In 2000, amid rising concerns that its painkiller Vioxx posed heart risks, Merck overruled one of its own scientists after he suggested that a patient in a clinical trial had probably died of a heart attack.
Evidence in Vioxx Suits ShowsBy ALEX BERENSON
Intervention by Merck Officials
In an e-mail exchange about Vioxx, the company's most important new drug at the time, a senior Merck scientist repeatedly urged the researcher to change his views about the death "so that we don't raise concerns." In later reports to the Food and Drug Administration and in a paper published in 2003, Merck listed the cause of death as "unknown" for the patient, a 73-year-old woman.
The discussion of the death is contained in several previously undisclosed Merck records, including e-mail messages from Dr. Edward M. Scolnick, Merck's top scientist from 1985 until 2002, and from Dr. Alise S. Reicin, a vice president for clinical research, that indicate Merck's concerns about data contradicting its view that Vioxx was safe.
In one e-mail message, Dr. Scolnick said the drug trial that included the woman's death had "put us in a terrible situation." In others, he fiercely criticized the F.D.A. and said he would personally pressure senior officials at the agency if it took action unfavorable to Vioxx. As lawsuits against Merck over Vioxx move toward trial, the documents could help plaintiffs paint a picture of the company that is at odds with Merck's public statements that it had no evidence of Vioxx's cardiac risks until last fall.
Theodore V. H. Mayer, a lawyer for Merck, said that it had disclosed all information from clinical trials to the F.D.A. and that Dr. Scolnick's e-mail messages merely reflected his concern that the F.D.A. weigh Vioxx's benefits and risks fairly. The e-mail discussion between the Merck scientists reflected an honest scientific debate over the cause of the woman's death, Mr. Mayer said.
Merck withdrew Vioxx in September after a different clinical trial found that the drug increased the risk of heart problems. More than 25 million Americans took Vioxx between 1999 and 2004, and at least 4,600 people or their survivors are suing Merck, claiming Vioxx caused their heart attacks or strokes. The first individual cases are scheduled for trial next month in Alabama and Texas, filed by the survivors of two men who the suits say died of heart attacks after taking the drug.
Merck, the nation's third-largest drug maker, has said it plans to defend every suit. The company says it did everything reasonably possible over the years to determine whether Vioxx caused heart problems and to disclose the drug's risks to patients and doctors. The e-mail messages and other internal Merck documents, including the report of the woman's death, were provided to The New York Times by a person working with plaintiffs.
The death of the 73-year-old woman - who was not identified by name in the documents and whose identity has not been disclosed - occurred during a 12-week clinical trial called Advantage that covered 5,500 patients. Clinical trials are at the core of the development of new medicines, providing data that enable the F.D.A. and doctors to weigh drug risks and benefits.
Mr. Mayer said the doctors involved in the e-mail exchanges could not be certain whether the woman who died was taking Vioxx or an older painkiller, naproxen, that was used in the trial, because information about which participant was taking which drugs was kept confidential. But at the time, there was widespread concern within the company about the relationship between Vioxx and heart attacks as a result of troubling earlier research.
During the Advantage trial, eight people taking Vioxx suffered heart attacks or sudden cardiac death, compared with just one taking naproxen, according to data released by the F.D.A. earlier this year. The difference was statistically significant, but Merck never disclosed the data that way.
Back in 2000, Merck was already struggling to explain the results of another study, called Vigor, which also indicated that patients taking Vioxx had more heart attacks than those taking naproxen, which is found in over-the-counter drugs like Aleve. Unlike the Advantage results, the Vigor results had been publicly disclosed by Merck.
Dr. Scolnick expressed his worry in e-mail messages to other senior Merck scientists that the Advantage results would encourage the F.D.A. to demand that Vioxx's label highlight its cardiac risks. Such a change would have damaged Vioxx's sales, especially because a competing drug, Celebrex, did not have heart risks prominently displayed on its warning label.
In e-mail messages on April 7, 2001, to Dr. Douglas A. Greene, an executive vice president at Merck Research Laboratories, Dr. Scolnick wrote that he was especially angry because the Advantage trial had no scientific purpose. In theory, Merck set up the trial to show that Vioxx caused fewer stomach problems than naproxen. But Merck had already demonstrated that with the Vigor trial, which tracked more than 8,000 patients for a year.
As it turned out, Merck's marketing department had created the Advantage trial as a promotional tool, to introduce about 600 doctors to Vioxx. "This course is just stupid," Dr. Scolnick wrote. "Small marketing studies which are intellectually redundant are extremely dangerous."
The Advantage trial was completed in 2000, but its results were not published until 2003, when they appeared in the Annals of Internal Medicine, a well-regarded journal. Dr. Jeffrey R. Lisse, a rheumatologist at the University of Arizona who is listed as the study's first author, said in an interview that at least two other journals had rejected the study because its results were not novel.
In the published study, Dr. Lisse reported that five patients taking Vioxx had suffered heart attacks during the trial, compared with one taking naproxen, a difference that did not reach statistical significance. But the paper never mentioned the three additional cardiac deaths of patients taking Vioxx, including the 73-year-old woman.
Dr. Lisse said that while he was listed as the paper's first author, Merck actually wrote the report, an unusual practice.
"Merck designed the trial, paid for the trial, ran the trial," Dr. Lisse said. "Merck came to me after the study was completed and said, 'We want your help to work on the paper.' The initial paper was written at Merck, and then it was sent to me for editing."
Dr. Lisse said he had never heard of the case of the woman who died, until told of it by a reporter. "Basically, I went with the cardiovascular data that was presented to me," he said.
The 73-year-old woman who became the subject of the debate inside Merck died on Oct. 21, 1999, a few minutes after calling her son to tell him she felt short of breath. By the time her son reached her house, she was dead. Records show that she had been taking 25 milligrams of Vioxx a day as part of the clinical trial.
Both the Advantage and Vigor trials were "double-blinded," a common practice in drug research. Neither patients nor their doctors were aware whether patients were receiving Vioxx or naproxen. Results from the trials were also supposed to be blinded when they were examined, so that Merck researchers could not bias the results.
In 1998, Merck had created a committee of academic researchers to review the case reports for many patients who had suffered suspected heart problems in clinical trials of Vioxx or Arcoxia, a Merck arthritis drug that has still not been approved. But the woman's case never reached the outside committee because the cause of death listed on the death certificate from an independent autopsy - hypertensive heart disease - did not fall into a category that would automatically prompt Merck to refer the case.
As a result, Merck reviewed the case internally. After examining the case, Dr. Eliav Barr, a Merck scientist, initially judged that the woman had probably died of a heart attack.
"Common things being common, the clinical scenario is likely to be MI," Dr. Barr wrote in an e-mail message in November 2000 to Dr. Reicin, the clinical research executive. MI is an abbreviation for myocardial infarction, or heart attack. "Certainly, it is not definitive. I just used my clinical judgment."
Dr. Reicin quickly responded, "I think this should be called an unknown cause of death." A few hours later, she wrote, "I would prefer unknown cause of death so we don't raise concerns."
Mr. Mayer, Merck's lawyer, said the exchange reflected that the scientists were working to classify the death properly, and probably did not know whether the woman had been taking Vioxx or naproxen.
But the scientists did already have the results of the Vigor trial, which had shown that Vioxx was associated with an increased risk of cardiovascular death compared with naproxen.
Dr. Robert J. Myerburg, director of cardiology at the University of Miami medical school, said he was taken aback by Merck's decision to reclassify the woman's case. Dr. Myerburg, a prominent cardiologist who is not involved in the Vioxx litigation, reviewed the e-mail exchanges at the request of The Times.
"A fatal event not being treated as objectively as possible surprises me," he said. "It looks like they're playing around with this death."
When Merck presented the data from the Advantage trial to the F.D.A., it classified the woman's death as unknown. But in November 2001, an F.D.A. reviewer who had examined all the company's data concluded in a report to other agency officials that Merck had misclassified the death and should have referred the case to its outside committee.
In her report, the reviewer, Dr. Maria Lourdes Villalba, said that the heart attacks and sudden cardiac deaths during the Advantage trial had heightened her concerns about Vioxx, because the participating patients were taking only 25 milligrams of the drug, the usual daily dose. In addition, many patients were also taking aspirin, which helps protect against heart attacks.
But the F.D.A. never publicly disclosed its concerns about the Advantage trial. And Merck discussed the results of the trial only once, at a conference in 2001, before the publication of Dr. Lisse's paper in 2003.
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