Fit for Purpose

ICH E8 now incorporates the concept that quality in clinical studies should be fit for purpose. That is, quality is most effective when applied in a way that aligns with the study intent and design. This customized approach to quality can be associated with all components of clinical development including the design and management of drug development programs and clinical studies. One way to achieve a fit for purpose approach is to apply quality by design principles enabling a proportional allocation of resource based on what is critical to quality.

Quality by Design

The premise of quality by design is simple: incorporate quality in the design from the beginning and focus on what matters to quality. ICH E8 describes quality by design for clinical development in that same spirit, reducing risks and issues for the benefit of study participants and the reliability of study results.

Defining quality underpins any approach to quality by design. ICH E6 and ICH E8 describe quality in a variety of ways; each connects to the protection of study participants’ rights, safety, and well-being and the reliability and interpretability of study results. These are core to the quality of clinical research activities across many stakeholders. Other factors that could be included in the definition of quality are company-specific or related to specific aspects of quality and compliance. Whatever quality definition is used becomes the basis for other elements of the quality management system, including the application of quality by design concepts.

Quality by design supports quality in all clinical programs including those which rely on real-world data and/or large interventional studies. The first step in applying a quality by design approach is defining factors that are critical to quality: those attributes that matter most to the clinical study outcomes, and for which errors cannot be tolerated without negatively impacting a quality outcome. Using critical to quality factors not only defines what matters most but also enables communication and the application of risk-proportionate controls across the Quality Management System (QMS).

Resources for supporting the implementation of successful quality by design are available in the TransCelerate Culture and Engagement Resources Pack.

Critical to Quality

ICH E6 expressed critical to quality factors as “critical processes and data.” ICH E8 takes a broader definition, widening the category of critical to quality factors to include any that may impact participant protection or the reliability and/or interpretability of trial results. For those who have already implemented ICH E6, critical processes and data are still useful to maintain, but now with additional factors to consider. ICH E8 emphasizes defining critical to quality factors early in clinical development planning and then periodically throughout the related studies. In addition, reassessment of critical to quality factors may be warranted when there is:

A significant change to the clinical development plan or to a study design, which may be indicated by a revision to the clinical development plan or a protocol amendment;

A significant or repeat quality issue/event;

A trend in quality performance;

An external factor that affects quality or quality controls;

A long period between study milestones.

A broad group of stakeholders can have input to defining what is critical to quality from their perspectives. This is described further in the “Stakeholder Engagement” portion of this Paper.

Critical to quality factors can be defined using a number of methods, including real-time or synchronous brainstorming sessions with stakeholders and use of critical to quality trees or other tools that support team decision making. Additional information is available in the TransCelerate Resources for the Application of Critical to Quality Factors.

ICH E8 section 7 lists possible critical to quality factors that can be used as a guide to inspire brainstorming or simply as a list of factors to consider. The list of critical to quality factors in section 7 is neither exhaustive nor a limit on which critical to quality factors may be used, nor is it a requirement to use all those listed. If all the factors identified on the list were applied to one clinical study, it would be difficult to determine and communicate what was important to quality, thereby defeating the objective of focusing on what matters most. Whichever method is employed to determine critical to quality factors, factors should be limited to those that matter most to quality, the implementation of the clinical study, participant protection and safety, the organization, and for the particular circumstance (Fig. 3).

Figure 3

TransCelerate quality by design key components.

Operational Feasibility

The foundation of a successful study is a protocol that is both scientifically sound and operationally feasible.Footnote 1

ICH E8 now highlights operational feasibility as a factor that directly affects quality. Operational feasibility promotes efficient and effective application of the protocol with quality and can be achieved by asking questions when identifying critical to quality factors, including:

What is essential to achieve the study objectives?

Are there operational limitations which impact what can be achieved and require the revision of critical to quality factors identified during study design?

Can sites and investigators (e.g., equipment, facilities, training, and qualifications) implement the protocol?

Are there country or site-specific differences or limitations?

What is the availability of participants based on the target patient population?

What are the risks in conducting the study, how can these be eliminated or managed through study design?

How can burden for sites, investigators and participants be minimized?

Are there challenges with retention and follow up of study participants?

While operational feasibility is not a new concept and currently many of these questions are being asked, ICH E8 expands on the “who” is being asked. ICH E8 advocates engaging with much broader and more diverse stakeholders like regulators, patients and patient advocacy groups, and other experts, and having those discussions as early as clinical development planning.

What Could “Good” Look Like?

Designing quality into clinical studies, as described above, is a prospective activity with the purpose of refining the study or development plan to generate accurate answers to clinical questions and to protect participants from harm. ICH E8 describes how the concepts could be applied to prioritize the elements that matter the most to the quality of the study and to streamline non-essential activities in study conduct and oversight. This means moving away from “inflexible, one-size-fits-all approaches”Footnote 2 dependent on retrospective quality control, audits, and inspections to detect errors.

At a minimum ICH E8 recommends the use of quality by design principles to create an operationally feasible and scientifically sound protocol based on the identification of critical to quality factors for associated risks and the implementation of appropriate controls to provide oversight of those factors. Designing quality into the a clinical study is not completed when the protocol is drafted, it should be a continuous and ongoing pursuit throughout the study lifecycle, building and course correcting the study design and the critical to quality factors based on knowledge and data gained during study conduct.

Where risk-based quality management is fully implemented the concepts of risk management (ICH E6Footnote 3: identification, evaluation, control, review, and reporting) are intertwined with the key elements of ICH E8.

What could good look like for designing quality into clinical studies?

How and what

Purpose

During clinical planning identify risks associated with critical to quality factors

The clinical plan can be altered to eliminate or reduce the risk and to focus on what matters most

For example, streamlining the number and type of studies and the being data collected could increase operational feasibility, and reduce burden for participants

Evaluate risks identified during study design

Critical to quality factors identified during design can be evaluated to determine appropriate risks and controls, including where applicable, the data to be collected, the measures, and the analytical approaches to be applied

Apply concepts of risk-based quality management to create appropriate study conduct strategy

Assess the processes involved in the conduct of the study to evaluate if they are essential to the outcome of the study. For those determined as critical, add measures to control those processes (e.g., edit checks, error-proofing site-based processes)

Assure that the data collected is of quality and addresses the question; address and limit missing data; Streamline data collection points and queries to remove those which do not support the critical to quality factors (e.g., prioritizing Protocol Deviations, quality events, and audits based on critical to quality factors)

Create the appropriate feedback loops, allow course corrections to be made when errors arise, and enable resources to be focused and refocused on what matters based on data and knowledge (e.g., monitoring, management, and oversight)

Eligibility Criteria

Create eligibility criteria which reflects the population with the disease or condition in the real world. Apply a proportionate approach to determine broad eligibility criteria to ensure thorough assessment of the safety and effectiveness of the study drug

Communication with Service Providers [i.e., Contract Research Organizations (CROs)]

Include the operational team, including the CRO and other Service Providers, in the study design process and in the identification of CtQs

Oversight Mechanisms

Adopt proactive mechanisms such as metrics, data analysis, and data review focused on the critical to quality factors to demonstrate oversight

ICH E8 acknowledges the increased complexity and changing nature of clinical studies and aims to provide direction for identifying and measuring errors during study conduct in order to understand and focus on what matters most. What quality looks like can and should be different from organization to organization and study to study.