Belgian Association of Clinical Research Professionals 11 th

1. Belgian Association of Clinical Research Professionals11th Annual ConferenceBrussels, Friday 28th November 2008Misconduct in Clinical Research:Prevention, Detection, Investigation and ProsecutionDr Frank WellsCo-Founder and former Medical Director, MedicoLegal InvestigationsCo-Chairman, EFGCP Ethics Working Party 

3. Misconduct in Clinical Research:Introduction

4. The conduct of most clinical research is honest and honourable   Occasionally the sponsor or organiser of a clinical research project may be faced with data which are suspect   Such data might or might not be fraudulent

5. Ideally, fraud should not occur at all  BUT We do not live in an ideal world

7. On June 28, 2006, Poehlman was ordered to serve a year and a day in a federal prison for using falsified data in federal research grants that he submitted for funding. In addition to jail time, Poehlman will be permanently barred from getting more federal research grants, and was ordered by the court to write letters of retraction and correction to several scientific journals.

8. Korean stem-cell case, Woo-suk Hwang

9. Jon Sudbø, Norwegian Radium Hospital, Oslo

10. Misconduct in Clinical Research:Prevention

11. Standards must be set in which all interested parties should be trained and to which all interested parties should adhere For research involving clinical trials, in Europe, these standards are now effectively set in the EC Directives on Clinical Trials (2001/20/EC) and on Good Clinical Practice (GCP) (2005/28/EC). They encompass the Good Clinical Practice (GCP) guidelines devised by the International Conference on Harmonisation (ICH) and are now enacted throughout the USA, Europe and Japan. 

12. Clinical Trial Directive 2001/20/EC 2. The Ethics Committee shall give its opinion, before a clinical trial commences, on any issue requested. 3. In preparing its opinion, the Ethics Committee shall consider, in particular: (a) the relevance of the clinical trial and the trial design; (b) whether the evaluation of the risk/benefit ratio is satisfactory; (c) the protocol; (d) the suitability of the investigator and supporting staff ; (e) – (k) etc. etc.

13. Corrective procedures must be in place if misconduct or fraud occurs despite the setting of these standards and training in their operation

14. In spite of the existence of GCP guidelines, or of the EC Directive, and of training in their operation, there is the possibility or risk that standards will slip

15. Notable Cases of Misconduct and Fraud in the United States. See 2nd edition of Lock & Wells (Bob Burt has the book), Chapter 1.See 2nd edition of Lock & Wells (Bob Burt has the book), Chapter 1.

16. Research Misconduct  William Summerlin (New York) faked transplantation results, darkening transplanted skin patches in white mice with a black felt-tip pen

17. The Fiddes Cases - 1 In an ear infection study, the protocol required subjects to have a certain bacterial infection. Some subjects had no such infection. Fiddes directed study coordinators to purchase the bacteria from a commercial supplier and introduced the infection into the ear, then treated it.

18. The Fiddes Cases - 2 In a contraceptive drug study, Fiddes substituted cervical smears, took blood from staff members (as if they were patients) and completed the records for any patients who dropped out. The company monitors and FDA personnel never noticed any problems. If it had not been for a disgruntled employee, who complained to the Office for Human Research Protection, this would have gone on ……

19. Robert Fiddes, MD, President of the Southern California Research Institute was sentenced in 1998 to 15 months in prison and ordered to pay $800,000 in restitution for the fabrication and falsification of over 200 studies sponsored by 47 drug companies

20. The Case of Dr. Robert Fiddes

21. Research Misconduct in the UK The Siddiqui case (reported in the British Medical Journal 1988;296:306) 12 patients with fabricated biochemistry 1 non-existent patient Blamed his junior colleague The sponsor was reluctant to take any action The doctor was erased from the medical register

22. (Notwithstanding any research governance procedures that may be in place) sponsors and research ethics committees have a responsibility to check that investigators who are too busy too arrogant too tired too lazy too greedy too careless ….. are not recruited

23. Misconduct in Clinical Research:Detection

24. What are we really talking about?

25. Misconduct in Biomedical ResearchU.S. Commission . . . (DHHS) Research misconduct as defined by the US Commission (DHHS) “is significant misbehavior that improperly appropriates the intellectual property or contributions of others, that intentionally impedes the progress of research, or that risks corrupting the scientific record or compromising the integrity of scientific practices.”

26. Clinical research fraud is best defined as: The generation of false data with the intent to deceive

27. The Prevalence of Clinical Research Fraud ….. is difficult to assess My own estimate is that it is at least 1% but probably higher and possibly much higher If we estimate that there are about 2,000 sponsored clinical research projects taking place within the UK at any one time, this means that at least 20 will include investigators who are generating false data

28. Why does it happen?

29. Some wrong reasons why investigators choose to do research:   (i) Pressure to publish - at all costs (ii) Pressure by sponsors   (iii) Greed  (iv) Vanity or arrogance (v) Sheer boredom of routine clinical practice (vi) Emotional disturbance or mental illness (vii) etc. etc.

30. Why have cases been ignored? Fear Recrimination Adverse publicity, Loss of favour and support Loss of prescriptions Asking embarrassing questions In the past, key concerns of Pharma Ind were inwardly focussed And we did not want to upset the medical profession!In the past, key concerns of Pharma Ind were inwardly focussed And we did not want to upset the medical profession!

31. Who finds fraud? Most commonly monitors Patterns or trends Wrong “feeling” Auditors Data monitors Statisticians In the past, key concerns of Pharma Ind were inwardly focussed And we did not want to upset the medical profession!In the past, key concerns of Pharma Ind were inwardly focussed And we did not want to upset the medical profession!

32. Warning signs (1) Immaculate CRFs NB Electronic Records Difficulty in arranging meetings Differences from other sites Faster recruitment Fewer adverse events Fewer withdrawals Odd hours worked Odd days of week/month worked In the past, key concerns of Pharma Ind were inwardly focussed And we did not want to upset the medical profession!In the past, key concerns of Pharma Ind were inwardly focussed And we did not want to upset the medical profession!

33. Warning signs (2) Suspect computer software Separate pages made for hospital notes Separate folders for GP notes Can’t find things “will send later” Notes/labs/drugs One pen used throughout But beware the eccentric! Marks on visual analogue scales Clean diary card No coffee/curry/dog tooth marks In the past, key concerns of Pharma Ind were inwardly focussed And we did not want to upset the medical profession!In the past, key concerns of Pharma Ind were inwardly focussed And we did not want to upset the medical profession!

34. Misconduct in Clinical Research:Investigation

35. Research Misconduct in the Nordic Countries Despite a widely recognised need, most countries still have no coherent system to deal with scientific misconduct. BUT, Committees have been established by the national medical research councils in Denmark (1992), Norway (1994), and Sweden (1997), and by the Ministry of Education in Finland (1994), to deal with scientific misconduct—ie, to initiate preventive measures, to investigate alleged cases, or both. Each committee includes both scientifically and legally qualified members. The employing institutions are responsible for possible sanctions or punishments.

36. Research Misconduct in the UK In 2004 Universities UK, as the representative body for the higher education sector, agreed to take forward the establishment of the UK Panel for Research Integrity in Health and Biomedical Sciences. This is an initiative providing independent support to the Health and Biomedical Sciences research community to establish and demonstrate effective systems for research integrity and share/promote best practice.

37. The UK Research Integrity Office (UKRIO) The aim is to provide a comprehensive service in support of research integrity to the health and biomedical sciences research community. A key element of the service will be access to a Register of Advisers, experts in systems for research management to promote good conduct, and those with experience in investigating allegations of misconduct.

38. The UK Research Integrity Office (UKRIO) The UK Research Integrity Office Fourth Floor Woburn House 20 Tavistock Square London WC1H 9HQ Telephone: 0207 419 5499 Fax: 0207 383 4573 Email: Info@UKRIO.org

39. COPE is a forum for editors of peer-reviewed journals to discuss issues related to the integrity of the scientific record; it supports and encourages editors to report, catalogue and instigate investigations into ethical problems in the publication process. Formed in 1997, the Committee on Publication Ethics' (COPE) major objective is to provide a sounding board for editors who were struggling with how best to deal with possible breaches in research and publication ethics.

41. Problems/dilemmas discussed* Duplicate/redundant publication 58 Authorship issues 26 No ethics approval 25 No or inadequate informed consent 22 Falsification or fabrication 19 Plagiarism 17 Unethical research or clinical malpractice 15 Undeclared conflict of interest 8 Reviewer misconduct 6 Editorial misconduct 3 Other 39

42. Medico-Legal Investigations Limited 00 44 1438 820000

43. Examples of cases considered A general practitioner fabricated research ethics committee approval, twice. Erased from the Medical Register. A second general practitioner committed suicide after, amongst other fraudulent activities, forging REC approval. An academic consultant in respiratory medicine forged REC approval twice for the same study. Admonished and registration conditional upon his conducting subsequent research under supervision.  

44. Examples of cases considered An academic consultant surgeon conducted two studies at once on the same patients without ethics committee approval. Found guilty of serious professional misconduct and admonished. Another academic consultant surgeon purported to have assessed a patient in a study for six months after the patient’s death and to have assessed other patients not attending the hospital. Found guilty of serious professional misconduct and struck off the medical register.

45. Examples of cases considered Two consultant gynaecologists, one academic and one non-academic, published articles purporting to report events that had not happened, as well as to have carried out studies known not to have been conducted, and to have reported findings known not to have occurred. Both were found guilty of serious professional misconduct: one was erased from the medical register, the other has been suspended.

46. Examples of cases considered A general practitioner forged multiple patient signatures (191 forgeries) and other data in 21 studies. Found dead in swimming pool after submission of two statutory declarations to the GMC. Another general practitioner offered a patient a bribe of £2000 when he realised he was being investigated.

47. Examples of cases considered A general practitioner who regularly conducted asthma studies used ECG traces to cover multiple attendances of the patients to which they refer and to use them as if taken for other patients. Found guilty of serious professional misconduct and erased from the medical register.

48. The Case of Dr E What the monitors found What the auditors found

49. Dr E Patient signatures on the study consent forms were not consistent with patient signatures elsewhere in the hospital notes. Treatment randomisation numbers were allocated after visit 2 instead of at visit 2. Patients were purported to have been seen on three separate Bank Holidays.  Patient visits were purported to have taken place when the investigator was on holiday but there was no evidence of recorded cover during this period.

50. Dr E Echocardiogram and nuclear medicine data for all patients were provided on forms that were no longer used in their respective departments. “Bogus” data were attributed by the investigator to another doctor who he alleged was his "research fellow" at the time, and whose qualification as a medical practitioner was never able to be verified. Letters to GPs indicated that certain patients were not stabilised on treatment, and thus ineligible to enter the study, even though they were entered into the study and the CRFs indicated that they were stabilised.

51. The hospital out-patient register verified the appointments for the patients in the study for their first and fourth visits, but their attendance for visits 2 and 3 could not be so verified. For ECG traces and X-rays either the date on which they were taken, or the patient identification, or both, had been cut off.  Drug accountability for patients who were withdrawn from the study at an earlier stage were completed in advance and then scored out when it was realised that the patients had withdrawn.

52. Misconduct in Clinical Research:Prosecution

54. Every person involved in clinical research should be committed to such a policy (of appropriate action) and to its publicity, not least to act as a deterrent, in a determination to stamp out fraud in clinical research, if that is humanly possible

55. Every pharmaceutical company, every regulatory authority, every research ethics committee and every pharmaceutical physician should strive to ensure that there is an effective mechanism in place, in every country where research is conducted, by which anyone who commits fraud can be summarily dealt with

56. Our aim – our is MLI and Pharma Ind Is to maintain and enhance the integrity of Clinical ResearchOur aim – our is MLI and Pharma Ind Is to maintain and enhance the integrity of Clinical Research

57. EFGCP Annual Conference 2009 Diplomat Hotel, Prague, Czech Republic 27-28 January 2009 www.efgcp.be