207070 tiotropium bromide spiriva_clinical_prea

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  • CLINICAL REVIEW

    Application Type Application Number(s)

    Priority or Standard

    Submit Date(s) Received Date(s)

    PDUFA Goal Date Division / Office

    Reviewer Name(s) Review Completion Date

    Established Name (Proposed) Trade Name

    Therapeutic Class

    Applicant

    Formulation(s)Dosing Regimen

    Indication(s)Intended Population(s)

    Template Version: March 6, 2009

    Reference ID: 3761634

    NDA 207-070 Standard

    August 15, 2014 August 15, 2014 September 15, 2014 DPARP / ODE II

    Stacy Chin, MD May 21, 2015

    Tiotropium Respimat Spiriva Respimat long-acting muscarinic antagonist Boeringher Ingelheim

    Inhalation Solution g once daily

    (b) (4)

    Asthma 12 years and older

  • Clinical ReviewStacy Chin, MDNDA 207-070Spiriva Respimat (tiotropium inhalation solution)

    Table of Contents

    1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT ......................................... 8

    1.1 Recommendation on Regulatory Action ............................................................. 81.2 Risk Benefit Assessment.................................................................................... 81.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies ... 91.4 Recommendations for Postmarket Requirements and Commitments ................ 9

    2 INTRODUCTION AND REGULATORY BACKGROUND ........................................ 9

    2.1 Product Information ............................................................................................ 92.2 Tables of Currently Available Treatments for Proposed Indications ................. 102.3 Availability of Proposed Active Ingredient in the United States ........................ 102.4 Important Safety Issues With Consideration to Related Drugs ......................... 112.5 Summary of Presubmission Regulatory Activity Related to Submission .......... 112.6 Other Relevant Background Information .......................................................... 13

    3 ETHICS AND GOOD CLINICAL PRACTICES....................................................... 13

    3.1 Submission Quality and Integrity ...................................................................... 133.2 Compliance with Good Clinical Practices ......................................................... 143.3 Financial Disclosures........................................................................................ 15

    4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW

    DISCIPLINES ......................................................................................................... 16

    4.1 Chemistry Manufacturing and Controls ............................................................ 164.2 Clinical Microbiology......................................................................................... 164.3 Preclinical Pharmacology/Toxicology ............................................................... 164.4 Clinical Pharmacology ...................................................................................... 16

    4.4.1 Mechanism of Action.................................................................................. 164.4.2 Pharmacodynamics.................................................................................... 164.4.3 Pharmacokinetics....................................................................................... 21

    5 SOURCES OF CLINICAL DATA............................................................................ 22

    5.1 Tables of Studies/Clinical Trials ....................................................................... 225.2 Review Strategy ............................................................................................... 255.3 Discussion of Individual Studies/Clinical Trials................................................. 25

    Trials 205.416 and 205.417 ................................................................................... 25Trials 205.418 and 205.419 ................................................................................... 39Trial 205.442 .......................................................................................................... 44Trial 205.444 .......................................................................................................... 48Trial 205.456 .......................................................................................................... 52Trial 205.464 .......................................................................................................... 55

    6 REVIEW OF EFFICACY ......................................................................................... 58

    Efficacy Summary...................................................................................................... 58

    2

    Reference ID: 3761634

  • Clinical ReviewStacy Chin, MDNDA 207-070Spiriva Respimat (tiotropium inhalation solution)

    6.1 Indication .......................................................................................................... 616.1.1 Methods ..................................................................................................... 616.1.2 Demographics............................................................................................ 646.1.3 Subject Disposition .................................................................................... 716.1.4 Analysis of Co-Primary Endpoints: Peak and Trough FEV1 ....................... 746.1.5 Analysis of Secondary Endpoints: Asthma Exacerbations......................... 796.1.6 Other Secondary Endpoints ....................................................................... 846.1.7 Subpopulations .......................................................................................... 876.1.8 Analysis of Clinical Information Relevant to Dosing Recommendations .... 876.1.9 Discussion of Persistence of Efficacy and/or Tolerance Effects................. 886.1.10 Additional Efficacy Issues/Analyses........................................................... 89

    7 REVIEW OF SAFETY............................................................................................. 89

    Safety Summary ........................................................................................................ 897.1 Methods............................................................................................................ 89

    7.1.1 Studies/Clinical Trials Used to Evaluate Safety ......................................... 897.1.2 Categorization of Adverse Events.............................................................. 907.1.3 Pooling of Data Across Studies/Clinical Trials to Estimate and Compare

    Incidence.................................................................................................... 917.2 Adequacy of Safety Assessments .................................................................... 91

    7.2.1 Overall Exposure at Appropriate Doses/Durations and Demographics of

    Target Populations..................................................................................... 91

    7.2.2 Explorations for Dose Response................................................................ 937.2.3 Special Animal and/or In Vitro Testing ....................................................... 947.2.4 Routine Clinical Testing ............................................................................. 947.2.5 Metabolic, Clearance, and Interaction Workup .......................................... 947.2.6 Evaluation for Potential Adverse Events for Similar Drugs in Drug Class .. 94

    7.3 Major Safety Results ........................................................................................ 947.3.1 Deaths........................................................................................................ 947.3.2 Nonfatal Serious Adverse Events .............................................................. 957.3.3 Dropouts and/or Discontinuations .............................................................. 987.3.4 Significant Adverse Events ...................................................................... 1017.3.5 Submission Specific Primary Safety Concerns ........................................ 104

    7.4 Supportive Safety Results .............................................................................. 1067.4.1 Common Adverse Events ........................................................................ 1067.4.2 Laboratory Findings ................................................................................. 1077.4.3 Vital Signs ................................................................................................ 1077.4.4 Electrocardiograms (ECGs) ..................................................................... 1077.4.5 Special Safety Studies/Clinical Trials ....................................................... 1077.4.6 Immunogenicity........................................................................................ 108

    7.5 Other Safety Explorations............................................................................... 1087.5.1 Dose Dependency for Adverse Events .................................................... 1087.5.2 Time Dependency for Adverse Events..................................................... 1087.5.3 Drug-Demographic Interactions ............................................................... 108

    3

    Reference ID: 3761634

  • Clinical ReviewStacy Chin, MDNDA 207-070Spiriva Respimat (tiotropium inhalation solution)

    7.5.4 Drug-Disease Interactions........................................................................ 1097.5.5 Drug-Drug Interactions............................................................................. 109

    7.6 Additi

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