A Food and Drug Administration meeting to review whether a recently approved antibiotic carries an unacceptably high risk of liver failure raised questions Thursday about the credibility of the agency’s internal decision-making.
The antibiotic, Ketek, was approved in 2004 to treat pneumonia and other severe respiratory infections. It appeared promising as a weapon against microbes resistant to older antibiotics. But this year a medical journal reported three cases of sudden liver failure, one fatal, in patients taking Ketek. That prompted the FDA and the manufacturer, Sanofi-Aventis, to warn doctors of rare grave risks.
Now, two of the FDA’s outside scientific advisory panels are considering whether to recommend that Ketek be taken off the market. The anti-infective drugs advisory committee and the drug safety committee will vote on that question today.
But the case has also generated criticism of behind-the-scenes FDA decision-making.
A congressional investigation found that before Ketek was approved
A congressional investigation found that before Ketek was approved, the agency gave the anti-infective drugs committee data from a clinical trial that key FDA officials knew was tainted by scientific fraud. That study of 24,000 patients had been commissioned to resolve questions about the liver risks of Ketek. Unaware of the study’s problems, which included some fictitious patients, the committee recommended approval.
FDA officials noted Thursday that they later privately informed members of the committee that the study had problems.
Before approving Ketek, FDA officials reviewed European reports to see whether its rate of liver damage was unusually high. Ketek had already been approved in Europe, where millions of patients had used it.
But the agency did not require Sanofi-Aventis to conduct another clinical trial to take the place of the compromised study. Such clinical studies, often called the “gold standard,” are considered superior to analyses of reports in drug safety databases, which may contain incomplete or inaccurate information.
“This meeting is focused on a drug, but underlying that are issues about how the FDA has handled it,” said Arthur A. Levin, director of the Center for Medical Consumers in New York City and a member of the FDA’s drug safety advisory committee.
“My question is: Is there any precedent to support a decision where [the FDA] said, ‘You need to do a study,’ and then that study has problems and the agency says, ‘OK, we’ll rely on spontaneous reports [in databases]?’ ” Levin added.
Dr. David J. Graham, an FDA safety reviewer and prominent in-house critic, told the panels that the agency’s decision was “an example of lowering the bar.”
In “how many cases in the history of the FDA has postmarketing data from another country been used in lieu of a clinical trial?” Graham asked.
The FDA received 110 reports through April of liver problems linked to the drug
The FDA received 110 reports through April of liver problems linked to the drug. They included 12 cases of acute liver failure and 23 cases of serious liver injury. Four patients died. Doctors have written more than 5.6 million Ketek prescriptions in the U.S.
Agency experts told the advisory committees Thursday that there was definite risk of liver failure associated with Ketek, marked by a rapid onset of problems.
Sanofi-Aventis said that there was no clear evidence Ketek was riskier than other drugs, and that the liver dangers could be controlled by doctors.
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