Real World and Natural History Data Comparable to Placebo in DMD Trials


Researchers noted that the findings are encouraging for the use of real-world data and natural history data to augment, or possibly replace, placebo controls in DMD trials.

Francesco Muntoni, MD

Results from the largest ever multi-national, multi-collaboration study in patients with Duchenne muscular dystrophy (DMD) revealed that both real world data (RWD) and natural history data (NHD) are highly comparable to data from patients treated with placebo in multiple recent clinical trials.1,2

The Collaborative Trajectory Analysis Project (cTAP), a multi-stakeholder, global research coalition, brought researchers together to analyze disease progression in 383 patients with DMD randomized to placebo arms in 6 clinical trials compared with data observed in a real-world setting for 430 patients from 5 clinical registries.

“The results of this landmark research effort have profound implications for clinical research in DMD and potentially many other rare diseases. We applaud cTAP for supporting this research effort and look forward to sharing these insights with all of the stakeholders in DMD research including regulators, industry, clinicians and patient advocates,” Francesco Muntoni, PhD, professor and chair of pediatric neurology, University College London, said in a statement.

The investigators examined the consistency of changes in the 6-minute walk distance (6MWD) across 48-week stretches. Mean 6MWD 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.

In total, 1200 patient-years of follow-up were observed. Differences in mean 6MWD between trial placebo arms and RWD/NHD cohorts ranged from –19.4 meters (better outcomes in RWD/NHD) to 19.5 meters (worse outcomes in RWD/NHD) and were not statistically significant before or after covariate adjustment.

Within the RWD/NHD cohorts, researchers found that the mean 6MWD was numerically smaller in magnitude of decline, indicating better preservation of function, than placebo in 17 comparisons, and larger than placebo in 7 comparisons. They also noted that none of the differences observed between trial placebo arms and RWD/NHD cohorts were statistically significant.

Means for 6MWD were all within 25 meters of both the harmonized RWD/NHD cohorts. Only 1 of the 46 pairwise comparisons of RWD/NHD cohorts reached a nominal P <.05.

"This rigorous study establishes a strong foundation for using natural history data as a substitute for placebo control in clinical trials and as a comparator to determine the effectiveness of prescribed drug treatments versus standard of care treatment,” Craig McDonald, MD, co-author of the study and professor and chair of the department of physical medicine and rehabilitation, University of California Davis, said in a statement.

Sensitivity analysis that assessed whether distribution of steroids type at baseline influenced the results used 6MWD in comparison with a subgroup of patients who received deflazacort, which was the most commonly used steroid in the RWD/NHD sources. As in the primary analysis, investigators observed a similar mean 6MWD between trial placebo arms and RWD/NHD sources in this subgroup.

Notably, this was the first study to demonstrate the comparability of disease progression inNH/RWD and placebo arms of clinical trials in DMD. Researchers found no evidence for systematic bias within the study.

cTAP was established in 2015 and partnered with Analysis Group, cTAP’s advanced analytics platform, to solve critical problems in drug development in DMD. The coalition has a global alliance of academic, industry, and patient stakeholders that enables therapy developers to conduct smarter trials and bring new therapies to patients sooner.

1. cTAP study shows real-world, natural history data comparable to placebo data from clinical trials in Duchenne muscular dystrophy. News release. Cambridge, MA: cTAP. September 8, 2020. Accessed September 8, 2020.
2. Goemans N, Signorovitch J, Sajeev G, et al. Suitability of external controls for drug evaluation in Duchenne muscular dystrophy. Neurology. doi: 10.1212/WNL.0000000000010170
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