Richey Elizabeth A, Lyons E Alison, Nebeker Jonathan R, Shankaran Veena, McKoy June M, Luu Thanh Ha, Nonzee Narissa, Trifilio Steven, Sartor Oliver, Benson Al B, Carson Kenneth R, Edwards Beatrice J, Gilchrist-Scott Douglas, Kuzel Timothy M, Raisch Dennis W, Tallman Martin S, West Dennis P, Hirschfeld Steven, Grillo-Lopez Antonio J, Bennett Charles L
Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, 303 E Chicago Ave, Chicago, IL 60611, USA.
J Clin Oncol. 2009 Sep 10;27(26):4398-405. doi: 10.1200/JCO.2008.21.1961. Epub 2009 Jul 27.
Accelerated approval (AA) was initiated by the US Food and Drug Administration (FDA) to shorten development times of drugs for serious medical illnesses. Sponsors must confirm efficacy in postapproval trials. Confronted with several drugs that received AA on the basis of phase II trials and for which confirmatory trials were incomplete, FDA officials have encouraged sponsors to design AA applications on the basis of interim analyses of phase III trials.
We reviewed data on orphan drug status, development time, safety, and status of confirmatory trials of AAs and regular FDA approvals of new molecular entities (NMEs) for oncology indications since 1995.
Median development times for AA NMEs (n = 19 drugs) and regular-approval oncology NMEs (n = 32 drugs) were 7.3 and 7.2 years, respectively. Phase III trials supported efficacy for 75% of regular-approval versus 26% of AA NMEs and for 73% of non-orphan versus 45% of orphan drug approvals. AA accounted for 78% of approvals for oncology NMEs between 2001 and 2003 but accounted for 32% in more recent years. Among AA NMEs, confirmatory trials were nine-fold less likely to be completed for orphan drug versus non-orphan drug indications. Postapproval, black box warnings were added to labels for four oncology NMEs (17%) that had received AA and for two oncology NMEs (9%) that had received regular approval.
AA oncology NMEs are safe and effective, although development times are not accelerated. A return to endorsing phase II trial designs for AA for oncology NMEs, particularly for orphan drug indications, may facilitate timely FDA approval of novel cancer drugs.
美国食品药品监督管理局（FDA）启动加速批准（AA）程序以缩短用于治疗严重疾病药物的研发时间。申办方必须在批准后试验中确认疗效。面对数种基于II期试验获得加速批准且确证性试验尚未完成的药物，FDA官员鼓励申办方基于III期试验的中期分析来设计加速批准申请。
我们回顾了自1995年以来，加速批准药物和FDA常规批准的新分子实体（NME）用于肿瘤适应症的孤儿药状态、研发时间、安全性及确证性试验状态的数据。
加速批准的NME（n = 19种药物）和常规批准的肿瘤学NME（n = 32种药物）的中位研发时间分别为7.3年和7.2年。III期试验支持75%的常规批准药物有效，而加速批准的NME中这一比例为26%；73%的非孤儿药批准有效，而孤儿药批准中这一比例为45%。2001年至2003年间，加速批准占肿瘤学NME批准的78%，但近年来这一比例为32%。在加速批准的NME中，孤儿药适应症的确证性试验完成的可能性比非孤儿药适应症低九倍。批准后，4种（17%）获得加速批准的肿瘤学NME和2种（9%）获得常规批准的肿瘤学NME的药品标签上添加了黑框警告。
加速批准的肿瘤学NME是安全有效的，尽管研发时间并未加快。回归支持肿瘤学NME加速批准的II期试验设计，特别是对于孤儿药适应症，可能有助于FDA及时批准新型抗癌药物。
