How drug-approval woes crept up on FDA

For many Americans, opening up the medicine cabinet may seem far more perilous than it did just a few months ago.

Revelations about potentially deadly problems with government-approved drugs - from Merck's painkiller Vioxx to Bayer's cholesterol-fighter Baycol - have prompted even the conservative Journal of the American Medical Association (JAMA) to charge that the Food and Drug Administration's system for protecting consumers is broken.

The JAMA's doctors are calling for an independent board to be set up to monitor the safety of drugs already on the market.

The pharmaceutical industry calls that "premature," noting that FDA has asked the prestigious Institute of Medicine to study the problem and then make recommendations. But consumer advocates and some members of Congress contend that change is long overdue, in part because of the FDA's financial dependence on the pharmaceutical industry. That, they say, creates a conflict of interest that undermines the agency's effectiveness.

"The FDA has a relationship with drug companies that is far to cozy," says Sen. Charles Grassley (R ) of Iowa, who chaired hearings last week on drug safety. "That's exactly the opposite of what it should be. The health and safety of the public must be FDA's first and only concern."

This growing conflict over drug safety illustrates the difficulty the nation has had in achieving the right balance in regulating drugs that, while intended to help save lives, can come with very serious risks.

In the 1980s, critics railed against the FDA for being too slow in approving drugs. One congressman referred to FDA investigators as "pusillanimous and faint-hearted" for their cautious approach.

It took more than two years, on average, for new drugs to be approved. That changed after a major shake-up in 1992, and so did the FDA's funding. Congress passed the Prescription Drug User Fee Act, which increased FDA funding for drug approvals by charging pharmaceutical companies a user fee. In the next 10 years, the drug companies paid $825 million dollars to the FDA, according to the JAMA. During that same period, the time it took for new drugs to be approved dropped by almost half, to just over a year. But that speed had a cost, according to the JAMA: "Drug recalls following approval increased from 1.56% for 1993-1996 to 5.35% for 1997-2001."

The Vioxx scandal indicates to many medical experts that the FDA's regulatory loosening up may now have gone too far.

It's one of a handful of drugs that have slipped through the FDA system completely. Despite studies that showed the aggressively marketed painkiller appeared to cause cardiovascular problems, Merck and high-level FDA regulators decided to leave it on the market and only put a limited warning on the label.

That distressed David Graham, a safety expert within the FDA's Office of Drug Safety. He continued to research problems with Vioxx, primarily because "millions of people" took it. He concluded it presented a "significant risk" of causing of heart attacks and sudden death. In last week's testimony he said that his FDA superiors, particularly in the Office of New Drugs which gives out drug approvals, pressured him to change his conclusions.

"An e-mail from the director for the entire Office of New Drugs was revealing," said Dr. Graham. "He suggested that since the FDA was not contemplating a warning against the use of high-dose Vioxx, my conclusions should be changed."

Another senior manager called Graham's conclusions "scientific rumor." Eight days later, Merck itself voluntarily pulled the drug from the market. Researchers estimate that between 139,000 people had strokes and heart attacks related to their Vioxx use since it went on the market. Of those, 55,000 people may have died.

Vioxx manufacturer Merck denies those numbers, saying they are only "speculation." It also insists the earlier studies showing cardiovascular problems were not conclusive and that it had full confidence in the drug. CEO Raymond Gilmartin said his wife was taking Vioxx the day Merck pulled it off the market.

But consumer activists say Vioxx is not the only problematic drug that has been given FDA approval. Public Citizen's Health Research Group did a survey in 1998 of FDA medical officers, and found 27 cases "in which they said a drug was too dangerous to be approved, but was approved over their heads anyway," says Sidney Wolfe, the group's director.

Fueled in part by the appearance that the FDA's Office of New Drugs could veto conclusions of the Office of Safety, the JAMA has called for a new drug safety board, one completely independent of the FDA. "It is unreasonable to expect that the same agency that was responsible for approval of drug licensing and labeling would also be committed to actively seek evidence to prove itself wrong," the JAMA editorial concludes.

But the industry contends that the Vioxx case is not indicative of the way the FDA usually functions. Jeff Trewhitt, a spokesman for the Pharmaceutical Research and Manufacturers of America (PhRMA), contends that the Office of Drug Safety is independent of the Office of New Drugs and has successfully raised red flags about drugs.

Calling the FDA the "gold standard" for drug regulation, he says less than 3 percent of some 10,000 drugs on the market are pulled for safety reasons.