Fraud

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Fraud Misconduct at Investigator Sites

• Paul Below
• Clinical Research Trainer
• Medical Research Management
• Red River Valley Chapter ACRP
• Fargo, ND
• January 18, 2007

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Disclosure Disclaimer

• I have a consulting relationship with the
  following companies
• MGI Pharma (project management)
• Medical Research Management (training)
• The views expressed here are my own and not
  necessarily those of the clients listed above or
  of the Minnesota Chapter ACRP. I am solely
  responsible for the content of this presentation.

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Presentation Topics

• Definition of fraud
• Prevalence
• Famous cases
• Consequences
• Reasons why fraud occurs
• Warning signs/identifiers
• Detection strategies
• Fraud prevention

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FDA Definition of Fraud

• Falsification of data in proposing, designing,
  performing, recording, supervising or reviewing
  research, or in reporting research results
• Falsification includes both acts of omission
  (consciously not revealing all data) and
  commission (consciously altering or fabricating
  data)

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Fraud Definition (cont.)

• Fraud does not include honest error or honest
  differences in opinion
• Deliberate or repeated noncompliance with the
  protocol and GCP can be considered fraud, but is
  considered secondary to falsification of data

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Who Commits Fraud?

• Investigators
• Study coordinators
• Data management personnel
• Lab personnel
• IRB staff
• CRAs and sponsor personnel
• FDA

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Who Gets Blamed?
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Source FDA Presentation, DIA 2000
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Prevalence of Fraud

• Difficult to determine but still considered rare
• Reported to significantly impact 1-5 of
  pharmaceutical clinical trials F. Wells,
  Reuters Health, January 2002
• Only 3 of FDA inspections uncover serious GCP
  violations resulting in Warning Letters

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Prevalence of Fraud (cont.)

• Survey of over 3000 NIH-funded scientists
  published in Nature (June 9, 2005) One in
  Three Scientists Confesses to Having Sinned
• 1.5 acknowledged falsification or plagiarism
• 15.5 admitted changing design or results in
  response to pressure from a funding source
• 12.5 admitted to looking other way when
  colleagues used flawed data

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Famous Cases - Investigators

• Robert Fiddes, MD Private practice, Whittier, CA
  1997
• Richard Borison, MD and Bruce Diamond, PhD
  Medical College of Georgia 1998
• Michael McGee, MDUniversity of Oklahoma, Tulsa
  2000
• Maria Kirkman (aka Ann Campbell), MDPrivate
  practice, Alabama 2003

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Robert Fiddes, MD Of Mice and Men, 60
Minutes, April 1, 2001
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Case Study - Dr. Fiddes

• Dr. Fiddes was president of a clinical research
  company in Whittier, CA
• Conducted over 200 studies beginning in the early
  1990s
• Engaged in extensive fabrication and
  falsification of data

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Dr. Fiddes (cont.)

• Removed exclusionary data from medical history in
  patient charts
• Made up fictitious study subjects
• Fabricated lab results by substituting clinical
  specimens and manipulating lab instrumentation

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Dr. Fiddes (cont.)

• Feb. 1997 Staffers blows the whistle and FDA
  special agents storm the site
• Aug. 1997 plead guilty to felony charge of
  conspiracy to make false statements to the FDA
• Sept. 1998 sentenced to 15 months in federal
  prison and ordered to pay 800,000 in restitution

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Dr. Fiddes (cont.)

• June 1999 disqualified as a clinical
  investigator by FDA
• Mar. 2000 medical license revoked
• Nov. 2002 debarred by FDA along with three
  study coordinators

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Dr. Fiddes and staff on the FDA Debarment List
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Federal Register Notice for Study Coordinator
Debarment
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Richard Borison, MD Drug Money, 48 hours,
July 31, 2000
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Richard Borison, MD Drug Money, 48 hours,
July 31, 2000
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Bruce Diamond, PhD Drug Money, 48 hours, July
31, 2000
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Bruce Diamond, PhD The Lessons of Greed,
PharmaVOICE, July 2004
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Famous Cases - Coordinators

• Anne ButkovitzPediatric private practice,
  Newton, MA 2005
• Paul KornakStratton VA Medical Center, Albany
  2005

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Paul Kornak Abuses Endangered Veterans in
Cancer Drug Experiments, New York Times,
February 6, 2005
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Consequences of Fraud

• Sponsor data validity compromised, submission
  jeopardized, additional costs
• Investigator fines, legal expenses,
  disqualification/debarment, license revocation,
  incarceration, ruined career
• Institution lawsuits
• Subject safety at risk, loss of trust in
  clinical trial process

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Consequences (cont.)

• Fraudulent investigators are often used by
  multiple sponsors on multiple trials
• A small number of investigators can have a broad
  impact on many NDA submissions
• One fraudulent investigator, Dr. Fiddes, was
  involved in 91 submissions with 47 different
  sponsors

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Why Does Fraud Occur?

• Lack of resources (staff, time, subjects)
• Lack of GCP training
• Lack of regulatory oversight
• Laziness
• Loss of interest
• Pressure to perform or to publish
• Money, greed

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General Warning Signs

• High staff turnover
• Staff are disgruntled, fearful, anxious,
  depressed, defensive
• High pressure work environment
• Obsession with study payments
• Absent investigators
• Lack of GCP training
• Unusually fast recruitment

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Data Identifiers of Fraud

• Implausible trends/patterns
• 100 drug compliance
• Identical lab/ECG results
• No SAEs reported
• Subjects adhering perfectly to a visit schedule
• Perfect efficacy responses for all subjects

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Layout the primary efficacy data for all subjects
at a site to look for trends
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Data Identifiers (cont.)

• Site data not consistent with other centers
  (statistical outlier)
• Source records lack an audit trail - no
  signatures and dates of persons completing
  documentation
• All source records CRFs completed with the same
  pen
• Perfect diary cards, immaculate CRFs

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Source British Medical Journal 324, 1193-1194,
2002
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Data Identifiers (cont.)

• Subject handwriting and signatures are
  inconsistent across documents (consents, diaries)
• Questionable subject visit dates (Sundays,
  holidays, staff vacations)
• Impossible events (eg, subject randomized before
  investigational product even available at the
  site)

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Data Identifiers (cont.)

• Subject visits cannot be verified in the medical
  chart or appointment schedule
• Data contains digit preference some digits
  used more frequently than others (0, 5, and even
  digits)
• Halo around the date or test value indicating
  the original was obliterated with correction fluid

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Detection Strategies

• Expect fraud start from the assumption that
  records are bogus and work backwards
• Question missing, altered, and/or inconsistent
  data offer to retrieve records yourself, keep
  pulling on loose ends and see what unravels
• Dont be intimidated challenge to explain
  suspicious data

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Detection Strategies (cont.)

• Be suspicious of blame shifting remind the
  investigator that he/she is responsible for study
  conduct
• Cultivate whistleblowers pay attention to staff
  complaints, listen to grievances, establish
  rapport, and be approachable

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Whistleblowers

• Many fraud cases uncovered by whistleblowers
• Ethical commitment to report fraud (ACRP)
• Members shall not participate in, condone or be
  associated with dishonesty, fraud or
  misrepresentation and be prepared to draw
  attention to, or challenge, practices of others
  that are detrimental to GCP or in the breach of
  relevant legal or ethical standards.
• Many institutions have an Office of Compliance
  with reporting hotlines
• US government encourages whistleblowers through
  False Claims Act awards

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False Claims Act

• Unlawful to submit a false or fraudulent claim
  for payment to the United States government
• Private citizens who know of people or companies
  defrauding the government may sue on the
  government's behalf (qui tam relator)
• Plaintiff shares in the proceeds of the suit
  (15-30 of amount recovered by government)
• Contains protections for whistleblowers who are
  harassed, threatened, discharged or otherwise
  discriminated against in their employment

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Recent False Claims Act settlement with the Mayo
Clinic (Rochester, MN)
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Other Recent FCA Settlements

• Cornell University4.4 Million (June 2005)
• University of Alabama at Birmingham3.4 Million
  (April 2005)
• John Hopkins University2.6 Million (June 2004)
• Northwestern University5.5 Million (February
  2003)

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Cherlynn Mathias - University of Oklahoma
Melanoma Trial Whistle Blower
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Complaints to FDA

• Reporting is encouraged
• All complaints assumed to be credible
• Prioritized evaluation according to subject
  safety concerns
• 25 of complaints are evaluated by an on-site
  inspection (audit)

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Complaints Categories
Source FDA, CenterWatch
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Whistleblower Required Reading

• How to Blow the Whistle and Still Have a Career
  Afterwards C.K. GunsalusScience and
  Engineering Ethics 4, 51-64, 1998

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Fraud Prevention

• During pre-study evaluation, sponsors should
  carefully scrutinize sites for interest in the
  study, stability of the staff, investigator/staff
  interactions, workload, and level of training
• Everyone involved in the clinical trial process
  should complete regular GCP training
• CRAs should be expert on the protocol
  particularly with parameters that determine
  eligibility (inclusion/exclusion criteria) and
  primary efficacy endpoints

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Fraud Prevention (cont.)

• Sponsors should emphasize their policy on fraud
  at the initiation visit
• Institutions should set-up systems to encourage
  fraud reporting and protect whistleblowers

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• This presentation and related references are
  posted on my corporate website atwww.pbelow-con
  sulting.com/fraud.html

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Thanks

• Kerrin Young, Study Manager, Takeda, Jeri
  Weigand, Quality Assurance Auditor, 3M
  Pharmaceuticals, for their collaboration in the
  development of this presentation
• Tim French, Red River Valley Chapter ACRP, for
  the invitation to present and the PRACS Institute
  for the use of their facilities

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Contact Information

• Office [phone]
• E-mail pbelow_at_cra-training.com