Managing Combination Products Post-Market
In this episode of The Combination Products Handbook: The Series, host Tom von Gunden discusses Chapter 8 on post-market lifecycle management from The Combination Products Handbook: A Practical Guide for Combination Products and Other Combined Use Systems (CRC Press) with the book’s editor, Susan Neadle, and chapter co-author Khaudeja Bano. Susan and Khaudeja outline product commercialization considerations such as design transfer, process validation, supplier quality agreement, post-market safety reporting, and change management.
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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 discussion of The Combination Products Handbook: A Practical Guide. My name is Tom von Gunden, Chief Editor at Drug Delivery Leader and your host for the series. Today we're going to discuss Chapter 8: “Combination Products Post-Market Lifecycle Management.” For today's discussion, I am joined by the chapter's coauthors, Susan Neadle and Khaudeja Bano.
Welcome, Susan.
Susan Neadle:
Hey, how are you doing? It's great to be here.
Good to be here, too. And welcome, Khaudeja.
Khaudeja Bano:
Hello.
I think we're ready to get started. Again, the chapter is entitled, “Combination Products Post-Market Lifecycle Management.” I think it would be helpful for our audience if you could talk to -- at a high conceptual level -- what we mean by post-market lifecycle management. As far as the chapter, what's the range of coverage folks should expect if they choose to dive in?
Neadle: If you look at the book, it walks through the regulatory strategy, development activities, human factors considerations, and risk management. When you've done all that, you’re ready to go commercial and need to do design transfer. This chapter starts out by talking about design transfer, process validation considerations, and design validation considerations. The things that you're doing to become commercial for that product and how you need to manage it post-market. This includes your purchasing controls, your CAPA [Corrective and Preventive Action], those key processes that you need to lean into now. The process validation section specifically focuses on how you do it for a combination product versus a drug or a device.
The thing that ties it all together is that once that product is in the marketplace, you’ve got to have some post-market surveillance, monitoring, and reporting activities. There are explicit requirements for that for combination products. This chapter wraps up the journey that you've been on to get your products to market and what that looks like in the marketplace and with post-market changes. Those are all coming to fruition in this chapter of the book.
Bano: There are a couple of avenues which trigger an emphasis on this aspect even more. As you see various drugs, biologics, and devices trying to stay competitive, one aspect that often does not get considered is the introduction of different platforms and different combination products to keep it competitive and create line extensions to expand your portfolio of influence. For example, consider a hospital healthcare professional delivery versus at-home use. These are certain aspects that fall very well under the post-market changes and lifecycle management. People usually think of these more in relation to issues and challenges or risk mitigation. It's both. It usually presents itself that way, but I do want to encourage people to think of this as providing that competitive advantage.
Before we move from talking about the range of activities and requirements that go under the concept of lifecycle management, is there anything else you would highlight among the most significant things to think about as you dive into this chapter and ponder the topics there?
Neadle: There are so many important topics in this chapter that it's hard to pick one. Design transfer is a blind spot for many organizations when it comes to drug-led combination products. They don't think about that device constituent part needing to go through process validation, and the integration of process validation for the drug and the device. That one is very important. That post-market change brings in bridging strategies. It brings in your regulatory strategies. It brings in the risk management aspects. It brings in human factors. Post-market change management is critical. My last but not least is Khaudeja’s favorite topic, the safety considerations.
Bano: Thank you, Susan, for leading into my favorite topic. There are a couple of things I want to highlight. Even after you've listened to all these chapters and understand what a combination product is, I still hear people not believing that their product is a combination product. If I can emphasize one thing, take a close look at your portfolio. Make sure you understand if there is a device constituent part in a drug and vice versa. Know that you have the obligation to comply with all combination product requirements.
With safety, there are two aspects that continuously catch people off guard. One is that you have to understand the risks of the combination product as a whole. People do a very thorough job with the drug or biologic constituent parts separate from the device. When they both come together, you have to assess the impact and the risk for safety, efficacy, and effectiveness. Make sure that is your area of focus and emphasis. The second thing is the organizational structure and the importance of cross-functional collaboration from end-to-end. The sooner you can identify your subject matter experts that cover different aspects of your combination product, including safety, medical, clinical, scientific affairs, and regulatory affairs, bring them around the table. Have the discussions as early as your Phase 2 studies. The sooner you can start the dialogue, the more effective your collaboration gets as your product is commercially available.
Thank you for the insights on that. We’ll move to the next topic, which is something that I noticed running throughout the chapter. That is the idea that all of these various aspects and efforts and activities under the umbrella of post-market lifecycle management are iterative in nature. What I'm particularly curious and interested in hearing is, when you think about the iterative nature, to what extent is any of that iteration proactively triggered versus reactively triggered?
Neadle: I always talk about proactive quality versus reactive quality. You have the capability to gain understanding about similar products in the market and issues or positive performance that are happening with those products and integrating your learnings into your risk assessment activities or new product design considerations upstream. When we were talking about our product development chapters, those things are part and parcel of your product development. That is a source of data that is reactive when you're having to deal with your CAPAs, non-conformance, and post-market change management. There's a reaction that's happening that you're having to manage through.
At the same time, you can take that information and prospectively apply it to products that are still in your pipeline. That’s where it becomes proactive. A piece of the CAPA process is preventive. You can be looking at trending signals and tracking information as part of your post-market surveillance and monitoring. You can be looking for signals and proactively identifying them and applying improvements to your processes to make a difference. Where it's reactive, though, is that you're going to have to react to things happening in your production environment, like changes to your suppliers or your raw materials. There are changes happening all over the place. You've got to manage that and use that continuous feedback loop. Use that information to inform your risk management files and see what other mitigation strategies need to be considered, evaluated, or implemented as part of your post-market lifecycle management. What else do you need to do to manage what is going on in the production environment in your downstream processes, even for distribution, shipping, and all the way into the hands of the patient.
When you get to the hands of the patient, that's usually where we're talking about more significant risks once the person who's using this product is involved. Now, not only do I have obligations to do post-market safety reporting and surveillance from that perspective, but I also have obligations to revisit my human factors and do bridging activities. This continuous feedback loop is all-encompassing. All of those different elements that you touched on going through development, validation, and verification, you're going to have to revisit holistically as you're dealing with the life cycle of the product.
Bano: One area that artificial intelligence and real-world evidence [RWE] has opened up for this aspect has to do with access to more diverse sources of data. When I think about the proactive expectations from a combination product, we have an obligation to demonstrate our investment, whether it's from a management responsibility perspective or that continuous improvement of the product itself, the processes that are involved, but also enhancing that patient experience. At the end of the day, it’s the patient at the center of all this.
Oftentimes, it's during this phase in the product lifecycle where you are getting that continuous feedback loop that expands your patient portfolio. That's where you get feedback of additional indications for use, additional utility, and additional environments in which the product can be used. We also have an obligation to continuously monitor the benefit/risk profile of the product. We often spend a lot of our energy, and rightfully so, on the risk profile enhancement.
I encourage people to look at the benefit profile also, because you get additional indications and additional populations that have a similar unmet need as part of this exercise. Watch for that data that enhances both your benefit profile and your risk profile. In fact, there are examples out there where you may be able to adjust and lower the risk profile because you are continuously introducing mitigations and design controls where you are designing out risks. To me, safety is the first and foremost area of emphasis where we continuously try to make the product safer with every iteration, enhancing efficacy, and getting the same kind of therapeutic benefit with lower doses. Thinking of that enhanced patient experience is what should drive our proactive thinking around this topic.
Neadle: When we think about bridging in the post-market changes, you are thinking about the approach to take to administer this dose. But when you think about that environment, it's also the frequency that somebody is having to take their dose. Maybe it starts out as a weekly regimen, then moves to monthly or quarterly or yearly. The lower the frequency, the more chances of that person being compliant, maybe. That compliance enhancement as part of what you're managing for post-market is important.
Bano: If I may add another aspect to this, we are now starting to see a push by many biologic manufacturers on adopting a platform approach that is often coming out of your post-market observation where you have a robust design of a drug delivery system. You then take that and see how you can utilize it in a broader therapeutic area with different molecules and biologics. There is a lot to be learned from your combination product in its post-market stages to inform, enhance, and cut down on a lot of your lifecycle on subsequent products.
Thank you both for the insights there. I'm thinking about our audience of folks who will be, hopefully, reading Chapter 8 or consuming this episode. What can you say to folks in terms of thinking about roles and responsibilities when it comes to post-market lifecycle management?
Neadle: When you think about your post-market lifecycle, you need the core competencies to span people that have expertise for that product from beginning to end. You're going to need clinicians engaged to understand the safety considerations and the impact to the people using that product. You're going to need to have your device engineers engaged because if there are any kind of performance issues or changes in the way you want to administer the product or any kind of post-market changes, they need to be engaged to make sure that whatever you're doing isn't going to have a negative impact or a change in risk profile for that product. You need your manufacturing engineers engaged. You need to have your procurement and purchasing controls folks engaged.
If your organization has many combination products, you may opt to leverage a CMO or CDMO. The supplier quality aspects of your post-market lifecycle management cannot be overstated. It is important to everything you're doing. If there is an issue that happens at your supplier or your CDMO, that can pull the rug out from under your product. It is to your benefit to make sure that the roles and responsibilities between your organization and any third-party suppliers or service providers are clearly laid out in your supplier quality agreements.
Your regulatory and quality functions are also critical to keep engaged, not quality control alone. Quality control has a critical job in making sure that whatever product is released is meeting all the expectations, but your quality assurance and quality engineering personnel make sure reliability expectations are being met. If there's any post-market change management, you need to update risk profiles and risk assessments; those are living documents. Your Design History File is considered a living document. Among all these different functions that were active in getting that product over the hurdles, nobody gets to completely let go because they’ve got to stay engaged to make sure that the things that you intended are realized post-market. There needs to be a mechanism in place through which the people that were active pre-market are touching base with the people post-market. I've seen companies where part of R&D is carved out to serve a role that supports supply chain as well as new products to keep that continuity and exchange of information. That’s critical.
Bano: I will do a deeper dive on post-market safety reporting because it's very important. The whole essence of post-market safety reporting as it relates to combination products was to lessen the burden, not increase the burden. What do I mean by that? For products, depending upon your primary mode of action or application as approved, you continue to follow those processes. I don't want people to think that combination product post-market safety reporting added more burden. In fact, there were organizations that were doing dual reporting. As part of this initiative, more emphasis from an FDA perspective but also globally, there is a desire to make sure that you continue to stay focused on your primary mode of action, continue to follow the processes, procedure, and mechanisms of reporting using that primary application and type, but with the need to understand the added responsibility for the other constituent part, whether it's a drug constituent part or device constituent part. Understand the safety and quality regulatory reporting requirements and add those to your existing infrastructure. Make sure your entire organization is aware of the different timeframes globally. There are very different time requirements for each of the types of reporting driven by the nature of the issue, the level of safety risk, the risk at a population level versus at an individual level, and the criticality of the quality issue.
Make sure that when you go back and look at your post-market safety reporting and post-market surveillance from an EU perspective, your entire organization end-to-end, all the way from intake of this data to submission and reporting of these regulatory reports, understands what the different requirements are. Keep them simple. Make sure they are embedded intuitively within your process.
And when in doubt, reach out to industry forums or to the regulatory agency in question to make sure you understand what needs to be reported when and how you go about submitting follow-ups. It’s equally important to be timely and not to have any compliance violations.
Neadle: If you think about what we have to do for post-market lifecycle management, a lot of it's around the production environment, your design transfer, your process validations, and making sure that you've got the right relationships with the suppliers and the appropriate controls. A lot of that activity is fairly agnostic of whatever region you're trying to market that product in. The moment you start talking about post-market change management and the submissions that need to accompany that as well as your post-market safety reporting, the convoluted mess around regulatory submissions and the complexities of people's differing interpretations of the exact same product – these hit you hard during this post-market stage.
A combination product under one application in the United States could be treated that way for post-market safety reporting or post-market change management. In Europe, it's two separate applications. In China, it’s two separate applications. The complexity of what you have to deal with post-market in other regions can blow up in your face when you're dealing with lifecycle management.
Bano: The sooner you can utilize your risk management files to set the stage for post-market safety reporting at the symptom level, for when customers and health care professionals call in the complaints and the adverse events, the more robust and streamlined the process is. I cannot emphasize enough, the more you can spend time upfront in setting up that infrastructure, the more seamless the process gets in order for you to meet the very stringent timelines from a post-market safety perspective.
One key blind spot that comes with devices specifically or device constituent parts: if you already have a commercially available device constituent part and you are the manufacturer or market representation holder that is used in clinical studies for a totally different drug product and indication, make sure you understand your safety and quality reporting obligations that go against your marketed products, especially based on similar attribution of those two device constituent parts. It’s a lot of technical terms we are throwing out, but please spend time to understand and decipher as you read the chapter.
Neadle: It’s a big point where a lot of organizations are so focused on getting all these efficiencies and benefits of using a “platform approach” to a device constituent part, but it can get you when it comes to the post-market management of that product. You're not free and clear. If there's an issue that happens to a different product that has the same device constituent part, that other product that you just developed is now implicated. It gets complex. Khaudeja and I spent a lot of time developing some tables [in the chapter] to try to help people proactively set themselves up for success.
We hope that folks dive deeply into the chapter and the rest of the book to see those details. For the purposes of our conversation today, I'm going to give you both an opportunity to look to the future. When it comes to post-market lifecycle management in the arena of combination product development and commercialization, where do you see opportunities and needs for advancements and where might those advancements emerge?
Neadle: The thing that sticks out to me is the post-market change management. There's no harmonization whatsoever going across the regions on what's expected. For the very same product that you're trying to make changes for from one region to the next, the documentation and data that you're going to have to put in place to support that proposed change in different markets can be quite different and pretty onerous. That one sticks out to me significantly, especially knowing that people go down this path of I got to get my drug to market, speed to market is the key. I got it out there as a vial and a syringe, but now I want to change it to a prefilled syringe. Now I want to change it to an auto injector. I want to change it to an on-body injector. It's a natural transition that a lot of these products take, and it must be managed from a post-market change control, submissions, validation, and human factors perspective. That’s a big hurdle for industry and regulators alike. If we can somehow get people to align on one path, there's the ISO 20069 for post-market changes, which is a really nice standard. It would be great if that could be something that was more globally recognized so that you're not having to take so many different pathways with different products down the pipeline.
The very end of the chapter is not something that's going to change; it’s pretty consistent. I have a figure that is a map of what you need to deliver in terms of device deliverables and drug CMC [chemistry, manufacturing, and controls] deliverables, stage-by-stage over the product lifecycle. That one page could be turned into a poster because it's a useful reference for people across the product lifecycle, regardless of which technology you're trying to manage through.
Khaudeja, any final comments as we look to the future?
Bano: There is definitely a desire and an aspiration for harmonization across the globe. It shouldn't be that hard anymore. The more we can use technology within our organizations to automate the repeatable, reproducible activities where data is collected and to generate and submit the right reports, the better. It will take at least four or five significant entities across the globe coming together and putting in an effort to harmonize the look, feel, timeliness, and details around the report to make it even less burdensome, both for patients and for us as an industry. It will help us focus on innovation and bringing better products to our patients.
A significant amount of resources are used and consumed in doing these activities to keep up with the constant evolution of the regulatory requirements. With different technologies in place, if we can work on harmonizing them, that would be a win-win for all, including regulators, who spend significant resources to do surveillance behind the scenes. The more we can get access to databases and transparency with all stakeholders, the more we can make a significant positive change.
Last but not least, we need to acknowledge that it's only going to get more complex. I'm now seeing drugs, biologics, devices, digital, and software as a medical device all encompassed into a combination product. Before it gets simple and easy, we need to brace ourselves and be prepared for it to get even more complex.
Susan Neadle and Khaudeja Bano, I want to thank you both for joining us for this coverage of Chapter 8 of The Combination Products Handbook, the chapter the two of you coauthored. I want to thank our audience for joining, and we hope to see you for other episodes of the series.