Developing Regulatory Strategies For Combination Products

In this episode of The Combination Products Handbook: The Series, host Tom von Gunden discusses Chapter 3 of The Combination Products Handbook: A Practical Guide for Combination Products and Other Combined Use Systems (CRC Press) with the book’s editor Susan Neadle. The conversation focuses on building into product development a regulatory strategy that incorporates key enablers of market success from early clinical studies, through the marketing application, to post-market changes.

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The Combination Products Handbook: A Practical Guide for Combination Products and Other Combined Use Systems Edited by Susan W.B. Neadle, CRC Press, 2023

Episode Transcript

Tom von Gunden, Chief Editor, Drug Delivery Leader:

Welcome to another episode of The Combination Products Handbook: The Series, a chapter-by-chapter walkthrough of the Combination Products Handbook, a Practical Guide, published by CRC press. My name is Tom von Gunden, chief editor of Drug Delivery Leader and your host for the series. Today, we are going to discuss Chapter 3: “Combination Products Regulatory Strategies.” And for that discussion I am joined, as I often am for these episodes, by the handbook’s editor, Susan Neadle.

Welcome, Susan.

Susan Neadle:

Thanks for having me, Tom. I'm really excited to be able to join you today on Chapter 3.

So, Susan, to start out, let's talk about the positioning of the topic covered in Chapter 3: combination products regulatory strategies. For those of you who have seen other episodes of this series, you will know that Chapter 1, penned by the FDA's John “Barr” Weiner, talked about the regulatory history and current state of that landscape.

Chapter 2, penned by you, Susan, tackled the topic of defining “what is a combination product?” So here we are at Chapter 3 with a deeper dive on regulatory strategies. Can you comment about the choice of that topic and its position in the handbook?

Yes. So, I very intentionally inserted this chapter early in the book because developing an effective regulatory strategy is a key enabler to get combination products to the market, whether it's the clinical studies that you want to do early on, to the actual marketing application, to post-market changes.

If you haven't intertwined and given forethought to what the regulatory expectations are going to be, then you're going to have a problem, right? So, the regulatory strategy is a key enabler. And as we talked about in the earlier chapter, when you think about “what is a combination product?” that definition changes from jurisdiction to jurisdiction.

And because of the different interpretations, it's so important right up front to think about, gee, where do I plan to market this product? What are the unique interpretations and expectations of each of those jurisdictions relative to this specific product type? And with that, what is it that I need to also think about for post-market? What are the things over the life cycle of this product in terms of the product configuration? Am I going to be modifying or adjusting that? I can start laying a positive foundation at this very first application to support those subsequent applications.

So really, the regulatory strategy is a key enabler for the entire combination product submission, marketing process, all that.

Okay, great. So, momentarily we're going to take a walk through some of the key topics covered in the chapter. But first, I'd like you to comment on your choice of authorship for the chapter, Suzette Roan. You recruited her for the writing of Chapter 3 on regulatory strategies. Why that choice?

Suzette Roan is very well respected in the industry. She currently is a VP of regulatory at Sanofi. She and I met at the Combination Product Summit through Xavier Health at the time. And we spoke together and presented together at PDA [Parenteral Drug Association] a couple of times, and a number of other forums. We've taught classes together.

So, the long and short of it is, I really respect the knowledge that she brings and her expertise, specifically relative to regulatory submissions. And there was nobody I could think of that was more perfect at this time to be able to pen this particular chapter.

And truly, there's a lot of tactical detail that's needed to be successful in the regulatory space. Recognizing how foundational it is to people being successful in getting their combination products to the clinic, as well as to market and the post-market changes. I just knew, she knows her stuff. And being able to include that in this book as a foundation was really key.

So, I noticed that, early in the chapter, folks who read the chapter are asked to consider the intended markets for their combination products and associated regulatory authorities in those markets. Can you talk a little bit about the significance and importance of early consideration of intended markets?

Just think about this one example, which I think is one I gave in Chapter 2 on “What's a combination product?” If I have a drug-eluting contact lens, in the United States that's considered a drug-led combination product. If I go to Europe, it's a medical device.

It's like, oh my gosh, it's the exact same product. And so, if I'm not thinking proactively about exactly how a product is determined, how is it designated within a given market, then all the different requirements — the data requirements, the quality system expectations, the documentation and technical rationale to support that product’s safety and effectiveness — the expectations market-to-market are different.

And so, I need to make sure proactively that I'm clearly identifying, where do I plan to market this product, and what are the unique regulations or standards that may be applied in each market? So that you can give that insight to the development team, and they can be building a product that's going to be compliant right up front, and that [they] provide the data to be successful in the regulatory application.

And then the chapter moves into considerations around developing a regulatory strategy before moving into some of the technical- and execution-oriented considerations. So, at a high level, what do we mean by a regulatory strategy? And why ask folks to consider it a regulatory strategy as a strategy within this context?

So, in the chapter, it really walks, it does a nice job walking through, what are the key elements or key questions that you need to be asking yourself in developing the strategy? So, first is, who are the health authorities that you're going to be working with? How do they designate your product? And what's their mechanism for that? Do they have [a system] like in the United States, where we have a request for designation process, or is it something different?

Where in Europe, maybe it's case by case. What are the standards and requirements for licensure? What are the clinical study expectations? Because a lot of these products, you're not just going [straight] to market with them — you've [first] got to do clinical studies.

So, you've got to be shaping that understanding right up front. And then moving into those regulatory requirements piece[s] of your strategy. What are the data requirements? What are your quality system elements? What are your design controls? How do you frame those out for your product? And what are the phases of development? [And what are] the key considerations based on those phases of development?

And you may even have situations where you're leveraging a third party’s device, for example, as part of that application. And oh, wait, how do I have to take that into account as part of my submission? And am I referencing a master file? Do I have a letter of authorization? So, you really have to think comprehensively.

Also, there's soft intelligence. And what we mean by that is, you go to industry conferences and review publications that have been out there, networking with others in the industry, benchmarking, looking at public information on approved or cleared products. And taking all that information and synthesizing it and going through, for this particular new product that I'm trying to bring to market, if I take into account all those things I've heard, for me to be able to get my submission “right the first time,” I want to take as much of those insights into play as I can in building my submission packages.

The next key step is the regulatory risk assessment. And again, some of this will tie to the soft intelligence that you've gotten. It will also tie to the evolving regulations that come out. But what are the potential risks for your approvability of your product? What are the mitigation strategies that you can take? Maybe you're making post-market commitments for that product. So those are pieces of what you have to take into account.

And then finally, the submission approaches. So, is this an investigational submission? Is this a marketing submission, or is this for a post-approval change? And each of those has some different nuances that you have to be able to address as you [are] putting together your regulatory packages.

So, obviously the chapter walks through, in great detail, some of the tactical and execution steps. Short of that kind of deep dive, which we hope folks will get when they actually consume that chapter as readers, can you provide some high-level or highlighted words to the wise when it comes to executing on a regulatory strategy?

So again, I will reference [that], in the chapter, there are some wonderful figures in the chapter. One of them talks about the sources of regulatory requirements, which I think is very helpful. But then also there's guidance out there, right? If I were to look at the FDA guidance, they issued a specific eCTD [electronic common technical document] guidance that walks through the different sections that you're expected to populate uniquely for your combination product or your device constituent of a drug-led combination part, for example.

And in this chapter, it walks through some of those expectations along with some explanation of, how could I really populate this and be successful? And so, looking at the regulatory guidance, pay attention to product-specific guidances and standards, as well as that eCTD guidance. That can be very helpful.

And the chapter also goes through, how would I approach it for Europe, where I'm under the medicinal product directive for that product? But I need a notified body opinion. Or perhaps I need EU certification for that device constituent part. So, the chapter walks through — like I said, it is very tactical. But it walks through, these are the things to do for you to be successful for that product.

Well, thank you, Susan, for joining me for a walkthrough of Chapter 3 of The Combination Products Handbook. We encourage folks to dive into the book and Chapter 3, of course, and to join us here again for another episode of the series. Thanks, everybody. See you next time.