FDA Announces Major Label Changes for Antibiotic

The FDA on Feb. 12 announced several changes to the package label of the antibiotic telithromycin, marketed as Ketek. Among those changes is removal of two of three previously approved indications for use of the drug based on postmarketing safety data.

In addition, the agency directed that a new boxed warning be added to the drug's label (PDF file: 21 pages 368 KB. More about PDFs.) and that other existing label warnings be strengthened. Finally, FDA officials called on the drug's manufacturer, sanofi-aventis, to create a Patient Medication Guide. (PDF file: 3 pages / 92 KB. More about PDFs.)

The agency's after-the-fact action is just one more indicator of systemic problems rampant at the FDA, say some federal lawmakers and others.

According to information on the FDA Web site, telithromycin was approved in 2004 for three indications: acute bacterial sinusitis, acute bacterial exacerbations of chronic bronchitis and mild to moderately severe community-acquired pneumonia. However, an assessment of postmarketing safety data completed last year showed that the drug's risk-benefit ratio no longer supported approval of the drug for the first two indications, although it remains indicated for treatment of community-acquired pneumonia of mild to moderate severity due to various pathogens in adult patients.

The "black box" warning -- the FDA's strongest label guidance -- to be added to telithromycin states that the drug is contraindicated in patients with myasthenia gravis. Other labeling changes the agency called for are a stronger warning section on specific drug-related adverse events, including visual disturbances and loss of consciousness. Warnings about hepatic toxicity were strengthened last summer following reports to MedWatch, the agency's adverse events reporting system.

Interestingly, the FDA's announcement came a day before the U.S. House Committee on Energy and Commerce's Subcommittee on Oversight and Investigations convened a hearing titled "The Adequacy of FDA Efforts to Assure the Safety of the Drug Supply." Testimony at that hearing focused on the FDA's procedures for reviewing new drug applications, with invited witnesses specifically addressing the agency's handling of telithromycin's approval.

Rep. John Dingell, D-Mich., chair of the Energy and Commerce Committee, welcomed the subcommittee's action in a Feb. 13 statement. In that statement, Dingell described the FDA as, by and large, "a fine organization where many good people do much good work for the American people." But, he added, the agency also has been plagued with difficulties, some of which he chalked up to a "breakdown in the policies and procedures that are critical to assure the safety of the food, drugs, blood, and medical devices that are essential to the health of the American people."

Former Senate Finance Committee Chair Chuck Grassley, R-Iowa, testified at the hearing (PDF file: 12 pages / 592 KB. More about PDFs.) about his concern that the agency continues to demonstrate an inability -- and, in his view, an unwillingness -- to adequately police itself.

In his testimony, Grassley identified four main problem areas at the FDA:

Specific to the telithromycin issue, Grassley noted that the FDA gave advisory committee members reviewing the drug's application for approval questionable study data and failed to inform them about problems with those data. It appeared, he said, that the drug's sponsor knew of the data problems but did not bring the issue to the attention of FDA reviewers. In addition, the agency had only limited U.S. clinical trial data to use in evaluating the application, instead basing its approval of the drug almost exclusively on foreign postmarketing safety data.

David Ross, M.D., Ph.D., a former FDA safety reviewer and leader of the telithromycin safety team, also testified before the House subcommittee. According to Ross' prepared testimony, (PDF file: 4 pages / 185 KB. More about PDFs.) Grassley's assessment is on the mark. In fact, Ross went even further in damning the drug, its sponsor and "senior FDA managers," whom he said were "so bent on approving Ketek that they suppressed evidence of fraud and pressured reviewers ... to change their reviews."

"FDA approved Ketek despite knowing that it could kill people from liver damage and that tens of millions of people would be exposed to it; despite FDA knowing that the drug's maker submitted fabricated data and despite knowing that Ketek is no better than other antibiotics and may not even work," said Ross.