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【drug-news】美国FDA审批药物及药物试验弄虚作假
美国食品药品监督管理局与泰利霉素事件
RESOURCE: NEJM,Volume 356:1601-1604 April 19, 2007 Number 16
AUTHOR: David B. Ross, M.D., Ph.D.
Three years ago, the Food and Drug Administration (FDA) approved the drug Ketek (telithromycin), lauding it as the first of a new class of antimicrobial agents that circumvent antibiotic resistance. Since then, Ketek has been linked to dozens of cases of severe liver injury, been the subject of a series of increasingly urgent safety warnings, and sparked two Congressional investigations of the FDA's acceptance of fraudulent safety data and inappropriate trial methods when it reviewed the drug for approval. As a former FDA physician who was involved in the Ketek review, I believe there are lessons to be learned from an examination of the events surrounding the approval of this product.
三年前，美国食品药品监督管理局批准Ketek(泰利霉素)上市，认为它是第一个可以有效的避免抗生素耐药的新型抗生素。自此以后，Ketek就与多起严重的肝损伤案例联系在一起，遭到一系列日益紧迫的安全性警告，国会也对FDA在药物Ketek审批过程中接受造假数据和不合理试验方法的行为进行了两次调查。作为曾参与Ketek审批的前FDA医生，我认为可从围绕药物审批的检查中汲取教训。
Ketek is a ketolide antibiotic manufactured by Sanofi-Aventis and proposed for use in community-acquired respiratory tract infections. It was reviewed by the FDA three times (see timeline). During the first round, reviewers identified substantial safety concerns, including multiple potential drug interactions, unique effects on visual acuity, and an apparent association with hepatocellular hepatitis, with pathological characteristics resembling those caused by drugs that have been withdrawn from the market because of hepatotoxicity. A federal advisory committee asked Sanofi-Aventis to obtain additional safety data by conducting a study involving patients who were likely to receive Ketek if the drug were approved.
Ketek是一类酮内酯类抗生素，由Sanofi-Aventis公司生产，被批准用于社区获得性呼吸道感染。此药曾被FDA审查了三遍（见时间表）。在第一轮审查中，审评专家关注此药的基本安全性问题，包括潜在的多种药物相互作用，对视力的特殊效应，及与由于肝毒性退出市场的药物引起的病理学特征相似的肝细胞性肝炎之间的表观联系。联邦顾问委员会要求Sanofi-Aventis公司通过Ketek适应症患者参与的临床试验，获得额外的安全性数据。
In the second review, the FDA examined the results of such a study. Known as study 3014, it was an unblinded, randomized, controlled trial comparing the incidence rates of hepatic, cardiac, and visual adverse events in patients receiving Ketek and those receiving amoxicillin–clavulanate. Sanofi-Aventis recruited more than 1800 physicians to conduct the study, many of them new to clinical investigation, and paid them as much as $400 per patient enrolled, primarily to cover the costs of recruiting and gathering research data; more than 24,000 subjects were enrolled. The study was completed in 5 months and purported to show that Ketek was as safe as the other treatment.
在第二轮审查中，FDA对补充试验的结果进行了审查。3014研究是一项开放，随机，对照试验，把服用Ketek和amoxicillin–clavulanate （阿莫西林/克拉维酸）的患者的肝脏，心脏和视力不良事件的发生率进行了对比。Sanofi-Aventis公司共招募了1800多名医生参与此项研究，他们中的很多人都是新人，并且每招募一名患者，公司将支付医生400美元，主要用于受试者的招募和研究数据的收集；此项研究一共招募了24000多名受试者。此项研究在5个月内完成，声称Ketek与其它药物一样安全。
A routine FDA inspection of the practices of the physician who enrolled the most patients — more than 400 — uncovered fraud, including complete fabrication of patient enrollment. The inspector notified FDA criminal investigators, and the physician is currently serving a 57-month sentence in federal prison for her actions. Inspections of nine other sites enrolling high numbers of patients revealed serious violations of trial conduct, raising substantial concerns about the overall integrity of the study. In the end, 4 of the 10 inspected sites were referred for criminal investigation.
在一次FDA对招募受试者最多（超过400名）的医生的例行检查中发现了医生的造假行为，包括伪造患者的入组。稽查员通知FDA的犯罪调查员，医生由此被判处57个月的监禁。在对其它九个受试者入组较多的研究点的检查中发现了严重偏离试验方案的情况，由此加重了对整个实验完整性的焦虑。最后，在已检查的10个研究点中有四个提交犯罪调查。
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作者:admin@医学,生命科学 2010-11-05 05:11
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