Is the TMF Reference Model applicable to the investigator site file / regulatory binder?

The TMF Reference Model is intended to cover the full scope of the Trial Master File as described in ICH E6 Good Clinical Practice Guidelines. ICH E6 GCP Guidelines include all the content that the sponsor is required to maintain in the sponsor TMF and all the content that the investigator is required to maintain in the investigator TMF; the latter is sometimes referred to as the ‘investigator site file’, the ‘ISF’, or the ‘regulatory binder’.

The structure of the TMF Reference Model spreadsheet includes two columns where artifacts are designated as being sponsor artifacts or investigator artifacts. These two columns are shown for non-device trials (columns N and O) and for device trials (columns P and Q). Any suggestion that the Reference Model does not include investigator site documents is incorrect.

The TMF Reference Model project team have received several comments over the years that suggest the Model can be difficult to apply to the investigator TMF and that it is not consistent with file structures that are typically used. The Steering Committee recently (January 2018) agreed to be involved with an industry initiative being organized by MAGI to introduce improvements. Representatives from the TMF Reference Model project team will participate in the MAGI project to produce an investigator TMF Reference Model that will be available as a standalone product from MAGI. Once this work is complete, it will be fully integrated into an update of the TMF Reference Model; we want to continue making available a single consistent Model across the sponsor and investigator TMFs. The objectives of this initiative are:

  • to identify any missing artifacts relevant to the investigator TMF;
  • to identify sub-artifacts that are relevant to the investigator TMF e.g. examples of source data that might be found in the investigator TMF;
  • to review the structure of the content to ensure alignment with regulatory expectations and industry best practice;
  • to ensure the content reflects requirements and best practice globally.

When is the next update to the TMF Reference Model due?

Change requests for the TMF Reference Model are being submitted on an ongoing basis via the website. In addition, some of our project initiatives produce deliverables that result in additional content to the Model. It is the responsibility of the Change Control Board to make an impact assessment of these changes to determine if they may be implemented immediately as a maintenance release (minor changes and no impact on current systems), as a minor release (significant change to content but no significant impact on current systems) or as a major release (impacts current systems). Once this assessment has been made, the Steering Committee will agree a release schedule. The schedule may include a maintenance release (e.g. v3.0.1), a minor release (e.g. v3.1) and may also include a major release (e.g. v4.0) but the schedule is based on proposed and accepted changes rather than by a predefined timeline. A public announcement will be made via this website and to registered stakeholders ahead of any release (maintenance, minor and major).

Filing at study, country and site level

According to the TMF Reference Model, the master Informed Consent Form should be filed as artifact 02.02.03 but I’m not sure where a site-specific ICF should be filed. As this is a site document, should it be filed somewhere in zone 5?

Several artifacts can be filed at multiple levels: study, country and/or site. However, the artifact number (e.g. 02.02.03) does not change. So in this example, the site specific ICF is still filed as artifact 02.02.03 but at the site-level of the sponsor TMF rather than at the study-level. Depending on the technology used in an eTMF, you may need to assign unique IDs for artifacts that exists at multiple levels within the TMF. In a paper TMF, the documents would be filed in the study-level binder, the country-level binder and/or the site-level binder(s), as appropriate.

October 24, 2016

v3 Query: IRB/IEC Artifacts

Question: It appears that “acknowledgement of receipt” is now specifically noted as a sub-artifact under IRB or IEC Submission, while “documentation received from the IRB/IEC in response to submission indicating acknowledgement” remains within the definition of IRB or IEC Approval. Can you confirm and clarify any intended distinction?
An Acknowledgement of Receipt in 4.1.1 is just to show the submission was received, but has no implications of approval. In 4.1.2, an acknowledgement can actually replace an approval in some circumstances. 4.1.2 is where you would look for any kind of approval or acceptance by the IRB/IEC. If confusing to users, the sub-artifact Acknowledgement of Receipt in 4.1.1 may be deleted.

February 24, 2106

I do not understand why artifact [xyz] is included in the TMF Reference Model


Question: I do not understand why artifact [xyz] is included in the TMF Reference Model as there doesn’t seem to be a regulatory requirement for it to be included.
If there is a specific regulatory requirement for an artifact or the general opinion of the TMF Reference Model Community based on past experience is that regulatory inspectors would usually expect the artifact to be filed in the TMF, the artifact is included as a “Core” artifact (column J).

However, there are other artifacts generated on a clinical trial where it is not so clear whether or not they should be considered part of the TMF. So these are either omitted from the Reference Model or are included as “Recommended” artifacts. Artifacts are included as “Recommended” if the overall opinion of the TMF Reference Model Community is that the artifact is study-specific and contributes to explaining how the study was conducted. In an inspection, it would therefore be helpful if these “Recommended” artifacts were treated in the same way as for the “Core” artifacts….. readily accessible, secure, retained in accordance with TMF requirements etc.

Let’s use an example: 05.04.07 Financial Documentation. Whilst there is not a specific GCP requirement to include them in the TMF, it is often helpful for certain financial records (for example spreadsheets that track payments) to be considered part of the TMF and be readily available to inspectors (and to the study team!). They demonstrate how the trial was managed.

Using 05.04.07 as an example, it is important to note that

(a) inclusion of 05.04.07 does not imply that ALL financial records should be in the TMF….. it simply provides a placeholder for those financial records that your company deems should be included (perhaps just the tracking sheets/reports?); and

(b) inclusion of an artifact does not necessarily mean the records should be in one, single TMF system….. it just means they are considered part of the Trial Master File and managed as TMF content, per your company SOP(s).

January, 2016

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