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Fraud & Misconduct at Investigator Sites. Paul Below Medical Affairs - 3M Pharmaceuticals Presented to the Great Plains Chapter ACRP March 27, 2003. Disclaimer / Disclosure.

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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
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
Introduction
  • Definition of fraud
  • Prevalence
  • Consequences
  • Reasons why fraud occurs
  • Case studies
  • Sponsor regulatory responsibilities
introduction cont
Introduction (cont)
  • Warning signs/identifiers
  • Detection strategies
  • Fraud Prevention
  • Questions
fda definition of research fraud
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
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 cont1
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
Who Commits Fraud?
  • Investigators
  • Study nurses / coordinators
  • Data management personnel
  • CRAs / sponsors
  • Lab personnel
  • IRB staff
recent examples of pharma corporate fraud
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
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
Who Gets Blamed?

4%

4%

39%

9%

9%

9%

9%

17%

Source: FDA Presentation, DIA 2000

prevalence of fraud
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
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
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
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
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
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 cont1
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 cont2
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
other famous cases
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
fda regulations
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 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 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 cont1
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
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
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
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
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 cont1
Identifiers (cont)
  • Subject visits cannot be verified in the medical chart, appointment schedule, or billing records
cra strategies for detecting fraud
CRA Strategies for Detecting Fraud
  • Ask for all information (data) pertinent to the study (CRFs, study specific source worksheets, clinic charts, sign-in sheets, lab requisitions, shipping records)
  • Accept no copies – review originals whenever possible
  • Get technical – read lab reports, x-rays, ECGs – don’t just inventory
detection strategies cont
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 cont1
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
Annual Complaints Received by FDA

Source: FDA Office of Compliance, CenterWatch

complaints to fda
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
Source of Complaints

17%

1999

53%

30%

Source: FDA - DIA 2000

complaints categories
Complaints Categories

1998-2001

Source: FDA, CenterWatch

fraud prevention tips for sponsors cras
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
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 cont1
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
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
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
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
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
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
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 cont1
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 cont2
ACRP Sessions (cont)
  • “The Risks Never Outweigh the Benefits”

Bruce Diamond & AttorneyChaired by Bart Denys, MD, FACC, FSCAI, CCRI

Closing Session (#81)Wednesday, April 91:30 pm - 3:00 pm

acrp sessions cont3
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 #21-24Sunday, April 6, 8:30 am - 5:00 pm (free - included in full registration fee)

thanks
Thanks
  • 3M Pharmaceuticals
  • Minnesota Chapter - ACRP
  • Volunteers of the Great Plains Chapter - ACRP
contact information
Contact Information
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