Uppsala Monitoring Centre

Abstract IntroductionPharmacovigilance is vital for detecting Adverse Drug Reactions (ADRs), with Individual Case Safety Reports (ICSRs) serving as the primary source, despite growing interest in other data sources like electronic health records and social media. However, ICSR reporting rates remain low in low- and middle-income countries due to weak pharmacovigilance systems. Furthermore, the impact of socioeconomic factors such as health, education, and income on reporting rates has not been studied on a global scale previously.AimsTo compare global ICSR reporting patterns and quantify potential differences in their characteristics across pre-defined socioeconomic strata.MethodsIn this observational descriptive quantitative study, numbers of ICSRs will be obtained from VigiBase for members of the World Health Organization Programme for International Drug Monitoring, from 01/01/2010 to 31/12/2022. Yearly total population data and Inequality-adjusted Human Development Index (IHDI) values will be obtained from the United Nations Development Programme (UNDP) for all countries, for the same interval. Yearly ICSR reporting rates for each country will be calculated by dividing the total ICSRs submitted to VigiBase each year, and median reporting rates computed across the study period. Similarly, the median IHDI and its dimensional indices (Health, Education, and Income) will be calculated for each country. Countries will be categorized into four human development groups based on the UNDP classification: low, medium, high, and very high. To assess the relationship between IHDI (and its dimensions) and reporting rates, a linear regression model will be applied, with adjustments made as needed based on the data characteristics. VigiPoint will also be used to compare the relative frequency of covariates between reports of low, medium, and high IHDI, against those submitted to VigiBase by very high IHDI countries. VigiPoint identifies key features for review using shrunk log odds ratios, highlighting the overrepresented characteristics of ICSRs. We will present descriptive and statistical analyses in tables and scatter plots will be used to examine the relationship between ICSR reporting rates and IHDI (and its dimensions), using the calculated median values for IHDI (and its dimensions). Trendlines will highlight temporal changes in population, IHDI, and dimensional indices.DiscussionThe findings will offer insights into how socioeconomic factors affect reporting practices and may guide targeted interventions to enhance global drug safety monitoring.

Background and ObjectivesReports of suspected adverse drug reactions are of a great importance for the safety monitoring of new vaccines to identify potential safety risks promptly and to ensure necessary measures for risk mitigation. We reviewed the reports of fatal adverse drug reactions after coronavirus disease 2019 (COVID-19) vaccination with Comirnaty®, Spikevax®, and Vaxzevria® during the national vaccination campaign in Sweden.MethodsSwedish reports of suspected adverse drug reactions with fatal outcomes after COVID-19 vaccines were retrieved from the EudraVigilance database. Vaccination data were obtained from the National vaccination register. Reporting rates were calculated by dividing the number of adverse drug reaction reports with fatal outcomes by the number of people exposed to at least one dose of the COVID-19 vaccines or by the number of vaccine doses given. A causality assessment of adverse drug reaction reports was performed by clinically qualified reviewers.ResultsMore than 26 million doses of COVID-19 vaccines were administered and 456 reports of suspected adverse drug reactions with fatal outcomes were reported during 27 December, 2020–31 May, 2023. The reporting rate was 5.7 fatal outcomes per 100,000 persons vaccinated with at least one dose of any COVID-19 vaccine or 1.7 per 100,000 vaccine doses given. Most of the fatalities were related to patients’ pre-existing conditions, predominantly among people aged 70 years or older. Only ten of the reported fatalities (0.1 per 100,000 persons vaccinated) were assessed as consistent with a causal association to COVID-19 vaccination.ConclusionsAdverse drug reactions with fatal outcomes after COVID-19 vaccines in Sweden were very rare. No new safety concerns were observed in this study.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40261-025-01466-3.

Individual case reports are the main asset in pharmacovigilance signal management. Signal validation is the first stage after signal detection and aims to determine if there is sufficient evidence to justify further assessment. Throughout signal management, a prioritization of signals is continually made. Routinely collected health data can provide relevant contextual information but are primarily used at a later stage in pharmacoepidemiological studies to assess communicated signals. The aim of this study was to examine the feasibility and utility of analysing routine health data from a multinational distributed network to support signal validation and prioritization and to reflect on key user requirements for these analyses to become an integral part of this process. Statistical signal detection was performed in VigiBase, the WHO global database of individual case safety reports, targeting generic manufacturer drugs and 16 prespecified adverse events. During a 5-day study-a-thon, signal validation and prioritization were performed using information from VigiBase, regulatory documents and the scientific literature alongside descriptive analyses of routine health data from 10 partners of the European Health Data and Evidence Network (EHDEN). Databases included in the study were from the UK, Spain, Norway, the Netherlands and Serbia, capturing records from primary care and/or hospitals. Ninety-five statistical signals were subjected to signal validation, of which eight were considered for descriptive analyses in the routine health data. Design, execution and interpretation of results from these analyses took up to a few hours for each signal (of which 15-60 minutes were for execution) and informed decisions for five out of eight signals. The impact of insights from the routine health data varied and included possible alternative explanations, potential public health and clinical impact and feasibility of follow-up pharmacoepidemiological studies. Three signals were selected for signal assessment, two of these decisions were supported by insights from the routine healthdata. Standardization of analytical code, availability of adverse event phenotypes including bridges between different source vocabularies, and governance around the access and use of routine health data were identified as important aspects for future development. Analyses of routine health data from a distributed network to support signal validation and prioritization are feasible in the given time limits and can inform decision making. The cost-benefit of integrating these analyses at this stage of signal management requires further research.

BackgroundStillbirth has been associated with low plasma vitamin D. Both Sweden and Finland have a high proportion of low plasma vitamin D levels (< 50 nmol/L). We aimed to assess the odds of stillbirth in relation to changes in national vitamin D fortification.MethodsWe surveyed all pregnancies in Finland between 1994 and 2021 (n = 1,569,739) and Sweden (n = 2,800,730) with live or stillbirth registered in the Medical Birth Registries. The mean incidences before and after changes in the vitamin D food fortification programs in Finland (2003 and 2009) and Sweden (2018) were compared with cross-tabulation with 95% confidence intervals (CI).ResultsIn Finland, the stillbirth rate declined from ~ 4.1/1000 prior to 2003, to 3.4/1000 between 2004 and 2009 (odds ratio [OR] 0.87, 95% CI 0.81–0.93), and to 2.8/1000 after 2010 (OR 0.84, 95% CI 0.78–0.91). In Sweden, the stillbirth rate decreased from 3.9/1000 between 2008 and 2017 to 3.2/1000 after 2018 (OR 0.83, 95% CI 0.78–0.89). When the level of the dose-dependent difference in Finland in a large sample with correct temporal associations decreased, it remained steady in Sweden, and vice versa, indicating that the effect may be due to vitamin D. These are observational findings that may not be causal.ConclusionEach increment of vitamin D fortification was associated with a 15% drop in stillbirths on a national level. If true, and if fortification reaches the entire population, it may represent a milestone in preventing stillbirths and reducing health inequalities.

IntroductionGenetic variations of enzymes that affect the pharmacokinetics and hence effects of medications differ between ethnicities, resulting in variation in the risk of adverse drug reactions (ADR) between different populations. Previous work has demonstrated that risk-group considerations can be incorporated into approaches of statistical signal detection. It is unknown whether databases of individual case safety reports (ICSRs) are sensitive to pharmacogenomic differences between populations.ObjectiveThe aim of this study was to explore the sensitivity of a global database of ICSRs to known pharmacogenomic risk variants common in Japan.MethodsThe data source was VigiBase, the global database of ICSRs, including all reports entered in the version frozen on 5 January 2020. Subgroup disproportionality analysis was used to compare ICSRs of two subgroups, Japan and rest of world (RoW). Reports for UGT1A1-metabolized irinotecan and the CYP2C19-metabolized drugs voriconazole, escitalopram and clopidogrel were selected for comparison between the subgroups based upon known genetic polymorphisms with high prevalence in Japan. Contrast between the subgroups was quantified by IC delta ({mathrm{IC}}_{Delta }), a robust shrinkage observed-to-expected (OE) ratio on a log scale. Harmonic mean p values (HMP) were calculated for each drug to evaluate whether a list of pre-specified ADRs were collectively significantly over- (or under-)reported as hypothesized. Daily drug dosages were calculated for ICSRs with sufficient information, and dose distributions were compared between Japan and RoW and related to differences in regionally approved doses.ResultsThe predictions of over-reporting patterns for specific ADRs were observed and confirmed in bootstrap HMP analyses (p = 0.004 for irinotecan and p < 0.001 for each of voriconazole, escitalopram and clopidogrel) and compared with similar drugs with different metabolic pathways. The impact of proactive regulatory action, such as recommended dosing and therapeutic drug monitoring (TDM), was also observable within the global database. For irinotecan and escitalopram, there was evidence of use of lower dosages as recommended in the Japanese labels; for voriconazole, there was evidence of use of TDM with an over-reporting of terms related to drug level measurements and an under-reporting of liver toxicity.ConclusionsPharmaco-ethnic vulnerabilities caused by pharmacogenomic differences between populations may contribute to differences in ADR reporting between countries in a global database of ICSRs. Regional analyses within a global database can inform on the effectiveness of local risk minimization measures and should be leveraged to catalyse the conversion of real-world usage into safer use of drugs in ethnically tailored ways.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40264-021-01063-1.

Angioedema in the mouth or upper airways is a feared adverse reaction to angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) treatment, which is used for hypertension, heart failure and diabetes complications. This candidate gene and genome-wide association study aimed to identify genetic variants predisposing to angioedema induced by these drugs. The discovery cohort consisted of 173 cases and 4890 controls recruited in Sweden. In the candidate gene analysis, ETV6, BDKRB2, MME, and PRKCQ were nominally associated with angioedema (p < 0.05), but did not pass Bonferroni correction for multiple testing (p < 2.89 × 10−5). In the genome-wide analysis, intronic variants in the calcium-activated potassium channel subunit alpha-1 (KCNMA1) gene on chromosome 10 were significantly associated with angioedema (p < 5 × 10−8). Whilst the top KCNMA1 hit was not significant in the replication cohort (413 cases and 599 ACEi-exposed controls from the US and Northern Europe), a meta-analysis of the replication and discovery cohorts (in total 586 cases and 1944 ACEi-exposed controls) revealed that each variant allele increased the odds of experiencing angioedema 1.62 times (95% confidence interval 1.05–2.50, p = 0.030). Associated KCNMA1 variants are not known to be functional, but are in linkage disequilibrium with variants in transcription factor binding sites active in relevant tissues. In summary, our data suggest that common variation in KCNMA1 is associated with risk of angioedema induced by ACEi or ARB treatment. Future whole exome or genome sequencing studies will show whether rare variants in KCNMA1 or other genes contribute to the risk of ACEi- and ARB-induced angioedema.

IntroductionUncovering safety signals through the collection and assessment of individual case reports remains a core pharmacovigilance activity. Despite the widespread use of disproportionality analysis in signal detection, recommendations are lacking on the minimum size of databases or subsets of databases required to yield robust results.ObjectiveThis study aims to investigate the relationship between database size and robustness of disproportionality analysis, with regards to limiting spurious associations.MethodsThree types of subsets were created from the global database VigiBase: random subsets (500 replicates each of 11 fixed subset sizes between 250 and 100,000 reports), country-specific subsets (all 131 countries available in the original VigiBase extract) and subsets based on the Anatomical Therapeutic Chemical classification. For each subset, a spuriousness rate was computed as the ratio between the number of drug–event combinations highlighted by disproportionality analysis in a permuted version of the subset and the corresponding number in the original subset. In the permuted data, all true reporting associations between drugs and adverse events were broken. Subsets with fewer than five original associations were excluded. Additionally, the set of disproportionately over-reported drug–event combinations in three specific countries at three different time points were clinically assessed for labelledness. These time points corresponded to database sizes of less than 10,000, 5000 and 1000 reports, respectively. All disproportionality analysis was based on the Information Component (IC), implemented as IC025 > 0.ResultsSpuriousness rates were below 0.15 for all 110 included countries regardless of subset size, with only seven countries (6%) exceeding the empirical threshold of 0.10 observed for large subsets. All 21 excluded countries had < 500 reports. For random subsets containing 3000–5000 or more reports, the higher end of observed spuriousness rates was close to 0.10. In the clinical assessment, the proportion of labelled or otherwise known drug–event combinations was very high (87–100%) across all countries and time points studied.ConclusionsTo mitigate the risk of highlighting spurious associations with disproportionality analysis, a minimum size of 500 reports is recommended for national databases. For databases or subsets that are not country-specific, our recommendation is 5000 reports. This study does not consider sensitivity, which is expected to be poor in smaller databases.

Pharmacovigilance is defined by the World Health Organization as the science and practice related to the detection, assessment, understanding and prevention of adverse drug reactions (ADRs). In a well-functioning pharmacovigilance system, information on possible ADRs is collected from patients, health professionals and marketing authorisation holders. Of all data sources for drug safety monitoring, spontaneous reporting systems provide the highest volume of information at the lowest maintenance cost and have proven their value in the early detection of product-related safety issues. At the beginning of 2018, the Brazilian Health Regulatory Agency (Agência Nacional de Vigilância Sanitária—Anvisa) decided to replace the national electronic reporting system in Brazil (Notivisa) with the system provided by Uppsala Monitoring Centre (VigiFlow) for ADR reporting. This paper describes that process and reports on the progress made by Anvisa in terms of making Brazil compliant with international pharmacovigilance standards as well as significantly increasing the number of individual case safety reports collected.

Abstract In this chapter, Ivor Ralph Edwards shares his reflections based on more than 20 years of international experience, both in clinical practice and in drug safety monitoring. Crucial for Edward’s work is the dispositionalist view that outlier cases and deviations from the norm have a great potential in advancing causal understanding, as discussed in the first part of this book. Through a number of examples drawn from his professional experience, Edwards here provides some advice on how the dispositionalist approach presented in Part I of this book can improve clinicians’ daily practice and can assist the process of differential diagnosis. Despite the time and other constraints placed upon practicing clinicians today, the urgency of taking causal complexity properly into account demands that a more personal and contextual approach be taken. This chapter highlights the urgency of the call for a new framework for medical practice, one that fully acknowledges patient narratives as evidential and emphasises the importance of understanding rare symptoms and responses as being nonetheless part of a larger pattern of dispositions and manifestations.