Two Strikes For Ketek: Cmtes. Want Bronchitis, Sinusitis Indications Rescinded

FDA's Anti-Infective Drug and Drug Safety and Risk Management Advisory Committees are recommending stripping Sanofi-Aventis' Ketek of its bronchitis and sinusitis indications.

The committees convened Dec. 14-15 to determine whether data support the continued marketing of Ketek (telithromycin) and what, if any, risk management efforts are needed for the antibiotic.

Based on updated information regarding liver toxicity, myasthenia gravis and visual disorders, as well as new standards for establishing efficacy in antibiotics, the committees concluded that Ketek should retain approval only for treatment of community-acquired pneumonia.

The "benefits outweigh the risks" when treating CAP, numerous committee members said in reaching a 16-3 decision to retain that indication for the medication.

With two 17-2 votes, the panel asserted that risks outweigh the benefits of Ketek use for treatment of acute exacerbation of chronic bronchitis and for acute bacterial sinusitis.

On the plus side for Sanofi with regard to AECB and ABS, most panel members agreed that superiority studies favoring Ketek in treating the two diseases would tip risk benefit considerations in the other direction.

A pivotal factor in the committees' risk/benefit deliberations was the spontaneously resolving nature of bronchitis and sinusitis. Members concluded that there was not sufficient proof of benefit in light of the risks given the non-inferiority design of Ketek's pivotal trial.

A non-inferiority study was used to support the drug's approval and panel members noted that there was not sufficient proof of benefit in light of the risks.

Panel members also insisted that there should be increased education of physicians and patients with regard to the side effects, particularly exacerbation of myasthenia gravis.

Responding to the need for more educational efforts, Sanofi-Aventis said it plans to develop and issue a Medication Guide.

[Editor's note: Further coverage of the Ketek advisory committee meeting will appear in "The Pink Sheet" Jan. 1, 2007.]

The first-in-class ketolide antibiotic has a long regulatory history, including two advisory committee reviews prior to its approval. A 2003 panel voted that telithromycin is safe and efficacious for all three indications (¹ (Also see "Aventis Ketek Recommended For Pneumonia, Sinusitis, And Bronchitis" - Pink Sheet, 13 Jan, 2003.), p. 13).

Following the committees' recommendation, data integrity issues emerged regarding a large safety study addressing Ketek's hepatotoxicity, which prompted an "approvable" letter from FDA. The NDA was approved in 2004 in part on the basis of international postmarketing surveillance data.

A recent letter to the editor in the Nov. 23 issue of the New England Journal of Medicine by FDA whistleblower David Graham calls into question the reliability of that data. The committee largely dismissed Graham's assertion that incidence of hepatotoxicity with telithromycin is significantly underestimated.

Most recently, a Public Health Advisory alerting physicians to reports of serious liver toxicity was issued in January, and the Ketek label was revised in June to elevate information about the risk of acute hepatic failure and severe liver injury from the Precautions to the Warnings section (² (Also see "Ketek Labeling Gets Updated Warning, But Not Format, After Liver Toxicity" - Pink Sheet, 3 Jul, 2006.), p. 7). At that time, FDA concluded that the risk of liver toxicity with telithromycin is not necessarily greater than macrolide antibiotics.

Concerns about telithromycin's efficacy have also emerged since its approval with FDA's recent establishment of superiority trials as the standard of evidence necessary to demonstrate efficacy for sinusitis (³ (Also see "Past FDA Action Is Not Necessarily Predictive Of Future Behavior – Temple" - Pink Sheet, 18 Sep, 2006.), p. 12).

The approval and marketing of Ketek has attained a high profile due to criticism from Sen. Charles Grassley (R-Iowa), who threatened to hold congressional hearings on the issue.

"Recognizing that this is a product that garnered a lot of public attention, we felt it was important to have a public discussion...before we decide whether any further regulatory actions are needed beyond what was put in place last June," Office of New Drugs Director John Jenkins said during a Dec. 14 press conference.

- Cathy Dombrowski