The European Medicines Agency (EMA) Guidelines on the content, management, and archiving of the clinical Trial Master File (paper and/or electronic), were finalised at the end of 2018 and became effective in June of 2019.
The guidance states that TMF trial stakeholders must have a quality management system (QMS) in place with procedures and processes established for TMF management that ensure its completeness, quality and accuracy.
One of the most important measurements in managing trial master files is TMF completeness. Being able to provide all documentation collected over the course of a clinical trial in an auditable way ensures that the trial can be reconstructed and demonstrates that proper controls were in place to protect patient safety throughout.
Traditionally, TMF managers have constructed complex Excel trackers to monitor TMF completeness and ensure that documentation is collected and completed contemporaneously. While this gave TMF managers some oversight on how healthy their TMF is, it required a significant amount of effort and time to maintain (there was also an increased risk of human error).
More sophisticated eTMF software vendors now provide greater insights into TMF health by adding business intelligence dashboards on top of content management tools. However, it is still important to understand what is truly required to measure and monitor quality and completeness before a study is locked for archival.
Quality and completeness are continuous processes
There are different types of checks performed on TMF content. Uploaders should perform a quality check prior to uploading a record and each should go through some type of QC workflow post-upload. Ideally, periodic risk-based completeness checks of the TMF throughout the life of the study should be undertaken and inspection readiness reviews may be required for some studies.
A TMF with inadequate quality checks can create risks as health authorities perform inspections as part of routine Good Clinical Practice (GCP) oversight. The expectation of regulatory authorities is that the TMF is maintained in a constant state of inspection readiness.
Each record in the TMF should be high quality which means that footers and headers are accurate, all pages are present, signatures are complete, and no unintended tracked changes are in the document. It is also important that the document meets the sponsor organisation’s requirements for Good Documentation Practices (GDP).
Where records are uploaded that do not meet quality requirements, they are often rejected during quality review workflows within the TMF which results in time-consuming efforts to remediate documents within the TMF.
Once uploaded, metadata is applied to the record including filing location and date. The record is often placed into a QC workflow where a second document review takes place and metadata is reviewed against the document to confirm that it is in alignment with the content of the document and business rules for the TMF. This is a critical quality check because if an inspector is unable to find a document in its anticipated filing location, then it will be considered a missing document which would raise questions about the quality of the TMF.
Archival and study lock
The TMF and any associated audit trails should be archived appropriately to enable supervision after the trial has ended. Sponsors should begin planning an eTMF preservation strategy early, preferably during the pre-clinical phase to ensure a robust and complete archive is created. A proactive approach like this ensures regulatory compliance and data integrity, which in turn reduces risk and can create efficiency in a trial data management.
Early planning also assists in the long-term management of documents once the study has closed. With the challenges in the section above in mind, if sponsors wait until the end of the trial, it is much more difficult to obtain records that are complete and ensure the TMF meets the requirements of authorities when under their review.
Retrieving documents at the end of a study can be time consuming and very difficult. When investigator sites are no longer involved in a study, it becomes increasingly difficult to gather any missing physical documents previously held at the site – they may be misplaced or lost, which can be compounded when study staff have moved on.
Plans for completeness review should be defined within the study specific TMF protocols and include assessments for content based on certain events or milestones. Regular reviews hold all parties accountable for the timeliness of filing documents in the TMF.
Archival and study lock should then take place after investigators and sponsors have reviewed that their filed TMF is complete.
A completeness review is not a to-do list, but a series of cross checks based on the risks of the study. They often include exporting documents and creating a pivot table to look for unexpected gaps in content or the presence of content in unexpected locations.
An example of a cross check review is checking for:
- Sub-investigator CVs
- Financial Disclosure Forms
- Protocol training
- Presence on the Delegation of Authority log for all sub-investigators listed on the Form FDA 1572
- Checking for IRB submission and approval, health authority submission and acknowledgement
- Investigator Protocol Signature Page
After every completeness review, all relevant parties are asked to collect any content identified as missing (misfiled records or incorrect metadata should be queried for correction in this process). Based on the findings of each completeness review, additional reviews may be expanded to ensure that the TMF remains inspection-ready throughout the life of the study and at the point of study lock and archival.
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