Transcript Fraud & Misconduct at Investigator Sites

Fraud & Misconduct at
Investigator Sites
Paul Below
Medical Affairs - 3M Pharmaceuticals
Presented to the Great Plains Chapter ACRP
March 27, 2003
Disclaimer / Disclosure
• The views and opinions expressed by
the presenter are not necessarily
those of the 3M Company, 3M
Pharmaceuticals or its subsidiaries
• The presenter does not have a
significant equity interest (>$50,000) in
any of the companies or products
cited in this presentation.
Introduction
• Definition of fraud
• Prevalence
• Consequences
• Reasons why fraud occurs
• Case studies
• Sponsor regulatory responsibilities
Introduction (cont)
• Warning signs/identifiers
• Detection strategies
• Fraud Prevention
• Questions
FDA Definition of
Research Fraud
• Research misconduct means
falsification of data in proposing,
designing, performing, recording,
supervising or reviewing research, or
in reporting research results.
• The FDA uses the terms “fraud” and
“misconduct” interchangeably
Definition (cont)
• Per FDA, falsification includes acts of
omission and commission
• Omission = consciously not revealing
all data
• Commission = consciously altering or
fabricating data (eg, lab values, lesion
counts, etc)
Definition (cont)
• Fraud does not include honest error
or honest differences in opinion
• Per the FDA, deliberate or repeated
noncompliance with the protocol and
GCP can be considered fraud, but is
secondary to falsification of data
Who Commits Fraud?
• Investigators
• Study nurses / coordinators
• Data management personnel
• CRAs / sponsors
• Lab personnel
• IRB staff
Recent Examples of
Pharma Corporate Fraud
• Bristol-Myers concedes accounting practices
for wholesale earnings “inappropriate”
(3/11/03). Also settled with FTC over
allegations of patent protection abuse
(3/10/03).
• Schering-Plough CEO being investigated by
SEC for insider trading (3/13/03).
• ImClone CEO settled with SEC over insider
trading violations (3/11/03).
Pharmaceutical Corporate
Fraud Examples (cont)
• TAP Pharmaceuticals paid $875 M fine over
pricing/marketing practices w/ Lupron (2001)
• J&J’s LifeScan paid $60 M in fines over
SureStep glucose monitoring device;
deficient labeling, failure to report problems
and submission of false reports (2000).
• Genentech paid $50 M to settle charges of
illegal promotion of Protropin growth
hormone for unapproved uses (1999).
Who Gets Blamed?
4% 4%
39%
9%
Study Coordinator
Nurse
Hospital
Sponsor
Self
Office Staff
Sub-investigator
CRA
9%
9%
9%
17%
Source: FDA Presentation, DIA 2000
Prevalence of Fraud
• Difficult to determine but considered
rare
• Reported to significantly impact 1-5%
of pharmaceutical clinical trials - Frank
Wells, Medico Legal Investigations
(Reuters Health, Jan 2002)
• Only ~3% of FDA inspections uncover
serious GCP violations
Consequences of Fraud
• Sponsor – data validity compromised,
submission jeopardized, additional
costs
• Investigator – disqualification, fines,
incarceration, legal expenses, ruined
career
• Institution – lawsuits
• Subject – safety at risk, loss of trust in
clinical trial process
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
submissions made by sponsors
• Disqualified investigator, Dr. Fiddes,
was involved in 91 submissions with
47 different sponsors
Why Does Fraud Occur?
• Not enough time or staff
• Not enough subjects
• Lack of GCP training and/or regulatory
oversight
• Laziness, loss of interest
• Money, greed
• Pressure to perform, publish
Case Study - Dr. Fiddes
• Dr. Fiddes was president of a clinical
research company in Whittier, CA
• Conducted over 200 studies beginning
in the early 1990’s
• Engaged in extensive fabrication and
falsification of data
Dr. Fiddes (cont)
• Made up fictitious study subjects
• Fabricated lab results by substituting
clinical specimens and manipulating
lab instrumentation
• Prescribed prohibited medications to
manipulate data
Dr. Fiddes (cont)
• 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
• June 1999 - disqualified as a clinical
investigator by FDA
Dr. Fiddes (cont)
• November 2003 - debarred by FDA
along with three staff (study
coordinators)
• Profiled on 60 Minutes and in the New
York Times in 1999
Recent additions to the FDA Debarment List
Federal Register Notice for Laverne
Charpentier Debarment
Other Famous Cases
• Richard Borison, MD and Bruce
Diamond, PharmD - Medical College of
Georgia - psych studies
• Thomas Jefferson University,
Philadelphia - NIH-funded HIV gene
therapy studies - False Claims Act
settlement
• Michael McGee, MD - University of
Oklahoma - melanoma vaccine trial
Recent
“Warning”
Letter
Warning Letter - Pg 2: Submission of False Information
FDA Regulations
• 21 CFR 312.56(b):
A sponsor who discovers that an
investigator is not complying with the
signed agreement (Form FDA 1572), the
general investigational plan, or the
requirements of this part or other
applicable parts shall promptly secure
compliance or discontinue shipments of
the investigational new drug to the
investigator and end the investigator’s
participation in the investigation.
ICH Guidance
• ICH E6 - 5.20.1:
Noncompliance with the protocol, SOPs,
GCP and/or applicable regulatory
requirement(s) by the investigator /
institution, or by member(s) of the
sponsor’s staff should lead to prompt
action by the sponsor to secure
compliance.
ICH Guidance (cont)
• ICH E6 - 5.20.2:
If the monitoring and/or auditing
identifies serious and/or persistent
noncompliance on the part of an
investigator/institution, the sponsor
should terminate the investigator’s /
institution’s participation in the trial …
and promptly notify the regulatory
authorities.
ICH Guidance (cont)
• ICH - E6 4.12:
If the trial is terminated prematurely or
suspended for any reason, the
investigator / institution should inform
the trial subjects, should assure
appropriate therapy and follow-up for the
subjects, and … should promptly inform
the regulatory authority(ies).
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
Data Identifiers
• Implausible trends/patterns:

100% drug compliance

Perfect efficacy responses for all
subjects

Identical lab/ECG results

No SAEs reported

Subjects adhering perfectly to visit
schedules
Data Identifiers (cont)
• Site data not consistent with other
centers (statistical outlier)
• Perfect diary cards, immaculate CRFs
• All source records & CRFs completed
with the same pen
• Source records lack an audit trail - no
signatures and dates of persons
completing documentation
Identifiers (cont)
• Subject handwriting and signatures
are inconsistent across documents
(consents, diaries)
• Questionable subject visit dates
(Sundays, holidays, staff vacations)
• Impossible events (eg, randomization
before drug delivery)
• Data contains “digit preference”
Identifiers (cont)
• Subject visits cannot be verified in the
medical chart, appointment schedule,
or billing records
CRA Strategies for
Detecting Fraud
• Ask for all information (data) pertinent
to the study (CRFs, study specific
source worksheets, clinic charts, signin sheets, lab requisitions, shipping
records)
• Accept no copies – review originals
whenever possible
• Get technical – read lab reports, xrays, ECGs – don’t just inventory
Detection Strategies (cont)
• 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
• Don’t be intimidated – challenge the
site to explain suspicious data
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
Annual Complaints
Received by FDA
200
106
118
131
145
100
11
9
1992
1993
13
11
1994
1995
8
15
9
0
1996
1997
1998
1999
2000
2001
2002P
Source: FDA Office of Compliance, CenterWatch
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)
Source of Complaints
17%
53%
30%
1999
Sponsors
Anonymous
Other
Source: FDA - DIA 2000
Complaints Categories
40%
35%
1998-2001
24%
19%
20%
14%
8%
0%
Protocol
Violations
Falsification of
Data
Informed
Consent
Noncompliance
Poor AE
Reporting
Poor Drug
Accountability
Source: FDA, CenterWatch
Cherlynn Mathias - University of Oklahoma
Melanoma Trial Whistle-Blower
Fraud Prevention Tips for Sponsors/CRAs
• During the pre-study evaluation,
carefully scrutinize sites in the
following areas:

Interest in the study

Stability of the staff

Investigator/staff interactions

Workload

Level of training
Fraud Prevention (cont)
• Conduct GCP training at the start and
throughout the study as necessary
• Emphasize company policy on fraud
at the initiation visit
• Be expert on the protocol particularly
with parameters that determine
eligibility (inclusion/exclusion criteria)
and primary efficacy
Fraud Prevention (cont)
• Minimize the use of enrollment
incentives and pressure to enroll
• Don’t place needless requirements or
unreasonable demands on sites
• Maintain frequent interaction with
sites through regular monitoring visits
and phone calls
References - Presentations
• “Who’s in Charge Anyway? Responsibility in
Today’s Clinical Trial Environment”, Stan Wollen,
DIA Meeting, June 2000.
• “Patient Misuse and Investigator Fraud in Clinical
Trials: What Can Be Done?”, Stan Wollen, DIA
Meeting, June 2000.
• “Detecting and Handling Scientific Misconduct and
Persistent Noncompliance”, Stan Wollen, DIA
Meeting, June 2000.
• “Scientific Misconduct – The ‘F’ Word”, Stan
Wollen and Antoine El Hage, FDA Clinical Trials
Meeting, October 2001.
Other References
• “A Doctor's Drug Studies Turn Into Fraud,”
New York Times, May 17, 1999, K. Eichenwald
and G. Kolata.
• “Drug Money,” CBS News 48 Hours, July 31,
2000.
• “At Your Own Risk,” Time Magazine, April 22,
2002, M. Lemonick and A. Goldstein.
• “Alleged Abuse of Research Grant Money Led
to False Claims Settlement”, Report on
Medicare Compliance, May 25, 2000.
Other References (cont)
• HHS Guidance (Office of Research Integrity):
Guidelines for Assessing Possible Research
Misconduct in Clinical Research and Clinical
Trials, January 2001
(available at ori.dhhs.gov/multimedia/acrobat/
clinicaltrialsguidelines.pdf)
• Book: Fraud and Misconduct in Medical
Research, Lock S, Wells F, eds., London: BMJ
Publishing, 1996.
Current Presentation
• This presentation and related reference
material is posted on the Minnesota
ACRP website at:
www.mnacrp.org/fraud.html
Related Sessions at ACRP
• “Fraud and Non-Compliance: How
Should an Independent Consultant
Respond?”
Ann Begely, JD, RN, Attorney,
Kirkpatrick & Lockhart
John Isidor, JD, CEO, Shulman
Associates IRB
Session #49 - Tuesday, April 8,
10:30 am - 12:00 noon
ACRP Sessions (cont)
• “Disqualification of a Clinical
Investigator by the FDA’s CDRH”
Gary Yingling, MS, JD, Kirkpatrick &
Lockhart
Rodney Allnutt, Consumer Safety
Officer, ORA, FDA
Session #67 - Tuesday, April 8,
3:30 pm - 5:00 pm
ACRP Sessions (cont)
• “Fraud and Misconduct: Who’s Doing
It and How Can We Stop Them”
Stan Woollen, Associate Director for
Biomedical Research, FDA
Session #71 - Wednesday, April 9,
8:30 am - 10:00 am
ACRP Sessions (cont)
• “The Risks Never Outweigh the
Benefits”
Bruce Diamond & Attorney
Chaired by Bart Denys, MD, FACC,
FSCAI, CCRI
Closing Session (#81)
Wednesday, April 9
1:30 pm - 3:00 pm
ACRP Sessions (cont)
• “FDA Bioresearch Workshop for
Investigators, CRAs, CRCs, IRBs, and
Sponsors”
Antonie El-Hage, PhD, Branch Chief,
Good Clinical Practices II, CDER, FDA
Pre-session workshop #21-24
Sunday, April 6, 8:30 am - 5:00 pm
(free - included in full registration fee)
Questions
Thanks
• 3M Pharmaceuticals
• Minnesota Chapter - ACRP
• Volunteers of the Great Plains
Chapter - ACRP
Contact Information
• Email: [email protected] or
[email protected]
• Home office phone: (952) 882-4083
• Don’t hesitate to call me with follow-up
questions!