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Dr. Vorapin Chinchalongporn, PhD
SC21 Bio-Pharma Laboratories
Thailand

Dr. Tongted Das, PhD
Monash Health
Australia

Adam Lee, MS
Thermo Fisher Scientific
United States

The 2025 Global Regulatory Perspectives (GRP), a flagship element of the ISCT annual meeting program since 2009 was held in New Orleans in May. This year GRP was presented as three related Roundtable sessions. The series of insightful and forward-looking sessions brought together regulatory experts, researchers, and industry leaders to address key challenges in cell and gene therapy development. The primary goal of the GRP sessions was to discuss regulatory challenges and strategies for optimising cell procurement for diverse geographies, donor selection, and regulatory pathways for development of curiglial cell therapies derived from umbilical cords for multiple indications, including Alzheimer’s disease (AD), retinitis pigmentosa (RP) and age-related macular degeneration (AMD). 

The GRP Roundtable Discussion featured three interconnected sessions: 

Session 1: How to Optimize Cell Procurement for Multiple Geographies and End Uses? 
This session set the stage by identifying the biological and logistical challenges in sourcing and expanding a hypothetical novel microglial-like cell (CD45+CD11b+) isolated from umbilical cords Curiglial. Manufacturing challenges were discussed including the need for weeks of culture to obtain sufficient cells, the need for suitable donors with low APOE expression and issues of donor variability leading to variability in cell product characteristics. The developer, NeuroMedica, wanted to expand to new markets and needed to source donors from different countries so turned to the 2025 GRP for guidance. 

Session 2: Donor – The Allogeneic Problem. 
Building on the foundation laid in Session 1, this session focussed on strategies to improve donor selection, manufacturing consistency, and regulatory compliance. Regulatory considerations were taken to address the variability of donor characteristics since it can greatly affect the outcomes of the cell therapy manufacturing process. Discussions included genetic screening and testing across geographies, machine learning/AI-driven donor prediction, and regulatory considerations for cell bank and process changes. 

Session 3: Beyond One Label: Accelerated Approvals and Risk Considerations for Cell & Gene Therapies.  
The final session tied these efforts together by exploring how to navigate regulatory approvals in developing therapies for small patient populations with varying risk profiles. The same Curiglial cells have demonstrated potential therapeutic applications not only for AD but also RP and AMD. The final session covered bridging preclinical studies, assessing disease administration risks, accelerated approval pathways, and strategies for regulatory filings including master IND structure, platform technology or adaptive trial designs that could be used to streamline clinical development for expanding the product label for Curiglial cell therapy to multiple indications. 

Together, the GRP sessions provided a comprehensive framework for advancing Curiglial from bench to bedside. Key takeaways highlight the innovative approaches and challenges that NeuroMedica encountered in developing Curiglial across multiple indications while navigating complex scientific, regulatory, and manufacturing landscapes. The discussions and insights shared during the GRP roundtables will help guide the strategy of future cell and gene therapy development. Details of panellists and key takeaways from the discussions are as follows.

Session 1: How to Optimize Cell Procurement for Multiple Geographies and End Uses? 

Moderator: Dominic Wall – Cell Therapies Pty Ltd & Peter MacCallum Cancer Centre, Australia
Panelists: 
Bethanie Kuker – NMDP, United States
Yusuke Nozaki – Pharmaceuticals and Medical Devices Agency (PMDA), Japan
Deborah Hursh – Hursh Cell Therapy Consulting, LLC., United States

Key Takeaways:

1. Challenges in Donor Screening for USA: Products going to the USA require donor testing in labs using FDA-approved kits, which is a major barrier for manipulated products manufactured from donor cells sourced outside the USA.
2. FDA Exemptions: In USA, FDA exemptions for expansion of donated cells from overseas are possible but difficult to obtain despite the rationale of scarcity, rarity, and uniqueness of the starting material.
3. Regional Testing Differences: Japan requires tests for viruses including Parvovirus twice within the window period, while Europe mandates CE-certified kits for donor screening. The mandated testing requirements vary between jurisdictions both in terms of what is tested and how it is must be tested e.g. regulatory agency licenced/inspected laboratory
4. ISBT 128 Labelling: There is a global effort to move towards ISBT 128 labelling for international standardisation.
5. Reimbursement vs Compensation: Reimbursement and compensation can be viewed differently between countries. For example, USA allows paid donation (compensation), while Japan and Australia prefer altruistic donation (reimbursement only).
6. Customs Complexity: Customs and import regulations across Europe and other regions are complicated. For directed donations, Registries such as the US National Marrow Donor Program (NMDP) manage these issues. However, commercial product developers would need to seek advice.

Session 2: Donors – The Allogeneic Problem

Moderator: Scott R Burger – Advanced Cell & Gene Therapy, LLC, USA
Panelists: 
Kathy Francissen – Genentech, United States
Glenn Smith – TGA, Australia
Don Fink – Dark Horse Consulting, United States

Key Takeaways:

1. Genetic Testing Limitations: Predictive power of genetic testing remains unclear, and there is an obligation to inform donors of results that indicate disease or carrier state.
2. Starting Material Variability: Understanding the starting material and donor-to donor variability and its impact on products is critical.  Accepting less than perfect starting materials might be an option to gain better knowledge and make further adjustments in manufacturing processes, but may can at the cost of batch failures.
   Machine Learning/AI for Donor Selection: To use ML/AI for regulatory purposes, a large data set is required to enable providing consistent results.
3. Potency Assay: Potency assays must relate to the disease curative function and mechanism of action (MoA) of the therapy in the final product. Master Cell Banks (MCBs) and Working Cell Banks (WCBs) should be fully characterised and potency testing done on both.
4. Production Process Changes: Expanding to a new indication may require more cells and therefore production process improvements. Changes to manufacturing and testing processes after approval will require extensive work and additional testing to ensure the product remains the same after the changes.
5. Pooling Donor Materials: It is important to talk to regulators early on in pre-IND or similar meetings if pooling of donor materials is proposed, to determine if this is acceptable. Pooling batches of product is not allowed.

Session 3: Accelerated Approvals and Risk Considerations for Cell & Gene Therapies 

Moderator: Kevin Bosse – Nationwide Children’s Hospital, USA
Panellists: 
Kiran Musunuru – University of Pennsylvania, USA
Melina Cossote Kumoto – ANVISA, Brazil

Key Takeaways:

1. Proof of Concept (POC) and Route of Administration (ROA): Developers are advised to prioritise POC and ROA early since the ROAs are different among the clinical indications, and the patients are complicated.
2. Animal Models: For the first POC and biodistribution studies, and the first variant in a platform study, an animal model is required even though FDA is trying to move away from animal testing. In some diseases and cell therapies, other non-clinical POC studies or other clinical data might be sufficient if relevant.
3. Regulatory Package: Each indication requires a separate regulatory package, calibrated to the disease risk. If the risk of disease is very high and urgent, there might be a scope to accept more risk in the therapy.
4. Leverage Clinical Data: Clinical data from the first indication can be leveraged for subsequent indications.
5. CMC Data: CMC data can be leveraged but comparability data is required for different indications. If the comparability data is not meaningful, potency assays should be emphasised.
6. Regulatory Approval: Developers should focus on getting approval for one indication before broadening to others, preventing wasting resources.
7. Adaptive Designs: Regulators are open to umbrella and adaptive designs, which can benefit developers.
8. Risk Mitigation Plans: A risk mitigation plan is required for changes in (but not limited to) manufacturing processes, routes of administration, or indications.

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