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Description and Validation of a Novel AI Tool, LabelComp, for the Identification of Adverse Event Changes in FDA Labeling. 描述并验证用于识别 FDA 标签中不良事件变更的新型人工智能工具 LabelComp。
IF 5.4 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-12-01 Epub Date: 2024-07-31 DOI: 10.1007/s40264-024-01468-8
George A Neyarapally, Leihong Wu, Joshua Xu, Esther H Zhou, Oanh Dang, Joann Lee, Dharmang Mehta, Rochelle D Vaughn, Ellen Pinnow, Hong Fang

Introduction: The accurate identification and timely updating of adverse reactions in drug labeling are crucial for patient safety and effective drug use. Postmarketing surveillance plays a pivotal role in identifying previously undetected adverse events (AEs) that emerge when a drug is used in broader and more diverse patient populations. However, traditional methods of updating drug labeling with new AE information have been manual, time consuming, and error prone. This paper introduces the LabelComp tool, an innovative artificial intelligence (AI) tool designed to enhance the efficiency and accuracy of postmarketing drug safety surveillance. Utilizing a combination of text analytics and a trained Bidirectional Encoder Representations from Transformers (BERT) model, the LabelComp tool automatically identifies changes in AE terms from updated drug labeling documents.

Objective: Our objective was to create and validate an AI tool with high accuracy that could enable researchers and FDA reviewers to efficiently identify safety-related drug labeling changes.

Results: Our validation study of 87 drug labeling PDF pairs demonstrates the tool's high accuracy, with F1 scores of overall performance ranging from 0.795 to 0.936 across different evaluation tiers and a recall of at least 0.997 with only one missed AE out of 483 total AEs detected, indicating the tool's efficacy in identifying new AEs.

Conclusion: The LabelComp tool can support drug safety surveillance and inform regulatory decision-making. The publication of this tool also aims to encourage further community-driven enhancements, aligning with broader interests in applying AI to advance regulatory science and public health.

导言:准确识别和及时更新药品标签中的不良反应对患者安全和有效用药至关重要。上市后监测在识别以前未被发现的不良事件(AEs)方面发挥着关键作用,这些不良事件是药物在更广泛、更多样化的患者群体中使用时出现的。然而,用新的 AE 信息更新药品标签的传统方法都是手动操作,既费时又容易出错。本文介绍了 LabelComp 工具,这是一种创新的人工智能 (AI) 工具,旨在提高上市后药品安全监测的效率和准确性。LabelComp 工具将文本分析与训练有素的变压器双向编码器表征 (BERT) 模型相结合,自动识别更新的药品标签文件中 AE 术语的变化:我们的目标是创建并验证一种高准确性的人工智能工具,使研究人员和 FDA 评审人员能够高效地识别与安全性相关的药品标签变更:我们对 87 个药品标签 PDF 对进行了验证研究,结果表明该工具具有很高的准确性,在不同的评估层级中,总体性能的 F1 分数从 0.795 到 0.936 不等,召回率至少为 0.997,在检测到的 483 个 AE 中只有一个遗漏 AE,这表明该工具在识别新的 AE 方面具有很高的效率:LabelComp 工具可为药物安全性监测提供支持,并为监管决策提供信息。该工具的发布还旨在鼓励进一步的社区驱动改进,与应用人工智能促进监管科学和公共卫生的更广泛兴趣相一致。
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引用次数: 0
Examining the Effect of Missing Data and Unmeasured Confounding on External Comparator Studies: Case Studies and Simulations. 检验缺失数据和未测量混杂因素对外部比较研究的影响:案例研究与模拟
IF 5.4 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-12-01 Epub Date: 2024-08-05 DOI: 10.1007/s40264-024-01467-9
Gerd Rippin, Héctor Sanz, Wilhelmina E Hoogendoorn, Nicolás M Ballarini, Joan A Largent, Eleni Demas, Douwe Postmus, Theodor Framke, Lukas M Aguirre Dávila, Chantal Quinten, Francesco Pignatti

Background and objective: Missing data and unmeasured confounding are key challenges for external comparator studies. This work evaluates bias and other performance characteristics depending on missingness and unmeasured confounding by means of two case studies and simulations.

Methods: Two case studies were constructed by taking the treatment arms from two randomised controlled trials and an external real-world data source that exhibited substantial missingness. The indications of the randomised controlled trials were multiple myeloma and metastatic hormone-sensitive prostate cancer. Overall survival was taken as the main endpoint. The effects of missing data and unmeasured confounding were assessed for the case studies by reporting estimated external comparator versus randomised controlled trial treatment effects. Based on the two case studies, simulations were performed broadening the settings by varying the underlying hazard ratio, the sample size, the sample size ratio between the experimental arm and the external comparator, the number of missing covariates and the percentage of missingness. Thereby, bias and other performance metrics could be quantified dependent on these factors.

Results: For the multiple myeloma external comparator study, results were in line with the randomised controlled trial, despite missingness and potential unmeasured confounding, while for the metastatic hormone-sensitive prostate cancer case study missing data led to a low sample size, leading overall to inconclusive results. Furthermore, for the metastatic hormone-sensitive prostate cancer study, missing data in important eligibility criteria led to further limitations. Simulations were successfully applied to gain a quantitative understanding of the effects of missing data and unmeasured confounding.

Conclusions: This exploratory study confirmed external comparator strengths and limitations by quantifying the impact of missing data and unmeasured confounding using case studies and simulations. In particular, missing data in key eligibility criteria were seen to limit the ability to derive the external comparator target analysis population accurately, while simulations demonstrated the magnitude of bias to expect for various settings.

背景和目的:缺失数据和无法测量的混杂因素是外部参照研究面临的主要挑战。这项工作通过两个案例研究和模拟,评估了缺失和未测量混杂的偏差和其他性能特征:方法:通过从两项随机对照试验和一个外部真实世界数据源中提取治疗臂,构建了两项案例研究。随机对照试验的适应症是多发性骨髓瘤和转移性激素敏感性前列腺癌。总生存期是主要终点。通过报告外部参照物与随机对照试验治疗效果的估计值,评估了缺失数据和未测量混杂因素对病例研究的影响。在两个案例研究的基础上,通过改变基本危险比、样本量、实验臂与外部参照物之间的样本量比、缺失协变量数量和缺失百分比,扩大了模拟设置。因此,偏差和其他性能指标可以根据这些因素进行量化:在多发性骨髓瘤外部参照研究中,尽管存在缺失和潜在的未测量混杂因素,但结果与随机对照试验一致,而在转移性激素敏感性前列腺癌病例研究中,缺失数据导致样本量较少,从而导致总体结果不确定。此外,在转移性荷尔蒙敏感性前列腺癌研究中,重要资格标准数据的缺失导致了进一步的局限性。我们成功地应用了模拟方法,从数量上了解了缺失数据和未测量混杂因素的影响:这项探索性研究通过案例研究和模拟,量化了缺失数据和未测量混杂因素的影响,从而确认了外部参照系统的优势和局限性。特别是,关键资格标准中的缺失数据被认为限制了准确推导外部参照系统目标分析人群的能力,而模拟则显示了不同环境下的预期偏差程度。
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引用次数: 0
A Comparison of Active Pharmacovigilance Strategies Used to Monitor Adverse Events to Antiviral Agents: A Systematic Review. 用于监测抗病毒药物不良事件的主动药物警戒策略比较:系统回顾。
IF 5.4 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-12-01 Epub Date: 2024-08-19 DOI: 10.1007/s40264-024-01470-0
Renato Ferreira-da-Silva, Joana Reis-Pardal, Manuela Pinto, Matilde Monteiro-Soares, Bernardo Sousa-Pinto, Manuela Morato, Jorge Junqueira Polónia, Inês Ribeiro-Vaz

Introduction: The safety of antiviral agents in real-world clinical settings is crucial, as pre-marketing studies often do not capture all adverse events (AE). Active pharmacovigilance strategies are essential for detecting and characterising these AE comprehensively.

Objective: The aim of this study was to identify and characterise active pharmacovigilance strategies used in real-world clinical settings for patients under systemic antiviral agents, focusing on the frequency of AE and the clinical data sources used.

Methods: We conducted a systematic review by searching three electronic bibliographic databases targeting observational prospective active pharmacovigilance studies, phase IV clinical trials for post-marketing safety surveillance, and interventional studies assessing active pharmacovigilance strategies, focusing on individuals exposed to systemic antiviral agents.

Results: We included 36 primary studies, predominantly using Drug Event Monitoring (DEM), with a minority employing sentinel sites and registries. Human immunodeficiency virus (HIV) was the most common condition, with the majority using DEM. Within the DEM, there was a wide range of incidences of patients experiencing at least one AE, and most of these studies used one or two data sources. Sentinel site studies were less common, with two on hepatitis C virus (HCV) and one on HIV, each relying on one or two data sources. The single study using a registry focusing on HIV therapy reported using just one data source. Patient interviews were the most common data source, followed by medical records and laboratory tests. The quality of the studies was considered 'good' in 18/36, 'fair' in 1/36, and 'poor' in 17/36 studies.

Conclusion: DEM was the predominant pharmacovigilance strategy, employing multiple data sources, and appears to increase the likelihood of detecting higher AE incidence. Establishing such a framework would facilitate a more detailed and consistent approach across different studies and settings.

简介:抗病毒药物在实际临床环境中的安全性至关重要,因为上市前研究往往无法捕捉到所有不良事件(AE)。积极的药物警戒策略对于全面检测和描述这些不良事件至关重要:本研究旨在识别和描述在实际临床环境中针对使用全身性抗病毒药物的患者所采用的积极药物警戒策略,重点关注不良事件的发生频率和所使用的临床数据来源:我们检索了三个电子文献数据库,针对观察性前瞻性主动药物警戒研究、上市后安全性监测的IV期临床试验以及评估主动药物警戒策略的干预性研究进行了系统综述,重点关注暴露于全身性抗病毒药物的个体:我们纳入了 36 项主要采用药物事件监测 (DEM) 技术的初步研究,少数研究采用了哨点和登记制度。人类免疫缺陷病毒(HIV)是最常见的病症,其中大多数采用 DEM。在药物监测(DEM)中,至少有一种 AE 的患者发生率差异很大,其中大多数研究使用了一种或两种数据源。哨点研究并不常见,其中两项研究涉及丙型肝炎病毒 (HCV),一项涉及艾滋病病毒 (HIV),每项研究都依赖于一种或两种数据源。唯一一项使用登记册的研究报告称,该研究重点关注艾滋病治疗,仅使用了一个数据源。患者访谈是最常见的数据来源,其次是医疗记录和实验室检测。18/36 项研究的质量被认为是 "良好",1/36 项研究的质量被认为是 "一般",17/36 项研究的质量被认为是 "较差":DEM是最主要的药物警戒策略,采用了多种数据来源,似乎增加了发现较高AE发生率的可能性。建立这样一个框架将有助于在不同的研究和环境中采用更详细、更一致的方法。
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引用次数: 0
Unveiling the Burden of Drug-Induced Impulsivity: A Network Analysis of the FDA Adverse Event Reporting System. 揭示药物诱发冲动的负担:美国食品和药物管理局不良事件报告系统网络分析》。
IF 4 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-12-01 Epub Date: 2024-08-15 DOI: 10.1007/s40264-024-01471-z
Michele Fusaroli, Stefano Polizzi, Luca Menestrina, Valentina Giunchi, Luca Pellegrini, Emanuel Raschi, Daniel Weintraub, Maurizio Recanatini, Gastone Castellani, Fabrizio De Ponti, Elisabetta Poluzzi

Introduction: Impulsivity induced by dopaminergic agents, like pramipexole and aripiprazole, can lead to behavioral addictions that impact on social functioning and quality of life of patients and families (e.g., resulting in unemployment, marital problems, anxiety). These secondary effects, interconnected in networks of signs and symptoms, are usually overlooked by clinical trials, not reported in package inserts, and neglected in clinical practice.

Objective: This study explores the syndromic burden of impulsivity induced by pramipexole and aripiprazole, pinpointing key symptoms for targeted mitigation.

Methods: An event-event Information Component (IC) on the FDA Adverse Event Reporting System (FAERS) (January 2004 to March 2022) identified the syndrome of events disproportionally co-reported with impulsivity, separately for pramipexole and aripiprazole. A greedy-modularity clustering on composite network analyses (positive pointwise mutual information [PPMI], Ising, Φ) identified sub-syndromes. Bayesian network modeling highlighted possible precipitating events.

Results: Suspected drug-induced impulsivity was documented in 7.49% pramipexole and 4.50% aripiprazole recipients. The highest IC concerned obsessive-compulsive disorder (reporting rate = 26.77%; IC median = 3.47, 95% confidence interval [CI] = 3.33-3.57) and emotional distress (21.35%; 3.42, 3.26-3.54) for pramipexole, bankruptcy (10.58%; 4.43, 4.26-4.55) and divorce (7.59%; 4.38, 4.19-4.53) for aripiprazole. The network analysis identified delusional jealousy and dopamine dysregulation sub-syndromes for pramipexole, obesity-hypoventilation and social issues for aripiprazole. The Bayesian network highlighted anxiety and economic problems as potentially precipitating events.

Conclusion: The under-explored consequences of drug-induced impulsivity significantly burden patients and families. Network analyses, exploring syndromic reactions and potential precipitating events, complement traditional techniques and clinical judgment. Characterizing the secondary impact of reactions will support informed patient-centered decision making.

导言:普拉克索(pramipexole)和阿立哌唑(aripiprazole)等多巴胺能药物诱发的冲动性可导致行为成瘾,影响患者和家庭的社会功能和生活质量(如导致失业、婚姻问题和焦虑)。这些次生效应在体征和症状网络中相互关联,通常被临床试验忽视,未在包装说明书中报告,在临床实践中也被忽视:本研究探讨了普拉克索和阿立哌唑诱发冲动的综合症负担,找出关键症状,以便有针对性地缓解冲动:美国食品和药物管理局不良事件报告系统(FAERS)的事件-事件信息组件(IC)(2004年1月至2022年3月)分别确定了普拉克索和阿立哌唑与冲动不成比例地共同报告的事件综合征。通过对复合网络分析(正向点互信息[PPMI]、Ising、Φ)进行贪婪模块化聚类,确定了亚综合征。贝叶斯网络模型突出了可能的诱发事件:7.49%的普拉克索受试者和4.50%的阿立哌唑受试者有疑似药物诱发冲动的记录。普拉克索的最高IC涉及强迫症(报告率=26.77%;IC中位数=3.47,95%置信区间[CI]=3.33-3.57)和情绪困扰(21.35%;3.42,3.26-3.54),阿立哌唑的最高IC涉及破产(10.58%;4.43,4.26-4.55)和离婚(7.59%;4.38,4.19-4.53)。网络分析确定了普拉克索的妄想性嫉妒和多巴胺调节障碍亚综合征,阿立哌唑的肥胖-过度通气和社会问题。贝叶斯网络强调焦虑和经济问题是潜在的诱发事件:结论:药物诱发冲动的后果尚未得到充分探讨,这给患者和家庭造成了沉重负担。探索综合反应和潜在诱发事件的网络分析是对传统技术和临床判断的补充。确定反应的次要影响将有助于做出以患者为中心的明智决策。
{"title":"Unveiling the Burden of Drug-Induced Impulsivity: A Network Analysis of the FDA Adverse Event Reporting System.","authors":"Michele Fusaroli, Stefano Polizzi, Luca Menestrina, Valentina Giunchi, Luca Pellegrini, Emanuel Raschi, Daniel Weintraub, Maurizio Recanatini, Gastone Castellani, Fabrizio De Ponti, Elisabetta Poluzzi","doi":"10.1007/s40264-024-01471-z","DOIUrl":"10.1007/s40264-024-01471-z","url":null,"abstract":"<p><strong>Introduction: </strong>Impulsivity induced by dopaminergic agents, like pramipexole and aripiprazole, can lead to behavioral addictions that impact on social functioning and quality of life of patients and families (e.g., resulting in unemployment, marital problems, anxiety). These secondary effects, interconnected in networks of signs and symptoms, are usually overlooked by clinical trials, not reported in package inserts, and neglected in clinical practice.</p><p><strong>Objective: </strong>This study explores the syndromic burden of impulsivity induced by pramipexole and aripiprazole, pinpointing key symptoms for targeted mitigation.</p><p><strong>Methods: </strong>An event-event Information Component (IC) on the FDA Adverse Event Reporting System (FAERS) (January 2004 to March 2022) identified the syndrome of events disproportionally co-reported with impulsivity, separately for pramipexole and aripiprazole. A greedy-modularity clustering on composite network analyses (positive pointwise mutual information [PPMI], Ising, Φ) identified sub-syndromes. Bayesian network modeling highlighted possible precipitating events.</p><p><strong>Results: </strong>Suspected drug-induced impulsivity was documented in 7.49% pramipexole and 4.50% aripiprazole recipients. The highest IC concerned obsessive-compulsive disorder (reporting rate = 26.77%; IC median = 3.47, 95% confidence interval [CI] = 3.33-3.57) and emotional distress (21.35%; 3.42, 3.26-3.54) for pramipexole, bankruptcy (10.58%; 4.43, 4.26-4.55) and divorce (7.59%; 4.38, 4.19-4.53) for aripiprazole. The network analysis identified delusional jealousy and dopamine dysregulation sub-syndromes for pramipexole, obesity-hypoventilation and social issues for aripiprazole. The Bayesian network highlighted anxiety and economic problems as potentially precipitating events.</p><p><strong>Conclusion: </strong>The under-explored consequences of drug-induced impulsivity significantly burden patients and families. Network analyses, exploring syndromic reactions and potential precipitating events, complement traditional techniques and clinical judgment. Characterizing the secondary impact of reactions will support informed patient-centered decision making.</p>","PeriodicalId":11382,"journal":{"name":"Drug Safety","volume":" ","pages":"1275-1292"},"PeriodicalIF":4.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11554833/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Paracetamol Dosing Errors in People Aged 12 Years and Over: An Analysis of Over 14,000 Cases Reported to an Australian Poisons Information Centre. 12 岁及以上人群中的扑热息痛剂量错误:对澳大利亚毒药信息中心收到的 14,000 多例报告的分析。
IF 5.4 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-12-01 Epub Date: 2024-09-02 DOI: 10.1007/s40264-024-01472-y
Annabelle S Chidiac, Nicholas A Buckley, Firouzeh Noghrehchi, Rose Cairns

Introduction: Paracetamol dosing errors can cause acute liver injury, with potentially toxic doses only slightly above the therapeutic range. This study aimed to characterise unintentional paracetamol overdose reported to an Australian poisons centre, including time trends, demographics, types of dosing errors, and outcomes.

Methods: Records regarding paracetamol dosing errors for individuals aged ≥12 years were extracted from the New South Wales Poisons Information Centre database, January 2017 to June 2023. Data from 2021 underwent an in-depth screening of free text case notes to examine: dose, duration, products involved, reasons for ingestion and outcomes including hospitalisation, treatment, liver transplantations and deaths. Where possible, complete outcome data were obtained from medical records of New South Wales hospitalised cases in 2021.

Results: There were 14,380 exposures due to paracetamol dosing errors (predominantly self-administered, median age 43 years, 62.6% female), with an average yearly increase of 2.5% (95% CI 1.6-3.8%; p < 0.0001). The in-depth analysis of exposures recorded during 2021 revealed 1899 exposures (median age 46 years, 63.4% female) with 26.8% requiring hospitalisation. Immediate- and modified-release formulations were highly implicated. Multiple paracetamol-containing products were ingested in approximately 20% of exposures. Hospitalised exposures were associated with paracetamol use for dental pain and ingested higher doses for longer durations. Over half of those hospitalised (52%) were treated with the antidote (N-acetylcysteine), and 6% of exposures developed hepatotoxicity.

Conclusion: Paracetamol dosing errors continue to occur, with relatively high rates of hospitalisation and liver injury. Many hospitalisations involved use for dental pain. Possible preventative measures include ingredient name prominence and increased education on appropriate dosing.

简介扑热息痛用药错误可导致急性肝损伤,其潜在毒性剂量仅略高于治疗范围。本研究旨在了解澳大利亚毒物中心接报的扑热息痛意外过量的特点,包括时间趋势、人口统计学、给药错误类型和结果:从新南威尔士州毒药信息中心数据库中提取了2017年1月至2023年6月期间年龄≥12岁的人的扑热息痛用药错误记录。对 2021 年的数据进行了深入的自由文本病例记录筛选,以检查:剂量、持续时间、涉及的产品、摄入原因以及包括住院、治疗、肝移植和死亡在内的结果。在可能的情况下,从 2021 年新南威尔士州住院病例的医疗记录中获取了完整的结果数据:共有 14,380 例因扑热息痛剂量错误(主要为自行用药,中位年龄为 43 岁,62.6% 为女性)而导致的暴露,平均每年增加 2.5% (95% CI 1.6-3.8%; p < 0.0001)。对 2021 年期间记录的暴露情况进行的深入分析显示,共发生 1899 次暴露(中位年龄为 46 岁,63.4% 为女性),其中 26.8% 需要住院治疗。速释和改良释放制剂受到的影响较大。在约 20% 的暴露事件中,摄入了多种含扑热息痛的产品。住院患者多因牙痛而服用扑热息痛,且服用剂量较大、持续时间较长。超过一半的住院患者(52%)接受了解毒剂(N-乙酰半胱氨酸)治疗,6%的接触者出现了肝中毒:结论:扑热息痛用药错误仍时有发生,住院率和肝损伤率相对较高。许多住院治疗涉及牙痛。可能的预防措施包括突出成分名称和加强适当剂量的教育。
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引用次数: 0
A Calculated Risk: Evaluation of QTc Drug-Drug Interaction (DDI) Clinical Decision Support (CDS) Alerts and Performance of the Tisdale Risk Score Calculator. 计算风险:评估 QTc 药物相互作用 (DDI) 临床决策支持 (CDS) 警报和 Tisdale 风险评分计算器的性能。
IF 5.4 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-12-01 Epub Date: 2024-07-09 DOI: 10.1007/s40264-024-01466-w
Rachel L Wasserman, Diane L Seger, Mary G Amato, Andrew Y Hwang, Julie Fiskio, David W Bates

Introduction: A risk factor for a potentially fatal ventricular arrhythmia Torsade de Pointes is a prolongation in the heart rate-corrected QT interval (QTc) ≥ 500 milliseconds (ms) or an increase of ≥ 60 ms from a patient's baseline value, which can cause sudden cardiac death. The Tisdale risk score calculator uses clinical variables to predict which hospitalized patients are at the highest risk for QTc prolongation.

Objective: To determine the rate of overridden QTc drug-drug interaction (DDI)-related clinical decision support (CDS) alerts per patient admission and the prevalence by Tisdale risk score category of these overridden alerts. Secondary outcome was to determine the rate of drug-induced QTc prolongation (diQTP) associated with overrides.

Methods: Our organization's enterprise data warehouse was used to retrospectively access QTc DDI alerts presented for patients aged ≥ 18 years who were admitted to Brigham and Women's Hospital during 2022. The QTc DDI CDS alerts were included if shown to a physician, fellow, resident, physician assistant, or nurse practitioner when entering the order in inpatient areas for patients with a length of stay of at least 2 days. Variables collected for the Tisdale calculator included age, sex, whether patient was on a loop diuretic, potassium level, admission QTc value, admitting diagnosis of acute myocardial infarction, sepsis, or heart failure, and number of QTc-prolonging drugs given to the patient.

Results: A total of 2649 patients with 3033 patient admissions had 18,432 QTc DDI alerts presented that were overridden. An average of 3 unique QTc DDI alerts were presented per patient admission and the alerts were overridden an average of 6 times per patient admission. Overall, 6% of patient admissions were low risk (score ≤ 6), 64% moderate risk (score 7-10), and 30% high risk (score ≥ 11) of QTc prolongation. The most common QTc DDI alerts overridden resulting in an diQTP were quetiapine and propofol (11%) and amiodarone and haloperidol (7%). The diQTP occurred in 883 of patient admissions (29%) and was more frequent in those with higher risk score, with 46% of patient admissions with diQTP in high risk, 23% in moderate risk, and 8% in low risk.

Conclusion: Use of the Tisdale calculator to assess patient-specific risk of QT prolongation combined with CDS may improve overall alert quality and acceptance rate, which may decrease the diQTP rate.

导言:潜在致命性室性心律失常 Torsade de Pointes 的一个风险因素是心率校正 QT 间期(QTc)延长≥ 500 毫秒(ms)或比患者的基线值增加≥ 60 毫秒,这会导致心脏性猝死。Tisdale 风险评分计算器利用临床变量来预测哪些住院患者发生 QTc 延长的风险最高:目的:确定每名入院患者QTc药物相互作用(DDI)相关临床决策支持(CDS)警报的超限率,以及这些超限警报在Tisdale风险评分类别中的发生率。次要结果是确定与超载相关的药物诱导 QTc 延长(diQTP)率:方法:使用本机构的企业数据仓库,回顾性访问 2022 年期间布里格姆妇女医院收治的年龄≥ 18 岁患者的 QTc DDI 警报。如果在住院区为住院时间至少为 2 天的患者输入医嘱时向医生、研究员、住院医师、医生助理或执业护士显示了 QTc DDI CDS 警报,则该警报将被包括在内。为 Tisdale 计算器收集的变量包括年龄、性别、是否使用环形利尿剂、血钾水平、入院 QTc 值、急性心肌梗死、脓毒症或心力衰竭的入院诊断,以及为患者使用的 QTc 延长药物的数量:共有 2649 名患者和 3033 名入院患者收到了 18,432 次 QTc DDI 警报,这些警报均被覆盖。每名入院患者平均出现 3 次独特的 QTc DDI 警报,每名入院患者平均有 6 次警报被覆盖。总体而言,6% 的入院患者为低风险(评分≤ 6),64% 为中度风险(评分 7-10),30% 为 QTc 延长的高风险(评分≥ 11)。最常见的导致 diQTP 的 QTc DDI 警报被覆盖的药物是喹硫平和异丙酚(11%)以及胺碘酮和氟哌啶醇(7%)。883例入院患者(29%)发生了diQTP,风险评分越高的患者发生diQTP的频率越高,46%的入院患者为高风险,23%为中度风险,8%为低风险:结论:使用 Tisdale 计算器评估患者 QT 延长的特异性风险并结合 CDS 可提高整体警报质量和接受率,从而降低 diQTP 发生率。
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引用次数: 0
Short-Term Training, a Useful Approach for Sustainable Pharmacovigilance Knowledge Development in Tanzania, Kenya, Ethiopia and Rwanda. 短期培训是坦桑尼亚、肯尼亚、埃塞俄比亚和卢旺达可持续发展药物警戒知识的有效方法。
IF 5.4 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-12-01 Epub Date: 2024-08-20 DOI: 10.1007/s40264-024-01469-7
Eugène van Puijenbroek, Abbie Barry, Christabel Khaemba, Lazare Ntirenganya, Tigist Dires Gebreyesus, Adam Fimbo, Omary Minzi, Eyasu Makonnen, Margaret Oluka, Anastasia Guantai, Eleni Aklillu

Continuous professional development among stakeholders involved in drug safety monitoring and surveillance is imperative in strengthening pharmacovigilance (PV) systems. The "Pharmacovigilance infrastructure and post-marketing surveillance system capacity building for regional medicine regulatory harmonization in East Africa" (PROFORMA) project aims to enhance the national PV infrastructure, post-marketing surveillance systems and clinical trial regulatory capabilities in Ethiopia, Tanzania, Kenya and Rwanda. To achieve this, training, including short-term training (STT) activities, at various levels is required. This article aims to describe the experiences of the authors during the development and implementation of STT in an attempt to improve the PV training landscape of these countries. To identify gaps, a baseline assessment of PV teaching and practices at the national medicines regulatory authorities (NMRAs) and medical universities was conducted. Five successive training sessions, tailored to each country's specific needs and regulatory environments, were conducted; three focusing on fundamental concepts in PV and two dedicated to training-of-trainers courses. The training targeted staff from PV units of the NMRAs and medical universities. Enabling participation from all four countries in the same training fostered cross-country learning and collaboration. The contribution of STT to university education and the operational methodologies within NMRAs are explored, showcasing the impact on knowledge transfer and skill development in each country. In conclusion, by investing strategically in STT activities and fostering partnerships with academic institutions and NMRAs, we demonstrated a sustainable approach to PV capacity strengthening in resource-limited settings. The success of this model underscores its potential for adoption and replication across the African continent, offering a valuable framework for strengthening drug safety regulation and ultimately protecting public health.

要加强药物警戒(PV)系统,参与药物安全监测和监督的利益相关方必须不断进行专业发展。药物警戒基础设施和上市后监测系统能力建设促进东非地区药品监管协调"(PROFORMA)项目旨在加强埃塞俄比亚、坦桑尼亚、肯尼亚和卢旺达的国家药物警戒基础设施、上市后监测系统和临床试验监管能力。为此,需要在各个层面开展培训,包括短期培训 (STT) 活动。本文旨在介绍作者在制定和实施 STT 期间的经验,以改善这些国家的 PV 培训状况。为了找出差距,我们对国家药品监管机构 (NMRA) 和医科大学的光伏教学和实践进行了基线评估。根据各国的具体需求和监管环境,连续举办了五次培训课程;其中三次侧重于光伏的基本概念,两次专门用于培训员培训课程。培训对象是来自国家医疗卫生机构光伏部门和医科大学的工作人员。让所有四个国家的人员参加同一培训促进了跨国学习与合作。我们探讨了 STT 对大学教育的贡献以及国家医疗资源管理局内部的操作方法,展示了 STT 对各国知识转让和技能发展的影响。总之,通过对 STT 活动进行战略性投资,并促进与学术机构和国家监测和评估机构的合作,我们展示了在资源有限的环境中加强光伏能力的可持续方法。这一模式的成功强调了其在整个非洲大陆采用和推广的潜力,为加强药品安全监管并最终保护公众健康提供了一个宝贵的框架。
{"title":"Short-Term Training, a Useful Approach for Sustainable Pharmacovigilance Knowledge Development in Tanzania, Kenya, Ethiopia and Rwanda.","authors":"Eugène van Puijenbroek, Abbie Barry, Christabel Khaemba, Lazare Ntirenganya, Tigist Dires Gebreyesus, Adam Fimbo, Omary Minzi, Eyasu Makonnen, Margaret Oluka, Anastasia Guantai, Eleni Aklillu","doi":"10.1007/s40264-024-01469-7","DOIUrl":"10.1007/s40264-024-01469-7","url":null,"abstract":"<p><p>Continuous professional development among stakeholders involved in drug safety monitoring and surveillance is imperative in strengthening pharmacovigilance (PV) systems. The \"Pharmacovigilance infrastructure and post-marketing surveillance system capacity building for regional medicine regulatory harmonization in East Africa\" (PROFORMA) project aims to enhance the national PV infrastructure, post-marketing surveillance systems and clinical trial regulatory capabilities in Ethiopia, Tanzania, Kenya and Rwanda. To achieve this, training, including short-term training (STT) activities, at various levels is required. This article aims to describe the experiences of the authors during the development and implementation of STT in an attempt to improve the PV training landscape of these countries. To identify gaps, a baseline assessment of PV teaching and practices at the national medicines regulatory authorities (NMRAs) and medical universities was conducted. Five successive training sessions, tailored to each country's specific needs and regulatory environments, were conducted; three focusing on fundamental concepts in PV and two dedicated to training-of-trainers courses. The training targeted staff from PV units of the NMRAs and medical universities. Enabling participation from all four countries in the same training fostered cross-country learning and collaboration. The contribution of STT to university education and the operational methodologies within NMRAs are explored, showcasing the impact on knowledge transfer and skill development in each country. In conclusion, by investing strategically in STT activities and fostering partnerships with academic institutions and NMRAs, we demonstrated a sustainable approach to PV capacity strengthening in resource-limited settings. The success of this model underscores its potential for adoption and replication across the African continent, offering a valuable framework for strengthening drug safety regulation and ultimately protecting public health.</p>","PeriodicalId":11382,"journal":{"name":"Drug Safety","volume":" ","pages":"1193-1202"},"PeriodicalIF":5.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11554700/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142003892","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
RETRACTED ARTICLE: Long-Term Safety Analysis of the BBV152 Coronavirus Vaccine in Adolescents and Adults: Findings from a 1-Year Prospective Study in North India. BBV152 冠状病毒疫苗在青少年和成人中的长期安全性分析:印度北部为期一年的前瞻性研究结果。
IF 5.4 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-12-01 Epub Date: 2024-05-13 DOI: 10.1007/s40264-024-01432-6
Upinder Kaur, Aakanksha Jaiswal, Ayushi Jaiswal, Kunal Singh, Aditi Pandey, Mayank Chauhan, Mahek Rai, Sangeeta Kansal, Kishor Patwardhan, Vaibhav Jaisawal, Sankha Shubhra Chakrabarti
{"title":"RETRACTED ARTICLE: Long-Term Safety Analysis of the BBV152 Coronavirus Vaccine in Adolescents and Adults: Findings from a 1-Year Prospective Study in North India.","authors":"Upinder Kaur, Aakanksha Jaiswal, Ayushi Jaiswal, Kunal Singh, Aditi Pandey, Mayank Chauhan, Mahek Rai, Sangeeta Kansal, Kishor Patwardhan, Vaibhav Jaisawal, Sankha Shubhra Chakrabarti","doi":"10.1007/s40264-024-01432-6","DOIUrl":"10.1007/s40264-024-01432-6","url":null,"abstract":"","PeriodicalId":11382,"journal":{"name":"Drug Safety","volume":" ","pages":"1441"},"PeriodicalIF":5.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140916302","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Signals of Possibly Persistent Gustatory, Olfactory and Auditory Adverse Drug Reactions to Antibiotic Drugs: A Disproportionality Analysis Using the EudraVigilance Database. 抗生素药物可能持续存在的味觉、嗅觉和听觉药物不良反应信号:利用 EudraVigilance 数据库进行的比例失调分析。
IF 4 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-11-08 DOI: 10.1007/s40264-024-01491-9
Sara Ferraro, Emiliano Cappello, Marco Fornili, Irma Convertino, Marco Bonaso, Ersilia Lucenteforte, Marco Tuccori
<p><strong>Background: </strong>In 2018, the European Medicines Agency issued some risk minimisation measures related to unresolved adverse drug reactions (ADRs) reported for fluoroquinolones, including sensory ADRs. Spontaneous reporting databases frequently report unresolved outcomes for gustatory, olfactory and auditory (GOA) ADRs. However, such a high volume of unresolved GOA ADRs could reflect an under-investigated clinical issue or an intrinsic difficulty in the outcome assessment.</p><p><strong>Objectives: </strong>The objectives of the study were: (1) to investigate whether unresolved outcomes are reported more frequently for GOA ADRs than for other ADRs to systemic antibiotics and (2) to identify possible signals of unresolved GOA ADRs for systemic antibiotics.</p><p><strong>Methods: </strong>We used the EudraVigilance database to extract the number of ADRs to systemic antibiotics of the Anatomical Therapeutic Chemical class J01 up to February 2019. We classified ADRs in "non-GOA ADRs" and "GOA ADRs". Adverse drug reactions were categorised in three groups according to the outcome: defined, persistent/permanent (unresolved) and undetermined ADRs. We performed disproportionality analyses with the case/non-case methodology, by calculating the crude reporting odds ratio (ROR) and 95% confidence interval (CI). Cases were all persistent/permanent ADRs, and non-cases were defined and undetermined ADRs. For the first objective, index groups were gustatory or olfactory or auditory ADRs, while reference group included all non-GOA ADRs. For the second objective, we performed a disproportionality analysis by using the sub-set of GOA ADRs. Index and reference groups varied with subgroups of drugs and drug class, so that each drug and drug class was compared with the others. We conducted two sensitivity analyses for each analysis by varying the case definition.</p><p><strong>Results: </strong>We extracted 748,798 ADRs, including 10,770 GOA ADRs. The first analysis showed that GOA ADRs were reported more frequently as unresolved events compared with all other ADRs (ROR: 2.68 95% CI 2.51-2.85; ROR: 5.20 95% CI 4.66-5.81; and ROR: 2.64 (95% CI 2.51-2.79, respectively). Gustatory ADRs were reported more frequently as unresolved for doxycycline (ROR: 1.69, 95% CI 1.18-2.41, p = 0.0038), azithromycin (ROR: 2.07, 95% CI 1.58-2.72, p < 0.0001) and levofloxacin (ROR: 1.59, 95% CI 1.22-2.07, p < 0.001) compared with GOA ADRs of all other antibiotics. Olfactory ADRs were reported more frequently as unresolved for doxycycline (ROR: 2.4, 95% CI 1.26-4.58, p = 0.0078) and levofloxacin (ROR: 1.92, 95% CI 1.28-2.86, p = 0.0014). Auditory ADRs were reported more frequently as unresolved for doxycycline (ROR: 1.52, 95% CI 1.09-2.12, p = 0.013) and clarithromycin (ROR: 1.31, 95% CI 1.09-1.59, p = 0.0049).</p><p><strong>Conclusions: </strong>We tested and used an appropriate expected frequency standard, which allows us to identify possible signals of unresolved GOA ADRs
背景:2018 年,欧洲药品管理局发布了一些与氟喹诺酮类药物(包括感官 ADR)报告的未解决药物不良反应(ADR)相关的风险最小化措施。自发报告数据库经常报告未解决的味觉、嗅觉和听觉(GOA)ADR 结果。然而,大量未解决的味觉、嗅觉和听觉不良反应可能反映出临床问题未得到充分调查或结果评估存在内在困难:本研究的目的是研究目的:(1)调查与全身用抗生素的其他不良反应相比,GOA ADR 的未解决结果报告是否更频繁;(2)确定全身用抗生素的 GOA ADR 未解决的可能信号:我们使用 EudraVigilance 数据库提取了截至 2019 年 2 月的解剖治疗化学类 J01 全身用抗生素的 ADR 数量。我们将ADR分为 "非GOA ADR "和 "GOA ADR"。药物不良反应根据结果分为三类:已确定、持续/永久(未解决)和未确定的 ADR。我们采用病例/非病例方法进行了比例失调分析,计算了粗报告几率比(ROR)和 95% 置信区间(CI)。病例是指所有持续性/永久性 ADR,非病例是指已确定和未确定的 ADR。在第一个目标中,指标组为味觉、嗅觉或听觉 ADR,参照组包括所有非 GOA ADR。对于第二个目标,我们使用全球海洋观测系统 ADR 子集进行了比例失调分析。指数组和参照组随着药物和药物类别的分组而变化,因此每种药物和药物类别都与其他药物和药物类别进行了比较。通过改变病例定义,我们对每项分析进行了两次敏感性分析:我们提取了 748,798 例 ADR,其中包括 10,770 例 GOA ADR。第一项分析表明,与所有其他 ADR 相比,GOA ADR 作为未解决事件报告的频率更高(ROR:2.68 95% CI 2.51-2.85;ROR:5.20 95% CI 4.66-5.81;ROR:2.64 (95% CI 2.51-2.79,分别为 2.68、5.20 和 2.64)。与所有其他抗生素的GOA ADR相比,多西环素(ROR:1.69,95% CI 1.18-2.41,p = 0.0038)、阿奇霉素(ROR:2.07,95% CI 1.58-2.72,p < 0.0001)和左氧氟沙星(ROR:1.59,95% CI 1.22-2.07,p < 0.001)的口腔ADR未解决的报告频率更高。多西环素(ROR:2.4,95% CI 1.26-4.58,p = 0.0078)和左氧氟沙星(ROR:1.92,95% CI 1.28-2.86,p = 0.0014)的嗅觉 ADR 更常被报告为未解决。多西环素(ROR:1.52,95% CI 1.09-2.12,p = 0.013)和克拉霉素(ROR:1.31,95% CI 1.09-1.59,p = 0.0049)的听觉 ADR 更常被报告为未解决:我们测试并使用了一种适当的预期频率标准,该标准使我们能够识别 EudraVigilance 数据库中可能存在的抗生素药物未解决的 GOA ADR 信号。这种方法可用于生成其他药物或不良反应的持续性甚至不可逆事件信号。不过,这些信号必须通过全面的临床评估加以确认。
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引用次数: 0
Teratogenic Risk Impact and Mitigation (TRIM): Study Protocol for the Development of a Decision Support Tool to Prioritize Medications for Risk Mitigation. 畸胎风险影响与缓解(TRIM):开发决策支持工具以确定药物风险缓解优先次序的研究方案》(Study Protocol for the Development of a Decision Support Tool to Prioritize Medications for Risk Mitigation)。
IF 4 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-11-05 DOI: 10.1007/s40264-024-01488-4
Almut G Winterstein, Celeste L Y Ewig, Yanning Wang, Nicole E Smolinski, Gita A Toyserkani, Cynthia LaCivita, Leila Lackey, Sara Eggers, Esther H Zhou, Vakaramoko Diaby, Amir Sarayani, Thuy Thai, Judith C Maro, Sonja A Rasmussen

Introduction: Preventing prenatal exposure to teratogenic medications is an important goal of regulatory risk mitigation efforts. In the USA, as of March 2024, 11 teratogenic medications have a required Risk Evaluation and Mitigation Strategy (REMS) program. It is unclear whether these programs target those medications with the most significant impact on public health and adverse pregnancy outcomes.

Objectives: This study aims to develop an innovative decision support tool that uses explicit, quantifiable criteria to facilitate prioritization of teratogenic medications for risk mitigation strategies.

Methods: The Teratogenic Risk Impact and Mitigation (TRIM) decision support tool will be developed by a national panel via a modified Delphi approach to define measurable criteria, and a multi-criteria decision analysis to estimate criteria weights within a discrete choice experiment. The TRIM scores will then be calculated for 12 teratogenic drugs with active or eliminated REMS programs and for 12 teratogenic drugs without REMS. These drugs will be identified based on highest prenatal exposure prevalence in claims data of privately and publicly insured individuals. Data for the TRIM criteria levels for these 24 drugs will be identified from evidence searches and ad hoc analyses of the same claims data.

Conclusions: Teratogenic Risk Impact and Mitigation is intended to inform regulatory decision making about the need for risk mitigation programs for teratogenic medications by providing explicit, quantifiable, evidence-based criteria. The TRIM scores of 24 teratogenic drugs may provide benchmarks for considering REMS for marketed and new teratogenic medications.

导言:预防产前接触致畸药物是监管部门降低风险工作的一个重要目标。在美国,截至 2024 年 3 月,有 11 种致畸药物必须实施风险评估与缓解策略 (REMS) 计划。目前尚不清楚这些计划是否针对那些对公众健康和不良妊娠结局影响最大的药物:本研究旨在开发一种创新的决策支持工具,该工具采用明确的、可量化的标准来帮助确定致畸药物在风险缓解策略中的优先次序:方法:致畸风险影响与缓解(TRIM)决策支持工具将由一个国家小组开发,该小组将通过改良的德尔菲法(Delphi approach)来定义可衡量的标准,并通过多标准决策分析法(Multi-criteria decision analysis)在离散选择实验中估算标准权重。然后,将为 12 种已实施或取消 REMS 计划的致畸药物和 12 种未实施 REMS 的致畸药物计算 TRIM 分数。这些药物将根据私人和公共投保人理赔数据中最高的产前暴露率来确定。这 24 种药物的 TRIM 标准水平数据将通过证据搜索和对相同索赔数据的特别分析来确定:结论:《致畸风险影响与缓解》旨在通过提供明确的、可量化的、基于证据的标准,为监管部门制定致畸药物风险缓解方案提供决策依据。24 种致畸药物的 TRIM 评分可为考虑已上市和新的致畸药物的 REMS 提供基准。
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引用次数: 0
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Drug Safety
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