Cell and Gene therapies (CGT, as referred by FDA [1]) or Advanced Therapy Medicinal Products (ATMP, as referred by EMA [2]) are innovative therapies that mainly target orphan diseases and high unmet medical needs. They include gene therapy medicinal products, cell therapy medicinal products, tissue-engineered therapies, and combined ATMP, which contain one or more medical devices as an integral part of the medicine. The key therapeutic areas include genetic disorders, haematological malignancies and other cancers or long-term, monogenic, and cartilage diseases. Since legislation opened in 2007, only 25 ATMPs have been approved in Europe by EMA, 27 CGT were approved by the U.S. FDA, and some were already withdrawn.  

Challenges associated with CGT and ATMP Development

Indeed, several challenges remain in CGT/ATMP development and market access:
  • CGT/ATMP is often developed for orphan diseases, which means that the patient population is limited for clinical trials, which can make it challenging to demonstrate their safety and efficacy,
  • Their complex nature poses significant Chemistry, Manufacturing, and Control (CMC) challenges: establishing well-defined and standardised analytical methods for products characterisation is an ongoing CMC challenge, ensuring an accurate assessment of product quality, identity, purity, and potency,
  • Developing CGT/ATMP is expensive due to the need for specialised manufacturing processes, making it challenging to scale up production to meet demand, limiting their availability and increasing costs. As a result of these high development and production costs, challenges in obtaining reimbursement from healthcare payers lead to limited patient access to these treatments. Indeed, 28% of ATMPs that were first approved were withdrawn from the EU market. 20% were withdrawn because of the closing of  EU manufacturing site reasons, and 80% for commercial reasons - mainly the lack of uptake and reimbursement in key European countries. Today this reimbursement is based on benefit-risk by national authorities rather than the EMA to ensure that ATMP is evaluated in the context of local healthcare contexts and resources,
Finally, CGT/ATMP face safety and efficacy challenges, with adverse events such as toxicity related to the use of viral vectors or cell therapy, starting material and donor-related aspects, in a context where administration is also often a complex procedure – limiting even more patient eligibility Considering these challenges, regulators have tempted to propose some guidance and solutions to support innovative therapies:  

EMA and FDA Guidelines providing recommendations for CGT and ATMP Development

The EMA and The FDA have published several guidelines : However, these guidelines do not address all types of products and applications (as the scope may be quite large), they do not address either specific guidelines for the development of combined ATMP, and they also lack specific guidelines for critical CMC development steps like process validation, control of raw materials, and quality control testing, which are crucial to ensure the safety, efficacy, and reproducibility of the products.  

Additional support for the assessment of CGT and ATMP dossiers

In addition, to speed up patient access to medications and to aid reimbursement in markets with minimal to no pricing and reimbursement infrastructure, the European Union (EU) passed new legislation on Joint Clinical Assessments (JCAs) in 2022: Regulation (EU) 2021/2282. It will be implemented by 2025, starting with oncology products and ATMPs. EUnetHTA 21 is actively working on providing guidance and templates to facilitate this process. The European Network for HTA (EUnetHTA) is a collaborative network that aims to facilitate and promote cooperation among health technology assessment (HTA) organisations across Europe. The main objectives of the JCA, in conjunction with Joint Scientific Committees (JSCs), are to expedite access to new therapies, minimise redundant efforts, and establish harmonised methodologies for clinical evaluations across various healthcare agencies within the EU. While considerable information is already available on the submission process and its requirements, the actual implementation of the JCA may encounter challenges. Some concerns and areas requiring clarification include how individual countries will utilise the JCA reports, the potential for duplicated efforts, and the additional evidence requirements specific countries may impose. It will be intriguing to observe how countries incorporate JCA data into their health technology assessment (HTA) processes and determine the overall success of the JCA in streamlining the HTA procedure and achieving harmonisation.

Finally, as for many product types *, developing standardised post-authorisation monitoring of the products or real-world evidence data generation may support the development of such innovative therapies.

Still today, the regulatory and market access pathways for CGT/ATMP are complex and vary between countries, making it challenging: first, to obtain compliance and approval, and second, to ensure market sustainability.  

Importance of a Strong Regulatory and Compliance Core Team

Meanwhile, a strong and specialised regulatory and compliance core team is key at all stages to ensure the central interface and coordination from product regulatory classification and strategy, CMC, preclinical and clinical development, to HTA, market access and commercial promotion in each targeted market, for the ultimate benefit of patients' quality of life and safety.

*As shown by the Horizon Europe call HORIZON-HLTH-2024-IND-06-08, Developing EU methodological frameworks for clinical/performance evaluation and post-market clinical/performance follow-up of medical devices and in vitro diagnostic medical devices (IVDs)\  

References

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https://www.ema.europa.eu/en/human-regulatory/overview/advanced-therapy-medicinal-products-overview (2018)
  1. Cellular & Gene Therapy Products. FDA
https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products (2023)
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  1. Verdera, H. C., Kuranda, K. & Mingozzi, F. AAV Vector Immunogenicity in Humans: A Long Journey to Successful Gene Transfer. Ther. J. Am. Soc. Gene Ther. 28, 723–746 (2020)
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  1. European Network for Health Technology Assessment and HTA regulation
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  1. Regulation on Health Technology Assessment
https://health.ec.europa.eu/health-technology-assessment/regulation-health-technology-assessment_en  
[1] Federal Drug Administration (in the U.S.A)
[2] European Medicines Agency
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