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US: Approval of Antibiotic Worried Safety Officials

by Gardiner HarrisThe New York Times
July 19th, 2006

In an internal review, a federal drug safety official concluded that a controversial antibiotic made by a French drug company should be withdrawn, according to e-mail messages exchanged among top agency officials.


The official, Dr. David Graham, part of the Food and Drug Administration’s drug safety office, wrote in a message dated June 16 that the agency’s approval of Ketek, an antibiotic made by Sanofi-Aventis that is also known as telithromycin, was a mistake.

“It’s as if every principle governing the review and approval of new drugs was abandoned or suspended where telithromycin is concerned,” Dr. Graham wrote.

Referring to reports of negative, or adverse, drug reactions voluntarily submitted to the agency, he continued, “We don’t really know if the drug works; no one is claiming it works better than other, safer drugs; and we’re flying blind as far as safety goes, except for our own A.D.R. data that suggests telithromycin is uniquely more toxic than most other drugs.”

Dr. Graham concluded that the agency should recommend the drug’s “immediate withdrawal.”

Melissa Feltmann, a spokeswoman for Sanofi-Aventis, said the company had already changed the drug’s label.

“We continue to believe that the benefits of Ketek outweigh the risks when it is used as directed for its approved indications,” Ms. Feltmann said.

An F.D.A. spokeswoman, Susan Bro, said, “Every issue or question raised during the Ketek review process and subsequently since approval has been rigorously reviewed by the nation’s best physicians, statisticians and epidemiologists both internal and external to the F.D.A.”

Dr. Graham’s e-mail message is one of dozens provided to The New York Times in recent weeks that reveal a fierce debate within the F.D.A. over the safety of Ketek and the appropriateness of the agency’s actions regarding the antibiotic.

The documents show that at least four agency safety officials — including Dr. Charles Cooper, Dr. David Ross and Dr. Rosemary Johann-Liang — expressed serious reservations about the safety of Ketek. Two weeks after Dr. Graham’s e-mail message, the agency announced changes to Ketek’s label emphasizing that the drug could in rare circumstances cause serious liver injury, liver failure and death.

In addition to liver problems, Ketek can cause blurred vision and loss of consciousness. In patients with myasthenia gravis, a rare neurological disorder, it can cause death.

More than five million prescriptions for Ketek have been written in the United States since its approval in 2004. Fourteen adult patients have suffered liver failure after taking Ketek. At least four of them have died. Twenty-three others have suffered serious liver injury. Most of the reported problems involving Ketek occurred in otherwise healthy patients.

In May, Dr. Johann-Liang called for a halt to Sanofi-Aventis’s tests of Ketek in children with ear infections, arguing that cutting the duration of ear pain by one day was hardly worth risking death. Shortly after these concerns were reported in The New York Times, Sanofi-Aventis announced a “pause” in its pediatric clinical trials.

Senator Charles E. Grassley, Republican of Iowa and chairman of the Finance Committee, who has been investigating the circumstances surrounding Ketek’s approval, called the assertions about Ketek “very serious.”

“It’s no surprise to learn that the F.D.A. didn’t listen to Dr. Graham on the dangers of Ketek,” Mr. Grassley said. “The F.D.A. has made it their business to discredit Dr. Graham and others who aren’t willing to cater to the drug companies.”
Approval of Antibiotic Worried Safety Officials


The company first sought approval for Ketek in February 2000. But hints in the company’s clinical trials that it could cause liver problems led the agency to ask for more information. The company began a study in 24,000 patients, but F.D.A. investigators found repeated instances of fraud in the study.

One agency document concluded that Sanofi-Aventis knew of some of the problems in this trial but failed to alert the F.D.A. before the agency discovered the problems on its own. The document also concluded that the company’s required reports about problems with the drug “have been incomplete or reported in a dilatory fashion.”

E-mail messages among agency safety reviewers reveal a growing distrust of Sanofi-Aventis.

“I tried to argue that given Aventis’s track record in which they have proven themselves to be nontrustworthy that we have to consider the possibility that they are intentionally doing a poor job of collecting the postmarketing data to protect their drug sales,” Dr. Cooper wrote. He added that he had made his opinion known to an agency official, who disagreed. The F.D.A. approved Ketek based partly on the company’s reported experience with the drug in other countries, which is called postmarketing surveillance. In the United States, many drug problems are not reported to the agency, and such surveillance is even less reliable in other nations, according to Dr. Graham’s e-mail message and other documents.

“For F.D.A. to refer to its being reassured by postmarketing data from Latin America and Europe as a basis for declaring ‘Ketek is safe’ is in my opinion a great abuse of such surveillance data,” Dr. Graham wrote.





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