FDA Is Flexing Less Muscle - Some Question Its Relationship With Drugmakers - adverse reactions increasing

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FDA Is Flexing Less Muscle

Some Question Its Relationship With Drugmakers

By Marc Kaufman and A. Masters

Washington Post Staff Writers

Thursday, November 18, 2004; Page A01

http://www.washingtonpost.com/wp-dyn/articles/A58470-2004Nov17.html

In the past four years, the Food and Drug Administration has taken a

noticeably less aggressive approach toward policing drugs that cause

harmful side effects, records show, leading some lawmakers, academics

and consumer advocates to complain that the agency is focusing more on

bolstering the pharmaceutical industry than protecting public health.

From 2001 to 2004, three important drugs were taken off the market,

compared with 10 that were recalled from 1996 to 2001.

Two of the three were withdrawn in the very early months of the Bush

administration. The third, the blockbuster arthritis drug Vioxx, was

pulled in September at the initiative of its maker, Merck & Co., without

FDA involvement.

In the same period, the number of warning letters sent by the FDA's drug

marketing office challenging misleading or dishonest drug advertising

also plummeted. From 1996 to 2001, the agency issued about 480

cease-and-desist letters. Over the past four years, the total has been

about 130.

The decrease in FDA enforcement has come despite a steadily rising

number of reports of potentially harmful side effects from approved

drugs. From 1996 to 2004, the annual number of these " adverse events "

almost doubled.

Few doubt the FDA remains the world's gold standard for drug regulation,

and the agency fiercely defends its record. Nonetheless, Galson,

acting director of the FDA Center for Drug Evaluation and Research

(CDER), said his agency " has learned some important lessons in the past

year and will make some changes " based on an upcoming Institute of

Medicine study and its own reviews. The agency has " taken the criticism

to heart, " he said. He added, however, that some of the falloff in

recalls may be the result of a decline in new drug approvals.

Concerns about the FDA's safety monitoring have been growing ever since

Congress required in 1992 that the industry assume a significant share

of the costs of evaluating new drugs. These " user fees " now pay for more

than half of CDER's annual budget of almost $500 million, and the

percentage is growing steadily.

Those concerns have taken on new urgency since the calamitous withdrawal

of Vioxx, a move that focused sharp attention on whether the agency has

become lax in overseeing the drug supply and too cozy with the industry.

Recent events " pretty clearly indicate the safety surveillance system

isn't working, " said Jerry Avorn, a Harvard University drug safety

specialist and author of " Powerful Medicines: The Benefits, Risks, and

Costs of Prescription Drugs. "

" It's a little like driving drunk, " he said. " You can go for a number of

trips inebriated and not get in an accident, but the risk is there and

eventually you'll have a crash. "

Some of the criticism comes from unexpected places. Sen. E.

Grassley (R-Iowa) has taken a lead role and will chair a Senate hearing

today regarding the agency's track record on drug safety.

The hearing will focus on how Vioxx stayed on the market despite early

warnings that it might increase the risk of heart attack and stroke --

allegations of foot-dragging that Merck and the agency say are

unfounded. But in a larger sense, the FDA's entire drug review and

post-market surveillance programs will also be on trial.

" The kind of mismanagement we've seen this year by the Food and Drug

Administration demands tough scrutiny, " Grassley said. " One of my

concerns is that the FDA has a relationship with drug companies that is

too cozy. That's exactly the opposite of what it should be. The health

and safety of the public must be the FDA's first and only concern. "

Among Grassley's proposals is that the agency's relatively small Office

of Drug Safety be beefed up and made more independent of the Office of

New Drugs, the division that reviews and approves drug applications.

(This year, the safety office received less than $24 million of CDER's

budget of almost $500 million.) Grassley and other critics contend the

safety office is reluctant to admit that drugs may have been approved in

error. An independent safety office, he said, would not feel as constrained.

Curt Furberg, a drug safety expert at Vanderbilt University and a member

of the FDA's advisory panel on drug safety and risk management, also

said the Office of Drug Safety should be more independent. Furberg, who

was uninvited from an important upcoming FDA drug advisory panel after

he publicly questioned the safety of other drugs in the same family as

Vioxx, argued that the FDA needs basic structural changes.

" I think what we've seen in the United States is that the FDA and

industry have gotten very successful at getting drugs to the market

based on their efficacy, " he said in an interview. " But that has come at

a cost: We are discovering the safety problems here after the drug has

been on the market and widely used. . . . This is why I say safety has

become a stepchild to the agency and the process. "

While acknowledging there have been weaknesses in the FDA's safety

oversight, Galson said there is no reason for an independent safety

office -- in part because that would deprive safety monitors who

evaluate a drug's risks of the best information about their benefits. He

also defended the drop in enforcement letters about misleading

advertising, saying the agency is relying more on providing companies

better guidance before they start marketing.

Galson said that he sees no meaning in the decrease in the number of

drugs taken off the market, but that the increase in adverse-event

reports " was of some concern. "

The perception that the FDA has tilted from its public health mandate

toward a focus on industry needs has been reinforced for some in

Congress by court cases in which the agency intervened on the side of

drug and medical device makers sued by patients claiming they were harmed.

Invoking the legal theory of " federal preemption, " the government has

argued in at least five cases that such lawsuits threaten to disrupt a

regulatory system established to ensure the flow of new and useful

products. Rep. Maurice D. Hinchey (D-N.Y.), saying the court filings

showed the FDA is being taken " in a radical new direction, " persuaded

the House to cut $500,000 from the general counsel's budget to show its

displeasure.

Industry officials disputed the notion that the FDA has become less

aggressive on safety issues.

The small number of drug withdrawals since 2001 reflects the fact that

fewer new drug applications have been submitted and approved, and that

the FDA has been more active in looking for signs of liver- and

heart-damaging side effects before approving new drugs, said Alan

Goldhammer, associate vice president of the Pharmaceutical Research and

Manufacturers of America (PhRMA). As a result, some potentially

dangerous drugs never made it to the market, he said. The FDA has

required stricter monitoring and management of patients to minimize the

risk for others, he added.

" Drugs are approved based on an evaluation of both the benefits and the

risks, " Goldhammer said. " There is no drug on the market without some

risk. "

He argued that the post-marketing surveillance system, which requires

manufacturers to report deaths and life-threatening reactions to drugs

within 15 days, is working well. The real problem, he said, is how to

draw conclusions from that data, which is why PhRMA has been working

with the FDA for more than a year to improve data-mining techniques for

combing through computer databases to find patterns.

When Congress introduced drug industry user fees in 1992, all the money

was earmarked for hiring people to speed the drug review process. It was

not until 2002 that Congress allowed some of the money to be used to

boost post-market drug safety surveillance.

The 2002 funding package set aside $75 million over five years from user

fees to add more than 100 positions to the drug safety office,

Goldhammer said.

The user fee funding has shortened the average time for new drug reviews

from 32 to 13 months, with some priority drugs passing muster in six

months, he said, but that has not led to less careful reviews.

" The FDA spends more than $2 million doing a new drug review, " he said.

" That's 13 person-years looking at safety, efficacy and the

manufacturing process. That is a significant effort that has been lost

in this whole debate. "

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