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What’s New in E6 R3? Sponsor Responsibilities, Part 1 – Trial Design

In the next few posts on changes in E6 R3, we will consider changes to the Sponsor Responsibilities section.  First we look at changes to the Trial Design section, which includes the phrase sure to appear on your 2023 Clinical Trial Bingo cards:  “Quality by Design.”

In R2, the Trial Design section simply stated that the sponsor should utilize qualified personnel for all stages of the trial, then referenced other resources for protocol and Clinical Study Report development.  This content has been moved to the more appropriate Qualification and Training section, and the Trial Design section R3 now includes the following requirements:

Supporting data. Sponsors should ensure that non-clinical and clinical data are sufficient to support the route, dosage, duration of exposure, and population for the trial, an expansion of the more general statement that is now expressed as principle 4.1.

Quality by design. Sponsors should incorporate “quality by design” by identifying factors “critical to quality” and managing risks to those factors. This requirement echoes new principle 6, which introduces critical-to-qualify factors, as well as ICH guideline E8 Revision 1, General Considerations for Clinical Studies, adopted in OCT-2021.

E6 R3 doesn’t provide much more information on quality by design, so we’ll hop on over to E8 R1 for a summary. This guidance tells us that the study team should identify the factors or attributes of each study whose “integrity is fundamental” to participant safety and data integrity.  Another way of thinking about it:  “If their integrity were to be undermined by errors of design or conduct, the reliability or ethics of decision-making based on the results of the study would be undermined.”  This approach aligns nicely with how we typically train study teams to evaluate risk by thinking of what adds value and, conversely, what destroys value in a study.

Unfortunately, E8 R1 doesn’t give too much practical advice on what “critical to quality” factors might look like, or how to identify them, other than helpfully telling us that “creating a culture that values and rewards critical thinking and open, proactive dialogue” may help.  The Clinical Trials Transformation Initiative (CTTI) has provided more concrete assistance in the form of a Critical to Quality (CTQ) Factors Principles Document, which groups Critical-to-Quality Factors into categories for feasibility, protocol design, patient safety, study conduct, study reporting, and third-party service providers, and details considerations for assessing risks to each, with examples.

Like the rest of us, the CTTI folks have probably sat through too many meetings completing voluminous risk assessment tools, because they have posted a warning on their website and on the footer of every page that this document “is NOT [emphasis theirs] intended to be used as a checklist.” So, please, resist the temptation to turn this 24 page document into a controlled form that must be filled out before any protocol can be approved.  Use only as intended!

Our flashbacks to long risk assessment meetings, however, raise the question:  How is “quality-by-design,” a risk assessment based on critical-to-quality factors, different from “quality and risk management,” a risk assessment based on critical data and processes? It’s murky.  Ostensibly, “quality-by-design” is a risk assessment undertaken during the design process, where there is still a chance to change the protocol, whereas “quality and risk management” is performed after the protocol is final, when your only choices are a costly amendment or mitigation. CTTI’s Critical to Quality Factors Principles Document, though, addresses plenty of questions that don’t impact trial design (for example, “What controls are in place to minimize data entry errors?” and “What specific activities are planned to ensure data are collected as required for trial participants who stop the assigned treatment but remain on study?”), so CTTI, at least, interprets “critical-to-quality” factors as encompassing both design and operations.  In our opinion, it would be easiest to use a single rubric to assess risk both during and after trial design.

Inputs to trial design. R3 now states that sponsors should consider inputs from a wide variety of stakeholders, “including healthcare providers and patients,” during development of protocols, informed consents, and participant-facing information. Patient-centric protocol design includes consideration of patient-desired outcomes while designing protocol objectives  and evaluating the patient “journey” (number of visits, hours spent at each visit, number of needle sticks, etc.) while designing the protocol.  Healthcare providers can give feedback on standards of care in different region and the impact of the patient “journey” on site resources.

Simplicity. R3 tells us that sponsors must ensure that protocols are operationally feasible and that protocols should avoid unnecessary complexity, procedures, and data collection. We hope that having this in black and white will give impetus to the pleas for simplicity that accompany any protocol design effort.

Other tools.  Other plans and tools should also be “fit for purpose, clear, concise, and consistent” according to R3. As noted before on this blog, ambiguous prose is the root cause of many a deviation, so it’s good to see clear writing featured as a requirement.



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