Hearing of the Oversight and Investigations Subcommittee of the House Energy and Commerce Committee - Ketek Clinical Study Fraud: What Did Aventis Know?

Interview

REP. STUPAK: This meeting will come to order. Today we have a hearing titled "Ketek Clinical Study Fraud: What Did Aventis Know?" Before I begin, I have a couple of housekeeping items to discuss.

On January 29th, the subcommittee held a business meeting to issue subpoenas for several outstanding requests the committee has made of the FDA. The subpoenas were approved unanimously on a 12- nothing bipartisan vote.

While we are pleased that the FDA has produced the agents for today's hearing, we are far less than pleased with the response we received yesterday by the committee regarding our subpoena for documents requested almost a year ago in March of 2007.

Yesterday afternoon, a letter arrived at the committee, signed by an assistant secretary for legislation at the Department of Health and Human Services, and signed by the chief of staff for the FDA, stating that they want to, quote, "reach alternative solutions," end of quote, rather than producing the documents we subpoenaed at our January 29th business meeting.

The letter is troubling on several fronts. First, the subpoena was served under secretary of health and human services, and he did not provide the committee the courtesy of a response under his signature. Second, there appears to be a continued effort to keep secret the documents we requested. This only causes members to further question what could be so damaging in the materials that the administration wants to stonewall our bipartisan subpoena.

There is a precedent for obtaining briefing book documents from both democratic and republican administrations without having to issue these subpoenas. The secretary was made aware of the precedents with the committee chaired by republicans Mr. Bliley and Mr. Barton, received briefing books of FDA commissioners in a democratic administration, Dr. Kessler.

They were also obtained when chaired by a Democrat, Mr. Dingell, receiving briefing books of a commissioner in republican administration, Mr. Frank Young. I find the letter yesterday -- I find the letter received yesterday to be very disconcerting, and we'll be discussing options with Chairman Dingell and Ranking Members Barton and Shimkus in the coming days.

On a separate note, due to a series of votes in the Senate, we'll need to call our second panel first, and have Senator Grassley present his testimony as our second panel. Or when the senator gets here, we will move to his testimony. Right now, let's begin this hearing. Each member will be recognized for five minutes for an opening statement. I will begin.

Today we hold the third hearing by the subcommittee on whether the FDA can fulfill its mandate to protect American people from unsafe drugs. Once again we'll be exploring this question in the context of the controversial antibiotic, Ketek. The deeper members of this subcommittee dig into Ketek approval process, the more disturbed we become about the entire drug approval process.

Today's hearing will shine a spotlight on a little understood and rapidly growing world of private drug research and clinical trials. Specifically, we will examine the data integrity lapses and fraud contained in the large Ketek clinical trial study 3014, which was initially commissioned to assure the safety of Ketek.

The Ketek clinical study illustrates the failure by all stakeholders -- FDA, drug companies, third party monitors, and institutional review boards -- to ensure the integrity of clinical trials that used to support the safety and approval of new drug applications.

A year ago, this committee heard testimony from Senator Charles Grassley about his repeated attempts to secure information from the FDA, and the obstacles the FDA erected to impede his investigation of the Ketek approval process. Senator Grassley also expressed concern that FDA manager -- management discourages, even muzzles scientific dissent.

Sadly, this committee's parallel investigation of Ketek over the past year has confirmed Senator Grassley's dismal assessment of the FDA. Senator Grassley returns today to share the findings contained in his recently issued report of the finance committee ongoing investigation into the safety of Ketek, particularly what he's uncovered regarding the criminal investigations conducted by FDA's Office of Criminal Investigations, OCI, into allegations of fraud in connection with Ketek clinical study 3014.

We also welcome back Ann Marie Cisneros, formerly a senior clinical research associate with PPD, the contract research organization, CRO, hired by Aventis to monitor study 3014. Ms. Cisneros will open the second panel by explaining why she was convinced that Aventis, PPD, and Copernicus, the institutional review board, all charged with protecting the patients in study 3014, were well aware of the faulty and possibly fraudulent data submitted to the FDA by Aventis in connection with the approval of Ketek.

We are particularly grateful to Ms. Cisneros for sharing her experience with this committee, despite attempts by her former employer to extort her silence. Ms. Cisneros was dispatched in February 2002 to inspect the site of Dr. Kirkman-Campbell who had enrolled more patients, 407 to be exact, into study 3014 -- more than any other investigator.

Prior to her visit, Ms. Cisneros was informed by Dr. Reynolds (ph) of extremely suspicious activity at the site by other PPD personnel, and was asked to scrutinize Dr. Kirkman-Campbell's site and try to bring back evidence of fraud. After only two days at the site, Ms. Cisneros found the site so troubling that she was afraid that Dr. Kirkman-Campbell was endangering patient safety.

Consequently, on February 21, 2002, Ms. Cisneros called Copernicus, the institutional review board working for Aventis, to urge them to intervene to protect patients. Copernicus did nothing. Dr. Kirkman-Campbell was ultimately convicted of fraud in connection with study 3014, and sentenced to nearly five years in prison. The fraud at the site was detected only after a routine audit by the FDA, not because Copernicus or Aventis had warned them.

Well before the FDA audit, however, Aventis, PPD, and Copernicus were all aware of scientific misconduct indicative of fraud at the site. Evidence before this committee suggests that only a company, intent upon ignoring the obvious, could have failed to detect fraud in study 3014.

At Kirkman-Campbell's site alone, obvious indicators of fraud included the following: errors in nearly every informed consent form, date modifications, initials differed from the signatures, study coordinator entering dates for subjects and the principal investigator, latently forged signature on a form -- consent form, medical records very limited, use of different color ink on medical charts, overwrites, crossed outs, inserts of diagnosed -- diagnosis in different colored ink, routine failure to give pregnancy tests to women of childbearing age, study investigator and coordinator unaware of definitions of serious adverse event or adverse event of special interest, no adverse events for the first 300 patients enrolled with drugs known to have adverse events, lab results indicative of blood splitting, lack of proper diagnosis for study eligibility, husbands and wives enrolling together, large number of patients randomized in the interactive voice response system in a short incremental time when the office was closed for lunch and not seeing patients, and 100 percent compliance by patients taking study medication.

Aventis, PPD, and Copernicus were aware of this misconduct well before Aventis submitted Dr. Kirkman-Campbell's data to the FDA to support the approval of Ketek. At a minimum, Aventis should have discontinued enrolment at the site and notified the FDA.

We will also hear today from three FDA criminal investigators who investigated misconduct and/or fraud in connection with Ketek study 3014. The FDA has done its very best to deny this committee access to these agents and their investigatory documents. These agents testify today under subpoena.

Be assured, however, that we do not lightly compel the appearance of witnesses before this subcommittee to discuss criminal investigative matters, and would not have done so with their testimony not of the utmost importance. I'd like to remind FDA managers that retaliation against any agent for their testimony will not be tolerated by this committee.

Office of Criminal Investigation Special Agent Robert West, led the criminal investigation which resulted in the August 2003 indictment and October 2003 conviction of Dr. Kirkman-Campbell for fraud in connection with study 3014.

Special Agent West will explain how he tried to convince FDA management in 2003 to expand the investigation of fraudulent submission of trial data to include other sites, and ultimately Aventis. However, FDA did not open an investigation in the possible misconduct of Aventis until 2006, over four years after the study ended.

In early March 2006, Special Agent Robert Ekey was assigned the criminal investigation of Aventis. Today he will confirm that his investigation revealed evidence indicating that Aventis was aware of serious data integrity problems at the Kirkman-Campbell site, but submitted the site data to the FDA notwithstanding.

The investigation languished until shortly after this committee's Ketek hearing last year when the case was reassigned to Special Agent Douglas Loveland. Special Agent Loveland conducted an extensive reinvestigation and became convinced of Aventis' guilt. On June 21, 2007, he presented FDA's evidence to Aventis to the United States attorney for the District of New Jersey, and recommended prosecution.

The U.S. attorney ultimately declined to prosecute Aventis, not because of lack of evidence against Aventis. The declination letter states instead -- put simply, FDA's lack of reliance under faulty study and its subsequent decision to approve Ketek despite ongoing investigation into Dr. Kirkman-Campbell conduct make any conviction against Aventis for fraud in connection with submission of the study highly unlikely.

Our final panel consists of the following industry officers: Dr. Paul Chew, president of the U.S. research and development, Sanofi- Aventis Pharmaceuticals; Fred Eshelman, CEO of PPD, the contract research organization hired by Aventis to study -- to monitor study 3014; and Sharon Hill Price, the CEO of Copernicus Group in institutional review board hired to protect human subjects of study 3014.

Evidence before this committee suggests that each of these firms had direct knowledge of serious misconduct and possible fraud in study 3014. Yet, none of them notified the FDA. We expect them to explain why they did not do so. Clinical research has changed dramatically within the last two decades. No longer anchored in public sector, clinical trial practice like PPD and Copernicus Group is currently big business and largely self regulating.

Today's hearing will demonstrate how some actors behave in a climate of self regulation, and may be time to seriously rethink the regulatory framework for the clinical trial industry and institutional review boards and contract research organizations. That concludes my opening statement.

I'd next like to turn to my colleague, Mr. Walden, for his opening statement, and thank you for being here today.

BREAK IN TRANSCRIPT

REP. STUPAK: Okay. We will go right to questions. And Ms. Cisneros, if I may? You indicated that after a couple of days you called the IRB Copernicus.

MS. CISNEROS: Yes, sir.

REP. STUPAK: Do you know when that was?

MS. CISNEROS: It was probably three or four days into my visit though either a Wednesday or a Thursday. I believe it was a Wednesday of that week.

REP. STUPAK: Okay. Why did you call Copernicus?

MS. CISNEROS: I knew fraud was being committed at the site, and I feared for patient's safety. I -- while I wanted to go up the chain of command at PPD I just felt like Copernicus could take immediate action against the site. And --

REP. STUPAK: Their responsibility is the patient's safety?

MS. CISNEROS: Right.

REP. STUPAK: Is that their main focus in any clinical trial, in IRB, Institutional Review Board?

MS. CISNEROS: Well, their main focus is approving informed consents and protocols that reflect patient's safety or to ensure that patients are kept safe, but there are other statements in the informed consent that that's said the patient's could have called the IRB if they had any concern.

REP. STUPAK: Sure. So any concerns about patient's safety should be directed to the IRB then?

MS. CISNEROS: Correct.

REP. STUPAK: Okay.

MS. CISNEROS: Now monitors aren't ever encouraged to call IRB, there's just not a relationship there. I'll just put that in the record.

REP. STUPAK: So this was unusual for you to do this?

MS. CISNEROS: Absolutely.

REP. STUPAK: Okay. But you felt compelled to call Copernicus?

MS. CISNEROS: Yes.

REP. STUPAK: And then how did you -- by telephone I take it?

MS. CISNEROS: Yes.

REP. STUPAK: And do you know who you called?

MS. CISNEROS: I believe there was the president of the company at the time.

REP. STUPAK: Okay. Right in front of Mr. Ekey there, could you hand her that big binder.

Would you please take a look at exhibit number 4?

MS. CISNEROS: Would you -- I am sorry. What number?

REP. STUPAK: Four, please.

MS. CISNEROS: Four.

REP. STUPAK: Okay. Exhibit 4 has two pages.

MS. CISNEROS: Uh-huh.

REP. STUPAK: And then while you are holding that tab would you also go to exhibit 33. I want to direct you to those two documents, 33 and 34 -- 33 and number 4, excuse me. Could identify number 33 for us?

MS. CISNEROS: Thirty-three is a telephone contact report taken by the IRB of my phone call.

REP. STUPAK: Okay. And it's dated February 21, 2002?

MS. CISNEROS: Yes.

REP. STUPAK: Okay. It says, "IRB staff member taking calls, Sara Wallis (ph)." Do you know who Sara Wallis is?

MS. CISNEROS: I don't recollect that name.

REP. STUPAK: Okay. Do you know if she is the president of Copernicus?

MS. CISNEROS: To my knowledge Sharon Hill Price was the president of Copernicus.

REP. STUPAK: Okay. Do you know Ms. Price?

MS. CISNEROS: I do not, no.

REP. STUPAK: Okay. But your recollection that that's who you spoke to on that day?

MS. CISNEROS: Yes.

REP. STUPAK: Okay. And does the "Cisneros, she" meaning you, "has reviewed 40 -- 50 of the 400 files and some other and some of her concerns are listed below." Do those accurately reflect your concerns?

MS. CISNEROS: Yes, they do. But I also remember saying that I was willing to furnish the IRB with patient names and phone numbers of patients I thought to be fraudulent. In an effort to, again, have some validity as to whether these patients were actually true patients or not. And then in do not see that noted in this.

REP. STUPAK: Okay. Did the president of Copernicus then ask you for those names or number of these patients?

MS. CISNEROS: No.

REP. STUPAK: Okay. Let me go to exhibit number 4, second page, again would you please review the second page, does that reflect any of the statements you may have made to Copernicus?

MS. CISNEROS: I didn't go into detail about each subject, I pretty much just said every informed consent had an issue, that one consent I believe to be a forgery. I didn't know what she was doing with the study drug, if patients were being given drug, and then not follow it up or anything, so no, I didn't go into specifics.

REP. STUPAK: Okay. On page 1 of that exhibit 4, it says it's from a Jessica Lacily (ph) and you're carbon copied on this. And this was a telephone conference to discuss findings for monitoring of Kirkman-Campbell, is that correct?

MS. CISNEROS: Yes.

REP. STUPAK: And this was a few days after you made the call on February 27, 2002?

MS. CISNEROS: Yes.

REP. STUPAK: Okay. Where you in on that conference call?

MS. CISNEROS: Yes, I was. If it's the one -- there was one teleconference that I was in on.

REP. STUPAK: Okay. And do you believe that this was the one and your listed there as the carbon copy was sent to Nadine Grethe, and then carbon copy to you?

MS. CISNEROS: Yeah, this is an e-mail setting up the teleconference, so I participated in that teleconference.

REP. STUPAK: Okay. Then down in the bottom last paragraph says, "Ann Marie" that would be you?

MS. CISNEROS: Yes.

REP. STUPAK: And, "John have assembled some examples of this information we can share with you, let us know. We've attached the summary of Ann Marie's findings during her visit."

MS. CISNEROS: Correct.

REP. STUPAK: And that would be you.

MS. CISNEROS: Yes.

REP. STUPAK: Okay. My time is up, I am going to want to come back to this witness, and let me -- I want to just ask one question, and one more question because -- did Dr. Kirkman-Campbell react to you monitoring her site, did she try to get rid of you during the course of your investigation?

MS. CISNEROS: Well, she was very uncomfortable with us being there, she constantly complained about how we were taking up space in her office. She couldn't see as many patients as she wanted to, that sort of thing.

After, I believe it was Thursday of that week; she was going to send me home. And I was in her office, and she was on a -- she was talking to Nadine Grethe and I heard her saying, "Nadine, I let Ann Marie stay if you can get me into more of Aventis Studies.

REP. STUPAK: Okay. So the "Nadine" that she was talking to was Nadine Grethe from Aventis?

MS. CISNEROS: Correct.

REP. STUPAK: And that's the same Nadine that's in exhibit number 4 that you had this telephone conference with on Wednesday then of that week you were down there?

MS. CISNEROS: Correct.

REP. STUPAK: And then the next day on Thursday did you leave then now Dr. Kirkman-Campbell's office --

MS. CISNEROS: I believe I left that day, yes.

REP. STUPAK: Okay. Thank you.

Now Mr. Walden, for questions please.

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REP. STUPAK: So this page 5, these sites -- Dr. Zakour (ph), Dr. Barbara (ph), Dr. Franklin (ph), Dr. Sagatti (ph), Dr. Gardner (ph), Dr. Manchochilibio (ph), Dr. Jeffrey McLeod, Dr. Stone (ph), Dr. Layne (ph), Dr. Tepstra (ph), and Dr. Anne Kirkman-Campbell; all that information about these sites then and the problems at these sites actually came from Aventis?

MR. LOVELAND: That's correct. They had this knowledge, we didn't have it.

REP. STUPAK: Right and you included this in your report?

MR. LOVELAND: Yes.

REP. STUPAK: So, and each one these they were alleging problems and protocol violations which were significant enough to effect the integrity of the Study 3014?

MR. LOVELAND: Data in it, yes, sir.

REP. STUPAK: So Aventis definitely knew about at least from 10 sites that they were significant problems?

MR. LOVELAND: In actual fact, during one of the interviews, the interviewee told me that Aventis had 18 clinical investigators with whom they had significant GCB problems.

REP. STUPAK: Associated with site 3014 -- I mean, study 3014.

MR. LOVELAND: That's correct. That's a 1 percent ratio. But some of these here are the highest enrolling sites.

REP. STUPAK: So it's not just necessarily the number of sites, but also number of patients that were enrolled at each site to make up your study, correct?

MR. LOVELAND: That's correct.

REP. STUPAK: And this is significant in even this one percent of the sites.

MR. LOVELAND: It was and the reason I put it in the report is because it was -- it explained the context of the data that were coming into the FDA from Aventis. It wasn't just Kirkman-Campbell; the data were not reliable in other locations.

REP. STUPAK: Did you reach conclusion in that the data relied upon or the data relied on 3014 that was unreliable?

MR. LOVELAND: I didn't have to the DSI did that, they get paid to make that decision and I do not disagree with it.

REP. STUPAK: Okay. DSI.

MR. LOVELAND: Division of Scientific Investigation is the division within the Center for Drugs Evaluation and Research, and they actually schedule inspections, they actually read the reports, and issue the instructions and all those sorts of things.

REP. STUPAK: Very good. Agent West, if I may you opened the criminal investigation shortly the FDA clinical site investigator Ms. Smith inspected Kirkman-Campbell's site, is that correct?

MR. WEST: That's correct, Sir.

REP. STUPAK: And that was in October, 2002?

MR. WEST: Yes, sir.

REP. STUPAK: Okay. What did Kirkman-Campbell do when you notify her as you were conducting this criminal investigation?

MR. WEST: When I approach Dr. Campbell at her clinic and asked to speak with her the first thing that came out of her mouth was, "I will not speak with you unless I speak with the Aventis personnel first."

REP. STUPAK: Okay. Do you know if she spoke with Aventis?

MR. WEST: I have no idea, but I am assuming after I left, she had to speak with Aventis because they had to prepare the 483.

REP. STUPAK: Okay. And that's a --

MR. WEST: That the response to the inspection.

REP. STUPAK: Okay. So Kirkman-Campbell had to file this report in response to your inspection?

MR. WEST: As a response to the regulatory inspection, not my criminal --

REP. STUPAK: Okay. Why were you convinced that Aventis should be criminal investigated for knowledge of Study 3014?

MR. WEST: My feeling at the time, it was based on what I was observing not only in Kirkman-Campbell's clinical trial, but also my interviews of PPD personnel along with Aventis personnel. And I felt at the time that it was sort of like blatant disregard, for information that they were receiving from the field and providing to the FDA.

REP. STUPAK: Do you still feel that today?

MR. WEST: Yes, sir.

REP. STUPAK: We understand that Dr. Kirkman-Campbell solicited drug companies sales representative to supply blood for the Ketek study. Is that correct?

MR. WEST: That's correct.

REP. STUPAK: Shouldn't the drug company representatives have known what the blood was being used for?

MR. WEST: Oh, I think they knew that Kirkman-Campbell was conducting a clinical trial. What they told me was that they were just going to allow her to use their name in a clinical trial so that they could continue to have her business as a pharmaceutical rep.

REP. STUPAK: By "they" you mean blood company representatives or Aventis?

MR. WEST: The company that each one of the pharmaceutical reps were representing at the time.

REP. STUPAK: In the course of your investigation, did Dr. Kirkman-Campbell -- did you learn that Aventis had flown her to California to teach, so she could teach other people how to do these clinical trials?

MR. WEST: Based on what she told us, is that, yes, Aventis flew her out to California so she could teach other PIs how to conduct clinical trials.

REP. STUPAK: PI, the Principal Investigators?

MR. WEST: Principal investigators?

REP. STUPAK: To your knowledge, did Kirkman-Campbell participate in another study with Aventis?

MR. WEST: I think when I was there conducting my criminal case, not only was she conducting studies for Aventis, but she was conducting studies for GSK, GlaxoSmithKline.

REP. STUPAK: Okay. Could you please take a look at the exhibit book, exhibit number 25, if you would? Can you identify what that exhibit is?

MR. WEST: This looks like an e-mail from Dr. Campbell to a member of Aventis basically saying thanks for assisting me in preparing the 483.

REP. STUPAK: And that's thanking Aventis for helping her fill out forms for another study, is that correct?

MR. WEST: That's correct.

REP. STUPAK: And that e-mail is dated November 17, 2002, is that correct?

MR. WEST: That's correct.

REP. STUPAK: Where you doing your criminal investigation of Dr. Kirkman-Campbell on Ketek then at that time?

MR. WEST: Yes.

REP. STUPAK: Okay. Turn to exhibit number 8, if you would, please.

MR. WEST: Did you say 8?

REP. STUPAK: Eight, yes. And this memo, you can describe, but it's -- you're recommending that the investigation should be undertaken by the FDA into whether Aventis knew that study 3014 contained fraudulent data when it was submitted to the FDA. Is that what that is about?

MR. WEST: That's correct.

REP. STUPAK: Okay. And who are you doing this study to in the FDA, or I'm sorry, directing the --

MR. WEST: This particular e-mail I was responding to Director Vermillion who is the director of OCI, but I -- the e-mail is in response to a conversation I had with CDER personnel Dr. Soreth, Dr. Goldberger, Dr. Cox and doctor -- this particular e-mail was just for those three individuals.

REP. STUPAK: Okay. When you say CDER, that's Center for Drug Evaluation and Research, right?

MR. WEST: That's correct.

REP. STUPAK: And you were trying to get them to allow you to continue the investigation into Aventis, whether or not Aventis knew the fraud before they submitted 3014 to the FDA, correct?

MR. WEST: That's correct.

REP. STUPAK: And what happened as a result of your conversations with officials at CDER?

MR. WEST Well, first of all I have to say that the reason why I needed CDER support is that I don't have the authority to go out and conduct inspections on PIs. I needed DSI to issue assignments to the regulatory so they could go out and do inspection.

REP. STUPAK: Okay.

MR. WEST: That's what I was recommending to Goldberger, Soreth, and Cox.

REP. STUPAK: Okay.

MR. WEST: And I did not hear anything, I did not get a response from them, but I heard through the grapevine that they declined to participate and -- because of personal problems and money.

REP. STUPAK: Okay. Would it be the huge financial commitment of resources or money to do this investigation?

MR. WEST: No, because I was only asking for their support. In other words provide assignments to regulatory to go out and actually conduct the inspections. OCI and other regulatory inspectors would've actually conducted the review of document.

REP. STUPAK: And in this exhibit number 8, you basically lay out how you would do it, correct, how you would go about it?

MR. WEST: Correct.

REP. STUPAK: If you have this opportunity, you would go out and do the investigation, and you were willing to go do it?

MR. WEST: That's correct.

REP. STUPAK: Okay. Did you believe there was a possibility of detecting fraud if they just filed your recommendations as you laid out in exhibit number 8?

MR. WEST: Oh, I believe that we would've detected fraud in other sites?

REP. STUPAK: In your opinion, didn't someone at CDER, Center for Drug Evaluation and Research at the FDA or elsewhere in the FDA, block your proposal to create this taskforce to go look and to criminally investigate Aventis in connection with study 3014?

MR. WEST: I believe someone above the individual that I was speaking to, which was Brenda Frant (ph), blocked the participation of the center to support OCI.

REP. STUPAK: Do you have any idea who that individual would've been?

MR. WEST: I have no idea.

REP. STUPAK: Is it possible that because of the failure to investigate, Aventis personnel and others may have committed criminal violations of the Food and Drug and Cosmetic Act without being charged?

MR. WEST: Almost definitely.

REP. STUPAK: Okay. Did you ever talk to the Dr. Quader (ph) from the FDA? Quader?

MR. WEST: I talked -- yeah, I spoke with Dr. Quader. I briefed her the same way I briefed Goldberger, Soreth, and Cox. I also provided her with the same recommendations. Then I also explained to every one of them that we couldn't -- as OCI, we couldn't demand, because there was legal issue. If we demand them to do something and they go out and do it, then we're kind of sort of conducting a search, which would've been -- which would've created a legal issue for us. So we recommended or suggested that they go out and do further inspections, which they declined.

REP. STUPAK: Okay. So besides exhibit number 8, this e-mail, you had other conversations with Dr. Quader, Cox, and others about where this investigation should go, and in your recommendation it should continue to look at what Aventis knew prior to submitting this data to the FDA on study 3014?

MR. WEST: Oh, yes. Not only those individuals, but I was in constant contact with DSI explaining to them what was going on in the criminal case so they could be aware because of the 3014 being submitted and up for approval.

REP. STUPAK: Thank you.

Mr. Ekey, we haven't asked you any questions. Do you have anything you'd like to add?

MR. EKEY: I'll wait until you have a question.

BREAK IN TRANSCRIPT

REP. STUPAK: Sure, Mr. Walden.

Mr. West, you may or may not know this. You talked about the migraine study. You said, you notified DSI, that's the Department of Scientific --

MR. WEST: Division of Scientific Investigations.

REP. STUPAK: Okay -- that's within the FDA?

MR. WEST: That's correct, within the Center for Drugs.

REP. STUPAK: Right, CDER, Center for Drug Evaluation and Research.

MR. WEST: That's correct.

REP. STUPAK: So FDA and the people responsible to making sure that drugs are safe, and the approval of drugs, they knew not only about Aventis but also about this migraine study that you mentioned?

MR. WEST: That's correct.

REP. STUPAK: Okay. And then I had asked you about exhibit number 25, which is actually where she thanked Aventis; that's my understanding actually, diet pill. So those are at least three different. Do we know of any other studies that, during this timeframe 2002-2003, Dr. Kirkman-Campbell was involved with? We know at least three? You know of any others?

MR. WEST: No, sir.

REP. STUPAK: Mr. Cisneros, would you know?

(No audible response.)

REP. STUPAK: Okay. Mr. Ekey, do you know of any other studies that Dr. Kirkman-Campbell or Mr. Loveland?

MR. LOVELAND: No, sir.

REP. STUPAK: Okay. Mr. Loveland, in your belated interview with the committee last Friday you summarized your findings regarding Aventis' complicity in study 3014 clinical fraud as follows.

And I'm quoting now, "Aventis should've known of the fraud, and if they really were unsure they should've contacted the FDA for assistance in substantiating the fraud." Is that true?

MR. LOVELAND: Yes.

REP. STUPAK: Okay. In the timeframe 2002-2003, what would Aventis have known or what red flags were they aware of to make you make that statement?

MR. LOVELAND: During the period of time that the trial was in rolling, they probably did not know very much. There was one monitoring trip very early, and they showed some small sloppiness and things that could adequately be dealt with memos-to-file if you had some training.

REP. STUPAK: Sure.

MR. LOVELAND: There was one auditing trip that was a catastrophe. The poor auditor, it was his first trip, he just joined the company, he walked in the door and expecting a 100 or so patients, found 360. He spent literally the entire two days going over informed consents. He never got the data in any meaningful fashion.

REP. STUPAK: And this auditor was an Aventis employee?

MR. LOVELAND: That's correct.

REP. STUPAK: Okay, so -- and what timeframe was that?

MR. LOVELAND: That was January, mid-January of 2002.

REP. STUPAK: Okay.

MR. LOVELAND: He -- in fact, it was January 22nd. He exited the place feeling uncomfortable, and he reported to the study team, I'm not terribly comfortable with this site.

REP. STUPAK: "Study team" being Aventis study team?

MR. LOVELAND: That's correct.

REP. STUPAK: Okay.

MR. LOVELAND: We need to increase the monitoring, we need to increase the source data verification, and we need to take a look at maybe some more training. But the trial was moving along so quickly that enrollment ended by January 30th. So new people came in -- stopped coming in just a few days later.

REP. STUPAK: So even at the beginning of the study Aventis had red flags or hoardings that things weren't -- even starting off on the right foot?

MR. LOVELAND: They -- I read that monitoring report. That did not look like a huge red flag. The first really serious sets of red flags started coming up with Ms. Cisneros' visit.

REP. STUPAK: Right.

MR. LOVELAND: And then during my investigation, I made it a point to go back and visit with her again and collect that -- what was typically known as the smoking gun document, that document which she forwarded to Aventis, because that imputed more knowledge to Aventis than any other document in the case.

REP. STUPAK: "That document," you mean the record of her phone call that we had cited earlier, in this hearing?

MR. LOVELAND: She actually typed up a memo Of this, perhaps it was.

REP. STUPAK: Okay, that would be exhibit number 4, I think, we talked about.

MS. CISNEROS: I believe he's talking about the forged document that was --

MR. LOVELAND: No, your list of all the patients.

MS. CISNEROS: All right, okay.

MR. LOVELAND: Exhibit number 4, I think we talked about.

MS. CISNEROS: Right.

REP. STUPAK: Okay. So that was the smoking gun that Aventis should've known and wouldn't have been --

MR. LOVELAND: That was the document, the teleconference.

REP. STUPAK: And that was in 2002?

MR. LOVELAND: That's correct.

REP. STUPAK: And Ketek was approved, what, 2004?

MR. LOVELAND: Four.

REP. STUPAK: Four. So two years before it was even approved, Aventis knew?

MR. LOVELAND: Oh, sure. But this was even before Aventis submitted the data.

REP. STUPAK: Correct.

MR. LOVELAND: So contemporaneously, with the March 4th telephone conversation, some other folks at PPD sent some data up to Aventis saying there's some problems over here as well. And then on the 6th of March, some more data came up saying there's problems with these new forms.

REP. STUPAK: And this is all 2002?

MR. LOVELAND: That's correct.

REP. STUPAK: Okay.

MR. LOVELAND: So the period of time that my investigation focused upon was from that period through the 23rd of July, because it was the 23rd of July that they submitted the data to the FDA. So during that period of time were they capable of learning that the data had been falsified. Well, employing the decision making process that they did, they contend they never discovered the falsity of it.

REP. STUPAK: So there's no doubt in your mind that Aventis knew before they submitted 3014, that there were major problems with the integrity of the data to support their conclusion that Ketek was based -- based on study 3014?

MR. LOVELAND: I'll accept that wording. They contend they didn't know it was fraudulent, but I'll accept what you said.

REP. STUPAK: But there's no way they would not know unless they just turned a blind eye to everything.

MR. LOVELAND: If you take a mathematical analysis and you take the first allegation you say, ah, first allegation is disproven. You take a mathematical analysis and you take that second allegation, and the mathematical analysis disproves it, okay, that one is not true. I'm now down to sloppy and a forgery. We can fix sloppy with the memos to file and if the forgery falls off the radar, I'm describing a fairly incompetent system here.

REP. STUPAK: Sure.

Mr. West -- excuse me.

I just got to go back to Agent Loveland, and let me ask you one quick question. Tab number 14, if you take a moment please, sir? Tab 14 is two pages.

It's like an e-mail you're receiving dated Wednesday, April 14, 2007, and then Tuesday, April 17, 2007.

MR. LOVELAND: Where would you like me to go, sir?

REP. STUPAK: Second page, last paragraph. Could you explain that? I think this is from you to Ann Walsh (ph) in Ketek. "New drug application. The sponsor clearly sent falsified data on study 3014."

MR. LOVELAND: Right.

REP. STUPAK: Explain that for us. "Aventis knew that such significant issues existed at so many sites that GCP" -- what is that? GCP, what does that mean?

MR. LOVELAND: Good Clinical Practices, it's a standard, sir.

REP. STUPAK: Right, "could not be claimed. Yet it claimed a study was conducted to good clinical practice, GCP. Think --"

Now, these are your words, right?

MR. LOVELAND: That's correct.

REP. STUPAK: "Think," quote, "'willful blindness'" end of quote, "on steroids, but they submitted anyways." What do you mean by "willful blindness on steroids"?

MR. LOVELAND: I had never seen, except in a trial conducted out of Florida -- that was intentionally falsified -- we put them in prison. I had never seen such a significant number of GCP issues. You referenced it earlier in the questioning, sir, when you took me to page 4 of my --

REP. STUPAK: Right, first -- (inaudible).

MR. LOVELAND: There's 11 different sites that they themselves wrote up, and during the interview --

REP. STUPAK: "They themselves," you mean Aventis wrote up?

MR. LOVELAND: That's correct. And then in the interview one of the managers said, we had 18 folks with significant GCP issues. If they had 18 sites with significant GCP issues, why did you submit their data?

REP. STUPAK: Correct. Because that will be for the Aventis panel -- that will be for them to --

Let me ask you this, Mr. West, since the period you dealt with the FDA -- (buzzer sound) -- we'll freeze buzzers.

Let me ask you this. Since you dealt with the FDA-CDER, Center for Drug Evaluation and Research, and also the DSI, Division of Scientific Investigations within the FDA, before Ketek was approved in 2004, was there any doubt in your mind that they knew that there was fraud with study 3014. By "they" I mean the FDA officials?

MS. WEST: Oh, I had conversations with Brenda Frant many times and she agreed with my recommendation that we needed to move forward because of the fact that it appeared that 3014 was just riddled with fraud.

REP. STUPAK: And she kicked it upstairs to CDER?

MS. WEST: She must have kicked it up somebody because she just -- I think she works the ground level of DSI, so she had to kick my recommendations above her and those -- the people above her must have declined.

REP. STUPAK: Okay. Let me ask you this. In your opinion, has the statue of limitations run on the possibility of indicting Aventis for a fraud in connection with study 3014.

MR. LOVELAND: If I may, sir?

REP. STUPAK: Sure.

MR. LOVELAND: It would be my case.

REP. STUPAK: Okay, I'm sorry.

MR. LOVELAND: And the answer is yes, the statute of limitation has run with 3014. They submitted the data on July 23, 2002. It's got five years. If I could find a law that went farther, I'd use it. If I could've found a strict liability statute, I would've pushed for that, but I only had a 1001. It's fixed on the guidelines. It's all I could do. That's run. I can't go back to it.

REP. STUPAK: Okay. If -- Ketek is used for one of the -- been used for three different -- bronchitis, sinus and pneumonia. Now, it's only supposed to be used for community-based pneumonia. If, after July of 2002, it's prescribed for bronchitis, contrary to what it's supposed to be, now, would that reinvigorate the statute of limitations? Would statute of limitations start to run from the time it's prescribed since this approval was based on 3014?

MR. LOVELAND: You know, I'm not a lawyer, and I'm not going to go there, but I don't believe so. The only thing that I'm aware of that would allow us to take the statute beyond would be a subsequent affirmative step from the commission of a conspiracy. And we use that to lengthen the statute of limitations. I didn't have that here.

REP. STUPAK: Okay. If it was submitted in '04, the study 3014 was submitted --

MR. LOVELAND: My statute of limitations would run next year.

REP. STUPAK: Right. So if they submitted the study, Aventis submit the study to the FDA, study 3014, in 2004, for approval of this drug, the safety indicators, would not your five years run from '04 then?

MR. LOVELAND: '04 to '09, correct.

REP. STUPAK: So you still have a statute of limitation opportunity for -- then for possibility of indicting Aventis for fraud in connection with the study of 3014, not only submitting a fraudulent study to the FDA.

MR. LOVELAND: 3014 was submitted to the FDA in July of '02, sir.

REP. STUPAK: Right, but it wasn't approved until '04, was it not?

MR. LOVELAND: I don't know that -- I'm afraid, I can't go there. I don't know that that ties.

REP. STUPAK: Sure, okay.

Mr. Ekey, I don't want to leave you out, and I said I'd ask you one. I'd like to read a short segment -- and I don't want to leave you out because of the work all four of you have done and the willingness to come forward and testify, even though it was under subpoena, it has been a great help to this committee. And institutional review boards and CROs, all the things we're looking at. So we certainly do appreciate all you've done. And we take great stock in what you say.

So let me just ask you this. Because I want to just ask a statement that you made in your report. A short segment from the last page of your report. It's exhibit number 9 in the book, if you care to look at it there.

"The reporting special agent," that be you (ph), "believes that the testimony and documentary evidence indicate that Aventis was well aware of serious data integrity problems at the Kirkman-Campbell site, yet submitted this data to the FDA.

"When questioned by the FDA review committee, Aventis stated they had knowledge of problems, but did not explain why this data wasn't excluded from their submission, nor did they explain why they did notify the FDA. Additionally, Aventis falsely claimed to have stopped enrollment at the Kirkman-Campbell site."

So is it fair to say, based on that statement, that you came to believe that Aventis was aware of the serious data irregularities when they submitted the data to the FDA?

MR. EKEY: Documents and interviews show that key Aventis personnel did know that there was serious integrity problems at that site.

REP. STUPAK: Okay. You also indicate, the last line, "Aventis falsely claimed to have stopped enrollment at the Kirkman-Campbell site." Explain that last paragraph. "So even after they knew it, they continued to have Dr. Kirkman-Campbell enroll the patients?"

MR. EKEY: Just for a little back story, I did leave the FDA in January of '07. So I'm doing a lot of this without the benefit of notes, documents like that.

REP. STUPAK: Sure.

MR. EKEY: My recollection is that this information I obtained from FDA doctors that were on that committee. That's my recollection, I don't have that document.

REP. STUPAK: Doctors on that committee?

MR. EKEY: I believe it's Dr. Ross (ph).

REP. STUPAK: Okay, would that be the advisory committee to the FDA that receive the information?

MR. EKEY: Yes.

REP. STUPAK: Okay. Thank you, I have no further questions. And again, I thank this panel.

Mr. Inslee, thanks for getting here. I know of the early start, flights, and all that. Thanks for being here. Do you have any questions?

BREAK IN TRANSCRIPT

REP. STUPAK: Ms. Price, you said in response to Mr. Walden's question that Senator Grassley asked for some documentation there and you found that memo but you didn't turn it over to Senator Grassley's committee?

MS. PRICE: No, Senator Grassley, requested us to look at a lot of documents and working with counsel they determined that the information that they wanted was 2006 onward.

REP. STUPAK: So you came -- became aware of this document at Senator Grassley's request. Right? And this is document --

MS. PRICE: This is on re review of the of information --

REP. STUPAK: Go to document number 33, right, to exhibit number 33.

MS. PRICE: And that is the telephone contact report.

REP. STUPAK: Correct.

MS. PRICE: 21.

REP. STUPAK: At Senator Grassley's request you came across this document correct?

MS. PRICE: In review the -- in preparation for the meeting with your staff we became aware --

REP. STUPAK: No, no, I am asking about Senator Grassley.

MS. PRICE: Senator Grassley?

REP. STUPAK: In your testimony in questions of Mr. Walden you said you came across this document when Grassley -- when Senator Grassley asked for it but it was outside of purview of his request therefore you did not give it to him, correct?

MS. PRICE: It wasn't responsive to his request.

REP. STUPAK: And when was that -- a year ago wasn't it?

MS. PRICE: That was 2006, that was a year before your all (ph) hearing.

REP. STUPAK: Okay, 2006, so you have known about this document till 2006 then, the existence of this document.

MS. PRICE: It appeared on a long listing of thousands of documents.

REP. STUPAK: Right, but you and you knew about it in 2006, correct?

MS. PRICE: That is what our investigation turned up as the --

REP. STUPAK: So then why did you sit on the document until the day before our committee staff interviewed you? Even though we had the request in for about a year? Why did you sit on it for a year until the day before the interview?

MS. PRICE: We didn't sit on it.

REP. STUPAK: What did you do with it then for a year?

MS. PRICE: We were aware of it on an electronic search, we hadn't --

REP. STUPAK: In 2006, you were aware of it?

MS. PRICE: Yes, in 2006, we hadn't opened the document in 2006 to look at it because it wasn't in response to what --

REP. STUPAK: Sure, so you looked at it and said this doesn't go before the senator?

MS. PRICE: Nobody -- it appears that nobody looked at it or --

REP. STUPAK: Well, then how would you know if it was in keeping of Senator Grassley's request then if you didn't look at it?

MS. PRICE: It showed up on an electronic data search. It showed up simply as a telephone contact report. It had a date of when it was written --

REP. STUPAK: Sure, and what was the date it was written?

MS. PRICE: I would have to look back but I think that the date --

REP. STUPAK: And that document -- and that electronic search would also have the person who entered the information on that document would it not?

MS. PRICE: The electronic search did not have an author, I don't believe, on it.

REP. STUPAK: You don't know or you don't remember?

MS. PRICE: I don't remember -- I don't remember.

REP. STUPAK: Is that a computerized form right there, exhibit number 33? Is that a computerized form?

MS. PRICE: Yes, it is. It is a Word document.

REP. STUPAK: So your backup files would have, when it was entered and who by, would it not?

MS. PRICE: Yes, that is why it turned up on the electronic search, when we narrowed down our search criteria to --

REP. STUPAK: Sure, so your electronic search would have who entered it in, correct?

MS. PRICE: The electronic search that I remember seeing did not have who entered it. No.

REP. STUPAK: So you have a document retention policy do you at your organization, at your company?

MS. PRICE: Yes, we do.

REP. STUPAK: So can you provide us with that, the electronic search log, which indicates this document was part of it?

MS. PRICE: I would be happy to.

REP. STUPAK: Okay. Let me ask you this, the telephone document -- I should say telephone contact -- indicates that Sarah Wallis (ph) to a great part right?

MS. PRICE: Yes, sir.

REP. STUPAK: But the testimony has been that Mr. Nellis (ph) talked to you? Correct?

MS. PRICE: That was her initial testimony and I noticed --

REP. STUPAK: And that was her testimony this morning too.

MS. PRICE: Today she said she thought she spoke to the president.

REP. STUPAK: Right, and she identified you as the president.

Right?

MS. PRICE: She did not identify me as the president until after you asked her who the president was.

REP. STUPAK: Right, right so she identified you as the president, okay. And you was claiming you never talked to her.

MS. PRICE: That is correct I never talked to her.

REP. STUPAK: What was your company's policy on filling out this form here, this telephone contact form? Is this supposed to be done when the contact was made or do you do it the next day? What was your company policy on filling out this document?

MS. PRICE: At the time the company policy was to fill out a telephone contact reports for any significant issues, and obviously, Sarah Wallis felt this is significant enough to fill out a telephone contact on --

REP. STUPAK: Right did you have a timeframe when she is supposed to fill out this contact?

MS. PRICE: There was no timeframe given in our --

REP. STUPAK: She could do it a week later if she felt compelled to do it a week later?

MS. PRICE: Yes, but she had been trained to do it soon after the call.

REP. STUPAK: And who trained her to do it soon after the call?

MS. PRICE: Training at that point was done by our director of IRB services and or myself and other experienced professionals.

REP. STUPAK: Okay, and Ms. Wallis left Copernicus shortly after this call was received is that correct?

MS. PRICE: Yes, she did. Within two weeks, I believe.

REP. STUPAK: And in the interview with Ms. Wallis she stated to the committee staff she did not remember getting this call but she was certain that if she had gotten a call she would have immediately notified you or Dawn Pope because of the extraordinary content of the call. Do you think she would have contacted you if she were to receive the call?

MS. PRICE: She must have told you all that, yes, and I feel that it is highly unusual to get a call like this and she would have remembered to forward that on to her supervisor.

REP. STUPAK: Okay. So who had been her supervisor then?

MS. PRICE: Director of IRB Services.

REP. STUPAK: And who is that?

MS. PRICE: Dawn Pope.

REP. STUPAK: Okay. Did Dawn Pope ever talk to you about receiving this call or the information she received from Sarah Wallis?

MS. PRICE: No sir.

REP. STUPAK: So what happened to this information when serious allegations like this are made what would happen if you were to have been informed, what would have happened?

MS. PRICE: This type of calls should have been forwarded to a supervisor and then would have eventually got into the Institution Review Board, where it would have been investigated and action taken by the board.

REP. STUPAK: So did you talk to Ms. Pope about whether or not she ever received this document?

MS. PRICE: Certainly, yes.

REP. STUPAK: And what is her response?

MS. PRICE: She does not remember this either.

REP. STUPAK: So, Ms. Wallis just filled out this form and it sat in your files?

MS. PRICE: It appears so. It appears to be a human error and I wish I could explain it but I cannot.

REP. STUPAK: Well, who would -- does it indicate who she had forwarded that to, Ms. Wallis, does it indicate who Ms. Wallis forwarded it to?

MS. PRICE: No.

REP. STUPAK: Would your electronic file indicate who she would have forwarded it to.

MS. PRICE: Excuse me.

REP. STUPAK: Would your electronic files show who she would have forwarded it to?

MS. PRICE: I don't know the answer to that I would have to find out but I think that when you look to see if it had ever been printed because that was one of our concerns too, this should have been not only generated but also printed and put in the investigator hard-copy file.

REP. STUPAK: So what happened did a hard copy go on to the investigator file then?

MS. PRICE: No, it did not and that was where the rub was. It should have gone into the file.

REP. STUPAK: So this serious allegation went through your organization and it just sat there -- (cross talk) --never forwarded, no hard copies ever made nothing.

MS. PRICE: That is correct.

REP. STUPAK: Would Ms. Wallis know to make a hard copy and put it in the file?

MS. PRICE: Would Ms. Wallis had what -- excuse me?

REP. STUPAK: Ms. Wallis would have made a hard copy right?

MS. PRICE: That too would be -- the person who took the call was --

REP. STUPAK: That is what she should have done.

MS. PRICE: Yes, sir.

REP. STUPAK: So -- okay, do you know how many protocol violations or deviation forms you received on Study 3014?

MS. PRICE: On the entire Study 3014?

REP. STUPAK: Yes.

MS. PRICE: No, but there were quite a few memos to file.

REP. STUPAK: What did you do with the information then -- you had quite a few complaints about Study 3014 what did you do with the information?

MS. PRICE: Our policy at the time was to not review protocol violations, we were concentrating on serious adverse events that were reported by the investigators for the study.

REP. STUPAK: So you are saying your violations that you heard of were only protocol violations and not serious adverse events, right?

MS. PRICE: That was our procedure at the time we have now certainly changed that.

REP. STUPAK: So protocol violations, no matter the number, wasn't alarming to you -- to your organization -- to Copernicus?

MS. PRICE: Not at the time yeah, no we felt that those were things that were picked up on the monitoring visit and were corrected at the site -- with the site at the time.

REP. STUPAK: How do you know if they were corrected? You said you assumed they were corrected, how do you know that?

MS. PRICE: In some cases it is an assumption, in some cases the actual memo to file did indicate that there was reeducation of the investigators.

REP. STUPAK: Turn to exhibit 32, if you would, in the book there.

This document has been titled procedure number 108, reflect the procedures that occur at Copernicus with respect to safety and noncompliance reporting requirements, correct?

MS. PRICE: Yes, that is correct.

REP. STUPAK: Okay, were you under a duty to notify the IRB when you receive protocol violations? Isn't that what it says?

MS. PRICE: Under a duty to inform the IRB of protocol violations?

REP. STUPAK: Yes, true.

MS. PRICE: Let me take a look here to see where that -- is it -- do you know which number it is addressed in?

REP. STUPAK: Number six.

MS. PRICE: The board is responsible for reporting investigator noncompliance as required by applicable federal regulation.

REP. STUPAK: Sure so were you required to notify the IRB when you received protocol violations?

MS. PRICE: Our interpretation of the regulations at that point did not constitute us -- our reporting violations to the board.

REP. STUPAK: So now you believe you are required to do so?

MS. PRICE: We have evolved a lot in 6 years as an institutional review board as has the industry. And --

REP. STUPAK: How long --

MS. PRICE: -- now require investigators to report unanticipated problems and that is what this would have arisen to.

REP. STUPAK: So when did Copernicus start -- when did your company start --

MS. PRICE: When --

REP. STUPAK: When did you start -- when did -- you said that you founded the company, when did you do that?

MS. PRICE: 1996, sir.

REP. STUPAK: 1996, so are in 6 years since the -- when you started seeing the problems then with Kirkman-Campbell right? Kirkman-Campbell 2002, when you are doing this work here for Aventis and all that, correct?

MS. PRICE: We became IRB of record or were asked to be IRB of record in 2001.

REP. STUPAK: Okay, but -- 1996, you have been an IRB right?

MS. PRICE: Yes, we started in 1996.

REP. STUPAK: So you had more than one IRB before 2001, right?

MS. PRICE: We had one -- I don't understand your question.

REP. STUPAK: Okay, you said you were asked to be an IRB in 2001, correct?

MS. PRICE: For 3014, yes sir.

REP. STUPAK: But before that you have been an IRB before right since 1996 you have been in -- served as IRB --

MS. PRICE: And we --

REP. STUPAK: So you certainly knew the requirements and even -- if you didn't know the understanding of procedure number 8 subtitle or paragraph number 6 there and title procedure 108 reflects procedures of Copernicus with respect to safety and noncompliance reporting requirements. Why would you have it if you didn't understand what it meant? Those are your own procedures.

MS. PRICE: We did understand what it meant. At the time, the interpretation was that protocol violations did not constitute serious adverse events or unanticipated problems.

The whole industry has evolved since then and we feel that we have systems in place now and policies and procedures that would address this.

REP. STUPAK: So this one case, this Study 3014 has changed the whole industry standard on the way you do things?

MS. PRICE: No, sir. There has been an evolution going on for a long time and I think the area of unanticipated problems is certainly one that we deal with constantly.

As late as April 2007, there has been some draft guidance from FDA regarding what needs to be submitted to the IRB and what would constitute an unanticipated problem.

REP. STUPAK: How many memos to the file or protocol violations did you receive just regarding the Kirkman-Campbell site alone?

MS. PRICE: We received 83, I believe, 83 memos to file, protocol violations, and we received them 3 months after she closed as an investigator.

REP. STUPAK: So you received 83 different complaints. Given the number and nature of the informed consent and other violations, didn't you have an obligation to ensure patient safety at these sites, or at least enquire from the sponsor to see what was taking place?

MS. PRICE: We had no authority after she was closed to do anything about it and, no, we did not report them to the FDA.

BREAK IN TRANSCRIPT

REP. STUPAK: Let's call back our last panel that was up there, third panel, Dr. Paul Chu, Dr. Fred Eshelman, and Ms. Sharon Hill- Price. Dr. Chu, Dr. Eshelman and Ms. Price, you remain under oath. Understood. Okay.

Ms. Price, let me ask you this. What's the purpose of an IRB? What is the main focus of an RBI?

MS. HILL-PRICE: Here we go. An institutional review board, or IRB, as it's called, review clinical research within an ethnical and regulatory framework --

REP. STUPAK: To protect --

MS. HILL-PRICE: -- to ensure -- yeah, to ensure subject protection according to the regulations.

REP. STUPAK: Patient safety.

MS. HILL-PRICE: Subject safety, yes.

REP. STUPAK: Okay. So if there's a concern about patient safety instead of the PPD, the Contractor Review Organization -- they would go to the IRB, correct?

MS. HILL-PRICE: We are one of the venues, yes, if there is a concern about subject safety.

REP. STUPAK: What other venue is there?

MS. HILL-PRICE: I think that subject safety is a shared responsibility, as I indicated in my opening statement.

REP. STUPAK: Okay. With the IRB -- in this case Copernicus on Study 4014 -- and with who else?

MS. HILL-PRICE: The sponsor, the investigator.

REP. STUPAK: That'd be Aventis.

MS. HILL-PRICE: The investigator, FDA --

REP. STUPAK: That'd be Dr. Kirkman-Campbell, FDA.

MS. HILL-PRICE: -- and even the subject to some extent. He needs to take some responsibility for participating in research.

REP. STUPAK: Sure. But the main focus and reason why IRBs came about was to protect patient safety, correct?

MS. HILL-PRICE: Yes.

REP. STUPAK: And that's the genesis of the IRBs, patient safety.

MS. HILL-PRICE: Yes.

REP. STUPAK: Okay. And you said you had 83 complaints when I was asking you questions before just on Kirkman-Campbell, right?

MS. HILL-PRICE: Yes, we had a number of the files submitted a few months after it closed.

REP. STUPAK: Right. And you said it was 90 days after Kirkman- Campbell closed out her work on Study 3014, correct?

MS. HILL-PRICE: Correct.

REP. STUPAK: Did you ever read any of the memos of those 83 memos that came to the file?

MS. HILL-PRICE: Only recently.

REP. STUPAK: So while the 83 memos came in, you weren't curious to see what the violations were?

MS. HILL-PRICE: They were in a file with 3,300 other investigators, and at the time our policy and procedures was not to review those protocol deviations.

REP. STUPAK: Well, how do you ensure patient safety then if you don't know what the memos and violations are saying?

MS. HILL-PRICE: It was not our policy at the time to review those. We were -- (inaudible) --

REP. STUPAK: But isn't that why an IRB comes to fruition? Isn't that why they were created, was to protect patient safety? You get 83 memos in and you don't look at them?

MS. HILL-PRICE: That was our policy at the time. And we have since revised that and -- (inaudible) --

REP. STUPAK: Why would Aventis or anyone hire an IRB if it wasn't to have patient safety as their goal and their mission?

MS. HILL-PRICE: The regulations required the review of clinical research by an institutional review board, whether it be independent or -- (inaudible).

REP. STUPAK: Right, whose main purpose is patient safety.

MS. HILL-PRICE: Correct.

REP. STUPAK: So why would anyone hire Copernicus if you're not reviewing the files?

REP. DINGELL: Would you yield?

REP. STUPAK: Sure, Mr. Dingell.

REP. DINGELL: I just wanted to note that I very much appreciate this hearing and I very much appreciate the work you're doing here in this matter. And I am listening most attentively to the matters you're discussing.

REP. STUPAK: Well, thank you. Well, are you not as the IRB, Copernicus -- are you not responsible for reporting non-compliance to the FDA?

MS. HILL-PRICE: Yes, we are. According to our -- (Buzzer sounds.)

REP. STUPAK: You may want to wait a minute here.

MS. HILL-PRICE: Okay.

REP. STUPAK: It's going to ring for a second. Okay.

MS. HILL-PRICE: Issues that arise to the level of non-compliance or investigator non-compliance would be reportable to the FDA according to the regulations.

REP. STUPAK: So did you report to the FDA? You had 83 violations alone just by Kirkman-Campbell. Did you report to the FDA?

MS. HILL-PRICE: No, we had no obligation at that point to report any of those violations -- (inaudible) --

REP. STUPAK: Why wouldn't you have an obligation? You're the IRB?

MS. HILL-PRICE: We received that information three months after her site was closed out -- (inaudible) -- status report.

REP. STUPAK: No, you received the memo that we talked about, number 33. It's exhibit number 33, the one from Ms. Sineros (ph) to Ms. Wallace. You received that. Didn't you have a responsibility to report that to the FDA?

MS. HILL-PRICE: It was human error that that didn't get elevated as it should have been.

REP. STUPAK: Well, besides this one right here, you had 83 more complaints about Kirkman-Campbell. You didn't report those to the FDA?

MS. HILL-PRICE: I want to clarify something, if you don't mind, on a former answer. We did not become aware of this telephone contact report until January 23rd, 2008, at which time you all were immediately (notified ?).

REP. STUPAK: No, wait a minute. You testified earlier you became aware of it in electronic format that was in your electronic files in 2006.

MS. HILL-PRICE: As we review our information, it did show up on an electronic report. However, we did not generate that report for Grassley's committee. It did not appear in our hard copy files, and we did not see that memo.

REP. STUPAK: Okay.

MS. HILL-PRICE: No one opened that memo until January 23rd, 2008, one hour before you all received it.

REP. STUPAK: Okay. Well, then let's go over this again then. Kyle, do you got that exhibit? Let me show you a letter, February 27th, 2007 from this committee signed by Mr. Dingell and myself addressed to you as executive officer and chairman of the Copernicus Group. Do you have that document, Kyle?

(Audio break.)

REP. STUPAK: (Inaudible) Okay.

MS. HILL-PRICE: Yes, sir.

REP. STUPAK: We're asking for certain documents, goes to page two, top of the page, "adverse events reported to Copernicus relating to the subjects in Study 3014 regardless of the source of these reports.

" You indicated you knew it existed electronically in about 2006 at the request of -- Senator Grassley's request. Now you're telling me today you didn't realize that exhibit 33 existed until 2008. So for almost a year you sat on it without giving us the information we requested, right?

MS. HILL-PRICE: No one had opened that document. After we received this letter dated February 27th, 2007, our council met with your staff and decided what --(inaudible) --

REP. STUPAK: In your council, or you did not tell us about this electronic file that you never opened, right?

MS. HILL-PRICE: Excuse me?

REP. STUPAK: You never told us -- you or your council never told us about the electronic file you saw in 2006.

MS. HILL-PRICE: We didn't know it existed. We only knew that after we investigated how this thing turned up now, because we thought that it was --

REP. STUPAK: So you expect me to accept -- you knew the report was there in 2006. You saw it for Grassley when Senator Grassley asked, but you expect me to accept the fact that since you didn't open it you had no obligation to produce it to us?

MS. HILL-PRICE: I think we had obligation if we would've opened it, but we did not, and I'm sorry for that.

REP.: So to get around requests you just don't open the file?

MS. HILL-PRICE: Not intentionally.

REP. STUPAK: I mean, the U.S. Senate ask, we ask? And then today you manage -- how is it you come to think about it the day before you're brought in before the committee?

MS. HILL-PRICE: It was discovered the day before I was to meet with your subcommittee or your staff, sir.

REP. STUPAK: Right. It was discovered two years earlier in 2006, but you just don't remember it until the day before you come to the committee. Isn't that rather a coincidence?

MS. HILL-PRICE: After further investigation it did appear in our electronic search for Grassley, but it wasn't prepared for Grassley.

REP. STUPAK: Okay. Then let's go back to -- I was just asking you about -- are you responsible for reporting -- and you never reported anything to the FDA about these 83 reports or this report that -- exhibit number 33 from Ms. Sineros, the telephone call to you. And you're responsible for reporting non-compliance to the FDA, correct? That is established, right?

MS. HILL-PRICE: Yes, sir.

REP. STUPAK: And all these reports you had, the 83, this one from Ms. Sineros -- you did not (submit ?) to the FDA, correct?

MS. HILL-PRICE: Correct. It did not rise to the level of unanticipated problems at that point in our history in (2006 ?).

REP. STUPAK: That's your judgment?

MS. HILL-PRICE: That was our policy and procedure at the time.

REP. STUPAK: Well, you're familiar with the 21CFR56, the IRB Functions and Operations, right?

MS. HILL-PRICE: Yes, sir.

REP. STUPAK: Doesn't it not say in that that any instance of serious or continuing non-compliance with these regulations or the requirements or determinations of the IRB -- are you not required to report that to the FDA in order to fulfill requirements (of these -- ?)

MS. HILL-PRICE: It does say that in words to that effect. I believe so.

REP. STUPAK: Okay, so you violate the policy too?

MS. HILL-PRICE: No, sir. I don't believe we do. That's your opinion, and I don't share that opinion -- (crosstalk) --

REP. STUPAK: So you don't feel you have to follow 21 CFR 56 Section 108 --

MS. HILL-PRICE: We did follow it.

REP. STUPAK: -- subsection (b), IRB functions -- (audio break) --

MS. HILL-PRICE: (audio break) -- 21 CFR -- (audio break) -- 83 memos to file three months after an investigator closed, and we had no obligation --

REP. STUPAK: But your responsibility doesn't stop when Ms. Kirkman stops the study. It continues.

MS. HILL-PRICE: According to the regulations, we review investigators and have that authority through the time that we're overseeing them as IRB of record. Once they have a Final Study Status Report, they are closed.

REP. STUPAK: Well, when is the final study status closed, when it's presented to the FDA?

MS. HILL-PRICE: No sir, when they close at our site -- (crosstalk) -- they close that IRB.

REP. STUPAK: So once the site the closes, you have no more responsibility to report problems with patient safety.

MS. HILL-PRICE: We have no regulatory obligation, no.

REP. STUPAK: How about legal obligation, under 21 CFR 56?

MS. HILL-PRICE: Our interpretation of that regulation would not have indicated that we would have needed to provide those -- (crosstalk) --

REP. STUPAK: Okay, that's your -- how about a moral obligation to the patients if you're there, the IRB is to protect patient safety? Don't you have a moral responsibility if you have questions on patient safety to report it to the FDA or to Adventist (ph) or to the PTD?

MS. HILL-PRICE: I started this company in 1996, and I have the utmost respect for the regulations and have run my business providing ethical review. And I do have obligations, according to our Standard Operating Procedures, which we had in place at the time, and I felt that it met the requirements.

REP. STUPAK: I'm not asking about Standard Operating Procedures. I'm asking if you have a moral obligation, since you're responsible for patient safety, when you see 83 reports just from one study to report that to somebody like the FDA to Adventist or PTD.

MS. HILL-PRICE: Adventist sent them to us and PTD sent them to us, so they were already aware of them.

REP. STUPAK: Okay, well how about do you have a moral obligation to the FDA?

MS. HILL-PRICE: Not at the time, according to our Standard Operating --

REP. STUPAK: How about today, do you have a moral obligation to the FDA to report documents to them that --

MS. HILL-PRICE: (Crosstalk) --

REP. STUPAK: -- concern patient safety?

MS. HILL-PRICE: If something came in similar to this today, number one, we've revamped our Standard Operating Procedures.

And as I've said, information about unanticipated problems is more clearly understood across the board for Institutional Review Boards. I feel confident that anything that would come in today that would rise to this level would be reported appropriately to the board. And they make a determination on what should be done, which would probably include notifying the FDA.

REP. STUPAK: Did you have reports from other sites other than Kirkman Campbell?

MS. HILL-PRICE: What type of reports, sir?

REP. STUPAK: On patient safety issues, protocol violations.

MS. HILL-PRICE: There were a number of memos -- (audio break) -- file. I would anticipate that there would have been others, yes.

REP. STUPAK: So you don't know if -- (audio break) -- others?

MS. HILL-PRICE: I know that there were other memos to file. I don't know the specifics of the content of those.

REP. STUPAK: Well, did you report any of those violations to the FDA?

MS. HILL-PRICE: No, sir. We weren't reviewing protocol deviations or memos to file at that point in 2002.

REP. STUPAK: So all these things come in, and it was your Standard Operating Procedure not to report them then, right, these violations to the FDA or anybody?

MS. HILL-PRICE: That -- (crosstalk) --

REP. STUPAK: So what are you there for? Why do you exist?

MS. HILL-PRICE: IRBs perform a very integral part of a role in clinical research -- (crosstalk) --

REP. STUPAK: I agree. I've done many hearings on IRBs. Their main focus is to protect patient safety. IRBs started in the university setting, in the public setting. But now they've gone to outside to private for profit groups like yourself. And if we don't hit the nail right on the head on Standard Operating Procedures, you just feel you have no responsibility for patient safety.

MS. HILL-PRICE: I disagree. We work very closely within and ethical and regulatory framework as put out --

REP. STUPAK: Well, when I asked about the ethics, you didn't have an answer. You just said that wasn't in your Standard Operating Procedures and under 21 CFR, you didn't think you had any legal responsibility, so where did the ethics come in now?

MS. HILL-PRICE: We review everything. Our board reviews everything according to the Belmont Report, the ethical principles in the Belmont Report, which talk about autonomy of individuals, which talks about risk benefit association and also it talks about distribution of justice.

REP. STUPAK: The bottom line, you blew it here, right? You didn't do your job here, correct, on this study?

MS. HILL-PRICE: We --

REP. STUPAK: Is that fair to say?

MS. HILL-PRICE: We had a human error in not addressing -- (audio break) -- call from an investigative site monitoring --

REP. STUPAK: Well, not just a call, but the other 83 other violations and the other violations from other sites that reported to you. You had a responsibility to tell the FDA. You didn't say, "Boo," to the FDA on any of them.

MS. HILL-PRICE: I'm sitting here today and telling you that I -- (audio break) -- what we did at the time.

REP. STUPAK: Good job of saying nothing to the people who needed to know, which was the FDA, right? I don't mean to be argumentative, but this is ridiculous. Mr. Chairman, you had a couple of questions on IRBs you want to ask?

BREAK IN TRANSCRIPT

REP. STUPAK: Thank you, Mr. Markey.

Dr. Chew, let me ask you this. Do you think PPD did a good job for Aventis?

MR. CHEW: Looking back, I think PPD did a good job. I believe --

REP. STUPAK: How about Copernicus? Did they do a good job for Aventis?

MR. CHEW: It would be harder for me to say because of the documentation of the exchange between Copernicus and Aventis at that time was not, I didn't see an awful lot of documentation.

REP. STUPAK: Should Copernicus have let you know about the 89 or 83 complaints they had about --

MR. CHEW: Well what the memo --

REP. STUPAK: Should they have let you know?

MR. CHEW: No, they came from Aventis.

REP. STUPAK: Okay.

MR. CHEW: In other words, Aventis --

REP. STUPAK: So you knew --

MR. CHEW: -- notified --

REP. STUPAK: -- you knew about --

MR. CHEW: They, those memos to file were sent --

REP. STUPAK: Should you expect the IRB, Copernicus here then to notify the FDA?

MR. CHEW: Well in hindsight, looking back I mean, I would have expected Copernicus not to have because it was the feeling when I looked --

REP. STUPAK: Well who does Copernicus work for? The patients or for you?

MR. CHEW: The patients' safety is the IRB responsibility, so their ultimate responsibility, as it is with the sponsor, is patient safety.

REP. STUPAK: Well, okay, then the 24,000 people you've enrolled in this Ketek study, have you contacted them and said there may have been some problems with this study to see how they're doing? Because you have liver toxicity, you have an eye problem associated, you also have, I think, toxicity around the heart, right? Don't you have a cardiac toxicity here, too? Three toxicities, eyes, liver, and heart, right?

MR. CHEW: When we, again in this trial --

REP. STUPAK: Did you contact the patients?

MR. CHEW: The patients were not contacted beyond the trial because it was, half the trial was another drug for which you could compare.

REP. STUPAK: Okay. Well how about the 12,000 then on Ketek. Did you contact them?

MR. CHEW: These 12,000 patients were followed for the trial, but they were not contacted, to my knowledge, after the trial was over.

REP. STUPAK: They were --

MR. CHEW: Unless they had an on-going adverse event.

REP. STUPAK: Okay. How do you know if there, if they're having an on-going adverse event if you don't contact them?

DR. CHEW: The study protocol had a five or ten-day treatment, but then there was a 35-day or 27 to 35-day follow up well beyond the distance of the drug on the body.

REP. STUPAK: How many of the people 12,000 people who were supposed to receive Ketek, how many actually received it?

MR. CHEW: The details, I would have to guess, back to --

REP. STUPAK: Give me a guesstimation. How many actually received it?

MR. CHEW: I'm guessing that those who were assigned more than -- now I'm just guessing -- but that it would be 90 percent or more.

REP. STUPAK: Okay. How many of Dr. Kirkman's patients, the 407 she had enrolled in her study, how many of them actually received Ketek, do you know?

MR. CHEW: I don't know. And that's because we didn't talk to the patients. The Aventis at that time did not speak with the patients to see if they actually had received the drug.

REP. STUPAK: Okay. Go to binder book. Ms. Price, if you could hand that down? Mr. Markey read parts of Exhibit number 21 to you and that was the memo there that from Nadine Greth that you said is no longer with Aventis. At this point, it's too late to change anything, database or they filled it out with an informed consent date and that is what we're going with. We're not changing this again. They screwed up. They will have to take blame and also if they keep changing their minds and they really do not believe them now. You followed up, Aventis followed up with this e-mail, right, this was in June of 2002? You followed up with an audit then, did you not, then of Ketek and your different sites?

MR. CHEW: I think the audits I believe went through this period. I have to get the precise date in which they stopped, but I think they did go through this period.

REP. STUPAK: Okay. So after this e-mail you went through to do an audit to see what was going on with Ketek right, and with this study?

MR. CHEW: It may have been, this I think would have been near the end of the monitoring period. By monitoring versus auditing, I mean, monitoring would be the PPD function. You'd have to kind of get the actual dates.

REP. STUPAK: Now let's go to Exhibit number 26 right there in front of you.

MR. CHEW: Okay.

REP. STUPAK: Now this is an audit by Aventis auditor, is it not?

MR. CHEW: Yes, it appears to be.

REP. STUPAK: And the date of the original message is Tuesday, October 29th, 2002, correct?

MR. CHEW: That's correct.

REP. STUPAK: So this is about what, three, four months after that Exhibit number 21 when you're --

MR. CHEW: That's right.

REP. STUPAK: -- concerned about it.

MR. CHEW: Um-hum.

REP. STUPAK: And what you did, you did an audit of this site that had enrolled more than 100 subjects in this Ketek study 3014, correct?

MR. CHEW: In this listing, yes.

REP. STUPAK: And every one of them, if you turn the next page, starting with Dr. Gardner, Dr. Anne Kirkman-Campbell, Dr. Lange (sp), Dr. Shumaker, Dr. Price, Dr. Penscal (sp), Dr. Stone, Dr. Blanchart (sp), Dr. Eguise (sp), Dr. Resnick (sp), they all had significant problems as the word of your own auditors, Aventis auditor, significant problems, correct?

MR. CHEW: Yes.

REP. STUPAK: And not just the informed consent, but significant problems that required corrective action, this auditor said, right?

MR. CHEW: I would, yes, corrective action.

REP. STUPAK: Right. And does that in every one of them, significant issues that required corrective action. What corrective action did Aventis take?

MR. CHEW: Without commenting specifically on each site in each intervention, I believe that at the time, you can see where the audit dates were, the audit dates were January, February, and March, the enrollment had been completed. The monitoring at that time or the auditing at that time was to document what was found.

REP. STUPAK: Significant problems were found?

MR. CHEW: -- what was found and that the investigator was aware of this and documented it. These were monitoring visits that occurred -- normally monitoring visits are to help future patients, not only to fix a problem you have now, but for future patients. To my knowledge, probably most of the patients had already come and gone --

REP. STUPAK: Sure. Let's get to the basis here.

MR. CHEW: Okay.

REP. STUPAK: Based on 21, you had a problem in June 2001, you knew there was a problem based upon Exhibit number 21, that there was serious problems here with your study. And you want to use this study to verify the safety of Ketek, Aventis does, right? That's the reason for this study?

MR. CHEW: The request was to get additional safety information.

REP. STUPAK: Right. So you do this barred study. You say you have to do it during the flu season, right? So you enroll 24,000 people, use these sites all around the country, 1,800 sites?

MR. CHEW: That's right.

REP. STUPAK: And you audit ten sites. Right? Usually you do 10 percent of your sites, do you not? Isn't that the general standard?

MR. CHEW: I don't know what the alga rhythm is but it's more than 10,

REP. STUPAK: Right, it should have been about 180 sites, but you only did 10. Aventis went through and audited 10 sites, the largest sites, correct?

MR. CHEW: Well I don't, I don't agree that it would have been 180, but it would have been more than 10.

REP. STUPAK: Okay.

MR. CHEW: Should have done more than 10 in my --

REP. STUPAK: Okay. Point is, you only audited 10 sites, 10 of the sites with the most patients in, correct?

MR. CHEW: They were the high enrolling sites, yes.

REP. STUPAK: Correct. The high enrolling sites. So you did 10. You didn't audit any other sites, they did just 10, right?

MR. CHEW: The auditing, the monitoring was done of course more extensively but the audit was on 10.

REP. STUPAK: Only 10 sites. Those 10 sites with the high enrolling patients, right, high number of patients in these sites, these are the ones you audited? And this is December, I'm sorry, October 29th, 2002, your auditor at every one of the sites, not just Kirkman-Campbell, but every one of the sites finds significant problems in which corrective action has to be taken. Correct?

MR. CHEW: There were issues found that needed corrective, action, correct. I think there were varying degrees of the intensity.

REP. STUPAK: Go through if you want. Every one of them says significant issues where corrective action is required. Every one of them. Significant GCP issues identified during the monitoring. They find it in the audit. Significant issues were required, corrective action. Dr. Lange, significant issues that required corrective action. Dr. Shumaker, significant issues that required corrective action.

MR. CHEW: I agree.

REP. STUPAK: So the whole basis of your safety study and your audit showed that you had significant issues that required corrective action, correct?

MR. CHEW: These were 10 sites that were audited. And all these --

REP. STUPAK: The only 10 you did, right?

MR. CHEW: These --

REP. STUPAK: All, in fact, if you could ask the question, all the sites you monitored, you found significant issues that required corrective action, isn't that right?

MR. CHEW: All, I would have, not all the sites monitored had significant GCPs that required action.

REP. STUPAK: Well you just said you just, you only did 10 sites, you only audited --

MR. CHEW: Talk about the monitoring. The monitoring --

REP. STUPAK: I'm not talking about monitoring. Don't, don't confuse this here. We're talking about audits.

MR. CHEW: Of the audit, yes.

REP. STUPAK: Okay. You only audited, Aventis only audited 10 sites in this big study. And every one of them had significant issues that required corrective action? Correct?

MR. CHEW: Had significant GCP issues that required corrective action, that's correct.

REP. STUPAK: So how in good conscience could Aventis submit the study, on every one of the audit sites there's significant problems, to the FDA to show the safety of Ketek?

MR. CHEW: My answer to that, Congressman, is that my knowledge, these actions were not ignored, they were discovered, and they were corrected and documented.

REP. STUPAK: No, no.

MR. CHEW: All of them effect to my knowledge, not all of them bore on the safety issue of Ketek.

REP. STUPAK: Well -- really? Significant issues that required corrective action? The study's over. You only had this window, the flu season as you said, to get it done. You can't go back and replace that flu season. It's over. You audit it. You find the basis during this limited period of time you had have significant issues at every site. And that's with the basis of the whole study. In every one of them you find significant issues. You didn't find any clean ones, every one of them were wrong, but yet you present that study to the FDA for safety of Ketek. How could you do that? How would Aventis? Why would you do that?

MR. CHEW: It's my belief that these problems were identified and documented by audits and subsequently corrected and documented.

REP. STUPAK: So how can you correct it? Flu season is done, the Ketek is over, you said they didn't have it anymore time, Ketek's over, these patients aren't getting it anymore, and these are the only patients you relied upon for the safety of the study that you presented to the FDA. How can you correct it?

MR. CHEW: The issues were documented and corrective action was taken in terms of documentation. You're right, the patients had come and gone.

REP. STUPAK: Yeah. How do you document blood splitting?

MR. CHEW: I'm sorry?

REP. STUPAK: How do you correct blood splitting? You know when you get blood you attribute it to different patients, even though it's not their blood, to show that everything was fine for the safety of Ketek. How do you correct that?

MR. CHEW: We, to my knowledge, there was no, in these cases, there was no evidence of blood splitting.

REP. STUPAK: Dr. Kirkman-Campbell had blood splitting.

MR. CHEW: Well Dr. Kirkman-Campbell had the suspicion of blood splitting. Both PPD and Aventis did statistical analyses that were not conclusive, they were not conclusive in terms of the blood splitting, to my knowledge.

REP. STUPAK: Ms. Price, did Copernicus check Dr. Kirkman- Campbell about blood splitting? Did you?

MS. PRICE: Yes, sir.

REP. STUPAK: No, you didn't, did you? Blood splitting, where you use blood from different -- you didn't, you didn't check that did you?

MS. PRICE: No, sir, that's not our role.

REP. STUPAK: How about your, Dr. Eshelman, did the PPD check for blood splitting?

MR. ESHELMAN: Yes. I believe that we turned up the suspicion of blood splitting.

REP. STUPAK: Did you go back and check it to verify it, to make sure it didn't have any effect on the integrity of the study?

DR. ESHELMAN: Oh, I think Dr. Reynolds reviewed all of these cases, and I believe that Dr. Reynolds talked to someone at Aventis. I can't swear that, but I believe that is true. I do know that the issue of the possibility of blood splitting was discussed between the two companies, and I think, as I said in my prepared remarks, this was evaluated statistically and otherwise by Aventis at the time. And their investigation did not seem to indicate mathematically that there was the type of variability that would be associated with blood splitting. Dr. Reynolds looked at it some more after that. Whether or not he did a mathematical analysis I cannot remember, frankly.

REP. STUPAK: So they didn't do the blood splitting. They didn't check it. So Aventis checked it and that was okay?

DR. CHU.: There's I believe an email from PPD indicating they did analyze for blood splitting, looking at the delta and comparing of other sites. As with the Aventis analysis, there was a suspicion, but no firm proof to my knowledge of blood splitting.

REP. STUPAK: Okay. Let me ask you this. You hired Dr. Kirkman- Campbell, right, Aventis?

DR. CHU: To my knowledge, the investigator selection was the responsibility of PPD.

REP. STUPAK: Dr. Eshelman, did you hire Kirkman-Campbell then?

DR. ESHELMAN: The answer to your question is I don't know. My recollection is that the --

REP. STUPAK: I love it. The main person -- no one knows who hired her. That's amazing.

DR. ESHELMAN: Well, if you'd let me finish --

REP. STUPAK: Yeah, sure. I'm trying to, but my disbelief is just overwhelming me. Go ahead.

DR. ESHELMAN: Okay. My recollection is that the identification and selection of investigators was a shared responsibility between Aventis and PPD. In other words, I believe that they had some investigator lists. I believe that we had some investigator lists and that those were merged, and then subsequently the ones that came out of that as qualified were selected. So in the particular case of Kirkman-Campbell, I can't tell you where that name came from. I'm sorry.

REP. STUPAK: Okay. PPD was hired by Aventis to monitor Study 3014 and detect non-compliance. Isn't that correct? Mr. Chu?

DR. CHU: They were hired to monitor the study, of course, to transmit to Aventis the findings.

REP. STUPAK: Okay. Several of the PPD personnel involved in the study of 3014 informed the committee staff that they were reasonably sure that Kirkland-Campbell submitted fraudulent data to Aventis. Did PPD then have a duty to notify the FDA in your estimation? Did PPD have a duty to notify the FDA when they reached this conclusion?

DR. CHU: I just have a personal opinion on that, because I don't know if it's a legal requirement. I believe anybody, anyone at any time if they suspect a problem should feel free to notify FDA. I don't know if there's a legal answer to that. That would be my personal opinion.

REP. STUPAK: Now, Dr. Eshelman sort of indicated that there's a contractual obligation that they could not do that. Do you disagree with that, or --

DR. CHU: Well, I think that by contract there are usually -- assignment of who does what, but most cases -- if there's a problem, you agree on who does what and you do it.

REP. STUPAK: Okay.

DR. CHU: That's the way I would do it.

REP. STUPAK: So did you require -- did Aventis require PPD not to report any problems?

DR. CHU: I'm not quite sure, but I think it's my recollection that Aventis had the regulatory liaison contact just to keep things clear of who was doing what.

REP. STUPAK: But as far as Aventis was concerned, Copernicus could notify the FDA? PPD could notify the FDA (underneath this ?) agreement?

DR. CHU: Again, I was speaking individually. If they were an issue, I think what would happen -- I'm just -- hypothetically -- is that Copernicus or PPD would discuss this and there would be a resolution as to who does what. That's been my experience, that there's usually a consensus.

REP. STUPAK: Well, how about Aventis? Did you ever notify the FDA that you had trouble with this study, 3014? Did you ever sit down --

DR. CHU: Yes, we did. Yes, we did.

REP. STUPAK: When was that?

DR. CHU: I believe in June of 2002, I believe, prior to the filing when there were two sides who persistently refused to cooperate.

REP. STUPAK: Well, June of 2002, but tab number 26 shows that's October of 2002. So after -- how about October -- after your audit of October of 2002? Did you notify the FDA of problems with the site?

DR. CHU: To my knowledge, the two that were notified did not cooperate. I'm assuming -- I would have to look individually -- that these sites were probably cooperative in coming into documentary compliance.

REP. STUPAK: After your audit, tab number 26?

DR. CHU: It could've been after the audit or the monitoring, because the monitoring was in parallel.

REP. STUPAK: Okay. Any time after tab 26, October of 2002, did Aventis contact the FDA and tell them we have trouble with this, Study 3014 that may be based on fraudulent activities?

DR. CHU: To my knowledge, the team that I was looking at just felt that they had to address many of the issues of GCP non- compliance, and when the auditor came from FDA to look at the Dr. Kirkman-Campbell site specifically over a nine-day period from October 15th to the 24th, the documentary evidence of that audit corroborated many of the same GCP violations that were found by the team.

REP. STUPAK: Right. Great. But my question was did Aventis after October of 2002 notify the FDA of problems? We're not just talking about Kirkman-Campbell. October, 2002 has nine other sites, and every one of them had significant issues that needed corrective action. Did Aventis notify the FDA of these other sites that had significant issues that needed corrective action?

DR. CHU: To my knowledge -- and I'd have to review -- I don't think so.

REP. STUPAK: Okay. Where does your responsibility come in then when you appear before the FDA and the FDA Advisory Committee to tell the FDA that you've had significant problems with the ten sites, the only sites you audited? All ten of them had significant problems that needed corrective action. When is it your responsibility to let the FDA know?

DR. CHU: Are you talking about hypothetically or a specific trial?

REP. STUPAK: I'm talking about Aventis here --

DR. CHU: And --

REP. STUPAK: (-- if -- on this ?) KeyTech. When did you have that responsibility?

DR. CHU: Of course, we do things differently now in the new company, but at that --

REP. STUPAK: Oh, I know everyone does everything different now, but --

DR. CHU: At that time it's my understanding that the company had reviewed these issues with the site, had documented these errors, again, in retrospect, and -- in other words, they had addressed the issues as they best they could in a retrospective fashion.

REP. STUPAK: Dr. Chu --

DR. CHU: Yes.

REP. STUPAK: -- the answer is just that. Look, after October, 2002, you did nothing to notify the FDA of the problems with the integrity of Study 3014. Did Aventis -- they did not, did they?

DR. CHU: I believe Aventis felt that the trial had integrity.

REP. STUPAK: That's not what I asked. Okay, so you think that's a -- you think this is -- this -- you believe this has integrity, this 3014 has integrity?

DR. CHU: I'm sorry. Could you repeat that? I'm sorry.

REP. STUPAK: Sure. After October, 2002 --

DR. CHU: Yeah.

REP. STUPAK: -- after your audit -- ten sites -- every one of them has significant issues that need corrective action. You never notified the FDA of possible integrity issues with Study 3014.

DR. CHU: The FDA had opened up a criminal investigation on October 4th --

REP. STUPAK: Not what I asked you.

DR. CHU: But we had not -- to my knowledge, there had been no notification because -- it's my review of the record -- that these issues with these other sites had been addressed in terms of memos to file. An inadequate approach -- (inaudible) --

REP. STUPAK: Memos to file from who, Aventis to Aventis?

DR. CHU: The memos to file usually were the investigator going to the file. And in other words --

REP. STUPAK: Your investigators going to your files.

DR. CHU: (Inaudible) -- no, this would be at the site so that they could be audited and reviewed by auditors, the specific point being have the documentation --

REP. STUPAK: No, no, they could be. But what's your responsibility here? October, 2002, ten sites, every one -- significant problems, need corrective action. Did you notify the FDA of that? That's all I'm asking you.

DR. CHU: At that time the answer to my knowledge is no.

REP. STUPAK: Okay. So even though you submitted this study, you never told the FDA that of the ten sites that were audited, you had significant issues with?

DR. CHU: It's my understanding that these issues had been addressed at the time they were documented at previous monitoring.

REP. STUPAK: Who addressed these issues? Aventis, right?

DR. CHU: Typically the PPD would identify these issues, report them to Aventis, and the site would be instructed to document what had happened and what -- (inaudible) --

REP. STUPAK: The sites were already closed. We've established that. That's already closed.

DR. CHU: When it came to the monitoring -- as usual with any trial, when there's monitoring, the issues have to be fixed and corrected. The enrollment had stopped, but the site may still have been in the process of regulatory and document assembly. So we have to separate out the enrollment of patients, which is three months, and the monitoring that went on for much longer obviously.

REP. STUPAK: Why do you do an audit?

DR. CHU: The audit is to generally look at processes to see if the processes have been fulfilled.

REP. STUPAK: And of these ten audits, every one of them failed, correct?

DR. CHU: Of these high enrolling sites, there were significant issues requiring action.

REP. STUPAK: Isn't an audit to help determine the integrity and the quality of the study you're doing?

DR. CHU: It's more than auditing to do that, but auditing is part of it.

REP. STUPAK: And you'd bet a big zero on that one, so there is a serious question about the quality of the report then, is there not, of the study you're doing?

DR. CHU: From my understanding, these issues were found and identified. It was not a blemish-free trial. These issues were identified after the patients had come through the trial, but it's my understanding that -- (inaudible) --

REP. STUPAK: What's your revenue -- what's the Aventis revenue from KeyTech back in 2005?

DR. CHU: I would have to -- I would have to (find that out ?).

REP. STUPAK: $264 million sound right?

DR. CHU: I would have to document that. I --

REP. STUPAK: Do you have any reason to dispute $264 million for the fiscal year?

DR. CHU: No. I just have no primary knowledge of that number.

REP. STUPAK: I see. A year ago the FDA finally removed bronchitis and sinusitis from the labeled indications for KeyTech, leaving only pneumonia as an authorized use for the drug. Is that correct?

DR. CHU: That's correct.

REP. STUPAK: Is Sanofi Aventis still detailing the drug to doctors?

DR. CHU: To my knowledge, no. There is no promotion.

REP. STUPAK: Okay. Your auditors were at Kirkman-Campbell's site one week before the FDA investigator, who told the congressional staff that Kirkman-Campbell's site was the worst she'd seen in 25 years. How did your auditors miss the fraud there at Kirkman-Campbell?

DR. CHU: It was the auditors who identified in January -- I think 17th, 18th, 2002 -- that there was a potential problem. Additional monitoring needed to be done. That's where PPD was sent on February 18th, 19th, and 21st. There were additional visits April 1 through 5. There were 165 calls to this site. There was extensive attention paid to this site.

REP. STUPAK: Right. And did you disclose all that to the FDA?

DR. CHU: Well, the -- no, the answer was no because the issues were addressed --

REP. STUPAK: So --

DR. CHU: -- and documented for the file, and the -- it's my knowledge that this was also documented by the 483 that was issued on October 24th by the FDA auditor.

REP. STUPAK: I asked the other investigators. I guess it's only fair to ask you about the -- let me find it here. The statute of limitations on the possibility of indicating Aventis for fraud in connection with Study 3014 when the investigators were kicking around the dates since the approval was, I believe, April 1st, 2004 for KeyTech.

DR. CHU: That's correct.

REP. STUPAK: And if that approval is based upon fraud, fraudulent Study 3014, do you think Aventis is liable then for fraud?

DR. CHU: Can I answer that -- but it's my understanding that FDA did not rely on 3014 for its approval, having 14 clinical trials, also having a German registry, and at that time four million patients' use. So it's my understanding that 3014 was not used. Now --

REP. STUPAK: But Aventis in submitting Study 3014 to the advisory panel, which I believe was on March 25th -- not advisory --

DR. CHU: The 15th and 16th, 2006.

REP. STUPAK: Okay. January. Why did you present Study 3014? It was to show the efficacy and the safety of KeyTech.

DR. CHU: Oh, you're talking about the second advisory committee. Is that right, 2003?

REP. STUPAK: Yes, yes.

DR. CHU: Yes, right.

REP. STUPAK: Why did you submit 3014? It would show the efficacy and the safety of KeyTech, was it not, for bronchiatitis, for sinus, and for pneumonia, correct?

DR. CHU: The primary was safety.

REP. STUPAK: It was for safety.

DR. CHU: Efficacy had been established according to the first --

REP. STUPAK: Okay.

DR. CHU: -- advisory committee for the 14 pivotal trials of phase three in those three indications.

REP. STUPAK: Okay. So you submitted it for safety, correct?

DR. CHU: Yes.

REP. STUPAK: Okay. And if there's fraud in that safety, would you then agree with us the statute of limitations run on possibly indicting Aventis for fraud in connection with the study -- with the safety of Study 3014?

DR. CHU: I can't comment on this legal -- (inaudible). I'm not competent to do that. But at the time of the submission it's my review that Aventis felt that this was a trial that was useful and that the issues of good clinical practice had been addressed.

REP. STUPAK: Useful. You said useful. But when you submitted, you thought that Study 3014 showed the safety of KeyTech.

DR. CHU: At that time --

REP. STUPAK: Yes.

DR. CHU: -- it's my understanding that this was submitted as a useful response to the request of the first advisory committee for a large safety study. And that was done.

REP. STUPAK: And it was submitted for the verification of the safety of KeyTech for these three problems, sinus, pneumonia, bronchitis, right?

DR. CHU: Correct, to get additional information as part of other experiences, but it was to provide a large safety experience for KeyTech and those three indications. compared to a commonly used antibiotic.

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