[The following is excerpted from an article that just appeared in the
New England Journal of Medicine:]

The FDA and the Case of Ketek
David B. Ross, M.D., Ph.D.

....Three years ago, the Food and Drug Administration (FDA) approved the
drug Ketek (telithromycin), lauding it as the first of a new class of
antimicrobial agents that circumvent antibiotic resistance. Since then,
Ketek has been linked to dozens of cases of severe liver injury, been
the subject of a series of increasingly urgent safety warnings, and
sparked two Congressional investigations of the FDA's acceptance of
fraudulent safety data and inappropriate trial methods when it reviewed
the drug for approval....

In the second review, the FDA examined the results of such a study.
Known as study 3014, it was an unblinded, randomized, controlled trial
comparing the incidence rates of hepatic, cardiac, and visual adverse
events in patients receiving Ketek and those receiving
amoxicillin–clavulanate. Sanofi-Aventis recruited more than 1800
physicians to conduct the study, many of them new to clinical
investigation, and paid them as much as $400 per patient enrolled,
primarily to cover the costs of recruiting and gathering research data;
more than 24,000 subjects were enrolled. The study was completed in 5
months and purported to show that Ketek was as safe as the other treatment.

A routine FDA inspection of the practices of the physician who enrolled
the most patients — more than 400 — uncovered fraud, including complete
fabrication of patient enrollment. The inspector notified FDA criminal
investigators, and the physician is currently serving a 57-month
sentence in federal prison for her actions. Inspections of nine other
sites enrolling high numbers of patients revealed serious violations of
trial conduct, raising substantial concerns about the overall integrity
of the study. In the end, 4 of the 10 inspected sites were referred for
criminal investigation.

Despite these discoveries, FDA managers presented study 3014 to the
advisory committee in January 2003 without mentioning the issues of data
integrity.1 The managers have stated that they were legally barred from
disclosing the problems to the committee because there was an open
criminal investigation, but they have not explained why the data were
presented at all, in view of the evidence of the study's lack of
integrity. Unaware of the integrity problems, the committee voted 11 to
1 to recommend approval of Ketek.

The undisclosed problems with study 3014 led to a third review, during
which FDA managers proposed using foreign postmarketing reports on Ketek
as evidence of the product's safety, despite the unreliability of such
data.2 Although drug sponsors are required to submit such reports as
part of an application, it is extremely unusual to use these data to
address critical preapproval safety issues in place of a controlled
study. The postmarketing data submitted by Sanofi-Aventis were reviewed
by the FDA without any verification of their accuracy or completeness,
even though 3 months before the third review, FDA criminal investigators
recommended examining whether Sanofi-Aventis had been involved in
systematic fraud in connection with Ketek. The FDA never conducted the
recommended investigation or reviewed study 3014–related records showing
that Sanofi-Aventis was aware of potential fraud in the study when it
submitted the results to the FDA. The failure to look into or respond to
concerns about integrity represented a marked deviation from FDA
policies....

Dr. Ross is a clinical assistant professor at George Washington
University School of Medicine and Health Sciences, Washington, D.C.

http://content.nejm.org/cgi/content/full/356/16/1601