从那他珠单抗不良反应处理看生物制剂风险监测——基于严重不良反应报告与相关管理文件的系统评价

Risk Monitoring of Biologicals Derived from Adverse Reaction Management of Natalizumab:A Systematic Review Based on Serious Adverse Reaction Reports and Related Regulatory Documents

目的基于导致那他珠单抗撤市的不良反应报告及其审评途径,深入分析其撤市原因,为更安全有效完善类似生物制剂的报告方法提供决策参考。方法计算机检索MEDLINE、EMbase、和美国FDA网站,纳入病例报道及审评途径、药品上市撤市审评相关情况的信息。结果最终纳入4篇病例报道及14篇官方文献。那他珠单抗第一次上市后的临床试验中有3例发生进行性多灶性白质脑病(PML),其中2例通过血透纠正。重新上市两年后,32000例受试者中共发现3例新发PML(0.06‰),但未见死亡报道。鉴于那他珠单抗其治疗多发性硬化(MS)、克罗恩病(CD)的不可替代性,FDA决定在严密监控下病人仍可用此药。结论①那他珠单抗治疗MS和CD的最严重不良反应均为PML,目前可防可治。上市期间其疗效及不良反应监测结果均提示现有审批制度相对完善可行,可供其他高风险药物如中药注射剂的快速审评或标准审评上市提供借鉴。②那他珠单抗重新上市对其他药物研发公司不仅是重要的风险管理先例,也为一些有可疑副作用的药物重返市场或重新开展临床试验的可能性带来了希望。③由于那他珠单抗是经快速通道审评,在研GoodClinicalPractice(GCP)研究与上市后评价是交叠进行,因此必须不断进行追踪,提供新证据。

Objective To analyze the withdrawal reason of natalizumab in depth based on the serious adverse reaction reports and approval channel, and to provide decision references for more safe and effective report method of other biologicals. Methods We searched MEDLINE, EMbase, and the official websites of Food and Drug Administration （FDA） for case reports, approval channel, and the relevant information of drug marketing or withdrawal. Results Four case reports and fourteen official reports were included. Three cases of progressive multifocal leukoencephalopathy （PML） were reported in the clinical trials after natalizumab＇s initially approval with two dead and one disabled, which could be retrieved by hemodialysis （2 cases hitherto）. Consequently, multiple sclerosis （MS） patients were willing to bear the risk. Two cases of natalizumab-related PML （0.06%0） were confirmed in 32 000 patients without death report after two years of its remarketing, in July 2008. Another PML patient was reported in October 2008. Because of its non-substitutability for treating MS and Crohn disease （CD）, FDA announced that patients could still use natalizumab under the close monitoring. Conclusion （1） The most serious adverse reaction of treating MS and CD with natalizumab is PML, but it can be preventable and curable now. The monitoring findings of efficacy and adverse reaction during the postmarketing indicate that the review system is perfect and practicable relatively, and can give references for other high-risk drugs on the fast or standard approval channel, for example, Chinese medicine injection can draw lessons from it. （2） The remarketing of natalizumab not only provide significant risk management precedent for other drug-development firms, but also brings hope to the remarketing or relaunching clinical trials for the suspected sideeffect drugs. （3） Because of the fast-track reviewing of natalizumab and the overlap between the research of Good Clinical Practice （GCP） and the post-marketing evaluation, we should continue to track the information and provide new evidence.