The trial master file (TMF) or the new modern version of TMF, the electronic TMF (eTMF), is the compilation of all essential documents that are collected before, during, and after the conduct of a clinical trial. This repository of documents and study artifacts referred to in Article 15(5) of Directive 2001/20/EC, collectively allows the trial to be evaluated and reconstructed at any time point and narrates a story of how the trial was managed and carried out by the Investigator, Sponsor/CRO, and all third party cross-functional teams. 

The ICH Guideline for Good Clinical Practices (E6 (R2)) Section 8 also specifies the minimum set of “Essential Documents” that the trial sponsor and/or clinical investigative sites should retain. These documents are usually audited by the sponsor’s auditors and regulatory inspectors, to confirm the validity of the trial conduct and data integrity. Hence the eTMF format and design must not only be regulatory compliant, but the system should be simple, synchronized, and easy to navigate for all the applicable end-users. 

We have compiled a list of 5 eTMF features that one should consider for implementation of a compliant and easy to use eTMF system. 

Configurable Filing System

Most of the eTMF platforms provide a clear cut “out-of-the-box” filing system based on Drug Information Association (DIA) reference model to help you transition from a paper-based trial master file to an eTMF. As much as standardization is important, it is equally essential to configure the workflows, nomenclatures, and indexation, as per the operational SOPs of the sponsor/CRO’s offline documentation practices. The TMF filing structure also needs to be customized as per the clinical trial requirements which differ from study to study based on the protocol design, phase of the trial, the geographic region where the trial is conducted, and other factors. 

A customized, purpose-built document filing system which is configured as per client requirements improves user acceptance and compliance, and drastically reduces document tracking and processing time. Moreover, it helps you measure the completeness of your TMF, since you know which documents and artifacts are expected in which eTMF sections, and when.

Once configured, the eTMF filing structure should be “locked” such that all users across the panel maintain a standardized hierarchy and follow a standardized process. The system should further allow for replicating a pre-defined filing plan to be saved as a template for future use in other studies.

Robust Search Engine

The very benefit of using an eTMF over physically stored paper TMF files is to overcome the redundancy of performing the mundane tasks of searching and retrieving the documents you need, which is not only time-intensive but is also physically exhaustive. Hence it is important that you should be able to search and retrieve the documents stored electronically, with the same ease that you store them in the eTMF.

A basic eTMF system has at the minimum the ability to search and retrieve documents, by striking a few keywords. Advanced search capabilities use the systems document classification, content indexing, and metadata coding features to search not only the documents but also the content within the documents using both structured and unstructured search tools. Formally defined and comprehensive metadata assigns consistent and unique attributes across all documents within the eTMF due to which the queried text in the search can be easily identified, cataloged, and quickly retrieved. E.g., you can search the documents based on the author, upload date, revision date, expiry date, and so on.

An intelligent eTMF system enables customization of metadata fields based on the study and client requirements and processes, to support the search functionality, automate workflows, and perform other critical processes within the eTMF system. E.g. perform a metadata action such as notification alert on the expiry date of the document.

Reporting TMF Metrics

The most commonly cited inspection findings related to TMF are related to missing or incomplete documents or documents that are missing a required signature. The regulators expect that the sponsor establishes a framework and process for reporting of the TMF metrics on an ongoing basis. Hence the eTMF should have a dynamic reporting system that allows you to perform the health-check of the requisite TMF metrics such as: 

• Completeness
• Timeliness
• Traceability and transparency
• Document quality
• Right artifact in the right file location
• Contemporaneous filing
• TMF governance process
• TMF oversight – artifact reviews, activity logs, minute of meetings, etc.
• Responsibility and accountability of TMF maintenance

A well-designed reporting tool with ad-hoc dashboards, KPIs, automated alerts, and triggers will allow you to track the metrics of your eTMF in real-time and alleviate errors that could occur due to staff attrition. With automated folder status updates, completeness statistics, missing documents reports, expected documents timelines, and role-based contextual information on what actionable needs to be followed up on; research teams can decrease the time required to push content through its lifecycle while becoming inspection-ready at all times.

Integrated Electronic Investigative Site File (eISF)

Most of the clinical sites collect essential documents and other trial-related documents in paper form in regulatory binders provided by the sponsor known as Investigative Site File(s) (ISFs). Traditionally sponsors rely on directing the site to email essential documents or wait until a monitor’s onsite visit to validate and collect these documents manually. 

An eTMF portal that provides controlled access to investigators and clinical site staff to upload essential documents directly into the ISF section of the TMF, not only improves the overall efficiency of your TMF filing process itself but also allows remote monitoring which is the need of the hour. It facilitates the site staff to contribute documents in real-time, directly to an established eTMF work-frame. Site users can be provided the same salient features of electronic filing and quality control systems such as version control workflows, task management, timeline tracking and online collaboration with CRO/Sponsor over document statuses and task completions to finalize the documents. 

This added feature not only improves site compliance and document security but also creates a centralized workstation for CRAs to remotely access ISF documents and complete the monitoring obligations. Also, having the eISF documents on the same platform as eTMF helps you cross-reference and reconcile both sets of documents and check the completeness of the dossiers. 

Content Exchange and Export      

Typically, most of the sponsor organizations outsource TMF management activities to multiple different CROs for different clinical trial studies. CROs/Sponsors often use variable filing systems provided by different eTMF vendors. Hence exchange of TMF content from one system to another becomes a painstaking task when interim or final transfer of eTMF content is required by the sponsor for long term archival.– 

The introduction of DIA eTMF Exchange Mechanism Standard (eTMF-EMS) v1.0.1 has clearly addressed this issue and is an emerging standard that defines specifications for transferring TMF data between different eTMF systems. The EMS compliant eTMF systems allow users to seamlessly export/import data and as a sponsor outsourcing to a CRO, you must select an eTMF vendor that supports this standard and eliminates bottlenecks associated with disparate data silos. 

Conclusion

Transitioning towards an eTMF system is the right step in the right direction. Not only will it add great value to your business processes, but it will also help you sail the regulatory landscape with ease. However, a system that is not user friendly and has complex processes, or complicated tools is challenging and may have a ripple effect and lead to change resistance.

Octalsoft’s eTMF application is a well-designed and well-integrated system customized with all contributors and participant inputs and interactions. It comes as an inbuilt module integrated with the CTMS, providing you with an ideal solution, so your efforts are not duplicated. To know more about Octalsoft eTMF application, click here.