Six critical eTMF retention requirements: complying with EU Clinical Trial Regulation

The EU Clinical Trial Regulation (EU CTR) has, to varying degrees, been in effect for several years now. First published in 2014, the regulation came into effect in January 2022 for new trials and, as of January 31st 2025, will apply to all active clinical trials being run in the EU.

While the regulation (sometimes referred to as its official name, EU Regulation 536/2014) covers the entirety of clinical trial regulations for organisations conducting trials in the EU or planning to sell their drug into the EU market, for the purposes of this post I will cover the key elements related to the retention of the trial master file (TMF/eTMF).

It’s also worth mentioning that I’m going to interchange between trial master file, TMF and eTMF throughout the post. If you’d like more information on what this is, you can read our post on ‘What is the Trial Master File (TMF)?’. 

What are the retention requirements of EU CTR?

Unless other Union law requires archiving for a longer period, the sponsor and the investigator shall archive the content of the clinical trial master file for at least 25 years after the end of the clinical trial. – EU CTR, Article 58 Clinical trial master file

A major change brought in with the new regulation was the requirement for both sponsor and investigator to archive the TMF for at least 25 years after the conclusion of the trial.

Retaining data for this length of time presents several challenges for organisations. If we are to maintain integrity (e.g. in line with ALCOA+) and inspection readiness throughout this entire period, we must actively maintain the data vs. leaving it somewhere and forgetting about it. 

We’ll explore this in more detail throughout this post.

Who does EU CTR say is responsible for retaining the TMF?

The sponsor and the investigator shall keep a clinical trial master file. – EU CTR, Article 57 Clinical trial master file

The sponsor shall appoint individuals within its organisation to be responsible for archives. Access to archives shall be restricted to those individuals. – EU CTR, Article 58 Clinical trial master file

I’ve pulled quotes from both article 57 and 58 to demonstrate that 1) both the sponsor and the investigator shall retain a TMF (usually, we would see the investigator refer to theirs as the Investigator Site File (ISF) and 2) an individual (or individuals) must be designated to be responsible for the retention of the documents.

This presents an operational challenge, that organisations must ensure they have the capability to control access to these records. This includes not only having appropriate access controls in place, but capturing a complete audit trail of who has accessed the documents to ensure no unauthorised access has taken place.

Does EU CTR reference the ALCOA+ principles in relation to retention?

While EU CTR does not specifically reference ALCOA+, the principles themselves are extensively used throughout, including within articles 57 and 58, that speak specifically to the retention of the TMF. Legible, complete and available are just three which are mentioned which we will explore in the next section.

It’s also worth mentioning that while EU CTR does not use the phrase ‘ALCOA+’, the EU’s published guidelines on the use of computerised systems in clinical trials does. This document provides guidance on how to comply with regulations, and places ALCOA+ at the centre of maintaining integrity when managing clinical trial records and data throughout its entire lifecycle (which includes the 25-year retention period referenced in EU CTR).

A readily available and accessible archive

The content of the clinical trial master file shall be archived in a way that ensures that it is readily available and accessible, upon request, to the competent authorities. – EU CTR, Article 58 Clinical trial master file

Another way of stating this requirement would be that the TMF needs to be inspection ready throughout the entire retention period. This presents organisations with the challenge of not only how to have processes which support this for +25 years, but also ensure that the archives are maintained and accessible for that length of time as well.

Several risks can threaten inspection readiness, including (but by no means limited to);

• Data is corrupted or lost
• Backup failures
• End-of-life systems resulting in vendor lock-in
• Audit trails expire or are deleted
• Data is distributed and can’t be found

Having an appropriate system in place, supported by robust SOPs, is crucial. If we take the example of mitigating the risk of data becoming corrupt, good practice dictates that you should;

• Store at least two copies of your data in separate geographic locations
• Regularly check for any data integrity/corruption issues
• Have a process in place to replace corrupted for healthy from your secondary storage location.

Ensuring legibility of the TMF for +25 years

The media used to archive the content of the clinical trial master file shall be such that the content remains complete and legible throughout the period referred to in the first paragraph. – EU CTR, Article 58 Clinical trial master file

EU CTR clearly states that retained documents within the TMF must be legible (note the direct use of an ALCOA+ principle) for the entire retention period.

The longer that data needs to be retained for, the harder it can be to maintain the legibility of that data. Over the next 25 years technology (both hardware and software) will change beyond what I can predict today. Accessing an TMF created today with a device used 20 years from now will likely result in either a ‘File not recognised’ or ‘This device cannot open this file’, ultimately rendering it illegible.

The process of digital preservation can address this challenge by maintaining a long-term preservation copy of every document that needs to be retained. In this way each document has the greatest chance of being recognised by whatever future device it is being accessed on, and legible to the human trying to read it.

You can find out more on our digital preservation page.

Capturing an audit trail

Any alteration to the content of the clinical trial master file shall be traceable. – EU CTR, Article 58 Clinical trial master file

The final part of the regulation (which I touched on earlier) that I want to highlight is the capturing of audit trails within your archive. Audit trails can, and arguably should, not only capture (as referenced above) any changes to the documents but also who has accessed what and when.

Any system which cannot capture an audit trail is not fit for purpose for retaining the eTMF.

In summary

Articles 57 and 58 of EU CTR total just over 300 words, and yet the requirements outlined within these sections create several challenges that sponsors and investigators have not had to address previously.

I hope that this article has provided some insight into not only what these requirements mean but how sponsors and investigators can start to prepare their long-term retention strategies.

For more information about how to approach retaining essential GCP records and archives, you can read our latest eBook.

Alternatively I’d be delighted to talk to you further about anything I’ve raised in this article. You can contact me via the Contact page on the website.