In our last blog post, we were confused by critical-to-quality factors as described in E8 R1, so we went on a quest for clarification. Saddle up your horse and ride along with us as we travel from consultant to consortium in search of enlightenment. 

Transcelerate, which favors a mixed-capital acronym "CtQ" over the full phrase, thus neatly sidestepping the hyphen question, has a number of resources on E8, including a white paper, case studies, and an infographic. One slide deck gives examples of CtQ Factors, which include patient safety, eligibility criteria, IMP management, study endpoints, data integrity, protocol deviation management, sample management, study design, site staff qualifications, and PK data. As with the Section VII/7 considerations above, these factors seem too general to be "critical" - when everything's critical, then nothing is critical. 

Transcelerate published a case study illustrating the application of this principle, which describes a study team who implemented quality by design: 

When planning their protocol, study team members collaborated to agree which factors were critical to quality for their early phase study. They agreed that patient eligibility was their most important quality factor....The risk assessment prioritized those [controls] most likely to ensure safety of the trial participants and reliability of trial data by protecting the integrity of the inclusion and exclusion criteria identified in the protocol....  In this case the controls included a technology solution to enable real-time monitoring of participant eligibility."

So... a clinical study team decided that ELIGIBILITY was important? And then they decided to MONITOR eligibility to reduce risk? What ARE they putting in the water in Kendall Square these days?

A second case study hits a bit closer to the mark.  It describes a Phase 3 study in which adverse events related to infections were considered a critical-to-quality factor. Here we see the "critical" in "critical-to-quality"; the study team has chosen one aspect of the study that is particular to the patient population. The risk to this factor is not named in the case study, but presumably involves the risk that participants may not report infections to the investigator since the trial was decentralized. The controls for the risk "included rules for safety management, patient notification to immediately contact the Principal Investigator at any sign of infection."

This hits much closer to what we would expect to see in a meaningful quality-by-design approach: It highlights a risk that's specific to the protocol, and it plans at least one mitigation that is not standard (reminding participants to contact the PI at any sign of infection). If infection control were really critical to safety, we could imagine more active mitigations - for example, regular check-in calls from study coordinators to the participants (low tech), or an ePRO device with alarms that would prompt participants to record any infection symptoms (high tech).

Next, we look at what CTTI has to say about quality by design.