Department of Clinical Pharmacology, University Medical Center Groningen, University of Groningen, FB20, P.O. Box 196, 9700 AD, Groningen, The Netherlands,
Drug Saf. 2013 Nov;36(11):1105-15. doi: 10.1007/s40264-013-0094-y.
At time of approval, knowledge of the full benefit risk of any drug is limited, in particular with regards to safety. Post-approval surveillance of potential drug safety concerns is recognized as an important task of regulatory agencies. For innovative, often first-in-class drugs, safety knowledge at time of approval is often even less extensive and these may require tighter scrutiny post approval.
We evaluated whether more post-approval serious safety issues were identified for drugs with a higher level of innovation.
A cohort study was performed that included all new active substances approved under the European Centralized Procedure and for which serious safety issues were identified post-approval from 1 January 1999 to 1 January 2012. Serious safety issues were defined as issues requiring a Direct Healthcare Professional Communication to alert individual healthcare professionals of a new serious safety issue, or a safety-related drug withdrawal. Data were retrieved from publicly available websites of the Dutch Medicines Evaluation Board and the European Medicines Agency. The level of innovation was scored using a validated algorithm, grading drugs as important (A), moderate (B) or modest (C) innovations or as pharmacological or technological (pharm/tech) innovations. The data were analyzed using appropriate descriptive statistics and Kaplan-Meier analysis, with a Mantel-Cox log-rank test, and Cox-regression models correcting for follow-up duration, to identify a possible trend in serious safety issues with an increasing level of innovation.
In Europe, 279 new drugs were approved between 1999 and 2011. Fifty-nine (21 %) were graded as important, 63 (23 %) moderate, or 34 (12 %) modest innovations and 123 (44 %) as non-innovative (pharm/tech), while 15 (25 %), 13 (21 %), 8 (24 %) and 17 (14 %) had post-approval safety issues, respectively (p = 0.06, linear-by-linear test). Five drugs were withdrawn from the market. The Kaplan-Meier-derived probability for having a first serious safety issue was statistically significant, log-rank (Mantel-Cox) p = 0.036. In the final adjusted Cox proportional hazard model there was no statistically significant difference in occurrence of a first serious safety issue for important, moderate and modest innovations versus non-innovative drugs; hazard ratios 1.76 (95 % CI 0.82-3.77), 1.61 (95 % CI 0.76-3.41)], and 1.25 (95 % CI 0.51-3.06), respectively.
A higher level of innovation was not clearly related to an increased risk of serious safety issues identified after approval.
在获得批准时，对于任何药物的全部获益风险的了解是有限的，尤其是在安全性方面。对于潜在药物安全问题的批准后监测被认为是监管机构的一项重要任务。对于创新性的、通常为同类首创的药物，在获得批准时，安全性方面的知识通常更加有限，这些药物可能需要更严格的批准后审查。
我们评估了具有更高创新水平的药物是否会出现更多的批准后严重安全性问题。
我们进行了一项队列研究，该研究纳入了所有于 1999 年 1 月 1 日至 2012 年 1 月 1 日期间根据欧洲集中程序批准的新活性物质，以及在批准后发现的严重安全性问题。严重安全性问题被定义为需要直接向个别医疗保健专业人员传达的问题，以提醒他们新的严重安全性问题，或与安全性相关的药物撤回。数据从荷兰药品评估委员会和欧洲药品管理局的公开网站上检索。使用经过验证的算法对创新性水平进行评分，将药物评为重要（A）、中度（B）或适度（C）创新，或药理学或技术（pharm/tech）创新。使用适当的描述性统计和 Kaplan-Meier 分析、Mantel-Cox 对数秩检验和校正随访时间的 Cox 回归模型来分析数据，以确定创新性水平不断提高与严重安全性问题之间可能存在的趋势。
在欧洲，1999 年至 2011 年期间批准了 279 种新药。其中 59 种（21%）被评为重要创新，63 种（23%）为中度创新，34 种（12%）为适度创新，123 种（44%）为非创新（pharm/tech），而分别有 15 种（25%）、13 种（21%）、8 种（24%）和 17 种（14%）在批准后出现安全性问题（p=0.06，线性-线性检验）。有 5 种药物被撤出市场。Kaplan-Meier 推导的首次出现严重安全性问题的概率具有统计学意义，对数秩（Mantel-Cox）检验 p=0.036。在最终调整的 Cox 比例风险模型中，重要、中度和适度创新药物与非创新药物首次出现严重安全性问题的发生率没有统计学差异；危险比分别为 1.76（95%CI 0.82-3.77）、1.61（95%CI 0.76-3.41）和 1.25（95%CI 0.51-3.06）。
较高的创新性水平与批准后发现的严重安全性问题的风险增加之间似乎没有明确的关系。
