Attachment: Extract from Clinical Evaluation Ocrelizumab
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AusPAR Attachment 2 Extract from the Clinical Evaluation Report for ocrelizumab Proprietary Product Name: Ocrevus Sponsor: Roche Products Pty Limited First round report: October 2016 Second round report: February 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 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 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-2016-01580-1-1 Extract from the Clinical Evaluation Report for Ocrelizumab Page 2 of 171 Therapeutic Goods Administration Contents List of abbreviations __________________________________________________________ 5 1. Introduction _____________________________________________________________ 8 1.1. Drug class and therapeutic indication ________________________________________ 8 1.2. Dosage forms and strengths __________________________________________________ 9 1.3. Dosage and administration ____________________________________________________ 9 2. Clinical rationale _______________________________________________________ 9 3. Contents of the clinical dossier_____________________________________ 11 3.1. Scope of the clinical dossier _________________________________________________ 11 3.2. Paediatric data _______________________________________________________________ 13 3.3. Good clinical practice ________________________________________________________ 13 4. Pharmacokinetics ____________________________________________________ 14 4.1. Studies providing pharmacokinetic data ___________________________________ 14 4.2. Summary of pharmacokinetics _____________________________________________ 14 4.3. Evaluator’s overall conclusions on pharmacokinetics ____________________ 18 5. Pharmacodynamics __________________________________________________ 19 5.1. Studies providing pharmacodynamic data _________________________________ 19 5.2. Summary of pharmacodynamics ___________________________________________ 20 5.3. Evaluator’s overall conclusions on pharmacodynamics __________________ 26 6. Dosage selection for the pivotal studies __________________________ 26 7. Clinical efficacy _______________________________________________________ 27 7.1. Pivotal efficacy studies in Relapsing MS ___________________________________ 27 7.2. Other efficacy studies ________________________________________________________ 72 7.3. Evaluator’s overall conclusions on clinical efficacy _______________________ 81 8. Clinical safety__________________________________________________________ 89 8.1. Studies providing evaluable safety data ____________________________________ 89 8.2. Patient exposure _____________________________________________________________ 92 8.3. Adverse events _______________________________________________________________ 95 8.4. Laboratory tests _____________________________________________________________ 118 8.5. Post-marketing experience_________________________________________________ 127 8.6. Safety issues with the potential for major regulatory impact ___________ 127 8.7. Other safety issues __________________________________________________________ 128 8.8. Evaluator’s overall conclusions on clinical safety ________________________ 140 9. First round benefit-risk assessment _____________________________ 141 9.1. First round assessment of benefits ________________________________________ 141 9.2. First round assessment of risks ____________________________________________ 144 Submission PM-2016-01580-1-1 Extract from the Clinical Evaluation Report for Ocrelizumab Page 3 of 171 Therapeutic Goods Administration 9.3. First round assessment of benefit-risk balance __________________________ 144 10. First round recommendation regarding authorisation _______ 145 10.1. Evaluator comments on round 1 recommendations ___________________ 145 11. Clinical questions ____________________________________________________ 145 11.1. Additional expert input ___________________________________________________ 145 11.2. Clinical questions __________________________________________________________ 145 12. Second round evaluation of clinical data submitted __________ 147 12.1. Efficacy question 1 ________________________________________________________ 147 12.2. Efficacy question 2 ________________________________________________________ 152 12.3. Efficacy question 3 ________________________________________________________ 153 12.4. Efficacy question 4 ________________________________________________________ 155 12.5. Efficacy question 5 ________________________________________________________ 161 12.6. Efficacy question 6 ________________________________________________________ 161 12.7. Efficacy question 7 ________________________________________________________ 162 12.8. Efficacy question 8 ________________________________________________________ 164 12.9. Efficacy question 9 ________________________________________________________ 166 13. Second round benefit-risk assessment __________________________ 167 13.1. Efficacy in RRMS ___________________________________________________________ 167 13.2. Efficacy in SPMS ___________________________________________________________ 168 13.3. Efficacy in PPMS ___________________________________________________________ 168 13.4. Risks of Ocrelizumab ______________________________________________________ 169 14. Second round recommendation regarding authorisation ___ 169 15. References ____________________________________________________________ 170 Submission PM-2016-01580-1-1 Extract from the Clinical Evaluation Report for Ocrelizumab Page 4 of 171 Therapeutic Goods Administration List of abbreviations Abbreviations Meaning 9-HPT 9-hole peg test ACR70 American College of Rheumatology score improvement of 70% ADA Anti≥ -drug antibody AE Adverse event ANCOVA Analysis of covariance ARR Annualised relapse rate BMI Body mass index CCOD Clinical cut-off date CDI Confirmed disability improvement CDP Confirmed disability progression CI Confidence interval CMH Cochran-Mantel-Haenszel CRF Case report form CSF Cerebrospinal fluid CSR Clinical study report DAS Disease activity score DIC Disseminated intravascular coagulation DMT Disease modifying therapy EDC Electronic data capture EDSS Expanded Disability Status Scale EULAR European League Against Rheumatism FS Function systems FSS Function Systems Score Gd Gadolinium Submission PM-2016-01580-1-1 Extract from the Clinical Evaluation Report for Ocrelizumab Page 5 of 171 Therapeutic Goods Administration Abbreviations Meaning HR Hazard ratio HRQoL Health-related quality of life HRQoL Health related quality of life IDP Initial disability progression IFN Interferon beta-1a IM Intramuscular IRR Infusion related reaction ITT Intent-to-treat IV Intravenous LLN Lower limit of normal LOCF Last observation carried forward MCS Mental component summary MFIS Modified Fatigue Impact Scale MMRM Mixed-Effect Model Repeated Measures MRI Magnetic resonance imaging MS Multiple sclerosis MSFC Multiple Sclerosis Functional Composite NEDA No evidence of disease activity OCR Ocrelizumab OLE Open-label extension PCS Physical component summary PK Pharmacokinetics PP Per-protocol PPMS Primary progressive multiple sclerosis