A Trial Master File (TMF) is a compilation of documents that prove that the clinical trial has been conducted following regulatory requirements (including Good Clinical Practice). The TMF plays a crucial role in ensuring that the trial has been managed successfully by the Investigator, Sponsor and Institution.
The TMF needs to be maintained throughout the trial with some documents being prepared before the trial, some during the trial and others after the trial has been completed. The documents included in the TMF should confirm the compliance with the clinical trial protocol, Good Clinical Practice, and the integrity of the data collected without any additional explanation from the Sponsor, Investigator and Institution.
Available in paper, electronic (eTMF) and hybrid forms, the TMF should be available and accessible upon request. There needs to be one TMF for each clinical trial.
Sponsor and Investigator Trial Master File
The TMF is made up of a Sponsor TMF (held by the Sponsor company) and an Investigator TMF (sometimes referred to as the Investigator Site File (ISF) (in possession of the Investigator/Institution).
Investigators are responsible for certain documents, while Sponsors are responsible for others. When Investigators are recruited by institutions that are Trial Sponsors (an entity that oversees and pays for the clinical trial), they take control of both the Investigator and Sponsor TMF. In this case, the Investigator and Sponsor TMFs can be combined to avoid any duplication.
Contract Research Organisations (CROs)
Sponsors may outsource duties to Contract Research Organisations (CRO’s) which means that the CRO will be in charge of some of the documents found in the TMF. The Sponsor should provide the CRO with the essential documentation needed to run the clinical trial. Before the clinical trial begins, it should be verified that the CRO’s quality management processes are followed.
If there are multiple CROs involved, the Sponsor needs to clearly define expectations, including the creation, management, exchange, remote access and retention of documentation amongst the various CROs.
Trial Master File Structure
When undertaking a clinical trial, the Sponsor, Investigator and Institution should identify and maintain the locations of the documents needed to complete the TMF. An index is the easiest way to track down the location of essential documents, which may be stored in different locations (email repository, SOP-management system and training records, etc).
The documents need to be placed in the TMF in chronological order. The dates used to identify the documents during filing include the date of receipt, the date of being added to the TMF, and the date of approval or expiration.
Trial Master File Contents
Essential documents play an important role in evaluating the conduct of the trial and the quality of the data produced. They ensure that the clinical trial is successfully managed with adherence to regulatory requirements.
The ICH Guideline for Good Clinical Practice Section 8 outlines the documents which are considered ‘essential’ and the other documents which need to be filed in the TMF.
Essential Documents
- Completed forms, checklists, and reports which have been collected from the trial activities carried out by the Sponsor, Investigator and Institution.
- A completed Investigational Medicinal Product (IMP).
- Traceability documents for the Advanced Therapy Investigational Medicinal Product (ATIMP).
- Validation documents that show proof of trial-specific software and computer systems like an electronic Case Report Form (eCRF) and Interactive Response Technologies (IRT).
- A Data Management Plan, Data Validation Plan and Data Review Meeting minutes.
- Statistical Analysis Software Program Validation, Statistical Analysis Plan and Sample Size Estimations.
- Documentation from Good Manufacturing Practice (GMP) processes including information about the packaging of the Investigational Medicinal Product (IMP) and compliance with the randomisation and blinding of the trial.
Superseded Documents
Documents that have been subjected to revision (although the meaning of the document remains the same).
The superseded documents of final documents should always be included in the TMF as they help to reconstruct the trial.
Correspondence
Pertinent correspondence that reconstructs the activities and decisions that were carried out during the clinical trial need to be included in the TMF. This includes:
- Any correspondence with ethics committees, safety monitoring committees and regulatory authorities.
- Emails between CROs, Sponsors and the Investigator/Institution should be accessible.
- Sent and received correspondence.
Access to Trial Master File
The TMF needs to be handled securely at all times with access depending on the role and permissions granted by the Sponsor and Investigator/Institution.
The TMF may contain sensitive information which could unintentionally harm the clinical trial (unblind personnel who need to remain blinded throughout the trial).
Storage for TMF
The storage for the TMF includes paper and electronic server rooms and media archive. They need to protect the documents and keep them eligible.
The storage facilities need to be secure with environmental controls and protection from physical damage. The security, location, environmental risk factors and size should all be assessed before storing the TMF.
Sponsor and CRO Electronic Trial Master File
Electronic TMFs should allow for appropriate security and reliability, ensuring that no documents are lost or corrupted. The primary Electronic Trial Master File (eTMF) manages documents which should contain:
- User accounts.
- Secure passwords.
- System in place for locking documents or the TMF to prevent any unauthorised edits.
- Regular backups.
- Audit trail to identify date/time/user details for creation and changes to a document.
- Position-based permissions for activities being undertaken (restricted access to documents).
Investigator Electronic Trial Master File
Needs to be available before, during and after the trial, and needs to be accessible under the control of the Investigator/ Institution.
Documents in an Investigator/Institution TMF are provided by the Sponsor and includes:
- Documents containing personal data (code lists, source documents and signed consent forms). These documents are the responsibility of the Investigation/Institution due to data privacy requirements.
- Clinical Trial Protocol.
- Investigator’s Brochure (IB).
- Procedural manuals.
Quality of the Trial Master File
To ensure the quality and the integrity of the TMF, the following steps need to be taken:
- Quality checks and review processes to ensure that the TMF is kept up-to-date and that all the essential documents have been added to the TMF.
- Documents are filed in the correct locations.
- Documents added to the TMF promptly.
- Documents are correctly indexed.
- Documents are only accessible to those with the correct permissions and roles.
- Audit trail review for the eCFM.
- The Sponsor needs to ensure that the TMF is available and accessible to regulatory authorities for inspection.
Scanning and Transfer to Other Media
Controls should be implemented to ensure that all documents in the TMF have been completed and can’t be edited without authorisation and an audit trail.
According to the ICH Good Clinical Practice (GCP) guidelines, the copies of the eTMF which replace the original documents should be certified copies of the original (verified by date and signature or created through certain processes which allows an exact copy to be produced).
Quality checks of certified copies need to be carried out before the destruction of the original documents, including:
- The similarity of the information contained between the original and certified copy.
- Accuracy of the file name.
- Quality of the images.
- Completed and detailed eTMF audit trail.
- Approval of certification processes.
Printing, copying or transferring documents depends on the nature of the data in question.
Validation of the Digitisation and Transfer Process
Paper documents may need to be digitised into eTMFs and electronic archiving. This process should be validated so that no important information is lost or changed.
Destruction of Original Documents after Digitisation and Transfer
A paper copy of an electronic document can be destroyed as long as the original document has already been filed in the TMF. Essential documents shouldn’t be destroyed before the end of the compulsory retention period.
Archiving and Retention of the Trial Master File
The documents in the TMF need to be archived so that it is available and easily accessible. This includes the audit trail which should be archived properly so supervision can continue after the clinical trial has been completed.
Access to the archived data should be maintained so that data can be accessed in its original form, or so it can be migrated to a new format.
Transfer to another media form may be needed in case the storage starts to deteriorate. Before transferring any documents, validation needs to take place to ensure that the migrated data has the same information as the original data.
In the case of external archiving, an assessment of the facility needs to be carried out before it’s utilised. There also needs to be a formal agreement between the Sponsor, Investigator/Institution and the external archive. If the external storage has multiple sites, the exact location of the TMF needs to be known at all times.
Retention Times of Trial Master Files
The Sponsor determines which requirements apply to each clinical trial about to begin, the end dates and whether the trial is used, or intended to be used.
The TMF Retention Depends On:
- Digitisation of participant’s medical files after validation, so that the data can be easily accessible in the future.
- The retention of documents and medical files should be agreed on between the Sponsor, Investigator and Institution.
- The Sponsor needs to inform the Investigator and Institution when the trial documents no longer need to be held.
Archiving, Retention and Change of Ownership and Responsibility
Before any transfer of files, the content of the TMF needs to be checked to ensure that the original archived documents are all accounted for. When the location of the stored TMF has been moved, it needs to be recorded to enable tracking.
When the responsibility of the TMF has been transferred, there need to be agreements between the Sponsor, Investigator/Institution and CROs to keep the Sponsor updated. The Sponsor needs to make sure that the TMF is always available for archive inspections.