In a warning letter sent by the FDA to Sanofi's CEO Gregory Irace and made publicly available on the agency's website, the drug maker was accused of knowingly submitting clinical study data that was obtained by investigators who had committed "multiple and significant violations of FDA regulations… that affected the integrity of data submitted".
The data in question was obtained as part of postmarketing study 3014, carried out between 2001 and 2002 after the FDA said that it needed more safety information on Ketek following fears that it could cause liver problems.
The studies were carried out by Pharmaceutical Products Development (PPD) on behalf of Aventis, prior to its merger with Sanofi-Synthelabo.
In July 2002, Aventis submitted the results of study 3014 to the FDA.
Subsequent data validation inspections by the agency of several clinical investigators participating in the study raised red flags and the FDA requested in January 2003 that Aventis provide information on its sponsor monitoring and auditing of clinical investigator sites for the trial.
Aventis subsequently provided this information to the FDA and following a lengthy investigation, the agency has now concluded that: "Aventis did not adhere to the applicable statutory requirements and FDA regulations governing the conduct of clinical investigations".
"Our investigation found that despite several clinical monitoring visits from Aventis' designated monitors (PPD)… and Aventis' own audits documenting serious protocol violations and regulatory noncompliance by multiple clinical investigators, these violations persisted", wrote the FDA.
"We were unable to find evidence that Aventis promptly secured compliance or terminated participation of these clinical investigators and notified the FDA".
In particular, the agency referred to the instance of Dr Anne Kirkman-Campbell, who in 2004 was convicted of fraud over the enrollment of patients and faking consent forms during the Ketek study and was sentenced to 57 months in prison, fined $557,251 (€423,636), and ordered to reimburse Aventis $925,774.
The agency said that a review of PPD's monitoring records, Aventis' quality assurance (QA) audit records, and email communications between PPD and Aventis disclosed that "Aventis knew of pervasive problems" at the clinical investigator site of Dr Kirkman-Campbell".
"Our review found that PPD identified significant problems at Dr Kirkman-Campbell's site and subsequently informed Aventis of its findings and concerns.
We note that Aventis failed to promptly secure compliance from Dr Kirkman-Campbell."
Salah Mayhaoui, head of product communications for Sanofi-Aventis told DrugResearcher.com that: "Study 3014 was the first large "real world" study of an antibiotic and Aventis conducted this study in good faith."
"However, non-conformance in the form of deviations [from protocol] and other issues occurred, including clinical investigator fraud."
Mayhaoui said that the firm would provide a "detailed response" to the FDA's letter in the coming days.
As part of this response we will "highlight some of the steps Aventis took to prevent the problems that occurred in 3014."
He said that at this point he did not know the next course of action that the FDA may take in regard to this matter.
"I think they will review our arguments and then it is up to them to decide what happens next."
The FDA's ongoing investigation into the matter was launched as part of its Bioresearch Monitoring Program, established to evaluate the conduct of research and to ensure that the rights, safety, and welfare of the human subjects of those studies have been protected, in addition to ensuring that data submitted in support of new drug applications (NDAs) are scientifically valid and accurate.
Concern over the issue also triggered a review by Congress and in February a former employee of PPD claimed that both Aventis and PPD were both aware of fraudulent data in trial 3014, during testimony before a US Congressional Subcommittee.
Ann Marie Cisneros was speaking as a witness at the hearing on the adequacy of the FDA to assure the safety of the drug supply, before the House Committee on Energy and Commerce members.
In her testimony, she said that both her former employer PPD and Aventis knew that there were discrepancies in the clinical trial data included in study 3014 and there were also problems at the site but said neither of the companies took any action.
Cisneros was a clinical research associate (CRA) for PPD and tasked to assist with the monitoring of Dr Kirkman-Campbell's site.
"From what I observed, Dr Kirkman-Campbell indeed had engaged in fraud," she said during the hearing.
"But what the court that sentenced her did not know is that Aventis was not a victim of this fraud.
On the contrary… I knew it, PPD knew it, and Aventis knew it," said Cisneros.
She added that even before conducting monitoring at the Kirkman-Campbell site, a number of "red flags" were apparent.
For example, over 400 patients had been enrolled, while Aventis was paying Dr Kirkman-Campbell $400 per patient.
By comparison, another site in Gadsden had enrolled just 12 patients.
In addition, no patients had withdrawn from the study and none of them were lost to follow up, "an unusual occurrence given the number of subjects", she said.
Sanofi-Aventis said at the time that its predecessor Aventis was not aware of the fraud until after it had submitted study 3014 to the FDA.
"It was only after FDA criminal investigators conducted an evaluation, having tools at their disposal that may not be available to study sponsors, that the fraud was discovered," said the company in a statement.
Since its approval in 2004, more than five million prescriptions for Ketek have been issued in the US.
Since then, 14 patients have suffered liver failure after taking Ketek and at least four of them have died.
23 others have suffered serious liver injury.
In addition to liver problems, Ketek has been known to cause blurred vision and loss of consciousness.
Most of the reported problems involving Ketek occurred in otherwise healthy patients.
The drug is still available but now carries a warning on the label about the potential for liver risk and the FDA has restricted its indication to the treatment of pneumonia and not less serious illnesses.
Both Sanofi-Aventis and the FDA have said that none of the data from the questionable 3014 study was relied upon when it originally approved the drug in 2004.