Australian Public Assessment Report for Sofosbuvir
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Australian Public Assessment Report for sofosbuvir Proprietary Product Name: Sovaldi Sponsor: Gilead Sciences Pty Ltd August 2014 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 <http://www.tga.gov.au>. About AusPARs • An Australian Public Assessment Record (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, in that it will provide 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 2014 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 Sofosbuvir Sovaldi Gilead Sciences Pty Ltd PM-2013-01283-1-2 Page 2 of 76 Final 5 August 2014 Therapeutic Goods Administration Contents List of abbreviations __________________________________________________________ 5 I. Introduction to product submission _____________________________________ 8 Submission details ____________________________________________________________________ 8 Product background __________________________________________________________________ 8 Regulatory status ____________________________________________________________________ 10 Product information _________________________________________________________________ 10 II. Quality findings ___________________________________________________________ 11 Drug substance (active ingredient) ________________________________________________ 11 Drug product _________________________________________________________________________ 11 Biopharmaceutics ___________________________________________________________________ 11 Quality summary and conclusions _________________________________________________ 13 III. Nonclinical findings _____________________________________________________ 13 Introduction __________________________________________________________________________ 13 Pharmacology ________________________________________________________________________ 14 Pharmacokinetics ____________________________________________________________________ 16 Toxicology ____________________________________________________________________________ 18 Nonclinical summary and conclusions _____________________________________________ 23 IV. Clinical findings __________________________________________________________ 25 Introduction __________________________________________________________________________ 25 Pharmacokinetics ____________________________________________________________________ 29 Pharmacodynamics__________________________________________________________________ 30 Dosage selection for the pivotal studies ___________________________________________ 31 Efficacy _______________________________________________________________________________ 31 Safety _________________________________________________________________________________ 34 First round benefit-risk assessment _______________________________________________ 38 First round recommendation regarding authorisation ___________________________ 41 Clinical questions ____________________________________________________________________ 41 Second round benefit-risk assessment ____________________________________________ 41 Second round recommendation regarding authorisation ________________________ 43 V. Pharmacovigilance findings ____________________________________________ 43 Risk management plan ______________________________________________________________ 43 VI. Overall conclusion and risk/benefit assessment __________________ 50 Quality ________________________________________________________________________________ 50 Nonclinical ___________________________________________________________________________ 50 Clinical ________________________________________________________________________________ 51 AusPAR Sofosbuvir Sovaldi Gilead Sciences Pty Ltd PM-2013-01283-1-2 Page 3 of 76 Final 5 August 2014 Therapeutic Goods Administration Risk management plan ______________________________________________________________ 63 Risk-benefit analysis ________________________________________________________________ 64 Outcome ______________________________________________________________________________ 74 Attachment 1. Product Information ____________________________________ 75 Attachment 2. Extract from the Clinical Evaluation Report __________ 75 AusPAR Sofosbuvir Sovaldi Gilead Sciences Pty Ltd PM-2013-01283-1-2 Page 4 of 76 Final 5 August 2014 Therapeutic Goods Administration List of abbreviations Abbreviation Meaning AE adverse event ALP alkaline phosphatase ALT alanine transaminase AST aspartate aminotransferase AUC area under the plasma concentration-time curve AUC area under the plasma concentration-time curve from time zero to ∞ infinity AUClast area under the plasma concentration-time curve from time zero to time of last measurable concentration AUCt1-t2 area under the plasma concentration-time curve within time span t1 to t2 BLoQ below the limitation of quantitation BOC boceprevir CC50 half maximal cytotoxic concentration CHC chronic hepatitis C CI confidence interval CL/F apparent total clearance of the drug from plasma after oral administration CLr renal clearance of the drug from plasma Cmax maximum plasma drug concentration CMI Consumer Medicine Information CNS central nervous system DAA direct-acting antiviral agent EC50 half maximal effective concentration ECG electrocardiogram EMA European Medicines Agency ESLD end stage liver disease AusPAR Sofosbuvir Sovaldi Gilead Sciences Pty Ltd PM-2013-01283-1-2 Page 5 of 76 Final 5 August 2014 Therapeutic Goods Administration Abbreviation Meaning ESRD end stage renal disease FDA Food and Drug Administration (US) FDC fixed dose combination GD gestational day GLP good laboratory practice GLSM geometric least squares means GT genotype HBV hepatitis B virus HCC hepatocellular carcinoma HCV hepatitis C virus HD high dose HIV human immunodeficiency virus IC50 half maximal inhibitory concentration IC90 90% maximal inhibitory concentration ICH International Conference on Harmonisation IFN interferon IVDU injecting drug use LLOQ lower limit of quantification MELD model for end-stage liver disease MHRA Medicines and Healthcare products Regulatory Agency (UK) MPA Medical Products Agency (Sweden) NMT not more than NOAEL no observed adverse effect level PEG pegylated interferon alfa Pgp P-glycoprotein PI product information AusPAR Sofosbuvir Sovaldi Gilead Sciences Pty Ltd PM-2013-01283-1-2 Page 6 of 76 Final 5 August 2014 Therapeutic Goods Administration Abbreviation Meaning PO oral administration PPK population pharmacokinetic PSP primary safety population PSUR periodic safety update report RAP resistance analysis population RBV ribavirin RNA ribonucleic acid SAE serious adverse event SC subcutaneous SOC standard of care SOF sofosbuvir SSP secondary safety population SVR sustained virologic response t1/2 half life Tmax time to reach maximum plasma concentration following drug administration TEAE treatment emergent adverse event TPV telaprevir Vc/F apparent volume of the central compartment AusPAR Sofosbuvir Sovaldi Gilead Sciences Pty Ltd PM-2013-01283-1-2 Page 7 of 76 Final 5 August 2014 Therapeutic Goods Administration I. Introduction to product submission Submission details Type of submission: New chemical entity Decision: Approved Date of decision: 30 June