Ketek: How did Ketek get approved and into the marketplace even though its efficacy was questioned every step of the way by many experts and every study is plagued by fraud and negligence?
Modern America is a pill-taking society (as is Canada, Europe, and Asia). Most people are like sheep when it comes to taking pharmaceutical drugs. Perhaps you're faithful to the process because the doctor or healthcare professional prescribed it. We assume that our doctors know what works best. The drugs have been approved by the Food and Drug Administration (FDA). We assume that the FDA has had the drug manufacturers produce rigorous results through numerous clinical trials. In a perfect world - yes - that would be true. But the FDA wais far from perfect when it came to Ketek.
It seems that everything that could go wrong with Ketek did. Yet, by large brush strokes of ineptitude and deceit, Ketek was approved and marketed for three indications - community-acquired pneumonia (CAP), acute exacerbation of chronic bronchitis [AECB], and acute maxillary sinusitis.
This article summarizes a 40+ page letter that was sent to the FDA by the U.S. Senate Committee on Finance reviewing the botched Ketek approval process.
The U.S. Senate Committee on Finance has exclusive jurisdiction over Medicare and Medicaid programs. The Committee has a responsibility to the more than 80 million Americans who receive healthcare coverage under Medicare and Medicaid to oversee the proper administration of these programs, including the payment for prescription drugs regulated by the Food and Drug Administration (FDA), and Department of Health and Human Services (HHS).
In spring 2006, the Committee on Finance began investigating extremely troubling allegations related to the approval and post-market surveillance of Ketek (telithromycin) by the FDA. As of December 2006, the FDA had failed to produce any of the documents and files for which they were subpoenaed.
Two of the allegations brought to the attention of the Committee relate to an FDA advisory committee meeting, specifically the Anti-Infective Drugs Advisory Committee (AIDAC or Advisory Committee) meeting held January 8, 2003. (According to the FDA, the value of an Advisory Committee is to provide independent expert advice, to lend credibility to the FDA's review process, and to allow for public discussion of controversial issues, among others.)
The two allegations are: 1-FDA management instructing FDA officials to present fraudulent data to the Advisory Committee because discussing issues regarding data
integrity and the conduct of a safety study would not be productive; and, 2-the FDA actually presenting fraudulent study data to the Advisory Committee.
In 2001, the Advisory Committee requested that a phase III safety study of patients in a usual care setting to examine the potential toxicities of Ketek with regard to cardiac, hepatic (liver), visual, and vascular safety.
In response, the manufacturer submitted an amendment on July 24, 2002, containing the large safety study requested by the FDA to evaluate adverse events in the usual care setting.
This phase III Ketek study became known as Study 3014.
About two months prior to the 2003 Advisory Committee meeting, the study site with the largest number of enrolled subjects (407) was under investigation by FDA's Office of Criminal Investigations. The FDA also inspected the second and third highest enrolling sites and found them to have similarly violated the protocol. In addition, 72 other sites raised red flags for FDA officials and investigators, including non adherence to the study protocol, which recommended between 4 and 50 study subjects per site. FDA officials also questioned how quickly more than 24,000 patients were enrolled in the study.
Doctors were paid well for subjects to enroll which led to fake subjects, family members and staff, and people who did not suffer from the indications (community acquired pneumonia, bronchitis, and bacterial sinusitis). In one study site, an entire weight loss group was enrolled. Of the top 30 enrollers, eight enrolled 1 percent or more of the adult population of their city; plus there was failure to maintain completed informed consents and case report forms for study subjects and failure to sign the return shipment form for investigational product. Several doctors are now under criminal fraud investigation.
The FDA official charged with presenting Study 3014 at the Advisory Committee stated that he was not satisfied with what he knew about the integrity of Study 3014 and was against presenting it at all. When asked why he did indeed present a study he knew to have data integrity problems, the official replied that he was asked directly by the FDA Division Director to present Study 3014 during a team meeting. He said he viewed this as a verbal instruction.
He said he proposed a closed session to discuss the agency's significant concerns with Study 3014 with the Advisory Committee members, but was told by his Division Director that FDA could not disclose information related to an ongoing FDA investigation. The official who presented Study 3014 later said the FDA should never have a role in deceiving the public.
Many FDA officials interviewed acknowledged that, at a minimum, data from the 407 subjects where the doctor was the first to be criminally investigated, should have been censored. Several officials acknowledged that, with hindsight, the Advisory Committee meeting should have been postponed or canceled.
The Advisory Committee members said they were not aware of the data integrity problems until receiving a letter dated July 7, 2006, from the FDA that included Senator Grassley's letter dated June 7, 2006, and subsequent materials from Senator Grassley's office dated October 27, 2006. Several Advisory Committee members also responded that knowledge of the data integrity problems might have affected their vote. An Advisory Committee member said that he/she would have recommended postponing the decision to approve Ketek until the extent and significance of the data integrity problems were better defined and would have sought more information about the nature and extent of the problems.
Most Advisory Committee members did not share the Office Director's opinion that it would not have been productive to spend time on issues regarding data integrity and
the conduct of Study 3014 and believed that all information of note or with significant ramifications should be made available to the Committee.
Aventis submitted Study 3014 to the FDA in July 2002. Its title page included a GCP (good clinical practices) statement: This study was conducted in accordance with standard operating procedures for clinical investigation and documentation. Aventis also provided verbal assurances to the FDA regarding the integrity of Study 3014 during a meeting held in late December 2002 to discuss the Advisory Committee meeting agenda, including the assurance, no more problems.
Aside from these written and verbal assurances to the FDA regarding the integrity of Study 3014, the vast majority of documents and information suggest that the FDA had sufficient information to determine that Study 3014 still had serious data integrity issues.
Despite the daily alarms as how the study was conducted, all concerns expressed by staff within the Review Division -- supervisory officials at the FDA continued to believe it was neither an option to disclose data integrity problems nor would it be productive.
The FDA did not ensure that the public received accurate, science-based information regarding Ketek. Advisory Committee members and the public who relied on the FDA's presentation of Study 3014 were misled because not all of the relevant findings and conclusions regarding Ketek were presented. If the FDA could not find a way to present only accurate, science-based information, the FDA should not have presented Study 3014 publicly or, alternatively, should have postponed or canceled the Advisory Committee meeting.
The FDA is broken.
Although the FDA seemed to ask the right questions and have the right doubts about the lack of study integrity - the buck stopped there. Why? Despite reaching the conclusion that data from the sites under criminal investigation should be censored, the FDA did not censor the suspect data before the Advisory Committee meeting.
This article and further investigation gives us pause. You have to wonder:
- Were there no checks and balances of Sanofi-Aventis studies?
- What happened to the FDA's compliances and reviews?
- Obviously, Sanofi-Aventis cannot police itself but what about the FDA?
- Are there not any whistleblowers at the FDA willing to call attention to the big unsafe gaping hole?
- With this kind of reckless behavior, doesn't it appear that the FDA needs monitoring, investigating, and overseeing by a trusted source? By an independent bureau that does not receive funds from drug companies?
- Who can you trust regarding prescription drugs?
If you have suffered liver damage or a loved one needs a liver implant or has died from taking Ketek - please consult a law firm specializing in unsafe drugs lawsuits.
