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Multi-Discipline Review CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 210595Orig1s000 MULTI-DISCIPLINE REVIEW Summary Review Office Director Cross Discipline Team Leader Review Clinical Review Non-Clinical Review Statistical Review Clinical Pharmacology Review NDA/BLA Multi‐disciplinary Review and Evaluation {NDA 210595} {Duaklir Pressair, Aclidinium Bromide/Formoterol Fumarate inhalation powder} NDA/BLA Multi‐Disciplinary Review and Evaluation Application Type NDA Application Number(s) 210595 Priority or Standard Standard Submit Date(s) May 31, 2018 Received Date(s) May 31, 2018 PDUFA Goal Date March 31, 2019 Division/Office Division of Pulmonary, Allergy, and Rheumatology Products Review Completion Date March 29, 2019 Established/Proper Name Aclidinium bromide/formoterol fumarate inhalation powder (Proposed) Trade Name Duaklir Pressair Pharmacologic Class Long‐acting muscarinic/Long‐acting B2‐agonist Code name Applicant AstraZenecaPharmaceuticals LP Doseage form Inhalation powder Applicant proposed Dosing One inhalation (400 µg aclidinium bromide/ 12 µg formoterol Regimen fumarate) twice daily Applicant Proposed ‐ (b) (4) maintenance treatment of (b) (4) Indication(s)/Population(s) patients with chronic obstructive pulmonary disease (COPD), (b) (4) Recommendation on Approval Regulatory Action Recommended (b) (4) maintenance treatment of patients with COPD Indication(s)/Population(s) (if applicable) Recommended Dosing One inhalation (400 µg aclidinium bromide/ 12 µg formoterol Regimen fumarate) twice daily 1 Version date: September 12, 2018 Reference ID: 44107284411515 NDA/BLA Multi‐disciplinary Review and Evaluation {NDA 210595} {Duaklir Pressair, Aclidinium Bromide/Formoterol Fumarate inhalation powder} Table of Contents NDA/BLA Multi‐Disciplinary Review and Evaluation ...................................................................... 1 Table of Tables ................................................................................................................................ 5 Table of Figures ............................................................................................................................... 7 Reviewers of Multi‐Disciplinary Review and Evaluation ................................................................ 9 Glossary ......................................................................................................................................... 13 1. Executive Summary ............................................................................................................... 15 1.1. Product Introduction ...................................................................................................... 15 1.2. Conclusions on the Substantial Evidence of Effectiveness ............................................ 15 1.3. Benefit‐Risk Assessment ................................................................................................ 17 1.4. Patient Experience Data ................................................................................................. 20 2. Therapeutic Context .............................................................................................................. 21 2.1. Analysis of Condition ...................................................................................................... 21 2.2. Analysis of Current Treatment Options ......................................................................... 22 3. Regulatory Background ......................................................................................................... 24 3.1. U.S. Regulatory Actions and Marketing History ............................................................. 24 3.2. Summary of Presubmission/Submission Regulatory Activity ........................................ 24 4. Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety ................................................................................................................. 24 4.1. Office of Scientific Investigations (OSI) .......................................................................... 24 4.2. Product Quality .............................................................................................................. 25 4.3. Devices and Companion Diagnostic Issues .................................................................... 26 5. Nonclinical Pharmacology/Toxicology................................................................................... 27 5.1. Executive Summary ........................................................................................................ 27 5.2. Toxicology ....................................................................................................................... 27 6. Clinical Pharmacology ............................................................................................................ 29 6.1. Executive Summary ........................................................................................................ 29 6.2. Summary of Clinical Pharmacology Assessment ............................................................ 30 6.3. Clinical Pharmacology Background ................................................................................ 31 6.3.1. Background ............................................................................................................. 31 6.3.2. What is the relevant regulatory background pertinent to this application? ......... 31 6.3.3. What are the clinical pharmacology studies submitted to support this NDA? ...... 32 6.4. Comprehensive Clinical Pharmacology Review ............................................................. 32 6.4.1. What are the proposed mechanism of action and therapeutic indications? ......... 32 6.4.2. What are the proposed dosages and routes of administration? ........................... 33 6.4.3. What are the design features of the clinical pharmacology and clinical studies used to support dosing or claims? .................................................................................... 33 2 Version date: September 12, 2018 Reference ID: 44107284411515 NDA/BLA Multi‐disciplinary Review and Evaluation {NDA 210595} {Duaklir Pressair, Aclidinium Bromide/Formoterol Fumarate inhalation powder} 6.4.4. What are the characteristics of the dose/exposure‐response relationship for the effectiveness? ................................................................................................................... 35 6.4.5. What are the characteristics of the dose/exposure‐response relationships for safety? ............................................................................................................................... 37 6.4.6. What are the PK parameters of aclidinium and formoterol in healthy subjects? .. 38 6.4.7. What are the PK parameters of aclidinium and formoterol in patients with COPD following multiple administration? .................................................................................. 40 6.4.8. How is the proposed to‐be‐marketed formulation linked to the clinical formulation? ..................................................................................................................... 41 6.5. Bioanalytical section ....................................................................................................... 41 6.5.1. What are the analytical methods used to measure aclidinium in plasma? ........... 41 6.5.2. What are the analytical methods used to measure formoterol in plasma? .......... 42 6.5.3. What are the results for the re‐analysis of the incurred samples? ........................ 43 7. Sources of Clinical Data and Review Strategy ....................................................................... 44 7.1. Table of Clinical Studies .................................................................................................. 44 7.2. Review Strategy .............................................................................................................. 45 8. Statistical and Clinical and Evaluation ................................................................................... 45 8.1. Review of Relevant Individual Trials Used to Support Efficacy ...................................... 45 8.1.1. Trials 30, 31, 01, and 02 .......................................................................................... 45 8.1.2. Study Results ........................................................................................................... 71 8.1.3. Assessment of Efficacy Across Trials ....................................................................... 91 8.1.4. Integrated Assessment of Effectiveness ................................................................. 99 8.2. Review of Safety ........................................................................................................... 100 8.2.1. Safety Review Approach ....................................................................................... 100 8.2.2. Review of the Safety Database ............................................................................. 100 8.2.3. Adequacy of Applicant’s Clinical Safety Assessments .......................................... 102 8.2.4. Safety Results ........................................................................................................ 103 8.2.5. Analysis of Submission‐Specific Safety Issues ....................................................... 118 8.2.6. Clinical Outcome Assessment (COA)
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