A Meditation on mRNA's Reputation & Regulatory Complexities

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

A few months ago at the Next-Gen mRNA Therapeutics Summit, the FDA’s Peter Marks shared the yet-to-be-fully-formed underpinnings of what, one day, we may affectionately call a gene therapy “platform designation.” When it comes to regulatory updates, it rarely gets sexier than that. As I emphasized in my previous article, such a designation has the potential to be revolutionary for the gene therapy field.

However, I’d also argue this conversation in the RNA therapeutics space is complicated by the fact we’re emerging from a pandemic during which many uncertainties, turmoil-inducing political agendas, and downright conspiracy theories (unfortunately) became synonymous with the mRNA modality.

Now, to be fair, public distrust of vaccines has been a centuries-long issue and is not exclusive to mRNA vaccines. But, as we strive to increase mRNA’s therapeutic relevance across the biologics/advanced therapies sector, we continue to see this distrust of mRNA appearing in some interesting ways (e.g., here & here).

For those of us working to demonstrate that RNA is an essential member of the ATMP space, the COVID vaccines were simply the first of many critical steps toward establishing a well-rounded RNA therapeutics industry. But regardless of whether we’re working on next-generation infectious disease vaccines or in vivo gene editing — which, regulatorily speaking, are two different classes of therapies — our RNA therapies will still share the same market origins or “ancestry,” if you will (i.e., the COVID vaccines). This ultimately means that (at least some of) the misinformation affecting the mRNA vaccines is likely to follow our RNA therapeutic products on their own commercialization journeys. In turn, I see our modality’s capability to be used in the vaccine and ATMP spaces posing some unique challenges for the RNA space moving forward — particularly as we strive to accomplish two key goals as a space: fleshing out the mRNA regulatory paradigm and confronting misinformation in the years ahead.

The Classification Matters… Depending On Who You Talk To

It's rare to see regulatory CMC and public perception “holding hands.” However, their currently close relationship in the RNA therapeutics space became particularly clear to me during a panel discussion at the mRNA Therapeutics Summit on the regulatory classification nuances for mRNA products.

As we already know, infectious disease mRNA vaccines are not regulated as gene therapies/an advanced therapy in the EU and U.S. (Please note, however, though most regulatory jurisdictions do not classify infectious disease vaccines as an ATMP/gene therapy, this is not a harmonized distinction at present.) Likewise, both the EMA and FDA have tried to draw a clear line between mRNA vaccines and gene therapy by clearly articulating their different clinical profiles.

“To me, the fundamental difference between mRNA vaccines and gene therapies is the fact that vaccines are transient and gene therapies are durable in terms of expression,” Marks explained.

This all seems relatively cut and dry. However, it gets a bit complicated when we think about the implications of mRNA’s therapeutic diversity on our mutual goals of building public trust and streamlining the regulatory and development paradigm for mRNA products.

On the one hand, this distinction/classification difference is essential for educating the broader public and building their trust in the possibilities and limitations of mRNA infectious disease vaccines (e.g., mRNA vaccines are not gene therapies. Nor can they, as some are wont to believe, be “reverse-transcribed into our DNA” or “contain microchips”...)

But on the other hand, such regulatory classification differences “muddy the CMC waters” when we start to consider how — if at all — we may be able to “platform” relevant prior knowledge across the mRNA vaccine and gene therapy modalities.

For example, as one speaker explained, infectious disease vaccines and mRNA therapeutics may have distinct differences clinically and be reviewed by different regulatory agency offices. But we can all imagine a world in which two products for different indications could — from a CMC perspective — have highly similar sequences, drug substances, and/or formulation, and be manufactured using the same or a highly similar manufacturing process. Despite these CMC similarities, there is a (as-yet theoretical) possibility that we could face challenges in leveraging or “platforming” relevant information should these two RNA products be classified differently and reviewed by two separate regulatory departments.

It’s worth noting that the EMA’s Marco Cavaleri (at present) doesn’t see these classification differences barring our ability to share information and data across different programs. As he briefly clarified, prior knowledge discussions are scientific in nature, and previous manufacturing experience can certainly be relied upon across products “if the manufacturing is done in the same way.”

Now, Cavaleri’s reassuring statement might be your biggest takeaway from this entire article, and I wouldn’t blame you. However, this conversation also revealed how easily our desire for regulatory efficiency could, at least at face value, be at odds with our broader efforts to increase public trust. We need to be having both discussions at equal frequencies. But in the present moment, our predominant focus as an industry has been to home in on the CMC/regulatory implications.

This became particularly clear as industry speakers raised questions about the ability to carry CMC data across vaccine and gene therapy programs. It was at this point in the conversation that Marks recentered us around the critical concept of trust.

“This is one of the things we’re struggling with,” he admitted. “It would be convenient to just stop and call everything that involves mRNA a gene therapy. But if you tell a country that everyone is getting a yearly ‘gene therapy’ to vaccinate against infectious diseases, that’s its own problem. So, we need to figure out how we’re going to distinguish this.”

Cavaleri also agreed that this distinction — regardless of the CMC similarities that may exist between mRNA vaccines and therapeutics — should not be blurred.

“We spent the last three years emphasizing that the COVID-19 vaccine was not gene therapy,” he explained. “It’s not a good idea to make a broad statement that everything utilizing mRNA is ‘gene therapy’ just because it will make things easier for submitting CMC packages.” Not to mention, as he also pointed out, the regulatory and infectious disease expertise required for reviewing vaccines would be out of the “wheelhouse” of the ATMP product committee reviewers.

Now, to be perfectly clear, no one on the panel suggested that grouping therapeutics and vaccines together from a regulatory classification standpoint should be the solution to as-yet theoretical inefficiencies in platform development. Nor do I anticipate or believe that we will need to communicate about regulatory/platform development nuances at depth (or at all) in our education campaigns for mRNA moving forward. But Marks’ and Cavaleri’s statements were a great reminder of how looking at the world predominantly through “CMC goggles” could — if we’re not careful — but detrimental to our efforts to build the public’s trust.

It goes without saying that having conversations about and pushing for greater regulatory efficiency is critically important, not just for us as drug makers, but also for our patients. Whether it be quicker market access and/or reduced COGS (or both!), these discussions will have positive implications for our patients in the long term. But we also can’t be putting “the cart before the horse,” so to speak. We can celebrate the fact that we’re working with a single modality that is capable of both shorter-term transient and (hopefully much) longer-term durable expression. We can also celebrate the overall “platform-ability” and efficiency this may bring to our manufacturing and regulatory paradigm. However, these helpful realities quickly become a double-edged sword — and, frankly, will be meaningless — if we have to an undereducated public.