Guidance for Industry Drug Development for Amyotrophic Lateral Sclerosis ALS Guidance Participants The following individuals were leading participants in the patient-centered, community-led ALS Guidance initiative. Steering Committee: • Barb Newhouse, Steering Committee Chair; President and CEO, The ALS Association • Lucie Bruijn, Steering Committee Vice Chair; Chief Scientist, The ALS Association • Hiroshi Mitsumoto, Steering Committee Vice Chair; Columbia MDA/ALS Research Center • Rick Bedlack, chair, Public Policy working group; Duke University Medical Center • James Berry, chair, Biomarkers working group; Massachusetts General Hospital • Benjamin Brooks, chair, Benefit/Risk working group; Carolinas Health System • Merit Cudkowicz, co-chair, Clinical Trials and Outcome Measures working group; Massachusetts General Hospital • Valerie Cwik, Muscular Dystrophy Association, EVP and Chief Medical and Scientific Officer • Ted Harada, co-chair, Patient & Caregiver Advisory Committee; Person with ALS, ALS Association National Trustee • Don Johns, Steering Committee Member; Vice President, Head ALS Neuroscience Discovery & Development, Biogen • Catherine Lomen-Hoerth, chair, FTD/ALS working group; UCSF • Nicholas Maragakis, chair, Diagnosis working group; Johns Hopkins Hospital • Tim Miller, chair, Natural History working group; Washington University School of Medicine • Elizabeth Ottinger, Steering Committee Member; NIH/NCATS • Steve Perrin, Steering Committee Member; ALS Therapy Development Institute, Chief Scientific Officer • Jeremy Shefner, co-chair, Clinical Trials and Outcome Measures working group; Barrow Neurological Institute • Stephen Winthrop, co-chair, Patient & Caregiver Advisory Committee; Person with ALS, ALS Association National Trustee, Research Ambassador 1 | Page Benefit/Risk Working Group: • Chair, Ben Brooks, Carolinas Neuromuscular/ALS-MDA Center • William Cho, Genentech • Stephen Finan, Person with ALS • Stephen Finger, HopeNow4ALS, Person with ALS • Eric Gascho, National Health Council • Kimberly L Goslin, Providence ALS Center • Stephen Aaron Goutman, University of Michigan Health System • Laurie Gutmann, University of Iowa Carver College of Medicine • Christopher Lee, Vanderbilt University Medical Center • Joseph Lewcock, Genentech • Björn Erik Oskarsson, University of California, Davis School of Medicine • Stephen N Scelsa, Icahn School of Medicine at Mount Sinai • Katalin Scherer, University of Arizona School of Medicine & Banner University Medical Center • Ericka P Simpson, Houston Methodist Neurological Institute & Weill Cornell Medical College • Andrew Wolff, Cytokinetics, Chief Medical Officer Natural History Working Group: • Chair, Tim Miller, Washington University School of Medicine • Mary Kay Floeter, NINDS, Chief NINDS EMG Section, Deputy Clinical Director • Matt Harms, Columbia University • Eric Macklin, Massachusetts General Hospital • Bernard Ravina, Voyager Therapeutics, VP Clinical Development • John Ravits, UC San Diego • Stacy Rudnicki, University of Arkansas • Steven Ziegler, Person with ALS Diagnosis Working Group: • Chair, Nick Maragakis, Johns Hopkins University, Professor, Dept. of Neurology • Nazem Atassi, Massachusetts General Hospital MDA ALS Clinic • Kevin Boylan, Mayo Clinic - Jacksonville • David Ennist, Origent Data Sciences, Chief Science Officer • Amanda Haidet-Phillips, MDA, Chief Science Officer • Carlayne Jackson, UT San Antonio • Sabrina Paganoni, Spaulding Rehabilitation Hospital and Massachusetts General Hospital • Karen Shideleff, Person with ALS • Bryan Traynor, NINDS, Chief, Neuromuscular Disease Research Section 2 | Page Biomarkers Working Group: • Chair, James Berry, Massachusetts General Hospital • Michael Benatar, University of Miami • Gil Block, Neuraltus Pharmaceuticals, Chief Medical Officer • Bob Bowser, Dignity Health • Terry Heiman-Patterson, Drexel University and ALS Hope Foundation • Andreas Jeromin, Iron Horse Diagnostics • Melanie Leitner, Biogen Idec, Associate Director, Clinical Research • Terry Ann McNearney, Eli Lilly & Co, Senior Medical Advisor • Lyle Ostrow, Johns Hopkins School of Medicine • Erik Pioro, Cleveland Clinic • Wes Rose, Person with ALS • Seward Rutkove, Beth Israel Deaconess Medical Center Clinical Trials & Outcome Measures Working Group: • Co-Chair, Merit Cudkowicz, Massachusetts General Hospital MDA ALS Clinic • Co-Chair, Jeremy Shefner, Barrow Neurological Institute • Jinsy Andrews, Cytokinetics, Director, Clinical Research and Development • Frank Bennett, ISIS Pharmaceuticals, SVP Research • Chris Coffey, University of Iowa • Robin Conwit, NINDS, Medical Director, Office of Clinical Research • David Ennist, Origent Data Sciences, Chief Science Officer • Toby Ferguson, Biogen Idec, Medical Director, ALS iHub • Madeline Kennedy, Person with ALS and Research Ambassador • Steve Kolb, Family Member and Research Ambassador • Michael McDermott, University of Rochester Medical Center • David Schoenfeld, Harvard School of Medicine and Professor in the Department of Biostatistics, Harvard School of Public Health Public Policy Working Group: • Chair, Rick Bedlack, Duke University Medical Center • Tricia De Santis, Biogen Idec, VP Regulatory Policy • Steve Gibson, The ALS Association, Chief Mission Strategy and Public Policy Office • Michael Gollin, Person with ALS • Ghazala Hayat, St. Louis University • Ed Kasarskis, University of Kentucky • Jon Katz, Forbes-Norris • Kim McCleary, FasterCures, Managing Director • Paul Mehta, CDC, Agency for Toxic Substances and Disease Registry • Jess Rabourn, ALS Emergency Treatment Fund, Managing Director • Kristin Stephenson, MDA, VP Policy and Advocacy 3 | Page • Pat Wildman, The ALS Association, VP Public Policy • Stephen Winthrop, Person with ALS, Research Ambassador and ALS Association National Trustee FTD and ALS Working Group (material was developed on FTD in ALS and then incorporated into other guidance sections as appropriate) • Chair, Catherine Lomen-Hoerth, UCSF • Sharon Abrahams, University of Edinburgh • Lora Clawson, Johns Hopkins • Laura Goldstein, Kings College • Murray Grossman, University of Pennsylvania • Jennifer Murphy, UCSF • Steve Reznick, Person with ALS and Research Ambassador • Susan Woolley, Forbes Norris ALS Patient & Caregiver Advisory Committee: • Co-Chair, Ted Harada, Person with ALS, ALS Association National Trustee • Co-Chair, Stephen Winthrop, Person with ALS, ALS Association National Trustee, Research Ambassador • Clay Ahrens, Person with ALS • Pat Bradley, Person with ALS • Steve Byer, ALS Worldwide, Co-Executive Director and family member • Mike Cherepov, Person with ALS • Clare Durrett, Team Gleason, Board Member • Stephen Finan, Person with ALS • Stephen Finger, HopeNow4ALS, Person with ALS • Deb Gaudet, Person with ALS • Michael Gollin, Person with ALS • Bob Hebron, HopeNow4ALS, family member • Shelly Hoover, Person with ALS • Madeline Kennedy, Person with ALS • Robert Kleiner, Project ALS • Steve Kolb, Family Member, Research Ambassador • Christopher Leidigh, Person with ALS • Jehad Majed, Family Member, HopeNow4ALS • Bob Murray, Family Member and Research Ambassador • Jess Rabourn, ALS Emergency Treatment Fund • Steve Reznick, Person with ALS, Research Ambassador • Shay Rishoni, Prize4Life, CEO and Person with ALS • Wes Rose, Person with ALS • Craig Sanderson, Kevin Turner Foundation • Karen Shideleff, Person with ALS • Kathy Thomas, Family Member and Research Ambassador 4 | Page • Joe Wise, Person with ALS • Evan Yegelwel, Person with ALS • Steven Ziegler, Person with ALS Technical Support: • Lisa Bain, Science & Medical Writer • Allison Durham, FaegreBD Consulting • Tim Franson, Chief Medical Officer, YourEncore • Steve Gibson, The ALS Association • Pat Wildman, The ALS Association • Dave Zook, FaegreBD Consulting 5 | Page ALS Guidance Outline I. INTRODUCTION II. BACKGROUND III. BENEFIT RISK A. General Comments B. Evidence of patient and caregiver preferences C. Implications of patient risk/benefit preferences in ALS. 1. Alternative endpoints. Proposed Guidance 2. Placebo Control Arm. Proposed Guidance 3. Threshold for statistical significance. Proposed Guidance 4. Method of delivery. Proposed Guidance 5. Role of expanded access and accelerated approval. Proposed Guidance 6. Patient protection and need for informed decisions in consultation with physician. IV. THE CURRENT UNDERSTANDING OF THE NATURAL HISTORY OF ALS A. General Comments B. Testing and evaluation across the course of the disease 1. ALS functional rating scales 2. Upper motor neuron involvement a. Quantification of clinical signs b. Direct assessments of UMN dysfunction and degeneration 3. Cognitive dysfunction a. Scope of cognitive dysfunction in ALS b. Influence of Cognitive Dysfunction on the Natural History of ALS c. Role of genetic mutations d. Detection and tracking of cognitive dysfunction in ALS e. Clinical characteristics of Frontotemporal Dementia and ALS 4. Muscle Strength a. Rationale for use b. Current practice 5. Respiratory Assessment a. Current practice 6 | Page b. Comparison of SVC, FVC, and supine FVC c. Assessing inspiratory function d. Evaluation of current assessments 6. Bulbar function tests a. Current Practice b. Future Assessments Needed 7. Following Nutritional Status a. Standard Measures b. Total Daily Energy Expenditure 8. Quality of Life and Survival Measures a. Rationale for Quality of Life Assessments b. Current practice 9. Electrophysiological Measures a. Rationale for electrophysiological measures b. Current practice 10. Laboratory measures 11. Biomarkers C.