electronic trial master file eTMF in clinical trials

The eTMF (Electronic Trial Master File) plays a crucial role in clinical trials and ensures that the trial has been managed successfully by the sponsor, investigators, and the Institution. Regulatory agencies like the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) developed initiatives to use technology that could help both expedite the clinical trial approval processes and lower regulatory costs.

electronic trial master file eTMF in clinical trials

What is a Trial Master File (TMF)?

A trial master file contains essential documents for a clinical trial that may be subject to regulatory agency oversight.

Every organization involved in clinical trials must maintain and store certain documents, images, and content related to the clinical trial to comply with government regulatory requirements. Depending on the regulatory jurisdiction, this information may be stored in the trial master file (TMF).

TMF contains study level, country level, and site-level documents, and those documents are collected at multiple points during the study (e.g. start-up to study close).

Nowadays, many organizations use electronic platforms to manage these Trial Master Files known as electronic Trial Master Files (eTMF).

Why do you need an eTMF?

It is difficult and time-consuming to capture and manage physical documents and may sometimes lead to costly errors that put clinical trials at risk. Adopting an eTMF allows for real-time oversight and manage of documents to ensure compliance and audit readiness throughout the trial.

The TMF is considered essential for Good Clinical Practice (GCP), and GCP is recognized as a requirement by regulatory agencies such as the FDA. However, the eTMF is not mandatory but holds many advantages.

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Key advantages of using eTMF

Some key advantages of eTMF include

  • Access, share, and manage clinical documents anytime using a web-based application
  • Documents and reports can be audit-ready quicker than traditional paper systems
  • Provides shorter trial start-up and close-out time
  • Using eTMF drastically reduces errors than traditional paper processes
  • eTMF improves clinical trial efficiency
  • Allows faster document searching and retrieval
  • Cost savings from increased filing efficiency, reducing paper and labour usage

TMF and regulators

The International Conference on Harmonization (ICH) published consolidated guidance for the industry on Good Clinical Practice in 1996. The objective of this guidance is to provide a unified standard for the United States of America, the European Union, and Japan, and to facilitate the mutual acceptance of clinical data by the regulatory authorities in those jurisdictions.

The ICH has published a minimum set of essential documents for the TMF which include a signed protocol, audit certificate, and subject enrollment log.

  • The FDA created regulation CFR 21 Part 11 to address the use of electronic records, digital media and digital signatures in clinical trials. 
  • The EMA, in Europe, also issued policies supporting the use of digital signatures in clinical trials.

What are the sponsor and investigator trial master files?

  • Investigators are responsible for certain documents and these are known as an Investigator TMF (sometimes referred to as the Investigator Site File (ISF)). 
  • Sponsors are responsible for certain documents, where the TMF is made up of a sponsor. TMF (held by the Sponsor company). 
  • When an institution recruits investigators who are Trial Sponsors (an entity that oversees and pays for the clinical trial), they take to handle both the Investigator and Sponsor TMF.

What are the essential documents managed by the eTMF?

  • Statistical analysis software program validation, statistical analysis plan, and sample size estimations. 
  • Documentation from Good Manufacturing Practice (GMP) processes including information about the packaging of the Investigational Medicinal Product (IMP) and compliance with the randomization and blinding of the trial.
  • Forms, checklists, and reports from the trial activities carried out by the Sponsor, Investigator, and Institution. 
  • An Investigational Medicinal Product (IMP). 
  • Traceability documents for the Advanced Therapy Investigational Medicinal Product (ATIMP). 
  • Validation documents that show proof of trial-specific software and computer systems like an electronic Case Report Form (eCRF) and Interactive Response Technologies (IRT). 
  • A data management plan, data validation plan, and data review meeting minutes. 

What does an eTMF contain?

Most eTMF software vendors approach differently in the functionality, design, and specifications of their eTMF. As per the regulatory agencies, systems/software used to store electronic records or digital documents and content are generally subject to the following requirements: 

  • Digital content archiving, 
  • Security and Access controls, 
  • Change controls,
  • Audit trails, and 
  • System validation. 

Most eTMF solutions vary in how they approach digitizing and managing the TMF, however, the above core requirements are almost always present.

eTMF is gaining importance worldwide

Though the developed countries are quickly adopting digital platforms for managing clinical trials, many researchers across geography are still using traditional paper-based Trial Master File. It may be due to various reasons such as

  • Lack of exposure to such new era software and clinical trial management tools,
  • Inefficient staff or lack of knowledge or exposure to such software
  • Budget constraints
  • Not all regulators still have proper guidance for using such software in clinical trials

But things are changing very quickly. Many CROs and pharmaceutical companies are adopting software and management tools in clinical trials. The market and demand for such software is increasing recently. The growing demand for such software can be attributed to the growing number of clinical trials.

How should an ideal eTMF be?

It is critical to choose the right eTMF. An ideal eTMF shall have features for smothering and a better experience

  • Site personnel and other stakeholders shall feasibly understand the system.
  • Receive email notification to complete, upload or approve documents in the eTMF
  • Must have Electronic & Digital Signature Technology
  • Should be accessible from anywhere and on any browser
  • Easy tracking of missing documents
  • Document lifecycle and version control
  • eTMF shall allow companies to create a File /Study Plan along with milestones at the study level, country level, and site level.​
  • Shall have advanced analytics to track completeness, quality, timeliness, and TMF compliance of a study.
  • The software should easily Integrate with CDMS/ CTMS systems to get the study, site, patient, and other information and dynamically create a directory structure.
  • It is crucial that the eTMF complies with DIA, 21 CFR Part 11, ANNEX 11, GxP, and GDPR guidelines.

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