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    Saturday, October 22, 2005

    FDA Watch Dogs: Used to be that critics of the FDA overwhelmingly considred the agency too cautious - an obstacle in the pipeline to new, lifesaving drugs. Now, it's just the opposite. This week, the Journal of the American Medical Association became an FDA watch dog when it published on its website a review of FDA data on a new diabetes drug called Pargluva. An FDA advisory panel voted in September to approve the drug, JAMA and the authors of the paper, disagree:

    A diabetes medicine poised to win government approval sharply increases the risk of heart problems, strokes and death, researchers reported yesterday in an analysis that raises pointed new questions about the Food and Drug Administration's handling of drug safety.

    The drug, Pargluva, more than doubles the risk for life-threatening cardiovascular complications, the researchers concluded after analyzing the studies the drug's maker presented in its application for approval. The researchers urged the FDA to withhold approval until additional research can be conducted on safety.

    That does sound pretty scary. Who would take such a drug? But, a look at the paper shows the absolute risks aren't quite as dramatic:

    The primary outcome measure (all-cause mortality, nonfatal MI, or nonfatal stroke) occurred in 35 of 2374 muraglitazar-treated patients (1.47%) vs 9 of 1351 control patients (0.67%) ...[relative risk assessments removed-ed].... . A more specific outcome measure, substituting cardiovascular death for all-cause mortality, occurred in 27 of 2374 muraglitazar-treated patients (1.14%) vs 7 of 1351 control patients (0.52%) ....[ditto].... A more comprehensive outcome measure adding CHF [congestive heart failure - ed.] and TIA [commonly called "mini-strokes"-ed.] events to the composite yielded an incidence of 50 of 2374 for muraglitazar-treated patients (2.11%) vs 11 of 1351 control patients (0.81%)....Individual components of the primary end point showed consistently greater incidence in the muraglitazar-treated group compared with controls. However, the number of events was small and differences for individual components of the primary outcome measure were not statistically significant.... The difference in the occurrence rate for adjudicated CHF was nearly significant.

    Translation: They had to play with the data just to get their relative risk numbers to sound impressively ominous. All of the events - from death from any cause to mini-strokes - occurred at very low rates (< 1%.) It was only by mixing and adding them that they could get the rates to go up into a statistically significant range. And they reached their highest rate - just a little over 2% by including every possible adverse event, including "mini-strokes," which the authors themselves acknowledge is the most subjective of their diagnoses. (Unlike heart failure or heart attacks, TIA's can not be diagnosed conclusively. They leave no trace on CT scans or MRI's, and they are often so transient that by the time a patient gets to the doctor, all the signs and symptoms are gone.)

    Further clouding the analysis is the fact that it is not a strict comparison of the drug to a placebo. It is a hodgepodge of data from different studies involving different combinations of drugs and placebos. In fact, when compared directly with placebo, 5mg of the drug was safer than placebo (no adverse events vs. one heart attack in the placebo group.) In addition, although we know that the patients in the studies were matched for things like age and severity of diabetes, we don't know how they compare when it comes to other risk factors, such as smoking and prior heart disease or other vascular diseases.

    It isn't quite the stunning condemnation that the newspapers would have you believe.

    What is interesting about that data, however, is that the adverse events seem to be higher when Pargluva is combined with other diabetes drugs. Perhaps the real lesson to be learned from this is not that Pargluva is dangerous by itself but that it doesn't mix well with others.

    UPDATE: More thoughts on this from research chemist Derek Lowe here.

    posted by Sydney on 10/22/2005 08:32:00 AM 0 comments


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