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FDA Exhibiting New Caution in Drug Approvals

May 9, 2008 | Parker Waichman Alonso LLP

In a move that shocked Merck and Wall Street analysts last week, Merck’s new and long-awaited cholesterol drug—Cordaptive—was rejected by the Food and Drug Administration (FDA).  Some leading heart researchers were not surprised, saying that the FDA is more reticent to approve new drugs in the wake of recent defective drug controversies and accusations the FDA might have approved several which were not fully tested.

"There is a shifting landscape in the medical community," said Cleveland Clinic cardiologist Steven Nissen.  Nissen’s outspoken criticism factored in painkiller Vioxx and diabetes medicine Avandia being withdrawn from market. 

"When you have a drug that has potentially widespread actions in the body, you would like to characterize its effects before using a drug in a number of patients," he said. "There is a question if we know enough about a new drug to go forward."

Merck and the FDA are not saying why Cordaptive was rejected, but Merck Chief Executive Richard Clark told analysts that the FDA's concern "is all around the science."  Cordaptive is made up of a new medicine—laropiprant—and niacin, one of the B vitamins, which can be difficult to tolerate because of flushing, itching, and hot flashes.  Laropiprant allegedly alleviates facial flushing; however, there have been no studies of laropiprant alone and its long-term effects are unclear.  Merck and the analysts wrongly assumed Cordaptive was a shoe-in for approval since niacin is widely used and viewed as safe for raising good cholesterol—HDL.  Because of its early confidence in Cordaptive, Merck placed “coming soon” advertisements in major medical journals as recently as November.

A few controversies this past year have thrown doubt on the FDA, its postulation that new drugs can provide long-term benefits, and its reliance on biomarkers, those substances in the blood that point to a drug’s effectiveness. 

With Cordaptive, the assumption is that by lowering HDL, patients will suffer fewer heart attacks and strokes, all allegedly verified by long-term clinical trials.  But, those trials generally do not start until long after FDA approval.  This timing is a huge problem.  Look at the FDA’s study of GlaxoSmithKlein's Avandia.  While Avandia did lower blood sugar, it raised heart risks; a surprising outcome given that it has been long believed that lowering sugar was good for diabetics.  Studies of Pfizer's torcetrapib found it raised HDL, but did not reduce artery blockages linked to heart attacks.  Most recently, Merck and Schering-Plough released a study that found Vytorin dramatically reduced LDL, but was no better at clearing clogged arteries than a generic drug five times less costly.

Allen Taylor, a prominent cardiologist at Walter Reed Army Medical Center, Washington, D.C., said these experiences suggest the FDA should demand Merck conduct more studies to fully explore the risks and benefits of laropiprant.  "There's a large degree of uncertainty and too much for use of the drug at this point," he said of Cordaptive. "There's a large amount of data that we don't have at this moment."

In a note to investors this week, Catherine Arnold, an analyst at Credit Suisse, speculated "cardiovascular signals" figured in the FDA's non-approvable letter and Merck may face "potential higher-burden" multi-year studies to win final approval.