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 F., Signorovitch J., Sajeev G., Goemans N., Wong B., Tian C., Mercuri E., Done N., Wong H., Moss J., Yao Z., Ward SJ., Manzur A., Servais L., Niks EH., Straub V., de Groot IJ., McDonald C., North Star Clinical Network, PRO-DMD-01 Study, The Association Française contre les Myopathies (AFM), The DMD Italian Group, and The Collaborative Trajectory Analysis Project (cTAP) None.
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.