Background: Although multiple post-licensure studies demonstrated that coronavirus disease-2019 (COVID-19) vaccines are safe for use during pregnancy, none of them have identified a signal of disproportionate reporting.
Aim: To assess the disproportionality in reported adverse events among pregnant persons receiving COVID-19 vaccination compared with influenza vaccines in spontaneous reporting databases.
Methods: Individual case safety reports (ICSRs) with COVID-19 vaccines (Pfizer, AstraZeneca, Moderna and Johnson & Johnson) and influenza vaccines were retrieved from spontaneous reporting databases in the Vaccine Adverse Event Report System (VAERS) and the EudraVigilance (EV) system between 1 December 2020 and 31 October 2023. Both datasets were combined through a common data model. Pregnancy-associated ICSRs were identified using adaptations to the European Medicines Agency (EMA) algorithm based on age groups and key medical conditions. We compared the disproportionate reporting of High-Level Terms (HLT) after COVID-19 vaccines of interest (e.g. mRNA vaccine) with another COVID-19 viral vector-based/protein subunit and influenza vaccines during pregnancy. The proportional reporting ratio (PRR) with 95% confidence intervals (CIs) was calculated using a combined dataset. PRR met the predefined criteria (PRR ≥ 2, lower 95% CI ≥ 2 and N ≥ 3), confirming a potential signal of disproportionate reporting (SDR).
Results: A total of 22,383 pregnancy-related ICSRs were included. Five associations met the PRR threshold: inborn errors of steroid synthesis 35.1 (95% CI 7.8-158.3); non-site-specific embolism and thrombosis 15.9 (95% CI 3.1-82.2); general signs and symptoms not elsewhere classified (NEC) 11.17 (95% CI 3.3-38.1); peripheral nervous system disorders congenital NEC 4.2 (95% CI 2.3-7.7); and vascular anomalies congenital NEC 3.7 (95% CI 2.4-5.6), all associated with viral vector-based/protein subunit.
Conclusions: Despite this analysis, several statistical disproportionalities were identified during pregnancy; the case-by-case analysis shows that embolism and thrombosis require prioritized investigation through proper causal inference studies.
Background and objective: Thrombotic thrombocytopenia syndrome (TTS) is a rare condition following vaccination with adenovirus-vectored coronavirus disease 2019 (COVID-19) vaccines. This retrospective analysis of England primary care data aimed to estimate TTS event rates before, during, and after the COVID-19 pandemic, and following AZD1222 (ChAdOx1-nCoV-19) vaccination.
Methods: Primary care data on TTS events were collected using the Oxford-Royal College of General Practitioners Research and Surveillance Centre sentinel network. TTS events were defined as thromboembolism with coincident (± 7 days) thrombocytopenia events using Systematized Nomenclature of Medicine clinical terms (the current Brighton Collaboration definition could not be used in the study as data related to specific parameters [e.g., D-dimer or PF4 antibodies] were not available in the primary care database). Multivariable logistic regression analyses were performed to assess the association between covariates and TTS.
Results: Incident TTS rates per 100,000 person-years were: 0.42 in a pre-COVID-19 cohort (1 January, 2011-31 December, 2019; 9,062,313 individuals); 0 in 39,448 individuals with confirmed COVID-19 (1 July-31 December, 2020); 0.48 and 0.47 during the pre-vaccination pandemic period spanning 1 January-14 August, 2020 (13,245,710 individuals) and 15 August-31 December, 2020 (13,347,462 individuals); 2.41 in an AZD1222-vaccinated cohort (5,544,761 individuals; 1 January, 2021-4 July, 2022). Multivariable logistic regression analysis of TTS events (- 7/+ 42 days event-window; pre-COVID-19 cohort) showed greater odds in older individuals and high-risk groups as defined by the Joint Committee on Vaccination and Immunization. Thrombotic thrombocytopenia syndrome was rare in all cohorts. Differential covariate distributions precluded comparisons of TTS rates across cohorts. Covariate distributions within thromboembolism and thrombocytopenia cases were comparable to those of TTS cases.
Conclusions: Our study, using a previous definition of TTS, reinforces the very rare nature of TTS before and during the pandemic, and before and after the introduction of the AZD1222 vaccine; it also confirms the established very low incident event rate in individuals vaccinated with AZD1222.
Introduction: The Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) receives duplicate reports of adverse events associated with drug and therapeutic biological products. Duplicate reports, defined as multiple reports of the same adverse event(s) related to the administration of the same marketed product(s) to the same individual patient at a particular point in time, may be received in FAERS for many reasons. The presence of duplicate reports can negatively impact public health surveillance efforts by impeding both safety signal identification and signal evaluation.
Objectives: To characterize the features and contributing factors associated with duplicate reports in FAERS.
Methods: We manually assessed a convenience sample of individual case safety reports (ICSRs) for duplication, resulting in two data sets: one consisting of non-duplicate reports and one with duplicate reports. We then compared key features of these two datasets, including both structured and unstructured data fields. Key comparison features included: report and reporter type, country of report origin, data source for report, and outcome. In addition, we evaluated information similarity of reports for seven data elements (e.g., age, sex, suspect products) within sets of duplicates using both structured and unstructured fields. We used pairwise sentence bidirectional encoder representations from transformers (SBERT) cosine similarity scores to examine free-text narrative similarity.
Results: Among the 2297 reports in the sample, 901 (39%) were classified as duplicates, consisting of 237 unique duplicate sets. Compared to non-duplicate reports, duplicates were more likely to be foreign reports (82% versus 37%), reported by healthcare professionals (89% versus 68%), mention other regulatory authority databases (42% versus 11%), describe published case reports (34% versus 11%), or have a serious outcome (97% versus 83%) (p < 0.0001). Within sets of duplicates (n = 237), coded information was frequently different, with only 16% (n = 39) having concordance of all 7 data elements. The narrative was highly similar among most sets of duplicates; we found that the median similarity score for the duplicate pairs was 0.87 compared to 0.48 for non-duplicate pairs.
Conclusions: We observed differences in the attributes of and potential contributors to duplicate reports in FAERS that may inform duplicate prevention, detection, and management strategies. However, further studies are needed to better understand the implications of these findings and how potential regulatory changes and technological advances can be leveraged to further address duplicate reporting in adverse event reporting systems.
Background: Exposure to anticholinergic drugs is associated with adverse outcomes, particularly among older adults. Limiting the anticholinergic burden (ACB) among older patients has been advocated for decades, but reliable population-level data on temporal trends are lacking. Here, we estimated the cumulative incidence and incidence rates (IRs) of a cumulative ACB score of three or more (cACB ≥ 3) among older adults in a community-dwelling population and described the changes in IR over the past 25 years.
Methods: Within the population-based Rotterdam Study, pharmacy dispensing records were obtained from 11,038 individuals aged 65+ years from 1996 to 2020. The cACB score was calculated with the Anticholinergic Cognitive Burden Scale and supplemented with drugs on the ACB scale by the Expertisecentre PHarmacotherapy in OldeR people (EPHOR). Age- and sex-specific IRs were calculated, and non-overlapping 5-year episodes were defined to determine time trends in IRs.
Results: The cumulative incidence of a cACB ≥ 3 was 25.3% between 1996 and 2020. Compared with 1996-2000, the IR of cACB ≥ 3 had declined by 54% between the 2016-2022 episode (IR ratio: 0.46, 95% confidence interval (CI): 0.41-0.52). Participants aged 86-90 years had more than 1.5 times the rate of a cACB ≥ 3 compared with participants aged 66-70 years (IR ratio: 1.67, 95% CI 1.46-1.91).
Conclusions: Exposure to anticholinergic drugs has decreased by over 50% between 1996 and 2020 in this population of community-dwelling adults. However, the oldest old had and remained to have the highest risk of a cACB ≥ 3 during our study period. Thus, prescribers and pharmacists should continue to regularly review the prescription of drugs with an ACB, especially among those vulnerable to adverse outcomes.
Background: Risk management plans (RMPs) are a critical element of pharmacovigilance. However, few studies have examined the quality and type of information included in RMPs, and none has examined the RMPs in the Australian medicines regulatory context.
Objectives: This study aims to characterise safety concerns, particularly missing information listed in the current Australian RMPs for commonly used biologic medicines, and identify additional pharmacovigilance and risk minimisation activities proposed to address identified gaps.
Methods: A descriptive review of RMPs included in the Australian Public Assessment Reports (2009-2024) was performed for 15 biologic medicines approved for use and universally funded in Australia for inflammatory arthropathies, inflammatory bowel diseases and inflammatory skin conditions. We extracted and quantified safety concerns (important identified risks, important potential risks and missing information) from the latest Australian Public Assessment Reports, and further categorised missing information by specific populations and conditions. We then qualitatively described the additional activities proposed.
Results: There were 246 safety concerns listed for the 15 medicines of interest: 85 important identified risks (34.6%), 81 important potential risks (32.9%) and 80 instances of missing information (32.5%). More than half (n = 9, 60%) of the reviewed medicines listed children and adolescents as the most common populations with missing information. Pregnant women (n = 8, 53%) and those with hepatic and renal impairment (n = 7, 47%) were also commonly listed as having missing information. Additional pharmacovigilance activities were proposed for two thirds of the medicines (n = 10, 77%) where missing information was listed. Only one third of the reviewed medicines (n = 5, 33%) had specific proposals or protocols listed in the current Australian Public Assessment Reports to address missing information.
Conclusions: Our study identified important gaps in RMPs for commonly used biologic medicines at the post-market phase. Despite some medicines having an extensive market history, these safety concerns remain unaddressed. Regular monitoring and critical review of RMPs are recommended to prioritise post-market studies and address outstanding safety concerns.
Introduction: Because of the novelty of advanced therapy medicinal products (ATMPs), pro-active risk management is needed post-authorisation; for example, through implementation of additional risk minimisation measures (aRMMs).
Objective: We described which aRMMs were introduced at marketing authorisation (MA) for ATMPs authorised in the European Union (EU), and for what safety concerns.
Methods: We included all ATMPs ever authorised in the EU until December 31, 2023. Data on safety concerns and aRMMs was collected from the European public assessment reports (EPARs) related to initial MA for each ATMP. Safety concerns were categorised using the Medical Dictionary for Regulatory Activities (MedDRA®) or context of use, where appropriate.
Results: Of the 25 included ATMPs, most (n = 23, 92.0%) were authorised with aRMMs. Of these 23 ATMPs, all (100%) had educational material for healthcare professionals. Additionally, educational material for patients/caregivers was in place for 18 (78.3%) ATMPs and a controlled distribution or controlled access programme for 16 (69.6%). Safety concerns related to 'Long term effects' (n = 23, 92.0%), 'Injury, poisoning and procedural complications' (n = 22, 88.0%), and 'Use in special populations' (e.g., use in pregnancy) (n = 20, 80.0%) were common among all 25 ATMPs. ATMPs often had aRMMs introduced that addressed safety concerns related to 'Injury, poisoning and procedural complications' (n = 19/23; 82.6%), 'General disorders and administration site conditions' (n = 8, 34.8%), and/or 'Immune system disorders' (n = 8, 34.8%).
Conclusion: The majority of ATMPs were authorised with aRMMs. Whilst educational materials were most prevalent, controlled distribution or controlled access programmes were also commonly introduced. For many ATMPs, aRMMs addressed risks related to 'Injury, poisoning and procedural complications'.
Signal management, defined as the set of activities from signal detection to recommendations for action, is conducted using different data sources and leveraging data from spontaneous reporting databases (SRDs), which represent the cornerstone of pharmacovigilance. However, the exponentially increasing generation and availability of real-world data collected in longitudinal healthcare databases (LHDs), along with the rapid evolution of artificial intelligence-based algorithms and other advanced analytical methods, offers a wide range of opportunities to complement SRDs throughout all stages of signal management, especially signal detection. Integrating information derived from SRDs and LHDs may reduce their respective limitations, thus potentially enhancing post-marketing surveillance. The aim of this position statement is to critically evaluate the complementary role of SRDs and LHDs in signal management, exploring the potential benefits and challenges in integrating information coming from these two data sources. Furthermore, we presented successful cases of the interplay between SRDs and LHDs for signal management, along with future opportunities and directions to improve such interplay.
Introduction: The use of incretin-based drugs may be associated with a decreased risk of endometrial cancer among women with type 2 diabetes.
Methods: Using data from the UK Clinical Practice Research Datalink and linked databases, two new-user active comparator cohorts of women with type 2 diabetes who initiated glucagon-like peptide 1 receptor agonists (GLP-1 RAs) or sulfonylureas (cohort 1) and DPP-4 inhibitors or sulfonylureas (cohort 2) were assembled. Propensity score fine stratification weighted Cox proportional hazards models were fitted to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for incident endometrial cancer.
Results: Cohort 1 included 9239 new users of GLP-1 RAs and 80,086 new users of sulfonylureas. The GLP-1 RAs were not associated with a decreased risk of endometrial cancer when compared with sulfonylureas (HR: 1.11, 95% CI: 0.66-1.88). In a duration-response secondary analysis, use of GLP-1 RAs for more than two years was associated with an increased risk of endometrial cancer (HR: 2.47, 95% CI: 1.37-4.43) when compared to sulfonylureas When analysed by drug type, exenatide was associated with an elevated risk when compared to sulfonylureas (HR: 2.26, 95% CI:1.06-4.82). Cohort 2 included 42,486 new users of DPP-4 inhibitors and 79,353 new users of sulfonylureas. DPP-4 inhibitors were not associated with a decreased risk of endometrial cancer compared with sulfonylureas (HR: 1.00, 95% CI: 0.76-1.32). In a duration-response secondary analysis, use of DPP-4 inhibitors for more than two years was associated with an increased risk of endometrial cancer (HR: 1.63, 95% CI: 1.14-2.33) when compared to sulfonylureas.
Conclusions: In this population-based study, the use of GLP-1 RAs and DPP-4 inhibitors was not associated with a decreased risk of endometrial cancer when compared with the use of sulfonylureas among women with type 2 diabetes.
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