A clinical trial of the blockbuster arthritis drug Celebrex was shut down Friday after researchers found an increase in the risk of serious heart disease and strokes in those taking the drug, the same side effects that caused the related painkiller Vioxx to be taken off the market this fall.
The manufacturer of Celebrex, Pfizer Inc., gave no indication that it would withdraw its product, saying the new results were at odds with other ongoing and completed clinical trials.
Lester Crawford, acting commissioner of the Food and Drug Administration, said the agency had “great concerns about this product and this class of products” the COX-2 inhibitors that tens of millions of Americans have taken. “We don’t have a decision yet on the fate of this product, but we’re leaving all regulatory options open,” he said.
COX-2 inhibitors were hailed in the late 1990s as a historic advance in arthritis and pain treatment, but the agency is now seriously considering regulatory action to limit their use or remove them from the market. Crawford said patients using Celebrex should meet with their doctors to discuss possible alternative therapies, and that those continuing on the drug should use the smallest dosage possible.
The worrisome results came from a clinical trial being conducted by the National Cancer Institute into whether Celebrex might protect people at risk of colorectal cancer. Ernest Hawk, chief of gastrointestinal research for NCI, said a team of cardiovascular specialists had been brought in to help analyze the cardiovascular risk of Celebrex for participants in the trial after Vioxx was withdrawn in late September.
Hawk said the experts, along with the safety monitoring board of the trial, found that patients on 400 milligrams of Celebrex were 2.5 times more likely to have a heart attack or stroke than the group taking a placebo. For patients taking 800 milligrams a day, the risk of serious cardiovascular events was 3.4 times greater.
National Institutes of Health Director Elias Zerhouni said the agency is now reviewing about 40 other studies using Celebrex to determine whether they should be discontinued.
The announcement that Celebrex may pose serious risks similar to those of Vioxx quickly led to a new round of calls for reform at the FDA, which has come under heavy criticism for its oversight of prescription drug safety in recent months. Sen. Charles Grassley, R-Iowa, who has been especially critical, called for creation of an independent blue-ribbon review to recommend reforms.
“At this point, no one can say with confidence whether the worst drug safety problems are behind us or ahead of us,” he said.
Friday’s announcement came as something of a surprise to regulators because previous large trials of Celebrex did not show worrisome cardiovascular risk.
“These clinical trial results are new,” Pfizer’s chairman and chief executive, Hank McKinnell, said in a statement. “The cardiovascular findings in one of the studies are unexpected and not consistent with the reported findings in (a) second study.” Results from that ongoing study to test Celebrex for prevention of colon polyps have not shown a similar increased rate of cardiovascular disease.
“Pfizer is taking immediate steps to fully understand the results and rapidly communicate new information to regulators, physicians and patients around the world,” McKinnell said.
Celebrex has been one of Pfizer’s biggest moneymakers, bringing in $1.9 billion in sales last year. Friday’s news sent stock in the company the world’s largest drug manufacturer down by more than 11 percent.
Indeed, the entire day was a miserable one for drugmakers. AstraZeneca announced that a study of its cancer drug, Iressa, demonstrated that the drug had no benefit. And the FDA announced new warnings for Strattera, a drug for attention deficit disorder made by Eli Lilly that is used widely in children.
Pfizer also got bad news Friday about Bextra, a newer COX-2 inhibitor that has been used by 7 million people worldwide. In a soon-to-be-published letter released early by the New England Journal of Medicine, three Vanderbilt University researchers recommended that doctors stop prescribing the drug because of its cardiovascular risks.
Two recently published clinical trials of patients who had undergone heart bypass surgery showed that those using Bextra were three times more likely to have serious cardiovascular problems than those who did not take the drug.
Celebrex, Vioxx and Bextra are the three COX-2 inhibitors that have come onto the market so far. The medications block the action of the COX-2 enzyme, which is associated with inflammation and pain. Researchers found in early studies that the enzyme has heart-protective qualities, and so eliminating or reducing its activity could, in theory, also reduce its beneficial effects.
Sidney Wolfe, director of Public Citizen’s Health Research Group and a longtime critic of COX-2 drugs, said it is time to take all of them off the market.
“The company and the FDA are saying these results with Celebrex are surprising, but they shouldn’t be,” he said. “There have been warning signs going back to the early animal studies of COX-2s.”
John Jenkins, director of the FDA’s Office of New Drugs, said the agency did not have any clear indications that Celebrex might cause heart and stroke problems until Thursday night, when Pfizer and the NCI reported that their Celebrex trial was being stopped.
Problems with a pain blocker
Arthritis pain medications Celebrex and Vioxx belong to a class of anti- inflammatory drugs that were devised to avoid the stomach irritation that can occur with asprin and ibuprofen.
COX enzymes produce chemicals that create the feeling of pain, produce mucus for the stomach lining and dilate blood vessels. Studies indicate that COX-2 inhibitors might be useful in cancer treatment by limiting the blood supply to tumors. But these drugs may also block processes that maintain proper cardiovascular functioning, increasing the risk of heart attacks in patients.