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Combo Products, Complex Rules: Regulatory Strategies for Combination Products
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Welcome back to the Ennovation Podcast, where we bring you the latest trends, insights, and expertise in Life Sciences and Regulatory Affairs. This time, I’m joined by Plamena Entcheva-Dimitrov, PhD, RAC, founder of Preferred Regulatory Consulting.
Combination Products Demystified
Combination products are more than the sum of their parts. From pre-filled syringes to gene therapies delivered via light-activated devices, these innovations span multiple product types as well as complexity levels. These variations and complexities can make a product's Regulatory journey challenging. Plamena walks us through the practical realities of navigating these challenges, with a few tips on how to make the journey a little less bumpy.
Our top resources:
- Understand combination product requirements. Read the global strategy essentials blog
- Align regulatory and quality from day one. Watch the Med Device RIM & QMS session
- Pharma-first RIM systems don’t work for devices. Learn about what you need instead
Recommended
Transcript
Introduction to the Podcast
00:00:00
Speaker
Welcome to the Innovation Podcast, your go-to source for the latest trends, insight, and expertise in life sciences and regulatory affairs, all in one place. At Inove, we're dedicated to empowering life sciences organizations with innovative solutions to navigate the complexities of their industry.
00:00:18
Speaker
I'm your host, Alice, and I've worked in regulatory operations for eight years. My background is in regulatory information management, and I bring my experience working in large pharmaceutical companies to supporting clients here at Inove.
Discussion on Drug-Device Regulatory Challenges
00:00:30
Speaker
This time on Ennovation, we discuss the regulatory challenges posed by drug device combinations with Dr. Plamina Ancheva Dmitrov, founder of Preferred Regulatory Consulting. Plamina, it's fantastic to have you on the podcast. Can you tell us a little about yourself?
00:00:45
Speaker
Well, Alice, thank you so much for having me and for the opportunity to join your podcast and share my experience with your listeners. I am a management consultant with over 19 years in the regulatory industry.
00:01:00
Speaker
I do some clinical and quality management work as well. um My consultancy specializes in combination products that makes about 80% of our portfolio.
00:01:13
Speaker
We also do small molecules, gene therapies and medical devices of various classes, ah submissions and quality systems. We do implantable devices, embedded and standalone software products and software as ah as a medical device as well.
00:01:30
Speaker
And over the last 19 or so years, I have myself and with my team supported patient access to novel technologies.
Expertise in Combination Products
00:01:40
Speaker
And we have brought innovative products on the market, helping our clients um expand and solidify their portfolios in the areas of cardiovascular, pulmonary, urology, women's health, um nephrology, ENT,
00:01:56
Speaker
ophthalmology, orthopedics, neurology, and metabolic diseases. I'm sure I'm missing some, but that's the bulk of our work. And we support ah very early stage companies. Usually start projects.
00:02:11
Speaker
as one of the first or or very early on invited to project. And then we support them to marketing submissions. So the full gamut of regulatory quality and clinical work that there is.
00:02:29
Speaker
Wow. That's quite some resume and a really broad experience. So I am really looking forward to talking to you about this. Um, perhaps we can start right from the beginning though. What makes a product a drug device combination rather than just being a drug product or just being a medical device?
00:02:45
Speaker
Well, as the name suggests, combination products are made by combining several different um parts, or we call them constituent parts. And those could be a device and a drug, a device and a biologic.
00:02:59
Speaker
ah It could be a ah ah biologic and a drug, and it could be all three in in the same product. um As some examples are dry powder inhalers, drug-coated patches, drug-eluting stents, ah antibody and drug conjugates, which is ah an example of drug in a biologic product. And when you combine, ah put the the antibody drug conjugates into a pre-filled syringe, then you have all three ah constituent parts in the same product. So ah they can be pretty ah simple conjugates.
00:03:35
Speaker
combination products and they can be pretty complex with multiple pieces. and And what drives ah ah the regulatory ah strategy usually is the primary mode of action. So in other words, what ah does the job in the combination product is what drives how the combination product is regulated and also how the quality system is built.
00:04:00
Speaker
ah There's some examples, a drug coated ah balloon, for example, is regulated as a device because the primary mode of action is the balloon, while a pre-filled syringe is regulated as a drug because the drug is what makes ah ah the therapeutic action.
00:04:21
Speaker
So it sounds like it. the way that it's regulated depends pretty heavily on on the product. And am I right in thinking that it also depends a little bit on where you're making your
Global Regulatory Differences
00:04:30
Speaker
submission? So which jurisdiction you're in as well?
00:04:33
Speaker
ah Absolutely. The country ah does have a huge impact on how combination products are regulated. For example, the U.S. has a very well established combination product regulations.
00:04:47
Speaker
ah We have in the Code of Federal Regulation very well defined definitions in part three of of ah what what is indeed a combination product.
00:04:58
Speaker
And like I said, it's ah it's a drug and a device, a biologic and a device, a drug and a biologic, and and all of them combined. And that is actually ah in the statute. And part four of the Code of Federal Regulation defines how the quality system needs to be built.
00:05:16
Speaker
And usually that follows the primary mode of action. But other countries have less defined um regulations of of for combination products.
00:05:28
Speaker
And for example, the EU has only two types of of combination products. They are integrated, such as a single entity, such as a draculuting stent.
00:05:40
Speaker
um Or they have co-packaged ah when you have, for example, a nebulizer that's co-packaged with the drug that it would be nebulizing. And depending on that, um you would be doing either one or two submissions, e etc. In Canada, combination products um are, again, they they all regulators acknowledge that combination products are multiple ah constituent parts, but the nuances exactly to what level you need to combine them ah in order to be considered a combination product. And in Canada, um it has to do with ah the the see it's its combination product is integrated into a single product.
00:06:25
Speaker
And that is, um, uh, with the distinct nature of the combination, essentially. um Other countries are trying to catch up on on regulatory requirements for combination products, such as China is trying to catch up and have more integrated um ah regulations for combination products, but not yet.
00:06:47
Speaker
And other countries like, for example, South Africa views combination products as two different parts and two different submissions. So, so it's very, ah diverse as, as to how regulators view combination products.
00:07:04
Speaker
I mean, it definitely sounds that way. If you've got the same sort of product or the same kind of set of products, I guess, and being presented to the regulators completely differently in so many different countries.
00:07:16
Speaker
I imagine that makes the timelines for approval in all of those countries quite different as well as the process. Yeah, in indeed it does. the The process is different in that depending on country, you either do one or multiple submissions, even at the clinical trial level and then ah following at the marketing submission level.
00:07:41
Speaker
But also timelines, obviously, because if you if you need a regulator to do two reviews, um then obviously that's does have an impact on on timelines.
00:07:54
Speaker
um In the US, were um we're lucky that we have a very ah well-established regulatory process for combination products. So depending on the primary mode of action, you would essentially be doing a one submission, and and that is driven by the center that um ah regulates the primary mode of action ah entity, drug or device or biologics.
00:08:20
Speaker
ah But like I said, if you go to, let's say, South Africa, you are definitely doing two submissions to even start a study. um EU and UK, a little kind of in between action where you would have to submit first the device piece. It has to clear through the the initial application.
00:08:39
Speaker
um review or validation and then the the CTA can be submitted with the drug portion and then they both get reviewed in parallel, so to speak. So ah kind in between and Canada, you're definitely also doing two submissions unless it's a one entity ah combination product. So um it it does impact timelines for sure and If you're doing one, let's say a phase two or phase three study in multiple geographies, then oh the regulatory strategy is pretty complex because you have to juggle multiple um multiple types of submissions in the different countries.
00:09:22
Speaker
And it becomes a little bit like a puzzle and I, and I love puzzles. So it's, it's good. So good fun. I always think that's the most fun and interesting part of our jobs in lots of ways is that kind of juggling the different requirements in different places. And the, like you say, the puzzle of what order do I have to do this stuff in and where do I need to do this bit first to this bit second? And how do I balance all those aspects?
00:09:46
Speaker
so It's always a really interesting challenge. And I know you've worked with, well, you've you've spoken a little bit about working with lots and lots of different companies and supporting their applications right from that very first clinical study all the way kind of through to approval.
00:10:01
Speaker
In your experience, what's the biggest thing that companies need to consider when they're they're developing these combination products? So at the start of of an idea of a combination product, I would say ah the team needs to be ah inclusive of um people who have done combination products. And I don't mean that just on the regulatory side, but also on the quality side and also on the development side, ah just because there's
00:10:33
Speaker
There's so many aspects of developing a combination priorities. It's not just regulatory. The regulatory, obviously, is is very important at the at the beginning. So identifying knowledge gaps and and fill them pretty quickly is is key. And then just be open to other people's experience and and try to learn the language of the other people.
00:10:55
Speaker
of the other constituent part, right? I mean, and and I'll give you an example. My career started in a device company. And so we had to bring in um drug expertise from outside of our team.
00:11:07
Speaker
And it so happened that it came from um the larger organization, because at the time I was working for a larger organization. Now, Like I said, 80% of my business comes from small companies that are developing
Strategies for Successful Product Development
00:11:22
Speaker
combination products.
00:11:24
Speaker
And so what we do is is we bring in the team that is specializes in combination products from the get-go. A lot of times it's consultants like like myself and and my team.
00:11:37
Speaker
And that's how you go about it and kind of look to, again, if you're a device person and you're brought in on ah on a project like that, learn be open to learn the language of the drug people and vice versa. And that always brings success to the project.
00:11:56
Speaker
That's such a good way of looking at it. It's kind of, we do end up speaking these different languages. And I imagine for a project like this, you need to be fairly bilingual. You need to be really comfortable with the drug sides and the device sides, and then the way that that's going to interact and combine.
00:12:12
Speaker
Yeah, and and I think that's the same at the regulator level, which is why ah i think my company has been pretty successful in communicating with regulators because I speak all of the languages. I learned device language, then drug language, then gene therapies, etc. And so we're um able to communicate to the the regulators in the right terminology and sometimes even translate terminology from one to the other regulator just because um it's absolute the must in these projects.
00:12:50
Speaker
So when you really start looking at that early regulatory strategy, I imagine some of that involves some early engagement with those different regulatory bodies. it Indeed, yeah. and And this is where it's important to identify what the primary mode of action is of the product.
00:13:10
Speaker
and um And once you have identified that, let's say it's ah it's a drug primary mode of action, for example, it would be a therapy that's eluting a drug for HIV treatment, right?
00:13:24
Speaker
Now, There's a device component, obviously, there's a drug component, and the drug is what's treating the patient, right, HIV. So in this case, it would be a drug mode of action. So we would be turning to, in the US, to CEDAR, ah which is our um center for for drugs, and we would be approaching them fairly early.
00:13:50
Speaker
And usually in the very early submissions, we would outline that that is our plan to follow a drug path of approval and and so on. And we get that solidified pretty early.
00:14:03
Speaker
So when you've kind of nailed down that mode of action, you then I suppose have to start looking at where you're going to be making your primary submissions and kind of what order you're gonna be moving through your market. So how much does that choice of country come into play at that at that point in the regulatory strategy?
00:14:21
Speaker
it It comes into play ah pretty early and it's pretty important. um There's some examples and i I'll give you an example of of why the choice of country could be important for, let's say, where you start your first team human, right?
00:14:38
Speaker
um Let's say you had a ah ah therapy that needs to, a vaginal therapy that needs to be delivered through an applicator, right? And let's say you looked around the world and so it happens that in Australia, that applicator is already on the market for vaginal delivery.
00:14:56
Speaker
then it would be a great country for other reasons, but also for this reason, to pick Australia for your first-in-human, because you wouldn't need to worry about the device aspects of the clinical trial application, because that applicator is already on the market. So there's a lot that can be leveraged ah based on that.
00:15:18
Speaker
And you would then focus on ah the CTA ah application for the drug piece, right? So that would be one example. ah Another example is, ah again, let's say in the US you have a nebulizer that already ah has a 510k clearance.
00:15:37
Speaker
You would then ride on the 510k clearance in the US and start your study with an IDE, but then very focused on the drug component or the biologic, let's say it's a gene therapy, um,
00:15:54
Speaker
that would be the way to go. So always ah look for if any country has either approval, let's say approval of a drug or um clearance or approval of the device and try to leverage that um for your first in humans so that you can quickly get into the clinic and get the proof of concept.
00:16:14
Speaker
um That would be one of the reasons why you would look ah globally at at starting the clinical study. So it's pretty clear that where you're making your submission is a huge part of that strategy and a huge part of what's going to determine the success of your combination product. and I think those two big markets we always tend to think of of the US and the EU. So are there any other kind of really critical differences that you want people to be aware of?
US vs EU Regulatory Processes
00:16:45
Speaker
I guess, yes. um In the combination product world, there's there's quite a bit of difference between the US and EU. ah One important difference is, for example, um ah the US FDA accepts what we call drug master files.
00:17:03
Speaker
And drug master files are submissions where you kind of conceal as, let's say, a... um a drug manufacturer or API manufacturer or excipient manufacturer. You conceal your information. FDA reviews it.
00:17:17
Speaker
They have it on file. And then company X comes along. They can leverage that drug master file. and essentially skip all that testing that is already on file with the FDA, and then go on and focus on testing that's specific to their product.
00:17:35
Speaker
So there are drug master files for some delivery devices, such as... um ah simple inhalers, ah that that could be leveraged, obviously.
00:17:46
Speaker
The Drug Master files for um different excipients, let's say silicon is one of those, or different variations of silicon. And those are common parts that we use in combination products. So you know Combination products are complex on their own.
00:18:02
Speaker
Why not ah be able to take advantage of drug master files as as a way to expedite your access to clinic and and you know lower the burden of of your first IND submission? that That is one of the things that make US a little more...
00:18:21
Speaker
um exciting or compelling to be your first jurisdiction to go for a clinical study, while in Europe there are no DMFs. So we then end up having to prepare a much more extensive regulatory submission to even start the study ah because you cannot write on anything that's on file.
00:18:42
Speaker
So that is one of the differences that I always point out to clients um to utilize ah as part of the decision making. Well, thank you
Conclusion and Listener Engagement
00:18:52
Speaker
so much. This has been absolutely fascinating and like a really interesting little window into the world of combination products.
00:18:58
Speaker
Thank you, Plamina, for joining us. ah You can find more from Plamina on LinkedIn and at Preferred Regulatory Consulting, which is at preferredregulatoryconsulting.com.
00:19:10
Speaker
Thank you so much. Thanks for tuning into the Innovation Podcast. At Inove, we help over 450 life sciences companies streamline compliance, enhance efficiency, and achieve their regulatory goals with our unified platform.
00:19:22
Speaker
Ready to learn more? Visit Inove.com or connect with us on LinkedIn to see how we can help your organization succeed.