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Pink Sheet – Cell Therapy Development: White Paper Urges US FDA To Allow Some Shortcuts

Pink Sheet – Cell Therapy Development: White Paper Urges US FDA To Allow Some Shortcuts

A Friends of Cancer Research white paper argues that the use of pre-clinical, dosing and manufacturing data from Gilead Sciences, Inc./Kite Pharma’s Yescarta CAR-T therapy to support approval of the follow-on Tecartus provides a model for the US FDA to use in streamlining iterative product development of cellular therapies.

“Yescarta and Tecartus provide an example of extrapolation in engineered cellular therapy products,” the white paper says. Yescarta (axicabtagene ciloleucel) was one of the first CAR-T anticancer therapies approved by FDA in 2017. Tecartus (brexucabtagene autoleucel), approved in 2020, “shares the same anti-CD19 CAR construct, the vector used in the manufacturing, the final drug product composition, and cryopreservation method as Yescarta,” the white paper notes.

However, Tecartus “has a modified manufacturing process, which includes a white blood cell enrichment process.”

The similarities of the two products led to important shortcuts in the development process of Tecartus, including reliance on preclinical toxicology, PK, and genotoxicity studies already done for Yescarta, dose selection based on experience with the earlier product, use of the existing REMS for post-marketing safety follow-up, shared CMC data, and – critically, given the COVID-related travel disruptions during the review – a waiver of the need for some facility inspections prior to approval. (Also see “Keeping Track: Kite’s Tecartus Is Third CAR-T With US FDA Approval; Submissions Round-Up” – Pink Sheet, 26 Jul, 2020.)

“The concept of leveraging prior data and the totality of evidence seen in this example can be extended to other engineered cellular therapy products in development,” the white paper states. FOCR released the paper in conjunction with a Friends of Cancer Research meeting on 22 May to continue the group’s discussion approaches to “accelerate development” of “the next generation of cellular therapies.”

The white paper fleshes out a concept proposed by Kite during a March FOCR webinar that kicked off the initiative. Global Regulatory Affairs Executive Director Jonathan Jazayeria suggested that FDA consider creating something akin to the existing oncology “Assessment Aid” as a framework to discuss and eventually employ extrapolation strategies in drug development.

Center for Biologics Evaluation & Research officials indicated interest in the idea. (Also see “US FDA Open To Cell Therapy ‘Assessment Aid’ That Could Speed Development Of Next-Gen Cancer Drugs” – Pink Sheet, 13 Mar, 2023.)

The framing of data extrapolation as an existing precedent for FDA underpins the white paper. In addition to the directly relevant experience with Tecartus/Yescarta, the FOCR group notes a long history at FDA of “data extrapolation to advance new versions of investigational products … across therapeutic classes due to an understanding of the biology, mechanism of action, and manufacturing processes.”

The white paper lists several examples in an appendix, including:

  • Approval of a controlled-release formulation of carvedilol (Coreg CR) based solely on PK/PD data comparing exposure to the original IR formulation;

  • Reliance on the QTc safety studies for the original liraglutide formulation (Victoza) for approval of a new weight-loss product (Saxenda);

  • Extrapolation of clinical and manufacturing data to support reformulations of Herceptin and Rituxan to incorporate the spreading agent hyaluronidase; and

  • Reliance on data from the original Prevnar vaccine to support approval of versions with additional strains (Prevnar 13 and Prevnar 20).

The paper also notes prior FDA guidance that includes advice on approaches to studying multiple versions of a cellular and gene therapy in a single umbrella trial. In the guidance, FDA outlines an approach to permit use of a “Primary IND” with related products filing “Secondary INDs” that rely on information in the primary filing.

During the meeting, FDA reported that uptake of the “umbrella” approach has been relatively slow, meaning it is too soon to offer any best practices or lessons learned.

The approach outlined in the guidance “is something that we believe is a great opportunity to improve the overall efficiency of development and to really save expenditures,” CBER official Larissa Lapteva said.

However, “sometimes we put out a new policy and we see a barrage of proposals coming in, because people have been expecting it. This is not something that happened with this guidance.” Instead, proposals to try out the approach are “coming slowly.”

“We are starting to see more and more of these proposals,” Lapteva said. But “we are still not having enough experience to really make any systematic conclusions about what are the successes versus failures.”

Looking on the bright side, Lapteva suggested one important lesson learned: “from the regulatory point of view, we were able to meet this need with adjustment of our administrative procedures in allowing manufacturers not to send in a fully-fledged IND every time.”

As an immediate step, the white paper offers a “prototype” assessment aid to use in framing FDA/sponsor discussions of potential extrapolation plans. FDA continues to see that concept as promising, but still at the “conceptual” level.

“We have used assessment aids before,” Lapteva noted. They “are helpful because they help to orient our review staff in the proposal, in the submission, understanding the rationale for what is being proposed. … Assessment aids are also helpful to industry to organize their thoughts, to crystallize their strategies for what they will put in that submission.”

In that light, the prototype is “a helpful tool.” However, “right now it is probably still more at the conceptual level. Obviously, as was alluded here before, different products will have completely different strategies. … Some time from now we will hopefully we will have an assessment aid oriented to, say, CAR-T therapies. And there could be an assessment aid oriented to T-cell receptor therapies, or an assessment oriented to another category of products.”

Lapteva stressed the importance of a statement of purpose. “It would also be helpful for us to know when these proposals are sent to us, what is the impetus for this next generation product? …Is it improving efficacy? Is it allowing more durability of the response? Does it lead to fewer or lessening of your side effects? Is it more convenient in administration, maybe less invasive? Or does it improve the manufacturing so much that the costs would be decreased significantly?”

“It would be helpful for us to know the driving factor behind this next product,” and “where we need to generate additional data perhaps to demonstrate that the product is as good or better.”