August 8, 2025 | The trial master file (TMF) is the backbone of clinical trials, ensuring completeness of documentation and compliance for studies. Yet, TMF is still perceived as a file repository.  Biopharma and CRO leaders are advancing their approach to make TMF a more strategic tool for study management and oversight.  

Supported by modern applications and a connected vision, the industry is making positive progress to keep up with market and regulatory changes. To continue to push TMF strategies forward, here are five trends shaping the future of TMF management 

TMF Reference Model V4: Moving Toward Global Standards 

In early 2027, Clinical Data Interchange Standards Consortium (CDISC) plans to launch the TMF Reference Model V4 to facilitate the industry’s move to digital. The model offers a standard taxonomy and metadata rules for TMF documents. Version 4 concentrates on driving digital efficiencies and interoperability across systems and teams. The goal is to make data sharing easier or in some cases, seamless.  

Since most data that reaches the TMF originates in other systems, CDISC’s updated model will focus on improving connection and streamlining data exchange. Influenced by ICH E6 and ICH M11, V4 helps keep TMF up to date. For example, adopting the standard structure provided in V4 can significantly reduce filing structures for different document types.  

Updating the TMF Reference Model, originally developed by Drug Information Association (DIA) and adopted by CDISC, will require cross-industry collaboration and alignment with regulatory bodies. Looking ahead, V4 will help drive consistency and adoption of risk-based approaches.  

Big Data: Improving Trial Oversight 

Biopharmas are navigating increasing complexity and growing data volumes in clinical trials. A typical Phase III trial now collects three times more data than it did 10 years ago. One way companies address this is by adopting big data strategies to gain better insights.  

The application of big data aligns with the broader move toward a data-centric model. Companies are now using TMF as a tool for trial oversight. For example, a TMF team can use an API to load an audit log into a data lake, analyzing the information to gain insights on specific audit updates. This level of data visibility enables clinical teams to make more informed decisions and lower risk. 

A Seat at the Table: Delivering Value Beyond Trials 

As TMF management becomes more strategic, TMF teams are being asked for guidance across clinical processes, including study start-up and monitoring. Involving the TMF team informs how new technology can best fit into a company’s ecosystem and adapt change management strategies to meet user needs.  

More organizations are involving TMF teams and establishing a partnership with the group to support critical decisions around product development. TMF expertise during consideration, evaluation, and decision-making benefits trial processes downstream and drives a complete and higher-quality TMF. 

Audit Trails: Driving Proactive and Continuous Inspection Readiness

More TMF leaders are leveraging audit trails to prepare for regulatory reviews. Companies are moving beyond inspection readiness toward inspection steadiness. The difference between the two is that a company will go from preparing for inspection once to continuously preparing throughout the trial.  

Audit trail reviews are key to this process, especially across system, document, and object-level audit trails. Areas where audit trail reviews inform readiness include deletion logs and user activity reports. Deletion logs illustrate high-level information on document details and the purpose of deletion, while user activity reports help identify individuals who need access to the TMF. 

During reviews, keep an eye out for unexpected events and anomalies. This type of review helps clinical teams stay ahead since regulators and quality teams will look for any unusual activities. Advanced TMF applications also prompt for specific activities, like large data downloads. Conducting reviews of document data and audit traceability each quarter helps prevent compliance issues and maintain continuous inspection readiness.  

Site Collaboration: Reducing the Burden on Sites Improves TMF Quality  

Clinical research sites account for nearly three quarters of the documentation filed in the TMF. To improve accuracy and completeness of TMF, industry leaders prioritize reducing the burden for investigators. Standardizing document and data sharing, reducing manual processes, and strengthening relationships collectively improve the site experience. 

The focus on improving site collaboration is also changing site engagement strategies. Biopharmas and CROs are looking for ways to reduce the number of systems and tools a site needs to work in and enable automation of tedious processes. Empowering sites with simple and standard ways of working and fostering a collaborative culture encourages TMF completeness.  

Elevating TMF as a Strategic Function 

Clinical trials and regulations are constantly evolving. While it isn’t easy to keep up, each change offers an opportunity to execute studies with more precision, speed, and effectiveness. Trends around leveraging big data for better insights, TMF Reference Model 4 for standard processes, and prioritizing site collaboration are helping companies to advance TMF strategies. 

Jason Methia has been with Veeva for over a decade and leads clinical operations strategy. Prior to joining Veeva, he was the TMF process owner at Vertex Pharmaceuticals responsible for all aspects of TMF across the organization globally.  Previously, he held clinical or regulatory roles at Pfizer Pharmaceuticals, Dana Farber Cancer Institute, and Wyeth Research. Methia earned a Bachelor of Arts degree from the University of Vermont and a Master’s Degree in regulatory affairs from Northeastern University. He can be reached at Jason.methia@veeva.com.