Characteristics of Novel Therapeutics and Postmarket Safety Events To the Editor Dr Downing and colleagues1 analyzed the frequency of postmarket safety events among 222 novel therapeutics approved by the US Food and Drug Administration (FDA) between 2001 and 2010 and found that 32% had a postmarket safety event during a median 11.7 years after approval. The authors prespecified 7 features to assess for differences in events over time: (1) class, (2) therapeutic area, (3) priority review, (4) accelerated approval, (5) orphan product, (6) near– regulatory deadline approval, and (7) total review time. However, we would like to raise additional features that need further consideration to interpret the study results. First, the length of treatment might be associated with the frequency of postmarket safety events (ie, drugs administered only for limited times or those administered continuously for a longer period). Unrecognized safety events would be more likely with drugs administered for a longer time. Second, the authors previously compared the regulatory review process for novel therapeutics among the FDA, the European Medicines Agency (EMA), and Health Canada from 2001 through 2010. Among the 289 unique novel therapeutic agents, 190 were approved in both the United States and Europe, of which 69 (36.3%) were first approved in Europe; 154 were approved in both the United States and Canada, of which 22 (14.3%) were first approved in Canada.2 In the case of novel therapeutics that were first approved by other regulatory authorities, it is conceivable that more safety information had already been accumulated at the time of the US approval compared with those that were first approved in the United States, leading to fewer postmarket safety events. Third, the precision and accuracy of submitted data of pivotal clinical trials for regulatory approval, such as the size of the trial and the length of follow-up, could matter. The authors previously reported that the precision and accuracy of clinical trial evidence used by the FDA varied widely; among 188 novel therapeutics for 206 indications approved between 2005 and 2012, the median number of patients enrolled per indication among all pivotal trials was 760 (interquartile range, 270-1550), and at least 1 pivotal trial with a duration of 6 months or greater supported the approval of 68 indications (33.8%).3 If the minimum requirements for the size and the duration of pivotal clinical trials that might lead to fewer postmarket safety events could be characterized, it would contribute to development of regulatory strategies for novel therapeutics.

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新疗法的特点和上市后安全事件

新型疗法的特征和上市后安全事件 致编辑 Downing 博士及其同事 1 分析了 2001 年至 2010 年美国食品和药物管理局 (FDA) 批准的 222 种新型疗法中上市后安全事件的频率，发现 32% 的上市后安全事件批准后中位数为 11.7 年的事件。作者预先指定了 7 个特征来评估事件随时间的差异：(1) 类别，(2) 治疗领域，(3) 优先审查，(4) 加速批准，(5) 孤儿产品，(6) 接近监管截止日期(7) 总审查时间。但是，我们想提出需要进一步考虑来解释研究结果的其他特征。首先，治疗的持续时间可能与上市后安全事件的频率有关（即，只服用有限时间的药物或连续服用较长时间的药物）。使用较长时间的药物更有可能发生未被识别的安全事件。其次，作者之前比较了 FDA、欧洲药品管理局 (EMA) 和加拿大卫生部从 2001 年到 2010 年对新型疗法的监管审查过程。 在 289 种独特的新型治疗剂中，190 种在美国和欧洲，其中69个（36.3%）在欧洲首次获批；154 种在美国和加拿大均获得批准，其中 22 种（14.3%）在加拿大首次获得批准。 2 对于其他监管机构首次批准的新疗法，可以想象，在美国获批时已经积累了比在美国首次获批时更多的安全信息，从而减少了上市后的安全事件。第三，提交监管部门批准的关键临床试验数据的准确性和准确性，例如试验规模和随访时间，可能很重要。作者之前报告说，FDA 使用的临床试验证据的精确度和准确性差异很大；在 2005 年至 2012 年间批准的 206 个适应症的 188 种新疗法中，所有关键试验中每个适应症入组的患者中位数为 760（四分位距，270-1550），并且至少有 1 个关键试验持续时间为 6 个月或更长支持批准68个适应症（33.8%）。