Fraud & Misconduct at Investigator Sites – A CRA’s Perspective

1. Fraud & Misconduct at Investigator Sites – A CRA’s Perspective Paul Below Clinical Research Consultant P. Below Consulting, Inc. Southeast Louisiana Chapter ACRPMarch 15, 2005

2. Disclosure • The presenter does not have a significant equity interest in any of the companies/products referenced here • The presenter has a consulting relationship with the following: • Mayo Alliance for Clinical Trials • Boehringer Ingelheim Pharmaceuticals • BioSante Pharmaceuticals • National Alopecia Areata Foundation • New England Chapter of the ACRP

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

4. Introduction (cont) • Warning signs/identifiers • Detection strategies • What to do if fraud is detected • 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 • PHS definition includes plagiarism

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 coordinators • Data management personnel • Lab personnel • CRAs and sponsors • IRB staff • FDA

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

10. Prevalence of Fraud • Difficult to determine but still 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

11. 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

12. 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 • Disqualified investigator, Dr. Fiddes, was involved in 91 submissions with 47 different sponsors

13. Why Does Fraud Occur? • Lack of resources (staff, time, subjects) • Lack of GCP training and/or regulatory oversight • Laziness, loss of interest • Pressure to perform, publish • Money, greed

14. 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

15. 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

16. Dr. Fiddes (cont) Fiddes had always found it easy to elude detection by the crews of company monitors and government auditors that visited his offices, even when his employees spelled out their suspicions about what was happening. It wasn't that he was particularly adept at dodging their questions; rather, they seemed reluctant to challenge such a prominent figure in the drug-testing business. This business can be run on words, and I have learned the words," Fiddes wrote in a 1995 memo. ‘We have no problems’ is our motto, and tell this to every monitor. Source: “A Doctor's Drug Studies Turn Into Fraud,” New York Times, May 17, 1999

17. Dr. Fiddes (cont) Several former coordinators for Fiddes said they had reported his unethical conduct to Pat Pryor, an independent study monitor working with Pfizer Inc. Tipped off to the discrepancies, Ms. Pryor sharply challenged Fiddes and his staff in her reviews of their paperwork. Fiddes chafed at the challenges, feigning outrage. ‘Our integrity and reputation for performing high-quality clinical trial work has been injured, and we are justifiably upset,’ Fiddes wrote in a July 1995 letter to Pfizer. He insisted Pfizer ‘have a new monitor assigned to our site immediately.’ Source: “A Doctor's Drug Studies Turn Into Fraud,” New York Times, May 17, 1999

18. Dr. Fiddes (cont) What could the watchdogs have seen that would have allowed them to detect his fraud? Nothing, Fiddes replied. Had it not been for a disgruntled former employee, he would have still been in business. Source: “A Doctor's Drug Studies Turn Into Fraud,” New York Times, May 17, 1999

19. Dr. Fiddes (cont) • Feb. 1997 – Staffers blows the whistle and federal 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

20. Dr. Fiddes (cont) • May 1999 – profiled on 60 minutes and in the New York Times • June 1999 – disqualified as a clinical investigator by FDA • Mar. 2000 – medical license revoked • Nov. 2002 – debarred by FDA along with three study coordinators

21. Recent additions to the FDA Debarment List

22. Federal Register Notice for Laverne Charpentier Debarment

23. Other Famous Cases • Thomas Jefferson University, Philadelphia - NIH-funded HIV gene therapy studies - False Claims Act settlement • Michael McGee, MD - University of Oklahoma - melanoma vaccine trial • Richard Borison, MD and Bruce Diamond, PhD - Medical College of Georgia – psych and neuro studies

24. Bruce Diamond, PhD – “The Lessons of Greed,” PharmaVOICE, July 2004

25. Recent “Warning” Letter

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

27. 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.

28. 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.

29. 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.

30. 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).

31. 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

32. 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

33. 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

34. 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 IP even available at the site)

35. 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

36. 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

37. 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

38. 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

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

40. 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)

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

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

44. False Claims Act • Civil war-era law created to protect government from unscrupulous defense contractors • Unlawful to submit false or fraudulent claim for payment to the United States government • False claim includes acts of “deliberate ignorance” or “reckless disregard” of the truth

45. False Claims Act (cont) • Used by Department of Justice to prosecute research fraud • 1994 - John L. Ninnemann, Ph.D., University of Utah and University of California, San Diego - $1,575,000 settlement repaying grants made by the National Institutes of Health

46. False Claims Act (cont) • Private citizens who know of people or companies that are defrauding the government may sue on the government's behalf (qui tam relators) • Plaintiff and share in the proceeds of the suit (15-30% of amount recovered by government) • Suit is filed confidentially under seal

47. False Claims Act (cont) • FCA contains protections for whistleblowers who are harassed, threatened, discharged or otherwise discriminated against in their employment because of their whistleblowing

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

50. What Should I Do If I Detect Fraud? (CRAs) • Follow your company SOP • Be a detective - collect evidence • Challenge but do not accuse • Conduct the rest of the visit as usual • Call your manager away from the site • Write a fact-based summary of findings