Healthy Skepticism Library item: 4732
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Publication type: news
Armstrong D.
Bitter Pill: How the New England Journal Missed Warning Signs on Vioxx
The Wall Street Journal 2006 May 15
http://online.wsj.com/article/SB114765430315252591.html
Keywords:
Vioxx NEJM
Notes:
Ralph Faggotter’s Comments:
“We can’t be in the business of policing everybit of data we put out,..”
Medical journal editors traditionally rely, in some measure, on a scientists’ honour system when they accept articles for publication – namely that the paper submitted accurately reflects the outcome of the research which was done.
But what if the editors are dealing with a soulless corporation for which the concept on honour has no meaning?
How much responsibility should a journal take on when it agrees to publish an article?
Full text:
THE WALL STREET JOURNAL
Bitter Pill: How the New England Journal Missed Warning Signs on Vioxx
Medical Weekly Waited Years To Report Flaws in Article That Praised Pain
Drug Merck Seen as ‘Punching Bag’
By DAVID ARMSTRONG
May 15, 2006; Page A1
BOSTON — 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.”
ON RECORD
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. 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 pu it out if
we believe that the re-analysis is correct.”
- * *
1 Listen to the full exchange
Puget Sound Public Radio. (Hrachovec’s call begins at about minute 44:30.)
Dr. Drazen was dismissive. “We can’t be in the business of policing every
bit of data we put out,” he told Dr. Hrachovec.
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.
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.
Stanford University medical professor Gurkirpal Singh, a rheumatologist who
was among the first researchers to raise questions about Vioxx’s cardiac
risks, says the affair shows that journals need to be more vigilant about
problems in what they publish. While praising the New England Journal for
eventually taking action, he says “They absolutely should have corrected in
2001.” Had it acted earlier, he says, sales of Vioxx “would have been
killed.”
Dr. Drazen, the editor, says in an interview that the authors of the
article, who included Merck employees and consultants, are the ones at
fault. “This was an episode where it was clear people had taken data and not
reported it fully,” he says in an interview. He adds: “I have now learned we
need to be much more careful.”
The questions about the New England Journal come as the flaws of leading
medical journals are receiving greater attention. Many articles lend an
academic imprimatur to messages hatched by drug companies as part of
publicity campaigns. Sometimes they fail to disclose authors’ financial ties
to companies or the involvement of company-hired ghostwriters.
Started in 1812, the New England Journal has 200,000 subscribers and is
considered must reading for doctors who want to stay current. Its
selectivity and editing practices are feared and respected. The weekly
rejected 93% of the 3,586 manuscripts it received last year. Accepted papers
typically undergo months of editing, including “peer review” by a secret
panel of experts and scrutiny by staff editors, many of whom are doctors.
The journal won’t disclose its revenue, but its owner, the nonprofit
Massachusetts Medical Society, listed $88 million in total publishing
revenue for the year ending May 31, 2005.
In May 2000, a team including Merck employees submitted to the journal an
article about Vioxx, a painkiller approved the previous year by the FDA. The
article presented the results of a human trial called Vigor that showed
Vioxx posed a lower risk of stomach ulcers and bleeding than naproxen, one
of a class of older pain relievers long associated with such complications.
The article said 0.4% of the Vioxx patients had suffered heart attacks,
compared to 0.1% for the naproxen group. It offered several reasons why that
wasn’t as worrisome as it seemed, including a theory that the difference
stemmed from naproxen’s supposed protective effect on the heart. The New
England Journal published the article on Nov. 23, 2000, and the occasion was
celebrated by Merck in a press release.
Merck submitted data from the Vigor study to the FDA because it wanted to
add the favorable information about stomach side effects to Vioxx’s label.
But the data it gave to the agency, posted on the FDA’s Web site in February
2001, did not square with the data in the New England Journal article. Merck
said Vioxx takers had 20 heart attacks, which translated into 0.5% of the
total, not 0.4% as the article said. The higher figure undermined an
assertion in the article that only those who were already at high risk of a
heart attack showed an increased risk after taking Vioxx. That’s because the
extra heart attacks were all in the low-risk group.
The FDA Web site said Merck submitted the revised heart-attack data in
October 2000, before the publication of the article. Dr. Curfman, the
journal’s executive editor and a cardiologist, acknowledges that he reviewed
the FDA Web site posting around September 2001. The journal says the editors
believed the FDA had posted late data from the trial that had not been
analyzed in time to be included in the article’s manuscript.
In June 2001, Dr. Hrachovec in Seattle and a doctor reviewing the drug for a
Seattle health insurer wrote to the New England Journal, noting the FDA
posting. They warned the journal that the Vioxx results it printed were
incomplete and made the drug appear safer than it was. The journal refused
to publish the letter, saying space was limited. It acknowledges that during
this period it never asked Merck, the FDA or the article’s authors about the
discrepancy, believing that it was the responsibility of the authors to
report new data.
Merck says the extra heart attacks, three in total, happened after a
predetermined cutoff date for recording events in the trial. Merck says the
article was properly done and doesn’t require a correction. That puts the
company at odds both with critics of the New England Journal and the
journal’s editors, who now are calling for a correction while defending
their failure to ask for one earlier.
Dr. Drazen says journal editors are “just the middleman in picking what goes
out there” and “when there are problems the onus lies with” authors to sound
the alert. “If you ask me, it is none of our concern about whether [Vioxx]
is a cardiovascular risk in the patients that are on trial,” he says. The
concern was making sure what was published was correct, he says, and “people
could have set the record straight.”
Early Criticism
Besides the article’s possible understating of the heart-attack numbers, its
theory that naproxen had a protective effect on the heart also came in for
early criticism. “This hypothesis is not supported by any prospective
placebo-controlled trials with naproxen,” an FDA official wrote in a memo
also published on the agency’s Web site in February 2001. In September of
that year, the FDA sent a public warning letter to Merck, criticizing the
drug maker for promoting the naproxen idea without explaining the lack of
evidence for it.
Curt Furberg, a Wake Forest University public health professor, says the New
England Journal should have challenged the authors on the naproxen theory
during the article’s editing. “Here we have an editorial board attacking the
company when they conducted an inferior review of the article,” says Dr.
Furberg, who is also an adviser to the FDA on drug safety. “The sad thing is
patients have suffered as a result.”
In September 2004, Merck withdrew Vioxx, citing the results of a new study
that showed the drug raised the risk of heart attack and stroke for those
using it at least 18 months.
Both sides in federal litigation over Vioxx conducted a deposition in
November 2005 of Dr. Curfman, the executive editor. Plaintiffs hoped to
bolster their allegation that Merck’s marketing of Vioxx was deceptive.
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.
FURTHER READING
Read the “Expression of Concern”
England Journal of Medicine Dec. 29, 2005, about the Vigor trial.
The journal’s editors grew alarmed about the potential for bad publicity
over the videotaped deposition, fearing it could be leaked or played in a
federal courtroom session on Dec. 8, according to internal emails and an
interview with Drs. Curfman and Drazen. After five years of silence on the
article, the editors started racing to prepare an “expression of concern”
about it.
The New England Journal says there was a good reason for the sudden decision
to rebuke the article’s authors. It says Dr. Curfman was surprised to
discover from a July 5, 2000, memo he was shown during the deposition that
two of the authors who worked for Merck knew of the extra three Vioxx heart
attacks well in advance of the November article.
However, that shouldn’t have been news to Dr. Curfman since he says he read
the FDA documents in 2001 showing Merck submitted information about the
three events to the FDA more than a month before the article’s publication.
Dr. Curfman says there was nothing in the FDA data to indicate the authors
knew of the additional heart attacks. Also, he says, “The data were in the
hands of a regulatory agency and we felt it was now up to them to take
appropriate action.”
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.
‘We Were Hoodwinked’
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.”
The day after the expression of concern, Mr. Cafasso emailed colleagues:
“The story is playing out exceptionally well.”
Write to David Armstrong at david.armstrong@wsj.com4
Copyright 2006 Dow Jones & Company, Inc. All Rights Reserved
Hyperlinks in this Article:
(1) http://www.kuow.org/defaultProgram.asp?ID=2123
(2) http://www.kuow.org/defaultProgram.asp?ID=2123
(3) http://content.nejm.org/cgi/reprint/353/26/2813.pdf
(4) mailto:david.armstrong@wsj.com
