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COMBINATION PRODUCTS AND MUTUALLY
CONFORMING LABELING
Tuesday, May 10, 2005
8:35 a.m.
Marriott Bethesda North Hotel
5701 Marinelli Road
Bethesda, Maryland
C O N T E N T S
Welcome and Meeting Introduction:
Mark Barnett
Opening Remarks:
Murray M. Lumpkin, M.D., M.Sc
Perspectives on Cross Labeling:
Suzanne O'Shea, Esq.
Public Comment and Open Discussion on
Public Health Issues
Moderator: Mark Barnett
Legal Panel Discussion: Speakers
Public Comment and Open Discussion on Legal Issues
Moderator: Mark Barnett
Closing Remarks:
Mark Kramer
Welcome and Meeting Introduction
MR. BARNETT: I would like to welcome you to this FDA/DIA Cross Labeling Workshop on Combination Products and Mutually Conforming Labeling. I am Mark Barnett. I am going to be serving as your moderator today.
Let me first briefly discuss the issue that we are going to be talking about today and then I will let you know something about the format we are going to be using for this meeting.
We are here, basically, to explore the cross labeling of combination products; that is, products that may combine a drug and the device or biologic and a device or a drug and a biologic. The basic question is what kind of labeling should be required when a new product is intended to be used with one that is already approved and the two of them are going to be continued to be separately manufactured and marketed.
We are going to talk about two aspects of that issue. One of them is the public-health concerns and legal ramifications that may arise if the two manufacturers are not cooperating and jointly developing adequate labeling fort new combination product.
We are going to do this in the context of a hypothetical situation involving two manufacturers, Company A and Company B. This hypothetical is outlined in the Federal Register Notice announcing this meeting and you will find that in your handouts. Dr. Mack Lumpkin is going to be reviewing and further explaining this hypothetical in just a few minutes in his opening remarks.
There are also some related questions in the Federal Register that the speakers today are going to be addressing in their presentations. What we need from everybody here today, and I am talking about the panelists, the people who have signed up to speak from the audience, and anybody else in the audience who wants to speak up later on his advice on whether the FDA ought to be requiring that labeling of Product A and Product B conform to each other and, if so, when that should happen.
So, in a sense, your assignment for today is to put yourself in FDA's shoes and tell us what you think our policy ought to be about this. FDA's assignment is listen to what you have to say, go home and digest it and to later take it into account as we develop a policy on this cross-labeling issue.
Now let me explain the format we are going to be using today for this meeting. As I just mentioned, Dr. Lumpkin, the Acting Deputy Director Commissioner for International and Special Programs who is sitting up here on the platform is going to being with some opening remarks. Then he will be followed by Suzanne O'Shea, the other person up here on the platform, who is a Product Classification Officer in the Office of Combination Products and she is also the hard-working, diligent, multi-talented Program Chair for this workshop.
Suzanne is going to give you a little more background on the Agency's perspective and why we think it is important to develop a policy on cross labeling.
After that is over, we get into the meat of the program. That is going to consist of two separate sessions. The first one, this morning, is on the public-health issues in cross labeling. That is going to take up the rest of the morning. Then, in the afternoon, we will have the second session on the legal issues.
In each session, we are going to begin with prepared presentations by speakers who represent the FDA, the pharmaceutical industry, the Combination Products Coalition and AdvaMed plus a few other speakers from government and industry who have some experience in these areas. These formal speakers are going to be joined by a panel of FDA managers who whose programs are directly affected by these issues and who are working on developing the policy for the agency.
After these formal presentations, we will have a short break. You will be able to get coffee and cookies outside. Then we will come back and hear from a number of people who registered to speak in advance to make a statement. You will find a list of these people in your conference materials.
If you have made a reservation to speak, please be available at the right time. Come up to the microphone. You know the drill about that. After we have heard from everyone who is registered to speak, we are going to open the floor to anyone else in the audience who has a question or a comment for the panel. I am hoping, at that point, that we get some lively discussion.
Again, we are going to follow this procedure twice, once in the morning and then again in the afternoon. Lunch is going to be served from 12:30 to 1:30 right out here and, at the conclusion of today's meeting, we are going to hear some closing remarks by Mark Kramer who is the Director of the Office of Combination Products at FDA.
So, at this point, we are ready to begin and ask Dr. Lumpkin to give his opening remarks.
DR. LUMPKIN: Good morning to all of you. I often feel like, at this hour of the morning, you need to be like that show--I don't if many of you have seen it; The Extreme Home Makeover Show. It was on last night. They have this huge great bullhorn and they go to the house, and they go, "Good morning, Johnson Family." And everybody comes running out and all of this.
I have always thought that would be nice, something like this at 8:30 in the morning to wake everybody up. We do, on behalf of Dr. Crawford, on behalf of Mark Kramer and myself and all of the colleagues that work with us in the Office of Combination Products.
I do want to welcome you here today and want to sincerely thank you for taking time out of your schedules to come here, as many of you have, to fill this room and to work with us today on this issue of combination products.
Obviously, you guys have looked at this issue. This is an issue that is important to you or you wouldn't be here today and it is clearly an issue that is important to us. It is not a new issue. As many of you know, the issue of combination products is one with which, I think, both the private sector and the agency have struggled for many, many years.
It is one of those quintessential FDA conundra where I think we often feel that we are trying to fit a square peg into a round hole both in terms, often, of science, in terms of regulation, in terms of the law, in terms of proprietary interests. It is what makes it interesting but it is also what makes it very, very difficult and a struggle to try to come up with some consistent policies and policies which are good for the public health of our country but also policies that recognize all these other interests that are clearly at stake in this particular issue.
So what we would like to do today is look at the issue of cross labeling. I want to thank Mark and the people in the Office of Combination Products for taking this issue on. As many of you know, several years ago, Congress mandated that the FDA form an Office of Combination Products. It gave certain statutory responsibility to that office. Mark and Suzanne and Patty and Patricia and all the others whom you meet here today from that office have been working diligently to deal with a host of very, very complicated issues involving combination products.
Many of you are seeing the fruits of their work, whether it is there proposed rule, and, hopefully the final rule on primary mode of action. It is dealing with issues like adverse-event reporting. It is dealing with user fees that are associated with combination products if it is one application, two application, the advertising regulations, what applies.
There are, it seems, an unending array of issues with combination products that really need focusing on and this group is trying very, very hard to do that. Today is part of their effort and, hopefully, it will now be part of your effort to help us all deal with the issue of cross labeling and what this means to these products.
In order to help us focus our discussion on this and to try to look at it from all the different perspectives that play, as you know, in the Federal Register, there was a hypothetical problem that was put forward. I think what we want to do is try to focus our discussions around that hypothetical problem this morning.
It is really kind of the worst-case scenario. Obviously, if you have got a combination product and the two manufacturers are working together and everything is wonderful, you can make the square peg fit the round hole much more easily.
But, in the hypothetical that we presented in the Federal Register Notice, it is very, very difficult. When we have been faced with these kind of situations in the past, obviously, they are issues with which we have struggled and with which we have not yet come up with a final policy and that is why we are here today.
The hypothetical is as follows. Here is Company A. It could be a drug company. It could be a biologic company. It could be a device company. But, for the sake of argument, let's just call it a drug company.
Company A has a drug that has an authorized new drug application. They are on the market. They have a label. They are legally out there marketing and selling their product and people are using it. Company B, which has no relationship whatsoever with Company A, develops a device with which one can deliver the product that Company A makes in a way that is different from what the approved labeling allows.
It could, perhaps, be a new indication. It could be a new method of delivery. It could be a new population. But Company B has this device and they are more than willing to develop the data to show that using this device and this drug together, at the end of the day, is safe and effective and they want to market this product and they want to be able to make claims about using their device with Drug A.
But Company A says no. They are not interested in being in any kind of business relationship or any kind of regulatory relationship with Company B. They simply have their product. This is the way this product fits in their corporate portfolio. This is the way they wish to look at this product. They know the liability that this product, when it is used, is the way that it is authorized.
They are willing to assume that. They, for their own corporate proprietary reasons, have no desire to be involved on this new device.
But there are those who think that, perhaps, there is a public-health benefit for having that drug used in combination with the device from Company B. Company B, clearly, has its own proprietary interests and its own desires as far as marketing their device and having an ability, legally, to make claims about how to use that device with drugs that are available on the U.S. market.
So that is our conundrum. The issues that surround that particular hypothetical are ones we would like for you to think about today. You are going to be hearing from a host of different perspectives. I think, for those of you have already looked around the room, you have got very senior leadership from the Center for Drugs, from the Center for Devices, from the Center for Biologics.
You have got the Deputy Counsel with us today from FDA. And you have got people from the private sector, from big companies, big PhRMA companies, big devices companies, from smaller device companies, people in the Food and Drug bar within our country.
There are people who are going to be presenting to you a whole series of perspectives. I think, from our perspective at FDA, there are really kind of four different elements that we have here. These elements, generally, we tend to think of them as being complementary interests. But, as the hypothetical has pointed out, there are times when they can become competing and then that is where it becomes a struggle for us. How do we balance (inaudible).
These are interests. Clearly, there is our interest in promoting innovation because we believe there are clearly times that this promotes the public health and our interest to protect the public health.
There is clearly the interest that we all have making sure that we all observe the law. Even if, at the end of the day, we don't think the law takes us to a good public-health outcome, it is, nonetheless, the framework within which we have to work and if, at the end of the day, the public health is not served by the law, we obviously don't just decide to break the law. We have a system for changing the law to make us give us the good public-health outcome that we want.
That is one of the questions we have for you today. Perhaps, at the end of the day, that is where we are, the sum of the problems that combinations confront us with.
The third interest is, obviously, the proprietary interests of the companies. There are certain proprietary rights and interests that clearly we, as a community and we as an institution have to respect and how does one respect the proprietary interests of companies and also deal with these other complementary or, perhaps, competing interests.
Finally, the fourth one is, I think, none of us at FDA want any one to short-cut good science or to short-cut statutory intent by what, at the end of the day, might be seen as regulatory gain (inaudible).
So here we have got all of these what should be complementary interests at times being competing interests and that is what we want to spend time on today. We want you, as Mark said, to put yourselves in our shoes. I mean, the many times I know those of you who are not from FDA here must sit back in your office and say, those people in Rockville, if I were at FDA, this would be easy. This is what I would do.
This is your day to do it. Okay? Pretend like you are one of us. These are issues that you have before you. What would be your way of approaching this? We are here to begin our discussion with the larger community on this particular policy item and we are, indeed, not bringing to you today answers. We are bringing to you today real-life situations that we have to deal with and we are very keenly interested in what you have to say.
Some of the questions in the Federal Register, just to remind you, we would be very interested in knowing how big a concern cross labeling really is to those of you in the private sector and, perhaps, would shed some light for us on why there are situations where companies choose not to cooperate.
I know, when we sit in Rockville and we look at these situations, it is easy for us to say, well, if I were at this company, this is what I would do. We would just cooperate with these people and this would be easy and we would go forward. But, perhaps, there are, indeed, legitimate reasons why there are times when companies choose not to cooperate. That is something that we have no expertise on. It would be very helpful to us if you could shed some light on why companies, perhaps, at certain times choose, for their own corporate reasons, not to cooperate.
Is there anything that FDA could do to encourage cooperation. If there are reasons that companies choose not to cooperate, if there are regulatory impediments, if there are regulatory policies, if there are things FDA could do to address some of those issues, we would be keenly interested in what you think those are.
From a public-health perspective, we would be interested in knowing how consistent you believe labels have to be in order to meet the public-health goal of not having consumer or practitioner confusion. So when we talk about conforming labels, when we talk about consistent labels, what do we mean? Do we mean word-for-word consistency? Do we mean message consistency?
What do we mean by conformity when we are talking about labeling, cross labeling, combination products? There are some special issues that people have brought to our attention about combinations and some of the critical problems that can arise after marketing. One of them is what happens when a drug is reformulated, if the companies don't have a working relationship and the reformulation actually then changes the characteristics of the way the device delivers the drug.
What happens in that situation? How do you make sure that doesn't become a public-health problem because the drug-device combination is now not performing with the characteristics that the safety and efficacy trials that were done would lead one to believe should happen.
So what happens when drugs are reformulated and there is no business relationship between the drug and the device company? From the device side, what happens, for example, when you have a reusable design and the labeling gets lost? It simply doesn't exist anymore. What is available at that point in time? How should one handle the instructions then for using a reusable device on combination with either a drug or a biologic?
There are some very interesting tricky eagle problems that we are interesting in hearing what people have to say and that is, if, in the situation where there is no relationship, no propriety relationship, between Company A and Company B, and Company A specifically says you cannot refer to the data in my NDA.
If FDA chooses to approve Device Product B, are we, indeed, relying on Company A's proprietary data inappropriately in way? And, in approving Product B, if we don't change anything in the labeling of Product A, has FDA misbranded Product A by its actions on Product B?
There are clearly issues relative to exclusivity. There are clearly issues related to the authority under which a product is approved and whether, and when, and if, and how, any generic version or follow-on version of that particular product might be authorized by FDA.
We would be very interested--particularly you will hear both the private sector and the FDA legal authorities talking about these issues and thoughts on how we might begin to deal with those issues.
Just a couple of things to, I think, keep in mind as we go forward so we can stay focused on the policy issues and the legal issues that we are talking about here. Let's just assume two things. Let's not get into big debates on whether, indeed, there will be adequate clinical safety and efficacy data to support the combined application.
There are clearly issues of how you get that. There are issues of whether one has to meet a substantial equivalence standard or whether one has to meet a substantial evidence standard or a reasonable evidence standard or whatever the legal and scientific standard is.
But let's assume that, for the combination product, that there will be adequate clinical safety and efficacy data because that is really not the focus of today's workshop.
Let's also not worry about where the product will be reviewed in FDA and whether FDA will have the expertise to review the product. Let us assume, as all of you know, that we actually talk to each other across centers at FDA and that we have the authority to do consults across centers and that all of our centers have the authorities to use the different regulatory authorities of all the other centers.
So let's not worry about will FDA have somewhere within its remit the expertise to review the product. Let's assume that we will for purposes of today's workshop.
As I mentioned a little bit earlier if, at the end of the day, you think this square peg is simply too big for this round hole and that we need to figure out a new way to go forward, we need a new statutory paradigm for this particular situation, then we would be interested in hearing that. Clearly, we can't change the statute. Only Congress can do that.
Obviously, we are trying to make this situation work given the regulations that we have, given the laws that we have, given the good science and practices that we have at this point in time. But, if you think we just can't get from here to there, that we need a fundamental change in the paradigm, by all means, we would be very interested in that particular comment.
That is kind of the remit for the day. This is a very challenging issue. This is one that, were it easy, I think we would have solved it many, many years ago. But it is one that is becoming more and more apparent and more and more acute because our impression is that these combination products are one of the waves of the future, that, indeed, this is where a lot of the innovation is going, where a lot of the new technology is taking us, of how we use older products in new ways and new ways of delivering them that make them, hopefully, more efficacious, more safe and, perhaps, able to be used in situations where they could not be used in the past, all marvelous public-health outcomes but outcomes that are often difficult to get to from a regulatory and statutory perspective.
I would like to finish by, again, thanking, first of all, Mark and Patricia and Suzanne and Patty and all the people here from OCP for having the courage to take this on and to have this meeting here today and try to begin to work through with the broader community coming up with an answer that we all can live with on this particular problem.
You are also going to be hearing from people beyond the Office of Combination Products. We have, as I mentioned, people here from the Combination Products Coalition, from AdvaMed, from PhRMA. There are speakers from all three human medical product centers at FDA, people from the Office of Chief Counsel and other parts of FDA.
I want to thank them for taking time for being with us here today because this is, obviously, as you can tell from the perspectives, something that all of these different perspectives have a very important role to play.
Last but not least, I want to thank you. If you were not here today, we obviously would be in even a deeper struggle than we are at this point because, indeed, you represent a perspective that is clearly important for us as we begin to go forward in this area of policy development.
So let me encourage you to have a lively discussion. I don't want to have to get the bullhorn out. We want people to be awake. We want you to use these microphones. We want you to challenge each other. We want you to put your ideas out here so that we can begin to synthesize the discussion and the ideas and begin to come forward with some policies and some new policy guidelines and guidance on these particular issues.
I want to thank Mark Barnett. For those of you that don't know Mark, he has been a marvelous M.C. for a lot of our internal discussions that we have had and a lot of our public discussions. I think he will do a very good job of keeping you focused and, when you kind of begin to get out into the periphery of the issue, Mark will be one to bring you back. So I want to thank Mark for doing that.
Again, thank you all for coming and we look forward, very much, to hearing from you today.
Thanks very much.
MR. BARNETT: Mack, thank you for your usual articulate and very well done preview of what you are going to be doing today. Mack kept referring to the courage of Mark. But the Mark with the courage is the one down there, and that is Mark Kramer, the Director of the Office of Combination Products. I am the one without the courage.
Anyway, our next speaker is Suzanne O'Shea.
Perspectives on Cross Labeling
MS. O'SHEA: Good morning. Thanks, Mark. It is good to be back. I am Suzanne O'Shea from the Office of Combination Products. Mack mentioned to you that this problem has been around for a long time. I thought I would just confess that I came to the Ombudsman's Office in November of 1992 on a detail from CDER. Amanda Peterson and Steve Unger, at that time, handed me a stack of paper about an inch high and said, see what you can figure out about this cross-labeling problem.
So I am delighted that this conference is happening and finally getting this item off of my "to do" list. But, in the ensuing 13 years, that inch-high stack of paper has turned into about a 2-foot high stack of paper. So I thought I would just give you a little bit of background about what is in some of those sheets of paper that will, hopefully, help us frame the discussion today.
Why do we think cross labeling is an important problem to work on. As Mack alluded to, we think there is certain amount of confusion in the world whether cross labeling is required in the situation laid out in the hypothetical; that is, where there is no cooperation between Company A and Company B.
We are a little concerned that the confusion, itself, may deter development of innovative products and so, hopefully, we would like to clear up the confusion. Is cross labeling required or isn't it? We would also like to get the process to be a little bit more efficient on deciding if cross labeling is required because, when the problems do come up to our office--usually, these days, it is the Office of Combination Products, it is time consuming for all of you and time consuming for us to figure it out. So we would like to be a little more efficient in it.
A quick note on terminology, just to clarify. Sometimes you will hear the word "cross labeling" used. Sometimes you will hear "mutually conforming labeling" used. Is there any difference between those terms? As far as I know, there isn't any difference. They mean, to me, exactly the same thing which is not completely clear in itself.
But I think mutually conforming labeling may be slightly more descriptive in that it does give you the sense of you want the two products to have the labeling conform. The cross labeling sort of sounds like the old scarecrow thing; he went that way. So, just to be clear, I think we are talking about the same thing when we use those two different terms.
I would like to just run through some of the different situations where we have seen cross-labeling issues arise. This may give you a little bit of a perspective on why it is so confusing, because the situations are different and different resolutions have come up depending on what the situation is. Throughout the day, I think it would be helpful, if we want to refer to Product A and Product B and Company A and Company B as a shorthand for what we are talking about, even though we all know that we don't really mean a drug company and a device company, but that does seem to be the way it works most often.
But on one end of the spectrum, sort of at the least troublesome end of the spectrum, is where Product A enhances the safety or efficacy--or Product B enhances the safety or efficacy of Product A. Same indication. Same patient population. Same dose and same route of administration. But it is a cross-labeling issue whether Product A should refer to Product B.
Slightly one step harder on the spectrum is where Product B uses Product A in a new route of administration. That can be a fairly small change such as between intramuscular and a subcutaneous route of administration but may have impact. Or it could even more dramatic from a Product A approved for I.V. administration where it would be administered intrathecally with Product B. Those raise obvious safety and efficacy concerns.
It is different even when it gets a little more complicated is when Product B uses Product A for a new indication. These indications, again, can be fairly closely related such as if Product A is already approved for treatment of a certain condition and then Product B comes along and wants to use Product A for prevention of a the same condition. That may be an example.
They may be wildly different indications which makes it even harder. You may have a product for heart disease that Company B wants to use it for wound healing or something like that. Those present very different issues.
You may have a new patient population involved where Product A is indicated for Stage 4 cancer and, with Product B, they want to use it for Stage 2 cancer and there are obviously different kinds of concerns there. It is very much dependent on the facts.
We have seen cases where Product B is a new component of an already existing combination product. Sometimes, we will have a combination product that is reviewed under two applications. The riboviron interferon product is an example of that. What would happen of Company B wanted to come in and make its own riboviron product to be used with the interferon product but the interferon product won't be labeled? That is cross labeling.
Another example is when a drug product is approved with a specialty delivery device and they are both approved under one NDA. What happens when a new device company wants to come in and make its own delivery device to be used with Product A? We are back to cross labeling again.
The differences in the labeling can be an issue for us. Sometimes, the labeling between Product B and Product A will just be slightly inconsistent. For example, we have seen cases where Product A contains a caution against using a product in a certain way and Product B comes along and wants to use it in this way that is cautioned against.
We have also seen cases where Product A is contraindicated for the way it would be used with Product B. So the labeling of the two products would be just clearly inconsistent, contradictory. Those might pose different situations with different solutions for us. So you have to think of all these different possible situations when we come up with our policy.
Another way to slice this problem is by considering the categories of issues. Mack alluded to these but it has been helpful to me to consider the different categories. The three main categories that we will go through in just a minute in more detail are the labeling issues, the no ongoing relationship between the two manufacturers issues and the pathway issues.
The labeling issues come up--they are the issues that derive from the fact that the physical labeling, the piece of paper that comes with the products, are inconsistent or contradictory. Some of the concerns might be that the end user could be confused by that contradictory labeling.
One of the things that we consider in this situation, or we might consider, is how awful it would be if the end user inadvertently used Product A as directed in Product A's labeling and so whether that would cause great harm to the patient if they used the wrong set of instructions.
The labeling for Product B could be lost and then there might not be any directions anywhere for how to use the two products together. Co-packaging has sometimes been offered as a solution to the labeling set of issues. I might ask you to consider that today.
To a big extent, I think mutually conforming labeling or cross labeling is sort of a short hand for the whole set of issues that arises from the fact that there is no ongoing relationship between the two companies. This is a concern not only during the approval process but through the life span of the two products.
So we have the issues, the approval product's proprietary information, whether we are inappropriately relying on Company A's data in approving Product B, the issues that Mack alluded to, the device redesign, drug reformulation may be an issue. Is it even possible for Company B to appropriately monitor Product A to make sure that there are no changes that make a difference.
So there will be degrees of cooperation that two companies can engage in. They might engage in cooperation for the approval process. They might give a right of reference. There are lots of different creative possibilities so we would like to hear about them.
Then the pathway issues that we have. 21 CFR 3.2(e)(3) is sort of the central pathway issue. I am sure everyone in this room has memorized this regulation. But, in case you haven't, it is included in your package. But, buried within this regulation is sort of the core question here of when does the labeling for Product A need to be changed.
That is something we would like to talk a lot about today is when it is necessary for this labeling to be changed. And then the issue becomes, according to this regulation as we read it, when the labeling needs to be changed, the two products become combination products with all the implications of being a combination product including assignment to a center based on primary mode of action.
When the labeling for Product A does not need to be changed, then the two products are two separate individual products that can go their separate ways.
Then the other pathway issues are all the legal issues that we will hear about this afternoon. They are sort of bumps on the road on the way to figuring out whether we are able to permit Product B to get onto the market without conforming labeling from Product A.
What is not an issue today--we ran through these earlier today. I will just reiterate them here; a conclusion that cross labeling is not required is not a data shortcut. We will require adequate--it is a presupposition here today that adequate safety and efficacy data will be available. The differences in the types of marketing applications we prefer not to get into today. We would like to assume that whatever information is required we could get under whatever kind of application it is. And we would also like to assume that there will be active consultation and collaboration across FDA centers.
Why is this such a challenging issue? Company A's proprietary interests. One of the little oddities of this whole situation for us is that we don't hear, at FDA--we don't hear from Company A very much. The people who come to us are Company B who wants to get on the market. So we would be delighted to hear from Company A about what their interests are.
We think we have our ideas but we are not sure. We think that it may be having to do with the confidential trade-secret information in their application. It may be broader property interests of why should Company B be benefiting from my product. We would like to hear that.
Also, one of the things that makes this difficult for FDA is that we have certain core beliefs about labeling. When you talk to people in FDA, it really is very disconcerting to think about FDA endorsing a product to be used in a certain way and that information is not included in that product's labeling.
We struggle with that a lot. So it may be a difficulty. Then another reason that makes this so difficult is because it is very hard for FDA to tell Company B, don't even bother trying because, unless you can get Company A to play with you, there is just no way you can get there from here. Then that hurts also, that we don't want to--we don't like to say, just go away. We want to find a way to give Company B an opportunity to try to prove that its product is safe and effective.
So we do have the dual missions of promoting and protecting the public health. In that connection, we agree up front that we prefer companies to work together. It just makes things so much easier for us. But, in the absence of that cooperation, our goal here today and our goal for the Office of Combination Products is to identify a pathway to enable Company B to try to obtain approval of Product B while ensuring adequate regulatory oversight.
One of the things that we might consider today, ask you all to consider today, is what should FDA's default position be in these situations. Should we take the position that cross labeling is required unless we say it isn't or should we say it isn't required unless we say it is.
So, today, I am saying to you what Amanda and Steve said to me 13 years ago; see what you can do about this cross-labeling problem. We want to ask your help in inventing the box. We need to develop the policy and we encourage you to be creative and bold and we want to hear what you have to say.
Thank you.
MR. BARNETT: Thank you, Suzanne. Creative and bold. Those are the key words here.
I want to call up the first panel which is the public-health panel now. I will introduce them once they are up on the stage.
MR. BARNETT: Let me introduce our speakers. I am going to ask you to--because people can't see the name tags. Raise your hand. Dr. Ramzi Dagher is Medical Team Leader in FDA's Division on Oncology Drug Products in the Center for Drug Evaluation and Research. Dr. Miriam Provost is Acting Director of the Division of General and Restorative Devices in FDA's Center--this is a misprint here in the program--Center for Devices and Radiological Health in the Office of Device Evaluation.
Leighton Hansel is Manager in Global Standards for the Medical Products Group at Abbott Laboratories. He is going to be speaking on behalf of AdvaMed. Dr. David Eveleth is Executive Director of Medical and Developmental Sciences at Pfizer. Dr. Paul Goldfarb is Consulting Medical Director at Genetronics. He is going to be speaking on behalf of the Combination Products Coalition.
Now our FDA folks are filing in. The FDA people are--and I have told people to raise their hand when I introduce you. Dr. Donna Bea-Tillman is Director of the Office of Device Evaluation at the FDA Center for Devices and Radiological Health. Dr. John Jenkins is Director of the Office of New Drugs in FDA's Center for Drug Evaluation and Research. Dr. Celia Witten is Director of the Office of Cellular Tissues and Gene Therapies at FDA's Center for Biologics Evaluation.
So let's begin. We will simply take them in the order that they are on the program and ask Dr. Dagher to start out.
DR. DAGHER: Good morning. I am Ramzi Dagher from the Division of Oncology Drug Products. I am asked to give a perspective from a drug division. Being from the Oncology Division, I will provide that perspective although I hope that some of the principles I describe will apply obviously not just to oncology but across other disciplines.
Whether it is in oncology or other disciplines, often the goal of combination therapy--and, again, whether it is a drug-device or even a drug-drug combination, there is a design to optimize efficacy and limit toxicity.
Just out of curiosity, I polled around in our division. I asked folks, what are the different approaches that we are seeing where these issues can come up. These are the four general areas where folks responded. Some are fairly obvious, the light activation where you have a drug and there is a device that is needed to activate the drug in order for it to have its activity. There are some maybe where it is not so obvious, the novel delivery formulations. What we are referring to here is that there are some delivery formulations that have been designated or could be designated as devices and the combination of the active drug and the novel delivery formulation. The Clinical Pharmacology group reminded me of that one.
Electroporation is one that you will hear more about this morning, but I just wanted to give you an idea that, even within one discipline, we have got a variety of approaches where these issues can come up.
Now, I have to admit, based on this morning's speakers and the advice they are giving--I have to say, I took some of their advice and, in some ways, I didn't take their advice entirely. One thing that I think has been reiterated is that we are asked today to assume that the issue of regulatory jurisdiction--i.e., is something going to be reviewed in one center or the other, what is the interaction between the centers, et cetera--we are asked to assume that that is addressed and that is not an issue. That is why I have here the first bullet, that there are some considerations that are taken into account regardless of the regulatory jurisdiction. So let's assume regulatory jurisdiction is not an issue.
Having said that, however, to me, once you have answered the question of whether or not you need cross labeling or mutually conforming labeling, the next challenge is going to be--let's say you have decided you need it, for whatever reason. To me, the next challenge is how do you go about it? What judgments do you make pursuing that labeling?
I think, before we answer those things, I do think we need to at least go through some of the basic issues that come up from a multidisciplinary standpoint from the drug viewpoint in trying to answer those questions.
So, actually, what I did is I pulled, again, some individuals from the different disciplines we work with. I asked them, well, when you are dealing with these approaches, what are the basic challenges that you have had to deal with and you think we are going to have to deal with, from chemists, from pharmacologists, from toxicologists.
I apologize for this part where this is maybe a little bit veering off the focus of the problem of A and B, but I think there are some basic principles to go through very briefly.
So, starting with the chemistry and manufacturing issues, obviously, chemists think in terms of a drug substance and the drug product. If we are talking about a drug substance, many times, with the combination approach, the drug substance is the subject of an approved NDA or NDA supplement in which case all that is required is the right of reference to that NDA.
However, if it is a new molecular entity and no NDA exists, you have an unapproved source, a reference to the drug master file or an active IND is the way to go. If there is no active IND, then complete EMC information will be needed over that and the next (inaudible). For the drug product, again, if you have an approved NDA or IND for that drug product, then simply referring to that is enough.
If there is an active IND for the proposed formulation, if there is a new formulation, then, obviously reference to that IND is needed. Finally, if there is no active IND, then the CMC information should be provided.
What are those critical chemistry issues? For the drug-substance side, they would relate to the manufacturing, controls, specifications and stability. If we are talking about the drug product, then you would have to address those same issues and edited onto that would be the description of the components or composition of the drug product and the sterility issues where we are talking about parenteral products.
From a toxicology standpoint, again, I asked, what are sort of the big picture issues that you have to deal with. One obvious one is the isolation of the drug versus the device effect. Many times, that can be a challenge from the preclinical standpoint because we don't have models that easily address.
Then, one recurring theme, whether it is for the toxicologist or for the clinical pharmacologist, is the requirement for establishing the systemic versus local effect and the concerns of systemic versus local toxicity. Many times, again, with approved drugs and drugs where there is a substantial previous use in humans, we already know a lot about the systemic toxicity. So, many times, the requirements for any further nonclinical testing would be waived if they are already addressed.
From a clinical pharmacology perspective, the first route is one that often comes to mind when we think about these approaches. Obviously, from a drug-division review, we are always concerned about what is going to be the effect of the device on the drug. How is the device going to affect the pharmacology, the metabolism and the elimination?
Obviously, that seems pretty obvious. But another side of this, and I have to admit it is from my colleagues from industry during our discussions about preparing for this that reminded me of this. I also went back to some in our division. The device, itself, has some characteristics that could have an influence from a clinical pharmacology perspective.
The device, itself; if we are talking about these novel delivery formulations, the device, itself, could be metabolized or eliminated and the characteristics of that could be important. Even when the device, itself, is not metabolized or eliminated, there could be some consequences.
For example, if the device is going to be implanted in the body for some period of time, there could be local effects from that. Or could it affect the general care of the patient. In oncology, we use, for example, imaging quite frequently as part of the care and decision making for the patient. So that is another issue that might come up, whether or not the presence of the device influences (inaudible) and, finally, as we described before, even if you have a drug-device combination where the intent is to provide the drug locally, there would still need to be some information on systemic exposure or lack thereof.
From a clinical standpoint, again, Dr. Lumpkin warned us against going to the details of our standards. But, again, I wanted to simply discuss some of them briefly because, again, they do provide some challenges in terms of how you decide on whether you need conforming labeling. And then, if you have, how would you address that?
So, obviously, whether it is for an oncology or any other drug intervention or device, for that matter, defining the patient population is important. Now, that seems obvious, but I want to emphasize one way in which oncology is different, perhaps, from some of the other disciplines is that we actually have at least 100 different diseases. So that is one thing, whether it is folks from devices or other areas find when they come to talk to us is that we often are used to thinking in very specific ways about the indication and the patient population.
Trial design, obviously, can take a number of forms. But one key area where we see a challenge we have had to deal with in the past and also where we see this becoming more and more of a challenge is in deciding on appropriate comparator, how that is described and how that is evaluated.
There may be multiple interventions, for example, that are available that clinicians and patients accept and medical team has accepted, but there may be no clear standard. There is no one clear intervention that provides the best survival outcome, let's say, in a specific cancer setting. But if there are multiple interventions that are available and we can't identify one that is a clear standard, you know, there may have to be a design where that comparator arm has multiple interventions described. You have to keep that in mind early on when you think about what is going to happen in the future when we talk about the labeling.
Obviously, there has to be some need to isolate the contribution of the device for the treatment effect. There are two sides to that coin. People think of, when they hear treatment effect, efficacy. That's true. But there is also a safety component. You can't always assume that the major adverse events, let's say, that are seen are being contributed mainly by one component or the other.
In oncology, we use multiple different endpoints that we consider of benefit. Some of these can be considered ones that sort of require sort of a systemic effect where you might see them, such as survival, time-to-progression, maybe, and other ones that even local effects could influence such as response rate or alleviation of certain symptoms.
However, it is not impossible that interventions which have local effects won't have any influence on the ultimate outcome such as survival if you are influence a very important component of the disease process.
One thing I want to touch on which I think we have to deal better with from the safety standpoint is that, in oncology, at least, we have had a certain systematic way of thinking about decategorization of safety events. To be honest about, it has been limited in the sense that it has been based on a view that we are really talking mainly about drugs. I think that it doesn't--perhaps, that classic approach doesn't always do the best service when we are talking about combinations.
For example, we have this National Cancer Institute Common Toxicity Criteria grading system where adverse events are graded by severity. Those categories are usually either laboratory parameters that can be influenced like liver function or also there are clinical categories such as rash or allergic reaction or cough or pain.
However, again, because those were designed mainly with the view in mind that we are evaluating drugs, they tend to focus on systemic toxicities. They don't always do a good job of potentially evaluating the issues that come up with device interventions as well. They don't really have a very good way necessarily of teasing out local effects so much as they should. That is something we need to keep in mind.
This is just, again, an example from oncology. I don't know, in other disease settings, whether the paradigm in terms of evaluation of safety also has to be modified when we are talking about a combination of issues.
This is an example of how we have classically thought of safety in oncology of the drugs is that, you know, patients come to us with advanced disease, often. They often have a lot of other comorbid conditions when they come for treatment irrespective of the cancer that they have. So when you have deaths occurring during the evaluation, it is hard to tell whether those deaths are due to drug intervention or the natural history of the disease or an infection or some other process.
So, classically, the way we try to get at this is to say that if a death occurs within a certain period vis-a-vis the administration of the drug, then may be that is more likely related to the drug.
In our classic paradigm where we have had classic cytotoxic chemotherapy drugs, we have used a 30-day time point. The reason for that is when you give cytotoxic drugs like doxirubicin or cisplatinum, et cetera, usually you get most of the effect from the side effects in the first week or two after administration and, by the third and fourth week, you have recovered. So you have made this empiric judgment, not just us at FDA but across the scientific community, that, somehow, if the death occurs within those 30 days, maybe that is more relevant to the effect of the drug than a death that occurs afterward. A death maybe that occurs three months out is probably not likely due to the drug.
Now, that has probably served us well so far. But, again, as we evaluate combination approaches that involve the device component, I think that has limitations and we need to be more creative about how we think of that. That is why the length of follow up is just as important as how you define the safety.
So, before we talk about the program of drug-device combinations, I wanted to just step back and say that a lot of disease settings and especially in oncology, we already have a track record in dealing with combination approaches to treatment, whether it is drug combinations where you have a chemotherapy regimen that involves two, three or more chemotherapy drugs that are given simultaneously or in sequence, or where we are talking about multiple modalities.
Even in the classic paradigm, there are disease settings, whether it is in pedestrian, Wilms' kidney tumor in children or adult breast cancer where, for many years now, the standard of care for some of those patients is, actually, a combination of surgery, therapy and radiation. So we have had to deal with this for quite some time.
The other part of this that, I think, from oncology we have some insight on is that we have to use aggressive supportive-care methods because our drug is going to be so toxic and, in order to assure the best outcome, we need supportive measures such as other drugs, growth factors, transfusions, et cetera.
We have had to deal with how we describe these in the Clinical Study Sections of our labeling for quite some time. Now, in the drug labels, if we are talking about supportive-care measures, obviously we usually don't refer to specific products. But we do, because of the safety concerns that can arise, we do want to make sure that there is some description of the supportive care that is needed for that.
If there are specific safety considerations which require us to describe a specific approach, we will try to do that as well. Obviously, drug combinations, where two drugs affect the treatment outcome, those have to be approached differently.
So I have provided one example which, hopefully, will just help to sort of kick off the discussion for this morning. As I mentioned, we have a lot of different combinations that we use in oncology. There are settings where simply using a single agent would not be considered appropriate standard of care and the standard of care would involve combination therapy.
One example we have is cisplatin. This is a drug that has been approved for many years. It is a DNA-binding. It came to fame in use with germ-cell tumors that now have a very high cure rate with the use of platinum and other drugs. What also, with combination therapy established a role in a variety of other settings, one example being the treatment of non-small-cell lung cancer in adults.
So here we have a situation, actually, where we have four different drugs whose labels describe an indication from the study description of a combination use for cisplatin with gemcitabine, with paclitaxel, commonly known as Taxol, vinorelbine and docetaxel commonly known as Taxotere.
With all of these individual labels, there is a combination use with cisplatinum described for the treatment of non-small-cell lung cancer. Yet, the cisplatinum label, itself, although it includes several oncology indications, does not specifically refer to these combinations.
So how have we dealt with that? Basically, the approach was that we made sure that the label with those individual drugs that I listed describing the combination use we had enough information regarding the safety considerations for cisplatinum and not just describing the safety considerations of the proper use of the other drug. So we have information about monitoring patients.
Cisplatinum is a drug that could have significant renal toxicity and ototoxicity. That is not just described in the cisplatinum label. That is, obviously, also described in combination labels. Also, the dose modifications that may be needed for cisplatinum and for the other drug in question, those are all described in those individual labels.
Another perspective that helps us address this challenge to some degree is that, whether we are talking about cisplatinum or some of these other drugs that I mentioned, or others, that, with many of the cytotoxic drugs, we generally try to make sure that there is labeling in the Warning Section and other parts of the label that emphasizes the need for the monitor for safety and supportive care and actually has wording about the need for having practitioners experienced in the use of therapy to give these drugs is true of the cisplatinum label, itself, of these other labels and many of the other drugs that are the cytotoxic drugs.
Now, where this could become somewhat of a challenge is where we now have potentially combinations where, obviously, we have one cytotoxic and another drug that really doesn't have those same (inaudible) or a device, for that matter.
So, in summary, again, as this morning's folks reiterated, there are multidisciplinary considerations that we have to think about when a component of the combination approach includes a drug. This is regardless of the "regulatory" jurisdiction that that applies
Where those challenges lie depends on the nature of the drug-device approach and the effect on the drug characteristics.
MR. BARNETT: Thank you, Dr. Dagher.
Dr. Miriam Provost, you are next.
DR. PROVOST: Good morning. Well, I am very happy to be here today to give you the CDRH perspective on the public-health issues related to mutually conforming labeling. I think some of the topics that I am going to talk about are going to be somewhat repetitive. I think, by the end of the day, we are all going to be a little bit sick of hearing about all these issues.
But I would like to come at the topic, some of the topics mentioned by Suzanne, with a little bit of the real-world perspective. I say that because I believe that CDRH is often the point of entry for people who are developing innovative new device technologies.
In my experience, many times they come to us. They submit a 510(k). They think that, in 90 days, their product is going to be on the market and then we have the unhappy task for calling them and telling them that they have a "drug" issue. That, often, is not a pleasant conversation. It often is a shock to them and a surprise and can make for some very unhappy investors, or so I understand.
So what I would like to talk about a little bit today is about a little bit of the perspective of how things are right now in terms of what is clear to us, what are the clear regulatory tasks, where some of the questions arise and then a little bit of a perspective from the public health, looking at the public-health side of it.
So I would like to start with just going over the FDA mission. I think it is interesting because there are three bullet points up there. I think all three bullets actually arise when you consider this whole issue of mutually conforming labeling.
So, stated most simply, FDA's mission is to promote and protect the public health by helping safe and effective products reach the market in a timely way, monitor products for continued safety after they are in use, and to help the public get accurate science-based information needed to improve health.
So, as I said, really, all three of those bullets have some impact on this issue. But what I would like to focus on, as Suzanne did, is the first bullet which is promotion and protection of the public health. That really is the balancing act that we deal with every day at the FDA.
When we think about this issue, if I am on the side of the scale that says FDA should be promoting the public health, then, clearly, we want to expedite approval of innovative products that have potential for positive impact. I think we are going to hear a lot about that today, what can FDA do to help expedite getting some of these innovative products on the market.
But I would like to suggest to you that there is another side of that scale and that is the protection of public health. If we are looking at it from that side of the scale, then we want to ensure that all medical products are adequately tested for safety and that labeling provides adequate directions for use.
So I am going to talk a little bit, I think, just to give equal time to both sides of the scale today. I want to talk a little bit, at the end of my talk, about the protection-of-public-health side of the scale.
First, I would like to start with explaining some of the flexibility that we already have at CDRH. I am going to start by explaining the whole product area of general-purpose drug-delivery systems. I think, as many of you know, CDRH has a long history of clearing unfilled general-purpose drug-delivery systems under 510(k).
I don't think you can read those small words on the screen, but you have them in your handout. These are quotes from the Code of Federal Regulations that describe device classifications that are general-purpose drug-delivery systems; external infusion pumps, I.V. administration set. What I would like to point out is that, if you read these, it is very descriptive of the mechanics of what this product does.
So, for example, an infusion pump is a device used in a healthcare facility to pump fluids into a patient in a controlled manner. No mention of any drug. No mention of any disease state. Then it goes on to actually describe the device.
You can see that in the next two device classifications as well. The nebulizer is a device intended to spray liquids in aerosol form into gases that are delivered directly to the patient for breathing. So, again, there is no mention of the drug or a combination of the drug and the device. It is just describing the device.
So, in general, for these products, mutually conforming labeling is not an issue. They are not prefilled with drug. There are no indications or claims for delivery of a specific drug or biologic. And, and this is very important, there are one or maybe many drugs that have already been approved by the FDA for delivery by this route.
So, when we get a 510(k) like this, it is fairly straightforward. The submitted of the 510(k) needs to show adequate safety and performance as a tool for delivery of drugs or biologics. So basically they just show they are substantially equivalent to a legally marketed predicate device as is done with any 519(k).
The submitter of the 510(k) does not need to show that the combination of this device and any drug, in specific, is safe and effective. So that is one kind of clear area.
The other end of the spectrum, we have more specific drug-delivery systems. For example, products that have a CDER lead are devices that are prefilled with drugs. You can tell them from CDRH because I think of them as devices prefilled with drugs instead of a drug in a delivery system. But these are things like pre-filled syringes, metered-dose inhalers. Those are straightforward.
Photodynamic therapy devices--this is an example of a product where the components along are not effective, that only together are they effective. So it would be difficult to think of how you would actually clear a device that is not effective on its own unless it is used with a drug. The regulatory path for these is also clear. Generally, they have either been done with A CDER lead or, perhaps, a two-application scenario in which there is an NDA and a PMA.
Then the last example is implanted infusion pumps. These are done with a CDRH lead with a consult to CDER or, perhaps, again, a two-application scenario where an NDA might be needed.
So those are specific drug-delivery systems. Now, let's talk for just a few minutes about some of those more discussion situations that I alluded to earlier. When I go through these examples, I want to point out that I don't have the answers or I am not going to say that, for every case like this, things go--cross labeling is required or cross labeling is not required. I just want to point out that these are examples that are not straightforward in which we have had internal discussions, or would have internal discussions, at FDA and with sponsors.
One example is cases in which the proposed indication for use for the device would necessitate a change in the route of administration for approved drugs. This would be an example, for example, of a device indicated for infusion of therapeutic drugs into the neurovasculature. There are no drugs approved, therapeutic drugs, approved. So, in this case, it would be difficult to clear or approve a device for that indication.
Another example that I think we are going to hear a little bit about are devices indicated for targeted delivery of chemotherapeutic agents. That is not on the label. If it is labeled for I.V. administration and this is a targeted administration, and a device application comes to us, we are going to have questions about that.
Another example, a device is intended for enhancement of drug effects in which the combined use may have a different safety or efficacy profile than the already approved use. One example might be devices used to prepare skin prior to administration of lidocaine. It wouldn't be clear, just upon inspection, that stripping off the stratum corneum would or would not affect, perhaps, the safety and effectiveness of the lidocaine.
A final example would be using devices as labeled may necessitate a change in dosing of approved drugs. A couple of examples here; the first one is breath-actuated nebulizers. With constant-flow nebulizers, a lot of the drug is just aerosoled and goes out into the room. Well, an innovative technology comes along that only activates the nebulizer when the patient takes a breath.
If you take that same dose of drug and put it in the breath-actuated nebulizer, the patient, in the end, could end up with a lot more--inhaling a lot more drug. The old dose was designed knowing that some of it was going to get lost, so questions can arise.
Then, finally, the product area of patient-controlled infusion pumps for pain medication. By allowing patients to dose themselves with a bolus of drug, are you, in fact, changing the dose such that the dose that the patient is receiving is one that hasn't been shown to be safe.
Okay. Now, those are some of the examples of the grey area. What I would like to suggest, something for everyone to think about, that, if we are the side of the scale that the FDA deals with--if we are on the side of the patient-protection scale, I would like to suggest that mutually conforming labeling can help FDA ensure patient safety.
This policy can do this by making sure that adequate information is provided to users on both drug and device labels, postmarketing safety information is collected on the combined use, and if important findings are made, both labels can be updated accordingly.
Finally, although this is really not supposed to be discussed today, the concept that, if we have mutually conforming labeling, the new uses are thoroughly evaluated by FDA experts at both centers according to their respective authorities. I certainly agree that we can work together and we do work together. We don't need to have mutually conforming labeling to ensure that we work together by any means.
But, if you are on the patient-protection side of the scale, mutually conforming labeling is certainly a sure-fire way to make sure that such cooperation and collaboration goes on.
Another issue that has been alluded to is manufacturing concerns. I think Suzanne mentioned this and it is the idea that, if there isn't this relationship, there can be situations that would be of concern. I think an example, kind of a classic example, is an I.V. drug that has a change in endotoxin level and an innovative device that using that for intrathecal delivery.
Or another example is a device that changes the laser output for a photodynamic therapy product and what effect will that have. So, if I am concerned, again, about public-health protection, then these are going to be concerns that I have and mutually conforming labeling and that cooperation between the two companies addresses those concerns.
So, finally, in summary, I just want to say, first, that I think the FDA regulations do allow flexibility to clear devices as general-purpose drug-delivery systems when appropriate. Questions arise when the device use requires an unapproved drug use. We have heard some examples of that. I think we will hear more about that today.
My suggestion to think about is that mutually conforming labeling can help FDA ensure safe and effective use of the combination products and also help us achieve our mission of promotion and protection of the public health.
Thank you.
MR. BARNETT: Next we will hear from Leighton Hansel speaking for AdvaMed.
MR. HANSEL: I would like to echo Dr. Lumpkin's comments about the Office of Combination Products and the staff. I predate Suzanne a little bit in Combination Products when I was at CDRH. Those were the days before it was mentioned in the statute--product like took three years for the agency to reach a conclusion on the status of medicated wound dressings. So people who have come into this area now really have a much better chance of getting a more timely and more coordinated view at FDA. I would also like to congratulate you--
MR. BARNETT: While we are waiting, Leighton, I just want to mention that our guideline for the speakers is 15 minutes and everybody has been great so far.
MR. HANSEL: AdvaMed, the Advanced Medical Technology Association is the world's largest association representing manufacturers of the devices and diagnostic products, medical information systems. More than 70 percent of our members have less than 30 million domestic sales annually.
We have paraphrased the questions on the slides and there is some repetitive statements since they aren't solutions to several of the questions are similar. Before we address FDA's questions, though, we think it is important to state the overarching principles AdvaMed supports with respect to the regulation of combination products.
Those are we believe that to encourage innovation and promote public health advancement, FDA must be flexible in applying its regulation to combination products. Inherent in this approach is the requirement for fairness, specifically with regard to the protection of proprietary information and intellectual property rights of a non-cooperating party.
Further, all potential issues of safety and effectiveness related to the development of a combination product must be addressed. Risk-management principles must be considered when making decisions on when and how to apply mutually conforming labeling. I would like to thank Suzanne for saying that cross labeling and mutually conforming labeling in her opinion are the same. We have had a lot of internal discussions about whether they were or they were different. We try to avoid using terms other than responding to the questions.
In those instance where a determination is made that a combination product exists and mutually conforming labeling is required, the impact on development could be significant depending on whether or not the drug or biologic company is willing to work with the device company.
It may result in the device company not proceedings with development of the device. This may result when clinical studies are required to prove that the device and drug labeling are mutually conforming, new drug application would be needed to revise or update the labeling to provide for mutually conforming labeling, or the public safety would be compromised is the companies do not cooperate.
Of course, there are examples of this. However, it is a very difficult document because the requirement for mutually conforming labeling may be one among many factors that would lead a company not to proceed with the development of new product.
Further, it may not be possible to assess the impact on product development. The device industry is make up of a large number of small but innovative companies that may not have the resources to proceed with development of a product if they are unable to establish a relationship with the sponsor of an approved or cleared product.
Additionally, the life cycle of a device is shorter than that of a drug as well as the market size. It is almost impossible to assess the loss of venture capital available for the development of novel products.
The labeling of a separate marketed drug and device does not need to be identical but should be not contradictory. There can be broad agreement of the intended use, dosage and route of administration to provide for the adequate directions for use of the drug and the device. If the result of a systematic risk analysis indicates that there are no issues with regard to safety and effectiveness, then minor differences such as in dose, dosing schedule should not be an issue.
We are in support of this position. We look to the principles of the Inter-Center Agreement between the Center for Devices and the Center for Drugs characterized as the ICH. Section 7(a)(1)(a) of the ICA states that there are three essential parameters required for mutual performance. The flexibility extends to the following; indications, general mode of delivery and drug dosage schedule equivalence.
If device labeling is consistent with these key parameters of drug labeling, the essential elements of mutual conformance are generally assumed to have been met. From a regulatory perspective, such products are classified as devices, in our opinion, not as combination products.
The ICA provides flexibility for two of the three key parameters, specifically the mode of delivery simply must be the same, general mode of delivery and the dosage schedule must be equivalent. The ICA also provides for all three parameters to be examined for significance of their change. The regulations likewise suggest flexibility by identifying a significant change in dose as triggering the need for labeling changes.
Examples of the application of this flexibility include FDA's clearance of lasermeric infusion pulse for continuing infusion with local anesthetics in either a hospital or home environment where drug labeling did not specifically address home use and scleronychia of continuous delivery systems for delivery of insulin where insulin was labeled for bolus administration by syringe.
Even if there are changes in the three essential drug parameters provided in the ICA guidance, nevertheless it affords CDRH further flexibility to consult with CDER and resolve these issues through device labeling. More specifically, the ICA support device labeling as a mechanism to resolve labeling differences because it expressly refers to CDER consult process which does not count out a separate drug in drug review.
The need for mutually conforming labeling should be determined on a case-by-case basis by the Office of Combination Products during the request for designation in the RFP process. To determine whether mutually conforming labeling is required, FDA should look to the flexibility established by the ICA. Further, decisions should be based on sound science and a thorough risk assessment.
Consistent with the concepts outlined by the ICA, the labeling of two products does not need to be identical but should be consistent where it matters. The ICA is flexible requiring that labeling must be mutually conforming with respect to, as noted, prior indications, general mode of delivery, drug dosage and schedule of the drug.
In addition, Section 7(A)(1)(a)(ii) of the ICA on mutual conformance does not purport to address any other aspects of drug labeling beyond the three stated parameters. For this reason, flexibility has historically been afforded with the secondary aspects of drug labeling; for example, clinical pharmacology and precautions.
Consistent with the ICA principles, wherever possible, device labeling alone should include adequate directions for use of a drug and a device. All relevant information would be included in the device labeling. Consistent with the flexibility afforded by 21 CFR 3.2, FDA is permitted device labeling alone to describe use of the device with the drug where the drug is not individually specified.
Examples of this approach can be with drugs and devices that have broad therapeutic classes such as off-patent generic drugs, U.S. Pharmacopoeia, U.S.P. Monograph drugs, grandfathered drugs, over-the-counter drugs, and drug-efficacy-implementation, DESI, drugs where there is public information to provide the device company with adequate information to develop appropriate labeling.
Finally, device labeling traditionally will contain more detail with respect to how to use the design with a drug or a biologic. The PCA and insulin pumps are the best examples of generic drugs. Changes in dosages and locations for use with no changes in drug labels with the instructions being provided by the device labeling.
The loss of instructions for use does not have any greater implications for combination products than for any other FDA-regulated product. Further access to current labeling is made easier for both drugs and devices as a result of the current electronic labeling initiative. There is not need for an FDA policy specifically directed as separately marketed combination products to address the possibility that labeling for a--component might be lost over time.
For a device being used with a branded proprietary drug, there should be collaboration between the parties to gain access to the proprietary information. For a variety of intellectual property and commercial reasons, the device manufacturer generally will not proceed to develop a device for use with a branded proprietary drug absent a contractual agreement before and between the parties.
Thus, it is in the interest of the drug manufacturers to identify changes in drugs. Notification processes covering these issues are incorporated in the standard commercial arrangements. The device sponsor would be aware of the changes to the drug as a result of the contractual agreement between the drug sponsor and the device manufacturer.
Consequently, there is no need for FDA to impose new regulatory notification requirements on these commercial drug-device manufacturer relationships. Moreover, irrespective of contractual agreements presented to the Quality and Systems Regulations, device manufacturers already have the obligation to routinely monitor changes, including changes to the drug, biological products or components of or used with their marketed combination products including changes in impacting the device's safety.
As part of their product life-cycle management, device manufacturers could conduct risk analysis and to make appropriate changes meant for any necessary regulatory approvals or notifications. Additionally, to the extent that there are concerns regarding postmarket changes to drugs that might affect the device or combination product regulated by CDRH, FDA has the adequate authority to require a sponsor monitoring and reviewing drug changes through conditions of approval and other postmarket mechanisms.
As such, AdvaMed believes that the agency need not create new regulatory requirements related to notification, postmarket changes to biologics, drugs used with devices or combination products regulated by CDRH or devices with biologics or drugs regulated by CBER or CDER.
For devices intended to be used with generic off-patent drugs, the device sponsor already has an obligation of the quality systems to independently monitor changes associated with the products. In addition, FDA can require the device manufacturer, the B Company in the hypothetical, to monitor and review changes to the drug via other postmarket mechanisms such as conditions of approval or special controls. As such, direct collaboration between the drug and the device manufacturer may not be necessary.
What process should be applied? We believe that a framework for the process has already been outlined in the ICA. To provide a predictable pathway, FDA should make the determination of whether mutually conforming labeling will be required early in the process at the RFD stage. Timing is particularly important for small, resource-limited companies. It is critical that the sponsor understand the regulatory path and the develop required early in the process for effective development of the products.
It is undesirable and potentially financially disastrous for a small company if additional significant data and regulatory requirements are opposed late in the product development after much of the work has been completed.
New combination products may raise new issues. OCP should be ready to address these new issues as they become apparent so the decisions FDA makes should remain consistent across reviewing divisions, encourage innovation and promote the public health.
We believe that OCP is best positioned to facilitate resolution of new controversies. AdvaMed would like to thank you for the opportunity for stating our position. We look forward to the Question and Answer Session.
Thank you.
MR. BARNETT: Thank you, Leighton.
Dr. David Eveleth from Pfizer.
DR. EVELETH: I would like to thank the organizers for putting this together and giving me the opportunity to speak.
Before I get into this, I want to say that--what I am going to say doesn't necessarily represent an official position of Pfizer, Incorporated. It does represent a lot of bias and I want to make sure that we identify the bias that we are bringing to this up front for everyone here because I think it is bit different from some of the other speakers.
The first part of this is that we look at this obviously, as in the hypothetical, we are Company A. We have a drug and somebody has come to us with a device that will enable the use of the drug in some fundamentally novel way, a new indication, a new patient population. We also look at this in the sense of not a minor change; that is, we are not really approaching this from the perspective of, for example, the insulin pump in diabetes but rather somebody has come to us and developed a device that will enable us to use a small-volume parenteral in an aerosol where the small-volume parenteral, for instance, is used in multiple sclerosis and the aerosol, or the nebulizer, is going to be used to cure the common cold.
If anyone doubts that these sorts of things come up, I mean, you are underestimating the creativity of the device companies. We get these all the time.
Another important part of what we bring as a bias is that these are not mature products. These are not generic products. These are products that are early in their life cycle where we look at it from the perspective of a product that we have launched maybe a year or two ago. We are diligently satisfying our postmarketing commitments to the agency. We anticipate changing the label with postmarketing safety surveillance information.
We either have it as an intent or already have programs in place to develop new indications for the product, and we are constantly changing our processes for manufacturers, trying to drive down our cost of goods.
Since it is early in the life cycle, many of the aspects of how the product is made are proprietary. They are not proprietary just from the perspective, necessarily, of it being something that we would rather--that is confidential to the agency, but are still the subject of not-yet-issued patents.
So, we see this as something for a product like that that is very difficult. There are issues that don't lend themselves to a regulatory solution.
I want to jump to the second bullet which is, I think, very important and that is if these companies are not cooperating, there is a reason. If there is an unmet medical need, if there is a public-health reason why this device, the use of this drug and this device, is good, then that is an opportunity for us to serve our stakeholders including our shareholders.
So there may be a fundamental disagreement among the companies about whether there is, in fact, an unmet medical need, but if there is a strong public-health reason for this to come forward, it doesn't make sense why the companies are not cooperating.
Over the long term, the fact that these are going to be evolutionary--Leighton mentioned that, I think, device labels, or device life cycle, is typically short and drug product that is early in its life cycle is typically going to have a lot of labeling changes as they go on.
A lot of this has to do not so much with whether or not you can get a snapshot in time and do this right but whether you can maintain this and develop a process wherein this works overtime for the life of the product.
I do want to stress that we don't see FDA's role as a broker business deal and urge a lot of caution.
That caution has to do with the fact that we see a lot of risk in some of these. The first step really is a risk assessment. It is not so much whether mutually conforming labeling is required or not. That is one solution to some of these problems. But the first thing that you have to look at is what is the risk in allowing this product to go forward.
The first is what is the consequence of a device not working as it should and how does the combination--how much is the combination linked in the patient or the physician line. This gets, I think, partially to what happens when you lose the label kind of thing.
If something goes wrong, is the use immediately going to think about the device or the drug? Or are they going to think that it has to do with the two together? Really, in a combination product, it is the two together.
Then there is a potential for variation within specifications to influence efficacy and safety. We will get into that more later. But the first issue really is what happens if something goes wrong.
If that is not a great big deal, then there are a lot of easier-solution kind of things. But some of these indications, certainly some of the ones that we have been approached with, if the device causes the drug--if the variability in the way the device-drug combination works causes a failure of efficacy, that is a severe problem and certainly, in oncology, that is a severe problem.
So some of the clinical-safety issues that we worry about are how do you manage safety reporting, how do you manage attribution, who is going to attribute an adverse event of the device or the drug, remembering that the assumption here is that the original drug approval is for a different patient population, maybe a different physician population, certainly a different indication.
How are you going to attribute the adverse event to the device or to the drug? Is the agency prepared to attribute? How do you manage a single safety database when you have got different under-reporting bias, different kinds of physicians looking at adverse events and different risk-management plans. Certainly, we have a lot of products for which the risk-management planning include a specific data-collection tool, specific types of postmarketing surveillance which are going to be different in these different indications and different for the device versus the drug.
I am not really sure how you would deal with two different risk-management plans if they were the kind of intensive risk-management plans that some products have.
Safety issues related to the chemistry, manufacturing and controls section are probably one of the biggest worries that we have. Specifications, as was mentioned before, of each component are not transparent to the other manufacturer. We, as Pfizer, typically manufacture products well within the safety specifications that are in file and changes to those specifications by either Company A or Company B are not going to be transparent to the other company.
When that has the potential to impact safety, efficacy and the performance of the combination, especially when failure of efficacy represents a serious safety risk, that is, to us, a big problem. We just don't see a practical way to determine that variance within a specification doesn't pose a safety risk, especially given that Company B is not going to know what the specification is.
So then we get to the issues around the evolution of the label. If we add indications into the label--that is, we, as the sponsor, add indications into the label and there is a potential to use the device for that indication or in a population that crosses into that indication, how do we define if it is necessary to conduct clinical studies.
If, for example, we think combination studies are required--that is, we need to test the device in that new population--whose label is out of compliance? Who is the enforcer here? We think that if you are going to have a mutually conforming labeling, you better make these issues relevant, the sections of the label, relevant to all the indications. That is going to be a big problem, is the labeling.
So I think there are significant safety issues here that arise in the absence of cooperation. Conforming labeling has an impact but I think it has a limited impact. There are issues that don't lend themselves to regulatory solution and, again, if companies are not cooperating, ask why.
It may be that Company A has every intention of developing the drug in Indication B without the device. That is just one possibility. We just don't see this as something--at least, early in a product's life cycle, that can be worked through. Again, the agency's role is not to force cooperation between the companies as in a broker business deal.
Thank you.
MR. BARNETT: Thank you, Dr. Eveleth.
Dr. Paul Goldfarb speaking for the Combination Products Coalition.
DR. GOLDFARB: Good morning. I am a medical consultant for a company called Inovio Now which Genetronics that works with a technology called electroporation. Although I have worked with Brad in developing this with the Combination Products Coalition, I would have to say that my view of collaboration on this is somewhat similar to my son's which is, "After me, you are first." So, basically, this is a presentation of where we have gone.
So the first question I have had, how many of you have heard of electroporation? This is the reality of the technology that the people who know about it are biochemists who use it in labs and regulatory people who have heard me do presentations. The challenge we have is it is still a very novel technology.
It is a technology that uses a reusable box that generates electric energy with a series of disposable hand pieces that is single-use for effecting ablation of solid tumors. The applicators are shaped in different sizes. The therapy, though, is a local therapy directed at tumors and causes a local ablation of the cancer.
The effect of the electroporation is you create an electric field around cells and that creates pores in the cells that facilitates the delivery that facilitates the delivery of drugs. So, in this case, we are using the drug bleomycin. I am banging through this part of it as quick as I can so we can address the regulatory issues.
The way it is used clinically is you would inject the drug directly into the tumor. After you have injected the drug, you then electroporate it with a series of pulses and you allow for the uptake the bleomycin specifically into the malignant tissue. The thing that makes the technology unique is you get ablation of malignant tissue without injury to the surrounding benign tissue even if the drug enters the tissue.
As a technology, we have used it in a whole variety of different histologies. That is significant. So this technology is really not histology-specific so it is not acting as a drug in the sense that this is a drug that is only active in certain tumors. It is really acting much more as an ablation technology that uses a drug.
If you can get the drug and the needles to the tumor, then you can actually necrose the tumor. I apologize for a few clinical pictures, but we will get through it quickly. This is a patient with a head-and-neck cancer. This is the typical cancer that you would approach. Surgically, we would remove half the tongue. What we are looking for is an alternative.
You inject the drug. You put the needles in and within ten minutes you can treat the whole tumor. The patient can go home the same day. Over a period of weeks, you get a necrosis of what is the tumor with no injury to the surrounding benign tissue.
We did a series of studies with the FDA. Initially, the first study we did is, on the yellow, what it shows is that, if you inject bleomycin into the tumor and you don't use electroporation, you have no impact. You don't necrose the tumor. You don't get any local reaction. Nothing happens. When you add the electroporation to injecting the drug locally, you get over a 50 percent objective response rate.
So, at the end of that, when we finished Phase 2, we felt that we had a technology which offered equivalent disease control to surgery. Potentially, it offered better tissue preservation which meant that you would have better function preservation and, theoretically, it should be less expensive than doing major surgical resections.
So the mirror of what was said at the beginning of the meeting, we are truly the square peg that has been trying to fit into the round hole provided by the agency for approval. So where we started was I would say I have been doing this since Mark came into position in the office. My impression of how long I have been here is when we had that first slide that the DIA put up, I thought that was me sitting up there with the brown hair and the clear face thinking that was the first meeting I went to on this topic. I can remember when that happened.
We felt that we had a novel ablation system that uses a well-characterized drug in a previously approved route of administration to ablate malignant tissue and spare non-malignant tissue. But it was used on conjunction with the device that uses brief pulses.
The negotiations with the FDA, we were seen by them as being a combination product with primary review by the drug group with consultative review and a recommendation that we use a 510(k) to get the device approved and do a standard approval which would be a standard survival-based study for people with advanced head and neck cancer which we were looking for an enhances survival because that is basically how you get a new oncology drug approved.
The issues that we had with that approach that made us the square peg was we had a local therapy that has not benefit in total tumor burden and is not addressed by what we do. A study looking at the survival endpoint really doesn't address the clinical benefit of the technology. This is not clinical benefit--i.e., survival--to local therapy when used in people with end-stage disease. The therapy would not be offered to patients in this clinical setting.
So we were being asked to do a study that was basically addressing a group of people for whom we would not be using it routinely and used in a model where you were looking to look for a local therapy to have overall survival advantage which seems inappropriate.
In negotiation with Mark's assistance, we moved forward. As you can see from these wonderful graphics, we are now sort of changing the square peg slightly and changing the round hole slightly. We have a study that is comparing the efficacy of electroporation to surgery. We are doing this on people with localized recurrent disease or second primary disease.
Now we are really asking the appropriate question. Does this local therapy work as well as another local therapy in a group of people for whom a local therapy would routinely be offered? Of course we are doing the study in a model in which a clinical benefit has to be defined. We are doing a study in which we are using functional outcome as the clinical benefit that we expect to demonstrate in the study.
We will also demonstrate that local control is the same and that survival is the same.
The issues that came up in discussing this trial as we have moved forward surround the drug bleomycin. So, specifically, bleomycin is a well-characterized generic drug. It is a Class 1 generic drug for parenteral administration which means that this drug is fixed in time and that anything called bleomycin has to meet USP standards, that the device acts with a class of drugs in the sense that there are several manufacturers of bleomycin and not a single manufacturer, that we are not the M.A. holder for bleomycin and we will not bring the drug into commerce at any time in the future and we have already explored with current drug manufacturers their interest in participating in this project, and there is no interest among the multiple manufacturers for them to participate in going forward with the combination approval.
The resolution to this that usually we have resolved with the FPA which, in a sense, is the real-life answer to the issues that we are dealing with today in a specific set of events, but, at least, I come here to say to you these things can be resolved in human lifetimes.
What we have agreed is that the label that is included with each of the disposable applicators will incorporate all of the relevant information regarding the use of the drug bleomycin when used as part of the procedure. So that means that, for each of the disposable applicators, there will be a set of instructions that reflect the use of bleomycin.
It addresses the issue of what happens when you lose the instruction because every time you open up a new applicator, there will be the instructions. We will continue to monitor the available formulations of bleomycin on a routine basis to make sure of this continued constancy of formulation and that the final approval of this will be through a device approval, a PMA.
It will be granted by CDRH, but there will be a collaborative review with CDER. It will review the clinical trial.
The implication for this, and so this last diagram shows that now we fit. Of course, one interpretation of this is that this is a company that got beat up, ground down and screwed by the agency. But, in fact, we see it as something that we have worked out together and we are comfortable with the result.
We think the implications are that new indications may not require relabeling of the drug and will be reflected in changes in the device label. So, as we look for new indications, and we are using this technology in treating other tumors, we can use this approach to move that forward and get supplements to a PMA to get new approvals for new indications.
Once initial safety issues related to bleomycin have been reviewed with CDER, future efficacy assessments of the ablation technology might be reviewed by CDRH and approved as supplements to a PMA. So we are moving, I guess, what I would say is the regulatory path more to be consistent with other ablation technologies because that is functionally what we do to patients and more away from drug approvals because we are really not using it as--drug.
In summary, I would say that the model provides an innovative, flexible pathway to review and approve and drug-device combination product that use specific generic drugs in a specific way.
Thank you for the time.
MR. BARNETT: That concludes the formal presentation in the first panel.
Open Discussion on Public Health Issues
MR. BARNETT: Before we get to the FDA folks and ask them for questions, we had two people signed up in advance to speak. I am wondering if they are here now. One of them was Mason Diamond. Raise your hand if you are here. Yes. And the other was Lee Ann Chambers. Good. You are both here.
If you don't mind, I will ask you to do your thing now. Let me first call on Dr. Diamond. If you don't mind, come up to microphone. Identify yourself and talk to us.
DR. DIAMOND: Thank you. I am Mason Diamond. I am the Vice President of Clinical and Regulatory Affairs at TyRx Pharma. I would like to thank the agency for allowing me this time to address you. I do not intend to discuss what the FDA can and cannot do. I think that we all understand that.
Similarly, I am reluctant to propose that the agency approach Congress to enact legislation given what is going on up there on Capitol Hill. While there is a spirit of cooperation in Rockville, it would nice if that same spirit extended itself a little further south.
But, in any case, I intend to focus my comments on the practical question, is mutually conforming labeling a need to have or nice to have? I think we all agree that there are many reasons why mutually conforming labeling and cooperation between companies would be of benefit as well as many reasons why they might now.
While it is true that the FDA cannot mandate that companies cooperate, the agency, in an effort to achieve the most ideal outcome, are in a position to ask the hard questions and make very pointed suggestions that we may not be able to because of internal company politics.
For example, in my previous life, I was working for a company that marketed a number of OTC anti-inflammatory drugs. During our pre-IND meeting, the FDA certainly asked, why do you need another OTC NSAID for, which was a very good question. I have always appreciated the agency sharing their insights, but these sorts of statements have never constituted a mandate in any way.
The topic of mutually conforming labeling seems the most significant aspect of 21 CFR 3.2(e)(3) relates to the section that states, labeling of an approved product needs to be change in some way, to reflect a change in intended use and so on. Given the change in how the existing product would be used, and in light of the current regulations, it is my understanding that an NDA or ANDA or similar type of filing would be required.
As a result, new labeling for the existing product would have to be drafted in any case, whether mutually conforming or not. So, if the cooperation between the relevant parties is not possible, that company developing the new use for the product would have to file to cover both the combination product and the new use for the existing product.
As well, they would also be responsible for any related labeling and any related product liability. One possible thing that the agency could do to make going the NDA route attractive to small companies possible would be revising the user-fee schedule similar to something that is done in devices where a small company has a benefit. It is less expensive to file a PMA, 90,000 as opposed to two-hundred grand, assuming the first PMA is free. So you really can't do a deal like that.
So, to get to the point of the question as relates to the public health, mutually conforming labeling would be nice to have but I don't think it is absolutely necessary.
Thank you.
MR. BARNETT: Thank you, Dr. Diamond. Does anyone on the panel, either the FDA folks or others, want to respond in any way or make any further comments on that?
Okay; if not, let me ask Dr. Lee Ann Chambers of Eli Lily to come up.
DR. CHAMBERS: Thank you very much--it has been very helpful. It has been, I think, a very useful and timely thing and we need this.
Just to preface my comments a little bit, I come from the trenches of trying to put some information on a drug-product label so my comments really come out of that experience. Lily is concerned about the current situation with general dose-delivery systems where a drug product is removed from its primary container closure and placed in a device for an extended period of time such as an infusion pump.
It is our understanding that review of the device submission for these products focuses only on the delivery accuracy and biocompatibility of the device components. It is not clear that the biocompatibility testing performed according to the ISO-10993 standard adequately addresses the performances of the device materials when exposed to various drug formulations that may be used in the device.
Could the drug formulation elute different substances from the device materials that are seen during the biocompatibility testing? A drug product with proven efficacy through discrete subcutaneous injections may not have the same efficacy when the drug is administered for continuous infusion.
Finally, there is no consideration of the impact of holding the drug product in the container other than its primary container closure for a time period of more than a few hours and at temperatures that may be higher than its regular storage conditions. While we agree that many devices may be considered general-delivery devices, we recommend that when a device is intended for a general class of drugs that the division at the Center for Drug Evaluation and Research who is responsible for that class be consulted.
They should be asked to review the indication, the mode of delivery and the drug dosage assumptions for concurrence that the device can be cleared for the drug class. If CDER agrees, it seems it should also be possible for the drug manufacturer to indicate the general class of devices that are appropriate for use with the drug product without generating additional data to support this information; that is, the device clearance should be sufficient evidence.
Thank you.
MR. BARNETT: Again, I will ask if anyone here wants to respond in any way or has a question or a comment. If that is the case, thank you very much.
Yes?
DR. WITTEN: I am wondering if the last speaker can give some examples of where these issues have come up and been shown to be problems.
DR. CHAMBERS: Our experience was trying to put infusion pumps on our drug-product label. The studies that we were requested by the Center for Drugs, we had to repeat some information that we found would have been addressed, or possibly should have been addressed, by the CDRH approval process.
MR. BARNETT: Anybody else? Let me ask if anybody in the audience has a question for this speaker. Yes; come on up. Identify yourself first.
AUDIENCE PARTICIPANT: (Inaudible) I have a question. Is it possible to ever submit a 510(k) for a device that will be a component in a combination product?
DR. JENKINS: The short answer to that is yes.
AUDIENCE PARTICIPANT: How would you handle that? Would the 510(k) is submitted to the division (inaudible) and the drug component would be submitted later?
DR. JENKINS: It depends on the determination of who has jurisdiction over the product. So I think that the short answer would be it would depend on the primary mode of action of the combination product.
AUDIENCE PARTICIPANT: Suppose the primary mode of action is the drug, would the device component still be submitted as a 510(k)?
DR. JENKINS: Yes; it really depends on whether or not you are going to have a single application or have several applications. There is a guidance document that is being held to address this. Mark, is there anything you would like to say about that? It just depends. There are too many factors and you would have to give a specific example. But it is certainly possible.
DR. PROVOST: If I could add that--the 510(k) couldn't be cleared if the drug was not approved yet. So if you are in a two-application situation, we wouldn't be able to clear the 510(k) if it is specifically for use for a drug and the drug is not approved.
MR. BARNETT: Let me take one more and then I want to go to the--go ahead.
AUDIENCE PARTICIPANT: To answer her question, there are some companies that have filed NDAs with pull-out sections of the 510(k) that related to it. There is no hard and fast rule, but that seems to have worked.
MR. BARNETT: Let me ask the FDA folks up here now. If they heard anything this morning from any of the other speakers that they would like to question, or to get clarification on. Celia?
DR. WITTEN: I have a question for the gentleman from Pfizer and that is that most of your talk was aimed at talking about novel drug-delivery products, devices. But many of what we see or have seen when I was at CDRH, anyway, or drug-delivery devices, actually what manufacturers came forward with were devices aimed at specifically doing what physicians had already been creatively using off-label, jerry-rigged, other kinds of devices, they used drugs off-label.
So, in other words, there might be a family of drugs that are used off-label for a long period of time by a new route and a sponsor wants to manufacture a device specifically aimed at accomplishing that which certainly is an advantage, I think, to have something that is designed to do what you want it to do.
How would you address that in the case where there were no drugs labeled for that use? It is a common route of administration, nonetheless, and the manufacturer wants to make a device specifically for that already commonly used purpose.
DR. EVELETH: We have had those kinds of experiences. The fact that the drug is commonly used off-label certainly indicates that there are a group of physicians that believe that there is an unmet medical need to be satisfied. It doesn't always mean that we and, in fact, in some cases, the agency would agree that that is a safe and effective use of the drug in question.
So I think that needs to be dealt with on a case-by-case basis. Again, if the company is manufacturing the device for the specific use with that drug and that drug only, they are facilitating a use that would sometimes would like to see and sometimes we are not necessarily supportive of that use because there are safety concerns.
There are examples today, in fact, of that. I can think of a specific example where there is a device that I know some people are working on to deliver a drug that, in fact, has the black-box warning, thou shalt not do this. So we, obviously, are not supportive of that kind of an effort.
I'm sorry; am I answering your question?
DR. WITTEN: Yes. So now I have a follow-on question. Now suppose--it is similar, just a different wrinkle on the same question. Device Manufacturer B, to use the terminology in the session, makes a device to deliver Drug A and does a study to show that you can do that. You have already expressed your position on that.
But now supposed Device Manufacturer B also does a study that it can work with Drugs Q, R, S, T, U, V, W, X, Y, Z. But none of the drug manufacturers want to participate in this labeling. Are we still in the same position that we were in with Drug A?
DR. EVELETH: I can think of cases where we probably are not. If there are that many other drugs, and one can think of a situation where there are many drugs in the class, and the drugs are well understood--that is, the EMC characteristics of the drugs--then, in some cases, we would--there are degrees of cooperation. There is a degree of cooperation where we say, that is okay, and we will provide you with access to information.
I think one of the problems with some of these generic drugs is that, even that involves an investment on the part of the generics company--I don't want to speak for my generics company colleagues, that it is a resource that they don't have and they don't seem to benefit in.
So if we see no safety issues ourselves, there are situations where we would not not cooperate, but we wouldn't invest a lot of money in it.
MR. BARNETT: Anyone else from the FDA want to question the panel?
DR. BEA-TILLMAN: I guess I have a question that I would like to direct toward the speaker from AdvaMed. One of the issues that, I think, concerns many of us is the ability of the Company B and the scenario we are talking about to adequately be able to monitor in the postmarket setting for changes that Company A makes in their product.
I know there was sort of a parallel issue that some of you who are familiar with the device world may remember when we dealt with re-use of single-use medical devices and the question of to what extent the third party reprocessors could adequately determine when the original equipment manufacturer had made changes to their product and redo their validation.
So I guess one of the questions I had for the speaker from AdvaMed, because he addressed this, is, realistically, is there enough information in the public domain about changes that the drug company might be making to their product that it is reasonable to expect that the device company would be able to determine when important changes were made.
MR. HANSEL: There are so many variations in the systems and it is hard to give a "one answer fits all." Certainly, in our internal discussions, we--my experience was, at Food and Drug and, as I think we are pointing out in our presentation, that a lot of this has to be on a case-by-case basis. When we were talking internally, we believe there are certain drugs that the very nature of how they are on the market as drugs and the controls they are under to be in a certain category would not likely make a change in the drug that would say, for instance, affect some of the more generic-type drug-delivery systems.
You could be using it in the context of activation of treating a disease condition where that might not be adequate. So I think, here, again, it is up to the device company to look at the intended use of the drugs that are out there and, as we acknowledged on a proprietary or traded drug, we don't believe it is likely that the device company could, in fact, have access to enough data to really make an adequate risk assessment.
MR. BARNETT: I thought that, in Suzanne's opening comment, she posed a very important, very simple but seminal question. I jotted it down here. She was saying, from a public-health perspective, what should FDA's default position be--that is, a mutually conforming label is required unless FDA says that it isn't or that mutually conforming labeling is not required unless FDA says that it is.
I think that is really an important issue. Anybody up here want to talk about that, any of our panelists?
MR. HANSEL: I think we were saying that, let's face it. FDA has access to information that no one company or group of companies would have access to based on analyzing that, they may determine that there is a need for mutually conforming labeling. What we are, I think, saying is that that should be the default that FDA concludes there is a need, not to say that the default is, you know--that, automatically, you need it, that it should be on a basis where FDA has concerns enough that they feel it is absolutely necessary.
Here, again, I think it depends on the product. I think this is something Food and Drug is going to have to address. The drug labeling, even in a generic drug, may be based on a traditional mode of delivery with the products that are in the marketplace.
I am a device company. I come in with a way to do it more safely or under more control. Then the public-health issues may be less even though the drug remains the same because there is new technology available to address the labeling limitations or precautions that were on the drug when it was introduced to the marketplace.
MR. BARNETT: Anybody else want to comment on that one? Anybody in the audience want to comment on that?
AUDIENCE PARTICIPANT: I am Ray Tessy from Celeron Therapeutics which is a microscopic biotech company. I think the issue of conforming labels, I think, is, quite frankly, a dream. I come from the side of not being a device company. The previous company, public company, I was with was huge. It was 300 people. My current company just hired its 21st on Monday.
So, compared to many in the room, it is a very different scale but I have dealt with the issue where we have drugs or biologics that are trying to be developed in combination with other drugs or biologics. It has been a bit of a sticky wicket.
In fact, asking another company to make changes in their labeling is universally impossible for whatever reasons that are out there. Quite frankly, it is usually about, I will say, risk management but I really mean money because if, in fact, it is financially attractive for the company to make a change, they will. Otherwise, they don't want the headache or the risk.
So I think having conforming labeling is going to be very difficult in general, certainly in the drug-biologic combination, or drug-drug or biologic-biologic. Maybe in the device world, it is different because of the nature of the beast.
But, if the FDA were to take the position that that is needed, I think they will stifle innovation. I think that, although it is not part of the FDA's mission statement to promote innovation, I think that the fact that they are having a meeting like this implies that their goal is to encourage innovation within the industry while supporting the other aspects of their mission which is safety and scientific merit.
So I would argue that conforming labels is a dream, particularly when you have the usual (inaudible) relationship equivalent to the Great Dane dating a chiuaua.
MR. BARNETT: Anyone want to respond to that? Yes?
DR. DAGHER: Not respond but just make a comment that we are talking about--just a comment that if we are talking about generic drugs, if there is consideration of having that default of that mutually conforming labeling will be required every time, there are disease settings where (inaudible) "off-label" use. It become a resource question also about whether there are resources there or if the effort, again, you have to balance safety--I am reserving that for generic drugs because, as Dr. Lumpkin said earlier, there are issues regarding the law that (inaudible).
MR. BARNETT: Any other responses from the FDA folks or anyone here to what this gentleman just talked about? Let me ask if anybody else in the FDA wants to respond to what they heard on the panel? John?
DR. JENKINS: I can see now why Susan has been working on this for 13 years. I think the guy who spoke earlier from the audience is correct. It is a dream but, in some ways, it is a dream would probably like to achieve because, if you can think of public-health goals, you would try to inform people about how to properly use the product. It would only lead to confusion if you have got disparate labeling.
On the other hand, the ability of FDA to force people to change their labeling if they choose not to, the ability to keep up with all of the changes that occur in the innovator product versus the device, is mind-boggling. So it is really hard to figure out how to get your arms around this.
I was thinking about the scenario that Ramzi described earlier in oncology where it is very frequent that there is not conforming labeling for the various regimens that are used in oncology and things seem to go okay. But then you also have to realize, and no offense to Ramzi, but the practice of oncology is really not always rational.
So people are often doing things in oncology that are not particularly rational, that are driven towards trying to find something that works. That is not the way we practice medicine in all the other areas and probably wouldn't be acceptable in a lot of other areas.
The example he gave in oncology for cisplatinum and there being other drugs that had mention of cisplatinum in their labeling, all that has been studied in clinical trials and you are at least aware of whether there is a drug-drug interaction. You are not always going to be aware of whether there is a drug-device or a drug-biologic or a device-biologic interaction. Even if you had studied it initially, later on, at the formulation changes or as the device changes, it is hard to keep track of all that.
So it is a huge problem to try to get your arms around the--I do think it is important to correct the speaker from the audience a moment ago. It is part of the FDA's m