Layton D, Heeley E, Shakir S A W
Drug Safety Research Unit, Bursledon Hall, Blundell Lane, Southampton, UK.
J Clin Pharm Ther. 2004 Apr;29(2):171-81. doi: 10.1111/j.1365-2710.2004.00550.x.
Identifying previously unrecognized adverse drug reactions (signals) is an important part of post-marketing surveillance. Automated signal generation now forms part of routine surveillance of spontaneous adverse drug reactions reported to the UK Yellow Card system. The Drug Safety Research Unit (DRSU) provides an additional post-marketing drug surveillance scheme in the UK, using the non-interventional observational cohort technique of Prescription-Event Monitoring (PEM), and systematically collects data on patients who were prescribed selected newly licensed drugs in primary care clinical practice. The introduction of a new computer system in January 2000 enabled the development of an automated signal generation system to compliment the process of identification of possible safety signals in drug data collected using PEM.
To use incidence rate ratios (IRRs) as a form of signal generation in the DSRU database, with particular interest in rofecoxib, plus further evaluation of any signal(s) of interest by requesting additional information from the general practioner (GP) of each relevant case.
Crude IRRs were calculated for each event term of interest by comparing the incidence rate for each lower term event reported in rofecoxib users with the comparable incidence rate for the whole PEM database (77 drugs of various therapeutic classes) from the total person-exposure time up to 180 days after starting the drug. To investigate a possible class effect, IRRs were also calculated using a second comparator cohort including only those PEM study drugs within the same therapeutic class (non-steroidal anti-inflammatory drugs, NSAIDs) and used for similar indications. Cases arising out of potential signals were followed up for additional information.
A potential signal of 'colitis' was identified when rofecoxib was compared with the rest of the database, IRR 5.8 (95% CI 2.7,11.3; z statistic 5.6), and when the comparator group was changed to include only the other four NSAIDs, IRR 4.3 (95% CI 1.4,14.5; z statistic 2.8). Other possible signals, compared with the rest of the database, included events deemed to be related to the underlying condition, labelled adverse events and events describing effectiveness of treatment. Further evaluation of this signal revealed that there were 11 reports of colitis (two reports for one patient) that occurred while taking rofecoxib and within 180 days of exposure. A causality assessment for these 10 patients did not confirm an association with newly developing colitis, but showed that the events were 'possible' exacerbations of pre-existing colitis during treatment with rofecoxib.
The use of IRRs for signal generation using PEM data is worthwhile and enables time to be taken into account. Previously unrecognized adverse events require further evaluation to confirm that a possible safety signal exists. In this study, the number of patients reported to have colitis was small but compared with other drugs on the database, the incidence rate was relatively high. Follow-up revealed a possible relationship between exacerbation of pre-existing colitis and treatment with rofecoxib. Hypotheses arising from signal generation require evaluation and cannot be taken as a conclusive evidence for clinical differences in the safety profiles of drugs.
识别先前未被认识到的药物不良反应（信号）是上市后监测的重要组成部分。自动信号生成现已成为向英国黄卡系统报告的自发药物不良反应常规监测的一部分。药物安全研究单位（DRSU）在英国提供了一项额外的上市后药物监测计划，采用处方事件监测（PEM）的非干预性观察队列技术，并系统收集在基层医疗临床实践中开具选定新许可药物的患者的数据。2000年1月引入的新计算机系统使得能够开发一个自动信号生成系统，以补充在使用PEM收集的药物数据中识别可能安全信号的过程。
在DRSU数据库中使用发病率比（IRR）作为信号生成的一种形式，特别关注罗非昔布，并通过向每个相关病例的全科医生（GP）请求额外信息，对任何感兴趣的信号进行进一步评估。
通过比较罗非昔布使用者中报告的每个较低级别事件的发病率与整个PEM数据库（77种不同治疗类别的药物）从开始用药到180天的总人暴露时间内的可比发病率，计算每个感兴趣事件术语的粗IRR。为了研究可能的类别效应，还使用第二个对照队列计算IRR，该队列仅包括同一治疗类别（非甾体抗炎药，NSAIDs）内的那些PEM研究药物，并用于类似适应症。对潜在信号引发的病例进行随访以获取额外信息。
当将罗非昔布与数据库的其他部分进行比较时，识别出一个“结肠炎”的潜在信号，IRR为5.8（95%CI 2.7,11.3；z统计量5.6），当对照群体改为仅包括其他四种NSAIDs时，IRR为4.3（95%CI 1.4,14.5；z统计量2.8）。与数据库的其他部分相比，其他可能的信号包括被认为与基础疾病相关的事件、标记的不良事件以及描述治疗效果的事件。对该信号的进一步评估显示，有11例结肠炎报告（一名患者有两份报告）在服用罗非昔布期间且在暴露180天内发生。对这10名患者的因果关系评估未确认与新发生的结肠炎有关，但表明这些事件是罗非昔布治疗期间先前存在的结肠炎的“可能”加重。
使用IRR通过PEM数据进行信号生成是值得的，并且能够考虑时间因素。先前未被认识到的不良事件需要进一步评估以确认是否存在可能的安全信号。在本研究中，报告患有结肠炎的患者数量较少，但与数据库中的其他药物相比，发病率相对较高。随访显示先前存在的结肠炎加重与罗非昔布治疗之间可能存在关联。信号生成产生的假设需要评估，不能作为药物安全性概况临床差异的确凿证据。
