Liver Failures Raise New Worries About Prescription Safety System

Four deaths from liver failure linked to a new antibiotic have renewed concerns about the nation’s drug safety program, leading some experts to question the effectiveness of internal fixes made at the Food and Drug Administration since the withdrawal of the discredited painkiller Vioxx.

“This is another example that we should see as a signal that the current system needs reform,” said Arthur A. Levin, director of the New York-based advocacy group Center for Medical Consumers and a member of the FDA’s drug safety advisory committee.

“It’s not about the FDA not doing its job -- it’s that the process we have in place, and the authority the FDA has at present, simply aren’t up to the task,” he said.

Marketed as Ketek, the antibiotic linked to the liver deaths was approved in 2004 as a treatment for serious respiratory infections that have become increasingly resistant to older drugs. At the time, government regulators recognized the potential for liver damage but concluded that the risk was about the same as for other antibacterial drugs.

After Vioxx was linked to higher rates of heart attacks and strokes and was removed from sale in 2004, the FDA set up an in-house drug safety board and pledged to improve communication about emerging problems.

Critics say the agency needs a stronger, more independent safety office; more funding; better databases; and new legal powers to compel manufacturers to track adverse drug reactions.

Doctors in North Carolina were the first to raise concerns about Ketek. They submitted an article to a medical journal, Annals of Internal Medicine, reporting three cases of acute liver failure in previously healthy patients who had taken the drug.

In January, the journal put an “early release” version of their findings on its website and followed up with a fuller article in the print edition two months later.

Drug reactions account for more than half of all cases of liver failure, a medical catastrophe that is otherwise extremely rare -- and in these cases, the doctors discovered, Ketek was the common denominator.

A May 16 internal memo by FDA safety investigators suggested that the problems with Ketek could be more serious than those identified in the journal article.

In the memo, a copy of which was reviewed by The Times, investigators described 12 cases of liver failure among Ketek patients. Four patients died, and one required a liver transplant. One patient had taken a single dose of the drug before becoming ill.

“The rapid tempo and severity of injuries ... suggest an acute hypersensitivity-like process,” the memo said. Patients suffered a “profound degree” of liver injury, it said.

The FDA investigators also compared data on three similar drugs and found that liver failure in patients taking Ketek -- although rare -- occurred at much higher rates than in patients taking the other medications.

The investigators recommended that the agency issue its strongest possible warning for Ketek -- an action that would probably lead to severely restricted use of the drug, which is manufactured by SanofiAventis.

More than 5 million prescriptions for Ketek have been written since it received FDA approval.

The company defends the drug and says it is cooperating fully with the FDA to address any new advice to doctors.

“Sanofi-Aventis continues to believe that the benefits of Ketek outweigh any known risks of this drug when used for FDAapproved indications,” spokeswoman Melissa Feltmann said.

An FDA spokeswoman said the agency had reached no decision. “There is an ongoing investigation looking into the safety of this drug, and we have made clear that, if the data warrant changes ... we will make them,” Susan Bro said.

The FDA issued a public health advisory when the medical journal’s article was published, urging doctors to closely monitor patients for signs of liver problems.

Dr. Mark Goldberger, an FDA expert on antibiotic drugs, said the apparently higher rate of liver problems with Ketek may have an innocent explanation: Doctors might be more prone to report problems because of the publicity the drug has received. Ketek is also used in Europe, where the data do not appear to show similar problems, he said.

The case is already prompting calls for more-demanding standards in the approval of new antibiotics. The standard now is that drug makers must demonstrate that a new antibiotic is not inferior to an older one.

But University of Washington biostatistician Thomas Fleming said that could put the FDA in an “untenable position” if safety problems were to arise, because the approval standard was so low that a new drug’s benefits were not always clear.

“What is an acceptable level of risk depends on what the benefit is,” he said. “When you have apparent safety problems, then there is greater concern because the level of efficacy hasn’t always been reliably established.”

Further complicating the controversy is a separate FDA investigation into alleged scientific fraud in a large safety study of Ketek. Criminal investigators from the agency discovered “serious data integrity problems,” including a fictitious patient, tests performed too late to be of use, and “suspiciously similar” results for multiple patients, according to a 2004 FDA memo reviewed by The Times.

The study relied on doctors from around the country to report results on 25,000 patients. But one doctor has pleaded guilty to mail fraud in connection with the case, and another lost his medical license after being arrested on suspicion of using cocaine. The Wall Street Journal reported on the criminal investigation in May.

Sen. Charles E. Grassley (R-Iowa), a leading congressional critic of the FDA, said he was considering holding hearings on Ketek. Although the antibiotic has been used by many fewer patients than Vioxx was, he said, there are parallels.

“The problems are the same or even worse,” he said. “It looks like the FDA is compromising public safety by going out of its way to accommodate the drug companies when problems and questions crop up.”

Such a comparison would be inaccurate, said Dr. John Jenkins, director of the FDA’s Office of New Drugs.

“Every drug that comes through the system is different,” he said, adding that the sequence of events for Ketek and Vioxx was “very different.”