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C. Russell Y. Cruz MD, PhD
Children’s National Hospital
Washington, DC, USA

THERE IS THIS EASE, THIS SIMPLICITY, THIS INSPIRATION, WHEN WE WRITE ABOUT REVOLUTIONS. “Chimeric antigen receptor (CAR) T cell therapies are here to change the world,” we say (and have been saying for over a decade – in grants, in lay articles, in interviews). The cancer-stricken can now be cancer-free. Every disease can potentially be targeted: HIV, autoimmune disease, many others. But the impact of revolutions is only as good as the governing that happens after – the boring, tedious, trial-and-error part of making the dream available to all.

This is why we care about guidance, about regulations, about the collective guardrails we put to ensure a methodical deployment of cell and gene therapies.

The recently released US Food and Drug Administration (FDA) Guidance Document, “Considerations for the Development of Chimeric Antigen Receptor (CAR) T Cell Products”  is an important step towards bringing the CAR T cell revolution into standard of care status. The Guidance Working Group was chaired by Dr. Kimberly Schultz, Director of Division 2, Office of Gene Therapy at the FDA, and is composed of Dr. Nirjal Bhattarai, Dr. Heba Degheidy, Dr. Graeme Price, Dr. Alyssa Galaro, Dr. Allen Wensky, Dr. Xiaofei Wang, Dr. Yixia Jia, Dr. Peter Bross, Dr. Mona Elmacken, and Dr. Upendra Mahat.

In a webinar  following publication of the guidance, several panelists from the FDA talked about developing safe and effective CAR T cell products. In this discussion, which took place March 7, 2024 (with a recording available online at the FDA website),  the FDA provided an overview of the final guidance, emphasizing points of interests for practitioners in the field, and answered the most common questions submitted by the community. The webinar was moderated by Dr. Denise Gavin, Director of the Office of Gene Therapy in the Office of Therapeutic Products (OTP), and the panelists included members of the working group - Dr. Kimberly Schultz, Dr. Allen Wensky (Division Director, Division of Pharmacology/Toxicology 1, Office of Pharmacology/Toxicology), Dr. Yuxia Jia (Medical Officer, Division of Oncology, Office of Clinical Evaluation), and Dr. Xiaofei Wang (Senior Clinical Pharmacology Reviewer, Division of Clinical Evaluation General Medicine, Office of Clinical Evaluation).

Here are some highlights:

GUIDANCE. “It’s clear there’s great enthusiasm in this area of research,” said Dr. Gavin. The FDA guidance document, released two months earlier, is “intended to assist sponsors, industry members, and other stakeholders by providing [them] with practical, multidisciplinary information on how to develop safe and effective CAR T cell products.” A draft guidance was made available in 2022, and comments on the draft were solicited shortly after. Over 650 comments from 85 companies, societies, and individuals were submitted and documented online.  Our society suggested “giving more detailed consideration to managing risks and the development of allogeneic CAR T cells as these are coming increasingly to the fore.” ISCT also suggested the mention of ICANS (immune effector cell associated neurotoxicity), which was increasingly used by practitioners of the field. Caring Cross, an organization dedicated to ensuring access to advanced cell and gene therapies for all patients, especially in low and middle-income countries, suggested the use of “place-of-care” instead of “point-of-care” to avoid the misconception that therapy is “adjacent to where the patient is being treated, as opposed [to] within the same or an adjoining facility.” The idea of “point-of-care” manufacturing is one that seeks to use automated devices and newer manufacturing models to circumvent the high costs and limited reach of centralized facilities. The American Society of Hematology, on the other hand, sought additional clarification in several areas – serial administration of CAR T, using cryopreservation for all studies, risk-benefit calculations, the special circumstance of pediatric patients, donor eligibility for autologous leukapheresis, the FDA’s dose escalation preferences, the challenge of developing immunogenicity tests, cytokine release syndrome monitoring, the use of poorly predictive mixed lymphocyte reactions for evaluating risks of graft versus host disease, and the capture of expected/associated cellular depletion. The Foundation for the Accreditation of Cellular Therapy (FACT) suggested references for maintaining the chain of identity. “We recommend that the guidance reference ISBT 128 as a potential coding and labeling system to maintain COI. ISBT 128, managed by the non-governmental, non-profit organization ICCBBA, is a global standard for the terminology, identification, coding, and labeling of Medical Products of Human Origin.” 

GENERAL CONSIDERATIONS FOR CAR T CELL DEVELOPMENT. FDA guidance emphasizes that making CAR T cells work consistently and safely is crucial. To achieve this, the guidance asks researchers submitting an IND application  to include a full drug substance section. The design of several product components – the construct, the vector, the cellular starting material, and the drug product formulation – should be the focus in early development. One specific scenario highlighted is the potential confounding effects of previously administered CAR T cells in the starting material on the new product in terms of manufacturing, potency, in vivo expansion, safety, and efficacy.

CMC RECOMMENDATIONS. Some chemistry, manufacturing, and controls (CMC) section recommendations included sufficient characterization of safety and quality of the vector, a well-controlled CAR T cell manufacturing process, proper management of changes (including assessment of comparability) during the CAR T manufacturing lifecycle, and the need to test individual biological activities of elements in the case of multiple transgenes. Some CMC related comments addressed in final guidance included clarification for the need of in-use stability, clarity on recommendations specific for autologous vs allogeneic products, and emphasis on characterization vs eligibility criteria for patients who previously received CAR T cells.

NON-CLINICAL TESTING. Non-clinical testing of CAR T cells should consider both the design of the novel construct (specificity of the CAR for targets, characterization of targets) and the cellular component (specific risks depending on cell source). Evaluation of CAR T cell safety and activity in vivo and in vitro, including use of immunocompromised animals and species-specific surrogates, is crucial for informing clinical trials. Since publication of the draft, several comments were addressed in the final guidance, including broadening text to describe vector types, added additional assays to evaluate CAR T, and included additional examples of newer CAR T components.

CLINICAL TESTING. Designing clinical trials for CAR T cell therapies requires careful consideration of both patient selection and potential risks. Sponsors need to weigh the potential benefits against risks when defining who can participate in the study, taking into account factors like disease severity and whether other treatment options exist. Early phase trials might face challenges in evaluating toxicity and optimal dosing due to differences in patients' underlying  comorbidities and dose response relationships. To ensure patient safety, the clinical protocol should outline clear guidelines for escalation/de-escalation of dose. Staggered treatment approaches can also be considered to minimize risk. The clinical protocol should include a comprehensive plan for monitoring patients during the trial, with specific criteria for grading potential side effects. Additionally, the follow-up duration should be tailored to the patient's underlying disease and how long the specific CAR T cell products are expected persist in their body. For trials involving CAR T cells derived from allogeneic sources, the panel emphasized the importance of monitoring for graft versus host disease (GVHD) using a standardized grading system and treatment plan. Finally, the discussion addressed clarifying language around dosing strategies based on weight vs surface area, and incorporated additional provisions for monitoring specific toxicities, such as cytokine release syndrome and immune effector cell associated neurotoxicity. Some comments addressed in the final guidance included clarifications for diagnostic tests in settings where commercially available assays are unavailable, the initiation of product use in children if appropriately justified, and clarification on toxicity.

Questions and Answers. Some common questions highlighted and answered by the panel included the following (edited and shortened for clarity):

Q: Can you explain the advantages of reporting vector copy number per CAR positive cell instead of per total cells?
A: Though neither are a perfect measure of vector integration, representation using per CAR-positive cell is more representative because CAR negative cells often don’t have integrated vector. Thus, this is more useful for assessing patient risk and allows for better comparison of product variability.

Q: What are essential non-clinical studies for the IND when submitting a new CAR/a new target?
A: This depends on many factors, including the nature of the product and additional components and modifications. Focusing on characterizing activity of the product, target specificity, and overall safety profile are recommended, as is early communication with the FDA.

Q: How do you incorporate additional safeguards for pediatric patients?
A: These safeguards are outlined in detail in 21 CFR Part 50 SubPart D

Q: What are recommendations for dose-finding studies?
A: Initial starting dose can be based on preclinical studies or clinical information from other similar CAR T products. A half a log increase for dose escalation schemes is recommended. 

Q: How should we control impact of donor variability on drug product variability in late phase CAR T cell development?
A: Control of manufacturing steps may include incoming material testing, cell selection, and other processes that will minimize variability – though it is still important that a range of donors still be included

Q: Is safety assessment in an immunocompromised tumor-bearing animal required?
A: Limited safety information can be obtained from these models because of the absence of an immune system, and animals often do not express the target antigen. Some safety information can be gleaned, like proliferation, but these do not provide the complete measure of a product’s safety

Q: How will retreatment with CAR T cells be addressed from a safety perspective?
A: Proposals will be evaluated on a case by case basis

Q: What are FDA’s recommendations for a clinical pharmacology package to support BLA submission? Would the agency like to review the translational/clinical pharmacology analysis plan, which specifies pharmacokinetics, pharmacodynamics, and response analyses up front during the clinical development process?
A: For submission, applicants should provide information to support dose selection from a kinetic or pharmacodynamic assessment. PK, PD, safety, and efficacy can provide important information about CAR T cell products. Though not required, providing this analysis plan is recommended.

Q: What are the FDA recommendations for allogeneic CAR T cell release testing?
A: In general release testing for allogeneic is similar to autologous, with additional safety tests like addressing  cytokine independent growth of residual alpha beta TCR positive G cells (posing risks for GVHD), testing of HHV6-8, donor screening/testing required in 21 CFR 1271. Recommended discussing these additional safety tests with the FDA during a Pre IND meeting.

Q: What are the expectations for visual inspection of the CAR T cell product?
A: Inspection of the products against white and black backgrounds to look for visible defects and particulates should be done, with final containers selected to reduce risk for particulates. Inspection of containers at multiple points may be a mitigation strategy. Visual inspection is separate from appearance testing.

Any additional questions about the document can be directed to the Office of Communication, Outreach and Development (OCOD). This office can be reached at 1-800-835-4709 or 240-402-8010, at ocod@fda.hhs.gov, or at https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics.

References

[1] https://www.fda.gov/regulatory-information/search-fda-guidance-documents/considerations-development-chimeric-antigen-receptor-car-t-cell-products

[1] https://www.fda.gov/news-events/otp-events-meetings-and-workshops/fda-cber-webinar-considerations-development-car-t-cell-products-03072024

[1]https://fda.zoomgov.com/rec/play/jtQ4sN5Kva5mfRpy64PpEuHWeG8Bn0C8mrqqEtLxaS249QFiOSezwl2LHTvWRP09lffvsg_vLjNggcFT.0DkunzdQXoYdSa8?canPlayFromShare=true&from=share_recording_detail&continueMode=true&componentName=rec-play&originRequestUrl=https%3A%2F%2Ffda.zoomgov.com

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[1] https://www.regulations.gov/docket/FDA-2021-D-0404/comments