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2014-02-11 识林

阿斯利康Brilinta的研究遭遇挑战—临床研究中心脏病发作统计受到质疑
2014年2月2日下午7:44

2011年6月，FDA批准了阿斯利康公司的抗凝血药Brilinta用于冠状动脉病情严重患者。一项研究已证明该药可并挽救生命并降低心脏病发作这的确是让人感到眼前一亮的药品。

但在幕后，有关这一药品是否应获批的戏剧性故事正在展开。在提交给哥伦比亚特区美国地区法院的一份未公开控诉中，约翰霍普金斯医学院专门研究此类药品的一位兼职教授Victor Serebruany指出相关研究数值涉嫌被篡改。

Serebruany博士告诉联邦调查员该研究服用对照药品对照组的死亡数目与早先研究相比高得不正常。根据知情人士的透露以及《华尔街日报》评议的文件，他还质疑该研究中对心脏病发作的统计，指控存在对Brilinta有利的偏倚。该项研究统计了心脏病死亡、心脏病发作以及卒中。

Serebruany博士按照联邦《反虚假陈述法案》提交投诉，根据这一法案，美国政府可以加入诉讼以追回款项。根据阿斯利康公司在去年十月份的一次披露以及知情人士，位于华盛顿特区的一家美国检察官办公室一直与Serebruany博士保持联系，并正在对这一临床研究展开调查。阿斯利康公司宣称，已收到来自美国司法部华盛顿特区检察官办公室的民事调查询问直接地讲，就是民事传票。

美国检察官办公室的代表拒绝发表评论。

该调查活动也可能无果而终，Serebruany博士的投诉中也未明确指出他个人所获知的任何不当行为。

阿斯利康则为该项名为“Plato”的研究以及此药品的有效性辩护。

“我们自信该研究流程的完整性，并为Brilinta给全球患者带来的重大获益而感到骄傲，”阿斯利康公司表示，并称公司将配合政府的调查。该公司称此药品已经“由多家顶尖学报广泛审查”并已在超过100个国家获批。

阿斯利康公司称，在不同临床研究之间比较死亡率不妥当，并指出心脏病发作统计并未偏倚。

Serebruany博士称,法规禁止讨论这桩诉讼，但相关材料表达了他的立场。溶栓药在发达国家名列使用最广的药品之列，赛诺菲公司出产的波力维（Plavix） 在阿斯利康研究中用于与Brilinta作对比 — Plavix在2012年专利到期前，位居全球最能盈利的药品之列。Brilinta在美国市场销量不温不火，2013年第三季度销售额为7500万美元。阿斯利康公司已将其视为疗效优于Plavix的潜在大众市场重磅炸弹式药品。

在美国合作销售Plavix的赛诺菲与百时美施贵宝公司拒绝就此事评论。阿斯利康在43个国家的18624名患者中开展“Plato”研究。《新英格兰医学学报》在2009年发表了结果，报道与服用Plavix相比，Brilinta给患者带来具有统计学意义的结果改善。文章称，在12个月的时间内，Brilinta组有9.8%的患者遭遇血管性原因的心脏病发作、卒中或死亡，这一比例优于Plavix组的11.7%。新英格兰医学杂志拒绝就此事评论。

即便在Serebruany博士卷入之前，“Plato”研究已在FDA引起广泛讨论。整个研究的美国部分所涉及的1413名患者中， Brilinta事实上劣于Plavix，血管性死亡、心脏病发作与卒中的发生率高出27%。

Serebruany博士首次被卷入Brilinta事件是在2010年，当时以为FDA高级官员希望其就“Plato”研究的数据向FDA提供咨询。Serebruany博士是知名的血小板专家，但部分由于他的财务关系以及近期有对药品研究细节反复批评的记录，也是一位有争议的人物。

他的公司，位于马里兰州陶森的HeartDrug Research有限责任公司，为与其共同经营另一该类药品的竞争品种Effient（普拉格雷）的礼来以及赛诺菲等大药企提供服务。与此同时，他收取阿斯利康公司（即他现在所批评的企业）的咨询费。他曾持有或仍持有大量药品的专利。

邀请Serebruany博士介入的FDA审评小组领导Thomas Marciniak，写道该研究记录凌乱，有12名患者打电话自报死亡。

“字面上看这是我所遇到的最差的提交——在严重不良事件信息的收集，或至少在这方面信息的提交方面”，Marciniak博士写道，建议该药品不应在有新的研究结果前获批。

对官方记录的审查显示，更高级别的FDA官员否决了他与其它审评员的意见，批准了该药。根据FDA的医学审评，这名高级官员表示，该药品在“Plato”研究美国部分中的不佳结果，可能源自美国患者使用大剂量的阿司匹林，从而削弱了 Brilinta的有效性。

. Marciniak博士的导师，Norman Stockbridge，在一份报告中称时间报道的许多问题可能都很轻微，而不至于影响到结果。阿斯利康公司拒绝对患者自报死亡的指控发表评论，并称Stockbridge博士的一份报告解决了Marciniak博士的关注。

博士与其它几位FDA高级官员拒绝讨论关于Brilinta获批的任何方面的请求。

在作为诉讼案件一部分提交的书面分析之中，对比之前的研究，Serebruany博士指称Plavix组患者死亡率“高得异乎寻常”。他表示，Plavix组患者5.9%的死亡率几乎是其它Plavix相关研究的2倍，也是过去十年中所报道的最高值。他对Plavix的问题—也就是Brilinta的获益—为何大量出现在患者服药3到6个月之后表示质疑。

阿斯利康则表示Brilinta的获益“很早就有并持续贯穿于整个研究中”。此外，Serebruany博士称，只有波兰与匈牙利两个国家的结果表现出Brilinta有具有统计学意义的优势。他指出，这两个国家共占所招募患者的21%，但其中服用Plavix的患者多达46%经历过多的卒中、心脏病发作以及血管性死亡。

阿斯利康公司则指出，即便剔除波兰与匈牙利部分，整项研究可仍体现出Brilinta的优势。该研究是设盲的，意味着医生与患者不应知道谁服用哪种药品。但Serebruany博士质疑医护人员是否已清楚药品具体是哪种。他指出，医护人员可以通过打开胶囊给患者服药来辨明药品，原因在于Plavix胶囊内使用分割片的形式。阿斯利康公司称，尚无此类“非盲”情况发生的证据。

该投诉还指出，最初基于治疗医生决定的研究结果统计，并未体现出Plavix组与Brilinta组心脏病发作统计显著性的不同。但是经过杜克大学临床研究所的审定（一种部分重新清点）之后， 额外的45例心脏病发作案例被计入Plavix组。这使得Brilinta在统计学上得以夸大，击败Plavix。

这家公司及其部分研究人员称，这一重新清点对确保所有医生使用同样标准判定患者是否遭受严重不良事件是必要的。Serebruany博士指出，杜克并未做错什么，但指责该公司挑选有利的病例用于审评。杜克将这一问题推给时任该大学临床研究部主任，现在在斯坦福大学的Robert Harrington。Harrington博士表示：“用这样实质上可以改变结果的的方式来改变事情，超出了我的信念”。

Doctor Challenges Testing of AstraZeneca's Brilinta Tabulation of Heart Attacks in a Study Is Questioned
Feb. 2, 2014 7:44 p.m. ET

In July 2011, the Food and Drug Administration approved AstraZeneca PLC's anticlotting drug Brilinta for patients with certain severe coronary conditions. A study had shown the pill saved lives and reduced heart attacks—a real eye-opener in medicine.

But behind the scenes, a drama is unfolding over whether the drug should have been approved. In a sealed complaint filed in U.S. district court in the District of Columbia, Victor Serebruany, an adjunct medical professor at Johns Hopkins Hospital who specializes in such drugs, contends the study numbers may have been manipulated.

Dr. Serebruany has told federal investigators that the number of deaths in the study's control group—those taking a competing drug—was unusually high compared with earlier trials. He also has questioned the tabulation of heart attacks in the study, alleging it was skewed in Brilinta's favor, according to people familiar with the matter and documents reviewed by The Wall Street Journal. The study measured cardiovascular deaths, heart attacks and strokes.

Dr. Serebruany filed his complaint under the federal False Claims Act. Under that law, the U.S. government has the option of joining the lawsuit to recover money.

The U.S. attorney's office in Washington, D.C., has been in contact with Dr. Serebruany and is investigating the trial's conduct, according to an October disclosure by AstraZeneca and people familiar with the matter. AstraZeneca said it had received a civil investigative demand—essentially, a civil subpoena—from the U.S. Department of Justice, of which the U.S. attorney's office in Washington is a part.

A representative of the U.S. attorney's office declined to comment.

The U.S. probe could end without action, and Dr. Serebruany in his complaint didn't assert direct personal knowledge of any wrongdoing.

AstraZeneca defended the trial, known as Plato, and the efficacy of its drug.

"We are confident in the integrity of the study process and proud of the important benefit Brilinta brings to patients around the world," AstraZeneca said, adding that it is cooperating with the government's inquiry. The company said the drug has been "extensively reviewed by top-tier journals" and approved in over 100 countries.

AstraZeneca said it wasn't appropriate to compare death rates between clinical trials because of differences in groups of patients, and it called the tabulation of heart attacks unbiased.

Dr. Serebruany said legal rules prohibit his discussing the lawsuit, but documents set out his position.Clot-busting drugs are some of the most widely used medicines in developed nations, and Plavix—the Sanofi drug to which Brilinta was compared in the AstraZeneca trial—was among the world's most lucrative drugs before it went off patent in 2012. While Brilinta's U.S. sales were a modest $75 million in the third quarter of 2013, AstraZeneca has pitched the pill as a potential mass-market blockbuster that beats Plavix in efficacy.

Both Sanofi and Bristol-Myers Squibb Co., which co-markets Plavix in the U.S., declined to comment.AstraZeneca conducted the Plato trial with 18,624 patients in 43 countries. The New England Journal of Medicine published the results in 2009, reporting statistically significant improved outcomes for patients on Brilinta compared with those taking Plavix. The article said 9.8% of patients on Brilinta suffered a heart attack, stroke or death from vascular causes over a 12-month period, better than the 11.7% in Plavix patients. The New England Journal of Medicine declined to comment.

Even before Dr. Serebruany's involvement, the Plato study was causing extensive debate at the FDA. In the U.S. portion of the overall study, among 1,413 patients, Brilinta actually did worse than Plavix and was linked to a 27% greater incidence of vascular deaths, heart attacks and stroke. Dr. Serebruany was first drawn into the Brilinta issue when a senior FDA official asked him to advise the agency about the Plato data in 2010. Dr. Serebruany is known for expertise in blood platelets, but is a controversial figure, partly because of his financial ties and his recent track record of repeatedly criticizing details of drug studies.

His firm, HeartDrug Research LLC in Towson, Md., has done work for major drug companies including Eli Lilly LLY & Co., co-marketer of a competing drug, Effient; and Sanofi. At the same time, he has received speaking fees from AstraZeneca, the company he is now criticizing. He holds or has held patents on numerous drugs.

Thomas Marciniak, the FDA review-team leader who asked Dr. Serebruany to get involved, wrote that the trial's records were sloppy, and wrote that 12 patients reported their own deaths by telephone.

"Literally this submission is the worst submission I have encountered for collecting—or at least submitting—information on SAEs," or serious adverse events, Dr. Marciniak wrote, recommending that the drug shouldn't be approved without a new trial.

Higher-ranking officials at the FDA overruled him and other reviewers and approved the drug, a review of the official file shows. The senior FDA officials said the drug's poor U.S. results in the Plato trial might have resulted from high-dose aspirin use by U.S. patients that diminished Brilinta's effectiveness, according to agency medical reviews.

Dr. Marciniak's supervisor, Norman Stockbridge, said in a report that any problems with reporting of events were probably too minor to affect the outcome AstraZeneca declined to comment on the allegation about patients reporting their own deaths and said a report by Dr. Stockbridge addressed Dr. Marciniak's concerns.

Dr. Stockbridge and other senior FDA officials declined requests to discuss any aspect of Brilinta's approval. Stockbridge

Dr. Serebruany, in his written analyses submitted as part of his court case, termed the death rates among Plavix patients "extraordinarily high" compared with those in previous studiesHe said the all-cause death rate of 5.9% in the Plavix patients was nearly twice that of other Plavix studies and was the highest reported over a decade. He questioned why the Plavix problems—and Brilinta's benefit—largely emerged three to six months after patients took the drugs.

AstraZeneca said Brilinta's benefit "started early and continued throughout the study." What's more, he said, there were just two countries, Poland and Hungary, that showed a statistically significant advantage for Brilinta. He said these two countries accounted for 21% of the enrolled patients but 46% of the excess strokes, heart attacks and vascular deaths experienced by those on Plavix.

AstraZeneca says that even without Poland and Hungary, the overall study showed an advantage for Brilinta. The study was blinded, meaning doctors and patients weren't supposed to know who got what drug. But Dr. Serebruany questioned whether the doctors and nurses might have known which drug was which. He said they could have figured it out by opening up capsules given to the patients because Plavix took the form of split tablets inside capsules. AstraZeneca says it has no evidence such "unblinding" took place.

And the complaint said that the first tabulation of trial results based on the treating doctors' decisions showed no statistically significant difference between the Plavix and Brilinta groups in heart attacks. But after an adjudication—a kind of partial recount—by Duke University's Clinical Research Institute, an extra 45 heart attacks were added to the Plavix group. This put Brilinta over the top statistically in beating Plavix, the complaint said.

The company and some of its researchers said the recount was necessary to ensure that all doctors used the same standards in deciding whether a patient had suffered an adverse event. Dr. Serebruany said Duke did nothing wrong, but he accused the company of cherry-picking the cases for review. Duke referred questions to Robert Harrington, who was then director of the university's Clinical Research Institute and now is at Stanford. "It stretches my belief that one could try to alter things in a way that could materially change the result," Dr. Harrington said.

原文请见 Doctor Challenges Testing of AstraZeneca's Brilinta