FDA Weighs Fate of Antibiotic Ketek

Expert Panel Hears Testimony on Safety of Controversial Drug

From the WebMD Archives

Dec. 14, 2006 -- An FDA panel is getting ready to decide whether to recommend that a widely used antibiotic be taken off the market.

The drug, known as Ketek, is used to treat respiratory tract infections like bronchitis, sinusitis, and pneumonia. Doctors have written an estimated 6 million prescriptions for the drug since it was approved in April 2004.

But the FDA is reconsidering that approval because of reports suggesting the drug could carry a higher risk of severe liver failure and other dangerous side effects than similar antibiotics.

A panel of experts is holding two days of hearings on Ketek safety. The hearings began Thursday. A recommendation is expected to be made on Friday.

This week, a Senate committee investigation blasted agency officials for their handling of Ketek's original approval. A committee report accuses officials of withholding details of a tainted Ketek safety study from the panel in 2003 as it was advising the FDA on the drug. The episode has led some FDA scientists to sharply criticize the decision to approve Ketek.

Ketek was never shown to be more effective than other antibiotics at curing infections. The FDA requires only that new antibiotics show evidence of "noninferiority" to existing drugs. The rationale, experts say, is to help ensure a steady stream of available drugs to combat antibiotic resistance.

The drug was judged to be as safe as other antibiotics when it was approved in 2004, based on premarket studies. But reports of a possible pattern of liver injuries while the drug has been sold in the U.S. prompted the FDA to reopen deliberations over Ketek.

"Ketek is being triggered because of the safety concerns that have arisen," said John Jenkins, MD, director of FDA's Office of New Drugs.

Reports of Liver Injury

Sanofi Aventis, which manufactures Ketek, reported to the FDA 212 cases of liver injury in patients who took the drug over the last two and a half years. Company and agency experts characterize the reports as initial signals of both minor and severe injuries that cannot be reliably blamed on the drug. Sanofi Aventis is a WebMD sponsor.


Company officials argued Thursday that the injuries occurred in 6 million uses of Ketek and that the drug, known generically as telithromycin, carries about the same overall risk as similar antibiotics.

"It's a drug with a signal of [liver] injury, but we always have to put it in perspective," said James H. Lewis, professor of medicine at Georgetown University, who testified on behalf of the company. "Take your pick of antibiotics, they are all associated with liver injury."

More Serious Cases

But an analysis commissioned by the agency found 35 cases of severe injuries -- including seven resulting in a liver transplant or death -- that analysts say were very likely attributable directly to Ketek.

"What we have is a higher number of these hospitalized patients" than are seen with other drugs, said William Lee, MD, director of the Clinical Center for Liver Diseases at the University of Texas Southwestern Medical Center and one of the analysts commissioned by the FDA.

The advisory committee is scheduled Friday to consider other data linking Ketek to other side effects, including temporary blindness and abnormal heart rhythms.

Senate Criticism

The meeting is taking place against a backdrop of stark criticism from the Republican chairman of the Senate Finance Committee, which has spent the last year investigating the FDA's handing of Ketek's approval.

A committee report released Wednesday concluded that FDA officials did not tell the advisory panel in 2003 that a Sanofi Aventis safety study, called 3014, was flawed.

"In sum, the FDA did not ensure that the public received accurate, science-based information regarding the Ketek (application)," Sen. Charles E. Grassley, R-Iowa, wrote in the report.

"If the FDA could not find a way to present only accurate, science-based information, the FDA should not have presented study 3014 publicly, or alternatively, should have postponed or canceled the [Senate committee] meeting," the report said.

FDA officials have said they did not take that study into account when they approved Ketek. They instead relied on European safety studies attempting to measure Ketek's safety on the market in France, Germany, and other countries.


Jenkins, who leads the FDA division in charge of approving new drugs, said he had not yet digested the 53-page report from Grassley's committee.

"I don't want to get into the details of that today," he told reporters.

Controversy surrounding Ketek's approval is also bringing harsh criticism from inside the agency.

David Graham, MD, a scientist in the FDA's Office of Drug Safety, wrote a brief article in the New England Journal of Medicine in November condemning agency officials for resorting to overseas postmarket safety studies to approve Ketek in 2004. Such data are generally considered far less reliable than controlled studies like the 3014 trial.

In an interview, Graham called the hearings an example of "damage control" over Ketek safety issues that have come back to haunt the FDA.

"This is medicine gone bad, basically," he tells WebMD. "This is FDA lying to the American people. If we can't trust them to be honest in this setting, why can we trust them to be honest with anything?"

Jenkins did not comment on the decision to present the data to the panel in 2004.

He said that no evidence of additional safety issues in 4 million European patients made the officials "comfortable making the decision for approval."

WebMD Health News Reviewed by Louise Chang, MD on December 14, 2006


SOURCES: John Jenkins, MD, director, Office of New Drugs, FDA. James H. Lewis, professor of medicine, Georgetown University. William Lee, MD, director, Clinical Center for Liver Diseases, University of Texas Southwestern Medical Center. Sen. Charles E. Grassley, R-Iowa. David Graham, MD, reviewer, Office of Drug Safety, FDA.

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