Trial Master File (TMF) , Trial Master File Reference Model (TMF RM) and Investigator Site File Reference Model or Regulatory Binder Reference Model

The TMF encompasses the filing of documents at the sponsor or at the CRO as well as at the Investigator Site with the Investigator Site File (name for the binder in the EU) or the Regulatory Binder (name for the binder in the US). The TMF can consist of paper, electronic or both formats. In the case one part is paper-based and another part is in electronic form, it is called a hybrid-TMF. CAVE: An electronic TMF does not mean documents which are scanned and uploaded as pdf documents to an electronic system. Instead it should be a validated, electronic system with an audit trail etc. No matter which format the TMF has - the essential documents should be completely filed at any time in order to meet the requirement of being Inspection ready.

Now what documents are the essential documents? The definition of the essential documents according to the ICH GCP E6 Guideline (R2) Section 8 states, "Essential Documents are those documents which individually and collectively permit evaluation of the conduct of a trial and the quality of the data produced". The Essential Documents are needed, to show that the investigator, the sponsor and the CRA followed GCP, the necessary regulations, SOPs and the protocol. In general, these are the documents that are being reviewed during an audit or an inspection to verify the validity and integrity of the data which was produced. With the addendum of the ICH GCP E6 Guideline (R2) it was stipulated that both the investigator and the sponsor should maintain documentation on the storage of the essential documents. This also includes the source data. In section 8.2 of the ICH GCP E6 Guideline (R2), we have an overview about the individual documents which are deemed essential and where (at the sponsor or at the investigator) these should be stored. This overview focuses solely on the most important documents - the essential documents.

However, there are numerous other documents that are also necessary for the complete reconstruction of a clinical trial. The TMF Reference Model was created by the TMF Reference Model Working Group of the DIA (Drug Information Association) to facilitate the filing of these documents and to minimize findings during inspections and audits. The TMF Reference Model working group was founded in 2009. In 2010 a first version of the TMF Reference Model was released. With the current version 3, the artifacts and zones were specified, the sub-artifacts were designed more clearly and the structure was improved.

The TMF Reference Model is subject to a constant adaptation to meet the expectations of the regulatory authorities and the changes of industry standards. In order to ensure a proper adaptation, all colleagues working in Clinical Research are invited to be participate in the working group. The cooperation is voluntary and on an unpaid basis. Anybody who is interested can find more information and can sign up on the webpage https://tmfrefmodel.com/.

The TMF Reference Model is primarily intended for storing documents that are filed at the sponsor or at the CRO. The TMF Reference Model is less suitable for filing of documents at the study site.

In order to standardize the filing of documents at study sites (in the ISF/Regulatory Binder), the ISF Reference Model or “Regulatory File Table of Contents” v 0.9 was published in February 2020 by MAGI (Model Agreements & Guidelines International).

The goal of MAGI is to harmonize processes within clinical research by sharing standardized processes as best practices.

The ISF Reference Model is much simpler as the TMF Reference Model. It consists of only three columns: 1. Documents, 2. TMF Artifact# and 3. TMF Artifact Name. The latter two columns are referencing to the respective document of which a copy or the original (according to the specification of the ICH GCP E6 Guideline (R2) section 8.2) is filed under the corresponding artifact in the TMF.

The ISF Reference Model only lists the documents that are relevant for the trial site. The ISF Reference Model in its current form is tailored for the use of the study sites in the US. However, the ISF Reference Model can and should be adapted for the use of the study sites in the EU.

Perhaps this step can subsequently be taken up by MAGI?

Furthermore, the ISF Reference Model is only available as a pdf document to be downloaded from the MAGI webpage and therefore cannot be easily adapted. In addition, the reference model, may only be used by members of MAGI (including their business partners), as stated in the footer of the document. However, a MAGI membership is free of charge.

As described above, the structure of the ISF Reference Models is considerably simplified compared to the structure of TMF Reference Model, which is divided into zones. The zones itself are divided into sections, which again are divided into artifacts.

Even if the TMF Reference Model is freely accessible, it should be verified whether the reference model in the present structure fits to own processes and to the TMF used. If necessary it should be adapted. Also it should fit the system being used - depending on whether an eTMF, a paper TMF or possibly even a hybrid TMF is used. In addition, it should also be verified whether the structure of the TMF Reference Model fits the respective laws and regulations of the corresponding country or region. Another point to consider is that clinical research is a dynamic field which needs to be adjusted as processes are changing or have to be changed, especially during a situation like the current COVID-19 pandemic.

Ultimately, working with the TMF Reference Model and the ISF Reference Model should be according to all other processes and guidelines within clinical research. Which should constantly being checked and adjusted in order to meet the current circumstances. The best document or the best process is completely useless if it cannot be worked with.

Sources - all pages were opened last on June 7th:

ICH GCP E6 Guideline (R2)

TMF Reference Model User Guide v. 16. Mrz 2018 (https://tmfrefmodel.files.wordpress.com/2018/03/tmf-rm-deliverable-user-guide-v1-2018-03-16.pdf)

Journal of Clinical Research Best Practices, Vol. 16, No. 2, February 2020 by Norman M. Goldfarb - Announcing the MAGI eRegulatory Binder Reference Model Version 0.9

(https://www.magiworld.org/resources/journal/2453_eRegBinders.pdf)

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