Cell & Gene Manufacturing Risk Vs. Benefit: How It's Reflected In Our FDA Interactions

By Anna Rose Welch, Editorial & Community Director, Advancing RNA

“Are OTAT’s expectations stricter than those of other FDA divisions?”

This was the loaded question that kicked off the first of two FDA CMC town halls late last year.

It’s certainly not a new question. The ATMP industry (or any new therapeutic sector) has always been keen on asking whether regulatory expectations are “getting harder” to meet or manage. In most cases, the answer to this question is “no,” with the occasional acknowledgement that learnings gleaned over time naturally lead to more “finely tuned” expectations and guidance.

The answer provided at the FDA gene therapy town hall was no exception. As one regulator explained, the CMC expectations for advanced therapy INDs and BLAs don’t necessarily stand out from expectations across the other FDA divisions. However, as they also went on to explain, an area that is more complex is the agency’s consideration of a therapy’s risk vs. benefit. If you watched the FDA’s advisory committee meetings for bluebird bio’s two (now approved!) gene therapies in June, you’d most certainly agree with this statement. If you missed these meetings or don’t have 15 hours to spare, check out my three biggest CMC-centric takeaways.

Though CMC and quality are core tenets of any commercialized therapy, our/the FDA’s nascent understanding of CGTs’ mechanisms of action and our limited clinical data ultimately leave us relying more heavily on our CMC to answer some significant questions earlier. Naturally, this can lead to anxiety over whether the processes and data we do have can or will sufficiently answer those questions — both now and in the future.

We most often approach risk vs. benefit through the lens of the clinical. However, as I read the transcripts for both the cell and gene therapy FDA CMC town halls, I began considering how this same consideration is also currently being grappled with in the manufacturing realm. In fact, many of the questions posed in the two separate events indicate that we as manufacturers are still trying to sus out where the “sweet spot” of our manufacturing risk vs. benefit will be.

Some of the overarching risk vs. benefit-centric questions I’d argue we as an industry are grappling with include:

• Where should companies be assuming more scientific and financial risk (i.e., focusing our time, employees, and finances more diligently), and why?
• Beyond the potential benefits of more efficient later-stage development and patient access, what other benefits can companies potentially realize long-term in embracing these risks earlier in development?
• And, just as important, in which areas could the burden of risk decrease as we and the agency learn more about our products?

Though many important topics of conversation were broached during the 2022 FDA CMC townhalls, there were two within which the industry is working to define how much is too much or not yet enough: the comparability exercise, and how we are internally and externally defining and measuring quality (esp. of our raw materials). What “just right” looks like will inherently be product and process specific. But in the following two parts of this article, I’ll briefly unpack some of the high-level best practices offered by the FDA to help you work your way towards “just right.” 

Part 1: Cell & Gene Comparability: FDA’s Recommendations For “Coping” With Change
Part 2: GMP Principles: The True Star Of Cell & Gene FDA Interaction