[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
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48-587 WASHINGTON : 2008
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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
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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?
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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:]
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