FDA Cautious on Pain Drugs

Experimental products must "fill an unmet need" if their heart risk is greater than that of similar drugs.
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The Food and Drug Administration says any experimental pain reliever, including

Merck's

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Arcoxia, must clearly "fill an unmet need" for specific patients if the drug's cardiovascular risk is greater than that of similar medications.

The agency's comments, posted on the FDA Web site Tuesday, come two days before a panel of outside medical experts review Arcoxia, an arthritis medication that is available in more than 60 foreign markets. The FDA isn't required to follow its advisers' recommendations, but it usually does.

Arcoxia is COX-2 inhibitor, the same class that includes Celebrex, from

Pfizer

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, and Vioxx, which Merck withdrew from the market in 2004 for cardiovascular safety reasons. Pfizer pulled

another COX-2 inhibitor, Bextra, in April 2005 after the FDA said the drug's risks exceeded its benefits.

The FDA staff hasn't made a specific recommendation about Arcoxia. Staff reports are routinely issued before FDA advisory committee meetings. Sometimes, the staff makes a recommendation, and sometimes it suggests questions for advisers to ask company representatives.

The staff did review clinical trials conducted by Merck involving some 34,700 patients. According to the FDA analysis, the test met the primary goal that Arcoxia's cardiovascular risks were similar to those of an older pain reliever. Other findings were mixed depending on the test, the Arcoxia dosage and certain side effects.

The FDA analysis was issued in the context of heightened concerns about cardiovascular safety for COX-2 inhibitors as well as for older drugs called nonsteroidal anti-inflammatory drugs, or NSAIDs. Celebrex and the NSAIDs, both prescription and over-the-counter, now carry tougher warnings about risks of heart problems and stroke.

"A new product that appears to have an increased overall risk profile for cardiovascular disease, particularly beyond that seen with other drugs in the class, would not be appropriate for marketing approval unless the product fills an unmet need for a particular patient population," says the FDA staff report.

Such a drug should only be approved for these patients if they can't find "relatively safer" medications, the FDA says. Even then, the drug shouldn't be approved unless it offers "a reasonable risk-to-benefit balance" for that group of patients, the agency says.

Merck's clinical trials of Arcoxia have been assailed by some critics and analysts who say Merck stacked the deck by testing Arcoxia against diclofenac, a now-generic drug also sold as Voltaren by

Novartis

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.

Merck says clinical trials showed that the two drugs had the same cardiovascular risk, but critics say diclofenac has a higher risk than several older pain relievers. Some analysts say Merck should have tested Arcoxia with a placebo. Merck says such as test, in patients seeking relief from arthritis, would have been unethical.

The FDA staff report on Tuesday said the clinical trials appear to have met their goal of showing that the drugs had similar dangerous side effects such as clots and artery damage. However, Arcoxia patients had a "significantly higher risk" of elevated blood pressure, fluid buildup and congestive heart failure. Arcoxia produced significantly fewer gastrointestinal problems than did diclofenac.

The FDA staff report also found, in comparison with diclofenac patients, that patients receiving 90 milligrams of Arcoxia had a higher side-effect risk than those taking 60 milligrams, which is the recommended dose.

The Arcoxia clinical trials are only part of the controversy surrounding COX-2 drugs. Six weeks ago, the American Heart Association issued

a warning against overusing COX-2 drugs.

Meanwhile, Merck continues to defend thousands of Vioxx lawsuits. Pfizer, to the vigorous objection of critics, has started running Celebrex television commercials for the first time since late 2004.

Celebrex took a big hit after the Vioxx and Bextra withdrawals, but it has made a modest comeback. Last year's sales were $2.04 billion, up from $1.73 billion in 2005 but down from $3.3 billion in 2004. Arcoxia had sales of $265 million last year.

And another COX-2 application is on the horizon. Novartis has said it will seek FDA approval this year for Prexige, which received

European Union clearance in November.