The antibiotic Ketek, manufactured by Sanofi-Aventis, had been reported to cause liver failure, blurred vision and loss of consciousness in adults. Twelve adults in the United States suffered liver failure, and four of them died. Twenty-three others suffered serious liver injuries.1
The company undertook a study of Ketek in 24,000 patients to prove its safety. The trial was marred by fraud, one of the investigators on the study is now in federal prison, and another lost his medical license.1
Sanofi-Aventis first asked the FDA to approve the drug in February 2000. But officials demurred because of reports of side effects. The FDA instead asked the company to report its experience with Ketek in Europe, where it had been approved in 2001. Although it is unusual for the FDA to approve a drug based upon its use elsewhere, the FDA did just that; in April of 2004 the FDA approved Ketek for treating sinusitis, bronchitis and pneumonia.1
By April of 2006, the FDA had reports of 110 cases of liver problems associated with Ketek, most of which occurred in otherwise healthy people. In one, a 49-year-old woman took no more than two doses of the drug before becoming nauseous and vomiting. She was hospitalized five days later and died.1
FDA officials estimated that Ketek caused acute liver failure in 23 people for every 10 million prescriptions, about four times the rate of such events seen in other antibiotics.1
Incredibly, Sanofi-Aventis sponsored four clinical trials in children as young as 6 months and up to 13 years in order to test Ketek as a treatment for ear infections and tonsillitis in nearly 4,000 infants and children. In May of 2006, Dr. Rosemary Johann-Liang, an official in the FDA’s Office of Drug Safety, called for Sanofi-Aventis to halt clinical trials in children because the drug could be deadly.1
On February 12, 2008, a hearing was conducted by the House Energy and Commerce’s Subcommittee on Oversight and Investigations. The FDA’s actions in regard to Ketek are being investigated by Senator Charles E. Grassley, the Iowa Republican who is chairman of the Senate Finance Committee, as well as by Representatives Edward J. Markey of Massachusetts and Henry A. Waxman of California, both Democrats.1
The hearing focused on Study 3014 of Ketek and the fraud committed by the clinical investigator who is serving a 57-month prison sentence for falsifying data in the study. Dr. Anne Kirkman-Campbell was the investigator who had enrolled the largest number of subjects in the trial. Dr. Kirkman-Campbell was a physician in Gadsden, Alabama. Her site enrolled over 400 patients, a number that some witnesses considered unusual given the size of Gadsden’s population. Kirkman-Campbell received $400 for each patient she enrolled, according to testimony at the hearing.2 There were also allegations of under-reporting of adverse events, and discrepancies in the informed consent forms and documentation in medical charts.3
The FDA’s Division of Scientific Investigations inspected Dr. Kirkman-Campbell’s offices and discovered multiple violations of Good Clinical Practices, including enrollment of patients who should have been excluded; documentation showing that certain patients received a course of Ketek when those patients stated that they did not receive the drug; and no reports of adverse reactions for the first 100 patients who were enrolled at the site. As a result, the OCI initiated an investigation of Dr. Kirkman-Campbell and she was indicted on 21 Federal felony charges. She eventually pleaded guilty to one count of Federal mail fraud and was sentenced to 57 months in prison.3
During the February 12, 2008 hearing, the most damning testimony appeared to come from Ann Marie Cisneros, a clinical research associate who, at the time of the study, worked for Pharmaceutical Product Development (PPD), a contract research organization. Ms. Cisneros accused both Aventis and PPD of knowing about Kirkman-Campbell’s research fraud but not reporting it to the FDA.4
Cisneros said there were a number of red flags that should have been discovered. Dr. Kirkman-Campbell “enrolled patients within minutes of each other and upwards of 30 patients per day. She enrolled patients at times and on days when the office was closed. Once we started reviewing patient charts, we discovered that every informed consent had a discrepancy. Most of the consents looked like they had been initialed by someone other than the patient.”4
Cisneros said that she was so concerned that she called Copernicus, the company that operated an Institutional Review Board (IRB) tasked with overseeing the safety of patients in the study. Cisneros testified, “I spoke with someone who I understood to be the president of the company and was told that, while she shared my concerns, she preferred to wait and see what actions Aventis took. I never heard from the IRB again.”4
Copernicus Group CEO Sharon Hill Price said she did not remember getting such a call and testified that the company was not aware of any such call being made to anyone at the company until Jan. 23, 2003, when “Copernicus found documentation of an anonymous call being taken by one of our professionals on Feb. 21, 2002.” No hard copy had been made of the electronic report, and a copy of the document concerning the “anonymous call” had not been placed in the investigator file as it should have been.4
Upon further questioning, Price said the record of the call had turned up during an electronic search of IRB records in 2006 during Sen. Grassley’s investigation of Study 3014. But the IRB’s attorneys determined that Grassley’s request for records covered only documents from 2006 on, so they did not bother to bring the record of the call to anyone’s attention then.4
Price added that the IRB’s policy at the time “was not to review protocol violations but only serious adverse events.” Therefore, in addition to overlooking the call, they also did not review 83 memos from Aventis concerning problems with Kirkman-Campbell’s site. This prompted House Energy and Commerce Committee Chairman John Dingell to ask her, “Why do you exist?” although it is assumed he was referring to the IRB and not Ms. Price.4
When the FDA was preparing to audit Kirkman-Campbell’s site, Cisneros “was told by a trusted and distressed former colleague at PPD that Nadine Grethe, project manager at Aventis, coached Dr. Kirkman-Campbell on how to explain away some of the site irregularities. I was called on two occasions by PPD lawyers who reminded me of the confidentiality agreement I signed and advised me not to speak with the FDA without Aventis’ approval and PPD attorneys present.”4
Cisneros testified that she also e-mailed results of the site visit to the head of quality assurance at PPD, copied Aventis personnel on the findings, and took part in a teleconference between PPD and Aventis in which she identified issues found in the site visit. “What brings me here today is my disbelief at Aventis’s statements that it did not suspect that fraud was being committed. Mr. Chairman, I knew it, PPD knew it, and Aventis knew it.”4
During the hearing, the Congressmen were repeatedly angered by the FDA’s failure to properly police the Ketek studies, and frustrated by the FDA’s refusal to provide information. Rep. Dingell said, “This committee and other committees in Congress have repeatedly been stonewalled” in investigating whether the FDA knew of or suspected the fraud. Three of the witnesses at the hearing were FDA criminal investigators who uncovered the fraud and misconduct, but they had to be subpoenaed to testify at the hearing because FDA Commissioner Andrew von Eschenbach and HHS Secretary Mike Leavitt refused to allow them to appear here voluntarily.4
Leavitt also refused to honor a subpoena relating to von Eschenbach’s briefing books for his testimony before the full committee March 22, 2007. Rep. Dingell called Leavitt’s justifications for this refusal “at best … specious. At worst, they border on contempt of Congress. If anything, his refusal to cooperate causes me to wonder what he is trying to hide.”4
In a related matter, Rep. John Shimkus (R-Ill.) pointed out that the FDA had yet to debar Kirkman-Campbell from serving as a clinical investigator in the future, although debarment proceedings were begun last year. This has been a trend in the FDA’s recent history, according to Rep. Shimkus: “FDA has failed to initiate debarment proceedings against several individuals and some companies even when the basis for debarment clearly exists.”4 A Minority Committee Staff Report released in February of 2008 showed that after more than 15 years of debarment authority, FDA has not debarred even a single generic drug company, although there were drug companies convicted of Federal criminal felonies that would have made them eligible for debarment.3 Between 2003 and 2005, there were 42 persons who were convicted of crimes relating to drug sales or studies and who should have been, but were not, debarred by the FDA.3
1. Gardiner Harris, “Halt Is Urged for Trials of Antibiotic in Children,” New York Times June 8, 2006. Original document here.
2. John Reichard, “Integrity of Drug Approvals in Doubt, Lawmakers Say”, Congressional Quarterly, February 12, 2008. Original document here.
3. Minority Committee Staff Report Prepared for the Honorable Joe Barton, Ranking member Committee on Energy and Commerce, U.S. House of Representatives, 110th Congress, February 2008. Original document here.
4. “Congressmen Fault FDA, Aventis, IRB in Ketek Study,” Drug Industry Daily, February 13, 2008.