Causality assessment of suspected adverse drug reactions: A transatlantic view

The European Community's (EC) pending requirement for a standard assessment of the causal association between a drug product and a reported drug-associated event prompts a review of this aspect of pharmaceutical safety evaluation. Pharmaceutical manufacturers who use various methods, or no methods, may need to consider these EC definitions and their interpretation for evaluating their current procedures and planning any future changes. This paper first describes the EC classifications and their basis as one statement on the status of causality assessment in Europe. Reflecting the rather different view of causality assessment in North America, this paper then briefly reviews the evolution and uses of causality assessment over the last two decades. The controversies over causality are next discussed, followed by examination of the diverse uses of assessment by a pharmaceutical manufacturer or a regulator. Finally, the paper concludes with thoughts on applying causality concepts as tools for enhancing drug-risk assessment.     

The quality of spontaneous adverse drug reaction reports from the pharmacovigilance centre in western China

Background: High-quality adverse drug reaction (ADR) reports are essential for conducting drug safety monitoring in pharmacovigilance. The study aim was to assess the current quality of ADR reports in western China, and to identify problems with ADR report quality.

Research design and methods: A sample of 1139 reports received by the Shaanxi ADR Monitoring Center from January 2015 to December 2017 was selected. ADR report quality was evaluated using an ADR report quality evaluation system.

Results: None of the reports were rated as excellent and 1.40% (n = 16) as good. Report quality was better for new and serious reports than for general reports. Medical institutions generated higher quality reports than pharmaceutical manufacturers. Nurses generated higher quality reports than doctors, pharmacists, and other professionals. Reporters of different occupations showed significant differences in the quality of the indicators Reporting time limit, Intervention ADR time, ADR termination time, ADR intervention measures, Original disease, and Cause of medication (P = 0.000).

Conclusions: The ADR data quality was poor in western China, and of lower quality than reported data from previous research in other regions. Improvements in the quality and availability of ADR reports are urgently needed.     

欧盟药物警戒检查制度简介

文章旨在了解欧盟药物警戒检查制度的背景与实施,为我国开展检查工作提供借鉴和参考。根据欧盟法规,欧洲药品管理局建立了一套包括检查程序、检查内容在内的完整体系。建立检查制度对于监督和促进生产企业开展药品不良反应报告和监测工作具有重要作用,我国《药品不良反应报告和监测管理办法》已为此奠定了实施基础,但尚缺乏具体实施的程序与规范,值得今后深入研究和实践。     

Development of pharmacovigilance system in Ukraine: first results

The article is devoted to the establishment and development of the National Pharmacovigilance system in Ukraine. A drug safety centre of Ukraine started to form a pharmacovigilance system in 1996. It has been operating on a regular basis since 2000 and now provides the regulatory services that include data collection and analysis, database management, education, international contacts, and the publication and dissemination of information. Our ultimate goal is to foster a rational and safe drug use and to improve the quality of pharmacotherapy in Ukraine.     

欧盟药物警戒额外监测制度简介与启示

2013年随着欧盟《良好药物警戒管理规范x》的生效,药品额外监测制度得到进一步完善。药品额外监测制度是一种通过建立监测目录、公开目录药品信息、采用特定标识等措施,鼓励医务人员和患者自发报告可疑不良反应,以便顺利开展上市后安全性评价,确保任何新的用药安全隐患能够被及时发现和有效避免的制度。通过介绍欧盟药物警戒额外监测制度,阐述我国药品不良反应（ADR）监测的现状,指出该制度是一种积极主动发现用药风险的尝试;学习和借鉴该制度,有助于我国弥补原有药品ADR报告系统低报、漏报等缺陷,主动开展用药安全监测,从而获得更加全面科学的结果。     

欧盟药物警戒额外监测制度简介与启示

2013年随着欧盟《良好药物警戒管理规范X》的生效,药品额外监测制度得到进一步完善。药品额外监测制度是一种通过建立监测目录、公开目录药品信息、采用特定标识等措施,鼓励医务人员和患者自发报告可疑不良反应,以便顺利开展上市后安全性评价,确保任何新的用药安全隐患能够被及时发现和有效避免的制度。通过介绍欧盟药物警戒额外监测制度,阐述我国药品不良反应（ADR）监测的现状,指出该制度是一种积极主动发现用药风险的尝试;学习和借鉴该制度,有助于我国弥补原有药品ADR报告系统低报、漏报等缺陷,主动开展用药安全监测,从而获得更加全面科学的结果。     

Reports of hyperkalemia after publication of RALES--a pharmacovigilance study

PURPOSE: A population-based study and anecdotal reports have indicated that the publication of the Randomized Aldactone Evaluation Study (RALES) was associated with not merely a broader use of spironolactone in the treatment of heart failure, but also with a coinciding sharp increase in hyperkalemia-associated morbidity/mortality in patients also being treated with ACE-inhibitors. Data mining algorithms (DMAs) are being applied to spontaneous reporting system (SRS) databases in hopes of obtaining early warnings/additional insights into post-licensure safety data. We applied two DMAs (i.e. multi-item gamma Poisson shrinker [MGPS] and proportional reporting ratios [PRRs]) to spontaneous reporting system (SRS) data to determine if these DMAs could have provided an earlier indication of a possible hyperkalemia safety issue. METHODS: MGPS and PRRs were retrospectively applied to US FDA-AERS, an SRS database. Year-by-year analysis and analysis of increasing cumulative time intervals were performed on cases in which both spironolactone and hyperkalemia and possibly related cardiac events had been reported. RESULTS: Neither of the DMAs initially provided a compelling signal of disproportionate reporting (SDR) for hyperkalemia after publication of RALES. However, using events consistent with clinical sequelae of hyperkalemia (e.g,. sudden death), SDRs were identified with PRRs. CONCLUSIONS: The quality and usefulness of data mining analysis is highly situation dependent and may vary with the knowledge and experience of the drug safety reviewer. Our analysis suggests that contemporary DMAs may have significant limitations in detecting increased frequency of labeled events in real-life prospective pharmacovigilance. There is a paucity of research in this area and we recommend further research for new approaches to detecting increased frequency of labeled events.     

欧盟化妆品不良反应关联性评价方法简介

通过从评价方法的制定原则、制定标准和应用操作3方面详细介绍了欧盟化妆品不良反应关联性评价方法。欧盟化妆品不良反应关联性评价方法有着严格和缜密的制定原则,以及易于理解的评价逻辑,并采用了操作性强的决策树模式开展评价。该方法对于我国化妆品不良反应监测工作有着积极的借鉴意义。     

社区卫生服务中心254份药品不良反应报告分析

目的:了解基层社区卫生服务中心药品不良反应(ADR)发生的规律及特点,为临床合理用药及药物安全性评价提供依据。方法:回顾性总结分析我中心从2010年8月-2011年7月的254例ADR报告。结果:抗高血压药的ADR发生率最高,口服用药是发生ADR的主要途径。结论:应合理使用抗高血压药;加强药品不良反应监测,保障用药安全。     

Social media and pharmacovigilance: A review of the opportunities and challenges

Adverse drug reactions come at a considerable cost on society. Social media are a potentially invaluable reservoir of information for pharmacovigilance, yet their true value remains to be fully understood. In order to realize the benefits social media holds, a number of technical, regulatory and ethical challenges remain to be addressed. We outline these key challenges identifying relevant current research and present possible solutions.     

药品不良反应报告因果关系评价方法概述

药品不良反应因果关系的评价方法是药物警戒过程中比较重要的一种工具,该研究提供一个这些方法总的概述,并阐述他们的特点.药品不良反应因果关系评价方法大致分为三种:专家判断或全面内省法、计分推算法、概率法或贝叶斯法.专家判断法是基于先前已有的知识和经验的非标准化方法对个案进行评估,以得出因果关系的结论;计分推算法是设计一系列的问题,通过计算回答问题的分数来判断因果关系的可能性;贝叶斯法是通过使用个例报告的相关信息把药品因果关系的先验概率转化为后验概率的过程.先验概率是用流行病学信息计算得来,后验概率与这个背景信息相比得出因果关系的可能性.另外,不同的评价方法因果关系的分类也不同,因果关系评价的标准也不同.总之,目前仍然没有一种通用的因果关系评价方法.     

世界卫生组织药物警戒指标的开发和应用

为了解世界卫生组织（WHO）有关药物警戒系统的评估指标的开发和应用情况，给我国药物警戒系统的建设情况和活动进展的评估提供参考，对2015年WHO出版的《世界卫生组织药物警戒指标体系：评估药物警戒系统的实践手册》（v1.0）的内容进行全面详细的介绍，并对该手册的实际应用做进一步分享。WHO致力于推动国际药物警戒的发展，不仅制定了专门的实践手册以促进全球对药物警戒指标的理解，还通过多方合作共同推动药物警戒指标的发展和应用，药物警戒指标的设置比较灵活，可根据使用环境的实际情况进行适当调整。     

Inter-expert agreement of seven criteria in causality assessment of adverse drug reactions

AIMS: To evaluate agreement between five senior experts when assessing seven causality criteria and the probability of drug causation. METHODS: A sample of 31 adverse event-drug pairs was constituted. For each pair, five experts separately assessed (i) the probability of drug causation, which was secondarily divided into seven causality levels: ruled out (0-0.05), unlikely (0.06-0.25), doubtful (0.26-0.45), indeterminate (0.46-0.55), plausible (0.56-0.75), likely (0.76-0.95), and certain (0.96-1); and (ii) seven causality criteria. To test discrepancies between experts, the kappa index was used. RESULTS: The agreement of the five experts was very poor (kappa = 0.05) for the probability of drug causation. Among the seven levels of causality, only 'doubtful' showed a significant rate of agreement (kappa = 0.32, P < 0.001). For all criteria, the kappa index was significant except for the item 'risk(s) factor(s)' (kappa = 0.09). Agreement between experts was good (0.64, P < 0.001) only for the criterion 'reaction at site of application or toxic plasma concentration of the drug or validated test'. However, the rate of agreement with kappa indices of the causality criteria ranged from 0.12 to 0.38. CONCLUSIONS: This study confirms that in the absence of an operational procedure, agreement between experts is low. This should be considered when designing a causality assessment method. In particular, criteria inducing a low level of agreement should have their weight reduced.     

药物警戒视角下黄体酮注射液致注射部位不良反应/事件原因分析及对策建议

目的 探讨药物警戒视角下黄体酮注射液致用药部位出现药品不良反应/事件（ADR/ADE）的原因，提出安全用药和风险管理建议。方法 对国家药品不良反应监测系统（https://www.adrs.org.cn）中涉及河南省行政区域的不良反应报告进行检索，检索时间2010年1月—2022年12月（按药品不良反应发生时间计），怀疑药品为黄体酮注射液，报告单位类别为医疗机构，筛选黄体酮注射液相关的ADR/ADE。在中国学术期刊全文数据库（CNKI）、维普生物医学数据库（VIP）和万方数据库（Wanfang Data）中，以“黄体酮注射液”“致”“不良反应”“不良事件”“风险”等为关键词进行组合检索，检索周期2000年1月—2022年12月，剔除非安全性文献和重复文献，检索黄体酮注射液ADR/ADE。基于黄体酮注射液ADR/ADE发生特点，分析黄体酮注射液致ADR/ADE的风险来源，进而探讨控制措施并提出建议。结果 通过国家药品不良反应监测系统检索河南省报告药品不良反应结果发现黄体酮注射液 ADR/ADE 个例报告 263例，涉及 ADR/ADE 表现 454例次，ADR/ADE例次数较多的损害表现为注射部位红肿、硬结、疼痛、脂膜炎、红斑、皮疹等。文献检索得到黄体酮注射液相关安全性文献 23篇，共提取出个例 ADR/ADE报告 125例，涉及 ADR/ADE表现 147例次，ADR/ADE例次数较多的依次为注射部位脂膜炎、硬结、疼痛、皮疹等。黄体酮注射液致用药部位损害的原因可能与不合理用药因素、辅料因素、说明书缺陷因素等有关。结论 建议提升黄体酮注射液质量标准、提高合理用药水平、修订完善药品说明书，最终保护患者用药安全。     

Estimation of the signal generating value of spontaneous reports of adverse reactions

The main function of drug adverse reaction spontaneous reporting systems is the generation of early signals of previously undocumented serious reactions to recently marketed products. To quantify the signal generating value of case reports we first score them on a 6-level causality/completeness scale combining the French and the European community assessment methods; prior documentation is scored on a 5-level scale inspired from the French method. Then the prior documentation value is subtracted from the imputability value and the resulting difference is considered as a signal generating value. The result is a scale of ranks ranging from 1 to 10, averaging 4.8 in the database of our regional program. It may serve to compare the usefulness of spontaneous reports originating from different sources and it may encourage clinicans to submit more informative case reports.