The Good, The Bad and The Ugly

2. The Good, The Bad and The Ugly of Clinical Research Sites

3. Includes FDA Documents as “Learning Tools” • Form 1572 • Warning Letters • Notice of Observations (483s) • Publications (FDA Consumer) • Investigator Lists • Debarment • Disqualification • Federal Register Notices AND

4. Features Clint Eastwood films • Titles • Phrases • Music • Photos

5. “Hang ‘Em High”Objectives • Define “Good Clinical Practice” requirements with investigator obligations • Review 3 cases of research misconduct • Read public documents available from FDA • Highlight some “signs and symptoms” of the misconduct • Examine investigator-study coordinator interactions

6. “Make My Day” Cases • Warning! Warning! Warning! Letter • Dr “Dirty Harry” Bear Investigator • “True Crime(s)” • The Borison – Diamond Affair • Dr. Robert “Every Which Way But Loose” Fiddes AND

7. Film Clues Music Titles Paint Your Wagon Pictures Quotes

8. Prizes • Correctly guess: • Total number of film clues in presentation • 12 clues, so far • Total number of unique film clues • 9 clues, so far

9. The “Good Clinical Practice” Definition ICH: “Perfect World” for Clinical Trials

10. Good Clinical Practice (GCP) • A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that • the Data and Reported Results are Credible, and Accurate, and that • the Rights, Integrity, and Confidentiality of Trial Subjects are Protected. = Quality Data = Ethics Quality Data + Ethics = GCPs

11. Investigator Obligations FDA Form 1572 “Absolute Power”

12. “Sudden Impact” GCP Document “Read the SMALL PRINTof the 1572” [Investigator Commitments: Box 9] upervise • S _______ • M ______ ______ • A _____ to _______ • L ____ __________ ________ • L etFDA Inspect • __P__ _______ _______ • R etainRecords • I _____ _______ • N ____ _ _ _ • T ____ ______ aintain Records dhere Protocol earn Investigator’s Brochure Re ort Adverse Events nform Subjects otify I R B rain Staff

13. How many clues do you have now?

14. Harry D. Bear M.D., Ph.D.(Virginia Commonwealth University) Case #1 Investigator with unqualified coordinators

15. “Dirty Harry’s” Warning Letter • A Sep 27, 2002 FDA communication for violations which are regulatory significant and that failure to adequately and promptly make corrections may expect enforcement action by FDA if the violation(s) continue. • FDA as “Enforcer” and Dr Bear as “High Plains Drifter” • http://www.fda.gov/foi/warning_letters/g3537d.htm

16. “Any Which Way You Can” • “People issues” are noted often in the warning letter: • “Not qualified,” “inexperienced,” “unauthorized” • Need to “supervise,” “monitor,” “train” S M A L L P R I N T [of the FDA Form 1572]

17. S upervise “It is your responsibility to monitor all personnel…” “There are several examples of…reports that were not signed or dated by you or a subinvestigator responsible to you.” “…please explain how you will supervise study staff to ensure…” “Your response is therefore inadequate to explain how a different person was granted the authority to…” T rain staff “…individuals who have prepared study drugs have not been registered pharmacists qualified by training and experience…” “…visits were conducted by personnel not medically qualified to evaluate the subject’ disease status,…” “…attributes these errors to the “initial inexperience” of the person who…” “Dirty Harry’s” Warning Letter

18. Dr. Bear: “High Plains Drifter” • “Several study visits were conducted by personnel not medically qualified to evaluate the subject’s disease status, including the study coordinator…” • “The study coordinator signed the “Request to Transfer Patient” form…even though the “Site Reference Manual” requires that “the investigator must review and sign…”

19. : “The Enforcer” • “These errors reflect a pattern of insufficient training and experience that may impact the safety and welfareof subjects, and the ability to determine the safety and efficacy of the study drug.” ethics data quality

20. FDA Timeline for Dr. Bear

21. More Clues Ahead!

22. Richard Borison M.D. and Bruce Diamond Ph.D (Medical College of Georgia?) Case #2 Investigators with “Rookie” Coordinators

23. Form FDA 483: Inspectional Observations for Richard L. Borison • Inspection Dates: 06 Nov 1996 – 22 Apr 1997 • 20 Significant Findings (I.e., 4 pages) • Added note: Dr Diamond received a separate Form FDA 483 with 13 of the exact same findings

24. “A Fistful of Dollars” • Wall Street Journal (15 Aug 1997) Headlines • Drug Makers Relied on Clinical Researchers Who Now Await Trial • Two Professors Are Accused of Endangering Patients and Stealing $10 Million • ‘Checks and Balances’ Failed

25. The “Rookie” Coordinators • “Two of their study coordinators had been hired after working as Girl Scout administrators; another had recently been a Delta Airlines flight attendant.” • Ms. A “who began working … as a study coordinator …, also had no medical training, yet was put to work interpreting electrocardiograms and blood tests. WSJ: 15 Aug 1997

26. The “Rookie” Coordinators • Ms. B “who coordinated Borison-Diamond drug trials at the VA hospital says Dr Diamond pushed her so to hard to recruit and retain subjects for a Sandoz study of a schizophrenia drug that she misled patients – claiming the experimental medicine may be the “next wonder” drug.” WSJ: 15 Aug 1997

27. “For a Few Dollars More” • CBS’ 48 Hours, The Ultimate Risk, aired on 15 Apr 1999 • Whistleblower was a study coordinator

28. “Thunderbolt and Lightfoot”

29. FDA Timeline for Dr. Borison

30. Robert Fiddes, M.D.(Southern California Research Institute) Case #3 Investigator with his “Beguiled” band of Coordinators

31. News Article in FDA Consumer • “Physician Sentenced for Doctoring Drug Data” by Tamar Nordenberg

32. “For a Few Dollars More” • New York Times (17 May 1999) Headlines • A Doctor’s Drug Trials Turn Into Fraud • “Companies large and small showered him not only with more than 170 studies to conduct, but with millions of dollars in compensation for his work.”

33. Band of “Beguiled” Coordinators • “Few employees other than the study coordinators – mostly women of limited financial means – aware of the magnitude of the swindle.” • “Like every other study coordinator who passed through Dr. Fiddes’s research center, Ms. C found herself being pushed to break the rules.” NYT: 17 May 1999

34. Band of “Beguiled” Coordinators • “Again and again, study coordinators were instructed by Dr. Fiddes and his top aide, Ms. Charpentier, to ignore the requirements of the drug studies.” • “Dr. Fiddes’s coordinators, paid bonuses for recruiting patients into studies, soon began improperly enrolling themselves and members of their families.” NYT: 17 May 1999

35. “Blood Work” Fraud • “Bodily fluids that met certain lab values were kept on hand in the office refrigerator, ready to be substituted for the urine or blood of patients who did not qualify for studies.” NYT: 17 May 1999

36. “In The Line of Fire” • “…Dr Fiddes laid much of the blame for everything that happened on his study coordinators – again, without providing evidence to support the assertion.” • “He told them that fraud was rampant in the research industry. He named names of doctors he suspected of engaging in practices similar to his own.” NYT: 17 May 1999

37. Fiddes: “Unforgiven?” • “But, the investigators asked, …What could the watchdogs have seen that would have allowed them to detect his fraud? • “Nothing, Dr Fiddes replied. ” • “Had it not been for a disgruntled employee, he would have still been in business.” • Disgruntled employee was a study coordinator NYT: 17 May 1999

38. The Final “Gauntlet” • Dr. Fiddes was sentenced to 15 months in prison, ordered to repay $800,000, and debarred. • 3 study coordinators were found guilty. • One study coordinator was debarred.

39. FDA Timeline for Dr. Fiddes

40. FDA Disqualification and Debarment Lists • Disqualification: • http://www.fda.gov/ora/compliance_ref/bimo/disqlist.htm • Debarment: • http://www.fda.gov/ora/compliance_ref/debar/default.htm

41. Some Final Thoughts

42. Final Advice • Conduct “ethical” clinical research • Protect the “needs of” and “risks to” patients • Generate “quality data” • Follow “GCP responsibilities” of the 1572 • Seek out more education in “GCPs” • Develop strong partnerships between investigator and study coordinator

43. Photos The Outlaw Josey Wales Dirty Harry Hang ‘Em High Space Cowboys Pink Cadillac The Bridges of Madison County Kelly’s Heroes Unforgiven (Oscar Night) Music The Good, The Bad, and The Ugly (title theme) A Perfect World (End Credits Medley) Quote “Make My Day” (Dirty Harry) Clint Eastwood Film Clues

44. The Good, the Bad, and the Ugly Dirty Harry (2) Hang ‘Em High Paint Your Wagon Absolute Power Sudden Impact A Perfect World True Crime Every Which Way But Loose Rookie (3) A Fistful of Dollars For a Few Dollars More (2) Clint Eastwood Film Clues (Titles)

45. Thunderbolt and Lightfoot Enforcer (2) High Plains Drifter (2) Any Which Way You Can Beguiled (3) Blood Work In the Line of Fire Unforgiven Gauntlet Clint Eastwood Film Clues (Titles)