Beyond definitions: The intricacies of cell therapy categorization

Regulatory distinctions

Despite efforts by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) to harmonize regulatory policy, challenges remain. Cell therapies have been broadly categorized by the FDA as products that “include cellular immunotherapies, cancer vaccines and other types of both autologous and allogeneic cells.”² The EMA classifies somatic-cell therapy medicines as those that contain living cells “used to cure, diagnose or prevent diseases.”³ Similarly, the American Society for Gene and Cell Therapy (ASGCT) adds that it involves the “transfer of a specific cell type(s) into a person to treat or prevent a disease.”⁴

Together, these definitions imply that there is a distinction between a well-defined cellular therapy product and a complex and variable tissue-based therapy or organ transplant that consists of many un-defined cell types and structural tissue elements. Regulators have expanded on this distinction: the FDA's guidance emphasizes the need for a defined composition, including the identification and characterization of the cell population, purity, potency, and viability [5],⁵ and the EMA specifies “the cell mixture needs to be characterised and its composition controlled.”⁶

Despite nuances in guidance language, regulators agree on a distinction between advanced cell therapy drug products and other transplant-based therapies due to differences in their biological nature and therapeutic mechanism.

Manufacturing and intended use

Similarly, a key differentiator between cell therapies and similar tissue-based products, such as allogeneic hematopoietic stem cell transplantation (HSCT), lies in nuances of the manufacturing process as well as intended use. For example, the EMA indicates that cells should “not [be] intended to be used for the same essential function(s) in the recipient and the donor”³ and should “contain or consist of engineered cells or tissues,”⁷ and must undergo substantial manipulation and/or have a different essential function as the starting material.

The FDA’s perspective is largely in agreement, in that cell-based biological drugs must be more than minimally manipulated and be intended for non-homologous applications.⁸ Here, the focus on both intended use and manufacturing (manipulation) eliminates organ transplants and HSCT products meant for bone marrow reconstitution from classification eligibility.

Interdisciplinary innovation

Another nuance regarding drug product composition is observed when scaffolds or matrices are necessary for developing a functional cell-based or engineered tissue drug product. The Alliance for Regenerative Medicine (ARM) emphasizes the importance of scaffolds and matrices in enhancing the therapeutic potential of cell-based therapies as these components can provide structural support, promote cell attachment, and facilitate tissue regeneration.⁹ From a classification perspective, the FDA specifies that products which combine cells with scaffolds or matrices are combination products, steered by both CBER and CDER guidelines, where relevant.¹⁰

Similarly, the EMA may classify these products as multidisciplinary tissue-engineered products under the ATMP framework.⁶

In both cases, it is necessary to have detailed characterization of both the cellular component and the scaffold/matrix, including biocompatibility, mechanical properties, and degradation profiles.

Decoding naming conventions in ex vivo gene therapy

Finally, it’s interesting to note the difference in the field’s naming convention for gene-modified cell therapies. For instance, cell-based immunotherapies like CAR-T are commonly referred to simply as cell therapy,¹¹ however gene-corrected hematopoietic stem cell therapies are often referred to as gene therapy.¹² This can cause confusion as both are gene-modified cell therapies, also known as ex vivo gene therapies. The reason for the discrepancy in naming convention lies within the focus of the therapeutic intervention: the genetic modification of cell-based immunotherapies is meant to enhance the functionality of the cells, while the primary focus of genetic modification in stem cell-based therapies is to serve as a vehicle for delivering a therapeutic or corrective gene.

While both approaches are in fact gene-modified cell therapies, cell-based immunotherapies may simply be referred to as "cell therapy" due to the focus on the cellular component's immune function, while stem cell-based gene-modified cell therapies are called "gene therapy" due to the emphasis on genetic correction.

Shifting paradigms

The evolving landscape of cell therapy signifies a shift in treatment approaches, showcasing the versatility and potential of cell-based interventions. Each drug product or candidate is truly unique, and as cell therapy becomes more interdisciplinary, understanding clear distinctions ensures a structured path for development, evaluation, and commercialization. Thoughtfully applying a standard naming convention will promote clarity and consistency in this complex and innovative field.

Citations

1. J.-J. Lefrère and P. Berche, "La thérapeutique du docteur Brown-Séquard," Histoire de la médecine, vol. 71, no. 2, pp. 69-75, 2010. 

2. U.S. Food and Drug Administration, "Cellular & Gene Therapy Products," 20 3 2023. Accessed 7 November 2024. Available online at: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products

3. European Medicines Agency, "Advanced therapy medicinal products: Overview," European Medicines Agency. Accessed 7 November 2024. Available online at: https://www.ema.europa.eu/en/human-regulatory-overview/advanced-therapy-medicinal-products-overview

4. American Society for Gene and Cell Therapy, "Cell Therapy Basics," 18 12 2023. Accessed 7 November 2024. Available online at: https://patienteducation.asgct.org/gene-therapy-101/cell-therapy-basics

5. U.S. Food and Drug Administration, "Guidance for Industry: Potency Tests for Cellular and Gene Therapy Products," 01 2011. Accessed 7 November 2024. Available online at: https://www.fda.gov/files/vaccines,%20blood%20%26%20biologics/published/Final-Guidance-for-Industry--Potency-Tests-for-Cellular-and-Gene-Therapy-Products.pdf

6. European Medicines Agency, "Guideline on human cell-based medicinal products," European Medicines Agency , 09 01 2008. [Online]. Accessed 7 November 2024. Available online at: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-human-cell-based-medicinal-products_en.pdf

7. European Medicines Agency, "Reflection paper on classification of advanced therapy medicinal products," 21 05 2015. Accessed 7 November 2024. Available online at: https://www.ema.europa.eu/en/documents/scientific-guideline/reflection-paper-classification-advanced-therapy-medicinal-products_en.pdf-0

8. C. Iglesias-Lopez, A. Agusti, M. Obach and A. Vallano, "Regulatory Framework for Advanced Therapy Medicinal Products in Europe and United States," Frontiers in Pharmacology, vol. 10, no. 2019, 2019. 

9. Alliance for Regenerative Medicine, "Tissue Engineering and Therapeutics: Takeaways from a Scientific Workshop," 06 09 2023. Accessed 7 November 2024. Available online at: http://alliancerm.org/wp-content/uploads/2024/02/20240215-ARM-Tissue-Engineering-White-Paper.pdf

10. U.S. Food and Drug Administration, "Guidance for Industry: Current Good Tissue Practice (CGTP) and Additional Requirements for Manufacturers of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps)," 12 2011. Accessed 7 November 2024. Available online at: https://www.fda.gov/media/82724/download

11. C. June, R. O'Connor, O. Kawalekar, S. Ghassemi and M. Milone, "CAR T cell immunotherapy for human cancer," Science, vol. 359, no. 6382, pp. 1361-1365, 2018. 

12. K. High and M. Roncarolo, "Gene Therapy," The New England Journal of Medicine, vol. 381, no. 5, pp. 455-464, 2019.