What does it take to make your TMF an eTMF?


A Trial Master File (TMF) is a comprehensive collection of documents that ensures the conduct of your clinical trials is properly recorded and evidenced according to GCP (Good Clinical Practice). Traditionally, the Trial Master File was paper-based, but an eTMF can accelerate and streamline your process. What’s the best and most cost-effective way to digitise your TMF?

What is a Trial Master File?

The TMF includes documents used by sponsors, investigators, and ethics committees to monitor, administer, and oversee clinical trials.

It ensures the rights, safety, and well-being of trial participants are protected and that the clinical trial is conducted in accordance with the relevant regulatory requirements.

It provides evidence as to how, when and by whom

  • Safety decisions were made
  • Consents were given
  • Data collected, shared, and approvals gathered

The TMF must be accessible to auditors such as the FDA and EMA. If it is collated and maintained in electronic format, it needs to adhere to their validation and control requirements for computerised systems.

But for those trying to build an eTMF without dedicated software, this can become a major challenge.

Are your e-signatures FDA compliant? Download our 21 CFR Part 11 checklist to  find out

Trial Master File

Trial management documents include:

  • Trial protocol and amendments
  • Investigator Brochure
  • Regulatory authority approvals
  • Ethics committee approvals
  • Trial monitoring reports
  • Communication records between regulatory authorities, ethics committees, and the sponsor
  • Master list of all documents and data

Site management documents:

  • Site selection and qualification documents
  • Site-specific training records
  • Signed informed consent forms
  • Recruitment tracking
  • Correspondence with investigators and site staff

Subject management documents:

  • Case report forms (CRF)
  • Source documents
  • Randomisation details
  • Subject screening and enrolment logs
  • Adverse event monitoring and reporting

Product management documents:

  • Investigational product accountability logs
  • Shipping and handling documentation
  • Storage and disposal records

Quality control documents:

  • Audit reports
  • Quality control checks and validation of study tools
  • SOPs relevant to the trial and any deviations from them

Study report:

  • Final study report
  • Statistical analysis plan and reports
  • Publications and presentations related to the trial

Closure documents:

  • Trial closure notification to regulatory authorities and ethics committees
  • Data management and archiving plan
  • Final trial master file index

Paper vs eTMF systems

Traditionally, TMFs have been assembled in a manual way with ever growing paper files crammed with all the required information and evidence for future audit. But manual collation is time-consuming and error prone. Paper filing is hard to maintain and index, and even tougher to scale and control over sometimes decades’ long trials.

"In the clinical trial world, if it isn't documented, it didn't happen. In a paper-based system, you have to keep every single piece of paper - every email that's come in has to be printed. Our Trial Master Files were typically 50 or more lever arch files long."

Julie Errington, Clinical Trials Analyst/Coordinator, NCCPG

What can an eTMF do for you?

An eTMF serves the same purpose as the traditional paper-based TMF but offers enhanced efficiency, accessibility, and compliance through digital means. It supports the management of documents across the entire lifecycle of a clinical trial, from planning and execution to closure, audit, and inspection readiness.

The challenge of creating an eTMF

But digitising TMF contents comes with its own set of challenges. Attempting to build your eFTM using a DIY approach with One Drive or Google Docs is always going to be hard. Without specialist document management tools the risk of document anarchy taking hold among expanding folders and files looms large.

To add more complexity, both the FDA and the EMA have added a further layer of integrity requirements that are difficult to achieve without specific document control levers.

Ensuring the eTMF system complies with regulatory requirements involves several critical components, including electronic signatures, audit trails, and document version control.

Electronic signatures

The eTMF system must support electronic signatures in a way that complies with regulatory requirements such as FDA's 21 CFR Part 11 and the EMA guidelines. You must have the tools to ensure complete control over e-signature authorisation within your system. You must be able to:

  • Authenticate the signatory to ensure a record was signed by the claimed signatory.
  • Ensure non-repudiation so the signatory can’t later deny having signed the record.
  • Ensure an unbreakable link between the electronic record and its signature, such that no one can later change the contents of a signed, approved version of a record.
  • Ensure the ‘meaning’ of each signature is captured with each application, and recorded in its audit history.
  • Ensure that external approvals can be managed with e-signatures that meet the regulatory bar for authentication  (i.e. through integration with DocuSign or similar).
  • Provide a timestamp so the date, time, and time zone when the signature was applied is recorded.

Audit trails

Audit trails are crucial for achieving regulatory compliance. The right eTMF should provide a detailed, time-stamped record of all actions and changes related to the decision making process. This should include provisions for: 

  • Traceability: Every action performed on the eTMF system should be traceable back to the individual who performed it, including document creation, modification, deletion, and access.
  • Integrity and security: The audit trail itself must be secure and immutable to prevent unauthorised alterations. It should accurately reflect the sequence of activities and be protected against tampering.
  • Comprehensive coverage: The audit trail should cover every aspect of the eTMF data lifecycle, from initial document creation through to archiving, ensuring a complete history of each document is maintained.

Document version control

Version control is essential for managing document updates and ensuring that only the current and approved versions of documents are accessible for trial conduct and regulatory inspection. This involves:

  • Document history: The eTMF system must maintain a history of all document versions, including draft and final statuses, revision dates, and details of the revisions made.
  • Access control: Users should only have access to the document versions relevant to their role and the current stage of the trial, with previous versions accessible as needed for audit or review purposes.
  • Change documentation: Every document change should be justified, documented, and approved within the eTMF system, ensuring transparency and accountability.

In addition to these core components, the eTMF system must also ensure data protection and privacy in line with regulations such as the General Data Protection Regulation (GDPR) in the EU, and comply with specific requirements for the secure storage, backup, and archiving of clinical trial data.

Ensuring compliance with these regulatory requirements necessitates a comprehensive understanding of the regulations, a well-designed eTMF system that embeds compliance features into its architecture, and ongoing vigilance to maintain compliance over the life of the clinical trial.

Organisations conducting clinical trials can invest in proprietary eTMF software to meet these demands, but this can be an expensive option. These tools also may not give you the flexibility you need to configure forms or workflows to support the way you run your trials. But going it alone with DIY tools can also be risky - the lack of compliant document control tools could leave you without the required structures and audit trails to prove compliance.

How to manage clinical trials and meet GCP guidelines with Cognidox

There is another way

For organisations struggling to find a flexible, cost-effective solution for supporting their eTMF it’s worth looking at more configurable eQMS options.

With a modern eQMS solution, you can create a framework for your own eTMF; building out your own forms and documentation workflows using a full range of document control tools.

With the right document management suite you can meet all the GCP and ALCOA++ requirements without incurring the costs of a full blown, proprietary eTMF solution.

Many teams have found this a more agile approach to digitising their process, while meeting the regulatory demands of clinical trial management.

“From a GCP perspective every document has a full audit trail that is updated in real time. You can always see what changes were made by whom. It gives you peace of mind that nothing can be changed without authorisation and audit trail - and auditors can see the complete history of your decision making as it happened”.

Julie Errington, Clinical Trials Analyst/Coordinator, NCCPG

Document control for medical device developers

Tags: Quality Management System

Joe Byrne

Written by Joe Byrne

Joe Byrne is the CEO of Cognidox. With a career spanning medical device start-ups and fortune 500 companies, Joe has over 25 years of experience in the medical device and high-tech product development industries. With extensive experience in scaling businesses, process improvement, quality, medical devices and product development, Joe is a regular contributor to the Cognidox DMS Insights blog where he shares expertise on scaling and streamlining the entire product development cycle, empowering enterprises to achieve governance, compliance, and rigour.

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