At F.D.A., Strong Drug Ties and Less Monitoring

[Guest guest]

[Vioxx really appears to be the turn of the tide for the building

realization of the true nature of the medical-pharmaceutical industry and

its involvement with government]

 

New York Times Feature Article

December 6, 2004

At F.D.A., Strong Drug Ties and Less Monitoring

By GARDINER HARRIS

http://www.nytimes.com/2004/12/06/health/06fda.html

 

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

that 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 that 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 pledged 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 agency drug center's budget

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 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 that 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 that 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.

 

Shifting Priorities

 

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 that 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 acceptedsuch 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 Kessler, former commissioner of the agency and now dean of the

University of California San Francisco Medical School, said that 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 that 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 steal 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 claiming 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 that 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 that the agreement saved the agency. In 1996, Republicans lawmakers

led by Speaker Newt Gingrich 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 that 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 that this criticism is dead 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 that 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 that 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 that the agency was now almost wholly reliant on the

drug industry for tests of side effects. He said that 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

that 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 that 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 that 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.