Haste in drug testing causes safety problems
Vioxx, Bextra, Rezulin, Baycol. Looking at drugs yanked off
the market, Harvard researchers found a disturbing pattern:
Medicines approved right on deadline by the Food and Drug
Administration are more likely to cause safety problems later
than those cleared with more time to spare.
Congress set strict deadlines for FDA to speed the arrival of
new medications, but critics have long complained that the
ticking clock spurred a dangerous rush to judgment.
The Harvard analysis of decades of drug approvals, published
in today's New England Journal of Medicine, provides the first
scientific evidence supporting some of those complaints.
The FDA challenged the findings with its own statistics.
Still, the study sparked calls to re-examine the balance
between speed and safety."The article is a wake-up call," said Dr. Steven Nissen, the
Cleveland Clinic's influential cardiology chief who helped
sound the alarm on the risks of some of those ultimately
doomed drugs "It puts the FDA in a very difficult situation
when they're trying to make complex decisions under these
very, very tight deadlines," he added.
Amid concern about risky drugs, Harvard Professor Daniel
Carpenter took a closer look at the impact of the deadlines.
First, he found approval is 3.4 times as likely in the two
months leading up to the deadline as at any other time.
Drugs approved in that just-before-deadline period had a four-to five-fold higher rate of later being withdrawn or requiring
serious safety warnings, compared with drugs approved faster —
presumably slam-dunks — or those that miss the deadline,
Carpenter concluded.
Further to the above
The rush to meet drug-approval
deadlines more than tripled the chances that products cleared
by U.S. regulators would be pulled from shelves later because
of safety, a Harvard University study found.
From 1993 to 2004, almost a third of all drugs were cleared in
the two months before deadlines set by Congress to speed new treatments to market, according to a report in yesterday's New
England Journal of Medicine. About 14 percent of the approved medicines were eventually withdrawn or had stiffer warnings
included in packaging, compared with 3.2 percent of the remaining drugs.
Sales of products including Merck & Co.'s Vioxx and Pfizer
Inc.'s Bextra, both painkillers, were halted after the
medicines were cleared late in the regulatory process, the
study said. The Prescription Drug User Fee act was passed in
1992 to speed approvals by imposing deadlines on the U.S. Food
and Drug Administration and giving pharmaceutical companies an
option to pay extra for an expedited process. "We need to take a hard look at how we've been reviewing
drugs,'' said Carpenter, a professor of government at Harvard
University in Cambridge, Massachusetts. "All of us work on
deadlines. They are a necessary part of life. The bigger
question is, should we rely so heavily on deadlines or more on
resources to make the FDA more predictable and efficient?''
Drugmakers now fund more than half the agency's drug-review
staff and budget, according to Carpenter's study.
Previous Studies In previous research, Carpenter found that approval speed is
directly affected by the size of the FDA's staff and budget.
His latest study is the first to link approval schedules with
safety, Carpenter said in a telephone interview yesterday.
The user fee act requires 90 percent of FDA approval decisions
to happen within 10 months of application. Speed and safety
could be increased by lowering the 10-month approval rate to
70 to 80 percent and by boosting the agency's budget,
Carpenter said.
Carpenter and researchers at Harvard Medical School in Boston
compared the timing of drug approvals before and after the
user fee act, dating from 1950. Before the act, approvals were
spread evenly across the year. After the act, approvals
clustered in the two months before deadline.
More than half of the priority approvals paid for by companies
were made in the two months before the deadline. Late-approved drugs were as much as seven times as likely to later
receive additional label warnings, known as black-box
revisions, according to the study.
FDA Commissioner Andrew von Eschenbach said yesterday that the
agency's ability to protect Americans' health is at risk
because responsibilities have increased and funding hasn't
kept pace.
The FDA "may fail in its mission to protect and promote the
health of every American,'' von Eschenbach said at a
conference in Washington. The agency's budget is more than $2
billion annually. President George W. Bush has proposed
increasing the budget by 5.7 percent to $2.4 billion for
fiscal 2009.
The Science Board, a panel of outside advisers to the FDA,
said the agency's budget will need to increase to $3.7 billion
by 2013, excluding rent for offices and revenue from the fees
drugmakers pay for the FDA to review new product applications.
The panel recommended increasing funding by $375 million to
$460 million each year.
Merck's Vioxx was withdrawn in September 2004 after
researchers showed it doubled the risk of heart attacks after
18 months. Pfizer's Bextra was halted in April 2005 when it was tied to a potentially fatal skin condition.
The Government Accountability Office, the investigative arm of
Congress, is examining whether the U.S. has approved drugs, including GlaxoSmithKline Plc's diabetes pill Avandia, without
enough evidence of safety and effectiveness.
Avandia was the world's best-selling diabetes drug until a
report in May in the New England Journal of Medicine tied the
drug to an increased risk of heart attacks. In November, Glaxo
agreed with the FDA to add a warning of the heart-attack risk,
outlined in a black box, to Avandia's prescribing information.
Avandia's revision came after data were collected for
yesterday's study and would have contributed to the
late-approved drugs with safety concerns, Carpenter said.