The company denied that the studies were suspended because of safety concerns. However, the move jives with the recently initiated investigations into the FDA's collusion with Aventis in the approval of Ketek by two powerful Congressional Committees.
The FDA's conduct regarding Ketek is under investigation by House Representatives Edward Markey (D-MA), and Henry Waxman (D-CA), senior Democrats on the House Energy and Commerce Committee. On May 1, 2006 the lawmakers sent a letter to the FDA questioning its actions surrounding the approval of Ketek.
In a press release announcing the investigation, the lawmakers said, "though the FDA has consistently assured the public of Ketek's safety and efficacy, public documents obtained and examined by Reps. Markey and Waxman's staff indicate that the approval process for this drug was seriously flawed."
Most recently, on June 8, 2006, the Senate Finance Committee sent a letter to the FDA asking: "Is the FDA considering temporary suspension of these trials until the serious concerns and issues related to Ketek are resolved?"
The company had been testing Ketek for treatment of ear infections and tonsillitis in nearly 4,000 children in the US and a dozen or so other countries. A search of the Clinical Trials.gov web site shows three ongoing trials in the US of children ages 6 months to 13 years, including:
- TELI COM - Telithromycin in Children With Otitis Media,
- TELI TON - Telithromycin in Tonsillitis, and
- Comparative Study to Evaluate the Efficacy and Safety of Telithromycin Given Once Daily Versus Cefuroxime Axetil Given Twice Daily in Children With Middle Ear Infections.
The FDA approved Ketek on April 1, 2004, for the treatment of adults with community-acquired pneumonia, sinusitis, and acute exacerbation of chronic bronchitis.
Over the past several months, several allegations related to the FDA's approval of Ketek have caught the attention of the Senate Finance Committee Chairman Senator Charles Grassley (R-Iowa).
The Senate Committee has jurisdiction over the Medicare and Medicaid programs and, accordingly, a responsibility to the more than 80 million Americans who receive health care coverage, including prescription drugs, under those programs.
Senator Grassley's intense oversight of the FDA began in 2004 over the agency's reluctance to allow information to become public about the risks of pediatric use of SSRI anti-depressants. He has since put pressure on the FDA to make administrative changes to improve its transparency and post-market surveillance of drugs, in addition to introducing legislation to implement these kinds of reforms.
Among the most serious allegations about Ketek is that the FDA approved the drug despite unresolved questions about the drug's safety and efficacy, with full knowledge that some of the clinical data submitted to support the drug's approval was tainted by integrity problems. Documents provided to the Senate Committee show that at least one of the clinical trials, Study 3014, was fraudulent.
In April 2001, Ketek's initial approval came before the Anti-Effective Drugs Advisory Committee to consider whether its efficacy in treating respiratory infections supported its use given the risks of cardiac and hepatic toxicity and vision problems associated with Ketek.
Based on these concerns, the AIDAC recommended that Ketek not be approved and said Aventis should conduct a large clinical study. A letter to Aventis dated June 1, 2001, said in part: "This study should include the monitoring and analysis of all adverse events, with particular attention to hepatic, visual, cardiovascular, and vasculitic adverse events."
Aventis subsequently hired Pharmaceutical Product Development (PPD) to conduct a study designed to enroll patients with respiratory infections in the offices of more than 1800 primary care physicians all across the country. Subjects were randomized for treatment with Ketek or Augmentin, another antibiotic.
In October 2001, 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 WSJ.
The potential for money-making by doctors enlisted for this study was enormous. A fact that obviously did not go unnoticed by certain physicians who signed on to the study.
On July 24, 2002, Aventis submitted the results of Study 3014 to the FDA, but without fully disclosing the study's integrity problems.
When the AIDAC reconvened to consider the study, the FDA presented it to the panel without disclosing that the agency's Division of Scientific Investigation and Office of Criminal Investigation were investigating both the conduct and integrity of the study. Without the benefit of this information, the AIDAC voted to recommend the approval of Ketek.
In the end, a March 25, 2004 memorandum, prepared by the 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."
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. Specific allegations under investigation by the Senate Committee include that FDA management:
- accepted the resubmission of a new drug application for Ketek, which included fraudulent data in support of approval;
- presented fraudulent study data to an advisory committee tasked with recommending Ketek's approval or disapproval;
- instructed FDA scientists appearing before an advisory committee that they should present fraudulent data because discussing issues regarding data integrity and the conduct of the safety study would not be "productive;"
- approved a pediatric clinical trial, involving infants as young as six-months old, despite concerns related to known toxicities, including hepatic, visual, cardiovascular, and vasculitic adverse events; and
- continued to knowingly cite the fraudulent study in publicly released safety information on Ketek.
The AIDAC members certainly would have been interested to know that the highest enrolling doctors were being investigated and that there appeared to be significant under reporting of adverse events.
For example, the investigator at the highest enrolling site, Dr Ann Campbell, was found to be enrolling patients when the clinic was closed, and patient consent forms had date modifications and signature inconsistencies.
Dr Campbell had a practice in Alabama, that attracted patients by advertising weight-control treatments. "By the middle of January 2002," according to the May 1, 2006 Wall Street Journal, "she had signed up 287 patients and was receiving enough of the drugs to enroll 30 new people a day, according to emails sent by a PPD employee on Jan. 15 and 17."
On February 27, 2002, Nadine Grethe, an Aventis manager overseeing the study, got an email from PPD warning that there were possible problems with Campbell including the lack of "proper diagnosis of an appropriate medical condition," medical charts described as "very limited," and lab test results that were "suspiciously similar" for multiple patients. PPD also found that many patients signed up during a lunch break when the office was supposed to be closed.
The suspicions were validated on August 29, 2003, in the case of Maria "Anne" Kirkman, MD, aka Maria "Anne" Kirkman-Campbell, DOH Case No 2004-20974, when Campbell was charged in a 21 count indictment in the US District Court for the Northern District of Alabama with 10 counts of using a scheme or fraud to obtain money and property by means of false pretenses and documentation, and 11 counts of knowingly and willingly making and using, and causing to be made and used false writing and document knowing it to contain a materially false, fictitious and fraudulent statement and entry.
The information alleged that Campbell falsified documentation released to a study to establish the safety and effectiveness of Ketek before it could be a approved by the FDA.
Despite all this, when Aventis submitted the results of Study 3014 to the FDA, they included 407 of Campbell's patients, and "did not alert the Agency to any problems" with Campbell, according to a review of Ketek's history, safety and efficacy by FDA official, Dr David Ross, on the FDA web site.
Campbell was eventually sentenced to 57 months in prison and was given an additional 3 years of supervised release after the prison term is completed. She was also fined $557,251 and ordered to make restitution to Aventis to the tune of $925,774.
An FDA inspector ended up at Campbell's office in late 2002, simply by chance because she had enrolled so many patients. The investigator found patients who said they had not received any medication, even though their records said they had, according to Dr Ross. Others patients were being treated for weight loss and not respiratory infections, and some subjects were friends and members of Campbell's family.
Dr Egisto Salerno was a study investigator in San Diego whose 214 patient recruitment made him the 3rd largest recruiter. Here is part of what was known about Salerno at the time he was conducting the study, according to a report by the Medical Board of California, Department of Consumer Affairs, on March 6, 2006:
Petitioner started using cocaine in 1994 on an occasional, recreational basis. His use gradually escalated from occasional use in the mid-1990s to using cocaine every weekend by 2001. He "extended" his weekends to use cocaine by taking time off from his practice on Fridays, and sometimes on Thursdays or Mondays as well. He did not use cocaine before seeing any patients. Petitioner testified his denial of his addictions was so intense he was unaware he was dependent. The use of cocaine became an essential part of petitioner and his wife's lives.Dr Jeffrey McLeod was another quack who participated in the study from Virginia. On August 24, 2005, the FDA recommended that he be disqualified as a trial investigator and sent him a letter outlining his fraudulent conduct in the Ketek study and said in part:
Petitioner admittedly ingested cocaine and drank alcohol Monday morning, April 22, 2002, after which he thought four or five people were inside his home. He armed himself with a loaded .45 caliber handgun. He threatened to kill his wife if she called the police. His mother in law found out what was going on and contacted the police, who responded to petitioner's home. Petitioner was armed and other weapons were in the home, but most of them were antiques. Petitioner was under the influence of drugs and was arrested.
The FDA's Center for Drug Evaluation and Research believes that you have repeatedly or deliberately violated regulations governing the proper conduct of clinical studies involving investigational new drugs as published under Title 21, Code of Federal Regulations (CFR, Part 312, and that you submitted false information in a required report to FDA or the sponsor.The FDA told McLeod: (1) You failed to obtain informed consent from seven subjects; (2) For six subjects you provided consent documents that were signed and dated after they had completed the study; and (3) For 17 subjects you provided documents in which the signatures were backdated to make it appear that informed consents were obtained prior to their enrollment in the study.
The investigation even found that consent forms for 22 of the 23 patients contained a date that preceded the date McLeod received the informed consent templates on March 4, 2002, including 13 documents with his own signature. A member of his staff also told the FDA investigator that McLeod instructed her to backdate the consent signatures.
In addition, the study protocol required clinical lab tests on subjects at visit 1 and 2, but there was no documentation to show that such tests were conducted on 11 subjects.
The protocol required that women of childbearing age have a urine pregnancy test before taking the study medication, but there was no documentation to show that the tests were done on 6 subjects.
The protocol also required McLeod to document adverse events and determine whether any events were of "special interest" as that term was defined in the protocol. The investigator said, that even though records showed that 2 subjects had lab tests to evaluate what was identified on the lab report as a "Cardiac Adverse Event," the case report submitted by McLeod states that these subjects experienced no adverse events.
For some subjects, McLeod failed to remove the tear-off labels and place them in the Case Report Form so it could not be determined which medication the subjects were given.
Finally, one subject was enrolled despite a documented allergy to the penicillin antibiotic.
Another ace investigator was Dr William Terpstra, of Indiana who had more than 150 patients enrolled in the study. However, an investigation found that he had over 20 violations of the study instructions.
All that said, in April 2006, the results of Study 3014 were cited in an article in the New England Journal of Medicine that claimed Ketek was as safe as other antibiotics. However, five of the six authors had to disclose that they had received consulting fees from Aventis, and that at the time of the study, the 6th author was an employee of Aventis.
In his June 8, 2006, letter, Senator Grassley asked the agency to explain what it is doing to inform parents about the safety issues surrounding pediatric trials of Ketek and pointed out that he had posed the same question to the agency 6 weeks earlier but had not yet gotten an answer.