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Pink Sheet – How Can FDA Advance Cell Therapy R&D? Issue Guidance in ‘Real Time,’ Encourage Collaboration With Industry, CBER’s Marks Says

Pink Sheet – How Can FDA Advance Cell Therapy R&D? Issue Guidance in ‘Real Time,’ Encourage Collaboration With Industry, CBER’s Marks Says

The Center for Biologics Evaluation & Research wants to publish guidance documents in “real time” and find ways to work more collaboratively with sponsors on fast-moving areas of drug development like cell therapies, while still being able to “hold ourselves accountable” as regulators, CBER Director Peter Marks said.

“We are trying to take a page out of CDER’s book, which is trying to do guidance in much more real time” because “serving up stale guidance isn’t really very helpful,” Marks acknowledged during a Friends of Cancer Research meeting on cell therapy development on 22 May.

CBER will try and “get out shorter guidances that get out of the agency in reasonable periods of time.”

In parallel, “we’re going to look for how we can work better with industry to address the key issues” on cell therapies.

“The only way we’re going to get to address some of these things is if we work collaboratively around trying to understand what the problems are, and then address them.” He added that CBER would be issuing requests for information to industry on ways to better collaborate.

Marks stressed that CBER can work alongside product developers on important issues while still being an effective regulator.

“I take the approach that we can work collaboratively with industry to try to identify and work on the problems, and still be regulators. We still can make sure that we meet our standards, and that we hold ourselves accountable. To me, that’s what being a good regulator is about.”

The CBER director also continued to emphasize that the center is trying to increase the lines of communication coming out of the COVID pandemic. Marks acknowledged the recent reliance on written responses to sponsor questions rather than more productive, in-person meetings.

He recalled his past experience in industry, trying to parse out what four words meant in a written response from FDA. “And that was back when we didn’t get as many written responses. So I get the point about written responses.”

Marks reiterated the steps CBER is taking to address those issues. “We’re trying to staff up to reduce the number of written responses and increase the number of real-time interactions. The communications pilot that we’re going to run in real in rare diseases is probably going to show us that just about every disease would benefit from real-time communication.” (Also see “US FDA’s Cell/Gene Therapy Office Looks To Improve Clarity Of Advice Through Written Responses” – Pink Sheet, 2 Jun, 2022.)

Marks made those remarks in response to a question from Kite Pharma Global Head of Regulatory Affairs Lana Shiu, who addressed the CBER director from the audience.

Shiu recalled that during her time at FDA (13 years on combination products) she would work on a guidance and it wouldn’t get published for another three years. For cell therapies, “if we do this in real time,” industry and the agency “can learn from each other.” She also noted the difficulty in relying on written responses, and asked for more “open dialogue.”

The Center for Drug Evaluation & Research has, for several years, issued “bulleted” guidance documents, using a “just say it” approach under then-CDER Director Janet Woodcock to get guidance documents out faster. (Also see “US FDA Blood Pressure Risk Assessment Guidance Uses Unique Format” – Pink Sheet, 11 Jun, 2018.)

During the meeting, Marks also suggested an important role for artificial Intelligence in streamlining the process to allow for iterative development of cellular therapies. (See boxes for the story on AI as well as an article on a FOCR white paper advocating data extrapolation for cell therapies.)

What Is A ‘New’ Product?

From a regulatory point of view, the science of cell therapies allows the products to improve with each new generation of product “and that’s going to present challenges,” Marks acknowledged. “There’s this the issue of how do you make what changes are acceptable before you have a new product. We’re trying to help define that.”

“The question is, where should that boundary be and what could we do to allow us to bootstrap from one product to the next without having to go through another full series of clinical trials? And again, I don’t know that we have all the answers, but I think we’re going to have to find our way through them.”

One challenge with cell therapies is “when you have something that’s working well, can you make it even better” without “going back to square one on development,” Marks continued. “In other words, something that is giving complete responses in 55% of people but you want to get it to 65% or 70% of people. How do we make that next step?”

Allogene Therapeutics Inc. Co-Founder Arie Belldegren agreed that what FDA believes is the definition of a “new” cell therapy is critically important. Sponsors need the agency to “send a clear message” – “is it a new drug, or not?”

Belldegren told Marks “what would I would like to see is CDER and CBER working together as a group and coming up with the solutions because you cannot work on one arm or the other. This is a combined effort of both agencies.”

“We may need to have some workshops on how you get there with products – in how you evolve without going through a whole new development program,” Marks said.

“You still need to have some data because you’re probably going to want to charge something different for the two products,” and “you’re probably going to want people to know that there is some difference. And how do you document that?”

Melanoma Vaccine As Case Study

Moderna, Inc. and Merck & Co., Inc.’s personalized melanoma vaccine mRNA-4157 is a case in point.

Former Moderna Chief Medical Officer Tal Zaks, who is now a partner at the private equity firm OrbiMed, noted that the vaccine just completed Phase 2 trials and showed a reduction in the risk of recurrence or death by 44% when used in combination with Merck’s PD-1 inhibitor Keytruda (pembrolizumab) versus Keytruda alone. (Also see “Could Moderna/Merck Cancer Vaccine Succeed Where Others Have Flopped?” – Scrip, 16 Apr, 2023.)

The sponsors used a 34 patient-specific tumor neoantigen version in the Phase 2 trials, and the Phase 3 trials will now run with the same vaccine. But what happens, Zaks says, when the sponsors want to move to a 50- or 60-epitope vaccine? “These are going to be interesting questions.”

Marks jumped in to say that the “key thing” is to make sure that we’re not “rolling backwards,” using the analogy of driving a stick shift car on a hill.

“You want to make sure that at least you’re not going backwards and that safety is not going in the wrong direction. Those are the kinds of key parameters that are the backstops. You can’t be somehow losing effectiveness when you think you’re going forward. And you can’t have new safety concerns that are dramatically different.”

“This is why there’s so much talk about real-world evidence,” Marks said. “Show that you’re safe” and “collect data while rolling forward in the real world. I don’t have the answer to it, but we’re being asked to think about how that could happen, because that may be the only way to get some of these answers without having to go back and do really large trials that people aren’t going to enroll in anyway. That’s part of the problem.”

On that point, “we get people to participate in clinical trials in a big way. That’s been an issue,” Marks acknowledged. Society was “lucky” with the COVID vaccines in that “people were very happy to participate in clinical trials.”

In cancer, adult patients “don’t participate in clinical trials as much as they should. Hopefully, there will be ways to help them do that.”

While FDA needs to keep pace with the scientific advances in cell therapy, so too does the Centers for Medicare and Medicaid Services, Marks said.

“We don’t live in an isolated world. We have we have CMS payers that are going to have to deal with this. So if we find ways to update products more frequently, based on some level of evidence, we’re going to have to make sure that that our colleagues are there with us.”