The data provide a good picture of “potential outcomes” and gives CBER a read on “what particular things we can look toward to ensure safety if we have concerns,” Kwilas said. However, characterizing expanded pools of edited cells is likely to require an “increase in the number of tests or the number of assays” that will be required before they are used in clinical trials, she acknowledged.

The discussion during the workshop illustrated the tension between researchers looking to trim the requirements for starting clinical trials and the FDA’s desire to move in a more step-wise fashion to ensure patient safety as the field moves into more complicated constructs.

With the availability of CRISPR Cas-9 gene editing capabilities, CBER is increasingly seeing sponsor interest move beyond CAR-Ts and into an expanded array of cancers, including solid tumors, as well as immune diseases and infectious diseases.  (Also see “Beyond CAR-Ts: Cell-Based Gene Therapy Sponsors Are ‘Branching Out,’ CBER’s Marks Says” – Pink Sheet, 8 May, 2024.)

Primacy Of Patient Safety

OTP Director Nicole Verdun declared that the FDA is “up to the challenge” of working with researchers to advance the development of new cell therapy constructs enabled by advanced gene editing techniques. She stressed the desire to “get therapies to patients faster” and said that the agency is ready to engage with academicians, sponsors and patient advocates on the development pathway.

However, Verdun forcefully reiterated the agency’s commitment to the primacy of patient safety.

The agency is going “to make sure we’re doing things in an appropriate way where we are not compromising safety,” she said.

The FDA’s position on gene-edited cell therapies is holding firm despite research community calls to move products into the clinic earlier and adapt trials to search for the most effective gene edits based on cell screening and early understanding of clinical effect or tumor response.

Seeing Which Gene Edits Win Out

Alex Marson, of Gladstone-UCSF Institute of Genomic Immunology, argued for an approach that enables studies looking at pools of cells with different modifications made possible by gene editing and designed to “find the winners inside the human tumor.”

“Let’s let various gene edits compete with each other and see which ones win out,” he said.

“I just want to be clear that in the first round of these trials that we’re talking about, our goal is to set up the experiments so that each cell is only getting one genetic edit,” Marson added. “We’re not thinking about how many edits per cell, we’re thinking about testing a population where each cell on average has one genetic modification.”

Kwilas was concerned about not fully knowing what each patient is receiving.

“Say one person got five micrograms of this and 10 micrograms of that, and another person got 15 micrograms of this and 20 micrograms of that,” she said. That type of variability “would make the data that comes out of that clinical trial even more confounded and more difficult to interpret … Knowing what the input is allows us to be able to interpret the output a little bit better.”

The intentional heterogeneity of the multi-attribute products adds to the FDA’s burden “to understand what’s in the product” and better assess “what’s coming out of the patients or what’s growing in the patients,” Kwilas said.

“To understand the meaningfulness and the impact of those results it is even more important to understand what actually went into the patient in the first place,” she said. “That is really what we’re looking at, because we want these clinical trials, if they go forward, to be able to be meaningful.”