AusPAR Attachment 2 Extract from the Clinical Evaluation Report for Baricitinib Proprietary Product Name: Olumiant Sponsor: Eli Lilly Australia Pty Ltd First round report: November 2016 Second round report: March 2017 Additional (third) 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 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 2019 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-2016-01468-1-3 Extract from the Clinical Evaluation Report for Olumiant baricitinib Page 2 of 135 Eli Lilly Australia Pty Ltd FINAL 21 March 2019 Therapeutic Goods Administration Contents List of abbreviations 6 1. Introduction _____________________________________________________________ 9 1.1. Submission type _____________________________________________________________ 9 1.2. Drug class and therapeutic indication _____________________________________ 9 1.3. Dosage forms and strengths ________________________________________________ 9 1.4. Dosage and administration _________________________________________________ 9 1.5. Proposed changes to the product documentation ______________________ 10 1.6. Information on the condition being treated _____________________________ 10 1.7. Current treatment options ________________________________________________ 10 1.8. Clinical rationale ___________________________________________________________ 11 1.9. Formulation development ________________________________________________ 11 1.10. Guidance ____________________________________________________________________ 11 1.11. Evaluator’s commentary on the background information ______________ 11 2. Contents of the clinical dossier ______________________________________12 2.1. Scope of the clinical dossier _______________________________________________ 12 2.2. Paediatric data _____________________________________________________________ 13 2.3. Good clinical practice ______________________________________________________ 13 2.4. Evaluator’s commentary on the clinical dossier ________________________ 14 3. Pharmacokinetics _____________________________________________________14 3.1. Studies providing pharmacokinetic information ________________________ 14 3.2. Summary of pharmacokinetics ___________________________________________ 15 3.3. Evaluator’s overall conclusions on pharmacokinetics __________________ 24 4. Pharmacodynamics ___________________________________________________26 4.1. Studies providing pharmacodynamic information ______________________ 26 4.2. Summary of pharmacodynamics _________________________________________ 26 4.3. Evaluator’s overall conclusions on pharmacodynamics ________________ 29 5. Dosage selection for the pivotal studies ___________________________30 5.1. Pharmacokinetic and pharmacodynamic studies _______________________ 30 5.2. Phase II dose finding studies ______________________________________________ 30 5.3. Phase III pivotal studies investigating more than one dose regimen __ 30 5.4. Evaluator’s conclusions on dose finding for the pivotal studies _______ 31 6. Clinical efficacy ________________________________________________________32 6.1. Studies providing evaluable efficacy data _______________________________ 32 6.2. Pivotal or main efficacy studies___________________________________________ 33 Submission PM-2016-01468-1-3 Extract from the Clinical Evaluation Report for Olumiant baricitinib Page 3 of 135 Eli Lilly Australia Pty Ltd FINAL 21 March 2019 Therapeutic Goods Administration 6.3. Other efficacy studies______________________________________________________ 57 6.4. Analyses performed across trials: pooled and meta-analyses _________ 74 6.5. Evaluator’s conclusions on clinical efficacy ______________________________ 74 7. Clinical safety __________________________________________________________77 7.1. Studies providing evaluable safety data _________________________________ 77 7.2. Patient exposure ___________________________________________________________ 79 7.3. Adverse events _____________________________________________________________ 79 7.4. Evaluation of issues with possible regulatory impact __________________ 94 7.5. Other safety issues ________________________________________________________ 102 7.6. Post marketing experience _______________________________________________ 103 7.7. Evaluator’s overall conclusions on clinical safety ______________________ 103 8. First round benefit-risk assessment ______________________________ 105 8.1. First round assessment of benefits ______________________________________ 105 8.2. First round assessment of risks _________________________________________ 106 8.3. First round assessment of benefit-risk balance ________________________ 107 8.4. First round recommendation regarding authorisation ________________ 108 9. Clinical questions ____________________________________________________ 109 9.1. Pharmacokinetics _________________________________________________________ 109 9.2. Pharmacodynamics _______________________________________________________ 109 9.3. Efficacy ____________________________________________________________________ 109 9.4. Safety ______________________________________________________________________ 110 9.5. Additional expert input __________________________________________________ 110 10. Second round evaluation of clinical data submitted in response to questions __________________________________________________________________ 110 10.1. Question 1 _________________________________________________________________ 110 10.2. Question 2 _________________________________________________________________ 111 10.3. Question 3 _________________________________________________________________ 113 10.4. Question 4 _________________________________________________________________ 115 11. Second round benefit-risk assessment ________________________ 115 11.1. Second round assessment of benefits ___________________________________ 115 11.2. Second round assessment of risks _______________________________________ 116 11.3. Second round assessment of benefit-risk balance _____________________ 116 12. Second round recommendation regarding authorisation __ 116 13. Additional evaluation material supplied following the second round evaluation _________________________________________________________ 117 13.1. TGA request for additional information following complete response letter from the FDA _______________________________________________________________________ 118 Submission PM-2016-01468-1-3 Extract from the Clinical Evaluation Report for Olumiant baricitinib Page 4 of 135 Eli Lilly Australia Pty Ltd FINAL 21 March 2019 Therapeutic Goods Administration 13.2. TGA request for response to main clinical evaluation report issues __ 129 13.3. Sponsor response to evaluator conclusions for PK/PD analyses _____ 130 14. Third round benefit-risk assessment __________________________ 132 14.1. Benefits ____________________________________________________________________ 132 14.2. Risks _______________________________________________________________________ 132 14.3. Assessment of benefit-risk balance _____________________________________