In July 2011, the Food and Drug Administration approved AstraZeneca AZN.LN -0.37%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 SAN.FR -0.79% 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. BMY -1.03% , 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 +1.39% & 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.
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 studies. He 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.
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