1. Fraud & Misconduct at Investigator Sites Paul Below Clinical Research Trainer Medical Research Management Red River Valley Chapter ACRP Fargo, ND January 18, 2007

2. 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. Disclosure & Disclaimer

3. Definition of fraud Prevalence Famous cases Consequences Reasons why fraud occurs Warning signs/identifiers Detection strategies Fraud prevention Presentation Topics

4. 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) FDA Definition of Fraud

5. 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 Fraud Definition (cont.)

6. Investigators Study coordinators Data management personnel Lab personnel IRB staff CRAs and sponsor personnel FDA Who Commits Fraud?

7. Who Gets Blamed?

8. 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 Prevalence of Fraud

9. 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 Prevalence of Fraud (cont.)

10. 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 Famous Cases - Investigators

12. 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 Case Study - Dr. Fiddes

13. 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 Dr. Fiddes (cont.)

14. 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 Dr. Fiddes (cont.)

15. June 1999 � disqualified as a clinical investigator by FDA Mar. 2000 � medical license revoked Nov. 2002 � debarred by FDA along with three study coordinators Dr. Fiddes (cont.)

22. Anne ButkovitzPediatric private practice, Newton, MA � 2005 Paul KornakStratton VA Medical Center, Albany � 2005 Famous Cases - Coordinators

24. 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 Consequences of Fraud

25. 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 Consequences (cont.)

26. 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 Why Does Fraud Occur?

27. 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 General Warning Signs

28. 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 Data Identifiers of Fraud

30. 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 Data Identifiers (cont.)

32. 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) Data Identifiers (cont.)

33. 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 Data Identifiers (cont.)

34. 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 to explain suspicious data Detection Strategies

35. 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 Detection Strategies (cont.)

36. 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 Whistleblowers

37. 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 False Claims Act

40. Cornell University$4.4 Million (June 2005) University of Alabama at Birmingham$3.4 Million (April 2005) John Hopkins University$2.6 Million (June 2004) Northwestern University$5.5 Million (February 2003) Other Recent FCA Settlements

43. 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) Complaints to FDA

45. Complaints Categories

46. �How to Blow the Whistle and Still Have a Career Afterwards� C.K. GunsalusScience and Engineering Ethics; 4, 51-64, 1998 Whistleblower Required Reading

47. 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 Fraud Prevention

48. Sponsors should emphasize their policy on fraud at the initiation visit Institutions should set-up systems to encourage fraud reporting and protect whistleblowers Fraud Prevention (cont.)

49. This presentation and related references are posted on my corporate website at:www.pbelow-consulting.com/fraud.html

51. 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 Thanks

52. Office: (952) 882-4083 E-mail: pbelow@cra-training.com Contact Information