AusPAR Attachment 2 Extract from the Clinical Evaluation Report for Aminolevulinic acid HCl Proprietary Product Name: Gliolan Sponsor: Specialised Therapeutics Australia Pty Ltd Date of CER: December 2012–February 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]>. PM-2012-03095-1-2 Extract from the Clinical Evaluation Report for Aminolevulinic acid HCl Gliolan Page 2 of 60 Therapeutic Goods Administration Contents List of abbreviations __________________________________________________________ 5 1. Introduction _______________________________________________________________ 8 2. Clinical rationale _________________________________________________________ 8 2.1. Orphan drug designation__________________________________________________ 10 2.2. Guidance ____________________________________________________________________ 11 3. Contents of the clinical dossier ______________________________________ 11 3.1. Scope of the clinical dossier _______________________________________________ 11 3.2. Paediatric data _____________________________________________________________ 12 3.3. Good clinical practice ______________________________________________________ 12 4. Pharmacokinetics ______________________________________________________ 12 4.1. Studies providing pharmacokinetic data ________________________________ 12 4.2. Summary of pharmacokinetics ___________________________________________ 13 4.3. Evaluator’s overall conclusions on pharmacokinetics __________________ 18 5. Pharmacodynamics ____________________________________________________ 19 5.1. Studies providing pharmacodynamic data ______________________________ 19 5.2. Summary of pharmacodynamics _________________________________________ 19 5.3. Evaluator’s overall conclusions on pharmacodynamics ________________ 21 6. Dosage selection for the pivotal studies ___________________________ 21 7. Clinical efficacy _________________________________________________________ 22 7.1. Efficacy for the proposed indication _____________________________________ 22 7.2. Evaluator’s conclusions on clinical efficacy for the requested indication38 8. Clinical safety ___________________________________________________________ 39 8.1. Studies providing evaluable safety data _________________________________ 39 8.2. Pivotal studies that assessed safety as a primary outcome ____________ 40 8.3. Patient exposure ___________________________________________________________ 40 8.4. Adverse events _____________________________________________________________ 41 8.5. Laboratory tests ___________________________________________________________ 46 8.6. Post-marketing experience _______________________________________________ 53 8.7. Safety issues with the potential for major regulatory impact __________ 53 8.8. Other safety issues _________________________________________________________ 54 8.9. Evaluator’s overall conclusions on clinical safety _______________________ 55 9. First round benefit-risk assessment ________________________________ 57 9.1. First round assessment of benefits _______________________________________ 57 9.2. First round assessment of risks __________________________________________ 57 PM-2012-03095-1-2 Extract from the Clinical Evaluation Report for Aminolevulinic acid HCl Gliolan Page 3 of 60 Therapeutic Goods Administration 9.3. First round assessment of benefit-risk balance _________________________ 58 10. First round recommendation regarding authorisation _______ 58 11. Clinical questions ____________________________________________________ 58 11.1. Pharmacokinetics __________________________________________________________ 58 11.2. Pharmacodynamics ________________________________________________________ 58 11.3. Efficacy _____________________________________________________________________ 58 11.4. Safety _______________________________________________________________________ 58 12. Second round evaluation of clinical data submitted in response to questions ______________________________________________________________________ 59 13. References ____________________________________________________________ 59 PM-2012-03095-1-2 Extract from the Clinical Evaluation Report for Aminolevulinic acid HCl Gliolan Page 4 of 60 Therapeutic Goods Administration List of abbreviations Abbreviation Meaning AA Anaplastic astrocytoma 5-ALA 5-Aminolevulinic acid hydrochloride ALAD Aminolevulinic acid dehydratase ALT (GPT) Alanine transaminase AP Alkaline phosphatase ARE Amount of drug to be renally excreted ASCO American Society of Clinical Oncology AST (GOT) Aspartate transaminase AO Anaplastic oligodendroglioma a.u. Arbitrary units AUC Area under the curve CI Confidence interval ClCr Creatinine clearance CNS Central nervous system CRF Case report form CT Computed tomography ECOG Eastern Cooperative Oncology Group FL (-group) Fluorescence light group (arm A) GABA Gamma-aminobutyric acid GBM Glioblastoma multiforme GCP Good clinical practice GI Gastrointestinal h Hour HPLC High performance liquid chromatography PM-2012-03095-1-2 Extract from the Clinical Evaluation Report for Aminolevulinic acid HCl Gliolan Page 5 of 60 Therapeutic Goods Administration Abbreviation Meaning IEC Independent Ethics Committee IM Intramuscularly IRB Institutional review board ITT Intention-to-treat IU International unit IV Intravenously KPS Karnofsky Performance Scale MED Minimal Erythema Dose Min Minute MR Magnetic resonance MRI Magnetic resonance imaging MRT Magnetic resonance tomography ND Not done NIH-SS National Institute of Health stroke score NOS Not otherwise specified NR Not reported NS Not statistically significant PBG Porphobilinogen PDD Photodynamic diagnosis PDT Photodynamic therapy PO Per os PPIX Protoporphyrine IX Pts. Patients RPM Risk Management Plan SAE Serious adverse event PM-2012-03095-1-2 Extract from the Clinical Evaluation Report for Aminolevulinic acid HCl Gliolan Page 6 of 60 Therapeutic Goods Administration Abbreviation Meaning sAP Serum alkaline phosphatase SEER Surveillance, Epidemiology, and End Results database from the NCI SD Standard deviation vs versus WHO World Health Organisation WL (-group) White light group (control group, arm B) PM-2012-03095-1-2 Extract from the Clinical Evaluation Report for Aminolevulinic acid HCl Gliolan Page 7 of 60 Therapeutic Goods Administration 1. Introduction Aminolevulinic acid (5-aminolevulinic acid HCl; 5-ALA or ALA) is a naturally occurring, endogenous substance, which belongs to the group of sensitizers used in photodynamic/radiation therapy. It has been previously developed and approved for local (topical) treatment of some kinds of skin cancer and pre-cancerous conditions. It is a pro-drug that is metabolised intracellularly to form the fluorescent molecule, protoporphyrin (PPIX). The exogenous application of 5-ALA leads to a highly selective accumulation of PPIX in tumour cells and epithelial tissues. Following excitation with blue light ( = 400 to 410 nm), the PPIX, which has accumulated selectively in the malignant tissue emits a red-violet