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Medical malaise: Meltdown at FDA
POSTED 13 JAN 2005

Vitiating Vioxx
Rwhite bottle of Vioxx with green and red labelemember the Pinto? Ford's economy car with the unfortunate tendency to explode after being rear-ended? Facing monster lawsuits, Ford eventually recalled and repaired "the bean's" gas tank. (Pinto courtesy Music TAP)

Small, yellow car Get ready for a druggy deja vu: On Sept. 30, drug maker Merck yanked its highly profitable anti-inflammatory drug Vioxx from the market. Eighteen months into a test for preventing cancer, those who got Vioxx had a doubled risk of heart attack and strokes.

That was not the first warning sign for the pain-killer, which reached the market in 1999 and was selling at a $2.5-billion annual clip. Merck was promoting Vioxx, its number-two seller, right up to the withdrawal. The humiliating announcement caused Merck's shares to plunge nearly 27 percent, erasing $28 billion in shareholder value. Hundreds of lawsuits have already begun; early estimates put their price at $12 billion.

round tablet with 'Vioxx' spelled on it Merck implemented a "voluntary withdrawal," but only extreme circumstances would cause it to withdraw its number-two product, says Lee Vermeulen, director of the Center for Drug Policy at the University of Wisconsin-Madison. "I assure you there would have been FDA [Food and Drug Administration] action on Vioxx had Merck not acted.2

In an "open letter" written after the withdrawal, Merck CEO Raymond Gilmartin said that the company had gone the extra mile with Vioxx. 3When questions arose, we took additional steps, including conducting further prospective, controlled studies to gain more clinical information about the medicine. When information from these additional prospective, controlled trials became available we acted promptly and made the decision to voluntarily withdraw Vioxx. We believe that a complete review of the facts will demonstrate that Merck1s conduct with respect to Vioxx shows both an ongoing commitment to study Vioxx and prompt and decisive action in response to data from prospective, controlled clinical studies.2

Diagram of heart, blood vessels clogged and dangerous.
Heart disease usually occurs when cholesterol accumulates and forms "plaque" in a coronary artery. With blood flow impeded, the heart becomes starved for oxygen, causing chest pain (angina). If a blood clot forms and completely blocks the artery, it's called a heart attack, or myocardial infarction. Image: FDA

Feeling inhibited
Vioxx is a "COX-2 inhibitor," since it blocks the enzyme COX-2, which plays a role in inflammation, a key source of pain in arthritis. ibuprofen bottle plus back warning label enlargedUpon introduction about five years ago, the COX-2 blockers were touted as selective, laser-like weapons that would be easy on the stomach and intestines. (People who control pain with the ibuprofens and other pain-relievers may experience serious, even deadly, bleeding.)

True. But easy on the gut did not mean easy on the heart, and the Vioxx withdrawal triggered a landslide of bad news about COX-2 inhibitors. In December, the FDA halted a large cancer-prevention test of Celebrex, after the 2.5 to 3.4-fold elevation in deaths, heart attacks and strokes shown in the graph on this page. Although Celebrex and Bextra, another COX-2 blocker, remain on the market, Vermeulen says, and the hazard data has not "reached the level we have seen with Vioxx." Still, he says, "I would not be surprised to see a voluntary withdrawal in the next 6 months."

graph shows higher event rate with celebrex than placeboThe Celebrex cancer-prevention trial, which was abruptly halted in December, caused excess cardiovascular death, heart attack, and stroke. Both doses were significantly more dangerous than control, but the effects of low and high doses were statistically the same. Data from JAMA

What about the human cost of Vioxx? On Nov. 18, David Graham, who is associate director for science in the Office of Drug Safety, whistleblew to Congress that a "more realistic and likely range of estimates for the number of excess cases would be from 88,000 to 138,000" heart attacks or sudden cardiac deaths (click "Dr. Graham's Testimony" here.

To put the death toll in context, Graham suggested that Congress view it as "the rough equivalent of 500 to 900 aircraft dropping from the sky. This translates to two to four aircraft every week, week in and week out, for the past 5 years."

Now, this atrocious toll is an estimate, although an informed one. But as the lawsuits and the bodies both pile up, we wonder how Vioxx got approved, and why it survived five years on the market.

Is the FDA doing its job? Is it too reliant on industry? Is it moving too fast? (Vioxx, after all, was hustled through on a "6-month priority approval," based on that reduction in bleeding.) Is it always possible to catch the side effects of drugs, especially those that might hide among the hundreds of thousands of heart attacks and strokes that "normally" strike Americans each year?

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Megan Anderson, project assistant; Terry Devitt, editor; S.V. Medaris, designer/illustrator; David Tenenbaum, feature writer; Amy Toburen, content development executive

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