Skip to main content

Archived Comments for: Assessment of global reporting of adverse drug reactions for anti-malarials, including artemisinin-based combination therapy, to the WHO Programme for International Drug Monitoring

Back to article

  1. On the Potential Pitfalls of Data Mining: Response to Kuemmerle et al. Assessment of global reporting of adverse drug reactions for antimalarials, including artemisinin-based combination therapy, to the WHO Programme for International Drug Monitoring

    Ushma Mehta, Independent Consultant

    30 June 2011

    The recent scaling up of access to Artemisinin-based Combination Therapies (ACTs), particularly in target populations frequently under-represented in clinical trials (e.g. infants, pregnant women, those with co-morbid HIV/AIDS and or malnutrition) highlights the importance of reporting, collating and analyzing data on adverse drug reactions. The WHO Programme for International Drug Monitoring plays a central role in these activities, disseminating signals of new adverse drug reactions arising from such data as described in the manuscript by Kuemmerle et al.1

    A crucial weakness of this analysis stems from the unclear definition and classification of ACTs. The only ACTs which are included in this report are Artemether-Lumefantrine and Artesunate-Amodiaquine. Despite their widespread use and recommendation by WHO as first-line treatment, the ACTs artesunate plus mefloquine, dihydroartemisinin plus piperaquine and artesunate plus sulfadoxine-pyrimethamine are surprisingly not reported in the database as ACTs.2 Could reports associated with these combinations have been misclassified as Artemisinin-based Monotherapies (AMTs)? The paper states (italics added for emphasis):

    •"antimalarials reported as concomitant medications were not included in the query".

    •"2781 case reports reported more than one anti-malarial evaluated by the national centre as suspected or interacting in causing the ADR. A mean of 2.4 antimalarials were incriminated in this subset of case reports. 2027 of those contained at least one artemisinin derivative and 1992 of these were transmitted by Thailand in the mid-1990s ."

    •“Of the AMT reported, Thailand reported 96% of them, but interestingly did not submit any ICSR (individual case safety report) suspecting ACT”

    Thus, it appears that in this manuscript and in figure 4 approximately 2000 cases have been misclassified as artemisinin monotherapy (AMT), or mislabeled as artesunate/artemether. Similarly, it appears that the fixed dose combination of dihydroartemisinin-piperaquine was misclassified as dihydroartemisinin AMT. Furthermore, lumefantrine, which is only available in combination with artemether, is also recorded as a “monotherapy” in Figure 4. This highlights the importance of naming the “concomitant” antimalarials.

    The omission of concomitantly reported antimalarials may also have led the authors to attribute the adverse reactions to the incorrect antimalarial (italics again added for emphasis):

    • "Many of the adverse events reported for ACT or artemisinin-based monotherapy could be potentially serious and involved cardiac, gastrointestinal, nervous and psychiatric systems ".

    The majority of reported artesunate “AMTs” ICSRs were more probably attributable to concurrent or sequential treatment of artesunate with with mefloquine.3. The organ systems involved suggest a more likely association with mefloquine, which is well known to exhibit psychiatric, nervous, cardiac and gastrointestinal problems (as does malaria).4 Mefloquine plus artesunate has been the recommended treatment in Thailand, where 96% of the reports were generated, since 1995 and was extensively studied in Thailand since the early 1990s.2 As the artemisinin derivatives are pivotal in the fight against malaria, it would be problematic if mefloquine-related adverse reactions were to be attributed to artesunate.

    To inform assessment of both risks and benefits by policy makers it is important to know what levels of seriousness were given by the national centre for these ICSRs. This was not reported in this manuscript, despite being routinely recorded in the database.

    The concerns identified highlight the importance of involving the national centres concerned in the analysis of such data and the potential pitfalls of mining pooled data without considering local practices and conditions from where the data are derived. This applies both in terms of medicine used as well as in terms of capture, management and interpretation of data. Malaria affects all organ systems, therefore adverse drug reactions that mimic the disease itself need to be analysed with great care.

    The success of pharmacovigilance programmes depends on healthcare providers being convinced that data is used well enough to justify the time and responsibility they take to submit spontaneous reports of adverse reactions.

    Ushma Mehta,
    Former Chairperson of Pharmacovigilance Committee, Medicines Control Council, South Africa (March 2008- April 2011) and Independent pharmacovigilance consultant.

    Alex Welte
    South African Department of Science and Technology/National Research Foundation Centre of Excellence in Epidemiological Modelling and Analysis (SACEMA), Stellenbosch University.

    Karen I Barnes,
    Division of Clinical Pharmacology, Department of Medicine, University of Cape Town

    1. Kuemmerle A, Dodoo ANO, Olsson S, Van Erps J, Burri C, Lalvani PS. Assessment of global reporting of adverse drug reactions for antimalarials including artemisinin-based combination therapy to the WHO programme for International Drug Monitoring. Malaria Journal 2011, 10:57.

    2. World Health Organization. Guidelines for the treatment of malaria. Second edition, WHO Press, 2010. Geneva.

    3. Wongsrichanalai C, Meshnick SR. Declining artesunate-mefloquine efficacy against falciparum malaria. Emerging infectious diseases 2008; 14(5):716-719.

    4. Roche (Pty) Ltd. Lariam® FDA Approved Label. (accessed 12 May 2011)

    Competing interests

    The authors have no competing interests to declare.

Advertisement