Trial master file

In order to comply with government regulatory requirements surrounding Pharmaceutical clinical trials, every organization involved in regulated clinical trials must maintain and store certain documents, images and content related to the clinical trial. Depending on the regulatory jurisdiction, this information may be stored in the trial master file or TMF. The European Parliament has published a directive that certain 'essential documents' shall be archived in a TMF for a period of at least 5 years past the date of the completion of a trial. For US-based clinical trials subject to FDA regulations, there is no specific requirement for a trial master file, as they are not considered part of a pharmaceutical product's marketing submission by the US FDA.

History

In a clinical trial involving human subjects, a set of content known as a trial master file (TMF) must be produced in accordance with applicable international and local regulations. TMFs are a collection of documents and other artifacts which "individually and collectively permit 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 Good Clinical Practice and with all applicable regulatory requirements." Historically, TMFs have been paper-based content sets stored in physical file cabinets, central file rooms, or shelved in binders. The size and complexity of a TMF is in direct proportion to the length and complexity of the trial. The TMF is actively built during a trial, and must be maintained during a post-trial period for possible regulatory agency inspection in alignment with GCP and local country regulations. Traditionally, the TMF content names and requirements varies from sponsor to sponsor, creating a high degree of variability and inconsistency.

TMF definition

A trial master file contains essential documents for a clinical trial that may be subject to regulatory agency oversight. In the European Union (EU), TMFs have a different definition and set of requirements than in the US. The EU Commission's Directive 2005/28/EC 63 Chapter 4 states 'the trial master file shall consist of essential documents, which enable both the conduct of a clinical trial and the quality of the data produced to be evaluated. Those documents shall show whether the investigator and the sponsor have complied with the principles and guidelines of good clinical practice and with the applicable requirements.' The US FDA recognizes the use of TMFs as a significant piece of information but unlike the EU with its TMF regulation, there is no formal requirement for maintenance of essential documents in a TMF in US-based clinical trials in the U.S. Code of Federal Regulations. However, since the U.S. FDA require trials to be conducted in compliance with ICH GCP, there is an expectation that a trial master file will be created and maintained in accordance with those guidelines.

TMF content

The United States, the EU and Japan support the International Conference on Harmonisation or ICH. The ICH has published a minimum set of essential documents for the TMF. The minimum essential documents that are required for the registration of pharmaceutical products designed for human use are specified in the document 'ICH Good Clinical Practices,' published in 1997 by the ICH Example ICH essential documents that would be required in any US, EU or Japan based clinical trial would include: SIGNED PROTOCOL, AUDIT CERTIFICATE, SUBJECT ENROLMENT LOG. Although the ICH guidelines are applicable to the three named ICH regions, many other countries have agreed to follow the guidelines and have incorporated the principles into their national medicines legislation. Creation of a TMF and inclusion of ICH essential documents is based on the discretion of the regulatory agency for the country in which the clinical trial is conducted. In addition, the submission of a marketing application will normally require compliance with the regulatory requirements of that country, including requirements specific to TMF content.

TMF content classification efforts

In 2008 a group of member volunteers within the Drug Information Association formed the TMF Subgroup, which was part of the Document and Records Management Special Interest Area Community (SIAC). The charter of the group was to create a common TMF reference model which would be used for TMF document classification. In 2012 the team released the trial master file reference model. The model is a list of document zones, artifacts and artifact descriptions. The DIA states on their website 'The TMF Reference Model provides an opportunity for standardization across the industry, and can be used by any company in an electronic or paper format'. In 2010, eTMF.org was formed as a non-profit effort 'To develop and publish a candidate standard that will enable global exchange, search and retrieval of TMF files. eTMF.org published a white paper in October 2010 on how paper TMF content could be organized and deployed with electronic systems, using an open source, machine-readable, standards-based content classification system. In September 2013 non-profit CareLex initiated an eTMF standards initiative under the OASIS standards organization to develop a consistent, machine-readable content classification model for eTMFs.

TMF reference model issues

As of May 2013, the TMF Reference model V2.0 was made available in an electronic spreadsheet format which is suitable for human viewing. The TMF Reference model is acceptable for paper TMFs where there is no expectation of eventually moving the TMF content to a searchable electronic TMF. In addition, the artifacts and structure contained within the spreadsheet can be used as the basis for a hierarchical file structure or metadata model in an electronic TMF, but such use is not without issue. In this scenario, the TMF artifact names are typically used as file folder names to classify documents, and documents are retrieved using the basic navigation and search utilities present in most operating systems. One issue with the use of the TMF as an eTMF classification model relates to duplicate artifact names in the TMF Reference model. The current release of the TMF Reference model (V2.0) contains many duplicate artifact names such as 'Communications' or 'General', each with different contexts and uses but the same name, which makes the TMF artifact names unsuitable for use in eTMF search and retrieval where a unique set of search results is desired. A second issue with the TMF Reference model relates to the length of the TMF Reference model artifact names - some are more than 64 characters. Different file systems have different limits on the depth of the filename path, creating potential problems and limitations based on the file system hierarchy in use. Third, the TMF Reference Model artifact names contain 'illegal' characters such as /, which are not allowed in many filesystem naming schemes. Fourth, with respect to the use of the TMF Reference Model as a database schema, the TMF Reference Model V2.0 spreadsheet cannot be used without manual modification as a classification taxonomy in an electronic database. Electronic systems which are not based on interoperability standards are often unable to communicate with other systems or applications. The TMF Reference model currently lacks a controlled vocabulary based on standards, which means that content indexed with the TMF Reference Model artifact names and terms could return duplicate records, incorrect records or possibly no records at all if the model is not implemented appropriately. The TMF Reference model doesn't provide standards-based methods to exchange the TMF model except for exchanging spreadsheet copies of TMF models. Today internet standards such as those promoted by the W3C are utilized for interoperable electronic exchange over legacy manual information exchange approaches.

Recent developments

In September 2013, the non-profit BioInformatics Research organization CareLex initiated an eTMF standardization effort with the global standards organization OASIS. A new eTMF Standards Technical Committee is forming under OASIS to develop 'An open, internationally recognized standard that will assure information interoperability among clinical trial stakeholders.' The eTMF standards initiative will be managed through a democratic, open process in a collaborative effort under OASIS.

In February 2013, the EMA (European Medicines Agency) created a guideline document that recognizes the importance and legal equivalence of the TMF and the eTMF, and provided guidance to organizations implementing TMFs and eTMF systems. In the guideline document, EMA inspectors state that paper TMF documents may be archived in electronic eTMF systems, and after this process, that the paper may be destroyed. The use of eTMF systems for archiving is fully supported by the EMA in clinical trials as a replacement for paper. In a cautionary statement, the agency cites quality problems with TMFs and eTMFs due to document quality and discrepancies such as missing pages, improper labeling or missing documents.