CAPA- corrective and preventative action– Are CAPA plans for clinical trials different than a CAPA for a GMP quality system? Do GCP regulations require CAPA plans? Is a root cause analysis necessary to develop a CAPA plan? What are FDA’s expectations for CAPA plans? These are some of the questions that were asked at EXL Pharma’s conference on CAPAs in the clinical trial environment held last month in Virginia. I then had the opportunity to ask them all over again during a “for-cause” GCP audit. The results provided for some interesting insight into how sponsors, CROs, and clinical investigators can investigate errors in clinical trials and put in place a process to prevent the errors from continuing.
First we should define our terms:
Corrective Action: –Immediate action to a problem that has already occurred or has been identified.
Preventative Action= Taken to eliminate the root cause of a potential problem including the detection/identification of problems.
Root Cause Analysis: A class of problem solving methods used to identify the root causes of problems or events.
These definitions hold true for all GxP quality systems. However, there are some basic differences that set GCP CAPAs apart from the manufacturing or GLP arena:
= FDA regulations assign responsibilities to Investigators, Sponsors, & IRBs- there are NO regulatory responsibilities for human subjects participating in clinical trials
= GMPs involve a manufactured product- GCPs involve a clinical investigation, an experiment- The “products” are the integrity of the data and the protection of human subjects in clinical research.
= GMPs largely involve a manufacturing process- GCPs largely involve the interactions of PeopleFDA has made it clear both in public presentations and in Warning Letters to sponsors and clinical investigators that they expect two responses to GCP problems once they have been identified. First, there should be an investigation regarding how widespread the problem is. In effect, conducting a root cause analysis and investigation into the problem. Next, FDA expects a description of efforts into the prevention of the problem in the future. This is essentially a plan of corrective and preventative action, a CAPA. So even though FDA’s GCP requirements don’t specify CAPA plans, if you receive a Form FDA 483, Inspectional Observations, you really need to put a CAPA plan into place. Here are two examples why:
= FDA Sponsor Warning Letter, January 2011 – “Your response is inadequate in that it does not describe your corrective and preventive actions in sufficient detail.”
= FDA NIDPOE letter to Clinical Investigator (potential disqualification warning) 2009: “…however, you failed to investigate for additional acts of falsification within the same clinical investigation or in other clinical investigations in which the study coordinator was involved.”The root cause analysis of a clinical trial problem should include an investigation into what happened. Different problems will need different levels of investigation depending on significance. In addition, the root cause analysis will need to determine if a CAPA plan is required. Not all problems or errors are both systemic and significant. You don’t want to institute a system of “Death by CAPA” by initiating a CAPA plan for each error that occurs. People make mistakes and a quality system should focus on the errors that matter. Sometimes you will see a “CAPA” that merely restates the error and then the ubiquitous note to file saying “retrained study coordinator.” This is not an appropriate CAPA plan and not an appropriate corrective action. Here are some points to include in a CAPA investigation:
= There can be multiple root causes- Always Look at Two Possible Root Causes
= “Always look at the raw data.” If you are not looking at original documents, then you are missing something of importance
= Why, why, why, why, why The “five why’s” of CAPA. Drill down to find the root cause.
= The “root cause” is not restating the error.
= PICCC: Problem, Investigate, Comparison, Clues, CausePICCC is a useful tool in a root cause analysis. What does “comparison” mean? It means to compare the problem across protocols and across clinical sites. If you have the failure to follow a point in the protocol at one site, do other sites have the same problem? If that is the case, the root cause may very well be that the protocol is poorly written, it may need an amendment. The corrective action would not read, “retrained study coordinator on the importance of protocol adherence.” The CAPA plan would look in a different direction, towards the sponsor. The ubiquitous note to file may not be necessary.
There is a wealth of resources on CAPA, root cause analysis, and conducting an investigation. I am including some of those that I used for this post as well as for presentations. There is still a lot to be developed on CAPAs for clinical trials. However, it is clear that regulatory agencies want to know what you have done to investigate clinical problems and what you are doing to prevent them from recurring. In short, they want CAPA plans.
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GxP Audit & Risk Management Congress: 20-21 October 2011, Philadelphia, PA. This conference combines both GMP and GCP tracks to maximize the opportunity for cross training, shared best practices, and networking. Two members of the GxP Perspectives LinkedIn group, Janice Wilson and Adi Lampmann, are among the faculty. The conference is sponsored by ExL Pharma and GxP Perspectives is a media partner.
SPECIAL UPDATE: 18MAR2011: FDA has released an updated version of the Compliance Program Guidance Manual 7348.810, Sponsors/Contract Research Organizations/Monitors. There are new sections on registration of clinical trials on ClinicalTrials.gov, Financial Disclosure, the Part 11 Scope & Application Guidance Document, and other issues. If you work for a sponsor, a CRO, or are a contract CRA you MUST read this document. Review Section III, Inspectional.
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