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
 How is Data Falsified
 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.
 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.
 How is Data Falsified
 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
 How is Data Falsified

 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
 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.
 How is Data Falsified

 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”
 Why is Data Falsified?

 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)
 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
 Why is Data Falsified?

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
 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
 Tips for Detecting Serious Misconduct

 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.
 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 data

and undermines the regulatory agency’s mission to
protect and promote the public health.
 Consequences of Fraud

 SPONSOR
 Data not usable
 Complete study not usable
 NDA may call it unfileable
 FDA inspections OAI
INVESTIGATOR
CRA