Protocol Development #26: Patient Engagement, DE&I, Study Design, QbD, DCTs, CIDs, Structured Content and Protocol Tech

I'm not sure where to start this issue - there's been some interesting resources coming out for every theme. My favorite is the structured content theme as there have been a number of informative and useful resources coming out - starting at the macro (conceptual level then pharma level) and then moving downwards to the micro (deliverables then style guides); starting out at more unfamiliar territory before being back on solid ground.

If that's not your focus, patient engagement and DE&I have some strong references around advocating for change, and key examples for how doing so enhances study conduct. In clinical study design we've got some great articles on QTLs that really help understand their purpose, as well as something more intangible - ethics. QbD and DCTs both have standout articles, QbD addressing the need and how - in part - it can be achieved, DCTs looking more towards the future and how DCTs will embed in the landscape. In terms of complex designs, a case study for a core master protocol and some food-for-thought for multi-regional platform trials gives some interesting reading. Last - but not at all least - in protocol tech we've got an interesting case study on applying simulations to study designs.

Patient Engagement

[Magazine] Braude et al published How Sponsors Can Use Health Decision Science to Improve Clinical Trial Recruitment and Retention which showed some interesting cognitive factors that influence investigator and clinical research coordinator behavior. Both Table 1 and Table 2 summarize feedback on recruitment and retention factors, respectively.?Of particular note, eligibility criteria are a common barrier to recruitment and investigators indicated they were 14% more likely to educate patients on the study when involved in designing the study (Figure 1, IKEA effect).

[Magazine] Denise Messner published The Impact of Trial Design on Interest by Race and Ethnicity where IQVIA surveyed 1693 US adults about study enrollment and participation. Visit length was a primary influencers across all ethnic groups, however, for Black/African American respondents this was not as significant as for others. For me, the standout information for protocol development was in the conclusions:

"Actively listening to patients via survey feedback and analysis, social listening, patient focus groups, desktop research, and more can provide a solid understanding of patient burden as well as insights into how patients feel about their disease and related treatment options."

This, again, reinforces the benefit of engaging with patients early in the study design stage - making sure the protocol accommodates appropriate burden and disease measures to ensure that the study attracts the participants needed to get quality, actionable data.

Diversity, Equity & Inclusion

[Article - Commentary] Valarde et al published Locking the Revolving Door: Racial Disparities in Cardiovascular Disease where they discussed the continued racial disparities in CVD in the US. Although this is not the first case study of a therapeutic area, the significance of this resource is in its ability to highlight how difficult it is to address racial disparities. Figure 2 (shown above) provides a concise summary of findings and actionable items. In their actionable items, diversification of the clinical workforce and diversification of research participants reflect the significance of more integrated DE&I strategies in clinical research and the impact they have on wider racial issues.?

Clinical Study Design

[Article - Case Study] Wolfs et al published Quality Tolerance Limits’ Place in the Quality Management System and Link to the Statistical Trial Design: Case Studies and Recommendations from Early Adopters where they shed light on the origins of QTLs, the relationship between QTLs and KRIs, how to select QTL parameters and how to determine QTL thresholds. They then supplement this guidance with case studies that help to provide a flavor of what happens in real-life settings. This is absolute "must read" article for protocol authors.

[Article - Commentary] Jerome Singh submitted an article (pending peer review) on Adaptive clinical trials in public health emergency contexts: ethics considerations which looks at the ethical balance of adaptive designs vs more traditional fixed designs. Arguments for adaptive designs (e.g., preventing participant receiving inefficacious treatments) and against (e.g., prematurely intervening before a treatment can be determined as efficacious or not) are weighed up before looking at the issue through the lens of public health emergencies where treatments may be receiving emergency use authorization/designation.

QbD

[Article - Commentary] Morton et al published Revitalising cancer trials post-pandemic: time for reform which discussed the opportunity to accelerate change in cancer studies due to the COVID-19 pandemic. In the "barriers to conduct of clinical trials" section well-known themes emerge, complex regulation, excessive procedural requirements, and increased protocol complexity. In terms of reform - master protocols, decentralization of procedures and reduction in data collection are all focal points (highlighted in the table above). From my perspective, this article should be mandatory reading when considering QbD for oncology.

[Blog post] Elvin Thalund published A Roadmap to Get Started With Quality by Design in Clinical Trials that takes a different - and exciting - angle on QbD at the process level rather than at the document level. Establishing a QbD culture has a similar need for incorporating critical thinking, where our lenses differ is that Elvin looks at study start up processes and how QbD can reduce SSU by months. One particular standout element in the article is the concept of QbD as a discipline - could it be that in the future that we'll have QbD analysts that help adjust processes to better suit current requirements?

DCTs

[Article - Commentary] Cooper and Jose published Despite negative perceptions of clinical trial conduct during the coronavirus disease 2019 (COVID-19) pandemic, are decentralized clinical trial methods here to stay? where they balance the positive and negative perceptions of DCT components. As the authors acknowledge - change is inevitable; although DCTs are not without their challenges, time and experience will play a major role in determining how far the pendulum will swing back towards "traditional" studies.

CIDs/Master Protocols

[Article - Commentary] Modlin et al submitted an article (pending peer review) Towards achieving transnational research partnership equity: lessons from implementing adaptive platform trials in low- and middle-income countries that weighs up the pros and cons for master protocol studies in LMICs. Examples (table above) include a number of well-known players, most notably SOLIDARITY - the WHO flagship COVID-19 trial (check out the geographic footprint!). The key themes include items such as funding (capital required to initiate and sustain such a study until completion or other sponsors are onboarded), ethics oversight, leadership, post-trial access, and others. One standout design-related aspect to me was in relation to funding:

"Much of the power asymmetry between HIC and LMIC partners is believed to be rooted in access to?funding and inequities that lead to writing a competitive grant proposal."

One of the points of friction in multi-regional studies is thus - establishing a study design that meets the needs of the most stringent regulators but at the same time serves the needs for all. Much in the same way, power/regulatory/funding/post-trial access/leadership themes suffer the same imbalances.

[Article - Case Study] McLeod et al published a Core protocol for the adaptive Platform Trial In COVID-19 Vaccine priming and BOOsting (PICOBOO) that, at the very least, gives an important reminder to have a good acronym. The protocol provides a good overview of a core master protocol structure and a good case study for anyone looking to understand the application of the SPIRIT statement items more thoroughly.

Structured Content

[Blog post] Colleen Jones published Modern Content Strategy: Letting Go of Unified, Leaning into Integrated. If there's one statement that encapsulates the drive for structured content it's this:

"I’ve said it before. I’ll say it again because it’s still happening and won’t stop anytime soon. As every business goes digital, content becomes critical. Content is part of every business function and every phase of customer, audience, and employee journeys."

Some say pharma is undergoing a digital revolution - If you agree then content is the next proving ground.

[Webinar Recording] Data Conversion Laboratory Inc. held a webinar on Making the Case for DITA in Pharma and Life Sciences Content where they discussed XML and structuring content in a pharma context. As we are, what seems like, "last to the table" in understanding how structured content can be applied, how early adopters have approached it will undoubtedly help new-arrivers avoid common pitfalls (and allow us to make whole new ones of our own).

[LinkedIn Post] Hilary Marsh published Your deliverables are not your content strategy that - to me - speaks to protocol authors. It's not the deliverable that's important in as much as it's what you've included, for whom, and why. Good content, correct audience, using standards when necessary, and collaborative content creation are key characteristics of a good protocol development process.

[Blog post] Michelle Guillemard published creating a medical writing style guide. How does this relate to structured content? Structuring content, by definition, is organizing and standardizing content to enhance utility and consistency. There is a significant time saving to protocol development if common standards and terminology are agreed at the beginning of protocol development (or before!) as this frees up reviewers to focus on the important content and not refining common terminology or style. In the post,?Michelle gives a good overview of style guides as well as some points to consider when developing one.

Protocol Tech

[Whitepaper] Heather Struntz published Optimizing Small Clinical Trials with Simulation-Guided Design: A Case Study where Cytel used their Solara platform to simulate the study and found a more optimal point for an interim analysis. With key details like interim analyses featuring in the protocol, the ability to run simulations prior to finalizing a protocol is an attractive feature as it provides a more robust study design.?