1. Scientific Misconduct -The “F” word-
Stan W. Woollen
Associate Director for Bioresearch Monitoring
Office for the Good Clinical Practices
and
Antoine El Hage, Ph.D.,
Chief
Good Clinical Practices Branch II, DSI
FDA
October 2001

2. Questions for the Session
"FDA Misconduct Focus Areas: What are They and Does the Data Reinforce the Agency Concerns?”
Falsification, yes
"How can Industry/QA Vigilance  Minimize Scientific Misconduct?”
QA Role=Prevention, detection, correction

3. What is Misconduct? FDA’s Focus
Recognizing Research Misconduct
Research misconduct means Falsification of data in proposing, designing, performing, recording, supervising or reviewing research, or in reporting research results.
Falsification includes acts of omission and commission.

4. Types of Falsification
Acts of omission
consciously not revealing all data
(e.g. reportable adverse events, concomitant meds., etc)
Acts of commission
consciously altering data or Fabricating data (e.g. lab values, BP readings, bogus specimens)
Data is interpreted broadly
individual facts, statistics, tissue samples, items of information, statements made by individuals

5. What is Misconduct? FDA’s Focus
Deliberate or repeated noncompliance with the regulations can be considered misconduct, but is secondary to falsification of data.
Research misconduct does not include honest error or honest differences of opinion.

6. Consequences of Fraud
If fraud takes place in a clinical trial, it places all subjects in that trial at possible safety risk
Fraud jeopardizes the reliability of submitted and/or published data and undermines the Agency’s mission to protect and promote the public health

7. Consequences of Fraud
Though Fraud is encountered on a relatively rare basis, its impact is broad.
Seriously noncompliant CIs are often used by multiple sponsors on multiple trials
Small number of investigators can have a broad impact on many applications by many sponsors

8. Applications and Sponsors Associated with Violative CIs
CI Applications Sponsors A B C D E F G

9. Falsification -A chronic problem-
Tony’s Tales
What types of data were falsified
How was data falsified
Why was data falsified
Who did it
How was it detected
QA- tips for preventing, detecting correcting

10. Types of Data Falsified
EKGs
Blood Pressure Data
Physical and lab examinations
Biological Specimens
Subject Identities
Drug Compliance Records
You name it

11. EKGs -a common problem Circa 1990 Kept stock files of EKGs etc.
Made identical/duplicate prints of x-rays with different names
Obtained blank copies of lab reports. Used a different numbering system than numbering system used by the lab
Multiple copy records:
No originals of a particular lab report - all were photocopies
Dr. S
Faked subjects: used names obtained from the obituary column
CRF completed after subjects died
Had unopened cartons of the investigational drug

12. EKGs a common problem
- 1998
Dates were misrepresented on EKGs to coincide with protocol required visits (5)
Used 5 year old EKG tracings
Dates were changed in 5 records to match the washout periods required by the protocol
Five subjects received prohibited medication while on the study
Five subjects did not sign consent forms before entering the study
Seven subjects EKGs were not done at Visit 1 per protocol
4 subjects had discrepancies between progress notes and what was reported in the CRFs

13. How is Data Falsified EKGs
Continuous strip run on one patient then torn in half and represented as coming from two subjects
Preprinted subject identifying information altered or obliterated on existing EKGs
Dr. Xerox will see you now

14. How is Data Falsified Blood Pressure Data
Blood pressure measurements and times changed in source documents to match CFR and vice versa

15. Blood pressure data questioned during in-house review
94 subjects Data Listing

16. Mind if we inspect? Sponsor’s answer-
It was concluded that inconsistencies in the source documentation would make it difficult to trace or verify some of the key information. As a result of our findings, we recommend that the agency’s planned visit to the study sites for June 1997 be cancelled.
NDA Withdrawn

17. What we see in the submission

18. What we find on site
Reading Week 4 Week 8 Week 4 * Week 8 * 10/30/92 11/27/92 10/30/92 11/27/92
First 195/ / / /95
Second 185/ / / /90
Third 198/ / / /90
Fourth 195/ / / /90
Average 193.2/85 185/ / /
Original Case Report Form
* Handwritten changes by G. Mon /18/93 - Changes are to reflect the medical chart (No source data)

19. The explanation How about the BP readings?
You cannot find them in “books”
They are “rare” but real, and they occur in this country
Our population is different from the U.S. population and that is why you see consistent BP readings over time (6 months)

20. How is Data Falsified Physical and/or Lab Exams
Documented only by checked blocks in CRF signed by study coordinator and co-signed by PI. No corroborating source documents.
Bogus lab results reported

21. Clinical Fraud Cases
Fabricated Data

22. How is Data Falsified Biological Specimens
Samples purported to come from a large number of individual subjects actually derived from only a few different subjects.

23. The “F” Case Robert Fiddes, MD
Guilty - Conspiracy to commit an offense against the United States
Guilty - Making false statements in matter within jurisdiction of the FDA (18 USC 1001)
Sentenced - 15 months in jail (see newspaper)
Fined - $800,000
Deported

24. New York Times May 17, 1999 RESEARCH FOR HIRE: SECOND OF TWO ARTICLES
A Doctor's Drug Studies Turn Into Fraud
By KURT EICHENWALD and GINA KOLATA

25. NY Times Allegation Fabrication the undetectable crime?
“Another study on an antibiotic required that patients have a certain type of bacteria growing in their ear. No problem for Fiddes. He bought the bacteria from a commercial supplier and shipped them to testing labs, saying they had come from his patients' ears.”

26. NY Times Allegation
The FDA investigators asked (Fiddes), what evidence of fraud is there in the records reviewed by monitors and the government? What could the watchdogs have seen that would have allowed them to detect his fraud?

27. NY Times Allegation
“Nothing, Fiddes replied. Had it not been for a disgruntled former employee, he would have still been in business.”

28. Bogus specimens A new era in detection?
Chronic Bronchitis Study
84 subjects enrolled, required to produce positive sputum samples to qualify for study
Monitor reported that sputum samples were not collected per the protocol (i.e. in presence of the investigator)
FDA inspected and sponsor audited to validate data. No direct evidence of a problem with specimen integrity

29. Clinical Fraud Cases detecting the undetectable
Sponsor performed DNA analysis on sputum and serum samples to put concerns to rest.
Analysis showed 35 of 84 sets of subject serum and sputum samples did not match
26 sputum samples were found to be derived from only 3 subjects

30. How is Data Falsified Subject Identities
Same subject enrolled more than once under two different names and subject numbers
Nonexistent subjects created

31. Clinical Fraud Cases Dr. P
Fabricated laboratory data and eye exams - all subjects
Created data for subjects by using available results from different subjects
Recycled subjects (3x) and invented data (EKG tracings, duplicate lab results)
Used 2 year old EKG tracings
Disqualified (Hearing)

32. Clinical Fraud Cases Dr. K. - 1987 Disqualified
85 cases submitted - ONLY 15 were real subjects
Faked approximately 70 subjects records
Never used test article - used marketed products
Did not obtain informed consent
Disqualified
Sentenced hours of community service
Fined - $30,000

33. How is Data Falsified Drug Compliance Records
Returned study drug dumped, 100% compliance in taking test medication recorded in CRF

34. Why is Data Falsified? We might be cynical, but we weren’t born that way
Reasons why records not available:
“They were destroyed in a hurricane”
“They were lost in a boating accident”
(burglary, robbery or vandalism)
“They were lost in the mail”
“The mover threw them out”
“My father-in-law threw them out”

35. Why is Data Falsified? We might be cynical but we weren’t born that way
I destroyed the records. You were not informed by the sponsor!!?
I did not know that the medical charts and CRFs (data) must correspond.
I do not remember why I changed the dates (visits)
I care for my subjects, used the “best available local therapy”
I do not see a problem with re-entering a subject 5 or 6 times (considering them as six different subjects)

36. Why is Data Falsified
Reasons are not always known or clear, and often can only be inferred
To qualify ineligible subjects to enroll or continue on the study
To please the bosses by filling in the blanks and making the source documents match the CRF
For fun and profit

37. Why is Data Falsified? “Edged into it” - rarely primary intent
Not enough time or loss of interest
Staff turnover
Not enough subjects
For “good of subject”
Pressure to publish
Power & prestige
Money

38. Who Does It?? Anyone at investigator’s site who has access to data
Principal Investigator
Study coordinator
Research Subjects
Study Nurse
?????????

39. NY Times Allegation THENURSEDIDIT Maneuver The last refuge of a scoundrel
"Dr. Fiddes replied that they were going to blame the study nurse for all of the problems, and he was going to say he had no knowledge of what was going on."

40. The Blame Game Who gets the blame?4% 4%
39% 9% 9% 9% 9%
n (parties blamed) = 23
n (cases) = 20
17%

41. QA’s Role in Dealing with Misconduct
Prevention
Identify and eliminate/minimize risk factors for misconduct
Detection
Monitor and recognize signs of fraud
Correction
Promptly investigate and report fraud

42. Tips for Preventing Fraud
Make sure all study staff have the necessary resources and support needed to accomplish their tasks
Don’t place needless requirements or unreasonable demands on the site
Monitor sites closely and pay attention to complaints from site personnel
Minimize the use of enrollment incentives

43. Approaches in Detecting Fraud (Rules?)
Tip/nose/experience/gut feeling
Understand the protocol or plan
Parameters that determine eligibility (inclusion/exclusion criteria)
Accept no copies - originals
Identify all source/supporting documents
Look for mistakes/changes/inconsistencies
Frequency of changes - identify who made them
Determine & document if changes are justified
Challenge suspicious data
Ask for all information (data) pertinent to the study (CRF, AB, CPF, MV-MR, X-R, EKG, DIA, etc.)

44. Tips for Detecting Serious Misconduct
Get Technical-Read x-rays, EKGs, lab results, don’t just inventory
Fill in the Blanks-Question missing dates, times, information,offer to retrieve records yourself
Don’t be intimidated-tell the emperor he has no clothes

45. Tips for Detecting Serious Misconduct
Don’t shoot the messenger-believe the monitor, put the burden of proof on the CI
Be suspicious of blame shifting-tell CI he/she is totally responsible for the conduct of the study
Expect Fraud-Start from the assumption the records are bogus and the study is a fraud, and work back

46. Tips for Detecting Serious Misconduct
Cultivate Whistleblowers-establish rapport with study staff, be approachable and available, listen to grievances, observe working conditions

47. Who Complains?---Everybody! FY 20002% 2%
14% 5% 8% 3% 3%
11% 9% 8% 8% 9%
19%
n = 118

48. What Are They Complaining About? Everything!!
Failure to follow the protocol (70)
Falsification (67)
Informed Consent Issues (55)
Failure to report adverse events (40)
Qualifications of persons performing physicals (27)
Inadequate Records (25)
Failure to get IRB approval, report changes in research (20)
Failure to follow FDA regulations (13)
Charging for the test article (9)
Drug accountability (7)
No active IND (7)
Violations of GLP regs (7)
Misleading advertisements (5)
Blinding (3)
No 1572 (2)
Monitoring practices (2)
IRB shopping (1)

49. Clinical Investigator Inspections* FY 1999
0.3% 3%
44%
52%
n= 306
*All inspections,
domestic & foreign

50. Complaints Inspected and Their Classifications
26%
26%
26%
(n= 27)
n= 27
n= 105
52%

51. Correcting Misconduct How You can help
FDA Wants You to Recognize and Report Research Misconduct

52. FDA Believes Sponsors should Promptly Report...
Any information they have that any person involved in human subject trials committed research misconduct
Whenever the sponsor discovers misconduct
Not just for clinical investigators and not just when a clinical investigator is terminated

53. Correcting Misconduct
Reporting Research Misconduct
Name of the person(s)
Contact information
Specific identity of the affected research
IND/IDE #, protocol, study title, and study dates
As much information regarding the research misconduct as is available to the sponsor.

54. Where to Report Misconduct
Drugs
Division of Scientific Investigations (HFD-45), Office of Medical Policy, Center for Drug Evaluation and Research, FDA, 7520 Standish Place, Room 103, Rockville, Maryland , (301) , fax (301)

55. Where to Report Misconduct
Biological Products
Office of Compliance and Biologics Quality, Division of Inspections and Surveillance, Center for Biologics Evaluation and Research, (HFM-650), FDA, 1401 Rockville Pike, Room 400S, Rockville, Maryland , (301) , fax (301)

56. Where to Report Misconduct
Medical Devices
Office of Compliance, Division of Bioresearch Monitoring, (HFZ-310), Center for Devices and Radiological Health, FDA, 2098 Gaither, Room 130, Rockville, Maryland 20850, (301) , fax (301)

57. Tips for Dealing with Serious Misconduct
Be Prepared- have a system in place to capture, document and deal with complaints of misconduct in a timely fashion. Follow your SOPs!!!!