By Bruce W. McNulty, MD
This article is part of our MedRIB project and was published July 31, 2008.

Let’s go back about a year to an article in the April 19, 2007 edition of the New England Journal of Medicine, which describes the FDA approval of the antibiotic Ketek (telithromycin) and the subsequent problems associated with it. The full text article can be found at :, and reply from the FDA can be found at :

The article is entitled The FDA and the Case of Ketek, by David Ross, M.D. Ph.D., who is a former FDA physician and was involved in the review of this medication. The paper presents a time line of the FDA’s review of this medication for eventual approval for use in bacterial sinusitis, exacerbation of chronic bronchitis, and community acquired pneumonia. According to Ross, in the first round of reviews, safety concerns were raised regarding drug interactions, effects on vision, and issues with liver toxicity. The FDA requested that the manufacturer, Sanofi-Aventis, undertake a study to investigate the safety of the medication in typical patients. That investigation, known as, “study 3014” was undertaken to look at adverse effects of this medication and compare them to a well known popular antibiotic, Augmentin. More than 1800 physicians, many of them new to clinical research, were recruited and paid up to $400 for every subject they enrolled in the study. In 5 months, 24,000 subjects were enrolled. According to Ross, soon after the study began a routine investigation of the physician who enrolled the most patients (over 400), revealed fraud and patient fabrication. Ultimately, a large number of research sites were referred for investigation, but the study was still allowed to be used in the FDA approval process. If you follow the time line in the paper, it can clearly be seen that there were serious problems with the study. Yet, despite all the issues raised, the drug was approved. In 2006, cases of Ketek-associated liver damage and failure began to surface, and the medication now has a ‘black box’ warning placed by the FDA. This has led to congressional investigations of the process of drug approval by the FDA. Type in Ketek in any search engine and you will find links to more law firms than health sites. This also got a fair amount of notice in the lay press, in articles such at this:

This case also shone a light on the practice of using ‘non-inferiority’ trials. To understand this, we should first note that there are conditions that often self-resolve with no treatment at all such as sinusitis, ear infections, and ‘bronchitis’. With these conditions, the appropriate first step in testing should be to compare the trial drug against a placebo. That way, only if the drug shows some significant benefit against a placebo, should it be considered for approval. With a “non-inferiority” trial, the new medication is tested against another drug on the market and if it is shown to be ‘non inferior’ to the older medication, it may be given approval – as was done for Ketec. Thus, this medication, which upon its wide scale release was found to have a variety of toxicity issues, was approved for rather benign conditions such as sinusitis and bronchitis. These conditions are often self limiting, and had this drug been tested against a placebo, it may have been shown not to be needed at all! The question must also be asked that if this new medication is really not better than an older (and invariable cheaper and better tested medicine on the market for years) medicine, why approve it at all?

So what we have illustrated by this case is a medication approved by the FDA for largely benign self limiting conditions, which appears to not have been properly tested, putting patients at risk. Furthermore, the credibility of the FDA in protecting consumer well-being in these matters was damaged.


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