The Center for Biologics Evaluation and Research is receptive to the idea of creating a regulatory framework on data extrapolation techniques to support the development of next-generation oncologics, CBER Senior Science Advisor Ingrid Markovic said during a Friends of Cancer Research webinar on 8 March.
Markovic, who is a CMC policy lead in the CBER Office of the Center Director, promised to “take back” a suggestion to develop an assessment aid or similar framework for sponsors to share and discuss data extrapolation techniques as the agency continues to gain experience with CAR-T and other cell therapies.
That suggestion came from Jonathan Jazayeria, Kite Pharma, Inc. global regulatory affairs executive director, which was based on his company’s experience developing Yescarta and Tecartus. Both products are distinct anti-CD19 CAR-Ts and use different manufacturing techniques that are tailored for their approved indications: non-Hodgkin lymphoma for Yescarta and mantle cell lymphoma and acute lymphoblastic leukemia for Tecartus. Kite has been a Gilead Sciences, Inc. company since 2017.
Jazayeria raised the potential benefits from data extrapolation, indicating that Yescarta’s development data helped shorten the time to first approval for Tecartus. He suggested the FDA could encourage similar data extrapolation for next-generation cell therapies by formalizing a pathway for sponsor discussions.
“FDA should formally encourage sponsors to introduce and discuss their extrapolation strategies, perhaps even preparing or developing some sort of a document similar to an assessment aid,” to explain their approaches and assign risk levels, Jazayeria said. “Once the agency gets more exposure and experience from different sponsors, they can begin to build that framework and have that comfort of when to allow extrapolation and when not to.”
“It may start off fairly conservative, but if we don’t build a path to having these conversations, then we will never be able to do so,” he added. “All of these things are issues that impact all sponsors in this space when we are trying to develop these next-gen assets.”
The Oncology Center of Excellence pioneered the assessment aid, which creates a shared review document for the agency and sponsor to comment on the same data or issues. (Also see “US FDA’s Assessment Aid May Spell The End Of Dueling Advisory Committee Briefing Packages ” – Pink Sheet, 26 Nov, 2018.)
CBER Encourages ‘Open Dialogue’
In response to the idea, Markovic said “this is really great feedback, and thank you so much for sharing. I am more than happy to take this back.” She then reflected on how far the field has already come, adding that “FDA is certainly willing to continue having an open dialogue as we all, as a field, learn what works best for this space to help formulate the best regulatory pathway to fit the product.”
“As we continue to inform the field through active listening and communication and outreach, it’s also important to reiterate that we certainly take these issues very seriously, and in a number of formal or informal ways, we are happy to communicate our current thinking” through guidance documents, town halls and public workshops, Markovic said. She also emphasized the need for an “open dialogue” and opportunities to exchange ideas.
CBER recently hosted separate town hall sessions on CMC issues with gene and cell therapies, as well as a more recent session on gene therapies for rare diseases. A September 2022 town hall on gene therapy garnered so much interest that the agency will host a second session on the same topic on 25 April. A town hall specifically on cell therapy CMC was held on 7 December 2022.
The public sessions on cell and gene therapy development are occurring just as CBER’s Office of Tissues and Advanced Therapies is transitioning to a “super office” with a new name (the Office of Therapeutic Products) and an interim head (Celia Witten) succeeding former director Wilson Bryan. (Also see “CBER’s New Home For Gene Therapies: OTAT Changes To OTP But Leadership Questions Remain” – Pink Sheet, 27 Feb, 2023.)
FDA As Barrier To Development?
Several of the speakers during the webinar identified ways the FDA can hinder development of next-generation cell therapies.
“The issue that impacts all sponsors is that we have these next-gen programs that seem to be promising, and we take them to the agency and the feedback that we tend to receive is that we are starting from square one: it’s a new product,” Jazayeria said.
He said sponsors could leverage existing data to help inform issues on the next-gen cell therapy, like toxicity or starting doses, and accelerate development.
When Tecartus was developed, Kite used data from Yescarta’s initial indication (MCL) to skip much of the dose-ranging or dose-staggering that would otherwise be typical in cell therapy development, Jazayeria said. Extrapolation was also used for stability data and confirmation of analytical methods, and the two products share the same REMS.
Julie Jadlowsky of the University of Pennsylvania said recent turnover at the FDA may have unintentionally created a period of disorganization. As an academic center researcher, she conducts many small, early-phase studies that are all relatively similar from a manufacturing and preclinical perspective. But when submitting INDs, she has seen “discord” among reviewers.
“It may be that they are newer reviewers and they don’t have the historical perspective, or there’s not a lot of alignment or talking that goes on behind the scenes about similar situations,” Jadlowsky said. “So especially in things like potency or specificity or release testing, when we are submitting these pre-clinical packages, we are getting a lot of divergent feedback.”
“It’s frustrating from our perspective, because at that point, we are looking at potentially a clinical hold because we haven’t addressed a particular issue that was never an issue in the past,” she added. “It would be great if we could have more conversation, maybe develop a framework or best practices that would help address some of these things.”
Volume Of Work A Factor In Clinical Holds
CBER Director Peter Marks acknowledged during the Prevision Policy/FOCR Biopharma Congress that a strain on center resources has increased the number of IND clinical holds issued by the office. But he also said that other problems, including IND packages that are missing “key pieces” of information, also contribute to the holds. (Also see “US FDA Cell/Gene Therapy Office ‘Aggressively Recruiting’ Amid Reorg, Senior Staff Departures” – Pink Sheet, 27 Feb, 2023.)
Workload is also a factor in the number of clinical holds and CBER’s ability to regularly communicate with sponsors. Marks said during the 8 March webinar that CBER received nearly 100 CAR-T submissions in 2022. The majority were in hematologic malignancies, but a growing number were submitted for solid tumor indications for more than 60 different targets.
“The real excitement in this field comes from the fact that with the advent of CRISPR genome editing, the accelerating technologies around the ability to manipulate cells to potentially have allogeneic” cell therapies is a reason for “a lot of excitement around here,” Marks said. “Once one can make multiple genome edits into these cells, one can potentially have more complex constructs in an allogeneic package. It will be interesting to see how the field develops.”
The FOCR webinar teed up what will become a longer and broader discussion about opportunities to accelerate the development of next-generation cellular therapies. FOCR is planning a second meeting on 22 May that will include a white paper with formal recommendations.