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FDA's Handling of the COX–2 Crisis

FDA Is Not Doing Enough to Protect Public, Medical Journal Article Charges

Washington, D.C. — March 25, 2005 — The Food and Drug Administration (FDA) does a poor job of monitoring approved drugs and discourages debate about product safety, an editor of the New England Journal of Medicine concluded in a recent article (N Engl J Med; Vol. 352: 1063–1066). Dr. Susan Okie wrote that lack of strong agency leadership, the pressure to approve drugs quickly, and the Bush Administration's anti–regulatory bias, have made the FDA "timid and toothless."

User fees from drug companies now account for more than 50% of the money that the agency spends on the review process, Dr. Okie noted. In the rush to approve new drugs on schedule, some claim that the FDA views industry as the customer. She quotes one long–time FDA scientist: "When I joined, there was an absolute emphasis on safety. It is very, very clear that the emphasis now is getting drugs approved. To justify not getting them approved is considerably more difficult."

In too many cases, FDA review teams have based their decisions on insufficient evidence, according to Jerry Avorn, a professor of medicine at Harvard Medical School cited by Dr. Okie. Companies may be allowed to submit pivotal studies that lasted a few months and to use subjects who do not represent the people who are most likely to take the drug.

Also, according to some reports, FDA scientists were discouraged from raising questions about drug safety. For example, a medical reviewer was not allowed to present an FDA advisory panel with his report linking the use of antidepressant drugs by teenagers to an increased suicide risk. The agency initially did not allow Dr. David Graham, a whistleblower employed at its Center for Drug Evaluation and Research, to publish studies showing the dangers of the arthritis drug Vioxx®. He finally did publish his results and presented his ideas before a Senate Committee hearing.

Reforming the FDA

The FDA usually engages in long negotiations with drug companies rather than requiring them to change product labels, to limit advertising, or to modify product indications, according to another article in the New England Journal of Medicine(COX–2 Inhibitors—Lessons in Drug Safety; N Engl J Med; Vol. 352: 1133–1135). The agency also does not ensure that companies complete post–marketing studies agreed to at the time of the drug approval, the authors charged.

Since the FDA claims that it does not have the authority to make such changes, the authors recommend that Congress act to give the agency the proper duties and powers. The authors also urge Congress to create an independent, separate Center for Drug Safety that would not have to rely on the rest of the FDA. This view is shared by Sen. Chuck Grassley (R–IA), who plans to introduce legislation to reform the agency.

"If you want accountability, it doesn't make sense to have the office that reviews the safety of drugs be under the thumb of the office that puts the drug on the market in the first place," Grassley said (Los Angeles Times, March 11, 2005). He proposes a drug safety office with its own independent director and the legal authority to require drug makers to change prescribing information. It is not clear whether the office would remain within the FDA. Sen. Grassley is also considering giving the office the power to suspend drug advertising.

The Vioxx® Disaster

In a hearing last month, the FDA concluded that the arthritis drugs Vioxx®, Bextra® and Celebrex® should remain on the market, despite serious safety concerns (See FDA Panel Confirms Link Between Heart Problems and COX–2 Arthritis Drugs). Consumers and medical experts have called this action another example of the agency's ineffectiveness. Many were outraged that the drugmaker, Merck, now has the go–ahead to put Vioxx® back on the market. The company had halted Vioxx® sales in September of last year because the drug increased the risk of heart attacks and strokes.

The warning signs about these three drugs, known as COX–2 inhibitors, were apparent for years, according to Dr. Jeffrey Drazen, Editor in Chief of the New England Journal of Medicine (COX–2 Inhibitors—A Lesson in Unexpected Problems; N Engl J Med, Vol. 352: 1131–1132). However, when early clinical trials of COX–2 inhibitors suggested a link to heart attacks, the manufacturers designed studies to look at various new uses for these drugs, he points out. They did not explore the safety issues.

Heart Problems Caused by Vioxx®, Bextra® and Celebrex®

Last week, the New England Journal of Medicine published the studies about COX–2 inhibitors that finally led to a public outcry about these drugs and to new scrutiny of the FDA and drug manufacturers. The study involving Vioxx® or rofecoxib was designed to find out if the drug could reduce the risk of developing colon polyps (N Engl J Med; Vol 352: 1092–1102). A total of 2,586 patients who were at high risk for colorectal cancer took part in the multicenter study over a three year period. About half received 25 mg of Vioxx®, and half received fake pills or placebos. Forty–six patients taking Vioxx® suffered heart attacks or strokes compared with 26 who took placebos. Vioxx® users had higher rates of congestive heart failure after taking the drug for five months, and increased risks of heart attacks and strokes after 18 months.

The purpose of the Celebrex® (celecoxib) study was also to find help for colorectal cancer patients (N Engl J Med, Vol. 352: 1071–1080). A total of 2,035 patients at high risk for colorectal cancer were divided into three groups—those receiving 400 mg of celecoxib per day, those receiving 800 milligrams, and those who took placebos. The study committee on heart safety found that compared with the group who did not take celecoxib, patients taking 400 milligrams were 2.3 times more likely to have heart attacks and strokes, and those taking 800 milligrams were 3.4 times more likely to develop these conditions.

The Bextra® (parecoxib and valdecoxib) study focused on patients receiving the drug for postoperative pain (N Engl J Med ; Vol. 352: 1081–1091). Bextra® users who had undergone coronary artery bypass surgery had an increased risk of further heart problems compared with coronary artery bypass patients who did not take the drug. Some Bextra® users may also develop a severe allergic skin reaction known as Stevens–Johnson syndrome. The study did not consider this allergy, which is now mentioned in a warning message on the Bextra® label.

Brayton Purcell is currently considering claims of Bextra®, and Celebrex® users who have suffered from heart attacks, strokes, or vascular disease. If you or a loved one has had these conditions while taking these drugs or after discontinuing their use, please fill out a contact form.

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