Healthy Skepticism Library item: 17527

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Publication type: news

Gever J
FDA Oversight of Postmarketing Studies Slammed
MedPage Today 2009 Oct 28
http://www.medpagetoday.com/PublicHealthPolicy/HealthPolicy/16670

Full text:

The FDA has allowed drug manufacturers to wriggle out of postmarketing study commitments for drugs approved with surrogate endpoints, the Government Accountability Office charged.

In a report released Monday, the GAO accused the drug regulator of failing to routinely review manufacturers’ annual submissions or otherwise supervise their postmarketing research.

The FDA “does not consider such oversight a priority,” the GAO report said.

It noted that never in the FDA’s history has it forced a drug off the market because its sponsor failed to confirm its clinical efficacy.

The report, requested by Sen. Charles Grassley (R-Iowa) also criticized the FDA’s admittedly poor record-keeping — which, ironically, undercut some of the GAO’s other findings.

Since 1992, the report said, the FDA has approved 159 drugs on the basis of surrogate endpoints — that is, efficacy measures that do not reflect actual clinical benefits such as increased survival or reduced symptoms, but instead are based on laboratory measures.

For example, several HIV drugs were approved because studies showed they reduced viral loads. The anticancer drug imatinib (Gleevec) was approved on the basis of its effects on tumor size or microscopic detection of tumor cells.

Ninety of these drugs were handled under the FDA’s “accelerated approval” process, under which drug sponsors are required to follow up with additional studies using actual clinical endpoints.

The other 69 went through the traditional approval process, which does not require postmarketing studies in all cases. But the agency chose to require them anyway, in many cases, as a condition of approval.

Under the law, the FDA can revoke these conditional approvals if these follow-up studies aren’t performed or fail to confirm a clinical benefit.

The GAO found that, of 431 postmarketing studies required for the 90 drugs approved under the accelerated process, FDA records indicated that 57 (18%) had not been started, 21 (7%) were ongoing, and six (2%) were delayed.

Thirty studies (9%) had been submitted but not yet reviewed by the agency, and 12% were considered no longer necessary.

Just over half (52%) of the studies were completed and found adequate by the FDA.

About half of the 175 postmarketing studies required for drugs approved under the traditional process were classified as closed — either completed and accepted or considered no longer necessary.

But the GAO obtained its data on the status of postmarketing studies from the FDA in January and February this year. In September, the FDA released results of an audit performed by the consulting firm Booz Allen Hamilton that revealed huge gaps in the agency’s database.

The audit found that many studies listed as ongoing or not having been started had actually been completed. (See FDA: Most Firms Keep Up with Postmarketing Studies)

The FDA said it had also approved more than 200 postmarketing studies that were awaiting review when the audit was conducted.

Marcia Crosse, PhD, director of GAO’s healthcare division and lead author of the report, admitted that some of its data may have been incorrect.

“It is possible that some of the studies we have reported as pending have been completed,” she said in an e-mail to MedPage Today.

But while the discrepancy’s scale is unknown, she added, “we believe that the information you appear to be interested in — drugs approved on the basis of surrogate endpoints in the accelerated approval process — is not too far off the mark.”

Crosse said GAO investigators worked with FDA staff to locate the most current information available on the status of outstanding studies.

The report recommended that the FDA “clarify the conditions under which it would utilize its authority to expedite the withdrawal of drugs under its accelerated approval process.”

The GAO added that, in reviewing the report prior to publication, the FDA “disagreed with the need to develop such clarifying guidance.”

An FDA spokesperson promised a response to the GAO report, but it had not been received at this writing.

Ironically, the report came out almost simultaneously with the FDA’s approval of a new cancer drug, ofatumumab (Arzerra), using the accelerated process and on the basis of tumor shrinkage, a surrogate endpoint. (See FDA Approves Ofatumumab for CLL)

The report was the second in recent days in which an oversight agency accused the FDA of going easy on sponsors of medical products.

Late last week, the Office of the Inspector General in the Department of Health and Human Services released results of an investigation into the FDA’s handling of adverse event reports for medical devices.

The Inspector General’s report said the Center for Devices and Radiological Health had no system in place for using adverse event reports to identify and address potential safety problems.

It found that CDRH staff did not even look at half of adverse event reports within two months of filing. Manufacturers who filed reports after the established deadline rarely faced any penalty, the report also charged.