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

Should draft documents be filed in the Trial Master File?

Unanimous opinion across the TMF Reference Model is that draft versions of documents should not be kept in the TMF, including versions with track changes.

Key reasons include:

  • Maintaining drafts and annotations can highlight issues that don’t exist such as comments not followed up or opinions not agreed with;
  • There is no obligation to action all comments on a draft version;
  • European Directive 2003/63/EC contains the requirement to retain “all written opinions on the protocol and procedures”, but not drafts;
  • Documentation / correspondence should demonstrate that the review process has been followed; and
  • Retention policy may dictate that drafts are destroyed.

Individual comments from Reference Model Team members:

“Most sensible SOPs on controlled documents would provide for the retention only of approved versions of documents and the discarding of drafts. It may also, depending on the document review and approval process, be necessary to keep sufficient documentation / correspondence to demonstrate that processes have been followed per SOP.”

“Drafts and annotations should be deleted upon promotion to approval.”

“From a potential litigation perspective, it can be extremely dangerous to retain draft documents following completion/approval of the final document. If there is a regulatory need – as sometimes there is – to maintain an audit trail to demonstrate that a document was properly reviewed as per an SOP, other means should be used to enable such an audit trail to be retained. For example, many sponsors maintain some kind of document review form (or electronic equivalent). This form contains signatures of reviewers and the version of document reviewed but does not contain their review comments. A sponsor has no obligation to either accept review comments or to respond to review comments. It is usually sufficient simply to demonstrate that a proper review was conducted and the final document was approved by a duly authorised individual.”

“Many sponsors include in their corporate retention policy a requirement to destroy drafts; retention would therefore be non-compliance with company policy.”

“There may be only one exception, namely protocols. European Directive 2003/63/EC contains the requirement to retain “all written opinions on the protocol and procedures”. However, even this does not suggest keeping drafts, merely any “written comments” on the protocol. Furthermore, the requirement to retain “all written opinions” could be interpreted to apply only to the final protocol and approved procedures, rather than to draft documents.”

“Some systems actually delete all draft version a specified number of days (e.g. 30 days) after the document is approved. Part of the discussion for that decision was performance concerns if having to maintain minor versions. Also it was augmented that only things relevant enough to actually be approved should be retained in the system.”

“Draft documents are not filed in the trial master file unless they report important decisions or new information about the trial. For example, the study team would file the Core ICF, Country-specific ICF or Site-specific ICF “Tracked Changes” documents if revised due to a protocol amendment.”

“Drafts should be administrative, and should be filed as such.  They can be kept in other storage locations and used for development reference.  No-one audits to drafts.”

“If a health authority is inspecting to Track Changes versions, then there is a bigger problem than just what is in the files.”

“Only the final document should be in the TMF. Drafts documents are working documents and if retained, should only be keep until the study is finished. They would only be archived if that is the company policy.”

June, 2015

Using the Reference Model in Non-Interventional Trials

Question: We are looking for the best way of standardizing our filing system of documents issued during non-interventional trials (e.g. Post-Marketing Surveillance). These trials are getting more and more structured and require a centralized approval for being conducted in a lot of countries. Do you know whether some guidance exists for structuring a TMF for these types of trials?
We are not aware of any guidance specific to filing of documentation for non-interventional trials. Whilst guidelines exist for the ethical conduct of such studies (for example, CIOMS International Ethical Guidelines for Epidemiological Studies), the guidance does not extend to TMF management.

Non-interventional trials are excluded from the requirements of ICH GCP and many other regulatory and legislative requirements that govern interventional trials. However, they should follow relevant national legislation where this exists (ref. Eudralex Volume 9A, Part 1, Section 7.7). For example, in the UK Clause 13 of the ABPI Code of Practice for the Pharmaceutical Industry requires that non-interventional trials comply with certain criteria, including having a written protocol, having written contracts and submission of the protocol to an Ethics Committee. When using the TMF Reference Model as the framework for the design of a TMF model for non-interventional studies, a repeatable corporate model can be created while remaining consistent to this industry model. It is recommended that when establishing a TMF for non-interventional studies, the principles of the TMF Reference Model are followed in terms of terminology and structure, recognizing that modifications to the taxonomy (e.g. removal of unnecessary artifacts) might be required to ensure alignment to standardized business processes.

May 8, 2015

Are all ICH codes included in the TMF Reference Model?

Every artifact that is specifically identified in chapter 8 of ICH GCP has the relevant citation listed. In addition, where text elsewhere in the ICH guideline refers to a trial artifact, that citation has also been listed. For example, ICH section 4.12 discusses the need for the investigator to notify the IRB/IEC of trial termination. Therefeore, 4.12 is cited against artifact 03.03.03 ‘Notification of Trial Termination’ in the Reference Model.

July 2, 2014

Which TMF documents require a signature?

ICH-GCP only uses the word “signed” in relation to 5 TMF documents:

  • protocols and amendments;
  • agreements/contracts;
  • completed consent forms;
  • completed case report forms;
  • and CRF correction signature sheet / signature log.

The MHRA have stated in the GCP Guide that “signatures on documents are recommended only where it adds value”.

May 17, 2103