Quality by Design (QbD) Intro: Let's get practical and tactical.

If you want to read up and learn more about QbD, here are some great resources:

• Introductory article from DIA

• ICH E8 R1

• CTTI website with resources

Remember what QbD for clinical trials is trying to achieve: "answer the research questions while preventing important errors" (per ICH E8, R1). First I want to spend a few minutes breaking down the terms...

"Quality" in QbD goes beyond quality assurance or quality control, which to be clear are critical functions in clinical trials. It's about focusing on what matters to achieve the stated aims.

Making sure the engine doesn't fall out of a new car that you just bought involves quality control, and that is vitally important. Having a highly enjoyable driving experience due to the design of the car involves quality of craftsmanship, a quality of that vehicle. What is the end goal and what will get us there, to achieve quality of that stated goal? If it's great handling, then we need to ensure the elements critical to achieving that are of the highest quality possible (well-made shocks and struts, advanced computer sensors, innovative manufacturing...).

Designing a study that efficiently and effectively collects the best possible information to determine a therapy's safety and effectiveness, and supports decision-making around the drug's future, ranks as quality of design. Envision your study as having high quality outcomes or outputs to answer your important questions. Go with stretch goals!

"by" -not much to say about it, though it helps me to substitute the word "through"

"Design" is not just how the protocol is written. The protocol is a critical blueprint, but supporting documents like the monitoring plan, risk management plan, data review plan and operations plan all provide outlines of how to drive quality from a study conduct standpoint. And design also includes how training is administered, patients are educated, sites are paid... ...it's everything! Because all of these aspects can potentially impact the quality outcomes. So it's important to broaden your thinking to every aspect of the study, not just the protocol.

Now let's get started on design considerations in relation to QbD:

Know thy protocol

So, I just said that the overall study is more important to consider than just the protocol. True! …But a thorough, well-designed protocol still contains the core components of the study, and a well-written protocol can hone in on the QbD elements that will help make it successful. The following are some key elements of a protocol:

Efficacy: assessments, biomarkers and endpoints are the ways in which the therapy is measured. Is the drug working better than placebo? Or a comparator? Or as an adjunctive?

Some QbD considerations:

• Primary endpoints should be given more weight than secondary or exploratory ones. And "critical primary" data (e.g. systolic BP as part of vital signs) should be given even more importance. Sorry if that's obvious!

• Secondary endpoints: are they helpful and informative for current or future decision-making? What happens if they aren't captured at all? ...if "not much" is the answer then maybe take a second look at them.

• Exploratory endpoints: are they adding burden to the degree that they are "excessive" for patients and sites to deal with? Perhaps consider a sub-study or exploratory cohort that sites and patients can sign up separately for (and get paid extra for).

Safety: tracked and assessed throughout the study to ensure patients are not being exposed to any untoward effects, even mild ones. Here are some things to consider from a QbD standpoint:

• Are we properly and proactively assessing safety as to minimize any potential adverse events for participants? E.g. in preventing AEs from becoming SAEs.

• Does our treatment, class of drug or mechanism of action have any known safety effects?

• Are there special safety assessments or tests specific to the disease or treatment that should be part of the protocol?

• Should we provide notifications or on demand reporting for participants so they can report adverse events or safety concerns, perhaps due to acute effects from the treatment or from their disease?

Treatment: it is important to gain an understanding of treatment impact, and sometimes finding a signal is hard. But always keep in mind any challenges that your treatment may cause patients and sites like stability, climate control, giant horse pills, weekly needle jabs... ...any of these characteristics could lower the likelihood of successful adherence. You should consider any burden of treatment for participants and sites and think about how best to reduce it or best support it within the protocol.

Schedule of events or visits: are your visit procedures and assessments lengthy or burdensome? Some considerations include:

• The resource-intensive need for specialized training and backup support.

• Involved registration or setup processes for protocol vendors or technologies.

• Requirements to access systems, dashboards or other technology; this may include a need to actively access and manage eSource during visit procedures.

• Time requirements for procedures and assessments, considering logistical aspects (x-rays in another building). Maximize windows for visits and assessments.

• Physically or emotionally challenging assessments for patients or sites. Are there alternatives or ways to scale down the demanding aspects?

Know thy regulatory requirements and industry standards

Regulatory requirements and standards should always be the priority. If you end up with a questionable protocol design, insufficient safety monitoring or unsecure deployment of technology you can undermine your trial results and worse. Some key regulatory guidances:

• Patient privacy, security: HIPAA

• Individual privacy, security (patients, sites): GDPR

• Trial conduct requirements and standards per the FDA: GCPs, 21CFR part 11

• International guidelines for conduct of trials: ICH guidance

  
  

Regulations get updated periodically, so stay on top of them!

Know thy patients

Patients or study participants are the most important contributors to clinical research. So keep in mind their challenges and needs when designing the study. Some considerations include:

• Disease-related: the target disease undoubtedly has some quality of life considerations, some of which may be:

  • Reduced mobility

  • Poor fine motor skills

  • Poor memory

  • Cognitive challenges

  • Lack of motivation

  • Acute physical or mental safety events

    
    

• Cultural: especially with so many international trials, it is important to consider the cultural norms and expectations for your study participants. Being inadvertently offensive or even just implementing a requirement that is somewhat uncomfortable can negatively impact enrollment and retention. Some cultures distrust science and research, so education can be an important part of the engagement process.

  
  

• Convenience: this can mean inclusion of virtual visits, perhaps optionally where possible, and also flexibility for visits and assessment scheduling. It should also consider the burden of the assessment or technology, e.g. having to set aside time each day to perform some task -life can get in the way!

  
  

• Financial: acknowledge the time and effort involved with taking part in the study, including sacrifices with work and personal time.

  
  

• Informational: patients are like us, or may even be us, and live in a world where information is readily available. Support understanding of their disease through educational materials and websites (especially for de novo patients), provide easily digestible information regarding the treatment and study and keep them posted on study progress and outcomes where possible. Explaining the scientific goals in layman's terms can help everyone keep the big picture in mind.

  
  

• Technical support: provide step-by-step guides and materials that can help the participant navigate the study requirements and expectations. Videos, informed consent tutorials and smartphone apps can all be great support systems. If implemented in a HIPAA and GDPR-compliant manner, you can also put in place live helpdesks or centralized patient support teams.

  
  

• Feedback: Well-crafted patient surveys or questionnaires can allow you to incorporate improvements to the patient experience. This could even be done during the trial to think about minor improvements (not requiring a protocol amendment or added into a planned amendment).

Patient-centered design: One approach the industry has discussed, and some have initiated, is engaging patient advocacy groups on protocol design. At a minimum it is important to map out the patient journey for your study and do some hard thinking around their experiences and potential challenges, especially considering their disease. If it's challenging to get hands-on patient input or involvement, then engaging with experienced clinical sites can be a great option as well. Experienced sites have the perspective of working with many patients with the disease in question and understand challenges from past trials.

Know thy sites

That brings us to the clinical sites. My personal experience is that sites are often willing to spend some time (as much as they can fit in their busy schedules!) providing input and feedback on protocol designs, discussing challenges for patient populations as well as challenges for themselves. After all, this input could make their own study experience better.

It is important to think about challenges for your clinical sites:

• Enrollment will be challenging for some, most or all; think through the most effective recruitment strategies; of course there is a whole industry dedicated to this!

  
  

• Scheduling and requirements for assessments: as discussed in the protocol design section above, assume that the protocol should reduce the burden of assessments as much as reasonable while also allowing maximum flexibility.

  
  

• Resources: sites have struggled with staffing, especially during and after COVID. This means they often appreciate any extra support, including virtual coordinators or centralized teams that can handle traditional site-based tasks.

  
  

• Support: the best companies in the world take care of their employees and focus on their happiness, which then spills over to the customers. Take care of your sites and then they can take care of their patients! ...that can include special concierge support, proactive outreach ahead of key visits or milestones (e.g. FPI) and providing opportunities at forums or periodic training refreshers to answer questions, retrain and provide feedback.

  
  

• Financial: sites are businesses, so assume they should be paid for their time and effort. Engage with industry experts on effective payment strategies.

Site-centered design: Similar to the patient journey, I would encourage mapping out a Study Coordinator and PI journey to help understand their study-related tasks and think about operational aspects that might be a challenge for them.

Quality by Design: Focus on what matters for the study, sites and patients

The principles of QbD should be woven into the processes and culture of your organization. However, as reviewed above there are some practical approaches to thinking about better design -focused around the right efficacy, ensuring patient safety, considering regulatory requirements and reducing burden for patients and sites. Ideas to improve the quality and success of the study design can be initiated through focused whiteboard sessions, journey mapping, direct patient and site engagement and subject matter expert discussion. A more systematic approach to QbD can be found here.

Additionally, once you have outlined your quality-driven design it becomes important to hone in on the Critical-to-Quality factors. These are already being considered as you think through the protocol design, but it's important to define them in specific. Doing so gives your team more focus and then allows for downstream considerations for risks of not achieving success for the CtQ factors. Learn more here.

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