Slide 1 of 57
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
Slide 2 of 57
Questions for the Session
-
"FDA Misconduct Focus Areas:
What are They and Does the Data
Reinforce the Agency Concerns?"
-
"How can Industry/QA Vigilance
ÝMinimize Scientific Misconduct?"
- QA Role=Prevention, detection,
correction
Slide 3 of 57
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.
Slide 4 of 57
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
Slide 5 of 57
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.
Slide 6 of 57
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 Agencyís
mission to protect and promote
the public health
Slide 7 of 57
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
Slide 8 of 57
Applications and Sponsors Associated
with Violative CIs
CI |
Applications |
Sponsors |
A |
91 |
47 |
B |
49 |
25 |
C |
43 |
21 |
D |
21 |
17 |
E |
12 |
6 |
F |
6 |
6 |
G |
92 |
48 |
Slide 9 of 57
Falsification -A chronic problem-
-
Tonyís Tales 1990-2001
- 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
Slide 10 of 57
Types of Data Falsified
-
Physical and lab examinations
Slide 11 of 57
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
Slide 12 of 57
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
Slide 13 of 57
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
Slide 14 of 57
How is Data Falsified
-
Blood Pressure Data
- Blood pressure measurements
and times changed in source
documents to match CFR and
vice versa
Slide 15 of 57
Blood pressure data questioned
during in-house review
94 subjects Data Listing
Slide 16 of 57
Mind if we inspect?
Sponsorís 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 agencyís planned visit
to the study sites for June 1997
be CANCELLED.
NDA Withdrawn
Slide 17 of 57
What we see in the submission
Slide 18 of 57
What we find on site
Reading |
Week
4
10/30/92 |
Week
8
11/27/92 |
Week
4 *
10/30/92 |
Week
8 *
11/27/92 |
First |
195/99 |
198/95 |
185/95 |
190/95 |
Second |
185/95 |
180/100 |
185/95 |
180/90 |
Third |
198/103 |
180/98 |
180/90 |
180/90 |
Fourth |
195/95 |
195/105 |
180/90 |
175/90 |
Average |
193.2/85 |
185/99.5 |
182.5/92.5 |
181.25/ 113.75 |
|
|
Original
Case Report Form |
* Handwritten changes by
G. Mon 11/18/93 - Changes
are to reflect the medical
chart (No source data)
|
Slide 19 of 57
The explanation
-
How about the BP readings?
- You cannot find them in ìbooksî
- They are ìrareî 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)
Slide 20 of 57
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
Slide 21 of 57
Clinical Fraud Cases
Fabricated Data
Slide 22 of 57
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.
Slide 23 of 57
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
Slide 24 of 57
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
Slide 25 of 57
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."
Slide 26 of 57
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?
Slide 27 of 57
NY Times Allegation
-
"Nothing, Fiddes replied.
Had it not been for a disgruntled
former employee, he would have
still been in business."
Slide 28 of 57
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
Slide 29 of 57
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
Slide 30 of 57
How is Data Falsified
-
Subject Identities
- Same subject enrolled more
than once under two different
names and subject numbers
- Nonexistent subjects created
Slide 31 of 57
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)
Slide 32 of 57
Clinical Fraud Cases
-
Dr. K. - 1987
- 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
-
Sentenced - 400 hours of community
service
Slide 33 of 57
How is Data Falsified
-
Drug Compliance Records
- Returned study drug dumped,
100% compliance in taking test
medication recorded in CRF
Slide 34 of 57
Why is Data Falsified? We might
be cynical, but we werenít 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"
Slide 35 of 57
Why is Data Falsified? We might
be cynical but we werenít 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)
Slide 36 of 57
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
Slide 37 of 57
Why is Data Falsified?
-
"Edged into it"-
rarely primary intent
-
Not enough time or loss of
interest
Slide 38 of 57
Who Does It??
-
Anyone at investigator's site
who has access to data
- Principal Investigator
- Study coordinator
- Research Subjects
- Study Nurse
- ?????????
Slide 39 of 57
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."
Slide 40 of 57
[Pie Chart]
The Blame Game: Who gets the blame?
39% -- Study Coordinator
17% -- Nurse
9% -- Hospital
9% -- Sponsor
9% -- Self
9% -- Office Staff
4% -- Sub-investigator
4% -- Monitor
n (parties blamed) = 23
n (cases) = 20
Slide 41 of 57
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
Slide 42 of 57
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
Slide 43 of 57
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.)
Slide 44 of 57
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
-
Donít be intimidated--tell
the emperor he has no clothes
Slide 45 of 57
Tips for Detecting Serious Misconduct
-
Donít 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
Slide 46 of 57
Tips for Detecting Serious Misconduct
-
Cultivate Whistleblowers--establish
rapport with study staff, be
approachable and available, listen
to grievances, observe working
conditions
Slide 47 of 57
[Pie chart]
Who Complains?--Everybody!
FY 2000
n = 118
14% -- Sponsors
11% -- Anonymous
9% -- Government Agencies
8% -- Private Citizens
19% -- IRBs
9% -- Health Professionals
3% -- CROs
3% -- Study Coordinators
8% -- Former Employees
5% -- Others
2% -- Universities
2% -- Informants
8% -- Subjects
Slide 48 of 57
What Are They Complaining About?
Everything!!
-
Failure to follow the protocol
(70)
-
Informed Consent Issues (55)
-
Failure to report adverse events
(40)
-
Qualifications of persons performing
physicals (27)
-
Failure to get IRB approval,
report changes in research (20)
-
Failure to follow FDA regulations
(13)
-
Charging for the test article
(9)
-
Violations of GLP regs (7)
-
Misleading advertisements (5)
Slide 49 of 57
[Pie chart]
Clinical Investigator Inspections*
52%-- VAI
44% -- NAI
3% -- OIA
0.3% --Pending
n = 306
* All inspections, domestic and
foreign
Slide 50 of 57
Complaints Inspected and Their
Classifications
First Pie Chart Shows:
Inspected = 26%
Not Inspected = 74%
n= 105
Second Pie Chart Shows:
OAI = 26%
NAI = 26%
VAI = 52%
n= 27
Slide 51 of 57
[Picture of Uncle Sam]
Correcting Misconduct
How You can help
FDA Wants You to Recognize and Report
Misconduct
Slide 52 of 57
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
Slide 53 of 57
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.
Slide 54 of 57
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
20855-2773, (301) 594-0020, fax
(301) 594-1204.
Slide 55 of 57
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
20852-1448, (301) 827-6221, fax
(301) 443-6748.
Slide 56 of 57
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) 594-4718, fax (301) 594-4731.
Slide 57 of 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!!!
GCP
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