“A trial master file is a collection of the important content for clinical trials that are overseen by the regulatory agency.
To meet government regulatory requirements for clinical trials, each company involved in clinical trials must preserve and store all clinical trial-related records, images, and content. This information can be contained in the trial master file or TMF, which today takes the form of an electronic trial master file (eTMF), depending on the regulatory jurisdiction.
In 1996, the International Conference on Harmonization (ICH) released a consolidated industry guidelines on good clinical practice with the goal of establishing a common framework for the European Union, Japan and the United States of America to promote the universal recognition by regulatory authorities of clinical data in those jurisdictions.
This guidance document set out the requirement for all ICH regions to create trial master files containing important documents that individually and collectively enable assessment of the conduct of a trial and the quality of the generated data.
There is no clear provision for a court master file in some jurisdictions, for example the US. However, if the regulatory authority requires ICH GCP to be followed, then there is consequently a requirement to create and maintain a trial master file.
A TMF is the compilation of important documentation used by promoters, CROs and investigators / institutions to manage the trial, and by supervisors, auditors and inspectors to review and check whether the trial was performed by the sponsor and the investigators / institutions in compliance with the relevant legal criteria and the GCP principles and standards.
Therefore, all basic requirements are the same for both formats or when used in combination as a hybrid TMF.
The TMF should provide for document recognition, version history, search and retrieval; as specified in both Directive 2005/28 / EC (Article 17) and Regulation (Articles 57 and 58), it should also be archived in such a way as to ensure that it is readily available and accessible directly to the competent authorities of the Member States upon request.
Article 47 of the Regulation states that sponsors and investigator/institution shall take appropriate account of the ICH GCP guideline and shall conduct the trial in accordance with GCP principles, two of which are:
· “All clinical trial information have to be recorded, handled, and stored in a way that allows its accurate reporting, interpretation and verification”
· “Systems with procedures that assure the quality of every aspect of the trial must be implemented.”
Aspects of the trial that are essential to ensure human subject protection and reliability of the trial results should be the focus of such systems.”
Trial master file contents
Essential documents: “Essential documents are documents that enable evaluation of the conduct of a trial and the quality of the data generated individually and collectively.” Essential documents allow the investigator / institution and sponsor to conduct the trial effectively and show compliance to the GCP guidelines and all other regulatory criteria that apply.
The TMF maintained by the investigator / institution and the one maintained by the sponsor have a different content, due to the different nature of the investigator / institution’s and sponsor’s responsibilities,6 as specified in the ICH GCP guideline. Article 57 of the Regulation declares the TMF necessary
Article 57 of the Regulation states that the quality of the necessary TMF documents shall take into account ‘all the characteristics of the clinical trial, including, in particular, whether the clinical trial is a clinical trial with low involvement.’
Therefore, some documentation specified in the ICH GCP guideline may not be necessary due to the implementation of a risk proportionate approach7. The justification for reducing documentation should be documented in the TMF.
The documentation specified in section 8 of the ICH GCP Guideline specifies the documents that are considered necessary (as applicable to the trial) and the documents should be submitted to the TMF investigator / institution or sponsor, or both; however, this list should not be used as a final checklist for TMF material.
It is not a complete list. Therefore, the sponsor and/or investigator / institution will provide any documentation that enables the reconstruction and review of the conduct of the trial as part of the TMF, depending on the activities being carried out. Unnecessary duplication of the documentation in the TMF should be avoided.
Examples of documents that are considered important when generated for a specific trial, but not listed in section 8 of the ICH GCP guideline include:
- Completed forms, checklists and reports etc. related to the case, produced by the sponsor, investigator or any third party performing testing activities on their behalf from the following quality system procedures;
- qualified person certification of the IMP;
- assay method validation report for the analysis of IMP or metabolite(s) in clinical samples;
- advanced therapy investigational medicinal product (ATIMP) traceability documents;
- Documentation showing validity of computer system test-specific constructs (e.g. electronic case report form (eCRF) and interactive response technologies (IRT) and electronic patient-reported outcomes);
- data management documentation, e.g. data management plan, data validation plan and data-review meeting minutes;
- statistics documentation, e.g. SAS program validation, statistical analysis plan and sample size estimations;
- Delegation log as part of TMF researcher / institution. Documentation showing software validation can be maintained by a CRO after the sponsor has contracted the operation, but the sponsor should ensure continuous access for the required archiving duration to such documentation in the contractual agreements with the CRO.
Documents relating to the trial-specific software configuration are part of the TMF and should be determined whether these are maintained/archived by the sponsor or CRO providing this service.
Some records from good manufacturing practice activities should also be defined as part of the TMF, for example, when these relate to the assembly and packaging of the investigational medicinal product (IMP) and confirm, as applicable, compliance with the randomisation schedule and blinding of the trial
Throughout the development of a document ( e.g., creation and release of a clinical trial protocol), the procedures of the sponsor / CRO that require input and review by various roles. The documentation to demonstrate that the process was followed should be retained.
Reconstruction of the trial includes superseded copies of the final documents and should therefore be maintained in the TMF.
Superseded versions of the documents generated by the sponsor (e.g. trial protocol, IB and eCRF) should be available at the TMF investigator / institution in such a way as to allow reconstruction without access to the TMF sponsor, with proof of the date of receipt, review and/or approval (if necessary) and date of implementation by the investigator/institution.
Relevant correspondence that is essential for reconstruction of key trial conduct activities and decisions should be retained.
This includes correspondence with the ethics committees, data safety monitoring committee and regulatory authorities (confirming sponsor approval of processes, documents and decisions and the communication concerning issues that arise in the trial conduct and how they are dealt with).
In the same way, electronic correspondence (e-mails and associated attachments between CROs, sponsor departments, investigator/institution) should be readily accessible and may be retained electronically. It should be ensured that both sent and received correspondence is filed in the TMF.
One or more separate central repository may be used (e.g. for e-mail), as long as they are evidently defined as being the part of TMF.
Care should be taken regarding e-mail ‘chains’ and attachments to ensure that relevant strands of conversations and their associated documents are maintained.
Contemporariness of trial master file
The requirement “at all times” within Article 57 of the Regulation means that the TMF must have all documentation added in a timely manner during the trial, as this greatly assists the successful 8 management of a trial by the investigator/institution, the sponsor and CROs to whom the sponsor has delegated its duties.
The deadlines for submitting and filing all documents to the TMF should be specified in the procedural documents or TMF plans. This is particularly important for more complicated TMF relationships involving multiple parties.
- SOP: Creation and Maintenance of Trial Master Files (5.6MB)
- Guideline on the content, management and archiving of the clinical trial master file (paper and/or electronic)
Quality of trial master file
Article 57 of the Regulation states “The clinical trial master file shall at all times contain the essential documents”. The sponsor and/or investigator/institution should implement risk-based quality checks (QC) or review processes to ensure the TMF is being maintained up-to-date and that all essential documents are appropriately filed in the TMF. Areas to consider during QC and review include the following:
- all necessary documents generated available in the TMF;
- documents filed in the suitable locations;
- documents added to the TMF on time;
- documents correctly indexed;
- documents only reachable according to the assigned roles and permissions;
- review of the audit trail (for eTMF).
The sponsor should also undertake routine QA measures, e.g. system audits of the TMF-management processes. Additionally, the sponsor should ensure the TMF is readily available and directly accessible to the competent authority, e.g. for inspection purposes.
Security and control of trial master file
Access to trial master file
To ensure completeness and to avoid accidental or premature loss, unauthorized modification or destruction of records, the TMF should be handled safely at all times.
Access to the TMF should be dependent upon a summary of the position and permission specified by the sponsor and/or investigator / institution.
The TMF sponsor and investigator/institution TMF that provide some details that may unblind personnel who need to remain blind during the conduct of the trial.
This should be properly managed, for example, by storing the documents in another system or archive and/or by a summary of the function and authorization that is specified by the sponsor and/or investigator/institution.
Storage areas for the trial master file
The TMF documents storage area (such as paper or electronic media archives and server rooms) will also be appropriate to maintain the records in such a way that they remain accurate and legible throughout the trial conduct and the required retention period and can be made accessible to Member States’ competent authorities upon request.
sufficient and suitable space should be provided for the storage of all the essential documents from completed studies. The facilities should be protected, with appropriate environmental controls and adequate protection from physical damage.
The factors to be considered when assessing a appropriate storage facility, should take into consideration certain factors such as security, location (e.g. environmental risk factors) and size.
Sponsors should make a documented assessment of the conditions at the investigator site/institution for storage of the investigator/institution TMF during the clinical trial and for archiving. The sponsor should be notified, if the agreed arrangements are changed (e.g. sub-contracting of storage).
Sponsor/CRO electronic trial master file
Electronic TMFs should enable suitable security and reliability, ensuring that no loss, alteration or corruption of data and documents occur. The primary eTMF is a system for managing documents that should hold the controls listed below:
- user accounts;
- secure passwords for users;
- a system in place locking/protecting individual documents or the entire eTMF (e.g. at time of archiving) to prevent changes to documents;
- regular backup;
- periodic test retrieval or restores to confirm the on-going availability and integrity of the data;
- an audit trail in the place to identify date/time/user details for creation and/or uploading deletion of and changes to a document (explanation of the deletion or modification, if necessary);
- role-based permissions for activities being undertaken, such as restricted access to the files/documents (e.g. randomisation codes and unblinded adverse event data);
- the appropriateness of the system for archiving purposes should be appropriate.”