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Two of the three were withdrawn in the very early months of the Bush administration.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, Steven 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. Charles 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 where 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.
Fewer new drugs
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 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."