The government’s watchdog agency is investigating whether the FDA’s review process cleared two blockbuster meds - Avandia and Vytorin - without sufficient proof of their safety or effectiveness, the Associated Press reports. Specifically, the GAO has agreed to study whether the FDA should approve drugs based on biological measures, like cholesterol and blood sugar, without evidence they improve more meaningful measures like survival.

“There’s enough of a pattern of problematic drugs to ask for an independent review of how the FDA follows up on the effects of medicines that it’s approved,” says Chuck Grassley, the Iowa Republican on the Senate Finance Committee who requested the investigation, in a statement.

The FDA cleared Avandia because it helped control blood sugar, which many docs believe decreases a diabetic’s risk of heart attack. But the agency came under fire last year when an analysis showed Avandia could actually increase heart attack risk. The FDA, however, argued that it has never required diabetes drugs to show lower heart attack risk, and that lowering blood sugar alone is an important benefit.

The agency approved Vytorin, which combines Schering-Plough’s Zetia with Merck’s older cholesterol drug Zocor, based on its cholesterol-lowering capability. But a study released earlier this year showed Vytorin was no more effective at limiting plaque buildup in neck arteries than Zocor alone, which is now available as a low-cost generic.

Bob Temple, the FDA’s Director for Medical Policy, says the agency has used several alternate study goals, often called surrogate endpoints, to approve drugs for decades. As an example, HIV drugs are cleared based on their virus-lowering power, an effective predictor of survival

Industry advocates favor shorter study goals because they involve smaller, less expensive and faster trials, while they maintain longer trials may actually jeopardize patients. “It’s probably unethical to do an overall survival study where you’re going to have HIV patients taking a placebo for 10 years,” Alan Goldhammer, a PhRMA vp, tells the AP.

But those who criticize the FDA’s handling of Avandia and Vytorin say surrogate endpoints aren’t the problem. Rather, it’s when the FDA doesn’t demand follow-up studies to prove drugs delivered on the predicted benefits. “These studies are often never done, so we’re left without the knowledge we need to use these drugs wisely,” Steve Nissen, chairman of cardiovascular medicine at the Cleveland Clinic, tells the AP. “And obviously we’ve paid the price for that with the safety issues and lack of efficacy issues with Avandia and Vytorin.”

Nissen wrote the analysis that showed Avandia raised the risk of heart attack. Last year, the FDA said the risks were still unclear and asked GlaxoSmithKline to study its effect on the heart. Results from that trial aren’t expected until 2014 - 15 years after the drug was approved.

Schering-Plough and Merck are working on a study to determine if Vytorin extends patients’ lives. Results from that study, which the FDA didn’t request or require, are expected in 2011.

When the agency does require follow-up studies of drugs, its track record is poor for making sure companies complete them. A 2006 investigation by the Health and Human Services Department inspector general concluded FDA could not readily identify what progress companies made on the studies. In its most recent report, the FDA said 900 of more than 1,200 studies required of drug makers had not even begun.

Under a law that takes affect next month, the FDA can fine companies up to $1 million for failing to honor drug study commitments. Grassley argued for higher fines, and in his request to GAO asked investigators whether the FDA needs more authority.

The agency shows no sign of scaling back its use of surrogate endpoints. Last month, the FDA cleared Genentech’s drug Avastin for use in breast cancer patients who have not taken other drugs. Agency reviewers based their decision on Avastin’s ability to slow the spread of cancer. Previously FDA had approved drugs as a first-choice option for cancer patients if they extended, or improved the quality, of patients’ lives.

Source: The Associated Press