The "Tourist's" Guide To Global C&G Therapy CMC Regulatory Convergence
By Anna Rose Welch, Editorial & Community Director, Advancing RNA
As C&G therapy manufacturing masterminds, you may not be entrenched in the world of regulatory affairs day-in and day-out. But if you and your company have hopes of seeing your product reach patients across oceans and on other continents (now or later), your CMC dossier is will need to please multiple global regulators. As this is still a nascent and scientifically advancing industry, those regulators may not necessarily have the same thoughts or expectations of what will be necessary from a CMC perspective. Look no farther than this latest example from Pfizer, in which the company was asked to provide additional data to the FDA on a supportive potency assay. The EMA did not have the same questions; in fact, the agency signed off on Pfizer’s potency assay strategy.
As companies find themselves confronting diverging demands for information, frustration inevitably ensues. Scientific alignment or convergence will not be achieved tomorrow or next year (or the year after that), by any means, and it will always be riddled with nuance. That said, in the past few months of reading and watching everything and anything that has crossed my path, I’ve now tasked myself with this challenge: to summarize where we are (or aren’t) in terms of reaching convergence for C&G therapies. Naturally, this will include a brief look at some of the most noteworthy scientific/manufacturing protocol differences that currently exist between the FDA and EMA.
However, first things first. Though we’re all aligned around wanting a thorough but not overly burdensome regulatory pathway, there’s a lot of terminology thrown about willy-nilly like rice at a wedding. And nobody wants to be the bird that eats all of that rice and explodes. So, before I dive into some of the pronounced differences in regulatory guidance, here’s how I am defining the work ahead of us.
Scientific Alignment Vs. Convergence Vs. Harmonization Vs...: Mapping Terminology & Expectations
Some of the most common terms used to describe the desired global regulatory consistency for C&G therapies include “standardization,” “regulatory convergence,” and “scientific alignment.” We even go so far as to throw out the term “harmonization.” Naturally, because harmonization is a gorgeous word and packs a pretty mighty punch, it features prominently in headlines and conference panel titles. But in the grand scheme of things, as we fight for near-term regulatory progress, I and several others would argue that “scientific alignment” or “convergence,” as opposed to “harmonization,” is the more realistic goal upon which to affix our sights.
This article from Molecular Therapy: Methods & Clinical Development spells the “why” out nicely. As the authors write, harmonization, which requires uniform or “shared technical guidelines,” is going to be a long, more extensive journey compared to “convergence,” which is the voluntary and “gradual adoption of internationally recognized technical guidance documents, standards, and principles.” Of course, movement towards convergence takes its own fair share of time, discussion, collaboration, and documentation. This in and of itself won’t be a mean feat; but there are a few factors currently pushing us closer to achieving regulatory convergence in the C&G space.
For one, there are the all-important efforts being tackled by the standards bodies (i.e., USP; the Standards Coordinating Body [SCB], and National Institute of Standards Technology [NIST]). As the authors of the Molecular Therapy article point out, these standards — particularly the most widely adopted — typically serve as a springboard to more unified regulatory expectations in the long-run. If you want to fall down the very best kind of rabbit hole and dig into what the world of C&G industry standards currently looks like, check out this portal from SCB.
There is also a strong push for cross-agency collaboration, and not just from industry players. The regulatory agencies have established several class- and topic-specific cooperative “clusters,” within which regulators from Health Canada, FDA, EMA, PMDA, and TGA work towards greater alignment/convergence and discuss divisive (hopefully not fist-fight-causing) scientific situations. The “ATMP Cluster” was formed in 2008 and meets five to six times a year to discuss scientific advice, market applications, and MAA/pre-IND/pre-BLA meeting minutes.
As the FDA’s Peter Marks acknowledged at ARM’s 2021 Meeting On The Med, there’s also nothing forbidding C&G companies from having both the FDA and any other regulatory agency at the same table during early regulatory meetings to eliminate redundancies and ensure alignment right off the bat.
Now, as I’ve just typed the word redundancy, I feel I’d also be remiss not to throw just two more terms at you here for fun, and those terms, dear reader, are “reliance” and “recognition.” “Reliance” is when a regulatory agency “totally or partially relies upon evaluations performed by another national regulatory authority.” Recognition, on the other hand, is one regulatory authority’s “routine acceptance” of an action/finding/ruling of another regulator. Though these terms stand separate from harmonization and convergence, such efforts are a fantastic example of how regulators currently can and do “see through each other’s eyes,” if you will.
The history of regulatory science is full of examples in which agencies have relied upon or recognized the efforts of their fellow regulatory authorities. Think, for example, of the EU’s mutual recognition procedure for marketing authorization applications across member states. Perhaps one of the most high-profile efforts is that of the Mutual Recognition Agreements struck between the FDA and EU/UK to eliminate redundancies in routine inspection of manufacturing facilities. (Please note, however, the MRAs currently don’t apply to ATMPs and a variety of other biological products.) Reliance/recognition has become buzzier over the past few years as time- and resource-strapped regulators face increasing industry demand and, in turn, must dedicate more resources to local priorities. In fact, the WHO just released a guidance in 2020 on Good Reliance Practices.
These are just a handful of the efforts that could establish someday and, in some cases, already are encouraging greater convergence on C&G regulations in the years ahead. No doubt, some of our current misalignments can be chalked up to the overall lack of experience with this scientifically diverse array of therapies. As regulators learn more individually and from each other, we can only assume their thinking and expectations will gravitate closer and closer.
That’s not to say that “harmonization” of guidelines will not always be a long-term goal for the C&G space — and the pharma industry as a whole. We’re all familiar with The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH), which exists to harmonize the pursuit of pharmaceutical safety, efficacy, and quality globally. Given the laborious nature and formality of ICH’s efforts, they will not be the answer to our most pressing C&G regulatory inefficiencies and grievances any time soon. However, I will say that gene therapy makers have recent cause to celebrate. In 2019, ICH set its sights on releasing new guidance specific to preclinical biodistribution studies — and, as of June 2021, a draft guidance is now available for public consult.
Similarly, at the Meeting on the Med, there was some discussion amongst agency representatives from FDA, EMA, MHRA, and PMDA around “harmonization” of the regulatory pathway for ultra-rare disease ATMPs. Though this term was used throughout the panel (and this article write-up on said panel), I’d offer a word of caution here. In my past life in the biosimilar industry, I found that regulators can be a bit squeamish about “harmonization” as it relates to shared technical documents and guidelines. After all, each agency has guidance documents for days and — even more challenging — different legislative structures within which they must operate.
In other words, the C&G space will not be a “One Guidance To Rule Them All” industry, even though the journey toward scientific alignment may feel as long and occasionally perilous as the Tolkien saga. However, I like to think each time you engage with the regulatory agency on your programs, you’re helping the whole industry arrive at a more unified understanding of the ATMP science.
In part 5, I’ll be providing an overview of where some of the most contentious (or just plain) differences exist between FDA and EMA ATMP guidance.