Hi everyone, and welcome to episode two of FDA Fridays, our special series from Cell and Gene, the podcast. I'm your host, Erin Harris, and in just a second you'll hear my conversation with Monica Spitlika, principal regulatory strategy at Hollerin Consulting Group. Monica is an industry expert whose previous appearance on the podcast resonated so strongly with our listeners. I invited her back for an insightful, practical conversation on navigating FDA requirements in our field. Monica draws on her extensive experience to break down why clarifying your therapy's intended role — curative, chronic, or adjunctive — is crucial before entering the IND process. And she illustrates how the FDA's benefit-risk assessments, expectations, and flexibility shift depending on patient populations, disease types, and levels of unmet need. We talk through strategies for managing CMC risks, building persuasive regulatory narratives, especially when precedent is lacking. We talk through negotiating the use of surrogate endpoints, and planning for long-term follow-up under uncertainty.
She emphasizes the value of early commercial thinking and transparent regulator engagement, and she provides actionable takeaways for anyone working in the cell and gene therapy space. So just like in episode one of FDA Fridays that featured K Sprat, I believe you'll also find this episode to be chock full of detail that will help you better navigate your engagement with the FDA. And so here's my conversation with Hollerin Consulting Group's Monica Spitlika. Enjoy.
Hi Monica, welcome to this special episode of Cell and Gene, the podcast. You were my guest on episode 104 of the podcast, in case listeners want to go back and listen to that, or listen to it again — which, exactly as expected, has really resonated with our listeners. And so when I started planning this special series based on the regulatory landscape, I knew I had to invite you back to be one of our experts in this special series. So thank you once again for being here and for your time. I appreciate it.
Thank you for having me. I'm so happy to be here again. I'm excited to continue this conversation with you.
Good, good. Well, we have a lot to get through, so we're going to jump right in. All right, so I want to talk a little bit about why defining a product's role in the treatment landscape is so critical before even initiating an IND. And so talk to us about the why behind that, and then perhaps if you can share an example of where this framing shifted the regulatory strategy.
Yes, that's a very good question. I think defining your product's role — whether it's curative, chronic, or adjunctive — is absolutely essential in cell and gene therapy because it directly anchors how the FDA will weigh benefit-risk. And it's not enough to generate high-quality data; the data has to be meaningful in the right context. So for example, the FDA doesn't — as we know, the FDA doesn't assess therapies in a vacuum. It uses a very structured benefit-risk framework that considers therapeutic contexts, unmet medical need, expected benefit, and with the benefit you have to define: is your product curative? Does it manage the disease? Does it support it in a way that improves the efficacy or a safety profile of existing therapies? So each of these roles will come with very different regulatory expectations. So for example, if your product is curative, let's say a therapy for a single-gene disorder, FDA will expect durability of effect — so for example long-term persistence, even if you're really early in development. They may allow smaller clinical trials, reliance on natural history data if the unmet need is high and the biology is compelling. So now, if it's a chronic-use therapy, the bar shifts. Now it's about consistency across dosing cycles, batch-to-batch reproducibility, long-term safety, and some of these could still be applied to a previous scenario, to curative — of course you need batch-to-batch consistency, but the scrutiny is different. And then if the product is adjunctive, meaning designed to add value on top of existing therapies, the FDA may then expect comparative data or a clear rationale why patients benefit beyond the current standard of care.
The risk-benefit profile is weighted throughout all the three scenarios we discussed here. So the FDA will weigh in the risk profile. They will also consider uncertainties — so not just in the clinical data, but manufacturing process, your product consistency, your ability to maintain efficacy over time. But in terms of, for example, one general example: let's say we have gene-modified immune cells that are being developed for different indications. So one may be positioned as a potential curative therapy, for example for a rare life-threatening disease, and in that case FDA may allow — I'll call it a stepwise approach focused on mechanistic justification, for example maybe an early-phase single-arm design and natural history comparison. And another product using a similar platform that could be developed for oncology, for example, as an adjunct to checkpoint inhibition in solid tumors. There the expectation is quite different: so early efficacy signals, additive value beyond existing options, and often a comparator strategy is needed. The clinical landscape is more crowded, and the intent is to support, not cure. So the regulatory expectations are a bit different. So even if the scientific backbone for the technology is different, the products are built for different purposes,
and then the FDA applies a bit of a different benefit-risk lens. So the key point, going back to your question, is really you have to define your product's role early, and you have to define: is it curative, is it chronic, is it supportive? And that will set your entire regulatory strategy. This will determine your clinical path, your CMC expectations, your flexibility on trial design, and how much uncertainty the regulators will tolerate. If you do not define it early from the beginning, I think you risk collecting a lot of data that may not answer the right question.
Sure, sure. That makes a lot of sense. Thank you for that. So I think again, summarizing: defining the product category — and as we mentioned, is it curative, is it supportive, or are you managing the disease? And of course we are discussing the cell and gene therapy space, and there's so much more that goes into it — the target patient population, adult versus pediatric, etc. So there's a lot to consider, but again in that landscape the risk-benefit profile and the requirements are considered differently.
Sure, sure. And that's kind of where I want to pivot to next, in terms of perhaps, say, the rare pediatric population versus adults with whatever indication we're talking about, specifically within cell and gene therapy. And being first-in-class is, as we know, the norm with cell and gene therapies. But why do two first-in-class therapies — so again, one for say a rare pediatric disorder and one for, you know, a high-prevalence cancer — face such different regulatory expectations?
That's such a good question. The truth is, first-in-class simply means there is no direct precedent for your modality, but it doesn't really eliminate the framework that FDA uses. It means that they will rely even more heavily on the disease context, the patient population, and the treatment intent to shape expectations. But to your question: for example, if you're developing a first-in-class therapy for a rare pediatric disorder, particularly one that is progressive and life-limiting, FDA will be a bit more flexible. It's not because the science is different; it's because the stakes are higher and the options are fewer. So you may leverage — and I think we touched upon this in the first question you asked — you may leverage natural history data, or propose novel endpoints, or even justify a single-arm study, especially if the therapy is curative. And again, it's that benefit-risk profile and unmet need: if there is no existing therapy, then the risk of no therapy is higher than maybe the risk of cell and gene therapy, so there's more flexibility.
Now if you compare it to a first-in-class product in high-prevalence adult oncology, for example — even if the modality is novel, let's say it's a new type of engineered immune cells — you're entering a space where there are multiple therapies that exist, and FDA is going to ask different questions. They will ask: what does the product add? How do you measure impact in a crowded space? Why would patients or physicians choose your product over a product that's already available? So that leads to different expectations, and you may need a randomized comparator, or a stronger efficacy signal and clearer evidence of additive benefit, because the threshold for risk tolerance is different — there's already a pre-existing standard of care. So yes, both products may be first-in-class, but from a technology standpoint and a regulatory standpoint, they are operating in very different ecosystems. I would say the novelty of the platform is one part of the equation, but the bigger driver is how the FDA will weigh again benefit versus risk in specific patient groups, in specific disease settings, and a specific set of available options of standard of care. So again, I think that's why defining your product's clinical positioning early on is very important, and it's quite critical in shaping a realistic development path.
Sure. And speaking of unmet need — how does urgency play into this equation? So how does the urgency of unmet need influence the FDA's tolerance for risk and its expectations around endpoints or, excuse me, durability of response? Like, how does urgency play a role in this?
The urgency of an unmet need is one of the most powerful levers in regulatory decision-making, especially in cell and gene therapy. I think it doesn't just influence the pathways you take; it fundamentally reshapes what success looks like in early trials. So when unmet need is high — say in a rapidly progressive, more complicated regulatory setting, a pediatric disease with no approved therapies — the FDA is often more flexible. They may accept a surrogate endpoint that's reasonably likely to predict clinical benefit. They may allow smaller data sets, smaller clinical designs, and maybe there's some uncertainty around long-term durability. But I can give you examples — and I'm digressing from answering your question, but just kind of thinking about my experience — even with high unmet need, I think your totality of the data has to be quite compelling, because with cell and gene therapy we already are in a high-risk category. So this risk-benefit balance has to be there, and your story has to be compelling, and the proof is in the science.
But going back to your question — it doesn't mean that the safety has to be ignored if there is urgency, but rather, again, the FDA will weigh in the risk-benefit and the consequence of doing nothing. So in that setting the tolerance for uncertainty is higher. So again: urgency, unmet need, patient population, and the risk of doing nothing versus taking on a novel treatment. But in contrast, just to wrap up the answer to your question: when you're in an indication with multiple approved therapies that we've talked about, the FDA expectations shift, and now it's about incremental benefit. They want to see head-to-head comparison, more mature data. So again, this urgency to find treatment just depends on what treatment is already in the market, and is yours safer, more efficacious — would that improve quality of life? And one example I can give: maybe there are treatments that are available that are managing disease but they're not curative, but they are standard of care that's been developed for a very long time, and your treatment may be riskier because it's cell and gene therapy but maybe curative. So I think it again goes back to the story: how you're comparing the benefit or incremental benefit over the existing treatment paradigm.
Sure, sure. Now what about when precedent is limited or non-existent? How should companies begin to structure that regulatory narrative? So in other words, what are some of the key elements regulators look for beyond the raw data?
That's a very good question, and oftentimes with first-in-human novel therapies there's truly no precedent. So it's all about the narrative and educating regulators, and really developing a strong story about unmet need, benefit-risk assessment, and your product. So in the absence of precedent, regulatory strategy really needs to rely on the strength — and I would say clarity — of the development narrative. So a well-structured regulatory narrative will help authorities see the benefit that your product offers in the unmet need. The regulators truly look for really consistent, coherent scientific justification that integrates the product's mechanism of action, disease biology, and intended therapeutic effect, and this needs to be really clearly articulated. So for example, when conventional biomarkers or assays or animal models are unavailable, the narrative must demonstrate that we have thoughtfully selected the vector or the way of manufacturing the product, and everything is grounded in biology. The science is solid, the execution is solid, and the intention is there. The sponsor really — again, going back to the first question — defined: is it curative, is it supportive, or is it for chronic use? But first-in-class, low-precedent scenarios are truly shaping the regulatory path for all the products that will come behind. So I think, to answer your question, connecting the scientific framework with a forward-looking plan will really de-risk the program and justify the steps for development under uncertainty. And I can dive into examples actually, when there was no precedent and how we were really having conversations with FDA and educating them. Maybe I'll just give one example.
Quickly. So often there may be a standard of care, an enzyme replacement therapy or something that's offered currently in, let's say, the lysosomal storage disease space, and the agency may not be aware of the unmet need. So sometimes sponsors go as far as contacting patient advocacy groups and performing surveys and asking what is the unmet need, and you may find things that the cell and gene therapy may fill. When it comes to lifestyle, a lot of those enzyme therapies may have to be infused once a week. The patients have to move closer to the infusion centers. It impacts their lifestyle. They can't travel. They can't go to work. It's just very disruptive. So I think a lot comes into these first-in-class, low-precedent scenarios for cell and gene, but it goes back to looking at the commercial space or what's currently available, identifying the unmet need, and building a strong narrative with the FDA of your product's benefit-risk.
Excellent, thank you. And I appreciate the example; that really helps highlight what we're discussing. I want to talk a little bit about, you know — we talk all the time about the uncertainties and the risks having to do with CMC. And so I wanted to get your take on, you know, how do you approach CMC risks, whether it be transduction variability or donor heterogeneity, excuse me, when developing a novel cell and gene therapy? And what's the key to managing these uncertainties proactively with the FDA?
This question could be answered some in a different way.
