PHAR4813 Novel Therapeutics - Regulation (2024) Lecture PDF

PHAR4813 Novel Therapeutics - Regulation Dr Orin Chisholm Program Director, Pharmaceutical and Medical Device Development postgraduate programs TEQSA PRV12057 CRICOS 00026A I would like to acknowledge the...

PHAR4813 Novel Therapeutics - Regulation Dr Orin Chisholm Program Director, Pharmaceutical and Medical Device Development postgraduate programs TEQSA PRV12057 CRICOS 00026A I would like to acknowledge the Traditional Owners of Australia and recognise their continuing connection to land, water and culture.  USER NOTE: There are more Content Slide options available to add to your presentation by going to: Home tab >New Slide > Drop down arrow Learning Outcomes - LO3. demonstrate an awareness of current biotechnologies and their impact on pharmaceutical health - LO4. explain the principles involved in drug discovery and the decision-making process involved in developing drugs The University of Sydney History of Pharma Industry 1962 thalidomide disaster – strengthening 1985 2012 first 1859 first of regulatory recombinant 1995 gene 2017 first factory requirements human TRIPS therapy CAR-T cell producing regarding insulin agreement product therapy medicines safety and registered in re 20-year approved approved (Beecham) efficacy US patent term (Glybera) (Kymriah) 1906 US 1976 1990 first HIV 2000 2015 first 2021 first Food, Genentech reverse Human 3D-printed mRNA Drug and founded transcriptase genome tablets vaccines Cosmetic approved sequenced approved approved Act (Spritam) (Comirnaty, Spikevax) The University of Sydney  Current directions and influence on pharma industry Science Policies Corporate oncology WHO: universal health coverage rare diseases WHO: future pandemic VALUE cell and gene therapy preparedness (pandemic treaty) ESG and climate change impacts mRNA-based therapies sovereign manufacturing EDI and increasing the patient AI in drug development capability voice precision medicine and data industrial and innovation new ways of working health funding and regulatory digital integration science and research codes of conduct and ethics export and trade transparency business and corporate policies The University of Sydney https://www.mtpconnect.org.au/images/2022_MTPConnect_SectorCompetitivenessPlan.pdf  Top Pharmaceutical Markets in 2022 The University of Sydney https://www-statista-com.ezproxy.library.sydney.edu.au/statistics/245473/market-share-of-the-leading-10-global-pharmaceutical-markets/  Top therapeutic classes by sales -2023 The University of Sydney Top Medtech market segments-2021 The University of Sydney  FDA - CDER Annual Novel Drug Approvals - 2023 The University of Sydney https://www.fda.gov/media/164429/download  Top 10 drugs by sales - global Medicine Indication Company Sales (2022) USD billion Comirnaty (Covid-19 vaccine) Covid-19 vaccine Pfizer $40.8 Spikevax (Covid-19 vaccine) Covid-19 vaccine Moderna $21.8 Humira (adalimumab) Anti-inflammatory- Abbvie/Eisai $21.6 Rheumatoid arthritis (RA), Crohn’s Keytruda (pembrolizumab) Oncology MSD $21 Paxlovid Covid-19 antiviral Pfizer $19 (Nirmatrelvir/ ritonavir) Eliquis (apixaban) Cardiovascular BMS/Pfizer $11.8 Biktarvy (bictegravir, emtricitabine, HIV Gilead $10.4 tenofovir alafenamide) Eylea (aflibercept) Macular degeneration Bayer/Regeneron $10.3 Stelara (ustekinumab) Crohn’s, psoriasis, Janssen $10.1 ulcerative colitis Revlimid (lenalidomide) The University of Sydney Blood disorders/ Celgene $10 Oncology-MM, MDS, MCL https://www.fiercepharma.com/special-reports/top-20-drugs-worldwide-sales-2021 Top PBS drugs by cost to Australian government – 2022-23 Drug Cost to Government Lagevrio (molnupiravir) $646,447,181 Trikafta (elexacaftor/ tezacaftor/ ivacaftor) $512,857,553 Eylea (aflibercept) $476,143,532 Keytruda (pembrolizumab) $447,023,724 Opdivo (nivolumab) $411,450,540 Stelara (ustekinumab) $355,959,026 Paxlovid (nirmatrelvir and ritonavir) $334,491,173 Eliquis (apixaban) $304,367,581 Humira (adalimumab) $282,747,367 The University of Sydney Prolia (denosumab) $272,776,093 Expenses and revenues curve for a new medicine The University of Sydney  How much does it a) $1-2 million typically cost to bring a new b) $50-500 million product to market? c) $ 1-3 billion d) More than $5 billion The University of Sydney  How long does it a) 1-2 years typically take to get b) 3-5 years a new pharmaceutical c) 6-11 years product to market? d) 12-16 years e) More than 16 years The University of Sydney  Pharmaceuticals – traditional development pathway What is the correct order for each step in the pathway? Drug Discovery, Reimbursement Development & Pre- clinical Studies Registration Clinical Trials Marketing Approval Marketing, PV, further Clinical Studies The University of Sydney Pharmaceuticals – traditional development pathway GLP GMP GCP GVP Marketing Approval | Drug Discovery, Development & Marketing, PV, Clinical Trials Registration Reimbursement further Clinical Pre-clinical Studies Studies pilot manufacturing commercial manufacturing 0-6 years | 6-7 years | 0.5-1 year | 5000 | 250 |5 | 1 GLP = Good Laboratory Practice; GMP = Good Manufacturing Practice; GCP = Good Clinical Practice; The University of Sydney GVP = Good Vigilance Practice; PV = pharmacovigilance Product Development Plan “If it’s not Situational analysis documented, it Competitor landscape didn’t happen!” Target Product Profile Pre-clinical studies plan Clinical development plan Formulation and manufacturing Regulatory strategy Health Technology Assessment strategy Timelines The University of Sydney Medical devices development pathway Initiation Formulation Design and development Verification and validation Manufacturing and testing Clinical development Regulatory submissions Launch Post-market compliance Reimbursement The University of Sydney Legal Basis of Medicines Regulation in Australia Laws Regulations Orders Guidances, Standards The University of Sydney  Australian Legislation Therapeutic Goods Act, 1989 Legislative Instruments Therapeutic Goods Regulations, 1990 Therapeutic Goods Orders (various) Australian Regulatory Guidelines for Prescription Medicines Australian Regulatory Guidelines for Medical Devices Object of the Act Australian Regulatory Guidelines for to provide a national framework Biologicals for the regulation of therapeutic Adopted International guidelines goods so as to ensure their quality, safety, efficacy and timely availability The University of Sydney https://www..gov.au/Home, http://www.austlii.edu.au/database-all.html, https://www.tga.gov.au/collection/argpm, https://www.tga.gov.au/ws-sg-index, https://www.ogtr.gov.au/ legislation What the Therapeutic Goods Act Does post-market establishes surveillance, establishes advisory monitoring evaluation committees and testing requirements of goods establishes establishes licensing and processes TGA inspection of for access to manufacturers unapproved medicines prohibits assessment manufacturing regulates or supplying a of medicines advertising good not on the for export ARTG applies to all establishes therapeutic the ARTG goods The University of Sydney Therapeutic Goods Administration (TGA) Pre-market evaluation and approval of therapeutic goods Licensing of manufacturers (GMP) Post-market surveillance through sampling, Adverse Event reporting, etc Development, maintenance and monitoring systems for listing of medicines Assessment of medicines for export The University of Sydney  Definition of a therapeutic good a good which is represented in any way to be, or is likely to be taken to be, for therapeutic use (unless specifically excluded or included under Section 7 of the Therapeutic Goods Act 1989) “therapeutic use” means use in or in connection with: preventing, diagnosing, curing or alleviating a disease, ailment, defect or injury influencing, inhibiting or modifying a physiological process testing the susceptibility of persons to a disease or ailment influencing, controlling or preventing conception testing for pregnancy or replacement or modification of parts of the anatomy The University of Sydney What types of products do you think would be classified as therapeutic goods? The University of Sydney Classes of Therapeutic Goods Prescription medicines Over-the-counter or non-prescription medicines Complementary medicines Sunscreens Medical devices and in vitro diagnostics (IVDs) Biologicals Blood and blood components The University of Sydney  A B What class of therapeutic good would the following products be? How much oversight should the TGA have of C D each of these products? The University of Sydney Risk-based approach to regulation The University of Sydney Medicine Scheduling Schedule 2 Pharmacy only Schedule 3 Pharmacist only Schedule 4 Prescription medicines Schedule 5 Caution Schedule 6 Poisons Schedule 7 Dangerous poisons Schedule 8 Controlled drugs Schedule 9 The University of Sydney Prohibited substances Inclusion on ARTG All goods must be entered in the ARTG before they can be supplied in, imported to, or exported from Australia The University of Sydney Prescription Medicines Prescription medicines New chemical New biologic Vaccines Recombinant entities entities products Plasma derived Gene therapy – products in vivo delivery The University of Sydney  Prescription Medicines Registration Process Manufacturing Pre-clinical process data Product Clinical data development Dossier NRA review The University of Sydney market  Submission basics Applications by Review Obtain Australian Obtain GMP sponsor – legal Guidelines, Approved Name Australian entity Orders, etc (AAN) certification Obtain Write AU-specific Pre-submission Scheduling (PM designations or Module 1 determinations meeting are S4 or S8) Publish dossier: Submit dossier Review dossier eCTD format and fees The University of Sydney https://www.tga.gov.au/publication/tga-approved-terminology-therapeutic-goods; https://www.tga.gov.au/collection/argpm; https://www.tga.gov.au/standards-guidelines-prescription- medicines; https://www.tga.gov.au/evaluation-plan-estimat or  Which registration pathway? Standard PM Pathway Second First round Expert Designation Submission round Decision evaluation advice evaluation TGA clock TGA clock TGA clock start stop for stop Sponsor (255 responses working days) Facilitated pathways ACCESS Provisional Priority review COR-A COR-B Work-sharing Project Orbis approval arrangement Canada USA Canada Singapore ACCESS Singapore Switzerland members Switzerland UK Brazil Japan Israel UK USA The University of Sydney EU  Standard/PR/PA Pathway Elements Standard Provisional Approval Priority Review Determination validity Not applicable 6 months; extension 6 months 6 months; no extension Legislative timeframe 255 working days 255 working days (TGA will 255 working days; target timeframe prioritise provisional medicines 150 working days within the timeframe) Phases and milestones - 8 phases, each resulting in a - 8 phases - 8 “dynamic” phases, each milestone - Milestone 1 (Planning letter) resulting in a milestone. - 8 milestones is not formal - 8 milestones, only milestone 2 (submission acceptance & clock start) and 7 (decision & clock stop) are formal Rolling questions No No Yes Rolling data submission No Yes; scope and timing prospectively No agreed Consolidated TGA request for Sponsor can choose to respond Sponsor can choose to respond Sponsor commits to respond within information (TG Act, Section 31) within 30 days or 60 days within 30 days or 60 days 30 days Contact with TGA Pre-submission meeting (optional, Pre-submission meeting (strongly Pre-submission meeting (optional) complex applications) recommended) Prior to PPF or application ~ 3 months prior to determination ~ 3 months prior to determination The University of Sydney lodgement application application  Designations and Determinations - Orphan, Priority Review, Provisional Approval Process and Criteria Orphan Priority Review (PR) Provisional Approval (PA) Pre-submission meeting Yes Yes Yes Designation/Determinati Designation Determination Determination on application Validity 6 months; one extension 6 months 6 months; no extension 6 months; one extension 6 months Eligibility criteria -Prevalence threshold: fewer than 5 in 10,000 -New prescription medicine or new -New prescription medicine OR individuals in Australia OR lack of financial indication AND new indications medicine AND viability -Life-threatening or seriously -For treating a serious condition -Life-threatening or seriously debilitating debilitating condition AND AND condition; medically plausible -No registered competitors or this -Favourable comparison against -No registered competitors OR this medicine medicine provides significant existing therapeutic goods OR no provides significant benefit benefit AND competitors AND -Has not been refused due to safety issues by -Provides major therapeutic -Major therapeutic advance AND FDA, Health Canada, EMA, MHRA advance -Evidence of a plan to submit comprehensive clinical data MAA timeframe 255 working days (wd) 255 wd (150 wd target) 255 wd Rolling questions/data No Yes, rolling questions Yes, rolling data submission Example sotorasib (Lumakras) tucatinib (Tukysa) mobocertinib (Exkivity) 244 wd 113 wd 199 wd The University of Sydney Medical Devices Medical Device definition A medical device is any material instrument, apparatus, appliance, implant etc, including any component part or accessory including software, and in-vitro diagnostics, which is used in health care. Which of the following items are medical devices? The University of Sydney Medical device classification Schedule 2, Therapeutic Goods (Medical Devices) Regulations 2002 Essential Principles Composed of: General principles to Listed in Schedule show benefits outweigh risks Fundamental 1, Therapeutic Principles regarding regulatory Goods (Medical design and construction requirements Devices) Principles regarding Regulations 2002 labelling Principles regarding standards and testing of the device The University of Sydney  Conformity Assessment Procedures Schedule 3, Therapeutic Goods (Medical Devices) Regulations 2002 Help demonstrate compliance with the Essential Principles Quality Management System requirements eg, ISO 13485 Design examination Third party assessment Declaration of conformity Manufacturer Evidence: Conformity assessment certificate (TGA, EU notified bodies, Medical Device Single The University of Sydney Audit Program, Japanese QMS certificate, US FDA PMA, HSA Singapore assessment) Supplying a medical device in Australia Confirm your product is a medical device that needs to be included in the ARTG Determine the kind of medical device - check GMDN code Determine the classification of the medical device – which Class? Prepare all documents required for medical device inclusion: Declaration of Conformity Manufacturer’s evidence (compliance with Essential Principles) Submit application for inclusion Print out your ARTG certificate Supply your device The University of Sydney In vitro diagnostic (IVD) medical device definition a medical device that is: (a) a reagent, calibrator, control material, kit, specimen receptacle, software, instrument, apparatus, equipment or system, whether used alone or in combination with another diagnostic product for in vitro use; and (b) intended by the manufacturer to be used in vitro for the examination of a specimen derived from the human body, solely or principally for: (i) giving information about a physiological or pathological state or a congenital abnormality; or (ii) determining safety and compatibility with a potential recipient; or (iii) monitoring therapeutic measures; and (c) not a product that is: (i) intended for general laboratory use; and (ii) not manufactured, sold or presented for use as an IVD medical device. https://www.legislation.gov.au/Details/F2023C00565 IVD regulation by TGA Step 1 – identify the class of IVD Step 2 – obtain GMDN and Declaration of Conformity from manufacturer Step 3 – prepare and submit TGA conformity assessment Step 4 – submit IVD application to TGA The University of Sydney https://www.tga.gov.au/guidance-ivd-sponsors-roadmap-market; https://www.gmdnagency.org/ Case Study Timeline for the clinical development of larotrectinib and entrectinib The University of Sydney Han S-Y. TRK Inhibitors: Tissue-Agnostic Anti-Cancer Drugs. Pharmaceuticals. 2021; 14(7):632. https://doi.org/10.3390/ph14070632  Receptor Ligand TRK signalling pathways TrkA NGF nerve growth factor TrkB BDNF/NTF 4 brain-derived neurotrophic factor/ neurotropin 4 TrkC NTF3 neurotropin 3 Imaoka H, Sasaki M, Hashimoto Y, et al. Impact of Endoscopic Ultrasound-Guided Tissue Acquisition on Decision-Making in Precision Medicine for Pancreatic Cancer: Beyond Diagnosis. Diagnostics (Basel). The University of Sydney 2021;11(7):1195. Published 2021 Jun 30. doi:10.3390/diagnostics11071195.  Non-clinical studies A-C: LOXO-101 inhibition of cancer cells harbouring oncogenic TRK D-F: inhibition of phosphorylation G: LOXO-101 inhibits tumor growth in a KM12 colorectal xenograft model The University of Sydney Doebele RC, Davis LE, Vaishnavi A, et al. An Oncogenic NTRK Fusion in a Patient with Soft-Tissue Sarcoma with Response to the Tropomyosin-Related Kinase Inhibitor LOXO-101. Cancer Discov. 2015;5(10):1049-1057. doi:10.1158/2159-8290.CD- 15-0443  Clinical studies Study Design, patient population Dose, formulation No. Patients Tumour types NCT02122913 Phase 1, open-label, dose escalation Doses up to 200 mg 13 Salivary gland (n=3) GIST (n=2) and expansion study; expansion phase once or twice daily (25 Soft tissue sarcoma (n=2) required tumours harbouring an NTRK mg, 100 mg capsules Thyroid (n=4) gene fusion Adult patients (≥ 18 years) or 20 mg/m oral Lung, NSCLC (n=1) with advanced solid tumours harbouring solution) Unknown primary cancer (n=1) an NTRK gene fusion NCT02576431 Phase 2 multinational, open label, 100 mg twice daily (25 98 Salivary gland (n=18) NAVIGATE tumour “basket” study mg, 100 mg capsules Sarcoma (n=16) Thyroid (n=23) Adult and paediatric patients ≥ 12 years or 20mg/ml oral Colorectal (n=8) Melanoma (n=6) Lung with advanced solid tumours harbouring solution) NSCLC (n=11) an NTRK gene fusion Lung, SCLC (n=1) GIST (n=2) Biliary (n=2) Pancreas (n=2) Breast, non-secretory (n=3) Breast, secretory (n=2) Other (n=4) NCT02637687 Phase 1/2 multinational, open-label, Doses up to 100 53 Infantile fibrosarcoma (n=32) SCOUT dose escalation and expansion study; mg/m2 twice daily (25 Soft tissue sarcoma (n=18) Bone Phase 2 expansion cohort required mg, 100 mg capsules sarcoma (n=1) advanced solid tumours harbouring an or 20mg/ml oral Congenital mesoblastic nephroma (n=1) NTRK gene fusion, including locally solution) Melanoma (n=1) advanced infantile fibrosarcoma Paediatric patients ≥ 1 month to 21 years The University of Sydney with advanced cancer or with primary CNS tumours  Indication USA EU AU Japan China VITRAKVI is a kinase inhibitor VITRAKVI is conditionally Vitrakvi (larotrectinib) has for the treatment of for the treatment of adult indicated for the treatment of approved as monotherapy is provisional approval in Australia Neurotrophic Tyrosine and pediatric patients with adult and pediatric patients with indicated for the treatment of for the treatment of adult and Receptor Kinase (NTRK) advanced solid tumors that solid tumors that: paediatric patients with locally adult and paediatric patients fusion-positive advanced or harbor a Neurotrophic have a neurotrophic receptor advanced or metastatic solid with solid tumours that recurrent solid tumors. Tyrosine Receptor Kinase tyrosine kinase (NTRK) gene tumours that: fusion without a known display a Neurotrophic have a neurotrophic tyrosine (NTRK) gene fusion. acquired resistance mutation, Tyrosine Receptor Kinase receptor kinase (NTRK) gene NTRK gene fusions should are metastatic or where (NTRK) gene fusion, - who fusion without a known be identified by a sufficiently surgical resection is likely to have a disease that is locally acquired resistance mutation, validated test. result in severe morbidity, and advanced, metastatic or are metastatic or where have no satisfactory where surgical resection is surgical resection is likely to alternative treatments or that likely to result in severe result in severe morbidity, and have progressed following have either progressed morbidity, and - who have treatment. following treatment or who have no satisfactory treatment Select patients for therapy no satisfactory alternative based on an FDA-approved options. therapy. test. The decision to approve this This indication is approved indication has been made on under accelerated approval the basis of objective response based on overall response rate rate (ORR) and duration of and duration of response. response from single arm Continued approval for this clinical studies. The sponsor is indication may be contingent required to submit further upon verification and clinical data to confirm the description of clinical benefit in clinical benefit of the medicine. confirmatory trials. The University of Sydney Regulatory milestones 11. 13. 1. US 3. US 5. EU 7. AU 9. EU AU China 2. US 4. US 6. US 8. AU 10. 12. 14. Japan Japan China 1. US: Orphan drug designation FDA 9 May 2017 2. US: Break-through designation FDA 13 July 2017 3. US: NDA/BLA 20 Dec 2017 4. US: Priority review 29 May 2018 5. EU: MAA 27 Aug 2018 6. US: Accelerated/conditional approval 26 Nov 2018 7. AU: provisional designation 20 Jun 2019 8. AU: Submission received 30 Aug 2019 9. EU: Approval 19 Sep 2019 10. Japan: filing 22 May 2020 11. AU: ARTG entry 7 Sep 2020 12. Japan: approval 23 Mar 2021 13. China: filing 25 May 2021 14. China: approval 13 Apr 2022 The University of Sydney Companion diagnostic test approved by FDA Oct 2020 Co-dependent health technology Generally: when patient outcomes with one health technology (eg, drug) are improved by the use of another (eg, pathology test, imaging technology), and the use of the technologies must be combined (sequentially or simultaneously) to achieve or enhance the intended clinical effect of either one primarily a drug-test combination where a drug seeking PBS listing has a related pathology test that may help to determine eligible patients See PBAC guidelines http://www.msac.gov.au/internet/msac/publishing.nsf/Content/Factsheet-09; Merlin TL, Hiller JE, Ryan P. Impact of the “Linked Evidence Approach” Method on The University of Sydney http://www.msac.gov.au/internet/msac/publishing.nsf/Content/Codependent-technologies-MSAC-and-PBAC; Policies to Publicly Fund Diagnostic, Staging, and Screening Medical Tests. https://pbac.pbs.gov.au/product-type-4-codependent-technologies.html MDM Policy & Practice. July 2016. doi:10.1177/2381468316672465  Reimbursement – PBS/MBS PBAC meeting Nov 2021 – deferred till MSAC determination on companion diagnostic test finalised PBAC meeting March 2022 – recommended – Paediatric: – The condition must be positive for a neurotrophic tropomyosin receptor kinase (NTRK) gene fusion confirmed by next - generation sequencing or fluorescence in-situ hybridisation – AND Patients must be diagnosed with a solid tumour – AND Disease must be metastatic OR unresectable locally advanced – OR locally advanced and would otherwise require disfiguring surgery or limb amputation to achieve a complete surgical resection – AND Patient must not have received prior treatment with a NTRK inhibitor – AND Patient must not receive more than 3 months of treatment under this restriction – Adult: – Locally advanced or metastatic salivary gland, secretory breast tumours harbouring NTRK gene fusion – Locally advanced or metastatic soft tissue sarcoma (STS), non-small cell lung cancer (NSCLC), thyroid cancer and colorectal cancer (CRC) tumours harbouring NTRK gene fusion Reimbursement of companion diagnostic test: NTRK fusion testing in patients with locally advanced or metastatic solid tumour to determine eligibility for larotrectinib (Vitrakvi) considered and recommended at MSAC meeting 25-26 November 2021 – Fluorescence in-situ hybridisation (FISH) test of tumour tissue – Next generation sequencing (NGS) test for neurotrophic tropomyosin receptor kinase (NTRK1, NTRK2, NTRK3) fusions by RNA or DNA in tumour tissue The University of Sydney https://www.pbs.gov.au/medicine/item/13027P-13029R-13031W-13043L-13281B-13289K https://www.pbs.gov.au/info/industry/listing/elements/pbac-meetings/psd/2022-03/larotrectinib-capsule-25-mg-capsule-100-mg-oral-solution http://www.msac.gov.au/internet/msac/publishing.nsf/Content/1602.1-public Biologicals Definition of a Biological A biological comprises, contains or is derived from human cells or human tissues (or specified by the Secretary to be a biological) AND IS USED TO - treat or prevent disease, ailment, defect or injury; or - diagnose the condition of a person; or - influence, inhibit or modify a physiological process in persons; or - test the susceptibility of persons to a disease or ailment; or - replace or modify parts of the anatomy in persons. The University of Sydney https://www.legislation.gov.au/Details/C2023C00102  Biologicals are grouped into classes based on level of risk Mesenchymal FMT products Acellular skin stem cell for Demineralised iPSC-derived CAR T cells (in hospitals) for wound treatment of bone mixed cell therapies covering graft-versus- with carrier (tissue banks) host disease Class 1 Class 2 Class 3 Class 3 Class 4 Class 4 The University of Sydney FMT faecal microbiotia transplants iPSC induced pluripotent stem cell CAR T Chimeric antigen receptor T cells Application process (Class 1) Must be listed in Schedule 16 of Therapeutic Goods Regulations, 1990 Currently only faecal microbiota transplant (FMT) material listed Submit application form Pay appropriate fees GMP not required The University of Sydney https://www.tga.gov.au/resources/resource/guidance/applying-inclusion-class-1-biological-artg https://theconversation.com/stool-transplantation-shows-promise-treating-cancer-therapy-side-effect-106657 Application process (Class 2, 3, or 4) First round Second First request Second round Third Expert Pre-sub- Sub- for inform- Post- round round request round advisory Decision mission mission for inform- decision evaluation ation evaluation evaluation review (Section ation 32) The University of Sydney https://www.tga.gov.au/resources/resource/guidance/applying-inclusion-class-2-3-or-4-biological-artg-step-step-guide Cell therapies - Alliance for Regenerative Medicine H1 2022 report: https://alliancerm.org/sector- snapshot-april-2024/ - Project A-CELL: https://alliancerm.org/manufacturing/a-cell-2022 The University of Sydney Genetically Modified Organisms (GMOs) Regulatory Integration of GMOs Biosecurity Australia Imports Pests/disease protection TGA APVMA GM, GM-derived therapeutics GM, GM-derived veterinary products; insecticidal, herbicidal crops OGTR Toxicity/allergenicity GM foods GM, GM-derived Industrial products FSANZ AICIS The University of Sydney Gene Technology (GT) Act 2000 a national scheme passed in came into effect on for the regulation of December 2000 21 June 2001 genetically modified organisms (GMOs) GT Regulations User’s Guide – plain legislation mirrored 2001 – day to day English aid to in State/Territory information on interpretation of Act, Acts operation of the Act Regulations The University of Sydney What is a GMO? an organism that has an organism that has inherited modified traits been modified by GT from a modified organism does not include humans who have received anything declared by the somatic cell gene therapy regulations to be a GMO or an organism declared by the regulations not to be a GMO The University of Sydney What are dealings with GMOs? propagate the GMO make, develop, produce or manufacture the GMO grow, raise or culture breed the GMO use the GMO in the course of manufacture of a thing that is not a GMO importation The University of Sydney GMO Authorisations Exempt dealings Knockout mice Notifiable low risk dealings Lab-based experiments Licence - does not involve intentional Some gene therapy, manufacturing, vaccines release into environment (DNIR) Licence - intentional release into the GM crops, some gene therapy, vaccines environment (DIR) Licence - inadvertent dealings Petunia plants GMO Register – no longer require Blue carnations licence, deemed safe Emergency dealing determination Equine influenza vaccine The University of Sydney Cell and Gene Therapy Products  Delivery methods for gene therapy The University of Sydney Which of the following gene therapy products are delivered in vivo or ex vivo? Kymriah (tisagenlecleucel) Luxturna (voretigene neparvovec) Zolgensma (onasemnogene abeparvovec) Yescarta (axicabtagene ciloleucel) Hemgenix (etranacogene dezaparvovec) The University of Sydney Which of the following therapeutic goods need a licence from OGTR? Kymriah (tisagenlecleucel) Luxturna (voretigene neparvovec) Zolgensma (onasemnogene abeparvovec) Yescarta (axicabtagene ciloleucel) Hemgenix (etranacogene dezaparvovec) The University of Sydney How are the following products regulated by the TGA? Choose Prescription Medicine or Biological Kymriah (tisagenlecleucel) Luxturna (voretigene neparvovec) Zolgensma (onasemnogene abeparvovec) Yescarta (axicabtagene ciloleucel) Hemgenix (etranacogene dezaparvovec) The University of Sydney Regulatory Pathways Regulatory Type of gene therapy Example For further information pathway Ex vivo (gene is delivered to cells CAR-T cells Australian regulatory Class 4 outside of the body, which are guidelines for biologicals biological then transferred back into the (human cells) (ARGB) body) In vivo Adeno- Australian Regulatory Prescription (gene is transferred to cells associated Guidelines for Prescription medicine inside the patient’s body) virus Medicines (ARGPM) The University of Sydney Presentation title 72  Genetically modified human therapeutics Product Name OGTR Licence Supply Date Issued ARTG Start Date AusPAR Luxturna DNIR-615 Commercial 26 May 2020 5 Aug 2020 https://www.tga.gov.au/auspar/a (voretigene uspar-voretigene-neparvovec neparvovec) Zolgensma DNIR-621 Commercial 24 Aug 2020 4 Mar 2021 https://www.tga.gov.au/auspar/a (onasemnogene uspar-onasemnogene- abeparvovec) abeparvovec AZ Covid-19 DIR-180 Commercial 8 Feb 2021 16 Feb 2021 https://www.tga.gov.au/auspar/a vaccine uspar-chadox-1-s (Vaxzevria) Influenza vaccine DIR-171 Clinical trial 10 Jun 2020 N/A Not registered, still in (Sing2016 H3N2 Phase 1b development M2SR) The University of Sydney Class 4 biological cell therapies - examples Product Name First ARTG Entry Kymriah 19 December 2018 (tisagenlecleucel) Yescarta 11 February 2020 (axicabtagene ciloleucel) Tecartus 21 July 2021 (brexucabtagene autoleucel) Carvykti 6 June 2023 (ciltacabtagene autoleucel) The University of Sydney Future Directions Future trends in therapeutic product development Precision medicine Cell therapies Gene therapies New genetic editing techniques 3D printing – implants, tablets, tissue reconstruction Brain-device interfaces Nanotechnology Synthetic biology The University of Sydney AI-driven devices Questions?  COMMONWEALTH OF AUSTRALIA Copyright Regulation WARNING This material has been reproduced and communicated to you by or on behalf of the University of Sydney pursuant to Part VB of the Copyright Act 1968 (the Act). The material in this communication may be subject to copyright under the Act. Any further reproduction or communication of this material by you may be the subject of copyright protection under the Act. Do not remove this notice