The FDA has continued to cite a fraudulent study in information released to the public about the safety of the antibiotic Ketek. On January 20, 2006, the agency issued a Public Health Announcement, in response to an article in the Annals of Internal Medicine, where researchers reported three cases of severe liver problems in patients taking Ketek.
The article reported one patient at the Carolinas Medical Center in Charlotte, NC, had died after taking Ketek, another required a liver transplant, and a third patient recovered from drug-induced hepatitis after treatment with Ketek was stopped. The Annals' report also said that Sanofi-Aventis reported 7 cases of hepatitis or hepatocellular damage in patients taking Ketek in data from Phase III trials.
On June 9, 2006, drug maker Sanofi-Aventis made the announcement that it had stopped enrolling children in clinical trials for Ketek and said it halted tests to ensure that clinical trials complied with FDA requirements. The company did not mention the heat coming from two powerful Congressional Committees.
As it turns out, the cases above are not the only serious Ketek related adverse events that have been reported to the FDA. According to a review by the staff of the Senate Finance Committee, of reports in the Adverse Event Reporting System between July 2005 and September 2005, the most recent 3 month period available, two deaths, 35 liver adverse events, 44 cardiac adverse events, and 80 visual adverse events have been recorded.
Because it is well-known that only between 1% and 10% of adverse events are ever reported to the FDA, the numbers above would have to be multiplied many times over to establish a true accounting of the adverse events associated with Ketek.
Along with the January 20, Public Announcement, the FDA posted a document titled, "Questions and Answers on Telithromycin (marketed as Ketek)," on its web site, that asked, "What information was known about liver problems related to telithromycin prior to approval?"
In response, the FDA said, "Based on the pre-marketing clinical data it appeared that the risk of liver injury with telithromycin was similar to that of other marketed antibiotics."
Prior to the approval of Ketek, the agency said, the FDA looked extensively at the potential for hepatic toxicity in patients treated with Ketek. The data examined included a 25,000 patient controlled study, as well as information in nearly 4 million postmarketing prescriptions outside the United States.
The release of this public announcement is what initially sent Senator Charles Grassley (R-Iowa), chairman of the Senate Finance Committee, on the warpath. He demanded an explanation as to why the FDA continued to cite Study 3014 without disclosing that the Anti-Effective Drugs Advisory Committee voted to recommend the approval of Ketek, without knowledge that the study was fraudulent.
In a press release on May 1, 2006, Senator Grassley said he was concerned about 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 Ketek.
On May 16, 2006, he called it "mystifying" that the FDA continued to provide information the agency knew was fraudulent, and said that he's keeping the pressure on the FDA for more information about the drug's approval and post-market surveillance. He continues to seek a face-to-face interview with the FDA investigator who discovered the fraud and misconduct in Study 3014.
The study began in October 2001, when doctors began enrolling subjects and were paid $100 for each patient they signed up, and another $150 when they submitted study results, as well as a final $150 after all questions were resolved, according to the May 1, 2006 Wall Street Journal.
On July 24, 2002, drug maker Aventis submitted the results of the study to the FDA, but without disclosing the study's integrity problems.
When the AIDAC reviewed the study, the FDA did not disclose that the agency's Division of Scientific Investigation and Office of Criminal Investigation were investigating the integrity of the study.
A memorandum dated March 25, 2004, by the FDA's Division of Scientific Investigations titled, "DSI Recommendations on Data Integrity," states 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."
The infractions discovered were not minor. The doctor with the highest number of patients, Dr Anne Campbell, was subsequently charged in a 21 count indictment related to her fraudulent conduct during the study, and in March 2004, she was sentenced to 57 months in prison.
The doctor with the 3rd most patients was in the chronic stage of cocaine addiction and was arrested the same month the study was submitted to the FDA with cocaine in his underwear while holding his wife hostage with a gun.
Another doctor engaged in such blatant misconduct that he was disqualified as an investigator and barred from participating in future clinical studies. Still another investigator with 150 patients was cited with 20 violations of the studies instructions.
"It looks like the FDA caught the drug company red handed," the Senator said in a press release, "and let them get away with it."
"On top of that," he said, "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."
The power struggle between the top dogs at FDA and Senator Grassley has been ongoing for nearly 2 months. In a letter to the FDA on April 26, 2006, Senator Grassley asked the FDA to: "Please explain in detail why the FDA has continued to cite Study 3014 in its safety information for Ketek."
Senator Grassley said the stakes continued to grow when it comes to overseeing Ketek, because it was being tested in children as young as 6 months old, and the Senate Committee has received equally serious allegations related to the post-market surveillance of the drug.
For example, in the FDA-approved pediatric clinical trial, known as "TELI COM - Telithromycin in Children With Otitis Media," despite the known toxicities of Ketek, including evidence of hepatic, visual, cardiovascular adverse events, the FDA was allowing Aventis to experiment on children as young as six months old.
The Senate panel reviewed a report from the Adverse Event Reporting System that details a suspected visual adverse event in a 15-month old girl participating in the study. According to the report, on 3 occasions the mother observed the girl having staring spells one day after taking Ketek, and one spell lasted for 60 seconds.
The investigator-doctor initially listed the event as related to Ketek and "serious." However, in addendums to the report, dated months later, the investigator downgraded the event and assessed it to be "non-serious," not interpreted as a "visual event," and that a "staring spell is considered unexpected."
"Given that the Ketek label warns of severe cases of visual problems," Senator Grassley wrote in the letter to the FDA, "please advise the Committee what action has been taken to fully inform the parents of infants and children enrolled in this study about the risks and benefits of Ketek, including its known liver and visual toxicities."
In addition, the Senator said he wants FDA staff to make "immediate arrangements" for his staff to review documents and information related to Ketek and Study 3014, including, but not limited to, the administrative files within DSI, OCI, and the Office of Compliance.
"Given the gravity of the Ketek allegations," the Senator wrote, "I respectfully request that your staff contact my Committee staff by no later than Friday, April 28, 2006, so that my Committee staff may travel to your offices as soon as possible to review the requested administrative files."
"As Chairman of the Committee," he added, "I also respectfully request that senior FDA management officials be prepared to brief my Committee staff within three weeks of the date of this letter."
The FDA's approval of Ketek is also under investigation by the House of Representative's Energy and Commerce Committee. On May 1, 2006, Representatives Edward Markey (D-MA), and Henry Waxman (D-CA), the senior Democrats on the Committee, sent a letter to the FDA questioning the approval process for Ketek and the potential dangers involved in conducting clinical trials on children.
In announcing the investigation, the Congressmen issued a press release saying, "public documents obtained and examined by Reps. Markey and Waxman's staff indicate that the approval process for this drug was seriously flawed."
Rep Markey said, "I am very concerned that the FDA approved Ketek even though it may be neither safe nor effective, and that FDA has allowed the sponsor to give this drug to children in clinical trials."
"Recently," he said, "the GAO found that the FDA does not have a good enough system in place to protect the public from drugs once they are on the market."
However, he continued, "the Ketek case shows that the FDA may also not be doing a good enough job deciding which drugs should or should not be approved in the first place."
"We need to look more closely at the Ketek case," Rep Markey advised, "to determine whether this approval was made in error, and we need to assess whether the Ketek approval process reflects broader systemic problems within the FDA."
"We cannot allow this critical public health watch dog agency," he warned, "to become a lapdog for the pharmaceutical industry."
Congressman Waxman is equally disturbed. "The Ketek case demonstrates the urgent need for reform at the FDA and in the pharmaceutical industry," he said.
"FDA approved the drug on flimsy data without resolving the safety issues, and it failed to penalize Aventis," Rep Waxman noted. "Americans deserve more vigilance from FDA and from the companies that make critical medical treatments."
"We know drug companies manipulate published studies on their drugs, hiding negative information from physicians," he added. But here, Aventis went even further he said, by "failing to disclose to the FDA grave flaws in a key safety study."
The Markey-Waxman letter, requests numerous documents and responses to questions on the approval process for Ketek, and other drugs, and states: "The public has a right to know how the FDA reached its decision to approve Ketek and whether they can rely on those conclusions."
The battle between the FDA and Senator Grassley intensified on June 8, 2006, when he once again wrote to the agency and pointed out that he had asked the exact same questions 6 weeks earlier in a letter but had received no answers.
The Senator said he was repeating his request for answers based on a New York Times article that revealed FDA experts' concerns about trials involving children and infants.
"The adverse events identified with Ketek are serious ones and the possibility that any six-month old child is being exposed to these kinds of risks unnecessarily is unconscionable," he wrote to Acting Commissioner, Andrew von Eschenbach.
The New York Times article titled, "Halt Is Urged for Trials of Antibiotic in Children," reported that this recommendation was made by FDA officials in the Office of Drug Safety and Dr Danny Benjamin, an infectious disease specialist at Duke University, who consulted on the pediatric trials.
According to the Times, an internal review of reports by ODS officials found 110 cases of liver failure or serious liver injury associated with Ketek, since the drug was approved, and most of the events occurred in otherwise healthy people. Twelve adult patients suffered liver failure, including four who died, and 23 others suffered serious liver injury.
A leaked internal FDA memo dated May 16, 2006, says Ketek patients have a higher rate of acute liver failure and deaths than those using other antibiotics.
Based on their review, these agency officials recommended that the FDA "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."
The NYTs also reported that in light of the risk of fatal liver failure, blurred vision and loss of consciousness, FDA official, Dr Rosemary Johann-Liang, questioned the agency's decision to allow pediatric trials to continue and whether it was even possible to assess blurred vision and loss of consciousness in very young children.
The article said that Dr Benjamin also "concluded that the pediatric trials with Ketek were a cause for concern and 'hard to support.'"
In a memorandum, Dr Benjamin noted that in up to 87% of the cases, ear infections resolve themselves within a few days without treatment and that tests of an unusually risky antibiotic in infants might only be justified if the infants had already been treated unsuccessfully with safer a antibiotics first.
In his letter, Senator Grassley said: "Now my concerns are even further heightened by the New York Times article on ODS's assessment of adverse events associated with Ketek and Dr. Johann-Liang's and Dr. Benjamin's conclusions regarding the pediatric trials."
"Let me reiterate," he wrote, "that more than 6 weeks ago I asked you to advise the Committee of "what action has been taken to fully inform the parents of infants and children enrolled in this study about the risks and benefits of Ketek."
"Unfortunately," he said, "I have not received a response to this important question, and I presume that parents who have enrolled their children in the trials have not been advised of anything either."
"If there are no plans to update consent forms and patient brochures at this time," he wrote, "please provide a rationale for the FDA's decision."
Senator Grassley also wants an interview set up with Dr Rosemary Johann-Liang no later than June 28, 2006 and instructed the FDA to make the arrangements no later than June 12, 2006.
"The adverse events identified with Ketek are serious ones," Senator Grassley wrote, "and the possibility that any six-month old child is being exposed to these kinds of risks unnecessarily is unconscionable."
Sanofi-Aventis is the world's third-largest pharmaceutical company with revenue in 2005 of $34 billion. 3.35 million prescriptions for Ketek were written in the US in 2005 amounting to $193 million in sales, according to IMS Health.
No doubt in response to all the bad publicity, sales of Ketek are in a freefall. According to Verispan LLC, a drug tracking firm, in the 22 weeks ending June 2, 2006, the number of prescription written for Ketek dropped 69%.
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