Individuals using assistive technology may not be able to fully access the information contained in this file. For assistance, please send an e-mail to: [email protected] and include 508 Accommodation and the title of the document in the subject line of your e-mail. Clinical Reviewer: Ann T Schwartz STN: 125563/0 Application Type Original Application STN 125563/0 CBER Received Date August 12, 2014 PDUFA Goal Date August 12, 2015 Complete Response Letter November 01, 2015 Resubmission Action Due Date December 29, 2018 Division / Office DVRPA /OVRR Priority Review No Reviewer Name(s) Ann Schwartz, M.D. Review Completion Date / Stamped Date Supervisory Concurrence R. Douglas Pratt, MD MPH Associate Director for Medical Affairs Concurrence Date / Stamped Date Applicant MCM Vaccine Co. [partnership between Merck Sharp & Dohme Corp. (a subsidiary of Merck and Co., Inc.) and Sanofi Pasteur Inc.] Established Name Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed, Inactivated Poliovirus, Haemophilus b Conjugate [Meningococcal Protein Conjugate] and Hepatitis B [Recombinant] Vaccine (Proposed) Trade Name VAXELIS Pharmacologic Class Vaccine Formulation(s), including Adjuvants Suspension for injection, each 0.5 mL dose contains: PT 20 μg FHA 20 μg FIM 5 μg PRN 3 μg Diphtheria 15 Lf Tetanus 5 Lf Vero-derived IPV-Type 1: 29 D-antigen Units Vero-derived IPV-Type 2: 7 D-antigen Units Vero-derived IPV-Type 3: 26 D-antigen Units HBsAg 10 μg PRP-OMPC 3 μg Aluminum (b) (4) μg Dosing Regimen Single intramuscular dose at 2,4 and 6 months of age Indication(s) and Intended Active immunization against diphtheria, tetanus, Population(s) pertussis, poliomyelitis (caused by poliovirus Types 1, 2, and 3), against invasive disease caused by Haemophilus influenzae type b and infection caused by all known subtypes of hepatitis B virus in children 6 weeks through 4 years of age. Orphan Designated (Yes/No) No Page i Clinical Reviewer: Ann T Schwartz STN: 125563/0 TABLE OF CONTENTS GLOSSARY ...................................................................................................................................... 1 1. EXECUTIVE SUMMARY ................................................................................................................ 3 2. CLINICAL AND REGULATORY BACKGROUND .............................................................................. 6 2.1 Disease to be Prevented and Available Interventions .................................................... 6 2.2 Currently Available, Pharmacologically Unrelated Treatment(s)/Intervention(s) for the Proposed Indication(s) ............................................................................................... 8 2.3 Safety and Efficacy of Pharmacologically Related Products ........................................ 9 2.4 Previous Human Experience with the Product (Including Foreign Experience) ...... 10 2.5 Summary of Pre- and Post-submission Regulatory Activity Related to the Submission ...................................................................................................................... 10 2.6 Other Relevant Background Information .................................................................... 13 3. SUBMISSION QUALITY AND GOOD CLINICAL PRACTICES ......................................................... 14 3.1 Submission Quality and Completeness ......................................................................... 14 3.2 Compliance with Good Clinical Practices and Submission Integrity ........................ 14 3.3 Financial Disclosures ...................................................................................................... 15 4. SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW DISCIPLINES ............... 16 4.1 Chemistry, Manufacturing, and Controls .................................................................... 16 4.2 Assay Validation.............................................................................................................. 16 4.3 Nonclinical Pharmacology/Toxicology .......................................................................... 17 4.4 Clinical Pharmacology .................................................................................................... 17 4.4.1 Mechanism of Action ..................................................................................................... 17 4.5 Statistical .......................................................................................................................... 17 4.6 Pharmacovigilance .......................................................................................................... 17 5. SOURCES OF CLINICAL DATA AND OTHER INFORMATION CONSIDERED IN THE REVIEW ......... 18 5.1 Review Strategy ............................................................................................................... 18 5.2 BLA/IND Documents That Serve as the Basis for the Clinical Review ..................... 18 5.3 Table of Studies/Clinical Trials ..................................................................................... 19 5.4 Consultations ................................................................................................................... 20 5.4.1 Advisory Committee Meeting (if applicable) ................................................................ 20 5.5 References ........................................................................................................................ 20 6. DISCUSSION OF INDIVIDUAL STUDIES/CLINICAL TRIALS .......................................................... 20 6.1 Study V419-005 (PR505): Phase 3 study to evaluate Safety and Immunogenicity ... 21 6.1.1 Objectives ...................................................................................................................... 21 6.1.2 Design Overview ........................................................................................................... 22 6.1.3 Population ...................................................................................................................... 25 6.1.4 Study Treatments or Agents Mandated by the Protocol ................................................ 26 6.1.5 Treatments ..................................................................................................................... 28 6.1.6 Sites and Centers ............................................................................................................ 29 6.1.7 Surveillance/Monitoring ................................................................................................ 29 6.1.8 Endpoints and Criteria for Study Success ...................................................................... 33 6.1.9 Statistical Considerations & Statistical Analysis Plan ................................................... 36 6.1.10 Study Population and Disposition ................................................................................ 39 6.1.11 Immunogenicity Analyses ........................................................................................... 46 6.1.12 Safety Analyses ............................................................................................................ 61 Page ii Clinical Reviewer: Ann T Schwartz STN: 125563/0 6.1.13 Study V419-005 Summary and Conclusions ............................................................... 75 6.2 Study V419-006 (PR506): Phase 3 Lot Consistency Study .......................................... 76 6.2.1 Objectives ...................................................................................................................... 77 6.2.2 Design Overview ........................................................................................................... 77 6.2.3 Population ...................................................................................................................... 79 6.2.4 Study Treatments or Agents Mandated by the Protocol ................................................ 81 6.2.5 Directions for Use .......................................................................................................... 82 6.2.6 Sites and Centers ............................................................................................................ 82 6.2.7 Surveillance/Monitoring ................................................................................................ 82 6.2.8 Endpoints and Criteria for Study Success ...................................................................... 87 6.2.9 Statistical Considerations & Statistical Analysis Plan ................................................... 87 6.2.10 Study Population and Disposition ................................................................................ 92 6.2.11 Primary Immunogenicity Analyses ............................................................................ 108 6.2.12 Safety Analyses .......................................................................................................... 116 6.2.13 Study Summary and Conclusions .............................................................................. 130 6.3 Study V419-003 (PR503): Supportive Phase 2 Trial (Dose/Formulation Finding) . 131 6.3.1 Objectives .................................................................................................................... 132 6.3.2 Design Overview ......................................................................................................... 132 6.3.3 Population ...................................................................................................................