Vioxx recall: FDA under fire

From: fresh~horses (fresh~horses_at_despammed.com)
Date: 10/04/04 

Date: 4 Oct 2004 12:52:53 -0700

Wall Street Journal

October 4, 2004
  
Vioxx Recall Raises Questions
On FDA's Safety Monitoring

By ANNA WILDE MATHEWS
Staff Reporter of THE WALL STREET JOURNAL
October 4, 2004; Page B1

Merck & Co.'s withdrawal last week of its blockbuster arthritis
medicine Vioxx lends new urgency to a congressional investigation into
how effectively the Food and Drug Administration handles drug-safety
concerns.

In June, House and Senate committees asked the Government
Accountability Office, the investigative arm of Congress, to examine
the relationship between the FDA's drug-review divisions and the
agency office that focuses on drug safety, to determine whether safety
researchers' views are taken seriously enough. The broad inquiry was
sparked by the FDA's response to the potential risks posed by
antidepressants, but the Senate Finance Committee has since asked the
FDA specifically about Vioxx.

How effective is the FDA in getting unsafe drugs off the market?
Participate in the Question of the Day2.

• Pfizer Says No Cardiac Risk in Drug3
 
• U.S. Seeks Johnson & Johnson Procrit Documents4
 
• Merck Pulls Vioxx From Market After Link to Heart Problems5,
10/01/04

Though FDA officials have said they believe that they took the proper
actions with respect to Vioxx, based on the information they had --
including warning language added to the drug's label in 2002 -- others
are raising questions. "I'm concerned about how the agency has been
handling matters of drug safety," Senate Finance Committee Chairman
Charles Grassley, an Iowa Republican, said in a statement. He added
that in the wake of Merck's voluntary recall of Vioxx he was worried
that the FDA might have been "foot dragging" in its handling of the
drug.

Merck's decision to withdraw the drug came after new data showed that
after patients had been on it for 18 months, there was a correlation
between low doses of the drug and an increased rate of heart attacks
and strokes. There had been years of studies showing potential
problems at a higher dose -- including a recent one led by an FDA
researcher.

The FDA has said it pressed Merck for a strong safety component in the
three-year study that ultimately found the increased risks. "You can't
look backward and say we should have known this at the point we had to
make the decision," said Steven Galson, acting director of the FDA's
drug center. He said that Vioxx held a "special benefit," because it
was supposed to be less likely to cause gastrointestinal problems.

"The signals beforehand were not black and white, were not
conclusive," said Brian Strom, a professor at the University of
Pennsylvania and a former member of the FDA's drug-safety advisory
committee. He adds that if there had been more safety studies of
Vioxx, the additional evidence might have led the FDA to more
aggressive action earlier.

The Vioxx recall also is casting the spotlight on other long-running
concerns about how regulators detect and respond to evidence of
possible risks once a drug has been approved. Among the issues
researchers have raised: the limited resources devoted to studying the
safety of medical products once they're already approved; weaknesses
in the current system for tracking drug reactions; and the difficult
question of what the FDA can -- or should -- do in striking a balance
between the risks and benefits of drugs.

Adverse reactions to drugs kill more than 100,000 Americans a year,
and injure another 1.5 million people badly enough to require
hospitalization, according to a 1998 paper in JAMA, the Journal of the
American Medical Association. That estimate was based on the patients
hospitalized in 1994.

Last year, a gathering of experts sponsored by federally funded
Centers for Education and Research on Therapeutics found that the
"current U.S. system for assessing the risks of therapeutics is
outdated and inadequate."

The U.S. "is not doing an adequate job of monitoring the safety of
drugs on the market," said Wayne Ray, a professor at Vanderbilt
University whose studies showed potential problems with Vioxx. "Maybe
this will...provoke us into doing a better job."

In the past, some researchers have called for increased funding for
detecting potential risks from medical products, including possibly
setting up an independent "office of drug safety" that would be in
charge of monitoring already approved drugs. Under a law that funds
FDA drug reviews with industry user fees and imposes deadlines on the
agency for completing them, pressure has grown on the FDA to move
quickly -- which has raised questions about whether reviewers have
time to fully explore potential risks. FDA officials, however, say the
rate of drug withdrawals hasn't increased since the user fees began.

The FDA, for its part, said it has taken a number of recent steps to
improve its ability to detect adverse drug reactions or side effects,
and has acted against drugs when the evidence warranted. "We are stuck
in the middle of a very contentious and fractious debate that has on
one side people saying 'we want more cures, shorter development
times'...and we have people on the other side saying we're too lax,"
said Dr. Galson, who is also an assistant surgeon general in the U.S.
Public Health Service. He added, "we're not sitting back and saying
everything's OK and perfect" in the agency's risk-detection tools.

Consumer groups have raised safety concerns about a number of other
drugs that remain on the market. Among them are Crestor, the
anti-cholesterol medication from AstraZeneca PLC, which may be tied to
serious muscle conditions; Meridia, an obesity drug marketed by Abbott
Laboratories that can raise patients' blood pressure; and Arava, an
Aventis SA treatment for rheumatoid arthritis that has been
potentially linked to rare instances of severe liver problems. All
three drugs already have warnings on their labels, and the FDA has
said it is monitoring them carefully.

The process for getting a drug approved in the U.S. is rigorous but it
isn't designed to detect every possible risk. That would require
studies so large and long that few new medicines would ever hit the
market.

After a drug or device is allowed on the market, the FDA and the
drug's maker are supposed to watch for evidence of new risks among its
users. The FDA oversees a database that gets reports of about 280,000
incidents a year of potential adverse drug reactions. About 90% of
those reports come from drug makers, who are required to disclose
them; doctors and other medical personnel aren't required to
participate. By some estimates, FDA's database may reflect as few as
10% of such incidents.

The reports are sometimes of limited value, since it is hard to
pinpoint for sure that a drug is the cause of a problem. Some
researchers have argued that the reporting database needs to be
supplemented by more active studies to search for and confirm safety
problems of drugs already in broad use. For instance, a 1998 editorial
in JAMA called for a new "office of drug safety with the authority,
independence, funds and legal mandate" to more actively track
problems.

Once a drug is approved, the FDA has limited authority to order a
company to do a safety study, but it has indirect leverage because if
it has strong enough evidence it can force labeling changes or take a
drug off the market.

As part of the approval process, the FDA can also sometimes require
that so-called phase four studies be done later, after the drug goes
on the market. An FDA report in March said that through Sept. 30,
2003, the agency had 1,338 outstanding post-marketing commitments for
drugs, with 65% of the studies not yet initiated. The FDA has said it
is monitoring compliance with such commitments.

A few years ago, drug companies pulled a number of medicines off the
market or severely restricted their use because of dangerous side
effects. Among them were Rezulin, a diabetes drug that could cause
liver damage, Baycol, an anti-cholesterol medication that was tied to
higher rates of muscle problems than its competitors, and the diet
drug Redux. The FDA has defended its decisions, generally saying it
relied on the evidence available at the time, and had to balance the
benefits against the risks.

The Senate Finance Committee and the House Energy and Commerce
Committee made their requests for the GAO study of how the FDA
responds to safety concerns after both panels investigated FDA
officials' initial decision not to allow a staffer to publicly present
his conclusion that antidepressants could be linked to suicidal
tendencies in young people. The FDA said it thought that conclusion
was premature when the staffer was supposed to present it in February.
The FDA later confirmed the finding through further analysis unveiled
in August and plans to put a warning on the drugs' labels.

An FDA spokeswoman said the agency's reviewers and its safety analysts
agree "the vast majority of the time" and have "a lot of collaborating
back and forth."

Dr. Galson said the agency is moving to improve how it finds and
responds to risks from medical products, including trying to do better
data-mining of adverse events and using electronic filing to process
reports. The agency is examining health-care provider data, he said.
It also hopes to stimulate new scientific research to improve the
design of clinical trials of drug safety and promote research on
pharmacogenetics, which may help to identify which people will react
badly to drugs. To limit potential risks, the FDA in the past few
years also has been more active in pushing for conditions on use at
the time a drug is approved.

Write to Anna Wilde Mathews at anna.mathews@wsj.com6

 
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