WASHINGTON – 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 alternate 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had been brought in to help analyze the cardiovascular risk of Celebrex for participants in the trial after Vioxx was withdrawn in late September.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 that 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.
“Right now we have a situation where the public is left wondering when the next shoe might drop when it comes to drug safety,” Grassley said in a statement.
“The Food and Drug Administration has earned a good reputation with decades of good work,” he said. “But serious mistakes have taken place and lives may have been risked and lost. By having scientific experts scrutinize what’s happened and make well-informed recommendations, both the executive branch and Congress could make reforms and strengthen public confidence in prescription drugs and the agencies that regulate those drugs.”
Friday’s announcement came as something of a surprise to regulators because previous large trials of Celebrex did not show worrisome cardiovascular risk. Prior to the withdrawal of Vioxx, for instance, FDA safety officer David Graham, who has since sharply criticized FDA’s handling of safety issues, had found that patients using Celebrex were significantly less likely to develop heart attacks and strokes than those using Vioxx.
“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.
Many former users of Vioxx switched in October to Celebrex, which Pfizer aggressively advertised this fall as not posing the same risks as its former competitor. The company says more than 27 million Americans have used Celebrex.
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 researchers recommended that doctors stop prescribing the drug because of its cardiovascular risks.
“We believe the doubts raised about the safety of (Bextra) constitute a potential imminent hazard to public health and thus require action,” three Vanderbilt University School of Medicine researchers wrote.
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.
Based on those findings, the FDA required an urgent “black-box” warning on the Bextra label saying that the drug should not be used in patients who have undergone bypass surgery. But the journal authors said the warning is not enough.
Celebrex, Vioxx and Bextra are the three COX-2 inhibitors that have come onto the market so far, but other related drugs are in drug company pipelines. 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 Friday that it was 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. He also said COX-2 inhibitors have helped many people because they do not cause the same kind of potentially serious gastrointestinal problems as other painkillers such as aspirin and ibuprophen.
Rejecting criticism that the agency does not have a strong system for identifying potential safety problems with drugs already on the market, Jenkins said the problems with both Vioxx and Celebrex came out during clinical trials designed to learn more about the drugs and their potential for preventing disease.
“It wasn’t by chance that these problems came out in these trials,” he said. “We can’t do studies on patients with arthritis because that wouldn’t be ethical.”
Also Friday, the FDA announced that the lung cancer drug Iressa had been shown to be ineffective in prolonging survival of patients with nonsmall cell lung cancer in a clinical trial by its manufacturer, AstraZeneca. The drug was approved in 2003 under an accelerated review process that required the company to continue conducting trials after it came on the market. The FDA recommended that patients using Iressa consult with their doctors about further treatment.
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