The recommended and required contents of the TMF, the trial master file, continue to be a concern for clinical trial professionals. This blog continues to support the efforts of the DIA working group for the TMF Reference Model, originally issued in 2010. The most recent updates to the TMF RM within Version 1.2, which was released in December 2011, featuring TMF components at the clinical sites along with those kept by the sponsor. The next version of the TMF RM is planned for release in June 2012. There is expected to be some updated content as a result of feedback received from broad industry use of the model, in addition to extension arms of the model for device and investigator-initiated trials. In this Guest Commentary, Lisa Mulcahy, co-chair for the TMF RM working group, explains the basics of the TMF RM.
The Trial Master File Reference Model
The Trial Master File (TMF) Reference Model (RM) is a supported initiative through the Document and Records Management SIAC of the Drug Information Association (DIA), a recognized and highly respected professional association. Creation of the TMF Reference Model has involved more than 230 representatives, all DIA members, from more than 150 bio-pharmaceutical companies, contract research organizations (CROs), consultancies, technical vendors, industry groups, healthcare, academia, non-for-profit / NGO and regulatory agencies. The attention of participants is drawn to the non-commercial nature of this forum. Although it is acknowledged that the resulting reference model ultimately needs to integrate with commercially available products, this was by no means a forum for promotion of products and companies.
The TMF RM was first released in June of 2010 and is a reference for the biopharmaceutical research industry. The model clearly outlines the content and organization of TMF content, at both Sponsor and Investigator site. TMF RM is a reference for the industry and should not be considered mandatory, but rather as an opportunity for standardization across the industry. The TMF RM can be adapted to an electronic or a paper TMF and does not endorse, nor by design, require, any specific technology for application.
The goal of the TMF RM 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.
Use of the model
The uptake of the TMF RM is broad and it is at a minimum being used as a tool to compare against sponsor already-defined TMF content. It is most often though being adapted or adopted by companies as it provides a comprehensive listing of content created in support of a clinical trial.
Rationale for the creation of a model
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).Regulatory guidance, such as ICH E6 section 8, addresses only a sub-set 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.
The following are additional reasons for creation of the TMF RM
• All companies and investigators conducting clinical trials in the pharmaceutical/biotech industry 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 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
Organization of the model
The artifacts have been organized by Zone – where like artifacts are grouped together:
• Zone 1 Trial Management
• Zone 2 Central Trial Documents
• Zone 3 Regulatory
• Zone 4 IRB/IEC and Other Approvals
• Zone 5 Site Management
• Zone 6 Investigational Product (IP) and Trial Supplies
• Zone 7 Safety Reporting
• Zone 8 Centralized Testing
• Zone 9 Third Parties
• Zone 10 Data Management
• Zone 11 Statistics
Artifacts are created and can exist at multiple 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 levels. These levels can be used to define the paper format TMF.
The TMF RM can be found, free to the public using the following link (cut and paste into web browser address bar:
The TMF reference model also details basic metadata which can be used as a starting point for building TMF electronic content management processes. This metadata model can be applicable in all electronic settings, from the straightforward file share to the complex enterprise system.The trial number is captured on each of the artifacts in the TMF RM. Since this model is designed to capture the unique set of documents associated with a single trial, the trial number is attached to each artifact. Inherited metadata such as Product/Compound, Indication, Trial Phase, and Route is also attached to each artifact and would be required to be entered only once, dependent upon system design.
Date format and convention for which date is captured on an artifact present on every artifact and has been left to those interpreting the reference model within already defined processes. Artifacts would have country metadata associated with them if they were to be created for a specific country and a site number/ID if created at the site level.
Please join your industry colleagues in completing the 2012 TMF Reference Model Survey, and use results to inform your TMF best practices.
This fifteen minute survey is designed by members of the TMF Reference Model team to provide valuable insight into Trial Master File practices, both paper and electronic, to identify common problem areas, assess changes in practice and reveal opportunities for improvement. All respondents who complete the survey and provide contact information will be provided with the survey results.
Data collection closes June 1st; please join us today.
======== A GxP Perspectives Editorial ========
It came as a surprise that Wikipedia, under Electronic trial master file, has a subjective entry regarding the TMF RM. Regarding the TMF RM it states: “it fails to specify any electronic format for consistent document and record exchange.” It then goes on to suggest another group is doing a better job: “In an effort to resolve the obstacles around the electronic exchange, sharing and interoperability of electronic trial master files, http://www.etmf.org eTMF.Org was formed in 2011 to develop a standard for the secure exchange and sharing of eTMF archives…” This is an organization that lists four experts on its website. This is in contrast to over one hundred industry professionals, including myself, who have worked over the past few years on the TMF RM.
Wikipedia can be a useful research tool when the articles are objective and well researched. This article is currently rated 3.6 of a possible 5.0 for objectivity. You can read it for yourself, and rate it accordingly at the following link.
GxP Perspectives welcomes all comments on the TMF and the efforts by the TMF RM working group and others on the best way to advance a coherent, usable TMF guidance.
Carl Anderson, GxP Perspectives
FDA has issued the final guidance, “IRB Continuing Review after Clinical Investigation Approval.” GCP Guidance Documents may be found here: FDA GCP Website. The new guidance is on the right in the section “In The News.”