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. 2020 Sep 8;95(10):e1381-e1391.
doi: 10.1212/WNL.0000000000010170. Epub 2020 Jul 1.

Suitability of external controls for drug evaluation in Duchenne muscular dystrophy

Nathalie Goemans  1 , James Signorovitch  1 , Gautam Sajeev  1 , Zhiwen Yao  1 , Heather Gordish-Dressman  1 , Craig M McDonald  1 , Krista Vandenborne  1 , Debra Miller  1 , Susan J Ward  1 , Eugenio Mercuri  2 ; investigators from PRO-DMD-01 Study, CINRG DNHS, ImagingDMD, and the DMD Italian Group
Collaborators, Affiliations

Suitability of external controls for drug evaluation in Duchenne muscular dystrophy

Nathalie Goemans et al. Neurology. .

Abstract

Objective: 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).

Methods: The consistency of changes in the 6-minute walk distance (Δ6MWD) was assessed 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 4 sets of inclusion/exclusion criteria (n = 383 patients in total). Five sources of RWD/NHD were contributed by Universitaire Ziekenhuizen Leuven, DMD Italian Group, The 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 inclusion/exclusion criteria of the trial for baseline age, ambulatory function, and steroid use. Baseline covariate adjustment was investigated in a subset of patients with available data.

Results: 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 m (i.e., better outcomes in RWD/NHD) to 19.5 m (i.e., worse outcomes in RWD/NHD) and were not statistically significant before or after covariate adjustment.

Conclusions: We found that 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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Figures

Figure 1
Figure 1. Study design diagram
6MWD = 6-minute walk distance.
Figure 2
Figure 2. Forty-eight-week changes in 6MWD in trial placebo arms and harmonized real-world data/natural history data
CI = confidence interval; CINRG DNHS = The Cooperative International Neuromuscular Research Group Duchenne Natural History Study; DMD = Duchenne muscular dystrophy; 6MWD = 6-minute walk distance.
See this image and copyright information in PMC

References

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