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Extract from the Clinical Evaluation Report for Sofosbuvir / Velpatasvir

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Extract from the Clinical Evaluation Report for Sofosbuvir / Velpatasvir AusPAR Attachment 2 Extract from the Clinical Evaluation Report for Sofosbuvir / Velpatasvir Proprietary Product Name: Epclusa Sponsor: Gilead Sciences Pty Ltd First round 21 April 2016 Second round 11 August 2016 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 the Extract from the Clinical Evaluation Report · This document provides a more detailed evaluation of the clinical findings, extracted from the Clinical Evaluation Report (CER) prepared by the TGA. This extract does not include sections from the CER regarding product documentation or post market activities. · The words [Information redacted], where they appear in this document, indicate that confidential information has been deleted. · For the most recent Product Information (PI), please refer to the TGA website < https://www.tga.gov.au/product-information-pi> . Copyright © Commonwealth of Australia 2017 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]> . Extract from the Clinical Evaluation Report for Epclusa - Sofosbuvir / Velpatasvir - Gilead Sciences Page 2 of 110 Pty Ltd - PM-2015-03984-1-2 FINAL 8 November 2017 Therapeutic Goods Administration Contents List of abbreviations __________________________________________________________ 5 1. Introduction ___________________________________________________________ 14 1.1. Drug class and therapeutic indication ______________________________________ 14 1.2. Dosage forms and strengths ________________________________________________ 14 1.3. Dosage and administration __________________________________________________ 14 2. Clinical rationale _____________________________________________________ 15 3. Contents of the clinical dossier_____________________________________ 16 3.1. Scope of the clinical dossier _________________________________________________ 16 3.2. Paediatric data _______________________________________________________________ 16 3.3. Good clinical practice ________________________________________________________ 16 4. Pharmacokinetics ____________________________________________________ 16 4.1. Summary of pharmacokinetics _____________________________________________ 18 4.2. Evaluator’s overall conclusions on pharmacokinetics ____________________ 34 5. Pharmacodynamics __________________________________________________ 38 5.1. Studies providing pharmacodynamic data _________________________________ 38 5.2. Summary of pharmacodynamics ___________________________________________ 38 5.3. Evaluator’s overall conclusions on pharmacodynamics __________________ 44 6. Dosage selection for the pivotal studies __________________________ 45 7. Clinical efficacy _______________________________________________________ 45 7.1. Pivotal efficacy studies ______________________________________________________ 45 7.2. Other efficacy studies ________________________________________________________ 69 7.3. Analyses performed across trials ___________________________________________ 77 7.4. Evaluator’s conclusions on clinical efficacy for the indication: ___________ 82 8. Clinical safety__________________________________________________________ 82 8.1. Studies providing evaluable safety data ____________________________________ 82 8.2. Pivotal studies that assessed safety as a primary outcome _______________ 83 8.3. Patient exposure _____________________________________________________________ 83 8.4. Adverse events _______________________________________________________________ 84 8.5. Laboratory tests ______________________________________________________________ 93 8.6. Post-marketing experience_________________________________________________ 100 8.7. Safety issues with the potential for major regulatory ____________________ 100 8.8. Other safety issues __________________________________________________________ 101 8.9. Evaluator’s overall conclusions on clinical safety ________________________ 104 9. First round benefit-risk assessment _____________________________ 105 Extract from the Clinical Evaluation Report for Epclusa - Sofosbuvir / Velpatasvir - Gilead Sciences Page 3 of 110 Pty Ltd - PM-2015-03984-1-2 FINAL 8 November 2017 Therapeutic Goods Administration 9.1. First round assessment of benefits ________________________________________ 105 9.2. First round assessment of risks ____________________________________________ 105 9.3. First round assessment of benefit-risk balance __________________________ 105 10. First round recommendation regarding authorisation _______ 106 11. Clinical questions ____________________________________________________ 106 11.1. Pharmacokinetics _________________________________________________________ 106 11.2. Pharmacodynamics _______________________________________________________ 106 11.3. Efficacy _____________________________________________________________________ 106 11.4. Safety _______________________________________________________________________ 106 12. Second round evaluation of clinical data submitted in response to questions _____________________________________________________________________ 107 12.1. Pharmacokinetics _________________________________________________________ 107 12.2. Efficacy _____________________________________________________________________ 108 13. Second round benefit-risk assessment __________________________ 109 14. Second round recommendation regarding authorisation ___ 109 Extract from the Clinical Evaluation Report for Epclusa - Sofosbuvir / Velpatasvir - Gilead Sciences Page 4 of 110 Pty Ltd - PM-2015-03984-1-2 FINAL 8 November 2017 Therapeutic Goods Administration List of abbreviations Abbreviation Meaning 3TC lamivudine Ab antibody ADME absorption/distribution/metabolism/excretion AE adverse event AFP alpha fetoprotein ALT alanine aminotransferase ANC absolute neutrophil count ANOVA analysis of variance ARV antiretroviral AST aspartate aminotransferase ATR Atripla ATV atazanavir ATZ atazanavir ATZ/r atazanavir/ritonavir AUC area under the concentration/time curve AUCinf area under the plasma concentration versus time curve extrapolated to infinite time, calculated as AUC0-last + (Clast z) AUClast area under the plasma concentration versus time curve from/λ time zero to the last quantifiable concentration AUCtau area under the plasma concentration versus time curve over the dosing interval BA bioavailability BCRP breast cancer resistance protein BID twice daily BLQ below the limit of quantitation Extract from the Clinical Evaluation Report for Epclusa - Sofosbuvir / Velpatasvir - Gilead Sciences Page 5 of 110 Pty Ltd - PM-2015-03984-1-2 FINAL 8 November 2017 Therapeutic Goods Administration Abbreviation Meaning BMI body mass index bpm beats per minute CatA cathepsin A CES1 carboxylesterase 1 CI confidence interval CL clearance CL/F apparent oral clearance after administration of the drug: CL/F = Dose/AUCinf, where “Dose” is the dose of the drug Clast last observed quantifiable concentration of the drug in serum, plasma, or PBMCs CLcr creatinine clearance CLr renal clearance CLss/F apparent oral clearance at steady state Cmax maximum observed concentration of drug in plasma CMH Cochran-Mantel-Haenszel COBI cobicistat CPT Child-Pugh-Turcotte CPT-A compensated cirrhosis CPT-B decompensated cirrhosis CsA cyclosporine (cyclosporin A) Ctau observed drug concentration at the end of the dosing interval CTCAE Common Terminology Criteria for Adverse Events Ctrough trough plasma concentration CV coefficient of variation CYP cytochrome P450 DAA direct-acting antiviral agent Extract from the Clinical Evaluation Report for Epclusa - Sofosbuvir / Velpatasvir - Gilead Sciences Page 6 of 110 Pty Ltd - PM-2015-03984-1-2 FINAL 8 November 2017 Therapeutic Goods Administration Abbreviation Meaning DBP diastolic blood
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