FDA's Review Process Under Investigation

WASHINGTON -

The government's watchdog agency is investigating whether the Food and Drug Administration's drug-review process cleared two blockbuster medications without sufficient proof of their safety or effectiveness.

Sen. Charles Grassley said Tuesday the Government Accountability Office has agreed to study a much-debated method for approving drugs used to clear GlaxoSmithKline PLC's diabetes pill Avandia and Merck & Co. Inc. and Schering-Plough's cholesterol drug Vytorin.

The Iowa Republican requested the investigation after recent studies suggested the drugs may not lower the risk of heart attack and artery-clogging plaque, as assumed by millions of patients and doctors.

"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," said Grassley, in a statement.

FDA cleared Avandia because it helped control blood sugar, which many doctors believe decreases diabetics' risk of heart attack. But the agency came under fire last year when an analysis showed Avandia could actually increase heart attack risk.

FDA 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.

At issue now is whether FDA should approve drugs based on biological measures, like cholesterol and blood sugar, without evidence they improve more meaningful measures like survival.

FDA's Director for Medical Policy Robert Temple said the agency has used several alternate study goals, often called surrogate endpoints, to approve drugs for decades.

For example, HIV drugs are cleared based on their virus-lowering power, an effective predictor of survival.

Drug industry advocates favor shorter study goals because they involve smaller, less expensive and faster trials.

Longer trials, they say, 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," said Alan Goldhammer, vice president with the Pharmaceutical Research and Manufacturers of America.

But those who criticize FDA's handling of Avandia and Vytorin say surrogate endpoints aren't the problem. Rather, it's when 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," said Dr. Steve Nissen, chairman of cardiovascular medicine at the Cleveland Clinic. "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 FDA said the drug's 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 FDA did not 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, 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 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 FDA needs more authority.

The agency shows no sign of scaling back its use of surrogate endpoints.

Last month FDA cleared Genentech Inc.'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.