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FDA Draft Guidance on Duchenne
PPMD and a broad coalition of stakeholders has submitted the first-ever patient advocacy-initiated draft guidance for a rare disease to the U.S. Food and Drug Administration (FDA) to help accelerate development and review of potential therapies for Duchenne muscular dystrophy.
More than 80 representatives of the Duchenne community - including parents and patients, medical experts, academics, and biopharmaceutical industry representatives - participated in seven working groups that met over the past six months to draft the guidance.
Community Imperatives & Cover Letter
The cornerstone of the guidance encourages the FDA and trial sponsors to engage patients and their families at all stages of trial development and to take into account what they consider acceptable risk in clinical trials. A recent PPMD study published in the journal Clinical Therapeutics shows that parents of children with Duchenne will accept substantial risk when balanced with noncurative slowing or stopping of the progression of muscle weakness, even with no improvement in life expectancy. The results came from the first-ever scientific survey of benefit/risk perspectives that PPMD conducted last year involving 120 Duchenne parents.
Areas of Focus
Each section of the guidance includes extensive published or in-press peer-reviewed articles and focuses on six areas aimed at overcoming the challenges in trial design and implementation:
Dr. Neera Gulati serves as a steering committee member for PPMD and is the mother of Suneel Ram, a 17-year-old young man living with Duchenne muscular dystrophy. She is a founding board member of Suneel's Light, a not-for-profit organization devoted to increasing awareness and funding research for effective treatments and a cure for Duchenne. Dr. Gulati is a family medicine physician who has been in solo-private practice for 16 years.
Dr. Bridges, an Associate Professor within the Center for Health Services and Outcomes Research (CHSOR), is an international leader in the application of both qualitative and quantitative stated-preference methods, especially as they pertain to benefit-risk analysis. He has completed several seminal benefit-risk preference studies, especially in the area of rare diseases, and has played a leading role in the development of consensus-based standards for stated-preference methods. In recent years, he has advocated for patients and caregivers to have a greater role in medical research and for the incorporation of preference data in regulatory decisions.
Justin Fallon is a Professor of Neuroscience at Brown University. After his Ph.D. work in cell motility at the University of Pennsylvania, he spent three year as an NIH Postdoctoral Fellow at University College London, where he worked on axonal guidance and regeneration with Martin C. Raff. Fallon gained further training with U.J. McMahan at Stanford University, where he began his interest in synapse formation and plasticity. He has a longstanding interest in developmental neurobiology and the mechanisms underlying neurological disease. More recently, he has been directly involved in developing a novel protein therapeutic for DMD. Fallon has been at Brown since 1996.
Kevin M. Flanigan, MD, is an Investigator at the Center for Gene Therapy and an attending neurologist at Nationwide Children’s Hospital in Columbus, Ohio, and Professor of Pediatrics and Neurology at The Ohio State University College of Medicine. Certified in both Neurology and Neuromuscular Medicine by the American Board of Psychiatry and Neurology, Dr. Flanigan is a member of the World Muscle Society Executive Committee, the international TREAT-NMD Executive Committee, and a core member of the Therapeutic Advisory Committee of TREAT-NMD. He is a co-editor of PLOS Currents Muscular Dystrophy, and a member of the Editorial Boards of Neuromuscular Disorders and Journal of Neuromuscular Diseases. He is an experienced clinical trialist and translational scientist whose primary research interest is in the genetic and molecular characterization of inherited neuromuscular diseases, and the development of therapies directed toward these diseases. A major focus of his laboratory concerns genotype/phenotype correlation in the dystrophinopathies, with the intention of increasing our understanding of disease pathogenesis and translating this understanding into improved therapies.
Dr. McDonald is an internationally recognized expert in the clinical management and rehabilitation of neuromuscular diseases including muscular dystrophies and the development of novel outcome measures for clinical trials. He also is widely known for his expertise in the management of children and young adults with spinal cord injury and spina bifida. He is Director of the NIDRR-funded Rehabilitation Research and Training Center in Neuromuscular Diseases and Principal Investigator of the UC Davis NINDS-funded site in the NeuroNEXT Neurosciences Clinical Trials National Consortium. Dr. McDonald is recipient of over $16 million in federal grant support over the past 12 years. He has been involved in a multitude of NIH, MDA, CDC and Shriners hospitals national committees and serves as a consultant to the pharmaceutical industry regarding clinical trials in Duchenne muscular dystrophy and other muscular dystrophies. He has been on many NIH study sections reviewing research proposals relating to neuromuscular diseases and rehabilitation sciences. His research has focused on novel clinical endpoint development in neuromuscular diseases, clinical trials and natural history studies in muscular dystrophies, metabolic syndrome, and energy expenditure in childhood disabilities.
Lawrence Charnas, MD, PhD is a Discovery Medicine Lead at Shire, and works in Lexington, MA. He received his B.A. from Cornell University, MD/PhD from University of Pennsylvania, and training at Crozer-Chester Medical Center (Internal Medicine), Johns Hopkins (Neurology), NIH (Medical Genetics) and Child Neurology (Univ of Minnesota). Since moving to Shire in late 2008, he worked in developing therapies in several rare diseases, including Duchenne muscular dystrophy. Prior to coming to Shire he was an Associate Professor of Pediatrics and Neurology at the University of Minnesota. His past clinical experience included positions within academia, private practice, and state and federal facilities.
Dr. Sweeney is William Maul Measey Professor and Chairman of Physiology at the University of Pennsylvania. His research program addresses the molecular basis of cellular movement and force generation. His approach encompasses investigations on single molecules, single cells, and whole organisms. At the level of the single molecule, the work examines the basic design and function of the molecular motor, myosin. These studies combine protein engineering with biochemical and structural analyses. At the level of isolated cells (cultured myocytes), the research program has two aspects: 1) investigation of the role of various proteins either in the generation of force, or in the transmission of force across the cell membrane, and 2) the process of assembly of the contractile apparatus. Studies at the whole animal level involve gene transfer into muscle (both germline and somatic cell). Somatic cell gene transfer (utilizing viruses) allows the assessment of acute alterations in cell structure and function following viral-driven expression of a single protein. In response to acute changes in properties, feedback pathways intrinsic and extrinsic to the muscle cell signal alterations in the muscle gene expression program that result in an adaptive response. This new approach allows critical evaluation of principles of muscle cell design, as well as, evaluation of possible causes of and treatments for muscle diseases. Currently, he is studying two diseases, Duchenne muscular dystrophy and hypertrophic cardiomyopathy, with this approach. Dr. Sweeney has been an advisor to PPMD since 1998.
Pat Furlong is the Founding President and CEO of Parent Project Muscular Dystrophy (PPMD), the largest nonprofit organization in the United States solely focused on Duchenne muscular dystrophy (Duchenne). When doctors diagnosed Pat’s two sons, Christopher and Patrick with Duchenne in 1984, she refused to accept “there’s no hope, and little help” as an answer. Instead, she immersed herself in Duchenne, working to understand the pathology of the disorder, the extent of research investment and the mechanisms for optimal care. Her sons lost their battle with Duchenne in their teenage years, but she continues to fight—in their honor and for all families affected by Duchenne. In 1994, Pat, together with other parents of young men with Duchenne, founded PPMD to change the course of Duchenne and, ultimately, to find a cure. Today, Pat continues to lead the organization and is considered one of the foremost authorities on Duchenne in the world. Pat also serves on the Board of Directors for the National Organization for Rare Disorders (NORD), the Institute of Medicine's (IOM's) Committee on Pediatric Studies, and is a member of the Muscular Dystrophy Coordinating Committee for the U.S. Department of Health & Human Services. In 2010, she was named a “World Changer” by The New Yorker magazine and a “Health Hero” by WebMD. In 2008, she received the Research!America Advocacy Award.
Dr. Timothy R. Franson is the Chief Medical Officer for YourEncore and serves as a steering committee member and advisor to PPMD. He has extensive clinical and regulatory experience in pre- and post-approval phases of pharmaceutical development relating to interactions with the FDA for policy and product issues. He also currently serves as President of the USP Convention (2010-2015). Prior to joining the YourEncore/FaegreBD Consulting team, Dr. Franson worked with Eli Lilly & Co. for more than 20 years, where he retired as Vice President of Global Regulatory Affairs & Patient Safety, led the company’s U.S. Clinical Research/Trials organization, and was responsible for over 20 new drug/biologic submissions and approvals. Dr. Franson has been a leader in many industry initiatives with the FDA, including his role as co-chair of the joint FDA-industry working group addressing clinical aspects of the FDA Modernization Act of 1997, and serving on NIH-NCATS, among others. He has authored more than 50 articles in the fields of infectious disease, epidemiology, pharmacoeconomics and antibiotic utilization, as well as four book chapters relating to innovation policy topics.
Working Group 1 – Benefit Risk
Working Group 2 – Diagnosis
Working Group 3 – Natural History
Working Group 4 – Biomarkers 1 (dystrophin/utrophin)
Working Group 5 – Biomarkers 2 (MRI/blood/urine)
Working Group 6 – Clinical Trial Design & Outcome Measure
Working Group 7 – Imperatives
Community Advisory Board
Managed by: Ryan Fischer (PPMD)
Patient and Parent Reps
The suggested FDA guidance represents the culmination of PPMD’s 20 year history of improving care and developing urgently needed therapies for Duchenne. PPMD led the effort to pass the MD-CARE Act, which created the Senator Paul Wellstone Muscular Dystrophy Cooperative Research Centers. The draft guidance builds on PPMD’s effort to shape federal policy that reflects the needs of families living with Duchenne, including the release of “Putting Patients First” which calls on the FDA to act more flexibly when reviewing applications for Duchenne therapies. PPMD also ensured that the FDA Safety & Innovation Act of 2012 (FDASIA) responded to the needs of the community; recently published a groundbreaking benefit/risk study which documented the willingness of families to live with risk; and held a national PPMD-FDA Duchenne Policy Forum where the community made its needs and preferences in drug development known to the Agency.
There has never been so much momentum in the Duchenne community. Help us keep moving forward by donating to fund CRISPR/Cas9 gene‑editing technology. Every gift to PPMD is being doubled until we raise $250,000—but we have to reach this goal by 12/31!