At F.D.A., Strong Drug Ties and Less Monitoring
By GARDINER HARRIS
Published: December 6, 2004
http://www.nytimes.com/2004/12/06/health/06fda.html?oref=login&th
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When federal drug officials suspected in 1992 that a popular allergy
pill might cause heart problems, they turned to their own scientists.
Their trial confirmed the danger, and the drug was pulled from the
market.
Eight years later, similar worries surrounded the arthritis pill Vioxx.
But by then, the Food and Drug Administration had shifted gears,
slashing its laboratories and network of independent drug safety experts
in favor of hiring more people to approve drugs, changes that arose
under an unusual agreement that has left the agency increasingly reliant
on and bound by drug company money. Discovering Vioxx's dangers would
take four more years.
That delay has led to a firestorm of criticism. Members of Congress, an
internal F.D.A. whistleblower and prominent medical journals have said
the agency is incapable of uncovering the perils of drugs that have been
approved and are in wide distribution. Some have accused it of being
cozy with drug makers.
Dozens of former and current F.D.A. officials, outside scientists and
advocates for patients say the agency's efforts to monitor the ill
effects of drugs that are on the market are a shadow of what they should
be because the White House and Congress forced a marriage between the
agency and industry years ago for the rich dowry that industry offered.
Under the 1992 agreement, the industry promised to give the agency
millions - in the 2003 fiscal year, $200 million - but only if the
agency spent a specified level of money on new drug approvals.
As Congressional support sank since then, the agency has cut everything
else but new drug reviews. In the past 11 years, spending on the reviews
has increased to more than four-fifths of the budget of the agency's
drug center from about half.
Among the priorities that took the worst hit was ensuring the safety of
the drugs that patients are already taking. Drug companies test their
products in people before they are approved, but sometimes potentially
serious problems arise only when they are being used by millions of
people. The F.D.A. has never been able to require drug makers to
undertake new safety tests once a drug is approved, so tracking the
safety of drugs already on the market is the agency's responsibility.
But as a result of the agency's shifting its resources, almost everyone,
including critics, outside drug safety experts, medical journal editors,
some industry executives and even top agency officials, now agrees that
its mechanisms for uncovering the dangers of drugs after they have been
approved are woefully inadequate, particularly, as was the case of Vioxx,
when the potentially damaging side effect is not an unusual ailment.
The F.D.A.'s present safety monitoring system "is not good for
determining if a drug increases the rate of a side effect already common
in the population," said Dr. Janet Woodcock, acting deputy commissioner
for operations at the agency.
Indeed, the agency now relies almost entirely on the willingness of drug
makers to report problems that crop up after a drug has been approved to
ensure the safety of the nation's drug supply. Some critics say this
dependency has gradually worn away at the agency's willingness to
confront drug makers, making it timid and leaving patients vulnerable.
"This is not just about dollars," said Dr. Jerry Avorn, a professor at
Harvard Medical School and the author of "Powerful Medicines." "It's a
cultural issue in which the agency feels it can't pressure drug makers."
Now lawmakers are considering proposals for a center for drug safety
that would be independent of the agency's new drug reviewers. The
departing health and human services secretary, Tommy G. Thompson, said
Friday that he favored creating such a center. After initially opposing
the idea, agency officials have said they will study any proposals.
These proposals may not have been needed if not for the details of the
1992 agreement, which began with the best of intentions. AIDS, cancer,
heart disease - all were terrible diseases that drug makers'
laboratories were confronting. But their remedies were languishing for
years on F.D.A. shelves because the agency did not have the money to
hire enough reviewers.
The drug industry agreed to chip in. Indeed, half of the budget for the
agency's Center for Drug Evaluation and Research, the principal office
that oversees drug reviews and safety, will come from drug industry user
fees, up from nothing in 1992 and 31 percent in 1998. But these millions
come with strings.
More Money for Reviews
The 1992 agreement provided that the F.D.A. could collect fees from
industry only if government financing of new drug reviews, adjusted for
inflation, never fell below 1992 levels (later revised to 1997 levels).
This stipulation was intended by industry to ensure that its money was
used to hire new drug reviewers and not simply substitute for government
support of those already on staff.
But Congressional financing has lagged the agency's escalating payroll
costs. To meet the "trigger" and keep fees flowing, agency officials
have been forced to shift dollars from other programs into new drug
reviews. This shifting has increased the agency's focus on the reviews
even beyond what the drug industry had negotiated.
In 1992, the agency's drug center spent 53 percent of its budget on new
drug reviews. The rest went to survey programs, laboratories and other
efforts that in part helped ensure that drugs already on the market were
safe. In 2003, 79 percent of the agency's drug center budget went to new
drug reviews. Everything else has gotten squeezed.
"We get increased user funds and not increased appropriated dollars,"
said Deborah Henderson, director of the office of executive programs in
the F.D.A.'s drug center. "We have stolen from the labs and other parts
of the non-user fee program."
Since the 1992 agreement, agency officials have eliminated half of the
scientists in the drug center's laboratories and starved them of new
equipment. They have ended many of the agency's collaborations with
academic groups that scrutinize the problems of marketed drugs. To pay
for a modest in-house effort to catalog some information on drug side
effects, a system called the Adverse Event Reporting System, the agency
has raided furniture and travel budgets.
Dr. Woodcock said she shut down laboratories and many outside grant
programs to try and raise the money to keep the agency's side effect
reporting system.
The industry's influence even extends to perks given agency employees.
Under the 1992 agreement, which was renewed in 1997 and 2002, new drug
reviewers have travel and training budgets that allow them to attend
far-flung conferences and courses. Those who work in the agency's office
of drug safety get two-thirds less, which keeps most at home.
The agreement that accepted such a large proportion of industry
financing "made a bad situation worse," Dr. David J. Graham, a reviewer
in the agency's office of drug safety who harshly criticized the agency
before a Congressional panel last month, said in an interview. "The
agency was already far too focused on approvals and not on safety."
"And if this problem isn't fixed," Dr. Graham said, "future Vioxx-like
catastrophes are inevitable."
Dr. David A. Kessler, former commissioner of the agency and now dean of
the University of California San Francisco Medical School, said the
financing agreements with industry "increasingly micromanage the F.D.A."
"They reinforce the focus on new drug review over the agency's field and
post-marketing surveillance efforts," Dr. Kessler said.
Sammie Young, a drug safety inspector for the agency from 1963 until
1992, said that by the time he left the agency had become wholly focused
on drug approvals - to the delight of industry. Those at the agency
"decided their main goal in life was to approve drugs," Mr. Young said.
The decline in the agency's commitments to monitor the safety of
approved medicines started in the Clinton administration and continues
today. Most experts who track drug side effects say the remedy is more
money, perhaps provided by a tax on prescriptions. But others complain
that the agency spends far too much already, and some agency critics
contend that, more than dollars, what it really needs is more courage to
confront drug makers about safety problems.
While its $1.8 billion budget and staff of 10,800 are small by federal
government standards, the Food and Drug Administration is among the most
important bodies of the federal government. It is the principal overseer
for the pharmaceutical, food, medical device and animal feeds
industries. Its rules affect nearly 100,000 businesses producing more
than $1 trillion worth of goods a year, or about a quarter of the
American economy.
Founded in 1906, the agency was at first charged simply with ensuring
that claims made on medicine packages were not demonstrably false. But
scandal after scandal in the intervening decades led to legislation
expanding its powers.
In 1984 a law established a generic drug industry that could capture
sales from drug makers once patents on medicines expired. The law led
brand-name drug makers to push for quicker review times to maximize
sales during the patented period.
And then came AIDS.
As the disease swept through gay communities in San Francisco and New
York, people desperate for remedies scoured the world. When AZT showed
promise in early trials, the F.D.A. allowed the drug to be distributed
to patients before its formal approval.
In 1988, AIDS protesters besieged the agency's offices, raising a black
flag on its flag pole and contending that it was actively delaying
treatments. The agency responded by allowing potentially life-saving
drugs to be widely distributed while undergoing review. Still, it was
not enough. Advocates for cancer patients complained about long review
times as well. With Congress feeling tightfisted, almost all agreed that
the agency needed more money and that the drug industry was the best
source to tap. A result was the 1992 agreement. The industry agreed to
underwrite the hiring of new drug reviewers if the agency would agree to
tight review timelines. Peter Barton Hutt, a former general counsel for
the agency, helped negotiate the agreement on behalf of drug makers.
"Clearly the industry forced F.D.A. to pay attention to the industry's
agenda, and that has always been to shorten the drug approval process,"
Mr. Hutt said.
Some who supported the agreement then regret it now. Dr. Sidney Wolfe,
director of Public Citizen's health research group, said it had pushed
the agency into the drug industry's arms and led to poorer drug reviews.
But William B. Schultz, who worked at Public Citizen and then in
Congress and was deputy commissioner for policy at the F.D.A. from 1994
to 1998, said the agreement saved the agency. In 1996, Republicans
lawmakers led by Newt Gingrich, the house speaker, proposed legislation
that would have allowed companies to market their products without
agency review, gutting its oversight authority.
Proof that the agency had halved its drug review times since the 1992
agreement passed undermined the proposals, Mr. Schultz said. "Their
argument was the drug lag, but it fell apart because by then the lag had
been eliminated," he said.
A Question of Care
Almost every argument about the 1992 agreement revolves around review
times and whether new drug reviews are as careful as in the past. Many
outside the agency say the rapid review timelines adopted as part of the
agreement have made the agency's drug reviews sloppy, leading the agency
to approve drugs like Vioxx that should never have gotten onto the
market. Merck withdrew Vioxx in September after a test showed that it
doubled the risk of heart attacks.
Top agency officials fiercely disagree with this criticism, pointing out
that the ratio of drugs withdrawn compared with those approved has held
steady for decades. Some dangerous side effects, they say, will never
reveal themselves until millions use a medicine.
Drug industry officials also say this criticism is wrong. New drug
reviews are at least as rigorous as they were a decade ago, they say.
Jeff Trewhitt, a spokesman for the drug industry's trade group, the
Pharmaceutical Research and Manufacturers of America, said the fees paid
by industry to the agency "do not pay for approval. They merely
guarantee review of a product application by the F.D.A. in a set period
of time."
Beyond new drug reviews, what is rarely discussed is the 1992
agreement's effect on post-approval monitoring of drug side effects.
Independent scientists had long helped the agency not only flag possible
problems, but also through tests confirm them. Some gave patients drugs
and measured the effects. Others combed through millions of patient
records at giant managed-care companies to spot problems among those
given certain medicines.
Dr. Susan Jick, co-director of the Boston Collaborative Drug
Surveillance Program, one of the nation's largest and longest-running
initiatives to uncover drug side effects, said F.D.A. officials told her
that the agency was ending its support after 20 years because her
program was using British data. Dr. Brian Strom at the University of
Pennsylvania, who worked with the agency on drug side effect issues for
decades until recently, was told that there was no money. Others were
told the same thing.
None knew that the reason was that money had to be shifted out of their
programs into new drug reviews to satisfy the requirements of the
agreement and industry demands.
Dr. Lou Cantilena, head of the division of clinical pharmacology and
medical toxicology at the Uniformed Services University of the Health
Science in Bethesda, Md., not only helped the agency study drug safety
issues for years but also trained its staff. Both programs were ended in
the late 1990's.
Dr. Cantilena said the agency was now almost wholly reliant on the drug
industry for tests of side effects. He said he was more aware than most
about the dangers of this situation.
In December 1989, a woman walked into Bethesda Naval Hospital
complaining that she kept passing out. Doctors placed her on a heart
monitor, and it showed a frightening heart arrhythmia. Dr. Cantilena and
his team of drug experts were called in. The woman was taking Seldane
for allergies. An overdose of Seldane was known to cause heart
arrhythmias, but the woman insisted that she had taken only a pill a
day.
The doctors were stumped until the woman revealed that she had also been
taking an antifungal drug to treat a vaginal yeast infection. The
antifungal was known to interfere with the breakdown of other drugs.
Blood tests showed high levels of Seldane. Dr. Cantilena concluded that
the woman had suffered from a drug-to-drug interaction.
At the time, Seldane was the fifth-most popular drug in the nation, and
the antifungal medicine was common, too. Such a serious interaction
between two popular drugs was worrisome. Dr. Cantilena reported the
problem to the F.D.A. and Seldane's maker, now known as Sanofi-Aventis.
The F.D.A. cannot require drug makers to test already-approved
medicines. Instead, it can urge companies to do more testing, can change
warning labels or, as a last resort, can take the product off the
market.
So the agency asked Dr. Cantilena to perform the study. He recruited six
healthy volunteers, hooked them up to heart monitors and gave them
Seldane and the antifungal. Four of the volunteers developed heart
arrhythmias so severe that Dr. Cantilena ended the study early.
Within weeks of reporting his results to the F.D.A., the agency
announced that it was placing a severe warning on Seldane's label about
the interaction. In 1997, the maker withdrew Seldane from the market
because of the problem.
The agency has almost no ability to perform similar tests now, Dr.
Cantilena said.
Tracking Safety
Perhaps even more pressing, the agency has no continuing ability to
uncover the kind of life-threatening drug side effects that sidelined
Vioxx.
Presently, the main drug program to catalog the dangers of drugs is a
computer listing of side-effects. It is a passive system, meaning that
doctors report side effects only when they think of it and have the
time. The system receives almost 400,000 reports a year, but these
represent a small fraction of the total, all agree. Most reports are
delivered by drug makers, who hear about side effects from physicians.
The side effects tracking system can signal problems only when a drug
causes an effect like liver failure that is normally very rare. If a
drug increases the number of heart attacks, a problem that is very
common normally, the system is useless, Dr. Woodcock of the F.D.A. said.
Realizing this weakness, Dr. Graham of the agency's office of drug
safety collaborated with Kaiser Permanente, a huge health maintenance
organization, to check its computer records to see if those taking Vioxx
had had more heart attacks. The study took nearly four years to
complete. Its results became known in August and demonstrated Vioxx's
dangers.
Dr. David Campen, medical director of Kaiser's pharmacy operations, said
the study would have taken half the time if the agency had had the money
to pay for drug monitoring programs with Kaiser or other large managed
care organizations. Dr. Graham has estimated that the delay in
uncovering Vioxx's dangers cost 55,000 Americans their lives, a number
top officials at the F.D.A. have labeled as "junk science."
An adequate system for monitoring side effects may have prevented some
of the deaths.
Dr. Strom of the University of Pennsylvania said the F.D.A.'s almost
complete focus on approving new drugs at the expense of ensuring the
safety of medicines that patients are already taking is wrong.
"They're getting all these drugs on the market a whole lot sooner and
not looking at what happens once they get there," he said.
Seeking Improvements
Some top agency officials are keenly aware of these problems. In 1999,
an agency task force wrote a 106-page report cataloging the agency's
weaknesses and calling for reforms. "F.D.A. is not funded, staffed or in
some cases authorized to collect" comprehensive reports of problems with
drugs once they are already being sold, the report concluded.
In a March 13, 2000, letter to Senator Jim Jeffords, an independent from
Vermont, Dr. Woodcock wrote that more than 1.6 million people in the
United States were hospitalized every year because of drug side effects.
Half of these problems are preventable, she wrote. The agency needed
more money for better systems to prevent these problems, she wrote. The
agency did not get them.
Sam Kazman, general counsel of the Competitive Enterprise Institute, a
libertarian group in Washington, said that is how it should be. Mr.
Kazman has been fighting for years against F.D.A. regulations, which he
said had kept important medicines away from patients. Doctors and
patients should decide what drugs are right for them, not the F.D.A.,
Mr. Kazman said. "Giving them more money is no reason to think they
would improve and it's possible that just the opposite would happen," he
said.
And Dr. Avorn of Harvard Medical School said that what the agency needed
more than money was courage. When doubts emerge about a medicine's
safety, the agency needs to insist that drug makers pay for independent
tests, he said. And continuing drug surveillance could also be paid for
by drug makers, he said.
If companies refuse, the agency "needs to call a press conference and
issue a public notice saying, 'There are unresolved issues and we are
trying to get the company to do a clinical trial and doctors should take
that into account,' " Dr. Avorn said. "The F.D.A. has moral authority
and extraordinary public relations power if they chose to use them."
The agency has asked the Institute of Medicine, the government's
principal scientific review agency, to study the agency's system for
monitoring the safety of marketed drugs. Pressure for an independent
drug safety center grew on Friday when Mr. Thompson of health and human
services said in a news conference to announce his resignation that he
supported such a move.
The reason to make decisions governing the safety of drugs already on
the market independent of the groups that approve new drugs, Dr. Graham
of the F.D.A. told a Senate panel last month, is the conflicts that
inevitably arise when those who approve a drug must later decide whether
their own decisions were mistaken.
"They approved the drug so there can't possibly be anything wrong with
it," Dr. Graham told the panel.
But many inside the F.D.A. say that separating the monitoring of side
effects from drug approvals would be a mistake because a drug's risks
cannot be assessed independently from its benefits. Besides, information
about the safety of drugs already approved should be used to assess
applications for experimental drugs in the same class, said Dr. David
Feigal, a top agency official who retired in May. An independent drug
safety center "is exactly the wrong way to go," Dr. Feigal said.
Agency officials initially opposed making an independent drug safety
center but have recently said they would study any proposals. Some have
privately said that if Congress agrees to give such an independent
center substantial resources the change could be worth the extra money.
John Schwartz contributed reporting for this article.
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