Vytorin Latest Drug Scandal to Raise Questions about FDA OversightJan 25, 2008 | Parker Waichman LLP
The Vytorin controversy has once again raised serious questions about the way the Food & Drug Administration (FDA) approves new drugs. At issue is the agency’s policy to allow drug clinical trials to measure only “proxy markers” and not the true outcome that the medication is supposed to provide.
According to The Wall Street Journal, a proxy measure is a clinical stand-in for a drug's broader and more important effect on the body. For example, the FDA approved Vytorin based on clinical trials that measured cholesterol reduction. It was believed that cholesterol reduction was an adequate proxy marker for reducing clogged arteries and heart attacks.
According to The Wall Street Journal, the rationale behind the use of such proxy markers is that they allow for shorter clinical trials, thereby lessening costs for drug makers. They also allow drugs to come to market quicker. Defenders of proxy markers point out that many life-saving AIDS drugs would never have been approved without the use of proxy markers.
But proxy markers are not always an accurate measure of a more important outcome. In the case of Vytorin, lower cholesterol did not translate into less artery clogging plaque. In the case of another drug, Avandia, clinical trials that measured only blood sugar reduction did not make it apparent that the diabetes drug carried significant cardiac side effects that outweighed its benefits.
To measure whether or not Vytorin really did reduce artery clogging plaque in the carotid artery, Merck and Schering-Plough designed the ENHANCE study. Vytorin is a combination of cholesterol lowering Zetia and the statin Zocor. The point of the ENHANCE study was to determine how well Vytorin prevented clogged arteries by reducing the formation of plaque. ENHANCE focused on a group of 720 patients with a rare condition predisposing them to high cholesterol. The patients were given either Vytorin or a high dose of simvastatin, the generic form of Zocor. Vytorin did not provide any significant benefit versus the statin drug Zocor in slowing down clogging of the arteries. Overall, the study failed to meet its primary goal, which was to show whether Vytorin was more effective than Zocor alone in preventing progression of atherosclerosis in the carotid artery, which is in the neck.
ENHANCE was finished in April 2006, but was delayed twice before Merck and Schering-Plough finally released its results in a press release on January 14. The nearly-two year delay in revealing that Vytorin was no better than a placebo has angered many, and sparked numerous Vytorin lawsuits, as well as a congressional investigation.
The Vytorin debacle has also caused criticism of the FDA policy that allows proxy markers. But eliminating the use of proxy markers would add to the cost of drug development and delay release of important lifesaving medications.
Some experts who spoke to The Wall Street Journal did not favor ending the use of proxy markers, but do want to see the FDA require follow up studies that measure the truly desired endpoint, and tight timelines for starting, completing and releasing data from such studies. “The FDA needs to have more teeth,” John Buse, a professor at the University of North Carolina, and a frequent critic of Avandia told the Wall Street Journal. “They need to demand hard endpoint studies at the time of approval and they need to have some system for monitoring progress."
Other sources interviewed for the Journal article agreed, and went even further, saying that drug makers should face marketing restrictions until a medications’ desired endpoint has been proven. One suggested that direct-to-consumer advertising shouldn't be permitted until those results are in. That expert also felt prescribing information, or labels, for such medicines should clearly reflect the uncertainty of the long-term benefit until the data are in.