Guest Column | December 12, 2023

Who Are Your TMF Customers? The Key To Greater Trial Efficiency & Quality

By Ken Keefer, MBA, PMP, Keefer Consulting Inc.

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Could your director of clinical operations or TMF manager identify all customers of the TMF? Perhaps they would first name the regulators who inspect your TMF when confirming GCP compliance? Meeting the needs of regulators is critical. Inspection-readiness is an essential objective in TMF planning.

Regulators are customers external to the sponsor organization, as are providers, patients, and payers. Internal TMF customers work for the sponsor organization or within its partner networks. Study management teams supply content to the TMF, but they can also benefit by consuming it. CROs, IRBs, and other partners who supply content are also potential TMF customers. A TMF that is current and complete can be a tool for managing more successful trials. Satisfying the needs of all TMF customers contributes to trial efficiency and quality.

TMF Quality Planning

Quality By Design

Customer identification is fundamental to quality by design (QbD). QbD requires planning for efficiency and quality from the outset when designing a product or service. The draft ICH GCP guideline, E6(R3), requires sponsors to employ QbD in planning clinical trials. E6(R3) adoption may prompt many companies to rethink how they plan their TMFs. Study designers and TMF planners will need to collaborate closely to address TMF customer needs. Effective collaboration will result in TMF inspection readiness from start to finish for every trial.

The draft guideline states that “[t]he sponsor and investigator/institution should ensure that the essential records are collected and filed in a timely manner, including those required to be in place prior to the trial start, which can greatly assist in the successful management of a trial.”1 Timely filing will assure that management can act on the information they find in the TMF. Access to trial-related records prior to the beginning of the trial could accelerate study startup. Evolving technology and standards will offer new opportunities for process improvement.

E6(R3) changes to essential record requirements could affect the number of internal TMF customers. Previous E6 versions listed certain types of records as essential TMF content for all trials. E6(R3) recognizes that "[t]he nature and extent of [records to be filed] are dependent upon the trial design, its conduct, application of proportional approaches and the importance and relevance... to the trial."2

E6(R3) continues to list records essential for all trials and lists additional records for which sponsors may determine essentiality based on specific trial requirements. This approach could result in fluctuations in the number of TMF customers for each trial.

Quality Control

The TMF Reference Model resource, Trial Master File Quality Control, defines TMF completeness as “[a]ll documents that enable the reconstruction of the study are available in the TMF contemporaneously of milestones and events.”3 GCP compliance has traditionally focused on producing a “final TMF” at end-of-study. Maintaining “inspection-readiness” over the life of a trial has been an elusive and challenging goal.

Expanding TMF use for study management will require changes to processes governing trial design. E6(R3) prescribes QbD as the approach to be taken in designing trial-related processes. The quality planning road map proposed by J.M. Juran offers a fitting blueprint for this approach4. His approach recognizes both internal and external customers as critical in implementing QbD. Planning begins by establishing quality goals and identifying all customers before taking a risk-based approach to assess their quality requirements.

Identifying TMF Customers

Milestones and Events

Identifying in advance everyone who will require access to certain records may prove difficult. It can be more practical to target potential TMF content audiences by developing requirements for content in support of specific trial milestones and events.

The CDISC TMF Reference Model defines milestone and event types at a trial, country, and/or site level and relates each to one or more types of records (Table 1). Each milestone involves one or more processes with which potential TMF customers interact.5


Pretrial collaboration to define event or milestone-based triggers could reduce dependence on discoveries of unanticipated needs during a trial for particular types of TMF content. A trigger to file a record to the TMF would result when a process reaches a particular step or event. Characterizing triggers involves identifying authoritative sources of inspection-ready records (Table 2). The TMF plan can serve as a location for an inventory of references to triggers and their requirements.

Metadata standardization may one day support the linking of milestones and events to record types applicable to particular types of trials. Industry adoption of such standards could encourage eTMF vendors to introduce configurable triggers.

Current technologies allow triggers to be embedded in user interfaces, applications, or databases but may involve significant costs to implement and maintain. Implementing triggers selectively with less expensive manual or semi-automated procedures might yield better returns on investment. Potential benefits would include greater efficiency and an ability to document compliance with ICH E6(R3) guidelines governing TMF management. Beginning to establish procedures now could help sponsors take advantage of future enabling technologies.

Process Flows

Analyzing existing processes can help identify customers while also revealing opportunities for improvement. Questions to ask may include the following:

  • What is the expected time frame for each milestone during the trial?
  • At what points in the trial may other events occur?
  • What milestones or events will occur prior to the start of the trial?
  • What documentation will each milestone or event require?
  • What processes would produce this content?

Techniques for soliciting requirements such as flow charts and quality function diagrams may be familiar to organizations with experience in Six Sigma or other quality improvement methods. Any technique that helps identify customer roles may also reveal process improvement opportunities. An almost inevitable benefit of process analysis is a greater understanding of critical TMF operations.

Customer Prioritization

Prioritizing processes helps identify the customers for whom TMF quality is most critical to trial success. Juran recommends classifying customers as the “vital few” versus the “useful many.”6 Classifying TMF customers in this way is consistent with the risk-based approach advocated by E6(R3).7

The vital few TMF customers would be those for whom having relevant information when needed is most critical to managing the trial. The availability of trial information for the useful many would have a smaller impact on trial management. However, the collective impact of the useful many may still be significant. Juran recommends working with individual members of the vital few to analyze the processes affecting them and with groups representing the useful many.

Managing TMF Quality

Quality planning is one of three main functions of managing quality under QbD.8 Having established quality goals and identified all TMF customers, it will be time to follow the remaining steps on the quality planning road map:

  • Determine customer needs.
  • Develop features of the product or service that customers will consume.
  • Develop processes capable of producing the product or service.
  • Establish process controls and transfer the quality plan to operations.

The remaining two functions of managing quality are quality control and quality improvement.

The traditional emphasis of managing TMF quality has been on quality control. The overriding goal of quality improvement under E6(R3) will be to replace any overreliance on quality control with processes supporting the design of quality into clinical trials. The role of the TMF will be to ensure whenever possible that record creation and approval processes will trigger the filing of inspection-ready content to the TMF.

QbD requires organizations to commit to long-term quality goals. Ongoing quality planning is vital to sponsors of all sizes wanting to strengthen clinical trial efficiency. A QbD mandate for GCP compliance will compel them to make this commitment. To incentivize support for compliance and efficiency, establish and track indicators demonstrating how improving TMF processes increase the organization’s ability to manage successful trials. Executive management’s role is to ensure an adequate quality planning process and structure are in place and apply quality planning to their own jobs.


The E6(R3) guideline advocates QbD for designing efficient trials that yield quality results. It shifts the view of the TMF as an end-of-trial archive to that of an ongoing trial record. Continuous TMF quality improvement will aim for a reduction in any overreliance on quality control.

The quality planning road map offers a vehicle for study designer and TMF planner collaboration. An important step on the road map is to identify both internal and external customers of the TMF. Access to TMF trial records by the “vital few” will likely have the greatest impact on trial success. Take a risk-based approach by first analyzing processes that support their needs. Look for opportunities to implement triggers to send inspection-ready records to the TMF.

Sponsors can begin now to adopt QbD principles to smooth the transition to E6(R3). Top management support will be critical on their road to greater trial efficiency.


  1. International Council For Harmonisation Of Technical Requirements For Pharmaceuticals For Human Use, ICH Harmonised Guideline Good Clinical Practice (GCP) E6(R3) Draft version, ICH, 19 May 2023, p. 68,
  2. ICH, E6(R3), p. 68.
  3. TMF Reference Model Resource: Trial Master File Quality Control, p. 7,
  4. J. M. Juran, Juran on Quality by Design, 1992, New York, The Free Press.
  5. CDISC TMF Reference Model, TMF Reference Model v3.3,
  6. Juran on Quality by Design, pp. 57-61, 63-65.
  7. ICH, E6(R3), p. 1.
  8. Juran on Quality by Design, pp. 14-15.

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