Guideline on the content, management and archiving of the clinical trial master file (paper and/or electronic)

EMA guideline adopted by the Good Clinical Practice Inspectors Working Group on 06 December 2018, coming into effect six months after publication. It focuses on the trial master file (TMF) and gives practical guidance on how to establish, maintain, secure and archive the TMF across the lifecycle of a clinical trial, in paper, electronic or hybrid format. 

• Defines the TMF as the collection of essential documents used by sponsors, contract research organisations and investigators/institutions to manage the trial, and by monitors, auditors and inspectors to verify compliance with regulatory requirements and Good Clinical Practice.
• Aligns TMF expectations with Directive 2001/20/EC, Directive 2005/28/EC, ICH E6 Good Clinical Practice and Clinical Trials Regulation (EU) No 536/2014, and confirms that the same core requirements apply to paper TMFs and electronic TMFs.

Core content is grouped into four operational areas: TMF structure and contents, TMF security and control, scanning or transfer to other media and certified copies, and archiving and retention of the TMF.

Trial master file structure and contents

• TMF usually consists of a sponsor TMF and an investigator TMF (investigator site file), which together form a single TMF for the trial.
• Sets expectations for roles, responsibilities and contractual arrangements when duties are delegated to contract research organisations or other third parties, covering who holds which parts of the TMF, access, indexing, archiving and oversight.
  Recommends identifying one primary TMF system (paper, electronic or hybrid) and clearly defining any other central systems (for example email, standard operating procedures, training, software validation, shared investigator’s brochures) that form part of the TMF, while minimising the number of systems.
• Requires an overall index or table of contents and chronological filing rules so essential documents can be located and traced.
  States that essential documents are all records needed to evaluate trial conduct and data quality; goes beyond ICH E6 Section 8 by including, where relevant, quality system records, Qualified Person certification, assay validation, advanced therapy investigational medicinal product traceability, validation of trial‑specific systems, data management and statistical documentation and delegation logs.
• Requires retention of superseded versions of key documents, filing of relevant correspondence (including email chains and attachments) and “contemporaneous” filing, with timelines defined in procedures or TMF plans.

Security and control of the TMF

• TMF must be protected against loss, unauthorised alteration or destruction, with access based on clearly defined roles and permissions, including controls for unblinding‑sensitive information and personal data.
• For electronic TMFs, specifies core controls: individual user accounts, secure passwords, document locking/protection, regular back‑ups with restore testing, audit trails (creation, upload, deletion and changes with date, time and user), role‑based permissions and system validation.
• Highlights the role of metadata (for example creator, dates, location, title, keywords, version, file type and size) for file management and retrieval, and requires verification of any migration of documents or data to new media or formats.

For electronic investigator TMFs, requires that a complete investigator TMF is available before, during and after the trial under the control of the investigator/institution, independent from the sponsor. Documents with direct identifiers (such as subject identification lists, medical files and signed consent forms) must remain solely under investigator/institution control; shared documents must be pseudonymised. The guideline calls for contractual arrangements to preserve investigator control when investigator‑generated essential documents are stored in sponsor or contract research organisation systems, and sets conditions for remote access and risk‑based quality control and quality assurance, including audit trail review.

Scanning, transfers and certified copies

• Media used to archive the TMF must preserve completeness and legibility for the full retention period, with any alteration traceable.
• Defines a certified copy as a paper or electronic copy verified or produced through a validated process to be an exact copy including context, content and structure; required when an eTMF copy irreversibly replaces an original.
• Outlines quality checks for certified copies (content concordance, metadata, file naming, image quality, audit trail) and distinguishes these from non‑replacing copies that do not require certification.
• Provides guidance on handling static files (for example scans) and dynamic files (for example spreadsheets), requiring preservation of necessary functionality and retention of original dynamic files even when static versions are filed in the primary TMF.
• Requires validation of digitisation and transfer processes so information is not lost or altered, and explains that, once certified copies are in place, destruction of certain paper originals may be acceptable within retention rules.
• Archiving, retention and change of ownership
• TMF, including audit trails in electronic systems, must be archived so that it remains readily available and directly accessible to Member State authorities, with restricted access and protection against unauthorised changes.
• Access must be maintained over the entire archiving period, for example by maintaining the original system environment, using emulation or migrating data to new formats; all migrations or transfers must be validated to preserve data and metadata.
• Sets retention times: minimum five years after completion for trials under Directive 2001/20/EC; at least 15 years or longer, linked to marketing authorisation status, for trials supporting marketing applications; at least 25 years after trial end for TMFs under Clinical Trials Regulation (EU) No 536/2014; and longer periods (for example 30 years) for certain advanced therapy investigational medicinal product traceability records.
• Clarifies responsibilities of sponsors, investigators/institutions and contract research organisations for archiving sponsor and investigator TMFs, including appointment and training of archive‑responsible individuals, archive indices/logs, control over document withdrawal and return, and requirements when using external archives or cloud solutions.

States that any transfer of TMF ownership must be documented and that the new owner assumes responsibility for archiving, retention and accessibility.