Evidentiary basis of the first regulatory qualification of a digital primary efficacy endpoint

Abstract

Stride velocity 95th centile (SV95C) is a wearable-derived endpoint representing the 5% fastest strides taken during everyday living. In July 2023, SV95C received European Medicines Agency (EMA) qualification for use as a primary endpoint in trials of patients with Duchenne muscular dystrophy (DMD) aged ≥ 4 years-becoming the first digital endpoint to receive such qualification. We present the data supporting this qualification, providing insights into the evidentiary basis of qualification as a digital clinical outcome assessment. Clinical trials, natural history studies, and patient surveys (ages 5 - 14 years) showed that SV95C is accurate, valid, reliable, sensitive, and clinically meaningful. SV95C significantly correlated with traditional DMD assessments, increased rapidly after steroid initiation (0.090 m/s 3 months post-treatment), and declined steadily in patients on stable steroid regimens. Compared with traditional assessments, SV95C demonstrated earlier sensitivity to disease progression (3 vs 9 months) and greater sensitivity at 12 months. Distribution- and anchor-based approaches revealed a change of - 0.10 to - 0.20 m/s as clinically meaningful. The EMA qualification of SV95C illustrates the willingness of regulators to accept novel digital endpoints for drug approval, setting an important precedent for the evidentiary basis of regulatory digital endpoint qualification that could transform clinical development in disorders affecting movement.

Keywords: Digital endpoints; Duchenne muscular dystrophy; Regulatory qualification; Stride Velocity 95th Centile; V3 framework; Wearables.

Fig. 1

Comparison of SV95C values measured 1 month apart in two successive recording periods. (A) SV95C measured during month 1 versus month 2, (B) Corresponding Bland–Altman plot. The gray line represents the mean of the difference between SV95C measured at month 2 and month 1 (mean SV95C difference –0.024 m/s). Dark lines represent the mean difference between the measurements ± 1.96 SD (SD 0.136 m/s). M month, SD standard deviation, SV95C stride velocity 95^th centile. Source: Qualification Opinion for Stride velocity 95th centile as primary endpoint in studies in ambulatory Duchenne Muscular Dystrophy studies © European Medicines Agency, 2022.

Fig. 2

SV95C variability, SV95C as a function of age, and influence of time of recording on SV95C in patients with DMD and controls (A) The variability of SV95C as a function of the number of recorded hours used to compute the variable. The variability was computed as follows: for each recording duration of X hours, the patient’s data were regrouped into periods of X hours and the variance of SV95C computed on each period was estimated. The bold line represents the mean across patients for each recording duration. The gray region is the mean ± 1 SD, (B) Individual SV95C values in patients and controls of different ages with > 50 recorded hours, (C) Comparisons of daytime versus evening SV95C recordings and weekday versus weekend SV95C recordings. Wilcoxon test between AM/PM distributions and weekday/weekend distributions in patients with DMD and controls. *p < 0.01. P values were as follows: 0.117 for AM/PM, DMD; 0.616 for AM/PM, controls; 0.00631 for week/weekend, DMD; 2.81e-07 for week/weekend, controls. DMD Duchenne muscular dystrophy, SD standard deviation, SV95C stride velocity 95^th centile.

Fig. 3

Responsiveness to change and comparison with other measures. (A) Median change from baseline in SV95C, 6MWD, and NSAA in patients with DMD who were on a stable steroid regimen. Asterisks denote significant changes from baseline. Respective participant numbers at months 3, 6, 9, and 12 were n = 91, n = 64, n = 58, and n = 34 for SV95C; n = 47, n = 56, n = 30, and n = 24 for 6MWD; and n = 51, n = 42, n = 32, and n = 18 for NSAA, (B) Relative evolution of SV95C according to age at baseline. Individual patient trajectories show SV95C plotted as a function of age, (C) Baseline-normalized SV95C trajectories showing relative evolution in patients initiating corticosteroids (darker line) versus those on a stable steroid regimen. Relative evolution is represented as the percentage of the baseline value. 6MWD 6-min Walk Distance, DMD Duchenne muscular dystrophy, NSAA North Star Ambulatory Assessment, SV95C stride velocity 95th centile.

Fig. 4

Importance of ambulation aspects according to patients with DMD and caregivers of patients with DMD, stratified by walking ability. Percentages are based on n = 44 ambulant and n = 38 non-ambulant participants with DMD who answered these questions. Source: Qualification Opinion for Stride velocity 95th centile as primary endpoint in studies in ambulatory Duchenne Muscular Dystrophy studies © European Medicines Agency, 2022. DMD Duchenne muscular dystrophy.