The EU Clinical Trials Regulation (EU CTR) 536/2014 has brought significant changes to clinical trial management across Europe, including how Trial Master Files (TMFs)—especially electronic TMFs (eTMFs)—are maintained at the site level. Understanding these changes is crucial for site teams, sponsors, and CROs to ensure compliance and efficient document management.

What is the EU CTR?

The EU CTR came into application on January 31, 2022, replacing the previous Clinical Trials Directive. It aims to harmonize clinical trial processes across the EU, increase transparency, and improve protection of trial subjects. One important outcome is how documentation requirements are standardized and how trial data and documents are shared through the Clinical Trials Information System (CTIS).

Impact on Site-Level Filing in the eTMF

Before EU CTR, each trial site was responsible for maintaining a set of essential documents in their site-level TMF. These documents supported regulatory inspections and audits, and some overlap existed between site files and sponsor files. The new regulation and its associated guidance have refined what is expected at the site level.

What Changed? Key Effects on Site-Level eTMF Filing

1. Centralized Document Submission via CTIS

• Before: Sites maintained many regulatory documents locally, including approvals, correspondence, and site-specific agreements.
• After: Many documents are now submitted centrally to CTIS by the sponsor or coordinating investigator, reducing the need for duplicative filings at the site.

2. Reduction in Site-Level Regulatory Documents

• Some documents that previously had to be filed at each site’s eTMF are now only maintained centrally. Examples include:
  • Clinical Trial Authorisation (CTA) approvals
  • Ethics Committee opinions
  • Investigator Brochure (IB) versions
• These are accessible through CTIS, so sites no longer need to maintain hard copies or local electronic copies unless otherwise requested.

3. Focus on Site-Specific Documents

• The site-level eTMF now emphasizes documents directly related to site operations and participant management, such as:
  • Site delegation logs
  • Informed Consent Forms (ICFs) signed by participants
  • Site staff CVs and training records
  • Local laboratory certification or equipment logs (if applicable)
  • Site visit reports and correspondence specific to the site

4. Streamlined Essential Documents

• The ICH E6(R3) Addendum and EU CTR guidance documents promote a risk-based approach, encouraging sites and sponsors to file only documents essential for the conduct and oversight of the trial at the site.
• This reduces clutter and focuses compliance on documents with direct regulatory or operational relevance.

Summary: Documents Typically Filed at Site Level Before EU CTR

• CTA approval letter and application
• Ethics Committee approvals and correspondence
• Investigator Brochure versions
• Site contracts and agreements
• Signed ICFs
• Delegation of authority logs
• Investigator CVs and training certificates
• Site-specific correspondence with sponsor/CRO
• Laboratory certifications or equipment logs
• Monitoring visit reports and follow-ups

Documents Not Typically Required at Site Level After EU CTR

• CTA approvals and Ethics Committee opinions (available in CTIS)
• Investigator Brochure versions (centrally maintained)
• Some regulatory correspondence now managed centrally
• Redundant copies of centrally filed documents

What This Means for Site Teams and Sponsors

• Sites should focus on maintaining accurate, up-to-date operational documents directly related to patient care and site responsibilities.
• Sponsors and CROs must ensure proper central filing and access to regulatory documents via CTIS, reducing the burden on sites.
• Efficient communication and clear role definition between sponsor and site are essential to maintain compliance and readiness for inspections.

Final Thoughts

The EU CTR simplifies and centralizes many regulatory document requirements, which changes how eTMF filing is handled at the site level. This shift promotes better transparency, reduces duplicative filing, and allows sites to focus on documents critical to their role. For clinical research teams, staying updated on these requirements is key to smooth trial conduct and regulatory compliance under the new regulation.

Helpful Resources

• EU Clinical Trials Regulation (EU CTR) 536/2014 Text (EUR-Lex)
• European Medicines Agency (EMA) – Clinical Trials Regulation
• Clinical Trials Information System (CTIS) Portal
• ICH E6(R3) Good Clinical Practice Guideline
• EMA Guidance on Trial Master File and eTMF