CAR T cell product development guidance: Comments ask for CMC details

Both industry and clinicians asked the US Food and Drug Administration (FDA) for clarification related to the evaluation of cellular starting materials in its draft guidance on chimeric antigen receptor (CAR) T cell product development.
 
The public comments also sought more details on change management and how the guidance applies to other genetically modified products.
 
The draft guidance, issued on 15 March 2022, provides recommendations on chemistry, manufacturing and control (CMC) elements; pharmacology and toxicology; clinical study design; and considerations related to autologous and allogeneic CAR T cell products. (RELATED: FDA drafts guidance on genome editing, CAR T cell therapies, Regulatory Focus 16 March 2022)
 
Starting materials
 
Several commenters asked FDA to provide more details about its recommendation that sponsors consider evaluation of previously administered CAR T cell levels in the starting material. Both the American Society of Hematology and the Foundation for the Accreditation of Cellular Therapy (FACT) pointed out that this recommendation would be challenging because the appropriate tests may not be available since they are often proprietary and earlier CAR T cell therapies would have come from other manufacturers. They asked the FDA for guidance on how to conduct the evaluations.
 
Kite, a Gilead company, echoed that concern, noting that evaluating the vector copy number for previously administered CAR T cells would be challenging if the CAR T cells were from another investigational product. “We ask that the agency acknowledge that this evaluation may only be accomplished if the patient is re-dosed with the same product as previously administered or another CAR T product from the same company,” Kite wrote in comments.
 
The American Society of Gene and Cell Therapy (ASGCT) went farther, saying that the recommendation to test for residual CAR T cells is unnecessary to assure safety and would not produce a clinical benefit for patients. “CAR T cell manufacturing includes evaluation of the product at multiple steps (e.g., expansion or transduction rates) as well as the quality attributes and potency of the final product. If previous CAR cells have an impact on the efficacy of the product, this will be caught as part of the existing manufacturing controls,” ASGCT wrote in comments.
 
Change management
 
The draft guidance notes that an Investigational New Drug (IND) application should be updated to reflect a change in the manufacturing process, regardless of the product development stage. ASGCT noted that the guidance covers major changes, but asked FDA to provide examples of minor changes, as well as the type of information sponsors should submit in updates to verify minor changes. ASGCT suggested that minor changes might include changes in cell hold times or the introduction of a new computer system or automation without a change in the manufacturing process.
 
“Providing examples such as these will help IND sponsors assess the regulatory expectations about what data are expected to support minor changes and would also help alleviate the 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 saying that recommendations in the guidance would be applicable to other genetically modified lymphocytes but noted that the guidance was short on specifics of how the principles would be applied beyond CAR T cell products. “We would suggest that FDA expressly expand the scope of this guidance and note more specifically where different cell types may raise unique scientific considerations,” BIO wrote in comments on the draft guidance.
 
Novartis also requested that FDA provide more details about which recommendations apply to other genetically modified lymphocyte products, such as CAR Natural Killer (NK) cells or T cell receptor (TCR)-modified T cells, possibly in future guidance.
 
Increased communication
 
In its comments, Novartis also called on the agency to increase communication opportunities with sponsors outside of the PDUFA (Prescription Drug User Fee Act) meeting structure.
 
Meetings with more than one sponsor could also be helpful in certain cases, Novartis wrote. “When several 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 noncompetitive development issues at the same time, such as at a regulatory workshop, leaving more time to focus on product specific issues at the product specific meetings.”
 
Public comments on CAR T cell guidance