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Vioxx Drama Echoes Earlier Concerns About Missing Data

Renewed outrage triggered by medical journal's charge that drug maker withheld heart risks

SATURDAY, Dec. 10, 2005 (HealthDay News) -- Revelations that a major drug company may have deliberately withheld data on the cardiovascular dangers of a popular painkiller are rapidly turning the Vioxx controversy into a consumer's worst nightmare.

Roughly 20 million people were using Vioxx before it was withdrawn from the market in 2004 because of heart risks. But those risks apparently surfaced as early as 2000, according to witnesses testifying at U.S. Food and Drug Administration drug safety hearings earlier this year and court testimony in three lawsuits against the drug's manufacturer, Merck & Co.

The drama gathered renewed intensity Thursday with the publication of a rare "Expression of Concern" by the editors of the New England Journal of Medicine. They charged that a major study called VIGOR, published in the journal in 2000 and subsequently used as strong argument for the drug's safety, was submitted to the journal after data on three heart attacks and other cardiovascular events among Vioxx trial participants was deleted by Merck, which funded the study.

"This is one horrible debacle in American medicine history," said Dr. Eric Topol, one of the nation's leading cardiologists, said Friday. "I've never seen the likes of this."

Topol, chairman of the cardiovascular medicine department at the Cleveland Clinic, has been in the forefront of efforts to reveal and publicize data on the cardiovascular risks of Vioxx, which was so popular that sales topped $2.5 billion in 2003. He has authored no less than 16 articles on the topic in the past five years, and has testified at the FDA hearings and in the ongoing litigation against Merck.

The NEJM editors said they first became aware of the missing data in 2001, but did not think the study authors had known about it. In late 2004, right after Vioxx was removed from the market, the editors opened a computer diskette that had been submitted with the study and "found a blank table with no data - lines had been drawn but not filled in. They did not know what should have been in there," Sandra Jacobs, a spokeswoman for the NEJM, said Friday.

"It raised some concern, but we didn't know enough to act on it," Jacobs added.

On Nov. 21, the journal's executive editor, Dr. Gregory D. Curfman, was deposed at the third Vioxx trial in Houston, which ended in a mistrial on Dec. 12. During the process, a memorandum dated July 5, 2000, came to light. The memo indicated that at least two of the VIGOR authors knew of the problems at least two weeks before submitting the first of two revisions, and four-and-a-half months before actual publication, of the study.

Further investigation revealed the authors had originally known of the data, the journal editors said.

And Curfman told HealthDay Thursday that electronic records showed "a pre-submission version of the study from which data, including the number of heart attacks and deaths, were deleted by a Merck editor two days before submission."

The missing data, he said Thursday, "would have given a more complete picture of the risks of Vioxx."

Dr. Claire Bombardier, who was the lead author of the 2000 study, told HealthDay Friday that she believed "the VIGOR paper appropriately disclosed the data as per the pre-specified plan of analysis. Events that occurred after the pre-specified cut-off date have been publicly known since the FDA advisory committee [meeting] in February 2001."

Asked if she had known that data on the three heart attacks had been deleted before the study was submitted, Bombardier, of the Institute for Work and Health at Mount Sinai Hospital in Toronto, said, "The authors of the paper have already begun the process of conducting an evaluation of the scientific facts and data that the NEJM published this week. We will make every effort to complete this process -- in full accordance with applicable medical and scientific standards -- as promptly as possible."

"Until that scientific analysis is complete, however, I will not be commenting on any of the specific statements made in the NEJM. I am first and foremost a scientist, and I will allow the data to speak for itself when it is complete," she added.

Merck, in a prepared statement, said the company "promptly and appropriately disclosed the results of the VIGOR study. Merck correctly communicated about the benefits and risks of Vioxx, and extensively disclosed the VIGOR data to the scientific and medical communities, and in the press."

In addition, the statement said, the VIGOR study "fairly and accurately described the results of the study as of the pre-specified cutoff for the analysis."

Topol disagreed with that interpretation.

In 2001, he was preparing to publish a manuscript on cardiovascular risks associated with Vioxx. He contacted Merck, pointing out discrepancies in the data and asking for input.

Topol has testified that Dr. Alise Reicin, vice president of clinical research at Merck Research Labs, paid him a personal visit after that request. That, he said, was "unprecedented."

"Reicin was the one who did all the talking, saying we'd be embarrassed, and we don't get it and we don't have access to all the data," Topol recalled.

In the journal on Nov. 23, 2000, Reicin was one of the 12 authors of the VIGOR trial, even though her affiliation with Merck not listed in the study's disclosure section.

Merck spokeswoman Janet Skidmore said Friday that Reicin was not available for comment.

According to the Associated Press, Merck later sent letters to doctors all over the country claiming Topol's analysis was faulty.

But efforts to discredit Topol didn't stop there, he charged. Merck's former chairman, Raymond Gilmartin, approached the chairman of the board of the trustees of the Cleveland Clinic to complain about Topol.

Merck exhibited similar behavior toward Dr. Gurkirpal Singh, an adjunct clinical professor of medicine at Stanford University who had been a consultant to the company, according to a report in the Toronto Globe and Mail.

When Singh tried to raise questions about missing data, he was contacted by a Merck official who threatened "serious consequences," the paper reported.

"These sorts of acts of intimidation and these sorts of activities, there's a lot of them," Topol said. "Stanford is just one example. They're all around the country."

For Topol personally, it has been a troubling episode. "I have to say that it's been a nightmare for me to try to stand up against Merck," he said. "They tried to discredit me. It doesn't feel good when you're the one."

Topol recently testified in the ongoing Vioxx trial in Houston, and, he said, he accused Merck of scientific misconduct and called their actions "appalling" and "repulsive."

"I genuinely feel that, and I think now the scientific misconduct trail is really fully backed up," he said Friday. "There's no question about it. The New England Journal doesn't publish an expression of concern for nothing."

"This is a very sad time in American medicine," Topol added. "The heavy direct-to-consumer stuff with this drug, and the manipulation of data in the most important medical journal. This is very sad."

More information

The U.S. Food and Drug Administration has more on Vioxx and other cox-2 inhibitors.

SOURCES: Eric J. Topol, M.D., chairman, department of cardiovascular medicine, Cleveland Clinic, Ohio; Claire Bombardier, M.D., University of Toronto; Janet Skidmore, spokeswoman, Merck & Co., Whitehouse, Station, N.J.; Dec. 29, 2005, New England Journal of Medicine; Toronto Globe & Mail; Associated Press
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