Part 1: Factors to Consider in Support of Clinical Readiness
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:
“It’s not just about what are the minimum requirements for FDA. Its about": Do you really know and understand the performance or the usability enough so you feel confident that the data that you're gonna get from that study is going to support your program?” - Stefanie Johns, PhD
“Things go wrong in clinical trials, why do they get wrong? Because you're exposing your product to a large group of individuals who have never seen it before. You know, and that's why, you know, human factors is so important.” - Stefanie Johns, PhD
“do I need human factors data to prepare for my clinical? And it always comes back to that safety question. And in some cases, your clinical study design is managing that risk. But when there is potential for use error, that's when you need to start thinking about the human factors in support of clinical readiness.” - Shannon Hoste
Transcript:
Intro - 00:00:04: Welcome to The Factor, a global medical device podcast series powered by Agilis by Kymanox. Today's episode is hosted by Shannon Hoste, president of Agilis by Kymanox. and assistant professor in the quality education program at Pathway for Patient Health. She's joined by Dr. Stefanie Johns, Director of Regulatory Affairs at Kymanox. With her PhD in biochemistry and her extensive background in drug device combination product development and regulation, Stephanie is the perfect guest to explore the intricate balance of regulatory requirements and business objectives. Stefanie and Shannon address the crucial question, what defines clinical readiness? And how can you ensure that your product is both safe for patients and equipped to yield meaningful clinical data? It's a question they get asked all the time. Here's Stefanie.
Stefanie - 00:00:57: As a consultant, this is a very common topic that we get questioned. How do I know that I'm really ready to put my combination product into a clinical study? And I think this is a twofold, you know, complicated question because on one side you have requirements from regulators, whether it's FDA or other global regulators. And on the other side, you have the business. Because what I always try and challenge sponsors, you know, that are, they want to get into the clinic with the most minimum amount of testing, you know, because every time you delay, you know, it's just another month that you delay getting data that you need to continue on your pathway. But I also challenge them and ask, you know, if your device, do you really know and understand the performance or the usability enough so then that way you feel confident that the data that you're gonna get from that study is going to support your program. And so it's not just about what are the minimum requirements for FDA. It's about, well, how do we really understand this product and what it's telling us and how it delivers a drug and how it interacts with the user? You know, one example where I think that this always comes into play are, you know, respiratory types of products where you have to have coordinated breathing. So nebulizers. Sometimes nasal sprays, where it gets very complicated on not only the device performance, the drug interface, as well as human factors, you know, as well as nebulizers. But then you have other types of combination products where you have a delivery device like a pre-filled syringe or an auto injector or infusion pump. And so each one of them, I feel like has to be considered a little bit differently. Like there is no one set of requirements. However, when it comes down to entering the clinic, you know, our number one focus is always patient safety. You know, we do not want to put any device in a clinical trial. You know, that could potentially jeopardize the patient safety. So that's why I think that's a great place to start, is how do you know this product is safe? How do you know that the device is safe for its intended use? So that's not just biological safety, but also how it's used. People forget about needle sticks in early phases where you could have mechanical errors that lead to needle stick issues, or also having the drug delivered not according to its intended dose. So you have to worry about overdose or underdose in certain cases. That's especially a big risk for drug eluding products where the drug could be extended release from a device. Where you have to worry about an early burst, where the drug all of a sudden is what we call dose dumping. So that's a little bit more on the technical verification side. And then you have on the other side, for patient usability, is there a way that someone could use this that could cause some harm? So, you know, it's a very broad spectrum and that's usually where I begin. Looking at, you know, and diving into, you know, how do I know that this is safe? What's the minimum requirements? And then start looking at how do I, how do I know that this is going to ensure the data resulting from this study to make sure that, you know, the millions of dollars that the company is putting into the study, you're going to be able to use it, you know, down the road and support which I think is you know, sometimes not as much of a focus because getting into the clinic in a hurry is our focus. And I totally understand. But it is a challenge if you can't analyze your data. I mean, it's disheartening when that happens.
Shannon - 00:05:00: Or you have boxed yourself in based on what was being evaluated and that's what you can get labeling approval for.
Stefanie - 00:05:09: Yes, absolutely.
Shannon - 00:05:11: Injection sights, for example, right?
Stefanie - 00:05:14: Exactly, yes. Yeah, and that's become a really big topic, I think from a regulatory perspective in understanding injection sites that you want to use in your label versus what were in your clinical study. And not all injection sites are the same. And I think that is becoming a big factor in review issues where companies really need to have multiple injection sites due to the frequency of injection. But they didn't actually do that in their clinical studies because they were smaller, where they were only injecting for a day or a week, because that's all they needed for bridging, not thinking about, well, they're actually going to be injecting every day, and now I need to have multiple sites. So. Yeah, that's a great point.
Shannon - 00:06:01: That play out as well in human factors. So now I'm thinking about a scenario where after clinical, you have clinical data for maybe one or two injection sites. But then in human factors data, when it gets into the end user's hands, particularly the lay users. They may be familiar with diabetes and so they're like, well, I can inject into my arm and my leg and my abdomen and maybe you don't have data to support that. So now it's an error, right?
Stefanie - 00:06:27: Yes, that's a great point. Another one actually along those lines with human factors. Having enough information about your product to know. Patients are going to administer it in the right route of administration. There is a product that was actually redesigned to prevent dosing errors as a respiratory device. It was with a capsule to make sure that you're expelling the full dose and then people were swallowing the capsules.
Shannon - 00:06:58: I think it was like a dry powder inhaler, I think, and it pushed the capsule in the device or something like that. Yes it was confusing.
Stefanie - 00:07:08: Yeah, because it was the first of its kind. More common now, I think. I think there's a couple of different ones on the market. It's things like that when we're so close to the development of a product, you forget that. Things go wrong in clinical trials, why do they get wrong? Because you're exposing your product to a large group of individuals who have never seen it before. You know, and that's why, you know, human factors is so important. Doing for design verification is so important. Really understanding your product is so important because we work with our products in controlled environments. We control everything during verification. But when a product is in the field, you no longer have that control. You're really pressing the robustness of your product, especially if a patient is taking it home. If you're taking home, you know, enough. Product to dose for a week, two weeks, a month, you know, depending on what the dosing frequency is and maybe, you know, I'm giving a patient a bag of three devices or combination products. Where you administer once per month. To me, that's like your worst case scenario, because every time you're gonna have to relearn it every time.
Shannon - 00:08:28: True. And your point to patient safety, I know with regards to human factors. To me when clients will come in and they'll ask about, do I need human factors data to prepare for my clinical? And it always comes back to that safety question. And in some cases, your clinical study design is managing that risk. So maybe you're having healthcare administered and everything's done in clinic. And so you're managing that use related risks within your clinical study design. But when there is potential for use error, that's when you need to start thinking about the human factors in support of clinical readiness.
Stefanie - 00:09:10: Absolutely.
Shannon - 00:09:10: At home or if you're having them self-administer, even under observation potentially, right? On the wrist.
Stefanie - 00:09:17: Yeah. And honestly, another consideration of human factors with the spectrum of clinical trials is also if you have a new endpoint assessment, like if you're validating a new primary endpoint and maybe you need to have the physicians follow a brand new scale of assessment and there's instructions, that's also, a great way to implement Human Factors is to make sure that your instructions are clear.
Shannon - 00:09:45: Yeah, that's a very good point. I want to back up. We're talking a lot about combination products and I know from my experience in the industry there's medical device and there's pharmaceutical product development. Those processes don't exactly align.
Stefanie - 00:10:03: Yes.
Shannon - 00:10:05: Precisely. And I want to come in from the perspective of your pharmaceutical company and you're now doing a combination product. What are some of the unique considerations you might have for clinical readiness when you now have a device in the mix?
Stefanie - 00:10:19: Okay, so I think, you know, if it kind of depends on if the product was already on the market, I think that's one consideration. Because if the product was already on the market, you have a nice pool of safety data. And so you really have that to rely on and understand, you know, if you're maybe you're changing a delivery device. And then you can understand, well, if I'm changing that delivery device, am I introducing new safety risks or changing the drug dose, which, you know, can be really challenging and that happens a lot when you change delivery devices. But also, if you're coming out, if you're a pharmaceutical company where you're used to doing standard toxicology studies and, you know, it's that you're starting over with a new drug product. And so you're on your pharmaceutical development pathway. A lot of times what happens, and I hate saying it, but the device can become an afterthought. And it's not as well coordinated in the early development. And so a lot of times what can happen is you end up seeing those differences in how the products were developed. Where now all of a sudden, like maybe your dose accuracy isn't right for the delivery profile. And so you could be getting some data maybe that you weren't expecting. And unfortunately, sometimes this even persists longer into the clinical program, into your pivotal trials, where it's not even just in your phase one studies. And I think that's sometimes what you know, that's the burden of combination product development in the clinic, is that you're not only controlling one product, you're now trying to understand two and how one influences the other. And then you're putting that into a very complicated biological system, you know, where individuals metabolize, absorb drugs very differently. And so I think sometimes we forget that, you know, any any source of variability is amplified when you get into the clinic. And that's where I think that piece of really understanding your product before you go to the clinic, really makes a big difference. Now, on the other hand, sometimes we have to do pilot clinical trials because you can't mimic how the drug is delivered. In an in vitro setting, you know, and really how it happens in a biological setting like nasal sprays, nebulizers, for example, like there are some models that are more established. But they're not as representative once you get into a human population. And so, what was, you know, what seemingly was a very simple program where you've got all your characterized data on the bench and now you get into, you know, delivering in humans. Now all of a sudden, like your data looks odd and why is that, you know? And then all of a sudden, now you're modifying the device design, changing your drug delivery profile just because of those factors. So I think that's some of the questions. Sometimes we have to do a pilot study to really. Understand the drug and device together, in which case then you get into this realm of early feasibility studies for investigational products. And there are some nice guidance documents out there. That I have had success with and working with FDA where you can take a risk-based approach and understand what aspects of your product. You know, control safety and go down your risk-based program and using those factors, kind of what we were talking about before. And then you provide that to FDA to justify. Doing a very small feasibility study. Before you get into a larger study to ensure success. So that's one aspect where maybe we do go into the clinic a little bit faster to better understand our product. But I think that's the biggest, for pharmaceutical companies that maybe aren't as used to having this additional device constituent, it's how complex is my device and how does it interface with the drug. And when does that interface need to be coming together? Maybe if it's a pre-filled syringe, I'm not quite as worried about it. However, if the drug was previously administered IV, and now all of a sudden you're administering it IM or sub-q, local safety is your biggest factor in there, which your device is a big component of that. So I think these are a lot of pieces that you kind of have to work through. And really assessing when and how you get to the clinic. And I would say for devices, it's usually about that local. Safety factor and, you know, intranasal inhalational, those have a what we call local safety factor for the respiratory tract. You know, it doesn't seem as obvious since the drug is having a systemic action, but you know, from a regulatory or clinical safety perspective, we do consider that. Local safety. And so that also has a whole gamut of non-clinical studies that are required in addition to maybe what you're used to if you're only developing oral tablets, for example.
Shannon - 00:15:56: Good point. I was thinking as you were talking, but then I think you answered the question as I was thinking it. I was thinking about some contingencies or contingency plans you might have in place to kind of de-risk getting into clinical readiness. And I heard a few of the examples you mentioned. One, go back to the risk-based. So assess where those risks are and understand what you need to control. The second I heard was some discussions around some of the, for the device side, some of those critical performance factors or essential performance requirements, if you want to go there. But so understanding what are those critical aspects of your product performance that could impact function in that clinical study, right? I mean, it's not necessarily just usability, but it's mechanical function as well. And going back to something you said earlier, I wrote it down as a quote because I think it is so true and it resonated. Any source of variability is amplified in the clinic.
Stefanie - 00:17:03: Yes.
Shannon - 00:17:04: And so I go back to my, you know, engineering test hat, my verification validation hat that I wear a lot. And I think about my key input variables. What are all of those sources of variability that I'm going into? That do I understand them or not
Stefanie - 00:17:20: Yes.
Shannon - 00:17:20: What do I know and what do I not know? So I heard you talking about some methodologies to try to evaluate those before you get in there, right? And then to the clinic.
Stefanie - 00:17:30: Yes. And I would almost even say then on the drug side, you need to understand your drug product because depending on what we call the therapeutic index. If you're a narrow therapeutic index drug, that means that you have a very small wiggle room in your dosing range, and going outside of that range could have very significant effects on the patient, both from safety and efficacy. Or are you a broad therapeutic index? Product where you have a little bit more wiggle room. And I've worked on products like that before where, you know, you can get into the plus or minus 20% range in dose delivery and it doesn't have a significant impact. But understanding that upfront and making sure that, your device matches that window, a lot of times that's what goes wrong in the clinic, is that, you think, well, this is the performance boundary of my device, it can only perform to this extent, but then that isn't communicated very well on the drug side. And it's that constant cross talk that, those of us who are into combination product development harp on so much, does your drug meet your device performance requirements and vice versa? And I think that's where that again comes back to that product variation that we see. And also considering that some products don't start at phase one studies. So, you know, your first clinical study may not be a phase one study in healthy subjects. Like you could be going right into a phase two or a phase three study that's pivotal. So your product has to be even more, you know, close to closer to a GMP, you know, commercial ready product. And it can't be just, you know, good enough to be, you know, clinical ready. And I think that's another. You know, common misstep that companies have where they're so focused on the finish line and just getting the data that they forget for pivotal studies. We have to be as commercial ready as possible because otherwise you may end up running another study at a bridge.
Outro- 00:19:56: And that's where we'll end for today. And next time, Stefanie and Shannon will start with that device company perspective on regulatory and timing. They'll touch on factors that can influence your regulatory strategy and variables that can occur during clinical trials and the management of your data package. You won't want to miss that, so be sure you're subscribed to this podcast on YouTube or wherever you get your podcasts. For more information on what Kymanox offers, visit kymanox.com. This episode was edited and produced by Earfluence. Thanks for listening, and we'll talk to you again soon on The Factor.
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