00:00:02 Speaker 1
Welcome to Chasing Compliance, the GLOBAL regulatory podcast, where we discuss all aspects of medical device and pharmaceutical regulatory and clinical strategy – from bench to bedside.
Today we are chatting with Julie Matison and Scott Michaels.
Julie Matison holds a Bachelor’s degree in Chemical Engineering and a Master’s degree in Mechanical Engineering, and recently earned the RAC-Drugs certification through RAPS. She has over 21 years of experience in the pharmaceutical industry, with a strong background in manufacturing, validation and quality.
Scott Michaels earned his Master’s in Pharmaceutical Chemistry from the University of Kansas and his Bachelor’s in Chemistry from McGill University. He has held a variety of regulatory and CMC product development roles over the past 20 years, working with both small molecules and biologics.
Thank you both for being here! On this episode, we are discussing CMC strategy around biologics IND submissions. I am sure our audience is looking forward to your insights, so let’s dive in. Cell therapy products represent some of the most complex and promising advancements in modern medicine, but they also pose significant regulatory challenges.
00:01:09 Speaker 1
Unlike traditional small molecules, cell therapies require detailed documentation around manufacturing processes, raw materials, cell sources, and potency assays, even at the earliest stages of development. Based on your experiences working in this space, what key points would you highlight for regulatory writers approaching biologics INDs?
00:01:30 Speaker 2
That's a great question and a very important one. Cell therapies are fundamentally different from small molecules, not just in like how complex they are, but in the way that the FDA evaluates them. For regulatory writers supporting INDs in this space, there are a few critical areas that you really need to focus on. First and foremost is CMC, and I can't stress this enough, with cell therapies, the product is the process. So writers need to clearly articulate the manufacturing workflow, including self-sourcing, handling of raw materials, in-process controls, and the release criteria. Every step must be described in a way that describes control, consistency, compliance, even in the early phases. Second, you need to pay close attention to the potency assays. The FDA expects you to define the mechanism of action and show that your assay reflects it. This is a true challenge for cell therapies, where often you don't know your mechanism of action and your potency upfront, and it's not always straightforward. Regulatory writers need to work closely with the scientists and the assay developers to ensure that the data and the narrative all align. The other big challenge is donor variability and traceability. If you have an autologous product or it involves multiple donors, the IND needs to clearly explain how that variability will be managed and how traceability is maintained throughout the entire process. And finally, regulatory writers should adopt a mindset of storytelling. It's not just about dropping in data, it's about helping the reviewer understand the rationale, the controls, and the risks in a cohesive, scientific way that brings the whole story together.
00:03:27 Speaker 3
Those are all great points, Julie. A big one here for me is the comparability strategy. Process changes are going to happen during scale up as clinical material is being manufactured. However, the complexity of cell and gene therapy products often makes demonstrating comparability through traditional comparison of critical quality attributes and process parameters quite difficult. So really understanding the changes that are going to be made throughout clinical development and ensuring that the right methods are in place to show product consistency is crucial. And as Julie mentioned, a key way of doing this is having a well-characterized potency assay that clearly links to the product's mechanism of action.
00:04:08 Speaker 1
Nice. Yeah, I think those are really key insights around the necessary details to get these submissions correct. And in a recent case study from Global, two companies took very different paths to their IND submissions with dramatically different outcomes. One was strategic and deliberate, and the other was more rushed and reactive. So from those case studies, what are the key takeaways? What can teams learn from these two contrasting approaches?
00:04:36 Speaker 2
Yeah, this case study really highlights the real-world consequences of how you approach your IND. The first company, they took a thoughtful, strategic approach. They engaged early with the FDA, had a well-defined development plan. They built a strong, cross-functional team. They also prioritized their pre-ID meeting. This gave them a chance to address FDA concerns before the submission, and this ended up resulting in them getting IND clearance in just 29 days and being able to dose their patient only a month later. And this is just a great example of how putting in that effort into your regulatory strategy will drive your clinical efficiency. On contrast, the second company, they were under intense pressure from their investor to be the first to clinic. They skipped the pre-IND. They ended up submitting incomplete data, hoping for the best, hoping they would provide whatever was missing during the 30-day review. Unfortunately, the FDA responded with a clinical hold. This ended up putting them in a six-month delay to resolve all those issues. And then in addition to that delay, they had financial costs, significant financial costs, damaged their credibility with the FDA and also their investors.
00:05:59 Speaker 3
Julie touched on a really important point here, and that's the credibility with the FDA. These early interactions with the agencies set the tone for how your company and program will be viewed throughout the rest of the application process. When regulators are confident that you understand their needs and are working hard to provide them with a quality submission, they will be much more open to working with you through the inevitable challenges that will occur. However, if they get the impression that you're cutting corners and sacrificing patient safety, it can result in an adversarial relationship that's really difficult to recover from.
00:06:32 Speaker 1
Yeah. And we hate hearing that, right? We want to see success across the industry. And this really sounds like an instance of short-term gain turned into long-term losses.
00:06:43 Speaker 2
Exactly. So there were some big lessons that we learned through these two situations. And one of the big ones, don't skip the strategic interaction with the FDA, especially the pre-IND. It's your opportunity to de-risk the submission. And quality beats speed. So even if it takes a little bit longer to get it done, it's going to be reviewed better and taken better. And being first doesn't matter if you get held back at the gate.
00:07:13 Speaker 3
That's so true, right? It's first to the clinic or first to market that truly matters. First to file doesn't mean anything if your submission's not accepted. Another kind of key learning from this is know your product and know your process. Be able to demonstrate to regulators through sound science that you have patient safety at the forefront of your development program.
00:07:33 Speaker 2
And I'd say another lesson would be, having that cross-functional planning upfront, making sure CMC, non-clinical, clinical, everyone needs to be aligned right from the start. And the last one, I would say regulatory trust is earned. Once it's broken with the FDA, it's very hard to rebuild that. So it's a very important lesson. So while internal and external pressures are real, cutting corners rarely pays off when it comes to the FDA interactions.
00:08:03 Speaker 1
Yeah, definitely. And we all want to make sure we're playing well in the sandbox for sure. So for companies developing biologics, especially cell and gene therapies, there's a lot of buzz around INTERACT meetings with the FDA. So why should early-stage biotech companies prioritize this meeting? And what's the real value from your perspective?
00:08:23 Speaker 2
Great question. The INTERACT meeting is one of the most underutilized but incredibly valuable regulatory tools available to early stage biologic developers. The INTERACT stands for Initial Targeted Engagement for Regulatory Advice on CBER products. It's designed specifically for novel products like cell therapies, gene therapies, or other complex biologics at the very earliest stages of development, even before a pre-IND. So why should you request one? Early FDA feedback equals early risk reduction. You can get input on your product concept, manufacturing strategy, and even proof of concept data. This can really help you avoid major CMC, non-clinical, or clinical missteps that might otherwise show up way too late in the program when you've already invested a lot of time and money.
00:09:14 Speaker 3
Another key reason to look at an interact meeting is you don't know what you don't know. When you're working with highly novel technologies like engineered cells, new viral vectors, or custom delivery systems, it's easy to miss critical regulatory expectations. The interact gives you a chance to hear what's missing or unclear before you're too far down the road. Regulatory agencies see all manner of advanced therapies. Their broad experience can really help you anticipate challenges that you may not have considered and avoid costly delays.
00:09:43 Speaker 2
Yeah, that's a great point. It also helps you build rapport with the FDA early, showing up early, being prepared, putting thoughtful, showing that you're putting a lot of thought into it gives them a strong signal. You're telling the agency, we're serious about getting this right, that you can go, that can go a long way in building trust that pays off at the pre-IND stages and definitely in the IND stages. It also de-risks for the investors. The more time you, the more questions, the more feedback you get up front, there's going to be less risk going forward in their time and money spent. So another reason for an Interact meeting is that they want you to have these. The FDA designed them for you so that you can get that information up front. They realize that there are a lot of highly innovative, novel products out there that don't fit neatly into any kind of existing regulatory framework. They want you to come and ask for advice upfront so that you guys can solve these things, create a path forward, and have a smooth submission later. So bottom line, if you're developing a novel biologic and you're unsure about how regulators might view your platform or your approach, an interact meeting can save you months, if not years, and lots of missteps.
00:11:00 Speaker 3
That's a great point, Julie. Regulators want you to be successful. They want these therapies to reach the market and be safe for patients and provide lifesaving care. So using this meeting is a great way to get their input, and they're typically happy to provide it and appreciate having an engaged sponsor as part of the submission.
00:11:23 Speaker 1
Yeah, that's great advice from both of you, and I think it really speaks to your experience and expertise in dealing with these meetings and these submissions. And ultimately, you know, we're all here for the same purpose if we're trying to drive science forward and get things through so we can help patients and help people. So I love that framework. Is there anything that we didn't cover that you would want to add to this conversation or any other bits of advice that you'd want to throw out before we wrap up?
00:11:50 Speaker 2
I think we covered it. Thank you. Thank you for having me.
00:11:54 Speaker 3
Yeah, thank you very much. This was great.
00:11:56 Speaker 1
Wonderful. Thank you both for being here and thank you for listening to this episode of Chasing Compliance. We're so grateful to have had Julie and Scott join us. And if you're interested in learning more about how Global can support your regulatory writing and consulting needs, please visit us at www..globalrwc.com or e-mail us at
[email protected]. And if you liked today's episode, please share it and leave a review. Until next time, we wish you continued compliance.
