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Real-world and natural history data for drug evaluation in Duchenne muscular dystrophy: suitability of the North Star Ambulatory Assessment for comparisons with external controls

Muntoni, Francesco; Signorovitch, James; Sajeev, Gautam; Goemans, Nathalie; Wong, Brenda; Tian, Cuixia; Mercuri, Eugenio; ... North Star Clinical Network, PRO-DMD-01 Study, The Association F; + view all (2022) Real-world and natural history data for drug evaluation in Duchenne muscular dystrophy: suitability of the North Star Ambulatory Assessment for comparisons with external controls. Neuromuscular Disorders 10.1016/j.nmd.2022.02.009. (In press). Green open access

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Abstract

Using external controls based on real-world or natural history data (RWD/NHD) for drug evaluations in Duchenne muscular dystrophy (DMD) is appealing given the challenges of enrolling placebo-controlled trials, especially for multi-year trials. Comparisons to external controls, however, face risks of bias due to differences in outcomes between trial and RWD/NHD settings. To assess this bias empirically, we conducted a multi-institution study comparing mean 48-week changes in North Star Ambulatory Assessment (NSAA) total score between trial placebo arms and RWD/NHD sources, with and without adjustment for baseline prognostic factors. Analyses used data from three placebo arms (235 48-week intervals, N = 235 patients) and three RWD/NHD sources (348 intervals, N = 202 patients). Differences in mean ΔNSAA between placebo arms and RWD/NHD sources were small before adjustment (-1.2 units, 95% CI: [-2.0 -0.5]) and were attenuated and no longer statistically significant after adjustment (0.1 units (95% CI: [-0.6, 0.8]). Results were similar whether adjusting using multivariable regression or propensity score matching. This consistency in ΔNSAA between trial placebo arms and RWD/NHD sources accords with prior findings for the six-minute walk distance, provides a well-validated framework for baseline adjustment of prognostic factors, and supports the suitability of RWD/NHD external controls for drug evaluations in ambulatory DMD.

Type: Article
Title: Real-world and natural history data for drug evaluation in Duchenne muscular dystrophy: suitability of the North Star Ambulatory Assessment for comparisons with external controls
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.nmd.2022.02.009
Publisher version: https://doi.org/10.1016/j.nmd.2022.02.009
Language: English
Additional information: © 2022 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
Keywords: Clinical trials, Drug evaluation, Duchenne muscular dystrophy, External controls, Natural history data, Real-world data
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Neurosciences Dept
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
URI: https://discovery.ucl.ac.uk/id/eprint/10147153
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