FDA's Platform Guidance Raises Long-Term Questions For mRNA Makers
By Anna Rose Welch, Editorial & Community Director, Advancing RNA
Last week, I published an article highlighting two preliminary takeaways I gleaned from the FDA’s highly anticipated platform technology guidance. Of course, public comments only just closed at the end of July, and there will no doubt be additional edits to the guidance in the future. But as we already know, this designation is only applicable to companies that have already commercialized a product or products. (To be clear, the FDA always specified this would be the case — even prior to the guidance.)
As I explained in the previous article, the guidance’s general lack of applicability to most RNA players in the space to-date, as well as terminology differences across international regulators are two of the most regularly professed qualms about the concept of a “platform designation.” However, as I read through the guidance and listened to various panel discussions the past few months, a handful of additional observations and considerations came to mind that are important to reiterate for the RNA space, particularly as we advance into therapeutics development. Though this may be a “new guidance,” it brings (back) to light a few challenges the broader advanced therapies space have struggled with in the past. And, as I’ve argued previously, these experiences can be immensely instructional to the RNA space as we are only at the start of our own regulatory journey.
FDA’s Platform Guidance A Compilation Of FDA’s “Greatest ATMP Hits”
As I articulated in my previous article, one of the biggest takeaways for early-stage development folks is that “prior knowledge” — not necessarily a “platform designation” — will be our saving grace in the short term. We can certainly appreciate a nod back to the familiar best practice of relying on prior knowledge to help streamline our biologics development efforts. However, it was also no doubt this “familiarity” that left many of us feeling slightly less enchanted with and questioning the general “noteworthiness” of the platform guidance.
The guidance doesn’t stop with prior knowledge though; in fact, this guidance and the discussions surrounding it so far have been deeply tied into some of the ATMP industry’s greatest regulatory hits, namely comparability and risk vs. benefit — topics that have provided their fair share of headaches in recent years.
A few months ago, Alliance for Regenerative Medicines hosted a scientific exchange meeting discussing the concept of the platform in AAV, iPSC, and LNP development. There is a lot to note in the whitepaper ARM released following this discussion, and I’d encourage you to read it if you haven’t already. However, I gravitated toward two (seemingly basic) takeaways from this discussion that are the most important to reiterate and acknowledge here:
“The developer must be able to demonstrate appropriate control and validation of any process being proposed as a building block.”
And:
“Developers must understand variability in the part of the process/product being proposed as a building block or platform.”
Based on these two takeaways alone, I dare say we can understand why the FDA has limited the platform designation to companies that have already commercialized a product using said-“building block”/“platform.” Most of us in the preclinical/early clinical mRNA space are still not equipped to meet these critical requirements nor do we have the clinical data to help us, first, deduce how our processes and/or any process changes impact our products’ quality and, second, where any differences/shifts in quality cause clinically meaningful differences. In the long term, the even bigger question we and regulators will need to address is “how far is too far?” when evaluating how manufacturing changes and/or variabilities within a “building block” creep beyond the “acceptable” boundaries of an FDA platform designation.
But even in instances where manufacturing changes may not ultimately impact a “building block,” our understanding of the inherent variability within that building block — and how those variabilities may translate in different indications/patients — remains a big question mark. Arguably, this complexity is augmented in the therapeutics space given our current challenges in targeting, accessing, and seeing sufficient translation of our products in different organs/cell types.
Though we often refer to “risk vs benefit” in the context of our products’ clinical performance and overall patient access, I also see this concept being broached throughout our discussions with regulators on where they’re currently most willing to “take risks” as it relates to product changes and/or reliance on prior knowledge.
When it comes to product changes, it was noteworthy to learn that, even on the “well-established” vaccine side, Marks has shared that the agency’s current level of comfort with sequence changes, for example, is limited to “a couple amino acids, a few dozen base pairs.” (And, as a reminder, the COVID mRNA vaccines have arguably been the most heavily scrutinized vaccine products the pharma industry has ever launched.)
Likewise, our ventures into certain development efforts — for example in vivo encoded antibodies — raise questions about where we may be able to lean upon prior knowledge from antibody development to streamline the data/studies we may need for our mRNA products. Of course, the companies pursuing this approach are in the minority today. But as luck would have it, I stumbled upon the following intriguing fragment of information shared in a company’s press release that at least suggests preliminary openness to such streamlining:
“The FDA also agreed with RNA Therapeutics’ composition, release specification, and nonclinical and clinical testing protocols substantially reduced compared to a new BLA, even though RNAT-89 is not considered a biosimilar.”
Though I acknowledge this is somewhat of a cliffhanger, this previous example nicely sets up/underscores what will be my third and final segment of this series on the FDA’s draft platform guidance. So, you’ll just have to stay tuned…
Missed part 1? Check it out here!