美国FDA审批药物及药物试验弄虚作假案例------泰利毒
本文太长，又非常重要，因为前段时间老外说中国的药品管理存在很大问题，我将本文分三部分，谢谢战友分领翻译，以了解美国一个药批准上市的过程。
http://www.med66.com/html/ziliao/yixue/6/772cf17cfbe478b49a62fc40c42fec68.htm
RESOURCE: NEJM,Volume 356:1601-1604 April 19, 2007 Number 16
TITLE: The FDA and the Case of Ketek
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.
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with hepatocellular hepatitis, with pathological characteristics resembling those caused by drugs that have been withdrawn from the market because of hepatotoxicity.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.
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.
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.
Despite these discoveries, FDA managers presented study 3014 to the advisory committee in January 2003 without mentioning the issues of data integrity.1 The managers have stated that they were legally barred from disclosing the problems to the committee because there was an open criminal investigation, but they have not explained why the data were presented at all, in view of the evidence of the study's lack of integrity. Unaware of the integrity problems, the committee voted 11 to 1 to recommend approval of Ketek.
The undisclosed problems with study 3014 led to a third review, during which FDA managers proposed using foreign postmarketing reports on Ketek as evidence of the product's safety, despite the unreliability of such data.2 Although drug sponsors are required to submit such reports as part of an application, it is extremely unusual to use these data to address critical preapproval safety issues in place of a controlled study. The postmarketing data submitted by Sanofi-Aventis were reviewed by the FDA without any verification of their accuracy or completeness, even though 3 months before the third review, FDA criminal investigators recommended examining whether Sanofi-Aventis had been involved in systematic fraud in connection with Ketek. The FDA never conducted the recommended investigation or reviewed study 3014–related records showing that Sanofi-Aventis was aware of potential fraud in the study when it submitted the results to the FDA. The failure to look into or respond to concerns about integrity represented a marked deviation from FDA policies.
Against this backdrop of concerns about both safety and fraud, critical questions also arose about the efficacy of Ketek, which had been examined only in noninferiority trials. Such trials are not designed to demonstrate directly a new intervention's superiority to an active control or a placebo but instead involve the selection of a maximum margin by which the new intervention may be less effective than older interventions but still be considered better than placebo.3 Throughout the 1990s, noninferiority trials had been standard procedure in the development of antimicrobial agents for the outpatient treatment of self-resolving respiratory tract infections. But by 2004, FDA workshops and advisory committee meetings on this topic had concluded that the use of noninferiority trials in this setting was not justifiable, since there is no evidence of a substantial treatment effect of antimicrobial drugs in self-resolving respiratory tract infections such as acute bacterial sinusitis and acute exACerbation of chronic bronchitis — the diseases for which clinicians most frequently prescribe antimicrobials, for which the market is largest, and for which treatment with Ketek was proposed.
Nevertheless, the FDA approved Ketek entirely on the basis of noninferiority trials. The reason given for the agency's continued acceptance of such trials in the study of antibiotics for self-resolving respiratory tract infections was the need to stand by prior agreements with industry sponsors regarding adequate trial designs — the Ketek trials, after all, had been designed and largely conducted before the adequacy of noninferiority trials had been called into question. Once it had been established that such trials could not demonstrate efficacy, however, it might reasonably have been argued that the welfare of prospective patients ought to outweigh any promise to manufacturers. Yet the FDA accepted the trials without discussion of either the patients who might be exposed to a drug that had serious toxic effects — and for which there was no evidence of effectiveness — or the failure of the trials to meet the FDA's own standards at the time of approval.
The review of Ketek was thus marked by pronounced departures from accepted review practices. In addition to the use of fraudulent data, the substitution of uncontrolled postmarket safety reports for controlled clinical trial data, and the acceptance of trials that could not show efficacy, there was also overt internal pressure brought to bear on FDA reviewers to alter their conclusions.
When the FDA approved Ketek on April 1, 2004, the approving officials stated in a memorandum that it was "difficult" to rely on study 3014 for approval4 but revealed neither the fact that they had known for more than a year about serious problems that compromised the study nor the conclusion by FDA investigators that fraud and a failure of monitoring by Sanofi-Aventis made the study unusable. In this memo, the foreign postmarketing data were put forward as an acceptable substitute for an adequate and well-controlled trial, without any discussion of the lack of precedent for this approach or the unreliability of such data. Nor did the officials discuss the problems involved with relying on noninferiority trials for treatments of self-resolving infections, the conclusions of previous FDA meetings on this issue, or the applicable FDA standards that had been violated.
When the FDA approved Ketek on April 1, 2004, the approving officials stated in a memorandum that it was "difficult" to rely on study 3014 for approval4 but revealed neither the fact that they had known for more than a year about serious problems that compromised the study nor the conclusion by FDA investigators that fraud and a failure of monitoring by Sanofi-Aventis made the study unusable. In this memo, the foreign postmarketing data were put forward as an acceptable substitute for an adequate and well-controlled trial, without any discussion of the lack of precedent for this approach or the unreliability of such data. Nor did the officials discuss the problems involved with relying on noninferiority trials for treatments of self-resolving infections, the conclusions of previous FDA meetings on this issue, or the applicable FDA standards that had been violated.
Sanofi-Aventis declared in advertisements that Ketek had the most successful launch of any antibiotic in history. In February 2005, 7 months after the drug was introduced to the U.S. market, the first death from Ketek-associated liver failure — in a patient treated for a mild respiratory tract infection — was reported to the FDA. The only formal response was an internal safety review written months later that devoted a few paragraphs to the event.
In January 2006, FDA management learned of the impending electronic report of a cluster of three cases of Ketek-associated acute liver failure at a single medical center, one of them the fatal case that had been reported almost a year earlier.5 An emergency meeting of FDA senior managers resulted in a public announcement that the FDA regarded Ketek as safe; this announcement cited study 3014 as part of the evidence the FDA had relied on in approving the drug. References to this fraudulent study soon started to creep into the biomedical literature.
In February 2006, I and other reviewers alerted FDA senior management to the irregularities in the Ketek case. FDA management took no substantive actions. In an internal e-mail, one senior manager, though aware of the fraud in study 3014, defended the agency's citation of it, stating that the review division responsible for Ketek had used it. (Three days after a Congressional hearing on Ketek, in February 2007, the FDA finally removed any mention of study 3014 from its Web site.)
In the face of Congressional subpoenas and unfavorable publicity, reviewers at the FDA were warned at a June 2006 meeting by Andrew von Eschenbach, then the acting FDA commissioner, not to discuss Ketek outside the agency. By this time, 23 cases of acute severe liver injury and 12 cases of acute liver failure, 4 of them fatal, had been linked to Ketek. By the end of 2006, Ketek had been implicated in 53 cases of hepatotoxic effects. The FDA did not relabel Ketek to indicate its possible severe hepatotoxicity until 16 months after the first liver-failure cases became public. The withdrawal of approval for two indications, acute bacterial sinusitis and acute exacerbation of chronic bronchitis, for which Ketek's efficacy had never been demonstrated, did not occur until February 12, 2007 — only a day before the Congressional hearing on Ketek.
To date, the agency has not addressed the actions taken by FDA senior managers in dealing with Ketek, but the hearings recently convened by Congress suggest that it is ready to do so, as part of its efforts to resolve broader problems at the agency. If the case of Ketek leads to important reforms, then the drug may have done some good after all.
本人已认领该文第一部分编译，48小时后若未提交译文，请其他战友自由认领。”
The FDA and the Case of Ketek
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。
Despite these discoveries, FDA managers presented study 3014 to the advisory committee in January 2003 without mentioning the issues of data integrity.1 The managers have stated that they were legally barred from disclosing the problems to the committee because there was an open criminal investigation, but they have not explained why the data were presented at all, in view of the evidence of the study's lack of integrity. Unaware of the integrity problems, the committee voted 11 to 1 to recommend approval of Ketek.
尽管有这些发现，FDA的管理人员还是在2003年一月将3014研究结果提交给咨询委员会，但却没有提到数据完整性的问题。FDA的管理人员认为他们已经合法地向委员会揭露了这个问题，因为有一个公开的犯罪调查，但他们却没有解释为什么在试验缺乏完整性的情况下提交实验数据。由于没有意识到试验完整性的问题，委员会以11：1投票赞成批准Ketek。
编译投稿
据新英格兰医学杂志4月19日报道：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。
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。
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。
尽管有这些发现，FDA的管理人员还是在2003年一月将3014研究结果提交给咨询委员会，但却没有提到数据完整性的问题。FDA的管理人员认为他们已经合法地向委员会揭露了这个问题，因为有一个公开的犯罪调查，但他们却没有解释为什么在试验缺乏完整性的情况下提交实验数据。由于没有意识到试验完整性的问题，委员会以11：1投票赞成批准Ketek。
本人已认领该文第三部分编译，48小时后若未提交译文，请其他战友自由认领。
Sanofi-Aventis declared in advertisements that Ketek had the most successful launch of any antibiotic in history. In February 2005, 7 months after the drug was introduced to the U.S. market, the first death from Ketek-associated liver failure — in a patient treated for a mild respiratory tract infection — was reported to the FDA. The only formal response was an internal safety review written months later that devoted a few paragraphs to the event.
Sanofi-Aventis公司在一则广告中宣称Ketek是抗生素历史上投放最成功的。2005年2月，在投放美国市场7个月之后，FDA接到了第一例使用Ketek治疗轻度呼吸道感染导致肝衰竭死亡病例的报告。官方唯一的反应就是这个事件发生几个月后进行内部安全性的检查。
In January 2006, FDA management learned of the impending electronic report of a cluster of three cases of Ketek-associated acute liver failure at a single medical center, one of them the fatal case that had been reported almost a year earlier. An emergency meeting of FDA senior managers resulted in a public announcement that the FDA regarded Ketek as safe; this announcement cited study 3014 as part of the evidence the FDA had relied on in approving the drug. References to this fraudulent study soon started to creep into the biomedical literature.
2006年1月，FDA接到同一医疗中心的三例与Ketek有关的急性肝衰竭的紧急电子报告，其中一例致死性病例一年前就已经报告过了。FDA的高层管理人员召开了紧急会议，达成一项公告：FDA认为Ketek是安全的；此公告引用FDA批准药物上市所依赖的3014研究作为证据的一部分。此项造假研究的参考文献不久开始悄悄地溜进了生物医学文献里。
In February 2006, I and other reviewers alerted FDA senior management to the irregularities in the Ketek case. FDA management took no substantive actions. In an internal e-mail, one senior manager, though aware of the fraud in study 3014, defended the agency's citation of it, stating that the review division responsible for Ketek had used it. (Three days after a Congressional hearing on Ketek, in February 2007, the FDA finally removed any mention of study 3014 from its Web site.)
2006年2月，我和其他审查员就Ketek事件中的违法情况提醒了FDA的高级管理层。但FDA的管理人员没有采取更进一步的行动。在一封内部的E-mail里，一名高级管理人员，虽然意识到3014研究的造假行为，但还是为管理机构引用3014研究进行了辩护，认为负责Ketek审查的部门已经使用过了。（2007年2月，在国会对Ketek举行听证会的三天后，FDA终于将所有有关3014研究的叙述从他们的网站上删除了。）
In the face of Congressional subpoenas and unfavorable publicity, reviewers at the FDA were warned at a June 2006 meeting by Andrew von Eschenbach, then the acting FDA commissioner, not to discuss Ketek outside the agency. By this time, 23 cases of acute severe liver injury and 12 cases of acute liver failure, 4 of them fatal, had been linked to Ketek. By the end of 2006, Ketek had been implicated in 53 cases of hepatotoxic effects. The FDA did not relabel Ketek to indicate its possible severe hepatotoxicity until 16 months after the first liver-failure cases became public. The withdrawal of approval for two indications, acute bacterial sinusitis and acute exacerbation of chronic bronchitis, for which Ketek's efficacy had never been demonstrated, did not occur until February 12, 2007 — only a day before the Congressional hearing on Ketek.
面对国会的传唤和不利的公众注意，FDA的审查员被通知2006年6月与来自Eschenbach的FDA代理专员Andrew会面，不在机构以外的地方谈论Ketek。到目前为止，有23例急性严重肝损伤和12例急性肝衰竭，其中4例是致死性的，与Ketek有关。到2006年底，Ketek牵涉到53例肝毒性。直到第一例肝衰竭病例公开后的16个月，FDA才重新在Ketek的标签中注明其可能具有严重肝毒性。直到2007年2月12日（国会召开Ketek听证会的前一天），由于Ketek对急性细菌性鼻炎和慢性支气管炎的急性恶化的疗效没有得到证实，两个被批准的适应症才被取消。
To date, the agency has not addressed the actions taken by FDA senior managers in dealing with Ketek, but the hearings recently convened by Congress suggest that it is ready to do so, as part of its efforts to resolve broader problems at the agency. If the case of Ketek leads to important reforms, then the drug may have done some good after all.
直到今日，FDA也没有宣布FDA高级管理人员在处理Ketek问题时所采取的行动，但最近由国会召集的听证会暗示作为解决管理机构主要问题计划的一部分，一切都准备好了。如果此次Ketek事件能带来重要的改革，对药物来说未尝不是一件好事。
Sanofi-Aventis公司在一则广告中宣称Ketek是抗生素历史上投放最成功的。2005年2月，在投放美国市场7个月之后，FDA接到了第一例使用Ketek治疗轻度呼吸道感染导致肝衰竭死亡病例的报告。官方唯一的反应就是这个事件发生几个月后进行内部安全性的检查。
2006年1月，FDA接到同一医疗中心的三例与Ketek有关的急性肝衰竭的紧急电子报告，其中一例致死性病例一年前就已经报告过了。FDA的高层管理人员召开了紧急会议，达成一项公告：FDA认为Ketek是安全的；此公告引用FDA批准药物上市所依赖的3014研究作为证据的一部分。此项造假研究的参考文献不久开始悄悄地溜进了生物医学文献里。
2006年2月，我和其他审查员就Ketek事件中的违法情况提醒了FDA的高级管理层。但FDA的管理人员没有采取更进一步的行动。在一封内部的E-mail里，一名高级管理人员，虽然意识到3014研究的造假行为，但还是为管理机构引用3014研究进行了辩护，认为负责Ketek审查的部门已经使用过了。（2007年2月，在国会对Ketek举行听证会的三天后，FDA终于将所有有关3014研究的叙述从他们的网站上删除了。）
面对国会的传唤和不利的公众注意，FDA的审查员被通知2006年6月与来自Eschenbach的FDA代理专员Andrew会面，不在机构以外的地方谈论Ketek。到目前为止，有23例急性严重肝损伤和12例急性肝衰竭，其中4例是致死性的，与Ketek有关。到2006年底，Ketek牵涉到53例肝毒性。直到第一例肝衰竭病例公开后的16个月，FDA才重新在Ketek的标签中注明其可能具有严重肝毒性。直到2007年2月12日（国会召开Ketek听证会的前一天），由于Ketek对急性细菌性鼻炎和慢性支气管炎的急性恶化的疗效没有得到证实，两个被批准的适应症才被取消。
直到今日，FDA也没有宣布FDA高级管理人员在处理Ketek问题时所采取的行动，但最近由国会召集的听证会暗示作为解决管理机构主要问题计划的一部分，一切都准备好了。如果此次Ketek事件能带来重要的改革，对药物来说未尝不是一件好事。
第二部分
The undisclosed problems with study 3014 led to a third review, during which FDA managers proposed using foreign postmarketing reports on Ketek as evidence of the product's safety, despite the unreliability of such data.2 Although drug sponsors are required to submit such reports as part of an application, it is extremely unusual to use these data to address critical preapproval safety issues in place of a controlled study. The postmarketing data submitted by Sanofi-Aventis were reviewed by the FDA without any verification of their accuracy or completeness, even though 3 months before the third review, FDA criminal investigators recommended examining whether Sanofi-Aventis had been involved in systematic fraud in connection with Ketek. The FDA never conducted the recommended investigation or reviewed study 3014–related records showing that Sanofi-Aventis was aware of potential fraud in the study when it submitted the results to the FDA. The failure to look into or respond to concerns about integrity represented a marked deviation from FDA policies.
3014研究中未揭露的问题带来了第三轮审查，FDA管理人员建议使用国外的Ketek售后报告作为产品安全性的证据，尽管这样的数据缺乏可信度。虽然要求药品赞助商提交这样的报告作为申请的一部分，但是却很少用这样的数据来替代对照研究对关键的批准前安全问题进行处理。售后数据由Sanofi-Aventis提交，FDA审查未对其准确性和完整性进行任何查证，就算在第三轮审查前的三个月，FDA犯罪调查人建议检查Sanofi-Aventis是否卷入了和Ketek相关的系统诈骗。FDA从未进执行过调查的建议或审查3014研究相关的纪录，显示Sanofi-Aventi在提交结果给FDA的时候知道研究中潜在的诈骗。对真实性的不调查或不反应和FDA的政策是背道而驰的。
Against this backdrop of concerns about both safety and fraud, critical questions also arose about the efficacy of Ketek, which had been examined only in noninferiority trials. Such trials are not designed to demonstrate directly a new intervention's superiority to an active control or a placebo but instead involve the selection of a maximum margin by which the new intervention may be less effective than older interventions but still be considered better than placebo.3 Throughout the 1990s, noninferiority trials had been standard procedure in the development of antimicrobial agents for the outpatient treatment of self-resolving respiratory tract infections. But by 2004, FDA workshops and advisory committee meetings on this topic had concluded that the use of noninferiority trials in this setting was not justifiable, since there is no evidence of a substantial treatment effect of antimicrobial drugs in self-resolving respiratory tract infections such as acute bacterial sinusitis and acute exacerbation of chronic bronchitis — the diseases for which clinicians most frequently prescribe antimicrobials, for which the market is largest, and for which treatment with Ketek was proposed.
对应安全性和诈骗担心的背景，关键性的问题还有Ketek的有效性。当时只做了非低级试验，这种研究不是直接证明新的干预措施比阳性对照或安慰剂要更高级，而是在选择了最大值界限的情况下，虽然新的干预比旧的干预要差但是仍然比安慰剂有效。90年代，非低级试验是门诊自限性呼吸道感染病人治疗用抗生素开发的标准程序。但到了2004年，FDA车间和建议委员会会议研究该议题，由于在象急性细菌性鼻窦炎和慢支的急性恶化等的自限性呼吸道感染中，医生通常开些抗生素药物，市场也最大，也是Ketek建议的应用范围，但没有证据显示抗生素具有实质性的疗效，会议总结指出这种情况下无理由使用非低级试验。
Nevertheless, the FDA approved Ketek entirely on the basis of noninferiority trials. The reason given for the agency's continued acceptance of such trials in the study of antibiotics for self-resolving respiratory tract infections was the need to stand by prior agreements with industry sponsors regarding adequate trial designs — the Ketek trials, after all, had been designed and largely conducted before the adequacy of noninferiority trials had been called into question. Once it had been established that such trials could not demonstrate efficacy, however, it might reasonably have been argued that the welfare of prospective patients ought to outweigh any promise to manufacturers. Yet the FDA accepted the trials without discussion of either the patients who might be exposed to a drug that had serious toxic effects — and for which there was no evidence of effectiveness — or the failure of the trials to meet the FDA's own standards at the time of approval.
然而FDA批准了完全建立在非低级试验基础之上的Ketek。FDA之所以连续的接受那些针对自限性呼吸道感染的抗生素研究的试验是因为考虑到有充足的试验设计而满足支持产业赞助商优先同意的要求—而Ketek试验的设计和大部分实施毕竟是在非低级试验被质问之前。一旦成立，那么这样的试验就无法证明有效性，但是可以认为，将来病人的利益一定是高于任何对制造商的承诺。然而FDA接受这样的试验，完全不讨论患者是否会服用具有严重毒副作用的药物—这些药还没有疗效的证据—或者在FDA批准时试验还根本没有达到FDA自身的标准。
The review of Ketek was thus marked by pronounced departures from accepted review practices. In addition to the use of fraudulent data, the substitution of uncontrolled postmarket safety reports for controlled clinical trial data, and the acceptance of trials that could not show efficacy, there was also overt internal pressure brought to bear on FDA reviewers to alter their conclusions.
对KekeK的审查就这样与公认的审查操作昭然背道而驰。除了使用诈骗的数据，用无对照的售后安全报告替代临床对照试验数据，和接受无法提供疗效的试验，还有明显的内部压力施加在FDA审查者的身上，让他们改变了结论。
When the FDA approved Ketek on April 1, 2004, the approving officials stated in a memorandum that it was "difficult" to rely on study 3014 for approval4 but revealed neither the fact that they had known for more than a year about serious problems that compromised the study nor the conclusion by FDA investigators that fraud and a failure of monitoring by Sanofi-Aventis made the study unusable. In this memo, the foreign postmarketing data were put forward as an acceptable substitute for an adequate and well-controlled trial, without any discussion of the lack of precedent for this approach or the unreliability of such data. Nor did the officials discuss the problems involved with relying on noninferiority trials for treatments of self-resolving infections, the conclusions of previous FDA meetings on this issue, or the applicable FDA standards that had been violated.
当FDA于2004年4月1日批准Ketek时，批准官员在备忘录中写道，依赖3014研究作出14号批准有些“困难”，但是透露的既不是他们已经知道一年多的使得研究的妥协严重问题，也不是FDA调查者的结论—Sanofi-Aventis监督的欺骗性和无效性。在该备忘录中，国外的售后治疗被认可为可以替代大样本有对照的试验，完全没有讨论这种数据的不可靠性，又无先例。官员也没有讨论对于自限性的呼吸道感染的治疗采用非低级试验所带来问题，先前FDA会议对该问题的结论，或者是已经被违反的FDA适用标准。
编译投稿
3014研究中未揭露的问题带来了第三轮审查，FDA管理人员建议使用国外的Ketek售后报告作为产品安全性的证据，尽管这样的数据缺乏可信度。虽然要求药品赞助商提交这样的报告作为申请的一部分，但是却很少用这样的数据来替代对照研究对关键的批准前安全问题进行处理。售后数据由Sanofi-Aventis提交，FDA审查未对其准确性和完整性进行任何查证，就算在第三轮审查前的三个月，FDA犯罪调查人建议检查Sanofi-Aventis是否卷入了和Ketek相关的系统诈骗。FDA从未进执行过调查的建议或审查3014研究相关的纪录，显示Sanofi-Aventi在提交结果给FDA的时候知道研究中潜在的诈骗。对真实性的不调查或不反应和FDA的政策是背道而驰的。
对应安全性和诈骗担心的背景，关键性的问题还有Ketek的有效性。当时只做了非低级试验，这种研究不是直接证明新的干预措施比阳性对照或安慰剂要更高级，而是在选择了最大值界限的情况下，虽然新的干预比旧的干预要差但是仍然比安慰剂有效。90年代，非低级试验是门诊自限性呼吸道感染病人治疗用抗生素开发的标准程序。但到了2004年，FDA车间和建议委员会会议研究该议题，由于在象急性细菌性鼻窦炎和慢支的急性恶化等的自限性呼吸道感染中，医生通常开些抗生素药物，市场也最大，也是Ketek建议的应用范围，但没有证据显示抗生素具有实质性的疗效，会议总结指出这种情况下无理由使用非低级试验。
然而FDA批准了完全建立在非低级试验基础之上的Ketek。FDA之所以连续的接受那些针对自限性呼吸道感染的抗生素研究的试验是因为考虑到有充足的试验设计而满足支持产业赞助商优先同意的要求—而Ketek试验的设计和大部分实施毕竟是在非低级试验被质问之前。一旦成立，那么这样的试验就无法证明有效性，但是可以认为，将来病人的利益一定是高于任何对制造商的承诺。然而FDA接受这样的试验，完全不讨论患者是否会服用具有严重毒副作用的药物—这些药还没有疗效的证据—或者在FDA批准时试验还根本没有达到FDA自身的标准。
对KekeK的审查就这样与公认的审查操作昭然背道而驰。除了使用诈骗的数据，用无对照的售后安全报告替代临床对照试验数据，和接受无法提供疗效的试验，还有明显的内部压力施加在FDA审查者的身上，让他们改变了结论。
当FDA于2004年4月1日批准Ketek时，批准官员在备忘录中写道，依赖3014研究作出14号批准有些“困难”，但是透露的既不是他们已经知道一年多的使得研究的妥协严重问题，也不是FDA调查者的结论—Sanofi-Aventis监督的欺骗性和无效性。在该备忘录中，国外的售后治疗被认可为可以替代大样本有对照的试验，完全没有讨论这种数据的不可靠性，又无先例。官员也没有讨论对于自限性的呼吸道感染的治疗采用非低级试验所带来问题，先前FDA会议对该问题的结论，或者是已经被违反的FDA适用标准。
漂亮瓶的选题非常好，编译者翻译得也很棒。但有个别地方值得切磋：
第一部分：
The managers have stated that they were legally barred from disclosing the problems to the committee because there was an open criminal investigation, ...
FDA的管理人员认为他们已经合法地向委员会揭露了这个问题，因为有一个公开的犯罪调查，...
FDA的管理人员认为他们从法律上不允许向委员会揭露了这个问题，因为有一个公开的犯罪调查，...
第二部分：
1. noninferiority trials /非低级试验，应为为“非劣性试验”；
2. FDA workshops /FDA车间， 应为“FDA研讨会”。
第三部分：
1. The only formal response was an internal safety review written months later that devoted a few paragraphs to the event.
官方唯一的反应就是这个事件发生几个月后进行内部安全性的检查。
官方唯一的反应就是这个事件发生几个月后做出的寥寥数语的内部安全性的检查。 （本人认为这几个字很关键，表明了FDA的态度，翻译时不应忽略）
2. In the face of Congressional subpoenas and unfavorable publicity, reviewers at the FDA were warned at a June 2006 meeting by Andrew von Eschenbach, then the acting FDA commissioner, not to discuss Ketek outside the agency.
面对国会的传唤和不利的公众注意，FDA的审查员被通知2006年6月与来自Eschenbach的FDA代理专员Andrew会面，不在机构以外的地方谈论Ketek。
面对国会的传唤和不利的公众注意，2006年6月在当时的FDA代理专员Andrew von Eschenbach召集的会议上，审查员被警告不要在机构以外的地方谈论Ketek。 |
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发表于 2010-7-20 10:33
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