Welcome to our series on Implementing E6 R3. We're looking at changes to the guideline that are interesting, challenging, or even problematic. Our story so far:
Today, one of my personal faves: Quality by Design. It's messy!
Very little regarding quality management has actually changed from R2 to R3. The subsection has been moved from the beginning of Sponsor Responsibilities in R2 to the middle of this section in R3, and it has been rewritten a bit, but it still traces the process of risk identification, evaluation, control, communication, review, and reporting. The big change is in this sentence inserted into the preamble:
The sponsor should adopt a proportionate and risk based approach to quality management, which involves incorporating quality into the design of the clinical trial (i.e., quality by design) and identifying those factors that are likely to have a meaningful impact on participants’ rights, safety and well-being and the reliability of the results (i.e., critical to quality factors as described in ICH E8(R1)).The sponsor should describe the quality management approach implemented in the trial in the clinical trial report (see ICHE3 Structure and Content of Clinical Study Reports).For more on quality by design and critical to quality factors, we turn to ICH E8, a guideline on General Considerations for Clinical Studies. It is indeed very general, more like a primer on clinical trials than a set of rules for conducting them, which is one reason it is less familiar than E6. E8 was originally published in 1997 and not revised until 2021, when it introduced the concepts of quality by design and critical-to-quality factors (a phrase it properly hyphenates to denote that "critical-to-quality" is an adjective modifying "factors," unlike the lawless E6 R3 folks, who throw punctuation to the wind.) This revision attracted attention but little action until 2023, when the draft E6 R3 was released with its requirement to report "the quality management approach" in the Clinical Study Report.
Here are the highlights from E8:
- Protocol design and operational criteria are important to protecting participants and ensuring meaningful results
- Study teams should identify factors for each study that stand out as critical to study quality.
- Critical-to-quality factors are those aspects that would harm participants or destroy he integrity of the study data if they were subject to errors.
- Study teams should also identify the risks to each critical-to-quality factor and determine how to mitigate them.
So far so good, right? It's basically risk mitigation, but before we start identifying risks, we need to figure out what's most important to the study. We can envision that at the end of this exercise, a study team would have a list of critical factors, the risks that could harm those critical factors, and mitigations to address each risk.
Hold up! Here's where it gets messy. Section VII/7, Considerations in Identifying Critical-to-Quality Factors, has been tacked on near the end of the guideline (helpfully labeled with both Roman and Arabic numerals for those of us who have forgotten how to count in Latin). This section provides a list of aspects that "should be considered, where applicable, to support the identification of critical-to-quality factors." The list includes the following:
- Engagement of stakeholders during planning and design.
- Nonclinical studies and prior clinical studies support the study design.
- Study objectives address relevant scientific questions.
- Adequate measures such as informed consent, IRB/IEC review, training, and pseudonymization) are used to protect participants' rights, safety, and welfare.
- The feasibility of the study should be assessed to ensure the study is operationally viable.
- Systems and processes are in place to ensure data integrity.
- The need for a data monitoring committee is assessed.
It feels like we've gotten off track here. These sound more like principles for protocol design and implementation than considerations in helping us identify critical-to-quality factors.
Confused, we turn to the internet to shed more light on "critical-to-quality" factors. Stay tuned for Part 2!
