New England Journal Missed Warning Signs on Vioxx

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There is more than just a hint of corruption in the American medical community. The NEJM/Vioxx story is one more piece of evidence of the influence of money over medical policy.

WSJ.com - How the New England Journal Missed Warning Signs on Vioxx

In August 2001, a Seattle pharmacist called a radio show on which Jeffrey Drazen, the top editor of the New England Journal of Medicine, was appearing. On the air, the pharmacist, Jennifer Hrachovec, begged Dr. Drazen to update an article in the journal that touted the benefits of the painkiller Vioxx while playing down its heart risks.

Dr. Hrachovec had been reviewing data on a Food and Drug Administration Web site indicating that patients in a Vioxx clinical trial had suffered more heart attacks than the journal article about the trial reported. “It bothers me there is more data from the trial than has ever been published and the New England Journal still hasn't published an editorial or any kind of update,” she said. “My concern is that doctors are still using this and exposing their patients to higher risks of heart problems and they just don't even know that that's the case.”


Pharmacist Jennifer Hrachovec challenged Jeffrey Drazen, editor of the New England Journal of Medicine, about the Vigor study in a call to a Seattle radio show Aug. 14, 2001. Dr. Drazen was dismissive. “We can't be in the business of policing every bit of data we put out,” he told Dr. Hrachovec

Below, excerpts.

Hrachovec: “With this study in particular, it bothers me that there is more data from the trial than has ever been published and the New England Journal still hasn't published an editorial or any kind of update to let readers and clinicians using this drug and giving it to patients who they think will benefit from a better side-effect profile. My concern is that doctors are still using this and exposing their patients to higher risks of heart problems and they just don't even know that that's the case.”
Drazen: “… We can't be in the business of policing every bit of data that we put out. We think that that's the role of people who know the field. And when they think that the field has advanced to the point where something which was true at the time it came out may no longer be true … having brought that evidence to our attention in the form of a manuscript or a letter, we can judge whether there's enough new information and put it out if we believe that the re-analysis is correct.”

Three years later, Merck & Co. pulled Vioxx from the market, citing higher risk of heart attacks and strokes in some patients. An estimated 20 million Americans took Vioxx, and more than 11,500 lawsuits have been filed against Merck alleging death and other damage from the drug.

here's the direct link to financial reasons for the NEJM's reluctance to say anything negative about Vioxx:

...Although the New England Journal wasn't on trial for anything, the deposition produced a number of damaging admissions by Dr. Curfman. He acknowledged that neither the peer reviewers nor journal editors challenged the authors' heart-attack theory about naproxen as it was presented in the article. “Yeah, we signed off on this,” he said, according to a transcript of his testimony. “And I have many times had second thoughts about having done that.”

Dr. Curfman also disclosed that the journal sold 929,400 reprints of the article -- more than one for every doctor in the country. Merck says it bought most of them. The reprints brought in between $697,000 and $836,000, using per-copy price estimates provided by the journal. If the New England Journal had questioned the article's findings earlier, the impact of the reprints likely would have been blunted because any corrections or official statements on a study must be included with the reprint. Merck says that after February 2001 it included a letter with the reprints telling doctors about the additional information submitted to the FDA.

While Merck has taken the brunt of criticism in the affair, the New England Journal's role in the Vioxx debacle has received little attention. The journal is the most-cited medical publication in the world, and its November 2000 article on Vioxx was a major marketing tool for Merck.

Last December, the journal repudiated the Vioxx article in an “expression of concern,” but only after the drug had been recalled and more than five years after the article appeared. Had the journal acted before the recall, its authoritative voice almost certainly would have damped the Vioxx boom.

Dr. Hrachovec's radio-show call was one of several early warnings about the article's flaws including its failure to mention the extra heart attacks. She and a colleague also submitted a letter to the New England Journal, which was rejected for publication. The Journal of the American Medical Association reported on Vioxx's cardiac risk in an August 2001 article. In April 2002 the FDA added a caution on Vioxx's label that warned of cardiovascular risks.

Internal emails show the New England Journal's expression of concern was timed to divert attention from a deposition in which Executive Editor Gregory Curfman made potentially damaging admissions about the journal's handling of the Vioxx study. In the deposition, part of the Vioxx litigation, Dr. Curfman acknowledged that lax editing might have helped the authors make misleading claims in the article. He said the journal sold more than 900,000 reprints of the article, bringing in at least $697,000 in revenue. Merck says it bought most of the reprints.


uhh, yes, we read that already....

...Dr. Drazen also received a clear description of the timing in a July 2005 email from Eric Topol, then a Cleveland Clinic cardiologist, who had criticized Merck and Vioxx. Dr. Topol, who had been contacted by a National Public Radio reporter asking about the November 2000 New England Journal article, told Dr. Drazen that the article's authors “clearly had ample time to correct the data when one compares the FDA Submission dates and the galley proofs (as relayed to me by Greg Curfman).”

On the night of Dec. 7, Edward W. Campion, a senior New England Journal editor, sent a note to his staff explaining why the statement had to be released the next day. The explanation didn't involve any late-breaking information obtained by Dr. Curfman. “The reason is that tomorrow's testimony in the Vioxx trial may involve part of a deposition that Greg gave,” Dr. Campion wrote. “It will be essential to notify press” about the statement “and make it prominent” on the journal's Web site, he added.

A public-relations specialist who has advised the journal since 2002 predicted the rebuke would divert attention to Merck and induce the media to ignore the New England Journal of Medicine's own role in aiding Vioxx sales.

“I believe that given what a public punching bag Merck has become, there is more than enough information and more than enough context in the statement to drive the media away from NEJM and toward the authors, Merck and plaintiff attorneys,” wrote Edward Cafasso, a Boston-based public relations consultant, in a late-night email to journal staffers hours before the expression was released. Mr. Cafasso later added, “In my view, this disclosure may very well be seen as the final straw for Merck on the Vioxx matter.”

Mr. Cafasso's prediction initially proved correct. The Texas court ended up delaying the release of Dr. Curfman's deposition, and the expression of concern released Dec. 8 received wide media attention.

A Dec. 12 list of talking points circulated among journal editors advised them to deny that the journal's statement was connected to the federal trial. If asked about the release date, editors were advised to say, “We made this information public as soon as we could, without regard to the trial.” It isn't clear who wrote the memo.

The editors now concede the timing was connected to the planned release of Dr. Curfman's deposition at the trial. “We wanted a coherent statement to go out before that,” says Dr. Curfman. However, they maintain that the statement was motivated by Dr. Curfman's discovery of new information about the Merck authors' advance knowledge of the three heart attacks.
...

Dr. Drazen says one discovery he made after the journal's statement was published shows how the authors deceived the journal. He found that the Vigor study of Vioxx continued to tally stomach-related events for several weeks after it stopped tallying heart-related events. “We were hoodwinked,” he says. Merck says these cutoff dates were determined ahead of time and weren't designed to reduce the number of heart events included in the totals.

Perhaps the most sensational allegation in the journal's expression of concern was that the authors of the November 2000 article deleted heart-related safety data from a draft just two days before submitting it to the journal for publication. The journal said it was able to detect this by examining a computer disk submitted with the manuscript.

The statement was ambiguous about what data the authors deleted, hinting that serious scientific misconduct was involved. “Taken together, these inaccuracies and deletions call into question the integrity of the data,” the editors wrote.

In reality, the last-minute changes to the manuscript were less significant. One of the “deleted” items was a blank table that never had any data in it in article manuscripts. Also deleted was the number of heart attacks suffered by Vioxx users in the trial -- 17. However, in place of the number the authors inserted the percentage of patients who suffered heart attacks. Using that percentage (0.4%) and the total number of Vioxx users given in the article (4,047), any reader could roughly calculate the heart-attack number.

Dr. Curfman says it would have been easier on readers to give the exact number and admits “both the authors and the editors slipped up” in not including it.

Many news organizations, including The Wall Street Journal, misunderstood the ambiguous language and incorrectly reported that the deleted data were the extra three heart attacks -- which, if true, would have reflected badly on Merck. The New England Journal says it didn't attempt to have these mistakes corrected. Dr. Curfman says the language about the deletions is “very precise and it is correct.”

read the entire damning article here (subscription required)

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Read about the drug companies business model:

The War On Unpatented Drugs.

BTW the same thing that happened to the Interstate Commmerce Comission is happening to drug regulation. Companies have taken to regulating themselves. Because the reguation is political.

What is needed is a Underwriters Laboratories for drug regulation.

Which will never happen. Every one likes the political regulation model.

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This page contains a single entry by Seth A. published on May 15, 2006 8:12 AM.

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