CRP 106 Lecture 11

Question 1

Importance of Data in Clinical Trials

Answer 1

-Data collected in a clinical trial can be submitted to a regulatory agency to obtain marketing authorization for a drug
-If regulatory inspection expresses concern about data or compliance with GCP and regulations, can cause delay or lack of approval of drug
-Data in academic clinical trials will likely be published in the medical/scientific literature possibly influencing care of patients
-Monitor plays an integral role in ensuring integrity by maintain continuous oversight of the clinical trial

Question 2

Factors influencing data integrity

Answer 2

-Well-designed protocols and/or investigational plans
CRFs that appropriately capture data and are appropriately designed
-Ensuring appropriate data management occurs during the study
-Ensuring high quality sites are selected to conduct research

Question 3

Protocols and CRFs

Answer 3

-Ensuring protocols and CRFs are adequate and match
-Ensuring protocol is well designed and outcomes will adequately answer the question being posed by the study
-Ensuring all members of the study team provide input in development of documents
-Quality by Design

Question 4

Data Management

Answer 4

-Real time or near real time entry of data
-As per previous lecture, EDC system can quickly find, prevent and reduce number of data errors
-Providing quick initial feedback to study sites regarding quality

Question 5

Site Quality

Answer 5

-EDC and RBM systems allow for sites to be assessed on quality
-Use high quality sites preferentially
Avoidance of sites with high number of protocol deviations, queries, etc
-Review this information for new sites to determine whether additional studies provided
-these metrics only provide a proxy of quality. Does not mean oversight is not required if using such sites.

Question 6

Consequences: Lack of Data Integrity

Answer 6

-Inspections observing issues with quality and data integrity can limit data from site being used in drug submission
-Potential under-powering of study outcomes
-Outcomes not significant between conditions
-Requirements to recruit further participants
-Delay of approval
-FDA inspection: significant concerns about sponsor/CRO oversight (GCP and regulatory compliance) FDA can place submission on hold
-Hold remains until sponsor can corrects issue and demonstrates GCP non-compliance at site does not invalidate conclusions or trial
-Clinical Hold = Application Integrity Policy
-Validity assessment required for ALL applications from sponsor with data integrity concerns

Question 7

Academic Centres

Answer 7

-Research conducted here is not free from consequences of lack of data integrity
-Retractionwatch.com
-Numerous instances of retractions due to poor data integrity practices

Question 8

Monitoring and data integrity

Answer 8

-Monitoring is a critical function in maintaining data integrity
-If you observe significant findings, document observation and action taken to address matter thoroughly
-Ensure sufficient CAPA undertaken
-In extreme circumstances, if compliance cannot be secured, site should be closed

Question 9

Fraud and Misconduct consequences

Answer 9

-Study not leading to marketing authorization/loss of credibility
-Drugs approved that are not efficacious
-Drugs approved that lack sufficient safety profile
-Effective and safe drugs are not approved and therefore not available to patients
-Lack of progress in medical advancements and science

Question 10

Why is fraud committed?

Answer 10

-Extreme competition for tenure/productivity
-Publish or perish
-Desire for fame and recognition
-Financial gains
-Lack of appropriate training (GCP and regulations)
-Insufficient mentoring

Question 11

Fraud vs. Misconduct

Answer 11

Fraud
-intentional deception for personal benefit or for detriment of another individual
Misconduct:
-Not necessarily due to intentional act
-Can be due to poor management
-Failure to follow protocol and leads to unreasonable risk or harm to participant

Question 12

Detecting Research Fraud

Answer 12

-Unlikely trends, specifically differences in trends between sites
-100% drug compliance
-No SAEs reported
-Perfect participant attendance/adherence to visit schedule
-Visits occurring commonly on odd dates and times (e.g.: holidays)
-Unusually fast recruitment
-observations on their own do not indicate fraud but should warrant a more in depth review by the monitor

Question 13

Misconduct examples

Answer 13

-Failure to follow investigational plan
-Inadequate and inaccurate records
-Inadequate drug accountability
-Inadequate completion of ICFs
-Failure to report ADRs
-Failure to obtain and/or document informed consent
-Failure to obtain and/or document REB/IRB approval
-Failure to notify REB of changes to documents

Question 14

Methods of Reducing Fraud

Answer 14

-Regular and continuous oversight by monitors
-Robust audit and quality assurance program
-Appropriate RBM system and algorithms that will detect trends in data as described above
-Providing diagnostic equipment used to make IC/EC determinations that automatically transmit data to sponsors

Question 15

Suspicion of Fraud or Misconduct

Answer 15

-If you suspect fraud or misconduct, review all available data
-Take notice of nuance differences in documents
-Review laboratory results, source documents and identifiers to ensure they all match
-If odd findings observed, speak with coordinator and investigator
If suspicion continues
-Ask for supervisor to review findings
-Ask supervisor to conduct a visit with you
-Ask for QA audit to occur at site

Question 16

Suspicion of Fraud

Answer 16

-Must be cautious about disclosing of suspected fraud to investigators and coordinators
-Ensure thoroughly discussed and addressed internally
-These are serious allegations and there must be sufficient proof of this occurring
-Relationship will be significantly affected if no fraud observed