Sanofi-Aventis Group - Controversy Over Ketek Study

Ketek

In 2006 the U.S. Senate Committee on Finance (Committee) contacted the Food and Drug Administration (FDA) regarding serious allegations of fraud and misconduct in the trials and approval of Sanofi-Aventis drug telithromycin (‘Ketek’).

Fraudulent 'Study 3014'

In April 2001, Ketek was first brought before the Anti-Effective Drugs Advisory Committee (AIDAC) due to continued concerns related to its toxicity. The AIDAC recommended that Aventis conduct a large clinical safety study. They stated that the

study should include the monitoring and analysis of all adverse events, with particular attention to hepatic, visual, cardiovascular, and vasculitic adverse events. Investigations of any mortality outcomes by investigators should be conducted to evaluate optimally possible cardiac or liver toxicities or evidence of systemic vasculitis.

Sanofi-Aventis then commissioned ‘Study 3014’ which was then submitted to the FDA ‘despite allegedly knowing and not fully disclosing that the study was fraught with data integrity problems’. It is reported that the ‘trial was marred by fraud’. One of the investigators involved in the study lost his medical license and another investigator (Anne Campbell) was indicted for falsifying study data. She pleaded guilty in October 2003 and in 2004 was sentenced to 57 months in jail.

When the AIDAC met to review Ketek for approval onto the market they were not made aware that the FDA’s Office of Criminal Investigation (OCI) was actively investigating both the integrity and conduct of the study. The Committee report that…

’Without the benefit of this relevant information, AIDAC members voted to recommend approval of Ketek. The AIDAC board members would undoubtedly have been interested to know that the highest enrolling sites in Study 3014 were being investigated for major problems and that there appeared to be significant under reporting of adverse events’.

Liver failure, injury and death

The Office of Drug Safety (ODS) at the FDA report 110 cases of liver problems (liver failure and serious liver injury) associated with the drug since it approval for use in 2004. The Senate Committee voice alarm as ‘most of these serious events occurred in otherwise healthy people’. They go on to report that the drug can also cause blurred vision and loss of consciousness. According to one review by FDA safety officials, twelve adult patients in the U.S. suffered liver failure, including four who died and a further 23 others suffered serious liver injury’. In the case of a 49-year-old woman who took only two doses of the drug, she soon became nauseous and started vomiting. She was hospitalized five days later and died. Whilst it is known that antibiotics can cause liver failure, the Committee reports that Ketek seems to do so almost four times more than is usual.

The Committee go on to comment that as the reported problems are submitted voluntarily, they tent to represent only a small fraction (between 1 to 10 percent) of the actual drug problems. They also state that the incidents highlighted through the FDA’s internal safety report are unusual because of their ‘rapid tempo and severity.’

Putting children at risk

Ketek was approved for adult use in the U.S. in 2004. In 2006, The Committee report that Ketek is being tested as a treatment for ear infections and tonsillitis in nearly 4,000 infants and children in more than a dozen countries. Sanofi-Aventis has three ongoing trials in children as young as 6 months old and a fourth trial involving adolescents 13 years of age and older.

6 weeks after the Committee first contacted the FDA to establish what action was being taken to inform the parents of infants and children enrolled in this study about the risks of Ketek, they had received no reply and again contacted the FDA. As they had not received a response, they ‘presume that parents who have enrolled their children in the trials have not been advised of anything either’. Safety officials recommend that the FDA ‘should consider forcing Sanofi-Aventis to withdraw Ketek from the market, severely restrict its uses, even in adults, or add a prominent warning to its label about potentially fatal side effects’.

'How does one justify balancing the risk of fatal liver failure against one day less of ear pain?' Dr. Rosemary Johann-Liang, an official in the Office of Drug Safety.

FDA's complicity with Sanofi- Aventis

The Committee voice concern at the ‘FDA’s complicity with the drug maker and subsequent failure to ensure the integrity of a pivotal study about the benefits and risks of this drug’

“The allegations of misconduct in this case are as bad as I’ve heard yet,” Grassley (the investigating officer) said. “It looks like the FDA caught the drug company red handed and let them get away with it. On top of that, the FDA failed to set the record straight and, in fact, continues to cite a discredited safety study as a principal reason to feel okay about using this drug.”

Continual use of fraudulent study

The FDA’s continue to use the study as evidence of Ketek safety, despite the FDA’s own determination that the study is riddled with fraudulent information. An example of this is given in relation to a response by the FDA (in the form of a Public Health Announcement in January 2006) to an article in the Annals of Internal Medicine which reported serious liver toxicity in three patients (one patient required a liver transplant and another died) following the administration of Ketek.

Additional allegations brought to the attention of the Committee assert that FDA management:

• accepted from Aventis the resubmission of a new drug application for Ketek, which included fraudulent data in support of approval of Ketek;
• instructed FDA scientists preparing to appear before an advisory committee that they should present fraudulent data because discussing issues regarding data integrity and the conduct of the safety study would not be “productive”;
• presented fraudulent study data to an advisory committee tasked with recommending Ketek’s approval or disapproval;
• approved a pediatric clinical trial of Ketek, involving infants as young as six-months old, despite concerns related to known toxicities, including hepatic, visual, cardiovascular, and vasculitic adverse events; and
• continued to knowingly cite fraudulent study data in publicly released safety information on Ketek.

According to the Committee, more than five million prescriptions for Ketek were written in the United States between 2004 and 2006. Ketek was approved for use in Europe in 2001.