"Just Pick [A CQA]!" & Other Super Important C&G Advice From FDA's Peter Marks

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

There’s an interesting battle of opposition taking shape in the world of C&G therapy manufacturing — especially as it relates to successfully telling a cell or gene therapy’s manufacturing story to regulators.  

For one, scientific and manufacturing technology advances continue to illuminate the extent and granularity of the quality data needed earlier in C&G therapy development. But the industry is also increasingly challenged to take that information and make sure it demonstrates that a product is well-controlled and highly similar throughout development and beyond. (If there were a hashtag phrase to express this opposition, it might be something like #ZoomIn but also, #ZoomOut.)

To demonstrate manufacturing consistency, the pressure is on for companies to find a suitable metric — a potency assay or a critical quality attribute, for instance — to demonstrate that the therapeutic has made it from point A to B (and on to C-Z) without transforming its structure into any functionally problematic ways.  

At the recent World Medical Innovation Forum, the FDA’s Peter Marks acknowledged the heavy lift of such a task, given that biologics are inherently rebellious and prone to “self-reinvention,” especially over longer periods of time. (Every batch of a biologic is a biosimilar to itself, after all.) In the C&G space, in particular, determining a product’s consistency is exceptionally tricky for the following reasons: immature analytical technologies/platforms; an evolving (or general lack of) understanding of complex mechanisms of action; variability in starting materials for autologous/ex-vivo treatments; and the hodgepodge of singularly complex biological materials that must play nice together in the same solution and, ultimately, in vivo. We also can’t overlook the very real fact that the science is what’s “hip” right now. Achieving reproducibility — and implementing the stepwise, systematic engineering principles to promote such consistency — is not nearly as exciting as observing a clinical response, especially when the mechanisms behind which remain shrouded in tantalizing clouds of scientific mystery.  

As Marks himself described, “People tend to underappreciate the need for some metric that allows one to follow that product through time. It sounds almost ‘sing-song-like,’ but many times, developers get excited about the fact that their product produces an important effect instead of thinking about reproducibly making that product…. And just as manufacturers like consistency, the FDA also likes consistency in a product.” As such, Marks acknowledged that the FDA has begun to more regularly push companies to define their CQAs early to show that the same product is being delivered over time.  

He acknowledged that selecting the CQAs will inherently be a challenge for C&G companies — especially early on. It’s not unusual for companies to admit to regulators that they don’t know where to begin with picking a CQA. In situations like this, Marks simply advises that they “pick something.” (He did laugh as he gave this advice because it’s certainly easier said than done.) This inscrutable “something” could be a cell surface marker or a specific quality of the cells.   

“Pick something that you think may correlate [with the data you’re seeing] and measure it,” he added. We’ll take any offers that are reasonable.”  

But while a number of other great articles (like this one) shared Marks’ calls for greater consistency from the C&G industry, there was one moment in this conversation that has generally gone uncited — but is just as important to note and, frankly, to celebrate. In the midst of giving out the aforementioned advice, Marks admitted that the agency didn’t communicate the importance of consistency and reproducibility as much as it should have in the earlier days of the C&G industry.  

Communicating what companies must keep in sight is an art that takes a significant amount of practice and revision. (#WordsAreHard; seeing and conveying the big picture through all the data is even harder.) I found this candid acknowledgement from Marks a great example of the agency’s growing self-awareness of the critical role it plays in shaping the C&G industry’s progress.  

Companies in this industry are continually challenging themselves to innovate, improve, and hasten their manufacturing efforts to ultimately reach more patients quickly. But they’re not the only ones that need to do some heavy lifting; we also need to see/hear the agency actively recognizing what it must do better to help the industry become the best version of itself, too. It would seem, based on Marks’ acknowledgement and all the positive industry feedback around FDA interactions thus far, that the FDA is doing just that.  

In Part 3, I’ll touch on why standardization of the regulatory pathway for cell and gene therapies is not exactly right around the corner for the industry — but what the industry is advocating for or doing in the meantime to pave the way.