Halt Is Urged for Trials of Antibiotic in Children

THE NEW YORK TIMES
June 8, 2006
Halt Is Urged for Trials of Antibiotic in Children
By GARDINER HARRIS

A Food and Drug Administration official called in May for a drug company to halt clinical trials of an antibiotic in children because the drug could be deadly, according to internal memorandums sent to other F.D.A. officials.

The drug, Ketek, made by Sanofi-Aventis, is being tested as a treatment for ear infections and tonsillitis in nearly 4,000 infants and children in more than a dozen countries, including the United States, according to postings on a government Web site. But Ketek, which is currently approved for use only in adults, has been reported to cause liver failure, blurred vision and loss of consciousness in adults.

"How does one justify balancing the risk of fatal liver failure against one day less of ear pain?" Dr. Rosemary Johann-Liang, an official in the Office of Drug Safety at the agency, wrote in one of the memorandums, a copy of which was obtained by The New York Times.

Sanofi-Aventis is sponsoring four clinical trials in children ages 6 months to 13 years, according the Web site posting. The drug agency approved plans for the trials.

There is growing evidence that Ketek is unusually toxic, according to a recent review by F.D.A. safety officials. Twelve adult patients in the United States have suffered liver failure, including four who died; 23 others suffered serious liver injury.

The safety officials wrote in their review that the agency should consider forcing Sanofi-Aventis to withdraw Ketek from the market, severely restrict its uses, even in adults, or add a prominent warning to its label about potentially fatal side effects.

More than five million prescriptions for Ketek have been written in the United States since its approval two years ago.

Asked about the memorandum written by Dr. Johann-Liang, an F.D.A. spokeswoman, Susan Bro, said that it was "a preliminary, raw assessment" and that "the final decision will be made by experts who have the full benefit of a large section of opinion and scientific fact."

Melissa Feltmann, a spokeswoman for Sanofi-Aventis, said in an e-mail message, "We are engaged in ongoing discussions with the F.D.A. regarding Ketek."

Other antibiotics cause liver failure, but Ketek seems to do so almost four times as often, the safety officials concluded in the review.

Ketek can also cause blurred vision and loss of consciousness, problems that are unique to it. In her memorandum, Dr. Johann-Liang asked how Sanofi-Aventis's investigators were going to assess whether infants were suffering blurred vision.

"If we cannot monitor for this event in infants/young children appropriately in the clinical trial setting, what can we conclude from the safety results of the trial?" she asked.

Dr. Danny Benjamin, an infectious-disease specialist at Duke University who was consulted separately by the drug agency, concluded that the pediatric trials with Ketek were a cause for concern and "hard to support," according to the memorandums obtained by The New York Times.

Dr. Benjamin did not respond to voice-mail or e-mail messages left for him yesterday.

In his memorandum, Dr. Benjamin said that in up to 87 percent of cases, pediatric ear infections resolved within a few days without treatment. Tests of an unusually risky antibiotic in infants with ear infections might be justified if the infants had already been treated unsuccessfully with safer antibiotics first, he wrote.

Sanofi-Aventis planned to give Ketek as a first-line therapy, according to the company's trial descriptions.

The drug agency's actions in regard to Ketek are being investigated by Senator Charles E. Grassley, the Iowa Republican who is chairman of the Senate Finance Committee, as well as by Representatives Edward J. Markey of Massachusetts and Henry A. Waxman of California, both Democrats.

Sanofi-Aventis first asked the agency to approve the drug in February 2000. But officials demurred, citing reports of side effects. So the company undertook a study of Ketek in 24,000 patients to prove its safety. The trial was marred by fraud. One of the investigators on the study is now in federal prison; another lost his medical license.

The F.D.A. said it dismissed the study's results and instead asked the company to report its experience with Ketek in Europe, where it was approved in 2001. Although it is unusual for the agency to approve a drug based upon its use elsewhere, in April 2004, it . did just that, approving Ketek to treat sinusitis, bronchitis and pneumonia.

Since then, problems with the drug have continued to mount. By April, the agency had reports of 110 cases of liver problems associated with Ketek, most of which occurred in otherwise healthy people, according to the safety review. In one, a 49-year-old woman took no more than two doses of the drug before becoming nauseous and vomiting. She was hospitalized five days later and died.

Since they are submitted voluntarily, these kinds of case reports usually represent only a small fraction - estimates range from 1 percent to 10 percent - of actual drug problems. The reports that the F.D.A. has received so far are unusual because of their "rapid tempo and severity," the agency's internal safety report said.

The agency officials estimated that Ketek caused acute liver failure in 23 people for every 10 million prescriptions, about four times the rate of such events seen in other antibiotics.

In 1999, sales of the antibiotic Trovan were severely restricted after it was shown to cause liver failure in 58 people for every 10 million prescriptions.

In her memorandum, Dr. Johann-Liang suggested that Ketek's risks outweighed its benefits.

She noted that powerful antibiotics known as fluoroquinolones can also damage the liver. But she said that those drugs were available in intravenous forms and "are also used for more serious infectious diseases rather than solely for minor upper respiratory indications," as Ketek is.

Dr. Johann-Liang wrote in her memorandum that the parents of patients in Sanofi-Aventis's pediatric trials must be better informed about Ketek's risks "in order for any of these trials to continue to proceed."

She added that the parents "need to know that the 'close monitoring' for visual events is not possible in very young children, and the long-term consequences of such adverse reactions are unknown for the developing system."

Dr. Benjamin agreed that the brochure about the trials and informed-consent material given to parents "must address in plain language the risks, and severity of risks, of adverse events."