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重新审视FDA对阿杜卡努单抗的批准
Revisiting FDA Approval of Aducanumab


G. Caleb Alexander ... 其他 • 2021.08.26
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• 阿杜卡努单抗治疗阿尔茨海默病——加速审批的合理应用 • FDA批准阿杜卡努单抗——有关阿尔茨海默病的争议与进展

2021年6月7日,美国食品药品管理局(FDA)加速批准阿杜卡努单抗(aducanumab,商品名Aduhelm)用于治疗阿尔茨海默病。该批准标志着一个极不寻常的监管过程的最终结局,而我们作为FDA周围和中枢神经系统咨询委员会(Peripheral and Central Nervous System Advisory Committee)成员全程见证了这一过程。阿杜卡努单抗获批之所以令人惊讶,部分原因是FDA并非根据其高度不确定的临床影响来批准该药物(我们委员会在2020年11月6日详尽讨论了这一问题),而是在后期决定因阿杜卡努单抗可降低正电子发射断层扫描脑成像(PET)观察到的β-淀粉样蛋白水平而予以批准。尽管β-淀粉样蛋白负担是阿杜卡努单抗关键试验中1/3左右参与者的探索性终点,但该药物减少可见β-淀粉样蛋白的能力已在早期安全性研究(研究103)中得到明确证明。然而,在阿杜卡努单抗获得批准之前,FDA并未表示将β-淀粉样蛋白视为有效的药效学生物标志物,更不要说是可接受的临床试验替代终点了。

鉴于该决定的科学、监管和临床意义,必须考虑β-淀粉样蛋白是否适合作为阿尔茨海默病疗法的替代终点。在临床研究中使用替代指标的原则已经确立。将这些原则应用于β-淀粉样蛋白,再考虑到整体证据的情况下,FDA的做法是否明智让人疑虑。





作者信息

G. Caleb Alexander, M.D., David S. Knopman, M.D., Scott S. Emerson, M.D., Ph.D., Bruce Ovbiagele, M.D., Richard J. Kryscio, Ph.D., Joel S. Perlmutter, M.D., and Aaron S. Kesselheim, M.D., J.D.
From the Center for Drug Safety and Effectiveness and the Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore (G.C.A.); the Department of Neurology, Mayo Clinic, Rochester, MN (D.S.K.); the Department of Biostatistics, University of Washington, Seattle (S.S.E.); the Department of Neurology, University of California, San Francisco (B.O.); the Bin Zhang Department of Statistics and the Sanders Brown Center on Aging, University of Kentucky, Lexington (R.J.K.); the Departments of Neurology, Radiology, Neuroscience, Physical Therapy, and Occupational Therapy, Washington University, St. Louis (J.S.P.); the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital, and the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Harvard Medical School — both in Boston (A.S.K.).

 

参考文献

1. Surrogate endpoint resources for drug and biologic development. Silver Spring, MD: Food and Drug Administration (https://www.fda.gov/drugs/development-resources/surrogate-endpoint-resources-drug-and-biologic-development).

2. Mintun MA, Lo AC, Duggan Evans C, et al. Donanemab in early Alzheimer’s disease. N Engl J Med 2021;384:1691-1704.

3. Combined FDA and Biogen briefing information for the November 6, 2020 meeting of the Peripheral and Central Nervous System Advisory Committee Silver Spring, MD: Food and Drug Administration (https://www.fda.gov/media/143502/download).

4. Transcript for the November 6, 2020 Meeting of the Peripheral and Central Nervous System Drugs Advisory Committee. Silver Spring, MD: Food and Drug Administration (https://www.fda.gov/media/145691/download).

5. Peripheral and Central Nervous System Drugs Advisory Committee Meeting script for FDA presentation: aducanumab for the treatment of Alzheimer’s disease Silver Spring, MD: Food and Drug Administration. November 6, 2020 (https://www.fda.gov/media/143505/download).

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