Regulatory Flexibility in CGT: Key Shifts and Implications with Monika Swietlicka

Thank you for inviting me, Erin. As always, it's a pleasure to have this conversation with you, and I'm excited for us to dive into the conversation.

It's a very good question, very important question, and thank you, Erin, for asking that. From my perspective, the FDA is not lowering the evidentiary bar for cell and gene therapies, but it's becoming more flexible in how that evidence is generated, particularly in the rare disease space. And so we are seeing increasing openness to alternate ways of collecting evidence. I would say, for example, incorporating — and we've done this for a while — incorporating natural history data, surrogate or intermediate endpoints, and how can we truly support this single well-designed clinical study. But at the same time, there are also signals that are evolving around CMC. For instance, some traditional expectations we've heard recently, like completing three formal engineering runs, may no longer be a requirement. So this requirement may not be applied as rigidly, especially for sponsors that can demonstrate sufficient process controls in different ways.

That said, I would use this flexibility with caution because, as you know, in rare disease where your clinical data set is very limited, your manufacturing control becomes essential. So you really need to have very deep understanding of your critical quality attributes and process parameters and variability around your process. So even if the agency is flexible on a path per se as no longer a requirement — I'm using this as one example of those three standard engineering runs prior to IND — you still need, the outcome hasn't changed, you still need to have a deeper understanding of your process. You still need robust, well-characterized manufacturing processes, and clinical endpoints need to be meaningful and clear demonstration of benefit. So I think the key signal for developers right now — and I feel like we had this conversation in the past — is about risk management.

So the smaller, more constrained your clinical trial, the higher the expectation, as we know, is that your CMC and overall development strategy are really tightly controlled. So I feel, if I were to summarize it, FDA is offering flexibility in how you generate data, but there are truly no shortcuts.

I think that regulators are increasingly taking a more holistic view, and cost and complexity at the center of that discussion. But they are not explicitly maybe discussed as cost, and I'll explain. So, as we know, in cell and gene therapy, the reality is that manufacturing and clinical development are really tightly linked, and both are major cost drivers. So when FDA evaluates elements like trial design, endpoints, comparability, there's a recognition that requirements can make development really infeasible, very costly in rare diseases. So for example, in trial design, we are seeing more openness to smaller, more targeted studies, in some cases reliance, as we will talk about this in a bit, on a single clinical trial, and that really truly impacts cost and timelines. And on the manufacturing side, there are signals that FDA may be more flexible in how comparability or process validation are demonstrated, especially when changes are needed to the process as you scale. So but that said, I wouldn't necessarily interpret that as cost-driven leniency from regulators. The agency is truly not lowering expectations. It's shifting again towards this more risk-based framework.

So if a sponsor would propose a more streamlined approach that could clearly demonstrate that the quality and consistency and performance are not compromised, then FDA would be more open to kind of this holistic approach. And so I think the way I think about this is FDA truly acknowledges the economic reality of cell and gene therapy development. We all know how costly it is. But the responsibility still sits with the sponsor to design really a development program that's really scientifically rigorous and feasible. So truly, I think for me, the biggest maybe cost saving or efficiency is when you really interact with regulators early in the development and truly integrate the CMC, clinical, regulatory strategy early, because I think what truly adds to the cost is when you have to redo something, when you have kind of delays. And so but ultimately the most expensive mistake in the space truly I feel like comes from misalignment between these functions: CMC, clinical, regulatory, nonclinical development. So maybe just to summarize,

I think a well-justified risk management strategy as you move through the development stages to approval will truly be a cost-saving driver, and the agency — we'll see, we'll talk about this some more — offers leniency on manufacturing, clinical trial design to hopefully streamline these activities and offers for some cost savings, even though they don't call them cost savings per se, just flexibility in our development.

I think the regulatory frameworks are moving that direction, but they are not fully there yet. It's exciting, but we are not fully there yet. I think that's my take. And today most regulatory systems, and while focusing on FDA, are still truly structured, in my opinion, around single product evaluation. So each product — what I mean by that, each product truly assessed based on its very specific risk-benefit profile, particularly in areas like delivery mechanism, editing specificity of target effects, durability of response. But that said, I think there's a clearly growing recognition that platform-based approaches, especially in gene editing, can generate repeatable knowledge across programs. We are starting to see openness of leveraging prior knowledge in areas like manufacturing processes, analytical methods, and maybe some elements in nonclinical development, but I would maybe describe it as selective leverage, not full platform acceptance. Maybe I'm a skeptic. But I feel like regulators will allow you to carry certain elements forward, but they still ask for product-specific justification.

So for the sponsors, the opportunity is truly real, but it requires discipline. And what I mean by that, the sponsor would truly need to clearly define what is truly platform-based versus what's product-specific and justify it scientifically. So simply calling it a platform wouldn't be enough. But with that said, I'm still full of optimism, and looking ahead, I think that those frameworks will evolve towards a more modular approach, and we can take validated parts of the platform and reuse them more efficiently. So in the near term, I think the companies should really plan for a hybrid model, I would say, so leveraging prior knowledge where appropriate and still building product-specific knowledge. So just to summarize, I think what I see, regulators are still very open to the concept, but they're still in the proof of concept, they still want the sponsors to decouple platform and product-specific risk, at least what I've been seeing coming across it.