Drug Safety Research Unit

PurposeApplying standardized Brighton Collaboration (BC) case definitions retrospectively to heterogeneous real-world data (RWD) is challenging due to inconsistent clinical detail and data structures across settings. To address this, the Vaccine Monitoring Collaboration for Europe (VAC4EU) developed a structured validation pipeline that operationalizes BC case definitions for vaccine safety outcomes in RWD in a harmonized, scalable, and reusable manner.MethodsVAC4EU developed a systematic, stepwise approach to validate vaccine safety outcomes. BC case definitions were utilized when available, adapted for RWD as needed, and newly developed for outcomes without an existing BC definition. The approach involves: 1) Critical review and adaptation of BC definition by clinical and RWD experts; 2) Creation of dummy cases based on published reports; 3) Creation of REDCap electronic data collection forms (eDCF) incorporating decision logic to assigned levels of certainty (LOC); 4) Iterative testing of decision logic; and 5) comprehensive training of abstractors with real-time feedback. A dedicated task force assigned reference LOCs for dummy cases. Inter-rater reliability was measured using Fleiss’ kappa (κ) by comparing abstractor LOCs to the reference standard.ResultsThe pipeline was applied to 16 COVID-19 vaccine safety outcomes, of which 13 had existing BC definition. In total, 78 dummy case descriptions were developed across the outcomes for training of abstractors, and 15 REDCap eDCFs were created. Myocarditis and pericarditis shared an eDCF. Across 33 abstractors, 747 dummy case abstractions were completed. Agreement analysis showed 93 discrepancies (12.4%) and moderate overall concordance (κ = 0.55, across all outcomes), with the lowest for thrombosis with thrombocytopenia syndrome (κ = –0.05).ConclusionThe VAC4EU validation pipeline provides a standardized framework for training and validating vaccine safety outcome in RWD. By adapting BC case definitions and dedicated training of abstractors, we will reduce variability in outcome validation in post-authorization safety studies.

A focus group organised by the Drug Safety Research Unit (DSRU) International Working Group (IWG) on New Developments in Pharmacovigilance discussed current challenges and opportunities in pharmacovigilance (PV), emphasising the need for a multimodal approach in data analysis and accessibility of diverse data sources for drug safety surveillance. Nine participants, selected purposefully for their multisectoral expertise in PV, discussed the value of various data types, including data from clinical trials and real-world data (RWD), each offering distinct strengths and limitations. Key challenges identified included data standardisation, quality variability, technological barriers and ethical concerns, particularly with data derived from social media. Emerging tools such as knowledge graphs were highlighted for their potential to enhance data integration and signal detection, however further research is required. The group also addressed disparities in data access, with particular attention to regulatory restrictions, limited infrastructure in low-resource settings and restricted access to industry-held data. Proposed solutions included fostering greater data transparency, establishing secure data-sharing platforms and forming collaborative consortia to facilitate responsible and ethical data use. Overall, the discussion underscored the need for improved integration, access and methodological rigour to strengthen PV practices and enhance global drug safety monitoring.

Abstract Despite decades of progress in reducing workplace non-fatal injuries, the global rate of fatalities has stubbornly plateaued across most nations and industries. While total recordable injury rates (TRIR) have steadily declined, SIFs have proven resistant to traditional safety strategies. This paradox highlights a critical gap: organisations are often measuring what is easy, not what truly matters. The need to address exposure - not just outcomes - is more urgent than ever. This paper explores how Behaviour-Based Safety (BBS), when strategically evolved, can become a key mechanism for SIF prevention. Drawing on over 30 years of DEKRA's global leadership in BBS, particularly the Behavioral Accident Prevention Process® (BAPP®), we examine how targeted observation, structured feedback, and critical behaviour focus can directly impact SIF exposure. Backed by cutting-edge research from the University of Cambridge's Judge Business School, BAPP® has demonstrated significant, sustained reductions in injury frequency - 25% in year one, 35% in year two, and 45% in year three - when properly implemented and aligned with cultural change strategies.

In this study, for analysis of primary aliphatic amines present in skin moisturizer samples, a dispersive micro solid phase extraction method using a mercaptoacetic acid-modified magnetic adsorbent (MAA@Fe3O4) was developed to eliminate matrix effects (while not adsorbing the studied analytes). This approach was combined with vortex-assisted liquid-liquid microextraction for the simultaneous derivatization and extraction of primary aliphatic amines present in these samples. To confirm the successful synthesis of the adsorbent, various characterization techniques were employed, including X-ray diffraction, Brunauer-Emmett-Teller surface area analysis, scanning electron microscopy, Fourier transform infrared spectrometry, energy-dispersive X-ray, thermogravimetric analysis, and vibrating sample magnetometry. ComplexGAPI software and analytical eco-scale index were employed to evaluate the greenness of the method. All key parameters affecting matrix cleanup, derivatization, and extraction were optimized. A gas chromatograph equipped with a flame ionization detector was used for the identification and quantification of the amine derivatives. The method demonstrated high unadsorbed percentage of the analytes (92–97%), significant enrichment factors (420–525), wide linear ranges (1.6–10,000 µg L− 1), excellent precision (1.4–2.7%), and low limits of detection (0.5–0.82 µg L− 1). This approach offered several advantages, including eco-friendliness, short extraction time, high matrix removal efficiency, simplicity, excellent precision, no need for specialized equipment, and adsorbent reusability for up to five cycles. The method also proved highly effective in the simultaneous extraction and derivatization of amines, further highlighting its potential for analytical applications.

Background: Conventional vaccines rarely cause severe allergic reactions. However, the rapid development and approval of COVID-19 vaccines left limited initial data on their adverse reactions, particularly in individuals with a history of allergy. The aim of this study was to assess and compare the safety profile of different doses and brands of COVID-19 vaccines in subjects with a history of allergy vs. those without a history of allergy. Methods: From February 2021 to February 2023, a web-based prospective study gathered vaccinee-reported outcomes using electronic questionnaires across eleven European countries. Baseline and up to six follow-up questionnaires captured data on vaccinee demographics, as well as both solicited and unsolicited adverse reactions. Results: Overall, 3476 vaccinees with a history of allergy were matched with 13,872 vaccinees from the general population at the first vaccination cycle and were included in the analysis. A total of 825 vaccinees with a history of allergy who had received a booster dose, matched to 3297 vaccinees from the general population, were included in the analysis. Higher rates of ADRs occurred after the first vaccination cycle compared to after the booster dose (64–91% vs. 56–79%). However, most reported ADRs were solicited and not serious, and no case of anaphylaxis was reported. Women and vaccinees with a history of allergy reported ADRs more frequently than men and the matched controls, respectively. Compared to other COVID-19 vaccines, a higher proportion of vaccinees experiencing at least one ADR following their first vaccination cycle was observed with Comirnaty and Vaxzevria. Statistically significant differences were observed among the study cohorts for median TTO after the second dose, and for median TTR following the first vaccination cycle and booster dose (p < 0.001). Conclusions: Typically, any drug or vaccine use carries a risk of severe allergic reactions, yet the benefits of vaccination generally outweigh these potential risks, as shown with the COVID-19 vaccines.

In all pivotal trials of COVID-19 vaccines, the history of previous SARS-CoV-2 infection was mentioned as one of the main exclusion criteria. In the absence of clinical trials, observational studies are the primary source for evidence generation. This study aims to describe the patient-reported adverse drug reactions (ADRs) following the first COVID-19 vaccination cycle, as well as the administration of booster doses of different vaccine brands, in people with prior SARS-CoV-2 infection, as compared to prior infection-free matched cohorts of vaccinees. A web-based prospective study was conducted collecting vaccinee-reported outcomes through electronic questionnaires from eleven European countries in the period February 2021-February 2023. A baseline questionnaire and up to six follow-up questionnaires collected data on the vaccinee's characteristics, as well as solicited and unsolicited adverse reactions. Overall, 3886 and 902 vaccinees with prior SARS-CoV-2 infection and having received the first dose or a booster dose, respectively, were included in the analysis. After the first dose or booster dose, vaccinees with prior SARS-CoV-2 infection reported at least one ADR at a higher frequency than those matched without prior infection (3470 [89.6%] vs. 2916 [75.3%], and 614 [68.2%] vs. 546 [60.6%], respectively). On the contrary side, after the second dose, vaccinees with a history of SARS-CoV-2 infection reported at least one ADR at a lower frequency, compared to matched controls (1443 [85.0%] vs. 1543 [90.9%]). The median time to onset and the median time to recovery were similar across all doses and cohorts. The frequency of adverse reactions was higher in individuals with prior SARS-CoV-2 infection who received Vaxzevria as the first dose and Spikevax as the second and booster doses. The frequency of serious ADRs was low for all doses and cohorts. Data from this large-scale prospective study of COVID-19 vaccinees could be used to inform people as to the likelihood of adverse effects based on their history of SARS-CoV-2 infection, age, sex, and the type of vaccine administered. In line with pivotal trials, the safety profile of COVID-19 vaccines was also confirmed in people with prior SARS-CoV-2 infection.

BackgroundThe safety profile of COVID-19 vaccines in immunocompromised patients has not been comprehensively evaluated.AimTo measure the frequency of patient-reported adverse drug reactions (ADRs) related to the first/second/booster dose of COVID-19 vaccine in immunocompromised subject versus matched cohort. As a secondary objective, the time course, evaluated as time to onset (TTO) and time to recovery (TTR), of COVID-19 vaccine-related ADRs was explored.MethodsA prospective cohort study, based on electronic questionnaires filled by vaccinees from 11 European countries in the period February 2021 to February 2023 was conducted. All immunocompromised vaccinees who provided informed consent and registered to the project’s web-app within 48 h after first/booster vaccine dose administration of any EMA-authorised COVID-19 vaccine were recruited. Participants filled baseline and up to six follow-up questionnaires (FU-Qs) over 6 months from vaccination, collecting information on suspected COVID-19 vaccine-related ADRs. As a control group, non-immunocompromised vaccinees from the same source population were 1:4 matched by sex, age, vaccine dose, and brand. A descriptive analysis of demographic/clinical characteristics of vaccinees was conducted. Heatmaps of the frequency of solicited ADRs, stratified by gender and vaccine brand, were generated. Median TTO/TTR of reported ADRs were visualised using violin/box-plots.ResultsA total of 773 immunocompromised vaccines were included in the analyses. Most participants were females (F/M ratio: 2.1 and 1.6) with a median age of 56 (43–74) and 51 (41–60) years, at the first vaccination cycle and booster dose, respectively. Injection-site pain and fatigue were the most frequently reported ADRs in immunocompromised vaccinees with higher frequency than matched control, especially after the first dose (41.2% vs 37.8% and 38.2% vs 32.9%, respectively). For both cohorts, all solicited ADRs were more frequently reported in females than males, and in those who had received a first dose of the Vaxzevria vaccine. Dizziness was the most frequently reported unsolicited ADR after the first dose in both groups (immunocompromised subjects: 2.5% and matched controls: 2.1%). At the booster dose, lymphadenopathy (3.9%) and lymphadenitis (1.8%) were the most reported unsolicited ADRs for immunocompromised subjects and matched controls, respectively. A very low number of subjects reported adverse event of special interest (AESI) (2 immunocompromised, 3 matched controls) and serious ADRs (5 immunocompromised, 5 matched controls). A statistically significant difference among study cohorts was observed for median TTO after the booster dose, and for median TTR after the first vaccination cycle and booster dose (p < 0.001).ConclusionThe overall safety profile of COVID-19 vaccines in immunocompromised people was favourable, with minor differences as compared to non-immunocompromised vaccinees. Participants mostly experienced mild ADRs, mainly reported after the first dose of Vaxzevria and Jcovden vaccines. Serious ADRs and AESI were rare.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40264-024-01449-x.

Abstract ImportanceThe overall effects of vaccination on the risk of cardiac, and venous and arterial thromboembolic complications following COVID-19 remain unclear.ObjectiveWe studied the association between COVID-19 vaccination and the risk of acute and subacute COVID-19 cardiac and thromboembolic complications.DesignMultinational staggered cohort study, based on national vaccination campaign rollouts.SettingNetwork study using electronic health records from primary care records from the UK, primary care data linked to hospital data from Spain, and national insurance claims from Estonia.ParticipantsAll adults with a prior medical history of ≥180 days, with no history of COVID-19 or previous COVID-19 vaccination at the beginning of vaccine rollout were eligible.ExposureVaccination status was used as a time-varying exposure. Vaccinated individuals were classified by vaccine brand according to the first dose received.Main OutcomesPost COVID-19 complications including myocarditis, pericarditis, arrhythmia, heart failure (HF), venous (VTE) and arterial thromboembolism (ATE) up to 1 year after SARS-CoV-2 infection.MeasuresPropensity Score overlap weighting and empirical calibration based on negative control outcomes were used to minimise bias due to observed and unobserved confounding, respectively. Fine-Gray models were fitted to estimate sub-distribution Hazard Ratios (sHR) for each outcome according to vaccination status. Random effect meta-analyses were conducted across staggered cohorts and databases.ResultsOverall, 10.17 million vaccinated and 10.39 million unvaccinated people were included. Vaccination was consistently associated with reduced risks of acute (30-day) and subacute post COVID-19 VTE and HF: e.g., meta-analytic sHR 0.34 (95%CI, 0.27-0.44) and 0.59 (0.50-0.70) respectively for 0-30 days, sHR 0.58 (0.48 - 0.69) and 0.71 (0.59 - 0.85) respectively for 90-180 days post COVID-19. Additionally, reduced risks of ATE, myocarditis/pericarditis and arrhythmia were seen, but mostly in the acute phase (0-30 days post COVID-19).ConclusionsCOVID-19 vaccination reduced the risk of post COVID-19 complications, including cardiac and thromboembolic outcomes. These effects were more pronounced for acute (1-month) post COVID-19 outcomes, consistent with known reductions in disease severity following breakthrough vs unvaccinated SARS-CoV-2 infection.RelevanceThese findings highlight the importance of COVID-19 vaccination to prevent cardiovascular outcomes after COVID-19, beyond respiratory disease.Key PointsQuestionWhat is the impact of COVID-19 vaccination to prevent cardiac complications and thromboembolic events following a SARS-CoV-2 infection?FindingsResults from this multinational cohort study showed that COVID-19 vaccination reduced risk for acute and subacute COVID-19 heart failure, as well as venous and arterial thromboembolic events following SARS-CoV-2 infection.MeaningThese findings highlight yet another benefit of vaccination against COVID-19, and support the recommendations for COVID-19 vaccination even in people at high cardiovascular risk.

BackgroundOvaleap® (follitropin alfa), a recombinant human follicle stimulating hormone, is a biosimilar medicinal product to Gonal-f® and is used for ovarian stimulation. The main objective of this study was to assess the safety and effectiveness of Ovaleap® compared to Gonal-f® in one treatment cycle in routine clinical practice.MethodsSafety of Ovaleap® Follitropin alfa in Infertile women undergoing superovulation for Assisted reproductive technologies (SOFIA) was a prospective cohort study conducted in six European countries. Eligible patients were infertile women undergoing superovulation for assisted reproductive technology, who were administered Ovaleap® or Gonal-f® for ovarian stimulation and were naïve to follicle stimulating hormone treatment. The recruitment ratio was 1:1. The primary endpoint was incidence proportion of ovarian hyperstimulation syndrome (OHSS) and the secondary endpoint was OHSS severity (Grades I, II, III). The effect of risk factors or potential confounders on the odds ratio for OHSS incidence as well as treatment effect on OHSS incidence was explored using univariate logistic regression. Pregnancy and live birth rates were also assessed.ResultsA total of 408 women who were administered Ovaleap® and 409 women who were administered Gonal-f® were eligible for analysis. The incidence proportion of OHSS was 5.1% (95% CI: 3.4, 7.7) in the Ovaleap® cohort and 3.2% (95% CI: 1.9, 5.4) in the Gonal-f® cohort. This difference in OHSS incidence proportion between the two cohorts was not statistically significant neither before (p = 0.159) nor after univariate adjustment for each potential confounder (p > 0.05). The incidence proportion of OHSS severity grades was similar in the two treatment groups (3.4% versus 2.0% for Grade I, 1.2% versus 1.0% for Grade II, and 0.5% versus 0.2% for Grade III, in the Ovaleap® and Gonal-f® cohorts, respectively), without a significant statistical difference (p = 0.865, for each grade). Among patients who had embryo transfer, clinical pregnancy rates were 33% and 31% and live birth rates were 27% and 26%, in the two cohorts, respectively.ConclusionsFindings from the SOFIA study indicate that the incidence proportions of OHSS and OHSS severity, as well as pregnancy and live birth rates, are similar between Ovaleap® and Gonal-f® treatments and corroborate the safety and effectiveness of Ovaleap® as a biosimilar to Gonal-f®.