Sobel Rachel E, Reynolds Robert F
Epidemiology, Safety and Risk Management, Pfizer Inc, New York, NY 10017, USA.
Curr Med Res Opin. 2008 Jul;24(7):1861-8. doi: 10.1185/03007990802128781. Epub 2008 May 27.
Recent high-profile medicine withdrawals have highlighted the complex decision-making process that regulators, pharmaceutical companies, prescribers, and patients must undertake in determining whether a drug has an appropriate benefit-risk balance. Our objective was to analyze the utility of different drug safety data sources and methods, using the experience of sildenafil citrate (Viagra) and post-approval concerns about its potential association with cardiovascular (CV) events (i.e., myocardial infarction [MI] and death) as a case study.
We evaluated safety data from three sources: the standard passive surveillance system (i.e., spontaneous reports filed to Pfizer Inc), pooled clinical trial data, and a prospective observational cohort study, the International Men's Health Study (IMHS).
More than 28 000 spontaneous reports were received in the first 7 years after approval. Between 2001 and 2005, the proportion filed by persons other than healthcare professionals (61%) was approximately double the proportion averaged across five other drugs from the manufacturer's safety database. CV events and/or deaths represented 22.0% of reports, and 23% of reported deaths were medically unconfirmed reports made by persons other than healthcare professionals. In contrast, MI and all-cause mortality rates for sildenafil from both the pooled clinical trial data and the IMHS were similar to placebo, despite differences in methods and populations.
These results suggest that passive surveillance may generate apparent signals of risk, as was the case with sildenafil and CV events. However, to adequately assess the benefit-risk profile of a drug, these signals must be evaluated via other data sources such as clinical trial and epidemiologic studies, as the apparent signal was not supported by more rigorously collected data. Our post-marketing analysis was unable to examine all potential influences of spontaneous reports, and the study data sources (although large for erectile dysfunction studies) were not designed to exclude small CV risks.
近期备受瞩目的药品撤市事件凸显了监管机构、制药公司、开处方者和患者在确定药物是否具有适当的效益风险平衡时必须进行的复杂决策过程。我们的目的是以枸橼酸西地那非（万艾可）的经验以及批准后对其与心血管（CV）事件（即心肌梗死[MI]和死亡）潜在关联的担忧为案例研究，分析不同药物安全数据来源和方法的效用。
我们评估了来自三个来源的安全数据：标准被动监测系统（即向辉瑞公司提交的自发报告）、汇总临床试验数据以及一项前瞻性观察队列研究——国际男性健康研究（IMHS）。
批准后的前7年共收到超过28000份自发报告。2001年至2005年期间，医疗保健专业人员以外的人员提交的报告比例（61%）约为制造商安全数据库中其他五种药物平均比例的两倍。CV事件和/或死亡占报告的22.0%，报告死亡中有23%是医疗保健专业人员以外的人员提交的未经医学确认的报告。相比之下，尽管方法和人群存在差异，但汇总临床试验数据和IMHS中枸橼酸西地那非的MI和全因死亡率与安慰剂相似。
这些结果表明，被动监测可能会产生明显的风险信号，西地那非和CV事件就是如此。然而，要充分评估药物的效益风险概况，必须通过其他数据来源（如临床试验和流行病学研究）对这些信号进行评估，因为更严格收集的数据并未支持明显的信号。我们的上市后分析无法检查自发报告的所有潜在影响，并且研究数据来源（尽管对于勃起功能障碍研究来说规模较大）并非旨在排除微小的CV风险。
