Acceleration of clinical trial design in Duchenne Muscular Dystrophy building a model-based Clinical Trial Simulation tool

Clinical Trials
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Ramona Belfiore-Oshan, PhD, Critical Path Institute
Varun Aggarwal, PhD, Critical Path Institute
Rhoda Muse, PhD, Critical Path Institute
Sarah Kim, PhD, Centre for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida
Stephan Schmidt, PhD, F.C.P., Centre for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida
Juan Francisco Morales, PhD, Centre for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida
Karthik Linganeni, PhD, Centre for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida
Sudhir Sivakumaran, PhD, Critical Path Institute
Diane Corey, Critical Path Institute
Klaus Romero, MD, MS, FCP, Critical Path Institute
Terina Martinez, PhD, Critical Path Institute

Duchenne muscular dystrophy (DMD) is a genetic, fatal, muscle wasting neuromuscular disease that affects 1 in 3,500-5000 boys around the world. Despite recent progress, the development of a resolutive or stabilizing therapy remains unaccomplished due to trial design challenges as well as lack of clinically meaningful endpoints that fully capture disease variability and progression.
The Duchenne Regulatory Science Consortium (D-RSC) is a neutral, non-profit partnership that supports collaborative research and regulatory acceptance of new drug development tools for DMD. To support the progress of new therapies for Duchenne patients, D-RSC is building a clinical trial simulation tool to accelerate clinical trial design by exploring variability across the patient population and analyzing natural history and placebo data to predict disease progression in silico. This effort will generate mathematical models that predict disease progression in DMD using trajectories from a set of 5 endpoints (velocity of completion of supine-stand test, velocity of completion of 4-stair climb test, velocity of completion of 10-meter walk/run test or 30-foot walk/run test, forced vital capacity, and the NorthStar Ambulatory Assessment).
The modeling analyses are based on data from a total of 18 datasets, with more than 24000 patient level observations and have been submitted to both the EMA (European Medicine Authority) and FDA (Food and Drug Administration) agencies. D-RSC is currently working on addressing regulatory feedback to finalize the submissions towards regulatory endorsement of these proposed drug development tools.
The D-RSC database is now comprised of 24 datasets. Together with its quantitative modeling work and numerous other collaborations that D-RSC has established, the recent opening of the D-RSC database further enhances the consortium’s impact throughout the Duchenne community and has already supported clinical trial design and research project development for more than 10 DMD investigators around the world.