Ketek first sought approval in 2000, but approval was denied due to indications of side effects such as liver damage, blurred vision, and others found in a review of the clinical trials submitted by Aventis.
The FDA requested more information so the drug maker hired Pharmaceutical Product Development to conduct a study known as 3014. Senator Grassley became alarmed after he learned that the FDA approved the drug knowing that some of the clinical trials involved in study 3014 were fraudulent.
And the allegations of fraud involved serious misconduct and they were confirmed. For example, the trial with the largest number of subjects was conducted at a weight loss clinic in Gadsden, Alabama, and Dr Maria Kirkman-Campbell, the doctor involved, is currently sitting in a federal prison serving a 5-year sentence for submitting falsified data to Aventis.
While enrolling patients at record speed she used relatives and friends, and subjects who did not have respiratory infections, and subjects who never received the drug. A former nurse at the clinic, Michelle Snedeker, told ABC News on June 14, 2006, that she was ordered to forge documents and report data on people who had never been given Ketek.
According to the ABC report, Dr Kirkman-Campbell was paid $400 for each of the 407 subjects enrolled which comes to $162,800.
Internal Aventis documents obtained and made public by the Wall Street Journal in May 2006, show that Aventis was worried about Dr Kirkman-Campbell early on but the drug maker did not inform the FDA about the fraud and an agency inspector subsequently discovered it during her own investigation.
Ketek was finally approved in April 2004 for the adult treatment of acute bacterial infections from chronic bronchitis, acute bacterial sinusitis and community-acquired pneumonia. The drug has since been linked to extremely serious adverse reactions.
In a January 27, 2006 statement, the European Medicines Agency said that it had asked Ketek maker, Sanofi-Aventis SA, to add stronger warnings about potential liver problems to the Ketek label. The EMEA statement included the following:
"Cases of serious acute hepatitis, including liver failure, some of which were fatal, have been reported to and assessed by the EMEA in the context of the continuous monitoring of the safety of Ketek.
"The reported serious liver reactions started during or immediately after treatment with Ketek and were, in most cases, reversible after use of this product was discontinued."
In this country, an article first published online in January 2006, and then in the print edition of the March 21, 2006, Annals of Internal Medicine, described three cases of liver damage in patients taking Ketek at a Medical Center in Charlotte, North Carolina.
One patient took the drug for only five days and died from liver failure two weeks later, another patient with liver failure required a liver transplant, and the third patient developed hepatitis.
To counter the bad publicity caused by reports of liver damage, an April 2006 article in the New England Journal of Medicine claimed that Ketek was as safe as other antibiotics. But in an all-too-common scenario these days, it turns out that all six authors of the article had financial ties to Sanofi-Aventis. Five authors earned consulting fees and one was an employee.
A little over 2 years after Ketek was approved, in May 2006, the FDA recommended that a black box warning be added to the Ketek label, stating that "severe, life-threatening, and in some cases fatal" liver toxicity has been reported in patients taking Ketek
In mid-June 2006, after months of trying to set up a meeting to obtain information from the FDA inspector involved in the investigation of the fraudulent Ketek study, which Senator Grassley described as, "key to understanding what the FDA did when it became clear that the safety study required by the FDA in order to approve the drug was fraudulent and faulty," he marched over to the Department of Health and Human Services insisting that he had a right to interview the investigator and obtain the information.