Combination Products Regulatory Considerations with FDA's Barr Weiner

From his roles and experiences in the combination products and combined use systems arena, John “Barr” Weiner offers perspectives on how to approach pre- and post-market activities with regulatory requirements and guidance in mind. Cross-functional coordination, integrated development, and primary mode of action (PMOA) designations are among the considerations Barr reminds organizations to implement thoughtfully as they work to advance combination products within a regulatory landscape.

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Episode Transcript

Tom von Gunden, Chief Editor, Drug Delivery Leader:

Welcome to Sit and Deliver, the series that provides timely insights from leading thinkers in the drug delivery industry. My name is Tom von Gunden, Chief Editor and Community Director at online information exchange Drug Delivery Leader. Today, I am joined by John “Barr” Weiner, Director of the Office of Global Operations at the FDA.

Welcome, Barr, and thank you for joining me.

John “Barr” Weiner, Director of the Office of Global Operations, FDA:

Thank you. Pleasure to be here.

I'd like to start by discussing some key considerations you mentioned in a chapter you wrote in The Combination Products Handbook. In that context, you identified, “the importance of collaboration and coordination to successful shepherding of combination products by sponsors and regulators.” Could you elaborate on what each type of role — sponsor and regulator — brings to that scenario?

The short answer is that one of the challenges for combination products is you're taking different kinds of products that raise different kinds of issues, depending upon differences in expertise, and putting them together into some kind of a system. So, as you can intuit, collaboration and coordination are critically important. It's always important for medical products, of course, but in this context you're bringing additional collaboration and coordination to bear that wouldn't be needed for just a drug or just a device, for example.

So, that's the core of the concept, and it can be important in a variety of ways and settings. But most fundamentally, it's really about making sure you've got complete expertise in a timely way for what you're doing, whether you’re the regulator or the regulated entity.

For example, if you're developing a product, you'd want to be thinking about — just to take a simple example like a prefilled delivery system — [how] the drug could affect the performance of the device or the device could affect the performance of the drug. Thinking about them together, of course, is critically important. That’s a very basic kind of framing of the concept in a simple fact pattern.

But it comes up in lots of settings. For design, for example, there can be real complexity to the design of a combination product, and you want to make sure that you're actually thinking through how everything fits together for that. And at least historically, design wasn't really quite as big a part of drug development as it was for devices. So, there's also a helpful opportunity to, in essence, mature the thinking in the medical product space by having that more rigorous engineering kind of mindset brought to bear for at least combination products. So, that's been helpful, I think, both for industry and for FDA.

And just thinking of a practical example of how this can work out: Labeling, of course, for drugs is something we typically think about as a late-stage question because you need to make sure you actually know what you should know about the product — that it's safe and effective, what the right dose is, etc. — and that's all reflected in the label. So, you tend to have that as a late-stage part of the review process.

But the label is also critically important as a source of instructions for use [IFU]. When you're talking about a combination product in terms of human factors considerations, how the user engages with the product, it's not just popping a pill in your mouth. It could be a multi-step process that can be fairly complicated. So, how do you ensure that your design of the device and your study of it is appropriately aligned with the labeling? That means you actually need to have the labeling, at least to some extent, considered earlier in the process.

One of the issues that came up several years ago at FDA, for example, was making sure that we had an earlier-stage process for labeling consideration for combination products. At least for the elements of the label that would matter to engaging with the whole system — with the device, for example — so you wouldn't have to redo your studies because suddenly the label isn't what it used to be. And you have to start, to some extent, from scratch on some of the other design study for the device. There are actually pretty significant issues that can come up sometimes if you don't really think about how the two systems fit together, so to speak.

So, essentially what it means is you have a complete team and you have a process to make sure that the various members of the team are coordinating in a timely way. If you look at regulators, for example, we put together a pretty significant process with IT system support to enable that so that, when an application comes in, for example, there would be an immediate mechanism to reach out across centers to make sure that the folks who you need to have expertise from — say, CDRH if it’s a CDER-led, drug-led combination product — are brought in early on and they know what's coming, what they're going to need to review, what the questions are that they need to answer, and the timing that's expected for it, so it can all fit into the overall time frame for the review.

As you may know, at FDA there are some user fee obligations and there are clocks attached to it. So, that timing can be quite important to making sure you got the right people involved with the right stages. It's critical. And it also enables you to make sure that those people can be involved in relevant meetings, etc., throughout the process.

Similarly for the regulated community, it's the same basic issue. We're starting with developmental work all the way through to finalization. From manufacturing for pre-market review and vial manufacture, etc. — all those different steps — the same things apply in terms of having a complete team of experts playing in a coordinated way.

And, obviously, that's not my world as much as the regulator side is. But the one thing I can say that is important to success is [that] there are silos that exist in companies, too, kind of like the centers, if you will, at FDA. And having those silos, they don't always have to be broken down, but you have to have connections between them.

For example, when you're talking about pre-market review and post-market regulation, there can be knowledge that would be important to have from the pre-market setting when you're thinking about safety post-market. So, having communication between those folks can be important, and vice versa, to some extent:  understanding as a post-market person what signals you're seeing about safety may depend upon having good engagement with folks from the pre-market side.

So basically, it's a similar concept: you've got your device folks; you’ve got your drug folks. You need to make sure they're all involved. The nuance, I guess, for industry is not every company has the capacity to have all the expertise in-house. So, some of what it also means is bringing in expertise, maybe on a piecemeal basis, with contractors, consultants, that sort of thing. If you're at a stage of development where it’s sort of a one-off product for you, perhaps where you need the expertise, but you're not really going to be in a position to have that all as part of your ongoing operations.

So, great. You also identified a key consideration as “embracing comprehensive integrated risk management.” Could you elaborate on both aspects of risk management, the comprehensiveness and the integration?

Sure. So, risk management is not a medical product-specific concept. It applies across all industries and various settings. And it applies to drugs as well as devices. We have FDA policies for both, for example. The interesting issue here is about how to approach it for a combined use situation for a system because you need to think about all the different parts together.

So, one of the issues we've been trying to focus on and foster thinking about, both inside the agency and with regulated entities, is the importance of having this comprehensive risk management approach, which is to say that it takes into account the full sweep of issues that need to be addressed for the combination product, for the combined use as a whole, across its whole lifecycle.

And the integrated part basically means you're talking about not just having an isolated thinking process about the drug and another about the device and hope that [they] come together. You really have to have an integrated process to make sure it actually does come together.

There's more than one way of doing that. You could, for example, have essentially a risk management approach for your device to some extent, and for the drug to some extent, where you think about them to the extent to which they can be thought about in isolation. And then add to that thinking the cross-cutting issues that need to be addressed for their combined use.

That, of course, can get a little confusing in terms of where you draw those lines because there may well be issues that could be considered to be in both categories. So, the critical issue is really to think through substantively what it is you actually need to know and make sure that the analysis is complete for the whole system.

Okay. Great. Can you tell us a little bit about where do, or should, efforts at integration occur? Where does that happen in an organization?

Sure. I can talk about that in terms of the organization and the process. Basically, where it should occur is essentially at each stage of development, at each step, each stage of the lifecycle. And the folks who are involved will vary from stage to stage.

So, when you are at the developmental stage, you'll have somewhat different teams, of course, for that part of the process, as for any medical product. As compared to, say, post-market, where we're talking mostly about inspectional and manufacturing kinds of issues and post-market change questions and that sort of thing. So, you'll have somewhat different teams at each stage.

But the main thing is, as we were discussing earlier more broadly, you want to have a complete team thinking in an integrated way. So, for example, when you're talking about developmental considerations, there's a temptation to just focus on the molecule if you're a drug company. And that's what's driving your timing, that’s what’s driving your market plans, your hoped-for income, etc.

But if you don't think about the device early enough, and the device has implications for whether that molecule can get where it needs to go or whether it's actually going to be in the right condition when it gets there, you can have a big problem in your hands. So, one of the things we've said to companies over the years is: When you're doing your Phase 3 studies, for example, you really want to have your device, if you can, pretty much fully designed before Phase 3, so you can actually use that to-be-marketed device in your Phase 3 studies and know that it actually is working appropriately with the drug, say.

Sometimes, that's not possible, and you may have to do some bridging back and that sort of thing. But the point of this is not really about the Phase 3 and Phase 2 studies; it’s about the risk management. And what the issue there is, you’re making sure you actually have the design work for the drug and the device being done together so the risks that are associated with the combined use can be adequately approached or adequately considered in a coordinated way.

You have identified the concept of primary mode of action, or PMOA, as having central significance to the development of combination products and the regulatory landscape around them. Can you comment on why that's so significant?

Sure. And I guess the short answer is, it sort of is and it isn’t, in a sense. Why it's important is that primary mode of action, I think pretty much in every jurisdiction, drives where you go for the review process, what the lead center or lead entity is. In some countries — at FDA, there’s different centers — other countries may have different regulatory bodies for drugs, for devices. So, knowing whose door you knock on to get your product reviewed will depend on PMOA, generally.

So, for example, if you have a prefilled syringe, that would be drug-led, would be a drug PMOA. And for FDA, that would mean you're going to CDER, say, even though there's a device involved. So, it basically determines who your contact point is, who the lead is for the product at the agency or among the agencies that are relevant, is one issue. It also tends to affect the process because you tend to be using the processes of that lead component.

So, for FDA again, for example, the user fees would be the user fees generally of a drug, which is a pretty big deal because the user fees for drugs are significantly higher than the user fees for devices. So, that's something that people might care about. But just the whole process — the kinds of meetings you have, the steps you go through, the submissions — all that tends to be driven by what the PMOA is. So that's, broadly speaking, at least some of why it's important.

At the same time, substantively, in terms of the data you need to develop, what you need to know about your product, what you need to do to keep it on the market and appropriate manufacturing controls, etc., that's not dependent on PMOA. That’s just dependent upon what the nature of the product is and the questions that it raises and what needs to be managed for its safety, effectiveness, and performance.

So, regardless of what the PMOA is, you need to think about those questions. And the questions may actually be quite similar for products that have different PMOAs. For example, a drug-eluting stent may be a device-led combination product. But you could have drug-eluting disks, which are pretty similar in some respects in terms of the issues they raise and that's drug-led, actually more about delivering the drug than about the drug as an ancillary support for the device. But a lot of the questions may be quite similar about the drug's connection with the device and whether things can flake off, or can we have the right dosing, the right release rate, etc. So, basically, PMOA is important in some ways and not critical, or not central, to the analysis in others.

So, is there anything about the definition of combination product that could be better understood, clarified, or perhaps even revisited?

That's a great question. It's been the center of a lot of discussion for years, so it's worth talking through a bit. The definitions for combination product, as you may know, vary from country to country. To some extent, there's some sort of core commonality, at least among jurisdictions that have a definition. But there are also differences.

And then there have been some conversions more recently, which is helpful. But looking back a few years, for example, it wasn't unusual for, say, some countries to have a prefilled syringe or a coated product be a combination product, but a co-package which had a syringe and the drug in the same package but not prefilled, not be a combination product, which is kind of weird because the questions are pretty similar that you wouldn't have in the same category. So, what are the implications of that?

Similarly, the U.S. had been unusual and still is sort of unusual, at least for having an express definition of combination products that includes situations where the drug and device, say, or the constituent parts are actually marketed or distributed separately. So, they're intended for combined use, and we consider them a combination product. But, nonetheless, they actually aren't in the same box and it's not a prefill either. That's a fairly unusual setting or situation, but it can happen.

And we had discussions for years about that in terms of should we clarify what that means? What do we do about other jurisdictions in terms of trying to work together if they don't have anything like that concept? Since then, Europe, for example, started to have a similar concept, which is helpful.

But one of the things that was really clarifying in thinking that through, which was discussed over a period of years with industry and inside the agency, was kind of an “A-ha!” moment saying, well, this isn't really the core question. We shouldn't be worrying about nomenclature. We should be worrying about regulatory questions, scientific issues, technical considerations. And those aren’t determined by the classification you give the product; those are determined by the nature of the product itself — the questions that need to be addressed to make sure it's safe, to make sure it's effective, to confirm its performance, etc. These are the underlying issues we need to worry about.

So, if you think in those terms, you can, to some extent, put the nomenclature to the side and just focus on that. And that, I think, has resonated and helped us to accelerate discussion, both in terms of discussion within the agency — it helps ensure a consistent approach to regulatory questions, regardless of nomenclature — but also talk with counterparts about it.

So, it's a significant question, but I think the practical answer is that we might be better off in some ways without the terminology because it may just confuse the issue. But, at least in the initial stages, I think it helps because highlighting the fact that there actually are combined uses and combination products — or suggest that concept — helps regulated entities [and] regulators think about the fact that we actually need to think about something different here. There are two different things being used together, and we need to think that through.

So, Barr, what do you see on the horizon of combination product development or regulation?

Well, it's an interesting question because one of the sort of fun things about combination products or combined uses is, the new issues tend to come from the constituents — something interesting about development in the drug space or the device space. So, substantively speaking, in the last few years — so, this is not exactly cutting edge, but still definitely a significant issue for folks has been, for example, digital health issues — software, that kind of thing. And that was something everyone talked about for several years now. And, of course, in the last couple of years, AI, in particular, has become a really big topic, not just for combination products, but, of course, significant in this context.

But answering that question in the context of combined uses, in particular: the reason you care, of course, is distinct. You can have novel devices and novel drugs, and that's just a question for devices or drugs, fundamentally. But when we talk about a combined use situation, what matters is, what are the implications for the combined use?

So, if you're going to introduce AI, for example, into a diagnostic system that's going to drive what medical product treatment you should have, what drugs you should use, etc., then the question is, really, is it raising any new risks for that relationship? Are you going to have greater or lesser reliability from the diagnosis? And what that means for whether you should be using that drug or that biologic, etc. So, that's the core question for a combination product or combined use situation.

The reason I keep saying combination product/combined use is because the deeper issue to me that’s really on the horizon, remains on the horizon, is getting that mindset straight — that, whether you're a regulator or a regulated entity, you are thinking in terms of combined uses and what the implications are for them.

So, whether something, as we were discussing earlier, is a “combination product” or not, or even packaged together, or even intended for specific use with one another, there still may be risk issues to think about there. So, when do you need to think about them? When can you dismiss them?

And it needs to be a conscious process that you're actually consciously considering that, in this situation, there are additional questions I don't need to ask. I know enough about these devices or this drug in this setting that I don't need to worry about revisiting the implications of the combined use. But that needs to be a conscious issue.

In terms of what I think is significant going on next, FDA, I think, is still pretty far ahead of the field, so to speak, or on the leading edge of thinking in this space. And I think we've done an awful lot of work. There's still more to do, but I think there's an awful lot of guidance either out or soon to come out on significant topics.

What had been a real focus for me when I was still in the Office of Combination Products, but actually the focus to some extent now for me as well in the Office of Global Operations, is the engagement with foreign counterparts. We've worked on that for many years, but I think it's getting livelier now. We've had some projects where we're trying to work collaboratively at a multilateral level to develop new standards or guidelines. And that work is continuing. And I think that will be very helpful for these themes of having everybody on the same basic philosophical page, so to speak. But also including, for example, the idea of risk management we discussed earlier. But also trying to really drive change in that context because, as you may know, multilateral work can take time. It's complicated. There are a lot of players.

One of the more exciting things that's happening recently is that, although we've been talking with our European counterparts, for example, for a while on this topic, that seems to be getting more traction now than it had been a few years ago. COVID slowed us down, for example.

And that's significant because, of course, those are two big markets in their own right. But also, when you think about multilateral work, if U.S. FDA and the European Commission EMA are on the same page about things, it can really help accelerate change and consensus-building at the multilateral level as well, which I think is one of the key things we need to work on here — trying to get as much coherence as we can across markets. It's good for regulatory practice. It's good for efficiency in terms of the resources we have to expend on products.

But also, I think the regulated community will tell you the same thing: it gets complicated, especially for combination products, where we go into multiple markets. Because if the expectations aren't the same, the standards are different, the processes are different. You may have to do the same thing multiple times and nobody wants to do that. So, trying to minimize that possibility of redundancy where it isn't necessary for some reason is an important regulatory goal.

Tremendous. And thank you, Barr, for joining me on an episode of Sit and Deliver and sharing your perspectives with the Drug Delivery Leader audience and community.

Thank you very much. It’s a pleasure.