Asthma drug may increase risk of heart attack and stroke

After a post-marketing study suggested a disproportionate increase in heart attacks and strokes in patients treated with Xolair (omalizumab), compared to those who were not given the drug, the U.S. Food and Drug Administration (FDA) announced last week that it is conducting a safety review.

Xolair, a drug administered by injection every other week, is manufactured by Genentech and co-marketed by Novartis and was approved by the FDA in June, 2003 to treat patients at least 12 years old with moderate-to-severe persistent allergic asthma unresponsive to inhaled steroids.

The study, begun in 2004 and conducted by San Francisco-based Genentech Inc., is an observational study of 5000 patients who took Xolair and 2500 who did not. Because it is not a randomized trial, which is considered by researchers to be the gold standard in determining cause and effect, its conclusions may have built in bias. For example, there could be differences in underlying risk factors for heart attack and stroke between the two study groups, making it difficult for the FDA to ultimately decide how to act on the information. Patients and their doctors have to deal with even greater uncertainty since neither the drug company nor the agency is making public the data that generated the alert.

An FDA Early Communication available online states that it “is in keeping with the FDA’s commitment to inform the public about its ongoing safety reviews of drugs”. While the investigation is still under way, the agency is not telling doctors to stop prescribing Xolair and is not recommending any changes to the prescribing information for Xolair. However, doctors and patients are being advised to report side effects from the use of Xolair to the FDA's MedWatch Adverse Effects Reporting program. Once its review is completed, the finding should be communicated to the public along with any resulting recommendations.

This issue with Xolair points out some of the problems with newly approved drugs. While all new drugs go through clinical testing to demonstrate safety and efficacy prior to approval by the FDA for sale in the United States, these premarket clinical trials involve relatively small numbers of individuals compared to the actual numbers who will eventually take the drugs. As a result, it is impossible to really know how the drug might affect the general population until it is widely used. As more and more drugs have been getting accelerated approval, the FDA has required postmarketing study commitments in writing from drug manufacturers to learn additional information about the risks, benefits and optimal use of an approved drug. About half of new drug applications approved in fiscal years 1990 through 2004 involved at least one postmarketing study commitment, according to the Department of Health and Human Services Office of Inspector General (OIG). Postmarketing study results often lead to labeling changes, such as new warnings or dosing instructions. Xolair is one such drug and the manufacturer seems to be following through on its commitment.

However,despite their many promises, pharmaceutical companies often fail to submit required annual status reports to the FDA about postmarketing drug safety and efficacy studies and unfortunately, regulators lack the authority to punish those companies. In a 2006 report, the OIG attributed failed oversight to a lack of manpower and resources at the FDA.

According to OIG, 35% of the 336 annual status reports that were or should have been submitted by drug makers in fiscal year 2004 were missing entirely or contained no information on postmarketing study commitments. About 40% of these reports were missing one or more items of required information, investigators added.

FDA reported in the March 3 Federal Register that drug companies in fiscal year 2005 had missed the deadline for submitting 47% of their annual status reports. The agency also reported that 65% of open postmarketing studies had not been started as of September 2005.

After the 2006 report, the FDA promised to do better regulation of the postmarkeing process. Nevertheless, according to a Bloomberg report, data released by the agency in 2008, indicated that drugmakers had made little progress in beginning studies they had promised to conduct after their products were approved. According to the FDA 62 percent (1044), of incomplete studies for drugs and biotechs had yet to be started as of Sept. 30, 2008. At the same time in 2006, 63 percent (1026), of the unfinished studies hadn’t begun.

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