1. Quality Assurance in Clinical Trials
Stephanie deRijke
Clinical Trials Audit and Compliance

2. Objectives
Discuss the importance of quality assurance in clinical research
Describe regulatory impact of monitoring and how to respond to monitoring reports
Outline the steps to take when a problem occurs
Detail the processes of root cause analysis and corrective and preventive actions

3. Quality Assurance: what
QA is the process by which sponsors and researchers monitor and evaluate the protocol implementation.
QA prevents patterns of error
QA leads to reliable research data

4. Quality Assurance: how
Sponsor monitoring
Self-monitoring
Self-checks
Standard tools
Written procedures

5. Monitoring process Site initiation visit Centralized monitoring
Periodic site monitoring
Close-out

6. Reports Ask monitor to send you a written report Verify findings
Use report as a to-do list
Write on report as you resolve things
Consider the IRB’s reporting requirements
Review with PI; PI should sign if possible

7. Tips on reviewing reports
First look for anything awful
Look for ongoing or pending items that weren’t resolved after the previous visit
Look for things they ask you to report to IRB
“Report to IRB” vs “Report per IRB policies”
Look for hidden attachments or appendices

10. Responding to monitoring findings
If findings are wrong, provide documentation to monitor and ask for a revised letter or at least keep documentation of correspondence
Report items to IRB if monitor asks
If something does not need to be reported to IRB, respond to the monitor that you don’t plan to report and provide them with IRB P&P
If there becomes a pattern of problems, respond with a CAPA

11. Self-monitoring Emory University Self-Monitoring Tool
Review a minimum of twice per year
More for high risk or high enrolling studies
Consider reporting requirements of sponsor and IRB

12. Problems in Research Steps to resolve problems Identify problems
Make immediate corrections
Evaluate risk
Identify root cause of each problem
Identify corrective and preventive action for each root cause

13. Problem Statement A problem statement should include
Description of the problem
Where and when it happened
Weight of the problem
Requirements that were not met
Evidence to show that requirements weren’t met

14. Corrections “Immediate corrections” include
Evaluating rights, welfare, and safety of subject
Reporting, if applicable: subject, subject’s family, sponsor, and/or IRB

15. Evaluate Risk

16. Risk Severity Frequency If Risk is there, move to RCA and CAPA
Rights, welfare, and safety of current and future subjects
Frequency
Systematic problem
Protocol design
Departmental, local problem
If Risk is there, move to RCA and CAPA

17. Immediate Corrections
Problem Occurs
Immediate Corrections
Assess Risk
No risk
Yes risk
Root Cause Analysis
CAPA Plan
If CAPA didn’t resolve root cause
Effectiveness Check

18. Root Cause
The root cause is the initiating, most basic cause of a problem that may or may not lead to a chain of causes or other problems (domino effect)
Eliminating the root cause should prevent recurrence of the problem

19. Root Cause Analysis (RCA)
The RCA is the process of identifying the root cause and the downstream effect on the causal chain
Since noncompliance is usually from a system failure, not a person failure, RCA should focus on identifying underlying problems that contribute to error rather than focusing on mistakes made by individuals

20. RCA Steps Questions to ask Why and how did the problem occur?
What were the steps?
Who was impacted by the problem?
Keep asking “why” and “how” until you reach the root cause

21. Documenting the RCA Summarize the problem or event
Note the sequence of events
Note the implicated processes
Summarize the immediate corrections taken
Summarize the root cause investigation

22. Corrections vs Corrective Actions
Immediate actions taken to resolve a problem before the root cause is known
Putting out fires
Could resolve minor deviations/noncompliance
Corrective Actions
If risk of problem (severity and frequency) is greater, do RCA and move to CAPA
Process

23. What is CAPA? Corrective and Preventive Actions Corrective Actions
The process of reacting to an existing problem and fixing it
Preventive Actions
The process of detecting potential problems and eliminating them

24. FDA Warning Letter Excerpts
“You failed to secure the investigator’s compliance and allowed subjects to be put at risk for potential adverse effects, such as…Your response is inadequate in that it does not describe your corrective and preventive actions in sufficient detail.”
“You stated that study subjects will be re-consented with a revised consent form after it is approved by the IRB. Your response is inadequate as it lacks a corrective and preventive action plan to ensure that adequate consent forms are provided to study subjects prior to any study related procedures in the future.”

25. CAPA Don’ts! We will retrain the study team…
Study team members have been terminated or will be reassigned…
We will have 5 people check….
Don’t overpromise with detailed CAPA plans that we can’t maintain

26. CAPA Musts!
Corrective: Assess and correct safety/rights/welfare of subjects. Report to subjects, IRB, sponsor, and/or internal department. Document corrections.
Preventive: Develop and document a process, train on the process, implement the process, evaluate the process, amend process as necessary.

27. “SMART” CAPAs

28. Effectiveness Check
Build in an effectiveness check as the final step of CAPA
Effectiveness checks verify that the CAPAs resolved the root cause

29. Documenting the CAPA Action type (corrective or preventive)
Action description
Owner
Due date
Plan for effectiveness check
Effectiveness check outcome

30. In Summary Problem occurs Immediate corrections taken
Determine impact of problem and risk of recurrence (risk = severity + frequency)
Root cause analysis
CAPA plan
Effectiveness check

31. CTAC Website

32. Contacts Stephanie deRijke
Emory University Clinical Trials Audit and Compliance
(404)