OCP s BARR WEINER ON CURRENT DEVELOPMENTS FOR COMBINATION PRODUCTS

OCP s BARR WEINER ON CURRENT DEVELOPMENTS FOR COMBINATION PRODUCTS At the FDLI Annual Conference in early May, Office of Combination Products (OCP) Associate Director Barr Weiner discussed the current wave of developments and initiatives at FDA to improve combination product development. He provided insights on: the CP post market safety reporting final rule the final guidance on cgmps for CPs the draft CP human factors guidance and industry comment the intercenter consult process and the pilot progress the pre-rfd draft guidance and comments, and the CP provisions of the 21 st Century Cures legislation. It is always great to be here. We have had a lot of talks in the last few years about combination products at FDLI, and I don t think it is because I am such a great speaker. I think it is because the topic has been of interest for quite a while now. I am excited about this year because it was kind of a big year. I think it was the biggest year we have had in at least in a quarter of a century for combination products in a lot of respects. There is a lot more work to be done here, but kind of recounting what happened, I think, is a useful exercise, which is most of what I will be focusing on. I think [Epstein Becker & Green s Jim Bolani] will be focusing a bit more on going forward, what we do with this what are the issues that are outstanding to work on and we can combine the two for questions. We will talk about some of the recent developments in brief what we actually did towards in 2016 to 2017 and then talk a bit about Cures and the council as two of the particular topics we have been hearing that people are interested in hearing more about, and go from there. So, current developments in brief: There are a variety of things that got published last year, or activities underway last year that are public, that I wanted to touch on, where the Office of Combination Products was pretty heavily involved or leading. There are some themes I want to touch on about processes as well as substance. Post Market Safety Reporting Final Rule The first is the final rule on post market safety reporting. It is big news I think in some respects. I think it stands for a couple of things: First of all, it sort of solidifies at least some of the thinking on how combination products are regulated by FDA in the post market setting, because it basically adopts the same basic approach as the final rule on CGMPs. I am not sure how familiar you guys are with either rule, but the basic concept in both is that there is a base set of requirements you comply with and then you comply with called-out provisions from another set of requirements. And by doing all of that, you kind of comply with both sets of requirements. So it is a sort of an efficiencies tool. We have done that twice now, so you could kind

of assume that we are comfortable with that principal in that setting at least, and I think that is interesting. The other thing I want to touch on on the rule is in terms of process how it got out. If you have been following this area, the proposal was published in 2009. So it is 8 years later that it got out, which is not great timing even for FDA. A part of that is just resources, to be perfectly frank. Every year as we got close, we could not quite get over the line because of other priorities for clearance at different parts of the agency that had to deal with it. We get cleared by a lot of people as you might imagine, being cross-cutting in nature, and it was just hard to get it out. We were not willing to really push too hard for it because other things needed to be done too and they got priority. But we started to hear more and more from industry that this needed to get clarified. There is too much uncertainty. This proposal has been sitting around too long and we do not know what to do. We have to make our investments in IT and what not, so you need to get this closed down. And frankly that is very helpful getting the word that you guys just really need clarity, and having that need in writing was probably useful. You combine that with the fact that we had a commissioner who was, as I am sure you know, pretty interested in combination products last year gave a lot of resources to it and gave a lot of political heft to it. There were a number of topics on combination products, and I will come more into that in a minute, that the commissioner s office level was interested in. This was not one of them to be frank. It was not on his agenda as something he wanted to get done, but it was something that was on our list, our agenda. When we presented it to him as one of our priorities, he adopted it as his. And that made a big difference to have that be on his list to have that be published as something the commissioner is committed to. It makes it a lot easier to have people get involved with getting it done. Part of how this kind of came to be, FYI, was a combination of significant engagement and support from the top and significant noise from outside that this needs to happen. Words to the wise. In terms of substance of it, the other thing I want to mention was that the base set requirements are basically the requirements associated with the application types. There is nothing really new there to worry about. For the new stuff, the compliance date that is published as July 2018. So that is something to keep in mind. We are planning on getting more information out about the rule in coming months, in terms of hopefully a draft guidance and of course information and instructions about filling out reports and things. There is more to come on that, but that is the overall timeline that we will be working to with folks, and we are starting to work through internally with some assistance from outside. Final Guidance on CGMPs Turning to the next topic the final guidance on CGMPs: This is a much more mature area of combination products policy. As you may know, the final rule has been out for a couple of years now. The draft guidance was finalized this year. In terms of substance, basically I think the main difference between the draft and the final is just a bit more clarity around topics that industry had comments on. I think the reviews of the draft were actually pretty good, which was reassuring that we were pretty thorough, pretty clear, and hit a lot of issues. We have added some bells and whistles as part of finalizing it.

The other thing, though, is that we really tried to address is some flexibility some questions about availability of alternative approaches and creative approaches to compliance for challenging issues. And I want to focus on that for a second. First, just the nature of the issue: There are a number of topics that we are paying attention to that are resource intensive for industry. If you are interested in those topics for instance, about stability, reserve samples, design controls and other things we actually have some language in there about how to approach the questions to help you see if flexibility doesn t make sense, given your products operations, and also how you might want to work with the agency to make sure we get to an outcome that doesn t bring on surprises because you tried something that we actually don t like on inspection. So that is the substance. But on the process again here: I think this is also a really exciting process story, because how this came about, the final guidance, was a ton of work between stakeholders and FDA. OCP kind of coordinated with AdvaMed and got this tremendously helpful input from the centers. And the centers were willing to put a lot of resources into this and brought people to the table with that for a series of meetings over the year to work these issues through. The reason why I drive this home is not just because it was a nice outcome. It is because I think, again, it stands for something important which is was we have been working with AdvaMed and the Combination Products Council and others for years now. And I think what this really represented was sort of a demonstration that I have trust and really getting to know each other. Because as you may know, I was in private practice before I came to FDA. You are probably in private practice working in companies. It is a bear to get real information even from your own client sometimes to share on policy issues. Trade associations cannot get great data to share with the regulators. It is all very broad. It is sort of we want this, and abstract arguments that are hard to sell because they are abstract. This was not that. This was companies coming together to give us very frank, pretty substantive, pretty detailed analysis of what they needed and why, and why their solutions made sense. It was terrifically helpful we could really work with that. We did not necessarily agree on every outcome, but we could actually get to the place where there were things we could agree to as possibilities that really were viable and we could publish on. So I think this was a terrific model. I hope we continue in that vein. Human Factors Draft Guidance and Comments The third item was human factors. This is a hot topic too. There is so much stuff to talk about... Human factors has been a hot topic for a while now. We have gotten feedback from industry that there are potential inconsistencies and lack of coordination on the topic from the centers. We have published a draft guidance with the centers in light of that. We have got some comments back that I think were fairly favorable. But I have not gone through them closely, so I don t want to speak too strongly to this. But I think we are in pretty good shape to push on getting final guidance out in fairly real time, all things being equal, given the nature of the comments, which is encouraging. There are also processes occurring inside the agency to really make sure we have good coordination and good understanding of where we should coordinate and not coordinate on given topics, given

expertise and whatnot. So I think the general principal of human factors we are getting some stability around, but there is definitely work to be done. There are two tracks to this, sort of related topics, that I am not going to go into detail on because it is really not a topic that OCP has the lead for. But as I know you have been hearing in some of the other presentations this week, there is sort of a comparative end-user interface analysis kind of work being developed as well led by CDER for both biosimilar and generics going into the issue of substitutability and interchangeability which are meaningfully distinct questions from this pure human factors story for any given product, and the approaches being discussed are meaningfully different. But that is kind of a dovetailing topic, which I know will be addressed collectively. And we recognize that we are trying to think about them collectively to the extent appropriate. In fact those draft guidances on interchangeability and substitutability both reference the draft guidance on combination products human factors. It is not that there are different things are going on that don t acknowledge each other, but they are somewhat different, and we try to be coordinated. I will leave it at that for now. Intercenter Consult Process In terms of process, not a lot here that matters as much to lawyers, but we are doing a lot work on intercenter consult updating. This is an area where we got a lot of support as well as direct engagement from the commissioner s office level and I think it is going very well. We had analysis beginning in 2015 on the topic, and I think it resulted in some very good thoughts on how to really update our systems to make them more efficient and to ensure intercenter consults were occurring when they should and they were being responded to in a timely manner. At least internally, people were pretty excited about this. The pilot has been growing to include more and more of the centers over time, more and more parts to centers, and we are hoping we can kind of put this thing to bed and final this year. It has already been very helpful. People are actually coming and asking to join the pilot, which I guess is a good sign. Interested to hear what you guys are thinking about it from the outside. We have probably seen some of the applications of this in the last several months. This has become more active, but it is still growing. So just an FYI on that. One thing also related to that that might be interesting to you guys is that it did involve a significant amount of training for review staff to make sure we could roll this out efficiently. I think it gave us a good opportunity to augment our training on combination products principles for premarket review people, which is great, to help them identify combination products, identify whether they might need to consult, because it might be a combination product, whether it is in the right center that kind of thing which helps everyone to operate more efficiently. Pre-RFD Draft Guidance and Comments The last development is the pre-rfd draft guidance. I will not go into a lot of detail here, but the basic point is that there is an RFD process, or request for designation process, to get your products classified and assigned. OCP acts as a delegation for FDA on whether medical products are drugs, devices,

biologics or combination products. There is a formal process that has a 60-day clock that has a hard stop. If we don t give you an answer, what you recommend is the answer, so we never miss our deadline. Because it is such a hard stop and we have to collaborate across the centers to do this work and it takes a lot of time with experts, and whatnot, 60 days is pretty tight. So it is a very tight process. We put our heads down and just get it done. The pre-rfd process guidance is reflecting a fairly established approach that we have been having, working with companies in a more informal way, getting them feedback, which is still robust feedback with the same input from the centers, but is not quite as binding. There is no definite clock, although we generally hit the 60-day timeline. But it is a way to really kind of work together have it be more of an interactive process. People were finding that pretty attractive. We were getting more and more of these kinds of requests, so we figured it was time to get the guidance out to clarify that this process exists and how people can take advantage of it. And we just got comments back the comment period closed last month and they were pretty light too. So I am pretty hopeful we can turn that around into final really rapidly, again all things being equal, as well. 21 st Century Cures Act on Combination Products Turning to Cures, which is obviously a pretty meaty topic so we will see how we do for timing here: The main section for Cures for combination products is Section 3038. The issues in play here are all issues that have been live for a long time and been addressed as best as possible by the centers and by FDA for a long time. But we add some real clarity and solidity in the statue now the first amendment of any really consequence since the 1990 s. It is a pretty significant issue for us. So I am just going to touch on the three basic buckets of classification, pre-market, and post market and a couple of other things that were addressed in the legislation. I will talk a little bit about what we are doing to implement this process. Classification and Assignment So in terms of classification and assignment, the one thing that Cures does is codify at statutory level the definition of primary mode of action, which is already a regulatory definition in Part Three. It is interesting that they decided to do that. It relates to some language in the legislation about not assigning based purely on the presence of chemical action which is not really consistent with the primary mode of action definition anyway, but I guess they wanted to drive that point home so they kind of made it all statutory. So that is one interesting issue. Another thing was they wanted to kind of codify that we should justify why we say what we say about classifications and assignments for combination products. We do this anyway, just so you know, in RFD responses. We routinely give pretty detailed analysis of why we are doing what we are doing.

But I am not sure if this is sort of public or transparent to everybody. In any case, this assures that is the case. If you get a response back and you don t quite get it, this gives you a chance to say we need more information about this, and we are supposed to provide it. The third thing it does is provide for a mechanism for developing new data. If you don t agree with what OCP has to say, you can come back in and say, look we would like to develop some studies to kind of prove a different outcome makes better sense, and we would like your help in designing it. We are supposed to help with that. Again, this is something we actually do with companies right now, but not very frequently. It is an interesting thing to me because the reality here to date has been that usually the issue is not that if only they had better data, we would assign the way they want to be assigned. It is usually that the data are not that ambiguous, but there are products already out there they think are like their products, and they want to be treated like those products. It is a sort of a precedent argument. It will be interesting to see if there is a shift here where people are more aware they can do this, maybe they will try to develop additional data. But often that is really not the issue. Often it is actually trying to just present the data in as favorable light as possible and focus on precedent. So we will see how that goes. Pre-Market Action In terms of premarket, this is where most of the action is. A few things: One major thing is this idea of a combination products agreements meeting. As I understood it from conversations during legislative development, this was basically intended to be something akin to a process that CDRH currently has underway, but of course it is not statutory. There is fully binding language for the commitments that are made through this process. So it is little bit of a different animal than just having a guidance on these kinds of concepts. But it has some flexibilities in in particular, that while you can talk about a wide range of topics in these meetings, it is up to the agency to decide which topics are ripe. You can potentially agree to part A, but to delay part B and deny part C. You can kind of have a mix and match based upon the nature of the questions and what information is available at the time for the topic. So I think that is helpful. That is a big issue, and we can talk more about that. Risk-Based Approach Another big issue is the risk-based approach. Again, you would hope this would be part of what the FDA does all the time. We should not be asking for things that we do not need. But there is some express language in the legislation, which I think is helpful. It kind of goes more directly to the question of leveraging data if you have already got knowledge about a product, that you should be able to rely upon that knowledge. The agency should rely on it and not be reliving it in questions. It should be focusing on incremental questions and incremental risks and that sort of thing.

Patent Issues In order to make that happen, the legislation incorporates through the Hatch-Waxman-like regime for device-led combination products vis-a-vis the drugs included in them, which I think goes probably to what leveraging would be possible. If you do not have the rights of reference if the exclusivity still exists etc. then the leveraging may have to be delayed. So that is an interesting complicated area. It is certainly novel in the legislation. Intercenter Coordination and Point of Contact It also spends a lot of time on inter-center coordination and collaboration and the importance of making sure the right people are engaged on the review and are in the meetings with the sponsor on the review. We have more express duties for OCP to make sure that is happening and for tracking that kind of thing. Also making sure the centers are aligned in their thinking on combination products, and that there is both a point of contact and a single voice. So when the agency says something to you, you can trust that that actually is the answer, and the answer that is coming to you is not some sort of a Frankenstein letter. It has actually got coherent views that are based upon an aligned set of thoughts from the agency. That is certainly very important and ties into our inter-center consult process that we have been working on. One Versus Two Applications One versus two applications: This, again, has been around for a while. As you might imagine, most combination products are reviewed under a single application, and that makes a lot of sense for efficiency and clarity and coordination. But in some cases two might make sense. For example, for a cross-labeled combination product where the different parts are sold separately, you might want to have one be a platform technology. You want to have some flexibility to develop that product for different uses, and not have to go back to the original application all the time. So there are reasons companies might like to have two. The authorities on this were a little bit murky before, and it seems pretty clear now from the legislation that the agency basically makes the call. We are supposed to use a single application when appropriate, and if the company wants to use two, that could be okay, unless we think one is necessary. So that comes back to the agency to resolve. Postmarket Regulation Post-market is a lot thinner. First of all, post market concepts can be addressed in the combination products agreement meetings. So that just reflects the desire to get some clarity on that even before you go to market, which is interesting. But again, there may be some timing issues about how to make that happen, given the knowledge you might have, given the developmental stage of your product. Also there is a requirement for us to develop a listing of flexibilities for compliance with CGMPs for combination products, which I think ties back to some of the issues that are addressed in the final guidance. So we will be working on that. That is the major post market stuff.

Other Issues Other things: It calls for industry to identify your product as a combination product when you are making submissions to the agency, which of course will help with clarity and efficiency, reduce surprises for you, and help make sure that our 510(k) reviewers don t just miss something, which is great. And then there are a few other bells and whistles, including some additional requirements for our reports to Congress, and, again, a bit more detail about what OCP should be doing to make sure that the trains are running on time. So that is it in a nutshell. In terms of implementation, this is a usual operation in some sense of implementing the legislation, so you can look to the past practice of the agency for some sense of how they do business. It also relates to what we do for combination products all of the time in terms of coordination, working groups to work through issues and whatnot. You can tell fairly readily from the list of topics, the kinds of things that we need to work through. There are some requirements for some guidance. There is some [areas] where guidance is needed in any case. SOP s, templates, training we are working through all that stuff right now. There of course may be some funding consideration, but that is all in motion. We will see where it heads. I think there is some pretty clear things that need to get done. But there are also going to be new folks to think about it and talk to about this in coming months. We will see what the overall vision is on some of the issues as we go forward. Combination Products Policy Council Turning quickly to the council: There were a lot of questions about this when it first came up because the initial publication was pretty broad as to what it was. My boss [OCP Director] Thinh Nguyen was getting questions like, So do you still have a job? Luckily, there was an official publication after that which I think kind of calmed the waters. The charter for the council was published. There was a blog about it. Basically what it stands for is something that we, again, needed to have all along, but it makes it a little more transparent and more structured. Combination products raise complex cross-cutting issues, which is why we are all here today. And when those issues are thorny enough either technically complicated enough, politically complicated enough, both legal or whatever you need to start elevating the conversation. We do that routinely with the centers as needed. We work closely with the deputies in the centers, most of the time on those kinds of thorny issues. And if it gets bad enough, the center directors have to get pulled in. So this is basically where we pull the center directors in. We have a regularly scheduled meeting right now, but the idea is that the council can kind of set its own agenda. The focus has been on topics where we think there is a need for that level of engagement if not so much to make a decision necessarily, although that certainly can be the case, at least to make sure you have the momentum and support for the activity, so it is clear to everybody this needs to get done.

So that is the basic purpose of it. The council does set its own the agenda. And it addresses basically any combination products topic that it thinks is appropriate. My boss, director Thinh Nguyen is on the council. So are the center directors. Deputies and policy folks like me go to the meetings generally as well. We bring in experts as needed. It is like a board meeting to think about the issues and make decisions. I think it is a very useful tool. I am excited about it for the long term as a way to keep things moving. And we will see how it develops. It is still early days frankly, but I think it has already reflected some real positive effects. The last point on it is that we opened up a docket on it in January for comment from the outside. It was interesting to frame this thing, saying look, you know we have got this council. We have processes for appeals, and for you to talk to us about guidance you want. But if there is something you think you need to have the council address instead, let us know you have until April to tell us. By the way, we won t tell you what we will did with it so it was an unusual process. We got five sets of comments. A number of comments spoke to issues we had been working on for a while through OCP. Some were newer, at least to me sort of a mixed bag. The interesting thing to me was what it reflected about thinking about the council itself and its purpose because some of the topics were clearly topics we can deal with without getting center directors to pay attention. Others, maybe, you could debate the point. But I wanted to kind of close on that issue in terms of developments, because OCP has been around for a long time and can help folks with whatever problems you may have with the agency on combination products. We are still here, and I think we still provide a good resource. But also, if there is a point where things just don t go the way you want them to go it is taking too long, or it is clear something is not working that is a great time to want to get the council involved. What I would suggest is in reaching out to OCP, as people routinely do: If you are getting frustrated about something we are already working on or you are coming to us and it has been a long time before you brought us in and you are thinking I know you guys can usually help, but this one is really a bear and I don t think you can take this on by yourselves that is a useful bit of the analysis to provide to take into account, in terms of the nature of the issue and what we think needs to happen. If you think it should go to the council, we would be very happy to hear your thoughts on that. And we can potentially put it on the agenda. So that is just FYI. In any case, council or no council, the basic point here is that if an issue is tough and not moving, we are trying to have mechanisms to help you get the job done. OCP continues to serve as a resource in that regard. The council is another resource that we take advantage of. Hopefully that will make things even more effective for you. That is basically it. This is a sort of a [summary] of the stuff we always do the way we think about things. I think it aligns pretty well with what the Cures legislation stands for and what we will probably be doing to implement it. But basically, we are trying to be efficient, consistent, and trying to make sure we are making risk-based decisions. We are trying to speak with one voice. And we really do want to hear from you. I can t emphasize enough what I was saying at the beginning of the presentation about the need for coordination and trusting engagement that is so incredibly helpful. You know OCP is here, along with the council and everybody else as resources for you to address your questions and try to get things moving.