Australian Public Assessment Report for purified antigen fractions of inactivated split virion A/Indonesia/05/2005 (H5N1), AS03 adjuvanted Proprietary Product Name: Prepandrix Sponsor: GlaxoSmithKline Australia Pty Ltd December 2015 Therapeutic Goods Administration About the Therapeutic Goods Administration (TGA) • The Therapeutic Goods Administration (TGA) is part of the Australian Government Department of Health and is responsible for regulating medicines and medical devices. • The TGA administers the Therapeutic Goods Act 1989 (the Act), applying a risk management approach designed to ensure therapeutic goods supplied in Australia meet acceptable standards of quality, safety and efficacy (performance) when necessary. • The work of the TGA is based on applying scientific and clinical expertise to decision‐ making, to ensure that the benefits to consumers outweigh any risks associated with the use of medicines and medical devices. • The TGA relies on the public, healthcare professionals and industry to report problems with medicines or medical devices. TGA investigates reports received by it to determine any necessary regulatory action. • To report a problem with a medicine or medical device, please see the information on the TGA website <https://www.tga.gov.au>. About AusPARs • An Australian Public Assessment Report (AusPAR) provides information about the evaluation of a prescription medicine and the considerations that led the TGA to approve or not approve a prescription medicine submission. • AusPARs are prepared and published by the TGA. • An AusPAR is prepared for submissions that relate to new chemical entities, generic medicines, major variations and extensions of indications. • An AusPAR is a static document; it provides information that relates to a submission at a particular point in time. • A new AusPAR will be developed to reflect changes to indications and/or major variations to a prescription medicine subject to evaluation by the TGA. Copyright © Commonwealth of Australia 2015 This work is copyright. You may reproduce the whole or part of this work in unaltered form for your own personal use or, if you are part of an organisation, for internal use within your organisation, but only if you or your organisation do not use the reproduction for any commercial purpose and retain this copyright notice and all disclaimer notices as part of that reproduction. Apart from rights to use as permitted by the Copyright Act 1968 or allowed by this copyright notice, all other rights are reserved and you are not allowed to reproduce the whole or any part of this work in any way (electronic or otherwise) without first being given specific written permission from the Commonwealth to do so. Requests and inquiries concerning reproduction and rights are to be sent to the TGA Copyright Officer, Therapeutic Goods Administration, PO Box 100, Woden ACT 2606 or emailed to <[email protected]>. AusPAR Prepandrix GlaxoSmithKline Australia Pty Ltd PM‐2013‐04610‐1‐2 Page 2 of 73 Final 23 December 2015 Therapeutic Goods Administration Contents About AusPARs _________________________________________________________________ ii Common abbreviations _______________________________________________________ 5 I. Introduction to product submission _____________________________________ 6 Submission details ____________________________________________________________________ 6 Product background __________________________________________________________________ 6 Regulatory status _____________________________________________________________________ 7 II. Quality findings _____________________________________________________________ 8 Introduction (if applicable) __________________________________________________________ 8 Drug substance (active ingredient) _________________________________________________ 8 Drug product __________________________________________________________________________ 9 Biopharmaceutics ____________________________________________________________________ 9 Quality summary and conclusions __________________________________________________ 9 III. Nonclinical findings _____________________________________________________ 10 Introduction __________________________________________________________________________ 10 Pharmacology ________________________________________________________________________ 12 Pharmacokinetics ____________________________________________________________________ 14 Toxicology ____________________________________________________________________________ 15 Nonclinical summary and conclusions _____________________________________________ 18 IV. Clinical findings __________________________________________________________ 19 Introduction __________________________________________________________________________ 19 Pharmacokinetics ____________________________________________________________________ 21 Pharmacodynamics__________________________________________________________________ 21 Dosage selection for the pivotal studies ___________________________________________ 21 Efficacy _______________________________________________________________________________ 25 Safety _________________________________________________________________________________ 33 First round benefit‐risk assessment _______________________________________________ 38 First round recommendation regarding authorisation ___________________________ 41 Clinical questions ____________________________________________________________________ 41 Second round evaluation ____________________________________________________________ 42 Second round benefit‐risk assessment ____________________________________________ 44 V. Pharmacovigilance findings ____________________________________________ 45 Risk management plan ______________________________________________________________ 45 VI. Overall conclusion and risk/benefit assessment __________________ 53 Introduction __________________________________________________________________________ 53 Quality ________________________________________________________________________________ 54 AusPAR Prepandrix GlaxoSmithKline Australia Pty Ltd PM‐2013‐04610‐1‐2 Page 3 of 73 Final 23 December 2015 Therapeutic Goods Administration Nonclinical ___________________________________________________________________________ 54 Clinical ________________________________________________________________________________ 54 Risk management plan ______________________________________________________________ 62 Risk‐benefit analysis ________________________________________________________________ 62 Outcome ______________________________________________________________________________ 72 Attachment 1. Extract from the Clinical Evaluation Report __________ 72 AusPAR Prepandrix GlaxoSmithKline Australia Pty Ltd PM‐2013‐04610‐1‐2 Page 4 of 73 Final 23 December 2015 Therapeutic Goods Administration Common abbreviations Abbreviation Meaning AE adverse event AESI adverse event of special interest AS03 Adjuvant System 03 ASA Australian Specific Annex CMI Consumer Medicine Information EMA European Medicines Agency GD gestational day GMT geometric mean titre GSK GlaxoSmithKline HA haemagglutinin HI hemagglutination inhibition IM intramuscular ISS Integrated Summaries of Safety MAE medically attended adverse event NOCD New Onset Chronic Disease RMP Risk Management Plan RR relative risk PI Product Information pIMD potentially immune mediated disease SAE serious adverse event SCF seroconversion factor SCR seroconversion rate SPR seroprotection rate VRR vaccine response rate AusPAR Prepandrix GlaxoSmithKline Australia Pty Ltd PM‐2013‐04610‐1‐2 Page 5 of 73 Final 23 December 2015 Therapeutic Goods Administration I. Introduction to product submission Submission details Type of submission: New biological entity Decision: Withdrawn Date of decision: 3 September 2015 Active ingredient: Purified antigen fractions of inactivated split virion A/Indonesia/05/2005 (H5N1), AS03 adjuvanted Product name: Prepandrix Sponsor’s name and address: GlaxoSmithKline Australia Pty Ltd Level 4, 436 Johnston Street Abbotsford VIC 3067 Dose form: Antigen as suspension and adjuvant as emulsion in separate vials Strength: haemagglutinin (HA) per dose Container: OnePotency carton is expressed of Prepandrix as 3.75 consists μg three packs, including one pack containing 50 vials each with 2.5 ml antigen suspension for 10 doses and two packs of 25 vials each with 2.5 ml adjuvant emulsion for 10 doses Pack size: As above Route of administration: Intramuscular Injection preferably into the deltoid muscle or anterolateral thigh (depending on the muscle mass) Dosage: Primary vaccination: Two doses of 0.5 mL of the reconstituted vaccine. The second dose is administered between 3 weeks ‐ 12 months after the first dose Product background This AusPAR describes the application by GlaxoSmithKline Australia Pty Ltd to register a new pandemic influenza vaccine, Prepandrix (also known as Prepandremix during the application process and in this AusPAR). Prepandemrix is a split virion influenza vaccine against a strain of influenza with pandemic potential. It contains antigen equivalent to A/Indonesia/05/2005 PR8‐IBCDC‐RG2 (H5N1) 3.75 micrograms (µg) adjuvanted with the GlaxoSmithKline proprietary Adjuvant System 03 (AS03) adjuvant system per 0.5 ml dose. The vaccine is presented as an emulsion and suspension which need to be mixed prior to administration. The proposed indication is: Prophylaxis of influenza caused by the H5N1 strain with a pandemic potential. Prepandemrix should