WSJ - Did FDA Staff Minimize Vioxx's Red Flags?

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>Date: Wed, 10 Nov 2004 10:20:38 -0800

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Did FDA Staff Minimize

Vioxx's Red Flags?

By ANNA WILDE MATHEWS

Staff Reporter of THE WALL STREET JOURNAL

November 10, 2004; Page B1

Even as Merck & Co. faces federal inquiries into its handling of Vioxx, the

Food and Drug Administration is undergoing intense scrutiny for its

oversight of the now-withdrawn painkiller.

Probes by two congressional committees and examination of government

documents are turning up new details about the FDA's response to safety

questions raised about Vioxx, which was pulled off the market by Merck on

Sept. 30. More than five years earlier, an agency doctor reviewing Vioxx

for approval raised what turned out to be the crucial question: Did Vioxx

pose a risk of blood clots or other cardiovascular problems? In her review,

she wrote it was " impossible to answer with complete certainty " without

more data.

[nowides]DRUGS UNDER FIRE

" Merck's Rating Gets Moody's Cut Amid Vioxx Woes

" Public Backs More OTC Medicines Despite Safety Concerns

" Video: AstraZeneca's CEO talks about the future of pharmaceuticals.

Now, Congress is trying to retrace the FDA's steps in the five years Vioxx

was on the market. Broadly, lawmakers want to determine how well the

government is policing the drug industry and whether the FDA is giving

enough credence to dissenting views within the agency, a question that has

lingered for years. If Congress concludes the FDA is falling short in

protecting consumers from potential hazards, it could call for broad

changes in drug-safety regulation.

" It looks like the FDA saw a lot of red flags from the beginning, " said

Sen. Grassley, the Iowa Republican who is chairman of the Senate

Finance Committee. " The agency must address what looks like systemic

problems when it comes to putting public health and safety first and public

relations second. "

The FDA, which has commissioned an outside review of its drug-safety

procedures, says it took the proper actions on Vioxx based on the

information it had, and pressed Merck to look at cardiovascular safety in

its clinical trials -- including the one that led to the drug's withdrawal.

That trial found that people taking the drug for at least 18 months had a

higher rate of heart attacks and strokes.

In addition, the FDA rebuked the company harshly in 2001 for playing down

Vioxx's potential risks in its promotions, and insisted that heart-safety

concerns be added to the label in 2002. " This was a very difficult

scientific issue, " says Kweder, acting director of the FDA's office

of new drugs. " We really left no stone unturned to get the answers. "

Still, lawmakers and others want to know why the FDA didn't move more

aggressively early on. Even before the agency approved Vioxx in May 1999,

an FDA reviewer, Lourdes Villalba, wrote of a " theoretical " risk of

problems from blood clots tied to regular use of drugs like Vioxx. The data

" seem to suggest that in six-week studies, thromboembolic events are more

frequent " in patients taking Vioxx than patients taking a placebo, she

wrote in her review. But there was no clear sign of increased risk with

higher doses, she wrote.

In 2000, results emerged from a big trial, called Vigor, that compared a

high dose of Vioxx with an older drug, naproxen. In a public

advisory-committee meeting in early 2001, FDA scientists highlighted

cardiovascular worries, but Merck argued that the results might be from a

benefit of naproxen.

The FDA's Dr. Villalba told the committee it was " not very convincing to us

that " good effects from naproxen were the whole explanation, according to a

transcript. A different FDA doctor wrote that that " it would be difficult

to imagine " including the Vigor results in Vioxx's label without flagging

the cardiovascular issues in the warnings sections.

NO RELIEF

Highlights from the Food and Drug Administration's oversight of Merck's

arthritis and pain drug.

May 1999: FDA approves Vioxx for sale in the U.S.

September 2001: FDA rebukes Merck for Vioxx promotion.

April 2002: New Vioxx label includes potential heart risk.

August 2004: FDA researcher presents study on potential Vioxx risk.

September 2004: Vioxx withdrawn by Merck.

Source: WSJ research

FDA documents show that the agency and Merck battled over the label. In a

call with FDA officials on Jan. 30, 2002, Merck said that other safety

findings shouldn't be as prominent as the conclusion that the drug was

safer on the stomach, the study's main focus. The agency argued that the

cardiovascular data were " relevant. " Merck wanted the more positive

cardiovascular results of other studies included.

The FDA wanted a graphic showing that the rate of cardiovascular events in

Vigor rose the longer patients were on the drug. Merck disagreed. In the

end, the new Vioxx label, unveiled in April 2002, had two tables about

cardiovascular risk. But they followed one on Vioxx's good stomach results.

The cardiovascular problems were in the " precautions " section, not the more

severe " warnings " section. The label mentioned two studies that showed

Vioxx with fewer cardiovascular serious events than a placebo. The overall

message: " Caution should be exercised " when patients with a history of

heart disease use Vioxx.

" We felt anytime you talk about potential cardiovascular risk, the public

ought to know about that, " says the FDA's Dr. Kweder. The label was

supposed to " put into balance all the information that was known as well as

what was unknown. " Merck said in a statement that it and the FDA " properly

and responsibly worked to incorporate the Vigor results and other

scientific data " on the label.

As studies raised further questions about Vioxx, an FDA drug-safety

official named Graham did research using a database of Kaiser

Permanente patients. His conclusion, included in a draft e-mailed to a

supervisor on Aug. 11, 2004, was stark: " Higher-dose rofecoxib [Vioxx's

generic name] should not be prescribed or used. "

Later that day, Seligman, director of the office of

pharmacoepidemiology and statistical science, complimented Dr. Graham on

the study. But he asked whether people were taking the high dose longer

than the recommended five days; " absent this information, " he added, " it

would be difficult to conclude that the higher dose should never be used or

prescribed. " Instead, he concluded that the high dose " may increase the

risk " of heart attacks or sudden cardiac death.

Another FDA official, Sharon Hertz, deputy director of the division that

reviews arthritis drugs, wrote that " it is inappropriate to draw any strong

conclusion about the higher dose rofecoxib " given the small numbers and

questions about whether the patients took aspirin.

Dr. Graham defended the results and said it was unlikely the aspirin issue

would confound the findings. On Aug. 13, he offered a reworked conclusion:

" This and other studies cast serious doubt on the safety of rofecoxib " at

doses greater than 25 milligrams a day " and its use by physicians and

patients. "

On the same day, , director of the FDA's office of new drugs,

wrote that the revised conclusion was " pretty strong language, " since the

agency wasn't considering such a warning for Vioxx's label. Instead, he

suggested something like: " This and other studies suggest an increased risk

of AMI [acute myocardial infarction, or heart attack] with rofecoxib use

and should be considered by prescribers when making individual treatment

decisions. "

Dr. Graham wrote that he had " gone about as far as I can without

compromising " his conclusions. In the end, he didn't include Dr. 's

suggested change in the poster presented at a conference on Aug. 25.

Dr. Kweder says the agency is " always cautious about making big

generalizations based on an epidemiological study " such as the one led by

Dr. Graham.

Dr. Graham says, " I wasn't trying to be obstinate, but I had an honest

conclusion that history and the scientific evidence have proven to be

correct. " The FDA recently announced a new procedure for resolving internal

differences of opinion.

Write to Wilde Mathews at anna.mathews@...

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