Suitability of external controls for drug evaluation in Duchenne muscular dystrophy

Neurology, 2020


To evaluate the suitability of real-world data (RWD) and natural history data (NHD) for use as external controls in drug evaluations for ambulatory Duchenne muscular dystrophy (DMD).


The consistency of changes in the six-minute walk distance (Δ6MWD) was compared across multiple clinical trial placebo arms and sources of NHD/RWD. Six placebo arms reporting 48-week Δ6MWD were identified via literature review and represented four sets of inclusion/exclusion criteria (n=383 patients, in total). Five sources of RWD/NHD were contributed by Universitaire Ziekenhuizen Leuven, DMD Italian Group, Cooperative International Neuromuscular Research Group, ImagingDMD, and the PRO-DMD-01 study (n=430 patients, in total). Mean Δ6MWD was compared between each placebo arm and RWD/NHD source after subjecting the latter to the trial's inclusion/exclusion criteria for baseline age, ambulatory function, and steroid use. Baseline covariate adjustment was investigated in a subset of patients with available data.


Analyses included ∼1,200 patient-years of follow-up. Differences in mean Δ6MWD between trial placebo arms and RWD/NHD cohorts ranged from -19.4 meters (i.e., better outcomes in RWD/NHD) to 19.5 meters (i.e., worse outcomes in RWD/NHD), and were not statistically significant before or after covariate adjustment.


Δ6MWD was consistent between placebo arms and RWD/NHD subjected to equivalent inclusion/exclusion criteria. No evidence for systematic bias was detected. These findings are encouraging for the use of RWD/NHD to augment, or possibly replace, placebo controls in DMD trials. Multi-institution collaboration through the collaborative Trajectory Analysis Project rendered this study feasible.

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Goemans N, Signorovitch J, Sajeev G, Yao Z, Gordish-Dressman H, McDonald CM, Vandenborne K, Miller D, Ward SJ, Mercuri E, investigators from PRO-DMD-01 study, CINRG DNHS, ImagingDMD, and The DMD Italian Group