RQM+’s Post

Transcript

Namaste, ladies and gentlemen, Welcome to considerations towards strategy and tactics for a combination device clinical trial. My colleague Chad Quista, who has developed and commercialized a number of combination devices during his time in industry, and I are going to discuss the strategic and tactical aspects of this very important category of devices. Very complicated rather. In the realm of clinical trials, Welcome to the chat, Chad. Thank you. Thank you. Yeah, Chad, please help us understand what are some examples of combination devices, what regulations alley to these combination devices and what are the regulatory pathways in the US and in the EU for these devices? So when we're talking about combination products, we're talking to some of the more popular ones that you may see out there auto injectors. Anytime you see someone auto inject something into their either their the back of their arm or into their thigh auto injector, you obviously have prefilled syringes that are now classified as a combination products popular. Yeah. And and the coronary world, one of the big ones is, is a drug eluting stents the and you have reusable pen injectors. And most popularly used for those is for for type one diabetes or type 2 diabetes for people need to take multiple doses within a week. You have drug reconstitution sets for infusions or an injection set injection kits. You have drug coded catheters that have someone do drug coding on them and you have more recent technology on body automatic software driven auto injectors. Until we talk about US regulations, combination products are defined in 21 CFR 3.2 E which defines the different types of combination products. So you have single entity combination products. It's pretty much an all in one package. A lot of your auto injectors are in all in one package. You have code package combination products. The good example though is would be say on body automatic injectors where injector is packaged separately but it's in a separate since in the same kit with a Co packaged drug product that's loaded. To that device and then you have cross labeled. Combination products where you have pen injectors that can be used with multiple different types of insulin. So you have multiple different headset in the FDA side and you're regulated by 21 CFR part four and CFR really breaks it down into you had your device side regulations. This is 21 CFR 820. And then you combine that with the 21 CFR 2:10 and 2:11 for. For for compound drugs and then 21 TFR 6600 for biologics. When you get into the you, you get into the definitions of combination products or their definitions, they don't really call them combination products. Article one, Section 8 and Section 9 where they talk about devices that incorporate the medicinal substance, which has an action that's ancillary to that the device, which means that the drug is not the primary mode of action for that system. Then you have devices that could have made some support that the drug has an action principle of that to the device. And then you have your devices generally intended to administer medicinal product and that's generally the same thing as sort of a cross labeled combination product here in the US where it's like an insulin pen where the insulin pen is sold separately and then you can use any type of insulin drug that's cross labeled with it as well. And then the EU bringing in Article 118 into consideration as well, right? That's right. So excellent. And so when you get into the US too is. The US has just a single pathway when you're talking about the, the primary mode of action. So when you're getting into the US, umm, one of the things in the regulatory strategy is to 1st determine your permanent mode of action. And if that property mode of action is the drug itself, the drug is doing the therapeutic effect or the main therapeutic mythology times, there's a Gray area, but it's really the one that creates the most therapeutic effect. So you're taking an autoinjector that would be a drug primary mode of action because the drug is delivering the therapeutic effect effect where if you say you take A and that would be you just follow the traditional, you go to Cdr, you follow the traditional and or out of its generic and NDA for new drug BLA if it's new biologic. And with the device primary mode of action. So take for example a drug eluting stent, the primary. The primary third therapeutic action is the extend itself trying to keep the vessel open, trying to red restenosis. The the drug part mainly reduces the immediate reaction to the device itself and prevents immediate scarring and reduces the rate of restenosis in the device and so that the skin can properly into feelings around the stent as well. And struggling since have been proven to be superior over regular last month itself. So that was sort of the things you go through. The device and with those you go through CDRH and you take the traditional slip PMA 52K denovo route. In the EU. You have to do if it's a device primary mode of action, you have to get the Device Control assessment per article 52, and you also require an scientific opinion from a notified body of the medication at the MPA. With with on the drug side, you need to get the CE mark of the device itself prior to filing your. Mm-hmm. And then and then like I was mentioning earlier, under Article 118, there is a notified body opinion process as well depending on how your device is classified. Great. Well, thank you chat, Chat. I want to delve a little bit into your industry product development experience right before we launch into the actual clinical trial design and conduct aspect of things. What are some of the product development related challenges associated with combination devices? But one of the biggest problems is when you especially depends on which side of the business you're coming from is in the drug world. It's a completely different, completely different obstacle when you're talking about just pure drug development when you're getting into devices a little. A lot of companies that I've seen, they've tried in the beginning initially to try to do everything from within. We're going to try and develop a device. We think we know everything in drugs complex. This device looks simple. We can do that. The biggest problem is they don't know how to write design history file documents in 21 CFR 20. They don't know how to write design inputs. They don't know what a design verification plan is. They don't really understand risk management because in their world the drug will. Risk management is really a process based off. And. Ishq, Ishq 9 and risk management device. What is ISO 1345? So getting under ISO I apologize and I so I saw 14971. And. They. They think they know everything and then when you come in and, and look at their, what they've done, they're going, yeah, they they just don't know what they're doing. And so in a lot of times they think it's a much easier thing to go through device when you realize the amount of documentation and traceability is a struggle for them to understand how things are traced throughout the system becomes difficult for them to understand and also when it comes to the submission part as well. Currently a lot of obstacles were not only companies I've worked in, but in companies I've consulted for is we've got a question back from the FDA. And it's a question of, you know, we don't understand what you test it, what your sample size was, what such disco relevance, you know, you have your confidence intervals and that's stuff that typically not needed in the drug submission. And a lot of times I've gotten the question, I know exactly what their submission looks like. So I'll ask first, what is your submission look like? And nine times out of 10, I know exactly what it looks like in the context of completely redo the device section, at least along the lines where design verification testing is documented. So it's a big, it's a big. She was in a company and they really have to, I mean, my recommendation for any drug company or any device company, if your device company hire drug experts, hire chemists, hire people who have analytical laboratory skills, who understand drug stability and stuff like that. The device, whether you're just not going to understand that, vice versa in the drug world, you need to people that understand how to do technical documentation with all the DHF, but also how you do the conformity assessment in the EU as well. So there are multiple different areas that you'll struggle with with the new company understanding how things are done in the opposite world. Great, Chad. Thank you for letting your experience shine through. I mean, that's years of experience that you've tried to summarize in a few sentences there, O. Four combination device what docs really need to be lined up to enable a robust clinical trial design and eventual conduct the one thing in the device side in the drug world you typically don't you don't encounter you don't have to worry about usability it's just someone either takes a pill or someone you know drink the fluid have a drug in the device world it's really understanding the usability of your system understanding the human factors behind your system and designing that device so that it actually. User can define it and you in medical devices, you're required most of the time to be doing formative studies and at least prior to a clinical trial to be doing. Do your formative human factor studies ahead of time, understanding those issues because the last thing you want in a clinical trial is human use issues getting in the way of your primary and secondary endpoints. You want to understand your usability. You don't have to do your summative study quite yet. You can do a lot of companies just do them in parallel, but at least you're formative studies done before you get to a clinical trial. To eliminate a lot of the headaches that may occur during the clinical trial. One of the things you need to understand is all the risks involving your system, starting with the ISO 14971 and having understanding use some design risks and that could be your hazard analysis understanding. You can go into individual use errors doing it's a critical task analysis. You can do Yusef MBA, you can do a design FMA, you can do fault tree analysis to understand all the risks because the last thing you want to do is any of those. Nine issues or usability issues that you could have caught early on affecting your clinical trial. One of the things is, and I'll go to an example of this, some next questions is an early stability studies don't wait till your validation batches to do stability. And a lot of drug companies think they can just throw any given drug into any given container and it will work like I work for this drug, so it's going to work for the next drug. That's not true at all. I've seen significant delays in programs because that assumption was made and luckily one couple of programs have been, we've been able to do that early and catching issues early on. We don't share what are the big things you you're gonna get in this submission at least from the CDRH side of traceability of component used to manufacture clinical trial product. Anything you do in your clinical trial product has to be commercially equivalent. And if you and if you especially we're talking about complex devices, you're talking electromechanical auto body injectors that have you know. 3 to 400, you know, Mayhem 3 to 400 components, you need to understand the traceability of each individual component even though they might be minor changes. You need to look at not only the individual changes, but the cumulative changes over time because I've seen cumulative changes over a period of year that have affected device performance even though individually they didn't do anything, but combined together because they won't look like cumulatively did create multiple issues and especially when you're dealing with clinical trials with a combination product, especially on a device. Pregnant, if you have a device technical team or especially on the device side for them to be on site during the clinical trials to address any issues on site with not only the clinical trial reps but with people actually using to make sure that things are happening correctly and that if something does go wrong, they can diagnose it on site. Because the last thing we want in design is to have a, you know, third party story about it. We want to see hands on what's really going on so we can resolve the issue. So those are some of the the main things that you need to do, period.