zostavax, inn-shingles (herpes zoster) vaccine (live) zostavax is indicated for prevention of herpes

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  • 30 Churchill Place ● Canary Wharf ● London E14 5EU ● United Kingdom

    An agency of the European Union Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5520

    Send a question via our website www.ema.europa.eu/contact

    22 October 2015 EMA/837681/2015 Committee for Medicinal Products for Human Use (CHMP)

    Assessment report

    Zostavax

    International non-proprietary name: shingles (herpes zoster) vaccine (live)

    Procedure No. EMEA/H/C/000674/X/0085

    Note

    Variation assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted.

  • Assessment report

    EMA/837681/2015 Page 2/29

    Table of contents

    1. Background information on the procedure .............................................. 4

    1.1. Submission of the dossier ..................................................................................... 4

    1.2. Steps taken for the assessment of the product ........................................................ 4

    2. Scientific discussion ................................................................................ 5

    2.1. Introduction ........................................................................................................ 5

    2.2. Quality aspects .................................................................................................... 5

    2.3. Non-clinical aspects .............................................................................................. 6

    2.3.1. Environmental Risk assessment .......................................................................... 6

    2.4. Clinical aspects .................................................................................................... 6

    2.4.1. Introduction...................................................................................................... 6

    2.4.2. Pharmacokinetics .............................................................................................. 8

    2.4.3. Pharmacodynamics ............................................................................................ 8

    2.5. Clinical efficacy .................................................................................................... 8

    2.5.1. Dose response study(ies) ................................................................................... 8

    2.5.2. Main study ....................................................................................................... 8

    2.5.3. Discussion on clinical efficacy ............................................................................ 18

    2.5.4. Conclusions on the clinical efficacy .................................................................... 19

    2.6. Clinical safety .................................................................................................... 19

    2.6.1. Discussion on clinical safety .............................................................................. 27

    2.6.2. Conclusions on the clinical safety ...................................................................... 27

    2.7. Risk Management Plan ........................................................................................ 27

    2.8. Pharmacovigilance ............................................................................................. 28

    2.9. Product information ............................................................................................ 28

    2.9.1. User consultation ............................................................................................ 28

    2.9.2. Labelling exemptions ....................................................................................... 28

    3. Benefit-Risk Balance ............................................................................. 28

    4. Recommendations ................................................................................. 29

  • Assessment report

    EMA/837681/2015 Page 3/29

    List of abbreviations

    °C Celsius degree

    AE Adverse Event ANCOVA Analysis of Covariance ANOVA Analysis of Variance Model BS Blood Sample CI Confidence Interval CMI Cell Mediated Immunity CSR Clinical Study Report ELISPOT Enzyme-Linked ImmunoSpot

    EMA European Medicines Agency ERA Environmental Risk assessment FAS Full Analysis Set GCP Good Clinical Practices GMC Geometric Mean Count GMFR Geometric Mean Fold Rise GMT Geometric Mean Titre gpELISA Glycoprotein Enzyme-Linked ImmunoSorbent Assay HZ Herpes Zoster

    IFN-γ Interferon gamma IM Intramuscular IMP Investigational Medicinal Product LDA Longitudinal Data Analysis MAH Marketing Authorisation Holder

    MedDRA Medical Dictionary for Regulatory Activities mL Millilitre PCR Polymerase Chain Reaction

    PEI Paul-Ehrlich-Institut PFU Plaque-forming units PHN Post-Herpetic Neuralgia PPS Per Protocol Set PT Preferred Term RCDC Reverse Cumulative Distribution Curve RSI Request for supplementary Information SAE Serious Adverse Event

    SAS Safety Analysis Set SC Subcutaneous SmPC Summary of Product Characteristics

    SOC System Organ Class from MedDRA SPS Shingles Prevention Study VZV Varicella-Zoster Virus

  • Assessment report

    EMA/837681/2015 Page 4/29

    1. Background information on the procedure

    1.1. Submission of the dossier

    The applicant Sanofi Pasteur MSD SNC submitted on 26 May 2005 an application for extension of a Marketing

    Authorisation to the European Medicines Agency (EMA) for Zostavax. The MAH applied for a new route of

    administration: intramuscularly use.

    The legal basis for this application refers to:

    Article 19 of Commission Regulation (EC) No 1234/2008, Annex I 2.(e) Change or addition of a new route of

    administration.

    Information on Paediatric requirements

    Pursuant to Article 8 of Regulation (EC) No 1901/2006, the application included an EMA Decision(s) EMA

    decision P/0309/2014 on the granting of a (product-specific) waiver.

    Information relating to orphan market exclusivity

    Similarity

    Pursuant to Article 8 of Regulation (EC) No. 141/2000 and Article 3 of Commission Regulation (EC) No

    847/2000, the applicant did not submit a critical report addressing the possible similarity with authorised

    orphan medicinal products because there is no authorised orphan medicinal product for a condition related to

    the proposed indication.

    Scientific Advice/Protocol Assistance

    The applicant did not seek any scientific advice or Protocol Assistance at the CHMP.

    1.2. Steps taken for the assessment of the product

    Rapporteur: Jan-Mueller-Berghaus Co-Rapporteur: N/A

    CHMP Peer reviewer(s): N/A

    • The application was received by the EMA on 19 December 2014.

    • The procedure started on 22 January 2015.

     The Rapporteur's first Assessment Report was circulated to all CHMP members on 13 April 2015.

     The PRAC Assessment Report was circulated to all PRAC members on 27 April 2015.

  • Assessment report

    EMA/837681/2015 Page 5/29

    • During the meeting on 18-21 May 2015, the CHMP agreed on a List of Questions to be sent to the

    applicant. The final List of Questions was sent to the applicant on 21 May 2015.

    • The applicant submitted the responses to the CHMP List of Questions on 20 August 2015.

    • The Rapporteur circulated the Assessment Report on the applicant’s responses to the List of Questions

    to all CHMP members on 28 September 2015.

    • During the meeting on 16-19 October 2015, the CHMP, in the light of the overall data submitted and the

    scientific discussion within the Committee, issued a positive opinion for granting a Marketing

    Authorisation for a new route of administration of Zostavax.

    2. Scientific discussion

    2.1. Introduction

    Zostavax is an attenuated live virus vaccine containing varicella-zoster virus strain OKA/Merck. It is a sterile

    lyophilized preparation supplied with water for injection as diluent. Following reconstitution each 0.5 ml dose

    contains a minimum of 19,400 PFU (plaque-forming units) of Oka/Merck varicella virus.

    Zostavax is indicated for prevention of herpes zoster (HZ) and herpes zoster-related post-herpetic neuralgia

    (PHN) in individuals 50 years of age or older. Currently, the vaccine has to be administered by subcutaneous

    (SC) injection preferably in the deltoid region.

    None of the Zostavax studies conducted during the clinical development assessed the safety, tolerability and

    immune response of Zostavax administered by intramuscular (IM) route. With this application, the final CSR

    of study ZTV03C was provided to seek approval for the administration of Zostavax by the IM route.

    On 3 July 2014, in view of the submission of the new route of administration application, the Applicant

    submitted under Article 13 of Regulation (EC) No 1901/2006 as amended, the request for a product-specific

    waiver for all paediatric subjects. The Paediatric Committee (PDCO) of the EMA agreed to grant a product-

    specific waiver for all subsets of the paediatric population and the condition ‘prevention of varicella

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