Fraud & Misconduct at Investigator Sites

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

2. 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.

3. Introduction • Definition of fraud • Prevalence • Consequences • Reasons why fraud occurs • Case studies • Sponsor regulatory responsibilities

4. Introduction (cont) • Warning signs/identifiers • Detection strategies • Fraud Prevention • Questions

5. 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

6. 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)

7. 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

8. Who Commits Fraud? • Investigators • Study nurses / coordinators • Data management personnel • CRAs / sponsors • Lab personnel • IRB staff

9. 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).

10. 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).

11. Who Gets Blamed? 4% 4% 39% 9% 9% 9% 9% 17% Source: FDA Presentation, DIA 2000

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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

20. Recent additions to the FDA Debarment List

21. Federal Register Notice for Laverne Charpentier Debarment

22. 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

23. Recent “Warning” Letter

24. Warning Letter - Pg 2: Submission of False Information

25. 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.

26. 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.

27. 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.

28. 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).

29. 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

30. 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

31. 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

32. 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”

33. Identifiers (cont) • Subject visits cannot be verified in the medical chart, appointment schedule, or billing records

34. 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

35. 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

36. 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

37. Annual Complaints Received by FDA Source: FDA Office of Compliance, CenterWatch

38. 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)

39. Source of Complaints 17% 1999 53% 30% Source: FDA - DIA 2000

40. Complaints Categories 1998-2001 Source: FDA, CenterWatch

43. Cherlynn Mathias - University of Oklahoma Melanoma Trial Whistle-Blower

44. 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

45. 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

46. 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

47. 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.

48. 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.

49. 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.

50. Current Presentation • This presentation and related reference material is posted on the Minnesota ACRP website at:www.mnacrp.org/fraud.html