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

Blog
10 May 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

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 letters 3 – 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 overall 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 website8. 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

In their associated clarification webinar, CAR T cell design was highlighted in particular with respect to changes made to the final guidance. As CAR T cell design has evolved to target multiple antigens, that is, when multiple CARs are expressed in a single drug product, FDA has observed that recombination events can occur during manufacturing which reduce product consistency and result in reduced expression of the CARs. These recombination events can adversely impact product development.  From a CAR design perspective, sponsors and developers need to reduce if feasible this risk of recombination events. This change to the final guidance reflects the rapidly evolving scientific knowledge and understanding that will continue to occur as these products develop further.

Vectors

Vector quality directly contributes to CAR T cell quality and consistency, described in the guidance as being ‘a critical component that furnishes a pharmacological activity for the treatment of disease’.  From a design and development perspective, a key element of the guide to note is the use of vectors that integrate into the DNA (e.g. retroviral based vectors or transposons). This is due to the potential for long term transgene expression compared to non-integrated vectors. Consequently, long term follow up is recommended, ‘because integrating vectors may increase the risk of delayed adverse events’.  In comments submitted by the Biotechnology Innovation Organization in 20229, they requested that as more safety related data becomes available based on real time clinical experience, that FDA remains flexible in its definition of ‘long term follow up’.  FDA has issued Guidance for Industry in 2020 – ‘Long Term Follow-Up After Administration of Human Gene Therapy Products’1

Cellular Starting Materials

The potential impact to patients who have been previously administered CAR T cells is emphasised in the updated guidance – Particular consideration should be given to patients who have received CAR T cells previously’. Such patients may be considered for different CAR T cell clinical studies due to lack of response. It is not yet clear how previously administered CAR T cells impact the safety and efficacy of the CAR T cells under development.  As noted in the guidance, ‘Previously administered CAR-T cells in the starting material may have unexpected effects on CAR T cell manufacturing (e.g., expansion or transduction rates), potency, in vivo expansion safety and efficacy’.  This impact can be assessed by performing an evaluation of previously administered CAR T cell levels in the cellular starting material, through the detection of common structural elements, although this monitoring may not necessarily impact patient eligibility.

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

As vectors are considered a drug substance (in contrast to the EMA position describing the vector as a starting material), all aspects of its manufacture according to phase specific expectations, including full GMP manufacturing for late-stage clinical studies and licensure need to be considered.  The current gene therapy CMC Guidance8 provides recommendations for manufacturing and testing of the vector. Lot release expectations are phase specific, with full safety testing and appropriate characterisation for early phase studies. FDA recommends that lot release testing includes the measure of vector concentration (i.e. strength), such as titre for viral vectors so the amount of vector can consistently be applied in CAR T cell manufacturing.  For biological activity, while transgene expression alone may be sufficient to support early phase IND studies, additional measures of biological activity are needed for clinical study(s) intended to provide evidence of effectiveness to support the market application. As noted above, there are additional safety concerns and testing expectations related to the use of retroviral-based vectors.

Collection, Handling and Testing of Cellular Starting Material

While CAR T cells can be manufactured from a variety of cells, this guidance focusses on leukapheresis derived materials as this is the most common sources at this time. Consistent leukapheresis procedures are important to support consistent product manufacturing, with a recommendation that procedures for collection are consistent across different sites. In particular, the maintenance of the Chain of Identity (COI) should be described and validated for licensure.

In the associated FDA Webinar at www.fda.gov, FDA responded to a query regarding controlling the impact of donor variability on drug product variability in late phase CAR T cell development. Donor variability is a significant contributor to lot-to-lot variability of the product. FDA recognizes that even with a consistent manufacturing process, there is going to be an expected level of lot-to-lot variation in the final drug product. For autologous products, it is recommended to include a sufficient number of product lots and patients in clinical studies, which should inform sponsors of the acceptable level of variability that will be apparent in the commercial product. For allogenic, while the incoming material is generally more uniform as it comes from healthy donors, it is recommended that a range of donors are used to manufacture different lots as part of the clinical study enabling the definition of a more robust manufacturing space and to understand the clinical impact of product attribute variability.

CAR T Cell Manufacturing

This section of the guidance provides details on process control expectation to address the inherent sources of variability within the manufacturing process as a result of use of different donors where applicable. Added to this is the variability associated with a multi-step manufacturing process. Ultimately, expectations for CAR T manufacture align with the normal product development expectations including progressive characterisation and control of the manufacturing process.

Changes to this section mostly include updates on the original text that in most cases, have not changed the original intent but do enhance the clarity of the requirements including. The following changes are points to note:

  • The extent of in-process testing and testing of intermediate and final product to be as appropriate for the phase of product development.
  • To assure product safety, the aseptic processing must be validated for licensure.
  • The updated guidance distinguishes between stability test requirements for fresh or cryopreserved product.
  • For stability studies, the final guidance expands on the use of health donor material for both early stability studies and licensure, taking into account the need to enable determination of product shelf life.

CAR T Cell Testing

The guidance gives direct advice on some assays that are particularly applicable to CAR T cells. It’s notable that the delineation between autologous and allogenic is made with respect to the requirement for additional testing for allogenic products may be required beyond what is currently outlined in the final guidance.

The assays outlined below are addressed in the guidance with additional specific examples for potency expectations.

  • Flow cytometry
  • Vector copy number
  • Identity
  • Potency

While the changes to this section are mostly clarification, it’s clear that the agency recognises the challenges for the developers who need to demonstrate appropriate control of the test methods as distinct from having validated methods for Phase 1 clinical studies.

With respect to Vector Copy Number (VCN), over recent years, the FDA had updated its recommendations for monitoring the average number of vector integrations in the final drug product is included in the draft guidance from 2022.  FDA in the past accepted vector copy number measurements as a function of total cells or as a function of total number of CAR positive cells. FDA now recommends, as it did in the draft guidance, reporting vector copy number per CAR positive cell on the final certificate of analysis provides a more useful assessment of patient risk and allows for a better comparison of product variability across lots.

For potency testing, the final guidance provides specific examples for different product design potency expectations. This additional detail is to support the need to address where CAR T cells express multiple transgenes.

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