From The Editor | July 28, 2025

5 Takeaways From The MHRA mRNA Guidance

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

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The arrival of a long-awaited regulatory guidance — despite being an incredibly auspicious event — is quite often inconspicuous. One second, a regulatory guidance “drop” is far from the top of your mind. The next, you see a single post on LinkedIn calling attention to the publication. By the end of the day, the guidance document is everywhere. And, dear reader, if you’ll permit me one instance of sentimentality: For one beautiful moment, I imagine the entire industry unified in a way that it rarely is, with every company and expert — regardless of function — united in reading that one single document at the same time. Sometimes, I even imagine I can hear the industry’s collective brain growing larger.

Whether it truly happens in this magical way is up for debate. But it certainly felt this way to me a few months ago when the MHRA became the first regulatory body to release an mRNA-specific guidance document for the industry.

I recently had the good fortune to hear from the MHRA at the inaugural CASSS mRNA Symposium, during which the MHRA’s Ka-Wai Wan presented the key features of the guidance, as well as revealed the most common feedback the agency received from the industry and the public. Having read and reread the guidance myself, the following five takeaways will function somewhat as a mind-meld, combining a few of my own thoughts/takeaways with those of the MHRA.

In no particular order, we start with:

Takeaway #1: This guidance is a “living” document — much like our scientific knowledge

You don’t have to read far into the guidance— in fact, you really only need to read one paragraph in — to see a great example of how this is a “living” document (a.k.a. one that will likely change with time and more experience). As the MHRA writes, “As we acquire experience of different technologies (e.g., peptides, non-integrative DNA, polymer delivery systems), the guidance will be updated accordingly.”

Likewise, in the last paragraph on page 8, the MHRA acknowledges our industry’s increasing awareness and exploration of synthetic DNA, a move which would make mRNA manufacturing truly a cell free/synthetic process. This move raises questions around the continued classification of fully synthetic nucleic acid products as ATMPS in the future — even if they no longer meet the definition of a biological product. (More on this in takeaway #2…)

Overall, there’s a lot of innovation yet to come in our space, whether it be the exploration of new delivery systems, next-gen RNA molecules, and/or therapeutic approaches — all of which come with their own individual questions and, in certain cases, quality considerations. As the MHRA clearly indicates, some of these additions to our industry may result in revisions of existing guidance documents/regulatory classifications.

This brings me to my next point:

Takeaway #2: The gene therapy classification isn’t perfect and may change

At the CASSS meeting, Wan came right out and acknowledged that many of us likely find the gene therapy designation for personalized mRNA immunotherapy products problematic. (In fact, she admitted to not liking it personally, either.) After all, these products are not integrated into the genome — a distinction which is critically important for our patients and their physicians and caregivers to understand. However, though we may not like it, the guidance and Wan both emphasized that such a designation enables us to take advantage of the (essential) risk-based approach afforded to ATMPs.

That said, it’s important to note that the agency is considering a handful of different approaches or maneuvers, if you will, to make the ATMP designation more multifaceted. As Wan explained at CASSS:

“Patients are afraid of the term gene therapy, and, obviously, we don’t want to scare patients. So, we are currently engaging in extensive discussions with patient groups and other stakeholders to see if we can have a new sub-classification under the ATMP regulations that would include these products that do not change the gene or integrate into the genome.”

Similarly, as I indicated in the previous section, our explorations of synthetic DNA would mean that we cannot legally classify fully synthetic mRNA products under the biological product framework. Seeing as an ATMP legally must be a biological product, Wan reiterated the potential of updating the regulations to ensure a fully synthetic product could still be regulated as an ATMP.

Takeaway #3: Patients were the stars of the guidance commentary

I was pleased to note that the MHRA had included a section — albeit a brief one — outlining the information necessary for patients, doctors, and the public. And, as it turns out, patients were one of the most engaged stakeholder groups in reviewing the guidance. Given the ATMP’s focus on CMC over the past few years, I, along with the regulatory agency, anticipated a much greater response rate from industry on the CMC sections.

“But no,” Wan revealed. “Lots of the questions were actually based on the last part of the guidance document, namely on what information we should be providing to patients and healthcare professionals.” In particular, their comments included requests for more educational materials, including sign posting, workshops, and webinars to better understand personalized mRNA therapies.

“They want to understand what they’re being treated with, and that’s exactly what we need to do as regulatory assessors and as a regulatory agency,” she added.

Takeaway #4: The concept of the “platform” remains ambiguous

Last year, I wrote a handful of articles on the FDA’s platform designation, sharing some of the biggest questions, considerations, concerns, and critiques that have been shaping the dialogue around this designation. (Part 1, Part 2, and Part 3).

In my first of three articles, I shared a fact that remains clear as day following a read-through of the MHRA guidance and Wan’s presentation at CASSS: International regulators (and everyone, really) has a different idea of what a platform is and how it should be functioning in the context of an ATMP. Rather than outlining them all here again, I’d encourage you to read my previous articles for more of the “why’s” behind this ongoing ambiguity. This is why the MHRA has crowned the concept of “prior knowledge” as “King.” Though the definitions of “platform” penned by both the European Commission and the FDA’s platform designation guidance do appear in the MHRA guidance, MHRA succinctly sidesteps the use of the term platform in the rest of its guidance.

“The FDA definition is broader than the EC definition in that it could encompass products that are not individualized,” the MHRA writes. “As there is no defined international consensus on the scope of what a platform technology entails, the term is not used in the remainder of this MHRA draft guidance. Developers, however, are able to utilize prior knowledge from previous regulatory submissions as supportive data if justified…”

Takeaway #5: mRNA is a jack of all trades… but our regulatory guidances might not be

I think it’s interesting to note that MHRA and EMA both began our industry’s regulatory journey by publishing considerations for specific types of mRNA products (i.e., cancer immunotherapies and vaccines). This suggests (or perhaps even reveals) that our molecules’ diversity and ability to be used in a variety of therapeutic contexts may dictate individual guidances for the different types of products utilizing mRNA/RNA — a supposition that would also call into question our ability to extrapolate across guidances.

For example, I appreciated former FDA reviewer Tiffany Baker’s explanation in my recent live event (starting at the 5:50 mark) that we shouldn’t extrapolate “too much” from a product-specific guidance.

Now, to be fair, personalized mRNA medicines come with a whole host of their own specific considerations. Likewise, mRNA vaccines are/will be different compared to most therapeutic mRNA products. This is perhaps why, when polled during my 2025 Advancing RNA Live regulatory discussion, 80+ percent of the audience wanted to see both modality-specific (i.e., circRNA, saRNA) AND product-specific guidance (e.g., gene editing, protein replacement) in the future.

Craving more regulatory updates? You’re in luck.