We're continuing to explore how well elements of the GMP-based quality management system support clinical trials. So far we've covered SOPs, vendor qualification, and training. Today, we're going to look at the CAPA system, which includes deviation tracking, root cause analysis, and determination of corrective and preventive actions.
The CAPA process makes absolute sense to clinical study teams, but it is a bear to operationalize due to three factors: scope, time, and attention.
Whose QMS? In a clinical trial, two ore more quality management systems govern any particular deviation. The sponsor has a quality management system, and each vendor has its own as well, so right from the start most deviations are being handled according to the processes of at least two quality management systems. If one vendor is overseeing or subcontracting to another, or an issue involves two or more vendors, addition QMSs may apply. On top of that, the protocol and study team make up a QMS-within-a-QMS, with its own processes for managing deviations. If a deviation involves a clinical site, the site should have its own processes for managing deviations. Imagine all those QMSs stacked on each other like a tottering Jenga tower.
When something goes wrong in a clinical trial, the first thing the team needs to do is determine whose processes will be followed to report, track, assess, and follow up the issue. Starting at the top of the stack, clinical sites will follow processes for issues that involve the site. The study team manages protocol deviations according to their study-specific processes, but some teams interpret the protocol deviation process narrowly, scoping out GCP deviations that are not a clear deviation from protocol requirements. Vendors may only report deviations from vendor SOPs or, if they report a deviation related to a study but conclude that the root cause did not involve a deviation from a vendor SOP, they may close the deviation without further investigation.
Many sponsors struggle to define when they should step in with their own root cause analysis and CAPAs. Conscious of the fact that so many other quality management systems are at work, they don't want to duplicate efforts, but the site, study team, and vendors may not have the breadth of vision to assess the issue systemically. Although the Quality Assurance team is available to facilitate and support investigation and CAPA activities, the study team knows that the burden will fall on them, which brings us to our second factor...
Investigations take time. Our team is frequently called upon to help study teams manage investigations. A proper investigation can span weeks and take up 40 hours or more of investigation time. Essentially, it's like conducting a complex audit - a task that most study team members have neither the time nor inclination to perform.
Is it any wonder most teams approach an investigation like a high school student trying to complete an essay? They just want to turn in the paper so you can mark it as complete! This is why so many root causes are "The CRA didn't follow the process" and so many corrective actions are "We fired the CRA." It's not that the study team doesn't understand the assignment; rather, they don't have time to do a good job on it. They could spend the time, but they are reluctant to, because...
Attention is a finite resource. Study teams put out fires. There are only so many hours in a day, so teams are conditioned to identify issues and correct them quickly. A team that spends too much time on today's problem could be distracted from identifying tomorrow's issue.
For example, let's say a team discovers toward the end of the study that there was an error in the programming of the IRT system. To protect participant safety and data integrity, the team must assess the scope of the error and fix it, if possible. Analysis of the issue is geared toward understanding the nature of the error - the "what." The "why" part of the root cause analysis feels like a luxury. Will it help the team to learn that start-up processes were inadequate when they're staring database lock in the face? Will it help the next team on the next study, even if the next study uses a different IRT vendor? QA will say of course it's always helpful to learn the root cause and apply corrective and preventive actions - but from the study team's perspective, it's not a good use of time.
My biggest take-away from supporting clinical teams with investigations and CAPAs is this: What we may perceive as shirking root cause analysis and CAPAs is actually an attempt to use resources effectively. Unlike a manufacturing environment, where the same methods are being repeated over and over again, and a significant deviation should "stop the line," a clinical trial cannot pause for most deviations. Study teams naturally focus on immediate risks to patient safety and data integrity for the current study.
If we in GCP QA want to help sponsors address systemic causes, we need better ways of differentiating systemic issues from isolated or time-bound issues, and we need to support teams with resources for investigations when they are warranted.
