Good Clinical Practice: A Question and Answer Guide2024/2025 Edition - 399

The Trial Master File
18.15 Q. Is an " intentionally left blank " page acceptable in the TMF?
A. If there are blank pages in your TMF, these should be explained. For example, if using an eTMF you can add a
comment to the metadata noting that the page is intentionally left blank. Paper TMFs can have a line drawn through
that page with initials and date added. The purpose of explaining a blank page is to confirm information is not
missing from the record. Ideally records do not have blank pages when filed in the TMF.
18.16 Q. Many sponsors use QC checklists for managing the review of records for finalizations (i.e. ICF,
protocols, CSR). Should these QC checklists be filed in the TMF?
A. Yes, any documentation that supports a quality system procedure should be retained as part of the TMF. This
includes such records as Investigational Product release, database lock forms and study record review checklists,
such as ICF QC checklists. These records can be co-located with the associated records. Some organizations add
metadata to identify the records as quality review records when filing in an eTMF.
18.17 Q. How does a sponsor ensure quality of the TMF?
A. TMF quality oversight is the responsibility of the sponsor even if they have transferred responsibility for
managing the TMF to the CRO. The principles of ALCOA++ should be applied to TMF documentation. Records
should be attributable, legible, contemporaneous - meaning they are added to the TMF in a timely manner, original
records of source, and accurate. Content should be complete and consistent. For example, filing locations and
metadata should be consistent throughout the TMF. Content should be enduring (maintained in a human readable
state) and available for review. Finally, content should be traceable. Traceable when moved from one organization
to another including the migration of content from one system to another.
There are two types of quality oversight activities that are critical to maintaining an inspection ready TMF
- record quality review and completeness quality review. Both of these activities should be performed by an
individual other than the person filing the TMF record. Record quality is generally performed at the time of filing
into the TMF and includes review of the following:
Record quality
1. Record is readable
2. Pages are not cut off
3. There are no post it notes on the page
4. pages are numbered correctly
5. Record is complete with all pages present and in the correct order
6. The headers and footers within the record match the record correctly
7. For records requiring a signature within the record, all signatures are present
8. It is a final record with no track changes
9. Metadata has been assigned correctly (eTMF)
10. The record has been filed correctly according to the TMF Index/Map
11. Record is not a duplicate of another record already filed in the TMF
The second type of review is completeness review. On 6 December 2018, the European Medicines Agency
published a " Guideline on the content, management and archiving of the clinical trial master file (paper and/or
electronic). " The EMA emphasizes the importance of the sponsor performing routine ongoing QC of the TMF to
ensure the TMF is up to date. This type of review can occur at regular intervals throughout the study or at specific
milestones (i.e. site start-up complete, last patient last visit, CSR finalization). This is a review to confirm that all
records are present in the TMF as expected. It is confirmed that all versions of all expected records are available,
including supporting records such as translations and certificate of translations. Often this is done through a riskbased
approach based on the regulatory significance of the record and the potential risk and implications of a
record gap. It is important that the individual performing this review is familiar with the expected records and the
version of TMF records such as the protocol, ICF, study plans, and investigator's brochure. Such a review often
includes cross check reviews of the Delegation of Authority Log, Form FDA 1572, monitoring visit records, site
visit logs, ethics committee submission and approvals, and regulatory submissions and approvals. The TMF is
reviewed to ensure that expired records have matching current records present. For example, if the investigator's
medical license has expired, there is a current version also available for the duration that investigator is involved in
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Good Clinical Practice: A Question and Answer Guide2024/2025 Edition

Table of Contents for the Digital Edition of Good Clinical Practice: A Question and Answer Guide2024/2025 Edition