Correlation Between Drug Market Withdrawals and Socioeconomic, Health, and Welfare Indicators Worldwide
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ORIGINAL ARTICLE Medicine General & Social Medicine http://dx.doi.org/10.3346/jkms.2015.30.11.1567 • J Korean Med Sci 2015; 30: 1567-1576 Correlation between Drug Market Withdrawals and Socioeconomic, Health, and Welfare Indicators Worldwide Kye Hwa Lee, Grace Juyun Kim, The relationship between the number of withdrawn/restricted drugs and socioeconomic, and Ju Han Kim health, and welfare indicators were investigated in a comprehensive review of drug regulation information in the United Nations (UN) countries. A total of of 362 drugs were Seoul National University Biomedical Informatics withdrawn and 248 were restricted during 1950-2010, corresponding to rates of 12.02 ± (SNUBI) and Systems Biomedical Informatics ± ± Research Center, Division of Biomedical Informatics, 13.07 and 5.77 8.69 (mean SD), respectively, among 94 UN countries. A Seoul National University College of Medicine, socioeconomic, health, and welfare analysis was performed for 33 OECD countries for Seoul, Korea which data were available regarding withdrawn/restricted drugs. The gross domestic product (GDP) per capita, GDP per hour worked, health expenditure per GDP, and elderly Received: 23 April 2015 Accepted: 10 July 2015 population rate were positively correlated with the numbers of withdrawn and restricted drugs (P < 0.05), while the out-of-pocket health expenditure payment rate was negatively Address for Correspondence: correlated. The number of restricted drugs was also correlated with the rate of drug-related Ju Han Kim, MD deaths (P < 0.05). The World Bank data cross-validated the findings of 33 OECD countries. Division of Biomedical Informatics, Systems Biomedical Informatics Research Center, Seoul National University College The lists of withdrawn/restricted drugs showed markedly poor international agreement of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 03080, Korea between them (Fleiss’s kappa = -0.114). Twenty-seven drugs that had been withdrawn Tel: +82.2-740-8320, Fax: +82.2-747-8928 E-mail: [email protected] internationally by manufacturers are still available in some countries. The wide variation in Funding: This research was supported by the Basic Science the numbers of drug withdrawals and restrictions among countries indicates the need to Research Program through the National Research Foundation of improve drug surveillance systems and regulatory communication networks. Korea (NRF) funded by the Ministry of Education, Science and Technology (2012-0000994) and by a grant of the Korean Health Technology R&D Project, Ministry of Health and Welfare Keywords: Product Recalls and Withdrawals; Product Surveillance; Postmarketing; (HI13C2164). Organization for Economic Cooperation and Development; Health Expenditures; Socioeconomic Factors INTRODUCTION withdraw of its approval. The type of regulatory decision can differ markedly between countries because it depends on each Drug market withdrawals (DMWs) may serve as an indicator country’s health care and drug approval system, the status of for an efficient drug-surveillance and better healthcare systems the adverse drug reaction (ADR) surveillance system, socioeco- of a country. Despite the length and cost of drug development, nomic factors, and cultural attitudes toward using and prescrib- potentially damaging drugs might still be approved (1). In the ing drugs. In an effort to overcome these drug regulatory varia- 1950s, soon after thalidomide was introduced for reducing mor- tions among countries, the World Health Organization (WHO) ning sickness, its terrible side effect causing limb malforma- has committed to working with more than 100 member coun- tions in the fetus resulted in its immediate withdrawal from the tries of the United Nations (UN) in designing a worldwide drug market (2). As other examples, rofecoxib and celecoxib were surveillance system since 1997 (6). However, some drugs that promoted as blockbuster drugs showing similar efficacy but are withdrawn in one country due to safety concerns are still fewer gastrointestinal side effects compared to traditional non- prescribed in other countries, and there is a wide variability in steroidal anti-inflammatory drugs, but they were recently vol- the lists of withdrawn drugs in different countries. Fung report- untarily withdrawn by the pharmaceutical companies from the ed that of 121 drugs withdrawn from the market between 1960 market because of increasing death rates (3). The frequency of and 1999 due to safety reasons, 42.1%, 5.0%, and 3.3% were with- drug withdrawals for newly approved and marketed drugs is drawn from the European, North American, and Asia Pacific reportedly as high as 4%-10% (4,5). markets alone, while 49.6% were withdrawn from multiple con- Drug withdrawals are classified into two categories: 1) the tinents (7). Moreover, only 19% of drugs were reportedly banned voluntary withdrawal of a drug occurs when a pharmaceutical worldwide among the 151 drugs that are withdrawn by at least company decides that the drug is to be withdrawn from the mar- 1 country (8). ket and it is withdrawn worldwide immediately, and 2) the man- These discrepancies in DMWs occur even among well-devel- datory withdrawal of a drug by regional regulatory bodies or oped countries (8,9). However, only a few studies have investi- © 2015 The Korean Academy of Medical Sciences. pISSN 1011-8934 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. eISSN 1598-6357 Lee KH, et al. • Drug Market Withdrawals and Health Care System Investments gated the causes of and factors associated with DMWs. More- Lists) (6,13-15), which are the most comprehensive lists of drugs over, evaluation studies have been conducted for the developed that have been withdrawn or severely restricted by at least one world only. Twice as many drugs were withdrawn from the Unit- government. The 8th UN Consolidated List was published in ed Kingdom (UK) market than from the United States (US) mar- 2003, which collected information about previously withdrawn/ ket from 1971 to 1992, with the main explanation being that the restricted drugs, and the 10th, 12th, and 14th lists provide up- US regulatory agency applied more stringent premarket reviews dated information only. Drugs that were withdrawn or restrict- and/or standards, which also took longer than the regulatory ed in use internationally by the manufacturer were annotated checks performed in the UK and so prevented unsafe drugs mar- in the lists as ‘World,’ and we defined these drugs as being in- keted in the UK from entering the US market (10). However, ternationally withdrawn. The WHO collected information about that study compared only the US and UK, whose drug regula- drug withdrawal and restriction in the UN Consolidated Lists tions are strict and include active ADR surveillance systems, from national authorities based on new regulatory decisions and so its results cannot be easily generalized to other coun- and from manufacturers on voluntary withdrawals on the grounds tries. Countries with more elaborate premarket evaluation sys- of safety concerns. This includes other drug-related informa- tems do not necessarily have fewer withdrawn drugs, since there tion issued by the WHO through WHO Rapid Alerts, the WHO a fewer withdrawn drugs in African countries and more with- Pharmaceuticals Newsletter, and the journal WHO Drug Infor- drawn drugs in North American and European countries (7). mation. A drug was considered to be withdrawn if it has been Countries with better health care systems probably have more withdrawn, removed, banned, or disapproved by at least one efficient drug surveillance systems, which would make it more country for any reason. Drugs that have not been withdrawn likely to filter out drugs with severe ADRs at an early stage (11, but have severe restrictions for their use were counted as restrict- 12). In contrast, countries with poor health care systems and/or ed drugs and used in further analysis in the present study. poor ADR surveillance systems probably have difficulties in de- We collected data from the OECD (16) and World Bank (17) tecting harmful drugs and making timely decisions to withdraw to allow the comprehensive evaluation of the factors associated them. The difference in DMWs among countries could be a use- with drug withdrawals and/or severe restrictions. We focused ful measure for comparing health care systems across countries. on OECD countries since these countries exhibit comparable Moreover, determining whether a drug that has been withdrawn levels of economic development. Among the numerous statis- internationally continues to be prescribed in a particular coun- tics offered by OECD, we selected 21 health-and-welfare-relat- try could be useful for evaluating the drug administration sys- ed factors based on a Korean report (18) that categorized 21 in- tem of that country. Previous studies on DMWs have only fo- dicators of health and welfare into the following 5 sectors to make cused on a few well-developed countries, such as the US, UK, composite indexes of health and welfare: France, and Germany (5,9). 1) Economic dynamism: employment rate, real gross domes- The present study investigated the distributions of withdrawn tic product (GDP) growth, GDP per hour worked, consum- and/or restricted drugs in 94 UN countries and three organiza- er price index, and GDP per capita. tions in Europe including European Commission, European 2) Financial sustainability: general government gross finan- Medicines Agency, and Council of Europe based on reports is- cial liabilities, general government net borrowing or net sued by the UN General Assembly since 1979. We also analyzed lending, and total tax revenue. the association between the number of withdrawn/restricted 3) Welfare demand: elderly population rate (percentage of drugs for each country and socioeconomic, health, and welfare population aged at least 65 yr), Gini coefficient, relative factors reported by the OECD and the World Bank.