FDA Finalizes Sets of Guidelines for Both CAR-T Products and Genome Editing Products

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According to Federal Register notices, the guidance documents are updated versions of drafts originally published in March 2022.

UPDATE: March 12, 2024  The FDA's Center for Biologics Evaluation and Research (CBER) hosted a webinar highlighting key points from the final version of the CAR-T guidance document on March 7, 2024.11 In the webinar, a recording of which is now available on the FDA's website, the speakers covered the main points from the general, CMC, nonclinical, and clinical considerations for CAR-T development from the document. The webinar also included a question-and-answer segment (which begins about 30 minutes into the presentation).

"We first posted the draft guidance on considerations for the development of CAR T-cell products in March of 2022..." Kim Schultz, PhD, the division director of Division 2 for the Office of Gene Therapy CMC, said at the beginning of the webinar. "We received over 650 comments from approximately 85 stakeholders, and we really appreciate your thoughtful insights into where more clarity would be helpful. After consideration of each comment and with revisions as needed, the final guidance was then published at the beginning of 2024."

Schultz and colleagues offered a review of the guidance and responded to several questions, including those about the advantages of vector copy number reporting, essential studies required for investigational new drug applications, considerations for the development of CAR T products for pediatric conditions, recommendations for dose-finding studies, the controlling of donor variability, animal model needs, and many more.

Click here to watch the FDA's webinar on the CAR T guidance.

January 31, 2024 The FDA has finalized 2 guidance documents focused on the development of chimeric antigen receptor T-cell (CAR-T) therapy products and gene therapy products that incorporate human genome editing, respectively.1,2

According to a Federal Register notice, the CAR-T guidance document is the finalized version of a draft originally published in March 2022.3 The document covers factors relevant to the development of CAR-T products, including chemistry, manufacturing, and controls (CMC); pharmacology; toxicology; and clinical trial designs for patients with cancer. Furthermore, the document includes recommendations for both autologous and allogeneic CAR-T products, as well as other types of engineered lymphocyte therapies, such as T-cell receptor T-cell therapies and CAR natural killer cell therapies. Although, the FDA notes that because of the highly specific and unique nature of many of these other advanced lymphocyte therapy products, it may be pertinent for sponsors developing these products to discuss concerns directly with the Office of Tissues and Advanced Therapies in the CBER prior to investigational new drug (IND) application submission.1

“In the Federal Register of March 16, 2022 (87 FR 14893), FDA announced the availability of the draft guidance of the same title dated March 2022,” the notice states.3 “FDA received numerous comments on the draft guidance and those comments were considered as the guidance was finalized. Changes to the guidance include clarifying the scope, focusing on treatment for oncology indications, and the recommendations for CAR T-cells manufactured using cellular starting material from patients who have received CAR T-cells previously, potency for CAR T-cells that express multiple transgene elements, stability studies, and clinical monitoring. In addition, editorial changes were made to improve clarity.”

READ MORE: FDA Approves Kite’s Axi-Cel Manufacturing Change to Reduce Turnaround Time

The gene therapy product guidance document is likewise the finalized version of a draft from March 2022, according to a separate Federal Register notice.4 Recommendations in this guidance document pertain to human gene therapy products that incorporate genome editing of human somatic cells. The guidance document is mainly focused on factors that should be covered in IND applications for these products, including product design, manufacturing, and testing; nonclinical evaluations of safety; and the design of clinical trials.

Key Takeaways

  • The FDA has finalized guidance documents on chimeric antigen receptor T-cell (CAR-T) therapy products, covering factors relevant to development and clinical trial designs for patients with cancer.
  • Another finalized guidance document pertains to gene therapy products incorporating human genome editing, offering recommendations for investigational new drug applications, including product design, manufacturing, nonclinical safety evaluations, and clinical trial design.
  • The finalized CAR-T guidance comes after the FDA requested companies with approved CAR-T therapies to add black box warnings related to secondary cancer risks to their product labels.

“FDA received numerous comments on the draft guidance and those comments were considered as the guidance was finalized,” the notice states.4 “Changes to the guidance include clarifying the recommendations for genome editing components used only once (for example, in the manufacture of a master cell bank), expectations for potency assays, considerations for nonclinical studies with respect to potential for off-target toxicity, and applicability of accelerated approval to genome editing products. In addition, editorial changes were made to improve clarity.”

Notably, the finalized CAR-T guidance document comes just a week after the FDA sent out public letters to the companies responsible for the 6 CAR-T therapies currently approved for use in the US requesting the addition of black box warnings related to secondary cancer risks to each product’s labeling.5-10 “T-cell malignancies may occur following treatment with BCMA- and CD19-directed genetically modified autologous T-cell immunotherapies,” each letter states. The agency also requested additional references to T-cell malignancies be added to the 'WARNINGS AND PRECAUTIONS' sections for each of the 6 CAR-T products' labels: “T cell malignancies have occurred following treatment with BCMA- and CD19-directed genetically modified autologous T-cell immunotherapies, including [product name].” Notably, the FDA amended one of its letters to Kite Pharma on January 24, 2023, removing references to T-cell malignancies having occurred following treatment with Tecartus specifically.

REFERENCES
1. Considerations for the development of chimeric antigen receptor (CAR) T cell products. Guidance Document. FDA. January 30, 2023. Accessed January 31, 2024. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/considerations-development-chimeric-antigen-receptor-car-t-cell-products
2. Human gene therapy products incorporating human genome editing. Guidance Document. FDA. January 30, 2023. Accessed January 31, 2024. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/human-gene-therapy-products-incorporating-human-genome-editing
3. Considerations for the Development of Chimeric Antigen Receptor T Cell Products; Guidance for Industry; Availability. Notice. Federal Register. January 30, 2023. Accessed January 31, 2024. https://www.federalregister.gov/documents/2024/01/30/2024-01789/considerations-for-the-development-of-chimeric-antigen-receptor-t-cell-products-guidance-for
4. Human gene therapy products incorporating human genome editing; guidance for industry; availability. Notice. Federal Register. January 30, 2023. Accessed January 31, 2024. https://www.federalregister.gov/documents/2024/01/30/2024-01788/human-gene-therapy-products-incorporating-human-genome-editing-guidance-for-industry-availability
5. Safety Labeling Change Notification Letter - ABECMA (idecabtagenevicleucel). News release. FDA. January 19, 2024. Accessed January 31, 2024. https://www.fda.gov/media/175623/download?attachment
6. Safety Labeling Change Notification Letter - BREYANZI (lisocabtagenemaraleucel). News release. FDA. January 19, 2024. Accessed January 31, 2024. https://www.fda.gov/media/175622/download?attachment
7. Safety Labeling Change Notification Letter - CARVYKTI (ciltacabtageneautoleucel). News release. FDA. January 19, 2024. Accessed January 31, 2024. https://www.fda.gov/media/175624/download?attachment
8. Safety Labeling Change Notification Letter - KYMRIAH (tisagenlecleucel). News release. FDA. January 19, 2024. Accessed January 31, 2024. https://www.fda.gov/media/175625/download?attachment
9. Safety Labeling Change Notification Letter - TECARTUS (brexucabtageneautoleucel). News release. FDA. January 19, 2024. Accessed January 31, 2024. https://www.fda.gov/media/175626/download?attachment
10. Safety Labeling Change Notification Letter - YESCARTA (axicabtageneciloleucel). News release. FDA. January 19, 2024. Accessed January 31, 2024. https://www.fda.gov/media/175627/download?attachment
11. FDA CBER webinar: Considerations for the development of CAR T cell products. Guidance Document. FDA. March 7, 2024. Accessed March 12, 2024. https://www.fda.gov/news-events/otp-events-meetings-and-workshops/fda-cber-webinar-considerations-development-car-t-cell-products-03072024

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