The U.S. Senate Finance Committee has some harsh words for GlaxoSmithKline and the way it handled reports of cardiovascular problems related to its diabetes drug Avandia.

In a 342-page report, committee staff members noted that the issue first piqued their interest in May 2007 with the publication of a study showing a link between rosiglitazone (Avandia) and heart attacks (N. Engl. J. Med. 2007;356:2457-71).

“The reviewed evidence suggests that GSK [GlaxoSmithKline] knew for several years prior to this study that there were possible cardiac risks associated with Avandia,” the authors of the report wrote. “As a result, it can be argued that GSK had a duty to warn patients and the [U.S. Food and Drug Administration] of the company’s concerns. Instead, GSK executives attempted to intimidate independent physicians, focused on strategies to minimize or misrepresent findings that Avandia may increase cardiovascular risk, and sought ways to downplay findings that a competing drug might reduce cardiovascular risk.”

The committee report continued: “When an independent scientist sought to publish a study in 2007 pointing out the cardiovascular risk of Avandia, GSK acquired a leaked copy of that study from one of its consultants prior to the study being published. The company’s own experts analyzed the study, found it to be statistically reliable, and then attacked the soundness of that study in press releases and public comments. GSK also sought to counter the study’s findings by quickly releasing preliminary results from its own study on Avandia, even though the company’s internal communications established that its study was not primarily designed to answer questions about cardiovascular risk.”

The authors noted that GSK was not the only pharmaceutical manufacturer to have participated in such unseemly activity. “In recent years, pharmaceutical companies have committed acts that forced them to pay the largest criminal fines in American history,” they wrote. “In cases involving Pfizer, Eli Lilly, Bristol Myers Squibb and four other drug companies, these fines and penalties have totaled over $7 billion since May 2004. ... Such an environment requires diligent oversight by the FDA to protect the citizens of this country and to ensure the safety of American medicine.”

GlaxoSmithKline said it rejected the report’s conclusions. The report “draws conclusions on the safety of Avandia (rosiglitazone) that are based on analyses that are not consistent with the rigorous scientific evidence supporting the safety of the drug,” the company said in a statement. “In addition, the report cherry-picks information from documents, which mischaracterizes GlaxoSmithKline’s comprehensive efforts to research Avandia and communicate those findings to regulators, physicians, and patients. In fact, the safety and effectiveness of Avandia is well characterized in the label approved by the FDA.”

In particular, GSK denied that Avandia posed a heightened cardiovascular risk. “Contrary to the assertions in the report, and consistent with the FDA-approved labeling, the scientific evidence simply does not establish that Avandia increases cardiovascular ischemic risk or causes myocardial ischemic events,” the statement said.

The committee report included additional allegations regarding what it said were the company’s efforts to silence critics of the drug. For example, the report noted that GSK attempted to intimidate Dr. John Buse of the University of North Carolina (UNC), who had argued at several medical meetings that Avandia caused cardiovascular problems.

“According to GSK e-mails made available to the committee, GSK executives labeled Dr. Buse a ‘renegade’ and silenced his concerns about Avandia by complaining to his superiors at UNC and threatening a lawsuit,” the report said. “The call to Dr. Buse’s superiors was made by Dr. Tachi Yamada, then GSK’s head of research. ... Dr. Yamada argued that he had made the call to determine if Dr. Buse was making legitimate statements or if he was possibly on the payroll of a GSK rival.”

GlaxoSmithKline denied that it tried to quash criticism of its products. “GSK welcomes and supports open and independent scientific debate about its products,” the company’s statement said. “To that end, we have posted the results of our clinical trials as well as meta-analyses and observational studies on our website for all to see. GSK does not condone any effort to silence scientific debate. When GSK believes that statements made by others don’t accurately present information on its products or its actions, GSK corrects inaccuracies and misstatements.”

GSK also has a problem on another front: at the FDA. Asked about a media report that some FDA scientists are urging removal of Avandia from the market because of the cardiovascular concerns, FDA spokeswoman Karen Riley said the agency “takes very seriously the concerns and issues raised in the recent inquiry from [Finance Committee chair Max] Baucus and [ranking member Charles] Grassley.”

Ms. Riley noted that Dr. Janet Woodcock, director of the agency’s Center for Drug Evaluation and Research, issued a memo in December 2009 requesting that “all appropriate offices within the center rapidly evaluate new data on Avandia with the aim of presenting it to an FDA advisory committee in the summer of 2010.” She added, “FDA awaits the recommendation of the advisory committee and in the meantime, [FDA] Commissioner [Dr. Margaret] Hamburg plans to meet with FDA scientists and outside experts to gain a full understanding of all the issues involved.”

The Finance Committee report is available at http://finance.senate.gov/press/Gpress/2010/prg022010a.pdf . GlaxoSmithKline’s statement is available at http://www.gsk.com/media/GSK-rejects-conclusions-of-Senate-Committee-on-Finance-20-Feb-2010.pdf .

Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

美国参议院财政委员会严厉指责葛兰素史克公司及该公司在处理其糖尿病药物文迪雅(Avandia)相关心血管问题的报告时采取的方式。

 

 委员会成员在一份长达332页的报告中指出，首次引起他们关注的是2007年5月发表的一项研究，该研究显示，服用罗格列酮(文迪雅)与心脏病发作有关(N. Engl. J. Med. 2007;356:2457-71)。

 

“审议过的证据表明，葛兰素史克公司(GSK)在此研究发表数年前已得知文迪雅可能与心脏病风险有关，”报告的作者写道。“因此可以说，GSK有义务将公司的顾虑告诫患者和美国食品药品管理局(FDA)。而事实上，GSK高层一直试图隐瞒情况，手段包括向医生施压、最大限度地掩盖或歪曲有关文迪雅增加心血管风险的说法，以及千方百计贬低可能降低心血管风险的竞争药物。”

 

委员会的报告还写道：“2007年有一位独立的科学家设法公布一项研究，该研究指出文迪雅有心血管风险，当时，GSK在这项研究发表前从它的一个顾问手中获取了该研究走漏的一个副本。该公司的专家分析此研究发现，其统计学结果可信，随后在新闻发布会和公开言论中攻击该研究的可靠性。另外，GSK还试图快速发布该公司的初步研究结果，以反驳上述研究，即使GSK的内部通信证实该研究的主要设计初衷并非回答心血管风险相关的问题。 ”

 

作者们指出，GSK并非惟一一个参与这类不体面活动的制药厂家。“近些年来，制药公司所做出的行为，使其付出的罚款创美国历史上罚款额度的最高记录，”他们写道。“自2004年5月份以来，在辉瑞、礼来、百时美施贵宝以及其他4个制药公司涉及的案例中，这些罚款和罚金总额逾70亿美元……这就要求FDA尽职尽责地监督，以保护本国公民和确保美国药品的安全性。”

 

GSK反对这项报告的结论。这项报告“是根据某些分析报告得出了文迪雅(罗格列酮)的安全性结论，而这些分析报告与大量的支持该药安全性的科学证据不一致，”GSK在一份声明中指出。“此外，文件中挑选的信息歪曲了GSK在从事文迪雅研究以及将这些结果传达给监管机构、医生和患者等方面所做出的巨大 贡献。实际上，文迪雅的安全性和有效性在FDA批准的说明书中已得到很好的描述。”

 

GSK尤其否认文迪雅可增加心血管风险。“与报告中的论断相反、而与FDA批准的产品说明书一致的是，科学证据实在无法证实文迪雅可增加心血管缺血的风险或可引发心肌缺血事件，”声明指出。

 

委员会的报告还包括与该公司用来平息对药品批评的手段有关的其他陈述。例如，报告指出，GSK试图向北卡罗莱纳大学(UNC)John Buse博士施压，这位教授此前曾在数次医学会议上提出文迪雅可引发心血管问题。

 

“据委员会得到的GSK的电子信件，GSK高层将Buse博士视为‘叛徒’，向他在UNC的上级投诉他，并以法律诉讼相逼，以平抑他的顾虑，”报告称。“给Buse博士的上级打电话的是Tachi Yamada博士，然后是GSK的研发领导……Yamada博士争辩说，他打电话的目的是判定Buse博士是否会做出合法的声明或他是否在GSK对手的付费名单上。”

 

GSK否认它曾试图平息对其药品的批评。“GSK欢迎并支持对其药品展开公开、独立的科学辩论，”公司的声明称。“为此，我们已在公司的网站上公布了我们的临床试验、荟萃分析以及观察研究的结果，各位均可查阅。对平息科学辩论的任何行为，GSK均予以追究。GSK在认为他人的表述未能准确描述其药品或功效时，会对错误的说法和表述进行纠正。”

 

在FDA方面还存在一个问题。曾有媒体报告指出，某些FDA科学家出于对心血管问题的顾虑，会敦促将文迪雅撤出市场，在谈及此问题时，FDA发言人Karen Riley表示，“FDA将慎重对待财政委员会主席Max Baucus及高级官员Charles Grassley在近期调查中提出的顾虑和问题。

 

Riley女士指出，FDA药物评估和研究中心的主任Janet Woodcock博士在2009年12月发表了一篇备忘录，要求“中心内部所有的办公室迅速对文迪雅的最新数据进行评估，争取在2010年秋季将评估结果交到FDA顾问委员会。”她补充道，“FDA等待着顾问委员会的建议。同时，FDA专员Margaret Hamburg博士计划与FDA科学家和外部专家会晤，以充分了解所有的相关问题。”

 

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