In another setback for the Food and Drug Administration's drug safety program, government medical advisors recommended Friday that sharp restrictions be placed on the use of a once-promising antibiotic that helps patients with respiratory infections but has also been linked to cases of sudden liver failure.
Used to treat a variety of respiratory infections, Ketek has been taken by more than 6 million patients in the United States since its approval in 2004 and had sales of $148 million last year for manufacturer Sanofi-Aventis. Though not considered a blockbuster drug, it has been promoted as particularly effective for battling microbes that have become resistant to older antibiotics.
But Friday, members of two FDA advisory panels overwhelmingly recommended withdrawing approval for the drug's two most common uses: treatment of sinusitis and bronchitis.
At the same time, a majority of the advisors felt strongly that Ketek should remain an option for doctors treating patients with pneumonia. Unlike sinusitis and bronchitis, which are not considered life-threatening and often clear up on their own, pneumonia can be fatal and is rarely overcome without treatment.
Even so, the advisory panels urged the FDA to issue its strongest possible caution to doctors and patients, a so-called black-box warning that would prominently identify Ketek's risks.
"This is a drug we need, but not something I would reach for," said Dr. Margo Smith of Washington Hospital Center, a member of the FDA's anti-infective drugs advisory panel. "I'd use it when I had no other alternative."
The concerns about Ketek follow other highly publicized safety problems involving the FDA, including the withdrawal of the painkiller Vioxx, warnings about the suicide risks of antidepressants and problems with an FDA-approved defibrillator designed to be implanted in the body.
A special Institute of Medicine panel recently called for an overhaul of the FDA's drug safety system, and Congress is expected to take up legislation next year.
John Jenkins, head of the agency's Office of New Drugs, said the committees' advice would be taken "very seriously" and regulatory action would be taken quickly. The FDA generally follows the recommendations of its outside advisors.
The anti-infective drugs panel and the FDA's drug safety committee heard two days of sometimes conflicting presentations that linked the drug to rare but serious complications including sudden liver failure, temporary blurring of vision, loss of consciousness and potentially deadly worsening of symptoms for patients with myasthenia gravis, an autoimmune disease that can paralyze muscles involved in breathing.
Another problem in the Ketek case is that a clinical trial designed to identify the risk of liver problems was tainted by scientific fraud. A congressional investigation found that even though the FDA knew of the problem, it presented data from the study to an earlier advisory committee, which unwittingly recommended the drug's approval. The agency says it did not rely on the tarnished study in ultimately approving Ketek.
Getting new antibiotics to market has long been a top public health priority for the FDA, because many common pathogens have become resistant to widely prescribed medications. As a result, approval standards are lower for antibiotics than for other types of medications.
Lately, however, the agency has begun to consider higher standards that would require a clearer demonstration of benefits.
Friday's committee recommendations were "the right verdict," said FDA safety reviewer David J. Graham, the agency's most prominent in-house critic.
"What this says is that Ketek poses unacceptable risks for 90% of the conditions for which it has been used," Graham said. "It raises in my mind questions about the whole process that led to its approval in the first place."
Sanofi-Aventis defended Ketek, saying its own studies showed the drug's risks were not appreciably greater than those for other antibiotics.
"Sanofi-Aventis respects the advisory committee process," Doug Greene, the company's chief medical officer, said in a statement. "Sanofi-Aventis will be in discussions with the FDA regarding today's recommendations. We treat patient safety as a matter of the highest priority."
The company also said it had nothing to do with the scientific misconduct in the earlier safety study but instead had been the victim of an unscrupulous doctor who ultimately pleaded guilty to mail fraud.
In a striking turn, a former FDA scientist who had been one of the lead medical reviewers for Ketek told the advisors that agency managers deliberately ignored serious implications of the compromised clinical study.
"Management was so bent on approval that I was pressured to 'soften' my review," said Dr. David Ross, who recently left the agency and still works in public health.
"The study that was supposed to answer critical safety questions was fatally corrupted; the post-marketing reports submitted in its place are no substitute for rigorous safety evaluation," he added. "It is up to this committee to demand that the [company] and the FDA provide real evidence of safety."
Ross also accused newly confirmed FDA Commissioner Andrew C. von Eschenbach of trying to stifle dissent about Ketek. He quoted Von Eschenbach as telling professional staffers at a meeting this summer that those who took their concerns outside the agency, "the first time they'll be spoken to, the second time they'll be benched, and the third time they'll be traded."
In a statement, the FDA responded that Von Eschenbach had not sought to silence internal debate over the drug. An official said Von Eschenbach was trying to indicate his displeasure over "selective leaking" of information.