Cell and gene therapy (CGT) products are gradually paving the path to provide novel treatment options for patients that have complex conditions related to cancers, genetic disorders, and other chronic conditions. However, CGT products are also associated with barriers related to cost that could significantly affect or delay patient access to these life-changing therapies. Indeed, CGT form a part of biological therapies that aim to diagnosis, prevent, and cure complex diseases. While there are several biosimilars of monoclonal antibodies and polypeptides, the next advancement would be to have biosimilars for CGT products to facilitate access to cost-effective and more advanced therapies for chronic conditions. But the development of CGT biosimilars has its own set of challenges pertaining to manufacturing, regulatory requirements, market size, and intellectual property. Let’s explore the evolving landscape of biosimilar cell and gene therapies, including key considerations, regulatory standards for submission.
Regulatory Challenges for Cell and Gene Therapy Products
There is a considerable number of CGT products being approved. For example, the U.S. FDA has approved 39 CGT products for the US market. These therapies modify cell properties for optimal therapeutic use and modify gene expression. Before getting into the development of biosimilars for CGT products, it is important to understand their regulatory environment… and for that, a robust understanding of the current regulatory landscape, including challenges, for CGT products is crucial.
Indeed, the development of regulatory pathways for biosimilar cell and gene therapies is challenging given the evolving regulations for both novel and biosimilar CGTs. While CGTs demonstrative transformative treatment options, there is still a need for better regulatory clarity given their complexity. CGT manufacturers face hurdles in ensuring safety, quality, and durability throughout development stages necessitating guidance on issues related to manufacturing and product stability. Inconsistencies have also been seen in reference to CGT products which further emphasize the need for more clear and robust framework for CGTs. The US FDA has started off with providing guidance on early-stage clinical trials and is encouraging umbrella trials to study multiple versions of CGTs for a given diseases while establishing the Office of Therapeutics (OTP) to expediting review of CGT products.
Key Considerations for Biosimilar Cell and Gene Therapy Products
Therapeutic protein products have traditionally been the focus of the regulatory pathway for biosimilars, with little overlap with emerging CGT space. However, CGT biosimilars that are to be developed in the future will need stakeholders to start by defining biosimilarity in complex CGTs before establishing the framework accordingly. Understanding terms like “highly similar” with “no clinically meaningful differences” will be imperative particularly given the primary mode of action for CGTs, which involve complex processes (i.e., cell modification in CAR-T therapies).
Cell Therapy Considerations
The challenges that are associated with biosimilar CGT development go beyond
“gene” and “vector-based” attributes- which tend to be the typical challenges associated with gene therapies. This adds more obstacles to the source and formulation of cellular materials. Inevitably, therapies derived from the patient’s own cells (autologous therapies) and those sourced from donors (allogenic therapies) present unique biosimilarization challenges.
For autologous therapies (i.e., CAR-T), in order to demonstrate biosimilarity, the biosimilar vector would have to closely match the reference products without affecting the viability of the cell. On the other hand, allogenic products may demonstrate more biosimilarity feasibility since autologous products may not fit biosimilarity given they are “self-donor”. The variability of donor material for allogenic therapies can bring complexities when demonstrating consistent efficacy and may require innovative methodologies & standardization. As technology further develops, and characteristics for quality for cell therapies become more clear, the biosimilar paradigm’s applicability to these therapies may evolve.
Gene Therapy Considerations
Gene therapy products are defined based on the unique genetic sequencing and “introduced” genetic material. These products depend on vectors to deliver this material into cells. The choice of the vector can have an impact on the delivery and effectiveness of the gene therapy, which may introduce unique considerations in determining biosimilarity. Compared to cell therapies, gene therapies have potential to be more adaptable to biosimilar development. This is because the transgene- the core element of gene therapy- could be identified and matched with a reference products, by examining genetic sequence. Biosimilar gene therapies would need to demonstrate a similar transgene and maybe even allow for vector variability to an extent, only if functional differences are well-characterized.
In order to establish biosimilarity for gene therapies, there needs to be an emphasis on the vector’s function and purity. Aspects such as DNA contamination and capsid fill rates (during manufacturing stages) need to be carefully considered. Long-term effects of gene therapy may need further investigation where durability becomes a major factor. New technologies also become important in analyzing gene therapy mechanisms, off-target impacts, and differences in vectors that could change the outcomes of genetic alterations.
Developing Standards for Submissions
In order to develop standards for biosimilar CGT submissions, production processes and product characteristics should be considered along with defining key quality characteristics for biosimilarity assessment. Requirements for manufacturing should cover aspects such as methods for cell harvesting, expansion, and transfection, proof of concept, safety, durability, & long-term efficacy data account for key evidence requirements. Furthermore, given the unique safety concerns related to CGT products, the role of animal studies and advanced in-vitro & in-silico technologies during pre-clinical testing is of high importance.
Conclusion
Developing biosimilar CGT products has demonstrated great potential for expanding access to more affordable life-changing treatments for chronic conditions and complex diseases. However, several hurdles related to regulatory, manufacturing, and scientific aspects need to be addressed. Establishing frameworks for biosmililarity is critical given the growth of CGT products in clinical use- but there needs to be an emphasis on defining quality attributes and making sure that the biosimilar product is safe, durable, and efficacious. Regulatory bodies, like the US FDA for example, have started to address these challenges but they still have a considerable way to go especially when it comes to clearly defining standards and methodologies.
Reach out to DDReg for end-to-end regulatory services for cell and gene therapy products. With over 15 years’ experience of navigating regulations for over 120 regulatory agencies and in-depth subject matter expertise, DDReg is your go-to-partner for rapid market access. Read more from experts here- Understanding Post-Approval Manufacturing Changes in Biosimilars and Interchangeable Products in USA