Guest Column | April 9, 2024

ICH E6(R3) And Defining What Is Critical To TMF Quality

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

standardization certification compliance-GettyImages-1733514056

eTMF technology has made significant strides in gathering and managing large amounts of clinical trial content from internal systems, partners, and service providers worldwide. Yet inefficiencies persist despite this progress and the efforts of sponsors to keep content flowing into the TMF while maintaining its quality.

Industry adoption of ICH E6(R3), possibly by the end of this year, promises to elevate the role of the TMF and increase trial efficiency. The updated GCP guideline will require sponsors to practice quality by design (QbD), an approach that starts with designing quality into every product and service. The emphasis on QbD in E6(R3) aims to ensure “appropriate quality and meaningful trial outcomes."1 Success in applying QbD to trials will depend on achieving ongoing ready access to critical information.

This article explores the following questions:

  1. How could ICH E6(R3) affect the scope of TMF services?
  2. Can understanding TMF customer needs lead to higher quality for the trial?
  3. How could sponsors apply QbD to improve TMF and trial quality?

TMF Scope

Current State Of TMF Quality

The current GCP guideline, ICH E6(R2), states that “[q]uality management includes the design of efficient clinical trial protocols and tools and procedures for data collection and processing, as well as the collection of information that is essential to decision making.”2 Sponsors employ quality control metrics to manage TMF quality, completeness, and timeliness, but this does not guarantee that relevant information is available when decisions are made.

Current technologies limit timely transfers of content to the TMF from various systems. Many TMF managers struggle to maintain inspection readiness, as an impending GCP audit or inspection can trigger intensive efforts to collect and file overdue content. Bringing the TMF fully up to date is often achieved only after the trial has ended.

Quality by Design

An early application of QbD to the TMF by Pfizer was reported in 2013.3 Pfizer aimed to reduce document defects and missing or incorrect documents, with a long-term objective of improving quality in the TMF process and lowering the cost of poor quality. Other companies have undertaken similar efforts to improve TMF quality and inspection readiness, though some would acknowledge that timeliness in filing documents to the TMF continues to lag.

Better system interoperability could accelerate the filing process, but industry efforts to develop a content exchange standard have proceeded slowly. The inclusion of QbD in ICH E8(R1) and E6(R3) coincides with new initiatives toward standardization, which could result in better integration between operational systems containing TMF content.

Qbd And Clinical Research

Companion guidelines set expectations for QbD in clinical studies, with ICH E8(R1) focusing on clinical trial design and ICH E6(R3) on good clinical practice.

ICH E8(R1) states that “[q]uality by design in clinical research sets out to ensure that the quality of a study is driven proactively by designing quality into the study protocol and processes"4 and suggests that practicing QbD could result in fewer protocol changes and greater adherence.5

ICH E6(R3) states that “[q]uality by design should be implemented to identify the factors (i.e., data and processes) that are critical to ensuring trial quality and the risks that threaten the integrity of those factors and ultimately the reliability of the trial results.”6 Critical data includes “essential records” and the metadata that describes them. Critical processes are necessary to gather, index, and store essential records in the TMF repository.

Qbd And The TMF

E6(R3) defines essential records as documents, metadata, and data that “facilitate the ongoing management of the trial” and describe how the sponsor has conducted the trial, what factors have affected its course, how the sponsor has confirmed trial results, and whether the sponsor has complied with GCP.  The guidance distinguishes between “essential records” the sponsor is to consider essential for every trial and “potential essential records” the sponsor may determine are essential according to criteria listed in the guidance and on “the trial design, its conduct and risk proportional management”.7 

E6(R3) states that “[c]linical trial-related records … should be available to regulatory authorities upon request to enable reconstruction of the trial conduct”.8 E6(R3) recognizes that essential records, including source records, may exist outside TMF or ISF repositories and requires sponsors and investigators to keep track of record locations and version histories.

Implications For TMF Scope

That essential records may reside in multiple repositories and be readily available to regulators suggests the scope of TMF planning can extend beyond eTMF systems.

Timely filing to the TMF will be necessary to meet regulatory expectations and to support internal decision makers including study designers, managers, and others who work directly for the sponsor or a delegated service provider. “Filing to the TMF” can be interpreted as making a record visible as an integral part of the TMF. Making it visible may result from transferring it from another system into an eTMF or by a mechanism that allows navigation to the record from related TMF content, regardless of which repository or repositories house that content.

Near real-time transfers will become increasingly practical as standardization and technological innovation improves systems interoperability. Realizing this vision will take time but will “greatly assist in the successful management of a trial” as both E6(R3) and the current version E6(R2) have suggested.9 Near real-time availability of information could expand TMF scope by attracting more internal customers.

Customer Needs

Roles And Perspectives

E6(R3) quality objectives include trial efficiency as well as the protection of the rights, safety, and well-being of participants and the production of reliable results. Sponsors are to consider priorities and risks during trial planning, with a focus on factors that are critical to quality (CTQs). TMF customer perspectives on priorities, risk, and CTQs can vary by the roles they will play in the trial.

Regulatory agencies ultimately expect an end-of-trial clinical trial report that includes a description of the quality management approach taken by the sponsor. Inspectors want to understand not only how quality is being managed but also how decisions are made and their impact on the trial.

Internal decision makers need ready access to current information. Content contributors value user interfaces that simplify TMF document creation. TMF planners may want to improve a process critical to resolving a chronic obstacle to quality.

Other Factors Affecting Needs

Long-running trials sometimes encounter changes that reveal quality-limiting inefficiencies. Health authorities introduce regulatory changes publicly or provide clarifications directly to sponsors. A protocol amendment may involve changes in study objectives or design.

Process inefficiencies may prompt TMF planners to ask questions pertaining to potential quality improvement. For example:

  • Does the sponsor create TMFs in time to supply information relevant for protocol development?
  • Do study start-up activities proceed before TMF creation, leaving records needed for decision-making scattered among various systems?
  • Are quality control steps redundant, for example, when creating a document in a CTMS and when receiving a copy of that document for filing to the TMF?

Recognizing limitations of existing services may reveal opportunities for improving TMF quality. For example, eTMF search functions do not generally access other systems containing TMF content. An undocumented practice may indicate a need for a process to replace the consolidation of information from multiple systems into a spreadsheet in order to assess progress toward a particular milestone.

Advantages may result from adding or revising processes in response to a technology change. Vendors continue to enhance eTMF applications to aid TMF management. Automation of informal manual processes may provide benefits, such as, for example, replacing a spreadsheet to more easily track multiple repositories and sources of record in compliance with E6(R3).

Standardization of eTMF outputs or inputs may make it possible to reduce the complexity of transferring content between collaborating parties and systems. A new release of Dynamic Data Flow (DDF) by Transcelerate or the TMF Reference model by the Clinical Data Interchange Standards Consortium (CDISC) could allow a sponsor to establish better integration between the eTMF and related applications.

Defining TMF Quality

Identifying TMF customers and the factors influencing their needs can help to envision better ways to serve them.

Quality Planning Road Map

QbD proponent J.M. Juran developed a “quality planning road map” in the early 1990s to guide companies in designing products that satisfy customer needs.10

The road map begins with setting quality goals and identifying customers who will either consume the end product or participate in processing at an intermediate stage of production. The next step is to define CTQs for these customers. The subsequent design of the product includes features that meet CTQ requirements. Development of quality controls and the transfer of the product or service to production follow. Companies instill a culture of continuous improvement by iterating these steps for every product.

Producers may also apply QbD and the quality planning road map to services. E6(R3) will require sponsors to assess CTQs for all process outputs, including TMF service outputs. Sponsors then make risk-based determinations of which outputs will be most critical for the trial. TMF planners would determine in collaboration with the study design team what documents will be essential and any process changes to improve the availability of TMF content for decision-making.

Adopting measures for assessing performance is an essential part of defining each CTQ. Although E6(R3) does not require specific measures for TMF completeness, timeliness, and quality, sponsors should review current metrics and change them if necessary to comply with the guidance. For example, making TMF content readily accessible to regulators and study management affects timeliness and efficiency and may require shorter target durations for approval and filing to the TMF.

Requirements Solicitation

Cross-functional representation when soliciting CTQ requirements is critical. Sponsors should seek input from subject matter experts representing every group that will potentially interact with the TMF, including service providers and TMF management. Facilitators who solicit TMF customer input should have process development expertise and be trained in QbD and E6(R3).

Sponsors who have implemented a quality program such as Six Sigma would recognize tools and techniques applicable to defining CTQs and mapping them to E6(R3) requirements: root cause analysis, house of quality, and others.

Understanding the needs customers express is key to gaining their trust and cooperation. Thoroughly exploring their stated needs may uncover additional needs having a potentially greater impact on the trial. Customers may also perceive different benefits from the same TMF service. Distinguishing real needs from initial statements and perceptions is critical to determining what TMF services to develop.

While identifying the needs of TMF customers promises to benefit them, it is important to recognize that satisfying those needs will introduce changes that may concern some. Consider potential effects on worker roles, plan for them, and keep stakeholders informed.


Better process design enabled by QbD adoption will yield better information to support higher quality and efficiency in conducting clinical trials. Understanding customers’ critical-to-quality needs will enable sponsors to serve what may become an expanding TMF customer base. Adopting QbD now could better prepare sponsors to comply with E6(R3) and assure interpretations of trial status and outcomes are valid.


  1. ICH HARMONISED GUIDELINE GOOD CLINICAL PRACTICE (GCP) E6(R3), Draft version Endorsed on 19 May 2023, p. 2, section II., retrieved February 28, 2024.
  2. INTEGRATED ADDENDUM TO ICH E6(R1): GUIDELINE FOR GOOD CLINICAL PRACTICE E6(R2), Current Step 4 version, 9 November 2016, p. 21, section 5.0., retrieved February 26, 2024.
  3. Pfizer's Quality by Design Approach to Trial Management", Pharmaceutical Executive, 1 April, 2013., retrieved February 28, 2024.
  4. ICH HARMONISED GUIDELINE GENERAL CONSIDERATIONS FOR CLINICAL STUDIES E8(R1), Final version Adopted on 6 October 2021, p. 3, section 3.1., retrieved February 28, 2024.
  10. J. M. Juran, Juran on Quality by Design, 1992, New York, The Free Press.

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