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Pink Sheet – Putting The Pieces Together For Combo Products Oversight

Pink Sheet – Putting The Pieces Together For Combo Products Oversight

Executive Summary

Bradley Thompson has been shepherding the Combination Products Coalition for more than a decade. In a recent interview, he said the recent policy spotlight on the combo-products space, including in a recent user-fee deal, is a welcome development after a period of neglect. He also spoke about the numerous reforms in the works and the state of the sector.


An eight-point plan recently hashed out between US FDA and the drug industry should go a long way to putting oversight of device-drug and device-biologic combination products on a more predictable path, says Bradley Thompson, the point person for a coalition representing combination-product industry interests.


The plan was included in the Prescription Drug User Fee Act reauthorization (PDUFA VI) commitment letter agreed to by the agency and key pharmaceutical industry trade groups this summer. The user-fee agreement is unusual because it includes, for the first time, some drug user fee income directed to the agency’s device center (CDRH) and includes some specific direction for CDRH with regards to its collaborative efforts on drug-led combination products. (Also see “PDUFA First: Fees To Support Device Center Staff” – Pink Sheet, 24 Aug, 2016.)


“You’ve got a drug user fee that typically gets a drug focus, and you’ve got device user fees, and it gets a device focus,” Thompson, who serves as general counsel for the Combination Products Coalition said in a recent interview. “Combination products were never really woven into those discussions. It finally happened, and that’s a very positive thing.”


Device companies have become more satisfied that the combo-products path is correct. Meanwhile, drug companies “have come on strong because there’s such an interest in drug delivery, and … there’s been some challenges in the regulatory process.”

Thompson, who is also an attorney with Epstein Becker & Green, spoke in advance of the upcoming Nov. 2-3 Combination Products Summit, a meeting he helped organize with Xavier University Health, FDA and industry officials. The meeting, and interview, comes in the midst of a focused period of reform for combination products at FDA and, potentially, within the US Congress. [Editor’s note: the interview was conducted by Medtech Insight, an affiliated publication to the Pink Sheet.]


In the interview, Thompson discussed why combination products received more attention in the drug user fee talks compared to the device talks, and how that illustrates a shift in the sector; he explained some of the reforms in the works; and he described the general state of the combination products sector. Excerpts of the conversation are below.


Hi Brad. Busy times in the combination products space.

Brad Thompson: It’s an interesting year for combination products. All of a sudden, a lot of policymakers, FDA and outside of FDA, are very interested in the area. Things like the Mylan EpiPen have only increased that recently. (Also see “Mylan’s EpiPen Nightmare Not Over Yet, But Will Congress Just Write?” – Pink Sheet, 30 Aug, 2016.) It’s been a busy year and that’s good because this is an area that requires some attention. It’s been a bit neglected in the past, but I think it’s now getting quite a bit of attention, so that’s a good thing.

PDUFA VI Combo Product Commitments

FDA will develop staff “capacity and capability” to more “efficiently, effectively and consistently” review and respond to submissions that include combination products
Sets deadline of Dec. 31, 2017, for FDA to complete a “lean” process mapping for combo product reviews and to begin tracking workload and timelines for cross-center collaborations, and Sept. 30, 2018, for the agency to internally document its process for resolving scientific or regulatory issues that arise during reviews.

Establish Manuals of Policy and Procedures, and Standard Operating Policies and Procedures, for human factors assessments by March 31, 2019; quality assessments, including coordination of facility inspections, for combo products by Sept. 30, 2019; and patient-oriented labeling for combo products overseen by the drug and biologic centers by Sept. 30, 2019.

By Dec. 31, 2018, FDA will post key contacts for combination products online and will update the list periodically.

By Dec. 31, 2018, FDA will establish procedures for companies to submit human factors protocols, and the agency will ramp up a 60-day performance goal for responding to the protocols beginning in FY 2019.

By Dec. 31, 2018, FDA will launch a training program for staff in all three medical-product centers and the Office of Combination Products, with a focus on drug- or biologic-led combination products.

FDA will contract with an independent third party to assess its combination products review process and will publish a final report of the assessment by the end of Sept. 30, 2020.

FDA will publish draft guidance documents by Sept. 30, 2019 and final guidances by Sept. 30, 2022 on bridging studies to support a switch in device components with the same drug or biologic, or a switch in a drug or biologic with the same device; and patient-oriented labeling.

It seems like a pretty vibrant time. And it seems that most of the attention is pushing in a positive direction for combination products. Is that your view?

Thompson: Yeah, I think so. Going back to earlier in the year when [Robert] Califf became commissioner and really took over the reins, I think combination products is an area of special focus for him, personally. I think he’s seen in practice at Duke and other places that we may be pushing some of the limits of devices alone or drugs alone, but when you start combining those modalities, all sorts of advancements become possible. I think Califf is personally excited by combination products.

From someone who hasn’t spent a lot of time with the agency, I think when he arrived, his impression – I don’t want to speak for him, but this is just my sense of it – his impression was the agency is pretty siloed. We’ve got these drug people doing their thing and the device people doing their thing and treating them as though they’re completely separate areas, when if you’re interested in cancer, you don’t look at it with blinders on. You don’t look at it as just a drug issue or a device issue. You think about what’s the best therapeutic intervention to help people with cancer.


Friends of Cancer Research and others have been encouraging him to look at ways to tear down the silos within FDA and get folks to collaborate more across the centers. I think it’s a real passionate area for him. That’s a real healthy thing. Honestly, silos don’t do anyone any good. That sort of broader thinking is very refreshing.

There have recently been some specific steps taken internally at FDA, with work on standard operating procedures to improve inter-center collaborations and “lean” mapping of the combination-products review process, among other things. Also, coming out of the Friends of Cancer Research ideas you mention, I think, is the recently announced oncology center of excellence that really builds on this idea of breaking silos, bringing different products together at FDA. (Also see “FDA Oncology Center Of Excellence Coming, Moonshot Or Not” – Pink Sheet, 20 Apr, 2016.)

Thompson: It really does, and I know you’re alluding to the PDUFA VI commitments, too. It was very interesting that the user-fee working groups spent as much time as they did talking about combination products, because that hasn’t really happened in the past. You’ve got a drug user fee that typically gets a drug focus, and you’ve got device user fees and it gets device focus. Combination products were never really woven into those discussions. It finally happened and that’s a very positive thing.

Yes, although it came up more on the drug side of user fee talks than on the device side. Why is that?

Thompson: Part of that is the passion that drug companies are currently exhibiting toward combination products. I think they, in particular, see drug delivery as an area where there can really be an opportunity for innovation, for lots of reasons. It’s getting tougher and tougher to develop entirely new molecules, but within existing drug technology, if you really put some thought and effort and development dollars behind creative solutions for the delivery of the drug, you can make them both much more effective, as well as reduce unwanted side effects. I think they just really see opportunity there, and that’s why in the PDUFA VI discussions it was such a prominent area.

“The culture at the center for drugs was to always talk about labeling last, but the culture with devices is to tackle that early on because validation studies of the human factors have to be performed.”

Historically, though, I’ve thought of the dynamic differently, where device companies, rather than drug firms, were more focused on combination products and the regulatory challenges, in part because of the more “blockbuster” type of opportunities, such as with drug-eluting stents. Would you say that was the case? And has there been a shift in this regard, with drug firms now taking more of an interest in the space and in improving the regulations?

Thompson: I think that’s a very astute observation. The coalition is 11 or 12 years old at this point. Early-on, it was really more device companies. It was the drug-eluting stent companies and so forth that were very passionate about it and very excited about it.

I think a lot of those issues, to FDA’s credit, frankly, got resolved. There became a reasonably well-defined path for a drug-eluting stent through the FDA. It was a fairly practical pathway. Over time, the device companies became more satisfied that the path was correct. When I look at our membership, it has swung from being sort of predominantly device in the first several years to now much more heavily weighted toward the drug companies. I think, when I looked last, we had 10 of the 15 largest international drug companies that were part of the coalition.


They really – especially in the last two years – have come on strong because there’s such an interest in drug delivery, and the other side of the coin is there have been some challenges in the regulatory process.


There is a difficulty when it’s a drug primary mode of action – the center for drugs takes the lead and they sort of treat the device piece as almost an afterthought, historically. That created a lot of problems.

Like what?

Thompson: For example, the drug process, the NDA process, has been around for decades. It’s very common in a straight-up drug review in the 11th-hour, 59th minute, for FDA to raise concerns about the drug labeling. It’s kind of the last thing that gets negotiated – warnings, any modifications or any massaging to the intended use and so forth.

The problem is when that process, which was well entrenched over decades, was used for the review of combination products, drug delivery products, the agency would raise at the 11th hour, 59th minute, questions about the device labeling. It just doesn’t work when you do that because device labeling is a key to the functionality of the device. The whole area of human factors, which really doesn’t exist in the same way, at least, on the drug side, has kind of thrown it up in the air because drug companies developing these products would go through elaborate human factors testing to make sure that people could use the device and understand the instructions for using the device. When FDA comes in at the very last moment and says, “You’ve got to change that,” it throws out the validation that the company has done to make sure that the device piece can be used safely.


That’s an area where friction evolved just because of the cultures – the culture at the center for drugs was to always talk about labeling last, but the culture with devices is to tackle that early-on because validation studies of the human factors have to be performed. It’s just an example of where there were real challenges in the review process, and the drug companies want to work constructively with FDA to figure out a better way.

With regards to human factors, there’s been a recent draft guidance. There’s been some work on inter-center consultations in general, I think, within FDA. Has that borne any fruit yet or is it still really just something that’s being figured out?

Thompson: It’s all headed in the right direction. All of it represents improvements over the historical approach, but I don’t think FDA has quite nailed improvements to its process, for example, with giving feedback on IFUs [instructions for use]. That’s an area of priority for us, to communicate to FDA the need to develop a process where, for example, if they’re going to consult with CDRH over the functioning of the device component, or the device constituent part, … that we get that feedback early enough that if it requires a redo of the human-factors validation, that there’s enough time to do that without it pushing back the approval of the ultimate product.

We’re seeing improvements there. FDA has developed this eCTD [electronic Common Technical Document] approach to collecting all the information for drug approvals. Unfortunately, when they did it, they were mostly focused on typical drugs, not drug-led combination products. The organization of the actual information that’s submitted to FDA still is not terribly tuned in or focused on combination products.


We’re in the middle of a good dialogue with FDA on that topic. We met with them. We heard their concerns from a review standpoint over inconsistencies as to where that information is provided. We took that to heart and we’re trying to develop a standardized approach, a standardize template, for how combination product information can be shared with FDA in an eCTD submission. The agency is working very well with us on that. We’re very excited about that.

What, in your view, are other key issues being hashed out with FDA right now for combination products?

Thompson: We’ve got issues about the modifications. The lifecycle of a device is very different from the lifecycle of a drug. It’s not unusual to want to make incremental improvements to devices, even when they are part, maybe, of an NDA-approved drug-delivery combination product. We’ve really got to work out more efficient, more effective, more appropriate pathways for those modifications.


FDA developed a draft [guidance] in 2013. It was a good draft, but it was an incomplete draft. It really didn’t address lower-risk devices that would be typically subject to a 510(k). Yet, there are very standardized auto-injectors and so forth that really are appropriate to deal with in the 510(k). The agency and we have some work to do there.


There are also clinical trial issues. One of the issues raised in PDUFA is the bridging issue because when you do make changes to a device, the question is how significant are those changes and what clinical validation needs to be done in order to resubstantiate the modified device. FDA has agreed in those PDUFA commitments … to develop guidance on that. We’re anxious to get going on the dialogue around that and providing information. There’s a lot of work to be done, but the relationship is good and we’re excited.

But what about proposals from Congress to change the statute with the goal of accelerating development and review of combination products, or to make more fundamental changes to the system?

Thompson: Right. We as a coalition spent a fair amount of time talking about the different legislative proposals that were being batted around. Basically the coalition decided not to get engaged in those discussions. We really are putting our energy and our focus on discussions with the agency on improvements. To be quite honest, we have not run into a single obstacle that would require a legislative change.


The kinds of things that we want done, things like clarity around bridging studies and improvements in the eCTD submission and improvements in the review process for labeling and stuff, none of that requires any statutory change. FDA has plenty of authority and latitude to do what it needs to do.

“To be quite honest, we have not run into a single obstacle that would require a legislative change.”

You’ve mentioned a few things about the coalition in terms of the pharma membership growing. How would you characterize the overall state the combination products industry and where it is heading?

Thompson: It really cuts across a number of areas because as I said, creative scientists and engineers are really thinking about the synergies that come with considering drugs and devices as a system and how they can support each other in various ways, whether it’s the physical delivery, the route of administration, or whether it’s software that brings to bear clinical intelligence on the optimal use of drugs.

For example, one of the big issues in personalized medicine is that any drug has a very widely differing impact on human beings. Some human beings will take a drug and it’ll just pass right through them without having any impact, where other human beings, a drug will have a tremendous impact. Figuring out which people should be receiving which drug, sort of the Holy Grail of personalized medicine, is facilitated largely through software, typically IVD medical devices that use testing to determine that qualification.


We’re just seeing tremendous scientific interest that, I think over the next 5-10 years, is projected to produce tremendous growth in terms of this industry. Right now, it is largely driven by the opportunities in improving pharmaceutical care. I’m sure if you ask me in five years, it’ll be altogether different, but for this next few years anyway, it seems to be the drug-led pharmaceuticals that offer this tremendous opportunity and, correspondingly, where there is a lot of friction that needs to be resolved in the FDA process.

So, I was prompted chat in part because you were part of the organizing group for the Xavier University Combination Products Summit, which is coming up soon in Cincinnati. Tell me a little bit about that.
Thompson: The conference is really important to us because Xavier as a university has a much deeper interest in really exploring these topics than other, sort of, seminar production companies.

One of the key things that we’ve focused on is to have really meaningful discussions. You have to have more specific facts. It’s hard to just talk at the 100,000-foot level because then it all sounds trite and not very useful. One of the things that the Xavier group has taken to do is developing each year a case study that is a very beefy document that gets sent out to all of the attendees in advance, so that they have to do homework before they even show up the day of.


This year, it’s a case study that is woven throughout the entire agenda so the facts don’t change and it sort of gets deeper and deeper and deeper. The version for this year is a four-page, single-spaced document that participants will read in advance. Then, throughout the two days, there’ll be references back to that document to really explore how things are done.

Is the idea more to get companies better at wading through the current regulatory processes, or is it also bout coming up with ideas for reform?

Thompson: I think it’s both. It’s identification of best practices; things that we and industry can do just to do a better job of what we do, whether it’s preparing submissions or preparing quality systems or whatever it might be. But then, it’s also a dynamic discussion with FDA to share with FDA where, from an industry perspective, the friction is, and to hear from FDA where their view of the friction is and then, try and figure out whether there are solutions that reduce that friction. It’s really a wonderful dynamic that just isn’t present in a lot of other programs.

Finally, Brad, how quickly do you expect to see the changes that are in the works at FDA start to impact how companies bring combination products to market?

Thompson: I’m pretty optimistic based on, for example, the PDUFA commitments. A lot of the key issues ended up in that document with plans to develop guidance to address these thorny issues. That’s really encouraging.


Now part of the problem of being as old as I am and having done what I’ve done for 30 years is I understand that good intentions often don’t translate into specific improvements. I’ve seen a lot of guidance that is announced that never gets done.


If I have a concern, it’s that we collectively won’t execute on this plan. I think the plan is a good one and I think we’ve got the right issues on the table and we’re having the right discussions. My concern is that … we would default into inaction.


With our presidential election, that means possibly we’ll have a new commissioner next year. It’s possible that the new commissioner will come in and won’t have any of the same passion for combination products that Califf has. If that happens, it’s not going to be good. I guess what I’m saying is, I’m pleased with everything that’s been done to date, but I always have great fear of the future, that we just won’t execute.…