Drug Development for Amyotrophic Lateral Sclerosis Guidance for Industry August 2017 Contents I. INTRODUCTION ................................................................................................................ 1 II. BACKGROUND ................................................................................................................... 2 III. BENEFIT RISK...................................................................................................................... 5 A. General comments .................................................................................................................. 5 B. Evidence of patient and caregiver preferences ....................................................................... 5 C. Implications of patient risk/benefit preferences in ALS ......................................................... 7 1. Alternative endpoints........................................................................................................... 7 2. Placebo control arm ............................................................................................................. 8 3. Threshold for statistical significance ................................................................................... 9 4. Method of delivery ............................................................................................................ 10 5. Role of expanded access and accelerated approval ........................................................... 11 6. Patient protection and need for informed decisions in consultation with physician ......... 11 IV. THE CURRENT UNDERSTANDING OF THE NATURAL HISTORY OF ALS ....... 13 A. General comments ................................................................................................................ 13 B. Testing and evaluation across the course of the disease ....................................................... 14 1. ALS functional rating scales ............................................................................................. 14 2. Upper motor neuron involvement ..................................................................................... 15 3. Cognitive dysfunction ....................................................................................................... 16 4. Muscle strength ................................................................................................................. 17 5. Respiratory assessment ...................................................................................................... 18 6. Bulbar function tests .......................................................................................................... 19 7. Following nutritional status ............................................................................................... 19 8. Quality of life and survival measures ................................................................................ 20 9. Electrophysiological measures .......................................................................................... 20 10. Laboratory measures ....................................................................................................... 21 11. Biomarkers ...................................................................................................................... 21 C. Phenotypes, phenotype heterogeneity, and disease progression .......................................... 21 1. Clinical phenotypes ........................................................................................................... 21 2. Staging ............................................................................................................................... 25 D. Genetic predictors of disease ................................................................................................ 26 i E. Effect of standard interventions on the natural history of ALS ............................................ 27 1. Nutrition management ....................................................................................................... 27 2. Physical and occupational therapy ................................................................................... 29 3. Respiratory management ................................................................................................... 30 4. Psychological support and end-of-life care ....................................................................... 32 V. DIAGNOSIS ........................................................................................................................... 34 A. General comments ................................................................................................................ 34 1. Who makes a diagnosis of ALS?....................................................................................... 34 2. Neurological history and examination ............................................................................... 34 B. Barriers to early diagnosis .................................................................................................... 34 1. Impact of diagnostic milestones on delayed diagnosis...................................................... 35 2. Financial barriers to diagnosis ........................................................................................... 35 3. Heterogeneity of ALS disease presentation and progression ............................................ 36 4. Frontotemporal dementia in ALS ..................................................................................... 36 C. Diagnostic criteria ................................................................................................................. 38 1. The El Escorial criteria-revised ......................................................................................... 38 2. Awaji diagnostic algorithm ............................................................................................... 39 D. Diagnostic laboratory investigations/Methods for confirming diagnosis ............................ 39 1. Blood and urine tests ......................................................................................................... 39 2. CSF studies ........................................................................................................................ 40 3. Electrophysiological studies .............................................................................................. 41 4. Imaging studies .................................................................................................................. 41 5. Nerve/muscle biopsy ......................................................................................................... 42 6. Genetic analyses ................................................................................................................ 42 VI. BIOMARKERS .................................................................................................................... 44 A. General comments ................................................................................................................ 44 B. Current state of biomarkers in ALS (369) ............................................................................ 46 1. Identifying and using biomarkers ...................................................................................... 46 2. Current promising biomarkers (limitations/strategic) ....................................................... 47 C. Use of Biomarkers in Trials ................................................................................................. 49 1. Context and illustrations of biomarker incorporation in ALS trials .................................. 49 ii 2. Defining biomarker utility for a trial; Context of use as a framework for maximizing biomarker benefit in ALS trials .................................................................... 49 D. Summary and Proposed Guidances ...................................................................................... 52 VII. CLINICAL TRIALS AND OUTCOME MEASURES .................................................... 54 A. General comments ................................................................................................................ 54 B. Clinical Trials ....................................................................................................................... 54 1. Inclusion/exclusion criteria ............................................................................................... 54 2. Feasibility issues ................................................................................................................ 58 3. Trial design ........................................................................................................................ 59 C. Outcome measures and endpoints ........................................................................................ 67 1. Outcomes sufficient to support approval ........................................................................... 67 2. Outcomes that would support approval secondarily ......................................................... 74 3. Outcomes that assay potential disease pathways ............................................................... 79 4. Time-to-failure endpoints .................................................................................................. 80 5. Safety outcomes................................................................................................................