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

Francesco Muntoni¹, James Signorovitch², Gautam Sajeev³, Nathalie Goemans⁴, Brenda Wong⁵, Cuixia Tian⁶, Eugenio Mercuri⁷, Nicolae Done³, Hallee Wong³, Jackson Moss³, Zhiwen Yao³, Susan J Ward⁸, Adnan Manzur¹, Laurent Servais⁹, Erik H Niks¹⁰, Volker Straub¹¹, Imelda Jm de Groot¹², Craig McDonald¹³; 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)

Affiliations

¹ Dubowitz Neuromuscular Centre, NIHR Great Ormond Street Hospital Biomedical Research Centre, Great Ormond Street Institute of Child Health, University College London, & Great Ormond Street Hospital Trust, London, UK.
² Analysis Group, Inc., Boston, Massachusetts, USA; The Collaborative Trajectory Analysis Project, Cambridge, Massachusetts, USA. Electronic address: James.signorovitch@analysisgroup.com.
³ Analysis Group, Inc., Boston, Massachusetts, USA.
⁴ University Hospitals Leuven, Child Neurology, Leuven, Belgium.
⁵ Department of Pediatrics, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
⁶ Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio & College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA.
⁷ Department of Pediatric Neurology, Fondazione Policlinico Gemelli IRCCS, Catholic University, Rome, Italy.
⁸ The Collaborative Trajectory Analysis Project, Cambridge, Massachusetts, USA.
⁹ UK Oxford Neuromuscular Center, Department of Paediatrics, University of Oxford, UK and Neuromuscular Center of Liège, Division of Paediatrics, CHU and University of Liège, Belgium.
¹⁰ Leiden University Medical Centre, Leiden, the Netherlands.
¹¹ John Walton Muscular Dystrophy Research Centre, Newcastle University, Newcastle, UK.
¹² Radboud University Nijmegen Medical Center, Donders Centre of Neuroscience, Department of Rehabilitation, Nijmegen, the Netherlands.
¹³ Department of Physical Medicine and Rehabilitation, and Pediatrics, University of California, Davis, Sacramento, California, USA.

PMID: 35396092
DOI: 10.1016/j.nmd.2022.02.009

Free article

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

Francesco Muntoni et al. Neuromuscul Disord. 2022 Apr.

Free article

. 2022 Apr;32(4):271-283.

doi: 10.1016/j.nmd.2022.02.009. Epub 2022 Feb 25.

Authors

Affiliations

¹ Dubowitz Neuromuscular Centre, NIHR Great Ormond Street Hospital Biomedical Research Centre, Great Ormond Street Institute of Child Health, University College London, & Great Ormond Street Hospital Trust, London, UK.
² Analysis Group, Inc., Boston, Massachusetts, USA; The Collaborative Trajectory Analysis Project, Cambridge, Massachusetts, USA. Electronic address: James.signorovitch@analysisgroup.com.
³ Analysis Group, Inc., Boston, Massachusetts, USA.
⁴ University Hospitals Leuven, Child Neurology, Leuven, Belgium.
⁵ Department of Pediatrics, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
⁶ Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio & College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA.
⁷ Department of Pediatric Neurology, Fondazione Policlinico Gemelli IRCCS, Catholic University, Rome, Italy.
⁸ The Collaborative Trajectory Analysis Project, Cambridge, Massachusetts, USA.
⁹ UK Oxford Neuromuscular Center, Department of Paediatrics, University of Oxford, UK and Neuromuscular Center of Liège, Division of Paediatrics, CHU and University of Liège, Belgium.
¹⁰ Leiden University Medical Centre, Leiden, the Netherlands.
¹¹ John Walton Muscular Dystrophy Research Centre, Newcastle University, Newcastle, UK.
¹² Radboud University Nijmegen Medical Center, Donders Centre of Neuroscience, Department of Rehabilitation, Nijmegen, the Netherlands.
¹³ Department of Physical Medicine and Rehabilitation, and Pediatrics, University of California, Davis, Sacramento, California, USA.

PMID: 35396092
DOI: 10.1016/j.nmd.2022.02.009

Abstract

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.

Keywords: Clinical trials; Drug evaluation; Duchenne muscular dystrophy; External controls; Natural history data; Real-world data.

PubMed Disclaimer

Conflict of interest statement

Declaration of Competing Interest Francesco Muntoni is a member of the Rare Disease Scientific Advisory Group for Pfizer and of Dyne Therapeutics SAB, and has participated to SAB meetings for PTC, Sarepta, Santhera, Wave Therapeutics. UCL and Great Ormond Street Hospital are recipient of grants from Pfizer, Italfarmaco, Wave, Santhera, Sarepta regarding clinical trials. James Signorovitch co-founded the collaborative Trajectory Analysis Project (cTAP) and is an employee of Analysis Group, Inc., a consulting firm that received funding from the membership of cTAP to conduct this study. Gautam Sajeev, Nicolae Done, Hallee Wong, Jackson Moss, and Zhiwen Yao are employees of Analysis Group, Inc., a consulting firm that received funding from the membership of cTAP to conduct this study. Nathalie Goemans has received compensation for consultancy services from Eli Lilly, Italfarmaco, PTC Therapeutics, BioMarin Pharmaceutical, Pfizer, Avidity, Daiichi Sankyo, Wave, Santhera and has served as site investigator for GlaxoSmithKline, Prosensa, BioMarin Pharmaceutical, Italfarmaco, Eli Lilly, Wave, and Sarepta. Brenda Wong has participated in advisory committee meetings for Prosensa and Biomarin and has received compensation for consultancy services for Gilead Sciences, Pfizer and GSK. Cuixia Tian has served as the site investigator for trials sponsored by PTC Therapeutics, Eli Lilly, GSK, Prosensa/Biomarin, Bristol Myers Squibb, Roche, Pfizer. Santhera, Sarepta, Fibrogen, Capricor, Pfizer, Avexis, and Catabasis. Eugenio Mercuri has served on clinical steering committees and/or as a consultant for Eli Lilly, Italfarmaco, PTC Therapeutics, Sarepta, Santhera, and Pfizer; has served as PI for GlaxoSmithKline, Prosensa, BioMarin Pharmaceutical, Italfarmaco, Roche, PTC, Pfizer, Sarepta, Santhera, Wave, NS and Eli Lilly. Susan J. Ward co-founded and manages the collaborative Trajectory Analysis Project and has received funding from the membership of cTAP to facilitate this study. Adnan Manzur has no disclosures. Laurent Servais is member of the SAB or has performed consultancy for Sarepta, Dynacure, Santhera, Avexis, Biogen, Cytokinetics and Roche, Audentes Therapeutics and Affinia Therapeutics; Laurent Servais has given lectures and has served as a consultant for Roche, Biogen, Avexis, and Cytokinetics. Laurent Servais is the project leader of the newborn screening in Southern Belgium funded by Avexis, Roche, and Biogen. Erik H. Niks is a member of the European Reference Network for Rare Neuromuscular Diseases (ERN EURO‐NMD). Erik H. Niks reports grants from Duchenne Parent Project, ZonMW and AFM, consultancies for BioMarin and Summit, and worked as local investigator of clinical trials of BioMarin, GSK, Lilly, Santhera, Givinostat, and Roche outside the submitted work. E.H.N. reports ad hoc consultancies for WAVE, Santhera, Regenxbio, and PTC, and he worked as investigator of clinical trials of Italfarmaco, NS Pharma, Reveragen, Roche, WAVE, and Sarepta outside the submitted work. Volker Straub has participated in advisory boards for Audentes Therapeutics, Biogen, Exonics Therapeutics, Italfarmaco S.p.A., Roche, Sanofi Genzyme, Sarepta Therapeutics, Summit Therapeutics, UCB, and Wave Therapeutics. He has research collaborations with Ultragenyx and Sanofi Genzyme. Imelda JM de Groot has no disclosures. Craig McDonald has served as a consultant for PTC Therapeutics, BioMarin Pharmaceutical, Sarepta Therapeutics, Eli Lilly, Pfizer Inc, Santhera Pharmaceuticals, Cardero Therapeutics, Inc, Catabasis Pharmaceuticals, Capricor Therapeutics, Astellas Pharma (Mitobridge), and FibroGen, Inc; serves on external advisory boards related to DMD for PTC Therapeutics, Sarepta Therapeutics, Santhera Pharmaceuticals, and Capricor Therapeutics; and reports grants from US Department of Education/National Institute on Disability and Rehabilitation Research, the National Institute on Disability, Independent Living, and Rehabilitation Research, US NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH/National Institute of Neurologic Disorders and Stroke, US Department of Defense, and Parent Project Muscular Dystrophy US.

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions

Grants and funding

DH_/Department of Health/United Kingdom

LinkOut - more resources

Full Text Sources
- ClinicalKey
- Elsevier Science

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources