Post-marketing Surveillance Research Articles

Participant-reported neurological events following immunization in the Canadian National Vaccine Safety Network-COVID-19 vaccine (CANVAS-COVID) study

IntroductionThe Canadian National Vaccine Safety Network (CANVAS) conducted active participant-based surveillance for adverse events following immunization during the COVID-19 vaccine campaign. This study evaluated the association between COVID-19 vaccination and neurological adverse events. MethodsParticipants were invited to complete online surveys to report health events that prevented daily activities and/or required medical attention within 7 days after COVID-19 vaccination or 7 days prior to the survey (unvaccinated controls); follow-up surveys were sent 7 months later. Neurological events were health events where the most severe symptom reported was ≥1 of: numbness/tingling, loss of taste or smell, vision loss, facial weakness/paralysis, seizure, weakness/paralysis of arms or legs, confusion, change in personality or behavior, or difficulty with urination or defecation. Data were extracted from the CANVAS-COVID database for analysis. ResultsCompleted survey responses were received from 15,273 unvaccinated controls, 758,619 dose 1 recipients, 406,884 dose 2 recipients, and 126,586 dose 3 recipients. Rates of neurological events ranged from 15.9 (95 % CI 13.6–18.4) per 10,000 dose 1 ChAdOx1 recipients to 8.4 (6.5–10.8) and 7.9 (5.7–11.0) per 10,000 dose 3 mRNA-1273 and BNT162b2 recipients, respectively. Multivariable regression adjusted for age, sex, previous SARS-CoV-2 infection, and baseline health status showed an increased risk of neurological event among ChAdOx1 dose 1 recipients versus controls (adjusted OR 2.3, 95 % CI 1.2–4.3), but not among mRNA vaccine recipients after any dose. Risk of anaesthesia/paresthesia were increased following ChAdOx1 dose 1 (aOR 4.7, 1.7–13.1), and consistently but not statistically significantly higher following any dose of either mRNA vaccine. Risk of loss of smell/taste was decreased among recipients of any dose of either mRNA vaccine versus controls. ConclusionsThe results support the safety of COVID-19 vaccines while confirming reported associations between ChAdOx1 dose 1 and neurological events. Participant-based AEFI surveillance is a useful component of post-market surveillance programs.

Empagliflozin-A Sodium Glucose Co-transporter-2 Inhibitor: Overview ofits Chemistry, Pharmacology, and Toxicology.

Empagliflozin is a sodium glucose co-transporter-2 (SGLT2) inhibitor that has gained significant attention in the treatment of type 2 diabetes mellitus. Understanding its chemistry, pharmacology, and toxicology is crucial for the safe and effective use of this medication. This review aims to provide a comprehensive overview of the chemistry, pharmacology, and toxicology of empagliflozin, synthesizing the available literature to present a concise summary of its properties and implications for clinical practice. A systematic search of relevant databases was conducted to identify studies and articles related to the chemistry, pharmacology, and toxicology of empagliflozin. Data from preclinical and clinical studies, as well as post-marketing surveillance reports, were reviewed to provide a comprehensive understanding of the topic. Empagliflozin is a selective SGLT2 inhibitor that works by constraining glucose reabsorption in the kidneys, causing increased urinary glucose elimination. Its unique mechanism of action provides glycemic control, weight reduction, and blood pressure reduction. The drug's chemistry is characterized by its chemical structure, solubility, and stability. Pharmacologically, empagliflozin exhibits favorable pharmacokinetic properties with rapid absorption, extensive protein binding, and renal elimination. Clinical studies have demonstrated its efficacy in improving glycemic control, reducing cardiovascular risks, and preserving renal function. However, adverse effects, for instance, urinary tract infections, genital infections, and diabetic ketoacidosis have been reported. Toxicological studies indicate low potential for organ toxicity, mutagenicity, or carcinogenicity. Empagliflozin is a promising SGLT2 inhibitor that offers an innovative approach to the treatment of type 2 diabetes mellitus. Its unique action mechanism and favorable pharmacokinetic profile contribute to its efficacy in improving glycemic control and reducing cardiovascular risks. While the drug's safety profile is generally favorable, clinicians should be aware of potential adverse effects and monitor patients closely. More study is required to determine the longterm safety and explore potential benefits in other patient populations. Overall, empagliflozin represents a valuable addition to the armamentarium of antidiabetic medications, offering significant benefits to patients suffering from type 2 diabetes mellitus. This study covers all aspects of empagliflozin, including its history, chemistry, pharmacology, and various clinical studies, case reports, and case series.

Who can benefit more from its twelve-week treatment: A prospective cohort study of blonanserin for patients with schizophrenia

BACKGROUND Blonanserin (BNS) is a well-tolerated and effective drug for treating schizophrenia. AIM To investigate which types of patients would obtain the most benefit from BNS treatment. METHODS A total of 3306 participants were evaluated in a 12-week, prospective, multicenter, open-label post-marketing surveillance study of BNS. Brief psychiatric rating scale (BPRS) scores were calculated to evaluate the effectiveness of BNS, and its safety was assessed with the incidence of adverse drug reactions. Linear regression was used to screen the influencing factors for the reduction of BPRS total score, and logistic regression was used to identify patients with a better response to BNS. RESULTS The baseline BPRS total score (48.8 ± 15.03) decreased to 27.7 ± 10.08 at 12 weeks (P < 0.001). Extrapyramidal symptoms (14.6%) were found to be the most frequent adverse drug reactions. The acute phase, baseline BPRS total score, current episode duration, number of previous episodes, dose of concomitant antipsychotics, and number of types of sedative-hypnotic agents were found to be independent factors affecting the reduction of BPRS total score after treatment initiation. Specifically, patients in the acute phase with baseline BPRS total score ≥ 45, current episode duration < 3 months, and ≤ 3 previous episodes derived greater benefit from 12-week treatment with BNS. CONCLUSION Patients in the acute phase with more severe symptoms, shorter current episode duration, fewer previous episodes, and a lower psychotropic drug load derived the greatest benefit from treatment with BNS.

Safety and Effectiveness of Elotuzumab in Japanese Patients with Relapsed/Refractory Multiple Myeloma: A Post-marketing Surveillance Study.

Objective Elotuzumab plus lenalidomide and dexamethasone (ELd) was approved in Japan in 2016 for the treatment of relapsed/refractory multiple myeloma (RRMM). This post-marketing surveillance study evaluated the safety and effectiveness of ELd in RRMM patients during routine clinical practice in Japan. Methods Elotuzumab safety was assessed by evaluating adverse drug reactions (ADRs), and effectiveness was assessed primarily by the best overall response. Patients The study enrolled patients with RRMM who received ELd therapy between November 18, 2016, and June 18, 2017. The safety and effectiveness analysis sets included 831 and 755 patients, respectively. Results In the safety analysis set, patients received a median (range) of 12 (1-40) elotuzumab administrations over 108 (1-728) days of treatment. The relative dose intensity of elotuzumab was ≥90% in 74.1% of patients. ADRs and serious ADRs were reported in 41.2% and 15.2% of the patients, respectively. The most common ADR was infection (12.0%), followed by lymphocytopenia (10.1%), infusion reactions (7.5%), secondary malignancies (e.g. gastric cancer and pancreatic carcinoma), cataracts, and interstitial lung disease (0.2% each). While most patients with ADRs recovered, 71 discontinued treatment, and 14 deaths were reported. The presence of comorbidities, particularly cardiovascular disorders, significantly affected the safety. The overall response rate was 41.1%. Conclusion This all-case post-marketing surveillance study showed that ELd had an acceptable tolerability profile and promising clinical activity in Japanese patients with RRMM.

The application study of harmonization code in medical device adverse event reporting.

The reporting of adverse events in medical devices (MD) is a starting point of post-market surveillance and the most common source of initial safety signals. Because MD adverse events (AE) occur globally and involve high-profile international public health crises, international regulators implanted standard codes for MDAE reporting. This study aimed to assess the application of MDAE terminology and codes by providing examples of virtual events. An online survey was conducted among participants of the MD Training Program for Regulatory Authorities which provide International Medical Device Regulators Forum (IMDRF) adverse event terminology and codes, and six virtual MDAE cases. All 29 of the 72 participants were regulators. In all cases, most participants selected the broad (level 1) codes rather than the detailed (level 2 or level 3) codes. While responders selected a variety of codes for all annexes in case 1, over 50% of responders selected the intended codes in case 6. The codes for cause investigation were chosen more frequently than other annexes for device problem, components, and health effect. No differences were observed in code selection amongst different stakeholders. We identified the diversification in terminology and code selection for reporting MDAEs.

Quantitative Structure-Activity Relationship Models to Predict Cardiac Adverse Effects.

Drug-induced cardiotoxicity represents one of the most common causes of attrition of drug candidates in preclinical and clinical development. For this reason, the evaluation of cardiac toxicity is essential during drug development and regulatory review. In the present study, drug-induced postmarket adverse event combinations from the FDA Adverse Event Reporting System were extracted for 2002 drugs using 243 cardiac toxicity-related preferred terms (PTs). These PTs were combined into 12 groups based on their clinical relevance to serve as training sets. The optimal classification scheme was determined using a combination of data sources that included drug labeling information, published literature, clinical study data, and postmarket surveillance data. Two commercial QSAR platforms were used to construct 12 models, including general cardiac toxicity, cardiac ischemia, heart failure, cardiac valve disease, myocardial disease, pericardial disease, structural heart disease, cardiac arrhythmia, Torsades de Pointes, long QT syndrome, atrial fibrillation and ventricular arrhythmia, and cardiac arrest. The cross-validated performance for the new models reached a sensitivity of up to 80% and negative predictivity of up to 80%. These new models covering a wide range of cardiac endpoints will provide fast, reliable, and comprehensive predictions of potential cardiotoxic compounds in drug discovery and regulatory safety assessment.

Abstract 4119094: Claims-Based versus Registry-Reported Stroke Events in the NCDR Left Atrial Appendage Occlusion Registry

Background: Administrative claims data are increasingly used for post-marketing surveillance of drugs and medical devices, though data reliability remains uncertain. Given their associated morbidity and mortality, stroke events are particularly important to monitor for cardiovascular therapies such as transcatheter left atrial appendage occlusion (LAAO). However, there are limited data comparing stroke events in contemporary claims data to events reported in large nationwide registries with comprehensive data collection. Aim: To compare stroke events in Medicare claims data with adjudicated registry-reported events in the National Cardiovascular Data Registry Left Atrial Appendage Occlusion (LAAO) Registry. Methods: LAAO Registry data were linked with 2016-2022 Medicare inpatient claims. Primary diagnosis ICD-10 codes from inpatient hospitalizations were compared to adjudicated registry-reported ischemic and hemorrhagic stroke events occurring after discharge with up to two years of follow-up. In multiple secondary analyses, primary and secondary diagnosis codes were counted as events in claims data and patients with prior history of stroke were also excluded. Results: The cohort included 71,043 adults ≥65 years old in the LAAO Registry with inpatient Medicare data. Following LAAO hospitalization discharge, there were 1405 claims-based and 1308 registry-reported total stroke events. Sensitivity and positive predictive value (PPV) of claims for identifying registry-reported events were 60.8% and 50.5% for ischemic stroke (kappa statistic 0.55), 42.7% and 50.5% for hemorrhagic stroke (kappa 0.46), and 58.1% and 54.1% for all stroke (kappa 0.55), respectively. Inclusion of secondary diagnosis codes improved sensitivity of claims (70.3% for ischemic stroke, 53.9% for hemorrhagic stroke and 67.0% for all stroke), but PPV decreased (44.8% for ischemic stroke, 34.8% for hemorrhagic stroke and 47.8% for all stroke). Specificity and negative predictive values of claims data were >98% for all stroke types. Findings were similar after excluding patients with prior history of stroke ( Table ). Conclusions: Among Medicare patients in the LAAO Registry, administrative claims data had moderate agreement with adjudicated registry-reported stroke events. Claims data may not reliably capture all stroke events in real-world practice, and additional event ascertainment methods may be needed to ensure accurate assessment of stroke in post-marketing surveillance efforts.

Abstract 4136286: Safety Events with a Large-Bore Aspiration Thrombectomy Device for Pulmonary Embolism: An analysis of the U.S. Food and Drug Administration Manufacturer and User Facility Device Experiences from 2018 to 2024

Introduction: Large bore thrombectomy is increasingly used to treat acute PE. Post-market surveillance using the U.S. FDA Manufacturer and User Facility Device Experience (MAUDE) database may capture serious device adverse events (AE) not described in small pre-market clinical trials. We aim to analyze serious AE associated with use of the Inari Medical (Irvine, California) large bore thrombectomy system to treat PE. Methods: All MAUDE events between January 1, 2018 and May 1, 2024 involving PE treatment with Triever and Flowtriever devices were reviewed and categorized based on device type, incident year, and clinical event. Based on narrative description, AE were placed into categories of cardiac, pulmonary, device malfunction, anemia, and other. Results: A total of 58 AE reports representing 50 unique clinical episodes were included. MAUDE event types were death (n=32), injury (n=23) and malfunction (n=3), and the majority (45/58) involved the larger aspiration catheters (Table 1). Death occurred in 27 of 50 unique episodes. Cardiac injury (n=19) and pulmonary injury (n=18) were most common and included 25 serious perforations. Serious AEs are listed in Table 2. Device malfunction/improper use was rare (n=7) and was not associated with death. Paradoxical embolism was described causing stroke and coronary occlusion. 3 of 4 blood loss AEs occurred prior to 2021. Conclusion: This report includes the largest description of reported AEs with large bore aspiration thrombectomy systems used to treat PE. This report describes serious events, often associated with death, that are likely infrequent and were not detected in pivotal studies or registries. Understanding these AEs may guide future technique and device refinement, and the current findings demonstrate the importance of large post-approval studies.

Narrow Therapeutic Index Drugs: FDA Experience, Views, and Operations.

The U.S. Food and Drug Administration (FDA) has defined narrow therapeutic index (NTI) drugs as "those drugs where small differences in dose or blood concentration may lead to serious therapeutic failures and/or adverse drug reactions that are life-threatening or result in persistent or significant disability or incapacity." FDA has undertaken efforts to develop NTI assessment criteria and enhance public confidence in generic NTI drugs through public workshops, research, and post-marketing surveillance. In 2015, FDA formed the NTI Drug Working Group to develop a consistent approach to identify NTI drugs and resolve NTI-related scientific and regulatory issues in a transparent and collaborative manner. One key objective of the NTI Drug Working Group is to evaluate potential NTI drugs based on five general characteristics of NTI drugs as highlighted in the case example for theophylline drug products. As of January 5, 2024, there are 33 drug products, with 14 distinct active ingredients, specified as NTI drugs in their respective product-specific guidances (PSGs) for generic drug development. Future collaborative efforts with other agencies to harmonize the terms and definitions for NTI drugs may help enhance clarity and consistency during the drug development and the regulatory review process.

Post-marketing surveillance of anticancer drugs using natural language processing of electronic medical records

This study demonstrates that adverse events (AEs) extracted using natural language processing (NLP) from clinical texts reflect the known frequencies of AEs associated with anticancer drugs. Using data from 44,502 cancer patients at a single hospital, we identified cases prescribed anticancer drugs (platinum, PLT; taxane, TAX; pyrimidine, PYA) and compared them to non-treatment (NTx) group using propensity score matching. Over 365 days, AEs (peripheral neuropathy, PN; oral mucositis, OM; taste abnormality, TA; appetite loss, AL) were extracted from clinical text using an NLP tool. The hazard ratios (HRs) for the anticancer drugs were: PN, 1.15–1.95; OM, 3.11–3.85; TA, 3.48-4.71; and AL, 1.98–3.84; the HRs were significantly higher than that of the NTx group. Sensitivity analysis revealed that the HR for TA may have been underestimated; however, the remaining three types of AEs extracted from clinical text by NLP were consistently associated with the three anticancer drugs.

Crowdsourcing Adverse Events Associated With Monoclonal Antibodies Targeting Calcitonin Gene-Related Peptide Signaling for Migraine Prevention: Natural Language Processing Analysis of Social Media.

Clinical trials demonstrate the efficacy and tolerability of medications targeting calcitonin gene-related peptide (CGRP) signaling for migraine prevention. However, these trials may not accurately reflect the real-world experiences of more diverse and heterogeneous patient populations, who often have higher disease burden and more comorbidities. Therefore, postmarketing safety surveillance is warranted. Regulatory organizations encourage marketing authorization holders to screen digital media for suspected adverse reactions, applying the same requirements as for spontaneous reports. Real-world data from social media platforms constitute a potential venue to capture diverse patient experiences and help detect treatment-related adverse events. However, while social media holds promise for this purpose, its use in pharmacovigilance is still in its early stages. Computational linguistics, which involves the automatic manipulation and quantitative analysis of oral or written language, offers a potential method for exploring this content. This study aims to characterize adverse events related to monoclonal antibodies targeting CGRP signaling on Reddit, a large online social media forum, by using computational linguistics. We examined differences in word frequencies from medication-related posts on the Reddit subforum r/Migraine over a 10-year period (2010-2020) using computational linguistics. The study had 2 phases: a validation phase and an application phase. In the validation phase, we compared posts about propranolol and topiramate, as well as posts about each medication against randomly selected posts, to identify known and expected adverse events. In the application phase, we analyzed posts discussing 2 monoclonal antibodies targeting CGRP signaling-erenumab and fremanezumab-to identify potential adverse events for these medications. From 22,467 Reddit r/Migraine posts, we extracted 402 (2%) propranolol posts, 1423 (6.33%) topiramate posts, 468 (2.08%) erenumab posts, and 73 (0.32%) fremanezumab posts. Comparing topiramate against propranolol identified several expected adverse events, for example, "appetite," "weight," "taste," "foggy," "forgetful," and "dizziness." Comparing erenumab against a random selection of terms identified "constipation" as a recurring keyword. Comparing erenumab against fremanezumab identified "constipation," "depression," "vomiting," and "muscle" as keywords. No adverse events were identified for fremanezumab. The validation phase of our study accurately identified common adverse events for oral migraine preventive medications. For example, typical adverse events such as "appetite" and "dizziness" were mentioned in posts about topiramate. When we applied this methodology to monoclonal antibodies targeting CGRP or its receptor-fremanezumab and erenumab, respectively-we found no definite adverse events for fremanezumab. However, notable flagged words for erenumab included "constipation," "depression," and "vomiting." In conclusion, computational linguistics applied to social media may help identify potential adverse events for novel therapeutics. While social media data show promise for pharmacovigilance, further work is needed to improve its reliability and usability.

Conflicting interpretations and FDA reputation: the case of post-market surveillance of breast implants

Conflicting interpretations regarding the severity of the adverse effects associated with FDA-approved drugs and therapies are common among the United States Food and Drug Administration (FDA), the medical community, patients, and the general public. However, scholars have paid little attention to how these conflicting interpretations may affect the FDA’s reputation for facilitating inclusive dialogue between competing policy actors. Focusing on breast implants, a medical device characterized by a stormy regulatory past, we observe that the design properties of post-market surveillance are adjusted to low-quality information. Such information-gathering mechanisms likely lead to underreporting by medical practitioners and patients, thus resulting in low-quality data. Given that the FDA cannot rely on congressional appropriations to ensure a stable flow of funding, the confusion and uncertainty created by conflicting interpretations enhance the FDA’s ability to appeal to different audiences simultaneously and thereby secure funding from industry-based user fees. This strategy may persist until the FDA’s reputation is challenged by critical information regarding adverse effects and the ensuing potentially negative media coverage. A stable appropriation-based funding model will likely encourage stronger post-market surveillance of medical devices.

Omalizumab Safety Concerns.

IgE and mast cells play key roles in the pathophysiology of allergic diseases, and omalizumab was the first monoclonal anti-IgE antibody licensed in the U.S. when initially FDA-approved for the treatment of allergic asthma in 2003. Since that time, the number of FDA-approved indications for treatment with omalizumab has grown to include chronic spontaneous urticaria, chronic rhinosinusitis with nasal polyps, and food allergy. Although omalizumab is generally considered relatively safe and well-tolerated, a number of safety concerns have been raised since its initial approval. These concerns focus on specific adverse events of interest that include anaphylaxis, pregnancy, malignancy, cardiovascular events, and infections. For each of these issues, data from clinical trials and post-marketing surveillance has been extensively evaluated. In this review, we examine this safety data, provide context for safety and risk assessments, and summarize a safety profile for each of the adverse events of interest. In doing so, we aim to provide a resource for shared-decision making when treatment with omalizumab is being considered.

Understanding Variation Among Medical Device Reporting Sources: A Study of the MAUDE Database

BackgroundIncreasing medical device usage raises concerns regarding unexpected, potentially life-threatening events that pose public health risks. Such events are reported to the Food and Drug Administration (FDA), and cataloged in the Manufacturer and User Facility Device Experience (MAUDE) database, a vital tool for post market surveillance that requires information of high quality and integrity, particularly concerning reporting sources. PurposeTo analyze reporting behavior among different reporters, including manufacturers, distributors, and user facilities, by examining differences in reported factors, namely: (1) device types, (2) product problem attribution, and (3) selection of Device Problem Codes (DPCs) associated with the root causes of events. MethodsData spanning from 2005 to 2022 was retrieved from the MAUDE database using Python. Reports were grouped by reporter type and divided according to device type, and the reporter's indication of association with a product problem. Furthermore, events were classified by their respective DPCs, which were manually grouped into four categories: device issues, user issues, clinical issues, or unknown. FindingsThe analysis revealed significant variations among reporters across all examined aspects (P < 0.00001 in all comparisons according to the proportion test). Manufacturers predominantly focused on infusion pumps (10.1%) and Implant, Endosseous, Root-Form (IER) devices (7.6%), with a product problem indication rate of 29.2% in their reports. Device issues codes were the most frequently observed category in their reports, comprising 36.3%, followed by unknown codes (32%) and clinical codes (19.3%). Distributors, on the other hand, primarily reported on IER devices (89%) and exhibited the lowest product problem indication rate at 2.7%. Clinical issues codes predominated in their reports, constituting 85.7%, followed by unknown codes (6.7%). User facilities concentrated on intravascular sets (4.7%), Electrosurgical, Cutting & Coagulation & Accessories (4.2%), and Ventricular (Assist) Bypass (4.1%). Remarkably, their product problem indication rate was the highest at 56.7%. They predominantly reported device issues codes (54.3%), followed by use codes (30.8%), and unknown codes (11.4%) ImplicationsThe notable variation among different reporters underscores the importance of incorporating diverse sources when analyzing the database, particularly in cases where majority of reports originate from manufacturers. Decision-makers must approach database information comprehensively, considering data sources and diverse perspectives to inform regulatory decisions effectively. Developing strategies that encourage various reporters to contribute their unique and complementary viewpoints is advisable.

A machine learning framework to adjust for learning effects in medical device safety evaluation.

Traditional methods for medical device post-market surveillance often fail to accurately account for operator learning effects, leading to biased assessments of device safety. These methods struggle with non-linearity, complex learning curves, and time-varying covariates, such as physician experience. To address these limitations, we sought to develop a machine learning (ML) framework to detect and adjust for operator learning effects. A gradient-boosted decision tree ML method was used to analyze synthetic datasets that replicate the complexity of clinical scenarios involving high-risk medical devices. We designed this process to detect learning effects using a risk-adjusted cumulative sum method, quantify the excess adverse event rate attributable to operator inexperience, and adjust for these alongside patient factors in evaluating device safety signals. To maintain integrity, we employed blinding between data generation and analysis teams. Synthetic data used underlying distributions and patient feature correlations based on clinical data from the Department of Veterans Affairs between 2005 and 2012. We generated 2494 synthetic datasets with widely varying characteristics including number of patient features, operators and institutions, and the operator learning form. Each dataset contained a hypothetical study device, Device B, and a reference device, Device A. We evaluated accuracy in identifying learning effects and identifying and estimating the strength of the device safety signal. Our approach also evaluated different clinically relevant thresholds for safety signal detection. Our framework accurately identified the presence or absence of learning effects in 93.6% of datasets and correctly determined device safety signals in 93.4% of cases. The estimated device odds ratios' 95% confidence intervals were accurately aligned with the specified ratios in 94.7% of datasets. In contrast, a comparative model excluding operator learning effects significantly underperformed in detecting device signals and in accuracy. Notably, our framework achieved 100% specificity for clinically relevant safety signal thresholds, although sensitivity varied with the threshold applied. A machine learning framework, tailored for the complexities of post-market device evaluation, may provide superior performance compared to standard parametric techniques when operator learning is present. Demonstrating the capacity of ML to overcome complex evaluative challenges, our framework addresses the limitations of traditional statistical methods in current post-market surveillance processes. By offering a reliable means to detect and adjust for learning effects, it may significantly improve medical device safety evaluation.

Quality evaluation of field safety notices of medical devices, across EU and non-EU countries

Abstract Introduction The EU Medical Device Regulation 2017/745 (MDR; article 87) requires device manufacturers to report to the relevant authorities any serious incident and any corrective action undertaken, through Field Safety Notices (FSN) whose content must be consistent in all Member States. Before MDR, due to the lack of harmonized global standards for reporting, FSNs were published independently by each country with different formats, styles, nomenclatures and languages. This heterogeneity makes it challenging to use such historical data for trend analysis in post-market surveillance (PMS). Purpose 1) To assess the quality of the FSNs issued by EU or non-EU national authorities for analysing historical trends. 2) To group countries based on such quality, and test for differences between EU and non-EU countries. Methods As part of the CORE-MD project coordinated by the ESC, all FSN information publicly available as HTML text (excluding linked PDFs) was retrieved automatically from national authorities’ websites, using the CORE-MD PMS tool [1]. For each FSN, a score was assigned to each field of interest (1 or 2, according to importance for building trends) (see Figure 1), and a Percentage Score (PS) computed as the % of the ratio between the scores’ sum and the maximum possible score (10). Based on PS, FSNs were categorized as Excellent (≥90), Very Good (80≤PS&amp;lt;90), Good (70≤PS&amp;lt;80), Medium (60≤PS&amp;lt;70), or Unqualified (&amp;lt;60). For each country, the distribution of FSN categories was computed. Hierarchical Agglomerative Clustering (HAC) was used to group countries based on their similarities, and differences between EU and non-EU countries were assessed by Mann-Whitney U test. Results 126,405 FSNs published before 31/12/2022 were retrieved and analyzed. The % of FSN in which each field was available is shown by country in Figure 1. Manufacturer and Device were clearly described, but more detailed device information was often absent. The Description, with the reason for publishing the FSN, and the Device Category, allowing nomenclature categorization, were provided only by a few countries. The % of FSNs in each quality category is reported in Figure 2: only Italy provided some FSNs (31%) classified as Excellent. The HAC analysis identified three clusters: "high-quality FSNs" (Czechia, Denmark, Italy, Sweden, the Netherlands, and the USA), "moderate-quality FSNs" (Australia, Canada, Greece, Ireland, Latvia, Slovenia, Spain, and the UK), and "low-quality FSNs" (Croatia, Estonia, France, Germany, Poland, and Portugal). There was no difference between EU and non-EU countries. Conclusions A significant discrepancy was observed in the quality of FSNs retrieved from different countries, highlighting the difficulty in using such data to analyse trends, for example in reports of cardiovascular devices. This study reinforces the need for a global minimum reporting standard, to facilitate more effective PMS.Figure 1Figure 2

Sex differences in reporting of statin-associated diabetes mellitus to the US Food and Drug Administration

Abstract Background Statins have been reported to precipitate diabetes mellitus (DM) in some patients. Limited evidence suggests that this occurs in women more frequently than men, but direct comparisons of rates of reporting of statin-associated DM between men and women are lacking. Purpose To determine whether there are sex-specific differences in post-marketing reporting of statin-associated DM. Methods We conducted a retrospective pharmacovigilance analysis of spontaneously reported adverse drug events (ADEs) submitted to the Food and Drug Administration (FDA) Adverse Event Reporting System between January 1997 and September 2023. A Proportional Reporting Ratio (PRR) was used to identify the rate of reported statin-associated DM ADEs relative to the rate of DM ADEs reported with all other medications. We compared signals of disproportionate reporting (SDRs) between men and women using a modified relative odds ratio (ROR). Results During the study period, there were two-fold as many reports of statin-associated DM in women than in men (14,793 versus 7,307, respectively), despite the fact there were only 7% more non-DM statin ADEs reported in women compared to men (512,134 versus 480,849, respectively). Compared to the background rate of reporting for all ADEs (0.6%), statin-induced DM was disproportionally reported for all subjects in aggregate (2.1%, PRR=3.7) as well as for men only (1.5%, PRR=2.4) and for women only (2.9%, PRR=5.3). Significant PRRs for DM were observed with each statin and for all statins collectively (Figure 1). Statins were reported as the primary- or secondary-suspected cause of DM in women with considerably greater frequency than in men (58% versus 29%, respectively). Rates of reporting of statin-associated DM were higher in women than in men for all statins, with the greatest difference being observed with atorvastatin (ROR 3.0), and the lowest difference being observed with rosuvastatin (ROR 1.2) (Figure 1). Conclusions Post-marketing ADE surveillance data suggest a markedly higher rate of incident DM associated with statins than with other medications and a higher rate of reporting of statin-associated DM in women than in men. Future studies should consider sex-moderated mechanisms of statin-associated DM.Figure 1

Updated insights into adverse events associated with mepolizumab: a disproportionality analysis from the FDA adverse event reporting system database

BackgroundMepolizumab, a monoclonal antibody targeting interleukin-5, is used to treat severe eosinophilic asthma and other eosinophilia-related conditions. Given its growing use, there is a pressing need for the latest data to improve the understanding and management of its adverse events (AEs). This study aimed to investigate the safety of mepolizumab by analyzing the pharmacovigilance database of the US Food and Drug Administration.MethodsThe AE signals associated with mepolizumab from 2015 to 2024 were analyzed and the correlations using reporting ratios (RORs) quantified. Subgroup analyses were conducted to understand AEs in individuals ≤ 18 years of age. We also used time-to-onset (TTO) analysis to examine AE occurrence patterns.ResultsIn total, 82,478 AE reports linked to mepolizumab therapy were included. Our analysis, involving 24,156 patients, revealed a predominance of female patients, with the highest incidence of AEs occurring in those aged 18–65 years. Disproportionality analyses revealed significant signals across various system organ classifications (SOCs), most prominently respiratory, thoracic, and mediastinal disorders (ROR = 5.12, 95% confidence intervals [CI] 5.03–5.21), infections and infestations (ROR = 1.86, 95% CI 1.81–1.90), and immune system disorders (ROR = 1.14, 95% CI 1.08–1.21). The highest ROR was found for asthma crisis (ROR = 104.90, 95% CI 95.31–115.44) at the preferred term (PT) level, and the other notables were coronavirus infection (ROR = 7.33, 95% CI 6.05–8.88) and coronavirus disease 2019 (COVID-19) (ROR = 1.34, 95% CI 1.23–1.47). A subgroup analysis of patients ≤ 18 years old identified four significant SOC signals, with the highest ROR in respiratory, thoracic, and mediastinal disorders (ROR = 5.28, 95% CI 4.17–6.68). PT analysis revealed significant AEs, such as wheezing, bronchospasm, and chest discomfort. TTO analysis revealed that 18.5% of AEs occurred within the first 30 days of treatment. The Weibull shape parameter indicated an “early failure-type” pattern for mepolizumab-associated AEs, underscoring the need for vigilant monitoring during the initial stages of therapy.ConclusionOur study highlights the importance of post-market surveillance for monitoring the safety of mepolizumab, which revealed significant AE signals, particularly for respiratory diseases, infections, and immune system complications. The association with opportunistic infections, including COVID-19, highlights the need for vigilant surveillance and further research.

Post-marketing study design to evaluate the effectiveness of the 9-valent and 4-valent HPV vaccines on serious HPV-related cervical disease in China.

The 4-valent (4 v) and 9-valent (9 v) human papillomavirus (HPV) vaccines are approved in China for females aged 9-45 years. However, the real-world impact of 4vHPV or 9vHPV vaccination for the prevention of high-grade cervical disease in Chinese women is lacking. Two post-marketing surveillance studies will be conducted to measure the occurrence of high-grade cervical lesions in Chinese women who had received ≥1 dose of the 4vHPV (aged 20-45 years) or 9vHPV (aged 16-26 years) vaccine in Ningbo, China. Vaccination data will be extracted from the Ningbo Regional Health Information Platform (NRHIP) from the date of the first 4vHPV (January 9, 2018) or the first 9vHPV (January 25, 2019) vaccination to March 31, 2021. The primary 4vHPV and 9vHPV vaccinated cohorts will include women vaccinated per protocol. The 4vHPV/9vHPV vaccinated test-negative (cervical HPV negative; ThinPrep cytology test negative) and corresponding matched unvaccinated HPV test-negative sub-cohorts will also be assessed. Outcomes will be the occurrence of new-onset cervical intraepithelial neoplasia grade 2/3, adenocarcinoma in situ, and invasive cervical cancer. This study aims to demonstrate that such a methodological approach is feasible and can be used to assess the impact of HPV vaccination in other regions across China.

Infectious etiology of intussusception in Indian children less than 2 years old: a matched case-control analysis

BackgroundEnteric infections are hypothesized to be associated with intussusception in children. A small increase in intussusception following rotavirus vaccination has been seen in some settings. We conducted post-marketing surveillance for intussusception following rotavirus vaccine, Rotavac introduction in India and evaluated association of intussusception with enteric pathogens.MethodsIn a case-control study nested within a large sentinel hospital-based surveillance program in India, stool samples from 272 children aged less than 2 years admitted for intussusception and 272 age-, gender- and location-matched controls were evaluated with Taqman array card based molecular assays to detect enteric viruses, bacterial enteropathogens and parasites. Matched case-control analysis with conditional logistic regression evaluated association of enteropathogens with intussusception. Population attributable fractions (PAF) were calculated for enteropathogens significantly associated with intussusception.ResultsThe most prevalent enteropathogens in cases and controls were enteroaggregative Escherichia coli, adenovirus 40/41, adenovirus C serotypes and enteroviruses. Children with intussusception were more likely to harbor adenovirus C serotypes (adjusted odds-ratio (aOR) = 1.74; 95% confidence interval (CI) 1.06–2.87) and enteroviruses (aOR = 1.77; 95% CI 1.05–2.97) than controls. Rotavirus was not associated with increased intussusception risk. Adenovirus C (PAF = 16.9%; 95% CI 4.7% − 27.6%) and enteroviruses (PAF = 14.7%; 95% CI 4.2% − 24.1%) had the highest population attributable fraction for intussusception.ConclusionAdenovirus C serotypes and enteroviruses were significantly associated with intussusception in Indian children. Rotavirus was not associated with risk of intussusception.