AusPAR Attachment 2 Extract from the Clinical Evaluation Report for Aclidinium bromide Proprietary Product Name: Bretaris Genuair Sponsor: A.Menarini Australia Pty Ltd First round report: 19 June 2013 Second round report: 25 October 2013 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 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 <http://www.tga.gov.au/hp/information-medicines-pi.htm>. Copyright © Commonwealth of Australia 2013 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-2012-04170-1-5 Extract from the Clinical Evaluation Report for Bretaris Genuair Page 2 of 174 Therapeutic Goods Administration Contents List of abbreviations __________________________________________________________ 5 1. Clinical rationale _____________________________________________________ 10 2. Contents of the clinical dossier_____________________________________ 11 2.1. Scope of the clinical dossier _________________________________________________ 11 2.2. Paediatric data _______________________________________________________________ 13 2.3. Good clinical practice ________________________________________________________ 13 3. Pharmacokinetics ____________________________________________________ 13 3.1. Studies providing pharmacokinetic data ___________________________________ 13 3.2. Summary of pharmacokinetics _____________________________________________ 14 3.3. Pharmacokinetics in healthy subjects ______________________________________ 15 3.4. Pharmacokinetics in the target population ________________________________ 27 3.5. Pharmacokinetics in other special populations ___________________________ 29 3.6. Pharmacokinetic interactions _______________________________________________ 31 3.7. Evaluator’s overall conclusions on pharmacokinetics ____________________ 31 4. Pharmacodynamics __________________________________________________ 33 4.1. Studies providing pharmacodynamic data _________________________________ 33 4.2. Summary of pharmacodynamics ___________________________________________ 33 4.3. Evaluator’s overall conclusions on pharmacodynamics __________________ 36 5. Dosage selection for the pivotal studies __________________________ 37 5.1. Study M34273/29 ___________________________________________________________ 38 6. Clinical efficacy _______________________________________________________ 44 6.1. Indication 1 ___________________________________________________________________ 44 6.2. Other efficacy studies ________________________________________________________ 69 6.3. Analyses performed across trials (pooled analyses and meta-analyses)107 6.4. Evaluator’s conclusions on clinical efficacy for Indication 1_____________ 117 7. Clinical safety_________________________________________________________ 123 7.1. Studies providing evaluable safety data ___________________________________ 123 7.2. Patient exposure ____________________________________________________________ 126 7.3. Adverse events ______________________________________________________________ 128 7.4. Laboratory tests _____________________________________________________________ 132 7.5. Other safety parameters. Analysis of TEAEs of special interest categorised by organ system or syndrome ________________________________________________________ 141 7.6. Post-marketing experience_________________________________________________ 150 7.7. Safety issues with the potential for major regulatory impact ___________ 150 Submission PM-2012-04170-1-5 Extract from the Clinical Evaluation Report for Bretaris Genuair Page 3 of 174 Therapeutic Goods Administration 7.8. Other safety issues __________________________________________________________ 151 7.9. Other safety issue: Use in pregnancy, lactation ___________________________ 155 7.10. Other safety issue- Overdose, drug abuse, withdrawal and rebound _ 155 7.11. Safety results from ongoing studies M/34273/39 and M34273/40 __ 155 7.12. Evaluator’s overall conclusions on clinical safety _______________________ 156 8. First round benefit-risk assessment _____________________________ 159 8.1. First round assessment of benefits ________________________________________ 159 8.2. First round assessment of risks ____________________________________________ 161 8.3. First round assessment of benefit-risk balance __________________________ 162 9. First round recommendation regarding authorisation _______ 162 10. Clinical questions ____________________________________________________ 162 10.1. Pharmacokinetics _________________________________________________________ 162 10.2. Pharmacodynamics _______________________________________________________ 162 10.3. Efficacy _____________________________________________________________________ 163 10.4. Safety _______________________________________________________________________ 163 11. Second round evaluation of clinical data submitted in response to questions _____________________________________________________________________ 164 11.1. Efficacy questions _________________________________________________________ 164 11.2. Safety questions:___________________________________________________________ 169 12. Second round benefit-risk assessment __________________________ 171 12.1. Second round assessment of benefits ____________________________________ 171 12.2. Second round assessment of risks _______________________________________ 171 12.3. Second round assessment of benefit-risk balance ______________________ 172 13. Second round recommendation regarding authorisation ___ 172 14. References ____________________________________________________________ 172 Submission PM-2012-04170-1-5 Extract from the Clinical Evaluation Report for Bretaris Genuair Page 4 of 174 Therapeutic Goods Administration List of abbreviations Abbreviation Meaning ADME Absorption, distribution, metabolism and excretion ADR Adverse Drug Reaction Ae Amount of unchanged drug excreted into urine. AEMPS Agencia Española de Medicamentos y Productos Sanitarios AEs Adverse events AFSSAPS Agence Française de Sécurité Sanitaire des Produits de Santé ALT alanine aminotransferase Am Amount of metabolite excreted into urine Am1 Amount of LAS34850 excreted into urine Am2 Amount of LAS34823 excreted into urine ANCOVA Analysis of covariance AST aspartate aminotransferase ATS American Thoracic Society AUC Area-under-the-curve AUC0-t Area under the concentration-time curve from time zero up to the last measurable concentration AUCo- Area under the concentration-time curve from time zero to infinity ∞ Area under the concentration-time curve during a dosing interval AUCτ AUC ,SS Area(τ) under the concentration- at steady state τ time curve during dosing interval (τ) BChE Butyrylcholinesterase BDI Baseline Dyspnoea Index BD Twice daily BLQ Below the lower limit of quantification BMI body mass index Submission PM-2012-04170-1-5 Extract from the Clinical Evaluation Report for Bretaris Genuair Page 5 of 174 Therapeutic Goods Administration Abbreviation Meaning BP blood pressure bpm beats per minute BUN Blood urea nitrogen CI Confidence interval CI Confidence interval CL Total body clearance from plasma CL/f Total body clearance from plasma after extravascular administration CLcr Creatinine clearance CLR Renal clearance Cmax Maximum