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. Cases AND “Make My Day” 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
Paint Your Wagon
Titles
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.
Cover the ICH definition (emphasize that the US has never defined the term GCP into any of its laws, but recently introduced formally the Office of Good Clinical Practice in its agency).
Emphasize the 3 parts of the GCP definition:
1. A standard for all aspects of clinical trials and research from conception to completion (refer to italicized words).
Deliberate (read aloud) the red highlighted phrases, the 2 main themes of GCPs, which can be reduced to 3 words:
DATA QUALITY = “the data and reported results are credible and accurate”
ETHICS = “the rights, integrity, and confidentiality of trial subjects are protected.”
End by stating the “formula” for GCP
= Quality Data
= Ethics
Quality Data + Ethics = GCPs

11. Investigator Obligations
FDA Form 1572
“Absolute Power”

12. “Read the SMALL PRINT of the 1572” [Investigator Commitments: Box 9]
upervise
S _______
M ______ ______
A _____ to _______
L ____ __________ ________
L et FDA Inspect
__P__ _______ _______
R etain Records
I _____ _______
N ____ _ _ _
T ____ ______
aintain Records
dhere Protocol
earn Investigator’s Brochure
Supervise (People-Study responsibility item)
Maintain Records (Data Quality item: during study process)
Adhere to Protocol (Data Quality item: 1 of 2 main documents)
Learn Investigator’s Brochure (Data Quality item: 2 of 2 main documents)
Let FDA Inspect (Data Quality item)
rePort Adverse Events (Data Quality item: Safety)
Retain Records (Data Quality item: after study process)
Inform Consent(Ethics item)
Notify IRB(Ethics item)
Train staff (People-Study responsibility item)
Emphasize the 2 main themes of GCPs (see parentheticals above) and link back to the GCP definition from ICH
Re ort Adverse Events
“Sudden Impact” GCP Document
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”

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. “Dirty Harry’s” Warning Letter
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…”

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

20. FDA Timeline for Dr. Bear
Inspection ended
29 Apr 2002
Warning Letter posted
27 Sep 2002
Disqualification process starts?
Unknown

21. More Clues Ahead!

22. Case #2 Investigators with “Rookie” Coordinators
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”
Borison
Diamond
Guilty! 54 36
Felony Counts
150K
125K
Fines
$4.26M
$1.1M
Restitution 15 5
Imprisonment 10
Probation

29. FDA Timeline for Dr. Borison
Inspection ended
22 Apr 1997
[No warning letter issued]
Prison term started
09 Oct 1998
Disqualified
10 Nov 1998
Debarred (10 yrs)
30 Sep 2003

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
Inspection ended
28 Feb 1996
[No Warning Letter issued]
Pleaded guilty
Aug 1997
Sentenced to prison
Sep 1998
Disqualified
01 Jun 1999
Debarred (20 yrs)
06 Nov 2002

40. FDA Disqualification and Debarment Lists
Debarment:

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. Clint Eastwood Film Clues
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)

44. Clint Eastwood Film Clues (Titles)
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)

45. Clint Eastwood Film Clues (Titles)
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
26 uniques Film Titles
40 Total