The Trial Master File (TMF) is the collection of essential documents that facilitates the conduct and management of the clinical trial and allows the evaluation of clinical trial conduct, integrity of trial data, and compliance with GCP (European Medicines Agency (EMA), 2017). Its contents, documents and associated meta-data, process, TMF metrics and data, enables the reconstruction of the trial activities during and after completion (Andy Fisher, Senior GCP Inspector, GCP Inspectorate, MHRA, 2015).
Many collaborators, often located in different locations or external to the sponsor, author this “story of the clinical trial.” Increasingly, the TMF paper process is replaced by using a cloud-based electronic TMF (eTMF) application. The main drivers for adoption and implementation of a robust eTMF are:
- Regulatory: Improved audit and inspection readiness, the need for remote TMF access to inspectors and auditors, and recent guidance on the management of electronic documentation/eTMF
- Technology: Cloud-based eTMF solutions provided as a Software as a Service (SaaS) allow all clinical partners (sponsor, CRO, sites, regulators, IRB) secure and global access to dispersed content
- Clinical trial data standardization: DIA TMF Reference Model taxonomy, DIA TMF metrics and OASIS content interchange standards allow clinical content and data to be shared between organizations
- Integration and collaboration: Ability to simply and effectively integrate with other systems and infrastructure, as well as collaborate across functions, locations and vendors
- Performance management: Quality metrics generated within the TMF improve inspection readiness levels and contribute to risk-based study and TMF document management strategies
- Study complexity: Improve operational productivity and reduce time to study milestone (e.g. start-up)
A recent TMF survey indicate that sponsor use of the eTMF increased from 13 percent in 2014, to 31 percent in 2017 (Veeva Systems, Inc., 2018). This adoption of the eTMF technology solutions follows Roger’s innovation diffusion curve, which suggests that a growing community of early adopters had been established that can drive further eTMF adoption and disseminate best implementation practices (Rogers, 2010).
Business Process Change is Inevitable
Implementation of an eTMF provides an opportunity to move from a passive TMF management process used in a paper-based or archive eTMF to an eTMF that is fully integrated with business processes and other eClinical systems. This can include: a Clinical Trial Management System (CTMS), Electronic Data Capture (EDC), electronic signature tools, standard operating procedures (SOPs), Safety Database, start-up applications, electronic health records, and other electronic systems used in the conduct of a clinical study.
In a truly integrated eTMF, all documents, real-time key performance indicators (KPIs) and metrics are generated and managed within the system using an automated workflow. Sites, contract research organizations, and sponsors have access to operational and subject-level data that represent the true status of the study at any time. Increased system integration could, for example, trigger the generation of placeholders for documents (e.g. monitoring visit report and follow-up letter) in the eTMF, and the associated specific workflow (e.g. monitoring visit report review and approval) in accordance with the study management plan and SOPs.
Effective implementation of an eTMF therefore requires a company to have the skills to develop and implement a robust and detailed change management and communication plan (socialize the change). A TMF champion or TMF process owner, typically with an IT and/or TMF operations background, provides a thorough assessment of the magnitude of the business process change (current vs. desired state), and the impact on the internal organization (roles and responsibilities, SOPs, eTraining) and partners (CROs, sites). This TMF innovator builds organizational ownership with senior-level sponsorship (top-down), establishes a steering committee, as well as a change network of subject matter experts that act as the “voice of the eTMF” in their functional groups, and contribute to new business process development and system implementation (bottom-up).
To reduce the risk associated with a full transition from a paper to an eTMF, sponsors may need to obtain change management skills and business practice experience externally. These can range from clinical operations consultants, TMF migration and implementation experts, to eTMF business and strategy teams at larger CROs (Chontas, 2016). With increased eTMF adoption rates, peer-to-peer networking, industry benchmarking, as well as published audit findings these become additional valuable sources of information.
Reimagined Business Process Yields Results
The current best practice is to pilot a sponsor managed eTMF solution in one-two active studies with “known behavior” before enterprise-wide deployment (Goldsmith, 2014). Similarly, when externalizing the eTMF, it is advisable to start implementation with a single study, with a CRO that the sponsor has a long-standing relationship with. Significant time upfront (up to six months) is required for the training and on-boarding of a partner. Furthermore, time is needed to set up the configuration of roles and responsibilities in the eTMF, availability of tech support, and SOP review to accommodate changed practices and workflow (e.g. signature requirements).
While an initial configuration of a pilot study may take 6-10 weeks, the implementation of an integrated eTMF as a corporate standard could take up to 24-36 months. Fortunately, the benefits can be demonstrated early, almost immediately, or gradually. For example, the externalization of the sponsor eTMF allowed for partnered sponsor/CRO management of artifact and milestone QC within a single system. This transparent eTMF review process generated quality metrics in a single dashboard and improved TMF audit readiness.
Meanwhile, the sponsor implements a risk-based approach to the document QC, based on milestone QC findings of approved content. This reimagined process reduces the amount of sponsor resources required for the overall TMF QC and minimizes duplication of effort. Furthermore, it also documents the sponsor’s CRO oversight while maximizing the use of their expertise in TMF QC management. The metrics gathered in this pilot can be incorporated into future quality agreement(s) with this and other vendors.
A CRO’s study start-up unit (SSU) integrated the Activate application with their eTMF. The SSU used their regulatory, country and site knowledge to identify documents and appropriate metadata that needed to be present in the eTMF for each study site. Submission and IP release (green light) packages were compiled in the application and, together with an audit trail, exported to the eTMF. An improved workflow with fewer QC and document handling steps resulted in fewer QC findings and rejects. The CRO reported that without any change in staff levels, a larger number of studies (estimated +20 percent) could be managed (Morgan, 2018).
Improvement in eTMF implementation components, such as process alignment, compliance, content management and operational TMF performance can be gradual, with each accomplishment informing the next steps in process improvement (see table for examples).
Successful eTMF Implementation Depends on Change Management Skills
Frequent and continued feedback on the implementation of eTMF implementation with internal and external stakeholders ensures that changes to processes and systems can be enacted as needed. This keeps users excited about the system itself as well as its capabilities.
While it may be difficult to quantify the benefit of lowered compliance risk and improved TMF user efficiency, comparing operational metrics against historical performance provides evidence of value to the entire organization. This reinforces the benefit of continued business process change.
Most importantly, successful adoption and implementation of an eTMF requires the appropriate skills to develop an organizational change management plan, as well as implementing new business processes that impact many functional areas.
1) Andy Fisher, Senior GCP Inspector, GCP Inspectorate, MHRA. (2015). Trial Master Files 4th European Trial Master File Summit. London: ExL Events.
2) Chontas, L. (2016, December). eTMF adoption and integration accelerating. Centerwatch Monthly, pp. 1-5.
3) European Medicines Agency (EMA). (2017, March 31). Guideline on GCP Compliance in relation to trial master file (paper and electronic) for content, management, archiving, audit and inspection of clinical trials. Canary Wharf, London, United Kingdom.
4) Goldsmith, J. (2014). Working in an Electronic World – How to Make a Smooth Transition to an eTMF. Applied Clinical Trials, 1-7.
5) Morgan, C. (2018). Improving SSU and the Clinical Trial Continuum. Pharmaceutical Engineering, 65-68.
6) Rogers, E. M. (2010). A Prospective and Retrospective Look at the Diffusion Model. Journal of Health Communication, sup1, 13-19.
7) Veeva Systems, Inc. (2018). Results from the latest annual Veeva Unified Clinical Operations Survey. Outsourcing in Clinical Trials West Coast. Burlingame: Arena International Events Group.