FDA Faulted for Spotty Oversight of Data Coming from Overseas

WASHINGTON -- The U.S. Food and Drug Administration hasn't done enough to monitor clinical trial data coming from overseas sites and patients, which increasingly dominate the studies used to support drug applications in the United States, according to a report from the Department of Health and Human Services' inspector general.

More than three-quarters of the patients participating in clinical studies submitted for 121 drugs approved by the FDA in fiscal year 2008 were from foreign sites, according to the report, submitted by HHS Inspector General Daniel R. Levinson.

For 10 of these drugs, all the supporting clinical data came from overseas trials, wrote Levinson, whose staff audited all marketing applications approved that year.

FDA Oversight Lacking

Yet despite this heavy reliance on foreign data, less than 1 percent of trial sites outside the U.S. underwent FDA inspection, the audit indicated.

Moreover, the HHS investigators found, "sponsors are increasingly conducting early-phase clinical trials outside the United States without INDs [Investigational New Drug applications]," leaving the FDA unaware that these studies are taking place.

Levinson wrote that the FDA should step up its inspection of foreign trial sites and work with its equivalents in other countries to share inspection findings and future plans.

He also recommended that the FDA begin "taking steps to encourage sponsors to voluntarily consult with FDA on their clinical trial protocols or submit INDs to the agency" when they begin human drug testing overseas.

Finally, the report suggested that the FDA should require that trial data be submitted in a standardized electronic format, after investigators found that the agency was unable to find some trial data because of missing files and incomplete submissions from sponsors.

Indeed, the audit excluded eight applications approved that year because the FDA couldn't locate them.

Dr. Joshua Sharfstein, the FDA's deputy commissioner, in a memo published with the report, agreed with the recommendations and said the agency was addressing each of the problem areas.

Disconnect with North America

Some of the potential problems by siting important trials overseas were highlighted in last year's PLATO study of the antiplatelet drug ticagrelor (Brillinta), which is expected to win FDA approval soon.

PLATO compared ticagrelor to clopidogrel in nearly 19,000 patients, about 90 percent of whom were from outside the U.S. and Canada.

Ticagrelor reduced the risk of cardiovascular events by 11.7 percent relative to clopidogrel overall. But a subgroup analysis found that ticagrelor apparently had no benefit for the study's 1,814 North American participants.

Cardiologists were divided as to whether that finding was anything more than a statistical fluke. But it certainly did nothing to dispel concerns that trials conducted overseas may be sloppier or that genetic, cultural, and environmental differences from Americans mean the data are of questionable relevance to U.S. patients.

As Levinson's report put it, "concerns cited by medical ethicists include the ability of local regulatory bodies and institutional review boards (IRB) to adequately monitor clinical trials to protect the rights and welfare of subjects and to ensure data integrity. Other critics question the extent to which the results from foreign clinical trials conducted in developing countries are generalizable to the U.S. population."

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