Trial Master File: Paper or Electronic?

The Trial Master File (TMF) is the central location for all clinical trial documents. From the start of a clinical trial through its conclusion, the TMF contains and secures a variety of information such as signature pages, study logs, ethics committee approvals, and reports provided by the sponsor, site, and/or clinical research organization (CRO). Documents contained in the TMF help study organizers adhere to International Conference on Harmonization (ICH) and Good Clinical Practice (GCP) guidelines by enabling them to demonstrate how the trial was conducted and verify the integrity of all clinical trial data.

There are guidelines that detail the minimum content required in the TMF, but the file itself is typically the responsibility of the study sponsor. Over the last few years, the electronic Trial Master File (eTMF) has been gaining widespread attention for integrating the TMF into a digital content platform. This column will compare the differences between a paper TMF and the validated eTMF.

Resources
While implementing another electronic system may seem burdensome, there are several cost drivers that must be considered with eTMFs, since the traditional paper model can be a cumbersome and costly choice.

Paper is an expensive, time consuming, and disorganized material to purchase and utilize. The preparation of folders, binders, and cabinets to house TMF content is inefficient and clearly more costly for businesses to maintain than electronic files. Transporting paper documents—either through standard mail or courier—can also be a waste of money, considering the shipping fees and increased staff hours required to manage the bulk of the documentation.

Storage can be a challenge, too. Paper TMFs produce a large number of documents and thus require a large amount of office space for lodging. Other factors adding to the total storage cost are best practices measures like limiting access to the documents and fire/water damage prevention and protection. Moreover, some national laws have document retention periods extended to 25 years after the end of a clinical trial, increasing the price of maintaining a paper TMF and often resulting in off-site storage fees. The eTMF, on the other hand, provides efficiencies in these same areas. Most eTMF systems offer cloud-based storage space, which makes document retention a far more cost effective and logical option.

Another advantage of eTMF systems is remote accessibility. Sponsors, remote employees, and other organizational personnel can access and review files from off-site locations. For example, clinical research associates have the ability to review files at an investigational site directly against the eTMF without incurring extra costs. Files can be accessed 24/7 and some eTMF systems have the capability of being smartphone compatible. 
 
Ultimately, an eTMF system decreases the margin of cost regardless of the complexities that impact the cost of paper TMFs, such as trial phase, number of sites, and patient total.

Inspection Readiness and Compliance
As mentioned at the beginning of this column, a TMF is created to comply with ICH and GCP requirements. An important consideration for companies maintaining TMFs during a clinical study is how to successfully prepare for regulatory inspections. Prior to an inspection, the CRO/sponsor must ensure all TMF documents are complete and readily accessible. It is imperative to know and differentiate between the documents that are complete and still outstanding. With a paper TMF, such a delineation can be an excruciating process that may involve traveling to sites and/or vendors to collect documentation for the inspection.

In contrast, a validated eTMF system that is compliant with 21 CFR Part 11 reduces these risks associated with non-compliance. The eTMF displays the document’s lifecycle, including any revisions and quality compliance checks, which an inspector might like to see. The system allows users to filter the view of the records and has reporting tools for users to navigate and find information. The system-generated reports also keep track of what required documents are missing. Proper utilization of many eTMF functionalities improve inspection readiness by ensuring all documentation and information have undergone thorough quality checks and are available for review.

Conclusion
Paper TMFs are slowly being phased out in favor of an eTMF system that creates a unified view of clinical operations and study status for all parties involved. Implementing change is rarely an easy endeavor. But sometimes change is needed to continue to produce high-quality work. The introduction of an eTMF system is an important change to clinical trial conduct. The daily management of a TMF is streamlined and the ability to track documentation and be updated with current statuses allows for a productive workspace. Finally—and perhaps most importantly—being prepared for a regulatory inspection is a critical component to running a successful clinical study.

Bibliography
Carter, Myles. “5 Ways an ETMF Will Yield Powerful ROI for Your Organization.” Montrium, Montrium, 29 Jan. 2018, http://bit.ly/odt190182.
Francis, Gail. “Inspecting Clinical Trials – The Trial Master File.” MHRA Inspectorate, Medicines and Healthcare Products Regulatory Agency, 2015, http://bit.ly/odt190180/.
Pearce, Oliver. “10 Benefits TMF Managers Are Achieving with ETMF Systems.” Montrium, Montrium, 27 Mar. 2017, http://bit.ly/odt190183.
“What’s New: The EMA Draft Guideline on a GCP Compliant Trial Master File.” A TransPerfect World, The TransPerfect Life Sciences Team, 8 June 2017, http://bit.ly/odt190181.

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Anuradha Nagulapati is a clinical research associate at Musculoskeletal Clinical Regulatory Advisers LLC (MCRA), primarily focused on supporting clinical trial management and consulting services for medical device companies. In addition to clinical trial support, Anuradha assists MCRA’s regulatory department with developing clinical evaluation reports (CERs) in support of CE marking. She attended George Mason University and graduated with a Bachelor of Science degree in Bioengineering with a concentration in Signals and Systems.