June 8, 2020

The Muscular Dystrophy Coordinating Committee (MDCC) met on June 8, 2020 via videoconference. As Chair of the Committee, Diana Bianchi, M.D., Director of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD/NIH), 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). 

Introduction and General Information

Dr. Nuckolls discussed the procedures for avoiding conflict of interest and other FACA committee policies.  He acknowledged NIH staff that helped organize the meeting and announced that the next MDCC meeting will be December 16, 2020 from 1-4 pm EST, which will be held virtually.

Chair Presentation

Dr. Bianchi discussed the NIH budget, COVID-19, and highlighted a few advances in muscular dystrophy research. She indicated that congress has provided stimulus funds for COVID-19 to NIH through H.R. 748 (CARES Act). The funding amount is $945.4 million.  Dr. Bianchi discussed two major efforts by NIH to address COVID-19, which are both large trans-NIH private / public partnerships: ACTIV (https://jamanetwork.com/journals/jama/fullarticle/2766371) and RADx. Dr. Bianchi stated that a concern to this committee and NICHD are manifestations of COVID-19 in children. Although many children only have mild respiratory symptoms from COVID-19, a small subset developed multisystem inflammatory syndrome in children (MIS-C), which occurred 3-4 weeks after the initial mild symptoms. A multi-institute (NICHD, NHLBI, and NIAID), CDC, and the Office of the Assistant Secretary for Health (OASH) partnership is underway to identify who is most at risk for MIS-C, best treatments, and long-term effects.

Dr. Bianchi discussed recent highlights from muscular dystrophy research.

1. Identification of utrophin up-regulators for Duchenne muscular dystrophy (DMD) therapy (supported by NINDS): https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005813/. Trichostatin A (TSA) and the other small molecules identified represent starting points for DMD drug discovery efforts.
2. Dual AAV delivery system using self-complementary AAV was used to enhance CRISPR-Cas9 genome editing in a mouse model of DMD to restore dystrophin expression and could represent a key tool in possible translation to DMD therapies (supported by NIAMS, NHLBI, and NICHD): https://advances.sciencemag.org/content/6/8/eaay6812.
3. New mouse models for facioscapulohumeral muscular dystrophy (FSHD) (supported by NIAMS): https://www.jci.org/articles/view/133303 and https://skeletalmusclejournal.biomedcentral.com/articles/10.1186/s13395-020-00227-4
4. Gene editing to identify therapeutic targets for FSHD (supported by NICHD and NIAMS): https://stm.sciencemag.org/content/12/536/eaay0271.full
5. Mutations identified for new phenotype of early onset muscular dystrophy (NINDS intramural research): https://onlinelibrary.wiley.com/doi/full/10.1002/ana.25772. Whole exome sequencing identified variants in GGPS1.

Meeting Reports

Ryan Fischer from Parent Project Muscular Dystrophy (PPMD) updated the group on PPMD Advocacy Conference Forum: The Duchenne Community & Federal Research Agencies: Yesterday, Today, & Tomorrow held March 9, 2020. Stephen C. Groft, Pharm. D., Senior Adviser to Director, NCATS, NIH received the first Stephen I. Katz Change It Champion Award and gave the first presentation of the meeting. Dr. Groft reflected on 20 years of progress since the first NIH workshop on Duchenne in 2000 and the areas of need moving forward. He also discussed the Duchenne drug development pipeline (there are currently over 30 clinical trials) and the establishment of the NCATS Toolkit for Patient-Focused Therapy Development (https://rarediseases.info.nih.gov/toolkit). Speakers from the NIH (Dr. Glen Nuckolls, NINDS; Dr. Thomas Cheever, NIAMS; Dr. Melissa Parisi, NICHD; and Dr. James Kiley, NHLBI) and from DOD (Marielena McGuire, Ph.D., CDMRP, DOD) highlighted current research, including Wellstone Centers, MRI quantification biomarkers, newborn screening advancements, and gene-editing and gene therapy advancements. To close the meeting a panel of speakers discussed what is needed in the future, which included building on advancements made in the last 20 years, continuing collaborations, further advancement of all therapeutic strategies (inflammation / fibrosis / underlying causes), advancing gene therapy and gene editing, improving knowledge of disease progression, diagnosing and treating early (newborn screening), and developing combination therapies.

Debra Miller, CEO and founder of Cure Duchenne, updated the group on the Cure Duchenne 2019 FUTURES National Conference and launch of Cure Duchenne Biobank. Cure Duchenne has several programs including Cure Duchenne Ventures, a research and investment arm; Duchenne Xchange, a free collaborative online platform for patients, families, and advocacy organizations to connect and share knowledge; and Cure Duchenne Cares, a national series of workshops for families and healthcare professionals that provides specialized training. The Cure Duchenne FUTURES 2019 Conference was held October 11-13, with 585 attendees and 43 speakers. The conference conducted focus groups with patients and caregivers to collect insight on clinical trial design and gene therapy education tools. The meeting was designed to hold comprehensive panels covering the multi-faceted aspects of Duchenne, including standards of care, genetic counseling, mental health, daily support, communication and relationship building, and gene therapy. The Cure Duchenne Biobank (https://www.cureduchenne.org/biobank/) was launched at FUTURES 2019 to provide a collection of biological materials (blood and skin samples) and data from Duchenne patients and immediate relatives that is accessible to all qualified Duchenne researchers. The Biobank partners include the University of California, Irvine and RUCDR Infinite Biologics (host of the biobank).

FDA Request for Information and Comments on Rare Disease Clinical Trials Network

Michelle Campbell, Ph.D., Office of Neuroscience, Center for Drug Evaluation and Research (CDER), U.S. Food and Drug Administration (FDA) spoke about the Rare Disease Cures Accelerator. In 2019 Congress appropriated funds to the FDA for investment and innovation for rare diseases. The Rare Disease Cures Accelerator has three key components: 1. Centralize standardized infrastructure to support and accelerate rare disease characterization. 2. Standard core set of COAs measuring impacts that matter most to patients, ideally applicable to more than one rare disease. 3. Global rare disease clinical trials network. The Rare Disease Cures Accelerator-Data and Analytics Platform (RDCA-DAP) was designed to be a neutral, independent data collaboration and analytics hub to promote data sharing across rare diseases to understand disease progression and optimize clinal trial design. RDAC-DAP has funded the Critical Path Institute (Tucson, AZ) to host the C-Path Online Data Repository as part of the RDCA-DAP Data Collaboration Center. Dr. Campbell also discussed the recently announced RFI on Rare Disease Clinical Trial Network. The FDA is interested in understanding what work is currently being done and what needs to be done to develop clinical trial infrastructure. The FDA is requesting input on practical steps and successful approaches to startup, implement, and sustain global clinical trials networks. The comments for the RFI are due by 11:59 pm EST on July 31, 2020.

Special COVID-19 Survey of Rare Disease Patients

Tiina K. Urv, Ph.D., Office of Rare Diseases Research, National Center for Advancing Translational Sciences (NCATS/NIH) spoke about an online survey to understand the impacts of COVID-19 on the rare disease community conducted by the NIH-funded Rare Diseases Clinical Research Network. The Rare Disease Clinical Research Network is comprised of 20 consortia, a Data Management and Coordinating Center, 140 Patient Advocacy Groups, and 10 NIH Institutes/Centers (https://ncats.nih.gov/rdcrn). The survey has collected 2,301 completed responses so far, with ~400 different disorders represented, and has a target of 5,000 completed surveys. Six individuals with muscular dystrophy have participated in the survey. To take the survey follow the link: https://www.rarediseasesnetwork.org/COVIDsurvey.

Gaps and Opportunities in Patient-Reported Outcome (PRO) Measures

Michelle Campbell, Ph.D., CDER/FDA, spoke about FDA guidance on the use of patient-reported outcomes (PROs) in the regulatory setting. She stated that patients with chronic serious disease are experts on what it’s like to live with their condition and their “chief complaints” should be factored into drug development plans. FDA next steps include conducting workshops and developing a series of guidance documents on, 1. Collecting comprehensive patient community input on burden of disease and current therapy. 2. Development of holistic set of impacts most important to patients. 3. Identifying and developing good measures for the identified set of impacts that can then be used in clinical trials. 4. Incorporating measures into endpoints considered significantly robust for regulatory decision making. Dr. Campbell stated that a clinical benefit is defined as a positive clinically meaningful effect of an intervention and clinical benefit is described in labeling in terms of the outcome of interest measured. There are 4 types of Clinical Outcome Assessments: patient reported outcomes (PROs), clinician-reported outcomes (ClinROs), observer reported outcomes (ObsROs), and performance outcomes (PerfOs). A PRO is a measurement based on a report that comes directly from the patient about the status of a patient’s health condition without amendment or interpretation of the patient’s response by a clinician or anyone else (e.g. pain intensity, health-related quality of life). Dr. Campbell also discussed the concept “fit-for-purpose” for medical product development tools, what makes a clinical outcome assessment (COA) “fit-for-purpose” for medical product development, and the importance of fit-for-purpose COAs. Fit-for-purpose is important because use of inadequately developed or tested instruments introduces risks and a lack of a thoughtful approach to measurement may lead to lack of a patient-centered instrument, content validity problems, and/or poor ability to detect change. The current “Guidance for Industry Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims” can be found at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM205269.pdf. Dr. Campbell discussed “Good Measurement Principles”, which include: Is the instrument appropriate for use in the study population? Does the instrument measure what is important to the patient? If there are multiple concepts/domains being measured, do they overlap? Is the instrument reliable? Does the instrument measure what it is supposed to measure? Is the instrument sensitive to detect change over time? Did a subset of questions drive the result?  What does a score improvement of X-points mean? To close her talk, Dr. Campbell discussed what interpretation of clinically meaningful change meant. Statistical significance alone is not sufficient, and changes have to reflect a positive clinically meaningful effect of an intervention (how an individual feels, functions, or survives).

Amanda Becker, a Duchenne parent and Parent Project Muscular Dystrophy Connect Coordinator, spoke about the Pediatric Outcomes Data Collection Instrument (PODCI) from the study participant perspective. Mrs. Becker has a 15-year-old son with Duchenne and described that much progress has been made in the field since her son’s diagnosis at age 1. Mrs. Becker is a volunteer for PPMD and other organizations for muscular dystrophy. She shared her experience with early clinical trials and her experience with PODCI. PODCI is the instrument most often used for ambulatory patients for Duchenne trials and clinical visits and is caregiver reported. She commented that the focus on ambulation is too narrow and tools are needed to cover non-ambulatory populations and all patients should be included: young, old, anyone fighting Duchenne, regardless of their severity or stage. Mrs. Becker commented that some questions made sense but were still difficult to interpret within the context of Duchenne. Although the questions seem basic, for Duchenne parents they are difficult because their child has difficulty doing these tasks (e.g. “Running short distances?”, “Bicycle or tricycle?”). The question, “During the last week, has it been easy or hard for your child to climb three flights of stairs?” is a difficult question because it would be unsafe to allow a Duchenne child to do this. Another question, “During the last week, has it been easy or hard for your child to walk three blocks?”, is difficult to interpret because it is not defined what the distance of a block is. She mentioned that other questions felt inappropriate for Duchenne or difficult to answer as an observer (e.g. “During the last week how happy has your child been with: How he/she looks?, His/her body?, What clothes or shoes he/she can wear?”). Mrs. Campbell felt that these questions were more appropriate for a teenager, as children are not particularly concerned with these topics and parents with young children are more concerned with just getting their child dressed. Many of these questions make sense for parents with a typical child but in the context of Duchenne, which is progressive, these questions “felt off the mark.” This tool does not capture muscle weakness, the primary symptom of Duchenne and many other muscular dystrophies. Furthermore, there is no measure of how weak your child is (i.e. my child can walk but too weak to walk on a beach, or too weak to lift a baseball bat, or too weak to pick up toys). Additionally, some questions did not match the expectations for what is hoped to be achieved with treatments. One particular question, “If your child had to spend the rest of his/her life with his/her bone and muscle condition as it is right now, how would you feel about it?” is particularly emotionally taxing because Duchenne is such a severe disease. To conclude, she summarized these thoughts about the PODCI: 1. Many questions didn’t reflect the severity/progression of Duchenne. 2. Lack of questions reflecting quality of movement and quality of life. 3. Lack of keeping track of meaningful challenges such as number of falls, difficulty getting in/out of cars, level of assistance needed. 4. The questionnaire was one of the many things she was filling out during a stressful trial appointment. 5. Emotional minefield. 6. Some questions related to muscle function were relevant. 7. Patient and caregiver input is valuable/relevant – it just needs to be captured appropriately.

Chad Heatwole, M.D., Professor of Neurology, University of Rochester, spoke about “Disease-Specific PROs: Optimizing Tools to Measure How Patients Feel and Function.” Dr. Heatwole discussed the need for disease-specific patient reported outcome measures as they provide a unique window by patients into treatment effectiveness, are more responsive to small clinically relevant therapeutic changes, and that therapies should be shown to have “patient-relevance” during clinical trials. Dr. Heatwole stated that when properly developed they can be used in clinical trials to measure disease burden and relevant therapeutic gains in a population of patients. There are nine characteristics that Dr. Heatwole strives to include in developing all PROs (meaningful to a patient population, adequate response range, valid, reliable, inter-item correlation, limited patient burden, ability to detect change, reasonable recall period, and limited question redundancy). To date Dr. Heatwole’s group has 62 completed and validated disease-specific instruments and 40 in progress. These have been translated and validated into 10 languages. The disease populations of instruments include: DM1, DM2, FSHD, Congenital DM1, DMD, HD, SMA, FA, CMT, ALS, SBMA, PD, CCM, AD, IBM, Lung cancer, Crohn’s disease, and Fibromyalgia. These instruments are being used by a variety of organizations: academic center initiated clinical trials, government (FDA) funded trials, pharmaceutical sponsored trials, foundation investigations (CureSMA), and registries. There are many advantages of using disease-specific instruments over generic or repurposed instruments, including, higher relevance and content validity, increased sensitivity to detect therapeutic change, higher precision, lower burden to patient, ability to emphasize relevant systematic themes while excluding non-relevant issues, scored to prioritize high-impact issues for a specific population, and disease-specific instruments are best suited to measure disease progression or therapeutic gain overtime. Dr. Heatwole discussed the Myotonic Dystrophy Health Index (MDHI) for DMI, which has 7 validation papers. The instrument takes ~12 minutes to complete and has over 100 questions. The instrument is extensively used in clinical trials worldwide and has been translated to English, Japanese, Italian, French, French-Canadian, German, Dutch, and Swedish. The MDHI has the status of supplemental-highly recommended by the NINDS Common Data Elements. MDHI has many subscales to measure: mobility, upper extremity function, ability to do activities, fatigue, pain, gastrointestinal health, vision, communication, hearing, sleep and daytime sleepiness, emotional health, cognition, social satisfaction, social performance, myotonia, respiratory function, swallowing, multifactorial patient-reported burden of disease. To conclude, Dr. Heatwole stated that disease-specific health indices provide a valid mechanism for serially monitoring the multifactorial disease burden of patients with muscular dystrophy and represent both how a patient feels and functions.

Laurence Mignon, Ph.D., Director, Translational Medicine, Ionis Pharmaceuticals, spoke about “Selection and Use of PROs in Industry Sponsored Studies.” In her talk, Dr. Mignon discussed PRO selection for clinical development, myotonic dystrophy as a case study, and the role of PRO post-approval. PROs are only included in a small percentage of FDA-approved orphan drug labels. There are PRO-dependent (e.g. irritable bowel syndrome, asthma, pain) and PRO-independent diseases (e.g. disease that rely on biomarkers or assessment by a clinician, or diseases that are asymptomatic). PRO selection depends on mechanism of action of therapy and should happen early on in development. PRO selection also depends on disease and patient population. The FDA encourages involvement of patients, their caregivers, and advocates in the rare disease drug development process. Patients can engage and provide input in numerous ways including participating in advisory committees to serve as disease-specific patient representative; contributing to patient-focused drug development initiatives; identifying most bothersome symptoms and which to track with PRO; and participating in natural history studies. Myotonic dystrophy type 1 (DM1) includes a broad spectrum of symptoms (muscle dysfunction, GI tract issues, and cognitive impairments) and when developing a disease-modifying therapy is was important to understand from the patient what is the most bothersome symptoms and what improvements will be clinically meaningful. The MDHI was used as the disease-specific PRO.

Closing Remarks

Dr. Bianchi provided a brief summary of the meeting’s discussions and thanked the presenters and committee members for participating in the meeting. 

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

Diana Bianchi, M.D.
Chair Muscular Dystrophy Coordinating Committee
Director, Eunice Kennedy Shriver National Institute of Child Health and Human Development