FDA warns Sanofi-Aventis over Ketek trial

Nov. 6, 2007 - PRLog -- The US Food and Drug Administration has sent a warning letter to Sanofi-Aventis, detailing failings in Aventis’s oversight of investigators involved in a clinical trial of the antibiotic Ketek (telithromycin) in 2001-02.

The FDA had earlier identified good clinical practice violations by several investigators that affected data integrity.  As a result, the FDA did not rely on this study, which involved 24,000 patients at 1,800 US study sites, in approving Ketek in 2004, Sanofi-Aventis points out.  However, in February 2007, the FDA removed two of the three previously approved indications - acute bacterial sinusitis and acute bacterial exacerbations of chronic bronchitis – leaving treatment of community-acquired pneumonia as the only approved use.

One of the trial investigators, Dr Maria Anne Campbell (also known as Anne Kirkman Campbell), was imprisoned after she was found guilty of fraud for falsifying case report forms and documentation to support the existence of a fictitious subject.  The FDA letter states that Aventis’s CRO, PPD Development, informed the company of significant concerns about Dr Kirkman Campbell’s conduct, but Aventis failed to promptly secure her compliance and did not adequately investigate fraud allegations.  Aventis’s method for securing compliance –generating 125 ‘memos to file’ noting protocol and informed consent deviations - was not adequate, the FDA points out.

Another investigator was subsequently disqualified from receiving investigational drugs, and is no longer permitted to conduct studies for FDA submission.  He did not obtain proper informed consents from trial subjects, instead backdating them or getting them signed after the study was completed.  In total, of eight trial sites inspected by the FDA, data from four were considered unreliable due to numerous regulatory violations affecting data integrity.

The letter charges Aventis with failure to select qualified investigators.  One of the highest enrolling investigators was at the time of his selection on probation by the California Medical Board for gross negligence and failure to maintain adequate and accurate records; his medical licence was later suspended.  The FDA also claims that Aventis did not monitor the study properly.  Under the original protocol, only 5-50 subjects were to be enrolled per site, but Aventis subsequently allowed this to be increased to a maximum of 500, without amending its monitoring adequately to adjust for the increase.

The FDA says that Aventis did not ensure compliance with the study plan and protocols, citing as one example the increase in maximum subjects per site without a protocol amendment.  Several sites enrolled more than 50 subjects, some without obtaining prior institutional review board approval.  Another protocol divergence was the enrolment by Dr Kirkman Campbell of several subjects who should have been excluded due to hypersensitivity to certain antibiotics.  Aventis did not give prior approval for these enrolments and created ‘memos to file’ only after completion of the study.

Moreover, the FDA points out that it could not ascertain whether trial subjects had the conditions required by the protocol.  During PPD monitoring visits to Dr Kirkman Campbell’s site, the disease diagnosed and reported on the case report forms could not be verified with information contained in source documentation.  The minutes of a teleconference at which PPD discussed this finding with Aventis indicated that “Aventis required minimal verification of diagnosis”, the FDA says.  The Aventis study manager said that merely asking a subject if they had bronchitis was sufficient.  Under this interpretation, the agency points out, no source documentation would be required, thus contradicting the protocol requirements for verification of source data.

Sanofi-Aventis has 15 days to respond to the warning letter, which was issued on October 23rd.  The company said it had co-operated fully with the FDA investigation and it intended “to provide a detailed response … addressing FDA's findings and communicating the steps Sanofi-Aventis has taken to prevent the problems that arose” in the study.  It was the first large study in the usual care setting to be performed pre-approval for an anti-infective drug, and Aventis conducted it in good faith, the company added. Submitted by www.jobs4dd.com - latest news and jobs in the Drug Development sector.

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