A veteran U.S. Food and Drug Administration scientist said Thursday the benefits of the pain relievers known as COX-2 inhibitors, a group that includes the withdrawn drug Vioxx as well as Celebrex and Bextra, do not appear to justify the risks of heart damage.
Dr. David Graham, associate director for science and medicine at the FDA’s Office of Drug Safety, spoke on the second day of an unusual three-day meeting called by the FDA after Merck & Co. pulled Vioxx from the market in late September.
The FDA, which has come under fire in recent months as being slow to respond to serious drug side effects of drugs, is asking an advisory panel if COX-2 inhibitors offer enough benefits to stay on the market, if they and other over-the-counter pain relievers need stronger warnings, and if further research is needed.
Graham said he saw a “class effect” of heart risk from the COX-2 inhibitors, and it appeared greater with higher doses. But he told the panel of FDA advisers that each drug should be evaluated individually.
“The bottom line conclusion I came to is there really doesn’t appear to be a need for COX-2 (inhibitors) ... I believe there is a (heart) effect and it’s dose related,” Graham told an FDA advisory panel.
So far, “I don’t believe the benefits are known well enough” to justify the risks, Graham said.
COX-2 inhibitors such as Pfizer Inc.’s Celebrex and Bextra were designed to ease pain as effectively as older, nonprescription drugs known as nonsteroidal anti-inflammatory drugs or NSAIDs, while being easier on the stomach.
Graham, who is regarded as a maverick for his criticism of the FDA’s ability to monitor the safety of drugs once they are on the market, presented preliminary, unpublished findings from his review of records of 15,000 patients in California covered by the Medicaid insurance program for the poor.
Some panel members challenged Graham’s findings.
“None of us have had a chance to review it,” making it difficult to “tease out” the meaning of the numbers, said panel member Annette Stemhagen, an epidemiologist.
Dr. Robert Temple, director of the FDA’s Office of Medical Policy, told the panel that Graham had based his conclusions on a “very small” number of cases and seemed to use only the data that backed his conclusion.
Graham's findings
Graham’s review linked Celebrex to a “probable increased risk” of heart attacks in higher doses, but found “no apparent effect” if patients take 200 milligram doses or less. Celebrex is sold at doses of 100 milligrams, 200 milligrams and 400 milligrams.
Bextra did not appear to carry a cardiac risk at approved doses of up to 20 milligrams, Graham said. The Bextra findings were derived from a small amount of data, he said.
Graham’s study also showed Vioxx had a “definite” increased risk of heart attacks in patients who took doses higher than 25 milligrams. He said the risk began early and is “apparent during days 1-30 of use.”
Merck repeated assertions that Vioxx, in the study that led to its withdrawal, showed cardiovascular problems starting after 18 months of daily use. That study found Vioxx doubled heart attack and stroke risk compared to a placebo.
Merck also told the panel its drug Arcoxia, which is another COX-2 inhibitor, “has a role” in pain treatment, and studies are ongoing to determine long-term risks. Arcoxia is approved in 51 countries but not the United States.
Graham also said the pain reliever Mobic, which has become popular since the Vioxx recall, showed an “increased risk” for heart attacks in preliminary data. A spokesman for Mobic maker Boehringer Ingelheim, a privately held firm, said the company saw “nothing to indicate excessive cardiovascular risk.”
Mobic is marketed in the United States by Abbott Laboratories .
Merck officials told the panel Wednesday the heart risks found with Vioxx were a problem for all drugs in the class, known as COX-2 inhibitors.
That clashed with comments by rival Pfizer, which said the heart attack and stroke risks reported with Vioxx appeared ”distinct” among the COX-2 class.
