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

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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

 

http://online.wsj.com/article_print/0,,SB110003733958669255,00.html

 

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oversight of the now-withdrawn painkiller.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.

 

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. Charles 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 Sandra 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, Maria 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 David 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, Paul 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, John Jenkins, 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.

Jenkins'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 Anna Wilde Mathews at anna.mathews

URL for this article:

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Hyperlinks in this Article:

DRUGS UNDER FIRE

• Merck's Rating Gets Moody's Cut Amid Vioxx Woes1

• Public Backs More OTC Medicines Despite Safety Concerns2

• Video: AstraZeneca's CEO talks about the future of pharmaceuticals.3

 

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(2) http://online.wsj.com/article/0,,SB109993009767767629,00.html

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hJkIjQLBNvXU8RU2KDzMD6l83tUd4,00.html?mod=ARTICLE_VIDEO

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