Study Closeout and the eTMF

March 28, 2014

  • eTMF Resources

Inspection of a paper TMF as part of the study closeout process has always been part of that process. A quick search of the Internet returns a number of posted procedures and checklists for study closeout that include finalization of the trial master file. The TMF aspects of these checklists generally focus on ensuring that all essential documents are filed in the TMF. This check is sometimes just a statement that essential documents should be filed, and sometimes includes a reference to a previously created essential documents list that is trial-specific. A few of these checklists also mention ensuring that all SAEs are filed, etc. Finally, they may address archive issues such as what types of boxes to use in packing documents, where and how to send them, and so forth.

A nice example can be found on the web site of Academic and Clinical Central Office for Research and Development (ACCORD), a partnership between the University of Edinburgh and NHS Lothian.
This approach depends heavily on having a very clear understanding of what documents should be present in the TMF in order to determine if all necessary documents are present. It also presupposes that any necessary QC has been performed in advance of closeout.

When an eTMF is used, greater insight is available – but also greater transparency into potential problems and shortcomings. For example, you – and an internal or regulatory inspector – can see which documents underwent QC processes and the outcome, when documents were uploaded to eTMF including those only uploaded at the end of the study, and more. Following good closeout procedures can usually address completeness issues, and usually address quality issues, but can’t address timeliness issues.

When closing a study in eTMF, it’s important to understand what automated functionality your eTMF provides. A good system should allow you to:

  • See missing and expired documents, including documents needed for all vendors
  • Identify documents still in draft, QC, or other review or approval workflows
  • Mark documents as no longer expected, providing a justification
  • Ensure that all sites initiated in CTMS are present and complete in eTMF
  • Ensure that all principal investigators, sub-investigators and (if applicable) subjects from CTMS have appropriate documents in eTMF

However, the system can’t tell you everything. Other checks that are most likely manual include:

  • Is all necessary correspondence accounted for in accordance with your SOPs or Work Instructions?
  • Are all documents exchanged with regulatory authorities available?
  • Are documents associated with events that occurred during the study (such as protocol amendments, deviations, etc.) present and quality checked?

If you have been performing QC throughout the trial, you will not need to do include processes common with paper TMFs, such as making sure all documents have been filed in the correct binders (eTMF locations or taxonomies).

Once your issues are addressed and your closeout process is done, your eTMF should enforce study lock by preventing the study and its documents from being modified in any way. Normally, access to the study is greatly restricted at this point – but it must remain available to users who have a need to consult it. Long-term archive and records management are outside the scope of this post, but of course need to be considered.

As usual, eTMF is an enabling technology that is very useful in improving quality and efficiency of formerly manual processes. Using both processes and technology to enforce quality requirements as the trial is ongoing will greatly reduce “fire drill” at study closeouts or during regulatory inspections.