By Ken Keefer, MBA, PMP, Keefer Consulting Inc.
Regulatory authorities hold clinical trial sponsors responsible for storing content that documents the conduct of trials and making this content accessible to good clinical practice (GCP) inspectors. The number of documents varies by a trial’s complexity and length, but anyone who has managed a trial master file (TMF) is likely to say that number can reach many thousands.
Regulatory inspectors may identify sets of documents to construct a view of an event or of patterns indicating the overall status of a trial. Metadata describing documents in an electronic TMF (eTMF) can help identify those containing relevant information. However, sponsors and clinical research organizations (CROs) often employ different conventions in defining metadata, as do the vendors that offer the eTMFs they use. Reconciling metadata from different organizations and systems is difficult.
There is a growing desire within the industry for better data integration — not just to help regulator, but also to help sponsors manage trials more effectively. Document metadata defined more consistently could help sponsors identify trials at risk for failure more quickly or concentrate resources on more promising ones. The recent affiliation of the TMF Reference Model with the Clinical Data Interchange Standards Consortium (CDISC) may become key to making this possible.
The Importance Of — And Complications To —TMF Integration
A well-managed TMF can become a primary source of trial history and status. The requirements for managing a TMF to comply with GCP are essentially identical to the requirements for managing it to run a trial successfully.
A 2017 guideline by the European Medicines Agency Good Clinical Practice Inspectors Working Group (EMA GCP IWG)1 presents criteria for assessing TMF compliance with GCP that are consistent with principles other global agencies have adopted. The guideline defines the TMF as files held by the sponsor plus the Investigator Site File (ISF) or Site Master File (SMF) held by each trial investigator.
The guideline refers to regulations that require storage of records in the TMF to be sufficient to support effective monitoring by the sponsor and regulatory inspectors. Filing of records to the TMF must be timely, as required by Article 57 of the Clinical Trial Regulation: “The clinical trial master file shall at all times contain the essential documents relating to that clinical trial…The TMF...shall be archived in a way that ensures that it is readily available and directly accessible upon request…”.2
The EMA guideline requires that the sponsor and investigator be responsible for maintaining TMF documents essential to monitoring the trial. The sponsor must oversee management of the TMF, including all relevant records maintained by any party to which the sponsor has delegated TMF management authority. GCP inspections of the TMF focus on its completeness, quality, and timeliness.
While the TMF is important in demonstrating GCP compliance, sponsors and regulators are becoming increasingly aware of its potential for improving efficiency and decision-making. A sponsor can avoid negative inspection findings by maintaining an inspection-ready TMF. At the same time, access to quality information when needed is vital to clinical operations.
Creating A Model To Enhance Industry-Wide Communication
Created in 2010 under the auspices of the Drug Information Association (DIA) and now affiliated with CDISC, the TMF Reference Model was a response to common document management problems across the industry. Each sponsor or CRO, guided by its standard operating procedures (SOPs), would typically define for each trial a structure for organizing trial-related documents in the TMF repository. Different naming conventions, folder structures, and record indexing schemes proliferated. These factors hampered communications among sponsors, partners, and service providers, and could deprive a sponsor of knowledge about how trials were conducted prior to the acquisition of an investigational asset from another organization.
Volunteers created the TMF Reference Model as a spreadsheet that lists “artifacts,” or document types, in rows and attributes for each artifact — like name and definition, its place in a hierarchical structure intended to organize the TMF, suggested identifiers, and whether the scope of the artifact is at a trial, country, and/or site level — in columns.
This structure and a common terminology have enhanced communication among sponsors, partners, and CROs. Vendors of eTMFs offer templates to help customers organize TMFs into TMF Reference Model structures. What’s more, the TMF Reference Model website provides downloadable copies of the Reference Model and related resources.
Recognizing A Need For Data Interoperability
Widespread adoption of the TMF Reference Model has made it a de facto, though unenforceable, standard. Sponsors may adopt all or part of the model to organize electronic and/or paper documents into a TMF. A sponsor may include a document in a TMF that an SOP requires but that its CRO does not recognize. Similarly, a CRO may not recognize a particular type of document that the CRO would name differently.
Such flexibility has allowed companies to adapt the model to trials involving new kinds of therapies and evolving regulatory pathways, while avoiding effects that a more rigid standard might impose on their ability to shape and control their internal operating procedures. Achieving interoperability to exchange documents between TMFs and with other computer systems would require more rigor.
Interoperability becomes important to the TMF under a variety of scenarios, such as an impending GCP inspection by regulators, confirmation that all documents essential for GCP compliance are in the TMF at the end of a trial, or the transfer from the TMF of an acquired investigational asset. Greater interoperability than is typical of current clinical operations environments would be critical to enable study managers to rely on the TMF for authoritative information about trial events and status.
Modern eTMF systems, especially when employing the TMF Reference Model, have improved the capabilities of organizations to store, track, and retrieve documents. However, making them available in response to a request by a study manager or GCP inspector often remains challenging. Documents essential to documenting the conduct of a trial may originate in systems external to the TMF, possibly under the control of a CRO or other organization having a role in managing the trial. Such documents may be awaiting approval or are simply not visible to the eTMF.
One solution would be to update the TMF with a copy of each document immediately on its approval. A more common solution is to transfer all copies in batches to the TMF at end-of-trial. Either approach entails the mapping of metadata from each document source system to the eTMF.
Mapping is time-consuming and resource-intensive. Nearly 60% of TMF stakeholders polled in 2022 rated mapping complexity and concerns over ensuring document and data integrity highest among factors affecting the transfer of TMF content between systems and organizations. A lack of technical expertise and other resources were cited by a quarter of respondents.3
Introducing The Exchange Mechanism: A Way To Reduce Complexity And Cost
A TMF Reference Model subgroup created the electronic Trial Master File Exchange Mechanism Standard (eTMF-EMS or EMS) to reduce the complexity and cost of exchanging TMF content. EMS offers a common protocol to which eTMF developers and others may map proprietary metadata. The standard is open, vendor-agnostic, and based on the electronic common technical document (eCTD) standard that pharmaceutical companies use to transfer information to regulatory agencies.
When implemented, EMS would support interoperability between parties and eTMF systems. It could enable consolidation of content from multiple sources without mapping. Investing in custom development of system interfaces would become unnecessary. EMS promises to reduce TMF update backlogs and reduce the risk of negative regulatory findings.
EMS adoption has been slow since its launch in 2018. Despite multiple presentations to the TMF community describing the advantages of EMS, vendors participating in EMS subgroup meetings reported a lack of customer demand for EMS extensions to eTMF products.
Some vendors have implemented exports of content and metadata to the EMS protocol, but there has been little or no reporting of actual transfers between systems provided by different vendors. Although change control conducted by the EMS subgroup yielded several new releases, there has been no formal development of an EMS road map.
Aligning With CDISC For Increased Support And Adoption
In 2021, the TMF Reference Model Steering Committee pursued affiliation with CDISC, recognized as a formal standards development organization by global agencies including the EMA, FDA, PMDA, and NMPA, to further align the model with regulatory requirements and develop materials to support expanded use and adoption. 4
CDISC has worked since 1997 to establish global standards that enable accessibility, interoperability, and reusability of data used by medical researchers. Its initiatives that may be particularly relevant to the affiliation include its Operational Data Model (ODM) and its collaboration with TransCelerate to develop its Digital Data Flow (DDF) solution.
ODM supports a vendor-neutral, platform-independent standard for exchanging clinical data captured in clinical trials and from electronic health records. Consideration of a possible alignment of the TMF Exchange Mechanism with ODM would be likely.
The DDF Project is developing a standard model for implementing a Study Definitions Repository (SDR). A deployment of the SDR Reference Implementation Model would use the CDISC Unified Study Definitions Model (USDM) standard to facilitate data exchange. Converting the TMF Reference Model into a formal standard could be key to aligning the Exchange Mechanism with DDF. For example, a scheduled study event in an SDR could trigger a transfer of relevant documents into an eTMF.
A newly formed TMF Standards Group will oversee standardization in three phases:
- Migrate the Reference Model into the CDISC Library.
- Migrate EMS into the CDISC Library.
- Align with CDISC standards and processes.
The CDISC Library is a database in which CDISC maintains its standards. Database access will enable capabilities that the current Reference Model spreadsheet and Exchange Mechanism Standard document formats cannot support, such as:
- Searching standard metadata terms
- Relating metadata terms to document types and other metadata
- Performing change control and versioning
- Mapping to other standards, such as Fast Healthcare Interoperability Resources (FHIR), a Health Level Seven (HL7) standard for exchanging healthcare information.
- Creating views of content and metadata for various types of trials.
A review of current Reference Model and EMS versions will identify changes that may be required for migration.
The Standards Group will oversee alignment of the Reference Model and EMS with CDISC standards and initiatives including CDISC Controlled Terminology and DDF. CDISC processes will replace development and change control processes that have governed development and management of the TMF Reference Model. Next steps will include publication of a TMF Standards Governance Committee charter, development of a road map, and formation of teams to begin various workstreams.
- Good Clinical Practice Inspectors Working Group (GCP IWG) (2017, March 31). Guideline on GCP compliance in relation to trial master file (paper and/or electronic) for content, management, archiving, audit and inspection of clinical trials. European Medicines Agency. Retrieved February 28, 2023, from https://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-good-clinical-practice-compliance-relation-trial-master-file-paper/electronic-content-management-archiving-audit-inspection-clinical trials_en.pdf
- Official Journal of the European Union, (2014, May 28). REGULATION (EU) No 536/2014 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC, Article 57. Retrieved March 10, 2023, from https://health.ec.europa.eu/system/files/2016-11/reg_2014_536_en_0.pdf
- Clinical Data Interchange Standards Consortium (2022, October 13). TMF Reference Model General Meeting. CDISC > Events > Public Webinars Archive. Retrieved February 28, 2023, from https://www.cdisc.org/events/webinar/tmf-reference-model-general-meeting
- Clinical Data Interchange Consortium (2022, January 27). Trial Master File Reference Model Group Officially Affiliates with CDISC. CDISC. Retrieved February 27, 2023, from https://www.cdisc.org/news/trial-master-file-reference-model-group-officially-affiliates-cdisc
About The Author:
Ken Keefer founded Keefer Consulting Inc. early in his career with a commitment to helping clients develop innovative computer-based solutions to business problems. Today, he applies his experience to transforming clinical operations through improved system interoperability and process efficiency. He envisions a world in which clinical operations can share information seamlessly with regulators, service providers, and partners through common standards and processes. The ultimate goal is to achieve positive outcomes for patients quickly and cost-effectively.
Ken holds an MBA from Temple University and a post-graduate certificate in pharmaceutical and healthcare business from the University of the Sciences in Philadelphia. Ken can be reached at firstname.lastname@example.org.