Evelyn Pringle September 26, 2006
In recent months Senator Charles Grassley (R-IA), is like a dog with a bone when it comes to investigating why FDA officials approved the antibiotic, Ketek, despite its knowledge that the main pre-approval study on the drug was riddled with fraud.
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.
After a brief conversation with senior officials from the HHS and FDA, and no luck in setting up the meeting, the Senator left the agency furious. "I'm tired of the runaround," he said outside the HHS headquarter.
He said he told the officials, "I know it's probably not your intent to protect companies, to cover for companies." But every time "you stand in the way of information getting out that ought to be public, that's the impression you give the American people."
He is “committed to getting to the bottom of the matter,” he told the Wall Street Journal on June 13, 2006.
About two week after his visit to the FDA, on June 30, 2006, the agency issued a warning that Ketek could cause acute liver failure after only a few doses and advised physicians to monitor patients on Ketek closely.
In the two years that Ketek was on the market through April 2006, the FDA said it received reports of 12 cases of acute liver failure, and 23 cases of serious liver injury. Of those cases, four people died and one patient required a liver transplant.
The debacle involving the FDA approval of Ketek has now become a bi-partisan battle against senior FDA officials by members of Congress from both sides of the isle.
On September 5, 2006, US Representatives, Edward Markey (D-MA), John Dingell (D-MI), Henry Waxman (D-CA), and Bart Stupak (D-MI), of the House Energy and Commerce Committee, and Chairman of the Senate Finance Committee, Senator Grassley, sent a letter asking the Government Accountability Office (GAO) to investigate the FDA's reliance on non-inferiority studies, which experts say are not appropriate for approving drugs like Ketek that have serious, even lethal side effects.
According to Rep Markey, who organized the group that sent the letter, “The Bush Administration’s FDA has been working hand in glove with the drug industry for six years, leaving Americans vulnerable to dangerous drugs and insufficient information about the side effects of those drugs."
"This practice," he stated, "has lead to growing bipartisan concerns about the direction the FDA has been taking."
The most common way of establishing the effectiveness of a drug is to compare the outcome of a patient taking the test drug to the outcome of a patient taking a placebo. However, if the likely outcome of taking a placebo might be death or other serious health conditions, then the effectiveness of the drug must be established by some other method.
One method used involves the use of a “non-inferiority” study, in which one group of test subjects is given a drug of known effectiveness and a second group is given the drug for which effectiveness needs to be established.
The new drug’s effectiveness is considered established if it performs in a similar manner, within some statistical range, to the known medication. Over the years, many concerns have been raised about the use of non-inferiority trials. So the letter from members of Congress asks the GAO to evaluate the FDA’s reliance on these studies.
"A comprehensive GAO study of the FDA’s use of these controversial studies and questionable approval processes," Rep Markey said in a statement, "is essential if we are to ensure that the FDA is not abandoning it’s commitment to safeguarding public health."
Senator Grassley said, "These studies which were used to approve the antibiotic Ketek – are dubious because they don’t provide any evidence that a particular drug is any better than nothing at all."
According to Rep Waxman, "An antibiotic that is no better than a placebo can’t fight off an infection."
"Worse," he added, "it can subject you to serious, even life-threatening side effects without any compensating benefit."
"Americans deserve to have confidence that an FDA-approved drug will be both safe and effective," Rep Waxman noted.
The dispute over the approval of Ketek follows in a line of similar disputes between the FDA and Senator Grassley over the agency's interest in protecting industry profits instead of alerting the public to the risks of adverse events associated with dangerous drugs, that began with SSRI antidepressants and Vioxx.
The benefits of the pharmaceutical industry's influence on senior Bush appointed officials within the FDA cannot be understated. These officials have the power to: (1) control billions of dollars in drug profits; (2) effect drug company stock value; (3) influence litigation; and (4) drive a company out of business.
For the past three years, Senator Grassley has pressured the agency to sever its alliance with drug companies and to act with more independence and transparency. He has also sponsored legislation to mandate a clinical trials registry and a stronger post-market surveillance process within the FDA.
In a September 20, 2006, letter to FDA acting commissioner, Dr von Eschenbach, Senator Grassley called on the FDA to address "persistent" problems at the agency, especially the “too-cozy” relationship with the industry and the inclination of agency leaders to suppress scientific dissent and drug-safety recommendations.
"I am writing this letter," he advised, "to encourage you to establish and implement a resuscitation plan to restore the FDA’s credibility in the mind of its own employees and the American public."
"I have frequently criticized the FDA for its relationship with the industry, which I believe is far too cozy," he wrote. "The FDA needs to distance itself from the industry and return to its role as regulator, not a facilitator," Senator Grassley told the acting Commissioner.
He said the most powerful message coming from increasing numbers of current and former FDA personnel is that the FDA has “sold out” to the industries it is charged to regulate.
"FDA’s handling of the antibiotic Ketek," Senator Grassley said, "is another example where the FDA appears to have accommodated a drug company despite the fact that the company submitted fraudulent data from a safety study to the FDA and repeatedly provided incomplete safety information."
"What baffles me even more," he continued, "is the fact that the FDA continued to cite Study 3014 in publicly released safety information for Ketek even after its Division of Scientific Investigations concluded that Study 3014 involved “multiple instances of fraud” and that “the integrity of data from all sites involved in [the] study…cannot be assured with any degree of confidence.”
Your recent meeting with FDA staff involved in the review of Ketek is a disturbing example that FDA’s internal dispute resolution processes are not working, he told the acting commissioner. "Instead of reassuring FDA employees that they can raise concerns without being subjected to retaliation or intimidation," he wrote, "the meeting itself appears to be an act of intimidation."
It is beyond dispute that FDA employees are being intimidated and muzzled. A survey released by the Union of Concerned Scientists (UCS) and the Public Employees for Environmental Responsibility (PEER) on July 20, 2006, found that approximately one-fifth of the nearly 1,000 FDA scientists surveyed said that they had been asked, for nonscientific reasons, to inappropriately exclude or alter technical information or their conclusions.
One-fifth of those responding said that they have been explicitly asked by FDA decision-makers to provide incomplete, inaccurate or misleading information to the public, industry, the media and government officials, and over one-third said they could not openly express any concerns about public health within the FDA without fear of retaliation.
Experts agree that all new drugs come with possible adverse reactions, and that the list of side effects on the label of a new drug is never complete because there are always cases where certain people may have an unpredicted adverse reaction to a new drug.
However, unfortunately nowadays, once a new drug is approved, mass-marketing campaigns result in millions of people being exposed to the drug long before the serious side effects and problems with long-term use are known.