The United States (U.S.) Food and Drug Administration (FDA) and the European Medicines Agency (EMA) provide several stringent regulations and guidelines within the pharmaceutical and clinical research industries to ensure the patient safety and internal validity of clinical trials. One of the most important tools used by pharmaceutical sponsors and contract research organizations (CROs) for navigating these regulatory requirements for clinical trials is the Trial Master File (TMF).

The TMF is a central repository of key documents that must be maintained consistently throughout a clinical trial by various stakeholders, including the Investigator, the Sponsor or Institution, and in many cases, the subcontracted CRO. Typically, a clinical research site cannot begin study activities until certain critical regulatory documents have been received from bodies like an Institutional Review Board (IRB) or Independent Ethics Committee (IEC). These documents must be stored inside the TMF prior to the start of a clinical trial by the sponsor or their CRO partner. As a study progresses and through to its completion, the TMF must continue to retain all relevant files and communications for reference by the sponsor or external bodies, such as regulatory agencies or auditors.

In this article, we will provide a detailed breakdown of the typical TMF in clinical trials, its contents and structure, as well as additional industry knowledge to ensure regulatory compliance. Read on to learn more about the TMF! 

 

What is a Trial Master File (TMF) in Clinical Trials?

According to a 2018 scientific guideline put forward by the EMA, a TMF is defined as a collection of essential documents that facilitate the conduct and management of a clinical trial, allowing for the evaluation of trial data integrity and compliance with Good Clinical Practice (GCP). It should be noted that all basic requirements outlined by regulatory bodies have traditionally not differentiated between paper TMFs, electronic TMFs (eTMF), or hybrid combinations of the two. Although specific guidance on TMFs is not currently available from the U.S. FDA, Article 57 of the European Clinical Trials Regulation (CTR) explicitly deems the TMF a mandatory component of clinical trials, dictating the following requirements:  

• The TMF should be updated in a timely manner, with any alterations traceable. 

• It should provide document identification, version history, search, and retrieval, and be readily available to competent authorities. 

• The TMF should be sufficient to reconstruct trial activities, decisions, and their justifications.

Overall, the TMF is considered essential for clinical trials to meet regulatory requirements because its contents provide a complete and accurate account of the trial’s conduct, data, and results. The TMF also helps ensure patient rights are respected, and the resulting clinical data are valid by documenting acceptable adherence to the clinical study protocol and international Good Clinical Practice (GCP) guidelines. 

 

Sponsor Trial Master File (TMF) versus Investigator Site File (ISF)

All TMFs for clinical trials consist of a sponsor TMF, maintained and accessible only to the study sponsor or its CRO partner, and an investigator TMF or investigator site file (ISF), managed by the individual clinical research site. These two components must be kept separate in most cases for two reasons. First is the need to protect subject confidentiality, as sponsors should not receive access to certain identifying documents if the patient has not consented to it. Second, it helps maintain the investigator’s control over the trial data. This segregation is especially important to provide restricted access to certain files containing information such as randomization codes or unblinded pharmacovigilance details. However, a situation when a TMF and ISF would be combined is for trials sponsored by healthcare institutions or universities, where the sponsor and the investigator are essentially the same entity. 

 

The Role of Contract Research Organizations (CROs) in Managing a Trial Master File (TMF)

Although the sponsor retains the ultimate responsibility and oversight of a clinical trial and, by extension, its TMF, they may subcontract its management out to a CRO in writing. The clinical trial contract should detail the TMF’s management, including structure, access, document types, correspondence, availability to authorities, and archiving arrangements. As stated in this guidance, if multiple CROs are involved, the sponsor should define expectations for document creation, management, and retention. The sponsor is also required to provide the CRO(s) with access to essential TMF documents and verify the CRO’s quality management measures during the trial. 

 

How Does an Electronic Trial Master File (eTMF) Differ?

An eTMF is a digitized version of a traditional TMF and serves the same purpose-to store and manage all trial-related documents and data-except it provides greater accessibility, convenient storage solutions, data security, and improved efficiency in document management processes. A TMF is always required for any clinical trial, but its format, whether paper, electronic, or both, is a matter of preference for the study sponsor

Although the EMA TMF guidance document does require eTMF systems to have additional features such as user accounts, secure passwords, document protection, regular data backups, complete audit trails, and role-based permissions. These platforms must also be validated with all relevant staff receiving training on their use. Common eTMF platforms available in the industry today include the Vault eTMF from Veeva Systems, the Trial Interactive eTMF, the eTMF from Florence Healthcare, and many more. The EMA also dictates that metadata should be applied to electronically retained trial-related documents for consistency and version control, as well as to maintain integrity and readability following any data migration. 

 

Trial Master File (TMF) Structure and Contents for Clinical Trials

There are several other systems that can be used in clinical trials to manage important documents, including a central email repository, SOP-management system, central training records, delegation logs, and more. However, the TMF platform must be prioritized above all these.  

 

Trial Master File (TMF) Structure 

To begin, this master file should contain a well-structured index or table of contents to enable easy tracking and retrieval of essential documents. Next, all filed documents should be filed in chronological order in their respective section of the TMF to show a clear historical record. To aid in this, sponsors and investigators can provide descriptions for the dates used for document filing, whether it be the date of receipt, filing in the TMF, approval, update, or expiration.

The TMF structure is primarily composed of the following sections for document filing, but certain sections may differ, or additional sections may be included depending on the needs of the clinical trial:  

1. Trial Management: Information on trial oversight, the trial team, the trial committee, meeting information, etc. 

2. Central Trial Documents: Information on investigational product (IP) and trial documentation, subject documentation, reports, etc. 

3. Regulatory: Information on trial approval, IP, trial status reporting, etc.  

4. IRB, IEC, and other Approvals: Independent ethics committee (IEC), and other information on approvals. 

5. Site Management: Information on site selection, set-up, initiation, management, etc. 

6. Investigational Product (IP) and Trial Supplies: Information on IP documentation, release process, allocation documents, storage, non-IP documentation, interactive response technology (IRT), etc.  

7. Safety Reporting: Consists of safety documentation, trial status reporting and general safety reports. 

8. Central and Local Testing: Information on facility documents, sample documentation, etc. 

9. Third Parties: Oversight, set-up, and general information.  

10. Data Management: Information on oversight, capture, database, electronic data capture management, etc. 

11. Statistics: Information on statistical oversight, randomization, analysis, statistical reports, and general statistics. 

 

Trial Master File (TMF) Contents

The EMA 2018 TMF guidance classifies the documents filed in a TMF as either an essential document, superseded documents, or correspondence.

Essential documents are considered files “which individually and collectively permit evaluation of the conduct of a trial and the quality of the data produced.” As with its structure, the sponsor TMF and ISF will usually have different contents due to their separate responsibilities in a clinical trial. Examples of essential documents include the delegation log, statistics documentation, data management documentation, advanced therapy investigational medicinal product (ATIMP) traceability documents, and computer system validation documentation for systems such as the IRT or electronic case report form (eCRF).  

 

Superseded documents are files that have been updated throughout the lifecycle of a clinical trial, but must still be retained in the TMF “to enable reconstruction without the need to access the sponsor TMF.” Examples of superseded documents include outdated versions of the trial protocol, Investigator’s Brochure (IB), or eCRF guidelines. 

 

Correspondence files refer to interactions with ethics committees, regulatory authorities, and others, pertaining to key activities and decisions made within a study. Both sent and received correspondence should be filed in the TMF, which can include electronic correspondence like emails. Sponsors and investigators should also ensure that any important conversation threads and associated documents are maintained in their entirety. 

 

Maintaining Trial Master File (TMF) Security and Control in Clinical Trials

Per the 2018 EMA guidelines on TMF management, a TMF or eTMF should be managed securely to ensure its contents are complete and without unauthorized alterations. As discussed previously, access to the TMF should be role-based and controlled to maintain blinding during trials. As for storage, the area in which TMF documents are kept should be secure, environmentally controlled, and adequately protected. Furthermore, quality checks and review processes should be implemented to ensure the TMF is up-to-date, and all essential documents have been filed in their appropriate sections. The sponsor is responsible for carrying out regular quality assurance checks such that the TMF is readily available for external inspection at any time. 

 

Scanning a Trial Master File (TMF) or Transferring to Other Media

As suggested by the EMA, certified copies of original documents, verified or generated through a validated process, should replace originals in the eTMF after having undergone regular quality control checks. However, some copies in the TMF do not replace the original and, therefore, will not require certification. In cases of document digitization or transfer, the system or process must be validated such that no information is lost or altered. Until the full TMF retention period has passed, no original document may be destroyed. 

 

Archiving and Retention of the Trial Master File (TMF) for Clinical Trials

To maintain the readability of TMF documents, they must be archived in a format that can last several years following the completion of the clinical trial. The standard document retention period for clinical trials will differ depending on the governing regulatory agency, but in any case, all documents must be stored in a secure environment while being readily accessible in the event an audit takes place or if any files are requested after trial completion. As of 2023, the EMA rule required that clinical trial data be kept for 25 years, including those based in the United States. However, in contrast, Health Canada announced in 2022 that they had reduced the period for keeping clinical trial records for drugs and natural health products from 25 years to 15 years. 

 

Conclusion

In conclusion, a TMF serves as a crucial tool for clinical trials, containing key documents that ensure regulatory compliance and facilitate the conduct and management of a study. Whether in a traditional paper format, an electronic version, or a hybrid, the TMF provides a comprehensive record of the trial’s conduct, data, and results accessible long after the study has been completed. There are several guidelines intact to ensure patient rights and data validity are robustly maintained, and it is the responsibility of the sponsor to adhere to these requirements with consistent quality assurance measures and oversight.  

 

About TFS HealthScience CRO

TFS HealthScience is a global, full-service, mid-size CRO that supports biotechnology and pharmaceutical companies throughout their entire clinical development journey. In partnership with customers, we build solution-driven teams working for a healthier future. As a trusted CRO partner throughout the entire clinical development journey, we understand the importance of providing essential and diverse services to streamline clinical trials for our clients. Visit our website to learn more about the solutions TFS can offer for your next clinical trial, or connect with a TFS representative today!