November 26, 2019

Meeting Summary
Muscular Dystrophy Coordinating Committee
November 26, 2019

The Muscular Dystrophy Coordinating Committee (MDCC) met on November 26, 2019, via webinar/teleconference. As Chair of the Committee, Walter Koroshetz, M.D., Director of the National Institute of Neurological Disorders and Stroke (NINDS), led the meeting with Glen Nuckolls, Ph.D., MDCC Executive Secretary. The entire meeting was held in open session and was in accordance with the Federal Advisory Committee Act (P. L. 92-463).

Report on NIH Support for the Muscular Dystrophies

Dr. Koroshetz welcomed the committee and thanked participants on the phone/online and in the room.

Dr. Koroshetz summarized historic and FY2019 NIH appropriations.  He highlighted several scientific advances including a comparative effectiveness clinical study of drug treatments for Duchenne related cardiomyopathy (Raman et al, J Am Heart Assoc, 2019) and results from a clinical trial demonstrating possible efficacy of novel steroid-like drug in Duchenne (Hoffman et al, Neurology, 2019). Dr. Koroshetz also described three preclinical studies exploring a potential therapeutic target for FSHD, a novel gene therapy approach for Duchenne and a strategy to reduce muscle inflammation and fibrosis, which is present in many muscular dystrophies.

Selection of MDCC Chair

As described in the MDCC charter, the Chair is selected by the Committee for a period of two years and is appointed by the Secretary of the Department of Health and Human Services.  Dr. Koroshetz expressed his appreciation in serving as Chair for 2018-2019.  Dr. Diana Bianchi, Director of the Eunice Kennedy Shriver National Institute of Child Health and Human Development was voted in as the chair of MDCC for the term 2020-2021, pending appointment by the Secretary.

New Member Presentation

Ms. Cheryl Williams, Director of Office of Medical Policy, gave an overview of their office’s basic policy areas: including listing of impairments (adults and children), childhood disability policy, age 18 redetermination policy, continuing disability review policy, diary policy, medical equivalence policy, and drug addiction and alcoholism policy. There are 237 different conditions listed. Compassionate allowances (CAL) speed access to services by speeding adjudication and there are currently five CAL conditions related to the muscular dystrophies.  This year there are four new CAL conditions (CDKL5, Pitt Hopkins Syndrome, Primary Peritoneal Cancer, Richter Syndrome). Information about adding new CAL conditions are all available on website SSA.gov with a link to submit a new condition.

Patient Focused Drug Development

Dr. Nuckolls introduced the topic of Patient-Focused Research (PFR), also called Patient-Centered Research.  Research is patient-focused when the experiences, perspectives, needs and priorities of patients are meaningfully incorporated into all stages of the research. Dr. Nuckolls described plans for PFR to be a recurrent topic of MDCC presentations and discussion.

Megahana Chalasani, M.H.A from the Center of Drug Evaluation and Research at the U.S. Food and Drug Administration (FDA) gave an overview of the FDA Patient Focused Drug Development (PFDD) program. The FDA’s vision of PFDD is to ensure confidence in reliability and accuracy of patient experience data for regulatory decision making, reduce regulatory uncertainty for sponsor, and promote rapid consistent adoption.

Ms. Chalasani described the FDA’s efforts to operationalize their vision of PFDD.  The initiative was introduced in the fifth authorization of the Prescription Drug Users Fee Act (PDUFA V 2013-2017).  Under this initiative, FDA conducted disease specific PFDD meetings in rare and common conditions to address questions from the patient perspectives such as “Which symptoms have the most significant impact?” and “What would you look for in ideal treatment?”  All reports from these meetings have been made publicly available.  These meetings demonstrated how patient input informs the therapeutic context, meaningful potential benefits, acceptability of risk and how benefit/risk profile changes in light of new information.

The next phase of PFDD was implemented in response to PDUFA VI and the 21st Century Cures Act with the goal of building patient input into research from the translational stage through clinical trials, pre-market review and through post-market activities.  A statement of patient experience has been incorporated into review documents and report on how patient experience data has affected regulatory decision making is released every five years.  The FDA is developing a series of guidance documents on potential research questions and methods to promote more rigorous approaches to patient reported data.  Draft guidance documents already posted include a glossary, guidance on comprehensive and representative input, and guidance on methods to identify what is important to patients.  Additional guidance documents under development describe fit for purpose clinical outcome assessments and incorporating clinical outcome assessments (COAs) into endpoints for regulatory decision making.  

There are additional patient-focused drug development resources are available through the FDA. Two kinds of meetings are available, both FDA led and externally led.  Patient organizations identify and organize patient-focused collaborations to generate public input on specific disease areas. While FDA will be open to participating inwell-designed and well-conducted meetings, an externally led PFDD meeting and any resulting products (e.g., surveys or reports) will not be considered FDA-sponsored or FDA-endorsed, but these products may be posted on the FDA’s website. The FDA also has a pilot grant program to support the development of publicly available standard core set(s) of COAs and their related endpoints for specific disease indications. With this grant program, FDA is looking to encourage a more collaborative, multi-stakeholder approach to the development, modification and/or selection of COAs within specific disease area(s) that incorporates input from patients and care partners, drug developers, researchers, regulators, payers, and other decision makers. For each award, it is expected that a standard core set be publicly available by the end of the grant period, at no cost or nominal cost.

MDCC member organizations were invited to describe PFDD meetings that they have conducted.

Ryan Fischer, PPMD, gave a summary of the Duchenne Patient-Focused Compass Meeting held in 2018.  PPMD had three major goals to 1) identify current policy, care, and clinical trial priorities among their Duchenne community members, 2) to renew engagements with existing federal and industry partners and, 3) to begin to identify measures of impact not currently captured in health economic models or value frameworks.  They brought together 15 patient groups to form a community advisory board. The audience was the Duchenne drug development “ecosystem” including families, industry partners, clinicians and federal agencies. While not an official externally led FDA PFFD meeting, this meeting was modeled after FDA externally led PFDD meetings. The meeting included panels organized by disease stage, Q&A and discussion sessions, and live polling about symptoms affecting daily life, expectations for new treatments, costs for families.  Live anonymous polling has now become a regular feature of their meetings with stake holders.  This meeting led to a report that has guided strategic direction.

Mr. Paul Melmeyer, MDA, gave a summary of the PFDD efforts of the MDA.  They have partnered with many other disease groups on PFDD meetings and related efforts. They planned an externally led PFDD meeting on Pompe disease, held on March 9, 2020, primarily intended to inform FDA reviewers. The meeting focused on symptom burden with input from patients and caregivers. MDA hopes that the voice of the patient report from this meeting will be useful in current and future clinical trials and during FDA review.

Dr. John Porter, Myotonic, summarized the externally lead PFDD meeting organized by Myotonic in September 2016 in conjunction with their annual meeting.  They had over 200 participants onsite or online including patients, families, and caregivers, researchers, clinicians and industry representatives.  There was both audience discussion and online polling, which was held open for 30 additional days post meeting to get a full picture of data. They collected anonymized demographic data (age of symptom onset, age of diagnosis, time since diagnosis) for both DM1 and DM2 patients to help interpret the data.  They worked with Mr. James Valentine, who has substantial experience working with the FDA and disease group in PFDD. The first panel was based on living with DM (eg. Which symptoms are most troublesome on a normal day? On your worst day? How have symptoms changed over time?). The second panel was based on attitudes on therapy development (What do you use for symptom management currently? What are the downsides/side effects? What would bean ideal treatment?).  FDA participation allowed immediate feedback.  From this meeting came a voice of the patient report that accompanied our independently developed benefit/risk assessment. These are intended to be valuable information for drug developers and regulators.  Limitations in CNS symptoms are seen as critical gaps in clinical endpoints. The FDA has provided great guidance on how to use the information coming out of these PFDD meetings.

Meeting Updates

Ms. Kristin Stephenson from Muscular Dystrophy Association presented an overview of the MDA’s inaugural combined clinical and scientific meeting. They had over a thousand participants including investigators, clinicians, and representatives from other patient foundations. There was a strong interaction between basic scientists and clinicians. Dr. Janet Woodcock, Director of the Center for Drug Evaluation and Research, FDA presented the keynote address.  

Ms. Molly White gave an overview of two meetings from Myotonic (formerly Myotonic Dystrophy Foundation).  Central Nervous System (CNS) Outcome Measures Development Workshop focused on identifying and assessing biomarkers and endpoints for CNS-targeting therapeutic trials because this area has lagged behind the focus on skeletal muscle.  They had 135 participants from academia, industry and venture firms at this meeting in Philadelphia. The meeting addressed structural changes in the CNS in myotonic dystrophy (DM), manifestations of sleep dysregulation, fatigue, neuropsychological impairment and intellectual disabilities in congenital patients.  These manifestations are variable among patients and increase the complexity of trials.    She also gave an overview of the 2019 Myotonic Annual Conference-Professional Track, which occurs in conjunction with the annual patient conference and included 165 attendees from academia, industry, venture investors and financial analysts. The topics covered in this one-day conference were DM biomarkers and their use in drug approvals, current therapeutic approaches, DM2 state of the science (which lags behind understanding of DM1), lessons learned from previous studies/trials, overview and application strategies for the Department of Defense’s Peer Reviewed Medical Research Program (which includes DM), and DM animal models. In response to questions after her presentation, Ms White described the current state of mouse models for DM phenotypes and remaining gaps.

Mr. Ryan Fischer gave and overview of two meetings from PPMD, The Duchenne Outcomes meeting May 14, 2019 and the Duchenne Platform Study Open Public Meeting September 2019.  The Duchenne outcomes meeting had representatives from all relevant stakeholders including clinicians, patients and representatives, industry partners, federal partners, and also included public and private payers, methodologists and health technology assessors.  The goals of the meeting were to understand what clinical outcome data is being collected, find gaps in collected data, and build prioritization of activities to fill data gaps.  Prior to the meeting there was an analysis of clinicaltrials.gov for outcomes being collected in DMD studies and expert interviews were conducted.  The meeting included videos of the patient voices, and presentations/discussions of landscape analysis and current research on functional outcome measures.  There were voting exercises and breakout sessions to identify gaps and strategies to advance the use of high-quality outcome measures.  In the voting exercise, parents viewed biomarkers (MRI or dystrophin levels) as very important but payers did not. All stakeholder groups viewed patient-reported outcomes as important and needing more attention in data collection.  The Duchenne Platform Study Open Public Meeting brought together stakeholders to discuss the status of the Duchenne field and the potential of a platform-style clinical trial system to advance therapeutic testing. The goal of such a platform trial system would be to make therapy testing more efficient and patient-centric (allowing wider inclusion, minimizing placebo, decrease participation burden) while allowing for the evaluation of multiple interventions individually or in combinations.  This meeting was organized in collaboration with the Critical Path Institute, the Institute for Advanced Clinical Trials for Children and Berry Consultants, and it included multiple stakeholders including the FDA.  Future work on this include infrastructure building, study design and developing operational plans. 

Jennifer Levy, PhD, from Coalition to Cure Calpain 3 (C3) gave a summary of the National Limb Girdle Muscular Dystrophy Conference, held in Chicago, IL Aug. 30- Sept. 1, 2019.  This meeting was a project of the Speak Foundation and included over 400 attendees from 16 countries. Dr Levy gave an overview of limb-girdle muscular dystrophies (LGMD), which manifest in proximal limb muscles and include over 30 subtypes categorized by disease gene and inheritance.  This was the first meeting to include all the subtypes of LGMD, and the goals were to share information, encourage engagement of the patient community in research and advocacy, unite patients, families, researchers and clinicians, and encourage industry involvement.  The meeting sessions provided an overview of LGMD, helped patients understand the process of drug development, their involvement in trial readiness, current trials and emerging treatments, and allowed the participants to ask questions of experts in this field.  Ms. Pat Furlong from PPMD gave the keynote address, describing lessons learned from progress in the Duchenne field.  This meeting also included breakout session on topics such as genetics and diagnosis, living with LGMD at different ages, cardiac and respiratory complications and participating in clinical trials.  Two clinical studies collected data and samples from patients at the meeting.  This meeting had a powerful impact on patients where they learned about their conditions and met other people like themselves.  Plans are underway to have another meeting in 2021.

Dr. Koroshetz thanked the members and participants.  The next MDCC meeting will be a web-assisted meeting June 8, 2020.

We certify that, to the best of our knowledge, the foregoing minutes are accurate and complete.

Glen Nuckolls, PhD,

Designated Federal Official, Muscular Dystrophy Coordinating Committee

Program Director, Division of Neuroscience, National Institute of Neurological Disorders and Stroke

Walter Koroshetz, MD,

Chair Muscular Dystrophy Coordinating Committee

Director, National Institute of Neurological Disorders and Stroke