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KETEK A Dangerous Antibiotic that Highlights the Flawed FDA Drug Approval Process

Sep 1, 2006 Over the course of the past few years, we have written many times about the serious problems at the Food and Drug Administration (FDA) when it comes to its drug approval, post-approval monitoring, and withdrawal processes as well as its regulation of direct-to-consumer advertising. (See, January 2005 Newsletter for a comprehensive analysis of each of these topics.)

Now, two years after the sudden withdrawal of the COX-2 inhibitor Vioxx, a dysfunctional FDA remains unable to adequately track the safety of new drugs or respond quickly to problems, a panel of experts said in a comprehensive report that details the agencies shortcomings and offers suggestions with respect to improving its image and its overall effectiveness.

The FDA remains short of resources and power to monitor the safety of new medications properly and to respond effectively when something goes wrong. In their report, The Future of Drug Safety, a panel of experts from The Institute of Medicine found that the FDA needs more resources - money, staff and powers - to effectively monitor and ensure the safety of medications.

One drug (among many we have already written about) that serves to exemplify the highly suspect nature of the drug approval process now in place at the FDA is Ketek, a powerful antibiotic many believe is the latest in a string of extremely dangerous drugs unleashed on an unsuspecting public with potentially disastrous results.
In April 2004, Ketek, an antibiotic manufactured by pharmaceutical giant Sanofi-Aventis, was approved by the FDA for the treatment of acute bacterial infections from chronic bronchitis, acute bacterial sinusitis and community-acquired pneumonia. Prior to its approval, however, problems with the drug had already begun to surface.  

Back in 2001, Ketek, otherwise known as telithromycin, was denied approval from the FDA because evidence of side-effects such as liver damage, blurred vision, and others was found in a review of the manufacturer’s earlier trials. Further support for the application was requested by the FDA before it would even reconsider Ketek for approval. The fact is there are many other effective antibiotics already approved for the same infections that are safer than telithromycin.

Sanofi-Aventis was eager to gain approval so it embarked on a study (labeled “3014”) that was contracted out to Pharmaceutical Product Development Inc. (PPD).  The study that involved over 24,000 subjects was rejected by the FDA as completely unreliable for several reasons, most of which had to do with the doctors who were responsible for enrolling test subjects and overseeing the study.

For example, one doctor, who was enrolling subjects at a record pace at her weight-loss clinic, turned out to have falsified data, used relatives and friends, used subjects who did not have respiratory infections, and used subjects who never even received the medication. This doctor, who enrolled 407 subjects at $400 per subject, is now in federal prison.

Another doctor, who enrolled 214 subjects, was found to be on probation for gross negligence and failing to keep adequate records.  He lost his license after an arrest for domestic violence, cocaine possession, and holding a loaded semi-automatic handgun.

Yet another doctor, who enrolled 150 subjects, was found to have committed over 20 violations of the study’s guidelines and a doctor, who enrolled 251 subjects, also disregarded the study guidelines and failed to report adverse drug reactions.

One doctor even agreed to stop doing research because of serious irregularities in his data including backdating consent forms and failing to record which drugs his patients were taking.

Finally, the study was rejected because representatives from PPD did not visit all of the test locations.

Thus, four doctors alone accounted for 1,021 (4.25% of the total) unreliable subjects whose data could not help but skew the overall results of the study. Given this extensive evidence of misconduct, it is reasonable to assume that the remainder of the study suffered from additional inaccuracies and questionable practices by the researchers.

The $408,400 billed for the completely useless data on 1,021 subjects was a strong incentive indeed for processing data with an eye toward quantity and not quality.

Remarkably, Sanofi-Aventis claimed that the study presented an accurate profile of Ketek despite these significant “deviations.” Moreover, an article in April’s New England Journal of Medicine suggested Ketek was as safe as other antibiotics. Significantly, all six of the articles authors were linked financially to Sanofi-Aventis - five by consulting fees and one as an employee.

When the clinical trial on which the renewed application for approval was based turned out to be full of inaccuracies, fraud, and otherwise unreliable data, the FDA was left with nothing new upon which to base an approval. Yet that was not enough, apparently, to deter the FDA from finally approving the drug.

An FDA advisory panel that met in 2003 recommended the approval of the drug without ever being told of the completely unreliable data contained in study 3014. The full FDA then declined approval only to do an about-face and grant it in 2004.

The FDA approved Ketek based on the prior data, which was already found to be inadequate, as well as the fact that the drug had been marketed in other countries with only minimal problems. Of course, this simplistic analysis ignored the well-known fact, often cited by the FDA itself that adverse events and side effects are grossly underreported by between 90% and 99%.

Now, the FDA is assessing the numerous reports of liver damage while it insists that the drug is “safe and effective when used according to the label.” The FDA is most-likely relying on the conjecture that Ketek’s risk profile for liver-related problems is probably similar to other antibiotics.

Other drugs have either been pulled from the market (Rezulin) or significantly restricted (Trovan) for similar incidence rates for liver failure.  

Even though study 3014 was thoroughly discredited by the FDA, the agency cited the study when agreeing with a report that suggested the drug’s safety record was reassuring. Of course, the report was based on the discredited study also.
Senator Grassley, along with other lawmakers, is already questioning the Ketek approval and the faulty and inadequate data that approval was based on.  In an April 27 letter to the FDA, Grassley pointed out that the data supporting the agency’s approval was "beset by systemic data integrity problems."

Grassley also warned that Ketek can cause acute hepatic failure and severe liver injury, which can, in some cases, be fatal. Incidents have already been reported in patients taking Ketek, including inflammation of the liver and hepatic necrosis or liver cell death which can require liver transplant. These incidents were reported and observed during or immediately after treatment. In some of these cases, liver damage occurred quickly and occurred just shortly after administration of a just few doses of Kete.

Grassley and other physicians warn that patients should be on the lookout for any signs or symptoms of hepatitis, such as fatigue, malaise, loss of appetite, nausea, jaundice, bilirubinuria (dark colored urine), acholic stools (pale or clay colored),  liver tenderness, or hepatomegaly, otherwise known as enlarged liver.  Patients who are experiencing these symptoms should discontinue Ketek and immediately seek medical attention, as well as receiving liver function tests.

Democratic Reps. Edward Markey of Massachusetts and Henry Waxman of California also questioned the Ketek approval in a separate letter to the FDA. According to a statement from Waxman, "The Ketek case demonstrates the urgent need for reform at the FDA and in the pharmaceutical industry. FDA approved the drug on flimsy data without resolving the safety issues, and it failed to penalize Aventis."

As expected, problems with Ketek are surfacing after it has been on the market for only a couple of years. On January 20, 2006, researchers reported three cases of severe liver problems related to Ketek in patients at a hospital in North Carolina. One death was reported as well.
The doctors at the hospital in North Carolina were the first to raise concerns about Ketek. They even submitted an article to the Annals of Internal Medicine, reporting the three cases of acute liver failure in previously healthy patients who had taken the antibiotic.

Most recently, in May of 2006 the FDA connected 12 cases of liver failure, including four fatalities, to Ketek.

On June 30, 2006, the FDA completed its safety assessment of Ketek and instructed Sanofi-Aventis to add a new warning to the drug’s label to warn patients about the potential risk of liver injury and failure.  

According to Dr. Steven Galson, Director for the FDA’s Center for Drug Evaluation, the FDA is “advising both patients taking Ketek and their doctors to be on the alert for signs and symptoms of liver problems. Patients experiencing such signs or symptoms should discontinue Ketek and seek medical evaluation, which may include tests for liver function."

Some signs and symptoms of liver failure include fatigue, malaise, loss of appetite, nausea, yellow skin and dark-colored urine.

Sanofi-Aventis released their own statement following the FDA’s safety assessment of Ketek, stating that the drug's prescribing information has now been changed to warn of a risk of liver damage. They are and also advising physicians against using Ketek in patients with a condition known as myasthenia gravis.
Sol Rajfer, president of U.S. science and medical affairs at Sanofi-Aventis said that "based on the in-depth review of the clinical trial and post-marketing data, we continue to believe that the benefits of Ketek outweigh the risks when the drug is used as directed for its approved indications." (No surprise there.)

Experts have argued that the reported four deaths from liver failure linked to Ketek have raised concerns about the drug safety program in the United States. Many are also skeptical of the effectiveness of internal adjustments made at the FDA since the massive withdrawal of the discredited painkiller Vioxx in 2004.

After it was discovered that Vioxx was linked to higher rates of heart attacks and strokes, it was removed from the market.  Following these events, the FDA set up an in-house drug safety board and said that they would strive to improve communication about emerging problems with approved prescription drugs.

An internal memo by the FDA safety investigators surfaced on May 16. The memo contained information about the problems with Ketek, stating that they may be more serious than those identified in the journal article.

Investigators reported a total of 12 cases of liver failure among Ketek patients.  Four patients died, and one required a liver transplant. One patient had taken only a single dose of the drug before becoming ill.

The Ketek saga has prompted requests for more demanding standards for the approval of new antibiotics. The current standard is simply that drug manufacturers must show that a new antibiotic is not inferior to an older one.

More than 5 million prescriptions for Ketek have been written since it received FDA approval.

Amazingly, Ketek is now being studied as a treatment for children with ear infections and tonsillitis although the FDA has rejected an application by Sanofi-Aventis to approve the drug for the same illnesses in adults.

The fact remains, however, that Ketek is not the only drug in its category and there are many, safer and more reputable alternatives that should be explored before choosing Ketek, especially based on its flawed track record.  Doctors agree that there is no specific medical reason Ketek should be prescribed because there are many safer alternatives.

Ketek is not approved to treat serious life-threatening infections. If you or anyone you know is experiencing any of the aforementioned signs or symptoms of potential liver toxicity, follow the directions in the new warnings to stop taking the drug and seek medical evaluation immediately.

If you believe you or a loved one has suffered an injury associated with the antibiotic Ketek, or any other prescription or over-the-counter medication, do not hesitate to contact Parker & Waichman immediately at for a free confidential case evaluation.  

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