CAR-T product development: an assessment of FDA’s final guidance for industry

Regulatory-blog-image_100x100.jpgThis blog is part of The Regulatory Navigator series, where we explore the evolving regulatory landscape with actionable insight from Parexel's experts, sharing their experience to maximize success for clinical development and patient access.


The FDA released its final industry guidance for CAR-T developers on January 29, following a draft published in March 2022. Experts from Parexel Regulatory Strategy, including ex-FDA and EMA regulators, share their insight into the guidance’s clinical, non-clinical and CMC recommendations.  

CAR T-cells are gene therapy products regulated under FDA’s existing framework for biological products. The agency recognizes the specific complexity and challenge of development in this space, with this document offering recommendations to further guide sponsors. It focuses on oncology indications, including hematologic malignancies and solid tumors without explicitly addressing other treatment areas, such as autoimmune diseases. Considerations for “non-traditional” indications are still being studied and may possess significantly different benefit-risk considerations due to concerns of secondary T-cell malignancy. 

Notably, the guidance does not specifically mention the recent FDA investigation into secondary T-cell malignancies in patients treated with approved CAR-T products. This absence indicates that the FDA is still interpreting and assessing the findings. Nonetheless, the content of the guidance does not imply a significant change in the FDA's benefit-risk assessment for CAR-Ts. For instance, the recommended long-term follow-up (LTFU) duration of 15 years for patients who have received CAR-Ts manufactured using integrating vectors remains unchanged in the final guidance, compared to the draft guidance that preceded the recent T-cell malignancy issue. 

Overall, this guidance balances class-wide regulatory considerations for CAR-Ts, while emphasizing the importance of individualized FDA review of benefit-risk, based on the unique characteristics of each investigational CAR-T product/indication.

Clinical design perspectives – key takeaways

The guidance emphasizes the need for careful consideration of safety and efficacy throughout the development process. There is ongoing discomfort with the use of basket study design for CAR-T therapy studies. However, some changes may have a positive impact on flexibility in study design and analysis including: 

  • Dosing strategies: Previously, weight-based dosing was preferred, but the guidance now implies that the Office of Therapeutic Products (OTP) may be more open to the use of flat dosing for CAR-Ts.  
  • Continual reassessment methods (CRM): Previously CRM was considered unsuitable, but the final guidance now states that CRM may be deemed appropriate with proper justification.

OTP still has reservations about using accelerated titration designs for dose escalation in first-in-human (FIH) CAR-T studies. The guidance indicates that they prefer a more conservative approach to dose escalation. There is also concern about the adverse effects of repeat lymphodepletion in CAR-T products that require multiple administrations to individual patients. This highlights the importance of carefully considering the potential risks and benefits of repeated lymphodepletion in CAR-T therapy. 

The FDA’s prior standpoint that a development program should first assess the effects of a single administration of CAR T-cells before considering repeat administration remains unchanged. This approach aligns with the OTP’s cautious approach to ensure patient safety in CAR-T investigational studies. 

Nonclinical perspectives – key takeaways

With clarity on the specific studies necessary for CAR-T nonclinical programs, the guidance offers approaches for evaluating specificity, which is determined by the accuracy of the T-cell receptor binding to the cancer cell surface antigen. Evaluating specificity is undertaken by using in vitro assay and tissue reactivity assays to determine on-target vs off-target binding – as sometimes binding can falsely interact or bind to a comparable surface antigen on other non-cancerous cells.     

Additionally, in vivo animal models are recommended to assess specificity. Animal models, specifically human xenograft models, are valuable in proof-of-concept studies. They can provide insights into cell trafficking, proliferation patterns, and assist in determining the first-in-human (FIH) dose based on cell expansion in vivo. The FIH dose determination also considers prior clinical experience, effector-target ratio, kinetics of cell expansion, and the pharmacokinetics/pharmacodynamics of anti-tumor responses. 

The agency also allows for alternative methods to animal models but requires a thorough explanation and justification of the proposed alternatives. 

Characterizing the target antigen before proceeding with clinical studies is highly recommended. These characterization studies, based on clinical experience, will aid in identifying potential off-tumor targets that may affect the therapy's specificity. 

One crucial aspect to consider is the potential for CAR-T cells to undergo uncontrolled proliferation, which can be an indicator of tumorigenesis. Section D of the guidance clearly outlines the parameters that define CAR-T safety, including uncontrolled proliferation assessment. While there is no explicit information regarding T-cell tumorigenesis, there is a strong emphasis on evaluating the potential for uncontrolled proliferation, particularly in terms of IL-2 independent growth. 

Along with an assessment of uncontrolled proliferation, T-cell clonality, karyotype analysis, T-cell receptor repertoire, and specificity for viral antigens should also be evaluated. These analyses are typically performed ex vivo. 

CMC perspectives – key takeaways

CAR-T therapy manufacturing inherently includes multiple biological materials and complex processes, leading to potential sources of variability. Therefore, it is crucial to have control over the manufacturing process and conduct appropriate testing to ensure safety, quality, and lot-to-lot consistency of CAR T-cells. 

The guidance provides important principles and recommendations for emerging and experienced developers. The need to understand the cellular starting material and establish specifications for leukapheresis is emphasized, to control process and product variability. Importantly, changes to critical starting material, e.g., the genetic cassette, are considered a new product, highlighting the importance of maintaining consistency throughout the development process. 

Several aspects of CAR-T therapy development are addressed in the guidance: 

  • Validation expectations for flow cytometry are outlined, providing a helpful overview for developers 
  • Guidance on life-cycle approaches to comparability is provided, offering improved information compared to previous resources 
  • Acceptable potency assays for different phases of development are clarified, addressing concerns frequently raised by developers 
  • Long-term follow-up is recommended for products that include cellular-DNA-integrating vectors, since these vectors are likely to increase the risk of delayed adverse events as compared to non-integrating vectors.  

Change management, such as those related to manufacturing process changes and revision of analytical methods is covered in the context of comparability and study design. The guidance also touches on the acceptability of vector copy numbers (VCN) per transduced cell, an area that developers have found challenging. While some aspects are addressed, the guidance falls short of providing detailed explanations on the risks of insertional mutagenesis associated with VCN  in T-cells compared to other cells. This lack of clarity leaves developers without explicit guidance on meeting regulatory approval. 

Our considerations above represent only a summary of the recommendations within FDA’s final guidance. We recommend reviewing the guidance in full to understand the implications for your CAR-T development program. Parexel’s experts are always available for a conversation to discuss your questions, and to support you in interpreting and actioning the latest guidance. Please contact us.

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