This is but one of a multitude of questions being considered by FDA and a group of biopharmaceutical companies as they design a framework to streamline regulation of gene and cell therapies. The effort is led by Friends of Cancer Research.
As more sponsors invest in novel immunotherapies for cancer, regulatory science experts are exploring the benefits of extrapolating data across product versions and building risk-based approaches to understand how data from one product can be used to support development of other cell therapies.
“Companies certainly have been discussing these concepts, but within their own individual silos and interactions with the agency,” Mark Stewart, vice president of science policy at Friends, said to The Cancer Letter. “And if we can have more of a shared approach here, I think at the end of the day it can help amplify the learnings that we can take and will then help provide meaningful examples of what worked and what didn’t work that I think’s then helpful for framing out what a guidance could look like.”
Friends is convening a meeting May 22 in Washington, DC, that will present development strategies and policy proposals that can accelerate development and commercialization of T-cell-based immunotherapies.
“I think you’ll hear from some very forward-leaning thinkers, both from the FDA with Peter Marks, who is the head of the Center of Biologics Evaluation and Research, and other leaders in the industry who are working on these types of products, other advanced cellular modalities, or even thinking about the future of cancer vaccines,” Jeff Allen, president and CEO of Friends, said to The Cancer Letter.
“Additional participants include innovative leaders like Arie Belldegrun, who was involved in the early days of Kite and is now working on other cellular therapies, Tal Zaks, who was involved in the Moderna mRNA cancer vaccine development, which we’re now starting to see some preliminary interesting data,” Allen said. “As cellular therapy research advances into the solid tumor space, we hope to explore how some of these principles can actually apply more broadly and to different immunotherapy technologies.”
A more robust regulatory framework focused on cell therapies has the potential to not only update and improve data packaging requirements for manufacturers, but also enable a more seamless review process for FDA.
“Even as a company is developing a cell therapy product, the technology is advancing so quickly that they may be considering whether it makes sense then to incorporate a new manufacturing process or tweak their product in a way that makes it more safe or more efficacious,” Stewart said. “But as you know, if you do that, it potentially means you have to start all the way from the beginning with your clinical development program.
“For example, rather than redoing all your dose optimization studies, could you, based on data from your prior product, at least be in the ballpark of what a starting dose could be and then go from there, for instance? And I think we are seeing this being recognized by FDA.”
Using all available data
To date, FDA has approved six autologous cell-based immunotherapies for hematologic malignancies—including CAR T frontrunners Kymriah (tisagenlecleucel) and Yescarta (axicabtagene ciloleucel) that were first approved in 2017, respectively, for initial indications in B-cell precursor acute lymphoblastic leukemia and certain types of large B-cell lymphoma (The Cancer Letter, July 14, Oct. 20, 2017).
I think it’s fair to say every company is interested in this concept. As these therapies move into other patient populations, in particular other cancers like solid tumors, I think the idea of making slight tweaks or modifications that makes it more active in other solid tumors is going to become more of an issue.
Mark Stewart
Leading up to the May 22 meeting, Friends will release a white paper that describes conceptual, risk-based approaches that have the potential to optimize development of next-generation engineered cell therapies.
To achieve this, FDA and sponsors would need to leverage the totality of evidence, including available manufacturing, product quality, analytical characterization, and non-clinical and clinical knowledge to support the development of multiple product versions and minimize data collection, according to the white paper.
“I think it’s fair to say every company is interested in this concept,” said Stewart, who is the primary author of the white paper. “They certainly can envision how such an approach is going to be impactful to their clinical development program. As these therapies move into other patient populations, in particular other cancers like solid tumors, I think the idea of making slight tweaks or modifications that makes it more active in other solid tumors is going to become more of an issue.
“And so, as companies make these tweaks, if there’s some understanding that there’s not going to be an expectation that they have to start all the way from the starting line again, it’s certainly going to be impactful for encouraging continued innovation.”
FDA has acknowledged that some characteristics are likely to be shared across gene and cell therapies, which means that these data can be collected and streamlined to inform approval of new products.
In November 2022, the agency released a final guidance document for sponsors interested in studying multiple versions of a cellular or gene therapy product in an early-phase clinical trial for a single disease.
“The potential benefits of this type of umbrella trial include flexibility and efficiency in product development,” the guidance states. “Instead of an iterative approach to clinical studies, multiple versions of a cellular or gene therapy product can be studied in parallel, which may streamline early clinical development by expeditiously identifying alternative versions of a product that may be safer or more effective.
“Such comparisons can be facilitated by randomization between the study arms, if feasible. Additionally, this trial design may facilitate sharing of the control group, potentially facilitating investigator participation and subject enrollment, and may simplify study management, relative to conducting a separate clinical trial for each product version.”
Extrapolating data and assessing risk
A primary objective of the Friends white paper and meeting is to determine how data extrapolation could be used in the development of cell therapies and when this approach is appropriate for extrapolating data from one product to another.
This would, in part, depend on the type of modification, the phase of development of the primary and secondary products, and potential similarities between product versions.
“Because cell therapy drug development is still immature and we’re still continuing to learn, I think the extent to which data extrapolation could be applied is still not fully known,” Stewart said. “Data extrapolation is not going to make sense in every instance. It’s not a one size fits all approach and it’s really going to be a product-by-product discussion that should involve FDA.”
Some of these considerations were in play in 2020 when FDA relied on extrapolated data from Yescarta—including preclinical, clinical, and chemistry, manufacturing, and controls data—in its review for approving Kite Pharma’s Tecartus (brexucabtagene autoleucel), the first cell-based gene therapy for adult patients diagnosed with mantle cell lymphoma.
“Tecartus is similar to other approved CD19-directed genetically modified autologous T cell immunotherapies, including Yescarta, and did not raise new or unique scientific or regulatory issues,” the agency’s review committee concluded in its approval summary.
Similarities across products also have implications for data collection in postmarketing surveillance: For instance, FDA merged the risk evaluation and management strategy for both therapies into a single “YESCARTA and TECARTUS REMS Program” due to the similar serious risks of cytokine release syndrome and neurological toxicities, and to minimize burden on the healthcare delivery system.
As cellular therapy research advances into the solid tumor space, we hope to explore how some of these principles can actually apply more broadly and to different immunotherapy technologies.
Jeff Allen
As FDA moves toward creating a guidance for data extrapolation in cell therapy development, the agency is expected to provide a framework for assessing risk, i.e., the probability and severity of risk to patients due to modifications in subsequent versions of cell therapies.
These modifications could result in changes to any number of critical quality attributes that, in turn, have the potential to affect the safety profile of the therapy.
“As sponsors are developing these therapies, they’re often monitoring certain attributes around that product and are required to stay within certain thresholds,” Stewart said. “And what’s not been fully teased out around these product attributes is often their relation or correlation to safety and efficacy.
“Once we’re able to make those connections, I think then sponsors and the agency might be more comfortable with some of the concepts around extrapolation. I think where we’re at now is having to really conduct this risk assessment with a product-by-product approach, and really just trying to evaluate based on a modification you’re proposing to introduce, what the impact that will have on the product quality and the biology of that product.”
The Friends May 22 meeting builds on the group’s previous work on cell and gene therapies that addressed development and regulatory hurdles encountered during early- and late-stage development, as well as reporting and characterizing emerging novel toxicities.
“This particular paper is building on recent FDA guidance documents that also leveraged a past project of ours looking at things to enhance development utilizing strategies like a parent/child IND or, as the FDA guidance refers to them, a primary and secondary IND, in order to help accelerate development,” Allen said
“Now, the overall goal is really to compress development times, to maximize manufacturing capabilities, and ultimately improve access and reduce costs of these types of therapies.”
