Drug Company Shenanigans

November 2, 2004

Thanks to Lynn for sending these articles which expose the

pharma-shenanigans employed to obtain approval for drugs, even when the

risks are known to outweigh any benefit.

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!' Company Says 'Out of

Context'

By ANNA WILDE MATHEWS and BARBARA MARTINEZ

Staff Reporters of THE WALL STREET JOURNAL

November 1, 2004; Page A1

When Merck & Co. pulled its big-selling painkiller Vioxx off the market in

September, Chief Executive 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, 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.

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

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 -- -1 and -2 -- that are involved in inflammation

and pain. Blocking -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 -2.

From early on, companies developing -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 on. 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.

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

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 -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.

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.

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

-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 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 -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. 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 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 -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 , 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.

Write to Wilde Mathews at anna.mathews@... and Barbara ez at

barbara.martinez@...

URL for this article:

http://online.wsj.com/article/0,,SB109926864290160719,00.html

Hyperlinks in this Article:

(1)

http://online.wsj.com/public/page/0,,8_0000-mCLnyvPda0bzwCDw7DRbfZBmtc73ptFs-hDs\

6f9S41khbsDKl8I|KHEFTwtJ69_NM,00.html?mod=

(2) mailto:anna.mathews@...

(3) mailto:barbara.martinez@...

(4) http://online.wsj.com/article/0,,SB109701306448137065,00.html

(5) http://online.wsj.com/article/0,,SB109654671320932405,00.html

This copy is for your personal, non-commercial use only. Distribution and

use of this material are governed by our Subscriber Agreement and by

copyright law. For non-personal use or to order multiple copies, please

contact Dow Reprints at 1-800-843-0008 or visit www.djreprints.com.

November 2, 2004