Grassley testimony regarding antibiotic Ketek before House Subcommittee on Oversight and Investigations
Statement of U.S. Senator Chuck Grassley of Iowa
"Ketek Clinical Study Fraud: What Did Aventis Know?"Subcommittee on Oversight and InvestigationsHouse Committee on Energy and Commerce
Tuesday, February 12, 2008
Chairmen Dingell and Stupak, Ranking Members Barton and Shimkus, and distinguishedcolleagues, thank you for inviting me to speak today about my investigation of FDA's handlingof the large safety study Ketek, Study 3014. It has been a long road and it's still not at an end.More than two years ago, in January 2006, the journal Annals of Internal Medicinereported three cases of liver damage in North Carolina patients who took Ketek. In response theFDA issued a public health advisory.
After all, suffering severe liver problems is quite a price to pay for taking an antibioticthat was being used for such conditions as sinus infections until that indication was removedfrom the Ketek label a year ago.
Soon after, I heard allegations and concerns regarding FDA's review of Ketek and Istarted asking questions. One of the more serious allegations was that the maker of Ketek,Aventis at the time, submitted clinical trial data to the FDA in support of approval, knowing itwas fraudulent.
So I asked FDA to make arrangements immediately for my staff to review documentsrelated to Study 3014 at the FDA's offices. Initially, FDA gave my staff access and agreed toprovide copies of documents my staff identified during their review. But then I asked for SpecialAgent Robert West from FDA's Office of Criminal Investigations and the FDA pulled a 180 onme.
I had good reasons for asking for Agent West. One of the other allegations I receivedwas that despite Agent West's concerns and recommendations, FDA never expanded itsinvestigation to determine if the company did "knowingly" submit fraudulent data. Agent Westplayed an integral role in the investigation of Study 3014, and I am delighted to see that he willbe testifying on the next panel along with two other special agents from the agency. Agent Westwas the lead agent on the investigation of Dr. Anne Kirkman Campbell, one of the principalclinical investigators for Study 3014. And as a result of that investigation Dr. KirkmanCampbell is currently serving a 57-month prison sentence. Agent West also was in frequentcommunication with the FDA consumer safety officers and reviewers involved in the Study 3014inspections.
But as I testified before this subcommittee a year ago, FDA and HHS wouldn't makeAgent West available-even after I went over to the HHS offices to ask personally to speak withAgent West and subpoenas were issued. After all, if FDA had nothing to hide about how ithandled Study 3014, why stop me from talking to Agent West? I smelled a "cover-up."Well, I now have a better understanding of why FDA did not want me to speak to AgentWest regarding Ketek. The answer to the "why" question is equally interesting. It seems to methat there were definitely reasons why the FDA did not want me to meet with Agent West or anyother agents for that matter. FDA, it appears, did not want anyone to know that it didn't furtherinvestigate whether or not Aventis submitted fraudulent data knowingly to the FDA. The FDAdid that even though Agent West recommended, in the summer of 2003-almost 5 years ago-tohigh level officials at the FDA that it needed to create a mini-task force to look into Aventis.When HHS and FDA finally made Agent West available a short time ago-18 months afterI first requested him-Agent West confirmed that no one acted on his recommendations. In fact, Ilearned from HHS more than a year after my visit to the Department, that the FDA didn't open aninvestigation into the company until March 2006. Interestingly, that was around the same time Istarted poking around Ketek.
Agent West told his supervisors, FDA investigators involved in the Study 3014inspections, as well as FDA directors overseeing the review of Ketek what he thought needed tobe done-inspect all the study sites that enrolled over 100 patients. The protocol for Study 3014had recommended a maximum enrollment of 50 patients per site, so that would have meantinspections of about 70 sites.
Agent West's supervisors told my staff that they supported him. The site investigatorsalso thought it was a good idea. But what happened?
The head of the Office of Criminal Investigations told my staff that Agent West'sconcerns and recommendations were referred up the food chain, and he assumed the matterwould be taken care of.
The Associate Commissioner for Regulatory Affairs at that time said he was prepared tooffer any assistance if needed but never heard anything more from the Office of CriminalInvestigations. One of Agent West's superiors said the CDER folks were briefed so the ball wasin their court. He also said that Agent West's task force proposal had nothing to do withconcerns about Aventis.
But I have since learned that that's not true.
Agent West sent an email in July 2003 to his superiors about his conversation withdirectors in FDA's Center for Drug Evaluation and Research. These directors oversaw thereview of Ketek.
In that email, Agent West said, "I told them that it was my opinion that Aventis knewsites were suspect but did nothing to prove or refute their suspicions." Agent West was not theonly agent who believed that the company or at least someone within the company knew therewere serious problems, particularly at Dr. Kirkman Campbell's site. You have the two agentshere today who were assigned to the criminal investigation that was opened in March2006-Special Agents Robert Ekey and Douglas Loveland.
Agent Ekey said during a joint interview with our Committees that he thought thecompany too easily dismissed the concerns that were raised by its own contract researchorganization, the organization hired to monitor Study 3014.
Agent Loveland wrote in an internal email dated April 17, 2007, that the company knewsignificant issues existed at many sites yet the company submitted the data to the FDA andclaimed the study was conducted according to good clinical practices. He also told my staffduring an interview yesterday that Aventis should have known that there were problems with theintegrity of the study data.
The case was closed in July 2007. FDA issued a warning letter in October to thecompany for failing to ensure proper monitoring of Study 3014 and not adequately investigatingallegations of fraud at Dr. Kirkman Campbell's site. The letter cited many of the same problemsthat FDA's staff raised back in 2003 and 2004. So why wasn't an investigation initiated then?Agent West stated in his July 2003 email, "I think the three individuals in CDERunderstood my feelings and opinions but I don't know whether or not the necessary steps will beaccomplished."
When my staff spoke with the three directors, one of them told my staff that if the Officeof Criminal Investigations wanted additional investigations, it was their call, not CDER's. Healso said that the Office of Criminal Investigations should have talked to the Division ofScientific Investigations since the division oversees clinical trial site inspections.So who's responsible?
Everyone seemed to be pointing the finger at someone else, with the exception of thehead of FDA's office of Division of Scientific Investigations. This FDA employee told my staffthat as far as additional inspections went, they didn't have the resources to do more. Andbesides, she said (1) the FDA didn't rely on Study 3014 for approval, (2) FDA completed 8 siteinspections for Study 3014, which is many more than the one or two it normally does, and (3)astonishingly, she also said that investigating drug companies is a "losing game" and the chancesof getting a warning letter is zero.
I find that attitude extremely troubling, as I'm sure you do as well.
We rely on the FDA to ensure that the drugs in our medicine cabinets are safe andeffective. That includes FDA making sure that the data supporting the safety and efficacy of adrug is sound. To do that adequately, FDA has to do its job of oversight over clinical trials.Data integrity isn't the only issue of concern here. FDA also has an obligation to protect humansubjects.
In December, I raised this matter to Commissioner von Eschenbach in a lengthy letterregarding my Ketek investigation. That letter I've been told is included in your exhibit books. Iasked Commissioner von Eschenbach: If it is FDA's position that no additional inspections arerequired once a study is no longer useful for regulatory action, then how can FDA protectresearch subjects from the harm that may be caused by clinical investigators?
Not relying on a study for approval does not absolve FDA of its responsibility to protectthe individuals who courageously volunteer in clinical trials so that we can all benefit fromlifesaving cures and medical innovation. I am still waiting for the Commissioner's comments onthis important matter.
Of course, this responsibility does not lie only with the FDA. The drug companies alsohave a responsibility to the people who participate in their clinical trials. They also need toensure that problems are adequately investigated and addressed.
In the case of Study 3014, there were sirens, red flags and bull horns, but it looks like thecompany and the FDA kept ear plugs and blinders on.
Before I conclude my statement today, there is something that strikes me as ironic aboutthe case involving Ketek and another investigation involving Dr. Victoria Hampshire, anemployee of the FDA. Today, we heard a lot about the missteps made by the FDA and Aventis.The culmination of those missteps led to a Warning Letter being sent to Aventis as opposed topotentially more serious action being taken. And then we have the case of Dr. Hampshire, wherethe FDA worked mightily to pursue her.
In fact, the FDA went so far as to send a criminal referral to the United States Attorney inMaryland to prosecute her for alleged wrongdoing. Disturbingly, the FDA wrote a criminalreferral that was riddled with inaccuracies about Victoria Hampshire. Perhaps in the future theFDA would pursue alleged bad behavior by corporations with the same vigor, persistence andcreativity with which it pursued Victoria Hampshire. So, if there is no objection, I request thatmy letter to Dr. von Eschenbach about the intensive investigation done by FDA against one of itsown be placed into the record.
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