The European Medicines Agency recently published a draft guideline titled “Good Clinical Practices (GCP) compliance in reaction to Trial Master Files (paper and/or electronic) for content, management, archiving, audit and inspection of clinical trials.”

Most of this guidance has been derived from the revised version of the reflection paper on TMF and includes detailed descriptions of content, management, archiving, audit, and inspection of clinical trials along with the latest ICH E6 revision. This guidance is still a draft for consultation, and they are accepting comments until July 11, 2017.

Designed to help sponsors and investigators comply with the requirements of the regulation on clinical trials (medicinal products) and the Trial Master File, the EMA states that “this guideline aims to collate and explain the requirements for the TMF as covered in the Regulation and ICH-GCP E6 to assist organizations in maintaining a TMF that facilitates trial management, GCP compliance, and inspection. The document also addresses archiving of the TMF, clarifying retention times, in particular expectations in case of digitization and consecutive destruction of paper documentation.”

The guideline covers both the paper and electronic versions of the Trial Master File, taking into account the challenges that an organization might face for implementing the latter. This draft provides detailed standards on how to implement and maintain TMFs that comply with the regulatory requirements. Section 7 of the guidance, “Inspection Readiness of TMF,” also emphasizes the need to ensure transparency, quality, and accessibility.

Some of the key takeaways from the guideline:

• With reference to Article 57 of the Regulation, direct access to the TMF is expected. The inspectors should have read-only access without any restriction (e.g., to final documents) to the entire TMF for inspection during preparation and conduct of the trial, which means that they can review the same TMF as used by the staff conducting the trial.
• Additional emphasis is placed on Article 57 of the regulation, which states that “the TMF at all times shall contain the essential documents relating to the clinical trial.” While most of the essential documents are listed in ICH-GCP E6 section 8, this cannot be considered definitive, and it may vary based on the importance and relevance of the specific documents to the trial.
• According to Article 58 of the clinical trial regulation, “any alteration of the content of the Trial Master File shall be traceable” and the sponsor and the investigator "shall archive the content of the clinical TMF for at least 25 years after the end of the clinical trial.”
• The TMF should provide for document verification, version history, search and retrieval, and “it shall be readily available and directly accessible upon request.”
• The EMA says that sponsors and investigators are expected to keep the TMF up to date and ensure that it is complete at the end of a trial, and sponsors are recommended to conduct routine quality assurance checks of the TMF.
• In terms of preparing for a TMF inspection, the guideline says inspectors should have read-only access, although organizations "should be aware that GCP inspectors may have rights to seize original trial documentation if circumstances arise that require it."
• The eTMF should allow review in an efficient manner, analogous to that possible with paper TMFs, and the experience should be similar to that of sifting through a paper file. This calls for a well-organized folder structure and naming convention to allow easy identification of TMF sections and multi-operative functionalities to enable ease of use.

With this guideline, the EMA aims to bring together TMF requirements covered in ICH E6 and the regulation to assist sponsors/CROs and other organizations in maintaining an inspection-ready TMF to achieve better trial efficiency.

The draft guideline is available on the EMA website, and is currently open for comment.

Please reach out to info@trialinteractive.com with any additional questions about the guidance or for information about our eTMF services.