Don’t Take Clinical Trial Master Files for Granted

The TMF is crucial to inspection readiness and the success of any clinical trial. Sponsors that approach TMF management passively lose the opportunity to drive strategic advancements in their trials and actively collaborate with sites, contract research organizations (CROs), and technology vendors.

Regulators — including the European Medicines Agency (EMA) — expect the TMF to document the trial’s history on its own, without supplemental information. As a result, the file needs to be comprehensive, yet accessible and outlined in a clear and logical way. It needs to summarize everything that happened during the trial and when, who was involved, and how they responded.

A strategic approach to TMF is especially important now that the industry is increasing its use of remote and hybrid inspections that involve virtual technologies. In addition, as a result of ICH E6 R2 and other new guidance, regulators expect TMFs to document how risk management principles and quality by design approaches are being used in the trial¹.

As new inspection approaches and digital, decentralized trial approaches gain ground, now is an ideal time to move from paper-based processes to electronic TMF systems. With eTMF, clinical operations teams can automate workflows, analyze trends, manage documents in real time, and move from passive to active trial management, all of which improve inspection readiness and reduce trial timelines.

The ability to automate processes and transfer data in real time makes it easier for sponsors, sites, and CROs to work together. It is also key to reducing errors and duplicate data; ensuring compliance with GCPs; and assuring regulators of data integrity. For these and other reasons, more companies have adopted eTMF, use of which grew by 51% between 2014 and 2020 to account for 68% of the market².

Big pharma moved to eTMF years ago, and a growing number of small- to medium-sized sponsors and CROs have realized significant improvements in timelines and efficiencies due to increased data visibility across functions. The ability to trend data and manage trials proactively reduces study start-up time. For one mid-sized CRO, use of eTMF cut study start-up time in half and sped TMF delivery to sponsors by 75%³.

Below are best practices to optimize TMF management and drive inspection readiness with eTMF.

Things to avoid in TMF management

Optimizing the TMF should be an integral part of broader initiatives to improve trial operations and control risks. Currently, regulators see lack of completeness as the top TMF compliance issue. Sponsors and all study partners must be aware of reviewers’ expectations and ensure that they collect all the information required. One area where inspectors often find insufficient documentation is with ancillary systems such as contract management and safety systems.

Regulators also cite lack of timeliness as another weak spot. Although eTMF can lead to significant gains in document management efficiency, its use requires discipline. Teams cannot simply slide a three-hole-punched paper into a clinical binder as the inspector walks through the door, as some may have been tempted to do in the past.

Proactive planning and access control

Proactive planning is required to make the trial master file as valuable as possible to all study partners. First, a TMF Plan should outline procedures spanning the lifecycle of the trial. Content should be well organized, arranged in a logical way, and aligned to a defined structure, like the TMF Reference Model. The TMF Plan should also list documents housed in ancillary systems, and the process for providing that content if it’s not direct access. A TMF Index presenting the document’s structure should be included as a separate attachment to the TMF Plan.

To ensure trial integrity, TMF access should be closely controlled. A paper TMF should be kept in a locked file room, while an eTMF should feature customized access controls. However, sponsors must consider that they cannot fully demonstrate inspection readiness with a paper TMF because content is not tracked while in progress and documents are stored in multiple locations — plus, remote and hybrid inspections are hindered.

Similarly, at research sites, investigators must control access to their own Investigator Site Files, whose content may overlap somewhat with that of TMF. Each site must own this content and control who has access to it. Chain-of-custody and other security procedures are especially important when the file is being transferred, for example, from a CRO or technology vendor to a sponsor.

Ensuring data integrity and quality

Content review and finalization should follow a well-defined, systematic process that allows the clinical operations team to build quality assurance and/or inspection readiness into the master file. The clinical study team, or a designated delegate, must establish review processes that will improve the master file’s quality, timeliness, and completeness. Sponsors are ultimately responsible for master files, and must establish processes to ensure control when a third party such as a CRO or vendor is managing them.

Content must meet the data-integrity principles defined by FDA’s ALCOA acronym, in that it should be: attributable (to a specific person or group); legible; contemporaneous, or as close to the data recording time as possible; original; and accurate. It should also be complete, comprehensive enough to enable regulators to recreate the events that surrounded it.

Best practices, greatly simplified by adoption of eTMFs, will improve results by empowering team members to file content directly and employing a standard structure and metadata schema for data entry. Leverage workflows to drive TMF content finalization by automating the documentation of activities and allowing qualified team members to provide input and make decisions proactively.

Planning should also account for validating the system’s conformance to regulatory requirements and standards, and should include the development of backup and disaster recovery plans. If a vendor is managing disaster recovery, the sponsor should develop business continuity plans that sync with its efforts.

To improve results, leverage system reporting whenever possible. The ability to see, report, and trend data has been a key reason why more pharma companies and their partners are switching from paper to electronic master files. Trending offers insights that can help sponsors and partners continuously improve clinical trial operations. As trials become larger and more complex, the ability to transfer trial data to the right function, whether sponsor, CRO, or research site, and at the right time, is crucial.

Finally, be sure to involve external trial collaborators such as CROs, consultants, and eTMF vendors in efforts to improve TMF and overall inspection readiness. They have experience in aspects of the work that you may not be familiar with, and their suggestions can only improve the end result.

In short, the TMF is a living document that is vital to inspection readiness and to improving overall trial efficiency and results. Take the time to approach it strategically with trial partners. Adopting eTMF to eliminate manual processes and share real-time data and trends with partners can only deepen collaboration, while ensuring compliance and greater efficiency.

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