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

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

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

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

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

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

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

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

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

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

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

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

Evaluate Risk

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

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

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

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

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

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

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

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

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.”

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

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.

“SMART” CAPAs

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

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

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

CTAC Website

Contacts Stephanie deRijke Emory University Clinical Trials Audit and Compliance www.ctac.emory.edu smickle@emory.edu (404) 712-5159