Document Management Systems

TMF and eTMF: What the Trial Master File Is and Which Requirements Apply to Keeping It Electronically

Last updated: 5 November 2026

Short answer: The trial master file (TMF) is the complete set of essential records of a clinical trial that allows its conduct and the quality of the data produced to be verified.[1][2][3] In the EU, sponsor and investigator must keep it up to date, directly accessible at all times and archived for at least 25 years after the end of the trial.[1] When kept electronically as an eTMF, requirements for validation, audit trail, access and long-term readability are added.[2]

What is the trial master file?

The EMA guideline on the TMF describes it as the collection of documents that allows the conduct of a trial to be reconstructed and evaluated; the documents should confirm compliance with the protocol and GCP and the integrity of the data without additional explanation from staff.[2] The MHRA calls the TMF “the story of how the trial was conducted and managed”.[4] ICH E6(R3) no longer speaks of “essential documents” but of “essential records”, which it addresses in Appendix C.[3]

A TMF consists of two parts: the sponsor TMF and the investigator’s TMF, the investigator site file (ISF).[2] Some documents belong on one side only, such as the randomisation list in the sponsor TMF and the subject identification code list in the ISF.[2]

  • EU Regulation 536/2014 (CTR): Under Article 57, sponsor and investigator keep a TMF that contains the essential documents at all times and is directly accessible to Member States on request. Under Article 58, they archive its content for at least 25 years after the end of the trial unless other Union law requires longer; media and archiving must keep the content complete and legible.[1]
  • EMA guideline EMA/INS/GCP/856758/2018: it sets out content, management and archiving for paper and electronic TMFs, including audit trail, copies, access and archiving.[2]
  • ICH E6(R3): the guideline requires essential records to be kept so that the trial can be reconstructed and provides for direct access for monitoring, audits and inspections.[3]
  • 21 CFR 312: in the US, sponsors (§ 312.57) and investigators (§ 312.62) generally retain records for two years after approval or after the investigation is discontinued and must allow FDA access (§§ 312.58, 312.68).[5] Records kept electronically are subject to 21 CFR Part 11.[6]

Under Article 71 CTR, the sponsor may delegate tasks to third parties such as CROs; the sponsor’s responsibility remains unaffected.[1]

How is a TMF structured?

The de facto standard is the TMF Reference Model, which originated at the DIA and is now maintained by CDISC. The current published version is v3.3.1 of 11 August 2023; a successor named “CDISC TMF Standard Model v1” was in public community review at the time of retrieval and should therefore be treated as a draft.[7] The model organises content hierarchically into zones, sections and artefacts and defines metadata and, since version 3, optional sub-artefacts.[7] The eleven zones are: Trial Management, Central Trial Documents, Regulatory, IRB/IEC and other Approvals, Site Management, IP and Trial Supplies, Safety Reporting, Central and Local Testing, Third Parties, Data Management and Statistics.[7] The model is not mandatory; it is tailored to the individual trial in a study-specific TMF plan with an index.[7][8]

What changes when moving from a paper TMF to an eTMF?

For an eTMF, the EMA guideline requires, among other things, a validated system, an audit trail recording date, time and user for the creation, upload and deletion of documents, protection against unauthorised changes, and documents that remain readable throughout the retention period.[2] Where paper originals are replaced by electronic copies, these must be certified copies produced through a validated process.[2] For the archived eTMF, the guideline requires the dynamic character of the audit trail to be preserved and read-only access to be granted with an audit trail of that access.[2] Monitors, auditors and inspectors need direct access; the 2024 FDA guidance also addresses certified copies and the retention of electronic records in clinical investigations.[2][9] From a technical and regulatory perspective, eTMF systems fall under 21 CFR Part 11 and, in the EU GMP context, Annex 11; details are covered in the article on 21 CFR Part 11 and electronic signatures.[6][10]

Paper TMF, general document storage and eTMF compared
FeaturePaper TMFGeneral document storage (e.g. network drive)eTMF
StructureBinders following an indexFreely defined folders, no mandatory metadataIndex based on the TMF Reference Model with metadata
Audit trailNone; evidence via logs and signaturesUsually no GCP-appropriate audit trailSystem-generated, with date, time and user
ValidationNot applicableUsually not validatedValidation required
Inspector accessOn siteDifficult to control without role-based read accessRole-based, logged direct access
CompletenessManual checkManual checkMeasurable against the index
ArchivingPhysical archive, 25 yearsReadability and integrity not assuredArchive with preserved audit trail and long-term readability

What makes a TMF inspection-ready?

An inspection-ready TMF is complete, filed in a timely manner and of demonstrable quality. The EMA guideline requires documents to be filed in a timely manner during the trial and filing timelines to be defined in procedural documents or TMF plans.[2] A TMF plan sets out structure, responsibilities, filing timelines and quality control; metrics on completeness, timeliness and quality make the status measurable.[2][8]

Typical findings: In the EMA-coordinated GCP inspections of 2024 (67 inspections), 335 critical and major deficiencies were recorded, 11 of them critical.[11] The largest category, “General”, comprised 137 findings, including 41 on essential documents and 38 on source documentation.[11] Examples include incomplete or poorly maintained TMF/ISF, missing version control, no formally documented TMF quality control process, no established process for certifying copies, and lack of access for monitors and inspectors to electronic systems.[11] The MHRA metrics report for April 2019 to March 2020 (36 GCP inspections) shows 4 critical, 17 major and 34 other findings for commercial sponsors and 4, 25 and 41 for CROs.[12] At the FDA, 15 of 609 clinical investigator inspections classified in fiscal year 2024 were rated OAI.[13]

Software solutions for the eTMF

The following solutions are listed alphabetically and described without evaluation; all information is taken from the vendors.

Docuply: According to the vendor, the Docuply eTMF already provides the CDISC TMF Reference Model as its structure.[14] The vendor states that new, verified document versions are automatically attached to the linked TMF.[14] The TMF can be shared with auditors, inspectors and other external parties through assigned access rights.[14]

Florence Healthcare (Florence eTMF): According to the vendor, Florence eTMF is compliant with 21 CFR Part 11 and EU Annex 11.[15] The vendor states that the eTMF can be used stand-alone or integrated into an existing eTMF system.[15] It enables document exchange with research sites and management of site workflows in a single system.[15]

Responsibility for validation, the TMF plan and completeness remains with the sponsor.[1][2]

Frequently asked questions (FAQ)

What is the difference between a TMF and an eTMF?

The TMF is the content, that is, the essential records of a trial; the eTMF is an electronic system in which that content is kept in a validated way, with an audit trail and controlled access.[2]

How long must a TMF be retained?

In the EU, for at least 25 years after the end of the clinical trial unless other Union law requires longer.[1] In the US, 21 CFR 312 generally requires two years after approval or discontinuation of the investigation.[5]

What is the TMF Reference Model?

A non-mandatory taxonomy maintained by CDISC that organises TMF content into eleven zones with sections and artefacts; the current version is v3.3.1.[7]

Who is responsible for the TMF, the sponsor or the CRO?

The sponsor. It may delegate tasks to a CRO but remains responsible under Article 71 CTR; the investigator is responsible for their part, the ISF.[1]

Further reading

References

  1. Regulation (EU) No 536/2014 on clinical trials on medicinal products for human use. https://eur-lex.europa.eu/eli/reg/2014/536/oj (accessed 5 November 2026)
  2. EMA. Guideline on the content, management and archiving of the clinical trial master file (paper and/or electronic), EMA/INS/GCP/856758/2018. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-content-management-and-archiving-clinical-trial-master-file-paper-andor-electronic_en.pdf (accessed 5 November 2026)
  3. ICH. E6(R3) Guideline for Good Clinical Practice (Principles and Annex 1, Step 4, 6 January 2025). https://www.ich.org/page/efficacy-guidelines (accessed 5 November 2026)
  4. MHRA Inspectorate Blog. Inspecting clinical trials – the trial master file. 30 July 2015. https://mhrainspectorate.blog.gov.uk/2015/07/30/inspecting-clinical-trials-the-trial-master-file/ (accessed 5 November 2026)
  5. 21 CFR Part 312 – Investigational New Drug Application. eCFR. https://www.ecfr.gov/current/title-21/chapter-I/subchapter-D/part-312 (accessed 5 November 2026)
  6. 21 CFR Part 11 – Electronic Records; Electronic Signatures. eCFR. https://www.ecfr.gov/current/title-21/chapter-I/subchapter-A/part-11 (accessed 5 November 2026)
  7. CDISC. Trial Master File Standard Model (TMF Reference Model v3.3.1, 11 August 2023; TMF Standard Model v1 community review). https://www.cdisc.org/standards/trial-master-file-reference-model (accessed 5 November 2026)
  8. Docuply. TMF Inspection Readiness 2026: The Guide with Checklist for Biotechs and CROs. https://docuply.io/en/tmf-inspection-readiness-2026-the-guide/ (accessed 5 November 2026)
  9. FDA. Electronic Systems, Electronic Records, and Electronic Signatures in Clinical Investigations: Questions and Answers. October 2024. https://www.fda.gov/media/166215/download (accessed 5 November 2026)
  10. European Commission. EudraLex Volume 4, Annex 11: Computerised Systems (2011). https://health.ec.europa.eu/system/files/2016-11/annex11_01-2011_en_0.pdf (accessed 5 November 2026)
  11. EMA. Annual Report of the Good Clinical Practice Inspectors’ Working Group 2024, EMA/INS/GCP/37608/2025. https://www.ema.europa.eu/en/documents/report/annual-report-good-clinical-practice-inspectors-working-group-2024_en.pdf (accessed 5 November 2026)
  12. MHRA. GCP Inspections Metrics Report, 1 April 2019 – 31 March 2020. https://assets.publishing.service.gov.uk/media/64357bfe89f19f00133cfb40/GCP_inspection_metrics_2019-2020.pdf (accessed 5 November 2026)
  13. FDA. Bioresearch Monitoring (BIMO) Fiscal Year 2024 Metrics. https://www.fda.gov/media/192870/download (accessed 5 November 2026)
  14. Docuply. Trial Master File (product page). https://docuply.io/en/trial-master-file/ (accessed 5 November 2026)
  15. Florence Healthcare. Florence eTMF Frequently Asked Questions. https://www.florencehc.com/florence-etmf-faq/ (accessed 5 November 2026)