Fraud and Misconduct in Clinical Trials

1. Fraud and Misconduct in Clinical Trials Dr Jane Barrett Consultant Pharmaceutical Physician MedicoLegal Investigations Ltd www.barrettconsultancy.com www.medicolegal-investigations.com

2. Learning outcomes • To understand the • Background of fraud and misconduct • Definitions and types of fraud and misconduct • Acceptance that misconduct occurs in biomedical research • Action to be taken if misconduct suspected Postgraduate course in Pharmaceutical Medicine

3. History of research fraud • Gregor Mendel 1865 • Ignored results that ‘didn’t fit’ • Cyril Burt 1966 • Fabricated data on inheritance of intelligence • William Summerlin 1974 • Drew black ‘skin grafts’ with marker • Andrew Wakefield 1998 • Link between regressive autism and MMR • Huang Woo-Suk 2004 • Faked stem cell colonies • Diederik Stapel 2011 • ‘Several dozen’ fraudulent psychology papers Postgraduate course in Pharmaceutical Medicine

4. Fraud or Misconduct • All fraud is misconduct • Not all misconduct is fraud Postgraduate course in Pharmaceutical Medicine

5. Definitions of Clinical Research Misconduct (1) • The generation of false data with the intent to deceive • Dr Frank Wells Postgraduate course in Pharmaceutical Medicine

6. Definitions of Clinical Research Misconduct (2) • Behaviour by a researcher, intentional or not, that falls short of good ethical and scientific standards • Joint Consensus Conference on Misconduct in Biomedical Research October 1999 Postgraduate course in Pharmaceutical Medicine

7. Definitions of Clinical Research Misconduct (3) • An insincere act of deception performed in order to harm the rights of others • French view Postgraduate course in Pharmaceutical Medicine

8. Definitions of Clinical Research Misconduct (4) • The fabrication, falsification, plagiarism or deception in proposing, carrying out or reporting results of research or deliberate, dangerous or negligent deviations from accepted practices in carrying out research • Wellcome Trust Postgraduate course in Pharmaceutical Medicine

9. The staircase of misconduct Marcovitch et al Croat Med J. 2010 doi: 10.3325/cmj.2010.51.7

10. Commonest type of fraud • Consent forms • Diary cards Postgraduate course in Pharmaceutical Medicine

11. Incidence of fraud • Not often, but not “never” • Realistic estimate at least 3% of trials • Approx. 15000 trials at any time in UK • 450 incidences of fraud in UK today • How many in the world? Postgraduate course in Pharmaceutical Medicine

12. Incidence of fraud • 33% of early/mid career scientists admitted one or more of ten examples of misconduct • > 15% had altered the design, methodology or results of their research • 12.5% had overlooked research misconduct in others • 8% had “circumvented requirements relating to human subjects” Martinson BC, Anderson MS, de Vries R. Scientists behaving badly. Nature 2005; 435: 737-738 Postgraduate course in Pharmaceutical Medicine

13. Incidence of fraud • Survey of 305 new medical consultants • 64% response • 55.7% observed misconduct • 5.7% committed misconduct in the past • 18% would commit in future • 17% had research ethics training Geggie D. A survey of newly appointed consultants' attitudes towards research fraud 2001; 27(5): 344-6 Postgraduate course in Pharmaceutical Medicine

14. Incidence of fraud • 40% of researchers • Were aware of research misconduct but had not reported it • In academic medical setting researchers believed junior researchers would do nothing if senior staff member involved in misconduct • 20% of those surveyed had first hand experience of actual research misconduct within the past year • Only a quarter would report to the appropriate authorities Sheehan JG. Fraud, conflict of interest, and other enforcement issues in clinical research. Cleveland Clinic Journal of Medicine 2007; 74 (2): S63-S67 Pryor ER, Habermann B, Broome ME. Scientific misconduct from the perspective of research coordinators: a national survey. Journal of Medical Ethics 2007; 33: 365-369 Postgraduate course in Pharmaceutical Medicine

15. Incidence of fraud – meta analysis • 18 studies analysed (21 reviewed) • Fabrication/falsification • Admitted by 1.97% • Other questionable practices • Admitted by 33.7% • Admitted more “modified research results” to improve outcome than “reported results they knew to be untrue”

16. Incidence of fraud – meta analysis • Personal knowledge of colleague fabricating or falsifying research data • 14.12% • Knowledge of any cases of fraud • 12% to 92% • 29% of cases of misconduct known by respondents never discovered Fanelli D (2009) How Many Scientists Fabricate and Falsify Research? A Systematic Review and Meta-Analysis of Survey Data. PLoS ONE 4(5): e5738. doi:10.1371/journal.pone.0005738

17. Examples of types of fraud • Fabrication • Malcolm Pearce • John Darsee • Falsification • William McBride • Robert Fiddes • Plagiarism • Committee on Publication Ethics • 40% of undergraduates admit plagiarism • 71% of students don’t see copying from web as cheating Postgraduate course in Pharmaceutical Medicine

18. My own experience • The cut-up ECGs • The research nurse who couldn’t count • The GP, bloods, EC forgery and a shotgun • The identical tubes of cream • The identical consent signatures Postgraduate course in Pharmaceutical Medicine

19. The Costs • Safety for patients • Unnecessary treatment • Unnecessary change of treatment • Drug registered on false data • Useful drug withdrawn unnecessarily • On study drug without full assessments • Risk without benefit Postgraduate course in Pharmaceutical Medicine

20. The Costs • Monetary for sponsor company • Lost data • Possible wasted study • Wasted staff time/effort Postgraduate course in Pharmaceutical Medicine

21. The Costs • Career destroyed for those found guilty • Career often jeopardised for the Whistleblower • Stress and unpleasantness for families Postgraduate course in Pharmaceutical Medicine

22. Actions possible in UK • Do nothing • Refer case to General Medical Council (GMC) • Refer case to police • Criminal offence of deception • Bring a civil action Postgraduate course in Pharmaceutical Medicine

23. Cases referred to GMC in UK • 27 cases since 1990 • 26 found guilty of serious professional misconduct • 3 admonished • 7 suspended • 12 erased from the register • 4 restricted with regard to future research activity Postgraduate course in Pharmaceutical Medicine

24. Situation in other Countries • Denmark, Sweden, Norway , Finland • All have Committees on Research Dishonesty • France • Officially recognised procedures • Germany • Ombudsman for Science • US • Office of Research Integrity (ORI) • Office for Human Research Protections (OHRP) • Food and Drugs Administration (FDA) Postgraduate course in Pharmaceutical Medicine

25. Nationalbody for UK • Proposed in 1999 • Committee on Publication Ethics • Pharmaceutical Industry • Royal Colleges • UK Research Integrity Office open 2006 • Remit • Code of practice for staff working in the NHS, universities and the health industry • Support to whistleblowers • Provide experts to ensure quality of future research • Not investigatory Postgraduate course in Pharmaceutical Medicine

26. Who finds fraud? • Monitors • Patterns or trends • Wrong “feeling” • Colleagues • Auditors • Data monitors • Statisticians Postgraduate course in Pharmaceutical Medicine

27. Warning signs (1) • Immaculate case record forms • Difficulty in arranging meetings • Differences from other sites • Faster recruitment • Fewer adverse events • Fewer withdrawals • Odd hours worked • Odd days of week/month worked Postgraduate course in Pharmaceutical Medicine

28. Warning signs (2) • Separate pages/folders made for notes • Can’t find things “will send later” • Notes/labs/drugs • One pen used throughout • Marks on visual analogue scales • Clean diary cards • No coffee/curry/dog tooth marks Postgraduate course in Pharmaceutical Medicine

29. What can be done to preventresearch fraud? • Standards must be set • All parties should be trained • International Conference on Harmonisation (ICH) • Good Clinical Practice (GCP) Guidelines • Declaration of Helsinki • EC Directives on Clinical Trials • Paediatric Regulation Postgraduate course in Pharmaceutical Medicine

30. Why fraud? • Pressure to publish - at all costs • Sheer boredom of routine clinical practice • Greed  • Emotional disturbance or mental illness • Vanity or arrogance Postgraduate course in Pharmaceutical Medicine

31. If fraud suspected • If beyond reasonable doubt • Essential to be dealt with appropriately in the interests of • The public • The profession • The pharmaceutical industry Postgraduate course in Pharmaceutical Medicine

32. Suspicion of misconduct • Report per SOPs • Selected staff for site visit • Consider professional assistance • Outcome • Careless investigator • Evidence of fraud • Must be capable of withstanding law court level examination Postgraduate course in Pharmaceutical Medicine

33. Action • Keep all hand-written notes • Document everything • Remove all trial-related documents from site • Destroy nothing Postgraduate course in Pharmaceutical Medicine

34. Standard Operating Procedures • Clear statement of policy towards the handling of suspect data • Stated policy of referral upwards • Of any cause for concern • At the earliest possible stage • Clear guidelines as to the path to be followed if fraud is suspected • Clear guidelines as to the right of appeal within the company Postgraduate course in Pharmaceutical Medicine

35. Conclusions • Fraud is out there • Not common, but not rare (3% sites?) • It can be difficult to detect • Full assessments must be made • To protect patients and industry • Failure to take action is not acceptable Postgraduate course in Pharmaceutical Medicine

36. Postgraduate course in Pharmaceutical Medicine