Officials at the U.S. Food and Drug Administration (FDA) ignored safety concerns raised by their own experts and hid evidence of clinical trial fraud when they approved the antibiotic Ketek in 2004. FDA managers continued to cite the fraudulent study when defending Ketek even after dozens of patients sickened or died of liver problems after taking the antibiotic. In response to criticism, the FDA barred its scientists from speaking about the drug to anyone outside the agency.
Fraud and Approval
Ketek (telithromycin) was proposed as a treatment for community-acquired respiratory tract infections, such as streptococcus pneumonia.1 The drug was the first in a new class of antibiotics meant to slow the development of antibiotic resistant bacteria.2
During the first FDA review of Ketek in 2001, agency drug reviewers raised concerns about the drug’s safety. Patients in Ketek trials reported blurred vision and symptoms of liver damage similar to those associated with related drugs that had been pulled from the market. The FDA drug review committee asked the drug’s manufacturer, Sanofi-Aventis, to conduct an additional clinical trial to address these safety concerns.
Sanofi-Aventis quickly responded to the reviewers, and completed a large-scale clinical trial, enrolling 24,000 patients, in only five months. The manufacturer reported to the FDA that the new study, known as Study 3014, showed that Ketek was as safe as alternative treatments for bacterial respiratory tract infections.
Sanofi-Aventis’ optimistic conclusion was thrown into doubt when a routine review of Study 3014 revealed that the doctor who enrolled the most patients—who were paid $400 a head by Sanofi-Aventis—had fabricated some patients entirely and submitted fraudulent data for others. (The physician was later sentenced to a five-year jail term for fraud.) Eventually, FDA investigators recommended that four of the ten clinical trial sites that were inspected be referred for criminal investigation.3 Evidence was also uncovered that Sanofi-Aventis was aware of the fraud when it presented Study 3014 to the FDA.4
Far from sounding alarms, in early 2003 the FDA prevented information about the ongoing fraud investigation from being presented to the advisory committee. FDA managers even went so far as to order an objecting FDA scientist to present the Study 3014 data to the committee without mention of the data integrity problems.5,6 Seeing only that the study had shown Ketek to be effective and not knowing of the irregularities, the advisory committee voted overwhelmingly to recommend approving Ketek for sale.
Growing concerns about Study 3014 were serious enough to lead to a third FDA review beginning in late 2003. With no other controlled clinical studies available, the third review relied entirely on post-marketing reports from Europe where Ketek had previously been approved. Post-marketing reports do not have adequate control groups and are generally not considered accurate enough to replace controlled clinical trials, and the FDA’s reliance on this weaker dataset to approve a drug with identified safety concerns went against standard drug review practice.7 Meanwhile, FDA officials never followed up with the suggested criminal investigations.
Nonetheless, on April 1, 2004 the FDA approved Ketek for the treatment of bacterial lung and sinus infections, in addition to cases of community-acquired pneumonia in adults.8 FDA drug reviewer, and whistleblower, Dr. David Ross later testified that “management was so bent on approval that I was pressured to soften my review.”9 Documents provided to the New York Times revealed that at least four FDA safety officials—Dr. Ross, Dr. David Graham, Dr. Rosemary Johann-Liang and Dr. Charles Cooper—had expressed reservations about the drug’s safety.10
Adverse Reactions
Seven months after the approval, a patient under treatment for a mild respiratory infection died of liver failure.11 In March 2006, researchers reported three more Ketek-related liver failures all from a single medical center; one of these three patients died.12 When FDA senior managers heard that news of this cluster was about to be published, they convened an emergency meeting. As a result the FDA issued a public announcement which stated that Ketek was safe and cited the fraudulent Study 3014 as evidence.13
By April 2006, the FDA had received 110 reports of adverse events associated with Ketek, including 23 cases of acute liver injury, 12 cases of liver failure, and four deaths, as well as blurred vision and other problems.14,15 Such voluntarily reported events often represent only a small-fraction of the total adverse reactions to the drug. A review by the FDA’s Office of Drug Safety found that Ketek caused liver failure about four times as often as other antibiotics.16
The mounting evidence of harm to patients led Dr. Johann-Liang to internally call for an end to the ongoing clinical trials aimed at gaining additional approval for Ketek as a treatment for ear infections and tonsillitis. These FDA-approved trials enrolled nearly 4,000 infants and children, some as young as six months old. As Dr. Johann-Liang stated, “How does one justify balancing the risk of fatal liver failure against one day less of ear pain?”17 In the face of negative publicity, the Sanofi-Aventis “voluntarily paused” its pediatric trial.18
Scientists Muzzled, Congress Investigates
In 2006 Senator Charles Grassley (R-IA) began questioning how and why Ketek had been approved and several media outlets published stories critical of both the drug and the FDA. In response, FDA Commissioner Dr. Andrew von Eschenbach reportedly met with Dr. Ross and Dr. Johann-Liang and told them to keep their disagreements “inside the locker room” and that anyone speaking outside the agency on this issue would be “traded from the team.”19
The Congressional investigation eventually exposed the FDA’s failure to reveal Study 3014’s fraudulent data to the advisory committee when the panel recommended that Ketek be approved. Senator Grassley commented that “The Food and Drug Administration can’t be in the business of misleading the public and hiding the truth.”20
Not until February 12, 2007—one day before a Congressional hearing on the matter—did the FDA make changes to the Ketek label.21 The drug label was changed to include a “black box” warning—the strongest type of safety warning issued by the FDA—for certain patients. Furthermore, two of the indicated uses of the drug were removed, leaving Ketek approved only for treatment of community-acquired pneumonia.22
The FDA leadership has never explained exactly why there was so much more pressure to move Ketek through the approval system than in protecting public safety. In an interview, Dr. Ross stated that the FDA has developed a “culture of approval” and pressure on managers to quickly approve drugs gets “transmitted down to the reviewers” even when there are unresolved questions about safety or efficacy.23 Such charges have been made by other FDA scientists as well.24
Still, Dr. Ross noted that if the Ketek scandal prompted meaningful reform in the FDA’s drug approval process and culture then “the drug may have done some good after all.”25
1. U.S. Food and Drug Administration (FDA). Telithromycin (marketed as Ketek) information.
2. Sanofi-Aventis. 2004. Antibiotic Ketek(reg) (telithromycin) tablets 99% effective in vitro against streptococcus pneumoniae bacteria. Medical News Today, May 25.
3. Ross, D. 2007. The FDA and the case of Ketek (Perspective). The New England Journal of Medicine, April 19, 356, 16.
4. Ross, D. 2007b. Interview with David Ross on the FDA review process for the antibiotic Ketek. The New England Journal of Medicine. Audio interview (mp3) supplement. Citation from 04:30 to 05:25.
5. Ross 2007b. Citation from 05:45 to 06:50.
6. Grassley, C. 2006a. Letter to FDA Commissioner Andrew von Eschenbach. April 27. Senator Charles Grassley (R-IA) was Chair of the Senate Finance Committee.
7. Graham, D.J. 2006. Telithromycin and acute liver failure. The New England Journal of Medicine, November 23, 355, 2260.
8. FDA Center for Drug Evaluation and Research, Ketek approval letters.
9. Saul, S. 2006. Antibiotic receives low grade from federal panel, which urges limits and warnings. New York Times, December 16; see also Ross 2007b.
10. Harris, G. 2006b. Approval of antibiotic worried safety officials. New York Times, July 19.
11. Ross 2007.
12. Clay, K.D., Hanson, J.S., Pope, S.D., Rissmiller, R.W., Purdum III, P.P. & Banks, P.M. 2006. Brief Communication: Severe Hepatotoxicity of Telithromycin: Three Case Reports and Literature Review. Annals of Internal Medicine, 144:415-420.
13. The original document has been removed from the FDA website, along with all other mention of Study 3014, however the pertinent section is reproduced in Grassley 2006a.
14. Harris, G. 2006a. Halt is urged for trials of antibiotic in children. New York Times, June 8. Online at .
15. Saul 2006.
16. Harris 2006a.
17. Harris 2006a.
18. Sanofi-Aventis. 2006. Sanofi-aventis announces update to Ketek(R) (Telithromycin) U.S. prescribing information. Medical News Today, June 30.
19. Harris, G. 2007. Potentially incompatible goals at FDA. New York Times, June 11.
20. Grassley, C. 2006b. Press release: Drug-safety agency withheld key information from expert panel. December 13.
21. FDA Week. 2007. Ketek label changes made one day before lawmakers tackle issue. February 16. (Subscription required.)
22. U.S. FDA. 2007. Press release: FDA announces label and indication changes for the antibiotic Ketek. February 12.
23. Ross 2007b. Citation from 09:05 to 09:32.
24. Deyo, R. 2004. Gaps, Tensions, and Conflicts in the FDA Approval Process: Implications for Clinical Practice. Journal of the American Board of Family Practice, 17:142-149.
25. Ross 2007.