Evidentiary basis of the first regulatory qualification of a digital primary efficacy endpoint
Por:
Servais L, Strijbos P, Poleur M, Mirea A, Butoianu N, Sansone VA, Vuillerot C, Schara-Schmidt U, Scoto M, Seferian AM, Previtali SC, Tulinius M, Nascimento-Osorio A, Furlong P, Singh T, Dreghici RD, Goemans N, Mercuri E, Straub V, Ormazabal MG, Braid J, Muntoni F, Tricot A, Annoussamy M and Eggenspieler D
Publicada:
29 nov 2024
Ahead of Print:
29 nov 2024
Resumen:
Stride velocity 95th centile (SV95C) is a wearable-derived endpoint representing the 5% fastest strides taken during everyday living. In July 2023, SV95C received European Medicines Agency (EMA) qualification for use as a primary endpoint in trials of patients with Duchenne muscular dystrophy (DMD) aged >= 4 years-becoming the first digital endpoint to receive such qualification. We present the data supporting this qualification, providing insights into the evidentiary basis of qualification as a digital clinical outcome assessment. Clinical trials, natural history studies, and patient surveys (ages 5 - 14 years) showed that SV95C is accurate, valid, reliable, sensitive, and clinically meaningful. SV95C significantly correlated with traditional DMD assessments, increased rapidly after steroid initiation (0.090 m/s 3 months post-treatment), and declined steadily in patients on stable steroid regimens. Compared with traditional assessments, SV95C demonstrated earlier sensitivity to disease progression (3 vs 9 months) and greater sensitivity at 12 months. Distribution- and anchor-based approaches revealed a change of - 0.10 to - 0.20 m/s as clinically meaningful. The EMA qualification of SV95C illustrates the willingness of regulators to accept novel digital endpoints for drug approval, setting an important precedent for the evidentiary basis of regulatory digital endpoint qualification that could transform clinical development in disorders affecting movement.
Filiaciones:
Servais L:
Department of Paediatrics, MDUK Oxford Neuromuscular Centre and NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK
Division of Child Neurology, Department of Pediatrics, Centre de Référence Des Maladies Neuromusculaires, University Hospital Liège and University of Liège, Liège, Belgium
Strijbos P:
F. Hoffmann-La Roche Ltd, Basel, Switzerland
Poleur M:
Department of Neurology, Centre de Référence Des Maladies Neuromusculaires, Citadelle Hospital Liège and University of Liège, Liège, Belgium
Mirea A:
University of Medicine and Pharmacy "Carol Davila", Bucharest, Romania
National Teaching Center for Children's Neurorehabilitation "Dr. Nicolae Robanescu", Bucharest, Romania
Butoianu N:
Faculty of Medicine and Pharmacy ?Carol Davila?, Pediatric Neurology Clinic, ?Prof. Dr. Al. Obregia? Hospital, Bucharest, Romania
Sansone VA:
The NeMo Clinical Center, Neurorehabilitation Unit, University of Milan, Milan, Italy
Vuillerot C:
Department of Pediatric Physical Medicine and Rehabilitation, Hôpital Mère Enfant, CHU-Lyon, Lyon, France
Neuromyogen Institute, Université de Lyon, Lyon, France
Schara-Schmidt U:
Department of Pediatric Neurology, Developmental Neurology and Social Pediatrics, Neuromuscular Centre for Children and Adolescents, University of Essen, Essen, Germany
Scoto M:
Dubowitz Neuromuscular Centre, NIHR Great Ormond Street Hospital Biomedical Research Centre, Great Ormond Street Institute of Child Health, University College London, London, UK
Seferian AM:
I-Motion, Hopital Trousseau, Paris, France
Previtali SC:
Neuromuscular Repair Unit, INSPE and Division of Neuroscience, IRCCS Ospedale San Raffaele, Milan, Italy
Tulinius M:
Department of Pediatrics, Queen Silvia Children's Hospital, University of Gothenburg, Gothenburg, Sweden
Nascimento-Osorio A:
Neuromuscular Unit, Department of Neurology, Hospital Sant Joan de Déu, Barcelona, Spain
Applied Research in Neuromuscular Diseases, Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Furlong P:
Parent Project Muscular Dystrophy, Washington, DC, USA
Singh T:
Sarepta Therapeutics, Inc, Cambridge, MA, USA
Dreghici RD:
Solid Biosciences, Boston, MA, USA
Goemans N:
Neuromuscular Reference Centre, Department of Paediatrics and Child Neurology, University Hospitals Leuven, Leuven, Belgium
Mercuri E:
Pediatric Neurology, Catholic University, Rome, Italy
Nemo Pediatrico, Fondazione Policlinico Gemelli IRCCS, Rome, Italy
Straub V:
John Walton Muscular Dystrophy Research Centre, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK
Ormazabal MG:
Roche Products Ltd, Welwyn Garden City, UK
Braid J:
Roche Products Ltd, Welwyn Garden City, UK
Muntoni F:
Dubowitz Neuromuscular Centre, NIHR Great Ormond Street Hospital Biomedical Research Centre, Great Ormond Street Institute of Child Health, University College London, London, UK
Tricot A:
SYSNAV, Paris, France
Annoussamy M:
SYSNAV, Paris, France
Eggenspieler D:
SYSNAV, Paris, France
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