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Attachment: Extract from Clinical Evaluation: Etanercept AusPAR Attachment 2 Extract from the Clinical Evaluation Report for etanercept Proprietary Product Name: Erelzi Sponsor: Novartis Pharmaceuticals Australia Pty Ltd First round report: June 2017 Second round report: August 2017 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 2018 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]>. Submission PM-2016-03159-1-1 Extract from the Clinical Evaluation Report for Erelzi 2 of 100 Therapeutic Goods Administration Contents List of abbreviations __________________________________________________________ 5 1. Submission details _______________________________________________________ 8 1.1. Submission type _____________________________________________________________ 8 1.2. Drug class and therapeutic indication _____________________________________ 8 1.3. Dosage forms and strengths ________________________________________________ 9 1.4. Dosage and administration _______________________________________________ 10 2. Background _____________________________________________________________ 10 2.1. Information on the condition being treated _____________________________ 10 2.2. Current treatment options ________________________________________________ 11 2.3. Clinical rationale ___________________________________________________________ 12 2.4. Guidance ____________________________________________________________________ 13 2.5. Evaluator’s commentary on the background information______________ 14 3. Contents of the clinical dossier ______________________________________ 14 3.1. Scope of the clinical dossier _______________________________________________ 14 3.2. Paediatric data _____________________________________________________________ 14 3.3. Good clinical practice ______________________________________________________ 15 3.4. Evaluator’s commentary on the clinical dossier ________________________ 15 4. Pharmacokinetics ______________________________________________________ 15 4.1. Studies providing pharmacokinetic information ________________________ 15 4.2. Summary of pharmacokinetics ___________________________________________ 38 4.3. Evaluator’s overall conclusions on pharmacokinetics __________________ 40 5. Pharmacodynamics ____________________________________________________ 41 6. Dosage selection for the pivotal studies ___________________________ 41 7. Clinical efficacy _________________________________________________________ 41 7.1. Studies providing evaluable efficacy data _______________________________ 41 7.2. Pivotal or main efficacy studies___________________________________________ 42 7.3. Justification for extrapolation to other indications approved for the reference product ______________________________________________________________________________ 65 7.4. Evaluator’s conclusions on clinical efficacy ______________________________ 66 8. Clinical safety ___________________________________________________________ 67 8.1. Studies providing evaluable safety data _________________________________ 67 8.2. Patient exposure ___________________________________________________________ 69 8.3. Adverse events _____________________________________________________________ 70 8.4. Evaluation of issues with possible regulatory impact __________________ 75 Submission PM-2016-03159-1-1 Extract from the Clinical Evaluation Report for Erelzi 3 of 100 Therapeutic Goods Administration 8.5. Post marketing experience________________________________________________ 80 8.6. Evaluator’s overall conclusions on clinical safety _______________________ 80 9. First round benefit-risk assessment ________________________________ 81 9.1. First round assessment of benefits _______________________________________ 81 9.2. First round assessment of risks __________________________________________ 82 9.3. First round assessment of benefit-risk balance _________________________ 83 10. First round recommendation regarding authorisation _______ 83 11. Clinical questions ____________________________________________________ 84 11.1. Clinical questions __________________________________________________________ 84 12. First round evaluation errata _____________________________________ 85 12.1. Minor editorial changes ___________________________________________________ 85 12.2. Minor errors of fact ________________________________________________________ 85 12.3. Significant errors of fact ___________________________________________________ 86 13. Second round evaluation ___________________________________________ 86 14. Second round benefit-risk assessment __________________________ 97 14.1. Second round assessment of benefits ____________________________________ 97 14.2. Second round assessment of risks________________________________________ 97 14.3. Second round assessment of benefit-risk balance ______________________ 97 15. Second round recommendation regarding authorisation ____ 97 16. References ____________________________________________________________ 98 Submission PM-2016-03159-1-1 Extract from the Clinical Evaluation Report for Erelzi 4 of 100 Therapeutic Goods Administration List of abbreviations Abbreviation Meaning Ab Antibody ABN Australian Biological Name ACM Advisory Committee on Medicines ADA Anti-drug antibody AE Adverse event (not necessarily treatment-related) Anti-CCP Anti-cyclic citrullinated peptide ALT Alanine aminotransferase ARTG Australian Register of Therapeutic Goods AST Aspartate aminotransferase ATE Averaged treatment effect BCC Basal cell carcinoma BDRM Blinded data review meeting BMI Body-mass index BSA Body surface area CNS Central nervous system COX-2 Cyclooxygenase-2 CPU Clinical pharmacology unit CRP C-reactive protein CSR Clinical study report CTCAE Common Terminology Criteria for Adverse Events DAS28-CRP Disease Activity Score 28-CRP DBL Database lock DLQI Dermatology Life Quality Index DMARD Disease-modifying anti-rheumatic drug Submission PM-2016-03159-1-1 Extract from the Clinical Evaluation Report for Erelzi 5 of 100 Therapeutic Goods Administration Abbreviation Meaning ECG Electrocardiogram EQ-5DTM EuroQoL five dimensions questionnaire ESR Erythrocyte sedimentation rate IP Investigational product IV Intravenous HAQ-DI© Health assessment questionnaire disability index Hb Haemoglobin HBsAg Hepatitis B virus surface antigen HBV Hepatitis B virus HCV Hepatitis C virus HIV Human immunodeficiency virus HRQoL Health-related quality of life IMP Investigational medicinal product INN International Non-proprietary Name LLOQ Lower limit of quantification LOCF Last observation carried forward LPLV Last patient, last visit mbTNF- transmembrane TNF alpha MedDRAα Medical Dictionary for Regulatory Activities MMRM Mixed-model repeated measures MTX Methotrexate NSAID Non-steroidal anti-inflammatory drug NYHA New York Heart Association OA Overall analysis (in the EGALITY trial) PASI Psoriasis Area and Severity Index Submission PM-2016-03159-1-1 Extract from the Clinical Evaluation Report for Erelzi 6 of 100 Therapeutic Goods
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