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Merck Knew Vioxx's Dangers at Early Stage

Merck Knew Vioxx's Dangers at Early Stage -- Posted by MrPepper11 on 11-01-04 05:07

November 1, 2004

Warning Signs
E-Mails Suggest Merck Knew Vioxx's Dangers at Early Stage
As Heart-Risk Evidence Rose, Officials Played Hardball; Internal
Message: 'Dodge!'
By ANNA WILDE MATHEWS and BARBARA MARTINEZ
Staff Reporters of THE WALL STREET JOURNAL

When Merck & Co. pulled its big-selling painkiller Vioxx off the
market in September, Chief Executive Raymond Gilmartin said the
company was "really putting patient safety first." He said the study
findings prompting the withdrawal, which tied Vioxx to heart-attack
and stroke risk, were "unexpected."

But internal Merck e-mails and marketing materials as well as
interviews with outside scientists show that the company fought
forcefully for years to keep safety concerns from destroying the
drug's commercial prospects.

Merck's first worry, in the mid-to-late 1990s, was that its drug would
show greater heart risk than cheaper painkillers that were harsh on
the stomach but were believed to reduce the risk of heart attacks.
Several company officials discussed in e-mails how to design a study
that would minimize the unflattering comparison, even while admitting
to themselves that it would be difficult to conceal.

By 2000, one e-mail suggests Merck recognized that Vioxx didn't merely
lack the protective features of old painkillers but that something
about the drug itself was linked to an increased heart risk. On March
9, 2000, the company's powerful research chief, Edward Scolnick,
e-mailed colleagues that the cardiovascular events "are clearly there"
and called it a "shame." He compared Vioxx to other drugs with known
side effects and wrote, "there is always a hazard." But the company's
public statements after Dr. Scolnick's e-mail continued to reject the
link between Vioxx and increased intrinsic risk.

As academic researchers increasingly raised questions about Vioxx's
heart safety, the company struck back hard. It even sued one Spanish
pharmacologist, trying unsuccessfully to force a correction of an
article he wrote. In another case, it warned that a Stanford
University researcher would "flame out" unless he stopped giving
"anti-Merck" lectures, according to a letter of complaint written to
Merck by a Stanford professor. A company training document listed
potential tough questions about Vioxx and said in capital letters,
"DODGE!"

The revelations shed new light on the interplay between marketing and
science at Merck as bad news piled up about a blockbuster drug used by
some 20 million Americans. Amid growing danger signs, Merck fought a
rearguard action for 4½ years, clinging to a hope that somehow Vioxx's
safety could be confirmed -- even though its research chief had
already privately acknowledged its risks.

Some of the internal documents may also prove damaging to Merck in
court, where it faces lawsuits by the families of those who suffered
heart attacks after taking the drug. Such lawsuits had begun before
Vioxx's withdrawal, and since the announcement the number of potential
plaintiffs has multiplied.

Merck said in a news release Friday that it "acted responsibly and
appropriately as it developed and marketed Vioxx." It added, "When
questions arose about the safety of Vioxx, Merck took steps to
investigate and address these issues." The study that ultimately led
Vioxx to be withdrawn was sponsored by Merck itself, the company has
noted.

Ted Mayer, a lawyer representing Merck, said the internal e-mails and
marketing materials were "taken out of context" and "do not accurately
represent the conduct of Merck and its employees." People with access
to a selection of internal documents that tend to reflect poorly on
Merck permitted The Wall Street Journal to review them, but Merck
didn't provide other documents to furnish context, citing ongoing
litigation.

Merck declined to discuss in detail the internal documents or make
their authors available for comment, citing ongoing litigation. The
Friday news release said "the business practices of Merck may well be
misrepresented in any reporting" because of the selective release of
documents.

Mr. Mayer also said Merck "is committed to open and vigorous
scientific debate" and "never has had a policy of retaliating against
scientists" but "has a right to defend its medicines against false
claims."

Older painkillers such as aspirin and Aleve, known generically as
naproxen, block two enzymes -- Cox-1 and Cox-2 -- that are involved in
inflammation and pain. Blocking Cox-1 can damage the stomach and
intestines but it also may prevent blood clots. Vioxx and another
drug, Pfizer Inc.'s Celebrex, were designed to block only Cox-2.

From early on, companies developing Cox-2 inhibitors faced a dilemma.
The drugs seemed to offer clear benefits to arthritis and other pain
sufferers who couldn't stand the stomach damage of aspirin, naproxen
or ibuprofen. But that was a relatively small market. The real bonanza
lay with the general mass of pain patients.

In the late 1990s Merck was facing the loss of patent protection on
several top drugs and needed a big hit. However, it would be difficult
to penetrate the mass market if doctors and patients believed that by
choosing Vioxx, they were forgoing a potential heart benefit.

A Nov. 21, 1996, memo by a Merck official shows the company wrestling
with this issue. It wanted to conduct a trial to prove Vioxx was
gentler on the stomach than older painkillers. But to show the
difference most clearly, the Vioxx patients couldn't take any aspirin.
In such a trial, "there is a substantial chance that significantly
higher rates" of cardiovascular problems would be seen in the Vioxx
group, the memo said.

A similar view was expressed in a Feb. 25, 1997, e-mail by a Merck
official, Briggs Morrison. He argued that unless patients in the Vioxx
group also got aspirin, "you will get more thrombotic events" -- that
is, blood clots -- "and kill [the] drug."

In response, Alise Reicin, now a Merck vice president for clinical
research, said in an e-mail that the company was in a "no-win
situation." Giving study subjects both Vioxx and aspirin, she wrote,
could increase the "relative risk," apparently referring to
gastrointestinal problems. But, she added, "the possibility of
increased CV [cardiovascular] events is of great concern." From the
context, it seems Dr. Reicin meant "increased" relative to older
drugs.

She added in parentheses: "I just can't wait to be the one to present
those results to senior management!" She proposed that people with
high risk of cardiovascular problems be kept out of the study so the
difference in the rate of cardiovascular problems between the Vioxx
patients and the others "would not be evident."

Vigor Trial

It's not clear what happened to the proposed trial discussed in the
1996-97 documents. But in early 1999, Merck started an 8,000-person
trial named Vigor -- for the Vioxx Gastrointestinal Outcomes Research
study -- to prove the drug's gastrointestinal safety benefits. The
trial compared people taking a high dose of Vioxx with those taking
naproxen. It excluded patients who were at high risk of heart
problems. No patients were allowed to take aspirin.

In March 2000, the results of Vigor came in. They showed that Vioxx
patients suffered fewer stomach problems than the naproxen group, but
significantly more blood-clot-related problems -- precisely the sort
of result anticipated in the 1996-97 internal documents. The
heart-attack rate in the Vioxx group appeared to be four times as high
as the naproxen group. (Later analysis would show it to be five times
as high.)

The difference was so wide that Dr. Scolnick, the Merck research
chief, appeared to recognize it couldn't come solely from naproxen's
protective effect but must involve some sort of risk inherent in
Vioxx. In a March 9, 2000, e-mail with the subject line "Vigor," Dr.
Scolnick said the results showed that the cardiovascular events "are
clearly there." In an apparent acknowledgment that Vioxx's own
mechanism was at least partially at fault for the heart data, he
wrote: "it is a shame but it is a low incidence and it is mechanism
based as we worried it was."

Dr. Scolnick wrote that he wanted other data available before the
results were presented publicly, so "it is clear to the world that
this" was an effect of the entire Cox-2 class, not just Vioxx. The
research chief, by then nearing retirement after 15 years in his post,
then recalled some of his greatest hits that also had side effects but
were big sellers. In Vioxx, he wrote, "We have a great drug and like
angioedema with vasotec and seizures with primaxin and myopathy with
mevacor there is always a hazard. The class will do well and so will
we." Dr. Scolnick didn't respond to phone messages seeking comment.

But in a news release that month, Merck offered no hint of Dr.
Scolnick's suggestion that there was a "mechanism-based" problem with
Vioxx or a "hazard" that went beyond Vioxx's failure to offer the
protective benefits of other painkillers. Merck said the Vigor trial
results were "consistent with" naproxen's favorable effects, implying
that this could explain why Vioxx didn't do as well.

The next month Merck issued another news release headlined, "Merck
confirms favorable cardiovascular safety profile of Vioxx." While
acknowledging the Vigor results, it said other trials and data had
shown "NO DIFFERENCE in the incidence of cardiovascular events"
between Vioxx and a placebo or between Vioxx and older painkillers.

Mr. Mayer, the lawyer representing Merck, says such statements
accurately reflected the state of scientific knowledge at the time.
"The known antiplatelet properties of naproxen strongly suggested that
a property of naproxen was responsible for the differential rates in
the Vigor trial," he says. Mr. Mayer declined to comment on Dr.
Scolnick's e-mail.

In November 2000, the Vigor results were published in the New England
Journal of Medicine. The article, written by academics who received
consulting contracts or research grants from Merck and by Merck
employees, discussed Vioxx's benefits for the stomach and heart-attack
rates. But it didn't include information that, in retrospect, was
important. Among patients who weren't already at high risk for heart
attacks, it said, Vioxx didn't show a significant rise in heart
attacks. That implied it was all right for people with healthy hearts
-- say, a jogger in his 30s with joint pain -- to take Vioxx. But the
article didn't provide detailed information about other serious
cardiovascular complications such as strokes or blood clots.

John Abramson, a family doctor and clinical instructor at Harvard
Medical School, scrutinized detailed data on the Vigor trial provided
by Merck to the FDA and posted on the FDA Web site. In a book
published this summer, "Overdosed America: The Broken Promise of
American Medicine," he concluded that even those without a history of
heart trouble doubled their risk of developing a cardiovascular
problem by taking Vioxx instead of naproxen.

Gregory Curfman, executive editor of the New England Journal, says the
journal "didn't have all the details that the FDA had later on." Given
the available data, he says editors "spent a great deal of time trying
to make sure that these unexpected cardiovascular side effects were
fairly and accurately represented" in the article.

By 2001, the Vigor data had clearly caused the debate to shift. The
main question was no longer whether Vioxx lacked the benefits of older
painkillers and if so whether that was significant. Now the issue was
squarely Vioxx itself: Was the drug intrinsically risky?

In February 2001, the FDA presented its analysis of the Vigor data to
an agency advisory committee. It showed that the number of people who
had a digestive problem while taking naproxen was about double the
figure for Vioxx takers -- but that difference was almost exactly the
same as the additional number of Vioxx users who suffered a
cardiovascular problem such as a stroke.

FDA officials wanted to highlight the cardiovascular risk prominently
on Vioxx's label. Merck resisted, complaining that the agency was
putting more weight on the negative findings than on the positive
gastrointestinal aspects. In the end, the two sides compromised. The
new Vioxx label, which went into effect in April 2002, listed the good
news about fewer upset stomachs first. Then it added two tables with
the bad news about more heart attacks and strokes.

The agency, meanwhile, had become increasingly concerned about Merck's
marketing of the drug to doctors. It complained in a Sept. 17, 2001,
warning letter about a Merck-sponsored presentation by a doctor in
June 2000. The doctor had said the Vigor trial showed that naproxen
was "a wonderful drug" for reducing the risk of heart problems -- not
that there was anything wrong with Vioxx. Such statements, the FDA
said, "minimized the potentially serious cardiovascular findings" of
Vigor.

A Merck internal marketing document reviewed by The Wall Street
Journal, addressed to "all field personnel with responsibility for
Vioxx," provided an "obstacle handling guide." If a doctor said he was
worried that Vioxx might raise the risk of a heart attack, he was to
be told that the drug "would not be expected to demonstrate
reductions" in heart attacks or other cardiovascular problems and that
it was "not a substitute for aspirin." This wasn't a direct answer.

One training document is titled "Dodge Ball Vioxx" and consists of 16
pages. Each of the first 12 pages lists one "obstacle," apparently
representing statements that might be made by a doctor. Among them
are, "I am concerned about the cardiovascular effects of Vioxx" and
"The competition has been in my office telling me that the incidence
of heart attacks is greater with Vioxx than Celebrex." The final four
pages each contain a single word in capital letters: "DODGE!"

Mr. Mayer, Merck's lawyer, declined to discuss the document
specifically but said sales representatives were trained to discuss
Vioxx in a manner "consistent with FDA-approved labeling" and "were
not trained to avoid physicians' questions."

Merck also went on the offensive against academic researchers who
began to question Vioxx's safety. Gurkirpal Singh of Stanford
University, a prominent Cox-2 expert who was giving lectures sponsored
by Merck and other companies, says he pressed Merck repeatedly for
more cardiovascular safety data. When Merck refused, Dr. Singh added a
slide to his presentations that showed a man -- representing the
missing data -- hiding under a blanket. "This was the first time they
didn't answer my questions," he says. "With Vigor, suddenly it was a
clampdown."

'Flame Out'

Merck canceled several presentations by Dr. Singh that it had been
scheduled to sponsor, and it didn't stop there. In October 2000, a
Merck official, Louis Sherwood, called James Fries, a Stanford
University Medical School professor, to complain that Dr. Singh's
lectures were "irresponsibly anti-Merck and specifically anti-Vioxx,"
as Dr. Fries described the call in a January 2001 letter to Mr.
Gilmartin, the Merck chief executive. The Merck official "suggested
that if this continued, Dr. Singh would 'flame out' and there would be
consequences for myself and for Stanford," Dr. Fries wrote.

Dr. Fries struck back. "There is a line that you can't go across. ...
It had gone over that line," he says. He wrote to the Merck chief that
researchers at several other top medical schools complained about "a
consistent pattern of intimidation of investigators by Merck" on
Vioxx.

Mr. Gilmartin responded that Merck had a "deep and abiding commitment
to the highest ethical standards in all our dealings with physicians
and other healthcare providers." Dr. Fries and other researchers
mentioned in the letter say the company did try to repair relations
subsequently. Dr. Singh, now an adjunct clinical professor at
Stanford, says he stopped using the blanket slide after Merck gave him
more data.

Lee Simon, a rheumatologist at Beth Israel Deaconess Medical Center in
Boston, says he publicly mentioned data showing Vioxx might be
associated with a risk of high blood pressure and swelling. While Dr.
Simon was closely involved with research on the rival Cox-2 drug
Celebrex, he had worked with Merck in another area. Merck's Dr.
Sherwood called Dr. Simon and one of his superiors at the hospital to
complain that Dr. Simon's lectures were slanted against Vioxx.

"I was shocked that there was a phone call made like that," Dr. Simon
says. "The company was attempting to suppress a discussion about this
data."

M. Thomas Stillman, a professor at the University of Minnesota, also
discussed the data on high blood pressure and swelling in his lectures
-- and also got a call from Dr. Sherwood. "We had a very direct
conversation that I wouldn't call friendly," Dr. Stillman says. "It
had a tone to me of, 'You better be careful of what you're saying.'
... I thought that was inappropriate." He had given Merck-sponsored
lectures but that ended after the disagreement, he says.

In August 2001, researchers at the Cleveland Clinic published an
analysis in the Journal of the American Medical Association that once
again raised concerns about Vioxx's cardiovascular risks. Before it
came out, Merck's Dr. Reicin and other officials met with the authors,
arguing that "they didn't think there was a problem with the drug,"
says Steven Nissen, one of the Cleveland Clinic researchers. The
company also asked the journal to run a Merck rebuttal but it refused,
people with knowledge of the matter said at the time.

One of Merck's most aggressive moves came against Joan-Ramon Laporte
of the Catalan Institute of Pharmacology in Barcelona, Spain. In the
summer of 2002, a publication of the institute edited by Dr. Laporte
repeated criticisms of Merck's handling of Vioxx that had been
published in the British journal Lancet. Soon after, Dr. Laporte says,
Merck officials sent him a "rectification" to publish, but he
responded that there would be no correction. After Merck officials
approached him twice more, the company filed suit in a Spanish court
against Dr. Laporte and the institute, taking advantage of a Spanish
law that allows plaintiffs to demand a public correction of inaccurate
published information.

In January of this year, a judge ruled that Dr. Laporte's publication
accurately reflected the medical debate about the cardiovascular
safety of Vioxx, and ordered Merck to pay court costs.

This March, Dr. Laporte was a featured speaker at an annual update on
the pharmaceutical world for about 1,000 Spanish family physicians.
Merck had helped pay for the meeting for the previous eight years. It
contacted the organizer, Ramon Morera i Castell, and told him that the
company "preferred" if Dr. Laporte stayed off the program this year,
says Dr. Morera. After Dr. Morera rejected the request, Merck withdrew
its financing -- about $140,000. Though there wasn't any specific
threat, "the message was clear," says Dr. Morera.

No one knows for sure why Vioxx might be tied to heart attacks and
strokes. Some scientists point to a class effect of the Cox-2
inhibitors, but several studies suggest that Pfizer's Celebrex doesn't
share Vioxx's risks. Pfizer says Celebrex might actually protect the
heart.

Throughout 2002 and 2003, critics of Vioxx had one problem: The
principal evidence against the drug came from a single source, the
Vigor study. Conducting a new prospective trial, in which patients
would be given Vioxx or a placebo and followed to see what happened,
would be expensive for academic researchers to conduct on their own.

Several groups did conduct "retrospective" analyses, trawling through
large databases of patient records for hints as to whether Vioxx was
risky. Such studies are prone to confounding factors but can add to a
body of evidence.

Merck itself sponsored one retrospective analysis by researchers at
Harvard. It found Vioxx was "associated with an elevated relative
risk" of heart attacks compared to use of Pfizer's Celebrex or no
similar painkiller. Merck asked the researchers to delete or tone down
the part of the statement about the no-painkiller group, but they
refused, according to Daniel Solomon, a Harvard professor who was the
lead author. "We made a decision that we should let the science rule
the day," he says. Just before the paper was to be published in May
2004 in Circulation, the journal of the American Heart Association,
Merck removed the name of an employee who had worked on the study from
the paper's list of authors.

On Aug. 25, data presented at a medical conference by a researcher
from the FDA's own drug-safety office showed that higher doses of
Vioxx correlated with a tripled risk of a heart attack or sudden
cardiac death compared to people who weren't taking any similar drug.

The evidence was now piling up, yet Merck stuck to the line it had
kept since March 2000. A news release said Merck "strongly disagreed"
with the FDA study's conclusion, noting that it was a retrospective
analysis. The top of the release read: "Merck stands behind the
efficacy, overall safety and cardiovascular safety of Vioxx."

The next month, company officials were informed that a safety
monitoring board wanted to stop an ongoing study of Vioxx's ability to
prevent colon polyps because people on the drug were having more heart
attacks and strokes. The numbers were small. Among patients taking
Vioxx for more than 18 months, there were 15 heart attacks or strokes
for every 1,000 patients compared with 7.5 per 1,000 who were on
placebo. For patients who took the drug 18 months or less, there was
no increased risk, according to Merck.

This was a prospective study comparing Vioxx to a placebo. Merck's
previous defenses -- criticizing retrospective studies or attributing
results to the benefits of a pill used for comparison -- collapsed,
and it withdrew the drug. Its stock price fell 27% and now stands
about where it was in early 1996.

PAINFUL PROCESS

• February 1997: Internal Merck e-mail warns that a proposed trial may
show Vioxx patients having more blood clots than those taking another
medication and "kill [the] drug."

• May 1999: FDA approves Vioxx for arthritis and other types of pain.

• March 2000: Vigor trial results available inside Merck. They
eventually show Vioxx group has five times the rate of heart attacks
as naproxen group.

• March 9, 2000: Merck research chief says in internal e-mail that
cardiovascular problems "are clearly there" in Vigor trial and appear
to be "mechanism based."

• April 2000: Merck press release says Vigor trial results are
"consistent with" clot-preventing effects of naproxen.

• October 2000: Merck official threatens that a Stanford researcher
will "flame out" if he continues "anti-Vioxx" lectures.

• September 2001: FDA sends Merck a warning letter, accusing it of
misleading public about Vioxx's cardiovascular safety.

• April 2002: FDA approves a label change for Vioxx, showing data
about potential heart risk.

• September 2004: Merck announces world-wide withdrawal of Vioxx.

Source: WSJ research

TRIAL RESULTS

A Merck trial compared people taking a high dose of Vioxx with those
taking naproxen.

VIOXX NAPROXEN
Total number in trial 4,047 4,029
Cardiovascular adverse events 101 46
Digestive system adverse events 48 97

Source: FDA analysis of Vigor trial data

-----------------------------------------------------------------------

Re: Merck Knew Vioxx's Dangers at Early Stage -- Posted by George Verak on 11-29-04 09:40

FYI
http://www.vioxxlitigator.us

MrPepper11@go.com (MrPepper11) wrote in message news:<57cfd534.0411010507.62688fb0@posting.google.com>...
> November 1, 2004
>
> Warning Signs
> E-Mails Suggest Merck Knew Vioxx's Dangers at Early Stage
> As Heart-Risk Evidence Rose, Officials Played Hardball; Internal
> Message: 'Dodge!'
> By ANNA WILDE MATHEWS and BARBARA MARTINEZ
> Staff Reporters of THE WALL STREET JOURNAL
>
> When Merck & Co. pulled its big-selling painkiller Vioxx off the
> market in September, Chief Executive Raymond Gilmartin said the
> company was "really putting patient safety first." He said the study
> findings prompting the withdrawal, which tied Vioxx to heart-attack
> and stroke risk, were "unexpected."
>
> But internal Merck e-mails and marketing materials as well as
> interviews with outside scientists show that the company fought
> forcefully for years to keep safety concerns from destroying the
> drug's commercial prospects.
>
> Merck's first worry, in the mid-to-late 1990s, was that its drug would
> show greater heart risk than cheaper painkillers that were harsh on
> the stomach but were believed to reduce the risk of heart attacks.
> Several company officials discussed in e-mails how to design a study
> that would minimize the unflattering comparison, even while admitting
> to themselves that it would be difficult to conceal.
>
> By 2000, one e-mail suggests Merck recognized that Vioxx didn't merely
> lack the protective features of old painkillers but that something
> about the drug itself was linked to an increased heart risk. On March
> 9, 2000, the company's powerful research chief, Edward Scolnick,
> e-mailed colleagues that the cardiovascular events "are clearly there"
> and called it a "shame." He compared Vioxx to other drugs with known
> side effects and wrote, "there is always a hazard." But the company's
> public statements after Dr. Scolnick's e-mail continued to reject the
> link between Vioxx and increased intrinsic risk.
>
> As academic researchers increasingly raised questions about Vioxx's
> heart safety, the company struck back hard. It even sued one Spanish
> pharmacologist, trying unsuccessfully to force a correction of an
> article he wrote. In another case, it warned that a Stanford
> University researcher would "flame out" unless he stopped giving
> "anti-Merck" lectures, according to a letter of complaint written to
> Merck by a Stanford professor. A company training document listed
> potential tough questions about Vioxx and said in capital letters,
> "DODGE!"
>
> The revelations shed new light on the interplay between marketing and
> science at Merck as bad news piled up about a blockbuster drug used by
> some 20 million Americans. Amid growing danger signs, Merck fought a
> rearguard action for 4½ years, clinging to a hope that somehow Vioxx's
> safety could be confirmed -- even though its research chief had
> already privately acknowledged its risks.
>
> Some of the internal documents may also prove damaging to Merck in
> court, where it faces lawsuits by the families of those who suffered
> heart attacks after taking the drug. Such lawsuits had begun before
> Vioxx's withdrawal, and since the announcement the number of potential
> plaintiffs has multiplied.
>
> Merck said in a news release Friday that it "acted responsibly and
> appropriately as it developed and marketed Vioxx." It added, "When
> questions arose about the safety of Vioxx, Merck took steps to
> investigate and address these issues." The study that ultimately led
> Vioxx to be withdrawn was sponsored by Merck itself, the company has
> noted.
>
> Ted Mayer, a lawyer representing Merck, said the internal e-mails and
> marketing materials were "taken out of context" and "do not accurately
> represent the conduct of Merck and its employees." People with access
> to a selection of internal documents that tend to reflect poorly on
> Merck permitted The Wall Street Journal to review them, but Merck
> didn't provide other documents to furnish context, citing ongoing
> litigation.
>
> Merck declined to discuss in detail the internal documents or make
> their authors available for comment, citing ongoing litigation. The
> Friday news release said "the business practices of Merck may well be
> misrepresented in any reporting" because of the selective release of
> documents.
>
> Mr. Mayer also said Merck "is committed to open and vigorous
> scientific debate" and "never has had a policy of retaliating against
> scientists" but "has a right to defend its medicines against false
> claims."
>
> Older painkillers such as aspirin and Aleve, known generically as
> naproxen, block two enzymes -- Cox-1 and Cox-2 -- that are involved in
> inflammation and pain. Blocking Cox-1 can damage the stomach and
> intestines but it also may prevent blood clots. Vioxx and another
> drug, Pfizer Inc.'s Celebrex, were designed to block only Cox-2.
>
> From early on, companies developing Cox-2 inhibitors faced a dilemma.
> The drugs seemed to offer clear benefits to arthritis and other pain
> sufferers who couldn't stand the stomach damage of aspirin, naproxen
> or ibuprofen. But that was a relatively small market. The real bonanza
> lay with the general mass of pain patients.
>
> In the late 1990s Merck was facing the loss of patent protection on
> several top drugs and needed a big hit. However, it would be difficult
> to penetrate the mass market if doctors and patients believed that by
> choosing Vioxx, they were forgoing a potential heart benefit.
>
> A Nov. 21, 1996, memo by a Merck official shows the company wrestling
> with this issue. It wanted to conduct a trial to prove Vioxx was
> gentler on the stomach than older painkillers. But to show the
> difference most clearly, the Vioxx patients couldn't take any aspirin.
> In such a trial, "there is a substantial chance that significantly
> higher rates" of cardiovascular problems would be seen in the Vioxx
> group, the memo said.
>
> A similar view was expressed in a Feb. 25, 1997, e-mail by a Merck
> official, Briggs Morrison. He argued that unless patients in the Vioxx
> group also got aspirin, "you will get more thrombotic events" -- that
> is, blood clots -- "and kill [the] drug."
>
> In response, Alise Reicin, now a Merck vice president for clinical
> research, said in an e-mail that the company was in a "no-win
> situation." Giving study subjects both Vioxx and aspirin, she wrote,
> could increase the "relative risk," apparently referring to
> gastrointestinal problems. But, she added, "the possibility of
> increased CV [cardiovascular] events is of great concern." From the
> context, it seems Dr. Reicin meant "increased" relative to older
> drugs.
>
> She added in parentheses: "I just can't wait to be the one to present
> those results to senior management!" She proposed that people with
> high risk of cardiovascular problems be kept out of the study so the
> difference in the rate of cardiovascular problems between the Vioxx
> patients and the others "would not be evident."
>
> Vigor Trial
>
> It's not clear what happened to the proposed trial discussed in the
> 1996-97 documents. But in early 1999, Merck started an 8,000-person
> trial named Vigor -- for the Vioxx Gastrointestinal Outcomes Research
> study -- to prove the drug's gastrointestinal safety benefits. The
> trial compared people taking a high dose of Vioxx with those taking
> naproxen. It excluded patients who were at high risk of heart
> problems. No patients were allowed to take aspirin.
>
> In March 2000, the results of Vigor came in. They showed that Vioxx
> patients suffered fewer stomach problems than the naproxen group, but
> significantly more blood-clot-related problems -- precisely the sort
> of result anticipated in the 1996-97 internal documents. The
> heart-attack rate in the Vioxx group appeared to be four times as high
> as the naproxen group. (Later analysis would show it to be five times
> as high.)
>
> The difference was so wide that Dr. Scolnick, the Merck research
> chief, appeared to recognize it couldn't come solely from naproxen's
> protective effect but must involve some sort of risk inherent in
> Vioxx. In a March 9, 2000, e-mail with the subject line "Vigor," Dr.
> Scolnick said the results showed that the cardiovascular events "are
> clearly there." In an apparent acknowledgment that Vioxx's own
> mechanism was at least partially at fault for the heart data, he
> wrote: "it is a shame but it is a low incidence and it is mechanism
> based as we worried it was."
>
> Dr. Scolnick wrote that he wanted other data available before the
> results were presented publicly, so "it is clear to the world that
> this" was an effect of the entire Cox-2 class, not just Vioxx. The
> research chief, by then nearing retirement after 15 years in his post,
> then recalled some of his greatest hits that also had side effects but
> were big sellers. In Vioxx, he wrote, "We have a great drug and like
> angioedema with vasotec and seizures with primaxin and myopathy with
> mevacor there is always a hazard. The class will do well and so will
> we." Dr. Scolnick didn't respond to phone messages seeking comment.
>
> But in a news release that month, Merck offered no hint of Dr.
> Scolnick's suggestion that there was a "mechanism-based" problem with
> Vioxx or a "hazard" that went beyond Vioxx's failure to offer the
> protective benefits of other painkillers. Merck said the Vigor trial
> results were "consistent with" naproxen's favorable effects, implying
> that this could explain why Vioxx didn't do as well.
>
> The next month Merck issued another news release headlined, "Merck
> confirms favorable cardiovascular safety profile of Vioxx." While
> acknowledging the Vigor results, it said other trials and data had
> shown "NO DIFFERENCE in the incidence of cardiovascular events"
> between Vioxx and a placebo or between Vioxx and older painkillers.
>
> Mr. Mayer, the lawyer representing Merck, says such statements
> accurately reflected the state of scientific knowledge at the time.
> "The known antiplatelet properties of naproxen strongly suggested that
> a property of naproxen was responsible for the differential rates in
> the Vigor trial," he says. Mr. Mayer declined to comment on Dr.
> Scolnick's e-mail.
>
> In November 2000, the Vigor results were published in the New England
> Journal of Medicine. The article, written by academics who received
> consulting contracts or research grants from Merck and by Merck
> employees, discussed Vioxx's benefits for the stomach and heart-attack
> rates. But it didn't include information that, in retrospect, was
> important. Among patients who weren't already at high risk for heart
> attacks, it said, Vioxx didn't show a significant rise in heart
> attacks. That implied it was all right for people with healthy hearts
> -- say, a jogger in his 30s with joint pain -- to take Vioxx. But the
> article didn't provide detailed information about other serious
> cardiovascular complications such as strokes or blood clots.
>
> John Abramson, a family doctor and clinical instructor at Harvard
> Medical School, scrutinized detailed data on the Vigor trial provided
> by Merck to the FDA and posted on the FDA Web site. In a book
> published this summer, "Overdosed America: The Broken Promise of
> American Medicine," he concluded that even those without a history of
> heart trouble doubled their risk of developing a cardiovascular
> problem by taking Vioxx instead of naproxen.
>
> Gregory Curfman, executive editor of the New England Journal, says the
> journal "didn't have all the details that the FDA had later on." Given
> the available data, he says editors "spent a great deal of time trying
> to make sure that these unexpected cardiovascular side effects were
> fairly and accurately represented" in the article.
>
> By 2001, the Vigor data had clearly caused the debate to shift. The
> main question was no longer whether Vioxx lacked the benefits of older
> painkillers and if so whether that was significant. Now the issue was
> squarely Vioxx itself: Was the drug intrinsically risky?
>
> In February 2001, the FDA presented its analysis of the Vigor data to
> an agency advisory committee. It showed that the number of people who
> had a digestive problem while taking naproxen was about double the
> figure for Vioxx takers -- but that difference was almost exactly the
> same as the additional number of Vioxx users who suffered a
> cardiovascular problem such as a stroke.
>
> FDA officials wanted to highlight the cardiovascular risk prominently
> on Vioxx's label. Merck resisted, complaining that the agency was
> putting more weight on the negative findings than on the positive
> gastrointestinal aspects. In the end, the two sides compromised. The
> new Vioxx label, which went into effect in April 2002, listed the good
> news about fewer upset stomachs first. Then it added two tables with
> the bad news about more heart attacks and strokes.
>
> The agency, meanwhile, had become increasingly concerned about Merck's
> marketing of the drug to doctors. It complained in a Sept. 17, 2001,
> warning letter about a Merck-sponsored presentation by a doctor in
> June 2000. The doctor had said the Vigor trial showed that naproxen
> was "a wonderful drug" for reducing the risk of heart problems -- not
> that there was anything wrong with Vioxx. Such statements, the FDA
> said, "minimized the potentially serious cardiovascular findings" of
> Vigor.
>
> A Merck internal marketing document reviewed by The Wall Street
> Journal, addressed to "all field personnel with responsibility for
> Vioxx," provided an "obstacle handling guide." If a doctor said he was
> worried that Vioxx might raise the risk of a heart attack, he was to
> be told that the drug "would not be expected to demonstrate
> reductions" in heart attacks or other cardiovascular problems and that
> it was "not a substitute for aspirin." This wasn't a direct answer.
>
> One training document is titled "Dodge Ball Vioxx" and consists of 16
> pages. Each of the first 12 pages lists one "obstacle," apparently
> representing statements that might be made by a doctor. Among them
> are, "I am concerned about the cardiovascular effects of Vioxx" and
> "The competition has been in my office telling me that the incidence
> of heart attacks is greater with Vioxx than Celebrex." The final four
> pages each contain a single word in capital letters: "DODGE!"
>
> Mr. Mayer, Merck's lawyer, declined to discuss the document
> specifically but said sales representatives were trained to discuss
> Vioxx in a manner "consistent with FDA-approved labeling" and "were
> not trained to avoid physicians' questions."
>
> Merck also went on the offensive against academic researchers who
> began to question Vioxx's safety. Gurkirpal Singh of Stanford
> University, a prominent Cox-2 expert who was giving lectures sponsored
> by Merck and other companies, says he pressed Merck repeatedly for
> more cardiovascular safety data. When Merck refused, Dr. Singh added a
> slide to his presentations that showed a man -- representing the
> missing data -- hiding under a blanket. "This was the first time they
> didn't answer my questions," he says. "With Vigor, suddenly it was a
> clampdown."
>
> 'Flame Out'
>
> Merck canceled several presentations by Dr. Singh that it had been
> scheduled to sponsor, and it didn't stop there. In October 2000, a
> Merck official, Louis Sherwood, called James Fries, a Stanford
> University Medical School professor, to complain that Dr. Singh's
> lectures were "irresponsibly anti-Merck and specifically anti-Vioxx,"
> as Dr. Fries described the call in a January 2001 letter to Mr.
> Gilmartin, the Merck chief executive. The Merck official "suggested
> that if this continued, Dr. Singh would 'flame out' and there would be
> consequences for myself and for Stanford," Dr. Fries wrote.
>
> Dr. Fries struck back. "There is a line that you can't go across. ...
> It had gone over that line," he says. He wrote to the Merck chief that
> researchers at several other top medical schools complained about "a
> consistent pattern of intimidation of investigators by Merck" on
> Vioxx.
>
> Mr. Gilmartin responded that Merck had a "deep and abiding commitment
> to the highest ethical standards in all our dealings with physicians
> and other healthcare providers." Dr. Fries and other researchers
> mentioned in the letter say the company did try to repair relations
> subsequently. Dr. Singh, now an adjunct clinical professor at
> Stanford, says he stopped using the blanket slide after Merck gave him
> more data.
>
> Lee Simon, a rheumatologist at Beth Israel Deaconess Medical Center in
> Boston, says he publicly mentioned data showing Vioxx might be
> associated with a risk of high blood pressure and swelling. While Dr.
> Simon was closely involved with research on the rival Cox-2 drug
> Celebrex, he had worked with Merck in another area. Merck's Dr.
> Sherwood called Dr. Simon and one of his superiors at the hospital to
> complain that Dr. Simon's lectures were slanted against Vioxx.
>
> "I was shocked that there was a phone call made like that," Dr. Simon
> says. "The company was attempting to suppress a discussion about this
> data."
>
> M. Thomas Stillman, a professor at the University of Minnesota, also
> discussed the data on high blood pressure and swelling in his lectures
> -- and also got a call from Dr. Sherwood. "We had a very direct
> conversation that I wouldn't call friendly," Dr. Stillman says. "It
> had a tone to me of, 'You better be careful of what you're saying.'
> ... I thought that was inappropriate." He had given Merck-sponsored
> lectures but that ended after the disagreement, he says.
>
> In August 2001, researchers at the Cleveland Clinic published an
> analysis in the Journal of the American Medical Association that once
> again raised concerns about Vioxx's cardiovascular risks. Before it
> came out, Merck's Dr. Reicin and other officials met with the authors,
> arguing that "they didn't think there was a problem with the drug,"
> says Steven Nissen, one of the Cleveland Clinic researchers. The
> company also asked the journal to run a Merck rebuttal but it refused,
> people with knowledge of the matter said at the time.
>
> One of Merck's most aggressive moves came against Joan-Ramon Laporte
> of the Catalan Institute of Pharmacology in Barcelona, Spain. In the
> summer of 2002, a publication of the institute edited by Dr. Laporte
> repeated criticisms of Merck's handling of Vioxx that had been
> published in the British journal Lancet. Soon after, Dr. Laporte says,
> Merck officials sent him a "rectification" to publish, but he
> responded that there would be no correction. After Merck officials
> approached him twice more, the company filed suit in a Spanish court
> against Dr. Laporte and the institute, taking advantage of a Spanish
> law that allows plaintiffs to demand a public correction of inaccurate
> published information.
>
> In January of this year, a judge ruled that Dr. Laporte's publication
> accurately reflected the medical debate about the cardiovascular
> safety of Vioxx, and ordered Merck to pay court costs.
>
> This March, Dr. Laporte was a featured speaker at an annual update on
> the pharmaceutical world for about 1,000 Spanish family physicians.
> Merck had helped pay for the meeting for the previous eight years. It
> contacted the organizer, Ramon Morera i Castell, and told him that the
> company "preferred" if Dr. Laporte stayed off the program this year,
> says Dr. Morera. After Dr. Morera rejected the request, Merck withdrew
> its financing -- about $140,000. Though there wasn't any specific
> threat, "the message was clear," says Dr. Morera.
>
> No one knows for sure why Vioxx might be tied to heart attacks and
> strokes. Some scientists point to a class effect of the Cox-2
> inhibitors, but several studies suggest that Pfizer's Celebrex doesn't
> share Vioxx's risks. Pfizer says Celebrex might actually protect the
> heart.
>
> Throughout 2002 and 2003, critics of Vioxx had one problem: The
> principal evidence against the drug came from a single source, the
> Vigor study. Conducting a new prospective trial, in which patients
> would be given Vioxx or a placebo and followed to see what happened,
> would be expensive for academic researchers to conduct on their own.
>
> Several groups did conduct "retrospective" analyses, trawling through
> large databases of patient records for hints as to whether Vioxx was
> risky. Such studies are prone to confounding factors but can add to a
> body of evidence.
>
> Merck itself sponsored one retrospective analysis by researchers at
> Harvard. It found Vioxx was "associated with an elevated relative
> risk" of heart attacks compared to use of Pfizer's Celebrex or no
> similar painkiller. Merck asked the researchers to delete or tone down
> the part of the statement about the no-painkiller group, but they
> refused, according to Daniel Solomon, a Harvard professor who was the
> lead author. "We made a decision that we should let the science rule
> the day," he says. Just before the paper was to be published in May
> 2004 in Circulation, the journal of the American Heart Association,
> Merck removed the name of an employee who had worked on the study from
> the paper's list of authors.
>
> On Aug. 25, data presented at a medical conference by a researcher
> from the FDA's own drug-safety office showed that higher doses of
> Vioxx correlated with a tripled risk of a heart attack or sudden
> cardiac death compared to people who weren't taking any similar drug.
>
> The evidence was now piling up, yet Merck stuck to the line it had
> kept since March 2000. A news release said Merck "strongly disagreed"
> with the FDA study's conclusion, noting that it was a retrospective
> analysis. The top of the release read: "Merck stands behind the
> efficacy, overall safety and cardiovascular safety of Vioxx."
>
> The next month, company officials were informed that a safety
> monitoring board wanted to stop an ongoing study of Vioxx's ability to
> prevent colon polyps because people on the drug were having more heart
> attacks and strokes. The numbers were small. Among patients taking
> Vioxx for more than 18 months, there were 15 heart attacks or strokes
> for every 1,000 patients compared with 7.5 per 1,000 who were on
> placebo. For patients who took the drug 18 months or less, there was
> no increased risk, according to Merck.
>
> This was a prospective study comparing Vioxx to a placebo. Merck's
> previous defenses -- criticizing retrospective studies or attributing
> results to the benefits of a pill used for comparison -- collapsed,
> and it withdrew the drug. Its stock price fell 27% and now stands
> about where it was in early 1996.
>
> PAINFUL PROCESS
>
> ? February 1997: Internal Merck e-mail warns that a proposed trial may
> show Vioxx patients having more blood clots than those taking another
> medication and "kill [the] drug."
>
> ? May 1999: FDA approves Vioxx for arthritis and other types of pain.
>
> ? March 2000: Vigor trial results available inside Merck. They
> eventually show Vioxx group has five times the rate of heart attacks
> as naproxen group.
>
> ? March 9, 2000: Merck research chief says in internal e-mail that
> cardiovascular problems "are clearly there" in Vigor trial and appear
> to be "mechanism based."
>
> ? April 2000: Merck press release says Vigor trial results are
> "consistent with" clot-preventing effects of naproxen.
>
> ? October 2000: Merck official threatens that a Stanford researcher
> will "flame out" if he continues "anti-Vioxx" lectures.
>
> ? September 2001: FDA sends Merck a warning letter, accusing it of
> misleading public about Vioxx's cardiovascular safety.
>
> ? April 2002: FDA approves a label change for Vioxx, showing data
> about potential heart risk.
>
> ? September 2004: Merck announces world-wide withdrawal of Vioxx.
>
> Source: WSJ research
>
> TRIAL RESULTS
>
> A Merck trial compared people taking a high dose of Vioxx with those
> taking naproxen.
>
> VIOXX NAPROXEN
> Total number in trial 4,047 4,029
> Cardiovascular adverse events 101 46
> Digestive system adverse events 48 97
>
> Source: FDA analysis of Vigor trial data
>
> -----------------------------------------------------------------------

FYI
http://www.vioxxlitigator.us

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