Experts Participate in DM Regulatory Workshop

Published on Sat, 10/10/2015

On September 17, 2015 MDF sponsored a regulatory workshop in Washington D.C. featuring speakers from academia, industry and the Food and Drug Administration (FDA).  As the therapeutic pipeline for myotonic dystrophy has started to fill, the “Myotonic Dystrophy Patient-Centered Therapy Development meeting” sought to explore the development of meaningful and measurable DM clinical endpoints and biomarkers, and to guide and advance the design of clinical trials for the care and cure of patients with myotonic dystrophy.  Click here for the agenda for that meeting, which was moderated by former FDA Deputy Director Dr. Stephen Spielberg, along with links to speaker presentations.


Dr. Spielberg made a few introductory remarks at the meeting, noting that we are in an age of revolutionary treatments for rare, genetic diseases and that successful treatment development for these diseases is dependent on patient and family advocacy.

Dr. Spielberg introduced Dr. Richard Moscicki, Deputy Center Director for Science Operations in the Center for Drug Evaluation and Research (CDER) at FDA, who gave an overview of the FDA’s history with orphan drugs.  He noted that more orphan drugs were approved in 2014 than ever before and that the FDA is willing to be very flexible in its approach to serious rare diseases with unmet needs.

Living with Myotonic Dystrophy

Dr. Spielberg introduced a ten minute video produced by MDF featuring individuals with myotonic dystrophy who described what it is like to live day-to-day with the disease, dealing with gastrointestinal symptoms that sometimes left them homebound or unable to eat, myotonia of the tongue and facial muscles that made it difficult for them to communicate, and cognitive symptoms that left one young woman wishing that she “were cleverer.”

The video was followed by a short presentation by Dr. Sarah Clarke, a physician who self-diagnosed and then diagnosed both her young daughters, who are more severely affected.  Dr. Clarke described the helplessness of knowing that she was gradually becoming more affected herself, leaving her husband, also a physician, to be the caretaker for the entire family.  She wondered what would happen to their daughters when they were gone.

Dr. Nicholas Johnson, Assistant Professor of Neurology, Pathology and Pediatrics at the University of Utah then gave an overview of myotonic dystrophy pathology and symptoms, and also provided a look at some new data from his group on the frequency of comorbidities.

Session One: Real World Patient Data

The first of the main meeting sessions explored “Real World Patient Data”—what we have learned from studies and surveys about what people affected by myotonic dystrophy view as their most burdensome symptoms and what therapeutic benefits they would value most highly, as well as what risks they were willing to tolerate for new therapies.

Dr. Richard Moxley described key findings from the University of Rochester PRISM-1 study initiated by Dr. Chad Heatwole to better understand symptom burden.  The data from the PRISM-1 study showed that there was a marked increase in frequency and impact of mobility issues between ages 25 and 35, and that, while the most prevalent symptom was problems with hands and arms, the most impactful symptom was fatigue.

Dr. Katherine Hagerman of Stanford University presented data from the “Christopher Project”, a mailed survey about myotonic dystrophy with over 1400 respondents sponsored by the Marigold Foundation. The survey highlighted that muscle symptoms and fatigue were the heaviest symptom burden and provided insight into numerous aspects of daily living with the disease.

Dr. Sharon Hesterlee, MDF’s Chief Science Officer, presented data from a pilot study that takes a quantitative approach to measuring benefit/risk preferences of those with myotonic dystrophy. The study analyzed the responses of 267 people with adult-onset myotyonic dystrophy about hypothetical treatments with benefits related to relief from muscle weakness, fatigue and myotonia, and symptoms related to fatigue, GI symptoms, and liver damage. The results showed that people with myotonic dystrophy found hypothetical treatments that could reverse, stop or slow muscle weakness to be of greatest value, while treatments that did the same for fatigue to be of least value. Respondents rated liver failure to be the worst risk.

Ms. Pujita Vaidya from the Office of Strategic Programs at CDER, FDA described the Program’s efforts to conduct a series of Patient Focused Drug Development (PFDD) meetings to better understand patient needs and priorities. The results of these meetings are used to complete the first two rows of CDER’s Benefit-Risk Framework, which in turn is used in making regulatory decisions. Although myotonic dystrophy was not selected as one of the disease areas for CDER’s official PFDD program, Dr. Vaidya pointed out that CDER encourages the development of externally-led meetings that use the official PFDD meetings as a template.

Session Two: Myotonic Dystrophy Trial Endpoint Selection

Dr. Charles Thornton of the University of Rochester described what his group has learned from a three year study of functional measurements in 58 people with myotonic dystrophy. He showed that there was a large variance between all subjects with all measurements; that the 30 foot walk/run had the greatest reliability among measurements to show decline; that grip strength is also a sensitive measurement for progression, although it has a floor effect; and that composite myometry of mid-limb and distal muscles may have advantages for detecting improvement in moderately and heavily affected muscles.

Dr. Cynthia Gagnon of the Université de Sherbrooke described the Saguenay Longitudinal Study with over 15 years of follow-up data on 125 people with myotonic dystrophy. The goal of this study is to have a more comprehensive model to understand the relationships between impairments, disabilities, activities and participation in DM1. For example, Dr. Gagnon was able to show that lower extremity strength reliably correlates with the degree of mobility-related participation in social activities.

Dr. Nikunj Patel of the Clinical Outcomes Assessment Staff in CDER’s Office of New Drugs described the FDA’s approach to outcome measure development or selection. Dr. Patel explained that clinical outcome assessments must measure the right thing, in the right way, with the right amount of reliability to be able to say that there is a clear treatment benefit. He provided numerous links to appropriate FDA Guidances.

Session Three: Trial Design for a Slow-Progressing Heterogeneous Disease

Dr. Ronald Farkas from the Division of Neurology Products at CDER discussed clinical trial design for slowly progressing, heterogeneous rare diseases. In general, he explained, the FDA is very flexible about things like the size of the trial, the size of the safety database, and the length and number of trials needed to submit a New Drug Application (NDA) as long as the studies are conducted rigorously and the results are very clear-cut and convincing. He also made the point that there is not currently an FDA “preferred endpoint” for myotonic dystrophy and that many different types of measurements could be considered.

Session Four: Candidate DM Biomarkers

Dr. John Day of Stanford University provided an overview of biomarker development for myotonic dystrophy. He showed that candidate biomarkers for DM currently include myotonia, cardiac conduction changes, gastroparesis, endocrine/metabolic changes, CNS functional changes and transcriptome panels.

Dr. John Carulli of Biogen Idec discussed muscle and blood-based biomarkers for myotonic dystrophy clinical trials, pointing out that we are beginning to understand sources of splicing biomarker variability, which allows us to distinguish therapy-related changes from normal fluctuation. He feels that we still need to understand which markers are most sensitive to CUG repeat changes, that we need a statistical framework by which to interpret changes in splicing patterns and that we need to better correlate molecular markers with clinical measures of disease manifestation.

Dr. Shashi Amur of the Biomarker Qualification Program in CDER’s Office of Translational Sciences described the difference between qualifying a biomarker for use in multiple drug development programs and using the biomarker in a single drug development program. Qualifying a biomarker is a very structured process that typically takes between three and a half and five and a half years. Dr. Amur provided numerous references to guidance from the FDA on the biomarker qualification process and suggested that early engagement with the FDA on biomarkers is encouraged. She emphasized that qualification is not required to use a biomarker in a single drug development program.


Dr. Spielberg summarized the day’s meeting, noting particularly that there is a need to develop earlier predictors of efficacy and to define go/no-go decision making points to cut time and effort and limit risk. He also noted the need to better define biomarkers and expedite studies, pointing out that the FDA has regulatory but not disease area experience and is listening to the experts.

Meeting agenda and presentation links.