The TMF Reference Model provides standardized taxonomy and metadata and outlines a reference definition of TMF content using standard nomenclature.
The TMF contains those essential documents that individually and collectively permit the evaluation of the conduct of a trial and the quality of the data produced. These documents serve to demonstrate the compliance of the investigator, sponsor, and monitor with the standards of GCP and with all applicable regulatory requirements (ICH Guideline for Good Clinical Practice, E6, Section 8).
All companies and investigators conducting clinical trials in devices, drugs, biologicals and combinations thereof maintain documentation for each clinical trial. Each company has their own unique TMF structure as defined by their SOPs. No comprehensive common model exists for managing TMF documents. Over the conduct of a trial many functions contribute to the TMF, although oversight of the content is usually not one function’s responsibility – resulting in a highly inefficient work processes including but not limited to:
* All drug and medical device development companies and CROs expend considerable resources defining the content of the trial master file for each clinical trial. Consequently,
* Investigators have the challenge of adapting to different formats and TMF content organization with each clinical trial.
* The burden is very high on smaller companies that usually have limited document management expertise and limited financial resources.
* Records and information exchange between collaborating companies is extremely cumbersome, potentially preventing the joint venture or transfer of an investigational product.
* Regulators are challenged with varying terminology and file structures, creating inefficiency and variability during audits
Regulatory guidance, such as ICH E6 section 8, addresses only a subset of TMF documents. Documentation requirements for the set-up and maintenance of quality systems, electronic systems, safety monitoring, and proof of an adequate and well-controlled trial, to name a few, exist in various regulations across many countries or regions, but not in ICH E6.
Defined in the model are document types, called artifacts, which one would expect to find in a TMF, at both Sponsor and Investigator site. It is important to note that progeny records such as artifact approval/signature pages, amended artifacts, or translation documentation are not called out uniquely since artifacts may have one or more progeny records depending on trial requirements or a company’s specific processes. In version 3, an option for a further level of granularity was added in the form of sub-artifacts. Example sub-artifacts were added - company specific customization to match SOPs and processes is required.
The artifacts are labeled either core, meaning that if such a record exists, it must be in the TMF as dictated by either the ICH Guidelines, regulations, or the TMF Reference Model group (ONLY if applicable for the trial), or recommended meaning the artifact does not have to be produced but if it is created or collected, it is recommended to be in the TMF. Since the industry often uses unique names, common alternate names (as relevant) and descriptions are supplied for each artifact. If the artifact is referenced in the ICH Guidelines, the reference is captured in the column “ICH Code”. Similarly, relationship to the sister Electronic Document Management (EDM) Reference Model is captured in the column “EDM Reference Model” and if overlap is present, the artifact name EDM Reference Model, version 1.3, is indicated. Each artifact has been given a unique Artifact ID Number, which will allow for the tracking of the artifacts and their changes through future updates to the model.
The artifacts have been organized first by Zones in which like artifacts are grouped together:
1 - Trial Management
2 - Central Trial Documents
3 - Regulatory
4 - IRB/IEC and Other Approvals<
5 - Site Management
6 - Investigational Product (IP) and Trial Supplies
7 - Safety Reporting
8 - Centralized and Local Testing
9 - Third Parties
10 - Data Management
11 - Statistics
The artifacts have secondarily been organized by Sections within each Zone.
Artifacts are created and exist at many levels such as trial, country, and site. An artifact, such as “Safety Management Plan” exists at only 1 of the levels, the trial level. In contrast, the artifact “Informed Consent” can exist at all three. These levels define the paper format TMF.
In summary, the goal of the TMF Reference Model is to provide a single, unified interpretation of the regulations via document listing which would be accepted across the industry. It does not provide guidance in the process by which the document is the output.