Beyond Moderna's Regulatory Legacy: (Re)defining The mRNA Regulatory "Norm"
By Anna Rose Welch, Director, Cell & Gene Collaborative
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This is part one of a three-part series showcasing Moderna’s regulatory experiences approving its mRNA vaccine. At the September 2022 mRNA Process Development and Manufacturing Summit, Moderna’s Global Director of Regulatory CMC Chris Kelly shared his experiences working with his colleagues around the clock to scale its manufacturing process, supply chain, and regulatory filings globally. There were many unique aspects to Moderna’s experience that we likely won’t experience with our own future mRNA products. However, the details Kelly provided around the as-yet unclear regulatory pathway for mRNA vaccines and therapeutics shed some light on how we as an industry need to prepare our minds, set reasonable expectations, and future-proof our development for more mRNA-specific regulatory guidance. Each article in this series will be framed as an individual takeaway for the industry based off of a specific aspect of Moderna’s regulatory story. For a quick primer on the mRNA regulatory paradigm and the implications its current "piecemeal" nature has for mRNA vaccine and therapeutics makers, be sure to check out my previous post.
Takeaway #1: Brace for more “realistic” post-pandemic regulatory interactions
During the pandemic and in the months post-vaccine approvals, there was great energy and excitement about carrying the pandemic-induced regulatory efficiency into a non-pandemic world. Though we acknowledged that the speed at which we regulated and commercialized the vaccines would not be sustainable for regulators and companies in the long-term, I’d argue a part of us still believed we could fundamentally change how we approach medicine regulation and collaboration.
I wouldn’t go so far as to say we no longer have this dream. In fact, we have been the beneficiaries of several new regulatory developments and initiatives which were no doubt informed or influenced by the pandemic’s disruption. The FDA’s new super office — the Office of Therapeutic Products — and its efforts to bolster hiring and offer broader, more regular industry-facing communication (i.e., CGT Town Halls/workshops) have been fantastic places to start.
Of course, there remains a lot of room for growth. But having heard what Kelly and his colleagues faced, I daresay we wouldn’t — and, frankly, shouldn’t — wish Moderna’s COVID-era regulatory experiences upon our regulatory CMC colleagues or regulators today.
“Between the time we initially filed our IND up to the EU authorization, we sent in 350 CMC submissions,” Kelly shared. “This was in the span of about 10-11 months. These were either major submissions, for example scale-up or comparability documentation, or they comprised interim or final reports, stability data, and COAs.” As he went on to detail, in many cases, data was still being generated while submission preparation was in progress — and it was not rare to push the “submit” button at the stroke of midnight. “But I knew if I was up at 11:30 PM sending off QC data for review and approval, I was not alone; there were other colleagues in different functional groups also awake with me pushing this product across the finish line,” Kelly added.
What’s also worth noting is that these 350 rolling CMC submissions did not include responding to agency questions — and, as you can imagine, there were thousands of questions across the collective agencies, not just from the FDA. As Kelly shared, the company answered a whopping 570 CMC questions from PMDA alone over the course of three months. “As we had priority review, there was very little turn-around time in responding to CMC questions,” Kelly said. “Traditionally, you would have two or three weeks; during the pandemic, dozens of responses were due by the end of business.”
Moving forward, it’s unlikely we will need to burn nearly as much “midnight oil” as Moderna and the regulatory bodies did during the pandemic. However, I share these rather extreme examples because they’re a great reminder that the mRNA therapeutics industry is set to face a much different regulatory challenge moving forward. We now need to define what “normal” means for mRNA therapeutics regulation — both in terms of pace/speed of development and in terms of burden of proof. While we can anticipate that future mRNA review timeframes will be comparable to those of other ATMPs, we’re still trying to align around which data will be most important to present for an mRNA product and what our CMC and manufacturing teams will need to do to obtain such data.
I appreciated Kelly’s acknowledgement that realigning development and regulatory expectations will be just as much of a challenge for the folks at Moderna and the regulatory agencies as it will be for those of us with aspirations to approve future mRNA products. Though we can be immensely grateful COVID was readily addressed using the mRNA vaccines, Kelly reminds us that each new treatment — whether it be a therapeutic or vaccine — comes with a new risk vs. benefit profile. In the near-term, this means that companies should not necessarily expect the same recommendations from agencies for their vaccines and/or therapeutic products. In the long-term, the industry and regulators will need to continue to discuss, collaborate, and politely debate what a more “traditional” route of regulation should look like for an mRNA vaccine and/or an mRNA therapeutic.
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