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Head of Pharmacovigilance, Merck Sharp & Dohme, Bogotá, Colombia
Manager of Regulatory Affairs and Quality Assurance, Johnson & Johnson Medical Devices & Diagnostics Group, Bogotá
Associate Professor, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada
Reprints: Dr. Einarson, University of Toronto, 144 College St., Toronto, ON M5S 3M2, Canada, fax 416/978-8511, t.einarson{at}utoronto.ca
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Abstract |
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OBJECTIVE: To review and quantify the published literature on pharmacovigilance in Latin American countries.
DATA SOURCES: We searched electronic databases including MEDLINE (1966-2004), EMBASE (1980-2004), International Pharmaceutical Abstracts (1970-2004), Toxline (1992-2004), Literatura Latino-Americana e do Caribe em Ciências da Saúde (1982-2004), Sistema de Información Esencial en Terapéutica y Salud (1980-2004), and the Pan American Health Organization Web site (1970-2004) for articles on pharmacovigilance or adverse drug reactions in any of the 19 major Latin American countries. Papers were retrieved and categorized according to content and country of origin by 2 independent reviewers.
STUDY SELECTION AND DATA EXTRACTION: There were 195 usable articles from 13 countries.
DATA SYNTHESIS: Fifty-one of the papers retrieved dealt with pharmacovigilance centers (15 national centers, 10 hospitals, 26 other), 55 covered pharmacovigilance itself (21 theoretical papers, 9 with description of models, 25 educational papers), and 89 were pharmacoepidemiologic studies of adverse drug reactions (69 case reports, 13 observational cohorts, 2 cohort studies, 1 randomized clinical trial, 4 clinical papers on adverse reaction management). Studies have increased exponentially since 1980. Five countries (Argentina, Brazil, Chile, Costa Rica, Venezuela) published reports from national centers. No studies were found from 6 countries: Dominican Republic, El Salvador, Honduras, Nicaragua, Paraguay, or Uruguay. Most studied categories were antiinfectives and drugs affecting the central nervous system, cardiovascular system, and musculoskeletal system.
CONCLUSIONS: Contributions of Latin American countries to the field of pharmacovigilence have been remarkable, considering the constraints on these countries. A need exists for an increased number of formal pharmacovigilance studies and research using methodologically stronger pharmacoepidemiologic models.
Key Words: adverse drug reactions, drug monitoring, Latin America, pharmacovigilance
Published Online, July 25, 2006. www.theannals.com, DOI 10.1345/aph.1H052
Recent additions have included several Latin American countries,2 which have organized a drug utilization group to research drug problems locally.3 Courses on pharmacovigilance have been presented as well and were well attended.4
Although interest in pharmacovigilance has continued to increase, little has been written about the contribution made by Latin America to this growing body of literature. We therefore undertook a survey to determine what that contribution has been, which countries have been involved, and the types of studies conducted in those countries. Our goal was to produce a summary update of these activities.
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Articles of interest included those that focused on pharmacovigilance or the safety of pharmaceuticals. We were interested in research articles, reports from national pharmacovigilance centers or hospitals, and papers reporting or discussing the treatment of adverse drug reactions or events.
We searched electronic databases including MEDLINE (1966-2004), EMBASE (1980-2004), International Pharmaceutical Abstracts (1970-2004), and Toxline (1992-2004), as well as Literatura Latino-Americana e do Caribe em Ciências da Saúde (LILACS, years 1982-2004),5 Sistema de Información Esencial en Terapéutica y Salud (SIETES; 1980-2004),6 and the Pan American Health Organization Web site (1970-2004).7 We used the search terms pharmacovigilance, drug safety, adverse drug events, and ADRs and the names of all of the involved countries. Two reviewers each searched half of the databases and each checked the results of the other. Discrepancies were resolved through consensus discussion.
Articles were classified by topic into 3 main categories, arbitrarily labeled A, B, and C. The first type dealt with pharmacovigilance programs, the second with pharmacovigilance itself, and the third with pharmacoepidemiologic research on adverse drug events. Table 1 lists the categories, the topics they address, and the subject matter they include. Category A studies were subdivided into articles reporting results from national pharmacovigilance centers (A1), programs in hospitals (A2), and other institutions or organizations (A3). Category B papers were subdivided into theoretical papers on pharmacovigilance, practical papers describing models, and miscellaneous articles on the topic. Papers in category C were further divided into 5 subcategories. Those included case reports of adverse drug events, observational cohort studies (without controls or comparison groups) investigating adverse drug events, epidemiologic models (ie, case-control or cohort studies), randomized controlled trials designed to assess adverse drug reactions, and clinical papers that describe the management or prevention of drug-related reactions.
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Studies were classified into one of the above groups/subgroups as well as by country and ATC category (ie, the Anatomic Therapeutic Chemical classification system of the WHO).8 The cumulative total of published articles was plotted over time to visually depict the productivity of literature from these countries as a whole (Figure 1).
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Figure 2 identifies the countries of origin of the studies. Thirteen countries had at least one relevant publication. However, no investigations were found from the Dominican Republic, El Salvador, Honduras, Nicaragua, Paraguay, or Uruguay. The number of studies has been increasing exponentially since the first ones appeared in 1980. Figure 1 depicts the growth in the number of those articles.
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There were 175 different drugs examined in the pharmacovigilance studies. Figure 3 depicts the distribution of those drugs, according to ATC classification.8 The most studied group was Category J (antiinfectives for systemic use, 28%), followed by Category N (nervous system, 21%), Category C (cardiovascular system, 14%), Category M (musculoskeletal system, 11%), and Category A (alimentary tract and metabolism, 6%). All others each comprised less than 5% of the total.
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Considering that 11 of the reporting countries belong to the WHO system,12 one might have expected more reports from the established centers. We have undertaken a survey to assess this and other questions about these programs.13
This research did not address issues of education, training, or deployment of persons having expertise in pharmacovigilance. It would be informative to survey the colleges and universities of Latin America to identify courses and training programs that would be beneficial for promoting drug safety.
It appears that the greatest numbers of reports have been produced by the most affluent of the nations involved in this survey. Little information was obtained from poorer regions. Six countries have never had an article published. That does not necessarily mean that no programs are operating there, but that no reports have yet reached the mainstream medical literature. It appears that these countries may require assistance in establishing and operating programs. Efforts should be expended to assist these countries in developing viable programs.
This region has many advantages over Europe or North America in that there is a great opportunity to study drug use in diseases that are not found in more temperate climates. For example, a report from Brazil examined reactions to yellow fever vaccine.14 Other diseases in Latin America that are considered rare in more northerly areas include leprosy15-20 and tuberculosis.21-25 Not only have the diseases been studied here, but their treatments,16 reactions to those treatments,17,20,21 and drug interactions have been investigated as well.24 Syndromes precipitated by the treatments in the presence of these diseases have also been reported.16,19
Drugs seldom used in other areas are often still in regular use in Latin America. One example is chloramphenicol26; largely abandoned in developed countries, it still needs to be monitored.
Latin America presents another opportunity in its large population base. This large base means that rare reactions are likely to emerge. For example, there have been reports from Argentina of Nicolau livedoid dermatitis,27,28 while cases of generalized acute exanthematous pustulosis29 have been reported in Brazil. Thus, it is essential that the region continue to actively report such events and expand its efforts.
Since most of the papers reviewed consisted of publications in local journals, we can assume that there is little or no access outside of the respective countries to the information that they have produced. Although LILACS and SIETES databases contain abstracts of the major publications, full access is recommended.
One aspect that warrants comment is the quality of those reports. It would be of interest to determine whether they are of comparable quality to reports from Europe or North America. Such an assessment was outside the scope of the present project. However, evaluation of the quality of these reports is highly recommended for future research.
It appears that Latin America has been making a substantial effort to contribute to the world's literature, for which the region should be commended. However, there is still much room for improvement. As new reporting centers are established and expanded, it is hoped that more reports and information will be generated and made available.
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