After more than 20 years, the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) Harmonized Guideline was updated to ICH E6 (R2) in November 2016. The revision was implemented to modernize clinical trials and takes into consideration the evolution in technology and quality management processes that offer new opportunities to enhance efficiency, focus, and oversight on relevant activities.¹ ICH E8 (R1) draft version was released in May 2019 and further supports a risk-based monitoring (RBM) strategy by providing general considerations for clinical studies.² These revised guidelines encourage implementation of improved and more efficient approaches to clinical trials, in such aspects as: trial design, conduct, oversight, documentation, and reporting to ensure human subject protection and reliability of trial results. Successful implementation of these guidance documents requires a well-orchestrated, collaborative, and cross-functionally supported effort between sponsors and their contracted vendors.

Within ICH E6 (R2), “The sponsor should implement a system to manage quality throughout all stages of the trial process. Sponsors should focus on trial activities essential to ensuring human subject protection and the reliability of trial results. Quality 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 decisio- making.”¹ While the guidance provides core recommendations, interpretation and implementation has varied greatly. ICH E6 (R2) highlights seven components necessary to manage quality through all stages of clinical trials. Those components are:

• Critical data and processes

• Risk identification

• Risk evaluation

• Risk control

• Risk communication

• Risk review

• Risk reporting

An effective-but often overlooked-component of clinical trial oversight is risk communication. ICH E6 (R2) states, “The sponsor should communicate quality management activities to those who are involved in or affected by such activities, to facilitate risk review and continual improvement during clinical trial execution.”¹ ICH E8 (R1) further supports that premise by indicating that “proactive communication of the critical to quality factors and risk mitigation activities will support understanding of priorities and resource allocation by the sponsor and investigator sites.”²

To address the possibility of overlooked risk communication, a basic set of factors relevant to ensuring study quality should be identified for each study. Emphasis should be given to those factors that stand out as critical to study quality. These critical to quality (CTQ) factors are attributes of a study whose integrity is fundamental to the protection of study subjects, the reliability and interpretability of the study results, and the decisions made based on the study results. The use of CTQ, such as critical data and processes, key performance indicators (KPIs), key risk indicators (KRIs), and quality tolerance limits (QTLs), presents an opportunity to proactively communicate CTQ factors and risk mitigation activities to support understanding of priorities and resource allocation by the sponsor and investigator sites.

CTQ factors function as communication vehicles to ensure quality alignment across the study. In this way, CTQ, KRIs, and QTLs aligned with critical data and processes to facilitate the alignment of project teams and organizations early while supporting study and vendor oversight throughout the clinical trial life cycle. ICH E8 (R1) recommends quality measures and performance indicators be aligned with a proactive design approach. In this framework, CTQ factors are what is to be focused on, whereas KRIs and QTLs are how the CTQ factors are safeguarded to prevent or mitigate important and likely risks to investigation quality, including risks to human subject protection and data integrity.

What follows within this article are practical methods for integrating CTQ factors within the operational execution life cycle of a clinical trial.

Early focus and alignment

Successful clinical trials begin with focus and cross-function alignment across departments and the third-party vendors that provide services, such as project management, clinical management, data management, biostatistics, medical monitoring, pharmacovigilance, and medical writing. Early risk management activities require project teams to have a strong understanding of the study endpoints and supporting CTQ factors. Those factors function as a compass to provide a common direction across the project team, helping them to focus not only on what is important, but, more notably, what is not important. Early identification of the critical risks that could affect subject safety or data integrity is paramount to driving further focus of the project team. In this way, early risk-management activities prioritize resources on the critical trial elements, impact the various functional/vendor trial plans (e.g., monitoring plan), align communication across organizations, and lay the foundation for downstream risk-based operational decisions.

Improve and communicate

Once CTQ factors are identified, the shift from planning to execution begins. Risks that are associated to CTQ factors are assessed to determine if they can be eliminated or sufficiently reduced. For those risks that cannot be eliminated or reduced, mitigation plans are established. For example, if the primary study endpoint is associated with a laboratory sample collection, the risks associated with collection of samples cannot be eliminated. Therefore, the associated risks should be effectively managed to reduce the risk to subject safety and ensure data quality. As mitigation strategies are established, detection mechanisms are determined to quickly identify if the established mitigation strategies are effective.

One method to monitor mitigation plans is via KPIs, KRIs, and QTLs. KRIs are metric indicators of the quality of study conduct in specific targeted areas. QTLs, introduced within ICH E6 (R2), “should be established, taking into consideration the medical and statistical characteristics of the variables as well as the statistical design of the trial, to identify systematic issues that can impact subject safety or reliability of trial results.”¹ Detection of deviations from the predefined QTLs should trigger an evaluation to determine if action is needed. In this context, it is important for clinical trial teams to regularly analyze and properly align trial-specific KRIs and QTLs. These activities support continuous clinical trial quality improvement as well as driving focused decision-making communication and actions.

A method of communication that reinforces CTQ factors is regular project team meetings. These meetings should be held in conjunction with dedicated cross-functional risk review meetings and become frequent quality check-ins for analyzing KPIs, KRIs, and QTLs to assess if established mitigation strategies remain effective and if existing or new risks are emerging (see Figure 1; click to enlarge).

Figure 1. Relationship of risk communication to CTQ factors and mitigation approaches.

Following a continuous process improvement model, such as those of Six Sigma, Lean, and Total Quality Management, ongoing improvement is achieved through incremental and breakthrough improvements. As demonstrated within Figure 2, the more often the project team evaluates performance based upon established parameters (KPIs, KRIs, and QTLs), the greater the resulting quality becomes.

FIgure 2. Following a continuous process improvement model, frequent quality check-ins focused on CTQ factors provide continual improvement over the clinical trial life cycle, supporting higher overall quality.

Coinciding with continuous process improvement is documentation to recreate the environment present when key decisions were made and what specific actions were taken as a result. These activities support ICH E6 (R2) recommendations for sponsor oversight and are included within the risk management section of the clinical study report. An example of questions project teams should consider when evaluating process improvement are:

• What are the downstream actions caused by the findings?

• Does the project team have evidence of study team members changing processes?

• Can the project team demonstrate they’ve made meaningful change?

As demonstrated within this article, KPIs, KRIs, and QTLs provide an opportunity to proactively communicate CTQ factors and risk mitigation activities to support ongoing sponsor oversight activities across vendors throughout the clinical study life cycle.

Brian Barnes is Director of Risk-Based Monitoring, PPD; Volker Hack is Executive Director of Centralized Services, PPD

References

1. International Council for Harmonization. 2016. Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice E6(R2), www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R2__Step_4_2016_1109.pdf

2. General Consideration for Clinical Studies E8(R1) Draft version Endorsed on May 8.  2019, https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E8/E8-R1EWG_Step2_DraftGuideline_2019_0508.pdf