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  • 1.
    Aagaard, Lise
    et al.
    University of So Denmark, Denmark FKL Research Centre Qual Medical Use, Denmark Danish Pharmacovigilance Research Project DANPREP, Denmark .
    Strandell, Johanna
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Melskens, Lars
    University of Copenhagen, Denmark .
    Petersen, Paw S. G.
    University of Copenhagen, Denmark .
    Holme Hansen, Ebba
    FKL Research Centre Qual Medical Use, Denmark Danish Pharmacovigilance Research Project DANPREP, Denmark University of Copenhagen, Denmark .
    Global Patterns of Adverse Drug Reactions Over a Decade Analyses of Spontaneous Reports to VigiBase (TM)2012In: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 35, no 12, p. 1171-1182Article in journal (Refereed)
    Abstract [en]

    Background: Although systems to collect information about suspected adverse drug reactions (ADRs) were established in many countries and by the WHO in the 1960s, few studies have examined reported ADRs related to national income. Objective: The aim of the study was to characterize ADRs reported to the WHO-ADR database, VigiBase (TM), and to relate data to national income. Methods: We analysed ADR reports submitted to VigiBase (TM) from 2000 to 2009 with respect to reporting rate, age and sex of patient, type, seriousness and medications. Reports were also analysed with respect to national income level, classified in accordance with the World Bank definition: low, lower-middle, upper-middle and high. Results: We analysed 1 359 067 ADR reports including 3 013 074 ADRs. Overall, 16% of reports were serious and 60% were reported for females. High-income countries had the highest ADR reporting rates (range 3-613 reports/million inhabitants/year) and low-income countries the lowest (range 0-21). Distribution of ADRs across income groups with respect to age group, seriousness and sex was non-significant. Overall, the majority of ADRs were reported for nervous system medications, followed by cardiovascular medicines. Low-income countries reported relatively more ADRs for antiinfectives for systemic use than high-income countries, and high-income countries reported more ADRs for antineoplastic and immunomodulating agents than lower-income groups. Conclusion: This study showed that high-income countries had the highest ADR reporting rates and low-income countries the lowest, with large variations across countries in each group. Significant differences in ADR reporting rates were only found for ADRs of the type skin and subcutaneous tissue disorders and for the therapeutic groups antiinfectives for systemic use and antineoplastic and immunomodulation agents. To strengthen ADR reporting rates, especially in low-income countries, more research is needed about the impact of organizational structures and economic resources of national pharmacovigilance centres and ADR reporting practices on the large variations in ADR reporting rates within income groups.

  • 2.
    Alfredsson, Joakim
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Roe, Matthew T.
    Duke University of School Med, NC USA.
    Risks and Benefits of Triple Oral Anti-Thrombotic Therapies After Acute Coronary Syndromes and Percutaneous Coronary Intervention2015In: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 38, no 5, p. 481-491Article, review/survey (Refereed)
    Abstract [en]

    The key pathophysiological process underlying symptomatic coronary artery disease, including acute coronary syndromes (ACS), is usually a rupture or an erosion of an atherosclerotic plaque, followed by platelet activation and subsequent thrombus formation. Early clinical trials showed benefit with long-term aspirin treatment, and later-based on large clinical trials-dual anti-platelet therapy (DAPT), initially with clopidogrel, and more recently with prasugrel or ticagrelor, has become the established treatment in the post-ACS setting and after percutaneous coronary intervention (PCI). Treatment with DAPT is recommended for both ST-elevation myocardial infarction and non-ST-elevation ACS, as well as after PCI with stenting, in American and European clinical guidelines. Notwithstanding the benefits observed with DAPT, including third-generation P2Y(12) receptor inhibitors plus aspirin, ACS patients remain at high risk for a recurrent cardiovascular event, suggesting that other treatment strategies, including the addition of a third oral anti-platelet agent or a novel oral anticoagulant (NOAC) to standard DAPT regimens, may provide additional benefit for post-ACS patients and for patients undergoing PCI. Adding a third anti-thrombotic agent to DAPT after an ACS event or a PCI procedure has been shown to have modest benefit in terms of ischemic event reduction, but has consistently been associated with increased bleeding complications. Therefore, the quest to optimize anti-thrombotic therapies post-ACS and post-PCI continues unabated but is tempered by the historical experiences to date that indicate that careful patient and dose selection will be critical features of future randomized trials.

  • 3. Bergvall, Tomas
    et al.
    Norén, G. Niklas
    Stockholm University, Faculty of Science, Department of Mathematics.
    Lindquist, Marie
    vigiGrade: A Tool to Identify Well-Documented Individual Case Reports and Highlight Systematic Data Quality Issues2014In: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 37, no 1, p. 65-77Article in journal (Refereed)
    Abstract [en]

    Individual case safety reports of suspected harm from medicines are fundamental to post-marketing surveillance. Their value is directly proportional to the amount of clinically relevant information they include. To improve the quality of the data, communication between stakeholders is essential and can be facilitated by a simple score and visualisation of the results. The objective of this study was to propose a measure of completeness and identify predictors of well-documented reports, globally. The Uppsala Monitoring Centre has developed the vigiGrade completeness score to measure the amount of clinically relevant information in structured format, without reflecting whether the information establishes causality between the drug and adverse event. The vigiGrade completeness score (C) starts at 1 for reports with information on time-to-onset, age, sex, indication, outcome, report type, dose, country, primary reporter and comments. For each missing dimension, a penalty is detracted which varies with clinical relevance. We classified reports with C > 0.8 as well-documented and identified all such reports in the WHO global individual case safety report database, VigiBase, from 2007 to January 2012. We utilised odds ratios with statistical shrinkage to identify subgroups with unexpectedly high proportions of well-documented reports. Altogether, 430,000 (13 %) of the studied reports achieved C > 0.8 in VigiBase. For VigiBase as a whole, the median completeness was 0.41 with an interquartile range of 0.26-0.63. Two out of three well-documented reports come from Europe, and two out of three from physicians. Among the countries with more than 1,000 reports in total, the highest rate of well-documented reports is 65 % in Italy. Tunisia, Spain, Portugal, Croatia and Denmark each have rates above 50 %, and another 20 countries have rates above 30 %. On the whole, 24 % of the reports from physicians are well-documented compared with only 4 % for consumers/non-health professionals. Notably, Denmark and Norway have more than 50 % well-documented reports from consumers/non-health professionals and higher rates than for physicians. The rate of well-documented reports for the E2B format is 11 % compared with 22 % for the older INTDIS (International Drug Information System) format. However, for E2B reports entered via the WHO programme's e-reporting system VigiFlow, the rate is 29 %. Overall, only one report in eight provides the desired level of information, but much higher proportions are observed for individual countries. Physicians and e-reporting tools also generate greater proportions of well-documented reports overall. Reports from consumers/non-health professionals in specific regions have excellent quality, which illustrates their potential for the future. vigiGrade has already provided valuable information by highlighting data quality issues both in Italy and the USA.

  • 4.
    Bloch, K. M.
    et al.
    Univ Liverpool, Liverpool, Merseyside, England..
    Carr, D.
    Univ Liverpool, Liverpool, Merseyside, England..
    Pirmohamed, M.
    Univ Liverpool, Liverpool, Merseyside, England..
    Morris, A.
    Univ Liverpool, Liverpool, Merseyside, England..
    Maroteau, C.
    Dundee Univ, Dundee, Scotland..
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Palmer, C.
    Dundee Univ, Dundee, Scotland..
    Alfirevic, A.
    Univ Liverpool, Liverpool, Merseyside, England..
    Whole exome sequencing in individuals with statin-induced myopathy2017In: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 40, no 10, p. 1026-1026Article in journal (Other academic)
  • 5.
    Caster, Ola
    et al.
    Uppsala Monitoring Centre, Sweden.
    Edwards, I. Ralph
    Uppsala Monitoring Centre, Sweden.
    Reflections on Attribution and Decisions in Pharmacovigilance2010In: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 33, no 10, p. 805-809Article in journal (Refereed)
  • 6.
    Caster, Ola
    et al.
    Stockholm University, Faculty of Social Sciences, Department of Computer and Systems Sciences. Uppsala Monitoring Centre, Sweden.
    Juhlin, Kristina
    Watson, Sarah
    Norén, G. Niklas
    Stockholm University, Faculty of Science, Department of Mathematics. Uppsala Monitoring Centre, Sweden.
    Improved Statistical Signal Detection in Pharmacovigilance by Combining Multiple Strength-of-Evidence Aspects in vigiRank2014In: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 37, no 8, p. 617-628Article in journal (Refereed)
    Abstract [en]

    Background

    Detection of unknown risks with marketed medicines is key to securing the optimal care of individual patients and to reducing the societal burden from adverse drug reactions. Large collections of individual case reports remain the primary source of information and require effective analytics to guide clinical assessors towards likely drug safety signals. Disproportionality analysis is based solely on aggregate numbers of reports and naively disregards report quality and content. However, these latter features are the very fundament of the ensuing clinical assessment.

    Objective

    Our objective was to develop and evaluate a data-driven screening algorithm for emerging drug safety signals that accounts for report quality and content.

    Methods

    vigiRank is a predictive model for emerging safety signals, here implemented with shrinkage logistic regression to identify predictive variables and estimate their respective contributions. The variables considered for inclusion capture different aspects of strength of evidence, including quality and clinical content of individual reports, as well as trends in time and geographic spread. A reference set of 264 positive controls (historical safety signals from 2003 to 2007) and 5,280 negative controls (pairs of drugs and adverse events not listed in the Summary of Product Characteristics of that drug in 2012) was used for model fitting and evaluation; the latter used fivefold cross-validation to protect against over-fitting. All analyses were performed on a reconstructed version of VigiBase® as of 31 December 2004, at around which time most safety signals in our reference set were emerging.

    Results

    The following aspects of strength of evidence were selected for inclusion into vigiRank: the numbers of informative and recent reports, respectively; disproportional reporting; the number of reports with free-text descriptions of the case; and the geographic spread of reporting. vigiRank offered a statistically significant improvement in area under the receiver operating characteristics curve (AUC) over screening based on the Information Component (IC) and raw numbers of reports, respectively (0.775 vs. 0.736 and 0.707, cross-validated).

    Conclusions

    Accounting for multiple aspects of strength of evidence has clear conceptual and empirical advantages over disproportionality analysis. vigiRank is a first-of-its-kind predictive model to factor in report quality and content in first-pass screening to better meet tomorrow’s post-marketing drug safety surveillance needs.

  • 7. Chandler, Rebecca E.
    et al.
    Juhlin, Kristina
    Fransson, Jonas
    Caster, Ola
    Stockholm University, Faculty of Social Sciences, Department of Computer and Systems Sciences. Uppsala Monitoring Centre, WHO Collaborating Centre for International Drug Monitoring, Sweden.
    Edwards, I. Ralph
    Norén, G. Niklas
    Current Safety Concerns with Human Papillomavirus Vaccine: A Cluster Analysis of Reports in VigiBase (R)2017In: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 40, no 1, p. 81-90Article in journal (Refereed)
    Abstract [en]

    Introduction A number of safety signals-complex regional pain syndrome (CRPS), postural orthostatic tachycardia syndrome (POTS), and chronic fatigue syndrome (CFS)-have emerged with human papillomavirus (HPV) vaccines, which share a similar pattern of symptomatology. Previous signal evaluations and epidemiological studies have largely relied on traditional methodologies and signals have been considered individually. Objective The aim of this study was to explore global reporting patterns for HPV vaccine for subgroups of reports with similar adverse event (AE) profiles. Methods All individual case safety reports (reports) for HPV vaccines in VigiBase (R) until 1 January 2015 were identified. A statistical cluster analysis algorithm was used to identify natural groupings based on AE profiles in a data-driven exploratory analysis. Clinical assessment of the clusters was performed to identify clusters relevant to current safety concerns. Results Overall, 54 clusters containing at least five reports were identified. The four largest clusters included 71 % of the analysed HPV reports and described AEs included in the product label. Four smaller clusters were identified to include case reports relevant to ongoing safety concerns (total of 694 cases). In all four of these clusters, the most commonly reported AE terms were headache and dizziness and fatigue or syncope; three of these four AE terms were reported in >50 % of the reports included in the clusters. These clusters had a higher proportion of serious cases compared with HPV reports overall (44-89 % in the clusters compared with 24 %). Furthermore, only a minority of reports included in these clusters included AE terms of diagnoses to explain these symptoms. Using proportional reporting ratios, the combination of headache and dizziness with either fatigue or syncope was found to be more commonly reported in HPV vaccine reports compared with non-HPV vaccine reports for females aged 9-25 years. This disproportionality remained when results were stratified by age and when those countries reporting the signals of CRPS (Japan) and POTS (Denmark) were excluded. Conclusions Cluster analysis reveals additional reports of AEs following HPV vaccination that are serious in nature and describe symptoms that overlap those reported in cases from the recent safety signals (POTS, CRPS, and CFS), but which do not report explicit diagnoses. While the causal association between HPV vaccination and these AEs remains uncertain, more extensive analyses of spontaneous reports can better identify the relevant case series for thorough signal evaluation.

  • 8.
    Chandler, Rebecca E.
    et al.
    Uppsala Monitoring Centre (UMC).
    Juhlin, Kristina
    Uppsala Monitoring Centre (UMC).
    Fransson, Jonas
    Uppsala Monitoring Centre (UMC).
    Caster, Ola
    Uppsala Monitoring Centre (UMC) ; Stockholm University.
    Edwards, Ralph I.
    Uppsala Monitoring Centre (UMC).
    Norén, Niklas G.
    Uppsala Monitoring Centre (UMC).
    Current Safety Concerns with Human Papillomavirus Vaccine: A Cluster Analysis of Reports in VigiBase®2017In: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 40, no 1, p. 81-90Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: A number of safety signals-complex regional pain syndrome (CRPS), postural orthostatic tachycardia syndrome (POTS), and chronic fatigue syndrome (CFS)-have emerged with human papillomavirus (HPV) vaccines, which share a similar pattern of symptomatology. Previous signal evaluations and epidemiological studies have largely relied on traditional methodologies and signals have been considered individually.

    OBJECTIVE: The aim of this study was to explore global reporting patterns for HPV vaccine for subgroups of reports with similar adverse event (AE) profiles.

    METHODS: All individual case safety reports (reports) for HPV vaccines in VigiBase(®) until 1 January 2015 were identified. A statistical cluster analysis algorithm was used to identify natural groupings based on AE profiles in a data-driven exploratory analysis. Clinical assessment of the clusters was performed to identify clusters relevant to current safety concerns.

    RESULTS: Overall, 54 clusters containing at least five reports were identified. The four largest clusters included 71 % of the analysed HPV reports and described AEs included in the product label. Four smaller clusters were identified to include case reports relevant to ongoing safety concerns (total of 694 cases). In all four of these clusters, the most commonly reported AE terms were headache and dizziness and fatigue or syncope; three of these four AE terms were reported in >50 % of the reports included in the clusters. These clusters had a higher proportion of serious cases compared with HPV reports overall (44-89 % in the clusters compared with 24 %). Furthermore, only a minority of reports included in these clusters included AE terms of diagnoses to explain these symptoms. Using proportional reporting ratios, the combination of headache and dizziness with either fatigue or syncope was found to be more commonly reported in HPV vaccine reports compared with non-HPV vaccine reports for females aged 9-25 years. This disproportionality remained when results were stratified by age and when those countries reporting the signals of CRPS (Japan) and POTS (Denmark) were excluded.

    CONCLUSIONS: Cluster analysis reveals additional reports of AEs following HPV vaccination that are serious in nature and describe symptoms that overlap those reported in cases from the recent safety signals (POTS, CRPS, and CFS), but which do not report explicit diagnoses. While the causal association between HPV vaccination and these AEs remains uncertain, more extensive analyses of spontaneous reports can better identify the relevant case series for thorough signal evaluation.

  • 9.
    de Boer, Hugo J.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Systematic Botany.
    Hagemann, Ulrich
    Bate, Jenny
    Meyboom, Ronald H. B.
    Allergic reactions to medicines derived from Pelargonium species2007In: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 30, no 8, p. 677-680Article in journal (Refereed)
    Abstract [en]

    Pelargonium (Pelargonium sidoides DC and P. reniforme Curtis) is reported to have immune modulating properties and antibacterial activity, and Pelargonium extracts have been used for the treatment of respiratory tract and gastrointestinal infections. Introduced in the early 1980s in Germany, Umckaloabo® (ISO Arzneimittel), an ethanolic extract of the roots of P. sidoides and P. reniforme, was the first Pelargonium-derived product to be commonly used in a country in the EU. According to the Umckaloabo® product information, this extract has no known adverse effects. However, there is a theoretical risk of interactions with anticoagulants such as warfarin, and antiplatelet drugs, such as aspirin (acetylsalicylic acid). To date, the Uppsala Monitoring Centre has, through the WHO international pharmacovigilance programme, received 34 case reports of allergic reactions suspected to be associated with the use of Pelargonium extract, all originating from Germany. In a number of these reports, the description and timing of the event was indicative of an acute Coombs and Gell Type I hypersensitivity reaction; two of these patients needed treatment for circulatory failure. So far, the experience of such reactions is limited to Germany. Since Pelargonium-containing herbal products have recently been approved in a number of other countries, the possibility of the occurrence of allergic reactions has become of more general interest and further information regarding these products is needed.

  • 10.
    de Boer, Hugo J.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Systematic Biology.
    Ichim, Mihael C.
    Newmaster, Steven G.
    DNA Barcoding and Pharmacovigilance of Herbal Medicines2015In: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 38, no 7, p. 611-620Article in journal (Refereed)
    Abstract [en]

    Pharmacovigilance of herbal medicines relies on the product label information regarding the ingredients and the adherence to good manufacturing practices along the commercialisation chain. Several studies have shown that substitution of plant species occurs in herbal medicines, and this in turn poses a challenge to herbal pharmacovigilance as adverse reactions might be due to adulterated or added ingredients. Authentication of constituents in herbal medicines using analytical chemistry methods can help detect contaminants and toxins, but are often limited or incapable of detecting the source of the contamination. Recent developments in molecular plant identification using DNA sequence data enable accurate identification of plant species from herbal medicines using defined DNA markers. Identification of multiple constituent species from compound herbal medicines using amplicon metabarcoding enables verification of labelled ingredients and detection of substituted, adulterated and added species. DNA barcoding is proving to be a powerful method to assess species composition in herbal medicines and has the potential to be used as a standard method in herbal pharmacovigilance research of adverse reactions to specific products.

  • 11.
    Farah, Mohamed
    et al.
    Uppsala Monitoring Centre.
    Olsson, Sten
    Uppsala Monitoring Centre.
    Bate, Jenny
    Uppsala Monitoring Centre.
    Lindquist, Marie
    Uppsala Monitoring Centre.
    Edwards, Ralph
    Uppsala Monitoring Centre.
    Simmonds, Monique
    Royal Botanic Gardens Kew.
    Leon, Christine
    Royal Botanic Gardens Kew.
    de Boer, Hugo J.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Systematic Biology.
    Thulin, Mats
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Systematic Biology.
    Botanical Nomenclature in Pharmacovigilance and a Recommendation for Standardisation2006In: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 29, no 11, p. 1023-1029Article in journal (Refereed)
    Abstract [en]

    Nomenclature of plants in pharmacology can be presented by pharmaceutical names or scientific names in the form of Linnaean binomials. In this paper, positive and negative aspects of both systems are discussed in the context of the scientific nomenclatural framework and the systems' practical applicability. The Uppsala Monitoring Centre (UMC) runs the WHO Programme for International Drug Monitoring and is responsible for the WHO Adverse Drug Reaction (ADR) database that currently contains 3.6 million records. In order for the UMC to monitor pharmacovigilance through ADRs to herbal medicine products the following nomenclatural criteria are important: (i) the name should indicate only one species of plant; (ii) the source for this name must be authoritative; (iii) the name should indicate which part of the plant is used. Based on these criteria, the UMC investigated four options: (i) adopt main names used in recognised (inter-) national pharmacopoeias or authoritative publications; (ii) adopt option 1, but cite the publication for all names in abbreviated form; (iii) three-part pharmaceutical names consisting of Latinised part name plus Latinised genus name, plus Latinised specific epithet; (iv) scientific binomial names, optionally with author and plant part used. The UMC has chosen the latter option and will at its adoption utilise the scientific botanical nomenclature as defined by the International Code of Botanical Nomenclature. This decision satisfies all criteria set by the UMC and renders the necessity of creating a new system or upgrading an old inconsistent system obsolete. The UMC has also issued an extensive synonymy checklist of vernacular, pharmaceutical and scientific names for the herbals in the WHO ADR database. We strongly recommend the adoption of scientific names to denote plant ingredients in medicine.

  • 12.
    Grundmark, Birgitta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. WHO Uppsala Monitoring Ctr, Uppsala, Sweden.
    Sartori, D.
    WHO Uppsala Monitoring Ctr, Uppsala, Sweden..
    Ellenius, J.
    WHO Uppsala Monitoring Ctr, Uppsala, Sweden.;Karolinska Inst, Dept Learning Informat Management & Eth, Stockholm, Sweden..
    Do they all agree?: comparing expert signal assessment2017In: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 40, no 10, p. 976-977Article in journal (Other academic)
  • 13.
    Gyllensten, Hanna
    et al.
    Nordic School of Public Health NHV, Gothenburg, Sweden.
    Jönsson, Anna K
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pharmacology.
    Rehnberg, Clas
    Karolinska Institutet, Stockholm.
    Carlsten, Anders
    Nordic School of Public Health NHV, Gothenburg, Sweden,/Medical Products Agency, Uppsala, Sweden.
    How are the Costs of Drug-Related Morbidity Measured?: A Systematic Literature Review2012In: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 35, no 3, p. 207-219Article, review/survey (Refereed)
    Abstract [en]

    Background: Drug-related morbidity has been associated with increased healthcare costs and has been suggested as one of the leading causes of death. Previous reviews have identified heterogeneity in research methods in studies measuring the cost of drug-related morbidity. To date, no attempt has been made to analyse different methods and cost sources used when estimating the costs of drug-related morbidity. Objective: The aim of this review was to evaluate and compare methods and data sources in cost estimates of drug-related morbidity. Methods: A literature search was conducted in three electronic databases (CINAHL, EMBASE and MEDLINE) to identify peer-reviewed articles written in English and published between January 1990 and November 2011. Articles were included if estimating the direct or indirect costs of drug-related morbidity based on clinical data from general patient groups. The general patient groups were defined as patients visiting, being admitted to, treated at or discharged from a general hospital, excluding studies from nursing homes or specialized hospitals. Study information was collected using a standardized data collection sheet. Studies were categorized according to the type of costs included in the cost analysis. Thereafter, the cost analyses of included studies were reviewed regarding viewpoint, costing methods and adjustments for timing of costs. Results: In total, 9569 articles were identified, of which 25 publications were included in this review, and four additional articles were identified from reference or citation lists of publications already included. Eighteen studies measured either the total or attributable costs of drug-related morbidity, while seven studies estimated the increased costs using matched controls or regression analyses. Six studies measured costs from a payer perspective, while the other 23 measured costs to the hospital. One study included costs resulting after discharge, and discounted future costs, while the remaining 28 studies measured costs during the initial admission only and involved no adjustment for timing of costs. Conclusions: The data sources and costs measured in the included studies varied considerably in terms of perspectives and use of data sources. Even though there is a trend towards more studies estimating costs from the payer perspective, the identified studies still focused on costs resulting from patients attending hospital, therefore underestimating the cost of drug-related morbidity. There is thus a need for more research on the costs of drug-related morbidity to providers other than hospitals, and costs occurring outside of hospitals and after the initial care episode. Such studies require clear descriptions of how the costs of drug-related morbidity are measured, and should adhere to published guidelines for observational studies and economic evaluation studies.

  • 14.
    Hakkarainen, Katja Marja
    et al.
    Nordic School of Public Health (NHV), Gothenburg, Sweden.
    Andersson Sundell, Karolina
    Nordic School of Public Health (NHV), Gothenburg, Sweden.
    Petzold, Max
    Nordic School of Public Health (NHV), Gothenburg, Sweden.
    Hägg, Staffan
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology.
    Methods for assessing the preventability of adverse drug events: A systematic review2012In: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 35, no 2, p. 105-126Article in journal (Refereed)
    Abstract [en]

    Background: Preventable adverse drug events (ADEs) are common in both outpatient and inpatient settings. However, the proportion of preventable ADEs varies considerably in different studies, even when conducted in the same setting, and methods for assessing the preventability of ADEs are diverse. Objective: The aim of this article is to identify and systematically evaluate methods for assessing the preventability of ADEs. Data sources: Seven databases (Cochrane, CINAHL, EMBASE, IPA, MEDLINE, PsycINFO and Web of Science) were searched in September 2010 utilizing the databases' index terms and other common terminology on preventable ADEs. No limits for the years of publication were set. Reference lists of included original articles and relevant review articles were also screened. Study selection: After applying predetermined inclusion and exclusion criteria on 4161 unique citations, 142 (3.4%) original research articles were included in the review. One additional article was included from reference lists. Outcome measures of included studies had to include the frequency of ADEs and the assessment of their preventability. Studies were excluded if they focused on individuals with one specific type of treatment, medical condition, medical procedure or ADE. Data extraction: Measurement instruments for determining the preventability of ADEs in each article were extracted and unique instruments were compared. The process of assessing the preventability of ADEs was described based on reported actions taken to standardize and conduct the assessment, and on information about the reliability and validity of the assessment. Data synthesis: Eighteen unique instruments for determining the preventability of ADEs were identified. They fell under the following four groups: (i) instruments using a definition of preventability only (n = 3); (ii) instruments with a definition of preventability and an assessment scale for determining preventability (n = 5); (iii) instruments with specific criteria for each preventability category (n = 3); and (iv) instruments with an algorithm for determining preventability (n = 7). Of actions to standardize the assessment process, performing a pilot study was reported in 21 (15%), and use of a standardized protocol was reported in 18 (13%), of the included 143 articles. Preventability was assessed by physicians in 86 (60%) articles and by pharmacists in 41 (29%) articles. In 29 (20%) articles, persons conducting the assessment were described as trained for or experienced in preventability assessment. In 94 (66%) articles, more than one person assessed the preventability of each case. Among these 94 articles, assessment was done independently in 73 (51%) articles. Procedures for managing conflicting assessments were diverse. The reliability of the preventability assessment was tested in 39 (27%) articles, and 16 (11%) articles referred to a previous reliability assessment. Reliability ranged from poor to excellent (kappa 0.19-0.98; overall agreement 26-97%). Four (3%) articles mentioned assessing validity, but no sensitivity or specificity analyses or negative or positive predictive values were presented. Conclusions: Instruments for assessing the preventability of ADEs vary from implicit instruments to explicit algorithms. There is limited evidence for the validity of the identified instruments, and instrument reliability varied significantly. The process of assessing the preventability of ADEs is also commonly imprecisely described, which hinders the interpretation and comparison of studies. For measuring the preventability of ADEs more accurately and precisely in future, we believe that existing instruments should be further studied and developed, or that one or more new instruments should be developed, and the validity and reliability of the existing and new instruments be established.

  • 15.
    Hauben, Manfred
    et al.
    Pfizer.
    Norén, G. Niklas
    Stockholm University, Faculty of Science, Department of Mathematics.
    A decade of data mining and still counting2010In: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 33, no 7, p. 527-534Article in journal (Other academic)
  • 16.
    Hedenmalm, Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hägg, Staffan
    Norrland University Hopital, Umeå.
    Ståhl, Malin
    WHO Uppsala Monitoring Centre, Uppsala.
    Mortimer, Örjan
    Spigset, Olav
    St Olav´s University Hospital, Trondheim, Norway.
    Glucose intolerance with atypical antipsychotics2002In: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 25, no 15, p. 1107-1116Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Previous studies have suggested that the atypical antipsychotics clozapine and olanzapine may be associated with an increased risk of glucose intolerance and diabetes mellitus. Early studies have also suggested an association between use of conventional antipsychotics and the development of glucose intolerance. OBJECTIVE: To examine quantitatively the association between glucose intolerance including diabetes mellitus and the use of the atypical antipsychotics clozapine, olanzapine or risperidone, and to identify possible risk factors for the development of glucose intolerance during treatment with these drugs. METHODS: All reports suggestive of glucose intolerance for clozapine, olanzapine and risperidone were identified in the WHO database for adverse drug reactions. In the analyses of possible risk factors for glucose intolerance all other reports of adverse drug reactions for clozapine, olanzapine and risperidone were used as reference. Using the Bayesian Confidence Propagation Neural Network method, the strengths of the associations over time between glucose intolerance and the use of these drugs were analysed. For comparison, the strengths of the associations between glucose intolerance and the use of the conventional antipsychotics haloperidol and chlorpromazine were also analysed. RESULTS: Clozapine, olanzapine and risperidone were significantly associated with glucose intolerance. In contrast, chlorpromazine and haloperidol were not associated with glucose intolerance. For clozapine, olanzapine and risperidone grouped together, the following potential risk factors for glucose intolerance were identified: an underlying diabetic condition (odds ratio [OR] 10.22, 95% CI 8.20-12.73), an increase in weight (OR 2.36, 95% CI 1.76-3.17), male gender (OR 1.27, 95% CI 1.11-1.47), and concomitant use of valproic acid (OR 1.97, 95% CI 1.61-2.40), selective serotonin reuptake inhibitors (OR 1.63, 95% CI 1.33-1.99) or buspirone (OR 2.24, 95% CI 1.33-3.77). CONCLUSION: Treatment with clozapine, olanzapine or risperidone appears to be associated with an increased risk of glucose intolerance.

  • 17.
    Hedenmalm, Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Samuelsson, Eva
    Fatal venous thromboembolism associated with different combined oral contraceptives: a study of incidences and potential biases in spontaneous reporting2005In: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 28, no 10, p. 907-916Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Fatal venous thromboembolism (VTE) is a rare complication of combined oral contraceptive (COC) treatment. This study aims to determine incidences of fatal VTE in relation to the type of COC and the percentage of cases reported to the Swedish Adverse Drug Reactions Advisory Committee (SADRAC). A further aim is to compare the characteristics of reported and not reported cases. METHODS: This retrospective study is a separate analysis using data from a larger study that included women aged 15-44 years between 1990 and 1999 with VTE coded as the underlying or contributory cause of death in the Swedish Cause of Death Register. COC use within 2 months of the date of symptom onset or death was identified in 28 cases. Sales data were obtained from the National Corporation of Swedish Pharmacies. Reported cases were identified in the SADRAC database. RESULTS: After excluding two cases where the type of COC was unknown, the crude incidences of fatal VTE were 5.1 (95% CI 2.3, 9.6), 8.6 (95% CI 4.3, 15.4) and 9.1 (95% CI 3.3, 19.8) cases per million women per year for levonorgestrel-, desogestrel- and norethisterone-containing COCs, respectively. Age-adjusted incidences were approximately twice as high for desogestrel- and norethisterone-containing COCs compared with levonorgestrel-containing COCs, although differences were not statistically significant. Thirty-six percent of cases were reported. Reporting was positively associated with information in medical records relevant to the VTE diagnosis that the patient was a COC user and was significantly higher in northern Sweden. CONCLUSION: Results from this study support a higher incidence of fatal VTE with desogestrel-containing COCs than with levonorgestrel-containing COCs.

  • 18. Hopstadius, Johan
    et al.
    Norén, G. Niklas
    Stockholm University, Faculty of Science, Department of Mathematics.
    Bate, Andrew
    Edwards, I. Ralph
    Impact of Stratification on Adverse Drug Reaction Surveillance2008In: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 31, no 11, p. 1035-1048Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND OBJECTIVES: Automated screening for excessive adverse drug reaction (ADR) reporting rates has proven useful as a tool to direct clinical review in large-scale drug safety signal detection. Some measures of disproportionality can be adjusted to eliminate any undue influence on the ADR reporting rate of covariates, such as patient age or country of origin, by using a weighted average of stratum-specific measures of disproportionality. Arguments have been made in favour of routine adjustment for a set of common potential confounders using stratification. The aim of this paper is to investigate the impact of using adjusted observed-to-expected ratios, as implemented for the Empirical Bayes Geometric Mean (EBGM) and the information component (IC) measures of disproportionality, for first-pass analysis of the WHO database.

    METHODS: A simulation study was carried out to investigate the impact of simultaneous adjustment for several potential confounders based on stratification. Comparison between crude and adjusted observed-to-expected ratios were made based on random allocation of reports to a set of strata with a realistic distribution of stratum sizes. In a separate study, differences between the crude IC value and IC values adjusted for (combinations of) patient sex, age group, reporting quarter and country of origin, with respect to their concordance with a literature comparison were analysed. Comparison was made to the impact on signal detection performance of a triage criterion requiring reports from at least two countries before a drug-ADR pair was highlighted for clinical review.

    RESULTS: The simulation study demonstrated a clear tendency of the adjusted observed-to-expected ratio to spurious (and considerable) underestimation relative to the crude one, in the presence of any very small strata in a stratified database. With carefully implemented stratification that did not yield any very small strata, this tendency could be avoided. Routine adjustment for potential confounders improved signal detection performance relative to the literature comparison, but the magnitude of the improvement was modest. The improvement from the triage criterion was more considerable.

    DISCUSSION AND CONCLUSIONS: Our results indicate that first-pass screening based on observed-to-expected ratios adjusted with stratification may lead to missed signals in ADR surveillance, unless very small strata are avoided. In addition, the improvement in signal detection performance due to routine adjustment for a set of common confounders appears to be smaller than previously assumed. Other approaches to improving signal detection performance such as the development of refined triage criteria may be more promising areas for future research.

  • 19.
    Hägg, Staffan
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Bate, Andrew
    Uppsala.
    Stahl, Malin
    Uppsala.
    Spigset, Olav
    Trondheim Norge.
    Associations between venous thromboembolism and antipsychotics: A study of the WHO database of adverse drug reactions2008In: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 31, no 8, p. 685-694Article in journal (Refereed)
    Abstract [en]

    Background: Concern has been raised about the occurrence of venous thromboembolism (VTE) during treatment with antipsychotics. However, to date, clozapine is the only antipsychotic agent for which recurring evidence supports an association with VTE. Therefore, the aim of this study was to investigate the association between antipsychotic drugs, including clozapine and VTE. Study design and methods: Data mining of the WHO database of adverse drug reactions (ADRs) using Bayesian statistics is in routine use for early alerting to possible ADRs. An information component measure was used to investigate the association between antipsychotic drugs and VTE reactions in the database. Results: A total of 754 suspected cases of VTE related to treatment with antipsychotics had been reported. After excluding cases related to clozapine, 379 cases remained. A robust association was found for the second-generation antipsychotics group but not for the high-potency, first-generation antipsychotics group or the low-potency first-generation antipsychotics group. The individual compounds with statistically significant associations were olanzapine, sertindole and zuclopenthixol. A time-dependent analysis showed that the associations were positive for these drugs in 2002, 2001 and 2003, respectively. Case analyses were undertaken after excluding ten suspected duplicate reports. Of the remaining 369 cases, 91 cases were associated with olanzapine, 9 with zuclopenthixol and 6 with sertindole. Conclusions: VTE was more often reported with the antipsychotic drugs olanzapine, sertindole and zuclopenthixol than with other drugs in the WHO database. Further studies are warranted to explain this disproportional reporting. Since the associations found were based on incomplete clinical data, the results should be considered as preliminary and interpreted cautiously. © 2008 Adis Data Information BV. All rights reserved.

  • 20. Härmark, Linda
    et al.
    van Hunsel, Florence
    Grundmark, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    ADR Reporting by the General Public: Lessons Learnt from the Dutch and Swedish Systems2015In: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 38, no 4, p. 337-347Article, review/survey (Refereed)
    Abstract [en]

    Consumer reporting of adverse drug reactions (ADRs) has existed in several countries for decades, but throughout Europe the role of consumers as a source of information on ADRs has not been fully accepted until recently. In Europe, The Netherlands and Sweden were among the first countries to implement consumer reporting well before it was mandated by law throughout the EU. Consumer reporting is an integral part of the spontaneous reporting systems in both The Netherlands and Sweden, with yearly numbers of reports constantly increasing. Consumer reporting forms and handling procedures are essentially the same as for healthcare professional reporting; the message in the reports, not the type of messenger, is what is of importance. Studies have established the significant contribution of consumer reporting to ADR signal detection. Combining all reports regardless of reporter type is recommended since it yields the largest critical mass of reports for signal detection. Examples of signals where consumer reports have been of crucial importance for signal detection are electric shock-like sensations associated with the use of duloxetine, and persistent sexual dysfunction after discontinuation of selective serotonin reuptake inhibitors. An example of consumer reporting significantly strengthening a detected signal is Pandemrix(®) (influenza H1N1 vaccine)-induced narcolepsy. Raising public awareness of ADR reporting is important, but time- and resource-consuming. The minimum effort taken should be to passively inform consumers, e.g. via stakeholders' homepages and via drug product information leaflets. Another possibility of reaching out to this target group could be through co-operation with other (non-government) organizations. Information from consumer reports may give a new perspective on ADRs via the consumers' unfiltered experiences. Consumers' views may change the way the benefit-harm balance of drugs is perceived and assessed today, and, being the ultimate users of drugs, consumers could have a relevant influence in the regulatory decision-making processes for drugs. All stakeholders in pharmacovigilance should embrace this new valuable source of information.

  • 21. Iessa, N.
    et al.
    Star, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Caring Sciences.
    Murray, M. L.
    Wilton, L.
    Curran, S.
    Edwards, R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Aronson, J. K.
    Besag, F.
    Santosh, P.
    Wong, I. C. K.
    An Evaluation of the Evidence of an Association between Montelukast and Suicide: A Publicity Exacerbated Signal?2012In: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 35, no 10, p. 901-901Article in journal (Other academic)
  • 22.
    Johansson, K
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Olsson, S
    Hellman, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Meyboom, RHB
    An analysis of Vigimed, a global E-mail system for the exchange of pharmacovigilance information2007In: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 30, no 10, p. 883-889Article in journal (Refereed)
    Abstract [en]

    Background and aim: The Internet provides novel ways for communication and data exchange between national regulators. One innovation was the introduction of Vigimed, an e-mail discussion forum for national pharmacovigilance centres (NPCs). We reviewed a sample of Vigimed messages to learn more about this new tool and about the problems encountered in everyday pharmacovigilance and how these are handled. Methods: We analysed the contents of 100 subsequent questions and the corresponding responses as stored in the Vigimed datafile. Results: To the 100 questions circulated through Vigimed, 575 answers were received; mean number of answers per question 6, range 0-20. Fifty-five (77%) of the 71 collaborating countries and 88 (43%) of the 204 individuals who had access in the study period had submitted at least one question or answer. These countries were in all parts of the world and in various phases of development. A total of 38% of the questions concerned the regulatory status of a drug; 30% safety issues; 13 % regulatory actions under consideration; and 10% drug use-related problems (more than one category possible). Of the questions, 89% concerned established drugs; 11% were classified as new. A total of 90% of the questions concerned specific active substances or drug groups. Of the drugs, 73% were classified as 'orthodox' and 9% as herbal; 4% were vaccines and 4% excipients. Emerging drug groups (anatomical therapeutic chemical codes) were NSAIDs and analgesics (M01, N02), antibacterials (J01), antiobesity drugs (A08), psychotropic drugs (N05) and antihistamines (R06). Discussion: NPCs operate in a restricted environment and there is little published information about the daily practices and experiences at NPCs. Our study concerned a sample in a limited period in time. In the meantime, the use of Vigimed has greatly expanded. The data in the Vigimed records are subjected to confidentiality in regard to the identities of countries, staff members, drug products and pharmaceutical companies, which tin-tits the presentation of data in a publication. For information about the actions taken to manage the matters and problems raised in Vigimed it would have been necessary to contact the NPCs and acquire follow-up data. Conclusions: The Vigimed e-mail discussion group was rapidly incorporated into the routines at NPCs in many countries around the world. When two or more persons per country have access, participation increases. The matters raised predominantly refer to regulatory policy, safety concerns and drug use-related problems, and mainly concern established drugs. The latter emphasises the need for persistent monitoring of all drugs. New safety concerns are often sensitive and uncertain; the timely and efficient communication of such suspicions benefits from an environment of confidentiality. The Vigimed records give a unique view of real-life pharmacovigilance, of the matters addressed, the problems encountered, the data needed and the ways in which NPCs help each other. Such information can help make pharmacovigilance more efficient and effective.

  • 23. Johansson, Saga
    et al.
    Wallander, Mari-Ann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Clinical Epidemiology.
    de Abajo, Francisco J
    Garcia Rodriguez, Luis Alberto
    Prospective Drug Safety Monitoring Using the UK Primary-Care General Practice Research Database Theoretical Framework, Feasibility Analysis and Extrapolation to Future Scenarios2010In: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 33, no 3, p. 223-232Article in journal (Refereed)
    Abstract [en]

    Background: Post-launch drug safety monitoring is essential for the detection of adverse drug signals that may be missed during preclinical trials. Traditional methods of postmarketing surveillance such as spontaneous reporting have intrinsic limitations, many of which can be overcome by the additional application of structured pharmacoepidemiological approaches. However, further improvement in drug safety monitoring requires a shift towards more proactive pharmacoepidemiological methods that can detect adverse drug signals as they occur in the population. Objective: To assess the feasibility of using proactive monitoring of an electronic medical record system, in combination with an independent endpoint adjudication committee, to detect adverse events among users of selected drugs. Methods: UK General Practice Research Database (GPRD) information was used to detect acute liver disorder associated with the use of amoxicillin/clavulanic acid (hepatotoxic) or low-dose aspirin (acetylsalicylic acid [non-hepatotoxic]). Individuals newly prescribed these drugs between 1 October 2005 and 31 March 2006 were identified. Acute liver disorder cases were assessed using GPRD computer records in combination with case validation by an independent endpoint adjudication committee. Signal generation thresholds were based on the background rate of acute liver disorder in the general population. Results: Over a 6-month period, 8148 patients newly prescribed amoxicillin/clavulanic acid and 5577 patients newly prescribed low-dose aspirin were identified. Within this cohort, searches identified 11 potential liver disorder cases from computerized records: six for amoxicillin/clavulanic acid and five for low-dose aspirin. The independent endpoint adjudication committee refined this to four potential acute liver disorder cases for whom paper-based information was requested for final case assessment. Final case assessments confirmed no cases of acute liver disorder. The time taken for this study was 18 months (6 months for recruitment and 12 months for data management and case validation). To reach the estimated target exposure necessary to raise or rule out a signal of concern to public health, we determined that a recruitment period 2-3 times longer than that used in this study would be required. Based on the real market uptake of six commonly used medicinal products launched between 2001 and 2006 in the UK (budesonide/eformoterol [fixed-dose combination], duloxetine, ezetimibe, metformin/rosiglitazone [fixed-dose combination], tiotropium bromide and tadalafil) the target exposure would not have been reached until the fifth year of marketing using a single database. Conclusions: It is feasible to set Lip a system that actively monitors drug safety using a healthcare database and an independent endpoint adjudication committee. However, future successful implementation will require multiple databases to be queried so that larger study populations are included. This requires further development and harmonization of international healthcare databases.

  • 24. Juhlin, Kristina
    et al.
    Karimi, Ghazaleh
    Ander, Maria
    Camilli, Sara
    Dheda, Mukesh
    Har, Tan Siew
    Isahak, Rokiah
    Lee, Su-Jung
    Vaughan, Sarah
    Caduff, Pia
    Norén, G. Niklas
    Stockholm University, Faculty of Science, Department of Mathematics. Uppsala Monitoring Center, Sweden.
    Using VigiBase to Identify Substandard Medicines: Detection Capacity and Key Prerequisites2015In: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 38, no 4, p. 373-382Article in journal (Refereed)
    Abstract [en]

    Background Substandard medicines, whether the result of intentional manipulation or lack of compliance with good manufacturing practice (GMP) or good distribution practice (GDP), pose a significant potential threat to patient safety. Spontaneous adverse drug reaction reporting systems can contribute to identification of quality problems that cause unwanted and/or harmful effects, and to identification of clusters of lack of efficacy. In 2011, the Uppsala Monitoring Centre (UMC) constructed a novel algorithm to identify reporting patterns suggestive of substandard medicines in spontaneous reporting, and applied it to VigiBase (R), the World Health Organization's global individual case safety report database. The algorithm identified some historical clusters related to substandard products, which were later able to be confirmed in the literature or by contact with national centres (NCs). As relevant and detailed information is often lacking in the VigiBase reports but might be available at the reporting NC, further evaluation of the algorithm was undertaken with involvement from NCs. Objective To evaluate the effectiveness of an algorithm that identifies clusters of potentially substandard medicines, when these are assessed directly at the NC concerned. Methods The algorithm identifies countries and time periods with disproportionately high reporting of product inadequacy. NCs with at least 20 clusters were eligible to participate in the study, and six NCs-those in the Republic of Korea, Malaysia, Singapore, South Africa, the UK and the USA-were selected, taking into account the geographical spread and prevalence of recent clusters. The clusters were systematically assessed at the NCs, following a standardized protocol, and then compiled centrally at the UMC. The clusters were classified as 'confirmed', 'potential' or 'unlikely' substandard products; or as 'confirmed not substandard' when confirmed by an investigation; or as 'indecisive' when the information available did not allow a sound assessment even at the NC. Results The assessment of a total of 147 clusters resulted in 8 confirmed, 12 potential and 51 unlikely substandard products, and a further 19 clusters were confirmed as not substandard. Reflecting the difficulty of evaluating suspected substandard products retrospectively when additional information from the primary reporter, as well as samples, are no longer available, 57 clusters were classified as indecisive. Conclusion While application of the algorithm to VigiBase allowed identification of some substandard medicines, some key prerequisites have been identified that need to be fulfilled at the national level for the algorithm to be useful in practice. Such key factors are fast handling and transfer of incoming reports into VigiBase, detailed information on the product and its distribution channels, the possibility of contacting primary reporters for further information, availability of samples of suspected products and laboratory capacity to analyse suspected products.

  • 25.
    Norén, G. Niklas
    et al.
    Stockholm University, Faculty of Science, Department of Mathematics.
    Bergvall, Tomas
    Ryan, Patrick B.
    Juhlin, Kristina
    Schuemie, Martijn J.
    Madigan, David
    Empirical Performance of the Calibrated Self-Controlled Cohort Analysis Within Temporal Pattern Discovery: Lessons for Developing a Risk Identification and Analysis System2013In: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 36, p. s107-S121Article in journal (Refereed)
    Abstract [en]

    Background Observational healthcare data offer the potential to identify adverse drug reactions that may be missed by spontaneous reporting. The self-controlled cohort analysis within the Temporal Pattern Discovery framework compares the observed-to-expected ratio of medical outcomes during post-exposure surveillance periods with those during a set of distinct pre-exposure control periods in the same patients. It utilizes an external control group to account for systematic differences between the different time periods, thus combining within- and between-patient confounder adjustment in a single measure. Objectives To evaluate the performance of the calibrated self-controlled cohort analysis within Temporal Pattern Discovery as a tool for risk identification in observational healthcare data. Research Design Different implementations of the calibrated self-controlled cohort analysis were applied to 399 drug-outcome pairs (165 positive and 234 negative test cases across 4 health outcomes of interest) in 5 real observational databases (four with administrative claims and one with electronic health records). Measures Performance was evaluated on real data through sensitivity/specificity, the area under receiver operator characteristics curve (AUC), and bias. Results The calibrated self-controlled cohort analysis achieved good predictive accuracy across the outcomes and databases under study. The optimal design based on this reference set uses a 360 days surveillance period and a single control period 180 days prior to new prescriptions. It achieved an average AUC of 0.75 and AUC >0.70 in all but one scenario. A design with three separate control periods performed better for the electronic health records database and for acute renal failure across all data sets. The estimates for negative test cases were generally unbiased, but a minor negative bias of up to 0.2 on the RR-scale was observed with the configurations using multiple control periods, for acute liver injury and upper gastrointestinal bleeding. Conclusions The calibrated self-controlled cohort analysis within Temporal Pattern Discovery shows promise as a tool for risk identification; it performs well at discriminating positive from negative test cases. The optimal parameter configuration may vary with the data set and medical outcome of interest.

  • 26.
    Norén, G. Niklas
    et al.
    Stockholm University, Faculty of Science, Department of Mathematics. Uppsala Monitoring Centre, Sweden.
    Caster, Ola
    Stockholm University, Faculty of Social Sciences, Department of Computer and Systems Sciences. Uppsala Monitoring Centre, Sweden.
    Juhlin, Kristina
    Lindquist, Marie
    Zoo or savannah? Choice of training ground for evidence-based pharmacovigilance2014In: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 37, no 9, p. 655-659Article in journal (Refereed)
    Abstract [en]

    Pharmacovigilance seeks to detect and describe adverse drug reactions early. Ideally, we would like to see objective evidence that a chosen signal detection approach can be expected to be effective. The development and evaluation of evidence-based methods require benchmarks for signal detection performance, and recent years have seen unprecedented efforts to build such reference sets. Here, we argue that evaluation should be made against emerging and not established adverse drug reactions, and we present real-world examples that illustrate the relevance of this to pharmacovigilance methods development for both individual case reports and longitudinal health records. The establishment of broader reference sets of emerging safety signals must be made a top priority to achieve more effective pharmacovigilance methods development and evaluation.

  • 27.
    Reichenpfader, Ursula
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Health Sciences.
    Gartlehner, Gerald
    Danube University of Krems, Austria RTI Int, NC 27709 USA .
    Morgan, Laura C.
    RTI Int, NC 27709 USA .
    Greenblatt, Amy
    RTI Int, NC 27709 USA .
    Nussbaumer, Barbara
    Danube University of Krems, Austria .
    Hansen, Richard A.
    Auburn University, AL 36849 USA .
    Van Noord, Megan
    Danube University of Krems, Austria RTI Int, NC 27709 USA .
    Lux, Linda
    RTI Int, NC 27709 USA .
    Gaynes, Bradley N.
    University of N Carolina, NC 27599 USA .
    Sexual Dysfunction associated with Second-Generation Antidepressants in Patients with Major Depressive Disorder: Results from a Systematic Review with Network Meta-Analysis2014In: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 37, no 1, p. 19-31Article in journal (Refereed)
    Abstract [en]

    Sexual dysfunction (SD) is prevalent in patients with major depressive disorder (MDD) and is also associated with second-generation antidepressants (SGADs) that are commonly used to treat the condition. Evidence indicates under-reporting of SD in efficacy studies. SD associated with antidepressant treatment is a serious side effect that may lead to early termination of treatment and worsening of quality of life. Our objective was to systematically assess the harms of SD associated with SGADs in adult patients with MDD by drug type. We retrieved English-language abstracts from PubMed, EMBASE, the Cochrane Library, PsycINFO, and International Pharmaceutical Abstracts from 1980 to October 2012 as well as from reference lists of pertinent review articles and grey literature searches. Two independent reviewers identified randomized controlled trials (RCTs) of at least 6 weeks duration and observational studies with at least 1,000 participants. Reviewers abstracted data on study design, conduct, participants, interventions, outcomes and method of SD ascertainment, and rated risk of bias. A senior reviewer checked and confirmed extracted data and risk-of-bias ratings. Random effects network meta-analysis using Bayesian methods for data from head-to-head trials and placebo-controlled comparisons; descriptive analyses calculating weighted mean rates from individual trials and observational studies. Data from 63 studies of low and moderate risk of bias (58 RCTs, five observational studies) with more than 26,000 patients treated with SGADs were included. Based on network meta-analyses of 66 pairwise comparisons from 37 RCTs, most comparisons showed a similar risk of SD among included SGADs. However, credible intervals were wide and included differences that would be considered clinically relevant. We observed three main patterns: bupropion had a statistically significantly lower risk of SD than some other SGADs, and both escitalopram and paroxetine showed a statistically significantly higher risk of SD than some other SGADs. We found reporting of harms related to SD inconsistent and insufficient in some trials. Most trials were conducted in highly selected populations. Search was restricted to English-language only. Because of the indirect nature of the comparisons, the often wide credible intervals, and the high variation in magnitude of outcome, we rated the overall strength of evidence with respect to our findings as low. The current degree of evidence does not allow a precise estimate of comparative risk of SD associated with a specific antidepressant. In the absence of such evidence, clinicians need to be aware of SD as a common adverse event and should discuss patients preferences before initiating antidepressant therapy.

  • 28.
    Sartori, D.
    et al.
    Uppsala Monitoring Ctr, WHO Collaborating Ctr Int Drug Monitoring, Uppsala, Sweden..
    Westerberg, C.
    Uppsala Monitoring Ctr, WHO Collaborating Ctr Int Drug Monitoring, Uppsala, Sweden..
    Grundmark, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Uppsala Monitoring Ctr, WHO Collaborating Ctr Int Drug Monitoring, Uppsala, Sweden.
    Natalizumab and rapidly evolving central nervous system lymphoma in VigiBase2017In: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 40, no 10, p. 974-974Article in journal (Other academic)
  • 29.
    Savage, R.
    et al.
    Uppsala Monitoring Ctr, WHO Collaborating Ctr Int Drug Monitoring, Uppsala, Sweden.;Univ Otago, Dept Gen Practice, Christchurch, New Zealand..
    Star, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Health Services Research. Uppsala Monitoring Ctr, WHO Collaborating Ctr Int Drug Monitoring, Uppsala, Sweden..
    Zekarias, A.
    Uppsala Monitoring Ctr, WHO Collaborating Ctr Int Drug Monitoring, Uppsala, Sweden..
    Brobert, G. Persson
    Bayer AB, Solna, Sweden..
    Ansell, D.
    IMS Hlth, London, England..
    Edwards, I. R.
    Uppsala Monitoring Ctr, WHO Collaborating Ctr Int Drug Monitoring, Uppsala, Sweden..
    Prescribing and Diagnostic Issues Associated with Sumatriptan Identified Through Open-ended Screening for Safety Signals in Electronic Health Care Records2016In: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 39, no 10, p. 1014-1015Article in journal (Other academic)
  • 30. Schulman, Sam
    et al.
    Majeed, Ammar
    Department of Medicine, Mälar Hospital, Eskilstuna, Sweden .
    A benefit-risk assessment of dabigatran in the prevention of venous thromboembolism in orthopaedic surgery2011In: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 34, no 6, p. 449-463Article in journal (Refereed)
    Abstract [en]

    Dabigatran etexilate is a novel orally administered anticoagulant that exerts its action through reversible direct thrombin inhibition. This anticoagulant has been approved for prophylaxis against venous thromboembolism (VTE) after hip or knee arthroplasty, and in a few countries also for atrial fibrillation. This article reviews the efficacy and safety of dabigatran for the prophylaxis of VTE-indication compared with data on the most common current regimen with low-molecular-weight heparin (LMWH), specifically enoxaparin. Alternative prophylactic agents are also discussed. The results regarding efficacy and safety are very similar for dabigatran and LMWH. Bleeding and gastrointestinal reactions are the most frequently reported adverse events with a comparable incidence on LMWH and are probably the result of surgery and anaesthaesia. No adverse event that is specific for dabigatran has been observed in these studies, although dyspepsia has been reported as significantly more frequent than warfarin in long-term studies on other indications. The fact that dabigatran has no antidote has so far not been a problem in patients undergoing orthopaedic surgery. The use of the lower dose of dabigatran (150 mg) appears beneficial to reduce the risk of bleeding in patients over 75 years of age and in those with moderate renal impairment to avoid drug accumulation. The convenience of oral administration is an advantage for dabigatran over LMWH, particularly for extended prophylaxis up to 1 month after surgery. In conclusion, the benefit-risk profile of dabigatran is favourable for use as prophylaxis against VTE after major orthopaedic surgery with its convenient oral administration without need for laboratory monitoring and a low risk of bleeding or other adverse events.

  • 31.
    Star, Kristina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Caring Sciences.
    Caster, Ola
    Bate, Andrew
    Edwards, I. Ralph
    Dose Variations Associated with Formulations of NSAID Prescriptions for Children A Descriptive Analysis of Electronic Health Records in the UK2011In: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 34, no 4, p. 307-317Article in journal (Refereed)
    Abstract [en]

    Background: NSAIDs, particularly ibuprofen, are commonly prescribed for children but there is limited published research on real-life prescribed doses for this class of drugs. Objective: The aim of the study was to investigate if variations in NSAID doses prescribed to children can be explained by patient age, indication, dosage form, type of NSAID or year of prescription. Study Design: Recorded daily doses for drugs within the 'Anti-rheumatics, non-steroidal plain' anatomical classification were studied. First prescriptions of a distinct NSAID substance within 13-month time periods in a patient's history were included. To enable grouping and comparison of NSAIDs, doses were analysed as prescribed daily doses (PDDs) relative to the adult defined daily dose, stated as the relative PDD (rPDD) in this study. Multiple regression analysis was performed with the rPDD as the response variable, and age, indication, dosage form, NSAID substance and year of prescription as the explanatory variables. Setting: Prescriptions from the Intercontinental Medical Statistics (IMS) Health Disease Analyzer database containing electronic health records of general practitioners in the UK issued from 1988 to December 2005. Patients: Data for children aged 2-11 years with NSAID prescriptions including daily dose information. Results: A total of 21 473 first prescriptions for 19 695 patients were studied. The vast majority of prescriptions were for ibuprofen (n = 20855), which were therefore analysed separately. The other NSAID prescriptions were grouped (n = 618), containing diclofenac, indometacin, mefenamic acid, naproxen and piroxicam ('NSAID group'). The rPDD varied considerably with dosage form in both the ibuprofen and NSAID groups. In particular, tablets/capsules were prescribed at higher doses than liquid dosage forms. In the NSAID group, naproxen was prescribed at noticeably higher doses. The rPDD varied only slightly with age in both groups. Prescriptions indicated for rheumatic disease were associated with lower doses than other indications in the NSAID group. The rPDD was not influenced by year of prescription. Conclusions: This study shows a correlation between higher prescribed NSAID doses and tablet/capsule formulation, and highlights the need for careful choice of dose formulation when prescribing medicines for children.

  • 32. Star, Kristina
    et al.
    Caster, Ola
    Stockholm University, Faculty of Social Sciences, Department of Computer and Systems Sciences. Uppsala Monitoring Centre, Sweden.
    Bate, Andrew
    Edwards, I. Ralph
    Dose Variations Associated with Formulations of NSAID Prescriptions for Children: A Descriptive Analysis of Electronic Health Records in the UK2011In: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 34, no 4, p. 307-317Article in journal (Refereed)
    Abstract [en]

    Background: NSAIDs, particularly ibuprofen, are commonly prescribed for children but there is limited published research on real-life prescribed doses for this class of drugs.

    Objective: The aim of the study was to investigate if variations in NSAID doses prescribed to children can be explained by patient age, indication, dosage form, type of NSAID or year of prescription.

    Study Design: Recorded daily doses for drugs within the `Anti-rheumatics, non-steroidal plain' anatomical classification were studied. First prescriptions of a distinct NSAID substance within 13-month time periods in a patient's history were included. To enable grouping and comparison of NSAIDs, doses were analysed as prescribed daily doses (PDDs) relative to the adult defined daily dose, stated as the relative PDD (rPDD) in this study. Multiple regression analysis was performed with the rPDD as the response variable, and age, indication, dosage form, NSAID substance and year of prescription as the explanatory variables.

    Setting: Prescriptions from the Intercontinental Medical Statistics (IMS) Health Disease Analyzer database containing electronic health records of general practitioners in the UK issued from 1988 to December 2005.

    Patients: Data for children aged 2-11 years with NSAID prescriptions including daily dose information.

    Results: A total of 21 473 first prescriptions for 19 695 patients were studied. The vast majority of prescriptions were for ibuprofen (n = 20 855), which were therefore analysed separately. The other NSAID prescriptions were grouped (n = 618), containing diclofenac, indometacin, mefenamic acid, naproxen and piroxicam (`NSAID group'). The rPDD varied considerably with dosage form in both the ibuprofen and NSAID groups. In particular, tablets/capsules were prescribed at higher doses than liquid dosage forms. In the NSAID group, naproxen was prescribed at noticeably higher doses. The rPDD varied only slightly with age in both groups. Prescriptions indicated for rheumatic disease were associated with lower doses than other indications in the NSAID group. The rPDD was not influenced by year of prescription.

    Conclusions: This study shows a correlation between higher prescribed NSAID doses and tablet/capsule formulation, and highlights the need for careful choice of dose formulation when prescribing medicines for children.

  • 33.
    Star, Kristina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Edwards, I. Ralph
    Pharmacovigilance for Children's Sake2014In: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 37, no 2, p. 91-98Article in journal (Refereed)
    Abstract [en]

    Child age-specific information on efficacy and risk of medicines can be limited for healthcare professionals and patients. It is therefore very important to make the best use of a risk planned approach to the pharmacological treatment of children. This means pharmacovigilance in the broadest sense of gaining the best data from the use of medicines in clinical practice. We consider issues that complicate safe medication use in paediatric care, as well as current progress and provide suggestions for building knowledge within paediatric pharmacovigilance to be used to minimise patient harm. The continuous development in children constitutes a challenge to prescribing and administering age-suitable doses for individual children. Children are not only different from adults but differ vastly within their own age group. Physical growth during childhood is apparent to the eye, but less obvious is the ongoing maturation of organ function important for drug disposition and action. Systematic issues such as medication errors, off-label use and the lack of age-suitable formulations are considerable obstacles for safe medication use in paediatrics. The recognition of emerging adverse drug reactions could be more challenging in developing children. Initiatives to improve the situation have been made by the WHO and regulators in the USA and EU. Age-specific changes in physiology, pharmacology and psychology, as well as systematic issues specific for children need to be considered in the work of assessing spontaneous reports in children. Pharmacovigilance needs to broaden its aims considerably beyond merely capturing new associations between drugs and events, and encompass careful collection on patient characteristics and circumstances around the reported adverse drug reaction to provide essential information that will give clues on how to prevent harm to children.

  • 34.
    Star, Kristina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Norén, Niklas G
    Nordin, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Edwards, Ralph I.
    Suspected Adverse Drug Reactions Reported For Children Worldwide: An Exploratory Study Using VigiBase2011In: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 34, no 5, p. 415-428Article in journal (Refereed)
    Abstract [en]

    Background

    As a first step towards implementing routine screening of safety issues specifically related to children at the Uppsala Monitoring Centre, this study was performed to explore reporting patterns of adverse reactions in children.

     

    Objective

    The first aim of this study was to characterize and contrast child reports against adult reports in an overall drug and adverse reaction review. The second aim was to highlight increases in reporting of specific adverse reactions during recent years subdivided by age group.

     

    Study Design

    This was an exploratory study of internationally compiled individual case safety reports (ICSRs).

     

    Setting

    Reports were extracted from the WHO global ICSR database, VigiBase, up until 5 February 2010. The reports in VigiBase originate from 97 countries and the likelihood that a medicine caused the adverse effect may vary from case to case. Suspected duplicate and vaccine reports were excluded from the analysis, as were reports with age not specified. The Medical Dictionary for Regulatory Activities (MedDRA (R)) and the WHO Anatomical Therapeutic Chemical (ATC) classification were used to group adverse reactions and drugs.

     

    Patients

    In the general review, reports from 1968 to 5 February 2010 were divided into child (aged 0-17 years) and adult (>= 18 years) age groups. To highlight increases in reporting rates of specific adverse reactions during recent years, reports from 2005 to February 2010 were compared with reports from 1995 to 1999. The ten adverse reactions with the greatest difference in the proportion of reports between the two time periods were reviewed. In the latter analysis, the reports were subdivided into age groups: neonates 27 days; infants 28 days-23 months; children 2-11 years; and adolescents 12-17 years.

     

    Results

    A total of 3 472 183 reports were included in the study, of which 7.7% (268 145) were reports for children (0-17 years). Fifty-three percent of the child reports were for males, whilst 39% of reports in the adult group were for males. The proportion of reports involving children among Asian reports was 14% and was 15% among reports from Africa and Latin America, including the Caribbean. Among reports from North America, Oceania and Europe, 7% of the reports involved children. For the ATC drug classification groups, the largest difference in percentage units between the child and adult groups was seen for the anti-infective (33 vs 15%), respiratory (11 vs 5%) and dermatological (12 vs 7%) drug groups. Skin reactions were most commonly reported for the children; these were recorded in 35% of all reports for children and 23% of all reports for adults. Medication error-related terms in the younger age groups were reported with an increased frequency during recent years. This was particularly noticeable for the infants aged 28 days-23 months, recorded with accidental overdose and drug toxicity. Reactions reported in suspected connection to medicines used for attention-deficit hyperactivity disorders (ADHD) completely dominated the 2- to 11-year age group and were also common for the adolescents. This study presents variations in the reporting pattern in different age groups in VigiBase which, in some cases, could be due to susceptibilities to specific drug-related problems in certain age groups. Other likely explanations might be common drug usage and childhood diseases in these age groups.

     

    Conclusions

    Reports in VigiBase received internationally for more than 40 years reflect real concerns for children taking medicines. The study highlights adverse reactions with an increased reporting during recent years, particularly those connected to the introduction of ADHD medicines in the child population. To enhance patient safety, medication errors indicating administration and dosing difficulties of drugs, especially in the younger age groups, require further attention.

  • 35.
    Strandell, Johanna
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Caster, Ola
    Uppsala Monitoring Centre, Uppsala Sweden. Department of Computer and Systems Sciences, Stockholm University, Stockholm, Sweden.
    Bate, Andrew
    Uppsala Monitoring Centre, Uppsala Sweden. School if Information Systems, Brunel University, London, UK.
    Norén, Niklas
    Uppsala Monitoring Centre, Uppsala Sweden. Department of Mathematics, Stockholm University, Stockholm, Sweden.
    Edwards, I Ralph
    Uppsala Monitoring Centre, Uppsala, Sweden.
    Reporting Patterns Indicative of Adverse Drug Interactions: A Systematic Evaluation in VigiBase.2011In: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 34, no 3, p. 253-66Article in journal (Refereed)
    Abstract [en]

    Background: Adverse drug interaction surveillance in collections of Individual Case Safety Reports (ICSRs) remains underdeveloped. Most efforts to date have focused on disproportionality analysis, but the empirical support for its value is based on isolated examples. Additionally, too little attention has been given to the potential value of the detailed content of ICSRs for improved adverse drug interaction surveillance. Objective: The aim of the study was to identify reporting patterns indicative of suspected adverse drug interactions before the drug interactions are generally established. Methods: A reference set of known adverse drug interactions and drug pairs not known to interact was constructed from information added to Stockley's Drug Interactions Alerts between the first quarter of 2007 and the third quarter of 2009. The reference set was used to systematically study differences in reporting patterns between adverse drug interactions before they are generally established and adverse drug reactions (ADRs) to drug pairs that are not known to interact, in the WHO Global ICSR Database, VigiBase. The scope of the study included pharmacological properties such as common cytochrome P450 metabolism, explicit suspicions of drug interactions as noted by the reporter, clinical details such as dose and treatment overlap, and the lower limit of the 95% credibility interval of a three-way measure of disproportionality, Omega(025) (Ω(025)), based on the total number of reports on two drugs and one ADR together. Analyses were carried out including and excluding concomitant medicines. Results: Five reporting patterns were highlighted as particularly strong indicators of adverse drug interactions before they are known: suspicion of interactions as noted by the reporter in a case narrative, the assignment of the two drugs as interacting or through an ADR term; co-reporting of effect increased with the drug pair; and, finally, an excess total number of reports on the ADR together with the two drugs, as measured by Ω(025). Overall, the inclusion of concomitant medicines led to a larger number of true adverse drug interactions being highlighted, but at a substantial decrease in the strength of most indicators. Notably, the inclusion of concomitant medicines completely eliminated the value of Ω(025) as an indicator of adverse drug interactions, in this systematic evaluation. Conclusions: Reported suspicion of interactions as noted by the reporter in a case narrative, the assignment of the two drugs as interacting or through an ADR term; co-reporting of effect increased with the drug pair and by the Ω(025) each provide unique information to highlight adverse drug interactions before they become known in the literature. To our knowledge, this is the first systematic analysis demonstrating the value of disproportionality analysis for adverse drug interactions using a comprehensive reference set, and the first study to consider a broader basis including clinical information for systematic drug interaction surveillance.

  • 36. Strandell, Johanna
    et al.
    Caster, Ola
    Stockholm University, Faculty of Social Sciences, Department of Computer and Systems Sciences. Uppsala Monitoring Centre, Sweden.
    Bate, Andrew
    Norén, Niklas
    Stockholm University, Faculty of Science, Department of Mathematics. Uppsala Monitoring Centre, Sweden.
    Edwards, I. Ralph
    Reporting Patterns Indicative of Adverse Drug Interactions: A Systematic Evaluation in VigiBase2011In: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 34, no 3, p. 253-266Article in journal (Refereed)
    Abstract [en]

    Background: Adverse drug interaction surveillance in collections of Individual Case Safety Reports (ICSRs) remains underdeveloped. Most efforts to date have focused on disproportionality analysis, but the empirical support for its value is based on isolated examples. Additionally, too little attention has been given to the potential value of the detailed content of ICSRs for improved adverse drug interaction surveillance.

    Objective: The aim of the study was to identify reporting patterns indicative of suspected adverse drug interactions before the drug interactions are generally established.

    Methods: A reference set of known adverse drug interactions and drug pairs not known to interact was constructed from information added to Stockley's Drug Interactions Alerts between the first quarter of 2007 and the third quarter of 2009. The reference set was used to systematically study differences in reporting patterns between adverse drug interactions before they are generally established and adverse drug reactions (ADRs) to drug pairs that are not known to interact, in the WHO Global ICSR Database, VigiBase. The scope of the study included pharmacological properties such as common cytochrome P450 metabolism, explicit suspicions of drug interactions as noted by the reporter, clinical details such as dose and treatment overlap, and the lower limit of the 95% credibility interval of a three-way measure of disproportionality, Omega025025), based on the total number of reports on two drugs and one ADR together. Analyses were carried out including and excluding concomitant medicines.

    Results: Five reporting patterns were highlighted as particularly strong indicators of adverse drug interactions before they are known: suspicion of interactions as noted by the reporter in a case narrative, the assignment of the two drugs as interacting or through an ADR term; co-reporting of effect increased with the drug pair; and, finally, an excess total number of reports on the ADR together with the two drugs, as measured by Ω025. Overall, the inclusion of concomitant medicines led to a larger number of true adverse drug interactions being highlighted, but at a substantial decrease in the strength of most indicators. Notably, the inclusion of concomitant medicines completely eliminated the value of Ω025 as an indicator of adverse drug interactions, in this systematic evaluation.

    Conclusions: Reported suspicion of interactions as noted by the reporter in a case narrative, the assignment of the two drugs as interacting or through an ADR term; co-reporting of effect increased with the drug pair and by the Ω025 each provide unique information to highlight adverse drug interactions before they become known in the literature. To our knowledge, this is the first systematic analysis demonstrating the value of disproportionality analysis for adverse drug interactions using a comprehensive reference set, and the first study to consider a broader basis including clinical information for systematic drug interaction surveillance.

  • 37. Strandell, Johanna
    et al.
    Caster, Ola
    Stockholm University, Faculty of Social Sciences, Department of Computer and Systems Sciences. Uppsala Monitoring Centre, Sweden.
    Hopstadius, Johan
    Edwards, I. Ralph
    Noren, G. Niklas
    Stockholm University, Faculty of Science, Department of Mathematics. Uppsala Monitoring Centre, Sweden.
    The Development and Evaluation of Triage Algorithms for Early Discovery of Adverse Drug Interactions2013In: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 36, no 5, p. 371-388Article in journal (Refereed)
    Abstract [en]

    Background Around 20 % of all adverse drug reactions (ADRs) are due to drug interactions. Some of these will only be detected in the postmarketing setting. Effective screening in large collections of individual case safety reports (ICSRs) requires automated triages to identify signals of adverse drug interactions. Research so far has focused on statistical measures, but clinical information and pharmacological characteristics are essential in the clinical assessment and may be of great value in first-pass filtering of potential adverse drug interaction signals. Objective The aim of this study was to develop triages for adverse drug interaction surveillance, and to evaluate these prospectively relative to clinical assessment. Methods A broad set of variables were considered for inclusion in the triages, including cytochrome P450 (CYP) activity, explicit suspicions of drug interactions as noted by the reporter, dose and treatment overlap, and a measure of interaction disproportionality. Their unique contributions in predicting signals of adverse drug interactions were determined through logistic regression. This was based on the reporting in the WHO global ICSR database, VigiBase (TM), for a set of known adverse drug interactions and corresponding negative controls. Three triages were developed, each producing an estimated probability that a given drug-drug-ADR triplet constitutes an adverse drug interaction signal. The triages were evaluated against two separate benchmarks derived from expert clinical assessment: adverse drug interactions known in the literature and prospective adverse drug interaction signals. For reference, the triages were compared with disproportionality analysis alone using the same benchmarks. Results The following were identified as valuable predictors of adverse drug interaction signals: plausible CYP metabolism; notes of suspected interaction by the reporter; and reports of unexpected therapeutic response, altered therapeutic effect with dose information and altered therapeutic effect when only two drugs had been used. The new triages identified reporting patterns corresponding to both prospective signals of adverse drug interactions and already established ones. They perform better than disproportionality analysis alone relative to both benchmarks. Conclusions A range of predictors for adverse drug interaction signals have been identified. They substantially improve signal detection capacity compared with disproportionality analysis alone. The value of incorporating clinical and pharmacological information in first-pass screening is clear.

  • 38.
    Strandell, Johanna
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. WHO Collaborating Centre Int Drug Monitoring, Sweden .
    Caster, Ola
    WHO Collaborating Centre Int Drug Monitoring, Sweden .
    Hopstadius, Johan
    WHO Collaborating Centre Int Drug Monitoring, Sweden .
    Edwards, Ralph I.
    WHO Collaborating Centre Int Drug Monitoring, Sweden .
    Noren, Niklas G.
    WHO Collaborating Centre Int Drug Monitoring, Sweden .
    The Development and Evaluation of Triage Algorithms for Early Discovery of Adverse Drug Interactions2013In: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 36, no 5, p. 371-388Article in journal (Refereed)
    Abstract [en]

    Background Around 20 % of all adverse drug reactions (ADRs) are due to drug interactions. Some of these will only be detected in the postmarketing setting. Effective screening in large collections of individual case safety reports (ICSRs) requires automated triages to identify signals of adverse drug interactions. Research so far has focused on statistical measures, but clinical information and pharmacological characteristics are essential in the clinical assessment and may be of great value in first-pass filtering of potential adverse drug interaction signals. less thanbrgreater than less thanbrgreater thanObjective The aim of this study was to develop triages for adverse drug interaction surveillance, and to evaluate these prospectively relative to clinical assessment. less thanbrgreater than less thanbrgreater thanMethods A broad set of variables were considered for inclusion in the triages, including cytochrome P450 (CYP) activity, explicit suspicions of drug interactions as noted by the reporter, dose and treatment overlap, and a measure of interaction disproportionality. Their unique contributions in predicting signals of adverse drug interactions were determined through logistic regression. This was based on the reporting in the WHO global ICSR database, VigiBase (TM), for a set of known adverse drug interactions and corresponding negative controls. Three triages were developed, each producing an estimated probability that a given drug-drug-ADR triplet constitutes an adverse drug interaction signal. The triages were evaluated against two separate benchmarks derived from expert clinical assessment: adverse drug interactions known in the literature and prospective adverse drug interaction signals. For reference, the triages were compared with disproportionality analysis alone using the same benchmarks. less thanbrgreater than less thanbrgreater thanResults The following were identified as valuable predictors of adverse drug interaction signals: plausible CYP metabolism; notes of suspected interaction by the reporter; and reports of unexpected therapeutic response, altered therapeutic effect with dose information and altered therapeutic effect when only two drugs had been used. The new triages identified reporting patterns corresponding to both prospective signals of adverse drug interactions and already established ones. They perform better than disproportionality analysis alone relative to both benchmarks. less thanbrgreater than less thanbrgreater thanConclusions A range of predictors for adverse drug interaction signals have been identified. They substantially improve signal detection capacity compared with disproportionality analysis alone. The value of incorporating clinical and pharmacological information in first-pass screening is clear.

  • 39.
    Strandell, Johanna
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Noren, Niklas G
    WHO Collaborating Centre Int Drug Monitoring, Sweden .
    Hägg, Staffan
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pharmacology.
    Key Elements in Adverse Drug Interaction Safety Signals An Assessment of Individual Case Safety Reports2013In: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 36, no 1, p. 63-70Article in journal (Refereed)
    Abstract [en]

    Background A large proportion of potential drug interactions are known from pre-authorization studies, but adverse drug reactions (ADRs) due to interactions (adverse drug interactions) are often first detected through astute observation in clinical practice. Individual case safety reports (ICSRs) are collected from broad patient populations and allow for the identification of groups of similar reports. Systematic screening for adverse drug interactions in ICSRs will require an understanding of which information on these reports can be suggestive of adverse drug interactions. less thanbrgreater than less thanbrgreater thanObjective The aim of the study was to identify what reported information may support the identification of drug interaction safety signals in collections of ICSRs. less thanbrgreater than less thanbrgreater thanMethods Three previously published safety signals of suspected adverse drug interactions were re-evaluated. To this end, 137 reports related to these signals were retrieved from the WHO Global ICSR Database, VigiBase (TM), and corresponding original reports were obtained from national pharmacovigilance centres. Criteria from an operational score for causality analysis of drug interactions of clinical cases, the Drug Interaction Probability Scale (DIPS), were applied to each of these reports with the aim of identifying what supportive information tends to be available in ICSRs. For three DIPS elements (plausible time course, resolution of the ADR after terminating the drug inducing the interaction without changes in affected drug therapy (positive dechallenge) and alternative causes of the reaction) we also compared the amount of information in VigiBase (TM) and in original reports, and in free text and structured data. less thanbrgreater than less thanbrgreater thanResults Commonly fulfilled DIPS elements on reports supporting an adverse drug interaction signal were plausible time course (50 reports; 36 %) and positive dechallenge (8 reports; 6 %). Alternative causes for the observed adverse reaction were observed in 72 (53 %) reports. We found limited differences between VigiBase (TM) and original reports for the structured data, although a substantial amount of additional information was available in free text in original reports. less thanbrgreater than less thanbrgreater thanConclusions Information on plausible time courses and resolution of the adverse reaction upon withdrawal of the drug suspected to have induced the interaction may be a useful element in identifying suspected adverse drug interactions from ICSRs. Of these, plausible time course is by far the most commonly reported element in the three signals studied here. Our analysis also demonstrated the importance of sharing and analysing information available in free text where relevant clinical details are often available, such as those mentioned above, along with severity and dosage changes.

  • 40. Sundström, Anders
    et al.
    Hallberg, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Data mining in pharmacovigilance detecting the unexpected: the role of index of suspicion of the reporter2009In: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 32, no 5, p. 419-427Article in journal (Refereed)
    Abstract [en]

    Background: One of the most important aims of pharmacovigilance is to detect signals of adverse drug reactions (ADRs) as early as possible. However, some ADRs are difficult to detect, one example being so called 'type C' reactions. These are effects that present as seemingly 'spontaneous' diseases occurring during treatment with a drug, such as the occurrence of a cardiovascular event while the patient is taking rofecoxib. As this type of ADR is often mistaken for a spontaneous disease, the causative agent may appear as an innocent bystander.

    Objective: The primary aim of this study was to investigate the possibility of using data mining approaches to detect signals of 'type C' reactions. We hypothesized that by including concomitant, and not only suspected medications in the calculations of disproportionality analyses, we would be able to identify such reactions.

    Study design: We used data from the Swedish Drug Information System, SWEDIS, which contains spontaneous reports submitted by Swedish physicians to the Swedish Medical Products Agency, and applied Bayesian confidence propagation neural network (BCPNN) methodology to calculate the information component (IC) value for drug-event combinations for drugs belonging to the Anatomic Therapeutic Chemical (ATC) classes cardiovascular system, musculoskeletal system and nervous system (number of reports = 51 270) where only the suspected drug was considered, and also where both concomitant and suspected drugs were considered. We then classified drug-event combinations that were signalled by a statistically significantly raised IC value as labelled or Unlabelled based on the approved summary of product characteristics (SPC) in Sweden as of November 2007, and further classified them as 'type C' reactions or not 'type C.

    Main outcome measure: The proportion of 'type C' reactions signalled when considering both concomitant and suspected drugs compared with suspected drugs only.

    Results: The proportion of labelled drug-event combinations when considering suspected drugs was 78.6%. Drug-event combinations classified as 'type C' reactions were more likely to be found when considering both concomitant and suspected drugs compared with suspected drugs only; 18/449 versus 0/248 when considering drug-event combinations that were signalled exclusively by one of the approaches. Such drug-event combinations included, for example, sudden death and celecoxib, myocardial infarction and diclofenac, suicide-related events and several antidepressants.

    Conclusion: Including both concomitant and suspected drugs in data mining practices may be a way of detecting 'type C' reactions earlier. This could constitute an advance in data mining for pharmacovigilance practices.

  • 41. Tregunno, Philip Michael
    et al.
    Fink, Dorthe Bech
    Fernandez-Fernandez, Cristina
    Lazaro-Bengoa, Edurne
    Norén, G. Niklas
    Stockholm University, Faculty of Science, Department of Mathematics.
    Performance of Probabilistic Method to Detect Duplicate Individual Case Safety Reports2014In: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 37, no 4, p. 249-258Article in journal (Refereed)
    Abstract [en]

    Individual case reports of suspected harm from medicines are fundamental for signal detection in postmarketing surveillance. Their effective analysis requires reliable data and one challenge is report duplication. These are multiple unlinked records describing the same suspected adverse drug reaction (ADR) in a particular patient. They distort statistical screening and can mislead clinical assessment. Many organisations rely on rule-based detection, but probabilistic record matching is an alternative. The aim of this study was to evaluate probabilistic record matching for duplicate detection, and to characterise the main sources of duplicate reports within each data set. vigiMatch (TM), a published probabilistic record matching algorithm, was applied to the WHO global individual case safety reports database, VigiBase(A (R)), for reports submitted between 2000 and 2010. Reported drugs, ADRs, patient age, sex, country of origin, and date of onset were considered in the matching. Suspected duplicates for the UK, Denmark, and Spain were reviewed and classified by the respective national centre. This included evaluation to determine whether confirmed duplicates had already been identified by in-house, rule-based screening. Furthermore, each confirmed duplicate was classified with respect to the likely source of duplication. For each country, the proportions of suspected duplicates classified as confirmed duplicates, likely duplicates, otherwise related, and unrelated were obtained. The proportions of confirmed or likely duplicates that were not previously known by the national organisation were determined, and variations in the rates of suspected duplicates across subsets of reports were characterised. Overall, 2.5 % of the reports with sufficient information to be evaluated by vigiMatch were classified as suspected duplicates. The rates for the three countries considered in this study were 1.4 % (UK), 1.0 % (Denmark), and 0.7 % (Spain). Higher rates of suspected duplicates were observed for literature reports (11 %) and reports with fatal outcome (5 %), whereas a lower rate was observed for reports from consumers and non-health professionals (0.5 %). The predictive value for confirmed or likely duplicates among reports flagged as suspected duplicates by vigiMatch ranged from 86 % for the UK, to 64 % for Denmark and 33 % for Spain. The proportions of confirmed duplicates that were previously unknown to national centres ranged from 89 % for Spain, to 60 % for the UK and 38 % for Denmark, despite in-house duplicate detection processes in routine use. The proportion of unrelated cases among suspected duplicates were below 10 % for each national centre in the study. Probabilistic record matching, as implemented in vigiMatch, achieved good predictive value for confirmed or likely duplicates in each data source. Most of the false positives corresponded to otherwise related reports; less than 10 % were altogether unrelated. A substantial proportion of the correctly identified duplicates had not previously been detected by national centre activity. On one hand, vigiMatch highlighted duplicates that had been missed by rule-based methods, and on the other hand its lower total number of suspected duplicates to review improved the accuracy of manual review.

  • 42.
    Watson, S.
    et al.
    Uppsala Monitoring Ctr, WHO Collaborating Ctr Int Drug Monitoring, Uppsala, Sweden..
    Star, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Caring Sciences. Uppsala Monitoring Ctr, WHO Collaborating Ctr Int Drug Monitoring, Uppsala, Sweden.
    Aoki, Y.
    Uppsala Monitoring Ctr, WHO Collaborating Ctr Int Drug Monitoring, Uppsala, Sweden..
    Caduff-Janosa, P.
    Uppsala Monitoring Ctr, WHO Collaborating Ctr Int Drug Monitoring, Uppsala, Sweden..
    Ladies' territory?: Patient Sex Distribution in a Global Database of Suspected Adverse Drug Reactions2017In: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 40, no 10, p. 973-973Article in journal (Other academic)
  • 43.
    Watson, Sarah
    et al.
    Uppsala Monitoring Ctr, Uppsala, Sweden..
    Chandler, Rebecca E.
    Uppsala Monitoring Ctr, Uppsala, Sweden..
    Taavola, Henric
    Uppsala Monitoring Ctr, Uppsala, Sweden..
    Harmark, Linda
    Netherlands Pharmacovigilance Ctr Lareb, Shertogenbosch, Netherlands..
    Grundmark, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Uppsala Monitoring Ctr, Uppsala, Sweden..
    Zekarias, Alem
    Uppsala Monitoring Ctr, Uppsala, Sweden..
    Star, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences. Uppsala Monitoring Ctr, Uppsala, Sweden..
    van Hunsel, Florence
    Netherlands Pharmacovigilance Ctr Lareb, Shertogenbosch, Netherlands..
    Safety Concerns Reported by Patients Identified in a Collaborative Signal Detection Workshop using VigiBase: Results and Reflections from Lareb and Uppsala Monitoring Centre2018In: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 41, no 2, p. 203-212Article in journal (Refereed)
    Abstract [en]

    Introduction: Patient reporting in pharmacovigilance is important and contributes to signal detection. However, descriptions of methodologies for using patient reports in signal detection are scarce, and published experiences of how patient reports are used in pharmacovigilance are limited to a few individual countries.

    Objective: Our objective was to explore the contribution of patient reports to global signal detection in VigiBase. Methods Data were retrieved from VigiBase in September 2016. Drug-event-combination series were restricted to those with[50% patient reports, defined as reporter type "Consumer/non-health professional'' per E2B reporting standard. vigiRank was applied to patient reports to prioritize combinations for assessment. Product information for healthcare professionals (HCPs) as well as patient information leaflets (PILs) were used as reference for information on adverse drug reactions (ADRs). Staff from the Uppsala Monitoring Centre and the Netherlands Pharmacovigilance Centre Lareb categorized the combinations. Potential signals proceeded to a more in-depth clinical review to determine whether the safety concern should be communicated as a "signal.''

    Results: Of the 212 combinations assessed, 20 (9%) resulted in eight signals communicated within the World Health Organization (WHO) programme for international drug monitoring. Review of PILs revealed insufficient ADR descriptions for patients and examples of poor consistency with product information for HCPs. Patient narratives provided details regarding the experience and impact of ADRs and evidence that patients make causality and personal risk assessments.

    Conclusions: Safety concerns described in patient reports can be identified in a global database including previously unknown ADRs as well as new aspects of known ADRs. Patient reports provide unique information valuable in signal assessment and should be included in signal detection. Novel approaches to highlighting patient reports in statistical signal detection can further improve the contribution of patient reports to pharmacovigilance.

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