Johnson John R, Bross Peter, Cohen Martin, Rothmann Mark, Chen Gang, Zajicek Anne, Gobburu Joga, Rahman Atiqur, Staten Ann, Pazdur Richard
Division of Oncology Drug Products (HFD-150), Center for Drug Evaluation and Research, United States Food and Drug Administration, Rockville, Maryland 20857, USA.
Clin Cancer Res. 2003 Jun;9(6):1972-9.
The purpose is to describe the Food and Drug Administration (FDA) review and approval of imatinib (Gleevec; Novartis Pharmaceuticals, East Hanover, NJ) for treatment of adult patients with newly diagnosed Philadelphia chromosome-positive chronic myelogenous leukemia (CML) in chronic phase.
The FDA reviewed data in electronic format from a randomized controlled clinical trial of 1106 adult patients with newly diagnosed Philadelphia chromosome-positive CML in chronic phase, comparing imatinib with the combination of IFN-alpha and cytarabine.
Imatinib showed clinically and statistically significantly better results for time-to-progression to accelerated phase or blast crisis, progression-free survival, complete hematological response rate, and cytogenetic response rate. With a median follow-up of 14 months, a maximum follow-up of 19.5 months, and an expected median survival of 5-6 years on the IFN-alpha/cytarabine control arm, few of the expected progressions to accelerated or blast phase or deaths have occurred. Imatinib was also better tolerated. Edema, nausea, rigors, neutropenia, and headache were more frequent in women. Only 57% of the IFN-alpha target dose was administered, and only 68% of patients received any cytarabine. However, this does not appear to adequately explain the superiority of imatinib observed in this trial. Results of a population pharmacokinetic study in a subgroup of 371 patients and a separate rifampin-imatinib drug-drug interaction study in healthy volunteers are presented.
On December 20, 2002, imatinib was granted accelerated approval under subpart H, rather than regular approval. Follow-up is short compared with the natural history of chronic phase CML or more mature results with established therapies such as IFN-alpha or transplantation. If imatinib should stop working after 1.5-2 years, the results could be importantly different from the present analysis. As a Phase IV postmarketing commitment, the applicant has agreed to provide follow-up reports on this imatinib study annually for the next 6 years.
描述美国食品药品监督管理局（FDA）对伊马替尼（格列卫；诺华制药公司，新泽西州东哈嫩）用于治疗新诊断的费城染色体阳性慢性期慢性髓性白血病（CML）成年患者的审评和批准情况。
FDA审查了一项针对1106例新诊断的费城染色体阳性慢性期CML成年患者的随机对照临床试验的电子格式数据，该试验将伊马替尼与α干扰素和阿糖胞苷联合用药进行了比较。
在进展至加速期或急变期的时间、无进展生存期、完全血液学缓解率和细胞遗传学缓解率方面，伊马替尼显示出临床和统计学上显著更好的结果。中位随访时间为14个月，最长随访时间为19.5个月，在α干扰素/阿糖胞苷对照治疗组中预期中位生存期为5至6年，很少出现预期的进展至加速期或急变期或死亡情况。伊马替尼的耐受性也更好。水肿、恶心、寒战、中性粒细胞减少和头痛在女性中更常见。α干扰素目标剂量仅给药57%，仅68%的患者接受了任何阿糖胞苷。然而，这似乎并不能充分解释在该试验中观察到的伊马替尼的优越性。文中还展示了对371例患者亚组进行的群体药代动力学研究结果以及在健康志愿者中进行的一项单独的利福平 - 伊马替尼药物相互作用研究结果。
2002年12月20日，伊马替尼根据H子部分获得加速批准，而非常规批准。与慢性期CML的自然病程相比，随访时间较短，与α干扰素或移植等既定疗法的更成熟结果相比也较短。如果伊马替尼在1.5至2年后不再起作用，结果可能与当前分析有很大不同。作为IV期上市后承诺，申请人已同意在接下来的6年每年提供有关该伊马替尼研究的随访报告。
