PDF《STN 125347.231》

Clinical Reviewer: [Clinical Reviewer] STN: [STN] i Application Type Efficacy Supplement STN 125347.

231 CBER Received Date

16 March

2015 PDUFA Goal Date

14 January

2016 Division / Office DVRPA/OVRR Priority Review No Reviewer Name(s) Ralph LeBlanc,M.D., Ph.D. Review Completion Date / Stamped Date Supervisory Concurrence Jeff Roberts ,M.D., Branch Chief CRB1 Lucia Lee, M.D. , Team Leader, CRB1 Applicant Glaxo Smith Kline Biologicals Established Name Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate) (Proposed) Trade Name HIBERIX Pharmacologic Class vaccine Formulation(s), including Adjuvants, etc Solution for injection supplied as a vial of lyophilized vaccine to be reconstituted with the accompanying vial of saline diluent. A single dose, after reconstitution, is 0.5 ml and contains

10 mcg of purified capsular polysaccharide conjugated to approximately

25 mcg of tetanus toxoid. Dosage Form(s) and Route(s) of Administration Solution for intramuscular injection Dosing Regimen ? Proposed: One dose each at 2, 4, and

6 months of age. The first dose may be given as early as

6 weeks of age. ? Current: One booster dose at

15 months through

4 years of age (prior to fifth birthday). Indication(s) and Intended Population(s) Active immunization for the prevention of invasive disease caused by Haemophilus influenzae type b Orphan Designated (Yes/No) No Clinical Reviewer: [Clinical Reviewer] STN: [STN] ii TABLE OF CONTENTS GLOSSARY

1 1. EXECUTIVE SUMMARY

2 2. CLINICAL AND REGULATORY BACKGROUND.5 2.1 Disease or Health-Related Condition(s) Studied

5 2.3 Safety and Efficacy of Pharmacologically Related Products.6 2.4 Previous Human Experience with the Product (Including Foreign Experience)6 2.5 Summary of Pre- and Post-submission Regulatory Activity Related to the Submission

6 2.6 Other Relevant Background Information

7 3. SUBMISSION QUALITY AND GOOD CLINICAL PRACTICES.7 3.1 Submission Quality and Completeness

7 3.2 Compliance With Good Clinical Practices And Submission Integrity.7 3.3 Financial Disclosures

7 4. SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW DISCIPLINES.8 4.1 Chemistry, Manufacturing, and Controls

8 4.2 Assay Validation

8 4.3 Nonclinical Pharmacology/Toxicology.8 4.4 Clinical Pharmacology

8 4.4.1 Mechanism of Action

9 4.4.2 Human Pharmacodynamics (PD)9 4.4.3 Human Pharmacokinetics (PK)9 4.5 Statistical

9 4.6 Pharmacovigilance

9 5. SOURCES OF CLINICAL DATA AND OTHER INFORMATION CONSIDERED IN THE REVIEW ....10 5.1 Review Strategy

10 5.2 BLA/IND Documents That Serve as the Basis for the Clinical Review.10 5.3 Table of Studies/Clinical Trials.10 Source: adapted from sBLA 125347.231, CSR HIB-097, table 27, p.196

11 5.4 Consultations

11 5.4.1 Advisory Committee Meeting (if applicable)11 5.4.2 External Consults/Collaborations

11 5.5 Literature Reviewed (if applicable)11 6. DISCUSSION OF INDIVIDUAL STUDIES/CLINICAL TRIALS

11 6.1 Trial #1.11 6.1.1 Objectives (Primary, Secondary, etc)11 6.1.2 Design Overview

13 6.1.3 Population.13 6.1.4 Study Treatments or Agents Mandated by the Protocol

15 6.1.5 Directions for Use.18 6.1.6 Sites and Centers.18 6.1.7 Surveillance/Monitoring

18 6.1.8 Endpoints and Criteria for Study Success.21 6.1.9 Statistical Considerations &

Statistical Analysis Plan

22 6.1.10 Study Population and Disposition.22 6.1.11 Efficacy Analyses

27 6.1.12 Safety Analyses.40 6.1.13 Study Summary and Conclusions

44 9.1.1 Human Reproduction and Pregnancy Data.44 Clinical Reviewer: [Clinical Reviewer] STN: [STN] iii 9.1.2 Use During Lactation.45 9.1.3 Pediatric Use and PREA Considerations

45 9.1.4 Immunocompromised Patients.45 10. CONCLUSIONS

45 11. RISK-BENEFIT CONSIDERATIONS AND RECOMMENDATIONS.45 11.1 Risk-Benefit Considerations.45 11.2 Risk-Benefit Summary and Assessment.48 11.3 Discussion of Regulatory Options.48 11.4 Recommendations on Regulatory Actions

48 11.5 Labeling Review and Recommendations

48 11.6 Recommendations on Postmarketing Actions

49 Clinical Reviewer: [Clinical Reviewer] STN: [STN]

1 GLOSSARY AE adverse event BLA biologics license application CFR Code of Federal Regulations CMC chemistry, manufacturing, and controls CSR complete study report DIS Division of Inspections and Surveillance eCTD electronic Common Technical Document ENERGIX-B? Hepatitis B vaccine, recombinant [GSK] ES Executive Summary FDAAA Food and Drug Administration Amendments Act of

2007 GSK GlaxoSmithKline Biologicals, Inc. HIB Haemophilus influenza type b HIBERIX? Haemophilus influenza type b conjugated to tetanus toxoid [GSK] ISE integrated summary of efficacy ITT Intent-to-treat MedDRA Medical Dictionary for Regulatory Activities OBE Office of Biostatistics and Epidemiology OCOD Office of Communication Outreach and Development (CBER) OSE Office of Surveillance and Epidemiology PD pharmacodynamics PEDIARIX? DTPa-IPV-HepB [GSK] PENTACEL? DTPa-IPV-HIB [SP] PeRC Pediatric Review Committee (CDER) PI package insert PK pharmacokinetics PMC post marketing commitment PMR post marketing requirement PREA Pediatric Research Equity Act PREVNAR13? Pneumococcal 13-valent Conjugate Vaccine [Diphtheria CRM197 Protein] [Wyeth Pharmaceuticals Inc.] PRP polyribosyl-ribitol-phosphate PRP-T polyribosyl-ribitol-phosphate-tetanus conjugate PRP-OMP polyribosyl-ribitol-phosphate-outer membrane protein conjugate PVP pharmacovigilance plan REMS risk evaluation and mitigation strategy ROTARIX? Rotavirus vaccine, live, oral [GSK] RMS/BLA regulatory management system for the biologics license application SAE serious adverse event SP Sanofi Pasteur, Inc. Clinical Reviewer: [Clinical Reviewer] STN: [STN]

2 1. Executive Summary Hiberix is a vaccine that contains capsular polysaccharide from Hemophilus influenzae type b (Hib) conjugated to tetanus toxoid. Hiberix is currently approved as a booster dose at

15 months through

4 years of age for the prevention of invasive Hib disease. The safety and immunogenicity data from a single study, study HIB-097, was submitted in this supplement to the Hiberix Biologics License Application (BLA) to support the use of Hiberix as a primary immunization series in children

6 weeks to

14 months of age. The primary series is administered at 2,

4 and

6 months of age. The first dose may be given as early as

6 weeks of age. Hiberix was approved in August

2009 under the Accelerated Approval (AA) regulations (21 CFR 601.41) to address the shortage of Hib vaccine in the U.S. at the time. Study HIB-097 was designed to generate the safety and immunogenicity data necessary to: (1) verify and describe the clinical benefit of Hiberix in

15 month to

4 year olds to satisfy AA requirements;

and (2) provide data to support the approval of Hiberix as a primary series in children

6 weeks to

14 months of age in accordance with the requirements of the Pediatric Research Equity Act (PREA) (21 U.S.C., 355c). Only the data related to the primary immunization series in infants were reviewed under this supplement. By agreement with CBER, safety and immunogenicity data in children

15 months and older will be submitted as a separate BLA supplement (sBLA). Separate sBLAs were needed since the data required under the AA regulations would not support extension of the indication to children less than

15 months of age, which would be outside the age indication under accelerated approval. Study HIB-097 was a phase 3, randomized, multicenter study. The treatment assignment was blinded in the following manner: double-blind for the immunogenicity and lot consistency evaluation of

3 lots of Hiberix, single blind and controlled for the evaluation of the safety and immunogenicity of Hiberix compared to a US licensed monovalent Hib vaccine, ActHIB (Sanofi Pasteur, Inc.), and open label for comparisons of Hiberix to DTPa-IPV/Hib vaccine (Pentace........