In a recent press release accompanying a letter to acting commissioner, Andrew von Eschenbach, Senator Grassley (R-Iowa) said his investigations of the FDA have "shed sunlight on how frequently differences of scientific opinion are quashed, the nature of the cozy relationship between the FDA and the industries it is supposed to regulate, and the failure of the agency to be adequately transparent and accountable to the public."
For months, the Senator has been requesting specific information from von Eschenbach, related to the FDA's approval of Ketek (telithromycin), on April 1, 2004, for the treatment of adults with community-acquired pneumonia, sinusitis, and acute exacerbation of chronic bronchitis. Ketek is made by French drug maker, Sanofi-Aventis, and is the first drug in a new class of antibiotics known as ketolides.
"FDA's handling of the antibiotic Ketek," Senator Grassley stated in the September 26, 2006 letter, "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."
"One of the most troubling allegations," Senator Grassley told von Eschenbach, "is that the FDA approved Ketek with full knowledge that some of the clinical safety data supporting its approval was beset by systemic data integrity problems."
Specifically, Senator Grassley is asking the FDA to allow one of its special agents who investigated and assisted in the prosecution of a doctor in a fraud case involving a Ketek study to meet with him. He is also seeking access to FDA documents, including emails about the drug.
"As Chairman of the Committee," he wrote, "I also respectfully request that your staff make immediate arrangements for my Committee staff to interview Special Agent, who successfully investigated and participated in the prosecution and sentencing of Dr. Maria Anne Kirkman Cambpell to nearly five years in prison for her fraud in Ketek Study 3014."
"In addition," he instructed von Eschenbach, "provide a copy of all documents and communications related to Ketek and Study 3014 in the possession of Special Agent, including, but not limited to, all emails related to Ketek and/or the Committee's investigation of Ketek."
The Senator says the FDA has an obligation to be "forthcoming and open" about its actions. "Serious allegations have been made about misconduct with the drug Ketek," he states, "and the public should not be mislead with statements about the safety of Ketek that cite a fraudulent study."
Senator Grassley has gone so far as to issue subpoenas in an attempt to interview the FDA investigator and the acting commissioner has simply refused to comply. One day last summer the Senator showed up at the FDA unannounced and requested a meeting with the agent, and that request was turned down flat.
Due to his knowledge of the FDA's practice of muzzling, intimidating and retaliating against agency employees who cooperate with his investigations, and most specifically Dr Andrew Mosholder and Dr David Graham, during the investigation of the FDA's handling of the SSRI antidepressants and Vioxx matters, Senator Grassley has taken measures to prohibit such behavior in the Ketek investigation.
In a letter, dated April 27, 2006, he told von Eschenbach to inform FDA employees of their right to speak with Congress and that no records, data or information related to Ketek should be destroyed, removed or otherwise made inaccessible to the Committee.
Furthermore, he said, if any FDA employee believes that he or she has been subject to retaliation for meeting with Committee staff for anything associated with the ongoing investigation of Ketek, the employee should contact the Committee immediately.
At one point, the Senator even hinted that he might cut off von Eschenbach's salary if he refused to cooperate or retaliated against any employee who does, citing a law that enunciates a prohibition on the use of federal funds to pay the salary of any official who prohibits or prevents or threatens to prevent or prohibit an employee from contacting Congress, and "any punishment or threat of punishment because of any contact or communication by an officer or employee with a Member, committee or subcommittee."
Dr Graham apparently feels protected because on November 23, 2006, the New England Journal of Medicine published his letter to the editor titled, "Telithromycin and Acute Liver Failure," in which he criticizes the FDA for failing to follow the recommendation of a 2001 FDA advisory committee which he said had "voted against the approval of [Ketek] primarily because of concern about hepatotoxicity."
According to Dr Graham, the FDA's decision to approve Ketek, "was made in the absence of reliable data disproving the concern expressed in 2001 by the advisory committee."
He reports that an analysis of the FDA's post-marketing database showed that the rate of reporting of acute liver failure was 3.5 to 11 times as high for Ketek as for other antibiotics on the market, with a reporting rate of 167 cases of acute liver failure per 1 million person-years of use, as compared with the expected rate of 1 case per 1 million.
In the NEJM letter, Dr Graham points out that without accounting for underreporting, which could be 10 times higher, this rate is greater than that of three other drugs previously removed from the market by the FDA because of the risk of acute liver failure.
For many months, Dr Graham has been unsuccessfully calling for the removal of Ketek from the market and in his NEJM letter, he offers some free advice "Given that telithromycin is neither clinically superior to other drugs prescribed for respiratory tract infections nor uniquely life-saving," he wrote, "physicians, patients, and third-party payers might wish to reconsider their choice of antibiotic for such infections."
In a recent statement refusing to fully respond to the latest round of questions from Senator Grassley, von Eschenbach said full disclosure of the information could not be released because it "poses an inherent threat to the integrity of the executive branch's enforcement and litigation functions," and there would be a "chilling effect" on employees.
That may be true, but Senator Grassley disagrees and that non-responsive comment is instead have a chilling effect on von Eschenbach's chances of becoming a full-time FDA commissioner because Senator Grassley has officially placed a "hold" on his nomination for commissioner.
The Senator announced his intention to block a Senate vote on the nomination in a November 16, 2006, letter to Senate Majority Leader Bill Frist, (R-TN), because of what he called von Eschenbach's "continued failure to comply with the Committee's subpoenas over the past six months."
In a November 29, 2006, letter to Health and Human Services Secretary Mike Leavitt, Senator Grassley said, "Selectively providing documents and access to executive agency officials pursuant to a congressional subpoena cannot constitute compliance."
According to the Senator, the questions he wants answered are proper as part of his oversight duties. "Congress has a constitutional responsibility," he said, "to oversee the executive branch of government, and the FDA as a public agency has a responsibility to be responsive."
The Senate Finance Committee, he says, has jurisdiction over the Medicare and Medicaid programs and a responsibility to the more than 80 million Americans who receive health care coverage and prescription drugs under those programs.
Among the most serious Ketek related charges under investigation are that top FDA officials: (1) knowingly accepted the resubmission of a new drug approval application which included fraudulent data; (2) instructed FDA scientists that they should present fraudulent data to an advisory committee because discussing issues regarding data integrity and the conduct of the safety study would not be "productive"; (3) approved a Ketek pediatric trial with infants as young as 6-months old, despite concerns about known toxicities, including hepatic, visual, cardiovascular, and vasculitic adverse events; and (4) continued to cite fraudulent study data in publicly released safety information on Ketek.
In mid-May 2006, the FDA's drug safety office 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.
An internal FDA memo dated May 16, 2006, by FDA safety reviewers said that Ketek was linked to 12 reported liver failures including 4 deaths, 23 reports of serious liver injury, and a higher rate of adverse reaction reports than other antibiotics on the market.
On June 29, 2006, Sanofi-Aventis, issued a press release saying the company was sending out a "Dear Doctor" letter to alert healthcare providers about new bolded text in the Warnings section of the Ketek label that stated:
"Acute hepatic failure and severe liver injury, in some cases fatal, have been reported in patients treated with KETEK. These hepatic reactions included fulminant hepatitis and hepatic necrosis leading to liver transplant, and were observed during or immediately after treatment. In some of these cases, liver injury progressed rapidly and occurred after administration of a few doses of KETEK."The same day, the FDA also issued an alert for both medical professionals and patients, with Dr Steven Galson, Director for FDA's Center for Drug Evaluation and Research, stating: "We are advising both patients taking Ketek and their doctors to be on the alert for signs and symptoms of liver problems."
The signs and symptoms of liver failure, the FDA said, include fatigue, malaise, loss of appetite, nausea, yellow skin and dark-colored urine. "Patients experiencing such signs or symptoms," Dr Galson warned in the alert, "should discontinue Ketek and seek medical evaluation, which may include tests for liver function."
An FDA advisory committee is scheduled to meet on December 14-15, 2006, to discuss the risks and benefits of Ketek and is expected to make a recommendation as to whether the drug should stay on the market.