Corrective and Preventive Action Plans
The IRB-approved research plan includes all information submitted and approved by the IRB, including 1) the scientific protocol, 2) information in the IRB applications, modifications and reported events, and 3) any other study-specific IRB determination or requirement. The federal regulations and Good Clinical Practice guidelines do not allow deviations from the IRB-approved plan except where necessary to eliminate apparent immediate hazards to human participants. Even with the most cautious and careful research and participant teams, however, protocol compliance can be difficult to maintain in the increasingly complex clinical trial environment. Studies are technical with multiple requirements and the human participants are volunteers with individual medical and life situations that may influence compliance.
The investigator and research team members must make a concerted effort to comply with the protocol and educate participants on the requirements through the continuing informed consent process. When deviations from the IRB-approved research plan occur, the investigator must act quickly to ensure participant safety and reporting to sponsor and/or IRB when necessary.
How to prevent deviations
- All study team members must be trained on the protocol before starting the research
- Ask the sponsor about confusing wording in the protocol
- Keep the protocol, or significant sections, handy with the participant charts for quick reference
- Communicate expectations to participants
- Talk to monitors about common deviations across sites
What to do when a deviation occurs
If study team members become aware of a deviation that has already occurred, taking immediate corrections will protect the rights, welfare, and safety of the participant(s). Immediate corrections may include a phone call or an office visit with a qualified research team member. The investigator may choose to order tests and other procedures to ensure the participant is safe. Document the deviation, reason it occurred, and immediate corrections taken. Consider the reporting requirements of the sponsor and IRB; report appropriately. Do not wait to report—if there isn’t time to complete an electronic application then report by phone and finish the application when time allows. The Emory IRB requires noncompliance and deviations meeting reporting criteria to be reported within 10 business days of becoming aware. The study team may also need to notify participant(s) of the problem; the IRB will advise on how to do this (e.g., letter to participants, phone, or reconsent). Immediate corrections should focus on rights, welfare, and safety of participants and reporting.
Evaluate risk
After immediate corrections have been taken, evaluate the risk of the severity and frequency of the deviation. To evaluate severity of a problem, start by using the Emory IRB reporting requirements, which considers events that adversely affect the rights, welfare, or safety of participants (among other things) to be major.
To evaluate frequency, consider recurrence of the problem in the future and history of the problem in the past. For future assessment, consider the risk of the event recurring in the same participant or other participants in the study. For past assessment, review the protocol deviation log for other occurrences of the event. If there is a risk of the problem recurring in the future or if you notice it becoming a pattern on the protocol deviation log, the risk of frequency is apparent.
If there is a risk of severity and/or frequency, continue to investigate the problem through root cause analysis. If there is no risk of severity or frequency, the immediate corrections taken initially should resolve the problem. Lastly, document the deviation, corrections, and risk assessment and continue to monitor the protocol deviation log for patterns.
Immediate Corrections
There are distinct differences between immediate corrections and corrective actions. Corrections are the immediate steps taken to resolve a problem and ensure the rights, welfare, and safety of participants and reporting. Corrections may resolve minor deviations, but they will not effectively resolve more significant noncompliance (reminder: risk = severity + frequency). Corrective actions are developed and implemented for more significant or systematic noncompliance once the root cause is known.
Root Cause Analysis
When significant deviations or noncompliance occur in research, it is important to identify the causes of the problem so that they can be resolved to prevent further noncompliance. There can be multiple reasons or causes that contribute to one single problem. Conversely, there may be multiple methods to resolve each 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. Eliminating the root cause should prevent recurrence of the problem.
A root cause analysis (RCA) is the process of identifying and documenting the root cause and the downstream effect on the causal chain. RCA should focus on identifying underlying problems that contribute to error rather than focusing on mistakes made by individuals.
Steps
1. Identify and document the problem with a problem statement
- Description of the problem
- Where and when it happened
- Weight/magnitude of the problem
- Requirements that were not met
- Evidence to show that requirements weren’t met
3. Questions to identify root cause
- What happened? What is the problem?
- Why and how did the problem occur? What were the steps?
- Who was affected by the problem? Was it one participant or all participants in the study?
- What is the magnitude of the problem? Is it in one study or does the problem exist in all studies under this PI or even in an entire clinical department?
- Keep asking “why” and “how” until you reach the root cause
Once the root cause has been identified, the next step is to develop a corrective and preventive action plan to eliminate the root cause.
Corrective and Preventive Action (CAPA) Plans
The FDA indicates that corrective and preventive actions (CAPAs) are necessary to resolve problems and noncompliance in clinical investigations. Corrective actions are those taken to resolve a problem and preventive actions are those actions that keep the problem from recurring. Although investigators have implemented CAPAs for decades, federal agencies, sponsors and IRBs now expect CAPAs to resolve problems in research. CAPAs must be thoroughly documented, implemented, and evaluated over time for effectiveness.
Corrective actions
The first and most critical corrective action is to ensure that the immediate corrections previously taken removed any risk of harm or further harm to the participant and future participants and that the deviation was appropriately reported to the sponsor and IRB. When study teams have assessed the rights, welfare, and safety of the participant and the root cause is known, they may consider additional reporting to the sponsor and IRB. Ensure that the report to the sponsor and IRB is accurate and thorough and that the CAPA is included.
Preventive actions
Preventive actions are necessary to ensure that the problem does not repeat in one or more participants. Preventive actions should be based on process. Create and document a process or standard operating procedure (SOP). Train on the process, implement the process, evaluate the process, and amend the process as necessary. Consider revising the protocol or informed consent as necessary.
CAPAs must be thorough (SMART CAPA)
Specific: Compliant with regulations, addresses the full observation or root cause, accountable to named individual or role
Measurable: Action can be measured to demonstrate whether it is adequate to address root cause
Achievable: Addresses all implicated processes and levels
Realistic: Plan can be carried out given resources, knowledge and expertise
Time-bound: Assigned to a person or role who can accomplish action in a given time period
CAPAs must be implemented
Ensure that the CAPA is well documented and that all study team members have been trained and understand their roles and responsibilities for successful CAPA implementation. The CAPA and associated SOP may be relevant only for the study or it may need to be implemented systematically across the clinical department. The CAPA and SOP can be rolled out in stages. The important thing is to take action and document it.
CAPAs must be evaluated over time
Effectiveness check is the final step of the CAPA process. Ensure that the CAPA has addressed the root cause and that the problem has not recurred. If the CAPA has not addressed the root cause, amend the CAPA as necessary, train on the process, implement the process, and re-evaluate.
CAPA must be well documented
Documenting the CAPA
- Action type (corrective or preventive)
- Action description
- Owner
- Due date
- Plan for effectiveness check
- Effectiveness check outcome
References
IRB Policies and Procedures #73