There are two times during the life of the study when the management of the Electronic Trial Master File (eTMF) is a buzz of activity: start up and end of study. Ensuring the integrity of the data through the entire study is critical, but how to handle that data at the end of the study tends to be the last thing on everyone’s mind until…well, the end! Sponsors should be thinking of this process long before it’s needed so they aren’t left scrambling.
I’m going to be focusing on the eTMF, but I want to acknowledge that the TMF may have a paper component. In this situation, the sponsor needs to ensure that there is a process around the archival of the paper TMF and/or have a documented certification process if they choose to scan it and not store the paper long term.
Those of us who live in the TMF have a saying: if it isn’t documented, it didn’t happen! Losing the data that shows the trial was conducted as required per study plans, SOPs, and regulatory requirements would be devastating to a trial as it can result in a regulatory authority not approving the application. This could impact thousands of lives who may depend on that drug or device! This is why it is important that both the close-out process and compliance of that process are clearly documented. The entire process that will be followed for the study needs to be documented in SOPs or, at a minimum, the TMF Plan. There should also be documentation of compliance (e.g., a form that is signed by both parties’ post transfer).
Ensuring study close-out success
There are several steps of the close-out process to consider to ensure success. For our purposes, let’s assume that a vendor is holding the eTMF, not the sponsor. This is not only common, but a process that requires more thought and steps. Here are some things to think about when planning the process:
- How will the records and their related data be transferred from the vendor?
- Is extensive mapping required to transfer them between the two systems?
- What will that data include, and will it be held in a format that is easily accessible and navigated in case of inspection?
- What will the sponsor do with the records and data once received?
- Sponsors need to ensure their post migration activities are compliant with ICH E6(R3)
I’d like to focus on the second bullet for a moment: what data will be included with the transfer. Per ICH E6(R3), the sponsor has the responsibility of oversight and ensuring that processes outlined in SOPs and study plans were followed. For example, if the record review process required records to go through a two-step quality review process, how is the oversight of that process documented? How is it documented within the metadata itself? This is only one example of why the audit trail needs to be provided to the sponsor along with the records. Another item that should be included in the transfer is a listing of the records and their associated metadata (e.g., document date, filing location, status, etc.).
One of the first steps in the process is to ensure that the study is complete before it is closed and transferred to the sponsor. This includes ensuring that all records expected are present, all records are marked as final, and all quality issues resolved. If the eTMF system is advanced enough, gathering this information should be relatively easy (such as running a report or dashboard that the system has available). But not all systems can function at this level. A few methods I’ve seen used include using estimated record count or performing a review using study records (trackers, plans, meetings, etc.) to determine an expected record listing. This review should also include focused time on the data to ensure accuracy.
TMF planning for the long-term
The sponsor should think about access updates to ensure the integrity of the data long term. For the sponsor, it means ensuring that only certain individuals have access to where the eTMF is stored. Also, they must appoint an individual within its organization to be responsible for the archives to be compliant with Article 58 of the Regulations. For the vendor, this may be switching users from an access with edit capabilities to read only. Or it may mean removing everyone except the system admin. The key is to ensure that the study can no longer be modified.
Once the eTMF is determined to be complete and transferred, the sponsor will need to ensure the integrity of the data and records received. Then the final step in the close out process for the eTMF is archiving. Per the EMA Guideline on the content, management and archiving of the clinical trial master file (paper and/or electronic):
- Articles 58 and 57 of the [Clinical Trials Regulation (EU) No. 536/2014], both state that “the content of the clinical TMF shall be archived in a way that ensures that it is readily available” “and directly accessible, upon request, to the Member States.”
- As per Article 58 of the Regulation “unless other Union law requires archiving for a longer period, the sponsor and the investigator shall archive the content of the clinical TMF for at least 25 years after the end of the clinical trial.”
This means the sponsor needs to determine where the content will be held so that it can be easily accessed in case of inspection while maintaining its integrity for at least 25 years. Studies completed only in the USA may choose to go with the FDA’s less strict standards. However, if there is any chance the study may be used in Europe in the future, this needs to be considered.
In summary: Focus on the end at the beginning
The close out and archival process may seem daunting at first. Break it down into three key areas to focus on one thing at a time:
- How will the sponsor ensure the eTMF is complete?
- How will the eTMF be transferred and with what metadata?
- What will the sponsor do with the eTMF once received?
Of course, the best way to ensure that the end of the study will be smooth for the eTMF is to plan and manage it from the very beginning. Throughout the years of a clinical trial, it is common to see team member turnover and a lack of documented historical knowledge. The study will start to lose team members, vendors will remove access, and the sites may no longer be willing to assist. By maintaining the eTMF throughout the life of the study, the entire process will be less stressful as the team won’t be trying to chase and locate records at the end of the trial. The longer it has been since a record was finalized, the more difficult it will be to find or collect. By ensuring the team is filing records contemporaneously throughout the trial, this risk is greatly reduced. Plan your close out process in advance, manage your eTMF throughout the life of the study, and your future selves will thank you!
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