you have glanced at this blog over the past week, you’ve noticed that I
wrote three posts about the opportunity — and the pressing need — for
reform at the FDA. Mike the Mad Biologist had an interesting
take on this, from an entirely different perspective: E.
coli Conservatives, E. coli Liberals, and the FDA.
His post is more amusing than mine were. Perhaps you were
wondering why I would put up three boring posts in a row. I
don’t usually do that. Or at least I hope I don’t.
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. As a former FDA physician who was involved in
the Ketek review, I believe there are lessons to be learned from an
examination of the events surrounding the approval of this product…
Yes, you read that correctly. There was overt, criminal fraud
involved. The FDA knew the data were suspect, and they went
ahead and approved Ketek
anyway. So if you were wondering if there really is a need
for reform, this post will answer that.
…It was reviewed by
the FDA three times (see timeline). During the first round, reviewers
identified substantial safety concerns, including multiple potential
drug interactions, unique effects on visual acuity, and an apparent
association with hepatocellular hepatitis, with pathological
characteristics resembling those caused by drugs that have been
withdrawn from the market because of hepatotoxicity. A federal advisory
committee asked Sanofi-Aventis to obtain additional safety data by
conducting a study involving patients who were likely to receive Ketek
if the drug were approved…
This sort of thing is not terribly unusual. Often (I would
like to say usually) the additional review is done properly, the
questions are settled, and the drug is either approved, or not.
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
Despite these discoveries, FDA managers presented study 3014 to the
advisory committee in January 2003 without mentioning the issues of
There is more, of course. The studies were not scientifically
sound, even aside from the fact that they were fraudulent. I
won’t bore you with the details. Let this suffice:
The review of Ketek was
thus marked by pronounced departures from accepted review practices.
You might well ask, “What the hell is going on over there?”