Trial Master File: what it is and what ICH E6(R3) and EU Regulation 536/2014 require

The Trial Master File (TMF) is the permanent record of a clinical trial: it holds the essential documents that make it possible to reconstruct how the study was conducted and to verify the quality of the data. It is the first thing an inspector asks to see. With the updated GCP guideline (ICH E6(R3)) and the EU Clinical Trials Regulation, the rules have changed: here is what to know.

What the TMF contains

The TMF includes documents produced before, during and after the study: protocol and amendments, ethics committee and competent authority approvals, contracts, staff CVs and training, informed consent (or its management), monitoring reports, investigational product documents, relevant communications and the final report. A distinction is made between the part held by the sponsor and the part held by the investigator site (often called the Investigator Site File).

What Regulation (EU) 536/2014 says

Regulation (EU) 536/2014 requires the sponsor and the investigator to keep a clinical trial master file (Art. 57) and governs its archiving (Art. 58):

the content must be kept for at least 25 years after the end of the trial, unless other EU law requires longer;
it must be readily available and directly accessible to competent authorities on request;
media must keep the content complete and legible for the whole period;
every change to the content must be traceable;
the sponsor appoints the individuals responsible for the archives, and only they have access;
any transfer of ownership of the content must be documented.

What changes with ICH E6(R3)

The ICH E6(R3) guideline has been effective in the EU since 23 July 2025; Annex 2, covering decentralised and pragmatic trial designs, becomes effective on 15 January 2027. For documentation it introduces a few key principles:

it refers to essential records, whose number and type should be proportionate to risk and to the trial design;
records must be identifiable and version-controlled;
blinding and data confidentiality must be protected when records are shared;
some records that are not trial-specific, such as SOPs or validation documentation, may be kept outside the TMF, as long as they can be retrieved.

Paper TMF or eTMF?

A TMF can be paper, electronic or hybrid, but with multicentre studies, large volumes of documents and 25-year retention, paper becomes hard to control. An eTMF (electronic Trial Master File) helps meet the requirements because it provides:

an audit trail of every action and version control;
role-based access, so each user sees only what is relevant;
compliant electronic signatures;
real-time completeness indicators instead of manual checks;
immediate access for monitors, auditors and inspectors.

The system must however be validated (EU Annex 11, FDA 21 CFR Part 11) and electronic retention planned for the whole required period.

The TMF Reference Model

The TMF Reference Model is the most widely used reference standard for organising the TMF: it defines zones and document types with a shared naming convention. It is not mandatory, but starting from it makes collaboration between sponsors, CROs and sites easier and speeds up document retrieval during inspections.

How Depalop can help

With eTMFlex, our eTMF, the TMF structure is configured through an Excel Data Dictionary, with an immutable audit trail, 21 CFR Part 11 compliant electronic signature and on-premise or European cloud deployment. A free Community Edition is available for non-profit research (details). We also provide eTMF implementation, migration and validation.