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FDA, Industry Taking Steps to Streamline Cell Therapy Regulation, Though Uncertainty Remains

FDA Building

NEW YORK – Regulators, industry players, and academic researchers see a need to streamline and better define the regulatory path for cell and gene therapies as they traverse from the lab to the commercial market.

To date, there's been little consensus on what a streamlined regulatory pathway might look like for cell and gene therapies, but in two discussions over the past week, stakeholders seemed to agree on several ideas, such as allowing sponsors to extrapolate data from earlier trials for new product iterations; taking a platform approach to potency assay requirements; moving away from sluggish written correspondences and toward real-time communication between regulators and sponsors; and facilitating greater alignment between international regulatory agencies.

In March, stakeholders from the US Food and Drug Administration, academia, and industry convened at a roundtable hosted by the nonprofit Friends of Cancer Research (FOCR) to discuss the barriers holding back next-generation cell therapy development. Sponsors and researchers bemoaned a lack of clarity from the FDA, particularly on where regulators draw the line in determining when a new iteration of a cell therapy becomes an entirely new product.

FOCR hosted a broader group of some 20 stakeholders this week, including several who'd been present at the March roundtable, to discuss concrete steps that could be taken to overcome the challenges previously identified.

The FOCR meeting followed the American Society of Gene & Cell Therapy's annual meeting last week, where Peter Marks, the director of the FDA's Center for Biologics Evaluation and Research (CBER), who also participated in the FOCR meeting, and Yoshiaki Maruyama, the director of the office of cellular and tissue-based products at Japan's Pharmaceuticals and Medical Devices Agency (PMDA), fielded questions about cell and gene therapy regulations in their respective countries.

Given the bespoke nature of many cell and gene therapies, particularly autologous cell therapies derived from a patient's own biological material, regulators and drugmakers often describe the treatment as a process and not merely a product.

"It's a process, not a product, but the two go hand-in-hand for this type of modality more so than in conventional therapies," Jonathan Jazayeri, executive director of global regulatory affairs at Gilead Sciences' Kite, said at the FOCR meeting. Jazayeri was one of 17 experts who contributed to a white paper that FOCR released during the meeting, entitled, "Accelerating The Development of Engineered Cellular Therapies: A Framework for Extrapolating Data Across Related Products," in which they outlined a series of best practices for extrapolating nonclinical, clinical, and chemistry, manufacturing, and controls (CMC) data from one product to develop another iteration.

"What changes are acceptable before you have a new product? We're trying to help define that," Marks said at the FOCR meeting. "Yes, we have a definition, but the question is, 'Where should that boundary be, and what could we do to allow ourselves to bootstrap from one product to the next without having to go through another full series of clinical trials?' I don't know that we have all the answers, but I think we're going to have to find our way through them."

The FOCR white paper represents a step toward figuring out the answers. In it, experts identified the types of changes that result in different versions of an engineered cell or gene therapy product, for example, when a drugmaker replaces a CAR transgene of a CAR T-cell therapy with a new CAR transgene or adds another transgene that expresses a costimulatory protein.

They also provided examples in the white paper of times when data extrapolation has been appropriately used in drug development.

Raj Puri, executive VP of regulatory strategy and translational medicine at Iovance Biotherapeutics, who spent the bulk of his career working at the FDA's CBER, noted at the FOCR meeting that data extrapolation could be valuable for moving forward the company's TIL therapies. Iovance has been trying for years to score FDA approval for its unselected autologous tumor-infiltrating lymphocyte (TIL) melanoma therapy, lifileucel, but its biologics license application is still under review at the FDA. The company recently began clinical trials of engineered versions of the TIL therapy to try to improve on the efficacy of the earlier non-engineered versions of the treatment.

In developing the engineered products, Puri said, the company can learn from first-generation products. "There is an opportunity to build upon [Iovance's] TIL therapy technology by evaluating genetically modified TILs," Puri said. "With genomic editing technologies, one can knock down PD-1 or any other inhibitory molecules on the T cells and create a next-generation T-cell therapy, and perhaps these cells may go on to survive better and do better in the tumor microenvironment."

Iovance has also faced challenges developing and validating a series of potency assays that the FDA will accept for defining the TIL product and ensuring the therapy behaves as intended. Puri acknowledged that a shift toward "platform" potency assay approaches might help ensure these next-generation TIL therapies aren't stuck in regulatory purgatory like lifileucel.

"When you come up with the potency assay, either by itself or as a potency matrix approach, that same approach that applies to Product A, applies to Product B, and you don't have to repeat the whole thing again," he said. "That's an opportunity to save time and resources."

Since the regulatory pathway for cell and gene therapies remains in flux and can differ case-by-case, sponsors and the FDA both appreciate the importance of transparent communications as early as possible in the drug development process.

While many have applauded the FDA for publishing frequent guidance documents to help sponsors understand its thinking, experts at the FOCR meeting agreed that written correspondences aren't always the most effective way for regulators and sponsors to communicate.

"Industry hates written responses; I get it," Marks said, noting that from his time in industry he knows sponsors really parse the agency's written communication down to why regulators might have chosen to use "the" versus "a." He noted at the FOCR meeting and at the ASGCT meeting that the FDA is trying to increase staffing to facilitate more real-time interactions with sponsors.

Reauthorization of the Prescription Drug User Fee Act did provide the agency funds to hire an additional 125 reviewers specifically for cell and gene therapies. "Hopefully, that will lead us to better consistency of communication and better staff happiness as the workload is not as taxing," he said at the ASGCT meeting.

As to forthcoming guidelines that could further elucidate the FDA's regulatory thinking, Marks added that CBER is trying to get these documents out faster since they can take so long for the agency to draft, tweak, and publish that drugmakers sometimes worry the final version might not even reflect the agency's current thinking.

This is all the more pressing given the rapid pace of cell and gene therapy development. "Serving up stale guidance isn't really helpful," Marks continued. "We're trying to get shorter guidances out of the agency in reasonable periods of time."

Given that drug development often happens at a global scale, Marks also acknowledged the need to better support drugmakers struggling to navigate different countries' regulatory standards in seeking to make their cell and gene therapies available to patients outside the US. One potential solution could be applying an approach like the FDA Oncology Center for Excellence's Project Orbis, which aims to make it easier for drugmakers to share and submit data to regulators from other countries who participate in the project.

"I think it can be done," Marks said of a Project Orbis-like project for cell and gene therapies. "[Although] it does mean that there will need to be some sitting down in advance to come to better convergence around some of the requirements that different countries tend to have."

Maruyama, from Japan's PMDA, noted at the ASGCT meeting, however, that currently regulators from his country don't partake in Project Orbis due to mainly logistical reasons. For instance, translating regulatory submissions into Japanese can take too long to allow for a simultaneous review process, he said, but acknowledged that such challenges aren't insurmountable. Artificial Intelligence could help with the translation issue, Maruyama pointed out, although highly technical administrative phrases are challenging for AI to translate into Japanese and vice versa.

Going forward, be it through a Project Orbis-type approach or other strategies, Marks underscored the importance of aligning global regulatory frameworks, to not only ease the path for sponsors but also ensure that patients around the world have better access to these therapies including in low- and middle-income countries.