> U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
>
> FOOD AND DRUG ADMINISTRATION
>
> CLONIDINE TRANSDERMAL SYSTEM MEETING
>
> Wednesday, April 29, 2003
>
> 12:30 p.m.
>
> Advisory Committee Conference Room 1066
>
> 5630 Fishers Lane
>
> Rockville, Maryland
>
> [C]{.underline} [O]{.underline} [N]{.underline} [T]{.underline}
> [E]{.underline} [N]{.underline} [T]{.underline} [S]{.underline}
>
> [AGENDA]{.underline} [PAGE]{.underline}
>
> Welcome and Introduction:
>
> Gary Buehler, Meeting Chair (FDA) 3
>
> Boehringer Ingelheim
>
> Steve Marlin 5
>
> Mylan Pharmaceuticals
>
> Tom Spencer 46
>
> Elan Pharmaceuticals
>
> David Rosen 83
>
> Discussion 84
>
> [P R O C E E D I N G S]{.underline}
>
> MR. BUEHLER: Welcome to our meeting. We\'re going to meet today at the
> request of Boehringer Ingelheim in conjunction with their citizen
> petition No. 01P-0470. And Boehringer\'s purpose in requesting this
> meeting is to seek to resolve on a scientific basis their concern
> about potential generic versions of the Catapres or Clonidine TTS that
> lack internal rate-limiting barriers.
>
> I\'d like to welcome everyone on behalf of myself. I\'m Gary Buehler.
> I\'m Director of the Office of Generic Drugs. Dave Read and Jane
> Axelrad are here. Jane is the Director for Policy. Dave is with the
> Office of Regulatory Policy.
>
> Well, today I was going to tell everyone to make sure to \[audio
> break\] microphone whenever \[audio break\] comments. That may not be
> necessary. But if we do get everything resolved with our electronic,
> it will be important for you to speak into the microphone, because we
> do want to make a transcription in this meeting.
>
> Again, this is a tentative comment, but transcripts would be available
> of this meeting seven to ten days after the meeting was over. If you
> wanted an expedited copy of the transcript, you could directly deal
> with the Miller Transcribing. And I understand they can provide a copy
> in 24 to 48 hours for an additional fee.
>
> As requested, Dr. Throckmorton from the Cardio-Renal Division and Dr.
> Wilkin from the Derm and Dental Division are with us today. I\'d like
> to thank them for their attendance in helping us with his very
> difficult issue.
>
> I\'d like that the presentations be made in their entirety without
> interrupting them. At the end of the presentations, we may have a
> brief five-minute period where we can ask specific questions to that
> particular presentation. I\'d like the presenters to please stay
> within their time frames. And I\'d also like to say that Elan has
> yielded five to ten minutes of the their time to the Mylan Company,
> because Mylan\'s presentation is a little bit longer and theirs is a
> little bit shorter. And we thank you for your cooperation.
>
> The first presentation will be by Boehringer Ingelheim. Don Beers.
>
> MR. MARLIN: Actually it will be me, Steve Marlin.
>
> MR. BUEHLER: Okay.
>
> MR. MARLIN: Good afternoon. I have to say first of all, my name is
> Steve Marlin and I\'m the Vice President of Business Development
> Alliances in Government Affairs for Boehringer Ingelheim. And I have
> to say true to my scientific upbringing, I was in the audiovisual club
> in high school, so I know the FDA staff pain when there\'s an
> equipment failure.
>
> The presentation today will be led by two scientists who have assisted
> Boehringer on the important issues related to potential generic
> versions of Catapres-TTS. Dr. Harold Hopfenberg, who is Professor of
> Chemical Engineering at North Carolina State University, and Dr.
> Maibach, who is Professor of Dermatology at the School of Medicine at
> the University of California in San Francisco. Also, accompanying me
> today is Tom MacGregor, who has a long history in our R&D unit of
> working on the development of Catapres-TTS; David Brill, from our
> Regulatory Affairs Department; Randy Zakreski from our Legal
> Department; and Don Beers from the consulting law firm that has helped
> us on this project.
>
> Our lawyers have promised to try to keep quiet. It\'s partially my job
> to keep them to their word. And I think my other role is probably to
> drive the presentation, as a consequence of my audiovisual training.
>
> One point that I\'d like to note before we start. We only recently
> received Mylan\'s submission to our citizens\' petition, and we assume
> and hope that we will have an opportunity to comment on that point by
> pointing to some time in the near future.
>
> Also before I turn this over to our experts, I do want to make one
> point that\'s probably obvious, but I think needs to be stated.
> Boehringer Ingelheim, like Mylan and Elan, does have an economic stake
> in FDA\'s decision with respect to generic versions of Catapres-TTS.
>
> I want to note, however, that Boehringer has not only an innovator
> drug division, but also a generic drug division. And from both
> perspectives we strongly believe in the integrity of the generic drug
> approval process, and the need for FDA to be able to say to the public
> that when a generic product is approved that it\'s the same and will
> be equally safe and effective as the innovator product it copies.
>
> Second, I\'d also like to note that the patent on Catapres-TTS expires
> this coming Sunday, next Sunday. We have not sought to extend our
> patent or our exclusivity on that product, either by additional
> patents or by mechanisms such as perienteric exclusivity. Thus for all
> we know, come next Monday there could be products approved that are
> generic and do, in fact, incorporate what we think is the key safety
> feature of the Catapres-TTS system, it\'s rate-limiting membrane. And
> any such approvals are independent of the discussions that go on here
> today.
>
> Today we\'ll be talking about what we believe is a potential safety
> risk associated with generic versions of our patch that do not share a
> key component of its design. As you\'re probably aware, there has been
> an ongoing debate for a number of years about the need for and the
> efficacy of the rate-limiting membrane barrier in the TTS system. And
> I know some of the individuals in this audience have been part of that
> ongoing debate.
>
> It\'s been my experience as a scientist that those kinds of debates
> are seldom settled by debates and by meetings, although they\'re
> certainly important. But by experiments and data. And that\'s
> basically what Boehringer Ingelheim is proposing today.
>
> We\'re asking that the FDA hear both sides of the argument and to
> determine whether, as we believe, that in vivo testing on patients
> with high-skin permeability should be performed. That would resolve
> this in a data-drive way one way or the other. The issue is one of
> patient and Boehringer feels an obligation to the patients who use its
> product to assure that FDA\'s decision is made on the basis of the
> best scientific data available.
>
> There\'s really two points for discussion today. The first is that we
> would like to maintain that for a generic transdermal Clonidine patch
> that lacks a rate-limiting membrane, there is a need for this in vivo
> study to determine equivalent absorption in subjects with high-skin
> permeability. And high-skin permeability there is the crux of the
> discussion because we think that is the major point in safety
> concerns.
>
> And then a secondary point in our discussion, assuming we get to that
> point is if there is agreement that this in vivo study in patients
> with high-skin permeability is needed, how should such a study be
> conducted? With that, I\'ll turn the discussion over to Dr.
> Hopfenberg.
>
> DR. HOPFENBERG: Thank you, Dr. Marlin and for the shakedown cruise and
> power point presentations. I\'m a little bit older, and I\'m
> accustomed to 35-mm slides. So this is an innovation for me. I\'m an
> innovator.
>
> It is a pleasure to share with you my perspectives today on the design
> and function of the Catapres system. And I\'m going to break down my
> presentation into three topics. I\'m going to discuss the structure of
> the Catapres-TTS system, its mechanism of action, and most importantly
> the significance of the rate-control membrane, which is an integral
> and important design feature in that device.
>
> So, here\'s a schematic of the Catapres system, and Catapres system.
> And I\'ll start at the very bottom with a removable slit release
> liner. The device that\'s packaged, of course, has that liner. It\'s
> removed and then the device is placed upon the stratum corneum of the
> skin. We\'ll move to the other end of the device, at the upmost
> element. It is simply an impermeable backing layer, and that is placed
> upon a drug reservoir, which contains drug that is both dissolved and
> dispersed. And that\'s also important to the device functionality.
>
> So there is drug that\'s dissolved at its characteristic saturation
> level, and then over and above that, there\'s excess drug markedly in
> excess of what is needed for the one-week therapy.
>
> Now, that reservoir overlays a porous polypropylene rate-control
> membrane. And the function of that membrane is to meter the flow of
> drug from the reservoir through the membrane, openly through the
> adhesive, and of course this is missing upon application into the
> stratum corneum and into the interior layers of the skin where is the
> capillary vein.
>
> Now, the adhesive layer itself is drug-containing, and that\'s to
> actually transmit, early on, drug from the adhesive layer into the
> stratum corneum, saturating sites that are in the stratum corneum that
> would otherwise prevent the continued flow into the capillary bed. So
> that this is a design system where the drug that\'s actually placed
> into the adhesive layer is adequate to saturate those sites. And then
> when the drug, which was initially formulated in excess of saturation,
> is now transferred into the stratum corneum, you enter into what\'s
> called a steady-state region, where there\'s a constant-rate delivery
> of drug from the reservoir, controlled by the membrane, it through the
> stratum corneum into the interior layers.
>
> The stratum corneum is itself a barrier. It also provides the
> resistance to transport other drug from the reservoir into the
> capillaries.
>
> So we have two parts of the device that confer a resistance. The
> membrane and the stratum corneum. And both are part of the design.
>
> The mechanism of action. As I discussed, there is an initial loading
> dose of drug that\'s in the adhesive layer. And when that transfer is
> completed, the Clonidine flows from the reservoir to the adhesive
> layer at the constant rate controlled by the polypropylene membrane.
>
> I think in fairness, I\'ll turn my attention over here a while. The
> result of all this is that the drug is released at a constant rate
> from the patch as long as saturation is maintained in the reservoir,
> due to the persistence of undissolved drug. So as long as I keep the
> concentration in that reservoir layer constant by having excess drug
> there to feed the saturation concentration, and I have a rate-control
> membrane, the release rate from the device will be controlled and be
> constant throughout the period of administration, after that initial
> phase when there was transfer from the adhesive layer.
>
> I think the best way to explain this is what has been accepted in the
> art, as we really have three separate variables. J is typically used
> in this art to describe the flux. And this could be the flux of the
> device, per se. This is a simple in vitro experiment, where you take
> the device and put it in the large excess of typically an aqueous
> system. It could be buffered, could have a specific pH. But what
> you\'re really doing is you\'re measuring the amount of drug per unit
> area per unit time that\'s leaving the device, controlled only by the
> device. And that\'s a in vitro experiment.
>
> You could take the reciprocal of that function\--I\'ll call it a
> function, the J\--and that will be the so-called resistance. So the
> higher the rate, the smaller the resistance. The smaller the rate, the
> larger the resistance. Most importantly the skin and the device
> contribute to control of transdermal devices. The skin does not
> completely control; the device does not completely control. They both
> contribute.
>
> So we have a skin resistance. What\'s actually measured typically is
> what I\'ll call the total resistance. And that\'s an in vivo
> experiment. That\'s what happens when I actually take this device, put
> it on the skin, administer drug through the skin. Part of the
> resistance comes from the device per se, and part comes from the skin.
>
> Maybe it\'s best exemplified by the actual data. Here are data that
> were published, showing functionality of the Catapres system. The
> upmost curve is a direct measure of what you\'ll call J device, or the
> flux that\'s characteristic of the device per se in an in vitro
> experiment.
>
> You\'ll notice that the uppermost data point corresponds to the
> short-term release for drug being released from the adhesive layer.
> That\'s followed by release that is pretty much constant over the
> course of the seven days of administration. And that\'s an in vitro
> experiment.
>
> Let\'s compare that with the in vivo experiment, looking at the total
> flux that actually is transported across the skin into the capillary
> vein. It\'s lower. Why is it lower? Why is this line, although a
> straight line, although a horizontal line, although showing constant
> rate, why is it constant first? It\'s constant because of the
> rate-control membrane. It\'s constant because of the rate-control
> membrane on top of skin. Why is it different than this number? Because
> the skin is contributing to the resistance.
>
> What would happen if the skin offered no resistance, if the skin was
> very high permeability? In this device, the flux you see observed
> would be J device. It couldn\'t be any higher, no matter how high the
> skin was. So that\'s the safety valve that\'s put into the system by
> the presence of that.
>
> If you had a monolithic device where the rate was ever-changing, where
> the initial rate was extremely high, where the intermediate rate was
> higher than the terminal rate, if that were the case, you could have
> rates that were markedly higher than this controlled excess. This
> actually controls any excess from permeating in. That\'s the highest
> you can get if the skin resistance were zero.
>
> This talk is not talking about monoliths versus rate-control membrane.
> It\'s talking about the need for a rate-control membrane for this drug
> when the drug is Clonidine. Why Clonidine? It\'s a potent drug. It\'s
> administered in very, very low concentrations. And it\'s recognized by
> the FDA as having a very narrow therapeutic index. So this is a
> conversation about why this is an issue for Clonidine and its
> transdermal delivery, not a conversation about generics per se.
>
> Here\'s the result. This is plasma concentration versus time. And this
> is for the Catapres-TSS system. And you do get this characteristic
> rate, which plateaus. You build up to that rate. You reach that rate.
> And then when you actually remove the device, quite predictably, you
> get a decrease in the plasma concentration, going back to the base
> case.
>
> The whole point of this is that this is a talk about Clonidine. It is
> not a talk about generics, of monoliths versus rate-control in the
> most generic sense of the word. It\'s talking about Catapres-TTS
> because of the high potency and the narrow therapeutic index.
>
> So what is the difference between Catapres-TTS and an historic system
> using nitroglycerin? Well I can talk about two systems that both use
> rate control with a membrane. But Catapres is potent; nitroglycerin
> less so. Catapres has a narrow therapeutic index; nitroglycerin a
> water index. This is a seven-day product. This is a one-day product.
> The drug is much less permeable through skin than is nitroglycerin.
>
> And in this case, although there\'s a membrane in both cases, his
> membrane is a porous membrane that has a polymeric membrane with pores
> in it, into which there is actually mineral oil, and this transdermal
> system, the transderm nitro, which is one of the embodiments of a
> controlled-release transderm nitro system, uses an actually intact
> polymeric membrane. So there are differences.
>
> And let\'s explore those differences and let\'s explore those places
> where there might be similarities.
>
> So here are data from the literature. Hadgraft and Wolff presented
> these data for four nitroglycerin systems, and we see there are the
> characteristic responses you expect from a monolith. It\'s well
> understood that Minitran and Nitro-Dur are both monoliths.
>
> On the other hand, this is the response from the transderm nitro
> system, which is a perfect straight line going through the origin.
> Now, let\'s take a look here. The early stages of release, which would
> be the slope of this curve, is extraordinarily high. There\'s no place
> on that curve where there are two rates that are identical. The rate
> starts out high and gets lower, gets lower, and lower. And for most of
> the release, there is a very, very limited, a very, very small rate.
>
> Remember, these are in vitro studies, without any resistance conferred
> by the skin. This is what the device does by itself. What do you do
> about controlling the initial rates that are so high?
>
> So we have these two monoliths, showing monolith behavior, and we have
> the transderm nitro system, which shows the perfect straight-line
> behavior, where the slope at every point is identical, the rate at
> every point is identical, controlled by the membrane. And then we have
> the hybrid system. Deponit is a hybrid system. It\'s not a monolith;
> it\'s a multi-layer system where each of the layers has a component of
> rate control and each of the layers has a component of being a
> reservoir. So it\'s a bit of hybrid, and it\'s showing results that
> are bit of a hybrid.
>
> You see the characteristic curvature? That comes to the monolith
> component and the fact that it has this sort of a rate is consistent
> with being a rate-control membrane system.
>
> But this key point is what you see when you have a monolithic system.
>
> I don\'t expect you to absorb these numbers. It comes from the same
> paper. To me, it tells a very important story that related to my
> little algebra lesson before.
>
> And this is the four nitroglycerin systems: Nitro-Dur, Minitran,
> Transderm Nitro, and Deponit. The important thing, there is no system
> here that doesn\'t in some measure depend upon the skin. In every
> case, the device has a control and the skin has a control. And
> they\'re all of the same order of magnitude. It\'s not that one is a
> half of one percent and one\'s 99.5 percent. There\'s no complete
> device control here. There\'s no complete skin control here. The
> nature of the skin contributes to the efficacy of the device. Whether
> it\'s a membrane device or whether it\'s a monolith device.
>
> In the case of a membrane device, I can tell you what the maximum rate
> of transport\'s going to be. In the case of a monolith device, I\'m
> not so sure. We have initial rates that can be very high. So the
> membrane does provide that maximum level of transmission. Even if the
> skin resistance were to go to zero.
>
> So, here is the understanding of how monoliths work. This is old work.
> This is work initially published by Takaguchi some 40 years ago. And
> this give you a sense of the concentration profiles that would take
> place in monolithic film containing both dissolved and dispersed drug.
> This Cs value is the characteristic saturation level that we\'ve
> talked about before, which certainly takes place in the Boehringer
> Ingelheim system, the Catapres system, because both the adhesive layer
> initially as well as the reservoir system have drug that is saturated.
>
> There\'s a market excess in the reservoir, though, of drug, just as
> this diagram shows, where I as a formulator decide upon this value Co.
> Nature tells me what Cs is. Once I pick the matrix and I pick the drug
> and I pick the temperature, I\'ll only get one Cs value. That will be
> the characteristic solubility of the drug in the matrix. Just like if
> I put sugar into iced tea, I can put in a cup of sugar into a glass of
> iced tea; not all of it\'s going to dissolve. A lot of it will sink to
> the bottom as undissolved crystals, but I will reach the saturation
> value, and that saturation value is Cs.
>
> Now, it\'s probably useful to take a look at this and say: The
> monolithic devices we\'re talking about here are only half of this
> diagram. That\'s why I put that red line down the middle. Let\'s just
> take a look at my side of it. I guess his would be stay left. And you
> see what happens is you denude the shell of undissolved drug, so you
> don\'t get a concentration anyplace that\'s higher than the saturation
> value.
>
> But in the core you still have excess drug. And what happens\--and
> I\'m going to just walk away for a second\--is when this front is over
> here, you have a very steep gradient, and that gradient never
> decreases, never decreases, never decreases. And it\'s this gradient
> that drives the outward flux.
>
> So the initial flux is predictably very high monolith, and gets
> smaller and smaller and smaller as you go in.
>
> So, that leads to some algebra. And I don\'t mean for you to follow
> the algebra except to understand the variables that are actually in
> the equations. Here is an equation that comes from the solution of the
> monolithic release. That\'s the amount of drug you lose at any time,
> or to be delivered at any time.
>
> It depends upon that value, Cs, the saturation concentration. It
> depends upon Co how much I\'ll load into the device. It depends upon
> the diffusion coefficient, which is the characteristic mobility of
> that drug in the matrix. But most importantly it depends upon time to
> the 1/2 power. That is not constant-rate delivery. That\'s delivery
> that is ever changing with time.
>
> I can take the derivative of that function and get the rate, which is
> down here. This is the rate, the MDT. Lo and behold, of course I have
> the same parameters. The diffusion coefficient, the loading, the
> saturation concentration, the area. But what do I have? T to the -1/2.
> That\'s T in the denominator raised to the 1/2 power. Once again, it
> will not be constant-rate delivery.
>
> And this shows you a graphical representation of what that would be
> for some selected values where you have a high loading compared to the
> saturation. It turns out as loading gets smaller, the curves even
> become more pronounced.
>
> And this shows that the initial rate would be extremely high and the
> rate will drop and drop, and continuously drop as long as there\'s
> unresolved drug time.
>
> So what you have in a monolithic device, predictably, is something
> which starts with an extremely high rate, and drops. That\'s what we
> see in the monolith.
>
> And this is recognized to be monolithic behavior, that the upper two
> curves are Nitro-Dur and Minitran, respectively, and they\'re behaving
> perfectly as monoliths. The two curves on here that are not monoliths,
> most importantly, the membrane-moderated system, gives you the kind of
> behavior that we\'re talking about today. Behavior that\'s understood,
> that\'s controlled, that\'s constant, that gives you an upper limit.
> And if that upper limit\'s a safe limit, you have a safe device.
>
> Which leads to my last slide, which is the actual meat of what
> Catapres does. This is the Catapres flux versus time behavior. It
> starts out with a slightly slow absorption because most of the initial
> drug is going into the stratum corneum. And then you end up with
> behavior which is essentially constant in time. And of course that
> number is a number which is lower than, LOWER THAN the in vivo data,
> because the skin is also contributing to the delivery for all these
> devices.
>
> But I can\'t get higher than that level I showed earlier. And that
> would not be the case if that membrane was missing.
>
> So, I appreciate your attention. And I want to just close by saying
> that these comments are all about Clonidine. It\'s all about the
> potential problems that come with a very, very potent drug with a very
> narrow therapeutic index.
>
> Thank you.
>
> DR. MARLIN: Thank you, doctor. Are there hard copies of the slides
> that the transcriptionist can follow from?
>
> \[Technical interruption.\]
>
> DR. MAIBACH: May I stray from the podium, or would you prefer that I
> not?
>
> DR. MARLIN: It would be helpful to the transcriptionist. Thank you.
>
> DR. MAIBACH: My responsibility here is far less complex than what
> you\'ve heard. It really relates to one question, and one observation.
> The one observation is I think that all of you in this room know that
> you\'re far more handsome than I am. You don\'t look like me. We\'re
> all individuals. You\'re smarter than I am. And the same holds true
> for all of the data that we have on permeability through human skin in
> vivo and in vitro.
>
> Secondly, if you accept that as true, and I\'ll try to give you just a
> token example or two, then you have the issue: Do we have the ability
> today\--I\'m talking of five years from now, I\'m talking about the
> spring of 2003 in the Bush Administration\--do we have the ability to
> look at an individual, to choose them to answer the question that our
> professorial colleague has raised in terms of in vivo data.
>
> I\'m going to try to convince you that although the data base isn\'t
> enormous, it is compelling. That unlike gastrointestinal absorption,
> we do have the way of looking at every one of you\--and I\'m using the
> word \'look\' in a very loose sense\--to tell what your permeability
> is. And if that\'s true, then we can answer the question that has been
> raised in the citizens\' petition; namely, is there a difference
> between the two different systems in high permeability citizens
> walking around the planet Earth?
>
> The method that I\'ll talk about is a surrogate method. It\'s not
> looking with my eyes; it\'s looking with two little sensors that
> measure the water coming out of your skin at rest. Simply
> transepidermal water loss.
>
> Are there differences in your skin and my skin? Well, of course there
> are. This is the earliest experiment that I was able to come up. The
> furthest removed from Clonidine, this has got to do with the
> absorption of hydrocortisone, a very useful representative of the
> therapeutic class of topical anti-inflammatory agents.
>
> So simplify the chemistry, this is not a blood level. This is simply
> giving this group of people\--and I\'m one of them, I will not
> identify myself, it\'s too embarrassing\--we applied four micrograms
> per centimeter squared of hydrocortisone on the forearm, and we
> collected the urine for five consecutive days. This is the largest
> experiment that I know of, and in this experiment you can see the
> median is about 9/10 of a percent.
>
> You will see on the lower left hand 9 of that applied. Hydrocortisone
> is not a well-absorbed compound. You\'ll see that there were four
> little guys on the left here, who absorbed about a third of the mean.
> And you\'ll see one person on the far right in a group of 25 people
> who is three times not the mean but the median.
>
> So, there seemed, using this reasonably good data, clear, compelling
> data way back in 1975 that our skins are not the same.
>
> Now, is it true in vitro as well as in vivo? The answer is yes it\'s
> true in vivo. This is a reference given to you from our laboratory in
> which it\'s just an example. We looked at a low dose of a compound.
> It\'s not relevant what compound it is. You put it on the skin in
> vitro and you\'ll see that in three subjects\--and we can do this day
> in and day out for you\--here\'s somebody the receptor fluid
> represents what would get into the blood if this were a human being
> and not a test tube. And you can see 3/10 of a percent to 4.4 percent.
>
> Well, what is the relevance of that to us? Well, the first question
> is: Is it all a mistake? Well, it\'s probably not a mistake. It\'s
> probably not analytic mistake, because today we do mass balance. We
> try to account for the whole dose. And you can see we accounted for
> about the same amount of dose in the three specimens.
>
> How do we use this in the laboratory? Well, the way we use it when we
> do an experiment to look for the difference between one treatment and
> another, we always compare it to the same piece of skin, because of
> these differences.
>
> Now, here is the last example, and it\'s one that many of the people
> in this room know about. This is transdermal nitroglycerin. Here, and
> the reference on the bottom, you see four doses of mass of
> nitroglycerin put on the skin, and you can see all of the mathematics.
> But to simplify it, in the next slide, all I would like you to see
> that the proportionality in four doses, again, you see the same large
> differences between permeability of one person and another. Next.
>
> Now, how do we go from that variation to trying to see if for once
> dermatology can get ahead of other parts of medicine, to actually do
> an experiment to see if the rate-control membrane is controlling in
> vivo in high-permeability subjects the way it is in vivo. And where
> does this crazy idea come from?
>
> Well, the crazy idea comes from the ability to measure water loss with
> a simple little inexpensive instrument called an evaporimeter.
>
> And the next slide simply shows, for those of you who have instant
> visual memory, I\'m going to show you some data, a small group of
> volunteers, in which we looked at permeability in different parts of
> those individuals. The joy of this is you get around some of the
> variation that you get from different individuals. And all I\'d like
> you to see is that there are ten anatomic spots marked. Next slide,
> now.
>
> What you see here is a plot of the relationship of these individuals\'
> water loss and their permeability. The permeability for benzoic acid
> is on the vertical axis. As you go up, there\'s more and more
> permeability. You can see the numbers. It goes for about 2 to 32 in
> terms of permeability. And on the horizontal axis, you simply see
> presumably, putatively normal individuals. I wasn\'t one of these
> people in this experiment. So you can say they were normal. And as you
> go from around 3 in terms of water loss\--I can give you the units
> later\--to about 12, you can see this linear relationship with an R of
> in excess of 0.9 and a P of less than 1/1,000.
>
> And this wasn\'t a study of hundreds of people; this was done in a
> handful of people. Because the power for measuring the penetration was
> accurate, the power for measuring water permeability is accurate. And
> when you combine the two together\--and I don\'t think this is a
> coincidence\--we don\'t understand why that that is a relationship.
> Next.
>
> Now, you should be saying, \"Well, Howard, that\'s true for benzoic
> acid. Do you know this for anything else?
>
> Well, we\'ve done the same experiment, this was when Andre Rougier was
> a guest scientist in our lab, with four chemicals of entirely
> different physical chemical properties, from benzoic acid, benzoic
> acid sodium salt, to aspirin, or acetylsalicylic acid, to caffeine.
> And in every case, here, the groups were smaller, you get a reasonable
> correlation. Next.
>
> Now, can you do this in vivo, for those of you who do in vivo
> experiments? The answer is: Yes. The standard method, when you send
> the specimen to the FDA in vivo labs run by Bob Bronaugh to determine
> who are the permeable people in test tubes and who are the less
> permeable people in test tubes, if you want to know, is to simply use
> tritiated water and relate that water to a population.
>
> Well, here is the same data from our lab. Avi Nangia simply took the
> tritiated water measurement on the horizontal axis, and on the
> vertical axis used the simple evaporimeter for looking at water
> permeability. And you can see with the interventions, here is normal
> skin, stripped skin. No matter what we did, if the tritiated waters
> goes through with the FDA in vivo method, the water loss comes through
> on a little evaporimeter just the way you\'d expect. Next.
>
> Now, how would we propose that if we are going to resolve the issue on
> in vivo data, would you do it? Well, very simply, we would segment a
> given population into those that allowed a lot of water to go through
> their skin and those that allowed very little water to go through
> their skin. Not to get involved in number-crunching here, which I saw
> one of your statisticians walk in. You guys can do far better than I
> can. Simply we would take this population. Next slide.
>
> And we would take roughly several measurements, two measurements,
> three measurements that could be done very quickly, in one day or in
> two days or in three days. And we\'d say: This is the population of
> leaky skin and not-leaky skin.
>
> And then in the next slide, we would simply do a standard imperative
> bioavailability test in the standard way that it\'s done elsewhere.
> The only thing that\'s different is instead of just taking all comers
> in the door, we could compare the highly permeable, which the membrane
> is supposed to protect, and the highly impermeable. Next.
>
> And then the simple mathematics that your people do night and day,
> with great reliability, would be done to compare the two. Next.
>
> Then, lastly, because I knew it would be brought up, do I think that
> just because I gave you some examples of in vivo data, that all of
> these answers can be worked out in vivo? Well, yes I do. But then I
> think it will be ten, 20, or 100 years from now. In the meanwhile, I
> think most of us agree here that the gold standard, the platinum, or
> the diamond standard is an in vivo human study.
>
> Well, I\'ve tried to answer the two questions. They\'re very simply:
> One, there is variability in the skin of human populations; and it\'s
> significant. And that furthermore, I think we will\--now we have some
> other hints which I won\'t go into today\--we will know this much more
> quickly than we\'re going to understand GI variability. And second,
> that if we want to answer the question, in vivo, in man, is there a
> difference in the rate-control membrane? I think we do have the
> techniques at hand. I think except for the analytic chemistry,
> they\'re modestly priced and rapidly produced.
>
> Thank you very much.
>
> MR. BUEHLER: Are we live on the lights? I\'ll take that as a no.
>
> \[Laughter.\]
>
> MR. BUEHLER: Are there any questions?
>
> MR. YU: In your presentation you basically have a formula that says
> (?) device. Now in the case for the Clonidine TTS systems, what is
> contributing of our device?
>
> DR. HOPFENBERG: I believe that the numbers that I\'ve seen of about 50
> percent is controlled by the skin, and about 50 percent is controlled
> by the device, in normal skin, on average.
>
> MR. YU: Thank you.
>
> MR. BUEHLER: Any other questions for the Boehringer folks?
>
> I just have one for Dr. Maibach. How many in this room, if there are
> 100 people, how many of them have highly permeable skin? About?
>
> DR. MAIBACH: From the data that we have now, it\'s a bell curve.
>
> MR. BUEHLER: Okay.
>
> DR. MAIBACH: You know who\'s on the left and you know who\'s on the
> right. And it would hold true with blood pressure, pulse, cardiac
> output, forced expiratory volume. Probably even weight.
>
> MR. BUEHLER: Thank you.
>
> One follow-up.
>
> MR. CONNER: So if we were to randomly pick people, normal people with
> normal non-diseased skin from the population, we would probably get
> representatives in any pick from the population. We could get highly
> permeable; perhaps a lot of in the middle; and perhaps low
> permeability at the other end.
>
> For example, as everyone does availability bioequivalent studies, they
> generally pick normal volunteers at random, usually within a certain
> age range. You know, race is not excluded and so forth. We would be
> expected to have representatives of all the permeabilities in that
> group picked, simply based on random choice. Correct?
>
> DR. MAIBACH: I\'m going to give you a yes-no answer, and then I\'m
> going to give you a qualification, if that\'s acceptable to you. The
> answer is: Yes, in 25 or 26 people, you\'d expect at least one to be
> in each stream. But you wouldn\'t know the answer, though, to the
> effect of a rate-limiting membrane, because you\'re averaging all of
> that out. You\'d lose that.
>
> MR. BUEHLER: Dr. Wilkin, do you have a question?
>
> DR. WILKIN: Well, actually I had several for Dr. Maibach. One\--was it
> nitroglycerin or nicotinic acid\--there were four different
> concentrations you showed in three subjects?
>
> DR. MAIBACH: Yes.
>
> DR. WILKIN: Recall early on. Can you come back to that?
>
> DR. MAIBACH: Yes, of course. And this time, Jonathan, I\'ll stand next
> to it, since the recording isn\'t working.
>
> \[Technical interruption.\]
>
> DR. MAIBACH: This is just a representative in vivo study that we did
> at a time when we were beginning to ask the question: When you see
> somebody like this who had 1/10 the delivery of a synthetic blood,
> namely the bottom part of an in vivo chamber, was this difference due
> to just sloppy technique, or was it really a difference in the skin?
>
> And the answer is: We then did mass balance and the mass balance
> seemed to agree reasonably well. So we believe that when you see
> something like this in vivo, it really is a difference.
>
> Now, in the FDA in vivo method, one of the many methods that\'s used
> by Bob Bronaugh, if you don\'t meet sharp criteria for water loss\--he
> happens to use tritiated water rather than a machine\--you just done
> use the specimen at all. It just has to be disregarded.
>
> DR. WILKIN: I guess my concern was whether that was a mistake, that
> 5.0 for subject number 3 in the receptor fluid. Was that 0.5 or 5.0
> for standard deviation? Because if in fact, it\'s standard deviation,
> then what it means is the reliability of the point estimate for
> subjects, especially subject 3, is rather difficult. Do you know what
> I\'m saying?
>
> DR. MAIBACH: Yes. And it\'s for that reason\--
>
> DR. WILKIN: So it\'s kind of hard to tell whether we really have faith
> in the 4.4 being a true value permeation all around it.
>
> DR. MAIBACH: It\'s for that reason, when we publish on the difference
> between intervention A and intervention B, we have to, because of the
> variance in these in vivo systems, we have to take subject 3 and use
> multiple samples from 3 so that we can get the power to show
> differences.
>
> DR. WILKIN: Again, I agree that you need multiple samples, but I think
> what the multiple samples are saying is: With that degree of standard
> deviation, it\'s still difficult to separate subject 2 from subject 3.
>
> But I had another question about where you had the four dissimilar
> chemicals.
>
> DR. MAIBACH: That\'s number 28.
>
> DR. WILKIN: They met correlation coefficients that were\--
>
> DR. MAIBACH: The lowest is 0.62 to 0.73.
>
> DR. WILKIN: I guess those, to me, are, you\'d sort of guess that they
> go, that they correlate, that they run together. Correlate just as a
> means that, you know. But can you use one to predict the other? I
> guess that\'s the difficult piece to that. Maybe looking at from a
> concordance, we can deal with it. Those are actually surprising. I
> thought they were surprisingly low correlation coefficients down there
> on point 6. I mean that\'s\--
>
> DR. MAIBACH: Well, if you go to the one just before this\--
>
> DR. WILKIN: Were those the only four chemicals that you looked at
> overall? Or did you select out the four that had the best?
>
> DR. MAIBACH: Those were the total that had been studied in man. But in
> the rat many more have been studied. And the relationship continues.
> The hairless rat. We chose that because this was human data.
>
> And I chose the slide before this, if I may. Number 27? Now, just one.
> Because this is the one that we had the largest amount of data. And
> here with a 0.92 with a P of under 1 in 1,000, gave me the confidence
> that it\'s worth going to the next step.
>
> DR. WILKIN: I thought this was on slide. The number 9 and the number
> 1, if I recall correctly, were from your anatomical cartoon, are
> actually the sites where the Catapres-TTS\--read the label and their
> dosage administration, I think that\'s the site (?) chest and the
> outer arm.
>
> So, ultimately a generic could also be applied to the same location,
> because it captures the identical dosage and administration. And I
> didn\'t hear you say it, but I guess part of your argument would be
> that there is the potential between those two sites alone, essentially
> five times the total penetration.
>
> DR. MAIBACH: I didn\'t quite extent it that far, to simply, to suggest
> that maybe the dermatologist sciences are advancing enough that we can
> do clinical biological studies that will answer engineering questions
> like the membrane.
>
> MR. BUEHLER: Yes?
>
> DR. HADGRAFT: I\'d like to provide some commentary to this analysis.
> I\'d like Howard\'s slide to stay behind me while I do that. There is
> a correlation between the permeability of benzoic acid and TEWL
> measure somewhere on the order of, at various sites, seven or eight
> different measurements on different people at a site. And we saw there
> were ten different sites.
>
> If you take these data, and you take away the date points, which
> involve post-auricular site, and which involve the forehead skin, you
> wind up with 82 values to correlate benzoic acid and TEWL. And when
> you do that, the correlation breaks down, so that R-squared takes a
> value of 0.29. So we\'re talking about if you correlate the data they
> have between TEWL and benzoic acid on sites which involve the arm and
> the chest, crossing the torso, places where Clonidine patches might be
> warn, the correlation breaks down.
>
> So, again if you look at that transparency now, and you look at the
> upper right hand corner, you\'ll see three data points that skew those
> data to make it look like there\'s a correlation. But I don\'t believe
> there is.
>
> I\'ll go further. Now, if you take out the sites where we actually
> wouldn\'t wear Clonidine patches, and just use the upper arm and the
> chest, the correlation on the data is 0.05. These data to not support
> the use of TEWL as a measure of skin permeability.
>
> MR. BUEHLER: Any further comments? Doug?
>
> DR. THROCKMORTON: Jonathan, I want to understand something. It sounded
> like you were going by which one of these methods, and I\'m certainly
> the wrong person to say which is the right one to measure permeability
> here. What kind of ranges are we talking about for low versus high
> permeability as far as transport rates and things? Is this it looks an
> order of magnitude, or is it two orders of magnitude. Just in general,
> what\'s the variability here? The average bell shape.
>
> DR. MAIBACH: Well to put this in perspective, Gordon\'s point is of
> course understood and taken. And that is why the experiment was done
> exactly the way it was. We didn\'t go to a large population; we went
> to a small population and looked at the permeability of various parts
> of their body. And what you saw is that if you take a look at the
> various anatomic sites\--some of which are used for transdermals\--of
> course Gordon knows that the retroauricular area is used for the first
> modern transdermal or the second one, scopolamine\--you\'d get a
> number like this.
>
> But in the tiny population that we studied to give us the power to get
> this answer, you\'re looking at this as 2 to a number of about 12. I
> would predict in a number of 100 subjects or 50 subjects, or 75
> subjects\--this has just gotten in a handful of subjects\--the number
> is obviously going to grow. So you\'re going to get from 2 to 15 or
> 18.
>
> \[Simultaneous conversation.\]
>
> MR. BUEHLER: I think we\'re ready for the Mylan presentation.
>
> MR. SPENCER: My name is Tom Spencer. I\'m the Vice President of R&D
> for Mylan Technologies. And we\'re here today in opposition to the
> Boehringer Ingelheim petition.
>
> I have with me Dr. Marv Meyer of the University of Tennessee, Dr.
> Jonathan Hadgraft of Kent University in England, and he is the author
> of the paper that Dr. Hopfenberg was just discussing. And Dr. Gordon
> Flynn, whom you\'ve just heard speak from the University of Michigan.
>
> We\'re here today to demonstrate the current FDA requirements are
> sufficient to show that the Mylan Transdermal Clonidine System is as
> safe and as effective as Catapres.
>
> And in the ensuing discussion, we will show data that the Mylan CTS is
> equivalent to Catapres in its ability to control Clonidine delivery in
> the clinic as well as in vitro; that the variation in plasma levels
> that we\'ve seen in our bioequivalent studies are equivalent to
> Catapres-TTS; that the drug release under same conditions that Dr.
> Hopfenberg has so carefully described will demonstrate that Mylan CTS
> is equal to Catapres in control of release of Clonidine; that the
> Catapres-TTS membrane does not completely control the release. And
> finally we will discuss the BI proposed study and demonstrate that
> that study has some serious flaws.
>
> The overall impact of the information we will present that no
> additional requirements are needed to approval a generic equivalent to
> Catapres. And Dr. Meyer will take over to discuss the clinical
> aspects.
>
> DR. MEYER: Thank you, Tom.
>
> I just have two slides, and I\'ll go over them fairly rapidly. First
> of all, in my opinion, I do not think there is a basis for imposing
> unique requirements for approval over generic equivalents of
> Catapres-TTS. Mylan has conducted a full bioequivalent study. They
> used their 0.3-mm-per-day patch and compared on a crossover design to
> the Boehringer Ingelheim Catapres-TTS, and they used a substantial
> number of healthy volunteers, 49 to be specific.
>
> In each of the parameters that are typically examined in a
> bioequivalent study, area under the curve last, area under the curve
> infinity, and CPEAK or CMAX, the Mylan/Boehringer ratio ranged from
> 115 percent for AUC Infinity to 107 percent for CMAX.
>
> The confidence limits that are required by the FDA all were well
> within the range of 80-125 percent. The conclusion, then, would be
> that the Mylan product is bioequivalent to the Boehringer product.
>
> One other set of data that could be captured from this study is the
> coefficient of variation for each of three key parameters. And those
> are shown in the second last two columns. If the Mylan product in fact
> suffered from some dose dumping, or had a premature release, or in
> some fashion was significantly different than the Boehringer product
> in this group of 49 subjects, one would expect the coefficient of
> variation to be larger for the Mylan product. And in fact it is
> virtually identical, or if anything slightly smaller.
>
> I also would like to briefly address the issue of NTI. There are no
> specific requirements that I know of for drugs that have been included
> in an NTI list. And, in my opinion, Clonidine is not an NTI drug. If
> you follow the characteristics of NTI and the 21 CFR citation there,
> Clonidine does not fit any of the three requirements.
>
> Finally, if you look in the labeling for the tablet and the patch in
> the BI labeling, you\'ll see that there adverse experiences or events
> are characterized, and this is \"mild,\' and that there is no mention
> whatsoever made in the labeling of any specific patient-monitoring
> requirements. So I think this NTI designation does not really fit
> Clonidine.
>
> And finally, the issue of: Do different release mechanisms, different
> structures of dosage forms, do they have an impact? And should that be
> really considered. And I believe the FDA and the courts have ruled
> that in the instance of controlled-released products, generic
> equivalents need not be of the same design, nor mechanism of release,
> as found in the innovator product.
>
> Now, Dr. Hadgraft will continue. Thank you.
>
> DR. HADGRAFT: Thanks, Marv.
>
> Good afternoon. What I\'ve been asked to do this afternoon is to talk
> to you about the mechanisms of release of Clonidine from different
> patches, and to show you how the Mylan system actually conforms to
> similar profiles to that of the Catapres-TTS.
>
> I\'d like to thank Dr. Hopfenberg for giving 95 percent of my talk,
> and I want to draw on some of his analogies in order to show you how
> the Mylan system works.
>
> What I\'ve got in this first cartoon is a diagrammatic representation
> of the Mylan system on the left hand side. And as you can see, it
> contains an adhesive in which there\'s a homogeneous dispersion of
> solid particles of Clonidine. There\'s an inner backing membrane, and
> also there\'s an adhesive ring that holds the adhesive in place. That
> you can compare with Catapres, which is very similar. It too has an
> adhesive with solid particles. And really the significant difference,
> as was pointed out earlier, is that Catapres has this microporous
> membrane associated with it.
>
> But in general terms, the basic release strategies for both of these
> products are one of dissolution, a dissolution of these dispersed
> particles and the subsequent diffusion to the skin\'s surface.
>
> I\'ve been working on the rates of release from transdermal systems
> since their inception back in the late 70s and early 80s. And I think
> that I\'m perhaps surprised that there are a lot of misconceptions
> about monolithic devices and exactly how they release materials
> through the skin.
>
> I think one of the basic misconceptions is that all monolithic devices
> are really likened to having the active present in the device in
> solution. And really it\'s the diffusion of the active to the skin\'s
> surface that then controls the rate of release. That can be contrasted
> with the dispersion of the drug in a homogeneous polymeric matrix.
>
> And then lastly this diagram here shows the Catapres system with a
> rate-controlling membrane.
>
> Now what I\'ve done is to simplify matters for you. I\'ve not tried to
> bamboozle you with hard mathematical equations. But I have in fact
> solved fixed laws of diffusion for these three different instances.
> And as Dr. Hopfenberg quite rightly said, if you solve fixed laws of
> diffusion for this first system, where the active is in solution, you
> do get a very rapid rate of release. Nearly all the drug is released
> very early on in the time profile.
>
> However, if you contrast that to the situation where you\'ve got the
> drug in suspension, you can see that I go from this very fast release
> to one that is really rather slow and controlled quite well over a
> long period of time, as these squares here. And I can now contrast
> that also with a membrane-moderated system. And you can see that in
> fact these two lines are almost coincident.
>
> And I think it\'s interesting in fact that one of my previous slides
> was used from a paper which described the differences between
> Nitro-Dur 2 and Transderm Nitro and Deponit. And in fact these
> profiles here do look very similar to Nitro-Dur 2, Transderm Nitro,
> and at the bottom here, Deponit, which I might have a debate about
> whether I believe that is a monolithic system or not. Personally I do.
>
> But I think the take-home message from this is that monolithic systems
> can be design with rate-control mechanisms similar to membrane
> systems.
>
> Now we\'ve heard a lot of talk about safety issues. And as Dr.
> Hopfenberg quite rightly said, perhaps the most stringent way of
> testing a device is to allow it to release into a sink. Because that
> would be equivalent to me of taking some sand paper, rubbing off all
> the skin from my arm, and then putting the device immediately on the
> arm, so that the device could release exactly or precisely in the
> blood supply.
>
> And so, one of the things that the FDA requested of Mylan was to look
> at the release profiles of the Mylan system and compare that to the
> Catapres system. And I\'ve just taken a representation sample here,
> where I\'ve compared the medium-strength one, the CTS 0.2, or the
> Catapres II. And you can see that this is the release profile over a
> seven-day period into an aqueous sink. So this is the ability to
> release the drug in the worst-case scenario. And you can see that in
> fact the one with the system with the rate-controlling membrane in
> fact releases slightly faster than this monolithic system where the
> rates of release to the skin is controlled by this dissolution and
> diffusion process.
>
> One of the things that Richard Guy and I did back in 1992 was to look
> at data and try and get an estimate of how much control there was from
> a device in the skin. And so I\'ve taken these data. In fact the data
> that I use with the CTS 0.3 system. And if I look at the fractional
> control from the device, it works out to about 0.53, whereas the
> Catapres system works out to about 0.4. So certainly I think just on
> the basis of this very simple in vitro release profile, that I can say
> that Mylan CTS is as safe as Catapres-TTS.
>
> And even if there were these high permeability skin people, then there
> would be no difference in applying the Mylan system to the TTS system.
>
> And for my final slide is really to take some data from the literature
> side. And there were two independent publications by two Toon and
> coworkers and Hopkins and coworkers where they took Catapres, they put
> that on volunteers and looked at the intersite and intersubject
> variability. And I think that we all know that if the rate-controlling
> membrane genuinely did control input into the body, then really you
> would not find any difference between different sites and the
> variability between subjects would be quite low as well.
>
> But in fact they did find variability, and \[?\] by Toon, he concludes
> that there is a substantial control of drug input by the skin. And in
> fact if you take the Toon data and use Richard\'s and my model in
> order to work out the fraction of control from the TTS system, then
> the estimates are that the fraction of control from the TTS is about
> 0.4.
>
> And so really there is rate-controlling membrane there. But I\'m not
> quite convinced that it\'s significance is that important.
>
> I think that\'s my part of the presentation. Perhaps if I could hand
> over to Dr. Flynn.
>
> DR. FLYNN: Good afternoon, ladies and gentleman.
>
> Let\'s be clear now where we are. It\'s been shown that from the
> standpoint of bioequivalence, Mylan CTS is bioequivalent to
> Catapres-TTS. And we saw that within the context of variability the
> data also suggest that there was as much control in the delivery of
> Clonidine as you find in the marketed product.
>
> We\'ve also seen Clonidine released from Mylan CTS is as
> well-controlled as from Catapres-TTS in the previous speaker,
> Jonathan. And it\'s therefore a certainty that Mylan CTS is as safe as
> Catapres-TTS from a standpoint of the concerns that have been raised
> here.
>
> We could end here, I think, and say well, therefore, no further study
> is necessary. But I think we do have to take a moment and look at the
> suggested clinical study. And so may I have the next slide?
>
> Like Dr. Hopfenberg, I don\'t use the computer when I teach, and so
> I\'m having the same kind of problems that you had.
>
> This is a strong statement at the top of this slide. I say the high
> skin permeability subject is mythical. Now, part of the reason for
> this, or perhaps the main for this is occluded skin is fully hydrated.
> An occlusion that you would get under a patch or under a similar
> application is a great leveler of skin permeability.
>
> I picked a few studies myself out of a far greater number to
> illustrate this point with a few examples. A lot of work was done in
> the San Francisco laboratories by a group led by Neil Benowitz. And I
> have one reference here. Their interest was with transdermal nicotine.
> And in one of their studies, 11 subjects, and one part of a table
> which included more data, which was comparably supportive of the
> point, that the average amount of nicotine which was delivered from a
> patch over the period of wear was 14 mg, and that was +/- only a 0.6
> mg. That\'s a very, very tight data set.
>
> And the rest of the data in that paper are equally tight.
>
> This particular number was gained by measuring the remaining amount of
> nicotine in the patches and then doing a calculation as to the amount
> that had left the patch at the end of the experiment. Bucks et al
> published an interesting paper and JID, the reference is given here.
> And they applied four steroids under occlusion. Under occlusion. In a
> manner in fact similarly with the way a transdermal system would work.
> I won\'t go through he individual steroids; you can look a the numbers
> and you can see that in terms of the percent of dose absorbed, percent
> of applied dose absorbed, they got a set of numbers which have
> relatively small standard deviations inconsistent with a wide range in
> skin permeability under the circumstances of delivering a drug from a
> transdermal system through intact healthy skin.
>
> Marquardt et al studied Fentanyl from a residual analysis standpoint,
> and came up with a similar conclusion. The n=5 is only a small part of
> a larger data set for one particular size patch. The entire study
> supports the idea that the amount of Fentanyl as absorbed from a patch
> is very tight. In this particular situation the 2.5-mg patch over the
> period of wear 1.5 mg, and the standard deviation was a small 0.22 mg.
> And it\'s consistent with the skin being very variable when it\'s
> normal and at a specific site.
>
> So I think we can conclude reasonably that the range of skin
> permeability at a given transdermal application site, chest or arm to
> be specific, is narrow.
>
> Let\'s turn our attention to TEWL. TEWL is one of the serious flaws in
> Boehringer Ingelheim\'s bioequivalent study. TEWL as a basis for
> assessing skin permeability is invalid, and is irrelevant to hydrated
> skin. And here are some examples where you find data and literature
> that make that statement. Chilcott et all. Very interesting and a
> very, very carefully designed, well-done study. They measure TEWL and
> they measure tritiated water permeated skin membranes, for which they
> had measured TEWL, and they came up with a correlation, R2 of 0.26.
> Conclusion: Tritiated water and TEWL don\'t correlate very well.
>
> More relevant to the interests here, they also measure the permeation
> of sulfur mustard. This is a small relatively lipophilic organic
> compound. And compare that with the values of TEWL that they assessed
> on the same pieces of skin. And they got an R2 in this particular case
> of 0.24. Little to no correlation.
>
> In Oestman et all you find an interesting study where hexyl nicotinate
> response, that\'s vasodilation produced by that, which first requires
> penetration of the skin, doesn\'t correlate with TEWL. There\'s
> another organic chemical, and it\'s response, which also includes the
> pharmacokinetics, the biopharmaceutics of the vasculature. But within
> there is a data set which fails to show a correlation with TEWL with
> an organic chemical that has to penetrate the skin.
>
> In Tsai et al with barrier disruption with acetone and measurements of
> TEWL, they find TEWL increases when the acetone treatment is done. And
> there\'s also an increased penetration of sucrose, caffeine, and
> hydrocortisone. But interestingly, there is no increase in penetration
> for estradiol and progesterone.
>
> If you look at these and the variations within these data sets, you
> have to come to the conclusion that TEWL does not predict
> permeability.
>
> And I have one more on transparency that I\'d like to show.
>
> \[Technical interruption.\]
>
> DR. FLYNN: We\'ll do this verbally and the information will be in your
> folders. All right? I can\'t show you a slide of the data.
>
> Dr. Maibach presented some information and I made a comment at the
> time. And that information is captured in several places in the
> literature, in the chapter, in percutaneous absorption and several
> references in the primary literature. And I\'ve already made the point
> that if you look at those data carefully, and you look at sites where
> a transdermal delivery system containing Clonidine would be applied,
> based on regular practice at this particular time, there was virtually
> no correlation; there is no correlation.
>
> And if you take out the high permeability sites above the shoulders,
> the correlation breaks down badly, and there\'s almost no correlation
> on those data, and those points have been made.
>
> In another paper by Aalto, Cort \[ph\] and Turpeinen, it was presented
> as a BI reference in some of written documentation, and this does not
> support TEWL as a measure of permeability either.
>
> Very quickly, in this particular study, it was done with the
> hydrocortisone ointments on patients who had severe dermatitis, on
> patients whose dermatitis was virtually full-body, ranged from about
> 50 percent of body surface to about 90 percent of body surface.
> Patients who were so troubled with their disease condition that they
> had an index of excoriation in the original paper presenting these
> data, which indicated that well over half of the subjects in the study
> had torn their skin open by scratching it, they were so uncomfortable.
> And they show that TEWL measured on several sites of the body, the
> body that certainly not covered with healthy normal skin, had shown
> some correlation with the amount of hydrocortisone that they could
> collect in the plasma in a subsequent experiment.
>
> In the plasma collection experiment there was no control for
> individual pharmacokinetics. The TEWL measurements were made in an
> uncontrolled fashion, there was no control of temperature; there was
> no control of humidity; there was no control of a sense of stress
> people feel when they\'re getting measurements made on their body.
> This is a study which is questionable and certainly cannot be used to
> make the case for TEWL as a general indicator of skin permeability.
>
> And now a close, my final points. I\'ve added to the discussion then
> my strongly-held opinions that no large variability in skin
> permeability exists at sites where Clonidine patches are used, or will
> be used. And furthermore, TEWL is not a valid measure of the
> permeability of skin, general measure of the permeability of skin.
>
> Thank you very much.
>
> MR. SPENCER: Thank you, Gordon.
>
> In conclusion, we would state that Mylan\'s Clonidine transdermal
> system meets all appropriate criteria for its approval as a safe and
> effective generic equivalent to Catapres-TTS. We\'ve provided
> information and data that Mylan CTS provides the same degree of
> control as Catapres. This addresses the issues of safety that have
> been brought up.
>
> There is no need for additional studies to approve a generic
> equivalent to Catapres. And for these reasons, we maintain that the
> petition should be denied.
>
> Thank you.
>
> MR. BUEHLER: Thank you to the Mylan presenters. Are there any
> questions to the Mylan presenters? Dr. Wilkin?
>
> DR. WILKIN: I have a question for Dr. Flynn. While you\'re getting to
> the slides, it\'s the one that there were I think 11 subject
> altogether. The first was the Neil Benowitz\'s transdermal nicotine.
> And I think making two sort of general conclusions. One is the TEWL,
> transepidermal water loss, is not a good way to ferret out those in
> the population who might have increased percutaneous
> penetration\--things applied to the surface, which is here. Actually
> could you go to the slide? I think\--
>
> DR. FLYNN: Yes. I made two points. That\'s the other point I made,
> Jonathan.
>
> DR. WILKIN: Yes.
>
> DR. FLYNN: This is where that came up.
>
> DR. WILKIN: And then this one is not so much about transepidermal
> water loss as it is about whether or not you\'re a believer, and that
> there may be some people out there, like on Dr. Maibach\'s slide, that
> had that really high hydrocortisone penetration rate. And you\'re
> generalizing on the basis of what looked like 22 subjects altogether.
> The Benowitz is 11, and Bucks et al is 6, and the Marquardt is 5. I\'m
> just wondering, I mean is that really the kind of numbers that we
> would need to rule out the possibility of having, you know, the
> occasional 1 in 25.
>
> Statisticians can take 0 out of 22 and calculate the upper 95 percent
> confidence layer \[ph\], what that might actually mean. That could be
> a substantial number of the population. I guess\--
>
> DR. FLYNN: It\'s a good point. And I can only tell you I pulled about
> 40 references after a very thorough literature search that I did
> myself. And in a very limited time today. And so I picked a few
> examples. Each of these has a limited number of cases.
>
> But if you take the Benowitz paper and you go to some of the other
> tables, which are the same subjects under some different conditions.
> Like getting nicotine given to them before they get the transdermal
> patch, there\'s a consistency in there, and that paper expands to at
> least twice that number.
>
> There are more numbers in the Marquardt paper, too. Although that
> paper has less than ten subjects in it. And I believe there were six
> subjects that received the treatments that were done in Howard\'s
> laboratory.
>
> But these are representative data.
>
> But the points of these particular studies, they were done in the way
> that we use transdermal systems. Or they were done with transdermal
> systems. And they were done under occlusion with an environment
> created under the surface between the outer covering of the patch, or
> the application, and the surface of the skin, which is relatively
> uniform in terms of the activity of the drug, and in terms of the
> activity of the other components of the delivery system.
>
> When you look at data where people induce hydrocortisone into the skin
> with an acetone application or something like that, you stray very far
> away from the way transdermal systems are used.
>
> I admit the number is small, but these are representative of what you
> find under transdermal delivery systems.
>
> MR. BUEHLER: Dr. Throckmorton?
>
> DR. THROCKMORTON: I\'d like to sort of pick up on that just a bit
> more. One of the things that we\'ve been told is that there are other
> circumstances where permeability might reasonably expect to vary
> fairly broadly, and I think exercise was one you talked about.
> Abrasion. Irritation. What Jonathan said, do we have the sort of data
> here to say that under those circumstances we wouldn\'t expect to see
> this sort of high permeability individual? Whether or not that\'s a
> myth, I don\'t know.
>
> DR. FLYNN: If you tear off the stratum corneum, if you abrade it, if
> you rip through it and break it up, you chance the surface
> sufficiently so that everything is more permeable. But we don\'t use
> transdermal systems. The directions are to apply it on a non-abraded
> surface of a healthy human being. And if that\'s the definition of the
> surface we\'re using, you do not see those kinds of things. Those are
> irrelevant to the issue at hand.
>
> DR. THROCKMORTON: Yes, but we certainly do see transdermal systems
> used under conditions of exercise. I think you probably wouldn\'t
> disagree with that. So, is that a situation where we need to do more?
>
> DR. FLYNN: I\'ve measured the studied systems that had been removed
> from patients, some of whom worked out every single day, seven-day
> systems. They are used by people who exercise.
>
> I don\'t think exercises changes the fundamental permeability of the
> tissue. It does create a different environment, different than you
> might get with non-exercise, in the sense of moisture and things. And
> in the Toon paper, they point out that there\'s also an increased
> blood flow. My own leanings would be it\'s more in terms of the
> environmental changes in the delivery surface that might happen, than
> increased blood flow. But I can\'t rule the latter out.
>
> But there can be more drug absorbed under that particular
> circumstance. We have at least one data point that we know of where
> that happened.
>
> MR. BUEHLER: Dr. Maibach?
>
> DR. MAIBACH: May I just clarify Dr. Wilkin about my own data?
>
> Just to keep it straight, Dr. Flynn is absolutely correct. This is not
> the experiment, simply six volunteers\--I don\'t remember if I was one
> of them in the one listed here, Bucks et all\-- covered with plastic.
> No attempt was made to manufacture the transdermal system. But the
> analytics, even though it is not a kinetic, a blood level, is
> reasonably sharp, because all of this was done with carbon-14, and we
> know how that these chemicals are excreted in the urine. They\'re
> extensively studied hydrocortisone, estradiol, testosterone, and
> progesterone.
>
> Now, since Dr. Wilkin is pretty good with the numbers, if you take a
> look at this, 46 percent of the testosterone is absorbed, +/- 15
> percent in six people. So obviously, if you go to 25, 100, or 1,000
> people, those numbers are going to broaden enormously, you know, into
> this distance. Which is very similar to what we showed in our first
> transparency, the data with 25 people with hydrocortisone.
>
> Secondly, although I don\'t want to speak for my colleague, Dr.
> Benowitz, I\'m reasonably confident that Dr. Flynn is right, Gordon,
> that this was done in an entirely different method, which mutes the
> real number. And I don\'t know that too many people use that analysis
> to improve transdermal delivery. That was done, the amount that
> remains in the patch at the end of the experiment and in the written
> response, if there is a written response, will go into the reason why
> that is not significantly used in regulatory considerations, because
> it doesn\'t in any way tell you what\'s in the plasma.
>
> MR. BUEHLER: Yes?
>
> MR. SPENCER: I believe that the question, though, was do we have a
> reason to be concerned about the safety of the patch. And the answer
> to that question is no. The Mylan CTS controls the rate of Clonidine
> delivery in a fashion that\'s equal or maybe slightly better than
> Catapres. And so it is not a safety factor.
>
> DR. THROCKMORTON: No. The only point was that was under normal
> circumstances. And the question was whether under other circumstances
> that we needed to be concerned about that. That was the source of
> that.
>
> The bioequivalent study was done with normal skin, but the release in
> reservoirs, as Dr. Hopfenberg points out to us, is the \[?\] extreme.
> There is no barrier to that release. And under those circumstances,
> under the transdermal system with the mechanism of release that it
> has, that is the solution of the solid, delivers or controls the rate
> of delivery of Clonidine equal to Catapres.
>
> DR. HADGRAFT: I think you\'ve raised a very interesting point.
> Certainly there is a limited amount of information in the literature
> about people exercising. And in fact, if you look at the Toon paper,
> there is one individual in that who has experienced higher Clonidine
> levels than the others. And that was attributed to the exercise. But
> again not really as an example of where the rate-controlling membrane
> didn\'t appear to do what it was supposed to do.
>
> DR. HOPFENBERG: I\'d like to make a couple of comments that I think
> will ultimately end up rhetorically as questions. And I\'ll probably
> need my colleague, Dr. Brill, to help me with some slides. Could you
> do that, Dr. Brill?
>
> \[Technical interruption.\]
>
> DR. HOPFENBERG: I want to address the first comment that was made. The
> Catapres-TTS membrane does not contribute significantly to the control
> of Clonidine delivery. I think I saw that on the slide. The
> Catapres-TTS membrane does not contribute significantly to the control
> of Clonidine delivery.
>
> Can we go to that? Do you know which slide I\'m talking about?
>
> DR. BRILL: Yes. It\'s coming up.
>
> \[Technical interruption.\]
>
> DR. HOPFENBERG: The statement I made was that in in vivo delivery,
> these are the experiment data. I then said that that\'s the largest
> amount you would ever get in any transdermal case in vivo. What we\'re
> seeing there is controlled by the membrane. The membrane\--
>
> \[Technical interruption.\]
>
> DR. HOPFENBERG: What we\'re seeing in that upper curve is completely
> controlled by the membrane. None of these systems are controlled by
> dissolution. Not the monoliths. Not this one. I\'ll go into that in a
> second.
>
> The upper curve is a curve completely controlled by the membrane. Is
> the total transdermal delivery controlled by the membrane? No! It is
> also affected by the permeability of the skin. That\'s why the in vivo
> data show fluxes which are lower than. The question was asked, \"What
> is the fractional control by skin in this device?\" Fifty percent.
> Fifty percent still depends upon it. But can it ever get higher than
> the upper curve? No. Why? The upper curve is the curve defined by the
> membrane.
>
> That\'s an important point. And to have a statement that the
> Catapres-TTS membrane does not contribute significantly to the control
> of Clonidine delivery: it does the most important thing! It gives me a
> fixed upper level. And that number is the number that was what? 11.6
> mcg per hour. Fact?
>
> Let\'s go to the monolith system. When I was discussing the monolith
> system\--let\'s go to slide 15\--it was a bit of an arcane
> presentation, but I hope I made it clear, I was not talking about a
> diffusional system that did not have dispersed drug. I was talking
> about a system to explain the effect of the overloading of dispersed
> drug; that here is a concentration that\'s a saturation, and the
> monoliths we\'re talking about have loaded drug in excess of that.
>
> There\'s nothing in the equation\--next slide, please\--there\'s
> nothing in the control with the rate of dissolution. The only kinetic
> parameter is D, the diffusion coefficient. There\'s nothing in there
> that depends upon the rate of dissolution. Nothing. What\'s it depend
> upon? The rate of diffusion of the drug through that barrier layer,
> which was the outer shell.
>
> Nothing happens in the core. Everything happens in the barrier layers.
> Is it a membrane? It\'s a monolith. What\'s the kinetic parameter?
> It\'s not a dissolution rate constant. It\'s a diffusion coefficient.
> The dissolution is rapid compared to the dissolution. It does not
> contribute to the rate of release.
>
> MR. BUEHLER: Dr. Wilkin had a question for
>
> DR. WILKIN: I actually\--
>
> MR. BUEHLER: Number?
>
> DR. WILKIN: Number. Well, actually it was Dr. Flynn\'s slide. It was
> the one where you had the four different\--
>
> \[Simultaneous conversation.\]
>
> DR. WILKIN: I do not have a copy of the paper. This is percent of
> applied dose. How, exactly was this done? Was this like looking in the
> urine at say day 6, or over six days, and then just ending up with one
> number that really reflected everything you possibly could find in the
> urine? Which may mass fluctuations that could occur in the blood
> stream on different days. I guess that\'s\--
>
> DR. MAIBACH: The dose for all four was the same: 4 mcg per cm of
> forearm adult skin. The measurement was as summarized here, the total.
> But in fact, the urine\--and it was measured in urine\--the urine was
> collected from 0-4 hours, 4-8, 8-12, 12-24, and then day 2, 3, 4, and
> probably 5. So yes, this is the total number, which of course does
> have considerable variation in itself. But hopefully the date the
> publication, if the reviewers didn\'t remove the raw data, would have
> the individual time periods, as well.
>
> MR. BUEHLER: Dr. Yu has one question.
>
> DR. YU: I have a question that I did ask about what is the
> contribution of the device, so that the data we are seeing is 50
> percent and 37 percent. Actually that\'s very close. And of course,
> not by chemistry engineering standards, but by biological standards.
> The question is that we do see the 40 or 50 percent contribution, and
> we also discussed high permeability, high skin permeability or low
> skin permeability. And the question that needs to be addressed is the
> \[?\] case or high-permeability case, what is the contribution of the
> device, or skin?
>
> DR. HOPFENBERG: If the skin became typically permeable\--
>
> MR. YU: \--so the skin permeability is not a reality. I\'m talking
> about a reality case, please. Thank you.
>
> DR. HOPFENBERG: All you can do is have in vivo data, to the in vitro
> data. If you remember the slide I\'ve now shown two or three times. So
> as the permeability of the skin goes up, the in vivo data \[?\] to
> that level. Now, if in fact the device were a monolith device where
> the initial rates are high, and the physics of the device say that
> early on the rates will be very high, so all you do is you don\'t
> really look in that initial \[?\] region. You extrapolate the initial
> \[?\] regions. That\'s what you should look in the in vivo study,
> because that\'s the place you expect the highest rates.
>
> The eight hour shouldn\'t be the first point. The first hour or the
> second hour or the third hour or the fourth hour. Those were important
> points for Clonidine delivery. They\'re all missing. What did happen
> at zero hours, one hour, two hours, three hours, four hours, five
> hours, six hours? In the nitroglycerin studies at six hours the
> release was completed.
>
> Everything depends upon initial time. In a monolith device we don\'t
> have this upper limit. It does not control. If you take a look at what
> the equations say, the T comes up in the denominator. The rate of
> delivery. So what happens if you put a zero into T? What happens if
> you put a small number into T? The rate\'s very, very high. And the
> data that Dr. Hadgraft showed for nitroglycerin systems for monoliths
> shows very, very high.
>
> If you want to show me in vitro data, don\'t take the in vitro data
> and give me a number where it\'s averaged over the entire 24 hours.
> That\'s the way the factual release was calculated. It never looked at
> the early time data. It looked at\--remember this, the curve that
> looked like this? Took the first point and the last point, and I drew
> a line between them. Ignored all the high rates in between. And
> that\'s the basis upon which the relative fractional control was
> calculated. Nothing could be more misleading.
>
> DR. HADGRAFT: I must say I\'m totally confused by the argument here. I
> really did those calculations and simulations based on the diffusion
> equations that my colleague showed you. And I think you can see that
> it\'s been compelling that the simulations from a monolith under the
> same conditions that he provided give a relatively slower rate than
> the membrane-moderated system.
>
> So I really don\'t understand why he feels that I\'ve got to look at
> Nitro-Dur 2 system as an example of the monolithic system; whereas if
> you look at the one where you\'ve got a dispersion, you don\'t get
> those release characteristics.
>
> And in fact, the other question that was asked was: What happens if we
> put those two systems onto high permeability skin? And in fact in my
> declaration, we did those calculations, and worked out that the
> Catapres-TTS would delivery Clonidine roughly two times higher when
> placed on high-permeability skin. And that\'s reducing the barrier
> function by a factor of ten. And the Mylan one delivers it was about
> 1.7 times. So it\'s a comparable increase in skin that\'s being made
> more permeable.
>
> But I really do think that there is a misconception, and that they are
> concentrating on those release profiles that look like Nitro-Dur 2.
> Well I can use those diffusion equations and show that the release
> properties are significantly slower than the membrane-moderated
> system.
>
> MR. BUEHLER: I think we\'d better have the Elan presentation now. We
> can continue this discussion afterwards. But our meeting was supposed
> to end at 2:30, but we can go to 3:00 as long as people can stay.
>
> MR. : Perhaps one final point. There was evidence presented from
> references that the TEWLs did not correlate. We need to go through
> those. We don\'t have time today.
>
> MR. ROSEN: Pretty good for a lawyer, right?
>
> MR. : Very good.
>
> \[Laughter.\]
>
> MR. ROSEN: I\'m David Rosen of McDermott, Will & Emery, and I have a
> few slides. I\'m here on behalf of Elan. We have a number of people
> here from Elan who are sitting on the side of the room. You can see
> who they are.
>
> But Elan wants to thank FDA for inviting us to participate in this
> meeting today. It\'s been a very interesting discussion to say the
> least.
>
> We have the following comments. They are summary comments with respect
> to the citizens\' petition that has been filed and the information
> that has been presented here today.
>
> FDA has established rigorous approval requirements for transdermal
> products. Elan has a number of approval NDAs, ANDAs, and active INDs
> for transdermal products, and fully supports the current approval
> requirements for these products. The current FDA approval requirements
> do safeguard the American public.
>
> The petitioner is trying to interfere with generic competition. We\'ve
> seen hypothetical scenarios being raised. These types of activities
> are consistent with other activities that have been taken by
> innovators at the end of patent expiration. We also know from public
> information that BI\'s Roxanne subsidiary has obtained formulary
> approval to market an authorized version of Catapres-TTS under the NDA
> as a generic listing.
>
> Elan firmly believes that FDA should continue to rely on its
> longstanding established criteria for ANDA seeking approval of
> transdermal products. And I don\'t know if there\'s a few people in
> the room. I think Florence being one of them, remembers that when we
> first started doing these in the Office of Generic Drugs with
> nitroglycerin, based on data that we had with the nitroglycerin
> ointments. And we made that leap, and there are establishment of
> criteria based on that for quite some time in the early \'80s.
>
> Elan\'s application has undergone a thorough technical review. It has
> met the criteria for being a safe, effective, and bioequivalent
> transdermal Clonidine patch. And we firmly believe and request the
> Agency to approve the Elan product, based on these standards, in hopes
> that it will be approved, so that we can market it as soon as the
> patents do expire.
>
> That\'s all I have to say, although we understand that this meeting
> and the information that\'s provided at this meeting will be put into
> the docket and we reserve the right to put in written formal comments
> in the future.
>
> Thank you.
>
> MR. BUEHLER: Thank you, David.
>
> Any questions or comments for Elan, or who wants to continue the
> discussion from the Mylan comments.
>
> MR. BEERS: I\'ll just break my promise with a point for clarification.
> I don\'t think there are any patents involved here that affect the
> Elan patch. Are there, David? You said as soon as the patents expire.
>
> MR. ROSEN: Oh, thank you. Then there\'s nothing holding up the
> approval of the Elan products at this point in time.
>
> MR. BUEHLER: Thank you, David.
>
> Any additional comments? Questions?
>
> \[No response.\]
>
> MR. BUEHLER: If not, I\'d like to thank everyone who was in attendance
> today. This was really a very impressive meeting. I think we had some
> of the really big names in dermatology here to testify on this very
> important topic. And I do thank everyone for their contribution.
>
> \[Whereupon, at 2:38 p.m., the meeting was
>
> concluded.\]