by
Gabrielle O’Sullivan PhD MPH (Hons) 1
1Executive Officer, Royal Prince Alfred Hospital Institutional Biosafety Committee, Royal Prince Alfred Hospital, Australia
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AUSTRALIAN AND NEW ZEALAND REGULATORY UPDATES
New Zealand Therapeutic Product Bill passed into law
The New Zealand Therapeutic Products Bill received Royal assent on 26 July 2023 becoming the Therapeutic Products Act (2023) and replacing the Medicines Act 1981. Most provisions in the Act will not commence (come into effect) until mid-2026. The Ministry of Health will be establishing the Regulator to administer the Act. The Act provides fit-for-purpose risk proportionate regulation of medical devices, and cell, gene and tissue therapies. It also covers natural health products, which will have their own regulations under the Act. [1]
Consultation on proposed changes to how New Zealand’s regulates GMOs
The New Zealand Government has consulted on proposed changes to New Zealand’s legislation and regulations for genetically modified organisms (GMOs) used in laboratory settings and for biomedical therapies. It proposes (among other things) a new risk-tiering framework for laboratory research, reducing the assessment and approval requirements for medicines that are, or contain, new organisms (which includes GMOs), and clarifying the regulatory status of certain biotechnologies such as mRNA and DNA vaccines, epigenetic modifications and gene editing. The consultation ran from 3 July 2023 until 25 August 2023. [2, 3]
NHMRC National Statement on Ethical Conduct in Human Research 2023 Update
The updated National Statement on Ethical Conduct in Human Research 2023 (National Statement) was released by the NHMRC in July 2023 and commences on 1 January 2024 [4]. The Statement sets out criteria by which Human Research Ethics Committees authorize clinical trials. This is the first update since 2018. Key changes include the introduction of a continuum-based risk model instead of the previous three level model of negligible, low, greater than low risk; and clarifications regarding harm, discomfort, burden, inconvenience, individual and collective harms, and risk-sharing. [5, 6]
TGA medical devices reforms and vigilance program
The TGA is implementing a range of medical device reforms, and has recently extended the deadline for certain medical device reforms because of the impact of the European Union Medical Device Regulations (EU MDR). The extended deadlines would give manufacturers time to obtain an EU MDR certificate before the end of the EU MDR transition on 31 December 2028, and for sponsors to use the MDR certificate to apply to the TGA before 1 July 2029. [7]
The TGA has also published a presentation on the new Medical Devices Vigilance Program (MDVP). The program is an initiative to improve sponsors' understanding of, and compliance with, their post-market vigilance regulatory requirements, through a self-assessment tool and program of desktop audits and on-site inspections [8]. This complements a new Medical Devices Vigilance Program Pilot, which Australian medical device sponsors who have an entry in the Australian Register of Therapeutic Goods (ARTG) are eligible to participate in [9].
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INTERNATIONAL REGULATORY UPDATES RELEVANT TO AUSTRALIA & NEW ZEALAND
Cynata has secured approval from the Netherlands’ regulatory authority to initiate a Phase 1 clinical trial on the application of CYP-001 in kidney transplant patients
Cynata Therapeutics Limited, has secured approval from the Centrale Commissie Mensgebonden Onderzoek (CCMO), the Netherlands’ regulatory authority, to initiate a Phase 1 clinical trial focused on the application of CYP-001 in kidney transplant patients. The trial is named “Safety and Efficacy of MCA-derived Mesenchymal Stromal Cell Therapy in Renal Transplant Recipients: The Nereid Study”. [10]
FDA decision date on Vertex CRISPR gene editing drug exa-cel for sickle cell disease expected in December 2023
The FDA decision date on the Vertex CRISR gene editing drug exagamglogene autotemcel (exa-cel) for sickle cell disease is expected on 8 December 2023. This could be the first marketed medicine based on CRISPR gene editing technology. The treatment has been developed by Vertex Pharmaceuticals and partner CRISPR Therapeutics. [11] There will be a FDA Cellular, Tissue, and Gene Therapies Advisory Committee meeting on 31 October 2023 to discuss and make recommendations on the biologics license application (BLA) 125787 from Vertex Pharmaceuticals, Inc. for exa-cel [12]. Use of the drug for beta thalassemia will be subject to a separate verdict under a standard review expected March 2024. [11]
Mesoblast announces next steps for Ryoncil® (remestemcel-L)
Mesoblast plans to generate new potency assay data and run a new trial of Ryoncil® (remestemcel-L announcement) to support a marketing approval application for remestemcel-L in the treatment of pediatric and adult steroid-refractory acute graft versus host disease (SR-aGvHD) following a Type A meeting held with the US FDA [13, 14]. FDA Type A meetings are reserved for discussions necessary for an otherwise stalled product development program to proceed or to address an important safety issue. [15]
Human embryo-like models created in lab from human stem cells
Recently, embryo-like models created in the lab from human stem cells have been reported by two research groups: one from Israel [16] and another at Cambridge University [17]. The models have morphological similarity to a human embryo at day 14. A number of other embryo-like models have been reported previously, including one by the Polo group at Monash in 2021 [18]. There are ethics and legal questions around the models. At present they are not equivalent to human embryos, and would not be allowed to be used, or transferred into a human being, for reproductive purposes. Current rules allow human embryos to be grown in vitro for up to 14 days, although there has been discussion about the appropriateness of the 14-day rule [19]. The models are expected to enable insights into embryo development, problems that may occur during development, and possible new drug targets. [20, 21]
ICH reflection paper on integrating real-world evidence into regulatory decision-making
The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) has consulted on a reflection paper for public consultation to harmonise real-world evidence terminology and enable the convergence of general principles for planning and reporting studies using real-world data to support regulatory decision-making [22]. It identifies the following areas for harmonisation: convergence on terminology, format for protocols and reports of study results submitted to regulatory agencies throughout the lifecycle of medicines, and registration of protocols and reports. The paper is co-authored by the EMA, U.S. FDA and Health Canada. It builds on a 2022 statement from the International Coalition of Medicines Regulatory Authorities (ICMRA) on a strategic approach for future ICH guidelines on the assessment of real-world data and real-world evidence. [23]
FDA draft guidance on “Demonstrating Substantial Evidence of Effectiveness Based on One Adequate and Well-Controlled Clinical Investigation and Confirmatory Evidence.”
The FDA has published this draft guidance which complements the draft guidance for industry “Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products” (December 2019) and the “Guidance for industry Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products” (May 1998). It supplements and expands the recommendations in the 2019 Substantial Evidence of Effectiveness draft guidance by providing further detail on the use of data drawn from one or more sources to support the results of one adequate and well-controlled clinical investigation. It also provides examples of types of data that could be considered confirmatory evidence. This guidance emphasizes the importance of early engagement with the FDA for sponsors that intend to establish substantial evidence of effectiveness with one adequate and well-controlled clinical investigation and confirmatory evidence. [24]
REFERENCES
1. Manatū Hauora (New Zealand Ministry of Health), Therapeutic products regulatory regime, https://www.health.govt.nz/our-work/regulation-health-and-disability-system/therapeutic-products-regulatory-regime#:~:text=The%20passing%20of%20the%20Therapeutic,Therapeutic%20Products%20Act%20(2023), Last updated 15 August 2023
2. Genetic modification and genetically modified organisms (GMOs) are primarily regulated in New Zealand under the Hazardous Substances and New Organisms Act 1996 (HSNO Act), its regulations, and related standards: https://www.legislation.govt.nz/act/public/1996/0030/latest/DLM381222.html, Version as at 24 August 2023
3. New Zealand, Improving our GMO regulations for laboratory and biomedical research: Consultation document, https://environment.govt.nz/publications/improving-our-gmo-regulations-for-laboratory-and-biomedical-research-consultation-document/, Published 3 July 2023
4. NHMRC National Statement on Ethical Conduct in Human Research 2023NHMRC, https://www.nhmrc.gov.au/about-us/publications/national-statement-ethical-conduct-human-research-2023#block-views-block-file-attachments-content-block-1, published July 2023
5. NHMRC FAQs, https://www.nhmrc.gov.au/research-policy/ethics/national-statement-ethical-conduct-human-research/2023-update-faqs
6. Kings & Wood Mallesons: https://www.kwm.com/au/en/insights/latest-thinking/update-to-the-national-statement-on-ethical-conduct-in-human-research.html, published 22 August 2023 (Article courtesy E O’Sullivan)
7. TGA, Deadline for certain medical device reforms to be extended, https://www.tga.gov.au/news/news/deadline-certain-medical-device-reforms-be-extended, published 7 July 2023
8. TGA, The new Medical Devices Vigilance Program- information session for medical device sponsors in Australia, https://www.tga.gov.au/resources/event/webinars/new-medical-devices-vigilance-program-information-session-medical-device-sponsors-australia#:~:text=The%20Medical%20Devices%20Vigilance%20Program,audits%20and%20on%2Dsite%20inspections, published 14 September 2023
9. TGA, Medical Devices Vigilance Program – Pilot, https://www.tga.gov.au/how-we-regulate/monitoring-safety-and-shortages/medical-devices-vigilance-program-pilot, published 8 September 2023
10. Healthcare & Biotech News, StockHound, Cynata Therapeutics Expands Its Clinical Horizons with Approval for a New Kidney Transplant Trial (ASX:CYP), https://stockhound.com.au/cynata-therapeutics-expands-its-clinical-horizons-with-approval-for-a-new-kidney-transplant-trial-asxcyp/, published 21 August 2023
11. C Newman, Biopharma Dive, FDA sets decision dates for Vertex, CRISPR gene editing drug, https://www.biopharmadive.com/news/vertex-crispr-priority-review-sickle-cell-gene-editing/652581/, published 9 June 2023
12. Cellular, Tissue, and Gene Therapies Advisory Committee October 31, 2023 Meeting Announcement, https://www.fda.gov/advisory-committees/advisory-committee-calendar/cellular-tissue-and-gene-therapies-advisory-committee-october-31-2023-meeting-announcement-10312023 (Information courtesy K Kime)
13. NP Taylor, Fierce Biotech, Take 3: Mesoblast plots path to market for twice-rejected cell therapy, https://www.fiercebiotech.com/biotech/take-three-mesoblast-plots-path-market-twice-rejected-cell-therapy, published 21 September 2023 (Article courtesy J Macpherson)
14. Mesoblast ASX Announcement: https://investorsmedia.mesoblast.com/static-files/adfc1ba0-bd4d-47bd-b0a0-a0b3516b0520, published 21 September 2023
15. Office of Therapeutic Products (OTP), FDA, https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/otp-type-meetings#:~:text=Type%20A%20meetings%20are%20reserved,address%20an%20important%20safety%20issue
16. Oldak, B et al. Complete human day 14 post-implantation embryo models from naïve ES cells, Nature, https://www.nature.com/articles/s41586-023-06604-5, published: 06 September 2023
17. Weatherbee, B A T et al.: A model of the post-implantation human embryo derived from pluripotent stem cells. Nature; 27 June 2023. DOI: 10.1038/s41586-023-06368-y, https://www.nature.com/articles/s41586-023-06368-y, published 17 August 2023
18. Liu, X et al, Modelling human blastocysts by reprogramming fibroblasts into iBlastoids. Nature (DOI: 10.1038/s41586-021-03372-y, https://www.nature.com/articles/s41586-021-03372-y, published 17 March 2021
19. Ball, P, Embryo Models’ Challenge Legal, Ethical and Biological Concepts, Quanta Magazine, https://www.quantamagazine.org/embryo-models-challenge-legal-ethical-and-biological-concepts-20230613/, published 13 June 2023
20. Insoo Hyun, Human Embryo Models Spark Needless Controversy, 13 July 2023
21. Reuters, Israeli scientists create model of human embryo without eggs or sperm, https://www.reuters.com/science/israeli-scientists-create-model-human-embryo-without-eggs-or-sperm-2023-09-07/, published 8 September 2023
22. EMA, ICH, https://www.ema.europa.eu/en/documents/scientific-guideline/ich-reflection-paper-proposed-international-harmonisation-real-world-evidence-terminology_en.pdf, published 30 June 2023
23. International Coalition of Medicines Regulatory Authorities (ICMRA), News, https://www.icmra.info/drupal/news/ich_reflection_paper, published 12 July 2023
24. FDA, Demonstrating Substantial Evidence of Effectiveness Based on One Adequate and Well-Controlled Clinical Investigation and Confirmatory Evidence, https://www.fda.gov/regulatory-information/search-fda-guidance-documents/demonstrating-substantial-evidence-effectiveness-based-one-adequate-and-well-controlled-clinical, published September 2023, for comment by 18 December 2023
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