AstraZeneca R&D, Mölndal, Sweden.
Drug Saf. 2010 Mar 1;33(3):223-32. doi: 10.2165/11319010-000000000-00000.
Post-launch drug safety monitoring is essential for the detection of adverse drug signals that may be missed during preclinical trials. Traditional methods of postmarketing surveillance such as spontaneous reporting have intrinsic limitations, many of which can be overcome by the additional application of structured pharmacoepidemiological approaches. However, further improvement in drug safety monitoring requires a shift towards more proactive pharmacoepidemiological methods that can detect adverse drug signals as they occur in the population.
To assess the feasibility of using proactive monitoring of an electronic medical record system, in combination with an independent endpoint adjudication committee, to detect adverse events among users of selected drugs.
UK General Practice Research Database (GPRD) information was used to detect acute liver disorder associated with the use of amoxicillin/clavulanic acid (hepatotoxic) or low-dose aspirin (acetylsalicylic acid [non-hepatotoxic]). Individuals newly prescribed these drugs between 1 October 2005 and 31 March 2006 were identified. Acute liver disorder cases were assessed using GPRD computer records in combination with case validation by an independent endpoint adjudication committee. Signal generation thresholds were based on the background rate of acute liver disorder in the general population.
Over a 6-month period, 8148 patients newly prescribed amoxicillin/clavulanic acid and 5577 patients newly prescribed low-dose aspirin were identified. Within this cohort, searches identified 11 potential liver disorder cases from computerized records: six for amoxicillin/clavulanic acid and five for low-dose aspirin. The independent endpoint adjudication committee refined this to four potential acute liver disorder cases for whom paper-based information was requested for final case assessment. Final case assessments confirmed no cases of acute liver disorder. The time taken for this study was 18 months (6 months for recruitment and 12 months for data management and case validation). To reach the estimated target exposure necessary to raise or rule out a signal of concern to public health, we determined that a recruitment period 2-3 times longer than that used in this study would be required. Based on the real market uptake of six commonly used medicinal products launched between 2001 and 2006 in the UK (budesonide/eformoterol [fixed-dose combination], duloxetine, ezetimibe, metformin/rosiglitazone [fixed-dose combination], tiotropium bromide and tadalafil) the target exposure would not have been reached until the fifth year of marketing using a single database.
It is feasible to set up a system that actively monitors drug safety using a healthcare database and an independent endpoint adjudication committee. However, future successful implementation will require multiple databases to be queried so that larger study populations are included. This requires further development and harmonization of international healthcare databases.
药品上市后安全性监测对于发现临床前试验可能遗漏的不良药物信号至关重要。传统的上市后监测方法，如自发报告，存在固有局限性，而通过额外应用结构化的药物流行病学方法可以克服其中许多局限性。然而，进一步改善药物安全性监测需要转向更主动的药物流行病学方法，以便在人群中及时发现不良药物信号。
评估使用电子病历系统主动监测并结合独立终点裁决委员会来检测选定药物使用者中不良事件的可行性。
使用英国普通实践研究数据库（GPRD）信息来检测与使用阿莫西林/克拉维酸（肝毒性）或低剂量阿司匹林（乙酰水杨酸[非肝毒性]）相关的急性肝障碍。2005 年 10 月 1 日至 2006 年 3 月 31 日期间，新处方这些药物的个体被确定为研究对象。使用 GPRD 计算机记录结合独立终点裁决委员会的病例验证来评估急性肝障碍病例。信号生成阈值基于一般人群中急性肝障碍的背景发生率。
在 6 个月的时间内，确定了 8148 例新处方阿莫西林/克拉维酸的患者和 5577 例新处方低剂量阿司匹林的患者。在此队列中，从计算机记录中搜索到 11 例可能的肝障碍病例：6 例阿莫西林/克拉维酸和 5 例低剂量阿司匹林。独立终点裁决委员会对这 11 例病例进行了细化，要求提供纸质信息以进行最终病例评估。最终病例评估确认无急性肝障碍病例。这项研究共耗时 18 个月（6 个月用于招募，12 个月用于数据管理和病例验证）。为了达到预期的目标暴露量，以提出或排除对公众健康有担忧的信号，我们确定需要比本研究中使用的招募期长 2-3 倍。根据英国 2001 年至 2006 年期间上市的六种常用药品（布地奈德/福莫特罗[固定剂量组合]、度洛西汀、依折麦布、二甲双胍/罗格列酮[固定剂量组合]、噻托溴铵和他达拉非）的实际市场占有率，如果仅使用一个数据库，要达到目标暴露量，需要在第五年才能实现。
使用医疗保健数据库和独立终点裁决委员会主动监测药物安全性是可行的。然而，未来成功实施需要查询多个数据库，以纳入更大的研究人群。这需要进一步开发和协调国际医疗保健数据库。
