AusPAR Attachment 2 Extract from the Clinical Evaluation Report for Retigabine Proprietary Product Name: Trobalt Sponsor: GlaxoSmithKline Australia Pty Ltd Date of CER: 9 July 2012 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. 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Submission PM-2011-04248-3-1 Extract from the Clinical Evaluation Report for Retigabine Page 2 of 89 Therapeutic Goods Administration Contents List of abbreviations __________________________________________________________ 5 1. Clinical rationale _________________________________________________________ 8 2. Contents of the clinical dossier ________________________________________ 9 2.1. Scope of the clinical dossier _________________________________________________ 9 2.2. Paediatric data _______________________________________________________________ 9 2.3. Good clinical practice ________________________________________________________ 9 3. Pharmacokinetics ________________________________________________________ 9 3.1. Studies providing pharmacokinetic data __________________________________ 9 3.2. Summary of pharmacokinetics _____________________________________________ 9 3.3. Evaluator’s overall conclusions on pharmacokinetics __________________ 22 4. Pharmacodynamics ____________________________________________________ 22 4.1. Summary of pharmacodynamics _________________________________________ 22 4.2. Evaluator’s overall conclusions on pharmacodynamics ________________ 23 5. Dosage selection for the pivotal studies ___________________________ 23 6. Clinical efficacy _________________________________________________________ 23 6.1. Pivotal efficacy studies ____________________________________________________ 23 6.2. Other efficacy studies _____________________________________________________ 43 6.3. Analyses performed across trials (pooled and meta-analyses) ________ 50 6.4. Evaluator’s conclusions on clinical efficacy ______________________________ 58 7. Clinical safety ___________________________________________________________ 59 7.1. Studies providing evaluable safety data _________________________________ 59 7.2. Patient exposure ___________________________________________________________ 60 7.3. Adverse events _____________________________________________________________ 61 7.4. Laboratory tests ___________________________________________________________ 68 7.5. Electrocardiograph ________________________________________________________ 70 7.6. Vital signs __________________________________________________________________ 71 7.7. Weight ______________________________________________________________________ 72 7.8. Urological and renal safety ________________________________________________ 73 7.9. Psychiatric safety __________________________________________________________ 75 7.10. Post-marketing experience _______________________________________________ 77 7.11. Safety issues with the potential for major regulatory impact __________ 77 7.12. Other safety issues _________________________________________________________ 80 7.13. Evaluator’s overall conclusions on clinical safety _______________________ 83 8. First round benefit-risk assessment ________________________________ 85 Submission PM-2011-04248-3-1 Extract from the Clinical Evaluation Report for Retigabine Page 3 of 89 Therapeutic Goods Administration 8.1. First round assessment of benefits _______________________________________ 85 8.2. First round assessment of risks __________________________________________ 85 8.3. First round assessment of benefit-risk balance _________________________ 86 9. First round recommendation regarding authorisation _________ 87 10. Clinical questions ____________________________________________________ 87 10.1. Pharmacokinetics __________________________________________________________ 87 10.2. Pharmacodynamics ________________________________________________________ 88 10.3. Efficacy _____________________________________________________________________ 88 10.4. Safety _______________________________________________________________________ 88 11. References ____________________________________________________________ 88 Submission PM-2011-04248-3-1 Extract from the Clinical Evaluation Report for Retigabine Page 4 of 89 Therapeutic Goods Administration List of abbreviations Abbreviation Meaning ADR Adverse drug reactions AE Adverse event AED Antiepileptic drug AUA American Urological Association ALT Alanine aminotransferase ANCOVA Analysis of covariance AST Aspartate aminotransferase AUA SI American Urological Association Symptom Index AUC Area under the plasma concentration-time curve AUC(0- AUC over the dosing interval AUC(0-τ) AUC from zero up to infinity BID ∞) Two times daily BSA Body surface area CBZ Carbamazepine CHMP Committee for Medicinal Products for Human Use CL Systemic clearance CL/F Apparent oral clearance Cmax Maximum concentration CNS Central nervous system CrCL Creatinine clearance CSR Clinical Study Report ECG Electrocardiogram EMEA European Medicines Evaluation Agency FDA US Food and Drug Administration GABA Gamma-aminobutyric acid Submission PM-2011-04248-3-1 Extract from the Clinical Evaluation Report for Retigabine Page 5 of 89 Therapeutic Goods Administration Abbreviation Meaning GCP Good Clinical Practice ICH International Conference of Harmonisation ILAE International League Against Epilepsy IR Immediate release ITT Intent-to-treat LEV Levetiracetam LTG Lamotrigine MR Modified release NAMR N-acetyl metabolite of retigabine NDA New Drug Application PB Phenobarbital PCC Potential Clinical Concern PCT Pivotal Controlled Trials PD Pharmacodynamic PDCO Paediatric Committee PHN Post herpetic neuralgia PHT Phenytoin PIP Paediatric Implementation Plan PK Pharmacokinetic popPK Population pharmacokinetic PPSR Proposed Pediatric Study Request PREA Paediatric Research Equity Act QTc QT interval corrected QTcB QT interval corrected with Bazett’s formula QTcF QT interval corrected with Fridericia’s formula QTcI QT interval Submission PM-2011-04248-3-1 Extract from the Clinical Evaluation Report for Retigabine Page 6 of 89 Therapeutic Goods Administration Abbreviation Meaning RTG Retigabine SAE Serious adverse event SD Standard deviation SPA Special Protocol Assessment SUDEP Sudden Unexplained Death in Epilepsy TEAE Treatment-emergent adverse events TESAE Treatment-emergent serious adverse events TID Three times daily Tmax Time to maximum concentration / reach Cmax TPM Topiramate VNS Vagus nerve stimulation VPA Valproic acid Submission PM-2011-04248-3-1 Extract from the Clinical Evaluation Report for Retigabine Page 7 of 89 Therapeutic Goods Administration 1. Clinical rationale Epilepsy is a common neurological condition, affecting 0.7-1% of the population.1 It is characterized by seizures, which are episodes of abnormal, synchronous neuronal firing, usually accompanied by a reduction in awareness or by focal neurological symptoms. Seizures are usually classified into focal (“partial”) seizures, which begin in one part of the brain, or primary generalised seizures, which involve the whole