and excellent [long] article from the Toronto Globe and Mail
-----------------------------------------------
The painful battle over the 'wonder drug'

CAROLYN ABRAHAM reports on the Canadian doctor who found herself smack in
the middle of the controversy over Vioxx
By CAROLYN ABRAHAM

Saturday, February 19, 2005
Updated at 4:01 PM EST

The night before Merck & Co. officials pulled Vioxx off the market last
September, after their popular painkiller was found to double the risk of
heart attack and stroke, they called a small, trusted group of scientists
for advice.

Claire Bombardier was one of them. Director of rheumatology at the
University of Toronto and holder of a prestigious Canada research chair in
the field, Dr. Bombardier has been a consultant to Merck on Vioxx since
1997.

That night, Merck officials described fresh evidence that Vioxx increased
heart risks. Dr. Bombardier agreed the data confirmed the problem. Still,
she told them, it would be a shame to lose it given that it was a matter of
weighing benefits and risk. "It was a good drug," she told them. Patients,
she said, would miss it: "I was on the fence."

It was a careful answer, as befits a physician who is both research
scientist and drug-company consultant -- and someone who is a key figure in
one of medicine's biggest drug controversies.

Dr. Bombardier headed the 1999 Merck-sponsored drug trial that first
provided evidence of the alarming heart risks of Vioxx, and she was the
lead author of the resulting study published in the New England Journal of
Medicine.

That study is now under attack for the heart-risk data it did not include.
Critics say the full information from the study should have prompted the
drug company and drug regulators to take swift action against Vioxx five
years ago.

This week, a special panel of the U.S. Food and Drug Administration held
hearings into the safety of Vioxx, and the new generation of painkillers to
which it belongs. The hearings are just one of several investigations and
legal actions surrounding the drug, and Dr. Bombardier says she must be
careful about what she says, since she might find herself on a witness
stand. As she puts it: "If you are in the car when there is a car accident,
you have to testify."

The FDA panel voted to allow the possible return of Vioxx, provided it
carries a black-box warning of heart-attack risks and faces other severe
restrictions that make people aware of its dangers. FDA whistleblower David
Graham, who earlier warned of the Vioxx risks, said those measures are
"five years too late."

A Globe and Mail investigation involving internal Merck documents,
congressional testimony, files made available through the FDA and
interviews, paints a disturbing picture about the way public safety seemed
to have taken a back seat on the road to turning a vaunted new drug into a
blockbuster marketing hit.

While Vioxx became one of the fastest-selling drugs in history -- with
sales of more than $2.5 billion (U.S.) -- behind the scenes, serious
concerns about whether it might be harming, even killing people were raised
steadily.

Documents show Merck fighting a war on a number of fronts: against its
chief competitor, Pfizer, and its drug Celebrex; against outside scientists
who questioned the drug's safety; and against drug regulators who seemed to
have been unable or unwilling to compel the company to do all the
investigations it wanted.

Marlene Gauthier, a spokesperson for Merck Frosst Canada, said due to the
ongoing legal proceedings against the company it could not respond to
questions about its actions at this time.

In the United States, the Vioxx saga has triggered not only government
hearings, but a criminal investigation and an inquiry by the Securities and
Exchange Commission. At least 700 lawsuits have been filed against the
company.

In Canada, where the drug was invented and where pharmacies dispensed
roughly three million prescriptions a year, 30 class-action lawsuits have
been filed, though not all have been certified.

There has been no public airing here of the events surrounding the
withdrawal of Vioxx, nor how Health Canada, which has also been named in
lawsuits, dealt with the drug. Health Minister Ujjal Dosanjh called this
week for public hearings into its class of medication and for greater
transparency. Due to the legal proceedings against it, Health Canada
officials would not answer key questions for this article.

Vioxx, one in a class of drugs known as cox-2 inhibitors, was once touted
to be the best remedy to hit medicine cabinets since a German chemist
turned willow bark into Aspirin. Now, the fallout from their explosion onto
the market is drawing comparisons to the lessons learned in the wake of
thalidomide.

"Potentially, out of all of this there may be a need to take a stronger
stand and not let drug companies dictate things," said James Wright,
director of the Therapeutics Initiative at the University of British
Columbia. "In the future, we'll look back at thalidomide as having had a
major impact [on the way new drugs are monitored] and these cox-2 drugs as
well."

Dr. Bombardier agrees: "There are lessons to be learned."

Vioxx was part of a revolutionary class of anti-inflammatory pain relievers
that promised to be easy on patients' stomachs.

The older generation of drugs -- such as Aspirin and ibuprofen -- worked by
blocking two cyclo-oxgenase enzymes, known as cox-1 and cox-2 for short.
Blocking cox-1, unfortunately, had the nasty effect of stripping the
stomach lining, which could cause ulcers, gastrointestinal tears and
stomach bleeds.

It was a painkiller market in desperate need of relief. When companies
found drugs that blocked only the cox-2 enzyme, they seemed to have hit on
the answer.

But Merck's own documents show that even before any drug approvals there
were concerns about the heart risk cox-2 drugs, specifically Vioxx, might
carry.

In 1998, as part of the drug trials leading up to approval, Merck submitted
information to the FDA from pharmacology tests that suggested these drugs
could contribute to blood clots.

Then, FDA reviewer Maria Lourdes Vilallba noted in 1999 in light of Merck's
submission that: "Thromboelic events [such as heart attack and stroke] are
more frequent in patients receiving Vioxx than placebo . . ."

Dr. Vilallba concluded that it was impossible to determine the
cardiovascular risk of the drug with the data the company had submitted.

Despite this, regulators both in Canada and the United States kept Vioxx on
a fast track for review.

In 1998, Pfizer's Celebrex was the first cox-2 inhibitor to be approved in
the United States. It came out in Canada in April, 1999. The United States
approved Vioxx in May, and the Canadian okay came in October of that year.

Testifying before a U.S. congressional hearing this month, Gurkirpal Singh,
a cox-2 expert and adjunct clinical professor of medicine at Stanford
University, noted that there were 30 similar painkillers on the market when
Vioxx was approved. "There was certainly no emergent need to approve Vioxx
without further studies if there were lingering safety concerns," he said.

But the war in the marketplace had begun. With more relaxed U.S. laws
governing direct-to-consumer advertising, companies pushed the drugs as
early designer compounds of the biotech era, just in time to ease the aches
and pains of aging boomers.

And Merck had catching up to do. Searle, then the makers of Celebrex, had a
six-month head start getting U.S. approval.

Merck still needed to prove the drug actually caused fewer stomach woes
than earlier drugs. It had been planning a "megatrial" for just that reason
as far back as 1996, but company researchers realized early they faced a
major problem in designing it.

If they stacked Vioxx up against an older pain reliever such as Aspirin,
which can harm the stomach but potentially prevent heart disease, the
overall results could backfire. Merck documents show company researchers
feared they were in a "no-win situation" because such a comparison might
suggest Vioxx was good for the stomach but bad for the heart.

One possible way to prevent the possibility of a bad-heart outcome would be
to test people at low risk of heart disease. This way, according to one
Merck researcher, "a difference between the two groups would not be
evident."

Eric Topol, chief of cardiovascular medicine at the Cleveland Clinic who
assessed the drug's heart risks in 2001, criticized the company's decision.
He said older people at risk of heart disease were among the prime
candidates to take the arthritis drug and yet were deliberately left out of
safety studies.

"There was a mismatch between who was taking these drugs in the real world
and who it was being it tested on," Dr. Topol said.

When it came to finding the right person to run the crucial trial, Merck
researcher Alise Reicin e-mailed a colleague in 1997 saying: "We want the
person to be academic and well-connected; ideally this person should play a
major role in helping to recruit other investigators."

Claire Bombardier fit the bill. Not only did she come with an impressive
list of academic credentials, she was a consultant to Health Canada and to
provincial governments. And she had also been a consultant to Searle in
their development of Celebrex.

"When you're an expert in the field, people come to you," Dr. Bombardier
said, explaining that she consults to six or seven drug companies and signs
confidentiality agreements with each of them. "I would be concerned by
someone who only consults for one drug company."

Asked how she reconciles advising drug companies as well as drug
regulators, Dr. Bombardier said, "You declare your conflict of interest, or
your potential conflict of interest. You have to be professional."

When Merck contacted her to run the trial, which began in January, 1999,
she was excited by the challenge of such a large study - 8,000 patients in
22 countries, including 300 in Canada.

"There had never been a trial of that size in rheumatology," she said.

It became known as the VIGOR trial, short for Vioxx Gastrointestinal
Outcomes Research, and Dr. Bombardier pegs its costs at roughly
$100-million. She stresses that she was not paid for her work as a
scientist to conduct the study, nor did she receive an honorarium. Her
consulting arrangement with Merck, she said, was separate.

The VIGOR trial compared the safety results of some 4,000 rheumatoid
arthritis patients taking Vioxx against an equal number taking the
traditional painkiller naproxen, sometimes sold under the brand name Aleve.

The final results became available to Merck in March, 2000.

As hoped, Vioxx users suffered half the gastrointestinal problems as those
taking naproxen. But, as feared, they were twice as likely to suffer
serious cardiac problems such as blood clots, strokes and, most
dramatically, a five-fold increase in heart attacks, meaning five in 1,000
patients as opposed to one in 1,000.

This striking difference, a trend visible after only one month of
treatment, prompted Merck research chief Edward Scolnick to write in an
e-mail to staff on March 9 that "the cardiovascular events are clearly
there." He wrote that "it is a shame but it is a low incidence and it is
mechanism-based, as we worried it was."

When the Wall Street Journal first published Dr. Scolnick's comments last
November, Merck issued a statement saying that in the selective release of
its documents "the business practices of Merck may well be misrepresented
in any reporting."

A Merck lawyer told the Journal that the internal Merck documents filed in
connection to ongoing proceedings "were taken out of context" and "do not
accurately represent the conduct of Merck employees."

Merck Frosst Canada said it could not respond to written questions from The
Globe about these documents.

Despite Dr. Scolnick's e-mail that seems to acknowledge the heart risks
linked to Vioxx, company officials later offered theories that would
otherwise explain the negative heart findings in meetings and articles.

They noted that Vioxx users in the trial had taken the drug at twice the
recommended dosage for chronic use. And though they had tried to exclude
high-risk heart patients, they said, in retrospect, some of those in the
Vioxx group were at increased risk.

But Merck's most forceful defence -- the theory Dr. Bombardier and her
Merck co-authors offered in the VIGOR report they submitted to the New
England Journal of Medicine in May, 2000 -- was that naproxen may prevent
blood clotting in the same way as Aspirin. In other words, Vioxx did not
increase heart risk, naproxen decreased it, making Vioxx look bad by
comparison.

Critics feel it would be implausible that naproxen could lower the
heart-attack risk by the magnitude seen in the VIGOR trial.

The VIGOR paper has since been widely criticized for the data that it did
not include. Critics complain that it left out detailed information about
the number of people who suffered from blood clots, strokes, hypertension
and heart failure. Neither, they say, did the paper note that Vioxx users
suffered more serious adverse events overall compared to those taking
naproxen, or discuss the fact that even those people with no history of
heart trouble appeared to face a higher risk of cardiovascular problems.

In an interview with The Globe, Gregory Curfman, executive editor of the
New England Journal of Medicine, said: "We reported what we had and I don't
know what else Merck had, if they had anything else, I don't know."

But Dr. Curfman stressed that "the editors here in our office spent a lot
of time with authors ensuring that those data [which had been submitted]
were accurately reflected in the article we published."

Doctors who eventually saw the data that Merck had available, which were
submitted to the FDA before the New England Journal article was published
in November, 2000, were scathing.

Dr. Singh at Stanford University described it as "selective reporting."

"I think that publication was scientifically inaccurate," Dr. Singh said in
an interview, insisting Merck "had data and they didn't show it."

Dr. Bombardier insists no information was deliberately left out: "It's
always easy with the eyes of retrospect."

Asked if she would report the paper differently if she had to do it again,
Dr. Bombardier said, "What we've learned from that is that we needed to
look at the totality [of the outcomes and adverse events], not just what
was statistically significant," adding that they had reported what was
statistically significant.

"The myocardial infarctions were clearly stated in the paper, that's what
brought up the whole debate [of the heart safety of cox-2 drugs] so you
could say it was helpful."

In response to complaints doctors sent to the British Medical Journal about
the VIGOR paper, Dr. Bombardier also suggested that some safety data were
left out due to the "limited space of a peer-reviewed journal."

She wrote: ". . . a figure highlighting withdrawals due to adverse events
that was submitted with the original manuscript was removed at the request
of the publisher."

This week, Dr. Bombardier also described receiving the reams of raw data as
an overwhelming experience and that the cardiovascular side effects seen in
the trial were, to her, a surprise. She said she did not know of internal
company correspondence suggesting Merck researchers had feared such an
outcome.

"I thought, 'Oh my God,' this was so unexpected," she said.

Dr. Bombardier explained that there were no neat tables available to her
comparing the various adverse cardiac events in each patient group. But it
was the heart-attack rate that jumped out at her, and the heart-attack rate
she reported, she said.

But the safety questions it raised, however, concerned her enough that she
went home to discuss the results with her husband, who had been taking
Vioxx for his arthritis, and asked him if he wanted to stop taking the
drug.

"He said, 'Claire, you told me the risks and I still want to take it.' "

Other doctors, meanwhile, complained that they were unable to have similar
discussions with their patients because Merck had not made the information
available to them.

James Fries, a professor of medicine at Stanford University wrote to Merck
CEO Raymond Gilmartin on Jan. 9, 2001, that doctors worry Vioxx has "some
serious and underemphasized drug-toxicity problems."

Dr. Fries said doctors turned out in big numbers to recent rheumatology
meetings to hear about VIGOR, but the talks "did not contain data on the
side effects."

Dr. Bombardier, who made several presentations of the trial shortly after
its completion, said she always included the data in her talks.

Arthur Schafer, director of the Centre for Professional and Applied Ethics
at the University of Manitoba, said, in relation to Dr. Bombardier: "Any
scientist associated with VIGOR ought to have vigorously spoken out against
this trial and demanded further research to test [the cardiovascular risks]
of this drug."

On this point, however, Dr. Bombardier said she is a rheumatologist with
expert knowledge in her field and its associated gastrointestinal side
effects, not cardiac matters. Dr. Bombardier said she could not offer
advice on how to design a cardiovascular clinical trial.

Dr. Bombardier said she was not involved in the internal Merck debates
about whether to conduct a heart-safety trial after VIGOR.

"I wasn't involved in all of that and ,to tell you the truth, I didn't want
to get involved in all of that," she said. "If you follow [the events], you
see I don't become visible after" the months following the VIGOR trial. She
explained that there was a point after the trial when she stopped giving
presentations on its results.

"It had gone beyond a scientific issue; it became a very big marketing
battle between the two cox-2 drug companies," said Dr. Bombardier, who did
continue to consult for Merck on scientific questions.

At the time, Merck officials were apparently debating conducting a pure
heart-safety trial, but decided against it. A New York Times article
reported that top Merck executives were told in a May, 2000, slide
presentation: "At present, there is no compelling marketing need for such a
study. Data would not be available during the critical period. The implied
message is not favourable."Despite the disturbing cardiovascular results
from VIGOR, Merck was determined to use the positive stomach data to
improve the safety information on its label and soon found itself in a
protracted debate with regulators.

They had turned their raw study data over to the FDA and Health Canada in
the summer of 2000, and that included the grim heart-risk numbers.

Yet it was two years before the FDA added the information to the Vioxx
package and two years before Health Canada issued a "public advisory" about
the cardiovascular problems linked to the drug.

Vioxx flew off pharmacy shelves during that time, for menstrual cramps,
migraines, stiff backs and tendinitis. In 2001, Canadian pharmacies
dispensed nearly four million Vioxx prescriptions.

Health Canada spokesperson Jirina Vlk said the department would not reveal
the substance of the discussions it had with Merck during that two-year
period due to pending lawsuits.

Health Canada has said in the past that "there was no consensus" on the
actual dangers associated with Vioxx, or any of the cox-2 class.

FDA documents suggest, however, that the company forcefully negotiated with
regulators during that time against unfavourable changes to its label.

An e-mail from Merck's Dr. Scolnick reveals the battle-ready mentality the
company was prepared to take to the FDA talks.

He e-mailed staff on Jan. 21, 2001, that they should push for a safer GI
label given data from Vioxx at a lower dosage: "The agency can moan and
groan as usual but we can win the argument [on GI safety] . . . we can now
formulate a correct strategy to the meeting and the upcoming round-two
battle with this group and win the public-affairs war."

In the February, 2001, meeting with the FDA, which Dr. Bombardier attended,
Merck officials pointed out other company studies testing Vioxx at a lower
dosage than the one used in the VIGOR trial showed no increased heart risk
was evident.

A timeline document the FDA released in the run-up to this week's hearing
reveals the vigorous back-and-forth debate that followed between Merck and
the agency.

On Nov. 6, 2001, the FDA file notes that Merck "rejected FDA proposed
labelling." Two weeks later, the FDA "requested that the sponsors [Merck]
reconsider their proposal in light of our comments . . ."

Negotiations continued into 2002 with the FDA noting repeatedly that there
was a "substantial distance" between the two sides.

Not until April, 2002, did they reach an agreement in which the positive
gastrointestinal data from VIGOR was added to the Vioxx label and the
cardiovascular risks were included on the box under "precautions."

Critics felt the FDA, which argued at this week's hearing that they "were
not asleep at the switch," had bent to drug-company pressure and that the
heart risks should have been prominently featured on the label in a
black-boxed warning.

Health Canada issued a public advisory in April, 2002, that discussed the
cardiovascular risks uncovered in the VIGOR trial.

But the information led to no changes of the Vioxx label in Canada.
Instead, Health Canada opted to have the company include both the positive
GI data and the heart-risk information in the product monograph in June,
2002. (The product monograph is the detailed small-print document often
folded inside medication packages. Patients do not often read it, Dr.
Bombardier agreed this week, adding: "A lot of doctors don't read it.")

Dr. Bombardier agreed that information from the VIGOR trial should have
been featured on the drug label in Canada.

Arthur Schafer, as the FDA's Dr. Graham has said, feels drug regulators
negotiating with drug companies are in a conflict of interest. "Both the
FDA in the States and Health Canada regard the drug industry as their
clients. It's not the safety of the public they're most concerned with."

FDA documents show the agency tried more than once to have Merck conduct a
study to explicitly investigate the heart risks of Vioxx.

Merck, meanwhile, had all along been testing Vioxx for other indications
and said in December, 2002, that it would pool data from these trials to
further investigate the drug's cardiovascular risks. These studies, testing
the power of Vioxx to prevent Alzheimer's disease, prostate and colon
cancers against a placebo, would offer strong data, the company said.

Still, FDA officials felt the approach "might not be sufficient to address
the ongoing cardiovascular safety concerns surrounding Vioxx." But the
agency did not compel the company to take another approach.

As Merck wrangled with drug regulators, it also found itself in tussles
with outside scientists raising questions about the safety of Vioxx.

In 2001, Dr. Topol and colleagues from the Cleveland Clinic analyzed all
the cardiovascular data available on cox-2 drugs and older pain relievers
and found that Vioxx carried an increased heart risk.

"I had sent a draft of the paper to Merck to check for accuracy," Dr. Topol
said in an interview. "When we did that . . . they had people come to the
Cleveland Clinic from Merck to tell us not to publish it. They said we
would be embarrassed, and that the study would be shown to be invalid.

"Never in 20 years had anyone asked me not to publish a paper."

In testimony to the U.S. Senate committee in November, Dr. Singh said that
when he called looking for more detailed information on the heart risks
from the VIGOR trial, the company refused to provide it.

Dr. Singh, who had been a Merck consultant at the time, continued to raise
questions about the unavailable safety data on Vioxx in his lectures and
told Merck he would stop speaking about its drug. Then, he said in an
interview, he had others, namely drug-purchasing groups, ask for the
information as well.

"That," Dr. Singh said, "is when they came after me."

Dr. Singh testified that a Merck official contacted him and said "there
would be serious consequences for me."

In the January, 2001, letter that Stanford's Dr. Fries sent to Merck's Mr.
Gilmartin, the professor of medicine wrote that he had received a call at
home from a Merck official complaining that Dr. Singh "had an anti-Merck
bias and was giving lectures that were irresponsibly anti-Merck and
specifically anti-Vioxx. . . . [The official] suggested if this continued
Dr. Singh would 'flame out' and there would be consequences for myself and
for Stanford."

Dr. Fries complained of "a consistent pattern of intimidation of
investigators by Merck staff," listing the names of eight researchers who
felt they had been "intimidated" by the company.

Mr. Gilmartin wrote back on Jan. 23, 2001, saying Merck had a "deep and
abiding commitment to the highest ethical standards in all our dealings
with physicians and other health care providers." Mr. Gilmartin said he
would hold an information meeting with interested doctors and look into Dr.
Fries' allegations.

Dr. Singh testified that the threats against him stopped immediately and
that the company subsequently made the data available.

Meanwhile, Merck continued with its massive marketing effort.

The company spent an unprecedented $100-million (U.S.) a year on
promotions, particularly high-priced television commercials featuring hit
songs, celebrities and people running marathons. Many were seen by
Canadians watching U.S. networks.

At the same time, drug representatives fanned out to pitch doctors. Many
were receptive.

Arthur Bookman, medical adviser to the Arthritis Society, said: "We had
drugs here that for the first time in my career patients could tolerate.
Usually three days after taking [the older drugs] I'd get a call saying,
'My stomach's burning.' "

But Dr. Bookman said he and many colleagues wonder if they were aggressive
enough in assessing the cardiovascular risks of Vioxx.

Drug representatives could be "defensive," he said, when dealing with the
difficult questions: "You know that when you're dealing with drug reps,
they are trying to sell drugs."

Internal Merck documents suggest company sales representatives were well
schooled to handle doctors' tough questions, with one training document
entitled "Dodge Ball Vioxx" featuring safety queries physicians might ask.

Another document instructs sales reps that it's time to target orthopedic
surgeons who write the fewest Vioxx prescriptions: "Why is this so crucial?
Orthopedic surgeons . . . write twice the number of scripts versus
rheumatologists!"

On Sept. 17, 2001, the FDA's Division of Drug Marketing, Advertising and
Communications wrote Merck a stern warning letter that certain Vioxx
promotions were "false, lacking in fair balance and otherwise misleading .
. ."

The letter said the campaign "minimizes the potentially serious
cardiovascular findings that were observed in the (VIGOR) study."

The letter goes on to state: "Your minimizing these potential risks and
misrepresenting the safety profile of Vioxx raise significant public health
and safety concerns."

The letter also pointed specifically to a May, 2002, company press release
that read, "Merck confirms favourable cardiovascular safety profile of
Vioxx." The FDA concluded that such a claim was "simply incomprehensible."

It is unclear what, if anything, Health Canada did in response to Merck's
promotional activities.

In its defence, Health Canada's Mark Bethiaume, director of the marketed
pharmaceuticals division, emphasized that the federal department didn't do
anything different on these drugs, or Vioxx, than any other regulatory
agency, namely the FDA. Yet, the FDA has come under criticism for its
approach, even from one of its own scientists.

Dr. Graham of the FDA said in an interview with The Globe, "Throughout the
world, many different countries look to the FDA to set the standard [on
drug safety]. Maybe they should reassess that wisdom."

By 2004, evidence was mounting that Vioxx could be linked to astounding
numbers of cardiovascular problems and deaths.

In May of last year, researchers from Toronto's Institute for Clinical
Evaluative Sciences found seniors who took Vioxx in Ontario had an
80-per-cent increased risk of being hospitalized for heart failure. The
study prompted Ontario government officials to schedule a meeting to review
the status of Vioxx that fall, said study author and senior scientist
Muhammad Mamdani, but the meeting was pre-empted when Merck withdrew the
drug itself.

Health Canada never issued a response to the report.

"I don't even know that they saw it," Dr. Mamdani said. "It's very
disappointing."

In an e-mail request for information, Health Canada said Vioxx-related
adverse-events reports, which are provided with limited information by
doctors on a voluntary basis, had prompted the department to consider
safety changes to the Vioxx label last summer.

At that time, the FDA's Dr. Graham had found evidence, which he alleges his
agency tried to suppress, to suggest that Vioxx might be responsible for
more than 80,000 excess heart- and stroke-related events in the United
States.

But by last fall, one of Merck's own trials led to the drug's undoing after
people taking Vioxx in a trial to prevent the recurrence of colon polyps
had twice the risk of heart attack and stroke compared to those taking a
placebo.

With yesterday's FDA panel decision, it is possible Vioxx will return. But
severe restrictions against its use will likely keep it from ever reaching
blockbuster status again, Dr. Graham predicts.

© Copyright 2005 Bell Globemedia Publishing Inc. All Rights Reserved.
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