CAR T cell product development advice: comments ask for CMC details

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Posted on June 29, 2022 | By Mary Ellen Schneider

CAR T cell product development advice: comments ask for CMC details

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Industry and clinicians have asked the United States Food and Drug Administration (FDA) for clarification regarding the evaluation of cellular raw materials in its draft guidelines for the development of receptor T cell products. chimeric antigen (CAR).

Public comments also requested more detail on the management of the change and how the guidelines apply to other genetically modified products.

The orientation project, issued March 15, 2022, provides guidance on Chemistry, Manufacturing and Control (CMC) elements; pharmacology and toxicology; design of clinical studies; and considerations related to autologous and allogeneic CAR T cell products. (RELATED: FDA drafts guidelines on genome editing and CAR T cell therapiesRegulatory guidance March 16, 2022)

Starting materials

Several commenters have asked the FDA to provide more details on its recommendation that sponsors consider evaluating levels of previously administered CAR T cells in the starting material. The American Society of Hematology and the Foundation for the Accreditation of Cellular Therapy (FACT) pointed out that this recommendation would be difficult because appropriate tests may not be available as they are often proprietary and prior CAR T cell therapies would come from other manufacturers. They asked the FDA for guidance on how to conduct the assessments.

Kite, a Gilead company, echoed this concern, noting that assessing vector copy number for previously administered CAR T cells would be difficult if the CAR T cells were from another investigational product. “We ask the agency to recognize that this assessment can only be performed if the patient receives a new dose of the same product previously administered or another CAR T product from the same company,” Kite wrote in his comments.

The American Society of Gene and Cell Therapy (ASGCT) went further, saying the recommendation to test residual CAR T cells is not necessary to ensure safety and would not produce clinical benefit for patients. “CAR T cell manufacturing includes product evaluation at multiple stages (e.g., expansion or transduction rates) as well as quality attributes and potency of the final product. If previous CAR cells impact on the efficacy of the product, this will be taken into account within the framework of existing manufacturing controls,” the ASGCT wrote in its comments.

Change management

The draft guidance notes that an investigational new drug application (IND) should be updated to reflect a change in the manufacturing process, regardless of the stage of product development. The ASGCT noted that the guidelines cover major edits, but asked the FDA to provide examples of minor edits, as well as the type of information sponsors should submit in updates to verify minor edits. ASGCT suggested that minor changes could include changes to cell hold times or the introduction of a new computer or automation system with no change to the manufacturing process.

“Providing examples such as these will help IND sponsors assess regulatory expectations for data expected to support minor changes and would also help alleviate uncertainty and reduce the burden on the Agency to provide feedback. to each individual sponsor,” ASGCT wrote.

Other genetically modified lymphocytes

The Biotechnology Innovation Organization (BIO) praised the agency for stating that the recommendations in the guidelines would be applicable to other genetically modified lymphocytes, but noted that the guidelines lacked specifics on how the principles would be applied to the beyond CAR T cell products. “We suggest that the FDA expressly expand the scope of these guidelines and more specifically note where different cell types may raise unique scientific considerations,” BIO wrote in its comments on the draft. guidelines.

Novartis has also asked the FDA to provide more details on the recommendations that apply to other genetically engineered lymphocyte products, such as CAR Natural Killer (NK) cells or receptor-modified T cells. T cells (TCR), possibly in future directions.

Increased communication

In its comments, Novartis also called on the agency to increase communication opportunities with sponsors outside of the Prescription Drug User Fee Act (PDUFA) meeting structure.

Meetings with more than one sponsor could also be helpful in some cases, Novartis wrote. “When multiple next-generation CAR T sponsors are considering the use of similar new technologies and have similar regulatory issues, it may be more efficient for multiple sponsors to meet with the FDA to discuss general non-competitive development issues at the same time, such as to a regulatory workshop, allowing more time to focus on product-specific issues during product-specific meetings. »

Public Comments on CAR T Cell Guidelines

© 2022 Society of Regulatory Affairs Professionals.


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