Protocol Development #3: QbD, DCTs, CIDs, Patient Engagement, Study Design

In this issue of the PD newsletter, two strong themes emerge. With regards to QbD, Margaret McShane and Stansbury et al provide context for how a successful QbD strategy can be initiated upstream of protocol development at the program level and how downstream KRIs/QTLs are gaining traction in new studies. Important lessons learnt from drug manufacturing are also provided by Kane et al from Thermo Fisher Scientific. With regards to DCTs, both David Coman and Craig Lipset provide some key insight into the origins of DCTs and how decentralizing trials relies on centralizing activities - commentaries that are supported by the CluePoints case study cited by the UK MHRA.

Additional articles cover estimands for CIDs, patient engagement to enhance inclusion of underrepresented women in clinical studies, and draft guidance by the FDA on human gene therapy study designs. In the education corner, there's an interesting article on the genetic bias in precision medicine towards people of European descent, and there are two upcoming webinars by CDISC and CTTI on technology and DCT related topics.

QbD

Kane et al provide an interesting insight into the application of QbD for drug manufacturing: Quality by Design: A holistic approach to drug development. As drug manufacturing has a more mature QbD strategy compared to clinical studies, there are many lessons that can be derived from experience. The sections on applying QbD, the benefits thereof, and the risks of delaying the application of QbD should serve as important reading material for individuals looking to apply QbD principles to clinical studies in response to the new ICH E8(R1) guideline.

Stansbury at al published Risk-Based Monitoring in Clinical Trials: Increased Adoption Throughout 2020. Of particular interest is Figure 3 that highlights the increased adoption of QTLs and KRIs in studies started up in 2020 compared to ongoing studies from 2019 and 2020. This is important for protocol development as the increasing adoption of QTL and KRI factors in relation to data and patient safety will increasingly impact study design development and subsequent operationalization as part of a QbD process. The article also provides some interesting insight into centralized monitoring and the associated centralization of risk.

In a whitepaper published by Advarra: The Clinical Development Plan: Executing the Clinical Strategy, Margaret McShane posits that QbD critical to quality factors should - in part - be defined at the program level. Program CtQ factors would then form a basis for a study-level QbD approach during protocol development.

DCTs

David Coman published a commentary in Endpoints news: Centralize Clinical Trials with DCTs. In the commentary David discusses the centralized oversight for Sponsors and how decentralizing clinical trials from brick and mortar investigative sites allows Sponsors to centrally collect data. The article is relevant to protocol development as centralized data collection/oversight are important technological and data details that should be included in the protocol as part of a robust DCT QbD strategy.

Similarly, Craig Lipset provides a fascinating insight into the origin of DCTs: DCTs - what's in a name?. In the LinkedIn post, Craig provides some clarification regarding current variability in terminology and shows a slide depicting how centralization of data collection decentralizes participation.

To reinforce the commentaries by David and Craig, CluePoints published a case study: UK’s MHRA Cites CluePoints Centralized Statistical Monitoring In Updated GCP Guidance.

CIDs/Master Protocols

Collignon et al published a review on Estimands and Complex Innovative Designs. The review provides an important summary of estimand considerations for umbrella and platform master protocols (Section 2 and Tables 1 + 2), as well as estimand considerations when adding therapies, changing controls, changing populations, and basket studies. Although generating estimands remains a challenge, the significance of this work for protocol development is that it provides a crucial starting point for developing estimands for complex designs.

Patient Engagement

Bierer et al published a commentary on Advancing the Inclusion of Underrepresented Women in Clinical Research. The article provides and important US-focused snapshot of female underrepresentation in some therapeutic areas of clinical research - with women of color being disproportionately excluded. Efforts to address barriers for study participation (box 2) focus on enhancing study flexibility to accommodate family responsibilities and work schedule - both of which can make on-site visits during conventional work hours more challenging.

Clinical Study Design

The FDA released their draft guidance for Industry for Human Gene Therapy Products Incorporating Human Genome Editing. In Section 5 the guidance details considerations for clinical study design including study populations, dosing, treatment schedules, monitoring, endpoints, and pediatric populations.

Education Corner

Baek and Farias published an interesting article Fixing the Patient Data Collection Process to Solve Bias in Precision Medicine where they outline the genetic bias in precision medicine towards people of European descent. The article provides and interesting perspective on the challenges of applying machine learning to precision medicine and highlights the risk of extrapolating data sets from one population to another.

Webinars

CDISC are hosting a webinar on 22 March 2022 11am-12:30pm EDT: Digital Data Flow Project Public Review. In collaboration with TransCelerate the DDF project is looking to define study definitions using technical and data standards. In this webinar.

CTTI are hosting a webinar on 6 April 2022 11am-12:30pm EDT: CTTI's New Digital Health Trials Hub. In its launch of the new Hub, CTTI are repackaging and refreshing digital health resources and recommendations developed over the last 5 years.