Hi everyone, welcome to episode 104 of Cell & Gene, the podcast. I'm Erin Harris. Thanks for tuning in. You're in for a wealth of regulatory landscape information because my guest is Monica Spitlika, Principal Regulatory Strategy at Haleran Consulting Group. Monica and I spend this episode discussing key regulatory challenges and potential solutions associated with advancing cell and gene therapies.
Monica highlights manufacturing complexities, especially in autologous therapies, alongside difficulties in clinical trial design for rare diseases, the necessity of long-term follow-up, and the rapidly evolving regulatory landscape. She explains that regulators, including the FDA, are adapting to innovations in gene editing with a focus on empirical evidence for safety and efficacy, particularly off-target effects.
She emphasizes the importance of early definition of critical quality attributes, robust analytical methods, and risk-based comparability strategies during scale-up. And she notes the growing role of real-world evidence in regulatory decision-making, particularly for rare diseases where traditional clinical trials are often unfeasible.
So listeners, whether you're navigating early-stage development or preparing for pivotal trials, understanding regulatory strategy is crucial to bringing safe, effective therapies to patients. And Monica's insights offer a real-world roadmap to avoid costly missteps and build the kind of FDA-ready foundation every cell therapy company needs. And so this is a conversation you won't want to miss. And so with that, here is my chat with Haleran Consulting Group's Monica Spitlika.
Enjoy. Hi Monica, welcome to Cell & Gene, the podcast. Thanks for being here.
Thank you so much, Erin. I'm really excited to be here. Thank you for having me.
Absolutely. So tell us a little bit about your professional background.
Sounds good. So I've spent over 18 years working in the biotech and pharmaceutical industry, specializing in regulatory strategy, cell and gene therapy. And over the years, I have helped companies of all sizes, I would say from seed-stage startups to established global biopharma, navigate complex regulatory landscapes, especially in the cell and gene therapy space. So currently, I serve as a Principal Regulatory Strategy at Haleran, a regulatory consulting firm.
Excellent. Well, thank you for your time, and I'm so glad you're here to talk us through our agenda today. So first up, I want to hear from your perspective, what would you say are the biggest regulatory roadblocks that cell and gene therapy companies face in securing market authorization in the United States?
I think there are several consistent regulatory hurdles that cell and gene therapy companies encounter, and I think I could list a few. So I would say my first one is manufacturing. I know you probably hear about this a lot. I think second would be clinical trial design, and long-term follow-up is number three for me, and I think the evolving nature of regulatory expectations. But I'll just double-click quickly on every single one.
I think manufacturing, as we hear about the autologous therapy and manufacturing of those highly specialized precision medicine therapies individualized for patients, we know that demonstrating process controls and consistency as they scale up is very difficult. So I think cell and gene therapies are inherently variable, and especially we know when we are using patient-derived autologous therapies. And I think those companies, when they move from small early clinical batches to commercial production, I think FDA expects a fairly high level of sophistication in manufacturing controls.
So just to highlight on manufacturing, I think defining critical quality attributes fairly early on and robust validation practices, comparability data early is key. And going to the second, I think challenge, the clinical trial design. And my expertise is in rare disease cell and gene therapy. It's quite difficult, as we know, in the rare disease space, ultra-rare disease space, there aren't enough patients often to support traditional randomized trials.
And I think in those cases, companies have to use creative solutions. So I think that's a challenge because then we reach for natural history data, historical controls, real-world comparators, longitudinal data. I think the whole gamut of creative solutions as we work with regulators. And I think in my experience, some trials are as small as a couple of patients. So when you think about a rationale or how you want to design the trial to reach statistical significance, that's I think quite a challenge.
And again, long-term follow-up, as we know, we have to really early in development add in that 15-year follow-up period, and that is quite an undertaking. And the companies have to really, really early on develop robust long-term safety monitoring plans.
But finally, I think the evolving nature of this regulatory expectation can be a hurdle in itself. I think the science, as we know, is moving so rapidly, faster than the infrastructure built to support it in the cell and gene therapy space. And I think regulators are learning alongside of sponsors. And I think as a result, guidance is being frequently updated, and we all participate as an industry in the responses to draft guidance. But the companies must really, truly stay engaged to keep up, to keep pace.
Sure. Sure. That makes a lot of sense. I want to talk a little bit about gene editing technologies. I want to get your take on. So they evolve rapidly from CRISPR, base editing, prime editing. You know, how are regulators adapting their frameworks to ensure both innovation and patient safety?
Thank you, Erin. That's a very important question, and I think just seeing everything that happened just in the past 10 years, I think regulators are working very hard to keep pace with this incredibly fast rate of innovation, as you mentioned, gene editing like CRISPR, base editing, prime editing. So as you know, we have FDA release guidance recently specifically addressing gene editing and kind of their take on the potentials and the potential and the risk of this technology.
And I think the focus of this guidance was truly on off-target effects, and FDA truly wants to understand a full spectrum of potential unintended edits and effect of the modality that you're using. So I think sponsors, what I've seen in the submissions that we've had last year, is that the sponsors must really go beyond in silico predictions, and they must really provide empirical data to characterize the specificity and fidelity of their editing tools.
But what's interesting, I think in the past what we might have seen is to show the agency that we edited the gene at the desired location. Now I think the emphasis is on genotypic and phenotypic characterization. So I think I feel like I see more and more sponsors must also demonstrate the intended biological function, that the intended biological function was restored without harmful downstream effects. So I think we see more and more of that.
And I think, let's see what else I would say, some encouraging trends that I see is that FDA is applying a risk-based approach. And what I mean by that is that the regulatory scrutiny is being adjusted based on factors like permanence or target tissue or disease severity. And for example, what I've seen, ex vivo editing of hematologic malignancies may receive a different regulatory scrutiny than if you were going to pediatric populations and of course trying to address the CNS disorders.
But I'll just add quickly a couple of final thoughts that globally I see convergence, which is very encouraging, with regulators in EU and Japan releasing guidance that aligns with US expectations. And I think the trend that I see is that regulators are really demonstrating a collaborative spirit and they are willing to adapt and work with us. But again, they stress that the science must be really robust and transparent to back the innovation. So you really need to provide a burden of proof and totality of the data for the agency to respond.
