(Part 2) Creating a Successful Roadmap: Lab, Clinic, Market.
Are you facing the daunting challenge of ensuring clinical readiness for your medical or combination product? The complexities of harmonizing drug and device elements, managing risks, and understanding variability can be overwhelming.
How do you know your combination product is ready for clinical trials? Will it pass the regulatory review for clinical approval to proceed?
If clinical readiness is on your product development plan, join the discussion on The Factor, with Dr. Stefanie Johns, Director of Regulatory Affairs at Kymanox.
Memorable Quotes:
“So it's all about managing it, documenting it, having good risk-based recipe. I mean, that's what I think what it always comes down to that we've always talked about. It's all about risk management.” - Stefanie Johns, PhD
“That's, you know, I would say the most powerful thing you can have if you have PK data with your device and your drug.” - Stefanie Johns, PhD
“But then the way that study is designed, is it designed in a way to match the performance of the device? Right? Are you thinking that far ahead or then you need to find a device that you can try to match to the data? ” - Shannon Hoste
Transcript:
Intro/Outro - 00:00:04: Welcome to The Factor, a global medical device podcast series powered by Agilis by Kymanox. Today we're back for part two of our conversation with Stefanie Johns, Director of Regulatory Affairs at Kymanox. In part one, Stefanie and Shannon Hoste discussed the balance of regulatory requirements and business objectives and what truly defines clinical readiness. Today, they jump back into discussing regulatory strategy and variables that can occur during clinical trials and the management of your data package. But we start with the device company perspective on regulation and timing. Here's Shannon.
Shannon - 00:00:45: We talked about the pharmaceutical company perspectives and the device company perspectives. So if you're a device company and you're now getting into combination products, when you need to have that commercial line ready can be different than maybe what you're used to for clinicals.
Stefanie - 00:01:02: Absolutely. Yeah, because for device submissions, we submit marketing applications sometimes as a 510k. During the GMP validation work. You know, like you're not even in full manufacturing, because you're just submitting verification, maybe not so for a PMA. You have to be a little bit more ready, but for sure you have to have that commercial readiness. And I mean, there's a reason for it, because once you make changes to your device, you need to know how that impacts your drug constituent part. And sometimes you can justify it based on, you know, all the other data that you have, especially if you have PK data. That's, you know, I would say the most powerful thing you can have if you have PK data with your device and your drug. And it's as close to commercial form as you believe it to be at the time you run that study, that is so much power to negotiate because you know if you make changes, you can do some modeling to justify it, the more verification testing you have. Over the product development cycle, that's power as well, because you can understand those boundaries of the performance of the product. I'd say maybe not as forgiving though on the human factor side.
Shannon - 00:02:27: Yeah, maybe not.
Stefanie - 00:02:28: Mission changes.
Shannon - 00:02:33: Well, and when actually, so we discussed earlier about making sure that you're scoping the study. So you talked about the safety aspect of studies, but then also does that study give you the information you need to support your long term program, product program? And we talked about it from the human factors perspective of, you know, does it support what the user needs to do? And then, but I think it also then, as well, needs to support what devices you might be bringing in. So for example, that I'm thinking of is when I've seen companies go into clinical and their device isn't ready yet, so they'll go in with maybe a pre-filled syringe or just a syringe and vial. But then the way that study is designed, is it designed in a way to match the performance of the device? Right? Are you thinking that far ahead or then you need to find a device that you can try to match to the data? And which way is easier? Right?
Stefanie - 00:03:31: Yeah, absolutely. Well, in a lot of companies, to your point, they start with IV injection for a new drug product, which absolutely, because you have to characterize systemic safety first. It's the most controlled mechanism to really understand your drug product,you don't want to introduce variation from your device at that point. But from a commercial viability perspective. You know, who is going to go to get an IV injection every day or every week? You know, that's challenging and that's where a lot of biologics. Even cell and gene therapy, they become very limited because different routes of administration may not be possible. You start with IV, but then maybe now in your future study, you decide, well, I'm going to try subcutaneous. Administration or intramuscular administration and all of a sudden you have a significant decrease in absorption because your product's getting degraded in the tissue, or it's just not getting absorbed because the molecule's too big or doesn't get transported properly. You introduce all these additional biological factors that really have nothing to do with the device or you can have injection site irritation. Know, which could be a combination of the drug and device together that are completely unexpected and you don't know that until you get into the clinic. And all of these factors could also lead to reformulation or changing the dose. So, you know, that becomes very complicated.
Shannon - 00:05:10: Absolutely. And the other example I was thinking of, circling back to the therapeutic index that you discussed, I've seen that play out, problematically in both directions. Where if there isn't proper constraints, so you're not hitting that therapeutic index, or if you have a large window, but you're not testing to that window, and then you're not introducing a device that has that level of variability, but you don't have data to support it.
Stefanie - 00:05:39: Yes, like you don't even know if it impacts clinical safety or efficacy.
Shannon - 00:05:43: Right, because yeah, you don't have the data.
Stefanie - 00:05:45: Yes, and that I have, I see that a lot actually, because they get so focused on one dose, or maybe they run clinical trials with a different device, and then you get to the final bridging study and you can't bridge because the variability is too wide. Mm-hmm. Actually, one other aspect where bridging and I would say combination products with respect to safety get very challenging when you enter the clinic is pediatrics. And I think that's a big hurdle for combination product developers, you know, and thinking about clinical readiness, you know, whether your product is meant for pediatrics from the start and maybe you're thinking in that direction. But in most cases, it's more you've developed a product for adults, but you also need to consider a pediatric cohort, whether they're adolescent or going on the way down to young children. And I think that's been one of the biggest things that I've learned through my regulatory career. One of a mentor very early on told me, children are not small adults. And that has resonated with me, you know, in every product review that I do, because it's so true, their metabolism is completely different. You know, all of the bio pharmaceuticals can be completely different because of the anatomical differences, you know, which has to be taking into consideration for the device and usability, absolutely. Even if your product is being used by a caregiver or a parent with a child. That's still a completely challenging situation from a human factors or safety perspective.
Shannon - 00:07:32: What challenges the companies face in assessing clinical readiness. I guess the follow on to that question though is how can we support that effort?
Stefanie - 00:07:45: Yeah, I think the number one thing, you know, in working with companies for clinical readiness, I mean, it starts early. And maybe not early enough for some companies, like one of the biggest things I do for pre-IND meetings is that entire clinical readiness package, depending on the product type. It could be their full development program, but really the focus of the meeting is, what do I need to do to get into the clinic? And sometimes it takes a couple of rounds of conversation with the agency,you may get initial feedback. That you have to do a second follow-up meeting, whether that's a CMC meeting, device meeting, having FDA review your clinical protocol. And I would say, If you have a novel drug and or novel device, you need to have some very good data safety monitoring included, make sure you have that group of individuals monitoring during the study. Because at that point, it's really not about just having really good toxicology data or design verification data. You're going to have a lot of unpredictable, you know. Safety related factors that occurred during the study. You're going to have events and how you manage them. And I think that, you know, is a critical part in showing regulators that it's not just about your data package, it's about how are you going to manage it during the trial. And that has been a big factor for clinical holds, you know, and making sure that one, you're not exposing,you know, not exposing too many people to a product that's very novel. And that has not anything to do necessarily with your data package, it's just, it's a novel product. So I think being reasonable in how you plan that and just talk to your regulator about will be reviewing your clinical trial application about that in advance, whether that's FDA or any country in Europe, Canada, wherever you're conducting your study, make sure you have that conversation and presenting all of your safety controls during the trial and how you'll maintain that during the study. And making sure that you have a mechanism to record device malfunctions or device safety events,because I think that's something that is new potentially for some pharma companies and clinical trial sites that maybe aren't used to running studies with a medical device because that I think is something that I've run into quite often.
Shannon - 00:10:31: That's a good point. I tend to think of the regulators and maybe because I have been one, but I still tend to think of regulators as, as an assistance, a guide in everything that we're doing, right? So the regulations are there put in place for specific reasons, but the regulators themselves are providing that critical I don't know, mirror or that critical feedback loop to make sure everything is in place and buttoned up.
Stefanie - 00:11:06: Yes.
Shannon - 00:11:07: Protects the patient, but it also protects you as a company developing the product.
Stefanie - 00:11:13: Yes, and to that extent, to collaborate well, you need to provide adequate information. And I think a lot of companies are a little hesitant to provide too much information. But for novel products,that's what regulators need to really understand how to control for safety in studies. And so you're only to me, in my opinion, limiting yourself and limiting your capabilities in the clinic by not providing that additional information. We learn a lot even when a product fails. And I would say you probably learn more when it fails than when it succeeds. So providing that information and showing how you developed or designed away from those failures is really just in your benefit, especially in early phases. And understanding your product.
Shannon - 00:12:08: Absolutely. And then each thing you learn along the way is helping you. The earlier discussion on variability, each thing you learn is helping you nail down and better understand that space that you're operating in.
Stefanie - 00:12:22: And actually, I guess on that point, one of the things that sponsors may ask, well, I know my device will have this particular performance failure, it's low risk. Can I still start a clinical trial with this design, or do I have to wait for a design change? And that's where that risk-based program really adds to your benefit. Because if you know that it's low risk to the patient, it doesn't happen very often, it's very easy to identify. Absolutely, you can still run your study just make sure that you account for that in your protocol and know that someone is monitoring for this particular malfunction or error. Make sure you collect them all, don't just toss them away, don't just hide them, just record it and it's not an issue. And then when you do have the device available with the design change and you show that that particular failure mode doesn't happen anymore, FDA is very happy and they're satisfied. Yeah, you close the loop, your data is intact and you can exclude all those people without an issue. So it's all about managing it, documenting it, having good risk-based recipe. I mean, that's what I think what it always comes down to that we've always talked about. It's all about risk management.
Shannon - 00:13:50: It really is, it really is. I'll go back into that. I agree. So, and also what I'm hearing is there are a lot of details and a lot of different disciplines that are coming into this design and strategy, but there also needs to be the long view. Starting early and taking that long view of how you're bringing, maybe orchestrating, how you're bringing those pieces together to make sure everything's in place, to collect data, to know what data to look for. Right, all of that along the way.
Stefanie - 00:14:21: Yes, target product profile. Yep.
Shannon - 00:14:28: All right. So, so we've covered a lot in our chat here. I was wondering if you had any last words or advice for our listeners?
Stefanie - 00:14:39: I guess my main take home message is that there isn't one particular way to be clinical ready. You don't have to complete all your validations, you don't have to know all the answers, you just have to know your product at that stage and make sure that that stage is commensurate with the stage of your clinical trial. So if you're running a pivotal study, you need pivotal product. If you're running an early phase study, you don't need to be completely validated. You just need to have enough controls in place, enough understanding your characterization, which is usually testing, test your product. Really know it. And then, you know, no issue to go into the clinic early.
Shannon - 00:15:26: That's much better than the it depends answer. I usually get.. Well Stefanie, thanks for joining me today. It's been great to talk to you.
Stefanie - 00:15:36: Absolutely. Anytime.
Intro/Outro - 00:15:46: That was Stephanie Johns and Shannon Hoste. Thank you so much for listening to or watching this episode. Please subscribe or follow this podcast in whatever app you're using right now, or follow Agilis by Kymanox on LinkedIn for all updates. This episode was edited and produced by Earfluence. We'll talk to you again soon on The Factor.
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