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Summary of FDA Guidance for Industry: Considerations for the Development of Chimeric Antigen Receptor (CAR) T Cell Products

Sep 16, 2024

Aidan Harrington

Principal Consultant

On Jan 29th 2024, FDA released their Guidance for Industry on Considerations for the Development of Chimeric Antigen Receptor (CAR) T Cell Products1. CAR T cell products as depicted in Fig 1 below are human gene therapy products in which the T cell specificity is genetically modified to enable recognition of a desired target antigen for therapeutic purposes.


Fig 1: Car T Therapeutic Pathway
Fig 1: Car T Therapeutic Pathway


This release follows the initial draft issued in March 2022, which was extensively commented on by the industry, with over 650 comments from approximately 85 stakeholders2 representing various professional societies, therapeutic developers, academics and industry. This final guidance is intended to assist sponsors, including industry and academic sponsors, industry members and other stakeholders through the provision of practical, multidisciplinary information on how to develop safe and effective CAR T cell products. It is notable that this final guidance was issued just one week after FDA sent out public letters3-7 to the companies responsible at that time for US approved CAR T therapies requesting the addition of black-box warnings related to secondary cancer risks to each product labelling. Despite this, at the time of this announcement, FDA stated that the over all benefits of the marketed CAR T products continue to outweigh their potential risks for their approved uses.

While the guidance addresses considerations specific to CAR T, it is not designed as a stand-alone guidance, and highlights the multitude of applicable additional guidance on cell and gene therapies from FDA’s website. This guidance focuses on ex vivo modified CAR T cells for oncology indications with recommendations based on FDA’s experience with CAR T cell development, including with currently approved CAR T cell therapies.

To support the release and FDA’s ongoing communication with relevant stakeholders, a webinar on the key points from the guidance presented on 07th March 2024 is available at www.fda.gov. In the introduction to this webinar, FDA highlights the ongoing ‘gaining of experience’ as the field evolves by both FDA and industry and their commitment through the publication of this guidance and other outreach activities to support the potentially diverse range of indications that can be addressed by these and similar products.

The guidance document addresses the following topics relevant to the development of CAR-T products:

  General considerations for CAR-T cell design and development

  Chemistry, Manufacturing and Controls (CMC) recommendations

  Non clinical and clinical recommendations

The guidance underpins the ambition of the both FDA and industry to achieving batch-to-batch consistency in CAT-T therapy manufacture. This is perhaps one of the greatest challenges to the industry due to primarily to the use of patient immune cells as starting materials, among other raw-materials that collectively introduce an inherently variable process. A consequence of this variability is the inability to supply product to patents. There is an onus on all stakeholders to investigate, understand and control the manufacturing processes for CAR T therapies which this guidance document is endeavouring to enable. It is clear that the guidance also has taken into account the FDA experience to date, and since the original draft release in March 2022 with the six currently approved CAR T therapies. Of course what this also highlights is the rapidly evolving scientific, medical and process understanding of CAR T therapies and the challenge for all to recognize that the final guidance is for this point and time, in the knowledge that it this too will continually evolve.

Outlined below is a summary of key points, with an emphasis on changes made since the 2022 draft. Also included are clarifications and responses to questions from the associated FDA webinar from 07th March, 2024.


General Considerations for CAR T Cell Design and Development

The complexity of CAR T cell manufacturing due to the involvement of multiple biological materials and complex multi-step procedures are recognized as potential sources of variability among product lots. The guidance presents key considerations for CAR T cell design and development that enable the manufacture of products that deliver from a product safety and efficacy perspective while also meeting the requirements of the current regulatory framework. The areas addressed are:

  CAR construct

  Vector type

  Cellular starting material

  Fresh or cryopreserved final products

  • CAR construct
  • Vectors
  • Cellular Starting Materials

Chemistry, Manufacturing and Controls (CMC) Recommendations

Establishing a realistic CMC strategy from early development that considers the molecule, its development and the costs supporting it is essential in enabling delivery of a well-controlled process. While general CMC aspects for cell and gene therapy products is addressed across other guidance documents8, this section of the guidance reflects specific CAR T complexities and challenges throughout its development lifecycle. This section of the guidance addresses the following:

  Vector manufacturing and testing

  Collection, handling and testing of cellular starting material

  CAR T cell manufacturing and testing

  Managing manufacturing changes and assessing comparability during CAR T cell product lifecycle

  Single site or Multisite CAR T cell manufacturing

Outlined below is a summary of the CMC changes in the final guidance.

  More clearly delineated between recommendations for autologous and allogenic products

  Clarified the need for in-use stability regardless of whether the DP is formulated fresh or cryopreserved

  Added phase specific expectations (g. analytical assay qualification)

  Added specific examples for potency expectations

 Added recommendations for rapid manufacture of products and multi target CAR T cells

  • Vector Manufacturing and Testing
  • Collection, Handling and Testing of Cellular Starting Material
  • CAR T Cell Manufacturing
  • CAR T Cell Testing

Nonclinical and clinical recommendations

Nonclinical evaluation of CAR T cells are necessary to support a conclusion that it is reasonably safe to administer a product for a particular clinical investigation. There were no major changes to content of the nonclinical recommendations. The guidance addresses the following aspects:

  Nonclinical considerations for the CAR construct

  Nonclinical considerations for the cellular component of CAR T cells

  In vivo testing of CAR T cells

  CAR T cells with additional modifications


Clinical recommendations

In the final guidance, FDA provided clarifications that generally afforded more flexibility to sponsors. The following areas are addressed:

  Study population

  Treatment plan

  Clinical pharmacology considerations

  Safety evaluation and monitoring

  CAR T persistence and long term follow up

  Allogenic CAR T cells

 

References

1. U.S. Department of Health and Human Services, FDA, CBER (January 2024). “Considerations for the Development of Chimeric Antigen Receptor (CAR) T Cell Products, Guidance for Industry”. https://www.fda.gov/media/156896/download
2. Public comments posted to Docket ID: FDA-2021-D-0404: https://www.regulations.gov/docket/FDA-2021-D-0404
3. Safety Labeling Change Notification Letter – BREYANZI (lisocabtagenemaraleucel). News release. FDA. January 19, 2024. Accessed 03rd April, 2024. https://www.fda.gov/media/175622/download?attachment
4. Safety Labeling Change Notification Letter – CARVYKTI (ciltacabtageneautoleucel). News release. FDA. January 19, 2024. Accessed 03rd April, 2024. https://www.fda.gov/media/175624/download?attachment
5. Safety Labeling Change Notification Letter – KYMRIAH (tisagenlecleucel). News release. FDA. January 19, 2024. Accessed 03rd April, 2024. https://www.fda.gov/media/175625/download?attachment
6. Safety Labeling Change Notification Letter – TECARTUS (brexucabtageneautoleucel). News release. FDA. January 19, 2024. Accessed 03rd April, 2024. https://www.fda.gov/media/175626/download?attachment
7. Safety Labeling Change Notification Letter – YESCARTA (axicabtageneciloleucel). News release. FDA. January 19, 2024. Accessed 03rd April, 2024. https://www.fda.gov/media/175627/download?attachment
8. https://www.fda.gov/vaccines-blood-biologics/biologics-guidances/cellular-gene-therapy-guidances.
9. Biotechnology Innovation Organization Comment Letter (CAR) T Cell Products Guidance FDA, June 2022. Accessed 28th Mar 2024 https://www.bio.org/sites/default/files/2022-06/BIO%20Comment%20Letter%20%28CAR%29%20T%20Cell%20Products%20Guidance%20FDA%202021%20D%200404.pdf
10. U.S. Department of Health and Human Services, FDA, CBER (January 2020). “Long Term Follow-Up After Administration of Human Gene Therapy Products Guidance for Industry” Accessed 02nd April 2024. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/long-term-follow-after-administration-human-gene-therapy-products

AUTHOR

Aidan Harrington

Aidan Harrington

Principal Consultant

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