Program On Regulation, Therapeutics, And Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts (L.B.).
National Center for Health Research, Washington, DC (D.M.Z., S.P.).
Ann Intern Med. 2023 Sep;176(9):1251-1256. doi: 10.7326/M23-1073. Epub 2023 Aug 22.
The U.S. Food and Drug Administration (FDA) approved eteplirsen (Exondys 51) for Duchenne muscular dystrophy in 2016 via its accelerated approval program on the basis of a study of 12 boys. After a contentious review process and a high-profile meeting of an external advisory committee, FDA leaders concluded that very small increases in treated patients' levels of dystrophin, a muscle protein, were reasonably likely to predict clinical benefit. The eteplirsen approval, which was followed by approvals of other drugs in the same class via the same pathway, has been controversial because of the questionable evidence underlying these decisions, delays in mandated postapproval testing, and high U.S. prices. Questions remain about the effectiveness and long-term safety of these products. Although the FDA initially set a November 2020 deadline for eteplirsen's manufacturer to complete a clinical trial determining whether the drug has clinical benefit, the company will not complete the trial until 2024 or later. The relationship between levels of truncated dystrophin, the muscle protein studied in eteplirsen's pivotal trial, and clinical outcomes remains uncertain. Despite recent legislative and regulatory changes to the FDA's accelerated approval pathway, the history of eteplirsen and similar drugs points to the need for additional reforms to better balance evidence generation with patient safety and access to promising medications. Lawmakers and regulators should take further action to limit excessive spending on unproven therapies and ensure that drug sponsors conduct robust and timely confirmatory trials after receiving accelerated approval.
美国食品和药物管理局（FDA）于 2016 年通过其加速审批程序批准了eteplirsen（Exondys 51）用于杜氏肌营养不良症，该程序是基于对 12 名男孩的研究。在经过一场激烈的审查程序和一个备受瞩目的外部顾问委员会会议之后，FDA 领导人得出结论，接受治疗的患者肌肉蛋白 dystrophin 水平的微小增加很可能预示着临床获益。eteplirsen 的批准，以及随后通过同一途径批准的其他同类药物，引起了争议，因为这些决定的基础证据存在疑问，强制性的批准后测试被延迟，而且美国的价格很高。这些产品的有效性和长期安全性仍然存在疑问。尽管 FDA 最初为 eteplirsen 的制造商设定了 2020 年 11 月的最后期限，以完成一项确定该药物是否具有临床获益的临床试验，但该公司要到 2024 年或更晚才能完成该试验。研究中截短的 dystrophin 水平与临床结果之间的关系仍然不确定，该药物是 eteplirsen 关键性试验研究的肌肉蛋白。尽管最近对 FDA 加速审批途径进行了立法和监管改革，但 eteplirsen 和类似药物的历史表明，需要进行额外的改革，以更好地平衡证据生成与患者安全和获得有前途的药物之间的关系。立法者和监管者应采取进一步行动，限制对未经证实的治疗方法的过度支出，并确保药物赞助商在获得加速批准后及时进行稳健的确认性试验。
