Errors, Fraud

ERRORS ,MISCONDUCT AND FRAUD
IN CLINICAL TRIALS
Dr Pratibha Nadig
ICRI
Good Clinical Practices
Essential elements:
 Ensuring the integrity of the clinical investigation.
 Protecting the rights of the human research subject
 Ensuring the quality and validity of the data.
 Good science+good statistical design+ethical

practice
Characteristics of a quality data
 Accuracy  Attributably
 Immediacy  Integrity
 Legibility  Consistency
 Durability  Honesty
DEFINITION
Fraud
↕
Misconduct
↕
Errors
Errors
 Deviation from the truth/accuracy
 Unintentional
 Due to ignorance,carelessness.
 Common
ERRORS
 What are the common types of errors
 Why do they happen


 What are the measures to correct them /
Errors
 CRF
 Drug dispensing
 Study documents
 Protocol violations/deviations
 No approval from IRB
 Informed consent incomplete
Errors-CRF
 Omissions-missing values leaving out data

 Inconsistencies
 Incorrect entries
 Out of range entries
 Illogical entries
 Undecipherable entries
Errors- drug disposition
 Drug accountability is not maintained

Errors- study documents
 Failure to keep adequate records

 Problems with the informed consent-no
informed consent
 Failure to report adverse events- not
recording AEs
Protocol deviation/violation
 Selection criteria not followed strictly

 IRB approval not taken.
Why do errors happen
 Errors are due most often to

misunderstanding or inattention on the part
of the study co-ordinator
How to minimise?
 Minimise the errors by

 Thorough review of the patients’ data soon after
1-2 patients’ enrollment
 Prepare and adhere to Check lists and SOPs
 Feed back to the site.
 Instruct the correct way to record the data
 Train effectively and retrain if required.
 Demand the a good work nicely
MISCONDUCT AND
FRAUD
 Misconduct- doing the mistake knowingly
 1.An investigator included patients with
DBP of 88 mm instead of 90 and matched
the source documents.
 2.Inclusion of 20-40 years-adjusted to 18-45

years.
Misconduct- impact
 More serious than errors because it cannot be

discovered and unfixable
 Affects the outcome of the result.The drug

may appear safe and effective when it is not
truly so.
Why do they occur
 Investigator under pressure-competitive

enrollment.
 Commited for expediency
How to minimise
 CRA has to be vigilant

 Source data verification has to be perfectly
done.
 Inclusion and exclusion criteria have to be
checked.
 Training and emphasising on the time and
money involved.
FRAUD
 Wilful deception
 Motivated by personal gain
 Fabrification: Invention of data or
cases
 Falsification: Wilful distortion of data
 Falsification includes acts of omission and
commission.
 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)
 Inventing the data
Misconduct vs fraud
 Difference lies in intensity of action and the

intention
 Both are not fixable but misconduct on
enquiry is detectable while fraud may be
covered up cleverly
 FRAUD does not include honest error or
honest differences of opinion.
How is Data Falsified
 Dr. S
 Faked subjects: used names obtained from the
obituary column
 CRF completed after subjects died
 Had unopened cartons of the investigational
drug
 C 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.
 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.
 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
 Sponsor performed DNA analysis on sputum

and serum samples.
 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
 Biological Specimens
 Samples purported to come from a
large number of individual subjects
actually derived from only a few
different subjects.
 Subject Identities
 Same subject enrolled more than once
under two different names and subject
numbers
 Nonexistent subjects created
 Drug Compliance Records
 Returned study drug dumped, 100%
compliance in taking test medication
recorded in CRF
Why is Data Falsified?
 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”
 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)
 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
Not enough time or loss of interest

 Staff turnover
 Not enough subjects
 For “good of subject”
 Pressure to publish
 Power & prestige
 Money
Who can be blamed
 Principal Investigator
 Study coordinator
 Research Subjects
 Study Nurse
 ?????????
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
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
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
Approaches in Detecting Fraud
(Rules?)
 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,X-RAY,ECG, MRI etc.)
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
 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
 Cultivate Whistleblowers-establish
rapport with study staff, be approachable and
available, listen to grievances, observe
working conditions
Consequences of Fraud
 Seriously noncompliant are often used by

multiple sponsors on multiple trials
 Small number of investigators can have a

broad impact on many applications by many
sponsors.
 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 data

and undermines the regulatory agency’s mission to
protect and promote the public health.
 SPONSOR
 Data not usable
 Complete study not usable
 NDA may call it unfileable
 FDA inspections OAI
INVESTIGATOR
CRA

Errors, Fraud

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ERRORS ,MISCONDUCT AND FRAUD

 Good science+good statistical design+ethical

 Deviation from the truth/accuracy

 What are the common types of errors

 Why do they happen

 Omissions-missing values leaving out data

 Drug accountability is not maintained

 Failure to keep adequate records

 Selection criteria not followed strictly

 Errors are due most often to

 Minimise the errors by

 2.Inclusion of 20-40 years-adjusted to 18-45

 More serious than errors because it cannot be

 Affects the outcome of the result.The drug

 Investigator under pressure-competitive

 CRA has to be vigilant

 Difference lies in intensity of action and the

 Had unopened cartons of the investigational

 Made identical/duplicate prints of x-rays with

different numbering system than numbering

sputum samples to qualify for study

collected per the protocol (i.e. in presence of the

data. No direct evidence of a problem with

 Sponsor performed DNA analysis on sputum

 They were destroyed in a hurricane”

 I destroyed the records. You were not informed by

 Reasons are not always known or clear,

Not enough time or loss of interest

 Make sure all study staff have the necessary

 Frequency of changes - identify who made

 Get Technical-Read x-rays, EKGs, lab

 Don’t shoot the messenger-believe the

 Seriously noncompliant are often used by

 Small number of investigators can have a

 If fraud takes place in a clinical trial, it places all

 Fraud jeopardizes the reliability of submitted data

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