Evelyn Pringle March 18, 2007
The new drug application for the antibiotic, Ketek, was rejected twice, in 2001 and 2003, before FDA management approved the drug on April 1, 2004, based on fraudulent studies, and over the objections of the agency's own scientists.
The approval of Ketek, marketed by Sanofi-Aventis, follows a pattern that has emerged since the Big Pharma friendly Bush administration took control of the FDA where the agency has overruled the findings of its own reviewers.
Doctors and patients alike have a paid a heavy price for trusting the FDA's approval of Ketek. According to a review by the staff of the Senate Finance Committee, of the Adverse Event Reporting System, between July 2005 and September 2005 alone, there were two deaths, 35 liver adverse reactions, 44 cardiac events, and 80 visual events in Ketek patients.
On January 20, 2006, the FDA issued a Public Health Advisory, in response to an article in the Annals of Internal Medicine, that reported 3 cases of severe liver damage in Ketek patients. One died, another required a liver transplant, and a third patient recovered from drug-induced hepatitis after Ketek was stopped. The report also said that Sanofi reported 7 cases of liver damage in patients taking Ketek in Phase III trials.
That said, it took more than year for the FDA to finally ban Ketek for use in two of its 3 approved indications, but the drug is still approved to treat pneumonia. The new labeling warns that cases of acute hepatic failure, including fatal liver injury, have been reported, with some requiring liver transplants, and some occurring after only a few doses.
The new labeling also includes a boxed warning that Ketek is contraindicated in patients with myasthenia gravis, and an update about visual disturbances and loss of consciousness, and a warning about reports of diarrhea, ranging in severity from mild to fatal colitis.
The FDA announced its decision to revise Ketek's label, on February 12, 2007, a day before a hearing was scheduled to review the FDA's drug approval policies, to include Ketek, before the House Subcommittee on Oversight and Investigation.
But the attempt to determine why Ketek was approved in the first place, has been an on-going battle. On November 17, 2006, the Senate Committee on Health, Education, Labor, and Pensions, held a hearing on FDA reform legislation, and the approval process for Ketek was discussed.
Jim Guest, president of the Consumers Union, testified about the fraudulent studies submitted by Sanofi, and told the panel, "the FDA found multiple instances of fraud in the company's clinical trial of about 24,000 patients, some cases of which the maker Sanofi already knew about yet failed to notify the agency."
Internal emails obtained by Congressional staffers, prove that the FDA was aware of the problems with Ketek before it was approved, and that FDA scientists, Dr David Ross, Dr David Graham, Dr Charles Cooper, and Dr Rosemary Johann-Liang, all warned FDA management about the serious adverse effects associated with the drug.
In fact, on November 23, 2006, Dr Graham sent a letter to the editor in the New England Journal of Medicine, in which he criticized the FDA for refusing to follow the recommendation of a 2001 Advisory Committee which voted against the approval of Ketek primarily because of concerns about liver damage.
According to Dr Graham, an analysis of the FDA's post-marketing database showed that the rate of acute liver failure was 3.5 to 11 times higher for Ketek compared to other antibiotics on the market, with a reporting rate of 167 cases per 1 million person-years of use, compared to the expected rate of 1 case per 1 million.
Dr Graham noted that, without accounting for underreporting, which can be 10 times higher, this rate is greater than the rate for 3 other drugs that were previously removed from the market because of their link to acute liver failure.
At the recent February 12, 2007, hearing, former FDA scientist, Dr Ross, testified as the safety team leader during the approval process for Ketek, and gave members of Congress some insight into what was going on inside the FDA at that time the drug was approved.
He explained that when the FDA has information that a drug may pose a risk, it weighs the effect of the adverse events against the benefits. The process includes many factors, he said, such as the importance of the drug, the extent of its usage, the severity of the disease treated, the drug’s efficacy, and the availability of other drugs to treat the condition.
"For example," he explained, "the FDA is more likely to tolerate certain side effects if the drug is the only drug on the market that treats a life-threatening illness than it is when a drug is one of many drugs available for treating a less serious condition."
In regard to Ketek, Dr Ross testified that the reviewers concluded that none of the safety study data submitted was reliable, but a week later, FDA managers approved it
anyways, "despite knowing that it could kill people from liver damage and that tens of millions of people would be exposed to it; despite FDA knowing that the drug's maker submitted fabricated data; and despite knowing that Ketek is no better than other antibiotics, and may not even work."
Dr Ross told the panel that the FDA also allowed Sanofi to experiment with the use of Ketek on children over the protests by reviewers.
Dr John Powers, a physician-scientist who until recently worked at the FDA, also testified that the initiation of a trial with children was inappropriate and unethical because it exposed children to harm without evidence of benefits.
He discussed the effectiveness of antibiotics and said Ketek as a symptom of a much larger problem. He explained that under the Food, Drug, and Cosmetic Act, there must be evidence of effectiveness to justify adverse events. "In the absence of evidence of effectiveness," he testified, "any adverse effect, no matter how rare, is not justifiable."
Over the last 25 years, Dr Powers said, the FDA has approved approximately 68 new drug applications for ear infections in children, sinus infections and bronchial infections in patients with underlying lung disease, based on so-called "noninferiority" trials.
An evaluation of previous placebo controlled trials, Dr Powers testified, shows that 12 of 17 studies in sinusitis and 9 of 14 studies in bronchial infections lack evidence of a benefit for antibiotics, and there was no evidence that Ketek is effective at all, and that this was clear when the drug was approved in 2004, he said.
Another witness, Ann Maria Cisneros, formerly worked as a research associate for PPDI, a Contract Research Organization, and assisted in monitoring the Ketek study site of Dr Anne Kirkman-Campbell, who was paid $400 for each patient she enrolled and is now serving a 57 month prison sentence for fraud.
Ms Cisneros testified that Dr Campbell enrolled up to 30 patients a day, often within minutes of each other, and sometimes on days when the office was closed. Dr Campbell even enrolled her entire staff in the study, she told the panel.
Ms Cisneros said, she reported her findings to the Research Organization and Aventis, but nothing came of the matter. "It is my understanding," she testified, "that when the FDA audited the Kirkman-Campbell site, she was participating in another Aventis clinical trial."
After Ms Cisneros left her employment at PPDI, she said, she learned that the Campbell site was being audited by the FDA, and that in preparation for the audits, Aventis coached Dr Campbell with leading questions on how to explain away improper conduct. As an example, she said, Aventis would say, "Is the reason you enrolled so many patients in one day because that is when your supply of the drug came in?"
The gross misconduct in the Ketek studies was not limited to Dr Campbell. The doctor with the third most patients was in the chronic stage of cocaine addiction while conducting the study and was arrested the same month his data was submitted to the FDA, while holding his wife hostage with a gun.
Another doctor was disqualified and barred from participating in any future studies, and another was cited for 20 violations of the study's instructions.
The ability of the Bush administration to muzzle scientific dissent within the FDA may be soon coming to an end. On March 14, 2007, the House of Representatives passed the, "Whistleblower Protection Enhancement Act," granting federal scientists the right to expose political interference in their research without fear of retaliation and to present their research at conferences and in peer-reviewed journals.
Francesca Grifo, senior scientist and director of the Scientific Integrity Program at the Union of Concerned Scientists, issued a statement praising the legislation and saying:
"Censoring scientists undermines our democracy and threatens public health. One stunning example: Vioxx. Fifty-five thousand Americans died because scientists at the Food and Drug Administration couldn't speak out. If this law had been in place at the time, those people might still be alive today."
The muzzling of scientists at the FDA first became evident when Dr Andrew Mosholder found a link between suicide and the use of SSRI antidepressants with children and was not allowed to present his findings at an advisory committee hearing, and when FDA management attempted to stop Dr Graham from testifying at a Congressional hearing about the agency's mishandling of the Vioxx disaster.