Trial Master File (TMF) Structure

What is the TMF Structure?

A trial master file (TMF) is the collection of documents and information that serves as evidence that a clinical trial is conducted in adherence with good clinical practices (GCP) and proves that the integrity of regulatory submissions data has been maintained.

The TMF structure for clinical trial submissions documentation is delineated in the globally recognized TMF Reference Model. This Reference Model was developed by a working group from the Drug Information Association (DIA) to provide the most effective and uniform method of organizing clinical trial documentation for submissions.

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The TMF structure is commonly broken down into the following zones:

  • Trial management (which includes sections dedicated to trial oversight, the trial team, the trial committee, meeting information, etc.)
  • Central trial documents (with sections focused on product and trial documentation, subject documentation, reports, etc.)
  • Regulatory information (with sections divided into trial approval, investigational medicinal product, trial status reporting and general categories)
  • Institutional review board (IRB), independent ethics committee (IEC), and other information on approvals (with sections focused on trial approval, other committees, trial status reporting, etc.)
  • Site management documentation (which includes site selection, set-up, initiation, management and general information)
  • Investigational product (IP) and trial supplies (with sections focused on IP documentation, IP release process, IP allocation documents, storage, non-IP documentation, interactive response technology and general information)
  • Safety reporting (which consists of safety documentation, trial status reporting and general safety reports)
  • Centralized testing (with sections devoted to facility documents, sample documentation and other general testing information)
  • Third parties (i.e., oversight, set-up and general information)
  • Data management (which includes oversight, capture, database, electronic data capture management and general data management sections)
  • Statistics (with sections devoted to statistics oversight, randomization, analysis, statistical reports and general statistics)

It’s an extraordinarily complicated endeavor to manage a TMF and all its content zones, especially in larger organizations where the TMF structure commonly includes many documents originating from multiple departments outside of clinical operations (i.e., quality, legal, regulatory affairs, pharmacovigilance, etc.). This complexity is magnified further when contract research organizations (CROs) are employed to conduct clinical research, since CROs generate and maintain their own collections of documents.

To help simplify TMF management, MasterControl has developed a useful TMF checklist template tool to help you create a foundation for your own TMF structure. The template is based on the DIA TMF Reference Model, the universally recognized blueprint for TMF structure.

DIA TMF Reference Model

The DIA TMF Reference Model trial master file structure allows organizations to meet the “essential documents” requirements of compliance established by global regulatory bodies. These essential documents, as outlined in various regulatory guidelines (such as the FDA’s regulations for the conduct of clinical trials and ICH GCP Section 8), are those documents that “individually and collectively permit evaluation of the conduct of a trial and the quality of data produced.”

Since regulatory agencies do not provide a comprehensive list of each individual content piece required for a compliant TMF, the DIA TMF Reference Model trial master file structure provides a generally accepted framework for TMF-related data, documents, artifacts and activities. This globally recognized trial master file management plan allows organizations to effectively compile the minimum list of essential data and documentation for regulatory purposes. It demonstrates good clinical practice (GCP) compliance and validates that the organization’s clinical practices are in alignment with other widely accepted regulatory requirements.

The DIA TMF Reference Model is not the trial master file structure required by a global regulatory mandate, per se, but it is the primary TMF structure that is extensively monitored, reviewed and recognized by the world’s major regulatory authorities. It's also widely acknowledged as an extension of the Electronic Document Management (EDM) Reference Model created for biopharmaceutical companies implementing a system to store and prepare documents for regulatory submissions of drugs or biologic products intended for human subjects.

There are many clinical research entities that can benefit from using the TMF Reference Model trial master file structure, including biopharmaceutical and medical device companies, CROs, clinical vendors, or any other organization engaged in the management or execution of study-specific TMFs. Investigators who manage site files or who conduct investigator-initiated studies also may find the TMF Reference Model trial master file structure useful. As proof of the efficacy and proliferation of the DIA TMF Reference Model trial master file structure within the industry, a recent survey conducted by DIA indicates that 85 percent of industry respondents either currently use the DIA TMF Reference Model trial master file structure, are in the process of implementing it or are considering using it in the future.

FAQs on TMF Structure

Is a TMF Required for Compliance?
Yes. Regulatory agencies throughout the world require trial master file documentation from clinical research to be filed in submissions. The primary function of the TMF is to confirm a trial’s compliance with regulatory acceptability standards, so it serves as the basis for all requisite regulatory inspections.

What Content is Required in a TMF?
The International Conference on Harmonisation (ICH) has established a minimum set of essential documents that should comprise the basis of the TMF structure. The minimum essential documents required for pharmaceutical products are outlined in the most current ICH E6 GCP guidance. Regulatory agencies in the United States, the EU and Japan, among other regions, all support the ICH guidelines.

How Should TMF Documentation Be Collected and Structured?
No regulation or guideline provides a comprehensive list of required TMF contents and the details provided in ICH E6 are minimal. The most commonly used TMF structure is based on the TMF zones/artifacts framework provided in the DIA TMF Reference Model. Note that trial master file structure can vary greatly depending on the size of the clinical trial and the size of the organization conducting the trial, as well as whether the trial is conducted in multiple sites or countries.

Is the DIA TMF Reference Model the Only TMF Structure Recognized by Regulatory Agencies?
No, but it is by far the most commonly accepted trial master file structure. In the place of a formal, published standard, the TMF Reference Model is helping the industry standardize TMF nomenclature and taxonomy and the overall trial master file structure.

Can a Trial Sponsor Subcontract TMF Management?
Yes. However, handing over TMF oversight to a CRO increases the complexity of managing and conducting a trial, since both parties generate documentation that is ultimately contributed to the trial master file structure. A trial master file checklist or management plan is essential to helping both parties clarify TMF management duties and expectations.

MasterControl and TMF

The MasterControl Clinical Excellence™ eTMF software solution suite enables organizations to streamline and enhance the management of clinical documentation and their trial master file structure. MasterControl provides real-time visibility into the status of all TMF activities involved in clinical studies. Built around the industry standard DIA TMF Reference Model trial master file structure, the MasterControl Clinical Excellence suite provides for the efficient management of critical documents, artifacts, tasks, milestones, and activities (such as monitoring visits and audits) that are required during the course of a clinical trial. It also allows both sponsors and CROs to track the progress of pending, ongoing, and completed trial master file structured actions. The MasterControl Clinical Excellence suite works in concert with the MasterControl TMF checklist template and the MasterControl TMF Reference Model JumpStart™, an out-of-the-box, document management preconfiguration that aligns all clinical activities with the TMF Reference Model trial master file structure.

MasterControl clinical software offers:

  • A preconfigured solution that is based on the trial master file structure outlined in the DIA TMF Reference Model

  • An integrated, out-of-the-box document management configuration of TMF document types, templates, metadata, version control, lifecycle management, routes and user roles for all TMF structure artifacts

  • A secure collaboration environment for sharing and exchanging trial master file structure-oriented content with teams in your organization as well as with external contributors (i.e., sponsors, CROs, study sites, etc.)

  • A user-friendly “project plan” view of all electronic trial master file structure artifacts and related actions that provides transparency and visibility into the status of all activities, documents and tasks relating to the trial master file management plan

  • Automated notifications of trial master file structure milestones and task assignments via email to assignees, including external parties

  • Easy-to-use bulk importing/exporting functionality that facilitates a smooth, simplified transfer of electronic trial master file structure documentation at study closeout

Implementation of the MasterControl Clinical Excellence suite simplifies adherence to the trial master file structure that is recognized and expected by regulatory agencies worldwide. External and mobile users can log in to MasterControl from anywhere and easily access data that is critical to their roles as monitors, auditors, investigators or any role in between. The greater accessibility and visibility provided by MasterControl helps accelerate the flow of a clinical study and streamlines the execution of TMF-structured tasks. In the long run, these efficiencies reduce the overall cycle times of critical TMF activities, such as reviews, approvals and training.

For more information about trial master file structure or MasterControl's TMF management software solutions, contact MasterControl online or call toll free at 1.800.825.9117 to speak with a representative.