In the April 19, 2007 edition of The New England Journal of Medicine, David B. Ross, M.D., Ph.D.,, a clinical assistant professor at George Washington University School of Medicine and Health Sciences took the FDA to task for its approval of Ketek, a ketolide antibiotic manufactured by Sanofi-Adventis, for use in respiratory tract infections. The drug underwent three rounds of review by the FDA and followed an unusual structure of review and approval that may suggest outside interference in the process.
According to Dr. Ross, reviewers initially identified concerns over multiple potential drug interactions, visual acuity, and an apparent relationship to toxic hepatocelluar hepatitis. In the second round, the FDA reviewed the results of an unblended, randomized study comparing adverse hepatic, cardiac and visual events of the drug with amoxicillin. Of concern to Dr. Ross was the fact that the trial was enormously flawed. The company apparently paid physicians $400.00 per patient recruited to the study. One physician received a 57-month criminal sentence in federal prison for fabricating patient enrollment. The investigation of 10 other high enrollment sites resulted in four of them being referred to federal authorities for criminal investigation. Despite the concerns about the integrity of the study it was referred to a FDA advisory committee without advisement of the study flaws and resulted in approval by an 11 to 1 vote.
The FDA managers apparently commenced a third review because of the problems related to the faulty integrity of the earlier study, refused to follow FDA investigators recommendations that the FDA commence an investigation of fraud related to the first study. The third review consisted of a review of foreign post marketing reports, which are not reliably used to establish safety.
Despite the concerns over Ketek related to safety and integrity, the FDA approved the use of the drug with no evidence of efficacy other than noninferiority trials, which only seem to establish some minimum level of efficacy above a pure placebo. Public concerns arouse in late 2005 and early 2006 over deaths apparently attributable to the drug. The FDA continued to insist on the safety of the drug, and did not re-label it to indicate possible sever hepatoxicity until 16 months after the first liver failure cases surfaced. According to Dr. Ross,
The withdrawal of approval for two indications, acute bacterial sinusitis and acute exacerbation of chronic bronchitis, for which Ketek’s efficacy had never been demonstrated, did not occur until February 12, 2007 – only a day before the Congressional hearing on Ketek.
Dr. David Graham, another FDA staffer, critical of the agency action was quoted in The New York Times on July 18, 2006 in article entitled "Approval of Antibiotic Worried Safety Officials". as saying,
It’s as if every principle governing the review and approval of new drugs was abandoned or suspended where telithromycin [Ketek] is concerned.
Dr. Ross hopes the Ketek story will result in some important reforms at the FDA. One gets a queasy feeling getting this close to the kitchen. Meanwhile back at the ranch, the mass tort lawyers are lining up with advertisements soliciting liver damaged Ketek patients.
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