[House Hearing, 110 Congress]
[From the U.S. Government Publishing Office]




           KETEK CLINICAL STUDY FRAUD: WHAT DID AVENTIS KNOW?

=======================================================================

                                HEARING

                               BEFORE THE

              SUBCOMMITTEE ON OVERSIGHT AND INVESTIGATIONS

                                 OF THE

                    COMMITTEE ON ENERGY AND COMMERCE
                        HOUSE OF REPRESENTATIVES

                       ONE HUNDRED TENTH CONGRESS

                             SECOND SESSION

                               __________

                           FEBRUARY 12, 2008

                               __________

                           Serial No. 110-87


      Printed for the use of the Committee on Energy and Commerce
                        energycommerce.house.gov


                  U.S. GOVERNMENT PRINTING OFFICE
48-587                    WASHINGTON : 2008
-----------------------------------------------------------------------
For sale by the Superintendent of Documents, U.S. Government Printing
Office  Internet: bookstore.gov Phone: toll free (866) 512-1800 Fax: (202) 512-2104  Mail: Stop IDCC, Washington, DC 20402-0001







                    COMMITTEE ON ENERGY AND COMMERCE

                  JOHN D. DINGELL, Michigan, Chairman

HENRY A. WAXMAN, California          JOE BARTON, Texas
EDWARD J. MARKEY, Massachusetts          Ranking Member
RICK BOUCHER, Virginia               RALPH M. HALL, Texas
EDOLPHUS TOWNS, New York             FRED UPTON, Michigan
FRANK PALLONE, Jr., New Jersey       CLIFF STEARNS, Florida
BART GORDON, Tennessee               NATHAN DEAL, Georgia
BOBBY L. RUSH, Illinois              ED WHITFIELD, Kentucky
ANNA G. ESHOO, California            BARBARA CUBIN, Wyoming
BART STUPAK, Michigan                JOHN SHIMKUS, Illinois
ELIOT L. ENGEL, New York             HEATHER WILSON, New Mexico
ALBERT R. WYNN, Maryland             JOHN B. SHADEGG, Arizona
GENE GREEN, Texas                    CHARLES W. ``CHIP'' PICKERING, 
DIANA DeGETTE, Colorado              Mississippi
    Vice Chairman                    VITO FOSSELLA, New York
LOIS CAPPS, California               STEVE BUYER, Indiana
MICHAEL F. DOYLE, Pennsylvania       GEORGE RADANOVICH, California
JANE HARMAN, California              JOSEPH R. PITTS, Pennsylvania
TOM ALLEN, Maine                     MARY BONO, California
JAN SCHAKOWSKY, Illinois             GREG WALDEN, Oregon
HILDA L. SOLIS, California           LEE TERRY, Nebraska
CHARLES A. GONZALEZ, Texas           MIKE FERGUSON, New Jersey
JAY INSLEE, Washington               MIKE ROGERS, Michigan
TAMMY BALDWIN, Wisconsin             SUE WILKINS MYRICK, North Carolina
MIKE ROSS, Arkansas                  JOHN SULLIVAN, Oklahoma
DARLENE HOOLEY, Oregon               TIM MURPHY, Pennsylvania
ANTHONY D. WEINER, New York          MICHAEL C. BURGESS, Texas
JIM MATHESON, Utah                   MARSHA BLACKBURN, Tennessee
G.K. BUTTERFIELD, North Carolina
CHARLIE MELANCON, Louisiana
JOHN BARROW, Georgia
BARON P. HILL, Indiana

                                 ______

                           Professional Staff

                 Dennis B. Fitzgibbons, Chief of Staff

                   Gregg A. Rothschild, Chief Counsel

                      Sharon E. Davis, Chief Clerk

               David L. Cavicke, Minority Staff Director

                                 7_____

              Subcommittee on Oversight and Investigations

                    BART STUPAK, Michigan, Chairman
DIANA DeGETTE, Colorado              ED WHITFIELD, Kentucky
CHARLIE MELANCON, Louisiana              Ranking Member
    Vice Chairman                    GREG WALDEN, Oregon
HENRY A. WAXMAN, California          MIKE FERGUSON, New Jersey
GENE GREEN, Texas                    TIM MURPHY, Pennsylvania
MIKE DOYLE, Pennsylvania             MICHAEL C. BURGESS, Texas
JAN SCHAKOWSKY, Illinois             MARSHA BLACKBURN, Tennessee
JAY INSLEE, Washington               JOE BARTON, Texas (ex officio)
JOHN D. DINGELL, Michigan (ex 
    officio)

                                  (ii)







                             C O N T E N T S

                              ----------                              
                                                                   Page
Hon. Bart Stupak, a Representative in Congress from the State of 
  Michigan, opening statement....................................     1
Hon. Greg Walden, a Representative in Congress from the State of 
  Oregon, opening statement......................................     5
Hon. John D. Dingell, a Representative in Congress from the State 
  of Michigan, opening statement.................................     6
    Prepared statement...........................................     8
Hon. John Shimkus, a Representative in Congress from the State of 
  Illinois, prepared statement...................................     9
Hon. Michael C. Burgess, a Representative in Congress from the 
  State of Texas, opening statement..............................    10
Hon. Charles Grassley, a Senator from the State of Illinois, 
  opening statement..............................................    76
    Prepared statement...........................................    82

                               Witnesses

Ann Marie Cisneros, Former Senior Research Associate, PPD, Inc...    12
    Prepared statement...........................................    14
Paul Herbert Chew, President, U.S. Research and Development 
  Division, Sonifi-aventis Pharmaceuticals.......................    38
    Prepared statement...........................................    40
Fred Eshelman, Chief Executive Officer, PPD, Inc.................    53
    Prepared statement...........................................    55
Sharon Hill Price, Chief Executive Officer and Chairman of the 
  Board of Directors.............................................    63
    Prepared statement...........................................    65

                           Submitted Material

Department of Health and Human Services, subpoena briefing book, 
  dated February 11, 2008, submitted by Mr. Dingell..............   118
Hon. Chuck E. Grassley, letter of February 6, 2008, to Secretary 
  Leavitt and Commissioner von Eschenbach........................   160
Chart entitled, ``Study 3014 Problem Sites''.....................   185
Chart entitled, ``Dr. Kirkman-Campbell Site, What Aventis Knew:''   186

 
           KETEK CLINICAL STUDY FRAUD: WHAT DID AVENTIS KNOW?

                              ----------                              


                       TUESDAY, FEBRUARY 12, 2008

                  House of Representatives,
      Subcommittee on Oversight and Investigations,
                          Committee on Energy and Commerce,
                                                    Washington, DC.
    The subcommittee met, pursuant to call, at 11:06 a.m., in 
room 2123, Rayburn House Office Building, Hon. Bart Stupak 
[chairman of the subcommittee] presiding.
    Present: Representatives Stupak, Dingell, Ex Officio, 
Walden, Burgess, and Barton, Ex Officio.
    Also Present: Representatives Markey and Shimkus.
    Staff Present: John Sopko, Joanne Royce, David W. Nelson, 
Kyle Chapman, Scott P. Schloegel, Alan Slobodin, and Karen E. 
Christian.

  OPENING STATEMENT OF HON. BART STUPAK, A REPRESENTATIVE IN 
              CONGRESS FROM THE STATE OF MICHIGAN

    Mr. 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 29, 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 12-0 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 received yesterday to the committee regarding our 
subpoena for documents requested almost a year ago, in March of 
2007.
    Yesterday afternoon, a letter arrived to 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 29 
business meeting.
    The letter is troubling on several fronts. First, the 
subpoena was served to the 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 precedent for obtaining briefing book documents 
from both Democratic and Republican administrations without 
having to issue a subpoena. The Secretary was made aware of the 
precedents. With the committee chaired by Republicans Mr. 
Bliley and Mr. Barton, we 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 a Republican 
administration, Mr. Frank Young.
    I find the letter received yesterday to be very 
disconcerting, and will 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 will 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 5 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 will be exploring this 
question in the context of the controversial antibiotic, Ketek.
    The deeper the members of this subcommittee dig into the 
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 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 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's ongoing investigation into the safety of Ketek, 
particularly what he has 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 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 
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 2 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 5 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 
different from the signatures, study coordinator entering dates 
for subjects and the principal investigator; blatantly forged 
signature on informed consent forms; very limited medical 
records; use of different color ink on medical charts-- 
overwrites, cross-outs--inserts of diagnoses in different 
colored ink; routine failure to give pregnancy tests to women 
of child-bearing age; study investigator and coordinator 
unaware of definitions of serious adverse event or adverse 
event 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 increment of 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 enrollment 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 were their testimony not of the utmost 
importance.
    I would 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 into possible 
misconduct of Aventis until 2006, over 4 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 of 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 on the 
faulty study and its subsequent decision to approve Ketek 
despite ongoing investigation into Dr. Kirkman-Campbell's 
conduct make any conviction against Aventis for fraud in 
connection with the submission of the study highly unlikely.
    Our final panel consists of the following industry 
officers: Dr. Paul Chew, President of U.S. Research and 
Development, Sanofi-Aventis Pharmaceuticals; Fred Eshelman, CEO 
of PPD, the contract research organization hired by Aventis to 
monitor Study 3014; and Sharon Hill Price, the CEO of 
Copernicus Group, an 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 
2 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.
    It 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.
    Mr. Stupak. I next would like to turn to my colleague, Mr. 
Walden, for his opening statement, and thank you for being here 
today.

  OPENING STATEMENT OF HON. GREG WALDEN, A REPRESENTATIVE IN 
               CONGRESS FROM THE STATE OF OREGON

    Mr. Walden. Thank you very much, Mr. Chairman, for calling 
this hearing so our committee can continue to shine a light on 
what transpired with Aventis' large safety trial of its 
antibiotic Ketek.
    Protecting the integrity of the FDA drug approval process 
is a priority for me and for all members of this committee. In 
order to achieve this, each and every person involved in the 
drug approval process must strictly adhere to the highest 
standards of conduct and maintain an unquestionable level of 
ethics.
    Unfortunately, from what this committee has learned through 
its year-long investigation of the issues and problems raised 
by the review and approval of Ketek, it appears that standards 
of conduct and ethics were only optional. Well before the time 
I arrived here in Congress, Chairman Dingell shepherded 
legislation through this House that granted the FDA the power 
to debar or, essentially, blacklist companies and individuals 
who are convicted of felonies for misconduct relating to the 
regulation of drug products. Individuals who are debarred, or 
disqualified by the FDA are then listed on the FDA Web site.
    Now, it is my understanding that some of the companies 
testifying here today rely on those lists when selecting 
physicians to serve as investigators in clinical trials, as 
they rightly should. Debarment is a powerful tool that FDA can 
use to protect the integrity of the drug approval process, and 
I applaud Chairman Dingell for giving FDA that authority. 
However, a minority committee staff report released yesterday 
shows that the FDA has failed to initiate debarment proceedings 
against several individuals and companies even when the basis 
for debarment, such as conviction of fraud for clinical trial 
misconduct, clearly exists. By failing to do so, individuals 
that are currently incarcerated, that are currently sitting in 
jail for felonies they committed, are still eligible to 
participate in administration of clinical trials. This is 
outrageous.
    When the FDA does pursue debarment, it is in a delayed or 
perhaps even a lackadaisical manner. According to the staff 
report, an average of 38 months passes between the date of 
conviction and the date that the FDA begins debarment.
    The FDA has a mandate to protect the American people from 
unsafe drugs and, as such, it must make it a priority to use 
its authority to immediately ban companies and individuals who 
are convicted of crimes that could jeopardize the safety of 
drugs from continuing to do business before the FDA. Both the 
FDA and the drugmakers that are developing new drugs must 
remain vigilant in their efforts to detect and eliminate fraud.
    Hopefully, today's hearing will help us understand what 
went wrong with Ketek Study 3014 and how we can make sure those 
mistakes and errors never happen again.
    Chairman Stupak, thank you for convening this hearing and 
your diligent work on this issue. And I yield back the balance 
of my time and look forward to hearing from all of our 
witnesses.
    Mr. Stupak. I thank the ranking member.
    Mr. Stupak. I would next call on the chairman of the full 
committee, Mr. Dingell, for an opening statement, please.

OPENING STATEMENT OF HON. JOHN D. DINGELL, A REPRESENTATIVE IN 
              CONGRESS FROM THE STATE OF MICHIGAN

    Mr. Dingell. Mr. Chairman, thank you for continuing to 
pursue this matter and for your leadership. I commend you for 
the vigor with which you are approaching these matters.
    I would like to remind all and sundry that this is an 
oversight hearing which will be conducted within the traditions 
and practices of this committee. It will be our expectation 
that all persons called upon to participate, either by 
deliverance of testimony or by presentation of books, papers 
and records, will cooperate.
    I would remind all and sundry that this is a proceeding 
which is being conducted in a bipartisan fashion; and we will 
address that matter a little further. This committee has, and 
this subcommittee has, a tradition of proceeding to see to it 
that the business of the committee is properly conducted, that 
all persons cooperate, and that they do so in response to a 
fair and a bipartisan inquiry by the committee, aimed at 
gathering the facts to see whether the law is properly enforced 
and whether or not the Federal officers and employees are 
carrying out their responsibilities in proper fashion.
    We also are looking into seeing whether or not the 
committee is receiving proper information, but also as to 
whether or not the committee will find it necessary to enforce 
its subpoenas in an appropriate way, looking to the possibility 
of not only seeing to it that the law is properly being 
enforced and carried out, but as to whether or not additional 
legislative work by the committee is required in order to see 
to it that the public is properly protected.
    We have here a question relating to the ill-advised 
approval of the antibiotic Ketek. Beyond the harm to the public 
health from millions of prescriptions written on this drug by 
doctors who relied on the FDA, this investigation raises 
questions about the integrity of the drug approval process and 
those who have engaged in that process.
    FDA is supposed to receive clinical data from manufacturers 
who have properly conducted designed studies that prevent 
serious misconduct or fraud. If FDA knows or suspects such 
fraud exists and then ignores it, then this committee has the 
duty to probe as deeply as necessary to determine whether the 
entire approval process itself has been compromised.
    Further, this committee expects the full cooperation from 
Federal agencies when we carry out our oversight responsibility 
to ensure that such agencies enforce the laws enacted by the 
Congress in a proper way.
    Given the allegations of wrongdoing in the Ketek matter, we 
have the duty to compel FDA and the Department of Health and 
Human Services to cooperate fully in the inquiries of the 
committee. Instead, this committee and other committees in the 
Congress have been repeatedly stonewalled on this matter.
    Our good friend, Senator Grassley, who will be appearing 
here before the committee, the former chairman of the Senate 
Committee on Finance, who is testifying before us today, 
initiated inquiries into Ketek during the last Congress. He 
encountered the same bad faith and obstruction from the 
administration.
    Three of the witnesses today are FDA criminal investigators 
who uncovered the fraud and misconduct that is the subject of 
our hearing. Unfortunately, the committee had to subpoena them 
to testify at this hearing because Food and Drug Commissioner 
von Eschenbach and Secretary Leavitt refused to allow them to 
appear here voluntarily. A similar refusal thwarted Senator 
Grassley's effort in the last Congress.
    This committee will not tolerate actions by the 
administration which would thwart a proper inquiry by this 
body. It is to be observed that, fortunately, with a bipartisan 
vote of 12-0 by this subcommittee, we issued subpoenas to these 
witnesses.
    My good friend, Mr. Joe Barton, the ranking member, and I 
have given the agency every opportunity to avoid this 
embarrassment, but apparently to no avail. Unfortunately, this 
obstructionist behavior continues. Just yesterday we received a 
letter from the Secretary's office, which I ask at this time, 
Mr. Chairman, be made a part of the hearing record.
    Mr. Stupak. Without objection, Mr. Dingell.
    [The information appears at the conclusion of the hearing.]
    Mr. Dingell. In that letter, the members of the Secretary's 
staff announced his refusal to honor the subpoena of the 
subcommittee for records relating to Food and Drug Commissioner 
von Eschenbach's briefing books.
    I want to remind my colleagues that similar records have 
been turned over to me, as well as to my good friend Mr. 
Barton, by both Republican and Democratic administrations in 
bipartisan investigations at FDA and other agencies in the 
executive branch. I must also remind all that these records 
were unanimously subpoenaed by this subcommittee with a 
bipartisan vote of 12 to nothing.
    I ask my colleagues to then scrutinize Secretary Leavitt's 
arguments in refusing to honor the subpoenas of the 
subcommittee. At best, I note they are specious. At worst, they 
are contemptuous of the Congress and of the committee. If 
anything, the refusal of the Secretary to cooperate causes me 
to wonder, what is the Secretary trying to hide? What is in 
these briefing books that he does not want either my Republican 
colleagues or my Democratic colleagues to see? Is there 
evidence of perjury? Are the statements embarrassing to the 
Administration?
    In any event, it is the right of this committee to have 
them, and we will do so. Let me make it clear on this point. 
Neither Chairman Stupak nor I, nor our colleagues of this 
committee on either side will tolerate a perversion of 
congressional powers to investigate and to probe. I fully 
support Chairman Stupak's request to enforce this subpoena by 
holding Secretary Leavitt in contempt.
    Mr. Chairman, there is an easy way for the agency to 
undergo congressional oversight. There is also a hard way. 
Commissioner von Eschenbach and Secretary Leavitt appear to 
have chosen the latter. I caution both gentlemen to reconsider 
their ill-conceived notion of congressional oversight and to 
allow the bipartisan policies that have long been the practice 
of this committee to be used for the service of the public 
interest.
    I yield back the balance of my time and I thank you, Mr. 
Chairman.
    Mr. Stupak. I thank the gentleman.
    [The prepared statement of Mr. Dingell follows:]

                   Statement of Hon. John D. Dingell

    Mr. Chairman, thank you for continuing to pursue the truth 
regarding the Food and Drug Administration's (FDA) ill-advised 
approval of the antibiotic Ketek. Beyond the harm to the public 
health from millions of prescriptions written for this drug by 
doctors who relied on the FDA, this investigation raises 
questions about the very integrity of the drug approval 
process.
    FDA is supposed to receive clinical trial data from 
manufacturers who have conducted properly designed studies that 
prevent serious scientific misconduct or fraud. If FDA knows or 
suspects such fraud and then ignores it, this Committee has 
every reason to probe as deeply as necessary to determine 
whether the entire approval process itself has been 
compromised.
    Further, this Committee expects the full cooperation from 
Federal agencies when we carry out our oversight responsibility 
to ensure such agencies enforce the laws enacted by Congress. 
Given the allegations of wrongdoing in the Ketek matter, we 
have every right to expect FDA and the Department of Health and 
Human Services (HHS) to cooperate.
    Instead, this Committee and other committees in Congress 
have repeatedly been stonewalled. Our good friend Senator 
Grassley, the former Chairman of the Senate Committee on 
Finance, who is testifying before us today, initiated inquiries 
into Ketek during the last Congress. He encountered the same 
bad faith and obstruction from this Administration.
    Three of the witnesses today are FDA criminal investigators 
who uncovered the fraud and misconduct that will be the subject 
of our hearing. Unfortunately, they had to be subpoenaed to 
testify at this hearing because Food and Drug Commissioner von 
Eschenbach and Secretary Leavitt refused to allow them to 
appear here voluntarily. A similar refusal thwarted Senator 
Grassley's inquiry in the last Congress. Fortunately, with a 
bipartisan vote of 12-0 by this Subcommittee, we issued 
subpoenas for these witnesses. My friend Joe Barton, the 
ranking Member, and I gave the agency every opportunity to 
avoid this embarrassment, but to no avail.
    Unfortunately, this obstructionist behavior continues. Just 
yesterday we received a letter from Secretary Leavitt's office, 
which I ask to be made part of the hearing record.
    In that letter, his minions announced his refusal to honor 
our subpoena for records relating to Food and Drug Commissioner 
von Eschenbach's briefing books. I must remind my colleagues 
that similar records have been turned over to me, as well as my 
good friend Joe Barton, by both Republican and Democratic 
Administrations. I must also remind you that these records were 
also unanimously subpoenaed with a bipartisan vote of 12 to 0.
    I ask my colleagues to analyze Secretary Leavitt's 
arguments in refusing to honor your subpoena. At best, they are 
specious. At worse, they border on contempt of Congress. If 
anything, his refusal to cooperate causes me to wonder what he 
is trying to hide? What is in those briefing books that he does 
not want either my Republican colleagues or our side to see? Is 
there evidence of perjury? Are there statements embarrassing to 
the Administration?
    Let me be clear on this point. Neither Chairman Stupak nor 
I will tolerate such a perversion of congressional powers to 
investigate and probe. I will fully support Chairman Stupak's 
request to enforce this subpoena by holding Secretary Leavitt 
in contempt.
    Mr. Chairman, there is an easy way for any agency to 
undergo congressional oversight. There is also a hard way. 
Commissioner von Eschenbach and Secretary Leavitt appear to 
have chosen the latter. I caution both gentlemen to reconsider 
their ill-conceived notion of Congressional oversight and 
follow the bipartisan policies that have long been the practice 
of this Committee.
                              ----------                              

    Mr. Stupak. Mr. Shimkus is delayed because of weather, but 
hopefully he will be here later today.
    Mr. Walden, do you want to make a motion?
    Mr. Walden. Mr. Chairman, I have his opening statement that 
I would like to have inserted into the record.
    Mr. Stupak. Mr. Shimkus's opening statement will be made a 
part of the record, as will the opening statement of all 
members of the subcommittee. Your statement will be made part 
of the record when they arrive or if they are presented to the 
committee.
    [The prepared statement of Mr. Shimkus follows:]

                     Statement of Hon. John Shimkus

    Thank you Chairman Stupak for convening this hearing to 
further examine the issues surrounding the antibiotic Ketek 
(``KEE-tek''), and how to protect the integrity of the FDA 
regulatory process.
    Today's hearing focuses on the conduct of Aventis 
Pharmaceutical Company, a drug company that was the subject of 
a criminal investigation. In the end, this investigation did 
not result in a prosecution.
    I think we are all trying to achieve the same thing in this 
investigation: we want a FDA drug review and approval process 
that promotes and protects the integrity of data gathered 
during clinical trials. But we will never achieve this goal if 
the individuals and companies who are prosecuted and convicted 
of crimes for misconduct in criminal trials are never debarred 
by FDA.
    Fifteen years ago, our colleague, Chairman Dingell, spurred 
the passage of the Generic Drug Enforcement Act. Through that 
Act, Congress gave FDA the power to debar companies and 
individuals who are convicted of felonies for misconduct 
relating to the regulation of drug products. Individuals who 
are debarred or disqualified by FDA are then listed on the FDA 
website. It is my understanding that some of the companies 
testifying here today rely on those lists when selecting 
physicians as investigators in clinical trials.
    However, as a report prepared by Minority Committee Staff 
and released yesterday shows, FDA.has failed to initiate 
debarment proceedings against several individuals and some 
companies even when the basis for debarment clearly exists. It 
has also initiated debarments in an uneven way; the Staff 
Report cites more than one example where FDA pursued debarment 
in one case, but did nothing in another case where the 
underlying facts and convictions were similar. FDA also takes 
years to initiate debarment proceedings after conviction; 
according to the staff report, an average of 38 months passes 
between the date of conviction, and the date FDA begins 
debarment. The delay has very real consequences for public 
health, as an investigator convicted of a felony relating to 
clinical trial misconduct can continue to receive 
investigational drug products and participate in trials up to 
the date debarment is finally imposed.
    As we now know, Dr. Kirkman-Campbell, one of the 
investigators in the Ketek trial, was indicted on fraud charges 
for her misconduct in Study 3014. During our investigation of 
Ketek, Minority Committee staff learned that, despite the fact 
that Kirkman-Campbell had been convicted of a felony and 
incarcerated in federal prison, FDA had never debarred her. In 
fact, sheis still not debarred today, even though FDA initiated 
debarment proceedings against her almost one year ago. This 
means that under federal law, she is still eligible to 
participate in clinical trials, even though she is currently 
incarcerated.
    We should not be surprised when there is a lack of 
vigilance and awareness of fraud when the industry's regulator 
does not make it a priority to ban companies and individuals 
who are convicted of crimes from continuing to do business 
before FDA. We need to have a system in whichpharmaceutical 
companies and clinical trial patients can have confidence. For 
this reason, Ranking Member Barton will pursue legislation that 
strengthens FDA's debarment authority. Under this legislation, 
FDA will have authority over not only generic drug companies, 
but any companydoing business before FDA. The Act will also 
clarify that FDA will have authority to debar companies not 
just'for their misconduct relating to the development and 
approval of a drug application, but any misconduct relating to 
the regulation of the drug. We should hold companies and 
individuals who do business before FDA to the same standard, 
without respect to thetype of drug product. I look forward to 
providing Ranking Member Barton with whatever assistance I can 
to help with this important bill. I hope my colleagues on this 
Committee will do the same.
    I am looking forward to the testimony from the companies 
involved in the Ketek safety trial: Dr. Paul Chew for Aventis, 
the sponsor; Dr. Fred Eshelman, of PPD, the study monitor; and 
Sharon Hill Price from Copernicus, the institutional review 
board. I expect that each of these witnesses will provide a 
candid assessment of their work during the trial; the 
procedures they had in place to detect and identify fraud; and 
how they dealt with concerns about fraud. Hindsight is always 
twenty-twenty. But even cursory review of the monitoring 
reports and emails exchanged among the parties during Study 
3014 shows that the parties were aware that fraud was 
apossibility as early as January 2002--a full seven months 
before Aventis submitted the results of the study to FDA.
    We want to know why Aventis felt it was appropriate to 
include data from Dr. Kirkman-Campbell's site, as well as other 
sites where the suspicion of fraud was raised, in its July 2002 
report on Study 3014 without noting the number of Good Clinical 
Practice violations and protocol violations. I understand that 
Study 3014 was a safety study, and that the point of thestudy 
was to collect as much data as possible on adverse events 
related to Ketek. However, in a case such as this where 
Clinical Practice Violations, fraud allegations, and other 
violations exist to a degree that may affect data integrity, at 
what point should a company begin to question the safety data? 
I would also like a better understanding of the roles of the 
study monitor, PPD, and the institutional review board, or IRB, 
Copernicus, in selecting thephysicians who participate in the 
study and dealing with the problems and violations that 
presented during the study.
    We are also joined today by the FDA criminal investigators 
who were assigned to investigate the allegations of fraud in 
Study 3014: Robert West, Robert Ekey, and Douglas Loveland. Two 
weeks ago, the Republicans on this Subcommittee supported 
Chairman Stupak's motion to subpoena the testimony of these 
criminal investigators. As the investigators who have 
interviewed the major players in the Ketek safety trials, your 
testimony is critical to helping us have the best possible 
understanding of the evidence in this case.
    Finally, I would like to thank Senator Chuck Grassley, for 
taking the time to be with us this morning. Senator Grassley 
has been investigating the Ketek safety trials and FDA's review 
and approval of Ketek for the last three years. I look forward 
to his testimony.
    Hopefully, today's hearing will help us understand what 
went wrong in Study 3014; whether those mistakes and errors 
could have been prevented; and how we can make sure they never 
happen again.
    I thank Chairman Stupak for convening this hearing and 
yield back the balance of my time.
                              ----------                              

    Mr. Stupak. Mr. Burgess for an opening statement, please.

OPENING STATEMENT OF HON. MICHAEL C. BURGESS, A REPRESENTATIVE 
              IN CONGRESS FROM THE STATE OF TEXAS

    Dr. Burgess. Thank you, Mr. Chairman. Mr. Chairman, I want 
to apologize in advance because I do have to leave this hearing 
early. Congress doesn't vote until much later this afternoon, 
but when this hearing was scheduled, I had made previous plans 
to travel to another key Federal agency over which this 
committee also has oversight.
    But I do believe this is an important hearing, and I only 
wish it had been scheduled when there was availability for more 
members to attend.
    Today, we are here to continue our discussion regarding the 
approval process for the antibiotic Ketek. When I was 
practicing medicine for over 20 years, my patients relied on me 
to administer safe medicine. In return, I relied upon the 
Federal drug approval process. I relied on the process to be 
prudent and cautious. I relied on the notion that the approved 
drugs were safe. However, when there is a breakdown in the 
process, and when there are fraudulent activities, this 
reliance can prove dangerous.
    As a physician, it is unfathomable that anyone would gamble 
with my patients' lives. I believe that any allegation of 
wrongdoing must be seriously investigated.
    It is important to note that the largest enroller of Ketek, 
Dr. Kirkman-Campbell, is now serving 4 years in Federal prison 
for her wrongdoings. I think it is important also to note and 
to thank the leadership of this committee, as well as the 
leadership of Senator Grassley, for their pursuit of truth in 
Ketek's approval process. It is my hope that this investigation 
is able to shed some light on troublesome allegations, and that 
we never again have to learn of another Study 3014 and, more 
importantly, that the confidence of America's doctors and 
America's patients and America's mothers and fathers are not 
further undermined.
    There are still many questions that need to be answered, 
and I am hopeful that the witnesses testifying before us today, 
including the FDA criminal investigators, as well as the 
companies involved in the approval process of this drug, will 
be able to address many of the allegations before the 
committee.
    While, clearly, the focus of this hearing is on Ketek, I 
would be remiss if I did not also briefly mention the minority 
staff report that was issued yesterday, detailing the problems 
with the FDA's debarment process. The report also makes some 
serious allegations, including the troubling fact that Dr. 
Kirkman-Campbell, now a convicted felon, is still eligible to 
work with the FDA because she has not been debarred. According 
to Ranking Member Joe Barton, who issued the report, quote, 
``When it comes to excluding the worst of the worst, convicted 
felons, the Food and Drug Administration's debarment process 
seems to be nonexistent,'' end quote.
    Now, the staff-prepared minority report does disclose an 
ongoing pattern of inaction and, perhaps, an almost 
institutional nonenforcement regarding the debarment 
proceedings. And this subcommittee, appropriately, is holding 
hearings. But, Mr. Chairman, I do have to say it seems like we 
are holding hearing upon hearing.
    We are now 13 months or more into this process--apparently, 
some of the problems go back at least as far as 15 or 16 
years--and I do have to ask the question, When are we going to 
get to the point where we actually legislate on this issue and 
stop just endless investigation after investigation?
    This is the type of product that America--America's 
doctors, America's patients, America's moms and dads--want to 
see out of this committee, indeed, what they have come to 
expect.
    I also feel it is my obligation to mention that we are now 
65 years into the availability of antibiotics for treating 
infectious disease. Antibiotics have changed the practice of 
medicine.
    Not every antibiotic that is out there is without risk. For 
example, penicillin, one of the early antibiotics to be 
introduced back in the early 1940s, would have a difficult time 
with the approval process today. I am allergic to penicillin; 
there is a chance I could die if I took that medication. Yet I 
am grateful that that medication exists.
    As someone who is allergic to penicillin, I am also 
grateful that there is ongoing research and development of 
antibiotics to treat community-acquired pneumonia for 
individuals who are allergic to penicillin. And Ketek would 
fall into that category.
    Other antibiotics that had been introduced, that had 
serious side effects, such as chloramphenicol, are now 
available to treat the most serious of infections; and it would 
be a mistake--it would be a mistake if those antibiotics were 
not still available. So we do have to balance what is in the 
broad public interest as we continue our efforts at oversight, 
to make certain that the FDA does indeed provide the level of 
commitment that we all wish it would.
    Now, this committee has jurisdiction over the FDA. We have 
a duty to the public to review and investigate this problem and 
to legislate solutions for this problem. And I thank Ranking 
Member Barton for having the minority staff report prepared and 
bringing this to our attention; and I hope we can work in a 
bipartisan manner to investigate and resolve this issue.
    Mr. Chairman, in the interests of time, I will yield back 
the balance of my time.
    Mr. Stupak. Thank you, Mr. Burgess.
    Mr. Stupak. Seeing no other members, we will begin with our 
panel of witnesses.
    On our first panel to come forward today we have Ms. Ann 
Marie Cisneros, former Senior Clinical Research Associate at 
PPD, Inc.; Mr. Robert West, Special Agent in the Office of 
Criminal Investigation at the Food and Drug Administration; Mr. 
Robert Ekey, Assistant to the Special Agent in Charge at the 
Special Investigations Division, Office of Inspector General at 
the Department of Housing and Urban Development--that's a long 
title--and Mr. Douglas Loveland, Special Agent in the Office of 
Criminal Investigation at the Food and Drug Administration.
    Welcome, all.
    It is the policy of this subcommittee to take all testimony 
under oath. Please be advised that witnesses have the right 
under the rules of the House to be advised by counsel during 
testimony.
    Do any of you wish to be represented by counsel today?
    All witnesses are indicating they do not.
    Therefore, I am going to ask you to please rise and raise 
your right hand and take the oath.
    [Witnesses sworn.]
    Mr. Stupak. Let the record reflect that the witnesses 
replied in the affirmative.
    You are now under oath. We will now hear a 5-minute opening 
statement from this panel. You may submit a longer statement 
for the record. Your statement will be part of the record.
    Mr. Stupak. Ms. Cisneros, we will start with you, please, 
if you would.

    STATEMENT OF ANN MARIE CISNEROS, FORMER SENIOR CLINICAL 
                 RESEARCH ASSOCIATE, PPD, INC.

    Ms. Cisneros. Good morning, Mr. Chairman and members of the 
committee. I am honored that you are giving----
    Mr. Stupak. Would you pull that mike a little closer?
    Ms. Cisneros. Sure.
    I am honored you are giving me the opportunity to tell my 
story.
    My name is Ann Marie Cisneros. I am currently an 
independent clinical research associate. I served in the U.S. 
Air Force as a Medical Technologist, have a Bachelor of Science 
degree in Occupational Education, Wayland Baptist University, 
and an MBA from Pfieffer University.
    I have worked as a clinical research associate for 
approximately 8 years. My first 3 years in the industry I spent 
at PPDI, a contract research organization, where I monitored a 
number of protocols that included the large Ketek study, called 
Study 3014. At the time of the Study 3014, I was a senior 
clinical research associate and was tasked to assist with the 
monitoring of Dr. Ann Kirkman-Campbell's site.
    Dr. Campbell is currently serving a 57-month prison 
sentence for fraud associated with Study 3014. In addition, she 
was ordered by the court to pay restitution to the drug sponsor 
Aventis, which had paid her $400 per patient enrolled.
    Mr. Chairman, based upon what I observed and learned in 
monitoring the Kirkman-Campbell site, Dr. Campbell indeed had 
engaged in fraud. But what the court that sentenced her did not 
know is that Aventis was not a victim of this fraud. On the 
contrary, let me explain.
    Even before conducting the Kirkman-Campbell site visit, a 
number of red flags were apparent. I knew that Dr. Campbell had 
enrolled over 400 patients, or 1 percent of the adult 
population of Gadsden, Alabama. By comparison, another site in 
Gadsden had enrolled only 12 patients.
    In a quality assurance audit by Aventis in early 2002, 
several informed consent issues were noted, as well as a 
significant underreporting of adverse events and no reports of 
serious adverse events. No patients had withdrawn from the 
study, and no patients were lost to follow-up, an unusual 
occurrence given the number of subjects.
    She enrolled patients within minutes of each other, and 
upwards of 30 a day. She enrolled patients at times and on days 
when her office was closed.
    Once we started reviewing patient charts, we discovered 
that every informed consent had a discrepancy. Most of the 
consents looked like they had been initialed by someone other 
than the patient. A lot of the consents were dated by someone 
other than the subject. One consent was a blatant forgery.
    There were date discrepancies as to when patients were 
enrolled in the study, had blood drawn, or had signed consent. 
Most patients diagnosed with bronchitis either had no history 
of the ailment or did not have a chronic condition.
    She enrolled her entire staff in the study. Frankly, all 
Kirkman-Campbell seemed truly interested in was getting more 
business from Aventis as an investigator. At one point during 
my site visit, she told Aventis Project Manager Nadine Grethe 
that I could only stay if Nadine got her other studies at 
Aventis. Nadine must have agreed, because it is my 
understanding that when FDA audited the Kirkman-Campbell site, 
she was indeed participating in another Aventis clinical trial.
    While at the site, I was so concerned about patient safety, 
I called Copernicus Independent Review Board or IRB to express 
my concerns and seek guidance. An IRB, which is under contract 
to the drug sponsor, has as its primary purpose patient 
advocacy. It is allowed to contact patients directly and is 
duty-bound to report to the FDA any unanticipated problems 
involving risk to subjects and serious noncompliance with 
regulations.
    I spoke with someone, who I understood to be the president 
of the company, and was told that while she shared my concerns, 
she preferred to wait and see what actions Aventis took. I 
never did hear from the IRB again, and to my knowledge, 
Copernicus never did audit or blacklist the site, or report any 
irregularities to the FDA.
    I e-mailed a summary of my site visit findings to Robert 
McCormick, head of quality assurance at PPD, and copied Aventis 
personnel. I also participated in a teleconference between PPD 
and Aventis, at which I discussed issues identified in my site 
visit.
    At some point after that, I understand that Aventis took 
site management responsibilities away from PPD because Dr. 
Campbell would not cooperate with anyone but the sponsor.
    I subsequently left PPD, but learned that the Kirkman-
Campbell site was being audited by the FDA. In preparation for 
the audit, I was told by a trusted and distressed former 
colleague at PPD that Nadine Grethe coached Dr. Campbell on how 
to explain away some of the site irregularities.
    I was called on two occasions by PPD lawyers who reminded 
me of the confidentiality agreement I signed, and advised me 
not to speak with the FDA without Aventis approval and PPD 
attorneys present.
    In my 8 years in clinical research work, this is the only 
instance I have come across of such abysmal behavior by a drug 
sponsor. I feel I can speak for those who agonized over the 
situation when I say we are pleased that Dr. Campbell is 
serving prison time for her actions, though what brings me here 
today is my disbelief in Aventis' statements that it did not 
suspect that fraud was being committed.
    Mr. Chairman, I knew it. PPD knew it. And Aventis knew it. 
Thank you.
    Mr. Stupak. Thank you.
    [The prepared statement of Ms. Cisneros follows:]

                     Statement of Ann Marie Cisneros

    Good morning Mr. Chairman and members of the Committee. I 
am honored that you are giving me the opportunity to tell my 
story.
    My name is Ann Marie Cisneros, I am currently an 
independent clinical research associate. I served in the United 
States Air Force as a Medical Technologist, have a Bachelors of 
Science Degree in Occupational Education from Wayland Baptist 
University and a Masters of Business Administration Degree from 
Pfieffer University.
    I have worked as a clinical research associate for 
approximately eight years. My first three years in this 
industry I spent at PPDI, a Contract Research Organization, 
where I monitored a number of protocols that included the large 
Ketek study called Study 3014. At the time of Study 3014, I was 
a senior clinical research associate and was tasked to assist 
with the monitoring of Dr. Anne Kirkman-Campbell's site.
    Dr. Kirkman-Campbell is currently serving a 57-month prison 
sentence for fraud associated with Study 3014. In addition she 
was ordered by the court to pay restitution to the drug 
sponsor, Aventis, which had paid her $400 per patient enrolled.
    Mr. Chairman, based upon what I observed and learned in 
monitoring the Kirkman-Campbell site, Dr. Kirkman-Campbell 
indeed had engaged in fraud. But what the court that sentenced 
her did not know is that Aventis was not a victim of this 
fraud. On the contrary. Let me explain.
    Even before conducting the Kirkman-Campbell site visit, a 
number of ``red flags'' were apparent. I knew that Dr. Kirkman-
Campbell had enrolled over 400 patients or 1% of the adult 
population of Gadsden, Alabama. (By comparison, another site in 
Gadsden had enrolled just twelve patients.) In a Quality 
Assurance audit by Aventis in early 2002 several Informed 
Consent issues were noted as well as a significant under-
reporting of Adverse Events and no reports of Serious Adverse 
Events. No patients had withdrawn from the study and no 
patients were lost to follow up, an unusual occurrence given 
the number of subjects. She enrolled patients within minutes of 
each other and upwards of 30 patients per day. She enrolled 
patients at times and on days when the office was closed.
    Once we started reviewing patient charts, we discovered 
that:
     Every informed consent had a discrepancy.
     Most of the consents looked like they had been initialed 
by someone other than the patient.
     A lot of the consents were dated by someone other than 
the subject.
     One consent was blatantly forged.
     There were date discrepancies as to when patients were 
enrolled in the study, had their blood drawn or signed their 
consent.
     Most patients diagnosed with bronchitis either had no 
history of the ailment or did not have a ``chronic'' condition.
     She enrolled her entire staff in the study.
    Frankly, all Kirkman-Campbell seemed truly interested in 
was getting more business from Aventis as an investigator. At 
one point during my site visit, she told Aventis Project 
Manager Nadine Grethe that I could only stay if Nadine got her 
other studies at Aventis. Nadine must have agreed. It is my 
understanding that when the FDA audited the Kirkman-Campbell 
site, she was participating in another Aventis clinical trial.
    While at the site, I was so concerned about patient safety 
I called Copernicus Independent Review Board or IRB to express 
my concerns and seek guidance. An IRB, which is under contract 
to the drug sponsor, has as its primary purpose patient 
advocacy. It is allowed to contact patients directly and is 
duty-bound to report to the FDA any unanticipated problems 
involving risks to subjects and serious noncompliance with 
regulations. I spoke with someone who I understood to be the 
president of the company and was told that, while she shared my 
concerns, she preferred to wait and see what actions Aventis 
took. I never heard from the IRB again. To my knowledge 
Copernicus never did audit or blacklist the site, or report any 
irregularities to the FDA.
    I e-mailed a summary of my site visit findings to Robert 
McCormick, head of quality assurance at PPD, and copied Aventis 
personnel. I also participated in a teleconference between PPD 
and Aventis at which I discussed issues identified in my site 
visit. At some point after that I understand that Aventis took 
site management responsibilities away from PPD because Dr. 
Kirkman-Campbell would not cooperate with anyone but the 
sponsor.
    I subsequently left PPD but learned that the Kirkman-
Campbell site was being audited by the FDA. In preparation for 
the audit, I was told by a trusted and distressed former 
colleague at PPD that Nadine Grethe, Proect Manager at Aventis 
coached Dr. Kirkman-Campbell on how to explain away some the 
site irregularities.
    I was called on two occasions by PPD lawyers who reminded 
me of the confidentiality agreement I signed and advised me not 
to speak with the FDA without Aventis approval and PPD 
attorney's present.
    In my eight years in clinical research work, this is the 
only instance I've come across of such abysmal behavior by a 
drug sponsor. I feel I can speak for those who agonized over 
this situation when I say we are pleased that Dr. Kirkman-
Campbell is serving prison time for her actions. But what 
brings me here today is my disbelief at Aventis's statements 
that it did not suspect that fraud was being committed. Mr. 
Chairman, I knew it, PPD knew it, and Aventis knew it.
    Thank you for this opportunity to tell my story.
                              ----------                              

    Mr. Stupak. Do either of--the special agents, my 
understanding, do not want to make a statement.
    Do you wish to say anything?
    Mr. West.
    Mr. West. Mr. Chairman, I don't have an opening statement.
    Mr. Stupak. Mr. Ekey?
    Mr. Ekey. No, sir.
    Mr. Stupak. No, Mr. Loveland?
    Mr. Loveland. No, sir.
    Mr. Stupak. OK, then we will go right to questions.
    Ms. Cisneros, if I may, you indicated that after a couple 
days you called the IRB, Copernicus.
    Ms. Cisneros. Yes, sir.
    Mr. Stupak. Do you know when that was?
    Ms. Cisneros. It was probably 3 or 4 days into my visit, so 
either a Wednesday or a Thursday. I believe it was Wednesday of 
that week.
    Mr. Stupak. OK. Why did you call Copernicus?
    Ms. Cisneros. I knew fraud was being committed at the site, 
and I feared for patient safety. While I wanted to go up the 
chain of command at PPD, I just felt like Copernicus could take 
immediate action against the site.
    Mr. Stupak. Their responsibility is the patient safety?
    Ms. Cisneros. Correct.
    Mr. Stupak. Is that their main focus in a clinical trial, 
an IRB, institutional review board?
    Ms. Cisneros. Well, their main focus is approving informed 
consents and protocols that reflect patient safety, or to 
ensure patients are kept safe. But there was a statement in the 
informed consent that said the patients could call the IRB if 
they had any concerns.
    Mr. Stupak. Sure. So any concerns about patient safety 
should be directed to the IRB, then?
    Ms. Cisneros. Correct.
    Now monitors aren't ever encouraged to call IRBs. There is 
just not a relationship there. So just to put that in the 
record.
    Mr. Stupak. So this was unusual for you to do this?
    Ms. Cisneros. Absolutely, yes.
    Mr. Stupak. But you felt compelled to call Copernicus?
    Ms. Cisneros. Yes.
    Mr. Stupak. How did you--by telephone, I take it?
    Ms. Cisneros. Yes.
    Mr. Stupak. Do you know who you called?
    Ms. Cisneros. I believe it was the president of the company 
at the time.
    Mr. Stupak. OK. Right in front of Mr. Ekey there, could you 
could hand her that big binder?
    Would you please take a look at Exhibit No. 4?
    Ms. Cisneros. I am sorry, what number?
    Mr. Stupak. No. 4, please.
    Ms. Cisneros. All right.
    Mr. Stupak. OK. Exhibit 4 has two pages.
    And 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 No. 4, excuse me.
    Could you identify number 33 for us?
    Ms. Cisneros. 33 is a telephone contact report taken by the 
IRB of my phone call.
    Mr. Stupak. OK. And it is dated February 21, 2002?
    Ms. Cisneros. Yes.
    Mr. Stupak. OK. This says IRB staff member taking call, 
Sarah Wallace.
    Do you know who Sarah Wallace is.
    Ms. Cisneros. I don't recollect that name.
    Mr. Stupak. OK. Do you know if she is the president of 
Copernicus?
    Ms. Cisneros. To my knowledge, Sharon Hill Price was the 
president of Copernicus.
    Mr. Stupak. OK. Do you know Ms. Price?
    Ms. Cisneros. I do not, no.
    Mr. Stupak. OK. But it is your recollection that that's who 
you spoke to on that day?
    Ms. Cisneros. Yes.
    Mr. Stupak. OK. And does the--it says in here ``she,'' 
meaning you, has reviewed 50 of the 400 files, 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. I don't see that noted in this.
    Mr. Stupak. OK. Did the president of Copernicus then ask 
you for those names or numbers of these patients?
    Ms. Cisneros. No.
    Mr. Stupak. OK. Let me go to Exhibit No. 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 said, every informed consent had an issue, and that 
one consent I believed to be a forgery. I didn't know what she 
was doing with the study drug, if patients were being given the 
drug and then not followed, that sort of thing.
    So, no, I didn't go into specifics.
    Mr. Stupak. OK. On page 1 of that Exhibit 4, it says--it is 
from a Jessica Lasley----
    Ms. Cisneros. Uh-huh.
    Mr. Stupak [continuing]. And you are carbon-copied on this. 
And this was a telephone conference to discuss findings from 
monitoring of Kirkman-Campbell; is that correct?
    Ms. Cisneros. Yes.
    Mr. Stupak. This was a few days after you made the call on 
February 27, 2002?
    Ms. Cisneros. Yes.
    Mr. Stupak. Were you in on that conference call?
    Ms. Cisneros. Yes, I was, if it is the one--there was one 
teleconference that I was in on.
    Mr. Stupak. And do you believe this was the one then?
    You are listed there as--carbon copy was sent to a Nadine 
Grethe and then carbon-copied to you.
    Ms. Cisneros. Yeah. This is an e-mail setting up the 
teleconference. So I participated in that teleconference, yeah.
    Mr. Stupak. Down at the bottom it says Ann Marie--that 
would be you?
    Ms. Cisneros. Yes.
    Mr. Stupak. And John have assembled some examples of this 
information we can share with you. Let us know. We have 
attached a summary of Ann Marie's findings during her visit.
    Ms. Cisneros. Correct.
    Mr. Stupak. OK. My time is up. I am going to want to come 
back to this witness. And let me just ask one question then, 
one more question.
    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 teleconference--or she was talking to Nadine Grethe. And I 
heard her say, Nadine, I will let Ann Marie stay if you can get 
me into more Aventis studies.
    Mr. Stupak. So the Nadine that she was talking to was 
Nadine Grethe from Aventis?
    Ms. Cisneros. Correct.
    Mr. Stupak. And that is the same Nadine that is in Exhibit 
4 that you had this telephone conference with on Wednesday, 
then, of that week that you were down there?
    Ms. Cisneros. Correct.
    Mr. Stupak. And the next day--on Thursday did you leave 
then, Dr. Kirkman-Campbell's office?
    Ms. Cisneros. I believe I left that day, yes.
    Mr. Stupak. Thank you.
    Mr. Walden for questions then, please.
    Mr. Walden. Thank you, Mr. Chairman.
    Ms. Cisneros, you participated in that conference call with 
Aventis in March of 2002 to discuss concerns with Dr. Kirkman-
Campbell's site, correct?
    Ms. Cisneros. Correct.
    Mr. Walden. And what follow-up did Aventis decide to do to 
address PPD's concerns?
    Ms. Cisneros. Well, unfortunately, I left PPD shortly after 
that teleconference, so I am not quite sure what took place 
after that teleconference.
    Mr. Walden. OK.
    At the time of the call did you believe this follow-up was 
appropriate? But if you have left, then--
    Ms. Cisneros. No, I just remember from the teleconference 
how laissez-faire Aventis personnel were about the study 
findings and the excuses they provided for some of the oddities 
at the sites. It was very frustrating, because they didn't seem 
to want to acknowledge fraud in the least.
    Mr. Walden. Do you believe Aventis intentionally ignored 
evidence of fraud? Or is it a matter that their processes and 
procedures for verifying fraud were faulty and couldn't have 
detected it?
    Ms. Cisneros. I personally believe they ignored evidence of 
fraud. You had to have your head stuck in the sand to have 
missed this.
    Mr. Walden. Agent Loveland, if I could address a question 
to you--you may want to pull that mike fairly close--what do 
you think about their follow-up procedures?
    Mr. Loveland. It is a catastrophic failure.
    Mr. Walden. In what respect?
    Mr. Loveland. The decision-making process that Aventis used 
to evaluate the warnings that Mrs. Cisneros and other PPD folks 
raised was illogical, ineffective. And it could have led them 
to not come to the proper conclusion; it was that bad.
    Mr. Walden. Do you think that that process and procedure is 
in place and used in other drug evaluations? Have you seen any 
evidence of that?
    Mr. Loveland. I don't know. I have seen other divisions of 
Aventis run clinical trials in other ways, and it was not this 
bad.
    Mr. Walden. What makes this unique?
    Mr. Loveland. From start to finish, their process for 
analyzing information coming out of the trial was poor.
    When you get into a traffic accident, you call a traffic 
cop. These folks came in and they said, We have indicators of 
fraud, and they called a mathematician.
    A mathematician didn't know what fraud looked like, and he 
couldn't identify it. He looked at all the data, couldn't 
figure out a rule to apply to the data set, came back and said, 
I don't see fraud. They took that to convince themselves that 
two of the most serious allegations raised by Ms. Cisneros and 
by other PPD folks weren't indicators of fraud.
    The next thing they did was, they said, Well, let's take a 
look at all these uses of different-colored inks and the cross-
outs and all the other things that teach us these are red flags 
when you see these in clinical trials. And they decided to fix 
them with a blizzard of memos to file that get filed with the 
IRB long after the patients were even enrolled.
    Mr. Walden. Explain what you mean by that.
    When you say ``memos to file'' and ``a blizzard'' of them, 
what were they saying in those memos?
    Mr. Loveland. Essentially, that the monitors or the 
auditors had found these problems in each informed consent or 
in each medical record; the clinical investigator--in this 
case, Kirkman-Campbell--was reeducated or trained on how to do 
this right.
    She signed the memo to file; and it was forwarded to the 
IRB, as though that had some sort of rehabilitative effect, and 
it didn't. In fact, the trial had stopped enrolling 2 months 
earlier. There is absolutely nothing the IRB could have done 
with them.
    And the final serious allegation, which they held to the 
very end, that just fell off the radar--it was the allegation 
of forgery.
    Mr. Walden. Have you found any evidence that this was 
intentional on Aventis' part? Or is it just sloppy? Or is it 
head-in-the-sand?
    Mr. Loveland. It is interesting you would use the word 
``sloppy.'' That's how they described Kirkman-Campbell. And the 
problem is not so much that it is--was it fraud or was it 
sloppy. We want reliable data at the FDA.
    Mr. Walden. Sure.
    Mr. Loveland. Whether it is fraud or sloppy, it is not 
reliable.
    Mr. Walden. Understood.
    Mr. Loveland. Their threshold was, they had to find fraud. 
Before they would not submit it to the agency, which leads me 
to believe they were willing to submit sloppy data.
    That is a flawed decision-making process.
    Mr. Walden. At Aventis or at----
    Mr. Loveland. At Aventis.
    Mr. Walden. OK. If you suspected Aventis intentionally 
designed a system to not let itself know or be able to detect 
criminal fraud, what evidence would you seek to substantiate 
that suspicion?
    Mr. Loveland. Well----
    Mr. Walden. And was such evidence sought?
    Mr. Loveland. Mr. West ran a great case with respect to Dr. 
Kirkman-Campbell.
    Mr. Walden. Right.
    Mr. Loveland. He proved in his investigation that falsified 
data was created.
    Mr. Walden. Got it.
    Mr. Loveland. Mr. Ekey did a great job during the 9 months 
he had the case of solidifying the complaint, making sure that 
he had all the complaining documents, that the data that were 
falsified were submitted to Aventis, and Aventis submitted them 
to the FDA.
    So when I came in, all I had to do was figure out whether 
or not Aventis knew on the day they submitted the data that the 
data had been falsified. That was the only question left for me 
to answer.
    Mr. Walden. And the answer was?
    Mr. Loveland. I can't prove that beyond a reasonable doubt, 
and that's the standard I have to eventually meet in court. I 
only have one institution of resolution. It is the U.S. court 
system, and that is the standard I have to meet.
    Unable to meet that, we refer it back to the FDA for 
regulatory action.
    Mr. Walden. And you weren't able to meet that because of 
all the memos to file: that they had identified this, they had 
attributed it to a sloppy process, they reeducated the doctor, 
and so, therefore, because they admitted to all those things 
and had their memos to file----
    Mr. Loveland. They actually took a number of steps. They 
had a meeting under their fraud SOP. They didn't do it very 
well, but they had one.
    They had a plan. They didn't follow it real well, and the 
plan wasn't terribly effective, but they had one. They could 
individually answer every single allegation.
    Collectively, you can look at it from 30,000 feet and show 
that it just didn't work, but they could individually answer 
each one. And what I described to you, sir, is more than 
reasonable doubt in the mind of a jury, and so at the end of 
the day, I would have failed in my only institution of 
resolution.
    Mr. Walden. Could you briefly address the issue of 
debarment?
    Mr. Loveland. No, sir. I don't know anything about it. That 
is a different part of the FDA.
    Mr. Walden. All right.
    Thank you, Mr. Chairman.
    Mr. Stupak. Thank you, Mr. Walden.
    Mr. Burgess for questions, please.
    Dr. Burgess. Thank you, Mr. Chairman. Let me ask any of the 
three investigators who would like to answer this: Is this an 
unusual situation? Have you investigated other companies for 
this type of allegation, and could you give us an idea as to 
how many companies have undergone such investigation?
    Mr. West. Well, I can address what I have done in my 11 
years. It is not normally the company that we are 
investigating; it is normally the PI who is conducting the 
clinical trial that we investigate.
    Dr. Burgess. So this was unusual in that it----
    Mr. West. This is unusual, yes, in my experience.
    Mr. Loveland. Those kinds of cases are actually handled by 
my unit. And this is not a very common type of an offense, 
where we have a major pharmaceutical corporation who has been 
accused of submitting intentionally falsified data.
    That is not unheard of, but it is not terribly common.
    Dr. Burgess. But there have been other cases?
    Mr. Loveland. I believe so.
    Dr. Burgess. And in those cases what did the fraud look 
like?
    Mr. Loveland. The ones I am familiar with, it is dry-
labbing, it is making up data.
    In one case I ran a case where one company stole another 
company's data and submitted it. But these are not typically 
large companies like Aventis was.
    Dr. Burgess. So there is not really an established pattern 
that someone could rely on when a company--or when there is a 
suspicion that a company is involved; is that correct?
    Mr. Loveland. This did not fit any pattern I have seen 
before, sir.
    Dr. Burgess. Then how did the company itself react to when 
you brought forth the issues that you have discussed with Mr. 
Walden?
    Mr. Loveland. At the beginning of the week, they were very 
cooperative, very friendly, very warm, very hospitable. They 
pledged that they just had--they didn't believe it was fraud, 
they didn't see fraud during the conduct of the trial. They 
thought everything was OK, and they would be happy to make 
anything available to me that I wanted.
    By the end of the week, they were saying, Gee, we have 
learned an awful lot here this week, because they sat in on all 
of the interviews.
    Dr. Burgess. So they learned a lot in the process of 
following you through your investigation?
    Mr. Loveland. Well, they learned a lot that week, I 
believe.
    Dr. Burgess. Well, was the kind of fraud that took place 
with Dr. Kirkman-Campbell, was it unusual in your experience 
for the pattern of fraud in a clinical study?
    Mr. Loveland. It is very typical type of PI-level fraud, 
making up patients. The only thing that was different here was, 
Kirkman-Campbell used actual patients with actual files. And in 
doing that, that does make it a little bit harder to detect, 
because when you just completely make a patient up out of whole 
cloth there are some indicators in the patient's file that you 
can see----
    Dr. Burgess. But surely a big company like Aventis that is 
in the practice of doing these types of investigations, if 
there is a graphite titration, they should be able to pick that 
up, correct?
    Mr. Loveland. They hire PPD to pick it up, and PPD picked 
it up. PPD sent signals to Aventis. They were loud signals, 
they were bright signals, and they were repetitive signals. 
Aventis should have known.
    Dr. Burgess. Well, in addition to the site that is under--
that we are focusing on today, was there fraud at other sites 
as well?
    Mr. Loveland. I believe there was.
    Dr. Burgess. Was that unusual, to find that there was this 
level of fraud at more than one site?
    Mr. Loveland. No. When you have 1,826 ``anybodies'' put 
together, you are going to have an offender in the mix. You are 
going to have more than one offender. There are criminological 
studies out there that show this.
    Dr. Burgess. So this level was not unusual--or it was 
unusual?
    Mr. Loveland. Eighteen hundred clinical investigators in 
one study is more than I have ever seen before. But what you 
have to have is a robust fraud detection and neutralization 
program to protect your clinical trial from the fraud and to 
preserve the sanctity of your data's integrity.
    Dr. Burgess. But could the company have anticipated this 
degree of misbehavior on the part of their investigators?
    Mr. Loveland. They should have.
    Dr. Burgess. Do you think the level of fraud found in this 
Study 3014 is a function of having such a large study?
    Mr. Loveland. That magnified it.
    Dr. Burgess. Was it the way in which the investigators 
themselves were selected?
    Mr. Loveland. I am sorry, sir?
    Dr. Burgess. Did it in any way reflect on how the 
investigators were selected, how they were trained?
    Mr. Loveland. I didn't look into that, and I wouldn't feel 
comfortable commenting on that.
    Dr. Burgess. In your opinion, would it be a lack of 
vigilance by the company in identifying and detecting fraud?
    Mr. Loveland. Absolutely.
    Dr. Burgess. Do you believe that a company has to have 
absolute proof of fraud before it reports a fraud to the Food 
and Drug Administration?
    Mr. Loveland. I don't. But again let's draw the distinction 
between what the FDA wants and what we are talking about here.
    The FDA wants reliable data. And whether it is sloppy or 
fraudulent, that is not reliable. So fraud would be to the far 
end perhaps of unreliable data, but we don't want sloppy data 
either.
    Dr. Burgess. Right. So at that point, regardless of whether 
it is--whether you believe it to be fraudulent or just simply 
sloppy, what then is your obligation to report to the Food and 
Drug Administration?
    Mr. Loveland. Well, I couldn't find an absolute written 
statutory obligation, but common sense says when you have this 
many indicators, if you can't figure it out yourself, pick up 
the phone and call FDA. The doctors and the scientists that I 
interviewed at Aventis, they knew DSI's telephone number. They 
could have used it.
    Dr. Burgess. So the level of concern should have been to 
notify the FDA.
    But you told Mr. Walden that you did not recommend that the 
FDA prosecute Aventis for fraud?
    Mr. Loveland. I can't because I know that at the end of the 
day reasonable doubt exists, and I can't get that past a jury.
    Dr. Burgess. Do you think Aventis actually knew of this 
going on at these sites?
    Mr. Loveland. They should have. If they didn't----
    Dr. Burgess. Knew it was sloppy or knew that it was 
intentionally fraudulent?
    Mr. Loveland. Either one.
    Dr. Burgess. Either one.
    Mr. Loveland. Well, they knew it was sloppy. They used 
``sloppy'' as an excuse not to throw the fraud flag.
    Dr. Burgess. What prevented Aventis from acknowledging 
either sloppy or fraudulent? What caused them to stop short of 
saying this was a problem for us, too?
    Mr. Loveland. The study director said that unless they had 
reasonable proof of fraud, the data were going to get 
submitted.
    Dr. Burgess. Thank you, Mr. Chairman. I will yield back.
    Mr. Stupak. We will be going another round, so we will 
continue questions.
    Mr. Loveland, on page 5 of your report it indicates that 
you inspected five sites; is that correct?
    Mr. Loveland. Sir, OCI does not do inspections.
    Mr. Stupak. It is on Exhibit No. 10 in the exhibit book 
there.
    Ms. Cisneros, if you could give it to him.
    We have your report there. And it looks like 19 or 11 sites 
you looked at.
    Mr. Loveland. I am sorry, the tab was 10?
    Mr. Stupak. Yes, page 5 of your report. That is your report 
there, right, on page 10?
    Mr. Loveland. That is correct, sir. These are actually 
paragraphs--I did not--for the record, I didn't go to any of 
these sites.
    Mr. Stupak. OK.
    Mr. Loveland. These were actually removed from Aventis' own 
files.
    Mr. Stupak. So this page 5, these sites--Dr. Sarkar, Dr. 
Barber, Dr. Franklin, Dr. Sghiatti, Dr. Garner, Dr. 
Monticciolo, Dr. Jeffrey McCloud, Dr. Stone, Dr. Lang, Dr. 
Terpstra, and Dr. Ann 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.
    Mr. Stupak. Right. And you included this in your report?
    Mr. Loveland. Yes.
    Mr. Stupak. And in each one of these they are alleging 
problems and protocol violations which were significant enough 
to affect the integrity of the Study 3014?
    Mr. Loveland. Data in it, yes, sir.
    Mr. Stupak. So Aventis definitely knew about--at least from 
10 sites that there 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 GCP problems.
    Mr. Stupak. Associated with the Study 3014?
    Mr. Loveland. That's correct. That is a 1 percent ratio. 
But some of these here are the highest enrolling sites.
    Mr. Stupak. So it is not just necessarily the number of 
sites, but also the number of patients enrolled at each site to 
make up your study, correct?
    Mr. Loveland. That's correct.
    Mr. Stupak. And this is significant then, even this 1 
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.
    Mr. Stupak. Did you reach the conclusion then that the data 
relied upon or the data relied on in 3014 was unreliable?
    Mr. Loveland. I didn't have to. DSI did that. They get paid 
to make that decision, and I do not disagree with it.
    Mr. Stupak. OK. DSI?
    Mr. Loveland. Division of Scientific Investigation is a 
division within the Center for Drug Evaluation and Research, 
and they actually schedule inspections. They actually read the 
reports and issue the instructions and all those sorts of 
things.
    Mr. Stupak. Very good.
    Agent West, if I may, you opened a criminal investigation 
shortly after the FDA clinical site investigator, Ms. Smith, 
investigated Kirkman-Campbell's site; is that correct?
    Mr. West. That's correct, sir.
    Mr. Stupak. And that was in October of 2002?
    Mr. West. Yes, sir.
    Mr. Stupak. What did Kirkman-Campbell do when you notified 
her that you were conducting this criminal investigation?
    Mr. West. When I approached 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 Aventis 
personnel first.
    Mr. Stupak. Do you know if she spoke with Aventis?
    Mr. West. I have no idea. But I'm assuming after I left she 
had to speak with Aventis because they had to prepare the 483.
    Mr. Stupak. And that's a----
    Mr. West. That's the response to the inspection.
    Mr. Stupak. OK. So Kirkman-Campbell had to file this report 
in response to your inspection?
    Mr. West. It's a response to the regulatory inspection, not 
my criminal case.
    Mr. Stupak. Why were you convinced Aventis should be 
criminally investigated for knowledge of Study 3014?
    Mr. West. My feeling at the time 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.
    Mr. Stupak. Do you still feel that today?
    Mr. West. Yes, sir.
    Mr. Stupak. I understand that Dr. Kirkman-Campbell was the 
drug company sales representative to supply blood for the Ketek 
study, is that correct?
    Mr. West. That's correct.
    Mr. Stupak. Should 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.
    Mr. Stupak. By ``they,'' you mean the blood company 
representatives or Aventis?
    Mr. West. The company that each one of the pharmaceutical 
reps were representing at the time.
    Mr. 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.
    Mr. Stupak. PI being principal investigators?
    Mr. West. Principal investigators.
    Mr. Stupak. To your knowledge, did Kirkman-Campbell do 
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.
    Mr. Stupak. Would you please take a look at the exhibit 
book, Exhibit Number 25, if you would. Could 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.
    Mr. Stupak. And that is thanking Aventis for helping her 
fill out forms for another study, is that correct?
    Mr. West. That is correct.
    Mr. Stupak. And that e-mail is dated November 17, 2002, is 
that correct?
    Mr. West. That is correct.
    Mr. Stupak. Were you doing your criminal investigation of 
Dr. Kirkman-Campbell on Ketek at that time?
    Mr. West. Yes.
    Mr. Stupak. Turn to Exhibit Number 8 if you would, please.
    Mr. West. Did you say 8?
    Mr. Stupak. Eight, yes. In this memo, 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 is correct.
    Mr. Stupak. And who are you doing this study to in the FDA? 
Or, I'm sorry, your recommendation?
    Mr. West. In this particular e-mail, I was responding to 
Director Vermillion, who is the director of OCI. But the e-mail 
is in response to a conversation I had with CDER personnel, Dr. 
Solif, Dr. Goldberger, Dr. Cox and Dr.--well, this particular 
e-mail was just with those three individuals.
    Mr. Stupak. When you say CDER, that's Center for Drug 
Evaluation and Research, right?
    Mr. West. That's correct.
    Mr. 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.
    Mr. Stupak. And what happened as the 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 
inspections. That's what I was recommending to Goldberger, 
Solif and Cox. 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 because of personnel problems and 
money.
    Mr. Stupak. Would it be a 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 have actually conducted the review of 
documents.
    Mr. Stupak. And in this Exhibit Number 8, you basically lay 
out how you would do it, correct?
    Mr. West. That's correct.
    Mr. Stupak. How you would go about it. If you had this 
opportunity, you would go out and do this investigation and you 
were willing to go do it?
    Mr. West. That's correct.
    Mr. Stupak. Did you believe there was a possibility of 
detecting fraud if they just followed your recommendations as 
you laid out in Exhibit Number 8?
    Mr. West. Oh, I believe that we would have detected fraud 
in other sites.
    Mr. Stupak. In your opinion, did someone at CDER, the 
Center for Drug Evaluation and Research at the FDA or elsewhere 
in the FDA block your proposal to create this task force to go 
look 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 Friend, blocked the participation 
of the center to support OCI.
    Mr. Stupak. Do you have any idea who that individual would 
have been?
    Mr. West. I have no idea.
    Mr. 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. Oh, most definitely.
    Mr. Stupak. Did you ever talk to the Dr. Kweder from the 
FDA?
    Mr. West. Yes, I spoke with Dr. Kweder. I briefed her the 
same way I briefed Goldberger, Solif and Cox. I also provided 
her with the same recommendations. And I also explained to 
every one of them that we couldn't, as OCI we couldn't demand, 
because there was legal issues. If we demand them to do 
something and they go out and do it, then we're sort of 
conducting a search which would have created a legal issue for 
us. So we recommended or suggested that they go out and do 
further inspections, which they declined.
    Mr. Stupak. So besides Exhibit Number 8, this e-mail, you 
had other conversations with Dr. Kweder, Cox and others about 
where this investigation should go, in your recommendation it 
should continue to look at what Aventis knew prior to 
submitting this data to the FDA in 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 3014 
being submitted and up for approval.
    Mr. Stupak. Thank you. Mr. Ekey, we haven't asked you any 
questions. Do you have anything you would like to add?
    Mr. Ekey. I'll wait until you have a question. Thank you.
    Mr. Stupak. OK. Mr. Walden.
    Mr. Walden. Thank you very much, Mr. Chairman. Mr. West, I 
want to follow up this notion about Dr. Campbell. You obviously 
found problems with her work in the Aventis case. I'm hearing 
for the first time she was involved in other trials, which I 
guess shouldn't be a surprise. Has anybody gone back to look at 
her work in those other cases?
    Mr. West. We did.
    Mr. Walden. And did you find any instances of----
    Mr. West. She was conducting a study for GSK. I can't 
remember the drug. But it was for migraines.
    Mr. Walden. OK.
    Mr. West. And I think it was a post market study. And we 
determined just by reviewing three or four records, which were 
provided to us by GSK, that they were fraud. And we provided 
that information to GSK and to DSI. We were not going to 
incorporate that in the criminal prosecution because we had 
enough on her regarding 3014, the Ketek study. But I made sure 
that both GSK and DSI were aware that we had proven that she 
committed fraud in the migraine study because she enrolled the 
same pharmaceutical reps in the migraine study. And we talked 
to them and they said, well, I didn't have the symptoms, I was 
just participating because she asked me to.
    Mr. Walden. That was the phase 4 four-person Lantis study?
    Mr. West. I'm not quite sure. All I remember was the 
migraine.
    Mr. Walden. Do you know how big a study that was? The one 
we're dealing with here with Aventis was what 12,000, 24,000 
people, 12 on a placebo, 12 not, and that was extraordinarily 
large. Do you know on the GSK study on migraine medicine?
    Mr. West. I believe that was a relatively small study.
    Mr. Walden. What would that be? Give me a number.
    Mr. West. I know for a fact that Campbell only had I think 
12 or 15 enrollees.
    Mr. Walden. Ms. Cisneros, do you know anything about that 
one?
    Ms. Cisneros. I do. Actually, when I was at Dr. Campbell's 
site, she had me make 50 copies of an informed consent for the 
GSK study. I had a colleague that worked at GSK in the neuro 
division that I made aware of the study. And to my knowledge, 
the study manager from GSK, as well as it was actually a PPD 
study as well, went out and auditing Campbell's site and didn't 
find any issues.
    Mr. Walden. Didn't find any issues? But Mr. West, you said 
you found obvious fraudulent issues. Do you want to pull that 
mike back over your direction. What's going on here?
    Mr. West. Well, I can tell you that Investigator Patty 
Smith and myself, we both reviewed records that were provided 
to us by GSK, and it was quite obvious that Campbell was 
committing fraud on that particular study.
    Mr. Walden. Do you know if GSK excluded her data from that?
    Mr. West. I have no idea. I provided the information to GSK 
and to DSI.
    Mr. Walden. Has that drug been approved, whatever it was?
    Mr. West. Well, it was already approved for one indication. 
I think this was a post market for an off label use?
    Mr. Walden. Do you know if that process has made its way 
through the system? Does anybody know?
    Mr. West. No.
    Mr. Walden. It just obviously troubles me that we seem to 
have the same doctor engaged in the similar sort of conduct 
allegedly involving yet another drug. And Ms. Cisneros, you 
indicate you were aware of this and made somebody else aware of 
this?
    Ms. Cisneros. I did.
    Mr. Walden. And they disagree?
    Ms. Cisneros. Well, they didn't have to report back to me, 
so I don't know what the outcome was.
    Mr. Walden. Who did you make aware of this?
    Ms. Cisneros. I would rather not say her name, but a 
colleague that worked at GSK in that division that was 
marketing that drug.
    Mr. Walden. Well, Mr. Chairman, we may want to find out who 
that person was.
    Ms. Cisneros. OK. Off the record.
    Mr. Stupak. Ms. Cisneros has been forthcoming in all 
matters. If she wishes to tell us privately, since we don't 
have an active investigation, maybe we should because we've 
uncovered some other stuff in working on this that there may be 
further investigations. So we'll get that information.
    Mr. Walden. Thank you, Mr. Chairman.
    Mr. Stupak. We certainly plan on following it up.
    Mr. Walden. Mr. Loveland, why do you believe it took almost 
5 years after the Study 3014 was submitted by Aventis for FDA 
to open an investigation of the company and its knowledge of 
fraud? Why did it take 5 years?
    Mr. Loveland. Because for the first 3 years following Mr. 
West's investigation throughout her indictment and her 
presentencing period all the way through her sentence, all the 
way through her appeals Kirkman-Campbell was convicted of 
defrauding Aventis. She never came forward and said Aventis 
knew also until the night of March 2, 2006. She had contacted 
Mr. West some time earlier that week or within a week or so. 
Mr. West went to the prison, interviewed her and sent an e-mail 
the following morning to my unit. The head of my unit at that 
time was Kathy Martin-Weis. And within an hour, that had been 
forwarded to Mr. Ekey and the case was undertaken.
    Mr. Walden. So nothing started from your perspective until 
Dr. Campbell?
    Mr. Loveland. We didn't have a complaint that Aventis knew 
about it.
    Mr. Walden. So there wasn't an effort not to investigate?
    Mr. Loveland. Right.
    Mr. Walden. You had no reason to investigate?
    Mr. Loveland. It never came to our office as a complaint.
    Mr. Walden. I see. Do you think it should have? Was there 
anything, Mr. West, that you found in the course of prosecuting 
or doing the investigation of Dr. Campbell that should have 
triggered somebody to look at Aventis?
    Mr. West. Well, we tried to get the support from the 
center. But in 2004, the drug was approved and we were involved 
with the Campbell prosecution.
    Mr. Walden. How many of these sorts of investigations do 
you undertake at a given time? What kind of caseload are we 
talking about here?
    Mr. West. Do you mean clinical trial investigations or all 
total?
    Mr. Walden. Give me a total.
    Mr. West. I probably am working right now on 15 criminal 
cases. And OCI cases are not ``wham bam thank you ma'am.'' They 
go on for 2 or 3 years, sometimes 4 years, sometimes 5. And 
they're very paper intense, so.
    Mr. Walden. All right. Mr. Ekey, how about you?
    Mr. Ekey. Yes, sir.
    Mr. Walden. The number of cases you're working on right 
now?
    Mr. Ekey. The group I was assigned to was the special 
prosecution staff which handled allegations on larger 
pharmaceuticals, so our caseload was lighter. We carried 
perhaps six, seven cases.
    Mr. Walden. All right. Mr. Loveland.
    Mr. Loveland. I currently have six cases, two or three of 
which are clinical trials.
    Mr. Walden. What kind of fraud training do you think 
pharmaceutical companies should provide to their employees? Do 
you think it's adequate? What should it be? How do we prevent 
this from happening again? What do we need to do?
    Mr. Loveland. It wasn't adequate in this case. I know of 
other companies that have very robust training programs and 
they manage to keep their clinical trials fairly fraud free.
    Mr. Walden. But as we look at the number of sites, I think, 
what, were there 1,800 sites in this 3014 study? And each 
doctor got paid, what, $100 for every person they signed up?
    Mr. Loveland. $400 for each randomization. And that's a 
very low number typically.
    Mr. Walden. Really?
    Mr. Loveland. Very, very small.
    Mr. Walden. So it's sort of like getting somebody's debit 
card and every time you sign somebody up you get another $400 
withdrawal?
    Mr. Loveland. Interestingly, in this case, that's part of 
what made this fraud work. Aventis uses the IVRS system to do 
basic data collection and drug randomization in many of its 
trials. It's a great system. It's a very good tool for 
capturing study data. What most people don't know is that when 
you hang up the phone, it also sends a message over to 
accounting in finance and says send this doctor another $400 
because they just randomized another patient.
    So what Kirkman-Campbell was doing, actually every 50 to 70 
seconds, was printing a new $400 bill, and it would get mailed 
to her at the end of every month. Think about an ATM machine, 
and that's how the system works. The system is actually 
constructed to have fraud indicators built in. And those fraud 
indicators were tripping. And PPD picked them up and PPD 
provided them to Aventis. And this is one of the two analyses 
that the mathematician did, not knowing that what he was 
looking at was a fraud indicator log.
    Mr. Walden. He didn't know that?
    Mr. Loveland. He didn't know it.
    Mr. Walden. Where did he think it came from then?
    Mr. Loveland. Well, it's an administrative printout. It 
looks much like a telephone bill.
    Mr. Walden. So what did he think, it was like the button 
stuck down?
    Mr. Loveland. No. What he decided it was is that this lady 
was very adept at using the IVRS system.
    Mr. Walden. I would say so. I was a journalism major, not a 
math major, but I can figure that one out.
    Mr. Loveland. OK. And the story he got was that this 
particular clinical investigator would see 10, 12 patients, 
agreed to enroll them and then on her time off or on her lunch 
hour or on her day that she was closed and doing office work 
she would sit and randomize them all.
    Well, if you take the protocol and you read the protocol, 
you know you can't do that. And one of the things that troubled 
me with the decision-making process is when I asked the 
management about that. They said, well, that's a plausible 
answer, it may not be a good practice of medicine, but it's a 
plausible answer, which immediately begs the question: Do you 
want not such a good practice of medicine in your clinical 
trial?
    Mr. Walden. Right. And it seemed like from the one tab I 
was reading, I think the chairman referenced, I don't remember 
the exact page number or tab, but the problem with Dr. Campbell 
wasn't unique--I mean, it may have been unique in that she's in 
jail and did fraudulent activity, but it seemed like there were 
a lot of discrepancies in multiple locations, is that correct?
    Mr. Loveland. I believe I was told by one member of 
management that there were problems with virtually every 
informed consent form, because doctors don't tend to do those 
in the course of--in the normal practice of medicine.
    Mr. Walden. Right. But they're not in the normal practice 
of medicine if they've agreed to participate in a clinical 
trial, are they?
    Mr. Loveland. That was one of the conflicts that was set 
forth in this whole case. One of the conflicts in this case was 
a large simple safety study, to my understanding, is typically 
done post marketing, not to good clinical practice standards. 
Every Phase III trial has to meet good clinical practice 
standards or the perception is the FDA will not accept the 
trial. So here we took a methodology that's typically used 
apparently in Phase IV, not to good clinical practices and we 
moved it into Phase III. Everybody has looked at that and said, 
OK, that's probably the last time we're going to do that, it 
just didn't work.
    Mr. Walden. All right. Thank you. Thank you, Mr. Chairman, 
for your indulgence on the time too.
    Mr. 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. The Division of Scientific Investigations.
    Mr. Stupak. That's within FDA?
    Mr. West. That's correct. Within the Center for Drugs.
    Mr. Stupak. Right. CDER, Center for Drug Evaluation and 
Research?
    Mr. West. That's correct.
    Mr. Stupak. So FDA and the people responsible for 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 mention?
    Mr. West. That's correct.
    Mr. Stupak. And I had asked you about Exhibit Number 25, 
which is actually where she faked Aventis, that's my 
understanding actually, a diet pill. So those are at least 
three different. Do we know of any other studies that during 
this time frame 2002-2003 Dr. Kirkman-Campbell was involved 
with? We know of at least three. Do we know of any others?
    Mr. West. No, sir.
    Mr. Stupak. Ms. Cisneros, do you know?
    Ms. Cisneros. No.
    Mr. Stupak. Mr. Ekey do you know of any other studies of 
Dr. Kirkman-Campbell? Or Mr. Loveland?
    Mr. Ekey. No, sir.
    Mr. Loveland. No, sir.
    Mr. Stupak. 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 have known of 
the fraud. And if they really were unsure they should have 
contacted the FDA for assistance in substantiating the fraud.'' 
Is that true?
    Mr. Loveland. Yes.
    Mr. Stupak. In a 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 
enrolling, they probably did not know very much. There was one 
monitoring trip very early and they showed some small 
sloppiness things that could adequately be dealt with memos to 
file and some training. 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 100 or 
so patients found 360. He spent literally the entire 2 days 
going over informed consents. He never got to data in any 
meaningful fashion.
    Mr. Stupak. And this auditor was an Aventis employee?
    Mr. Loveland. That's correct.
    Mr. Stupak. In what timeframe was that?
    Mr. Loveland. That was mid-January of 2002.
    Mr. Stupak. OK.
    Mr. Loveland. 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.
    Mr. Stupak. The study team being the Aventis study team?
    Mr. Loveland. That's correct. 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--or stopped coming in just a 
few days later.
    Mr. Stupak. So even at the beginning of this study Aventis 
had red flags or warnings that things weren't even starting off 
on the right foot?
    Mr. Loveland. 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. And during my 
investigation, I made it a point to go back and visit with her 
again and collect what is typically known as a smoking gun 
document, that document which she forwarded to Aventis, because 
that imputed more knowledge to Aventis than any other document 
in the case.
    Mr. 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. Perhaps it was.
    Mr. Stupak. OK. It would be Exhibit Number 4, I think we 
talked about.
    Ms. Cisneros. I believe he's talking about the forged 
document.
    Mr. Loveland. No. Your list of all the patients.
    Mr. Stupak. Exhibit Number 4, I think we talked about. So 
that was the smoking gun that Aventis should have known and 
went there then?
    Mr. Loveland. That was the document, the teleconference.
    Mr. Stupak. And that was in 2002?
    Mr. Loveland. That's correct.
    Mr. Stupak. And Ketek was approved in 2004. So two years 
before it was even approved Aventis knew?
    Mr. Loveland. Oh, sure. But this is even before Aventis 
submitted the data. So contemporaneously with the March 4th 
telephone conversation, some other folks at PPD sent some data 
up to Aventis saying there's some problems here as well. And 
then on the 6th of March some more data came up saying there's 
problems with these new forms.
    Mr. Stupak. And this is all 2002.
    Mr. Loveland. That's correct. So the period of time 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.
    Mr. 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 conclusions 
that Ketek was safe 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.
    Mr. 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 and you say the first allegation is 
disproven, you take a mathematical analysis and you take that 
second allegation and the mathematical analysis disproves it, 
OK, 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.
    Mr. Stupak. Sure. Mr. West--excuse me one minute. I just 
want to go back to Agent Loveland. I want to ask you one more 
question. Tab number 14, if you take a moment, please, sir. Tab 
14 is two pages. It looks 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?
    Mr. Stupak. The second page, last paragraph. Could you 
explain that? I think this is from you to Ian Walsh. In Ketek 
new drug application, the sponsor clearly sent falsified data 
on Study 3014?
    Mr. Loveland. Right.
    Mr. Stupak. Explain that for us. Aventis knew that such 
significant issues existed. It had so many sites that the GCP--
what is that, GCP, what does that mean?
    Mr. Loveland. Good clinical practices. It's a standard, 
sir.
    Mr. 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.
    Mr. Stupak. Think, ``willful blindness,'' on steroids, but 
they submitted anyway. 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 first RRI, there's 11 different 
sites that they themselves wrote up. And during the interview--
----
    Mr. 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 you had 18 sites with significant GCP issues, why 
did you submit their data?
    Mr. Stupak. Correct. I guess that will be for the Aventis 
panel. Let me ask you this, Mr. West. Since it appears you 
dealt with the FDA--wait for these 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, is there any doubt in your mind that they 
knew there was fraud with Study 3014? By they, I mean the FDA 
officials.
    Mr. West. Oh, I had conversations with Brenda Friend 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.
    Mr. Stupak. And she kicked it upstairs to CDER?
    Mr. West. She must have kicked it up to somebody, because 
she just--I think she works the ground level of DSI, so she had 
to kick my recommendation above her, and the people above her 
must have declined.
    Mr. Stupak. Let me ask you this. In your opinion, has the 
statute of limitations run on the possibility of indicting 
Aventis for fraud in connection with Study 3014?
    Mr. Loveland. If I may, sir, that would be my case.
    Mr. Stupak. OK.
    Mr. Loveland. And the answer is yes the statute of 
limitations 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 would use it. If I could have found a strict 
liability statute, I would have pushed for that. But I only had 
1001, it's 6 on the guidelines, it's all I can do, that's run, 
I can't go back to it.
    Mr. Stupak. OK. If Ketek is used for one of the, being used 
for three different; bronchitis, sinusitis 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 the statute of limitations start 
to run from the time it's prescribed since its approval was 
based on 3014?
    Mr. Loveland. 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 in the commission of a conspiracy. 
And we use that to lengthen the statute of limitations. I 
didn't have that here.
    Mr. Stupak. OK. If it was submitted in '04, if Study 3014 
was submitted----
    Mr. Loveland. My statute of limitations would run next 
year.
    Mr. Stupak. Right. So if they submitted the study, Aventis 
submitted the Study to the FDA, Study 3014, in 2004 for 
approval of this drug, the safety indicators, would not your 5 
years run from '04 then?
    Mr. Loveland. '04 to '09, correct.
    Mr. Stupak. So you still have a statute of limitations 
opportunity then for the possibility of indicting Aventis for 
fraud in connection with Study 3014 knowingly submitting a 
fraudulent study to the FDA?
    Mr. Loveland. 3014 was submitted to the FDA in July of '02, 
sir.
    Mr. Stupak. Right. But it wasn't approved until '04, was it 
not?
    Mr. Loveland. I don't know that that--I'm not--I can't go 
there. I don't know what that ties.
    Mr. Stupak. Sure. OK. Mr. Ekey, I don't want to leave you 
out, and I said I would ask you one.
    Mr. Ekey. Thank you, sir.
    Mr. Stupak. I want to read you a short segment. And I don't 
want to leave you out because the work all four of you have 
done and the willingness to come forward and testify, even 
though it was under subpoena, has been a great help to this 
committee, in the 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 just want to ask the 
statement that you read 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. The reporting special agent, 
that would be you, 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 didn't 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 serious data irregularities when they submitted 
the data to the FDA?
    Mr. Ekey. I believe so, sir. I believe documents and 
interviews show that key Aventis personnel did know that there 
was serious integrity problems at that site.
    Mr. Stupak. 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 enroll 
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. My recollection is that 
is information I obtained from FDA doctors that were on that 
committee. That's the best of my recollection. I don't have 
that document.
    Mr. Stupak. Doctors on that committee?
    Mr. Ekey. I believe it was Dr. Ross.
    Mr. Stupak. OK. Would that be the advisory committee to the 
FDA that received the information?
    Mr. Ekey. Yes.
    Mr. Stupak. Thank you. I have no further questions. And 
again, thanks to this panel. Mr. Inslee, thanks for getting 
here. I know at the early start, flights and all that, thanks 
for being here. Do you have any questions?
    Mr. Inslee. I do. Thank you. Just for the whole panel, I've 
been looking at this issue of fraudulent medical devices, 
alleged medical devices, that are used to take advantage of 
people who are in distress. And a local newspaper in Seattle 
has done some really good work looking at how many of these 
devices are now marketed to people who are in desperate 
situations. A lot of these electrical devices that have screens 
and sparks and everything else, but no medical validity. And 
one of the ways that folks have been able to do this is by 
using these independent review boards to sort of purport to be 
in some trial when they're really just scams of the darkest 
dimension.
    I just want to ask you if you have any thoughts about these 
institutional review boards and how they are working or should 
work or may or may not be able to use to really cover up things 
that are not medically appropriate? Just looking for your 
advice. That's an open question to any of you. Looking for free 
advice.
    Mr. Loveland. Sir, this really is not OCI's bailiwick.
    Mr. Inslee. I hear you. We'll take advice from anywhere in 
America, though. We're sort of an open review concept. Well, 
with that I'm going to thank you for your testimony. Thanks, 
Mr. Chairman.
    Mr. Walden. [Presiding.] You're welcome, Mr. Inslee, and 
it's great to be back in the Chair, if only by accident and for 
a very short period. I just have one question, Mr. Loveland, 
because you talked about statute of limitations and all that. 
It seems to me that there's a disconnect in the FDA statutes. 
Are you familiar with the 331q for medical device prosecution?
    Mr. Loveland. Yes.
    Mr. Walden. So if it was a medical device issue you could 
still pursue that under a different standard, correct, than 
drug issues? You could file a false statement and prosecute 
under a misdemeanor statute?
    Mr. Loveland. Well, 21 U.S.C. 331(q)(2) makes it a 
prohibited act to make a materially false statement to the FDA 
in any matter--in a required report in a matter involving a 
medical device.
    Mr. Walden. Right.
    Mr. Loveland. There is no similar statute for a drug, a 
food, a biologic or anything to regulate.
    Mr. Walden. Why is that?
    Mr. Loveland. I don't know, sir. I thought laws come from 
you folks, not from us.
    Mr. Walden. The good ones do. Obviously, I'm feeling a new 
one coming on.
    Mr. Loveland. Let's not make any new laws, just erase the 
last few words.
    Mr. Walden. Well, that takes a law to do that.
    Mr. Loveland. Instead of making it medical devices only, 
let's make it a prohibited act to make a false statement to the 
FDA in any required report. Now, the beauty of the FDNC Act is 
that at the misdemeanor level it's a strict liability statute. 
And in a case like this what the prosecutor and I discussed was 
sending a message to industry and what is the best way to do 
this. We can't prosecute because the facts just aren't there 
that will support a criminal prosecution at 18 U.S.C. 1001, 
which is the typical false statement statute. When we discussed 
that had, in fact, 331(q)(2) not been limited to medical 
devices, I would very much have been advocating to send a 
strict liability misdemeanor. And misdemeanors are not fun to 
prosecute. They take up a lot of time and they're typically 
thought to----
    Mr. Walden. But it does give you a hammer.
    Mr. Loveland. But it would have sent a message to industry 
that you are responsible for your data, all of them. You have 
to protect your clinical trials and you have to protect the 
sanctity of your data. It just wasn't available to us.
    Mr. Walden. It would seem to me if it is good enough for a 
medical device, it should especially be good enough as another 
tool for you to use for the safety of our food and drugs.
    Mr. Loveland. I would have liked to have it that day, sir.
    Mr. Walden. All right. Thank you. I don't think we have any 
other witnesses. I'll let the chairman make that decision, 
though.
    Mr. Stupak [presiding]. Again, let me thank this panel and 
thank you very much for being here and thank you for your work. 
We'll call our third panel. Senator Grassley is still delayed. 
He will be here. We do plan on hearing from Senator Grassley 
today. He has just asked for our indulgence. And we'll 
certainly accommodate the Senator.
    We will call our next panel. Dr. Paul Herbert Chew, 
President of U.S. Research and Development Division at Sanofi-
aventis Pharmaceuticals; Dr. Fred Eshelman, Chief Executive 
Officer at PPD; and Ms. Sharon Hill Price, Chief Executive 
Officer and Chairman of the Board at the Copernicus Group IRB. 
It is the policy of this Subcommittee to take all testimony 
under oath. Please be advised you have the right within the 
Rules of the House to be advised by counsel during your 
testimony. Do any of our witnesses wish to be represented by 
counsel? Dr. Chew, would you please state the name of your 
counsel.
    Dr. Chew. Mr. Chairman, the counsel for the company is Mr. 
Daniel Kracov from Arnold and Porter.
    Mr. Stupak. OK. Dr. Eshelman.
    Mr. Eshelman. Counsel is present. Mr. Robert Nicholas from 
McDermott Will.
    Mr. Stupak. And Ms. Price.
    Ms. Price. My counsel are Ann Begley and Gary Yingling from 
K&L Gates here in D.C.
    Mr. Stupak. OK. I'm going to ask you to please rise, raise 
your right hand and take the oath.
    [Witnesses sworn.]
    Mr. Stupak. Please let the record reflect that all 
witnesses replied in the affirmative. Each and every one of you 
are under oath. We will take an opening statement for 5 
minutes. You may submit a longer statement for the record if 
you wish.
    Mr. Stupak. From our left, we'll start with you Dr. Chew. 
If you would start please, sir, for an opening statement.

 STATEMENT OF DR. PAUL HERBERT CHEW, PRESIDENT, U.S. RESEARCH 
    AND DEVELOPMENT DIVISION, SANOFI-AVENTIS PHARMACEUTICALS

    Dr. Chew. Thank you. Chairman Stupak, Congressman Walden 
and Members of the Subcommittee, I'm Dr. Paul Chew, President 
of Research and Development for Sanofi-aventis U.S. Sanofi-
aventis is a global research-based company dedicated to 
improving human health and addressing unmet medical needs. 
Patient safety is our highest priority. I'm here today to 
provide the Sanofi-aventis perspective on the issues raised 
regarding our antibiotic Ketek, and in particular, the conduct 
of Study 3014. I'll focus first on the issues that arose in 
Study 3014 and then on what we learned from this experience. 
While I was not directly involved in the design or conduct of 
Study 3014, I've carefully reviewed the matter. Let me begin by 
stating that we fully acknowledge that Aventis made several 
incorrect assumptions about achieving compliance in Study 3014.
    We greatly regret that Dr. Kirkman-Campbell's fraud and 
certain problems at other sites were not identified or 
confirmed during the study. And we respect FDA's actions 
regarding Study 3014. We strongly believe however, that Aventis 
submitted the Study 3014 report in good faith believing that 
the good clinical practice issues that had been addressed--that 
had been addressed under the preestablished monitoring plan and 
that the integrity of the safety data had not been effected. 
Study 3014 was the first large preapproval anti-infective drug 
study conducted in a usual care setting.
    The purpose of this supplemental study, which was conducted 
after the completion of the pivotal studies for the drug, was 
to further assess adverse events of special interest seen in 
the earlier pivotal studies, but in the real world physician's 
office setting and patient population. Study 3014 was never 
intended to find every possible adverse effect event that could 
occur in the future Ketek population. No single study can 
accomplish that goal. In conducting the study Aventis at its 
contract clinical research organization, PPD identified and 
addressed a range of deviations from good clinical practice. At 
the highest enrolling site, that of Dr. Kirkman-Campbell, 
numerous GCP violations were identified during the trial and 
questions were raised at that time regarding the legitimacy of 
certain practices and data.
    Those questions were actively investigated by Aventis and 
PPD under a documented investigation plan. And Aventis and PPD 
required Dr. Kirkman-Campbell to act upon their findings. As 
you know, however, FDA subsequently documented investigative 
fraud at that site and Dr. Kirkman-Campbell pled guilty to 
falsifying clinical records. Aventis cooperated fully in that 
initial investigation and Sanofi-aventis has cooperated fully 
on all subsequent investigations. While numerous GCP violations 
were identified, it's our belief that Aventis was unable to 
confirm actual fraud at the Kirkman-Campbell site. It's 
important to know that FDA criminal investigators have tools at 
their disposal that are typically unavailable to study sponsors 
and monitors. So what have we done to address what we know now 
about Study 3014?
    Since 2004, when Sanofi acquired Aventis to sponsor the 
Study, we've undertaken a comprehensive review of our policies, 
procedures and training. Let me share a few of these lessons 
learned. First, it's important to improve our ability to 
address investigator fraud. Sanofi-aventis has enhanced its 
approach to investigating potential fraud and persistent GCP 
noncompliance. We have also mandated additional training in 
these areas for all personnel engaged in study activities. This 
experience has also reinforced the importance of transparency 
in our interactions with FDA. In retrospect, Aventis could have 
been more proactive in bringing the issues encountered at high 
enrolling sites, and particularly the Kirkman-Campbell site, to 
the attention of the agency.
    In addition, more real-time on-site monitoring may have 
mitigated many of the issues in Study 3014. Thus we've revised 
our approach to site initiation and monitoring to ensure that 
study sites are visited shortly after the first subjects are 
enrolled to help ensure protocol adherence and to detect 
potential problems. Sanofi-aventis has also implemented systems 
and procedures to strengthen the evaluation, the selection and 
training of investigators.
    Finally, many of the problems in Study 3014 occurred at 
high enrolling sites. We recognize that strict controls of site 
enrollment are essential in every study. Our current procedures 
incorporate new provisions limiting the number of patients 
enrolled and the rate of enrollment.
    In closing Mr. Chairman, we recognize the serious nature of 
the problems identified in Study 3014. However, I urge you to 
separate out what we know now about Dr. Kirkman-Campbell and 
other sites from what Aventis was able to determine at the time 
as the study sponsor. We have provided FDA with detailed 
information on the comprehensive steps that we've taken. The 
FDA, Congress and the American public have the unequivocal 
commitment to Sanofi-aventis to rigorous and compliant clinical 
research.
    On behalf of Sanofi-aventis, thank you for the opportunity 
to participate in today's hearing. We understand your interest 
in these important issues and I look forward to answering your 
questions. I ask that my statement be included in the record of 
today's hearing. Thank you.
    [The prepared statement of Dr. Chew, M.D. follows:]

    [GRAPHIC(S) NOT AVAILABLE IN TIFF FORMAT]

    Mr. Stupak. Your statement is included in the record, as 
all statements are. Dr. Eshelman, do you have an opening 
statement please, sir?

 STATEMENT OF DR. FRED ESHELMAN, CHIEF EXECUTIVE OFFICER, PPD. 
                              INC.

    Mr. Eshelman. Yes, sir, I do have a statement. Good 
morning, Chairman Stupak, Congressman Walden and members of the 
subcommittee. I'm Fred Eshelman, founder and CEO of 
Pharmaceutical Product Development, also known as PPD. It is my 
pleasure to be here today as a representative of PPD. At this 
time, I also ask that my written statement be made part of the 
record. PPD is a global contract research organization or CRO. 
We provide drug development services to pharmaceutical, 
biotechnology and medical device companies and also government 
organizations, all of which are referred to as sponsors. As a 
CRO, PPD is hired by sponsors of clinical trials to perform 
obligations of the sponsors arising under the Federal Food Drug 
and Cosmetic Act and FDA's clinical study related regulations. 
Principally, 21 C.F.R. Parts 50, 56, 312 and 812. Under FDA 
regulations a sponsor may transfer the legal obligations for 
compliance with regulatory requirements to a CRO. FDA 
regulations require that any delegation of authority be set 
forth in a written agreement.
    Under FDA regulations any obligation that is not 
specifically transferred to the CRO is retained by the sponsor. 
These requirements are set forth in 21 C.F.R. Section 312.52. 
In the fall of 2001, PPD contracted with Aventis to perform 
specific services in connection with the study of Ketek Study 
3014. These obligations are set forth in detail in my written 
testimony. Other than these enumerated obligations Aventis did 
not contract with PPD to perform additional services. With 
regard to addressing investigative misconduct Federal 
regulations require that the sponsor either secure compliance 
or end the investigator's participation in the study. If an 
investigator is terminated then the FDA must be notified. This 
requirement is set forth in 21 C.F.R. Section 312.56(b).
    Under our contract with Aventis, PPD was to report any 
investigator that did not comply with the study plan to 
Aventis. We did not, however, have the authority to end an 
investigator's participation in the study or to report an 
investigator's conduct to the FDA.
    During Study 3014, PPD staff uncovered compliance concerns 
at the site of an investigator now familiar to this 
subcommittee, Dr. Anne Kirkman-Campbell. PPD's monitoring team 
made its first visit to the Kirkman-Campbell site in late 
November of 2001. In February of 2002 PPD's monitoring team 
visited the Kirkman-Campbell site for a second time. During the 
visit, PPD personnel determined that the site failed to 
document critical source information.
    PPD staff also found many inconsistencies and modifications 
regarding patient signatures on informed consent forms. 
Further, subjects appeared to have been randomized to the study 
in extremely high volumes during short time intervals. 
Additionally, PPD monitors found staff at the Kirkman-Campbell 
site to be uncooperative.
    At the same time with the February visit, PPD also analyzed 
data from the Kirkman-Campbell site regarding patient blood 
samples due to concerns raised by our staff. Based upon PPD's 
review, there appeared to be a lack of variability among blood 
samples shared by many patients. The data suggested that the 
Kirkman-Campbell site engaged in blood sample splitting, which 
is assigning a patient's blood sample to one or more patients 
in order to maximize enrollment totals. In light of these 
concerns, PPD staff asked for a conference call with Aventis.
    On the March 4, 2002 call, PPD personnel set forth in 
detail their concerns about the Kirkman-Campbell site. At the 
conclusion of that call, Aventis said that it would look into 
Kirkman-Campbell's compliance issues and devised an action 
plan. First, Aventis said that it would initiate its own 
analysis of the Kirkman-Campbell lab data to determine the 
probability that the site had engaged in blood sample 
splitting. Ultimately, Aventis informed PPD that it had 
analyzed the lab data and that the data was not indicative of 
scientific misconduct. Second, the Aventis study manager was 
tasked with contacting Dr. Kirkman-Campbell about the site's 
informed consent and randomization problems raised by PPD. 
Ultimately, Aventis and PPD sent a follow-up letter to Dr. 
Kirkman-Campbell raising these issues. Mr. Chairman, on behalf 
of PPD, I would like to thank you for the opportunity to 
testify before this subcommittee. I hope that my testimony 
provides the subcommittee with a better understanding of PPD, 
the regulatory and contractual framework that governs our 
conduct and our role in the Kirkman-Campbell matter. I would 
welcome any questions that you have. Thank you.
    [The prepared statement of Mr. Eshelman follows:]

    [GRAPHIC(S) NOT AVAILABLE IN TIFF FORMAT]

    Mr. Stupak. Ms. Price, for your opening statement, please.

  STATEMENT OF SHARON HILL PRICE, CHIEF EXECUTIVE OFFICER AND 
   CHAIRMAN OF THE BOARD OF DIRECTORS, COPERNICUS GROUP IRB.

    Ms. Price. Thank you.
    Mr. Stupak. Press that button there.
    Ms. Price. I found it now. OK.
    Mr. Stupak. Thanks.
    Ms. Price. Good morning. My name is Sharon Hill Price, and 
I am the chief executive officer of Copernicus Group 
Institutional Review Board. I would like to thank the committee 
for providing me an opportunity to make a statement today.
    An IRB's regulatory mandate is to assure the protection of 
the rights and welfare of human subjects in clinical trials. In 
our current system, the IRB's responsibility to protect 
subjects is shared with the investigators, the institutional 
sponsor, and the government. An IRB carries out its unique role 
by reviewing study information provided by sponsors and 
investigators and determining whether the research adheres to 
the ethical principles of the Belmont Report and Federal 
regulations. As CEO, my responsibilities are to direct the 
administrative functions at Copernicus, while the separate 
ethical review function is conducted and controlled by our 
independent Institutional Review Board.
    On a personal note, I built this company from the ground 
up, and have always strived to assure that Copernicus provides 
the highest quality ethical review. We are deeply troubled with 
what has happened in 3014, and I, along with the dedicated 
employees at my site, certainly are interested in the findings 
of this committee.
    In August 2001, Copernicus was contacted by PPD and asked 
to serve as IRB of record for Study 3014, a clinical trial 
sponsored by Aventis. This was a large, multicenter trial, as 
you know, conducted over a relatively short duration of 
approximately 6 months.
    Copernicus initially reviewed and approved the protocol as 
well as the consent document that was be to used by each 
investigator as they worked in the process with their subjects. 
Additionally, the IRB reviewed information for each of the 
investigators selected by the sponsor and provided oversight 
for any information that was provided by the investigator 
throughout the study.
    One of those investigators was Dr. Kirkman-Campbell. Dr. 
Kirkman-Campbell's submission packet was reviewed around 
October 2001, and she was granted IRB approval to serve as a 
Study 3014 investigator.
    At a committee hearing last year, Ann Marie Cisneros, a 
former PPD employee, testified that during a monitoring visit 
to the Kirkman-Campbell site in February of 2002, she had 
called Copernicus and spoken to the President and informed her 
of concerns found at the site. Her statement surprised us at 
Copernicus, because no one on the staff at that time was aware 
of any such call having been made. And I, as President, did not 
recall any such call. Furthermore, at the time, our searches of 
documents did not turn up any evidence of a call from Ms. 
Cisneros.
    However, on the afternoon of Wednesday, January 23rd, 2008, 
in preparation for a meeting with the committee staff, 
Copernicus did find documentation of an anonymous call being 
taken by one of our professionals on February 24th, 2002--
excuse me, February 21st, 2002. Based upon its content, this 
memo appears to describe a call from Ms. Cisneros, and it was, 
I think, briefly mentioned earlier this morning. For some 
reason, and contrary to both procedure and training, this memo 
was not forwarded to a supervisor by the employee or to the 
Institutional Review Board, as it should have been at the time. 
Neither was the document placed in the investigator file as it 
should have been.
    We have intensely investigated this matter, but we simply 
do not have an answer for why this lapse occurred. Had the 
Board received the information, as it should have at the time, 
I am confident that the Board, the IRB, would have investigated 
the matter and taken appropriate action. While I cannot speak 
specifically to the independent decision the Board would have 
made, the action most likely would have included notifying the 
FDA about concerns of the investigator. This call should have 
been elevated to the Board. It was not. And on behalf of my 
company, I offer an apology for this deviation from our 
standard operating procedure.
    In a recent interview in the Journal of Clinical Research 
Best Practices, Ms. Cisneros encouraged individuals to reach 
out to someone if they have concerns about research study 
conduct. I wholeheartedly agree with this advice. There are a 
number of options open to individuals faced with similar 
concerns, and the IRB should certainly be one of those options. 
The IRB is a place where both subjects and members of the 
research community can turn when issues about how a clinical 
trial is being conducted arise or if unanticipated problems 
that affect subject safety are suspected.
    As additional regulatory guidance has been released over 
the years, Copernicus has continually reviewed and strengthened 
its policies and procedures in the past 6 years since Study 
3014 ended. The IRB and professional support staff have been 
trained on existing policies, including those that govern the 
handling of unanticipated problems such as the kind that arose 
in Study 3014. Our ongoing process improvement efforts continue 
to strengthen our ability to recognize and appropriately 
address serious issues that rise to the level of unanticipated 
problems that pose risks to subjects or others.
    Of additional significance, I think, to the committee is 
that Copernicus was one of the first groups to achieve a 
voluntary accreditation of our human subject protection 
program, this done by the Association for the Accreditation of 
Human Research Protection Programs, or AAHRPP, that is based 
right here in D.C. In order to attain this voluntary 
accreditation, Copernicus went through a rigorous self-
assessment of our policies and practices and peer-review 
process to determine or to demonstrate that strict practice 
standards had met or exceeded the Federal human subject 
protection Requirements. Copernicus was recently reaccredited 
this past October.
    In closing, I would like to say that Copernicus takes its 
role as a human subject protection entity very seriously, and 
has done so for the past 12 years since opening our doors in 
1996. Although we sincerely apologize for the call that was not 
handled as it should have been 6 years ago, we remain proud of 
the important and integral role that IRBs plays in providing 
ethical review into clinical research.
    Again, I appreciate the opportunity to testify today, 
although a little nervous, and I am prepared to answer any 
questions you might have. Thank you.
    Mr. Stupak. Thank you.
    [The prepared statement of Ms. Price follows:]

                     Statement of Sharon Hill Price

    Good morning. My name is Sharon Hill Price and I am the 
Chief Executive Officer of Copernicus Group Institutional 
Review Board. I would like to thank the Committee for providing 
me an opportunity to make a statement and testify today.
    An IRB's regulatory mandate is to assure the protection of 
the rights and welfare of human subjects in clinical trials. In 
our current system, the IRB's responsibility to protect 
subjects is shared with the investigators, the institution or 
sponsor, and the government. An IRB carries out its unique role 
by reviewing study information provided by the sponsor and its 
agents, and by investigators engaged to perform the study, and 
determining whether the research adheres to the ethical 
principles outlined in the Belmont Report as set forth in 
federal regulations. As CEO, my responsibilities are to direct 
the administrative functions at Copernicus, while the separate 
ethical review function is conducted and controlled by our 
independent Institutional Review Board. On a personal note, I 
built this company from the ground up, and I take what happened 
in Study 3014 very seriously. I have always strived to assure 
that Copernicus provides high quality ethical review.
    In August 2001, Copernicus was contacted by PPD and asked 
to serve as IRB of record for Study 3014, a clinical trial 
sponsored by Aventis Pharmaceutical, now known as the Sanofi-
Aventis Group. This was a large, multi-center trial conducted 
over a relatively short duration of approximately 6 months. 
Copernicus initially reviewed and approved the protocol as well 
as the consent document that was to be used by investigators 
during the informed consent process with study subjects. 
Additionally, the IRB reviewed information for each of the 
investigators selected by the sponsor. One of those 
investigators was Dr. Kirkman-Campbell. Dr. Kirkman-Campbell's 
submission packet was reviewed and in October 2001 she was 
granted IRB approval to serve as a Study 3014 investigator.
    At a committee hearing last year, Ann Marie Cisneros, a 
former PPD employee, testified that during a monitoring visit 
to the Kirkman-Campbell site in February 2002, she had called 
Copernicus and spoken to the President and informed her of 
concerns found at the site. Her statement surprised us at 
Copernicus because no one on our staff was aware of any such 
call having been received. Furthermore, at the time, our 
searches of documents did not turn up any evidence of a call 
from Ms. Cisneros.
    However, on the afternoon of Wednesday, January 23, 2008, 
Copernicus found documentation of an anonymous call being taken 
by one of our professionals on February 21, 2002. Based upon 
its content, this memorandum appears to describe the call from 
Ms. Cisneros. For some reason, and contrary to both procedure 
and training, this memorandum was not forwarded to a supervisor 
or to the Institutional Review Board as it should have been at 
the time. Neither was the document placed in the investigator 
file as it should have been. We have intensively investigated 
this matter, but we simply do not have an answer as to why this 
lapse occurred. Had the Board received the information, as it 
should have, I am confident that the Board would have 
investigated the matter and taken the appropriate action. While 
I cannot speak to the independent decision that would have been 
made by the Board, this action most likely would have included 
notifying the FDA regarding concerns about the investigator. 
This call should have been elevated to the Board. On behalf of 
my company, I offer an apology for this deviation from our 
standard operating procedure.
    In a recent interview in the Journal of Clinical Research 
Best Practices, Ms. Cisneros encouraged individuals to reach 
out to someone if they have concerns about research study 
conduct. I wholeheartedly agree with this advice. There are a 
number of options open to individuals faced with similar 
concerns and the IRB should certainly be one of those options. 
The IRB is a place where both subjects and members of the 
research community can turn when issues about how a clinical 
study is being conducted arise or if unanticipated problems 
that affect subject safety are suspected.
    As additional regulatory guidance has been released, 
Copernicus has continually reviewed and strengthened its 
policies and procedures in the six years since Study 3014 has 
ended. The IRB and professional support staff have been trained 
on existing policies, including those that govern the handling 
of unanticipated problems such as the kind that arose in Study 
3014 in 2002. Our ongoing process improvement efforts continue 
to strengthen our ability to recognize and appropriately 
address serious issues that rise to the level of unanticipated 
risk to subjects or others.
    As part of that effort at strengthening our procedures, and 
of additional significance, Copernicus was one of the first 
groups to achieve accreditation of our human research 
protection program by the Association for the Accreditation of 
Human Research Protection Programs (AAHRPP). In order to attain 
this voluntary accreditation, Copernicus went through a 
rigorous self-assessment and peer review process to demonstrate 
strict practice standards that meet or exceed federal human 
subject protection requirements. Copernicus was reaccredited 
this past October.
    Copernicus has taken its role as a human subject protection 
entity seriously for the 12 years since first opening its doors 
in 1996. Although we sincerely apologize for the call that was 
not handled as it should have been six years ago, we remain 
proud of the important role that IRBs play in providing ethical 
review of clinical research. Again, I appreciate the 
opportunity to testify today and am prepared to answer any 
questions that you have.
                              ----------                              

    Mr. Stupak. Mr. Walden for questions, please.
    Mr. Walden. I appreciate that, Mr. Chairman. Unfortunately, 
I have to leave for another meeting, so I appreciate your 
courtesy.
    Ms. Price, this issue of the call sheet that appeared that 
you found----
    Ms. Price. Yes.
    Mr. Walden [continuing]. Obviously must be very troubling 
to you to have provided so many documents to various 
investigations and not had that among them in the past. Where 
did you find it?
    Ms. Price. We found that in an electronic file in a shared 
drive that was shared by different personnel at Copernicus. And 
it was not made part of the hard copy file, which is, 
unfortunately, what we tended to look at mostly during the 
course of this investigation.
    Mr. Walden. So you never looked at that drive before when 
you were producing documents?
    Ms. Price. No, we didn't look particularly at that drive. 
We had done electronic searches on the drive and had come up 
with that document back in 2006 when Senator Grassley requested 
information about----
    Mr. Walden. You had come up with that document?
    Ms. Price. We had--an electronic search had come up with 
that document at the time that Grassley requested information. 
However, Grassley's investigation centered on information 
received 2006 and after.
    Mr. Walden. OK.
    Ms. Price. And so that wasn't looked at as part of that.
    Mr. Walden. OK. So you had--you knew you had that document.
    Ms. Price. It came up in a search. We hadn't looked at it, 
you know.
    Mr. Walden. I see. And you said you had done a thorough 
investigation on all of this. Did you do a forensics 
investigation, then, on the computer drive just to make sure, 
you know, when it was done?
    Ms. Price. Yes, as part of that investigation was looking 
at the properties--I think that is what you are referring to, 
the properties of the document. And it was generated and only 
touched on one day, and that was February 22nd, 2002, the day 
after it was supposedly--the call was supposedly made.
    Mr. Walden. I think the document actually says the 21st on 
it.
    Ms. Price. The document actually says the call was made on 
the 21st. But the document, according to the properties, was 
generated on the 22nd.
    Mr. Walden. Thank you. That helps clear that up.
    Dr. Chew, I would like to ask you a couple of brief 
questions. Do you agree or disagree with the contention of an 
FDA criminal investigator that Aventis's system for overseeing 
the clinical trials in the 3014 study was not designed to 
enable your company to detect criminal fraud?
    Dr. Chew. Congressman Walden, there was a specific process 
in the former company looking for scientific fraud. And in the 
case of Dr. Kirkman-Campbell, the teleconference that was 
alluded to on March 4th, 2002--the minutes were March 6th, but 
the meeting clearly had as its title ``The Discussion of 
Scientific Misconduct.'' And it is my belief, looking back at 
those records, that the team, both Aventis and PPD, were 
following the process of trying to look at scientific fraud. 
And it was clear that the team--in fact, it was an Aventis 
employee that in January, 17th and 18th, had gone to the site 
and reviewed 327 informed consents. That was in January, and it 
was at that charge that PPD was asked to make the February 
visits--which Ms. Cisneros was there.
    So there was an early detection of a potential problem. And 
the monitoring responsibility was clearly delegated, and where 
we found out even more issues that needed to be addressed. And 
these are minuted in the scientific fraud discussion of March 
4th.
    Mr. Walden. What would you do differently today than what 
was done then? Because it sounds like you are describing for me 
a system that worked. And yet we know it didn't work.
    Dr. Chew. Well, as I said, I was not involved in the trial.
    Mr. Walden. Right.
    Dr. Chew. And looking back at the record, and with the 
benefit of hindsight I wished, for transparency, that the FDA 
had been called. As you heard this morning, there is really no 
clear guideline on when to call, short of scientific 
misconduct. I wish they had been called. I wish Aventis had 
picked up the phone and said, We have a problem. We can't 
document it.
    What I saw, though, was an enormous amount of resources 
were spent at Dr. Kirkman-Campbell's site, with over 165 phone 
calls. I think she had four monitoring visits. Probably more 
was expended trying to look at that.
    And the other problem, and you heard that this morning, is 
when you do a big trial, 24,000 patients, among physicians who 
are not used to doing that, frankly, this was the first trial 
of an antibiotic of that scale done preapproval.
    Mr. Walden. Why did Aventis take such efforts to bring her 
into compliance?
    Dr. Chew. Why did Aventis?
    Mr. Walden. Yeah.
    Dr. Chew. I think as a matter of course when you do 
monitoring, even though be it by the nature of the program it 
was retrospective, is to identify issues, to document issues, 
and that they were not overlooked.
    Mr. Walden. Now, we heard earlier that--from I think Mr. 
Loveland--that basically Aventis brought in mathematicians to 
do statistical analyses of data that were coming out of a 
system designed to identify potential fraud. The phone records, 
the fact that Dr. Campbell was dialing every 50 to 70 seconds. 
Can you speak to that?
    Dr. Chew. From my review of the record, first of all I 
think it is--it was identified that there would be a 
statistical approach to look at the variations in blood 
samples. Because if there were split blood samples, they might 
tend to look more alike than normally would occur between 
people. So that there was an attempt by the statistician. 
Unfortunately, not enough baseline data was there for his 
preferred analysis. So what he did was to compare the 
variability of blood samples at Dr. Kirkman's site with another 
site. And there was not conclusive data to show that this was a 
fraudulent blood sample. So that was the purpose of looking 
statistically at the blood samples.
    Mr. Walden. Well, do you believe that extensive violation 
of GCPs in a clinical trial can affect data integrity, even 
when there is not fraud?
    Dr. Chew. Congressman, we believe that is possibly the 
case. In this particular case I am talking about Dr. Kirkman-
Campbell. What we heard was that it was not so much a question 
of whether the patients existed, because from my review of the 
record she randomized 407 patients. I believe there was only 
one case--of course it is very serious--but I believe there was 
only one case in which there was a patient made up of whole 
cloth.
    Mr. Walden. But didn't she have a lot of patients that 
didn't fit the requirements for the trial?
    Dr. Chew. The requirements of the trial, in a real-world 
setting of a real-office practice, was to look at patients who 
had acute exacerbations of chronic bronchitis, sinusitis, or 
walking pneumonia, community-acquired pneumonia.
    Mr. Walden. So all of her patients had that?
    Dr. Chew. Well, she was asked--all investigators were asked 
to use their clinical diagnosis. It was not required, just like 
it isn't in the real world, to require----
    Mr. Walden. So you are not telling me that she diagnosed 
that all those people on her trial had walking pneumonia or one 
of the other two issues, right?
    Dr. Chew. It is my understanding that she represented that 
these patients had the qualifying diagnoses.
    Mr. Walden. And you say there is only one patient that was 
made up. Do you think those data, out of the 400 patients, 
should have been used in this evaluative process?
    Dr. Chew. Well, again looking back, I could see that the 
data was addressed, it was documented. I think the best efforts 
were made--I don't think, I don't think----
    Mr. Walden. There were forgeries, though, weren't there?
    Dr. Chew. There was one alleged forgery.
    Mr. Walden. What was she convicted of, then?
    Dr. Chew. She was convicted of falsifying clinical records 
using interstate mail.
    Mr. Walden. And how many clinical records did she falsify?
    Dr. Chew. I would have to review that.
    Mr. Walden. Only one?
    Dr. Chew. No, she pled guilty, I believe, to one count, but 
there were many allegations.
    Mr. Walden. So you have reviewed all 400 records, and you 
still only believe there was one that was bad?
    Dr. Chew. From my review of the criminal documents, there 
was one that was made up out of whole cloth. But there were 
serious problems with the other patients because--and this is 
very important--these patients were not properly consented. 
Many did not know they were participating in a clinical trial. 
Because the investigators were able to talk to patients. And 
from my review of the record, sponsors, and, in this case, 
Aventis, did not talk to patients and inquire about their 
status.
    Mr. Walden. Do you have to talk to patients to find fraud?
    Dr. Chew. In this case I think the bulk of the issues were 
informed consent--the bulk of the issues were involving 
patients who were not aware.
    Mr. Walden. That they were in a clinical trial.
    Dr. Chew. That they were in a clinical trial, that they 
were taking experimental medicine, the reasons their bloods 
were drawn. That is very serious.
    Mr. Walden. Do you think Aventis has any liability in a 
situation like that, since you are responsible for the trials 
and overseeing them?
    Dr. Chew. Any pharmaceutical company, in particular in this 
case Aventis, has to submit, to the best of their knowledge, 
the highest quality data. I don't want to make any ambiguity 
about that. And they need to submit that with all the due 
diligence possible. One of the lessons learned, again, was not 
only could Aventis in retrospect have called, but also they 
could have put in more documentation in the final study report 
of gray-area issues, even if fraud had not been actually 
documented.
    Mr. Walden. Can you assure the committee that your standard 
operating procedures today have changed sufficiently that this 
won't be replicated?
    Dr. Chew. I can assure you, Congressman Walden, that the 
procedures and the training--we have even brought in the 
former, I think, deputy head of DSI to talk with and train our 
people. We have now also made a very big change in the standard 
operating procedure. Not only is it scientific fraud, but it is 
serious noncompliance with the GCP that will raise the bar for 
detection and procedures throughout the company.
    Mr. Walden. And one final--well, did Dr. Kirkman-Campbell 
participate in any other Aventis trials?
    Dr. Chew. Yes, she did.
    Mr. Walden. And have you reviewed that work?
    Dr. Chew. Yes, I have.
    Mr. Walden. Have you found any problems with any of those 
data?
    Dr. Chew. To my knowledge this was an insulin trial, with 
four patients, that was started. She was recruited, to my 
knowledge, independently of the Ketek team.
    Mr. Walden. Right.
    Dr. Chew. They were unaware at the time when they included 
her that there was a problem, but once this was found, when she 
requested additional patients, the answer was no. And she was 
shortly thereafter, I think----
    Mr. Walden. Right. But of those she already had in the 
other trial, were there any problems with her data?
    Dr. Chew. To my knowledge there were no issues.
    Mr. Walden. Have you reviewed her data? Do you have any 
knowledge----
    Dr. Chew. I have not been made aware of any issues. We 
could provide----
    Mr. Walden. My question is, Have you reviewed those data?
    Dr. Chew. I have only reviewed issues that have come up 
with her data. And that was not listed as one of the issues.
    Mr. Walden. All right. Have you or have you not looked at 
the data out of the other trial?
    Dr. Chew. In the other trial, I have not looked at her 
four-patient data.
    Mr. Walden. All right. So of course you wouldn't have any 
knowledge that there is a problem there, because you never 
looked at those data.
    Dr. Chew. I believe----
    Mr. Walden. That's fair. I am just trying to get an answer.
    Dr. Chew. No, I believe if there had been an issue in the 
records with Dr. Kirkman-Campbell, with any of her 
participation, I am confident I would have been made aware.
    Mr. Walden. So somebody else in your company has looked at 
those data?
    Dr. Chew. I am confident they have, because this was 
approximately 2003 we are talking about.
    Mr. Walden. I will leave it up to the Chairman, but it 
would be interesting to know for sure. Thank you.
    Mr. Stupak. Ms. Price, you said in response to Mr. Walden's 
questions 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.
    Mr. Stupak. So you became aware of this document at Senator 
Grassley's request, right? And this document----
    Ms. Price. This is on rereview of information.
    Mr. Stupak. Document number 33, right there. Exhibit No. 
33.
    Ms. Price. That's the telephone contact report of February 
21.
    Mr. Stupak. At Senator Grassley's request you came across 
this document, correct?
    Ms. Price. In review--in review and preparation for the 
meeting with your staff we became aware----
    Mr. Stupak. No, no. I am asking about Senator Grassley. In 
your testimony and questions with Mr. Walden, you said you came 
across this document when Grassley--when Senator Grassley asked 
for it, but it was outside the purview of his request; 
therefore you did not give it to him. Correct?
    Ms. Price. It was not responsive to his request.
    Mr. Stupak. When was that? That was about a year ago, 
wasn't it?
    Ms. Price. That was 2006. That was a year before your 
hearing.
    Mr. Stupak. 2006. So you have known about this document 
since 2006, then, the existence of this document.
    Ms. Price. It appeared on a long listing of thousands of 
documents.
    Mr. Stupak. Right. And you knew about it in 2006, correct?
    Ms. Price. That's what our investigation turned up as we 
were looking into this.
    Mr. Stupak. So then why did you sit on the document until 
the day before 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.
    Mr. Stupak. What did you do with it, then, for a year?
    Ms. Price. We were aware of it on an electronic search.
    Mr. Stupak. In 2006 you are 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 
Senator Grassley----
    Mr. Stupak. Sure. So you looked at it and said, This 
doesn't go for a Senator.
    Ms. Price. It appears that nobody looked at it.
    Mr. Stupak. How would you know if it was in keeping with 
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.
    Mr. Stupak. Sure. What was the date it was written?
    Ms. Price. I would have to look back, but I think that the 
date----
    Mr. Stupak. 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.
    Mr. Stupak. You don't know or you don't remember?
    Ms. Price. I don't remember--I don't remember.
    Mr. Stupak. Is that a computerized form right there, 
Exhibit No. 33? Is that a computerized form?
    Ms. Price. Yes, it is. It is a Word document.
    Mr. Stupak. So your backup files would have when it was 
entered and by whom, would it not?
    Ms. Price. Yes. That's why it turned up on the electronic 
search. When we narrowed down our search criteria to----
    Mr. Stupak. Sure. So your electronic search would have who 
entered it, then, correct?
    Ms. Price. The electronic search that I remember seeing did 
not have who entered it, no.
    Mr. Stupak. So you have a document retention policy, do 
you, at your organization, at your company?
    Ms. Price. Yes, we do.
    Mr. Stupak. OK. So can you provide us with that electronic 
search log which indicates this document was a part of it?
    Ms. Price. I would be happy to.
    Mr. Stupak. OK. I am going to ask you this. The telephone 
document--I should say telephone contact--indicates that Sarah 
Wallace took the report, right?
    Ms. Price. Yes, sir.
    Mr. Stupak. But the testimony has been that Ms. Cisneros 
talked to you. Correct?
    Ms. Price. That was her initial testimony.
    Mr. Stupak. And that was her testimony this morning, too.
    Ms. Price. Today she said she thought she spoke to the 
President.
    Mr. 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.
    Mr. Stupak. Right. So she identified you as the President. 
OK. And you are claiming you never talked to her.
    Ms. Price. That's correct. I never talked to her.
    Mr. Stupak. What is your company's policy on filling out 
this form here, this telephone contact form? Is it 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 
telephone contact reports for any significant issues. And 
obviously, Sarah Wallace felt this was significant enough to 
fill out a telephone contact.
    Mr. Stupak. Right. Is there a time frame when she is 
supposed to fill out this contact?
    Ms. Price. There was no timeframe given in our----
    Mr. Stupak. So 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.
    Mr. Stupak. 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.
    Mr. Stupak. OK. And Ms. Wallace left Copernicus shortly 
after this call was received. Is that correct?
    Ms. Price. Yes, she did. Within 2 weeks, I believe.
    Mr. Stupak. And in an interview with Ms. Wallace, she 
stated to committee staff she did not remember getting this 
call, but she was certain that if she had gotten the 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 would have 
received 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.
    Mr. Stupak. OK. So who had been her supervisor then?
    Ms. Price. Our Director of IRB services.
    Mr. Stupak. Who is that?
    Ms. Price. Dawn Pope.
    Mr. Stupak. OK. Did Dawn Pope ever talk to you about 
receiving this call or the information she received from Sarah 
Wallace?
    Ms. Price. No, sir.
    Mr. Stupak. So what happens to this information when 
serious allegations like this are made? What would happen if 
you would have been informed? What would have happened?
    Ms. Price. This type of call should have been forwarded to 
a supervisor, and then would have eventually gotten to the 
Institutional Review Board, where it would have been 
investigated and action taken by the Board.
    Mr. Stupak. So did you talk to Ms. Pope about whether or 
not she ever received this document?
    Ms. Price. Certainly, yes.
    Mr. Stupak. And what is her response?
    Ms. Price. She does not remember this either.
    Mr. Stupak. So Ms. Wallace 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.
    Mr. Stupak. Well, who would--does it indicate who she 
forwarded that to, Ms. Wallace--does it indicate who Ms. 
Wallace forwarded it to?
    Ms. Price. No.
    Mr. Stupak. Would your electronic file indicate who she 
forwarded it to?
    Ms. Price. Excuse me?
    Mr. 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 we looked 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.
    Mr. Stupak. OK. So what happened? Did a hard copy go into 
the investigative file then?
    Ms. Price. No, it did not. And that was where the rub was. 
It should have gone into the file.
    Mr. Stupak. So this serious allegation went to your 
organization and it just sat there. Never forwarded it, no hard 
copies ever made, nothing.
    Ms. Price. That's correct.
    Mr. Stupak. Would Ms. Wallace know to make a hard copy and 
put it in the file?
    Ms. Price. Would Ms. Wallace what? Excuse me?
    Mr. Stupak. Ms. Wallace would have made a hard copy, right?
    Ms. Price. The person who took the call would have 
normally----
    Mr. Stupak. That's what she should have done?
    Ms. Price. Yes, sir.
    Mr. Stupak. So--OK. Do you know how many protocol 
violations or deviation forms you received on Study 3014.
    Ms. Price. On the entire Study 3014?
    Mr. Stupak. Yes.
    Ms. Price. No, but there were quite a few memos to file.
    Mr. 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.
    Mr. 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.
    Mr. Stupak. So protocol violations, no matter the number, 
wasn't alarming to your organization, to Copernicus?
    Ms. Price. Not at the time, no. We felt that those were 
things that were picked up on the monitoring visits and were 
corrected at the site--with the site at that time.
    Mr. 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.
    Mr. Stupak. Turn to Exhibit 32, if you would, in the book 
there. This document is entitled procedure number 108. It 
reflects the procedures at Copernicus with respect to safety 
and noncompliance reporting requirements. Correct?
    Ms. Price. Yes, that's correct.
    Mr. Stupak. OK. Were you under duty to notify the IRB when 
you received protocol violations? Isn't that what it says?
    Ms. Price. Under duty to inform the IRB of protocol 
violations?
    Mr. Stupak. Sure. Sure.
    Ms. Price. Let me take a look here and see--do you know 
which number it's addressed in?
    Mr. Stupak. Number 6.
    Ms. Price. The Board is responsible for reporting 
investigator noncompliance as required by applicable Federal 
regulations.
    Mr. 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 reporting protocol violations to 
the Board.
    Mr. 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 now 
require the investigators to report unanticipated problems. And 
that's what this would have arisen to.
    Mr. Stupak. So when did Copernicus start, then? When did 
your company start? When did you start? You said you founded 
the company. When did you do that?
    Ms. Price. 1996, sir.
    Mr. Stupak. 1996. So you are in 6 years since when you 
started seeing the problems, then, with Kirkman-Campbell, 
right? Kirkman-Campbell, 2002, when you were 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.
    Mr. Stupak. OK. But in 1996 you had been an IRB, right?
    Ms. Price. Yes, we started in 1996.
    Mr. Stupak. So you had more than one IRB before 2001, 
right?
    Ms. Price. We had one--I don't understand your question.
    Mr. Stupak. OK. You said you were asked to be an IRB in 
2001. Correct?
    Ms. Price. For 3014, yes, sir.
    Mr. Stupak. But before that, you had been an IRB before, 
right? Since 1996 you had served as an IRB.
    Ms. Price. Yes.
    Mr. Stupak. So you certainly knew the requirements. If you 
didn't know the understanding of procedure number 8 or 
paragraph number 6 there, entitled Procedure Number 108 
reflects procedures of Copernicus with respect to safety and 
noncompliance reporting requirement, why would you have it if 
you didn't understand what it meant? It is your own procedures.
    Ms. Price. We did understand what it meant at the time. The 
interpretation was 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.
    Mr. 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.
    Mr. 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 of 
protocol violations, and we received them 3 months after she 
closed as an investigator.
    Mr. 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 inquire 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.
    Mr. Stupak. OK. Well, I have got plenty more questions, but 
Senator Grassley is here. So I think we are going to suspend 
this panel for now. We will ask you to stay.
    Senator Grassley would like to testify. And we will 
accommodate the Senator. We are going to have him come up and 
testify.
    Mr. Markey. Mr. Chairman?
    Mr. Stupak. Yes.
    Mr. Markey. May I be recognized?
    Mr. Stupak. No. We are going to do the courtesy to Senator 
Grassley. He is going to testify.
    Mr. Markey. Oh, I am sorry.
    Mr. Stupak. And this panel will be back, so you will have a 
chance to ask questions. I didn't mean to cut you short, but we 
want to get the Senator in.
    Mr. Stupak. Senator, welcome. It is the policy of this 
committee to take all testimony under oath. I am sure you are 
not represented by counsel, sir? No? I will ask you to rise and 
take the oath.
    [Witness sworn.]
    Mr. Stupak. Senator, you are now under oath. I would ask 
you to give your opening statement, please, sir.

OPENING STATEMENT OF THE HON. CHARLES GRASSLEY, A UNITED STATES 
                 SENATOR FROM THE STATE OF IOWA

    Senator Grassley. OK. I thank you very much for the 
invitation to come and testify.
    Mr. Stupak. Senator, you want to turn your mike on?
    Senator Grassley. It is not on. OK. Thank you.
    I thank you very much for the opportunity to be here. Thank 
you for your leadership in this area. Thank you for your 
investigation.
    I am going to limit my remarks to my work on what is called 
Study 3014. And that involves the safety of the drug Ketek. It 
has been a long road, and it still is not at an end.
    More than 2 years ago, in January 2006, the journal Annals 
of Internal Medicine reported three cases of liver damage in 
North Carolina patients who took Ketek. In response, the FDA 
issued a public health advisory. After all, suffering severe 
liver problems is quite a price to pay for taking an antibiotic 
that was being used for such conditions as sinus infections, 
until that indication was removed from the Ketek label a year 
ago.
    Soon after I heard allegations and concerns regarding the 
FDA's review of Ketek, and I started asking questions. One of 
the more serious allegations was that the maker of Ketek, 
Aventis at the time, submitted clinical trial data to the FDA 
in support of approval, knowing it was fraudulent.
    So I asked FDA to make arrangements immediately for my 
staff to review documents related to Study 3014 at the FDA's 
office. Initially, FDA gave my staff access and agreed to 
provide copies of documents my staff identified during their 
review.
    But then I asked for Special Agent Robert West from the 
FDA's Office of Criminal Investigation, and the FDA then pulled 
a 180 on me. I had good reasons for asking for Agent West and 
being able to question him. One of the other allegations I 
received was that despite Agent West's concerns and 
recommendations, FDA never expanded its investigation to 
determine if the company did, quote-unquote, knowingly submit 
fraudulent data.
    Agent West played an integral role in the investigation of 
Study 3014, and I am delighted to see that he will be 
testifying before your committee today, if he hasn't already.
    Agent West was the lead agent on the investigation of Dr. 
Ann Kirkman-Campbell, one of the principal clinical 
investigators for Study 3014. And as a result of that 
investigation, Dr. Kirkman-Campbell is currently serving a 57-
month prison sentence.
    Agent West also was in frequent communication with FDA 
consumer safety officers and reviewers involved in Study 3014 
inspections. But as I testified before this subcommittee a year 
ago, FDA and HHS wouldn't make Agent West available, even after 
I went over to the HHS offices to ask personally to speak with 
Agent West and subpoenas were issued. After all, if FDA had 
nothing to hide about how it handled Study 3014, why stop me 
from talking to Agent West?
    Obviously, not being able to talk to him at that point, I 
smelled a cover-up; in fact, even before then.
    Well, I now have a better understanding of why FDA did not 
want me to speak to Agent West regarding Ketek. The answer to 
the ``why'' question is equally interesting. It seems to me 
that there were definitely reasons why the FDA did not want me 
to meet Agent West, or any other agents for that matter. FDA, 
it appeared, did not want anyone to know that it didn't further 
investigate whether or not Aventis submitted fraudulent data 
knowingly to the FDA. The FDA did that even though Agent West 
recommended in the summer of 2003, almost 5 years ago now, to 
high-level officials at the FDA that it needed to create a 
mini-task force to look into Aventis.
    When HHS and FDA finally made Agent West available a short 
time ago, and that was 18 months after I first requested him, 
Agent West confirmed that no one acted on his recommendations. 
In fact, I learned from HHS more than a year after my visit to 
the Department that the FDA didn't open an investigation into 
the company until March 2006. Interestingly, that was about the 
same time that I started poking around the Ketek issue itself.
    Agent West told his supervisors, FDA investigators involved 
in the Study 3014 inspections, as well as FDA directors 
overseeing the review of Ketek what he thought needed to be 
inspected; in other words, inspect all of the study sites that 
enrolled over 100 patients. The protocol for Study 3014 had 
recommended a maximum enrollment of 50 patients per site, so 
that that would have meant inspections of about 70 sites.
    Agent West's supervisors told my staff that they supported 
him. The site investigators also thought that it was a good 
idea.
    So then what happened? The head of the Office of Criminal 
Investigations told my staff that Agent West's concerns and 
recommendations were referred up the food chain, and he assumed 
the matter would be taken care of. The Associate Commissioner 
of Regulatory Affairs at that time said he was prepared to 
offer any assistance, if needed, but never heard anything more 
from the Office of Criminal Investigations.
    One of Agent West's superiors said that the Center for Drug 
Evaluation and Research folks were briefed, so the ball was 
then in their corner. He also said that Agent West's task force 
proposals had nothing to do with concerns about Aventis.
    But I have since learned that that was not true. Agent West 
sent an e-mail July 2003 to his superiors about his 
conversation with directors in the Federal FDA Center for Drug 
Evaluation and Research. These directors oversaw the review of 
Ketek. In that e-mail, Agent West said, quote, I told them that 
it was my opinion that Aventis's new sites were suspect, and 
did nothing to prove or refute their suspicions, end quote.
    Agent West was not the only agent who believed that the 
company, or at least someone within the company, knew that 
there were serious problems, particularly at Dr. Kirkman-
Campbell's site.
    You have the two agents here today who were assigned to the 
criminal investigation that was opened in March 2006, Special 
Agents Robert Ekey, and Douglas Loveland. Agent Ekey said, 
during a joint interview with our committees, that he thought 
the company too easily dismissed the concerns that were raised 
by his own contract research organization, the organization 
that was hired for the specific purpose of monitoring Study 
3014.
    Agent Loveland wrote in an internal e-mail dated April 
17th, 2007 that the company knew significant issues existed at 
many sites, yet the company submitted the data to the FDA and 
claimed the study was conducted according to good clinical 
practices. He also told my staff during an interview yesterday 
that Aventis should have known there were problems with the 
integrity of the study data.
    The case was closed July 2007. FDA issued a warning letter 
in October to the company for failing to ensure proper 
monitoring of Study 3014 and not adequately investigating 
allegations of fraud at Dr. Kirkman-Campbell's site. The letter 
cited many of the same problems that FDA staff raised back in 
2003 and 2004. So why wasn't the investigation initiated at 
that time?
    Agent West stated in his July 2003 e-mail, quote, I think 
the three individuals in CDER understood my feelings and 
opinions, but I don't know whether or not the necessary steps 
will be accomplished, end quote. When my staff spoke with the 
three directors, one of them told my staff that if the Office 
of Criminal Investigation wanted additional investigations, it 
was their call, not CDER's. He also said that the Office of 
Criminal Investigations should have talked to the Division of 
Scientific Investigations, since the division oversees clinical 
trial site inspections.
    So who was responsible? Everyone seemed to be pointing a 
finger at somebody else, with the exception of the head of the 
FDA's Office of Division of Special Investigations. This FDA 
employee told my staff that as far as additional inspections 
went, they didn't have the resources to do more. And besides, 
she said, one, the FDA didn't rely on Study 3014 for approval. 
Two, FDA completed eight site inspections for Study 3014, which 
is many more than the one or two it normally does. And three, 
astonishingly, she also said that investigating drug companies 
is a, quote-unquote, losing game, and the chances of getting a 
warning letter seemed to be near zero.
    I find that attitude, as you should, extremely troubling. 
We rely on the FDA to ensure that the drugs in our medicine 
cabinets are safe and effective. That includes FDA making sure 
that the data supporting the safety and efficacy of the drug is 
sound. To do that adequately, FDA has to do its job of 
oversight over clinical trials.
    Data integrity isn't the only issue of concern here. FDA 
also has an obligation to protect human subjects. In December I 
raised this matter with Commissioner von Eschenbach in a 
lengthy letter regarding my Ketek investigation. That letter, I 
have been told, is included in your exhibit books.
    I asked Commissioner von Eschenbach if it is FDA's position 
that no additional inspections are required once a study is no 
longer useful for regulatory action. Then how can FDA protect 
research subjects from the harm that may be caused by clinical 
investigators? Not relying on a study for approval does not 
absolve FDA of its responsibility to protect the individuals 
who courageously volunteer in clinical trials so that we can 
all benefit from life-saving cures and medical innovations. I 
am still waiting for the Commissioner's comments on this very 
important matter.
    Of course, this responsibility does not lie only with the 
FDA. Of course this responsibility goes beyond FDA. The drug 
companies also have a responsibility to the people who 
participate in their clinical trials. They also need to ensure 
that problems are adequately investigated and addressed.
    In the case of Study 3014, there were many sirens, red 
flags, bullhorns, but it looks like the company and the FDA 
kept ear plugs in and blinders on.
    I would like to close with this. There is something that 
strikes me as ironic about the case involving Ketek and another 
investigation involving Dr. Victoria Hampshire, an employee of 
the FDA. Today we heard a lot about the missteps made by FDA 
and Aventis. The culmination of these missteps led to a warning 
letter being sent to Aventis, as opposed to potentially more 
serious action being taken.
    And then we have the case of Dr. Hampshire, where the FDA 
worked mightily to pursue her. In fact, the FDA went so far as 
to send a criminal referral to the United States attorney in 
Maryland to prosecute her for alleged wrongdoing. Disturbingly, 
the FDA wrote a criminal referral that was riddled with 
inaccuracies about Victoria Hampshire. Perhaps in the future 
the FDA would pursue alleged bad behavior by corporations with 
the same vigor, same persistence and creativity, with which it 
pursued Victoria Hampshire.
    So, if there are no objections, I would request that my 
letter to Dr. von Eschenbach about the intensive investigation 
done by the FDA against one of its own, meaning Victoria 
Hampshire, be placed into the record.
    Mr. Stupak. Without objection, it will be part of the 
record.
    [The information appears at the conclusion of the hearing.]
    Senator Grassley. So I thank you for your invitation and 
your patience with my schedule today, because we had nine votes 
on the Senate floor that kept me from being here at the 
appropriate time. I would like to not take questions, if that 
is possible.
    Mr. Stupak. That is possible. Would you take a question 
from Mr. Dingell?
    Senator Grassley. I will take questions.
    Mr. Stupak. Mr. Dingell, do you have a question for Senator 
Grassley?
    Senator Grassley. When you say I learned all my oversight 
work from him, how could I ignore him?
    Mr. Stupak. I agree. I agree. Go ahead.
    Mr. Dingell. You are very kind, Mr. Chairman. I was waiting 
to hear your questions.
    Mr. Stupak. Senator Grassley is on a tight schedule, so I 
would defer to the full Chairman for any questions.
    Mr. Dingell. Then let me first welcome Senator Grassley. It 
is wonderful to see my old friend back here. Welcome back to 
the House, where you started. And it is a pleasure to see you 
in this room again, where we have done great work together, you 
and I, and I am very proud of your labors.
    So I will give you questions that in view of your time 
constraint, I think most of these will be answerable ``yes'' or 
``no.''
    Senator, from your testimony today and that which you 
graciously provided this committee a year ago, I take it you 
believe FDA and the Department of HHS have been extraordinarily 
uncooperative in your inquiry into the matter. Is that correct?
    Senator Grassley. The answer is yes, and I think Agent West 
is the best example of that.
    Mr. Dingell. Now, I note that lack of cooperation, 
including defying one or more lawful subpoenas issued by you as 
Chairman of the Senate Finance Committee. Is that correct?
    Senator Grassley. We have had difficulty getting those 
responses even with a subpoena. And again, Agent West is an 
example.
    Mr. Dingell. That related both to appearances of personnel 
and also production of papers. Is that correct?
    Senator Grassley. Very true.
    Mr. Dingell. I take it that you still have serious 
questions as to exactly what the Department wished to avoid 
revealing to your committee. Do you agree that FDA has been 
forthcoming with the public regarding the safety of this drug 
Ketek?
    Senator Grassley. Very definitely.
    Mr. Dingell. So now, FDA, after acknowledging that the 
pivotal safety study for Ketek was full of clinical fraud, 
approved the drug anyway, claiming there were insufficient 
adverse events reported in countries such as Italy and Brazil 
to prove that it was not safe. Is that correct?
    Senator Grassley. Well, that's correct from the standpoint 
that I think that those are things that Agent West pointed out 
that needed to be further investigated. I am not sure that I 
can speak to the points about the other countries that you made 
mention of. But basically, I am referring now to my staff, and 
they said basically the answer is yes.
    Mr. Dingell. And it doesn't make sense to you, does it?
    Senator Grassley. No, obviously not. I hope my testimony 
made very clear that I am incensed that, when we are doing our 
constitutional job of oversight, that we don't get the 
cooperation from the executive branch of government.
    Mr. Dingell. Now, I believe it is sort of the fact, the 
rule of thumb in the United States is that only about 10 
percent of adverse events get reported. Is that right?
    Senator Grassley. Approximately. Yes.
    Mr. Dingell. Now, Senator, in fact, has FDA ever before or 
since made a safety determination for a new drug primarily on 
the basis of the lack of adverse event data in the United 
States, much less in countries such as Brazil and Italy?
    Senator Grassley. I think I will have to take a pass on 
that question. I am not sure I can answer that.
    Mr. Dingell. It is my understanding that this is 
unprecedented.
    Senator Grassley. OK.
    Mr. Dingell. Would it be fair to say that the FDA officials 
that approved this drug discouraged information from their own 
investigators, and those were investigators trained both in the 
detection of scientific misconduct and criminal fraud, in an 
attempt to get the advisory committee reviewing the data from 
the fraudulent study to recommend approval?
    Senator Grassley. The answer is yes, and that is a fair 
summary of some of the points I was trying to make.
    Mr. Dingell. Now, Senator, did Aventis inform the advisory 
committee of data problems? Much less did they inform them of 
the existence of a fraud investigation when they presented the 
Study number 3014, the pivotal study in January 2003?
    Senator Grassley. The answer is no.
    Mr. Dingell. Do you believe that the field investigators, 
when they were allowed to do their jobs, worked diligently and 
competently to uncover wrongdoing at Aventis?
    Senator Grassley. The answer is yes. And I refer 
specifically to Agent West that I worked so hard to get in 
contact with, but also others as well. But the others my staff 
were more involved with.
    Mr. Dingell. Now Senator, do you believe that the primary 
reviewers, the whistle-blowers that came to your committee and 
testified here last year, raised appropriate concerns about the 
safety and efficacy of Ketek?
    Senator Grassley. Of course. They are a major source of 
information on this specific case. But I want to point out, to 
encourage whistle-blowers everywhere in government, that they 
are a very important part of the process of congressional 
oversight. We can't know where all the skeletons are buried, 
and we want to find out where those skeletons are, not just in 
this administration but every administration in the past when 
it has been difficult, and in the future.
    Mr. Dingell. We happen to agree very strongly on that, 
Senator.
    Now, if the investigators did a good job in detecting 
problems and the reviewers did a good job in assessing their 
implications, what does this say about the supervisors in CDER, 
that is the Center for Drug Evaluation and Research?
    Senator Grassley. Well, it seems to me that they were not 
doing their job.
    Mr. Dingell. It seems to be very clear from the record 
here.
    Now, Senator, you referred to Dr. Victoria Hampshire. And 
you have indicated that she is essentially a whistle-blower who 
is now being, quite frankly, inquired into in ways that I think 
you indicated are less than fully correct by FDA and by the 
Justice Department and others.
    Senator Grassley. Yeah, and by a company that worked with 
FDA to implicate her.
    Mr. Dingell. Would you want to tell us a little bit more 
about that?
    Senator Grassley. Well, for instance, we know of an 
instance in which there was a PowerPoint program put together 
to come in to show why Dr. Hampshire ought to be fired.
    Mr. Dingell. I think we will be asking for that.
    Senator Grassley. Would you please contact my staff in 
regard to the details of that?
    Mr. Dingell. I would certainly do so.
    I wanted to ask you, Senator, because I think this is an 
important question, you did a superb job as Chairman of the 
Finance Committee and we have much to thank you for for your 
labors on this particular matter. Would you suggest that this 
committee ought to have a look maybe at the behavior of FDA 
with regard to Dr. Hampshire?
    Senator Grassley. I would. It would be very helpful, 
because you as the Chairman will get the attention much more 
than a Ranking Member, even considering I am in the higher 
body.
    Mr. Dingell. We will try and get their attention. And I 
think working together we can perhaps procure some more focused 
and proper care, concern and attention at FDA. Senator, it is a 
privilege to see you again.
    Mr. Stupak. Thank you, Senator.
    Mr. Dingell. And thank you for your courtesy to me, Mr. 
Chairman.
    [The prepared statement of Senator Grassley follows:]

                  Statement of Senator Chuck Grassley

    Chairmen Dingell and Stupak, Ranking Members Barton and 
Shimkus, and distinguished colleagues, thank you for inviting 
me to speak today about my investigation of FDA's handling of 
the large safety study Ketek, Study 3014. It has been a long 
road and it's still not at an end.
    More than two years ago, in January 2006, the journal 
Annals of Internal Medicine reported three cases of liver 
damage in North Carolina patients who took Ketek. In response 
the FDA issued a public health advisory.
    After all, suffering severe liver problems is quite a price 
to pay for taking an antibiotic that was being used for such 
conditions as sinus infections until that indication was 
removed from the Ketek label a year ago.
    Soon after, I heard allegations and concerns regarding 
FDA's review of Ketek and I started asking questions. One of 
the more serious allegations was that the maker of Ketek, 
Aventis at the time, submitted clinical trial data to the FDA 
in support of approval, knowing it was fraudulent.
    So I asked FDA to make arrangements immediately for my 
staff to review documents related to Study 3014 at the FDA's 
offices.
    Initially, FDA gave my staff access and agreed to provide 
copies of documents my staff identified during their review.
    But then I asked for Special Agent Robert West from FDA's 
Office of Criminal Investigations and the FDA pulled a 180 on 
me.
    I had good reasons for asking for Agent West. One of the 
other allegations I received was that despite Agent West's 
concerns and recommendations, FDA never expanded its 
investigation to determine if the company did ``knowingly'' 
submit fraudulent data.
    Agent West played an integral role in the investigation of 
Study 3014 and I am delighted to see that he will be testifying 
on the next panel along with two other special agents from the 
agency. Agent West was the lead agent on the investigation of 
Dr. Anne Kirkman Campbell, one of the principal clinical 
investigators for Study 3014. And as a result of that 
investigation Dr. Kirkman Campbell is currently serving a 57-
month prison sentence. Agent West also was in frequent 
communication with the FDA consumer safety officers and 
reviewers involved in the Study 3014 inspections.
    But as I testified before this subcommittee a year ago, FDA 
and HHS wouldn't make Agent West available-even after I went 
over to the HHS offices to ask personally to speak with Agent 
West and subpoenas were issued. After all, if FDA had nothing 
to hide about how it handled Study 3014, why stop me from 
talking to Agent West? I smelled a ``cover-up.''
    Well, I now have a better understanding of why FDA did not 
want me to speak to Agent West regarding Ketek. The answer to 
the ``WHY'' question is equally interesting. It seems to me 
that there were definitely reasons why the FDA did not want me 
to meet with Agent West or any other agents for that matter. 
FDA, it appears, did not want anyone to know that it didn't 
further investigate whether or not Aventis submitted fraudulent 
data knowingly to the FDA. The FDA did that even though Agent 
West recommended, in the summer of 2003--almost 5 years ago--to 
high level officials at the FDA that it needed to create a 
mini-task force look into Aventis.
    When HHS and FDA finally made Agent West available a short 
time ago--18 months after I first requested him--Agent West 
confirmed that no one acted on his recommendations. In fact, I 
learned from HHS more than a year after my visit to the 
Department, that the FDA didn't open an investigation into the 
company until March 2006. Interestingly, that was around the 
same time I started poking around Ketek.
    Agent West told his supervisors, FDA investigators involved 
in the Study 3014 inspections, as well as FDA directors 
overseeing the review of Ketek what he thought needed to be 
done--inspect all the study sites that enrolled over 100 
patients. The protocol for Study 3014 had recommended a maximum 
enrollment of 50 patients per site, so that would have meant 
inspections of about 70 sites.
    Agent West's supervisors told my staff that they supported 
him. The site investigators also thought it was a good idea. 
But what happened?
    The head of the Office of Criminal Investigations told my 
staff that Agent West's concerns and recommendations were 
referred up the food chain, and he assumed the matter would be 
taken care of.
    The Associate Commissioner for Regulatory Affairs at that 
time said he was prepared to offer any assistance if needed but 
never heard anything more from the Office of Criminal 
Investigations.
    One of Agent West's superiors said the CDER folks were 
briefed so the ball was in their court. He also said that Agent 
West's task force proposal had nothing to do with concerns 
about Aventis.
    But I have since learned that that's not true.
    Agent West sent an email in July 2003 to his superiors 
about his conversation with directors in FDA's Center for Drug 
Evaluation and Research. These directors oversaw the review of 
Ketek.
    In that email, Agent West said, ``I told them that it was 
my opinion that Aventis knew sites were suspect but did nothing 
to prove or refute their suspicions.''
    Agent West was not the only agent who believed that the 
company or at least someone within the company knew there were 
serious problems, particularly at Dr. Kirkman Campbell's site. 
You have the two agents here today who were assigned to the 
criminal investigation that was opened in March 2006--Special 
Agents Robert Ekey and Douglas Loveland.
    Agent Ekey said during a joint interview with our 
Committees that he thought the company too easily dismissed the 
concerns that were raised by its own contract research 
organization, the organization hired to monitor Study 3014.
    Agent Loveland wrote in an internal email dated April 17, 
2007, that the company knew significant issues existed at many 
sites yet the company submitted the data to the FDA and claimed 
the study was conducted according to good clinical practices. 
He also told my staff during an interview yesterday that 
Aventis should have known that there were problems with the 
integrity of the study data.
    The case was closed in July 2007. FDA issued a warning 
letter in October to the company for failing to ensure proper 
monitoring of Study 3014 and not adequately investigating 
allegations of fraud at Dr. Kirkman Campbell's site. The letter 
cited many of the same problems that FDA's staff raised back in 
2003 and 2004. So why wasn't an investigation initiated then?
    Agent West stated in his July 2003 email, ``I think the 
three individuals in CDER understood my feelings and opinions 
but I don't know whether or not the necessary steps will be 
accomplished.''
    When my staff spoke with the three directors, one of them 
told my staff that if the Office of Criminal Investigations 
wanted additional investigations, it was their call, not 
CDER's. He also said that the Office of Criminal Investigations 
should have talked to the Division of Scientific Investigations 
since the division oversees clinical trial site inspections.
    So who's responsible?
    Everyone seemed to be pointing the finger at someone else, 
with the exception of the head of FDA's office of Division of 
Scientific Investigations. This FDA employee told my staff that 
as far as additional inspections went, they didn't have the 
resources to do more. And besides, she said (1) the FDA didn't 
rely on Study 3014 for approval, (2) FDA completed 8 site 
inspections for Study 3014, which is many more than the one or 
two it normally does, and (3) astonishingly, she also said that 
investigating drug companies is a ``losing game'' and the 
chances ofgetting a warning letter is zero.
    I find that attitude extremely troubling, as I'm sure you 
do as well.
    We rely on the FDA to ensure that the drugs in our medicine 
cabinets are safe and effective. That includes FDA making sure 
that the data supporting the safety and efficacy of a drug is 
sound. To do that adequately, FDA has to do its job of 
oversight over clinical trials. Data integrity isn't the only 
issue of concern here. FDA also has an obligation to protect 
human subjects.
    In December, I raised this matter to Commissioner von 
Eschenbach in a lengthy letter regarding my Ketek 
investigation. That letter I've been told is included in your 
exhibit books. I asked Commissioner von Eschenbach: If it is 
FDA's position that no additional inspections are required once 
a study is no longer useful for regulatory action, then how can 
FDA protect research subjects from the harm that may be caused 
by clinical investigators?
    Not relying on a study for approval does not absolve FDA of 
its responsibility to protect the individuals who courageously 
volunteer in clinical trials so that we can all benefit from 
lifesaving cures and medical innovation. I am still waiting for 
the Commissioner's comments on this important matter.
    Of course, this responsibility does not lie only with the 
FDA. The drug companies also have a responsibility to the 
people who participate in their clinical trials. They also need 
to ensure that problems are adequately investigated and 
addressed.
    In the case of Study 3014, there were sirens, red flags and 
bull horns, but it looks like the company and the FDA kept ear 
plugs and blinders on.
    I like to close by saying that it troubles me that the FDA 
failed to act on the serious concerns raised by Agent West 
until almost 2 years after Ketek was approved and almost 3\1/2\ 
years after Study 3014 was submitted to the FDA. It troubles me 
that an FDA manager would say that investigating a company is a 
``losing game'' because in the case of Ketek, after the FDA did 
do the investigation, a warning letter was issued. This same 
individual, however, hasalso said that more oversight of 
clinical trials was needed.
    FDA officials have told me that some initiatives are 
underway, including making sure that there's proper oversight 
and authority over all the parties involved in clinical trials. 
I hope we see significant improvements in the near future.
    There's also been a lot of talk over the last several 
months about FDA inspections, especially foreign inspections. 
FDA has limited resources to perform this important function. 
Just as more and more drugs are being manufactured overseas, 
more and more studies are being conducted outside of the United 
States.
    I look forward to working with this Committee and in 
particular with you, Chairmen Dingell and Stupak and Ranking 
Members Barton and Shimkus, as well as my colleagues in the 
Senate to ensure that FDA has the resources and tools to do its 
job.
    Thank you.
                              ----------                              

    Mr. Stupak. Let's call back our last panel that was up 
there. Third panel, Dr. Paul Chew, Dr. Fred Eshelman, and Ms. 
Sharon Hill Price.
    Dr. Chew, Dr. Eshelman and Ms. Sharon Hill Price, you are 
remaining under oath, understood? OK.
    Ms. Price, let me ask you this. What is the purpose of an 
IRB? What is the main focus of an IRB?
    Ms. Price. An Institutional Review Board, or IRB as it is 
called, review clinical research within an ethical and 
regulatory framework to assure----
    Mr. Stupak. To protect----
    Ms. Price. Yeah, to assure subject protection according to 
regulation.
    Mr. Stupak. Assure patient safety.
    Ms. Price. Subject safety, yes.
    Mr. Stupak. OK. So if there was a concern about patient 
safety, instead of PPD, the contract review organization, they 
would go to the IRB, correct?
    Ms. Price. We are one of the venues, yes, if there is 
concern about subject safety.
    Mr. Stupak. What other venue is there?
    Ms. Price. I think subject safety is a shared 
responsibility, as I indicated in my opening statement.
    Mr. Stupak. With the IRB, Copernicus in this case on Study 
3014, and who else?
    Ms. Price. The sponsor, the investigator.
    Mr. Stupak. That would be Aventis.
    Ms. Price. The investigator.
    Mr. Stupak. That would be Dr. Kirkman-Campbell.
    Ms. Price. And the FDA.
    Mr. Stupak. The FDA.
    Ms. Price. Even the subject to some extent needs to take 
some responsibility for participating in research.
    Mr. Stupak. Sure. But the main focus, the reason why IRBs 
came about was to protect patient safety. Correct?
    Ms. Price. Yes.
    Mr. Stupak. And that is the genesis of the IRB, is patient 
safety?
    Ms. Price. Yes.
    Mr. Stupak. OK. And you said you had 83 complaints when I 
was asking you questions before just on Kirkman-Campbell, 
right?
    Ms. Price. Yes, we had 83 memos to file submitted 3 months 
after she closed.
    Mr. Stupak. Right. And you said it was 90 days after 
Kirkman-Campbell closed out her work on Study 3014. Correct?
    Ms. Price. Correct.
    Mr. Stupak. Did you ever read any of those 83 memos that 
came to the file?
    Ms. Price. Only recently.
    Mr. Stupak. So while 83 memos came in, you weren't curious 
to see what the violations were?
    Ms. 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.
    Mr. Stupak. Well, how do you ensure patient safety then if 
you don't know what the memos and violation are saying.
    Ms. Price. It was not our policy at the time to review 
those.
    Mr. Stupak. But isn't that why an IRB comes in 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. Price. That was our policy at the time. And we have 
since revised that.
    Mr. Stupak. Well, why would Aventis or anyone hire an IRB 
if it wasn't to have patient safety as their goal and their 
mission?
    Ms. Price. The regulations require the review of clinical 
research by an institutional review board.
    Mr. Stupak. Right. Its main purpose is patient safety?
    Ms. Price. Correct.
    Mr. Stupak. So why would anyone hire Copernicus if you're 
reviewing the files?
    Mr. Dingell. Would you yield? 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'm listening 
most attentively to the matters you're discussing.
    Mr. Stupak. Well, thank you. Well, are you not as an IRB, 
Copernicus, are you not responsible for reporting noncompliance 
to the FDA?
    Ms. Price. Yes, we are. According to our--
    Mr. Stupak. You may want to wait a minute here. It's going 
to ring for a second. OK.
    Ms. Price. Issues that rise to the level of noncompliance 
or investigator noncompliance would be reportable to the FDA 
according to the regulations.
    Mr. Stupak. So did you report to the FDA? You had 83 
violations alone just on Kirkman-Campbell. Did you report to 
the FDA?
    Ms. Price. No. We had no obligation at that point to report 
any of those violations.
    Mr. Stupak. Why wouldn't you have an obligation, you're the 
IRB?
    Ms. Price. We received that information 3 months after her 
site was closed out.
    Mr. Stupak. No, you received the memo that we talked about, 
memo number 33, it's Exhibit No. 33, the one from Ms. Cisneros 
to Ms. Wallace, you received that. Didn't you have a 
responsibility to report that to the FDA?
    Ms. Price. It was human error that that didn't get elevated 
as it should have been.
    Mr. Stupak. Well, besides this one right here, you had 83 
more complaints about Kirkman-Campbell. You didn't report those 
to the FDA?
    Ms. 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 23, 2008, at which time you all 
were immediately notified.
    Mr. Stupak. Wait a minute. You testified earlier you became 
aware of an electronic format that was in the electronic files 
in 2006.
    Ms. Price. As we reviewed our information, it did show up 
on our 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. No one opened that 
memo until January 23, 2008, one hour before you all received 
it.
    Mr. Stupak. OK. Well, then let's go over this again then. 
Kyle, do you have that exhibit? Let me show you a letter of 
February 27, 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? I 
think your counsel has it right there. He's handing it to you. 
OK?
    Ms. Price. Yes, sir.
    Mr. Stupak. We're asking for certain documents. It goes to 
page 2, 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. Price. No one had opened the document. After we 
received this letter dated February 27, 2007, our counsel met 
with your staff and decided----
    Mr. Stupak. And your counsel or you did not tell us about 
this electronic file that you never opened, right?
    Ms. Price. Excuse me?
    Mr. Stupak. You or your counsel never told us about the 
electronic file?
    Ms. 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----
    Mr. 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. Price. I think we had an obligation if we would have 
opened it, but we did not and I'm sorry for that.
    Mr. Stupak. So to get around a request you just don't open 
the file?
    Ms. Price. Not intentionally.
    Mr. Stupak. I mean, the U.S. Senate asks, we ask, and then 
the day you manage--how is it you come to think about it the 
day before you're brought in before the committee?
    Ms. Price. It was discovered the day before I was to meet 
with your subcommittee or your staff, sir.
    Mr. Stupak. Right. It was discovered earlier in 2006, but 
you just don't remember it until the day before you come to the 
committee. Isn't that a coincidence?
    Ms. Price. After further investigation it did appear in an 
electronic search for Grassley, but it wasn't prepared for 
Grassley.
    Mr. Stupak. Then let's go back to what 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, Exhibit No. 33, from Ms. Cisneros, the telephone call 
to you? And you're responsible for reporting noncompliance to 
the FDA, correct, that is established, right?
    Ms. Price. Yes, sir.
    Mr. Stupak. And all these reports you had, the 83, this one 
from Ms. Cisneros, you did not give that to the FDA, correct?
    Ms. Price. Correct. It did not rise to the level of any 
anticipated problems at that point in our history in 2002.
    Mr. Stupak. That's your judgment?
    Ms. Price. That was our policy and procedure at the time.
    Mr. Stupak. Well, you're familiar with 21 C.F.R. 56, the 
IRB functions and operations, right?
    Ms. Price. Yes, sir.
    Mr. Stupak. Does it not say in that that any instance of 
serious or continuing noncompliance with these regulations or 
the requirements or the determinations of the IRB, are you not 
required to report that to the FDA in order to fulfill 
requirements----
    Ms. Price. It does say that in words to that effect. I 
believe so.
    Mr. Stupak. OK. So you violate this policy, too?
    Ms. Price. No sir, I don't believe we do. That's your 
opinion and I don't share that opinion.
    Mr. Stupak. So you don't feel you have to follow 21 C.F.R. 
56, Section 108, subsection (b), IRB functions and operations?
    Ms. Price. We do follow up 21 C.F.R. We received 83 memos 
to file 3 months after an investigator closed and we had no 
obligations.
    Mr. Stupak. Your responsibility doesn't stop when Ms. 
Kirkman stops the study; it continues.
    Ms. 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 
status report they are closed.
    Mr. Stupak. Well, when is the final study status closed, 
when it's presented to the FDA?
    Ms. Price. No, sir, when they close at our site--when they 
close the IRB.
    Mr. Stupak. So once the site closes you have no more 
responsibility to report problems with patient safety?
    Ms. Price. We have no regulatory obligation, no.
    Mr. Stupak. How about legal obligation under 21 C.F.R. 56?
    Ms. Price. Our interpretation of that regulation would not 
have indicated that we would have needed to provide those.
    Mr. Stupak. Well, that's your interpretation. How about 
moral obligation to the patients? If your IRB is there 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 Aventis or to the PPD?
    Ms. 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.
    Mr. Stupak. I'm not asking about standard operating 
procedures. I'm asking you if you have a moral obligation since 
you're responsible for patient safety when you see 83 reports 
just from one site to report that to somebody, like the FDA to 
Aventis or PPD?
    Ms. Price. Aventis sent them to us and PPD sent them to us, 
so they were already aware of them.
    Mr. Stupak. OK. Well, how about do you have a moral 
obligation to the FDA?
    Ms. Price. Not at the time, according to our standard 
operating procedures.
    Mr. Stupak. How about today, do you have a moral obligation 
to the FDA to report documents to them that refer to patient 
safety?
    Ms. Price. If something came in similar to this today, 
number one, we revamped our standard operating procedures. And 
as I 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 would make a determination on what should 
be done, which would probably include notifying the FDA.
    Mr. Stupak. Did you have reports from other sites other 
than Kirkman-Campbell?
    Ms. Price. What type of report, sir?
    Mr. Stupak. On patient safety issues, protocol violations.
    Ms. Price. There were a number of memos to file. I would 
anticipate that there would have been others, yes.
    Mr. Stupak. So you don't know if there were others. Do you 
anticipate there were others?
    Ms. Price. I know that there were memos to file. I don't 
know the specifics of the contents of those.
    Mr. Stupak. Well, did you report any of those violations to 
the FDA?
    Ms. Price. No, sir. We weren't reviewing protocol 
deviations or memos to file at that point in 2002.
    Mr. Stupak. So all these things come in and it was your 
standard operating procedure not to report these violations to 
the FDA or anybody?
    Ms. Price. That's right.
    Mr. Stupak. So what are you there for? Why do you exist?
    Ms. Price. IRBs perform a very integral part of a role in--
--
    Mr. 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 a public setting, but now they've gone 
to outside the 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. Price. I disagree. We work very closely within an 
ethical and regulatory framework as put out.
    Mr. Stupak. When I asked about the ethics you didn't have 
an answer. You just said that was in your standard operating 
procedures and under 21 C.F.R. You didn't think you had any 
legal responsibility. So where do the ethics come in now?
    Ms. 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.
    Mr. Stupak. The bottom line, you blew it here, right? You 
didn't do your job here, on this study, correct? Is that fair 
to say?
    Ms. Price. We had a human error in not addressing this call 
from an investigative site monitor.
    Mr. Stupak. Not just a call, but the 83 other violations 
and the other violations from other sites are reported to you, 
you had a responsibility to tell the FDA and you didn't say 
anything to the FDA on any of them?
    Ms. Price. I'm sitting here today telling you that I think 
we did a good job for what we did at the time.
    Mr. Stupak. Good job of saying nothing to the people who 
need to know, which was the FDA, right? I don't mean to be 
argumentative but this is ridiculous. Mr. Chairman, you had a 
couple questions on IRBs you want to ask?
    Mr. Dingell. Mr. Chairman, I think you're raising more 
questions than we're getting answers to. The witness here that 
you've been just inquiring of, what is the name of your firm, 
ma'am, if you please?
    Ms. Price. Copernicus Group IRB.
    Mr. Dingell. What is your relationship to that company?
    Ms. Price. I'm the founder and CEO.
    Mr. Dingell. How many employees do you have?
    Ms. Price. We currently have about 70 employees.
    Mr. Dingell. What is the net worth of the company?
    Ms. Price. Net worth meaning?
    Mr. Dingell. What's the net worth?
    Ms. Price. I would say in the millions of dollars.
    Mr. Dingell. Now, tell me, how long has the company been in 
existence?
    Ms. Price. I started the company in 1996.
    Mr. Dingell. Are you a publicly held company?
    Ms. Price. No, sir, privately held.
    Mr. Dingell. Privately owned?
    Ms. Price. Yes.
    Mr. Dingell. Do you file annual reports with anybody?
    Ms. Price. We file taxes.
    Mr. Dingell. Taxes, that's all?
    Ms. Price. And annual corporate reports.
    Mr. Dingell. You don't file any reports to the SEC or any 
of the State regulatory agencies?
    Ms. Price. No, sir.
    Mr. Dingell. What was your earnings last year?
    Ms. Price. Earnings last year? Revenue top line was about 
$13 million.
    Mr. Dingell. And from where did you earn that $13 million?
    Ms. Price. A number of clients.
    Mr. Dingell. From what?
    Ms. Price. A number of clients and sponsor organizations 
that submitted studies to us.
    Mr. Dingell. You earned it then functioning as an IRB?
    Ms. Price. Yes, sir. That's the basic function of the 
company.
    Mr. Dingell. Did you earn money from any other source?
    Ms. Price. No, sir.
    Mr. Dingell. Now, how are you retained to do this work? Are 
you retained by the companies that have these matters before 
Food and Drug or does Food and Drug appoint you or how are you 
appointed?
    Ms. Price. In the case of Kirkman-Campbell or in the case 
of 3014 we were contacted by the CRO. We are usually paid by 
the sponsor companies, and that would be like the 
pharmaceutical sponsors.
    Mr. Dingell. So you're paid by the sponsor company, but by 
whom are you selected?
    Ms. Price. The pharmaceutical company or their designee, 
which would be sometimes CROs select us, or investigators 
sometimes approach us to serve as an IRB of record for their 
studies.
    Mr. Dingell. How many companies do you work for? Could you 
submit us a list of the companies for whom you have worked?
    Ms. Price. Yes.
    Mr. Dingell. And could you submit us also a list of the 
companies to whom you have provided or rather--by whom you have 
been paid and for what, to what, let's see, for what, for 
inquiries in what matters were you paid by what companies over 
the period since this matter of Ketek? And starting with Ketek 
and those matters and the years in which you worked on that 
going forward, what companies--would you submit to us what 
companies you have worked for as an IRB?
    Ms. Price. Certainly. You're asking for a list of studies 
we have reviewed since 2001?
    Mr. Dingell. Yes. I want it going back to the year on which 
you worked with or for Ketek, the companies.
    Ms. Price. Yes, I can do that.
    [The information was not submitted for inclusion in the 
record.]
    Mr. Dingell. And how much you were paid on each. And on 
which matters and on which pharmaceuticals you served as an 
IRB. Now, is your company a for-profit or nonprofit company?
    Ms. Price. A for-profit.
    Mr. Dingell. For-profit. And I believe you told me that all 
you do is function as an IRB, is that correct?
    Ms. Price. Our basic function is to provide ethical review 
for clinical research.
    Mr. Dingell. Now, what does this involve? What do you do 
here when you do this?
    Ms. Price. Institutional review boards will receive 
information. Are you familiar with protocols? Protocols are 
actually submitted by the sponsor company. We're usually--
protocols and informed consent documents are submitted by the 
sponsor companies. We have our board members, who are a group 
of diverse individuals with scientific and nonscientific 
backgrounds, who review the informed consent documents as well 
as the protocols. And based on the ethical framework of the 
Belmont Report and the clinical regulations we decide whether 
there is more risk than--more benefit than risk to doing the 
studies and conducting the research. We then take a look at the 
informed consent document. And we determine whether that 
information is sufficient for an investigator to use to do the 
informed consent process. The document includes certain things 
as listed in the regulations, certain elements, letting a 
subject know that they can voluntarily be in the study and come 
out, back and forth, at any time, risk benefits and that sort 
of thing.
    Mr. Dingell. Now, tell us, do you review testimony or 
review documents that are submitted by the company in 
connection with the questions before Food and Drug? Do you 
review the competence or the qualifications of the persons who 
are doing the research or presenting papers or testimony?
    Ms. Price. Yes. Per the regulations, the investigators are 
selected by the sponsor company. And part of our review is to 
look at the submission packet for the investigators. And in the 
case of Study 3014 we did spot checks of licensure.
    Mr. Dingell. I'm trying to understand here with more than a 
little difficulty exactly what you do.
    Ms. Price. I think that institutional review boards have 
always had difficulty explaining what they do. I wish I could 
explain it better. We review clinical research from an ethical 
perspective. We are not on the ground monitoring at the 
investigator site. We try to assure the subject safety through 
ethical review.
    Mr. Dingell. You do an ethical review?
    Ms. Price. Yes, sir, of the protocol, the informed consent 
document.
    Mr. Dingell. What is an ethical review? What constitutes an 
ethical review?
    Ms. Price. We base our ethical review on the Belmont 
Report, the issues released in the Belmont Report. And those 
are ethical principles that reflect the conduct of good 
clinical research. As I stated before, that has to do with 
autonomy of subjects, making sure that there is an informed 
consent process that takes place. We look at the research or 
the IRB will look at the research and determine if there is 
enough benefit to do the study, if something, generalizeable 
knowledge can come out of it. And thirdly, we look at justice. 
Is the--is there one group that is receiving most of the burden 
of research or is it equitable across the board. In addition, 
our IRB will look and see that there is a monitoring plan in 
place, that there is going to be some type of monitoring for 
the study. Then ongoing investigators are obligated per the 
regulations to submit----
    Mr. Dingell. Does your work require you or permit you to 
look to see whether the data is true, factual and correct?
    Ms. Price. No, sir, we don't deal with data.
    Mr. Dingell. Now, how do you make an ethical review without 
knowing whether or not the information received is true, 
factual and correct?
    Ms. Price. That is not our role.
    Mr. Dingell. That's not your role.
    Ms. Price. No, sir.
    Mr. Dingell. Do you look to see whether the proper 
information has been submitted to support the allegations and 
the statements made either by Food and Drug or by the 
applicant?
    Ms. Price. No, sir. That's a monitoring function that's the 
responsibility of the sponsor.
    Mr. Dingell. Do you look for whether false statements are 
made in connection with the application or whether the studies 
that are submitted are in fact valid, truthful, factual, 
correctly and honestly done?
    Ms. Price. No, sir, we don't per se.
    Mr. Dingell. Do you do that?
    Ms. Price. We rely on the investigators to communicate with 
us. And in this case sponsors.
    Mr. Dingell. So then do you know whether the studies that 
are submitted as a part of your ethical evaluation are factual, 
truthful, correctly done?
    Ms. Price. We don't have a role after the study is 
completed to follow up on the analysis of the data or the 
submission to the FDA.
    Mr. Dingell. Now, you got $375,000 for this matter, I 
believe, is that right?
    Ms. Price. Yes, sir. That was how much we made off the 
study.
    Mr. Dingell. Exactly what did you do for this $375,000?
    Ms. Price. We reviewed the protocol, the informed consent 
document.
    Mr. Dingell. You reviewed what?
    Ms. Price. We reviewed the protocol, the informed consent 
document, we reviewed investigator packets and we looked at 
serious adverse events as they came in. We fashioned an 
informed consent document that was to be used by investigators 
for the informed consent process.
    Mr. Dingell. Did you ever go into the question of whether 
or not the studies were factual or adequate?
    Ms. Price. That determination was made--I'm a little 
unclear on your factual comment. But certainly the assessment 
of the institutional review board members themselves would have 
gone into whether they felt the study was designed in an 
appropriate way and would----
    Mr. Dingell. Did you ever interview anybody about the 
studies as to whether they were factual or correctly done or 
included all the persons that should have been interviewed or 
whether or not all the persons upon whom the tests were 
supposed to have been performed were either properly treated or 
in fact existed or had had the results that would indicate a 
proper study?
    Ms. Price. No, sir, we didn't interview anyone.
    Mr. Dingell. Did the Ketek study comply with the Belmont 
review?
    Ms. Price. In the opinion of the institutional review 
board, yes, it met the requirements, yes, sir.
    Mr. Dingell. It did.
    Ms. Price. Yes, sir.
    Mr. Dingell. Why do you say that?
    Ms. Price. Our board is trained to look for certain things. 
And they use the Belmont Report for their guidance, and then 
the regulations. And our preliminary review is initially to 
review the protocol and informed consent document.
    Mr. Dingell. Now, could you pass the Belmont review and 
still have fraud?
    Ms. Price. A study could certainly be approved. And it was 
in this case. The study was approved on the Belmont principles; 
however, there was fraud by an investigator or investigators in 
the study.
    Mr. Dingell. So you couldn't ask the Belmont review if 
there was fraud there, is that right?
    Ms. Price. Yes.
    Mr. Dingell. Can you make the bold statement that there was 
no fraud in connection with Ketek or any of the studies that 
were made with regard to the approval of their applications by 
Food and Drug?
    Ms. Price. Can I make the statement that there was no 
fraud? I think that it has been found that there was fraud.
    Mr. Dingell. Say that again.
    Ms. Price. There has been found that there was fraud.
    Mr. Dingell. There was fraud.
    Ms. Price. According to the Food and Drug Administration, 
yes.
    Mr. Dingell. I'm sorry.
    Ms. Price. According to the Food and Drug Administration. 
That was not our assessment. That was the assessment of the 
FDA.
    Mr. Dingell. So you don't know whether there was fraud or 
not or you do know there was fraud?
    Ms. Price. According to the FDA there was fraud, so I would 
say yes, there was fraud.
    Mr. Dingell. And your ethical review did not reveal that 
there was fraud here?
    Ms. Price. No, sir, it did not.
    Mr. Dingell. I find that a curious ethical review. Mr. 
Chairman, I thank you.
    Mr. Stupak. Thank you, Mr. Chairman. Mr. Barton for 
questions. We've been going around more than once for this 
panel since we're only on Ms. Price, it seems like.
    Mr. Barton. Thank you, Mr. Chairman. I apologize. I've been 
stuck in airports most of the day. My plane was delayed, so 
I've not been able to attend the entire hearing. My questions 
are going to be for Dr. Eshelman. It's my understanding, 
Doctor, that the Aventis PPD contract for this Study 3014, that 
Aventis was responsible for bringing the investigators into 
compliance; if that wasn't possible, terminating their 
participation in the study. Is that your understanding?
    Mr. Eshelman. PPD was not responsible for the termination 
of an investigator, if I understood your question.
    Mr. Barton. Well, the question is the staff has informed me 
that Aventis was responsible for bringing investigators into 
compliance, but if they couldn't do it, then Aventis had to 
terminate their participation into the study?
    Mr. Eshelman. That's correct, sir.
    Mr. Barton. Did the contract specify which party should 
notify FDA in the event that it did discover fraud?
    Mr. Eshelman. I think that the regulatory communication 
function was retained by Aventis under the terms of the 
contract.
    Mr. Barton. Did anything in the contract prevent your 
company, PPD, from notifying FDA about your concerns?
    Mr. Eshelman. I guess only under the terms of 
confidentiality as they might or might not have applied. I mean 
there was certainly nothing explicit or implied by Aventis or 
anyone else that would have otherwise prevented us from 
contacting a regulatory body with the exception of the 
particular retention by Aventis of regulatory communication in 
this instance, which is a long-winded way of saying all that 
stuff notwithstanding we could still do whatever we wanted to.
    Mr. Barton. In other studies that PPD has been involved 
with with the FDA, has your company ever notified the FDA about 
fraud when it wasn't directed to do so by the particular drug 
sponsor?
    Mr. Eshelman. I can't say with assurance because I don't 
have the facts in front of me. But on occasion PPD is assigned 
all of the responsibilities for a particular study, including 
communication with regulatory bodies. And in such an instance 
if there were reason for disqualification of an investigator we 
certainly would communicate that with FDA and other appropriate 
bodies. I don't know whether we have specifically done that or 
not. I certainly know that in the course of our work over the 
years we have made recommendations to sponsors on a large 
number of issues. And sometimes they are followed through and 
sometimes they're not because sometimes there is a bona fide 
difference of opinion on a site.
    Mr. Barton. Please describe your company's role in vetting 
physicians for participation as clinical investigators. Do you 
rely on the FDA debarment and disqualification list as part of 
your vetting?
    Mr. Eshelman. Yes, sir. And we screen investigators against 
that list all of the time. And it's typical that when we 
contract with a company like Sanofi-Aventis we warrant that in 
fact we have done that. When we sign up investigators, also we 
try to qualify them on a basis of their training and 
experience. We also request a copy of the medical license that 
is valid at that time.
    Mr. Barton. Do you conduct any other research to determine 
whether the physician has been convicted of a felony relating 
to a drug product?
    Mr. Eshelman. My assumption is that if a physician has been 
convicted of a felony, their license would be revoked. Now, I'm 
not a lawyer, I don't know if that's true. That's my 
assumption.
    Mr. Barton. Well, I mean the basic question is do you do 
any outside independent research or do you rely strictly on the 
list that the FDA provides in terms of debarment and 
disqualification?
    Mr. Eshelman. No, sir. We get a copy of their current 
medical license. I'm also informed that post, I think 2004, we 
became aware of certain Web sites that we could go to, which 
would indicate whether or not there had been sanctions by 
medical licensure boards against particular physicians. So we 
can also go to those in most States. I believe that maybe this 
is not true in Wisconsin, but in most States it is.
    Mr. Barton. I'm a little bit confused. Is all you basically 
do, you do a status check on the license that the physician 
under review for participation, that that license is current, 
is that the extent of your investigation?
    Mr. Eshelman. No, sir. We also look at their curriculum 
vitae to be sure that they are in fact trained appropriately 
for what they are supposed to do.
    Mr. Barton. Do you believe that the debarment and 
disqualification lists that the FDA provides accurately reflect 
the number of individuals who have been convicted of crimes 
relating to drug products?
    Mr. Eshelman. Based on the testimony that I've heard today 
with particular reference to Dr. Kirkman-Campbell, I guess I 
would have to say no.
    Mr. Barton. Well, we're releasing a report today, if we 
haven't already, that shows that the FDA has been hardly 
stalwart in pursuing debarment even when the factual and 
legislative predicates are met. Even when they're mandated do 
they seem to drag their feet. So if we rely on these debarment 
and disqualification lists as provided by the FDA, there are 
going to be lots of doctors out there and lots of folks that 
probably shouldn't be allowed to participate. And that's a 
personal opinion of mine. That's not necessarily an opinion of 
the committee.
    If what I just said is true, how does that impact your 
ability to screen clinical investigators?
    Mr. Eshelman. Well, you know, if the debarment process is 
flawed----
    Mr. Barton. Well, it's almost nonexistent.
    Mr. Eshelman. Well, that could present some serious issues 
for us obviously and also sponsors. I'm not sure how that would 
go to our contracts because they, in most cases, do rely on 
screening against this debarment list. But it's a serious 
issue.
    Mr. Barton. My last question, Mr. Chairman. In a conference 
call with Aventis in March of 2002, PPD discussed the problems 
it had identified at Dr. Kirkman-Campbell's site. According to 
the minutes of that phone call found at tab 5, Aventis tried to 
take certain steps to identify whether the fraud had occurred. 
At the time of this call, Dr. Eshelman, did you agree with 
Aventis' response as to how it could address or how it would 
address the fraud concerns?
    Mr. Eshelman. I was not aware of the details of that at 
that time.
    Mr. Barton. OK. So you had no reason at that time to 
dispute one way or the other Aventis' concerns?
    Mr. Eshelman. No, sir.
    Mr. Barton. Thank you.
    Mr. Stupak. No further questions from the ranking member.
    Mr. Markey, a member of the full committee, is here and 
would like to ask some questions of this panel. With unanimous 
consent, I recognize Mr. Markey for 5 minutes for questions. 
Mr. Markey, please.
    Mr. Markey. Thank you, Mr. Chairman, very much. Ms. Price, 
after everything that you've experienced, what reforms has 
Copernicus put in place to make sure this does not happen 
again?
    Ms. Price. Thank you for that question. I've tried to make 
it clear that we have, we've always looked at ways that we can 
improve our process.
    Mr. Markey. How have you improved it?
    Ms. Price. We have redone our--or our standard operating 
procedures have evolved immensely over the past 6 years. We 
participated in a voluntary accreditation program.
    Mr. Markey. Do we need mandatory policies that are on the 
books in terms of how Copernicus and companies like Copernicus 
operate? Should we put mandatory controls on the books that are 
explicit?
    Ms. Price. Mandatory controls? The regulations are already 
in place about institutional review boards. I think it would be 
difficult. Are you asking if there should be mandatory standard 
operating procedures?
    Mr. Markey. To avoid problems in the future should we go 
back and write in specific rules, regulations and laws to make 
sure that there are tighter safeguards in the future?
    Ms. Price. I'm not sure how to answer that because I think 
that the regulations are in place and they leave some 
interpretation. It's definitely open for interpretation. FDA 
and OHRP are certainly trying to----
    Mr. Markey. So you're saying that the regulations in your 
opinion just aren't explicit enough and that they have to be 
rewritten in order to be clear that you are violating a policy, 
a law, if you act in a way that is inconsistent with those 
regulations? So you think we should go back again and rewrite 
those regulations, is that what you're saying?
    Ms. Price. I think that there needs to be some looking at 
the regulations. But no, I'm not saying that we need to rewrite 
the regulations.
    Mr. Markey. OK. I wish that you were saying that, but it 
would be helpful to us that you admitted that there were 
serious problems that existed.
    Dr. Chew, it is well established that at some point during 
the completion of Study 3014 all of you knew that there were 
breaches in the study protocol. Dr. Chew, did Aventis contact 
the FDA?
    Dr. Chew. In the case of Dr. Kirkman-Campbell, no. But in 
the case of two other investigators, yes.
    Mr. Markey. Now, Dr. Eshelman, did PPD contact the FDA?
    Mr. Eshelman. No, sir, we did not.
    Mr. Markey. You did not. And why not?
    Mr. Eshelman. Well, first of all, it was a contractual 
obligation reserved by Sanofi-Aventis. Secondly, there was some 
disagreement between the two firms as to whether or not the 
events at Dr. Kirkman-Campbell's site rose to the level of 
fraud or if they were just GCP violations.
    Mr. Markey. Dr. Chew, when did Aventis first become aware 
of the anomalies associated with the study?
    Dr. Chew. From my review of the record, Congressman, on 
January 17th or 18th of 2002 an Aventis audit was done. And at 
that time with 327 sites having been randomized, and all 
informed consents being reviewed, there were issues then raised 
of dating of the consent forms by staff when the informed 
consent expressly states that the dating must be done by the 
patient. And there were other irregularities in the informed 
consent. There were also issues raised at that time of 
randomization clusters that needed to be evaluated, as well as 
documentation errors, as well as questions about the blood 
sample.
    Mr. Markey. And what did you do to address these anomalies 
at that time, in January 17th?
    Dr, Chew. Well, at that time there was a request for 
additional data. Because at that time the number of actual 
cases that were reviewed, because of the volume of the 
randomization, the number of cases, individual patient records 
actually reviewed was 10. And I believe on November 29 of 2001, 
three by PPD. So clearly there needed to be more in-depth 
information obtained. And that was obtained by PPD on their 3-
day monitoring on February 18th, 19th and the 21st, and that 
culminated in the teleconference on March the 4th to evaluate 
the potential for scientific misconduct and fraud.
    Mr. Markey. Now, on June 19, 2002, Ms. Jean Noon from PPD 
e-mailed Ms. Nadine Grethe of Aventis informing her we are 
still getting conflicting information from site S. They will 
tell us one thing, then the next time we call they tell us the 
opposite. This is particularly problematic when it comes to 
whether a subject was ever consented or not and what effect the 
drug subject took. Ms. Noon then continued the e-mail with 
specific examples of multiple treatment and informed consent 
problems. To this e-mail Ms. Grethe replied, quote, at this 
point it is too late to change anything in the database. They 
filled it out with an informed consent date. And this is what 
we are going with. We are not changing this again. They screwed 
up. They will now have to take the blame. Also, if they keep 
changing their minds, then I really do not believe them now.
    Dr. Chew, what should Ms. Grethe have done in response to 
this e-mail?
    Dr. Chew. Congressman, I saw that e-mail. It was difficult 
to know specifically which sites and which patients were 
discussed. With hindsight of course I think that more 
information could have been found out. I'm just inferring now 
that there probably were differences in documentation and 
inconsistencies in correspondence. And it's my inference that 
they, the team, went with the best documentation they had.
    Mr. Markey. Is she still with Aventis?
    Dr. Chew. Ms. Nadine Grethe is no longer with Aventis.
    Mr. Markey. And why did her separation occur?
    Dr. Chew. I'm not quite clear, but I believe it was for 
other professional opportunities, to my knowledge.
    Mr. Markey. What has Aventis done to make sure that these 
kinds of errors do not recur in conjunction with future 
studies?
    Dr. Chew. There has been a tremendous effort in looking at 
the lessons of 3014. Investigator selection, investigator 
training, investigator retraining, especially if they're naive. 
One of the issues of this trial is it enrolled so fast. It was 
24,000 patients in 3 months, one winter season, to catch the 
infections. This was reviewed with FDA. One winter season was 
felt to be adequate. One of the issues with such a large trial 
when it is recruiting so fast is the monitoring of these sites 
has to be on top of the situation. And when you look at the 
monitoring plan, which was designed for a typical controlled 
clinical trial, not a real world study, immediately I saw that 
there was a disconnect. Most of the patients had been 
randomized in the 3-month period before the monitoring could 
get on top of it. So one of the things we've done now is to 
control the rate of enrollment and put a cap on the enrollment. 
And you don't go above that cap until you've been validated 
that you have good quality data that has been looked at 
internally.
    So the quality has to keep up with the quantity. That's one 
of the key things. You see in this trial there was not a cap. 
There was a recommendation. Now there's a cap. And so that we 
go lockstep, quantity and quality. So that's one of the big 
things. Training, new SOPs and just a heightened awareness. 
Fraud is a very uncommon issue.
    Mr. Markey. Well, in light of your experience could this 
sort of situation happen again?
    Dr. Chew. I will never say never, but I will say we will 
take all that's humanly possible to minimize the chance of this 
happening again. I think fraud--we heard this morning fraud is 
something that does occur. But we're going to minimize the 
scope, the scope, of this. And also not only fraud, but its 
serious GCP noncompliance. That's not fraud, but that's enough, 
that's enough, in retrospect that I wished Aventis had called 
FDA to share their concerns and some more clarity on the 
threshold, and it may be difficult, the threshold of contacting 
to not be burdensome to the agency, but to be responsive to 
problems. That's an area that I think the industry would 
appreciate some guidance on.
    Mr. Markey. Well, I think you're going to get all the 
guidance you need going forward, and this committee will 
provide that guidance for you and for other companies that will 
perhaps be in doubt as to what their responsibility is once 
potential fraud is identified to disclose it in a reasonable 
fashion so that the public health is protected. And I thank 
you, Mr. Chairman, for allowing me to participate.
    Mr. Stupak. Thank you, Mr. Markey. Dr. Chew, let me ask you 
this. Do you think PPD did a good job for Aventis?
    Dr. Chew. Looking back, I think PPD did a good job for 
Aventis.
    Mr. Stupak. How about Copernicus, did they do a good job 
for Aventis?
    Dr. Chew. It would be harder for me to say because the 
documentation of the exchange between Copernicus and Aventis at 
that time was not--I didn't see an awful lot of documentation.
    Mr. Stupak. Should Copernicus have let you know about the 
89 or 83 complaints they had?
    Dr. Chew. Well, the memos to file, they came from Aventis. 
In other words, Aventis notified them.
    Mr. Stupak. So you knew about it?
    Dr. Chew. Those memos to file were sent to them.
    Mr. Stupak. Did you expect the IRB, Copernicus here, then 
to notify the FDA?
    Dr. Chew. Well, in hindsight I--looking back, I mean I 
would have expected Copernicus not to have, because it was the 
feeling when I----
    Mr. Stupak. Who does Copernicus work for, the patients or 
for you?
    Dr. Chew. The patient's safety is the IRB responsibility. 
So the ultimate responsibility, as it is with the sponsor, is 
patient safety.
    Mr. Stupak. OK. 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? Didn't you have a cardiac toxicity here, too; three 
toxicities, eye, liver and heart, right?
    Dr. Chew. Again, in this trial----
    Mr. Stupak. Did you contact the patients?
    Dr. Chew. The patients were not contacted beyond the trial 
because half the trial was another drug for which you could 
compare.
    Mr. Stupak. OK. Well, how about the 12,000 then on Ketek, 
did you contact them?
    Dr. Chew. The 12,000 patients were filed before the trial, 
but they were not contacted to my knowledge after the trial was 
over, unless they had an ongoing adverse event.
    Mr. Stupak. OK. How do you know if they're having an 
ongoing adverse event if you don't contact them?
    Dr. Chew. The study protocol had a 5- or 10-day treatment, 
but then there was a 35-day or 27- to 35-day follow-up well 
beyond the existence of the drug in the body.
    Mr. Stupak. How many of the people, 12,000 people, who were 
supposed to receive Ketek, how many actually received it?
    Dr. Chew. The details I would have to get back to you on.
    [The information was not submitted for inclusion in the 
record.]
    Mr. Stupak. Give me an estimation, how many actually 
received it?
    Dr. Chew. I'm guessing that those who were assigned more 
than, I'm just guessing, but that there would be 90 percent or 
more.
    Mr. Stupak. 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?
    Dr. Chew. I don't know, and that's because we didn't talk 
to the patients. Aventis at that time did not speak with the 
patients to see if they actually had received the drug.
    Mr. Stupak. OK. Go to the binder book. Ms. Price, if you 
could hand that down. Mr. Markey read parts of Exhibit No. 21 
to you. That was the memo there from Nadine Grethe, who you 
said is no longer with Aventis. At this point it is too late to 
change anything databased. They filled it out with an informed 
consent date and that is what we're going with. We are not 
changing this again. They screwed up. They will have to take 
blame. And also if they keep changing their minds then 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, 
did you not, in Ketek and in your different sites?
    Dr. 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.
    [The information was not submitted for inclusion in the 
record.]
    Mr. Stupak. OK. So after this e-mail you went through to do 
an audit to see what was going on with Ketek, right, with this 
study?
    Dr. Chew. There 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 
would have to kind of get the actual dates.
    Mr. Stupak. Let's go to Exhibit No. 26 right there in front 
of you. Now, this is an audit by Aventis auditors, is it not?
    Dr. Chew. Yes. It appears to be, yes.
    Mr. Stupak. And the date of the original message is 
Tuesday, October 29, 2002, correct?
    Dr. Chew. That's right.
    Mr. Stupak. So this is about 3 or 4 months after Exhibit 
No. 21, right, when you're concerned about it?
    Dr. Chew. That's right.
    Mr. Stupak. And what you did, you did an audit of the sites 
that had enrolled more than 100 subjects in this Ketek Study 
3014, correct?
    Dr. Chew. In this listing, yes.
    Mr. Stupak. In every one of them, if you turn to the next 
page starting with Dr. Gardner, Dr. Anne Kirkman-Campbell, Dr. 
Lang, Dr. Shoemaker, Dr. Price, Dr. Tenscal, Dr. Stone, Dr. 
Blanchard, Dr. Glice, Dr. Resnick, they all had significant 
problems as to the review of your own auditor, Aventis auditor, 
significant problems, correct?
    Dr. Chew. Yes.
    Mr. Stupak. And not just the informed consent, but 
significant problems that required corrective action this 
auditor said, right?
    Dr. Chew. Yes, corrective action.
    Mr. Stupak. Right. It said in every one of them significant 
issues that require corrective action. What corrective action 
did Aventis take?
    Dr. Chew. Without commenting specifically on each site and 
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 completed. The monitoring at the 
time and the auditing at that time was to document what was 
found.
    Mr. Stupak. Significant problems were found.
    Dr. 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 the problem you have now, but for 
future patients. To my knowledge, probably most of the patients 
had already come and gone.
    Mr. Stupak. Sure. But let's get to the basis here.
    Dr. Chew. Yes.
    Mr. Stupak. Based on 21 you had a problem. In June of 2001 
you knew there was a problem based upon Exhibit No. 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?
    Dr. Chew. The request was to get additional safety 
information.
    Mr. Stupak. Right. So you do this large study. You say you 
have to do it during the flu season so you enroll 24,000 
people. You use these sites all around the country, 1,800 
sites.
    Dr. Chew. That's right.
    Mr. Stupak. And you audit 10 sites, right? Usually you do 
10 percent of your sites, do you not? Isn't that the general 
standard?
    Dr. Chew. I don't know what the algorithm is, but it's more 
than 10.
    Mr. 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?
    Dr. Chew. Well, I don't agree that it would have been 180, 
but it would have been more than 10. They should have done more 
than 10, in my view.
    Mr. Stupak. The point is you only audited 10 sites, 10 of 
the sites with the most patients in, correct?
    Dr. Chew. They were the high enrolling sites, yeah.
    Mr. Stupak. Correct, the high enrolling sites. So you did 
10. You didn't audit any other sites, they did just 19, right?
    Dr. Chew. The monitoring was done of course more 
extensively, but the audit was on 10.
    Mr. Stupak. Only 10 sites. Those 10 sites with the high 
enrollment patients, right, high enrollment patients in these 
sites, these are ones you audited. And this is October 29, 
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?
    Dr. Chew. There were issues found that needed corrective 
action, correct. I think there are varying degrees of 
intensity.
    Mr. 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 in the audit significant issues requiring 
corrective action. Dr. Lang, significant issues that require 
corrective action. Dr. Shoemaker, a significant issue that 
required corrective action.
    Dr. Chew. I agree.
    Mr. Stupak. So the whole basis of your safety study in your 
audit showed that you had significant issues that required 
corrective action, correct?
    Dr. Chew. These were 10 sites that were audited.
    Mr. Stupak. These are the only 10 you did, right? In fact 
you could ask the question, all the sites you monitored you 
found significant issues that required corrective action, isn't 
that right?
    Dr. Chew. Not all the sites monitored had significant GCPs 
that required action.
    Mr. Stupak. Well, you just said that you only did 10 sites.
    Dr. Chew. I'm talking about the monitoring.
    Mr. Stupak. I'm not talking about the monitoring. Don't 
confuse this here. We're talking about the audit.
    Dr. Chew. Of the audits, yes.
    Mr. Stupak. Aventis only audited 10 sites in this big study 
and every one of them had significant issues that required 
corrective action, correct?
    Dr. Chew. They had significant GCP issues that required 
corrective action, that's correct.
    Mr. Stupak. So how in good conscience could Aventis submit 
the study when every one of the audit sites there were 
significant problems to the FDA to show the safety of Ketek?
    Dr. Chew. My answer to that, Congressman, is that to my 
knowledge these actions were not ignored, they were discovered 
and they were corrected and documented. Not all of them 
affect--to my knowledge, not all of them bore on the safety 
issue of Ketek.
    Mr. Stupak. Well, really? Significant issues that require 
corrective action? The study is 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 audited. 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--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? Why would you do that?
    Dr. Chew. It's my belief that these problems were 
identified and documented by the audit and subsequently 
corrected and documented.
    Mr. Stupak. How can you correct it? The flu season is done, 
the Ketek is over, you said they didn't have any more time. 
Ketek is over. These patients aren't getting it any more. And 
these are the only patients you relied upon for the safety of 
the study that present to the FDA. How can you correct it?
    Dr. Chew. The issues were documented and corrective action 
was taken in terms of documentation. You're right, the patients 
had come and gone.
    Mr. Stupak. Yeah. How do you document blood splitting?
    Dr. Chew. I'm sorry?
    Mr. Stupak. How do you correct blood splitting? 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?
    Dr. Chew. To my knowledge there was no--in these cases 
there was no evidence of blood splitting.
    Mr. Stupak. Dr. Kirkman-Campbell had blood splitting.
    Dr. Chew. But Dr. Kirkman-Campbell had the suspicion of 
blood splitting. Both PPD and Aventis did statistical analyses 
that were not conclusive, that were not conclusive in terms of 
the blood splitting, to my knowledge.
    Mr. Stupak. Ms. Price, did Copernicus check Dr. Kirkman-
Campbell about blood splitting?
    Ms. Price. No, sir.
    Mr. Stupak. No, you didn't, did you?
    Ms. Price. Excuse me?
    Mr. Stupak. Blood splitting where you use blood from 
different--you didn't check that, did you?
    Ms. Price. No sir, that's not our role.
    Mr. Stupak. How about you, Dr. Eshelman? Did the PPD check 
for blood splitting?
    Mr. Eshelman. I believe that we turned up the suspicion of 
blood splitting.
    Mr. Stupak. Did you go back and check it to verify it to 
make sure it didn't have any effect----
    Mr. Eshelman. Dr. Reynolds reviewed all of these cases, and 
I believe that Dr. Reynolds talked to someone at Aventis. I 
can't swear to 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 a 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.
    Mr. Stupak. So they didn't do the blood splitting, they 
didn't check it, so Aventis checked it and that was OK?
    Dr. Chew. There is I believe an e-mail 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.
    Mr. Stupak. OK. Let me ask you this. You hired Dr. Kirkman-
Campbell, right, Aventis?
    Dr. Chew. To my knowledge, the investigator selection was 
the responsibility of PPD.
    Mr. Stupak. Dr. Eshelman, did you hire Kirkman-Campbell 
then?
    Mr. Eshelman. The answer to your question is I don't know. 
My recollection is that the----
    Mr. Stupak. I love it. The main person and no one knows who 
hired her. It's amazing.
    Mr. Eshelman. If you would let me finish.
    Mr. Stupak. Yeah, sure. I'm trying to, but my disbelief is 
just overwhelming me. Go ahead.
    Mr. Eshelman. 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 list. I believe that we had some 
investigator list. 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.
    Mr. Stupak. OK. PPD was hired by Aventis to monitor Study 
3014 and detect noncompliance, isn't that correct, Mr. Chew?
    Dr. Chew. They were hired to monitor the study and of 
course to transmit to Aventis the findings.
    Mr. Stupak. Several of the PPD personnel involved in Study 
3014 informed the committee staff that they were reasonably 
sure that Kirkman-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. Chew. I just have a personal opinion on that, because I 
don't know if there is 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 is a legal answer to that. 
That would be my personal opinion.
    Mr. Stupak. Dr. Eshelman sort of indicated that there is a 
contractual obligation that they could not do that. You 
disagree with that or----
    Dr. Chew. Well, I think that by contract there are 
usually--assignment who does what. But in most cases if there 
is a problem, you agree on who does what and you do it. That is 
the way I would do it.
    Mr. Stupak. So did you require that--did Aventis require 
PPD not to report any problems?
    Dr. Chew. I am not quite sure, but I think it is my 
recollection that Aventis had the regulatory liaison contact. 
Just to keep things clear, who was doing what.
    Mr. Stupak. But as far as Aventis was concerned, Copernicus 
could notify the FDA, PPD could notify the FDA----
    Dr. Chew. Again, I am speaking individually. If there were 
an issue, I think what would happen--I am just hypothetically--
is that Copernicus or PPD would discuss this, and there would 
be a resolution as to who does what. That has been my 
experience that usually there is consensus.
    Mr. Stupak. How about Aventis? Did you ever notify the FDA 
that you had trouble with this Study 3014? Did you ever sit 
down----
    Dr. Chew. Yes, we did. Yes, we did.
    Mr. Stupak. When was that?
    Dr. Chew. I believe in June of 2002, I believe, prior to 
the filing, when there were two sites who persistently refused 
to cooperate.
    Mr. Stupak. 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 
sites?
    Dr. Chew. To my knowledge, the two that were notified did 
not cooperate. I am assuming, and would have to look 
individually, that these sites were probably cooperative in 
coming into documentary compliance.
    Mr. Stupak. After your audit, tab number 26.
    Dr. Chew. It could have been after the audit or the 
monitoring, because the monitoring was in parallel.
    Mr. Stupak. OK. At any time after tab 26, October of 2002, 
did Aventis contact the FDA and tell them, We have trouble with 
this Study 3014 and it may be based on fraudulent activities?
    Dr. Chew. To my knowledge, the team that was looking at 
this felt that they had addressed many of the issues of GCP 
noncompliance. And when the auditor came from FDA to look at 
Dr. Kirkman-Campbell's site specifically over a 9-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.
    Mr. Stupak. Great. But my question was did Aventis, after 
October of 2002, notify the FDA of problems? We are not just 
talking about Kirkman-Campbell. October of 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. Chew. To my knowledge--and I would have to review--I 
don't think so.
    Mr. Stupak. OK. Where does your responsibility come in, 
then, when you appear before the FDA and the FDA advisory 
committee, to tell the FDA that you have had significant 
problems with the 10 sites--the only sites you audited, all 10 
of them had significant problems that needed corrective 
action--when is it your responsibility to let the FDA know?
    Dr. Chew. Are you talking about hypothetically or this 
specific trial?
    Mr. Stupak. I am talking about Aventis here and on this 
Ketek. When did you have that responsibility?
    Dr. Chew. Of course, we do things differently now with the 
new company.
    Mr. Stupak. I know everyone does everything different now, 
but----
    Dr. Chew. But at that time, at that time it is my 
understanding the company reviewed these issues with the site, 
had documented these errors, again in retrospect, and in other 
words they had addressed the issues as best they could in a 
retrospective fashion.
    Mr. Stupak. Dr. Chew----
    Dr. Chew. Yes.
    Mr. Stupak. The answer is just that. Look. After October of 
2002, you did nothing to notify FDA of the problems with the 
integrity of Study 3014. Did Aventis? They did not, did they?
    Dr. Chew. I believe Aventis felt that the trial had 
integrity.
    Mr. Stupak. That's not what I asked. OK. You think this 
is--you believe this has integrity, this 3014 has integrity?
    Dr. Chew. I am sorry, could you repeat that? I am sorry.
    Mr. Stupak. Sure. After October 2002----
    Dr. Chew. Yes.
    Mr. Stupak [continuing]. After your audit, 10 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. Chew. The FDA had opened up a criminal investigation.
    Mr. Stupak. That's not what I asked.
    Dr. Chew. But to my knowledge, there had been no 
notification, because it is my review of the record that these 
issues with these other sites had been addressed in terms of 
memos to file. An inadequate approach----
    Mr. Stupak. Memo to file from who, Aventis to Aventis?
    Dr. Chew. The memos to file would usually be the 
investigator going to the file.
    Mr. Stupak. In other words, your investigators going to 
your files?
    Dr. Chew. No, this would be at the site. So that they could 
be audited and reviewed by auditors. The specific point being 
to have the documentation.
    Mr. Stupak. They could be. But what is your responsibility 
here? October 2002, 10 sites, every one significant problems, 
need corrective action. Did you notify the FDA about that? 
That's all I am asking you.
    Dr. Chew. At that time, the answer, to my knowledge, is no.
    Mr. Stupak. OK. So even though you submitted this study, 
you never told the FDA that of the 10 sites that were audited 
you had significant issues with?
    Dr. Chew. It is my understanding that these issues had been 
addressed at the time they were documented at previous 
monitoring.
    Mr. Stupak. Who addressed these issues? Aventis, right?
    Dr. Chew. Typically, the PPD would identify these issues, 
report them to Aventis, and the site would be instructed to 
document what had happened.
    Mr. Stupak. Sites were already closed. We have established 
that. That is already closed.
    Dr. Chew. When it came to the monitoring, as usual in any 
trial when there is monitoring, the issues have to be fixed and 
corrected. The enrollment had stopped, but the sites may still 
have been in the process of regulatory and document assembly. 
So we have to separate out the enrollment of patients, which is 
3 months, and the monitoring that went on for much longer, 
obviously.
    Mr. Stupak. Why do you do an audit?
    Dr. Chew. The audit is to generally look at processes to 
see if the processes have been fulfilled.
    Mr. Stupak. And of these 10 audits, every one of them 
failed.
    Dr. Chew. Of these high enrolling sites, there were 
significant issues requiring action.
    Mr. Stupak. Isn't an audit to help determine the integrity 
and the quality of the study you are doing?
    Dr. Chew. There is more than auditing to do that, but 
auditing is part of it.
    Mr. Stupak. Correct. And you batted 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 are doing?
    Dr. Chew. 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 is my understanding----
    Mr. Stupak. What was your revenue, what was Aventis's 
revenue from Ketek back in 2005?
    Dr. Chew. I would have to find that out.
    Mr. Stupak. 264 million sound right?
    Dr. Chew. I would have to document that.
    Mr. Stupak. You have any reason to dispute 264 million?
    Dr. Chew. No, I just have no primary knowledge of that 
number.
    Mr. Stupak. I see. A year ago the FDA finally removed 
bronchitis and sinusitis from the labeled indications for 
Ketek, leaving only pneumonia as an authorized use for the 
drug. Is that correct?
    Dr. Chew. That's correct.
    Mr. Stupak. Is Sanofi-Aventis still detailing the drug to 
doctors?
    Dr. Chew. To my knowledge, no, there is no promotion.
    Mr. Stupak. OK. 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 had seen in 25 years. How did your auditors miss the fraud 
there at Kirkman-Campbell?
    Dr. Chew. 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.
    Mr. Stupak. Right. And did you disclose all that to the 
FDA?
    Dr. Chew. Well, no. The answer is no because the issues 
were addressed and documented for the file. And it is my 
knowledge that this was also documented by the 483 that was 
issued on October 24th by the FDA auditor.
    Mr. Stupak. I asked the other investigators, I guess it is 
only fair to ask you--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 date, since the approval was, I believe, 
April 1st, 2004 for Ketek?
    Dr. Chew. That's correct.
    Mr. Stupak. And if that approval is based upon fraud, 
fraudulent Study 3014, do you think Aventis is liable then for 
fraud?
    Dr. Chew. Can I answer that by it's my understanding that 
FDA did not rely on 3014 for its approval, having 14 clinical 
trials, also having the German registry, and at that time 4 
million patients' use. So it is my understanding that 3014 was 
not used.
    Mr. Stupak. But Aventis, in submitting Study 3014 to the 
advisory panel, which I believe was on March 25th--not 
advisory, the advisory----
    Dr. Chew. September 15th and 16th, 2006.
    Mr. Stupak. OK, January. Why did you present Study 3014 to 
show the efficacy and the safety----
    Dr. Chew. Are you talking about the second advisory 
committee? Is that right? 2003?
    Mr. Stupak. Yes. Yes.
    Dr. Chew. Right.
    Mr. Stupak. Why did you submit 3014, which showed the 
efficacy and the safety of Ketek, was it not, for bronchitis, 
for sinus, and for pneumonia, correct?
    Dr. Chew. The primary was safety. Efficacy had been 
established according to the first advisory committee with the 
14 pivotal trials of phase 3 and those three indications.
    Mr. Stupak. OK. So you submitted for safety. Correct?
    Dr. Chew. Yes.
    Mr. Stupak. OK. And if there is 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 
safety of Study 3014?
    Dr. Chew. I can't comment on this legal term. I am not 
competent to do that. But at the time of the submission, it is 
my review, that Aventis felt that this was a trial that was 
useful and that the issues of good clinical practice had been 
addressed.
    Mr. Stupak. Useful. You said useful. But when you 
submitted, you thought that Study 3014 showed the safety of 
Ketek.
    Dr. Chew. At that time----
    Mr. Stupak. Yes.
    Dr. Chew [continuing]. It is 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.
    Mr. Stupak. And it was submitted for the verification of 
the safety of Ketek for these three problems: sinus, pneumonia, 
bronchitis.
    Dr. Chew. It was to get additional information as part of 
other experiences, but it was to provide a large safety 
experience for Ketek in those three indications, compared to a 
commonly used antibiotic.
    Mr. Stupak. Mr. Shimkus for questions.
    Mr. Shimkus. Thank you, Mr. Chairman. And I am not going to 
be that long. You have spent a lot of time.
    Mr. Stupak. I have more questions.
    Mr. Shimkus. I am sure here they are waiting for them, too.
    I do want to follow up with what the Chairman mentioned, 
the 10 sites out of 1,800 sites. You know, when we in any--I 
have got an engineering background to some extent, although I 
am a politician. And polling is an important aspect of our job 
and what we do. Of course we are having a lot of polling now 
with the Presidential race. There are legitimate polls and 
there are illegitimate polls, and it is based upon how really 
the science is conducted by the sample size, the randomness, 
and all the other aspects.
    Is there any such standard as to what is an acceptable 
universe of study on percentages when you have--this is for Dr. 
Chew--when you pull out 10 sites out of 1,800 sites?
    Dr. Chew. It is my feeling--I am not a statistician--there 
should have been more sites audited. The pattern in this case, 
though, of the 10 sites that were audited, is that they were 
chosen because of their higher enrollment. And high enrollment, 
as you might suspect, is where people who might commit fraud, 
especially for monetary gain, may be concentrated. So it may 
not be truly a random sample of the 1,800 sites; it is 10 out 
of 1,800, but it is the high enrolling sites.
    Mr. Shimkus. Yeah. If all those sites had problems, then 
what does it tell you about the process of choosing the 10 
sites?
    Dr. Chew. About choosing? Well, I think it is more than 
choosing. It is the training, and it has to be more in time 
monitoring. You can't show up after the trial is over. So it is 
selection, training. These are all the things that are done 
now. And more in time monitoring. Putting a cap on enrollment. 
And you don't go above that cap until you have had your data 
validated.
    Mr. Shimkus. If we have identified, obviously, a problem, 
let's go back to the basic premise of the initial question 
again. A credible poll has to have a sample size over 300, has 
to be random, it has to go across the demographics of the 
particular area. You can't weigh it to one side over another. 
How do we get a credible scientific sample, or is there a 
formula by which we would be deemed legitimate?
    Dr. Chew. You are talking in general?
    Mr. Shimkus. Yeah. Because part of this is identifying this 
error.
    Dr. Chew. Right.
    Mr. Shimkus. But also part of oversight is identifying this 
error so we can make sure these errors do not happen in the 
future.
    Dr. Chew. Sure.
    Mr. Shimkus. So how do we make--how do we ensure that there 
is legitimate randomness and a sample size big enough that 
covers? I think most people would say 10--I guess the point is, 
a number of enrollees in a site may affect that, but still 10 
out of 1,800 sites, I think just a casual observer would say, 
well, no wonder there's problems.
    Dr. Chew. I am not a statistician. I don't think 10 is 
enough. This was not a random sample. This is where the high 
enrollers were. And I believe that the FDA also takes a similar 
approach, which is to go where the high enrollers are because--
--
    Mr. Shimkus. Just because the FDA does something doesn't--
--
    Dr. Chew. No, no, I am not saying. I mean that is where you 
are likely to find problems. It is not a random sample. I think 
a random sample, of course, would choose these sites randomly 
in terms of the demographics either by the type of doctor, the 
type of illness. It would probably have to be on a case-by-case 
basis and would have to be truly random, not skewed toward one 
end of the enrollment spectrum, because you may find the 
problems there but then attribute that to the whole sample.
    Mr. Shimkus. The other aspect, I was county treasurer at 
one time for 6 years. And one basic management principle is 
management by walking around, which means you walk around all 
your employees' offices, you visit with them, you see them, you 
see what is on their desks, you come at different times. 
Visiting 10 sites out of 1,800 sites on a research isn't really 
perceived--would be perceived as good management by walking 
around when you are talking about the health and welfare and 
the safety and the efficacy of drug testing. And so maybe there 
is an attempt or we need to be more specific on a formulary 
basis about where we have to be and in what numbers and in what 
percentages and the like.
    Dr. Chew. Well, you know, the auditing is to be different 
from the monitoring. And I did want to clarify that. Monitoring 
of these 1,800 sites was that--I believe 99.6 percent, a very 
high number of sites that recruited 15 or more were visited 
physically. And I believe that--and that accounts for 80 
percent of the patients.
    There were also weekly phone calls to all the sites, 26,000 
phone calls in this trial. And apart from the weekly status, 
there were additional phone calls, of course, as the need 
arose, to over 90,000 phone calls. And overall, I believe 
approximately 58 percent of the sites, more than 900 during the 
study, received on-site visits.
    Now, those are the statistics. But the issue was the trial 
recruited so fast that I believe most of the visits occurred 
after the randomization and treatment period had gone through. 
So monitoring ideally should be not only an educational 
training repair process for patients who have been through, but 
for patients yet to come. That did not occur in 3014, and that 
is what has been changed for the large trials that Sanofi-
Aventis is doing now--for all trials that Sanofi-Aventis is 
doing now.
    Mr. Shimkus. If these 10 were the top sites, if they were 
the top sites you could almost conclude that most sites had 
problems, then.
    Dr. Chew. Well, I think it is hard to say that, because it 
is the expectation that the high enrolling sites, if there is 
monetary reward as the goal for the fast enrollment and the 
high enrollment, may concentrate or be where the issues may 
concentrate. It is not a random sample. It is everything but a 
random sample. It is the highest enrollers out of 1,800.
    Mr. Shimkus. When you get this information, what is the 
conclusion that you draw about the integrity of the whole 
thing? What would be the conclusion then?
    Dr. Chew. As I said, I think it is investigator selection, 
training, retraining, monitoring. And you got to get on top, 
you got to get on top----
    Mr. Shimkus. The conclusion would be the data integrity was 
not solid.
    Dr. Chew. The data integrity was looked at not only by what 
was found, but what was done about it. Now, as we said, what 
was done about it was to document in retrospect, because in 
most cases the monitoring occurred after the thing. So that if 
you had a high enrolling site, it is likely that you would not 
have gotten out there to stem the bad practice. So when you got 
there it would be documenting with memos to file. Not adequate, 
very helpful, but in this case not adequate because it was 
retrospective.
    Mr. Shimkus. Dr. Eshelman, I saw you nodding or showing 
some signs along this line of questioning. Is there something 
you want to add? What about data integrity? And what 
conclusions should have been drawn?
    Mr. Eshelman. No, sir, I didn't have anything to add on 
that particular issue. As it goes to data integrity. I think 
that is a case-by-case basis and determination made by the 
sponsor of the trial. I spent some time in big pharma prior to 
my CRO experience, so I am familiar with what goes on there as 
well, what the requirements are, what the standards are and so 
forth. And, you know, this case notwithstanding, it has always 
been my experience over the years that the sponsors, the CROs, 
everybody, is after data integrity. We know what we are here 
for. And the down side of not doing that is so steep that only 
a fool would go there, in my view.
    Mr. Shimkus. I would like to follow up with you on the 
monitoring plan for this Study 3014. Was there dedicated 
sufficient resources for the implementing of the program?
    Mr. Eshelman. By whom?
    Mr. Shimkus. By you.
    Mr. Eshelman. By PPD?
    Mr. Shimkus. Yeah.
    Mr. Eshelman. Actually, I was on the phone over the weekend 
with the person who was the project coordinator at PPD for this 
trial, and I put that very question to her. I said, Were you 
adequately resourced? And she said, yes, at the beginning of 
the trial that she felt like she was adequately resourced. We 
were resourced to the contractual requirements and so forth.
    But to Dr. Chew's point, I think certainly PPD, and it 
sounds like perhaps Aventis as well, underestimated the 
workload that was suddenly going to appear here because of the 
24,000 patients, how quickly they were randomized. And I think 
more importantly, perhaps in this instance, as it has to do 
with short-term therapy on an antibiotic, by the time some of 
the problems are identified and so forth, the therapy is so 
short that you really don't have time to make some corrections 
in real time. And therefore, you are doing it after the fact. 
This was also targeted monitoring.
    So by definition we were not going to look at every site in 
every case and so forth as you might do in a standard phase 3 
trial. So, you know, in retrospect, in some respects we were 
almost set up for some of these problems.
    Mr. Shimkus. And finally, on the resource question, did 
Aventis give you all the tools you needed to do your part?
    Mr. Eshelman. Yes. I think so.
    Mr. Shimkus. And let me just add--I am going to end with 
this, Mr. Chairman--back to Dr. Chew. I would like to discuss 
the research and development of antibiotics. Since Ketek's 
approval, how many antibiotics has Sanofi-Aventis developed or 
begun to develop?
    Dr. Chew. None. There may be something very early, but 
there is nothing in the late stage.
    Mr. Shimkus. Has the company's experience with this study, 
especially 3014 and the events thereafter, caused it to reduce 
its research and development efforts and develop new 
antibiotics?
    Dr. Chew. Well, I don't want to speak about the antibiotic 
program in general. Let me say that R&D has always been 
challenging. We realize that this is a heavily regulated 
industry, as it should be. I only got involved in this 
personally, because of my own commitment as a physician, to go 
beyond individual patient care to broader patient care. So we 
recognize the hurdles are high, and we have not reduced R&D 
development in general.
    Mr. Shimkus. Thank you, Mr. Chairman.
    Mr. Stupak. Thank you, Mr. Shimkus. Thanks for getting 
here. I know it has been a hassle today.
    Dr. Eshelman, if I say that right, adequately resourced; 
PPD was paid close to $30 million to do their work here, were 
they not?
    Mr. Eshelman. My recollection is the payment for direct 
costs was somewhere around 20, and the pass-through costs, in 
other words the payments to the physicians, were somewhere 
around 8. So ours was 20, investigators 8. That is my 
recollection.
    Mr. Stupak. OK. So $20 million to do it. What was your 
response--I asked Dr. Chew, it is probably better to ask you--
what was your responsibility as the contract research 
organization to report the sites to the IRB when there was 
suspicion of fraud or other problems with this study?
    Mr. Eshelman. I believe we have such responsibility. And it 
sounds like, from the testimony of Ms. Price, that in fact a 
lot of that reporting did occur.
    Mr. Stupak. OK. Nothing would have stopped PPD from 
alerting Copernicus, correct?
    Mr. Eshelman. No, sir. I am not aware of anything.
    Mr. Stupak. OK. Did you notify Copernicus of the 
irregularities and possible forgery found by PPD at the 
Kirkman-Campbell site?
    Mr. Eshelman. I assume that we did. And it certainly sounds 
like there were a number of memos and so forth. I can't comment 
factually on exactly what we communicated to Copernicus at any 
given time on the Kirkman-Campbell site, but I assume that this 
went on.
    Mr. Stupak. Well, Ms. Cisneros worked for you, right?
    Mr. Eshelman. Yes.
    Mr. Stupak. Made the first telephone call. And I think Ms. 
Price said 83 other complaints came from the Kirkman-Campbell 
site and other sites. Did you feel compelled, then, to notify 
Aventis about all these complaints?
    Mr. Eshelman. Yes, sir.
    Mr. Stupak. OK. How about the FDA? Did you feel compelled 
to tell the FDA?
    Mr. Eshelman. No, sir, not in this case, because of the way 
the contract read, number one. And number two, there was some 
debate over whether or not this was to the level of fraud. I 
think the issue of data integrity that goes along with how you 
present data to the FDA or otherwise is a determination that 
has to be made by the sponsor.
    Mr. Stupak. How can you say--in fact, Dr. Chew said the 
same thing--didn't know if it went to the level of fraud, when 
the complaint said errors on just about every informed consent, 
date modifications, initials different from signature, study 
coordinator entering date for subjects and principal 
investigator, blatantly forged signature on informed consent, 
medical records are very limited, use of different color ink on 
medical charts, overwrites, crossouts, inserts of diagnosis in 
different color ink, routine failure to give pregnancy tests to 
women of childbearing years, study investigator and coordinator 
unaware of the definitions of serious adverse events, no 
adverse events for the first 300 patients enrolled with drugs 
known to have adverse events, lab results indicating blood 
splitting, lack of proper diagnosis for study eligibility, 
husbands and wives being enrolled together, large number of 
patients randomized in the interactive voice response system in 
a short increment of time when the office was closed. I mean, 
how would that not indicate fraud?
    Mr. Eshelman. If I could cut to the chase here.
    Mr. Stupak. Yeah, please, I wish someone would.
    Mr. Eshelman. Had I known in detail at the time what was 
going on, I would have picked up the phone.
    Mr. Stupak. Whose responsibility is it? I mean we are 
hearing all these reports of all this stuff going on.
    Mr. Eshelman. It is mine. It is my responsibility.
    Mr. Stupak. OK.
    Mr. Eshelman. In fact, I did not have all the facts at my 
disposal at that time. Had I known what I know now, in 
retrospect I would have picked up the phone and I would have 
called--Dr. Chew wasn't there at the time, I don't think--but I 
would have called someone at Aventis at a high level of 
authority and expressed my concerns about this. And I believe 
that if that had occurred there may have been a different 
response out of Aventis.
    Mr. Stupak. You know Robert McCormick?
    Mr. Eshelman. Sure.
    Mr. Stupak. Isn't he your Vice President of Quality 
Management Systems?
    Mr. Eshelman. Yes.
    Mr. Stupak. He didn't talk to you about this? About all the 
problems?
    Mr. Eshelman. Not in detail about the Kirkman-Campbell site 
at the time.
    Mr. Stupak. Not just Kirkman-Campbell. Any of the problems 
with the----
    Mr. Eshelman. Certainly with Dr. McCloud.
    Mr. Stupak. OK. So you knew about it then?
    Mr. Eshelman. About Dr. McCloud? Yes, I did.
    Mr. Stupak. And about the other problems with Study 3014.
    Mr. Eshelman. No, sir, I did not know the magnitude of 
those problems.
    Mr. Stupak. So if Mr. McCormick said he informed you, that 
wouldn't be right?
    Mr. Eshelman. Informed me about what?
    Mr. Stupak. About the problems at Kirkman-Campbell and all 
the other issues involving this study, since you were the CEO 
of PPD.
    Mr. Eshelman. No, at the time, I don't think that's 
correct. I think subsequent to that it certainly is. It 
certainly is correct with respect to Dr. McCloud. He informed 
both myself and Dr. Covington. Mr. McCormick, Dr. Covington and 
myself were in total agreement about how the situation should 
be handled at Dr. McCloud's site. And in fact, we made a no-
name call to the FDA asking for guidance on that issue, and we 
never----
    Mr. Stupak. Just on McCloud. That's the only one you 
talked----
    Mr. Eshelman. Yes, sir. And we never got a response.
    Mr. Stupak. So when McCormick says, tells our staff that it 
is your policy, PPD's policy, to communicate significant 
complaints issues to you as CEO and that you are personally 
made aware of the large-scale irregularities and noncompliance 
of Dr. Kirkman-Campbell, that is not true?
    Mr. Eshelman. The policy is certainly correct.
    Mr. Stupak. OK.
    Mr. Eshelman. It is not my recollection that I knew in 
detail at the time about Kirkman-Campbell, nor is it my 
recollection that I understood and appreciated the magnitude of 
the overall issue.
    Mr. Stupak. Did PPD or anyone on your staff, did they 
recommend that Aventis call the FDA on these irregularities? 
Did you advocate--anyone from your company advocate to Aventis 
that they call the FDA on the irregularities on this study?
    Mr. Eshelman. I don't know the answer to that.
    Mr. Stupak. OK. Take a look at Exhibit No. 21. It is the 
one that Mr. Markey had asked about.
    Your employee, PPD's employee, is notifying the Aventis 
study manager, who is no longer with Aventis, that she is 
receiving conflicting information from sites, including 
subjects who were never receiving--who never signed informed 
consents, and subjects who were treated with a different drug 
than that indicated in the existing database.
    And the Aventis study manager says, well, we can't unlock 
the database. So is it ever acceptable to run with the data 
when you are unsure if the subject signed the consent form or 
if the data integrity issues that are listed here remained with 
the study?
    Mr. Eshelman. I think generally all of us in this business 
try to have a pristine database before we lock. So in other 
words, all of the outstanding queries have been answered and 
this and that and the other. If, however, you stumble across 
something post-lock that indicates that, in fact, your 
procedure was not robust, then generally speaking you unlock 
the database and you make whatever the corrections are.
    Mr. Stupak. But that didn't happen here. Did anyone unlock 
the database?
    Mr. Eshelman. I don't know. I am sorry, I don't know.
    Mr. Stupak. Shouldn't this e-mail have sent a red flag to 
your company that Aventis was not acting in good faith?
    Mr. Eshelman. I don't know. I mean I am just not qualified 
to say. I don't know--I don't have any idea what was going on 
at Aventis.
    Mr. Stupak. OK. But this is your employee, right?
    Mr. Eshelman. Yes.
    Mr. Stupak. Who wrote this?
    Mr. Eshelman. Yes, sir.
    Mr. Stupak. Shouldn't you have done something about it, 
PPD? You have people that were allegedly in here, but they have 
no informed consent. This questions the integrity of the study.
    Mr. Eshelman. It is not our responsibility to dictate to a 
client what they do or do not put into a submission, nor is it 
our responsibility generally to dictate to them how they do 
their analyses.
    Now sometimes, as you know, there will be two sets of 
analyses. There will be an intent to treat that has everybody 
that ever received the drug, no matter what. OK. And then there 
will be what we would call a primary set of efficacy and safety 
data on----
    Mr. Stupak. And this would deal with the primary set of 
efficacy and safety with this drug, are we not? That was the 
purpose of this study.
    Mr. Eshelman. Ordinarily, that's the set of data upon 
which----
    Mr. Stupak. This study right here. It is safety, right? 
Wasn't it the main purpose for the study?
    Mr. Eshelman. Yes, sir.
    Mr. Stupak. OK.
    Mr. Eshelman. But the primary database, the one that you 
think is clean, would be the one that ordinarily I think a 
regulatory body would rely upon if they were going to rely upon 
the study. And it is my understanding they didn't even rely on 
this study.
    Mr. Stupak. So what are you saying, you keep two sets of 
books, you give the FDA the one that's the best for your drug?
    Mr. Eshelman. No, sir. You give them both the analyses. 
This is standard practice. Because we want to be sure that we 
fully report everybody that got the drug for safety purposes. 
For that very reason, you report all of them.
    Mr. Stupak. But if people in your study did not receive the 
drug and there is no informed consent, doesn't that question 
the integrity of the study?
    Mr. Eshelman. Yes, sir, and therefore there might be more 
than one analysis done.
    Mr. Stupak. And therefore shouldn't PPD have done something 
about it, then, since your own employees questioned the 
integrity of the study?
    Mr. Eshelman. I don't know what we would have done. We 
weren't responsible for the submission.
    Mr. Stupak. What is your responsibility then?
    Mr. Eshelman. Our responsibility was to monitor and to 
report to the sponsor.
    Mr. Stupak. So outside that, you have no obligation to 
report to the FDA or anything else that there is some question?
    Mr. Eshelman. Not in terms of what was sent in a 
submission. Number one, we would have no way of knowing that.
    Mr. Stupak. And if you think there's questions about the 
integrity of data that's going to be submitted to the FDA for 
drug safety, you have no responsibility to contact the FDA and 
say, Hey, take a closer look at this? I guess it's more an 
ethical question.
    Mr. Eshelman. Obviously, if we were in a situation where we 
thought a sponsor was doing something egregious and they wanted 
us to be party to that, that would not happen.
    Mr. Stupak. OK. I am not asking to be a party, but if you 
have knowledge that could go to the question of veracity of the 
study, that goes to the safety of a drug, do you have a 
responsibility then?
    Mr. Eshelman. But it wasn't our determination to make, Mr. 
Chairman.
    Mr. Stupak. By choice or by contractual obligation?
    Mr. Eshelman. I think by contractual obligation. I mean we 
just weren't assigned that responsibility.
    Mr. Stupak. How about company ethics then? Your first 
bullet in PPD's mission statement says, as it says on your Web 
site: We will work with pride and unwavering integrity to help 
our clients accelerate delivery of safe and effective 
therapeutics to patients.
    In this case do you think you lived up to that mission 
statement? Don't you think you had a responsibility for safe 
and effective therapeutics to patients?
    Mr. Eshelman. I think under the conditions, we absolutely 
did our job in trying to identify departures from GCP, and data 
integrity issues, and, to some extent, fraud. I think Aventis 
did so as well with all of their checks and their audits and so 
forth and so on. To me, the issue of what did or did not get 
into a submission is--it is related, but it is a different 
issue.
    Mr. Stupak. Well, I guess it is just not me thinking this. 
If I may go to Barron's newspaper on November 12th, 2007, it 
reported that PPD, unlike many CROs, is willing to take a stake 
in some drugs being tested in exchange for free or cut-price 
monitoring service. Does that put you in a dangerous conflict-
of-interest position? That is, you are essentially monitoring a 
drug in which you have a financial interest?
    Mr. Eshelman. Well, first of all, I don't agree with all of 
that statement in Barron's. We don't do anything in exchange 
for cut-rate monitoring. I don't know what that means.
    But in terms of monitoring studies where we have a 
financial interest in the drug, I really don't see how that is 
different from any sponsor monitoring studies because, you 
know, the drug came out of their research. So I don't see how 
that is any different.
    Mr. Stupak. But don't you have the--isn't PPD's duty, one 
other duty in this and in 3014 was to train and select 
qualified investigators for the study?
    Mr. Eshelman. Certainly to select. We were not responsible 
for the training. That was another third-party vendor.
    Mr. Stupak. OK. OK. Were you familiar with the Barron's 
newspaper report, ``The Very Pictures of Health,'' by Jay 
Palmer, dated November 12th, 2007, in which they mentioned PPD, 
unlike other CROs, take a financial interest----
    Mr. Eshelman. I can't say that I was, because I might have 
called them up and taken exception to their statement.
    Mr. Stupak. OK. I have nothing further. Mr. Shimkus, 
anything further?
    Mr. Shimkus. No, I don't.
    Mr. Stupak. OK. Then we will excuse this panel. Thank you 
all for coming today. That concludes all the questioning. I 
want to thank all the witnesses for coming here today, and for 
their testimony and their information they provided us.
    I would note that I am troubled by a number of the answers 
we have heard today. And accordingly, we will be considering 
referral of some of the materials to the FDA and to the 
Department of Justice. I don't think it is just this panel. I 
think it was all the panels. We had troubles with these 
witnesses. Overall, I thought it was a good hearing, but many 
of us here are very troubled at what we heard today.
    So with that, I will ask for unanimous consent that the 
record remain open for 30 days for additional questions for the 
record. Without objection, the record will remain open.
    I ask unanimous consent that the contents of our document 
binder be entered into the record. Without objection, documents 
will be entered into the record.
    That concludes our hearing. And, without objection, this 
meeting of the subcommittee is adjourned.
    [Whereupon, at 3:39 p.m., the subcommittee was adjourned.]
    [Material submitted for inclusion in the record follows:]

    [GRAPHIC(S) NOT AVAILABLE IN TIFF FORMAT]


                                 
