2017. “Lack of essential information in spontaneous P 4th levels are often used to identify pharmacological subgroups reports of adverse drug reactions in Catalonia-a restraint to the when that is considered more appropriate than therapeutic or potentiality for signal detection”. Eur J Clin Pharmacol. 73(6):751–758. chemical subgroups. Available at https://www.who.int/tools/atc- doi: 10.1007/s00228-017-2223-5. Epub 2017 Mar 1. PMID: 28251276. ddd-toolkit/atc-classification. 3. Monitoring the Safety of Drugs and Medicines in Korea 13 “nervous system” was the most frequently reported pharmacoepidemiologic assessment methodologies group (18.7 percent) and “parathyroid hormones and guidelines. and analogues” (treatments for osteoporosis) was Methods for Causality Assessment. For individual reported most frequently in the pharmacological case reports, KIDS applies causality assessment subgroup (23.7 percent). Teriparatide, a drug used to algorithms, which are based on decision criteria treat osteoporosis, had the most reports (11.0 percent). including the temporal relationship (i.e., the sus- Therapeutic ineffectiveness reports may be used as a pected medicine was administered before the body scientific tool for the reevaluation of respective drugs had time to develop the reaction), previous bib- in order to confirm of its therapeutic effects. liographic descriptions, and other etiologic alterna- tives. Once the signal of a potential drug safety issue Pharmacoepidemiology is generated, a signal evaluation is performed. It KIDS conducts in-depth reviews of serious ADE includes amplification of the signal (estimulating reports and important safety signals. This is done similar reports at the local, national or international by conducting field pharmacoepidemiologic inves- level), analysis of national and international data- tigations on clusters of reports, and by conducting bases to find similar reports, and reviews of relevant strategic pharmacoepidemiologic investigations on literature and pharmacoepidemiologic studies either medicinal products with drug safety issues (Figure 7). on an ad hoc basis or as database analysis. To do this, the KIDS team keeps up-to-date with Figure 7  Pharmacoepidemiology Activities in Korea Request for Spontaneous Drug Safety Pharmacoepidemiologic ADE Reports Issue Investigation In-depth case review Prioritization criteria Target Prioritization of Label information Pharmacoepidemiologic Severity Literature review Epidemiologic Previous findings Investigation Previous spontaneous reports Clinical/Public importance Signal Investigations Strategic Pharmacoepidemiologic Investigations • Interview of patients and related • Systematic review of literature healthcare professionals • Analysis of automated DB (claims DB, • Hospital record review of drug hospital EMR, etc.) administration and adverse events • Cohort or case-control studies with • Assessment of additional ADE patient recruitment occurrences (claims DB, hospital DB, etc.) Causality Assessment on ADES Drug Safety Information Source: Adopted from KIDS, https://www.drugsafe.or.kr/iwt/ds/ko/report/WhatIsADR.do 14 Overview of the Republic of Korea Pharmacovigilance System Pharmacoepidemiologic studies can provide high continuing study that reviews, analyzes, and quality of evidence for clinical decision-making by interprets patterns of drug usage in a given health empirically specifying the nature and magnitude care delivery system against predetermined of the risk of having a particular adverse outcome standards. DURs play a key role in improving the associated with a medication. To evaluate the quality of pharmaceutical care by striving to prevent causality between a drug and an adverse event, KIDS inappropriate drug use and adverse drug reactions. monitors and observes the case and control groups DUR programs provide prescribers and pharmacists of a study and uses research designs like cohort with feedback on their performance and prescribing (all users of a drug are identified and followed up behaviors. DUR information allows health care to determine what events or ADR occur) and case-­ practitioners to provide safe and effective care control study (all cases of the disease are identified to patients. and the use of the drug of interest is compared with In Korea, the concept of DUR was first introduced controls without the disease). in the late 1980s. The MFDS has developed and announced lists of drugs that are contraindicated in Drug Utilization Review (DUR) pregnant women, drugs with drug-drug interactions, and drugs with age limits. As DUR criteria have been Program in Korea developed, the Korea Health Insurance Review & KIDS also performs drug utilization reviews Assessment Service (HIRA) has set up a concurrent (DURs). A DUR is an authorized, structured, and DUR system that provides real-time information on Figure 8  DUR as Part of the COVID-19 Response Airlines, Shipping Companies, Telecom Providers, Foreign Ministry, Justice Ministry entrant information KCDC (Quarantine Support Division) overall management of traveler history data and policies travel history database travel history database Checking Travel History Information Recipient Qualification DUR System Check System link Health Insurance ITS Program (KCDC) National Health Review and Insurance Service Assessment Service reception stage reception/ examination stage prescription stage Pharmacy Medical Institution Medical Institution Source: Korea Ministry of Health and Welfare, adapted from National Information Society Agency (NIA). 2020. “KOREAN ICT services against COVID-19 pandemic”. https://dgovkorea.go.kr/contents/library/267 3. Monitoring the Safety of Drugs and Medicines in Korea 15 contraindicated drugs to physicians and pharmacists. administrative data from HIRA.24 The claims Since 2012, KIDS has developed DUR criteria for data for all adult patients with adverse drug rational drug use, to investigate drug utilization events (ADE)-related diagnoses from 2009 to patterns and to distribute educational resources 2014 were obtained. Incidence rates of first-time for health care professionals. and repeat pADR prior to and after DUR program implementation were evaluated. Quarterly trends The following illustrate DURs done in Korea: A DUR in incidence rates of overall ADE, allergic reactions, found a rise of sedative use in endoscopic examina- and ADR were analyzed. tions and several patient cases of repeated sedative administration that suggested a potential risk for Data extraction covering the period from 2009 to abuse. Another DUR found that Korean regulatory 2014 led to the identification of 3,927,662 records. actions regarding the overuse of the fluoroquinolones First-time pADR rates decreased gradually after antibiotics had a positive effect of reducing use implementation of the DUR program (change in in the pediatric population.21,22 As illustrated in slope: –0.016, p = 0.02). The program had a similar Figure 8 above, the DUR system also contributed to influence on repeat pADR rates (change in slope: the COVID-19 response. By using DUR and ITS, all –0.006, p = 0.01). The program did not decrease medical institutions in Korea were enabled to identify rates of first-time or repeat allergic reactions patients with a high likelihood of COVID-19 infection. (change in slope: 0.018, p = 0.07 and 0.003, p = 0.04, Additionally, the Korean government was able to take respectively). In the cohort aged 65 years, first-time preventive measures via a smart quarantine system pADR rate reduction was significant (28.2 percent which helped to efficiently check the information of [27.1–29.3] in 18 years, and 19.8 percent [18.1–21.5] in travelers entering Korea via a third country.23 the cohort aged 19–64 years). In contrast, the first- time pADR rate increased by 0.6 percent [–0.7–1.9] in patients aged 65 years. Influence of Drug Utilization Reviews The findings of the study show that the implemen- tation of the prospective DUR program effectively To evaluate the influence of the DUR program in reduced the number of pADR. reducing incidence of preventable adverse drug reactions (pADR), a study was performed using 21   hin, JY, et al. 2015. “Prescribing patterns of the four most S commonly used sedatives in endoscopic examination in Korea: propofol, midazolam, diazepam, and lorazepam”. Regul Toxicol Pharmacol. 71(3):565–70. doi: 10.1016/j.yrtph.2015.01.007. Epub 2015. 22   hin, JY, et al. 2014. “Dramatic decrease in fluoroquinolones in S the pediatric population in Korea”. Pharmacoepidemiol Drug Saf. 12:1320–4. doi: 10.1002/pds.3696. Epub 2014 Aug 14. PMID: 25124740. Feb 7. PMID: 25659208. 24  J  . Lee, Y. Noh, and S. Lee, “Evaluation of Preventable Adverse 23   aewoo Nam. 2020. “How did Korea use technologies to T Drug Reactions by Implementation of the Nationwide Network manage the COVID-19 crisis?” A country report, International of Prospective Drug Utilization Review Program in Korea,” PLoS Review of Public Administration, 25:4, 225-242, DOI: One (April 11, 2018) 13(4): e0195434. https://doi.org/10.1371/journal. 10.1080/12294659.2020.1848061 pone.0195434. 16 Overview of the Republic of Korea Pharmacovigilance System 4. Safety Measures Safety Measures Based on Information on Pharmaceutical Based on Safety from Abroad Pharmaceutical The MFDS collects safety information from abroad by monitoring information posted by international Safety Information organizations, foreign regulatory agencies, and overseas media in real time. In 2018, the ministry Reports implemented safety measures to revise the label information of about 4,400 items including 195 ingredients in total (e.g., issuing a letter of safety regarding extended-­ release tablets of acetamino- phen, revising precautions on the label information of anti-hypertensive amlodipine-­ containing products, etc.). Setup of a Ground to Safely Use Vaccines over the Entire Lifecycle and Provide Technical Support for the WHO’s Safety Measures Based on Pre-Qualification (PQ) Domestic Pharmaceutical Safety In 2018, the MFDS published and released guidelines for safe use of vaccines not subject Information Reports to national v­ accination, viz. rotavirus vaccines The MFDS develops safety information after statis- (January 2018), yellow fever/cholera vaccines tical analysis and review of relevant data including (July 2018) and so on. The MFDS formulated the literature based on the reports on domestic adverse “Roadmap to Integrate and Manage Information reactions, followed by consultations with the Central on Vaccine-Related Abnormal Cases” (2016) and Pharmaceutical Affairs Council. As a result, safety the “Plan for Establishing a System to Share and actions such as license changes of 24 ingredients Link/Manage Information on Vaccine-Related were taken. Such safety measures were implemented Abnormal Cases” (2018) to share information for 6 cases in 2012, 25 cases in 2013, 14 cases in 2014, on vaccine-related abnormal cases and analyze 17 cases in 2014, 21 cases in 2016, 29 cases in 2017, and data. Based on such efforts, the MFDS is trying to 34 cases in 2016. establish the grounds to safely use vaccines over the entire lifecycle. 5. Adverse Drug Reaction (ADR) Relief System 17 5. Adverse Drug • April 2015: First payment decision on lump sum for death and payment of compensation – toxic Reaction (ADR) epidermal necrolysis from lamotrigine and DRESS25 syndrome from carbamazepine. Relief System • Damage relief consultation and cases received. The Relief Scheme for Drug Side Effects provides relief funds to claimants from the reserve of funds collected from all manufacturers, importers, and marketing authorization holders of medicinal products through the KIDS (Figure 9 and Figure 10). The reserve funds consist of: • A basic contribution from pharmaceutical compa- nies representing 1/1,000 of the total price of drugs manufactured or imported during the immediately preceding year Every medicine has some side effects due to • An additional contribution for a drug product its diverse features, and unpleasant adverse designated by the MFDS as requiring side effect reactions may occur even with proper use relief in the amount of 25 percent of the total depending on individual characteristics. The relief payment paid out for the drug MFDS introduced a damage relief system for adverse drug reactions, through which the gov- ernment compensates the victims who die, or are Product Liability Act injured or hospitalized due to unexpected adverse Manufacturers of medicinal products can be events despite proper care on their part. The relief exempt from liability if they can prove any of system is operated with financial assistance from the following: pharmaceutical companies. The system operates without any legal proceedings. • The manufacturer did not supply the product. This system was established in Korea to socially • It was impossible for the manufacturer to discover admit the risk of side effects due to drug and the defect based on the level of scientific or medical supplies, and to protect all victims, drug technical knowledge available at the time of manufacturers, and medical suppliers from serious supplying the product. damages that can happen to anyone, including • The product defect is due to compliance with serious damage that are very uncommon. The steps the applicable law at the time of supplying in the process that established the system were the product. the following: • If raw materials or components of the product have the defect, the defect is produced by the design • July 2013: Initiation of amendments to the of the product or the manufacturing instructions Pharmaceutical Affairs Act. from the manufacturer. • March 2014: National Assembly adopts the amendment for enforcement of relief of injury However, if appropriate preventive measures are not from adverse drug reaction. taken to prevent damage upon discovery, or becom- • December 2014: Implementation of receipt, ing aware of, a defect in the product, manufacturers investigation, indemnification of relief of injury cannot assert defenses in the second, third, and from ADR. fourth bullet points above. collection • February 2015: First-half year allotment ­ – 378 out of total 380 pharmaceuticals paid collection rate 99.7 percent). (­ 25  DRESS = drug reaction with eosinophilia and systemic symptoms.  18 Overview of the Republic of Korea Pharmacovigilance System Figure 9  Adverse Drug Reaction Relief System Flow Chart Request for relief Ministry of Food Claimant Consignment Compensation and Drug Safety Notify investigation result and request deliberation Medicines and ADR Deliverative Contribution medical supplies manufacturer Committee Charge allotment Notify deliberation result /importer Expert Committee Receiving request Information Causality Preparing written invest- for relief, and review gathering and assessment igation and appraisal document & possi- site investigation for ADR for submission to bility of exceptions deliberative committee Source: Adopted from KIDS, https://www.drugsafe.or.kr/iwt/ds/ko/report/WhatIsADR.do. Figure 10  Types of Relief Benefits Lum sum benefits for bereaved family Pharmacy Act Article 86(3) 5 years worth of minimum wage Medical Expenses Lum sum benefits for disability (hospitalization) Lump sum compensation on death x Ratio following disability level (100%~25%) Lump sum compensation on disability and funeral cost Medical expenses Own expenses spent on hospitalization treatment Lump sum compensation on death Funeral cost 3 months worth of average wage 2015 2016 2017 (Dec 19) Source: Adopted from KIDS, https://www.drugsafe.or.kr/iwt/ds/ko/report/WhatIsADR.do. Product Liability Claims In relation to latent damage, the symptoms of which appear after a certain period has lapsed, the ten-year The period in which a claim can be brought is both: limitation period starts from the date on which the • Three years from the date when the injured person symptoms appear. became aware of the damage and the person liable • Ten years from the date of supply of the product by the manufacturer 6. Challenges and Future ­ Improvements in Korea’s Pharmacovigilance System 19 Challenges 6.  the FDA to use existing electronic health care data in near real-time, helping the FDA’s regulatory decision and Future making and informing agency actions, such as recalls, withdrawals, label changes, safety, and risk ­Improvements communications. Korean academia and government have researched in Korea’s and cooperated to develop a new active pharma- covigilance system in Korea. Recently, KFDA ‘s Pharmacovigilance research service developed a common data model that can be applied for the electronic medical System data of various hospitals.29 This common data model is a fundamental tool for establishing an active pharmacovigilance system like the Sentinel program from the United States. The next step is to build a competent cooperation center, such as the Harvard Pilgrim Healthcare Institute, to send queries to various data partners using the common data model and interpreting the results. Korea can build a pharmacovigilance system based on big data covering a large population due to the broad distri- bution of electronic medical recording systems and a nationwide single health care insurance system. The study recommends that the current voluntary ADR As noted in a recent study by D.Y. Kang et al., the reporting system should be expanded by including voluntary ADR reporting system in Korea has not only tertiary hospitals, but also primary and ­limitations.26 Researchers have suggested an secondary medical care facilities, pharmacies, phar- ­ alternative: the development of an active surveillance maceutical companies, other related professional system linked to large-scale, computerized data, groups, and consumer organizations. In addition to similar to the one developed by the U.S. Food and ­ ADR reporting, RPVCs should maintain public safety Drug Administration (FDA) and its cooperating functions like education and counseling on the safe center, the Harvard Pilgrim Healthcare Institute use of medicines. (the Sentinel Program).27, 28 Unlike passive surveil- lance, Sentinel’s active surveillance system enables 26   .Y. Kang et al., “Past, Present, and Future of Pharmacovigilance in D Korea.” 27   .M. Seong and B.J. Park, “Recent Advance in Pharmacovigilance J Activities of World Health Organization and U.S. Food and Drug Administration,” Korean Public Health Res. (2015) 41:19–28. 28   . Platt, R.M. Carnahan, J.S. Brown, E. Chrischilles, R L.H. Curtis, S. Hennessy, J.C. Nelson, J.A. Racoosin, M. Robb, S. Schneeweiss, S. Toh, and M.G. Weiner, “The U.S. Food and Drug Administration’s Mini-Sentinel Program: Status and Direction,” 29   onhap News, “KFDA Developed ‘Korean Common Data Model’,” Y Pharmacoepidemiology & Drug Safety (January 19, 2012) Yonhap News Agency (April 24, 2017) https://www.yna.co.kr/view/ 21 Suppl. 1:1-8, https://doi.org/10.1002/pds.2343. RPR20170424002300353. 20 Overview of the Republic of Korea Pharmacovigilance System 7. Takeaways: from each regional center. The Korean drug safety monitoring system is expected to further improve by Lessons from transitioning to active surveillance from traditional spontaneous reporting. Korea’s Experience A computerized adverse drug events (ADEs) reporting system, the Korea Adverse Event Reporting Monitoring the System (KAERS), developed by KIDS to facilitate reporting of ADEs by different sources. Anyone who Safety of Medicines experiences ADEs can report to KIDS using KAERS: consumers, health care professionals, RPVCs, and pharmaceutical companies. Linkage of data reporting and analysis to policy making, regulatory action, and risk communi- cation. KIDS analyzes the data and provides the Ministry of Food and Drug Safety (MFDS), with statistics, safety information, and reports of all ADEs. MFDS requires swift reporting upon any drug-related irregularities, based on which necessary measures follow, including changes to drugs’ earlier approval for sale, recalls or market withdrawals as well as Korea’s pharmacovigilance system is an international investigations or inspections into the determination best practice. It is the result of a continuous and of causes. The collected information is made sustained government effort over the past three available to doctors, pharmacists, consumers and decades—from small pilot projects to a nationwide relevant organizations. The information generated monitoring network—and offers valuable lessons from the reporting and analysis of ADE can also to other countries on the vital role that such a help address public safety concerns and stimulate system can play in ensuring the safety of drugs prompt action, including action under the Korea’s post-marketing. ADR Relief System. KIDS data also feed into VigiBase, a global database managed by the WHO Program The effectiveness of the Korea’s pharmacovigilance for International Drug Monitoring. Moreover, KIDS system relies on five pillars: contributes to effective, comprehensive data man- Strong legal and institutional foundations (involv- agement on adverse effects of drug intake through ing close coordination between two ministries), and regular reports made with Uppsala Monitoring including a strong human resources base (i.e., PV Center (UMC) under WHO. teams and reporters) at different levels. Sustainable funding arrangement from different A decentralized drug safety monitoring system, sources. KIDS operates with funding from the overseen by the Korea Institute of Drug Safety and central government via the Ministry of Food and Risk Management (KIDS). In this system, a central Drug Safety (MFDS), which provides about 68 percent center functions as the coordinator for regional of total revenue. Additional funding comes from pharmacovigilance centers and collects data contracting out research, evaluation, and services. 8. Conclusion 21 8. Conclusion correctly and that their health benefits outweigh their known risks. The Korean experience is an example of PV systems contributing to strengthening the health system, particularly for countries where there is a single ministry of health, and the PV function may get lost. The Korean experience clearly illustrates that The example of having a dedicated entity for drug building capacity in countries to conduct thorough regulation and safety monitoring is an effective surveillance of the use of all newly authorized approach. Hence, countries that are developing their medicines, both brand-name and generic, is a critical systems may start with establishing a dedicated “public good” investment to ensure that drugs work division for pharmacovigilance. 22 Overview of the Republic of Korea Pharmacovigilance System Korea Acronyms