Understanding The Global Regulatory Landscape For Combination Products

In this videocast episode, host Tom von Gunden discusses Chapter 14 of The Combination Products Handbook (CRC Press) with the book’s editor Susan Neadle, along with chapter coauthors Stephanie Goebel, Cherry Malonzo Marty, and Viky Verna. The group provides overviews of the commonalities and variances in regulatory definitions and guidances for combination products across global jurisdictions and agencies. 

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Episode Transcript

Tom von Gunden, Chief Editor, Drug Delivery Leader:

Welcome to another episode of The Combination Products Handbook: The Series. I am Tom von Gunden, Chief Editor of Drug Delivery Leader and your host for the series. Today we're going to discuss Chapter 14, which is “General Overview of Global Combination Product Regulatory Landscape.” And for the conversation, I am joined by the editor of the handbook and coauthor for the chapter, Susan Neadle, as well as chapter coauthors Stephanie Goebel, Cherry Malonzo Marty, and Viky Verna. So, welcome all of you, and let's get started.

So, Susan, I'm going to start with you as the overarching editor of the book. As we've often done, can you tell us a little bit about why this topic focus in Chapter 14, which, as it turns out, is actually the last chapter in the handbook? Can you just give us some context-setting?

Susan Neadle, Editor and Chapter Coauthor:

Sure. So, as we were going through the book, most of the focus was on the United States and Europe. And what really became evident, even going from the very beginning of the book, where we actually referenced this chapter, is that the regulations and the interpretations going across jurisdictions around the world are not the same. And not everybody even calls a combination product a combination product. So, we mentioned that in Chapter 2, but it's like, okay, well we mentioned it, now we need to talk about it.

So, really this chapter is a culmination of. once you've gone through everything and you now understand there's pre-market classification and then there's the development considerations that you need to take into effect and that you need to take into account, and what do I need to put into my submission going around the globe — marketing authorization, the actual approval process, and then to post-market.

So, we really were stepping through that in all the other chapters in depth, but now we needed to be able to see, what does that look like going around the globe? So, that's why this is really a concluding chapter in the book.

And there's actually a very important, and I think helpful appendix that was added to the book. I think I mentioned it in one of the very first episodes. Diraj Bell, who's now PhD, helped me put together this appendix that is a survey of the international regulations including Asian region, European Union, Middle Eastern, North Africa, Latin America, Switzerland, North America, the World Health Organization. So, it's a nice survey that goes into detail by country in each of those different parts of the world, what the interpretation is. But just having that as an appendix isn't adequate. It needs more conversation, which is why we chose to go ahead and create a chapter on this.

And I can honestly say this was the hardest chapter in the entire book to write because the regulations in all the different regions kept evolving. And finally, it's like, draw a line in the sand. We have to get this book out. Let's finish this chapter and move forward. And I think the whole change, all the changes with the EU were happening as we were writing it, Brexit, as we were writing it. It was like, oh my gosh! So yeah, this was the crowning chapter of the book, and I was so glad when we finally completed it.

Yeah. Well, just as a reminder, you have mentioned that appendix in previous episodes. We certainly encourage folks who consume the handbook to move from Chapter 14 into the appendix. Obviously, I'm glad to have all four of you here [for], as you mentioned, a complex and wide-ranging chapter. So, it's good to have all four of you here to talk about it.

So, let's get started on the jurisdiction-by-jurisdiction take. Obviously, there's a lot of effort around regulatory that goes on in the U.S. and extends beyond.

So, Susan, do you want to just take the first run and talk about the United States picture?

Neadle: Yes, and I'll be fairly brief about it mostly because that has been the focus in most of the rest of the book. But an important context to it is that the United States regulations, when they went into effect for combination products, that was kind of a turning point or a trigger that I think drove the cascade to all these other regions to start implementing regulations around what I'm calling combination products or combined use systems or however they want to refer to it country-by-country. And so, the U.S. regulations are the most mature going across all these regions. But that framework also set into motion some work with the Global Harmonization Task Force, which then eventually became the IMDRF [International Medical Device Regulators Forum]. Under the Global Harmonization Task Force, there was an effort to publish an initial attempt at some level of harmonization, at least harmonizing definitions for combination products.

And interestingly, that was like 2016, I think, when that originally published. It kind of fell on its face because you couldn't get the regions to align with each other. And as you keep getting into conversations with different regions, you still run into the same situation where, well, we interpret it differently than X, Y, Z region; therefore, we can't leverage what that region's doing. And unfortunately, that's really still the case today. But I'm sure we'll talk more about that as we go through this.

But the United States, we've gone through what is it to classify a combination product. We've talked about the RFD [Request for Designation] and the pre-RFD process. We've talked about how you have to be able to bring together the evidence for the primary mode of action [PMOA] as well as whatever other constituent parts may be part of that combination product.

And then. what does that journey look like going into the FDA as part of your submission, whether it's device-led, drug-led, biologic led. And then, after going through that submission, now we've got post-market safety reporting expectations.

So. one thing that I thought was very helpful at the beginning of the chapter is that there is a nice overview of the evolution of all of the different FDA regulations over time, which it continues because even this year there's been more.

But when you look at that layout and the journey of, wow, we realize that this is something we have to address, and there was something more we have to address and there's something more we have to clarify — that's now what a lot of the other regions are also contending with. The U.S., in a way becomes the settled space because we understand it, and the other regions are where it's really dynamic.

So, I guess that's pretty much what I have to say about the U.S. for right now. Maybe we could turn the focus to the other jurisdictions that are covered in the chapter, maybe Stephanie for Europe.

Yeah, that sounds good. And Stephanie and others, when you give an overview and hit the highlights of what's on your mind, if you can talk about current state of the regulatory landscape as well as challenges that folks are currently facing, but also opportunities for advances in additional harmonization efforts. So yes, Stephanie, dive in on the EU, please.

Stephanie Goebel, Chapter Coauthor:

With the EU, I think one of the biggest challenges is already coming with the definition, and I think we outlined this in the book: We do not have a separate definition of a combination product in the European Union. So, you always have to make, in the first step with the principal mode of action: is it a medicinal product or is it a medical device? Of course, there are products that have both aspects: the one of the medicinal product, as well as the device. But this is, I think, already the biggest challenge for most of the companies that they have to handle, then, based on the decision: two different jurisdictions and two different entities.

This is then the second biggest difference: In the U.S. there's the FDA overarching, handling every kind of product. In Europe we have the respective EMA or the national competent authority for the medicinal products, and then for medical devices, the notified bodies.

So, I think what we really nicely outlined is that it's important to handle your way through these different jurisdictions, the different players, but that, in the end, when we look at the final results, so entering the market as well as staying on the market, it's almost the same rules. You always have to show your data. There may be slight differences in how it's presented. For example, in the EU, when we look at the GSPR [General Safety and Performance Requirements] checklist, that's a specific way of presenting data for the device part. But in the end, I think this is something that is harmonized at least not only between the EU and the U.S., but it's about that we have data on safety and efficacy. And I think this is also something that we see in Chapter 14 that this is common for all the regions.

But maybe Viky and Cherry can continue for other regions.

Yes, and please do.

Cherry Malonzo Marty, Chapter Coauthor:

I'd like to add a little to that because it's really true that there are some principles that are eminent for all: You need the data. But what I find interesting is that, as we said, it evolved earlier for the U.S. and there is even a definition of the different kinds. We're not just talking about PMOA, but we also have different types of combination products like the single entity, co-packaged, and cross-labeled. And those are actually regulations. You can find definitions of those.

But those, when you go to the EU, there is a specific guidance on borderline. They say, as soon as it's not a single entity or single integral in EU, this is not a combination product. So, you have to figure out who is it, who you're going to go to. Both of those products — the medicinal product and the device — will require assessment from two different regulatory authorities. And that just puts the burden on the manufacturers because then in the U.S. for a co-package, they just go to whoever is leading. But in the EU, now you're going to two different at the same time and waiting for the other. And coordination is not always as fluid as if you're dealing with one authority.

Neadle: Yeah, it's like the systems approach is not a systems approach. When I think about the U.S. versus different regions globally, the U.S. really has driven home this idea of a holistic approach to thinking about the product. In the EU, they've improved; there is more systems thinking to it because I need a notified body opinion for that secondary constituent part. However, hey, wait, nope, sorry. The focus is the drug, the focus is the drug. It's a medicine or it's a device. It's not its own separate category of a product, which is a combination product.

And I think when you went into some of the other regions, Cherry and Viky, right? One of the big take homes is, nobody else but the U.S. Well, Saudi Arabia, I think, right? Saudi Arabia …

Marty: Yeah. They're aligning it.

Neadle: But the other regions, it's very much more like Europe where you're treating it as they're separate products that are making up this combined use system. So, go get separate approvals.

Marty: I just wanted to say because of that comparison, we were trying to really sort it out and put it in an image. So, there's this table that we put also towards the end of the chapter where we're saying, look here, there's no clear equivalent. First, we put the U.S., this is how it's laid out. It's pretty clear where you're going. And for the rest, it starts to go, it’s no clear equivalent, no clear equivalent. So, what do you do there?

Viky Verna, Chapter Coauthor:

So that's why I would say, in general, I mean because the more that we go to different jurisdictions, you start realizing that those different jurisdictions can converge quite a bit, not just because of the natural evolution of the different jurisdictions, but also because of the current status of those different organizations where they have different departments, different organizations, let's say, assigned to review and regulate the different components of a combination product.

For example, if we consider China: there are two different departments, where they actually do the reviews separately or because of the way that they actually perform their reviews that could be different than the EU or in the U.S. creates an additional complication.

But while we know, just like Stephanie mentioned regarding the end goal of being able to prove the safety effectiveness and efficacy of these combination products, then you also get a whole lot of administrative challenges. Because if you're going to Japan, for example, you need to have everything in Japanese. And the same in China, which adds a whole lot to the overall planning activities into the level of challenges in addition to the differences of regulatory framework.

Yeah. I apologize to all four of you in advance of a question I'm about to ask that we didn't even consider as we were prepping for this. So, if it falls flat, you can look at me. But what comes to mind right now that hopefully is of interest to our audience is: For all of the stakeholders are out there who may have to think about multiple jurisdictions, and maybe this is more of a question about harmonization as a concept and secondarily as it applies to combination products. But thinking of harmonization as it applies to combination products, what comes to my mind is: How idealistic do people have to be about harmonization? How complete does it have to be versus where might it even be, by nature, inevitably different or possibly even desirably different? Could you talk through what do we think we're moving toward and why?

Neadle: Well, I'll jump in really quick and then I really do want to turn the floor to everybody else. But one thing that I think speaks to exactly the question that you're asking is the fact that, currently, like the U.S. FDA, they've come up with the new QMSR [Quality Management System Regulation], which is to be effective in February of 2026. Under the QMSR, they state outright, there is no mutual recognition agreement for combination products, and there's no MDSAP, Medical Device Single Audit Program, for combination products. And right away that's this big like, wait, what do you mean there's not? There’s not. Why? Because the interpretation of what is a combination product is different from region to region. And those differences in interpretation around, well, wait, how is the U.S. FDA going to inspect a company that is manufacturing combination products? They're looking at the call that provisions as well as their base quality system. So, they're always thinking systemically for the combination product.

If I go to Europe, the focus there is, well, I'm using the EU. The notified body is going to assess conformance to the GSPRs, the General Safety and Performance Requirements. But when they're making that assessment for a notified body opinion, they're doing a paper exercise; they're not necessarily coming in to do an inspection of your CGMPs [Current Good Manufacturing Practices]. And the overall authority for a drug-led combination product would be under the medicinal products directive. So, the focus of those inspections is probably more the medicine side of things. So, it's not that same systems approach.

So, it shows up so fundamentally at that very raw stage of, wait, I can't even leverage these mutual recognition things. And it's not a trust issue. I don't think that there's any question. There's so much mutual recognition agreement for drugs, for the MDSAP for devices, for all these different jurisdictions. But the issue is that the interpretation specific to combined use systems and what's considered a combined use system or combination product is different. So, it just lands very hard on industry because you've got to be able to meet all those requirements of each jurisdiction.

Goebel: Yeah, I agree. It's hard for industry, but maybe what is also an opportunity for industry is that we can set up regulatory intelligence and also use artificial intelligence or lots of good software that is upcoming. Because like we already discussed, in the end it's all about having the data ready. And it's just a different way of presenting it to the different authorities.

So, if we have this all in the system, and we know, like Susan said, one agency has a focus on inspections, the other one doesn't; one wants to see it in a table-like format, the other one doesn't. But in the end, it's all coming back to the data and to the evidence that we have. Then it's up to us to handle it. And this is also why I think this chapter is really helpful because it outlines, these are the rules, we have to handle the rules. There are some steps forward that it's harmonized, some are going slowly, some are faster. But in the end, if we know the rules, then we can also take our tools and adapt them. And I think this is really something that is evolving.

Verna: I wanted to add one additional aspect, especially based on how Tom phrased the question as well, regarding what is really causing some of the divergence in this sense. I would say in my opinion, the interest of the different regions in their history could have also influenced that quite a bit.

One specific aspect that I can think of right off the top of my head is the requirements regarding clinical trials. So, you will find that, for example, in the U.S., there is a big interest in making sure that the population that is used for the clinical trials is representative of the American population, for example. But it's not to say that they only want clinical trials to be performed in the U.S. Whereas in other jurisdictions, trying to justify that other population — for example, if you go to Japan or to China — could be a little bit more difficult.

So, some of these jurisdictions automatically also tend to require clinical trials to be performed for combination products in other types of products in their jurisdictions. But I'm still bringing it up in the context of combination products because it does become pretty relevant for combination products that are often seen as being innovative products. So, that is just to give you a context of why some of those have been converging as well.

Marty: I think additionally, I think we cannot rule out the fact that different jurisdictions, different cultures, different means of communicating, different expectations through the communication between manufacturers and regulatory authorities. And I think we can always say, but on paper, this is how it's supposed to run, but it requires more than this and the daily work and the daily relationships. You still have to build those relationships with the regulatory authorities or vice versa, even with your contract manufacturers, the whole system. And that plays so much into that as well.

Verna: And that's why, just like Cherry mentioned, one of the aspects that I very often promote is the aspect of initiating and engaging with the different jurisdictions early on. And you'll be surprised how you will notice the differences in how the engagement is because of the differences in culture that you can adapt your overall regulatory or global regulatory strategies according to that. And that can be very, very helpful.

I wonder as all of you look toward convergence versus divergence, if there's anything that remains divergent: Is there anything that you would say would be unfortunate if it remained that way? Are there ones that you'd say, it really might matter if we can get this to converge?

Goebel: If I may start again with the European Union, I'm still hoping that there will be some kind of, at least, a forum where the EMA national competent authorities and notified bodies come together. Because I think this missing dialogue is at the moment the biggest challenge, right? They are separated, they are separated by law, and I think this dialogue is also inhibited as notified bodies are not allowed to consult. And there's lots of discussion if this is already consulting. So, if this could somehow change, that there is an option for a structured dialogue. This is something that would be great.

Neadle: I wholeheartedly agree with that. Can't say that one enough. I think the other opportunities where it would make a big difference is the post-market safety reporting. Because companies right now, partly because of the different interpretations of what's a combination product, what's not, the lead jurisdiction that I need to report on country to country: If I have a safety and performance issue with a product, I think it's really pretty painful to have to worry about formatting of my report country to country to country because there's a different lead center or a different lead in each jurisdiction for that information. The focus should be on, we need to fix this issue. Let's get the information out there so that everybody involved is aware of the safety signal. And now let's focus on fixing it versus, well, the reporting has to be approved by this person for this country, and it has to be in this format for this country, and they want only this information. I think that it's not a valued use of time because the focus should really be on its safety and efficacy regardless of what kind of product you want to call it. So, I think that one's a number one opportunity.

And the other one is the inspections. I think that there would be a huge benefit to companies to be able to find a way to get countries to align on an inspection approach that would allow mutual recognition agreements and MDSAP, let's say, to apply even for combination products. But there's a lot of homework that would have to be done in countries that currently don't inspect the other constituent part. I don't foresee the FDA backing off, and I wouldn't really expect them to back off of the approach that they take today in doing those inspections.

Marty: I do have something coming from Stephanie's idea of having everybody at the table. And this really comes from the idea of the pre-submission that we see in the U.S. And you hear a lot about people in Europe also saying, why can't we have something like this? Because by the time the manufacturers get to a point where they want to submit, they might have missed something they could have gotten earlier. But if there is no way, there is no means of communicating, or you lose time trying to figure out how to even communicate or get into a pre-sub, it’s just costing so much time. And also, it's killing innovation. I know some cases where, because there is a dead end, doors are closed, you don't even know which door to knock on. You just don't. You just go to the U.S., which is great for the US population, but the rest of the world or whoever else could benefit from these technologies.

Neadle: And they don't have an office of combination products in these other jurisdictions that you can say, hey, I really can't figure out who to go to and I don't know who to even engage in this conversation. They have their inter-center consult process. They can pull in the right parties across the FDA. You don't have that in these other jurisdictions. So, I agree with you, that's a real challenge for people.

Verna: You mentioned something that got me thinking of a couple of cases when it comes to challenges due to the differences in auditing approaches or inspection approaches. So, there would be some projects that I would work on and they would, depending on the different departments, they would feel comfortable. They've been inspected by multiple countries and so on. And then once they would get inspected by a new jurisdiction, and then they would get a long list of everything that they would not expect to have violations for. And that's more from a quality control or regulatory aspect.

But the funniest part is when some of them would ask, but how many inspectors would come for a finished combination product, a finished assembly process? And then you'll say, well, maybe two auditors. And that could be coming from the U.S. or from the FDA. And then I've had examples where, coming from South Korea, they would have a team of 14 or 15 auditors. So, you would probably never think about it, but it's not impossible, and it adds a different level of stress because then different countries have different aspects that they pay very close attention to that you might not expect.

Neadle: That's a really good point. I think I've been in inspection where MHLW [Ministry of Health, Labor and Welfare] came in from Japan, and that was definitely a new experience. I mean, the level of scrutiny that goes into it and the attention to detail, it is culturally dependent, and it's also the regulations- dependent.

Goebel: And of course the auditory viewer, him or herself. And I think that's also what we potentially do not want, that there is just artificial intelligence sitting and asking us. So that's also something that we still have to consider. It also depends on the factor of human beings, and again, there can be positive and negative experience.

However, I still think it's learning and coming back to this topic of regulatory intelligence. We should also consider such aspects as collecting questions and answers, collecting certain interpretations. And then maybe also confronting the respective agency if we have really diverging opinions from various reviewers of the respective authority. So, think this is also something that we can use and, again, go into a dialogue and discuss.

So. to move into the final commentary from each of you, I'm going to bring this up to a super high level, and you can take a run at this with any of these groups that come to mind based on fitting into the context of this question. So, my question is a super high level one, and it's looking out over of the horizon of potential opportunities and challenges to be addressed and avenues to pursue. Thinking in terms of any of these three groups — the folks in industry who have a stake in bringing products to market, the regulatory agencies themselves, and/or actual patients out there: What would be something that comes front-of-mind to you as you look to the horizon of something that could be addressed or pursued or fixed, whether it's a challenge or an opportunity in terms of any of those groups? How would any of those folks be more effective and benefit from these advances, whether they're in the industry, the agencies, or the patient population? And I'll start with you, Viky.

Verna: Well, actually, as you were asking the question, I had so many ideas that came to mind, but to address what you asked specifically, I think the different stakeholders may have some homework.

So, on the regulatory side, of course, it will be important for the regulatory agencies or authorities. They definitely need to try to keep up with the industry, with technology advancement and evolution.

And I know it's always very hard, but unfortunately the industry usually tries to get everything out as fast as possible or to do their development as fast as possible. But very often they get to a point where they need to pause and figure out how they're actually going to get the products out, especially when everything is unclear. And that can impact the entire project timeline substantially. So, I think these are the main two, but when we're talking about global regulations in general, really having the different regions and authorities on the same table is definitely a must.

We have seen some progress with ICH [The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use], with IMDRF, but there is still more to be done. And I'm very hopeful and I think there can be more done because we have noticed lots of harmonization activities being done primarily for, let's say, oncology drugs or for very unmet needs where for these cases, the top scientists, the top regulatory folks, they do get on the same table. In the top pharmaceutical and medical device companies, they do get on the same table to share data to advance their technologies. I think it's just that we have to keep on going in that same direction. I think we should be getting closer to making it easier for combination products.

That was great.

Cherry, do you want to give it a run?

Marty: Yeah, so for me, from how I see it, of course I agree with Viky. There is a movement towards that, and I think we are going in the right direction. We have to also remember that the EU is an example of this convergence. They used to be under the MDD [Medical Device Directive], where they interpreted things on their own, separately. And now — this is from coming from the devices perspective —but that is also part of it. That's the other half of those combinations. And so coming at least into this direction where, okay, we are trying to converge, we have the same regulation, we're moving towards that communication. It's of course taking it slow. It's too many stakeholders all across the board. But there are programs that are coming out. And I think that's also helping industry.

And that's what it is related to what Stephanie is also saying, that regulatory intelligence is also so important because there are opportunities out there, but you need to watch and be updated and know how you're going to approach the authorities because there might be programs that would be applicable to your device and your technology if it's so innovative. There are those opportunities.

And I think for patients, I know that there are also patient advocacy communities now, and they're slowly also coming to conferences, for regulatory conferences, where they also present their side. Because I think we always talk about the patient as the end user, right? They will benefit. They'll benefit, but we don't really represent them as much as now I feel like they're coming in more and more. And I think that's good. Then you have these stakeholders all coming together.

Great.

Stephanie?

Goebel: Yes, maybe taking up Cherry's point about the patients, that we also had before. The patient, in the end, wants to have a product. And the patient doesn't care if the product is already existing or maybe hopes that the product is already existing on the U.S. market that he or she living, for example, in the UK can also use it. Right? And that's why I personally like these upcoming initiatives, especially from Switzerland and the UK, that they will recognize, respectively, approvals and make sure that products will come to their countries earlier.

And I think this is something that should continue, that the respective countries check, what can I accept? Is it possible to ensure an easier and faster pathway? Because in the end, that's what counts, right? We have patients, we have patient needs, and they want the products. And it's often not understandable for someone outside why there are so many differences between a product that is potentially exactly the same in the U.S. as well as in another country. So, I hope that this continues. I think there are already good initiatives happening. And, if this continues, then I think we're on a good way forward.

All right.

Well, Susan, you had the first word. How about the last word for today?

Neadle: The last word for today. So. I echo wholeheartedly what each of Cherry and Viky and Stephanie have said and just add in that point: The patients, in the end, care about making sure that that product that they receive is safe and effective. And all the logistics and whether or not you're using ICH Q9(R1) or ISO 14971, or you're using separate notified body opinions — they don't care. They want to make sure that the product that they're getting is going to be safe and effective.

And speed-to-market is obviously key, both from industry perspective and for that patient. They really want to be able to get access to that drug as quickly as they can and with the easiest delivery mechanism possible to be able to help them gain the benefits that they're hoping to realize with that product. And we really just, I think as an industry as a whole — regulators and industry alike — need to work together to figure out how can we make a pathway forward that universally is going to be something that helps out populations globally. I know World Health Organization is trying in some ways, but we really need to get everybody together and say, you know what? It's been a priority to drive convergence for drugs. It's been a priority to drive convergence for medical devices. Can we please drive convergence for combination products? It's really needed.

All right. Well, thanks to all of you: Stephanie, Cherry, Viky, Susan. It has been a great conversation. And, as I look out on the horizon, I have a couple of hopes. One is that folks check out more episodes in this series about The Combination Products Handbook, and that they also, if they haven't already, dive into the handbook itself and read it thoroughly — particularly, Chapter 14.

So, folks, we'll see you next time.