Stride Velocity 95th Centile Detects Decline in Ambulatory Function Over Shorter Intervals than the 6-Minute Walk Test or North Star Ambulatory Assessment in Duchenne Muscular Dystrophy.

Background: Stride Velocity 95th Centile (SV95C) is the first wearable device-derived clinical outcome assessment (COA) to receive European Medicines Agency (EMA) qualification as a primary endpoint in ambulant patients with Duchenne muscular dystrophy (DMD) aged ≥4 years. Objective: To compare SV95C-in its first-ever clinical trial application as a secondary endpoint-with established motor function COAs used in the trial (Four-Stair Climb [4SC] velocity, North Star Ambulatory Assessment [NSAA], and Six-Minute Walk Distance [6MWD]). Methods: SV95C was a secondary endpoint in a subset (n = 47) of participants in the SPITFIRE/WN40227 trial of taldefgrobep alfa, which was discontinued due to lack of clinical benefit. Participants in the ≤48-week SV95C sub-study were 6-11 years old and received corticosteroids for ≥6 months pre-treatment. Pearson correlations were used to compare SV95C with the other COAs. Responsiveness and changes over time were respectively assessed via standardized response means (SRMs) based on absolute changes and mixed models for repeated measures. Results: SV95C change at Week 24 was -0.07 m/s, with limited variability (standard deviation: 0.16, n = 27). The SRM for SV95C indicated moderate responsiveness to clinical change at the earliest timepoint (Week 12, n = 46), while those of the other COAs did not indicate moderate responsiveness until Week 36 (6MWD, n = 33) or Week 48 (4SC velocity, n = 20; NSAA total score, n = 20). Baseline correlations between SV95C and other COAs were strong (r = 0.611-0.695). Correlations between SV95C change from baseline to Week 48 and changes in other COAs were moderate to strong (r = 0.443-0.678).∥. Conclusions: Overall, SV95C demonstrated sensitivity to ambulatory decline over short intervals, low variability, and correlation with established COAs. Although the negative trial precluded demonstration of SV95C's sensitivity to drug effect, these findings support the continued use of SV95C in DMD clinical trials.

Qualitative Insights into Key Angelman Syndrome Motor Related Concepts Reported by Caregivers-A Thematic Analysis of Semi-Structured Interviews.

Previous patient-centered concept models of Angelman syndrome (AS) are integral in developing our understanding of the symptoms and impact of this condition with a holistic perspective and have highlighted the importance of motor function. We aimed to develop the motor and movement aspects of the concept models, to support research regarding motor-related digital outcomes aligned with patients' and caregivers' perspectives. We conducted a qualitative analysis of semi-structured interviews of 24 caregivers to explore AS motor-related features, factors influencing them and their impact on patients and caregivers.The most impacted motor features were gait, walking and stair-climbing. Half of caregivers ranked motor symptoms as one of the most burdensome symptoms of AS. Caregivers frequently reported physical therapy, motivation, medical management and age as factors influencing motor function in AS and reported that impaired motor function affected both patients and caregivers. Measures of lower-limb motor function were identified as relevant to monitor drug effectiveness in AS. Caregivers discussed expected benefits of a digital outcome and potential issues with wearable technology in the context of AS. We propose a new motor function patient-centered concept model, providing insights for the development of relevant, motor-related, digital outcomes in AS.

Reverse Engineering of Digital Measures: Inviting Patients to the Conversation.

Background: Digital measures offer an unparalleled opportunity to create a more holistic picture of how people who are patients behave in their real-world environments, thereby establishing a better connection between patients, caregivers, and the clinical evidence used to drive drug development and disease management. Reaching this vision will require achieving a new level of co-creation between the stakeholders who design, develop, use, and make decisions using evidence from digital measures. Summary: In September 2022, the second in a series of meetings hosted by the Swiss Federal Institute of Technology in Zürich, the Foundation for the National Institutes of Health Biomarkers Consortium, and sponsored by Wellcome Trust, entitled "Reverse Engineering of Digital Measures," was held in Zurich, Switzerland, with a broad range of stakeholders sharing their experience across four case studies to examine how patient centricity is essential in shaping development and validation of digital evidence generation tools. Key Messages: In this paper, we discuss progress and the remaining barriers to widespread use of digital measures for evidence generation in clinical development and care delivery. We also present key discussion points and takeaways in order to continue discourse and provide a basis for dissemination and outreach to the wider community and other stakeholders. The work presented here shows us a blueprint for how and why the patient voice can be thoughtfully integrated into digital measure development and that continued multistakeholder engagement is critical for further progress.

Evolving regulatory perspectives on digital health technologies for medicinal product development.

Digital health technology tools (DHTTs) present real opportunities for accelerating innovation, improving patient care, reducing clinical trial duration and minimising risk in medicines development. This review is comprised of four case studies of DHTTs used throughout the lifecycle of medicinal products, starting from their development. These cases illustrate how the regulatory requirements of DHTTs used in medicines development are based on two European regulatory frameworks (medical device and the medicinal product regulations) and highlight the need for increased collaboration between various stakeholders, including regulators (medicines regulators and device bodies), pharmaceutical sponsors, manufacturers of devices and software, and academia. As illustrated in the examples, the complexity of the interactions is further increased by unique challenges related to DHTTs. These case studies are the main examples of DHTTs with a regulatory assessment thus far, providing an insight into the applicable current regulatory approach; they were selected by a group of authors, including regulatory specialists from pharmaceutical sponsors, technology experts, academic researchers and employees of the European Medicines Agency. For each case study, the challenges faced by sponsors and proposed potential solutions are discussed, and the benefit of a structured interaction among the different stakeholders is also highlighted.

First Regulatory Qualification of a Novel Digital Endpoint in Duchenne Muscular Dystrophy: A Multi-Stakeholder Perspective on the Impact for Patients and for Drug Development in Neuromuscular Diseases.

BACKGROUND: Functional outcome measures used to assess efficacy in clinical trials of investigational treatments for rare neuromuscular diseases like Duchenne muscular dystrophy (DMD) are performance-based tasks completed by the patient during hospital visits. These are prone to bias and may not reflect motor abilities in real-world settings. Digital tools, such as wearable devices and other remote sensors, provide the opportunity for continuous, objective, and sensitive measurements of functional ability during daily life. Maintaining ambulation is of key importance to individuals with DMD. Stride velocity 95th centile (SV95C) is the first wearable acquired digital endpoint to receive qualification from the European Medicines Agency (EMA) to quantify the ambulation ability of ambulant DMD patients aged ≥5 years in drug therapeutic studies; it is also currently under review for the US Food and Drug Administration (FDA) qualification. SUMMARY: Focusing on SV95C as a key example, we describe perspectives of multiple stakeholders on the promise of novel digital endpoints in neuromuscular disease drug development.

Normative data on spontaneous stride velocity, stride length, and walking activity in a non-controlled environment.

BACKGROUND: Normative data are necessary for validation of new outcome measures. Recently, the 95th centile of stride speed was qualified by the European Medicines Agency as a valid secondary outcome for clinical trials in subjects with Duchenne muscular dystrophy. This study aims to obtain normative data on spontaneous stride velocity and length in a non-controlled environment and their evolution after 12 months. METHOD: Ninety-one healthy volunteers (50 females, 41 males), with a mean age of 16 years and 2 months, were recruited and assessed at baseline and 12 months later. The 4-stair climb, 6-min walk test, 10-m walk test and rise from floor assessments were performed. Stride length, stride velocity, and the distance walked per hour were studied in an everyday setting for one month after each evaluation. RESULTS: Of the 91 subjects assessed, 82 provided more than 50 h of recordings at baseline; and 73 subjects provided the same at the end of the year. We observed significant positive correlations of the stride length with age and height of participants, and a significant increase of the median stride length in children after the period. In this group, the 95th centile stride velocity was not correlated with age and was stable after one year. All measures but the 10MWT were stable in adults after a one-year period. CONCLUSION: This study provides with data on the influence of age, height, and gender on stride velocity and length as well as accounting for natural changes after one year in controls.

E-Health & Innovation to Overcome Barriers in Neuromuscular Diseases. Report from the 1st eNMD Congress: Nice, France, March 22-23, 2019.

By definition, neuromuscular diseases are rare and fluctuating in terms of symptoms; patients are often lately diagnosed, do not have enough information to understand their condition and be proactive in their management. Usually, insufficient resources or services are available, leading to patients' social burden. From a medical perspective, the rarity of such diseases leads to the unfamiliarity of the medical staff and caregiver and an absence of consensus in disease assessment, treatment, and management. Innovations have to be developed in response to patients' and physicians' unmet needs.It is vital to improve several aspects of patients' quality of life with a better comprehension of their disease, simplify their management and follow-up, help their caregiver, and reduce the social and economic burden for living with a rare debilitating disease. Database construction regrouping patients' data and symptoms according to specific country registration on data privacy will be critical in establishing a clear consensus on neuromuscular disease treatment.Clinicians also need technological innovations to help them recognize neuromuscular diseases, find the best therapeutic approach based on medical consensus, and tools to follow patients' states regularly. Diagnosis also has to be improved by implementing automated systems to analyze a considerable amount of data, representing a significant step forward to accelerate the diagnosis and the patients' follow up. Further, the development of new tools able to precisely measure specific outcomes reliably is of the matter of importance in clinical trials to assess the efficacy of a newly developed compound.In this context, creation of an expert community is essential to communicate and share ideas. To this end, 97 clinicians, healthcare professionals, researchers, and representatives of private companies from 9 different countries met to discuss the new perspective and challenges to develop and implement innovative tools in the field of neuromuscular diseases.

Deterministic order in surface micro-topologies through sequential wrinkling.

Ordered herringbone patterns with deterministic long and short wavelengths are created using a sequential wrinkling strategy (SWS). Patterns with a prescribed zig-zag turning angle less than 90° are obtained upon sequential wrinkling of non-equi-biaxial prestrain for the first time. SWS provides a new method for measuring thin-film mechanical properties simply through the wrinkling metrology without measurement of film thickness.