The Ketek controversy continues to resonate. And so The New England Journal of Medicine this week invited David Ross, a former FDA medical reviewer who exposed flaws in the Ketek review process, and ageny officials to weigh in.

Here is an excerpt from Ross’ essay:

Ketek “was reviewed by the FDA three times. During the first round, reviewers identified substantial safety concerns…A federal advisory committee asked Sanofi-Aventis to obtain additional safety data by conducting a study involving patients who were likely to receive Ketek if the drug were approved…In the second review…a routine FDA inspection of the practices of the physician who enrolled the most patients..uncovered fraud, including complete fabrication of patient enrollment…The physician is currently serving a 57-month sentence in federal prison…

Despite these discoveries, FDA managers presented study 3014 to the advisory committee in January 2003 without mentioning the issues of data integrity. The managers have stated that they were legally barred from disclosing the problems to the committee because there was an open criminal investigation, but they have not explained why the data were presented at all, in view of the evidence of the study’s lack of integrity….

The undisclosed problems with study 3014 led to a third review, during which FDA managers proposed using foreign postmarketing reports…as evidence of the product’s safety, despite the unreliability of such data…The FDA never conducted the recommended investigation or reviewed study 3014–related records showing that Sanofi-Aventis was aware of potential fraud in the study when it submitted the results….

The review of Ketek was thus marked by pronounced departures from accepted review practices. In addition to the use of fraudulent data, the substitution of uncontrolled postmarket safety reports for controlled clinical trial data, and the acceptance of trials that could not show efficacy, there was also overt internal pressure brought to bear on FDA reviewers to alter their conclusions.”

From rhe FDA reply:

“First, safety concerns were identified by the FDA early in the review process and taken very seriously throughout four years and three review cycles. The FDA’s approval decision followed a careful review of the safety data submitted, including foreign postmarketing adverse-event reports that accumulated during the FDA’s review of the application. Although the FDA did not rely on study 3014 to support approval, we reviewed the study for safety findings that would have counted “against the drug,” as is consistent with good review practice.

Second, there was no intention to deceive the advisory committee or the public…Before the second advisory committee meeting, the FDA had only preliminary info regarding inspections of a few of over 1800 clinical study sites…The FDA did not discuss data-integrity issues at the second advisory committee meeting to avoid compromising the ongoing investigations, recognizing that the FDA retained the ultimate decision authority.

Finally, noninferiority studies were considered acceptable as the basis for approval…Concurrent with the Ketek review, our thinking on noninferiority studies was evolving. Today, noninferiority studies are no longer considered acceptable for two of the three indications for which Ketek was originally approved. We are applying this new regulatory position to more recently submitted and planned applications.”

Please look here for complete comments;
David Ross essay;
The FDA perspective.

[tags]David Ross, FDA, Ketek, Sanofi-Aventis[/tags]