The following are questions related to the management of TMF content that has been raised by the TMF community and answered by the TMF Reference Model industry group.
VERSION 3.0 QUERIES:
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 acknowledgment can actually replace 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.
Yes, but you will likely need to make more adaptations of the TMF content than for a trial using an investigational medicinal product.
No, there is a separate Reference Model for these types of studies available.
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).
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.
“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 the 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 versions 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 kept until the study is finished. They would only be archived if that is the company policy.”
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.
Metadata is defined as “Data that describe other data, for example XML tags characterizing attributes of values in clinical data fields” (Source: CDISC Glossary v7). Metadata is sometimes referred to as “attributes” or “properties”. Metadata refers to information that describes certain characteristics of a file, document or record rather than information that is contained within the record content itself. In the context of creating documents, metadata could include properties such date of creation, document title, author, version number. In the context of the TMF Reference Model, metadata might also include study number, country, document language.
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.
ICH-GCP only uses the word “signed” in relation to 5 TMF documents:
– protocols and amendments;
– 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”.