UNITED STATES OF AMERICA

	DEPARTMENT OF HEALTH AND HUMAN SERVICES

	FOOD AND DRUG ADMINISTRATION

	CENTER FOR DRUG EVALUATION AND RESEARCH

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	ADVISORY COMMITTEE FOR PHARMACEUTICAL SCIENCE

	and

	DERMATOLOGIC AND OPHTHALMIC DRUGS ADVISORY COMMITTEE

	JOINT MEETING

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	FRIDAY
	NOVEMBER 17, 2000

		The Committees met at 8:30 a.m. in the Potomac Ballroom, Quality Suites, 3 Research Court, Rockville, Maryland 20850, Dr. Lynn A. Drake, Acting Chairperson, presiding.

PRESENT:

LYNN A. DRAKE, M.D.              Acting Chairperson
ELIZABETH A. ABEL, M.D.          DODAC Consultant
GLORIA L. ANDERSON, PhD   	Consumer Representative
JOSEPH BLOOM, PhD                ACPS Member
JUDY BOEHLERT, PhD               ACPS Member
JOHN DiGIOVANNI, M.D.            DODAC Consultant
ROBERT E. JORDON, M.D.           DODAC Member
LLOYD E. KING, JR., M.C., PhD    DODAC Consultant
KATHLEEN R. LAMBORN, PhD         ACPS Member
HENRY W. LIM, M.D.               DODAC Member
FRED O. MILLER III, M.D.         DODAC Member
JOEL MINDEL, M.D., PhD           DODAC Consultant

PRESENT:  (Continued)

NAIR RODRIGUEZ-HORNEDO, PhD      ACPS Member
ROBERT S. STERN, M.D.            DODAC Consultant
MING T. TANG, PhD                DODAC Consultant
JURGEN VENITZ, M.D., PhD         ACPS Member
JAIME HENRIQUEZ              	Executive Secretary, DODAC

	I-N-D-E-X

	Page

Call to Order/Conflict of Interest 	4
  (Chair)

Dermatopharmacokinetics (DPK)	10

DPK Perspective from Bioequivalence	14
Viewpoint (Vinod Shah, Ph.D.)

Issues and Opportunities	42
(Jonathan Wilkin, M.D.)

Methods for Assessing Bioequivalence of	55
Topical Products: Regulatory Research
Opportunities (Ajaz Hussain, Ph.D.)

Committee Discussion	111

Open Public Hearing	133

Committee Discussion/Summary	163

	P-R-O-C-E-E-D-I-N-G-S
	(8:32 a.m.)
		ACTING CHAIRMAN DRAKE:  Good morning.  I would like to welcome everyone to the Advisory Committee for the Pharmaceutical Science and -- it's a combined meeting of the Advisory Committee for Pharmaceutical Science and the Dermatologic and Ophthalmic Drugs Advisory Committee.
		To that end, I would like to begin by first asking our staff to read the conflict of interest statement.  I should introduce Mr. Jaime Henriquez.  I'm sorry.
		MR. HENRIQUEZ:  Thank you.  Good morning.  The following announcement addresses the issue of conflict of interest with regard to this meeting and is made a part of the record to preclude even the appearance of such at this meeting.
		Based on the submitted agenda for the meeting and all financial interests reported by the committee participants, it has been determined that all interests in firms regulated by the Center for Drug Evaluation and Research which have been reported by participants presents no potential for an appearance of a conflict of interest at this meeting with the following exceptions.
		Since the issues to be discussed by the committee at this meeting will not have a unique impact on any particular firm or product but rather may have widespread implication with respect to the entire class of products in accordance with 18 U.S.C. 208(b), each participant has been granted a waiver which permits them to participate in today's discussion.  
		A copy of these waiver statements may be obtained by submitting a written request to the agency's Freedom of Information Office, Room 12A-30 of Parklawn building.  
		With respect to all other participants, we ask in the interest of fairness that they address any concerns of previous financial involvements with any firms whose products they may wish to comment upon.  
		ACTING CHAIRMAN DRAKE:  Thank you very much.  
		First of all, I would like to go ahead then and call the meeting officially to order.  I will introduce myself.  I am Lynn Drake, Acting Chairman of this joint committee this morning.
		I would like to now go around the room and ask each member of the committee to give us your name and your affiliation, since this is a joint committee and we may not all have met before.  I would like to start right down there.  It's Dr. Bloom.  Is that correct?
		DR. BLOOM:  Yes.  Joseph Bloom from the University of Puerto Rico.
		ACTING CHAIRMAN DRAKE:  Would you mind telling us kind of what you do so that, at least as Chairman, I have in context who I can really rely upon for specific expertise.
		DR. BLOOM:  I'm Professor at the University of the School of Pharmacy and analytical chemist.
		ACTING CHAIRMAN DRAKE:  Thank you.
		DR. ANDERSON:  I'm Gloria Anderson, Morris Brown College in Atlanta.  I'm Callaway Professor of Chemistry, and I am a physical organic chemist.
		DR. BOEHLERT:  I am Judy Boehlert.  I have my own pharmaceutical consulting business.  I consult in the areas of quality, drug development and regulatory affairs, and I have a PhD in analytical chemistry.
		DR. RODRIGUEZ:  Nair Rodriguez, University of Michigan.  I am Associate Professor at the College of Pharmacy, and my expertise is in material science and solid state.  
		DR. LAMBORN:  Kathleen Lamborn, University of California San Francisco, Professor in the Department of Neurological Surgery, and I also direct the biostatistics corps for the cancer center there.  My field is biostatistics.
		ACTING CHAIRMAN DRAKE:  I'm not sure her mike was on, Ms. Lamborn's mike.  Can we check, sir?  I'm not sure her mike was on.  Could you guys hear her in the audience.  I didn't think hers was on.  Would you do it again, Dr. Lamborn.  I'm sorry, and maybe we can do it with the mike on, because I think our audience would like to know who is on the panel also, please.
		DR. LAMBORN:  Kathleen Lamborn, Professor in the Department of Neurological Surgery and also director of the Biostatistics corps of the cancer center at the University of California San Francisco, and my field is biostatistics.
		DR. TANG:  Ming Tang, St. Jude Children's Research Hospital, biostatistics.
		DR. MINDEL:  Joel Mindel from the Department of Ophthalmology and Pharmacology at Mt. Sinai Medical Center, New York.
		MR. HENRIQUEZ:  Jaime Henriquez, CDER, FDA.
		ACTING CHAIRMAN DRAKE:  And I forgot to tell you what I do.  I told you my role here today, but I am a dermatologist, and I am on the faculty at Harvard Medical School.  This year I happen to be on a paid sabbatical.
		DR. ABEL:  Elizabeth Abel, clinical professor of dermatology at Stanford and private practice of dermatology.
		DR. JORDON:  I am Bob Jordan, University of Texas Medical School at Houston where I am Professor and Chairman of the Department of Dermatology.
		DR. VENITZ:  Jurgen Venitz, Virginia Commonwealth University, Associate Professor in the Department of Pharmaceutics and clinical pharmacologist.
		DR. DiGIOVANNI:  I'm John DiGiovanni.  I am a dermatologist on the faculty of Brown University in Providence, Rhode Island, and I am the Director of the Division of Dermatopharmacology.
		DR. STERN:  I am Robert Stern.  I am a dermatologist in Boston at the Beth Israel Deaconness Medical Center.
		DR. LIM:  I am Henry Lim, Chairman of Dermatology at Henry Ford Hospital in Detroit, Michigan.
		DR. KING:  I am Lloyd King.  I am Professor and Chairman of Dermatology at Vanderbilt University and at the Nashville V.A. Medical Center.
		DR. MILLER:  I am Fred Miller, Chairman of Dermatology at Geisinger Medical Center in Danville, Pennsylvania.
		DR. WILKIN:  Jonathan Wilkin, Director, Division of Dermatologic and Dental Drug Products, FDA.
		DR. HUSSAIN:  Ajaz Hussain, Acting Director, Office of Testing and Research, CDER.
		DR. SHAH:  Vinod Shah, Office of Pharmaceutical Science in FDA.
		ACTING CHAIRMAN DRAKE:  Thank you very much.  I would like to now ask Dr. Wilkin to make an opening comment or two about what we are about here today.
		DR. WILKIN:  Well, we have quite a few chemists here with us today.  So they will resonate with the concept of an elegant synthesis, and my understanding of an elegant synthesis is one that requires the fewest number of steps and gets the highest yield in the end.
		There is also the notion in mathematics of elegance, and it would be a mathematical proof that takes the fewest number of logical steps to get to the answer.
		I submit that there is also the notion, at least we should think actively about the notion of regulatory elegance where, when we are working with the industry group, be it innovator or generic, that what we are thinking about is that informational need that represents what is necessary and sufficient so that we are not really asking for anything more, that there is no excessive regulatory burden.
		Part of what our role is at the agency and, of course, working with academicians and those in industry, is to continuously think about how we can reduce that regulatory burden in a scientifically sound manner.
		I would argue that there are actually three R's of regulatory elegance that we should always be thinking about.  The first is reduction, decreasing the number of tests or the extensiveness of the tests required; refinement, optimization of the test design to generate the maximum amount of relevant data for the least cost; and the final is replacement, substitution of a simpler, cheaper, more informative test for a complicated, expensive, less informative test currently used.
		I think we have an opportunity in the area of topical drug products to think about a variety of alternative methodologies to the clinical trial which may be a more elegant way of achieving our regulatory informational needs.
		We are going to be talking about one of those methods this morning, dermatopharmacokinetics, DPK, but I am happy to tell you that I have really enjoyed working with the OPS group, the different folks who are not thinking only about dermatopharmacokinetics but also other alternative methodologies and working to figure out what exactly the informational base needs to be before such methods are adopted.
		We are going to speak to that this morning.  Dr. Shah is going to present many of the studies, talk about the kinds of evidence that already exists.  In the next presentation I am going to talk about some of the concerns I have with actually the current information base and moving forward without some additional information.  
		Then Dr. Hussain is going to talk about the kinds of additional information that we can obtain, and also his endeavors and others' endeavors into additional alternative methodologies.
		Thank you.
		ACTING CHAIRMAN DRAKE:  Thank you, Dr. Wilkin.  Some of the committee asked me earlier what is our primary role here today.  I think our primary role here today is to be questioners, thoughtful participants.
		As you know, some of you have been on some of these committees before.  This is almost a continuum of looking at alternative ways to evaluate pharmacological agents.  So this is a continuum.
		We have had previous hearings on this, and this will be just one more in a series.  We will not come to any final closure today on any subject, but what we want to do is truly be advisory.  
		We want to ask good questions.  We want to bring up honest concerns.  We want to offer positive suggestions or offer thoughtful critique, when appropriate and when it is helpful.  
		So that is kind of our goal, is to be an information body and a thoughtful body, to help the FDA and industry and users and, ultimately, our end users, our patients, to have a better product that is developed in a cheaper and more efficient manner.
		Do I have any questions from my committee about how we are going to progress today?  Great.  With that then, we will -- There will be an open hearing.  Just so that everybody knows, we have had four individuals ask to speak, plus we have a written statement that I have been asked to just make a comment or two on that will be submitted for the record.
		With that, I believe we will begin.  As I understand it, Dr. Shah, you are starting today.  It's nice to see you again, sir.
		DR. SHAH:  Same to you, too.  Good morning and thank you for giving me again the opportunity to talk with the joint advisory committee meeting with respect to the pharmaceutical science of as well as the dermatological individuals.  
		There are quite a few new members and, as you indicated, Chairman -- Chairwoman, that we would be providing you the information updated to where we are, and try to seek input from you so that we move in the proper direction for finalizing.
		So with that view in mind, I will be documenting the dermatopharmacokinetics from the bioequivalence viewpoint.  I would like to here indicate I am going to be primarily focusing my presentation on the bioequivalency, and the bioequivalency, I mean comparing the test product and the reference product.  The reference product would be the best product, so how I see that the DPK could be useful for achieving this information.
		With that, I will also provide the historical background and some of the make-up on the pharmacokinetics or the dermatopharmacokinetics.
		In my presentation I will briefly discuss the methods to assess the bioequivalency of the topical drug products, history of the DPK, the draft guidance which you already have in your handouts and also it was issued about in June 1998, and some of the ongoing studies at University of Utah.
		I will indicate here that these studies are the ones which came out as a recommendation from this Joint Advisory Committee Meeting when you met about a year, year and a half ago.
		Now what are the different methods to document the bioequivalence?  Again, here I am talking about comparing the two products, the test product and the reference product.
		The first method commonly used in the dermatological field is the clinical studies, because we make a comparison of the test and the reference product.  The clinical studies, at least in my opinion, are comparatively slightly difficult, slightly expensive and at times they are insensitive, because they require large number of subjects in order to achieve the comparison and say whether the two products are equivalent or not.
		The other way of comparison is the pharmacodynamic studies.  Now this is applicable only to a few types of drug products like the Glucocorticoids where the Glucocorticoids provide a pharmacodynamic form, and you can then make a comparison.
		There is some indication that maybe in some of the data there is, like tretinoids, the transepidermal water loss might be used in this area, but it has lots of questions and has not proved responsive.
		The other one is the dermatopharmacokinetic or the pharmacokinetic principles applied to the stratum corneum concentrations, and that is the refer to as the dermatopharmacokinetics.
		In my opinion, this is one of the methods that we are exploring in products.  This is the method on which we have more information gathered together over the last 13 years or so, more or less slowly, and have -- because, as you can see, it is a very logical way of doing it, primarily because we are measuring the drug concentration in the stratum corneum which is very close to the site of action. 
		In some cases this may not be exactly the site of action, but it is fairly close to the site of action, and I think it is universally applicable.
		The fourth method offered to document bioequivalence is the in vitro drug release, which is something similar to the dissolution of the product, but even though that is universally applicable, we don't think we are ready to move forward only using this method for the bioequivalency process, and we think that this data may provide a signal for the possible inequivalence.
		Okay.  Let's talk about what is dermatopharmacokinetics.  The dermatopharmacokinetics is the pharmacokinetics principles applied to drug concentration measurements in the stratum corneum, and that is what we call dermatopharmacokinetics or briefly abbreviated as the DPK.
		In order to achieve this, we use a method what is known as the tape stripping method.  So the tape stripping method is a tool to measure the drug concentration in the stratum corneum and to determine the drug uptake and elimination or the disappearance from the stratum corneum.
		I would like to indicate here that these principle of the dermatopharmacokinetics has been discussed and talked about for over the last -- more than 30 years.  In fact, in some of the earlier work I do recall that we were measuring the pharmacokinetics or the dermatopharmacokinetics after the drug the drug is already administered.
		We measured how rapidly the drug is appearing in the stratum corneum and how it is disappearing from the stratum corneum.  Using the pharmacokinetic principles we have tried nearly 30 years ago in some of the earlier work done with Professor Sidney Riegelman and Professor Epstein from University of California San Francisco where I did my post-doctoral work.
		So these principles have been studied for a long time, and some of these principles have been presented and discussed at lots of international meetings that I will show you in a minute.
		Just to provide the knowledge that this is a method which we thought might be used and be applicable for the topical drugs, we have started out with a research in 1987 at University of Utah.  Since then, we have several workshops and presentations, for example, the AAPS/FDA workshops in May 1989 and March of 1990, December 1991; FDA/Industry conference in March '92; Advisory Committee meetings, first one after the Drug Advisory Committee Meeting which is now a new name.  It's the Pharmaceutical Sciences Advisory Committee meeting.  It was also discussed at international meetings like Bio-International and in the PPP conferences in Europe; also the EUFEPS Conference, again the Bio-International and several other workshops.
		Continuing on that, we have the meetings with the Advisory Committees.  Also we had two meetings, a Joint Advisory Committee meeting similar to this, and this is the last Joint Advisory Committee meeting we have.
		Since then we had the meetings with the expert members and the special government employees meetings in July 1999.  The expert members consisted of the people from the academia, from industry and the general drug industry.  
		We had two such meetings.  We had a symposium just a few weeks ago at the annual AAPS meeting, and again today we are meeting here with the Joint Advisory Committee on November 17 to discuss the dermatopharmacokinetics.
		We have quite a lot of knowledge, and that is what we would like to share it with you to move forward in this area.
		As I indicated, the draft guidance was issued in June 1998, and we have requested the comments from the people by August 17, 1998, and the guidance is already on the Internet.
		We did receive a few comments, total about 15 comments also, but the comments were not on the DPK.  Even so, we have asked the sponsors or the commenters to please provide the data which are in support of the use of the DPK.  We did not get any such information.
		The comments were clearly divided into two blocks, one supporting it,saying it's a great idea; another group saying, no, it's not a great idea.
		So just to produce you with the guidance process:  Initially, we need to define the process -- the problem and the issues.  That's what we defined by having a lot of discussions and coming up with the solution, that let's move forward with the DPK.
		We get a lot of scientific input, do some research, some workshops, Advisory Committee meetings, and then we have come out with the draft guidance.
		After the draft guidance, we received the comments.  We reviewed it.  We are doing some research.  Again we are discussing with the experts and the Advisory Committee meetings and, hopefully, with the input from all this area, we will revise the draft guidance and, hopefully, come up with the final guidance.
		So our main concern is what is needed to have a confidence in the DPK?  That's what we are looking for, because many times a new technology, a new method comes up, there is always a question as to why we are doing this.  Is it going to be useful?  So what kind of information do we need so that we get a good confidence in applying this new technique?
		In my way of thinking, at least there are these three issues which needs to be addressed very clearly so that we can get a good confidence in the dermatopharmacokinetic application principles, again primarily for determining the bioequivalency of the two products.
		The first important factor is the relevance to the clinical efficacy or the data.  Is there any data results that can say that, yes, the DPK and the clinical data could be joined together and they go hand in hand?
		The other factor is the ability of the DPK to differentiate between the formulations, such as maybe there are minor changes or the manufacturing changes or any other changes, and can DPK predict the properties of the vehicle, because we all know that for the topical drug products, the vehicles, even though they are inactive, they are primarily also functioning as a source for driving the actual drug substance -- So can we determine the properties of the vehicle by using this method, and also to find out the reliability and the reproducibility of the method?
		So let's take one question at a time.  The first one is the relevance to the clinical efficacy or the data.  Can the DPK differentiate the products with the same concentration of the active drugs but with a different clinical efficacy?
		Now this was the question we were really raising in the last Advisory Committee meeting, Joint Advisory Committee meeting, that we would like to have the data such that maybe there are products which shows the same clinical efficacy, and it should show the same DPK values.  And the product that showed differences in the clinical efficacy should show the differences in the DPK.  
		That was an excellent idea, but the problem comes up is where shall we go and find such products?  Well, this is one example where we are talking about the clobetasol propionate.
		This is a topical steroid, and two different -- slightly different forms of products that are on the market.  One is called the emollient cream, and the other one is called just the plain cream or the Temovate cream and the Temovate emollient.
		Here are the two products.  One is the innovative product, and this is the generic product.  We see that both products have the same clinical efficacy, because they are both based on the data, and this is the Temovate-E product, which is supposed to be different clinically, because the labeling of these products indicate that these two are not the same.
		This is more potent than this one.  Now all these products contain exactly the same amount of the active ingredient, which is 0.05+ clobetasol propionate.  
		So here we can see clearly that the products which has same pharmacodynamic response, same clinical response, same DPK response, the products with different clinical indications having the different DPK response.
		Also there was one more challenge which has come up of the same nature that we need to take a look at the products similarly.  That was the glucocorticoid but not directly applicable, plus there were some concerns that when we take a look into the DPK, we are really trying to move away maybe to some extent for some of the products like tretinoin where a follicular pathway is supposed to be playing some role.
		So we started looking for a product, and we are fortunate enough to find this product.  We have three products here.  One is called the Retin-A gel, which is the innovator company; another product which was first based on the clinical data, which is the Tretinoin gel, same concentration made by Spear; and the third product, which is the Avita tretinoin gel, .025 percent, made by Bertek.
		Now the clinical findings were the product A is equal to product B.  These two products were equivalent, and they were both approved, and they are labeled as interchangeable products.  But when the studies were done comparing the product A and product C, the finding was they were clinically different.  They were not the same.  But the product C was approved primarily because it was effective.
		Now these three products contain exactly the same amount of the active drug, all in the form of a gel.  So we thought it would be a good idea to take these particular products, these three products, and do DPK dermatopharmacokinetic studies, because the clinical is already established.  So let's do that.
		So we are doing the research right now at University of Utah to confirm and validate the clinical findings that A is equal to B, and A is not equal to C.  This is then the ongoing study, and I would really indicate here that this was the example which was again discussed at the last Joint Advisory Committee meeting and the strong recommendation had come from this Advisory Committee meeting that the study of this nature needs to be done, and that is the ongoing study right now.
		May I have the next slide?
		Okay.  then coming back to the second question as to whether can the DPK differentiate between the different formulations.  Now what do we mean by that?	
		Well, it should be having the same vehicle but different concentrations of the active.  by that, we mean it may be the different concentration/dose response relationship.  Very often we know that it cannot be achieved with the clinical findings or the pharmacodynamics findings, but can we see such responses with respect to the DPK?
		The second question was can the same concentration of the active drug but different vehicles could be differentiated by the DPK, which meaning that they are significantly different formulations.
		The third question which also comes up is can the DPK predict the properties of a vehicle?
		With these questions, the first question was can we see a good dose response relationship or not, and we see here that there is an excellent dose response relationship between the concentration of the tretinoin preparation and the concentration of the amount of the drug in the stratum corneum, and we see there is a nice, clear response.
		On this side, what is shown is by the tape stripping method, as you go deeper and deeper inside, the concentration starts falling down, and that is exactly what is being observed here.  So again, this shows that we can very easily see a nice dose response relationship with the tretinoin.
		Now we have seen this kind of dose response relationship for several other glucocorticoid drug products like betamethasone dipropionate and quite a few others, this kind of response is seen, but this is just only one example to show that.
		Now here is the example of the Temovate preparation which we saw before, that there are two preparations which have almost the same formulation, the brand name and the generic name, and there is a Temovate E which is a slightly different formulation.
		We can see that with the differences in the formulation, again it could be easily picked up by the DPK.  This is the same slide that I had shown earlier which can differentiate between the clinical efficacy or the clinical settings and the DPK concentration.
		So to summarize these concerns, the relevance to the clinical efficacy data, I think it could be done.  Ability of the DPK to differentiate the formulations, I think it can be done.  And then the question comes up can the DPK predict the properties of the vehicle?  I think, yes, that could be done also.  We have several example with the glucocorticoids, especially that when the formulation is different in terms of the vehicle like betamethasone dipropionate, Diprolene and Diprosone creams, which the major difference between the two is the vehicle, that can be easily picked up by the DPK data.
		The question comes up with the reliability and the reproducibility of the method.  At least in my opinion, we have shown that the method is very reliable and reproducible, because we have in-house a study right now where the same product has been studied by two different investigators, and we come up with the same results, or a same product studied by the same investigator a year later, we come up with the same kinds of results.
		So at least in essence, in principle, the reliability and the reproducibility of the method has already been established.
		Okay.  Then what are the applications of the DPK?  Again, my main question again is to take a look into the bioequivalence assessment, comparing the test product and the reference product.
		So at least the way I see it is it could be definitely used for the comparison of the two products, test and the reference product, but there is also a possibility, which I hope that Dr. Wilkin will go into more details about it, that the DPK could also be applied in terms of the bioavailability assessment, especially when you are measuring the bioavailability of the product and the application of line extensions.
		That's where the DPK could be useful, during the bioavailability area.  But again I want to go back and say that my focus is going to be taking a look into the bioequivalency areas.
		Okay.  Just to summarize and come back to the conclusion, what do we mean by the bioequivalence and what type of products we are looking at:  We are looking at the same percent of the active drug.  
		We are looking at the same route of administration or the same type of application, the topical application, and we are also looking at the same dosage form category; that is, comparing the cream versus cream, ointment versus ointment, and gel versus gel.  
		We are not going to use the DPK for the bioequivalency purposes to compare like cream versus gel or ointment versus gel or anything like that.  Our comparison is going to be strictly between the cream versus cream and so on and so forth.
		Generally, in our comparisons, as it is required for the generic products in our 21 CFR, that inactive ingredients of the generic product has to be essentially the same, and nearly the same amount.  So what we are indicating is generally it should have qualitatively the same ingredients, which we are identifying it as Q1, and also the same amount of ingredients, which is approximately +5% of the composition.  
		So we are looking at nearly the same composition, same inactive ingredients for the bioequivalency purposes of making the comparisons.
		Sometimes what happens is, even though it may have the same inactive ingredients, same composition, depending upon the rate that people are manufacturing it, the rate is prepared.  It may end up in a slightly different finished product.
		In order to take care of both types of issues and the scenarios, we have added what we call as an in vitro release or the drug release from the formulation itself.  
		So for the bioequivalency comparisons comparing the test and the reference product, we would imagine that the bioequivalence documentation would require the dermatopharmacokinetics.  Also the product has to be Q1 and Q2, and we would also add an in vitro drug release, which will take care of the manufacturing variabilities that might be seen with the same formulations.
		Now I should indicate that there has been a lot of work done in this area by Professor Flynn and other people who have really clearly indicated that this would be a good approach to do that.
		In addition to that, we have the guidance out which is called the SUPAC-SS, which is for the semi-solid preparations, and even in that guidance we are allowing for the site of manufacturing changes and the other changes, the in vitro drug release to be a key factor.  If the drug release is the same, then we would imagine that -- We would assume there is no further change in terms of the activity of the product, and we would be approving that.
		So -- Okay, this I just talked about.  I didn't know that I had the slide.  In vitro release can differentiate between the different formulations, between the two products manufactured differently, and the products containing the different particle size of the active drugs.  This has been also used in the SUPAC-SS.
		So then what is really needed for us to accept the DPK?  Number one, we need to have a validated tape stripping or the skin stripping procedure, validated analytical methodology.  We also require a mass balance of the information/study data on that.
		The sponsor needs to conduct a pilot study, the pivotal bioequivalency study and the DPK data which should meet the 90 percent confidence interval for the bioequivalency limits of 80-125 for AUC and Cmax.  This is exactly the same kind of criteria we have now for all orally administered products.
		The advantages of the dermatopharmacokinetic technique is:  It is a noninvasive procedure.  It shows a good dose response effect.  It can differentiate significantly different formulations.  It measures the drug concentration in the vicinity of the action in the skin.  It is a  sensitive, reliable, reproducible and cost effective measure.
		Very recently we heard, just before I came up, a nice presentation from Dr. Wilkin who indicated that we need to be aware of the three R's.  At least I think that this does fall into the same category that we can meet all these requirements of the three R's of the regulatory people with this DPK methodology.  It is applicable to all topical dermatological drug products.
		The only disadvantage I see is it requires the validation of a tape stripping procedure.  It's not that easy, but it is not that difficult either.  Somebody has to spend some time just like people learning the use and operation of the HPLC or a DC or any other technique.  They need to spend some time so that they can do it, and it could be done, but that's a slight disadvantage.  It requires a good sensitive analytical methodology and validation.
		Okay.  Now what is the skin stripping procedure?  This is just in brief.  You apply the test and the reference drug products concurrently at the multiple sites.  It's on the forearm.  I'll show the picture in a minute.
		After a certain time interval, you clean the area, and apply the adhesive tape.  At least some of the different work that we have been doing in the different laboratories is using either Transpore tape or a Cuderm tape, but people can use any other adhesive tapes, as long as they validate the information.  With uniform pressure, remove and discard the first stripping, because we feel that the drug has not been completely penetrated, and what is remaining on the top is removed.
		We apply and remove, collect nine successive tape strips at the same spot.  Extract the drug, and determine the concentration using the appropriate validated analytical method, and express the results as amount per surface area.
		It is important to know that each application site yields a single drug concentration in the stratum corneum, and this is just an example, that the drug uptake,  how long it takes for the drug to come up to the maximum concentrations.  It could be done -- The samples could be removed at the end of 15 minutes, half an hour, one and three hours, and you can follow the same drug elimination pattern, like making the tape stripping and concentrations at three, four, six, eight and 24 hours.
		This slide just shows an example as to how the arms are being used, the left arm and the right arm, for the drug uptake and the drug elimination.  Also in order to make sure that we take care of the variability information, it is the same -- applied for the same time duration in both the sites, and this data would provide us the variability between the active procedure of the skin sites, the site of application and all.
		Similarly then we have a system where we can do the drug uptake and elimination for the test and the reference product, and that would result into the bioequivalency study.  Only important factor is we have to use the sufficient number of samples.
		What we end up is in a profile of this nature, this is the true data from 40 subjects for product A and B.  One of them is the generic product.  The other one is the reference product, and you see that both of them are almost giving us the same kind of information, how rapidly the drug is penetrating or being absorbed into the stratum corneum, and how it is eliminated after it is absorbed.
		So that's in terms of the DPK information.  In the draft guidance we had indicated that it should be applicable to all topical products, including the vaginal drug products, retinoids and all the other classes.  
		We had also indicated that we would like to shift the envelop a bit more and go up to -- Q1 has to be the same, the same inactive ingredients, but Q2 can be +10%.  But there were some comments from some of the folks and the experts that, no, we should not do that; we need to be a little bit more considerative, and in order to achieve that, they said that, okay, you remove this from the -- that it will not be applicable for the vaginal drug products, and change this Q2 from 10 to 5%.
		That's what we intend to do in the revised guidance when it will be coming out, that it will be applicable to all the products, to retinoids and the other products, and not applicable to the vaginal drug products, with the Q1 and Q2 being +5%, and also we will be adding the in vitro release test.
		The reason why we feel that the retinoids should be also included is, as you may recall, just a few minutes ago I showed a slide where we are right now doing the studies using three different tretinoin gels at University of Utah.  
		Those products were also selected not only from the clinical endpoint but also to take a look into consideration that people feel that those products has a follicular pathway as an important route for the drug to reach its effective concentrations.
		If we find that our clinical data and the DPK data are in agreement with one another, then this would be applicable.  That's why we are leaving the retinoids into this.  We hope to have the final data completely analyzed of that nature before we come out with the final guidance on that.
		So with that, if we take the different classes of the drugs, starting with the antifungals, glucocorticoids, antibiotics, antivirals, the retinoids and the vaginal drug products, using the DPK, I think the vaginal drug products might be at the highest risk, and the antifungals are at the lowest risk; because these are the ones where you measure the concentration in the stratum corneum, and that's the site of action, whereas the others are slightly different.  This would be from low risk to high risk, would be the assessment of all these topical drug products.
		So in my conclusion, then I would indicate that for the bioequivalence determination, the primary means to document the bioequivalency will be the dermatopharmacokinetic data, and the supportive information will be coming from the in vitro drug release, the particle size distribution of the active material of the drug substance.
		The DPK is a reliable, reproducible and relevant method to document the bioequivalence between the test and the reference products, and again it is applicable to all the drug products, and is also cost effective, because it is less expensive and more reliable compared to the clinical studies.
		Again, this is only for the bioequivalency purposes.  There are other methods also that could be used, but right now we have more information on the DPK.  That's what I mean here by saying that DPK is a reliable method, and some of the other approaches that we are trying to study and look will be discussed later on by Dr. Ajaz Hussain.
		So I think this is my last slide.  With this, I would like to thank the Committee for listening to me, and will be happy to answer the questions either now or towards the end, as the Chair decides.
		ACTING CHAIRMAN DRAKE:  Dr. Shah, I think I'll use the Chair's prerogative and save questions until we have heard the three presentations, because often these questions get answered.  But I thank you for an excellent presentation.
		I believe now, Dr. Wilkin is coming next.
		DR. WILKIN:  Dr. Drake, members of the Committee, members of the audience, I would like to talk about the issues and opportunities.  I think there is some potential here that certainly needs to be explored, not only for DPK but for other alternative methodologies.
		I would like to say, though, at the beginning that I think there are two ways to get to DPK at the moment.  One would be from the database or from first principles; that is, logical, inferential kinds of steps.
		I would make the argument that we don't really have the logical structure to get to DPK at the moment inferentially, and that the database is -- It's got some important and supportive kinds of information, but it really is not sufficient at the moment.
		DPK -- If you really think about it, DPK is intended to pick up the differences in the vehicle between two topical products where we know that the active is going to be there.  It's the same identical active, and it's in the same identical concentration.
		So what we are really thinking about is how well does DPK tell us what is going to happen in the clinical setting because of a different vehicle?
		So I would say that there is probably insufficient evidence to adopt DPK now, but I think there is hope for the future, and it absolutely must be explored.
		There are three parts of validation of any assay technique.  The first is:  Is it reproducible within a laboratory.  I think this probably has already  been accomplished for DPK. 
		The second is: Can it be reproduced among different laboratories, looking at some written recipe?  I believe that there is great potential for that.  I'm not sure that I have seen the evidence, but I think that is extremely likely that that will occur.
		Then the third level of validation is understanding how it relates to the current standard.  The current standard is the clinical trial.  Is it really answering the same question that the clinical trial would be answering?
		Now this is a graphic from one of Dr. Shah's earlier papers, and he emphasizes what eventually I will be calling the grand analogy, that the plasma concentrations for drugs that are given orally -- that that area under the curve really has a lot of the same logical content as the area under the curve for  dermatopharmacokinetics.
		So what is dermatopharmacokinetic?  Kinetics of drug in the skin, pharmacokinetics applied to the skin.  
		Now there is a difficulty for me with the word  dermatopharmacokinetics, because that means skin.  What we are really talking about is stratum corneum.  If you look, this is the epidermis up here.  It's the baklava type layers on top of the sea of collagen that has the blood vessels and the other ingredients that sits on the butter.
		What we are talking about with the stratum corneum is not really the entire stratum corneum in DPK.  We are talking about just the upper layers of the stratum corneum.  It is not even all of the stratum corneum.
		So I would point out that we are really talking about a very tiny, very superficial portion of the skin, even though we are referring to this as DPK.
		So again, perhaps this could be misleading to someone who reads about DPK very superficially, and I have suggested that, you know, some other terms might be identified to really more properly identify next.  But that is really a minor, trivial issue compared to the fundamental issue of the analogy between the plasma area under the curve and the stratum corneum area under the curve.
		The question is:  Is the DPK area under the curve truly analogous to the plasma area under the curve for oral dosage forms?
		I've got a catalog of concerns that I have with this grand analogy.  The first is that, of course, the stratum corneum is not the same thing as the skin.  The skin has a lot of structures in it.  It is very heterogeneous.
		The stratum corneum is not the sole pathway to get from the surface down to where the action site is.  There is a follicular pathway, and the follicular pathway in the literature has been regarded as quite important for some agents.
		The stratum corneum is not a real compartment.  Unlike the blood, which is well mixed and which the active is an equilibrium with the active site, the stratum corneum is not well mixed, and the drug that is the -- the active drug that is in the stratum corneum is not an equilibrium with the actual target within the skin.
		Then my final concern is that this is all based on this superficial portion of the stratum corneum, and that anatomic area is actually absent in much of the skin diseases, and it really has no cognate in the lip or in the vaginal mucosa.  There has been some consideration that DPK would be used to approve products for these sites.
		Okay.  We will go through that list in just a little bit of detail. For the oral dosage forms, again they get dissolved in the gastrointestinal juices, and that really represents the vehicle, if you will.  There's a lot of homeostasis that keeps that gastric fluid relatively similar.
		So in essence, for solid oral dosage forms, the vehicle is pretty much the same for all of those forms, and yet DPK -- that's what we are interested in, is how does the vehicle differ from one topical to another -- The active then migrates through the gut wall.  That's the biological limiting membrane area.
		To my way of thinking, that corresponds, really, to the stratum corneum.  Then once you get beyond the gut wall, for these agents that are circulating in the blood stream, they are intended to have some activity in the heart, the kidneys, the brain and so on.  
		It is important to have the active in the blood, be able to make it to the target organ, and then it's an equilibrium, and that equilibrium is an important aspect of our modeling and interpretation of what the plasma blood level can actually mean.
		So again, the plasma blood level -- this is well mixed, and there is an equilibrium with the target organ.
		Equilibrium is essential to the notion of interpreting plasma AUCs.  Plasma levels produced by two generic formulations should be similar at equilibrium, as their plasma level tissue/tissue level ratio will remain constant at equilibrium.
		Now let us evaluate what happens in normal healthy skin, which is where DPK is going to be studied.  The vehicle will be applied to the surface of the skin.   There are two pathways to get the active down to the action area, which might be the viable epidermis or it might be in the superficial dermis.
		One pathway is through the stratum corneum.  The other pathway is through the follicle, and then again there is really no equilibrium here.  There is more of a kinetic flow kind of mathematical model for this.
		Again, one of the key questions is that healthy stratum corneum does not exist in most skin disease and, certainly, in the lip and the vaginal mucosa.  So that what will happen is the vehicle will be applied to the remnants of the stratum corneum, and the remnants will be those lower levels.
		So that the upper levels tested in DPK will not be there for most of the disease entities in dermatology for which these topical products will be indicated.  Next slide.
		Okay.  So Jamoulle & Schaefer have actually commented on this.  When a dermatologic drug is used, it is usually applied to diseased skin, which may not have the same permeability as healthy skin.  To simulate diseased skin, the stratum corneum can be removed.
		So to recap the concerns about the analogy with the plasma area under the curve, for topically applied products the vehicle is actually the in constant that we really want to know something about, what its attributes are, how it is altering the performance of the topical product, and it is again in constant.
		On the other hand, for solid, oral dosage forms, they make it to the gastric juice which is relatively constant, and so that I see a substantial difference there.
		The stratum corneum is the biological  membrane that is the penetration barrier that needs to be crossed for topical products.  For oral products, it is the GI mucosa.  One of two pathways to the target is the stratum corneum.  The other is the follicular pathway.
		The stratum corneum amounts may not predict the follicular pathway.  There is certainly a huge difference in the stratum corneum between healthy and diseased conditions.
		The stratum corneum is not well mixed.  There is no equilibrium with the target, and it is absent in the lip and in the vaginal mucosa.
		I don't think there is a cognate with the topical pathway and getting from the surface, the area of application, to the action site that exists for the organs like the brain and the heart and the kidneys when you are giving a solid, oral dosage form.
		Here you have the plasma or the blood.  It's the single path to the target.  In healthy and in diseased states, it's generally very much the same with only a few exceptions.
		It is well mixed, and there is an equilibrium with the target, very important for interpreting this model.
		One of the other difficulties in the dataset for DPK as I have seen it is that it is looking at initial doses, and there is the concern about the metabolic activity and permeability of the skin may be changed under the effect of repeated exposure to the product during a toxicity or clinical study.  The longer one is using the product, one can alter enzymes.
		Dr. Shah mentioned the enormous history of DPK being discussed, and I did attend one of those workshops, and a document emerged from that workshop,  "The Bioequivalence of Topical Dermatological Dosage Forms: Methods of Evaluation of Bioequivalence."
		This was one of the key lines that -- It was a consensus document, and I would just remind everyone that what a consensus document is, is that you get lots of people signing off on a document that, if they were going to be the only signatory, they probably would not have signed off on it.
		This was the line that, I think, helped a lot of us who participated in this consensus document.  "Before a DPK method is adopted as a basis for bioequivalence, it must be shown that the differences in  dermatopharmacokinetics capture or reflect significant clinically important differences in formulations."
		Now Dr. Shah has also mentioned that at the October '98 Joint Advisory Committee meeting we talked about what kinds of evidence might be very helpful to meet this informational need.
		First of all, I think, if the DPK is going to be accepted for all topical products -- you know, a really wide variety -- that we ought to have evidence from several therapeutic classes that represent different targets within the skin.
		The second aspect of this is the evidence should come from blinded, three-arm comparisons where there is a reference product, a product that has been found to be bioequivalent in clinical studies, and a product that has been found to be bioinequivalent in clinical studies.
		If we had data from that kind of comparison, that would truly be supportive for DPK.  While I find it difficult to accept DPK on first principles, I think we could get there pragmatically with a database that showed that, in fact, it does do what the intended claim is.
		Again, I think DPK cannot be derived from first principles, that it is underdetermined by the current dataset, and my thought is that the really broad applications that are within the current draft guidance, that either the draft guidance could be withdrawn until adequate evidence exists for all of those or, alternatively, based on some new information that is coming in once that information has been evaluated and we have had -- perhaps the Advisory Committee has been involved in looking over the dataset, it might be that the draft guidance, instead of really being withdrawn, would be modified to really match the data.  In other words, it might be limited to one particular class of compounds at the very beginning.
		Next slide.  So although there are insufficient data to support the regulatory utility o dermatopharmacokinetics at present, I do believe the assay has potential for bioavailability and bioequivalence determinations for topical products that should be investigated.
		I also salute Dr. Hussain's efforts to look at other methodologies beyond DPK for this same end.
		I do have another difference with Dr. Shah's interpretation.  That is, I see the potential regulatory utility of dermatopharmacokinetics exceeding the limitations imposed by qualitative and quantitative similarity between the comparator products. 
		I actually believe that, if DPK works, it is going to work independently of that attribute.  So that it would lessen the burden not only for the generics but also for new drug products.
		Thank you.
		ACTING CHAIRMAN DRAKE:  Thank you, Dr. Wilkin.  As usually, a very excellent presentation and thoroughly understandable.  Again, I would beg the indulgence of the Committee to defer the questions until we have our third speaker.
		Dr. Hussain, I believe, you are on.
		DR. HUSSAIN:  Good morning.  My presentation will focus on methods for assessing bioequivalence for topical products.  The question I am posing here is how should FDA redirect its research program?
		In my handout material to the Advisory Committee, I have included a number of slides which deal with some ongoing efforts, such efforts on vaginal products.  My intention is not to really discuss those, but have those for the Advisory Committee as an example of what could be done from a reductionist approach.  So let me have the next slide.
		I would like to start with some distinction between bioavailability and bioequivalence so that we provide a framework for thinking about research approaches for assessing bioequivalence.
		Clearly, the factors that affect bioavailability and bioequivalence are similar, but bioavailability tends to be in an absolute term.  What amount of drug gets absorbed, and at what rate does it get absorbed?  It is more of an absolute value.
		Bioequivalence tends to be a relative comparison.  I just want to share some thoughts on that.  Factors that affect bioavailability include:  Drug attributes.  This will include solubility and dissolution rate of the drug in the vehicle itself, size of the drug molecule, the charge on the drug molecule, membrane permeability characteristics, and metabolism characteristics of the drug molecule.
		The vehicle, obviously, has a significant impact on bioavailability, and here you could also look at how efficient is the vehicle in dissolving the drug and allowing dissolution to occur, how quickly the vehicle spreads, does it adhere to the skin or to the membrane applied, and also its ability to change the characteristics of the membrane on which it is applied.
		Clearly, the membrane attributes are of importance:  Status of the barrier function, exudates and other fluid secretions that may or may not be present, blood flow to the organ or the tissue site of application, its metabolic capacity and so forth.
		Also, I think bioavailability clearly is impacted by method of application.  For example, if you apply a gel and just simply leave it or you rub it in, and so forth, could have a impact.  
		If you focus on bioequivalence of a topical product, I think the question we are asking is:  Do we see equal rate and extent of exposure at the intended site of action or sites of action?
		With respect to understanding the basic absorption processes, I think equivalent rate of membrane penetration and permeation is a must to see equivalent rate and extent of exposure, and rates of membrane penetration and permeation will depend on function of the vehicle and its effect on these processes, as well as how the rate of drug release is effected from the vehicle itself.
		Also important in this equation is equivalent application site, formulation contact time and area, and also inherent in that is I think you would like to see equivalent or better systemic exposure, because systemic exposure is a body burden and not truly a desired exposure pattern.
		In order to talk about how should FDA redirect its research program, I would like to share with you some brief information on the current research projects.  We are doing some work on DPK, as you heard from Dr. Shah, as well as just a brief mention.
		We started a project last year to address issues, concerns that were brought to us by the medical -- or clinical sciences here, and there is a working group called Topical Microbicides Working Group.  These product are being developed to prevent STD and AIDS transmission in women.
		We had concerns with respect to the deployability or distribution of these formulations in the vaginal cavity.  So we started some work, and we are using a sort of reductionist approach, trying to identify the key processes, the critical processes that would affect the way a formulation was spread and for what coverage in the vaginal cavity.
		So that is the research as an example of the reductionist approach.  As I said, I will not discuss that at length here.
		I would like to then share with you some thoughts and proposals of such projects.  What body of evidence is needed for regulatory acceptance of DPK is sort of a question?  Other tests to complement DPK, is that a way to go, or do we need to go and look at new methods for bioequivalence assessment?
		The current activities with respect t dermatopharmacokinetics research:  You heard from Dr. Shah, we have a study which is essentially almost complete now with Professor Lynn Pershing at the University of Utah.  The key FDA investigators on this have been Surendra Shrivastava and Don Hare.
		We are not presenting this dataset here today, because this was done in a blinded fashion, and we will complete the analysis and bring it back to the Advisory Committee when the study is complete, and you already have the information on what that study is.
		What we are doing at present in our labs is actually trying to repeat some aspects of the study.  There have been some concerns raised that this method may or may not be reproducible in different labs.
		We felt that, if we are able to have some hands-on experience with DPK and actually are able to show that this is a reproducible method, using individuals in our lab who have not worked with this technique before, that would add to a level of confidence with this method.  
		So you have FDA investigators from the lab as well as from different areas of review sciences who will be doing the study.  So they will have their own hands-on experience.
		In addition to that, what we are doing is we are exploring the feasibility of other techniques.  At present, we are looking at -- we have the capability in-house, and we are looking at using near infrared spectroscopy as a means for quantifying drug levels in stratum corneum.
		We are also exploring different methodologies from spectroscopic methods as well as imaging methods to see how one can quantify drug levels in skin in a noninvasive manner.  
		I think we will be planning to present some of our thoughts and feasibility data next time when we meet with you.  However, I think the question here is:  Even if both studies that we are doing are positive, would this evidence be sufficient to introduce DPK in regulatory practice?
		I think the answer will be yes or no, depending on -- I think that is the discussion we are having.
		Clearly, Dr. Wilkin has pointed out several concerns with respect to this approach.  In order to address those concerns, we have to take a look at those concerns and try to elucidate a reasonable process to address those concerns.
		Let me start with some of those concerns. Stratum corneum is not skin.  I think that is obvious.  I think the other is it cannot be derived from first principles.  
		The way I look at that concern, I think from my perspective, it deals with the issue of generalization.  Can we generalize the available data which may be limited to certain classes of drugs to the rest of the population of formulations out there, and so forth?  
		Generalization of regulatory finding, if it's empirical, is always a challenge, and we will try to address that.  Obviously, clinical relevance is a question.  
		I just wanted to share my personal opinion with respect to DPK.  I think with respect to the technique itself, if we are going to measure bioavailability on a healthy stratum corneum, obviously, that is not going to give us accurate information on bioavailability under disease conditions, as the lips, vaginal, for example, different routes of administration.  So that is not the intention.
		So the key questions, I think, in my mind are as follows:  Can comparable DPK profiles be used to assess bioequivalence between two pharmaceutical equivalent products; and the pharmaceutical equivalence is quite rigid in this particular scenario, not only that products have to be cream versus cream, but in addition to that, the strict requirement on quantitative and qualitative similarity of excipients.
		So if we pose the question now as equal in stratum corneum exposure -- and I'm showing that as a ratio or reference to stratum corneum levels -- is that equivalent to follicular exposure?  That means having the same ratio between test and a reference formulation for stratum corneum levels.  Would that imply that the follicular or appendagial concentration ratios would be similar?
		Secondly, we could ask, equal in stratum corneum, exposure is equal to exposure in disease states.  Thirdly, I would like to share some of my thoughts on does Q1 and Q2 criteria ensure equivalent physical attributes of a multi-phasic system?
		Dr. Wilkin has alluded to the fact that I think this probably is too restrictive, and I actually would like to see if we can expand and move away from this criteria, not only because I think it is an artificial divide, but there are several management issues that it sort of brings to FDA, and I think if we can move away from this, that will be a better approach.  However, since excipients vehicles are being applied directly to a membrane without dilution, the challenge is how do you address the effect of these vehicles on skin or any of the membrane that they are being applied to?
		Let me go on.  So let me rephrase the concerns that we have heard into something which we could sort of reduce it to, projects that might be helpful to move forward.
		The postulate here is that two topical products applied to skin surface provide equivalent rate and extent of drug exposure in all layers of skin when these products exhibit:  (1) equivalent thermodynamic activity of drug in vehicle; the two vehicles have similar interfacial transport kinetics, and I think that is where the concern or the issue between stratum corneum versus follicles come into play.
		The effect of excipients on skin permeability has to be similar, and this is where the concern between healthy versus disease conditions come into play.  And then skin contact time and area:  here also, I believe, healthy versus disease questions can come into play.
		To give you an example, if you are comparing formulations on healthy stratum corneum, the rate at which water evaporates from that is pretty much fairly, I would say, constant among individuals.  Constant is the wrong word, but I think -- But now if you are comparing that to a diseased skin where stratum corneum is damaged, you have exudates.  You have secretions that come in.  Would the two formulations absorb those exudates to the same extent or similarly?  So that becomes a question there.
		Let me use the follicular -- next one -- transport issue and try to see what sort of -- how do we move forward in this arena.
		As I said earlier, equivalent stratum corneum exposure is equal to stratum follicular exposure.  That is the question.  Clearly, from a basic physical chemistry and diffusion perspective, I think -- and knowledge of the distribution of follicles and their prevalence on skin, we could say likely -- this is likely when drug is in solution and the formulation is a simple formulation, as the single phase formulation.  However, at the same time, you have to look at what does equivalent stratum corneum exposure really mean?
		Equivalent stratum corneum exposure implies that you have equivalent thermodynamic activity plus the impact or effect of those excipients on the stratum corneum was similar.  So there are two components to that equation.
		I think equivalent thermodynamic activity is not really a concern here because of the nature of what we are doing.  We are comparing to pharmaceutical equivalent products.  But the issue comes on effect of excipients on stratum corneum.
		Clearly, there will be a higher potential for seeing differences between stratum corneum and follicular exposure when the drug is either encapsulated in the formulation or is a suspension where particle size differences could contribute, and/or it is a multi-phasic system.  You have a cream formulation, and the distribution of drug in the cream, depending on the droplet size and so forth.
		However, I think we could also address that.  I was looking at the Physicians Desk Reference, PDR, and you see there is already a product on the market which I believe -- at least my sense is -- was intended to essentially improve or reduce the adverse effects of this drug, Retin-A Micro. 
		It is an acrylate copolymer porous microspheres.  So this product contains microspheres with the drug.  However, if you further read in the PDR, it has not been able to claim -- and I will quote from the PDR -- "contribution to decreased irritancy by Microsponge system has not been established."
		There is a body of evidence saying that targeting two follicles using encapsulation, liposomes and so forth, have not really been very successful to date.
		So there are means for modulating exposure to follicles, and I think that could be used as a challenge to the question that we have set.  Let ;me go to the next one.
		I think I have tried to sort of put a cartoon together to explain what that really is.  What you see here in this figure is you are looking at a multi-phasic system with different droplet size of particle size.
		Based on the anatomy of the follicles, some might get in.  Some might not.  I think that is what we are talking about in this case.  Also, I think there have been numerous reports where -- or tools available now that could modulate or that could change the distribution of drug.  
		I am talking about techniques such as iontophoresis which can enhance follicular penetration, or you could look at low intensity ultrasound.  That could actually shut the follicular penetration down.   
		So you have tools available that could be used to modulate distribution, and then see whether that could be used as a challenge to the DPK and probably compare that.  There are opportunities in that regard.  Go on.
		At the same time, I think we can bring to bear some mechanistic and other techniques to evaluate this issue.  So there is a possibility of developing a mechanistic evidence base plus distribution and imaging approaches.
		I think, just to go down on this side, what I would like to say is supporting evidence can be generated via in vitro experiments using excised human skin.  In vitro experiments using excised human skin is a well established technique in industry, and that is quite used with respect to when formulations are being developed.  
		It has not been accepted in regulatory practice, and I think we have been looking at that as a means of bringing back and looking at some mechanistic analysis.  I think one concern is the viability of the skin, and that can be addressed also.
		If we use this tool, what can we do?  We could look at different anatomical sites.  We can obtain skin samples from different sites, and it is possible to maintain viability, if necessary, for, say, about 24 hours.
		We could emulate compromised stratum corneum barrier functions, and provide indirect supporting evidence via transport and skin distribution studies.
		We could also get direct supporting evidence via visualization of follicular and nonfollicular transport, and bringing into play techniques such as laser scanning confocal microscopy.  That is not the only one.  There are other techniques available.  Next one.
		So I think the question is what body of evidence is needed here?  Clearly, we have empirical evidence, and this comes in the form of comparative evaluation between DPK and clinical studies.
		I think it is always a challenge when you deal with empirical studies as generalization.  Empirical data essentially provides proof of concept for products that are being evaluated.  Generalizations beyond that is a challenge.
		For generalization, obviously, I think at least my way of thinking is mechanistic and reductionist approach might be a way to do this.  Clearly, DPK has been in development for a long period of time.  I think I am correct, Dr. Shah mentioned about ten, twelve years.
		It is time to look at other methods, too.  In the last ten years, there has been such a dramatic increase in development of new analytical tools and so forth, and we would really like to explore some new methods and new spectroscopic imaging techniques.
		We hope to provide to you next time when we meet some assessment of feasibility, but just wanted to let you know that any new method would take a significant amount of time.  
		DPK at present is the most developed technique in this area, and I think we would like to continue to provide the support for generalization and in the meantime work toward methods other than DPK.
		Just wrapping up, one more slide I will show you is the vaginal products.  The slides you have, the intention I had was to share with you a reductionist approach that we have initiated for this area.
		We are working with Professor Katz and the biomedical engineering school at Duke to do this.  The reductionist approach is simply identified as a processes, understand the mechanistic basis, and then bring them together.  So you have slides which essentially show that.
		At the same time, toward the end of the slides you will see in vivo analysis that show differences between formulations.  Just an example.
		I'll stop with that here.  
		ACTING CHAIRMAN DRAKE:  Dr. Hussain, thank you so much.  We appreciate all this information that's been put before us.
		What I would like to do now is take a few moments before we begin a full scale discussion to make sure if there's any questions.  I would ask the Committee to distinguish between discussion and questions that relate to clarification.
		So I would now call upon the Committee to see if you have questions for clarification from our three speakers before we begin the discussion.  Dr. Abel?  I don't think your mike is on.
		DR. ABEL:  Thank you.  I have a question as to the physical mechanics of tape stripping.  How is it done to ensure consistency between different researchers who are doing this?
		There is pressure involved.  Could someone describe the actual tape stripping technique?
		ACTING CHAIRMAN DRAKE:  Dr. Shah?
		DR. SHAH:  Yes.  We -- I can describe to you very clearly, and in case if you are not too clarified, we can have Dr. Lynn Pershing, who is here -- she can describe it in farther details, because she is the one who is actually performing it.
		What we do is we mark the forearm area with respect to the eight different spots and apply the tape.  The tapes also come exactly in the square, in the round size edge so that you can apply it to the spot.  Apply the pressure uniformly.
		DR. ABEL:  How?
		DR. SHAH:  By rubbing it, using a plastic ruler so that there is no effect on the tape itself, and that's how it is applied.  But additional work by Dr. Chris Surber and others has shown that, even though there may be differences in the pressure, it does not make any difference with respect to the amount you are removing it.
		We have also made available rollers by which you can apply the rollers and have the uniform pressure, but there is no need to do that.  So there are different techniques of doing it, but it has been indicated that it is not really necessary; because the different pressures do not make any difference in terms of the amount removed.
		ACTING CHAIRMAN DRAKE:  Other questions?  Yes?  Dr. Lamborn, right?
		DR. LAMBORN:  Right.  I'd like to --
		ACTING CHAIRMAN DRAKE:  Mike for Dr. Lamborn, please.  Thank you.
		DR. LAMBORN:  I'd like to ask Dr. Wilkin:  You had noted that you thought there was potential --
		ACTING CHAIRMAN DRAKE:  I still don't think we have her mike on.  Now let's try it.  Do we have all of your attention now?  Yes.  Now, Dr. Lamborn, would you try one more time?  If not, would you just speak real loud?
		DR. LAMBORN:  I can do that, too.  Basically, my question is:  You said that you feel there is potential, but that we are not there yet.  I would like your sense of what is it that you would think we would need, and do you think that Dr. Shah's studies that he is describing -- are they addressing that need, should they be positive, or are you saying that you would be looking for something very different from that in terms of what you would want to see in order to be convinced that this methodology was appropriate?
		ACTING CHAIRMAN DRAKE:  That question was addressed to Dr. Wilkin.  Try it again.  Can we get Dr. Wilkin's mike on?  Speak loudly.  You know, usually it's just a matter of pulling it closer to you, but I think that it actually is not working very well.
		DR. WILKIN:  Well, again I think Dr. Shah and his colleagues and those with whom he has been working, Dr. Pershing and others, have accumulated a lot of supportive evidence.  I think they have convincingly demonstrated that you can look at the same vehicle and detect different concentrations.  They will lead to different AUCs, if you will, in the superficial stratum corneum.
		So I think there is a really good substrate on which the critical test against the gold standard needs to be considered.  The gold standard is the clinical study, which is imprecise, admittedly, huge confidence intervals; but the important thing about the clinical study to compare a topical innovator and a topical generic is that, even though the answer is imprecise, it's the right answer to the question.
		What we are thinking about with DPK is we are going to have a precise answer, but is it the answer to the right question?  The question is does DPK tell us what is going to happen in the clinical setting?  Is it a surrogate for that?
		So I think it's just -- Basically, my way of thinking is a standard is the clinical study, and DPK needs to be validated against that particular standard.  The USP describes how validation can occur for CMC types of methods.  
		There has been -- I think it was perhaps NIOSH or Environmental Sciences, there was a commission that considered this for nonclinical animal types of toxicity studies:  How does one end up with a "validated" test.  
		I think that's the right learning piece for me, is that I would really like to see that there is a known product that has a certain efficacy and safety outcome in a clinical trial, there is a separate product that has the same kind of efficacy and safety profile in a clinical trial, and there is a third product that has the same active and the same concentration but, for one reason or another, doesn't have the same efficacy and safety.
		To my way of thinking, that kind of three-arm trial done in a blinded manner would at least tell us about that particular active ingredient.  
		DR. LAMBORN:  Well, that is actually my question.  As I understand it, that study is ongoing.  So my question to you is:  If that study, which is ongoing, turns out to be able to distinguish, will that meet the concern that you have or did you envision something broader?  Did you have the feeling that there needed to be multiple studies in multiple areas?
		Just as we are going to be getting the question as a group, if we feel that this study that is ongoing is sufficient, since you have specifically said you wanted something more, I would like to know if you feel that the study that is ongoing meets your -- what you would hope to see.
		DR. WILKIN:  Yes.  Well, I've seen the protocol, and I would say the protocol looks quite good, but it's always difficult to say before you see the results and the outcome of the study exactly what one would derive from it.
		Studies can end up being sufficient and determinative.  Studies can end up being -- I mean, the outcome of the study, to my way of thinking, could be that it does work, it doesn't work, or it might and we still don't know.  I think it depends on what the dataset look like.
		DR. LAMBORN:  But it is the type of study that --
		DR. WILKIN:  It is absolutely the type of study, yes.
		DR. LAMBORN:  Thank you.
		ACTING CHAIRMAN DRAKE:  Dr. Stern, and then Dr. Anderson.
		DR. STERN:  Thank you.  I have two questions, and I am not sure whether they are more for Dr. Wilkin or Dr. Shah.
		First question is:  Does it concern either of you that, when you look at a single preparation at various doses by this method, it looked like the curve showed very great differences in what the method showed; whereas, in clinical experience the differences in clinical response between those different doses is rather modest?  
		In a certain sense,  you are having a very much more sensitive measure of what is getting into the stratum corneum, but compared to at least the clinical impression of the magnitude of difference of clinical response.  That's my first.
		The second is in a certain sense a related question.  My understanding that the period of application before the tape stripping are relatively short, how long you apply it, how many days, how many applications; and I'm sorry, I missed exactly what the standardization is there; whereas, we are often talking about products that are typically used in the case of some at least for a week or two, and in the case of others sometimes we don't expect to get to a clinical endpoint with acne products for one to two months.
		So how much does stratum corneum concentration after one or two days tell us about equivalency at the end of two weeks for a topical steroid and perhaps two months for a retinoid or topical antibiotic?
		Those are my two questions.
		ACTING CHAIRMAN DRAKE:  Gentlemen?  Dr. Shah, then Dr. Wilkin.  Can we get that second mike working over here now?  It's on?  Bingo.  Thank you, sir.
		DR. SHAH:  Okay.  With respect to your first question as to whether, when we see the different concentrations in the stratum corneum when you are applying the different concentrations clinically:  Yes, that's true that the DPK is definitely more sensitive, and it is easy to pick up the differences than what the clinical is.  
		Now when we are making the comparison between the two products, the bioequivalency -- that's where again we plan to use the DPK to start with as a considerative approach.  We do want to make sure that the products are at least the same type of potency.
		That's why we take a look if there is 20 percent difference in the activity, can that be picked up easily by the DPK or not.  That's why we are moving toward a more specific, more sensitive analytical method.
		ACTING CHAIRMAN DRAKE:  Please?
		DR. STERN:  May I just respond, because --
		ACTING CHAIRMAN DRAKE:  But discussion, no.  If it's a question, yes.
		DR. STERN:  It's the issue of what it means to be sensitive.  The way I think about this is we have whatever we want to call the gold standard on the right side of the equation as the dependent variable, which is clinical response.  On the left side of the equation we have DPK.
		If there is more variance in DPK than there is in clinical response, that is not more precision but, in fact, that's a less good predictor of clinical response.
		So the idea of sensitivity for things on the left side of the equation that have more variance and are not well correlated with the -- are not good predictors on the right side, to me, does not mean sensitivity.
		So that is, I guess, a difference in interpretation.
		DR. SHAH:  No.  It is actually the opposite, and we are trying to --
		ACTING CHAIRMAN DRAKE:  I'd like to let Dr. Wilkin -- I want to make sure everybody gets to address a question.  Dr. Shah, we will come back to you.  Yes.
		DR. SHAH:  Could I respond to the second question, please?
		ACTING CHAIRMAN DRAKE:  Yes, you may.  Please.  Then I'll have Dr. Wilkin respond.
		DR. SHAH:  Second question was with respect to how long do we keep the drug on the stratum corneum before we take the samples.  More or less, that's what it was.
		Well, we have seen in the experiments that the drug diffusion through the stratum corneum is very rapid.  In fact, within 15 minutes you can see the drug has already gone down into the deeper layers.
		So the prime reason why we are trying to take a look and see these samples at earlier time point is really to pick out any differences between the test and the reference product with respect to its ability to penetrate, the rate at which it is going down, the rate at which it is diffusing through the stratum corneum, and then trying to see how long it remains into the stratum corneum, the rate of disappearance.
		These factors would really add in our estimation of the rate and extent of variability between the two products.
		ACTING CHAIRMAN DRAKE:  Dr. Wilkin.
		DR. WILKIN:  Well, I think Dr. Shah responded to the second, and I will just respond to the first question, and perhaps Dr. Tang may want to jump in on this, because I think it has to do with the statistical notion of the difference between accuracy and precision.
		In essence, we are going to have a DPK output.  We are going to compare that with a clinical trial output.  The first question is are they -- is the point estimate going to be the same for both?  Are they answering the same kind of question?
		A different way of looking at it is how closely the actual data points cluster about what the true meaning is.  There can be a lot of precision for -- and I think there probably will be a lot of precision for DPK.  The question is, is it really accurate?  Is it going to give us a precise answer to the right question?
		In the end, it may actually -- With the kinds of studies we have been talking about, we may believe that it is going to be an accurate predictor, but then precision may be a problem.  It may be overly precise.
		It may actually be a less expensive way to develop generic products, but it actually might be a higher hurdle.  You can think of it as a goal post, a couple of feet wide, because it's the dataset.
		ACTING CHAIRMAN DRAKE:  Dr. Anderson and then somebody else had their hand up.  Dr. Lamborn, okay, and Dr. Miller.  Okay.  But Dr. Anderson first.
		DR. ANDERSON:  Dr. Wilkin, you listed a number of concerns during your presentation.  I would just like to know if there exists a brief analysis of your concerns and a side-by-side response to those, what is being done or what could be done, etcetera, etcetera.
		DR. WILKIN:  Well, I haven't seen a side-by-side response to those particular concerns, but I think it's because my concerns are based on the -- I see two ways to getting to the acceptance of the DPK methodology, as Dr. Shah has proposed its regulatory utility.
		One would be getting there with first principles, and the other would be there on a more pragmatic pathway with substantive data.  I don't think that the first principles pathway is going to work.  I haven't heard responses actually to each one of my concerns about getting there with first principles, but I think Dr. Shah and others have focused instead on that second pragmatic pathway of, you know, how do we come up with the correct dataset that they can bring back to the Joint Advisory Committee.
		So that's my interpretation, but since I was the one that came up with the list of concerns, I am maybe not the one to really ask about the response to those concerns.
		ACTING CHAIRMAN DRAKE:  Dr. Shah, did you want a moment to respond to that?
		DR. SHAH:  Well, as you saw it in my presentation, we have moved away from calling this dermatopharmacokinetics as the skin level concentrations to the stratum corneum concentration.  I think this was again brought up at the last meeting, and we have changed that.
		So today, like I have referred to as definitely a stratum corneum concentration.  We are definitely not taking a look at the vaginal drug products.  I clearly indicated that we are moving away from that.
		So, you know, we have taken some of these concerns very clearly to address the issues, because as it comes up -- Our goal is not to keep on saying exactly the same thing, but try to make an improvement and move so that we can move forward with it.
		ACTING CHAIRMAN DRAKE:  Dr. Lamborn, and then Dr. Miller, and then Dr. -- Well, just let me interrupt.  Dr. Tang, is yours in reference to this question?  Okay, I'll come to you in a minute then.  Okay, Dr. Lamborn.
		DR. LAMBORN:  I'd like to follow up on the question of potentially over-precision of the DPK, because it is my understanding that, obviously -- that the thought was that, if the DPK was the same, then this would result in clinical equivalence.
		The question was then if, in fact, it was different, does that imply that it is going to be meaningful clinical differences?  Are you planning with this guidance to say that you must demonstrate DPK equivalence or I know in some instances you provide alternative ways which would say that you may demonstrate it either by DPK or by demonstrating equivalence in a clinical environment, if you felt that that was an alternative method?  What is the intent at this point of the guidance?
		DR. SHAH:  Right now the intent is it should be documented as bioequivalence using the DPK methodology.
		DR. LAMBORN:  And the clinical would not be an alternative?
		DR. SHAH:  That's right.
		ACTING CHAIRMAN DRAKE:  Dr. Miller.
		DR. MILLER:  This is for Dr. Shah, just clarification.  On the clinical data, Dr. Shah, that you presented on the tretinoin, you said that B equaled A, but C did not; but C was efficacious.
		Was it as efficacious as B and A?  Then are there preliminary dermatopharmacokinetic studies on C at this point?
		DR. SHAH:  Okay.  That's a very good question, and that question comes back, really, to the heart of the whole discussion which Dr. Wilkin had even pointed out in his slide that he would like to see this as a three-prong study completely blinded, and that's the way we are doing it.
		You are correct in identifying that A and B and the same, clinically exactly the same.  They are completely interchangeable.  But A and C are clinically different.  They are not the same, but the product was approved because it was shown to be superior than the placebo.
		So that is the way we are doing it.  It is completely blinded, and we are hoping next time when we meet we would be able to present this data, and again going back to what Dr. Lamborn indicated, hopefully, the DPK would be the same for the two products and different for a different product.
		Again, we don't know.  It's a completely blinded study, and it is ongoing.
		DR. MILLER:  Then my second question was on the clobetasol studies.  The emollient -- The  dermatopharmacokinetics, there was less concentration with the emollient product.  Is that correct?
		DR. SHAH:  That is true.
		DR. MILLER:  And do we have clinical correlation there?  Is the emollient less effective clinically than the others, but had the higher --
		DR. SHAH:  Yes, that's true, Doctor.  The PDR very clearly says that the emollient could be applied up to four weeks, whereas the non-emollient should not be applied for more than two weeks, again indicating that the potency -- how it could be applied.  That's an indirect evidence of its activity.
		I was very, very much surprised to see that type of DPK data, which again starts supporting some of our thinking process that we have.
		ACTING CHAIRMAN DRAKE:  Okay.  I have Dr. Tang, Mindel, DiGiovanni, and King.  Dr. Tang.
		DR. TANG:  Is this one?
		ACTING CHAIRMAN DRAKE:  Yes.
		DR. TANG:  This is regarding to the rationale issue.  You have the DPK and the two drugs are reference and the to-be-tested ones.  You have to see that clinical efficacy is reflected in the reference gel, for example.
		I know you show the equivalence.  I know you infer that the new drug is going to be effective.  I think right now what is lacking is from this DPK, how do you infer that this is clinically -- you infer clinical efficacy.  This will also depend on, as Dr. Wilkin showed Netter, that not only the type of gel or retinoids and also depends on the type of diseased skin.
		I think you ought to factor the type of diseased skin into this study design, because the key thing, I think, is generalizability.  How can you generalize this to a future product?
		ACTING CHAIRMAN DRAKE:  The question -- If I may just add a little point of clarification, and this was brought up at the previous Committee meeting, is the issue of diseased versus healthy skin, a very important point.
		I didn't see any data presented today regarding that, and I think the question is do you have data regarding diseased versus healthy skin?  I mean, that's at least a part of what you are asking.
		DR. TANG:  Right.  I think you ought to -- I mean, the dermatologists can really say more about it.  Maybe you should somehow classify the disease types, skin types.
		ACTING CHAIRMAN DRAKE:  Yes.  That's kind of getting into discussion, but let me just ask a very -- For those of you who haven't been with me in a committee meeting before, I try to get all the fact on the table.  Then it saves a lot of time when we get to discussion, because we've got all the facts there.
		So factually, have you done, as suggested in one of the previous committee meetings, studies on diseased versus healthy skin?
		DR. SHAH:  If you are thinking about having a stratum corneum concentrations on the diseased skin, which is DPK, it's impossible to get the stratum corneum.  When there is no skin, how can we get that?
		So, but we have some evidences, done by Dr. Lynn Pershing again, which would be supporting the fact that indirectly how it has been measured, but there is no direct measurement of the diseased versus healthy skin.
		ACTING CHAIRMAN DRAKE:  Dr. Mindel.
		DR. MINDEL:  I have been on the previous two committees that looked at this methodology.  The new data is the clobetasol data.  I had trouble -- a little trouble following that slide. 
		I want to ask one specific question, but first I would like to know where is that published?  Is it in the peer reviewed literature, you know, so it could be referenced, because since it is the only new data since '98, it would have been nice to have been able to look at it prior to seeing a slide that was very small.
		One of the questions I have -- I mean, I would like to understand what the ordinates and so forth are, but for the drug that has lower equivalency it says that -- it indicates that the neighboring region has a higher level.  At least, that's my interpretation.
		I'd like some explanation as to what neighboring region, how it was measured, and what that interpretation means, if there is more drug there than in the other products that have the better bioavailability.
		ACTING CHAIRMAN DRAKE:  Dr. Shah?
		DR. SHAH:  It's published in the journal called Skin Pharmacology and Applied Skin Physiology, Volume 12, page 34-45.  I think that is in 1999.
		ACTING CHAIRMAN DRAKE:  Just as an aside, for future reference, when this committee meets in the future, I would respectfully ask that any pertinent publications like that be included in our packet ahead of time, because that would help us all understand it a little better, and I think help us address your questions a little better.
		DR. SHAH;  Sure.  I will definitely try to do that.  This reference as well as any of the pertinent papers that might be coming out on this research.
		ACTING CHAIRMAN DRAKE:  Then just quickly, maybe you could help address Joel's other question.
		DR. SHAH:  Yes, that's true.  What happens is the neighboring area is one centimeter away from the main area where the drug was applied.  This being an emollient in nature, the drug spreads out, and as a result in the main area you do not see it, but with the emollient it just goes out, and that's where the higher concentration was seen.s
		So the adjacent area is about a centimeter away from the main application of the area.
		ACTING CHAIRMAN DRAKE:  Joel?  Okay?
		DR. MINDEL:  Well, I think that raises questions, I think, that are better asked by the dermatologists than by me.
		ACTING CHAIRMAN DRAKE:  Okay.  Dr. DiGiovanni, I had you down next.
		DR. DiGIOVANNI:  I had two questions, the first one, I believe, for Dr. Shah, and the second one for Dr. Wilkin, and it has to do with the tretinoin research that is apparently ongoing.
		I don't believe we are privileged to see the protocol or how that research is being done, but it was implied that, if there was a correlation between the stratum corneum kinetics and clinical efficacy between different tretinoin products, that that would be evidence supporting its predictability.
		My concern is that, as the FDA well knows, it is very difficult with different products to do clinical studies -- to compare different clinical studies and to do clinical studies to show small differences between products.
		Are these clinical studies now ongoing together in a blinded fashion?  Is the Retin-A gel being compared directly to the tretinoin gel and the Avita gel or is this something that has been extracted from prior studies which have been done at different times in different places and with different parameters?
		ACTING CHAIRMAN DRAKE:  Dr. Shah?
		DR. SHAH:  Okay.  Just to answer, the clinical studies are not being conducted.  Well, now when you say the clinical, you mean the actual on the patients.  That information was derived from the submissions.
		What is being done right now exactly is the DPK study which will correlate with the clinical studies done earlier.  So we are doing a DPK study comparing these three products at the same time on the same subjects, on the same set of subjects.
		DR. DiGIOVANNI:  My second question is for Dr. Wilkin.  That is:  If this sort of a study done in this fashion demonstrates the predictability of stratum corneum kinetics for correlating with efficacy with respect to tretinoin in acne, would you expect that that would hold for other agents which have actions at different end organs?  For example, if someone wanted to show effect of minoxidil on hair growth on different preparations, would you think that that would also -- and that all other agents -- that this would support all of those different agents which act at different places?
		DR. WILKIN:  No.  But I can always add a few words to that.  No, I showed, you know, the Netter cartoon of the histology of the skin.  The skin is composed of a lot of different components.  It really is not just Saran wrap covering human beings.  It's got a lot of different pieces to it.  There are different ways that topical products get to those sites of action.
		So I think that the kind of information coming out of the dataset that we are talking about will have a limited but possibly useful utility.
		ACTING CHAIRMAN DRAKE:  Dr. King?
		DR. KING:  I guess where I came in on this was we were considering the issue of antifungals plus topical steroids that are potent.  So one of the thoughts I came away from that was there's a difference between bioavailability and clinical response.  That's a given.  Okay?  
		Then the question I have really is quite simple.  If we have such differences in sites, thick skin versus thin skin, face, eyelid, etcetera, and then we have differences in age such as pediatrics and geriatrics, and then we have a difference in gender, how can some testing of forearm with think skin on the normal adult be predictive in a reliable way for the whole body, including stratum corneum anywhere else and dermis in the follicles?
		It seems to me a great leap of faith which I would not like to take that parachute.
		ACTING CHAIRMAN DRAKE:  Okay.  Is there a question tagged onto that?
		DR. KING:  The question is how are they going to get to the issue --
		ACTING CHAIRMAN DRAKE:  To all these other things?
		DR. KING:  Other issues, which is site, age, gender.
		ACTING CHAIRMAN DRAKE:  Site, age, gender, hydration, hair bearing versus non-hair bearing?  I mean, there is a whole plethora of diseased versus nondiseased.
		DR. KING:  Right.  Well, you can add to addendum that.  For cosmetics, you have to make sure the irritancy rate is something less, like one percent, because lots of us are atopic, and you put certain kinds of things around the eyes, you are going to get a bad response.  So one percent of a huge number is still a huge number.
		ACTING CHAIRMAN DRAKE:  Okay.  We are drifting just a little bit toward discussion, but it's okay just to touch.  Dr. Hussain and then Dr. Shah.
		DR. HUSSAIN:  No, I was trying to respond to that question.
		ACTING CHAIRMAN DRAKE:  I'm asking you to respond to it, yes.  I'm sorry.  I was hoping you would respond.  I saw your hand.
		DR. HUSSAIN:  I think the key issue here is, in the sense, when you are comparing two formulations which will be used in different clinical scenarios, situations, sites and so forth, would they provide the same exposure under those conditions?
		We have sort of debated this issue quite a bit 30 years ago.  The same debate is coming back.  We debated this with orals, for example.  The science -- The physical sciences and the biopharmaceutical sciences essentially are focused on the drug concentration, dynamic activity.   
		Once you start with that as a starting point, irrespective of the membrane that you use, whether you don't even use a membrane, I think the comparative effect of the two products will generally be similar.
		So in the dermatopharmacokinetics we are  essentially, in many ways, looking at somewhat of a worst case scenario where you have an intact stratum corneum.  That is the rate limiting step.  What that is suggesting is the dynamic activity is essentially the same.  
		So extrapolating to other disease conditions on the mechanistic basis is feasible, and I think I was alluding to that.  You probably develop that mechanistic support through mechanistic studies.
		ACTING CHAIRMAN DRAKE:  Okay.  In the interest of time, I'm going to keep trying to track through the questions.  Dr. Lim and then -- I have Dr. Lim, Lamborn and Jordan.  Dr. Lim.
		DR. LIM:  My question is for Dr. Shah.  My concern has been voiced, as many of my colleagues.  As clinicians we do treat patients with skin diseases in which there is no normal stratum corneum.
		I'd like Dr. Shah to expand for us, if this DPK method is to go forward, would this replace clinical trials with this?  Then if it does, how does one correlate the efficacy of that medication, the topical treatment, in terms of treating the various skin diseases in which there is no normal stratum corneum?
		ACTING CHAIRMAN DRAKE:  Dr. Shah?
		DR. SHAH:  I think this question has been addressed from the earlier discussions we had.  It goes back to the same standard thing, that for all the older products we do the bioequivalency study in healthy subjects, same way we are doing the bioequivalency using the DPK in the most ridiculous area which is the healthy stratum corneum.  If it is equivalent, it is assumed that under the diseased stratum corneum it will be the same.
		This is the same principle now we are using it for the approval of the topical glucocorticoids.  What are we doing?  We are measuring the pharmacodynamic response.  Where?  On the healthy subjects.  That has been the situation for the last so many years.  
		So we are doing it in a similar manner.  We are not trying to come up with something new.
		ACTING CHAIRMAN DRAKE:  Dr. Lamborn, and then Dr. Jordan.
		DR. LAMBORN:  This goes back to my earlier question.  I just would like a clarification.  You stated that you propose to substitute the DPK for the clinical, and I know that one of the objects of these is to say that the intent is to reduce the burden on industry, but now this is not a case of necessarily reducing burden if you require a substitution.
		Could you clarify why you wish to make the DPK a requirement rather than an alternative to a clinical demonstration of bioequivalence?
		DR. HUSSAIN:  I think the understanding here is I think for bioequivalence you have a variety of different methods available to you.  DPK will be one of those methods.
		DR. LAMBORN:  But that's the question I specifically asked earlier, and I was told that it was not going to be an option to do a clinical, that it was going to be only the choice to do a DPK.  
		So could you clarify that?
		DR. HUSSAIN:  No.  I think, with respect to bioequivalence, you always have different methods available to you, and this or any other method that will come about would be one of those options, and the company might obviously choose to use that or may prefer to use a different method.
		DR. LAMBORN:  I think that's an important distinction based on the earlier question, which was if this was overly sensitive to what was felt to be not meaningful clinical differences.  So we are now saying that it would be an option and not the only choice.
		DR. SHAH:  Well, we'll take your point into consideration and discuss it as to which way we are going to be leading into, because normally for the bioequivalency we have a method that we provide.  So--
		ACTING CHAIRMAN DRAKE:  We're going to get into -- I say this.  We'll get into this in discussion.  I understand your point, and I think it needs to be discussed thoroughly.  I think we are getting a sense that some of the questions aren't being addressed as specifically as we might like.
		So I would ask -- Dr. Shah, I would ask you and Dr. Hussain, the committee, I think, is expressing through their questions some concerns, legitimately so.  The more specific you could be with your answers, I think the more helpful we can be in return.
		So if you could help focus the answer specifically, that would be very helpful.  Dr. Jordan?
		DR. JORDAN:  My question is for Dr. Shah as well, and probably concerns the standardization of this test that was to be used, and I will stay away from the diseased skin.  I think we will get into that later.
		What about different skin types?  If we look around the room, there's a variety of different skin types that are represented here, Type 1, Type 2, so on.  I've got Type 1 which is the atopic burn-type skin.  You certainly have a different texture to your skin than I have.
		Have studies been done comparing different skin types and, if a standardized test is applied to those situations, are they equivalent?
		DR. SHAH:  Studies have been done, and with respect with the bioequivalency the advantage is we do the test in the reference product in the same subject at the same time.  So whatever value we get should be the test, and the reference would be the same, and it will take care of the different types of the subjects that are involved.
		ACTING CHAIRMAN DRAKE:  Dr. Tang?
		DR. TANG:  Just to make sure, the intent is if you have DPK, it will be considered adequate if it works in a future NDA?  
		DR. SHAH:  Sorry.
		ACTING CHAIRMAN DRAKE:  Dr. Tang, could you put that in the form of a question for us?
		DR. TANG:  If you have the DPK data, you can show equivalence.  Was that being considered adequate, is an option.  Right?  You said it's an option.  Would it be adequate without a clinical trial?
		DR. SHAH:  For new drug applications?
		DR. TANG:  To license the product.
		DR. SHAH:  No.  For new drug or the abbreviated new drug?
		ACTING CHAIRMAN DRAKE:  Why don't you do for both, for either new drug or --
		DR. SHAH:  Well, I cannot answer it for the new drug.  That will be with Dr. Wilkin to answer that.
		ACTING CHAIRMAN DRAKE:  Fine.  Then answer for your part.
		DR. SHAH:  My question is, yes, it will be adequate for a generic drug product.
		ACTING CHAIRMAN DRAKE:  So you think it would be adequate without a clinical trial, is your proposition?
		DR. SHAH:  Yes.
		ACTING CHAIRMAN DRAKE:  Okay, thank you.  That answers that question.  Other questions?  Joel?
		DR. MINDEL:  Along the same lines, bioavailability of oral products can be tested on a batch basis.  One of the failings of the present system is that, once a drug product is approved for topical use, the manufacturer can change the ointment and doesn't have to have, as I understand it -- doesn't have to report it and doesn't have to undergo testing again.  Is that so?
		DR. SHAH?  No, that's incorrect.
		ACTING CHAIRMAN DRAKE:  Would you tell us what is the case?
		DR. HUSSAIN:  The post-approval changes have to be done and reported in accordance to several guidances, especially for topical products.  We have a guidance called "Scale-up and Post-Approval Changes for Semi-Solids."  So changes cannot occur arbitrarily, and each change has to be justified, and there are different ways of justifying, depending on the magnitude of the change.
		DR. MINDEL:  Well, let me then say I'm glad that is clarified.  I don't know what exactly those changes are, but would this test be used on a per batch test, the way -- In other words, the original manufacturer runs another lot.  Would it be expected that this is now going to be -- since this is an objective test, that it's going to be used every batch?
		DR. HUSSAIN:  Bioequivalence methods are generally -- they are not quality control tests.  Batch to batch differences or acceptability, you have in-process controls and release testing, which will be chemistry tests that will be done for batch to batch.
		For bioequivalence assessment, we generally will take one lot of innovator, compare it to one lot of the test material.  That could be a generic material.  So --
		ACTING CHAIRMAN DRAKE:  Does that answer your question?  While you are thinking, Dr. Abel has a question.
		DR. ABEL:  Well, relating to that same issue, we've been advised that that is one of the problems between generics and the reference drug, is the great variability from lot to lot, so that there is more of a standardization and uniform quality control with the reference drug, and the generics can vary quite a bit.
		So if you are only testing one lot or batch of a generic, then maybe that is not sufficient data.
		DR. DR. HUSSAIN:  Quality control aspects of generic and innovator -- they are the same standards.  The standards for quality do not change between innovator and generics.
		ACTING CHAIRMAN DRAKE:  Do you want a follow-up question?
		DR. ABEL:  I don't know.  I don't have that data.  Perhaps the FDA could clarify that or pharmacologist.
		DR. HUSSAIN:  The standards required are the same.  So the quality control procedures, the test methods that one would use would be of the same standards, and eventually the products become -- you have pharmacopeias which define common standards also.
		DR. ABEL:  Well, perhaps one of my colleagues could help me.  I think there have been articles written in the dermatologic literature regarding differences in generics and reference drugs.
		DR. STERN:  But those aren't differences in the same product over time.  I agree, there are standards -- you know, the USP standards and other standards are applied, once something is approved.
		So what we are all getting to is the difference between the innovator compound and possible generic equivalents, and there is a big literature on that of varying quality.  But I think the rules are the same once you are approved, whether it is under an NDA or ANDA, but manufacturing processes, all these kinds of things -- that's all the same for everybody, once you are in the door.
		So the variability within a product is similarly regulated.  What we are looking at here is really between products, innovator and another one.  But over time, once a product is approved, the variability in what is going on there should be -- The rules are the same.  Isn't that correct?
		DR. ABEL:  Thank you.
		ACTING CHAIRMAN DRAKE:  I don't have anybody else that I have noted that has a specific question before we begin the discussion.  Are there any -- Anybody I have overlooked on questions?
		All right.  Now we will begin the discussion, and the discussion is wide ranging.  I give you leeway to express opinions, ask further questions, and generally just be yourselves.  Dr. Stern -- On second thought, Rob, I may just correct that.  Just give me a little hand signal.  I put you on my list, and I call you in the order that I spot you.  So try to make sure that I catch your eye.
		I just want to point out, and mindful on the time, we will take a brief recess.  I'm going to shorten it to just ten minutes, because we do have to -- I want to make sure we make available to the public comment at 11:15, and I have the times down, and I will hold the public comment to time, and I want to make sure that we at this table allow the courtesy for everyone at the table to have a comment.
		So please try to keep your comments pertinent and concise so that we get the -- the FDA gets the benefit of the whole committee's opinions or comments or concerns.
		All right.  So I've got Stern, Lim and -- is it Venitz.  All right.
		DR. STERN:  Well, I have a number of concerns.  One is:  In all of this, as in my question, we are dealing with -- principally with diseased skin.  If this discussion was only about the equivalent for stratum corneum active compounds such as emollients, I would say this is terrific, but we are dealing diseased skin where, in fact, the stratum corneum, if present at all, its penetration characteristics vary over time as the disease heals and, further, things that may not affect with a single application the characteristics of the stratum corneum or, in fact, inflammation.  
		So for example, the analogy -- I was trying to think of an analogy with oral drugs.  I think, if there was an oral drug that was used to treat gastritis and was only biologically equivalent if taken with two shots of rye whiskey, with one single application of that, two shots of rye whiskey probably don't change your gastritis very much, and the drug might be biologically equivalently available.  But I doubt the FDA would look on that product as a good drug, a biologically equivalent drug for another anti-gastritis product that had systemic effect if you had to keep on taking those two shots of rye whiskey every day.
		We, in fact, have various vehicles in terms of inflammatory dermatosis that may, in fact, be irritants, especially in diseased skin.  I don't see that single applications and subsequent tape stripping really get to what I would call both the safety aspect and the unintended effects of the incipients on either penetration with long term application or, in fact, the inducing of inflammation and side effects.
		So, to me, if you are looking at something -- If you want to measure something that the clinical effect is likely to be a number of weeks, you want to know what the safety profile, what the unintended effects that might both lead to a side effect, and perhaps also change what's going on.
		You know, we've spent what I found an interesting day yesterday talking about a product that my inferences are that its biologic effects when applied topically on normal skin or skin with enhanced stratum corneum are virtually immeasurable.  This is Protopic.  
		My understanding is when they tried it on psoriasis where you have an enhanced stratum corneum, not a heck of a lot happened, and I thought we saw  very persuasive evidence that in diseased skin with an altered stratum corneum there were substantial clinical effects.
		So I really have real concerns about agents that are utilized for many of our diseases where either the epidermis is not the primary target, a follicle or something else, or in fact, they are used in conditions with an altered stratum corneum.
		I guess those are my two biggest concerns.  The other one, I must admit, is completely a bias.  I see here that we are trying to validate or discuss the validation of a methodology that's been around for a dozen or 15 years which, to me, as has sort of been implied, is really perhaps not where measurement sciences are now.
		I think one should look at it in terms of where the science has moved in terms of the ease of measurement, and secondarily, the elegance of measurement.
		Why is this important to me?  I think, as Dr. Wilkin implied, if we had a noninvasive measure where for drugs that are effective for skin disease where we could measure equivalence in both the entire epidermis and the dermis over time as they are applied noninvasively, that to me would be very persuasive.  
		Instead, here we are having something that I actually fooled around with for years.  Twenty-five years ago, Irv Blank at our institution was very much into stratum corneum and percutaneous penetration, and it didn't seem very elegant when I was less than 30, and it seems even less elegant with the changes in science when I'm over 50.
		So I really have a problem with endorsing something that, if we endorse it, is going to take at least ten or 12 years to replace when all sorts of measurement are moving so rapidly.  So I don't want to put yesterday's science in, even if all these other issues are addressed.
		Then I just want to make one final comment.  I always thought a consensus document was something you had to sign before they would let you go to your airplane.  
		ACTING CHAIRMAN DRAKE:  Dr. Lim?
		DR. LIM:  This discussion reminds me quite a bit about the discussion that we had many times, actually, with sunscreen.  There are very good multiple studies on sunscreen that have been done -- that has been done, using in vitro method as well as in vivo method.  I think the conclusion generally is that the in vitro method is helpful, but in order for the medication, in this particular case the agent sunscreen, to be appropriately evaluated, it should be done in human beings.
		The part that I have concern about is that again -- it has been expressed previously in various questions and discussions before -- that we are treating diseased skin.  I am not comfortable replacing the clinical trials even for an equivalent product in the diseased skin condition by a one-time in vitro measurement.
		ACTING CHAIRMAN DRAKE:  Dr. Venitz.
		DR. VENITZ:  Yes.  I would like to comment that in my mind the discussion that we are having or at the heart of the very discussion that we are having is the different perspective that biopharmaceutical scientists and clinical scientists have on how those drugs work, and I find it interesting as a member of the Pharmaceutical Sciences Advisory Committee that I end up sitting with all those clinicians.  I think in the final analysis, I am probably going to agree with those clinicians, even though I am representing biopharmaceutical sciences.
		In my mind, DPK is really a surrogate of drug release, and it's a sophisticated release test.  We just use human bodies or human skins as opposed to doing it in vitro.
		Apparently, there is a very precise way of measuring drug release.  The clinical meaning of it, though, is questionable, to say the least.  I think I would agree with what Dr. Wilkin was saying.  Based on first principle, we won't be able to explain any mechanistic or any mechanism of action for any drug that can be caused by some kind of a DPK profile, because of their different mechanisms of actions, their different targets.
		I am also less optimistic than Dr. Hussain that we'll be able to use empirical data to justify the use for every single drug, unless you literally wanted to do some kind of validation for every single active ingredient.  Then you are defeating the purpose of the whole thing, which is to relieve the burden, the regulatory burden.
		Finally, I do see some use, at least on a, I guess, probationary period, for this three-arm design that Dr. Wilkin favored where at least you have some idea whether you have a suitable test where you compare not only a bioequivalent but also bioinequivalent product with your test product.
		My main concern, though, is that we are measuring something very precisely, but we really don't know what it means for most drugs in clinical use.
		ACTING CHAIRMAN DRAKE:  Okay.  Dr. DiGiovanni, I had you next.
		DR. DiGIOVANNI:  I have a number of concerns, but I am not going to express them, because they have been -- Most of them have been more eloquently expressed.  But one issue I don't think that's been addressed in great detail that I am concerned about is that the equivalent in content is not the equivalent in quality and in product, particularly when one refers to vehicles.
		There may be two preparations, one of which is a proprietary preparation.  It may be prepared in ways that are not publicly available and has been extensively tested and while another product may have the identical chemical composition, it doesn't have the identical physicochemical properties and ability to release the drug to wherever it has to go.
		I think that that is an issue that has not been at all addressed with respect to stratum corneokinetics and ability of that to predict clinical efficacy.
		ACTING CHAIRMAN DRAKE:  Do I have other -- I can't believe my committee, all of a sudden, is quiet.  I don't have any -- Okay, Dr. Tang.
		DR. TANG:  I think the key issue we have discussed so far is really whether DPK is generalizable, whether you can generalize these results.  I have no doubt that indeed the case is going to be very precise, but how this is linked to the clinical efficacy is unknown.
		So I think there must be a finite number of disease types in a skin disease.  So the question is whether to decide whether you are going to go with DPK so you can study.  It is possible -- It is feasible to study more different types of skin.  Then the study has to be the -- The DPK has to be validated for each type.  
		If you can do that, then there is hope.  If you cannot do that, I think it is very hard to make the quantum leap from DPK to a specific disease type.
		ACTING CHAIRMAN DRAKE:  Dr. Abel?
		DR. ABEL:  I agree with all of the previous speakers who have expressed the view that the DPK is accurate, but not necessarily relevant in the clinical setting.
		A follow-up to the last comment, it would be very interesting to know -- have more information on DPK in different disease states, because not only are there disorders where there's absence of stratum corneum, but on the other side of the pole there is thick, lichenified, chronic eczematous disorders where there is very thick stratum corneum.
		So we should look at diseases where there is acute inflammation, acute eczematous dermatitis, for example, and on the other pole, the chronic lichenified, thick, scaly conditions.
		ACTING CHAIRMAN DRAKE:  Okay.  I have Lamborn, Mindel and King so far.
		DR. LAMBORN:  Actually, I have a question.  The issue of skin types keeps coming up, and not being routinely on the dermatology committee, I would be interested in knowing, for the current bioequivalence methodology which is a clinical one, what adjustment is made in terms of assurance that, in fact, you have bioequivalence on the multiple skin types or how is that beyond simply the same rule of you are looking at it within the same individual?
		ACTING CHAIRMAN DRAKE:  Okay.  Dr. Jordan just commented he had exactly the same question, and Dr. Wilkin, would you like to -- I don't know who is the most appropriate person to take a shot at answering that question.
		DR. WILKIN:  Well, for the new drugs we are not looking at bioequivalence type questions, but what we do -- What the innovator pharmaceutical companies do in their Phase III clinical trials is they take all comers.  We encourage a wide demographic representation.  
		We clearly want minorities to be part of the Phase III.  So for the new drug products, I think we have very good information in terms of the clinical assessment, the efficacy and safety studies.
		I think what the question, though, was, was how does that happen then when generic companies do their clinical trials for topical products?  I would have to defer to the Office of Generic Drugs for that.
		ACTING CHAIRMAN DRAKE:  Okay.  Dr. Shah or Dr. Hussain, one of you want to --
		DR. SHAH:  I would like to keep one thing for the committee members to think about.  There is a clear difference between the bioavailability and the bioequivalence.
		When we are talking about bioequivalence, we are talking about the same type of formulation, which means it has qualitatively and quantitatively the same ingredients.  So some of the discussions which came about the different ingredients going through or affecting it -- It's out.  It is not development when we are talking about a bioequivalence.
		The only difference comes up in the nature of manufacturing, how they are manufactured, using the same components.  That, we can very easily detect using the in vitro drug release profiles.
		So I will appreciate if the committee gets these two points slightly clear and different when we are talking about all these skin types, skin diseases, this, that and all, between the bioavailability and the bioequivalence; because whatever happens with the one formulation, the same thing should be happening with the other formulation when we are taking a look into the same formulations made by two different companies.
		DR. LAMBORN:  But that does not address my question.  My specific question is:  In bioequivalence studies, approximately how many individuals would be involved, and what is done to look at the issue about whether there is any difference, depending on skin type?
		DR. SHAH:  The study will take anywhere between 36 to 48 subjects for the bioequivalency, and I think that randomly picked up the subjects.
		DR. HUSSAIN:  For clinical trials, for bioequivalence clinical trials -- I think that is the question here.
		DR. LAMBORN:  Yes, bioequivalence -- to prove bioequivalence by clinical trials is the question.
		DR. HUSSAIN:  That's an excellent question, I think.  The issue of skin types, disease and so forth, even in big clinical trials, I don't think we cover all bases when we approve safety.  It is difficult to do that, I think.  But when do bioequivalence based on clinical trials, there is an attempt to try to do that, but how far is successful is difficult to say.
		DR. LAMBORN:  Because I know historically in bioequivalence one of the issues was that they tended to use -- you know, I'm talking about oral dosages now -- there was a tendency to use all males in a certain category, and I was wondering whether we had the same situation in the clinical trials for -- historically, for clinical trials with bioequivalence for dermatology products, whether there is a tendency to look for consistency and that they went for a certain type.
		You are saying it tends to be random?
		DR. HUSSAIN:  Before answering that, if you permit me, I haven't dealt with that issue.  I may wish to consult later on with somebody who has and answer that at that point.  So --
		ACTING CHAIRMAN DRAKE:  We are getting very close to time.  So I have Dr. Mindel, Dr. King and Dr. Lim, and I will stop the discussion for a quick break to go to the public comment, and then we will take up some issues.  Tom, did you have -- Dr. Wilkin?
		DR. WILKIN:  Well, actually, I could comment later.  I was going to -- because it may not be all wrapped in my response.
		The Q1 and Q2 -- Perhaps after the break I could come back to some thinking.
		ACTING CHAIRMAN DRAKE:  I think this is important while everybody is thinking on it.  So go ahead.  I might put off these three comments until right after the break and then move to the public.
		Is anybody in the public comment section that that would present a problem to, if we move the public comment five minutes?  Okay, then we are in good shape.  
		Dr. Wilkin, would you go ahead, and then I'll take up these other three right after the break.
		DR. WILKIN:  Again for those who do not think about Q1 and Q2 all the time, the Q1 is qualitative.  It means the list of inactive ingredients is the same for the innovator and the generic product.  
		Q2 means that there is a quantitative similarity.  It doesn't have to be exactly on the money.  It can be five percent or at times it's been suggested to have a ten percent excursion, but it's close.
		If you think about topical products -- and let's think about at the very beginning the simplest phasic kind of structure.  Let's think of a topical product that is a complete solution.  It might have an active and multiple inactive ingredients, but they are all in solution, all in one phase.
		Q1 and Q2 is enormously powerful in understanding and predicting what the attributes of that particular product are going to be, because it really does not matter the manufacturing. 
		A simple example would be a salt solution.  If you take your beaker, if you put the salt in first or you put the water in first, it really doesn't matter the order, whether you heat it, cool it, that sort of thing.  In the end when it's sitting there at room temperature in solution, how you got to that solution is -- it's manufacturing insensitive.  Okay?
		Now for the kinds of products that we are talking about, these semi-solid sorts of things, they are not simple solutions.  The active agent may be in solution, but typically these are at least two-phase or multi-phasic kinds of structures.
		There may be a continuous phase, and that may be where the active is or there may be a discontinuous phase.  It might be in both.  My thinking there is actually that Q1 and Q2 do not adequately describe the product at the end of manufacturing.
		I think of this as the -- I call it the Duncan Hines theorem.  If you think about cake mixes, you know, you can go to the store.  You can get your three eggs.  You can get your cup of milk and all the sorts of things, and everyone across the country, when they are using that cake mix, they are starting out the same.  But some people forget to preheat the oven.  Some people move it to the wrong place on the dial.  Some people leave it in longer than others.
		The quality of the material that comes out -- It still has the same chemicals in it and the same flavor and probably the same calorie content, unfortunately, but at the end of the day it can be -- the physical properties can be very different.
		That's the concern about Q1 and Q2 underdetermines the physical attributes of these kinds of products which may be manufactured in somewhat different ways.  I mean, I've heard of one example where, instead of using the cooling coils, they didn't have them on.  So things cooled to room temperature, and they ended up with a very different feel to the topical product.
		So I think there are limits to what Q1 and Q2 can tell us about these products.  I just wanted to add that.
		ACTING CHAIRMAN DRAKE:  What I am going to do is we are going to take a very quick break.  I am going to ask -- What time do you have, Mr. Henriquez?  You are going to be our timekeeper.  We have about eight minutes past.  I would still like to aim toward reconvening at 11:15.  So can everybody hurry, to the best of your ability.
		(Whereupon, the foregoing matter went off the record at 11:05 a.m. and went back on the record at 11:20 a.m.)
		ACTING CHAIRMAN DRAKE:  Would everybody please reconvene.  I'm reconvening the session effective immediately.
		The next person I'm going to call upon right quick is -- and I'm going to ask us to be quick, because we are about out of time here -- Dr. Mindel, you had a quick question, and I've got three quick questions, Mindel, King and Lim.  Then we are going to move right into the public comment phase.
		DR. MINDEL:  My question has to do with the noninvasible aspect of the assay which, when you start getting down to, I guess, the seventh and eighth strips, can be pretty uncomfortable.
		There are some pediatric preparations, dermatologic preparations.  How would they be handled with this type of assay?
		ACTING CHAIRMAN DRAKE:  Do you have a comment, Dr. Hussain?
		DR. HUSSAIN:  I was hoping Vinod was here to answer.
		ACTING CHAIRMAN DRAKE:  I'm sorry.  He is not here, and I'm pressing on.  
		DR. HUSSAIN:  All right.  Well, generally, I think, for bioequivalence we do it in normal, healthy human volunteers.  So that would be on healthy human volunteers. So not on pediatric.
		ACTING CHAIRMAN DRAKE:  Okay, but I think that is a legitimate concern of the committee, is the age.  We've heard that before.  It's another issue.  Dr. King?
		DR. KING:  This is, hopefully, a short comment.  I remain unconvinced that this methodology is useful other than comparing generics versus the reference drug or those coming off patent.  So I am not going to go any further to say my comments.  I don't think it's feasible under Dr. Wilkin's first principles at this point.
		ACTING CHAIRMAN DRAKE:  And Dr. Lim?  Dr. Tang, I mean.  I'm sorry.  Not Lim, Dr. Tang.
		DR. LIM:  Dr. Lamborn was asking about what is currently being done for the bioequivalency study.  
		ACTING CHAIRMAN DRAKE:  Quickly.
		DR. HUSSAIN:  Quickly, this would be sort of a crossover, and each subject becomes its own control.  But I do wish to request, Madam Chairperson, a five-minute time, if we could answer the question I deferred and have Dale Conner answer that.
		ACTING CHAIRMAN DRAKE:  I am going to let you have it, but I want to go to the public comment section first, since they have been very indulgent with letting us run late.  I do plan to adjourn at 12:30.  I have already got committee members who have made plane reservations and what-not based upon that assumption.  So I would like my committee to be thinking about -- although there is no vote, I certainly having some recommendations might be helpful.
		I am going to now call upon the first public comment, and we will keep -- I will call time. Dr. Spear for Spear Pharmaceuticals, which is listed here as generic R&D, asked for ten minutes.  You shall have ten minutes, and then I'll call time, and I don't mean to be rigid, but we are just about out of time here, and I wanted to make sure everybody gets heard.  Thank you, Dr. Spear.
		DR. SPEAR:  Thank you for the opportunity to speak.  Is the mike on?
		ACTING CHAIRMAN DRAKE:  Yes.
		DR. SPEAR:  As you can see, I'm a dermatologist, and also I've been involved in the generic industry for the last five years, and I am from Fort Myers, Florida.  Now that's not Palm Beach County.  So please don't -- you know.
		Some of the generic industry claim that the draft guidance must be accepted, because generics cannot be approved in any other way.  I am here to report that clinical studies can show bioequivalence, and we have performed acne studies to prove bioequivalence to our Tretinoin products.
		For anti-acne drugs, which act in the pilosebaceous unit, one can never be certain that stripping the stratum corneum layers ever is better than a clinical study.
	The gold standard, double-blind placebo controlled acne bioequivalence studies can be done with reasonable cost.  Our generics are Q1 and Q2, and additionally, as has been discussed here, we take a lot of time and constraints to make sure that as manufactured they have the same physiochemical parameters or viscosity.
		We have filed three acne clinical trials showing bioequivalence to the originator.  Here is an example of one of our clinical studies for the highest strength of 0.1 percent.  You can see the improvement over 12 weeks in 398 patients.
		Another way to look at this is for the 0.1 percent improvement acne at 12 weeks is approximately 71 percent in a 400 patient trial.  
		We did another trial on 0.025 percent. About 52 to 53 percent improvement.  We have also studied the Retin-A gel versus our Tretinoin gel, and around 56 percent improvement.
		We received approval of the middle 0.05 percent cream by clinical bracketing of the studies and in vitro release.  We also -- Since we showed bioequivalence in the 0.025 percent gel, we asked for a waiver of another acne study with some supporting data.  
		Now remember, the 0.01 percent gel only differs from the 0.025 by the concentration of active ingredient.  In vitro release studies cannot easily be done on gels.  So we had a meeting at the Office of Generic Drugs, and I would just like to provide you with this information.
		For both the .025 percent and .01 gel strengths, we provided TEWL, which is transepidermal water loss, and that is in vivo.  Our data showed equivalence of our products and originator.  
		Also in the same lab, TEWL showed differences between different formulations with the same active ingredient.  
		We also provided in vitro cadaver skin studies and, as has been mentioned in this committee, this is some of the newer technology, and cadaver skin, I think, is actually somewhat better.  We showed equivalence of our products and the originator.
		Also in vitro cadaver skin can show differences of the products with the same active and different inactives, and you can look at the patent for Avita Gel where they showed these studies.
		There is also a clinical correlation.  The Avita gel in clinical studies wa not bioequivalent to Retin-A gel and did not get an AB rating.  
		Even though the data was convincing, the agency felt, regulatory speaking, that they could not accept this.  Therefore, we have done another 400 patient acne study on the lowest strength, and results are being tabulated.  So far, they show bioequivalence.
		Therefore, in total, we have done four acne bioequivalence studies, both of the creams and both the gels. We have set the standard for approval of tretinoins, and I am saying this can be done.  I'm not that big of a company.
		Spears' experience with the Office of Generic Drugs has been very positive.  OGD staff have been willing to help, accessible, and genuinely motivated to help bring high quality generics to the public.
		Let's talk about the controversies.  I'm going to go quickly through this, for this has already been discussed well.
		One can show equivalence between a proposed generic and the originator by squeezing it out of the tube and comparing the concentration of active ingredient.  Then you would say it's equivalent.  But there is more to it than that.
		Similarly, if you place it on the skin and strip it off and measure the cream on the tape, one can show that it is the same concentration, I have no doubt.  But the issue is can you show with tape stripping differences between tretinoin products with the same active and different inactives?  I think this is what is going to be discussed.
		Also we have talked about the effect of diseased skin.  In dermatology we are dealing with diseased skin.  Don't forget, we are talking about acne, psoriasis or eczema where the normal stratum corneum is disturbed.
		It is a leap of faith to say that how it behaves on the inner arm of normal skin is how it is going to behave in the diseases that we are treating.  I'm really concerned that this would be the only method that we can show, and that we would drop away and can't use clinical studies.  That is very, very concerning to me, to bring generics to people.
		The draft guidance admits that for anti-acne drugs, those targets are deeper.  The draft guidance tries to make the case that what is happening here happens in the deeper glands.  It is still a leap of faith.
		Summary of my position:  Acne bioequivalence studies and other clinical trials can be done without excessive expense to the generic industry.  
		Skin striping may make sense for anti-virals and anti-fungals.  When I made this slide, I didn't think about all the stratum corneum effect on the anti-virals in the vaginals.  So I might even move the anti-virals out of there.
		Embracing skin stripping as a surrogate for anti-acne and corticosteroid products will always be suspect, since they do not act in the stratum corneum.  
		Cadaver skin, which is another technology, may be a better DPK marker, and that should be looked at.
		There is also a potential negative effect here on this guidance.  The intent of this guidance is to bring more generics to the public, but this guidance could backfire and hurt the reputation of generics, which has really been a hard fought and gradually earned reputation.
		Brand companies will be easy to go into the dermatologist's office and just slam generics by saying skin stripping is not good science, and products approved in this way are suspect.  At the end of the day, we do not want generic drugs' reputation tarnished.
		Thank you very much.
		ACTING CHAIRMAN DRAKE:  Thank you, Dr. Spear.  You know, you're a wonderful human being.  You saved me several minutes, and I appreciate your excellent presentation.  That was very, very well done.  Thank you.
		Dr. Pershing, I believe, is next, and I will hold you to the same time commitments.  You know you have a good meeting going on when there is this much lively discussion and interest.  
		DR. PERSHING:  Thanks for allowing me to talk today.  I want to address some of the issues that have been brought up during this discussion.  I'm going to talk about DPK, the skin stripping model, and its uses and bioequivalence and bioavailability.
		As was mentioned in the guidance, there's a number of issues that need to be validated with each drug product that you evaluate, and a lot of those issues are illustrated here.  
		I want to confirm that you can validate this skin stripping method for bioequivalence and bioavailability assessment.  In fact, we've done that for a variety of drugs that cross four different drug classes that represent different dermatological products in about eight different kinds of vehicles.
		ACTING CHAIRMAN DRAKE:  Dr. Pershing, maybe it would be better, if you could, to use the mike.  That one, you're breathing in it.  You clip it on so that it doesn't -- Okay.
		DR. PERSHING:  So these have been answered, and it is not that hard to do.  It does take some diligence in doing so.
		My point today is about topical drug delivery, and this is the problem I'm not sure everyone understands.  Efficacy:  Therapeutic efficacy requires -- of a topical drug product -- that the drug leaves the applied vehicle and gets into the skin.
		The rate limiting step to getting drug into the skin is that outer layer called SC on this slide, stratum corneum.  This dictates how much will eventually get into the other skin layers.
		If you don't get drug into this skin layer, you don't get drug past that skin layer.  That's true, whether you have an altered stratum corneum or not.  Okay?
		One of the issues we talked a lot about this morning is Q1 and Q2, and I want to show you some examples of DPK profiles of two products, in this case a test and a reference, that were Q1 and Q2 similar.  So qualitative similarity in the vehicle composition as well as similar concentration of those vehicle components.
		If you meet Q1/Q2, you see similar uptake an elimination profiles in the dermatopharmacokinetic profile.  That was for an antifungal.
		Here is an antiviral.  Again, if you meet Q1 and Q2, you will produce a similar  dermatopharmacokinetic profile.  But here's the case where they are bioequivalent.  They meant to be the same, but in fact Q1 and Q2 were both different.  You will note that now the test is not bioequivalent to the reference product.
		Another example, an antibacterial.  This shows bioavailability where you are comparing a solution to a semi-solid.  Here you see that the semi-solid doesn't deliver as much drug into the stratum corneum, and that it is basically displaced in almost an isothermic kind of situation.  
		So this really, truly is bioavailability differences, and the vehicle composition changes that.
		Here is an example of tretinoin in a 0.1 percent cream and two different gels that are .025 percent.  Again, you see that there is a difference in the extent, the amount that's delivered, higher concentration in the cream than the gel, and that you see differences in the dermatopharmacokinetic profiles.
		Here is another bioavailability difference where we have compared four different imidazole drugs, all in a cream formulation, different concentrations.  But you can see, their profiles are actually different.
		Finally, the glucocorticosteroids, that if you apply different potency corticosteroids, you can see that the uptake of those drugs into the stratum corneum can be differentiated, both as a basis of the physical properties of the individual corticosteroid, the concentration and, in this case, they were all cream.
		The other issues that has been brought up is about does stratum corneum predict good drug concentrations in deeper skin layers?  I spent the first ten years of 1987 to 1997 developing an in vivo human skin model where we take abdominal skin, and we graft it onto acymic mice.  
		This allows the skin to be living on an alternate skin source -- I mean alternate model source, and we can actually take multiple biopsies or single biopsies after drug treatment.
		In doing that, we then took biopsies after a two-hour application of a variety of glucocorticosteroids, and we quantitated the glucocorticosteroid concentration in the different skin layers.
		You will note that if you get more into the stratum corneum, you also get more into the epidermis.  You also get more into the dermis.  So what you get into the stratum corneum is reflected in the deeper skin layers.
		Another example with Monistat-Derm, which is miconazole nitrate cream, and you will see that if you look at over multiple time points the concentration of stratum corneum, that as this stays the same dose, so does the epidermis and the dermal concentrations.
		So the amount of drug you get into the stratum corneum reflects the concentration in the deeper skin layers.
		Do differences in DPK predict differences in the pharmacodynamic activity of that drug?  That's what we are really talking about here.  Can DPK predict clinical performance?  Can DPK predict in vitro bioassay performance?
		This is an example of some recent work on betamethasone diproprionate in seven different formulations with and without propylene glycol that cover both ointment, cream and lotion and gel vehicles.
		You will note that all the formulations, independent of vehicle composition, reach a steady state within the skin after about two hours, and that whether you have with propylene glycol or without propylene glycol between the matched vehicle types, you can differentiate how much gets into the skin.
		We compared this data in the same subjects in a pharmacodynamic response.  Indeed, the more you get into the skin of this particular drug, the more negative your Emax value and, therefore, the more potent your corticosteroid.  That's a beautiful correlation coefficient of .82.  Therefore, the more you get in the skin, the better response you get.  
		Here is an example, however, where the two products were not the same, either qualitative or quantitative, and that a fungal.  And you see the differences I've showed you before in the dermatopharmacokinetic profiles.
		I show you this because, while the DPK methodology differentiated these two products, clinical efficacy, safety and bioassay results did not.  Those differences in the DPK profile were such that they were less than the critical value that was required to differentiate them by either bioassay methods or clinical efficacy methods.
		Why did that happen?  That happened because -- let me see if I have a slide there -- pharmacodynamics is nonlinear.  Pharmacokinetics is linear.  So you can deliver more and more and more and more drug.  At some point you don't see any difference in the clinical efficacy response.
		This is typical with dermatological products, because we always deliver more drug than we need to, because it's not going to stay there very long.  Okay?  That's why we make them at higher concentrations.
		Nonetheless, what's very important here is that DPK was able to differentiate these products, and all the other pharmacodynamic models were not.  When you are picking a gold standard, you want the very highest ability of your method to discriminate.  That's very important.  It's a safety net issue for consumers.
		I want to show you, you can also do DPK in diseased skin, that if you just account for the differences in the amount of skin you remove from a state like psoriasis where you have a hyperproliferative stratum corneum, you have a lot more of it.  
		It is not biochemically the same.  But what I want to show you in the next graph is that, if you correct for the amount of skin you remove from those skin sites, you get a similar response.
		Here's a study on psoriatic elbows.  We don't like to use psoriasis for corticosteroids, but it's a bilateral disease.  If you have it one elbow, you are going to have it on the other elbow, and they are going to be very similar.
		What we showed clinical efficacy-wise, we followed the target lesion scar with erythema scaling and duration.  There was no significant difference between the trade and generic and, in fact, the DPK profile at multiple doses over time showed no difference between the products.
		Another example of tinea pedis where again you have a hyperproliferative inflammatory situation, and we compared whether -- this is kind of hard to see probably, but with seven doses that helped forearm skin and diseased skin, when you account for the amount of skin removed, is the same.  Okay?
		So in conclusion, the skin stripping methodology does require validation, but you can do it.  We have done it with four different drug classes, multiple types of drug within those classes across vehicle types.  You can use it for bioequivalence, and you can use it for bioavailability.
		Pharmacokinetics does predict PD, that the drug products actually deliver more drug than is necessary to achieve a maximal effect, and that's why you don't always pick the up in a bioassay in a clinical efficacy study; that DPK is actually more discriminating than the pharmacodynamic assays.
		The stratum corneum drug concentrations are relevant to deeper skin layers, and DPK predicts the pharmacodynamics.
		ACTING CHAIRMAN DRAKE:  Thank you very much, Dr. Pershing.  May I ask for Dr. -- and I'm not sure I am pronouncing this right.  Is it Parab?  Did I get that right?  Hot dog.  
		He is a senior principal scientist from Bristol-Myers Squibb, representing PhRMA.  Is that correct?  All right.  You have asked for ten minutes, which you shall have, starting now.
		DR. PARAB:  Yes.  Thank you very much, the Committee, for giving me a chance to present.  I am Prakash Parab from Bristol-Myers Squibb, and I will be presenting PhRMA view on this topical guidance.  Next slide, please.
		The oral presentation is shown here.  There are many issues.  First is methodology issue.  Stripping technique for DPK has not been validated, and I'll give you these three examples.  
		There is a question of the target tissue.  Inadequate DPK data exist to correlate stratum corneum drug concentrations to concentrations at different tissue types.  I will give you two examples. 
		Lastly, DPK has not been correlated to clinical efficacy and systemic safety for any therapeutic category, class of compounds or formulations.  I will give you two examples.
		Let us look at the acne study done on  Retin-A in human subjects.  You see that about 82 percent of the unabsorbed surface drug is recovered in washings, and only .2 and .80 percent is found in feces and urine after seven days.
		This shows that most of the topical product can be recovered in surface washing, and minimum goes into the skin and systemic circulation.
		Now let us look at the acne study.  This is shown in many meetings, and it was shown as accent today also.  The authors applied .025, .05, and .1 percent Retin-A, and they got a very good dose of same concentrations in the stratum corneum, very good dose response.  But when we assumed that the authors had applied 5 milligram per centimeter scale of the product, we calculated how much of the applied dose is found in the stratum corneum.  We found that about 76 to 86 percent of the drug is found in the stratum corneum.
		This brings into question whether this number represents the residual unabsorbed drug on the skin surface and skin furrows rather than drug penetrated into stratum corneum.  The dose proportionality described above is shown in many studies.  It may simply reflect an increase in concentration in the applied product is not increased amount absorbed.  Just it is an error.
		Let us look at a micrograph of the skin, dermis, epidermis and furrows in stratum corneum.  Even after 20th stripping you can see these furrows where the unabsorbed drug can be present, and there are upper layers of the stratum corneum which cannot be reached, and these can contaminate the strips.  So you may not get actually absorbed drug.  You may be contaminated drug you will be seeing in the strips.
		Next slide, please.  Now this is a titanium dioxide product applied.  First strip was taken.  You can see all these spots, white spots, all over the place in the first strip. 
		Now you look at the tenth strip.  You see titanium dioxide, the unabsorbed product in the furrows, and the tenth strip is contaminated with the surface product, not the penetrated product.
		Now look at the methodology issues, variability, 20 subjects.  At subject seven, you can about 175 micrograms.   In another subject you get 425 micrograms of the stratum corneum, two fold difference, a lot of variability.
		Let us look at with-subject variability.  In the same subject you can have minimum stratum corneum recorded at Site A, and a lot of stratum corneum recorded at Site B.  Next slide, please.
		So methodology issues:  This is most important.  A reliable measure to distinguish between residual surface drug and drug that has been penetrated into the stratum corneum has yet to be established.
		Clinical mass balance studies have to be done.  Using first 10-20 strips has not been validated to represent the stratum corneum.  These strips may be contaminated with unabsorbed drug, calling into question relevance of the data.
		Even after 40 strips, furrows still contain stratum corneum tissue and unabsorbed drug.  Variability in collection of biosample makes it difficult to normalize the data for evaluation of DPK.  So we question whether the DPK is precise.
		Now let us look at the stratum corneum and target sites, stratum corneum concentration, follicular concentration for three compounds.  
		As the stratum corneum concentration increases, follicular concentration decreases.  The ratio varies from 2-37.  Thus, DPK cannot be used to assess BA/BE for follicular drug delivery system, because there is no correlation.  
		Let us look at acyclovir data.  This was done on a human skin grafted on nude mice after topical and oral administration.  If you look at stratum corneum, epidermal and dermal concentration, topical concentrations are 44, 11 and 57-fold higher.
		So one can assume that topically acyclovir is more effective, but in real life oral acyclovir is more effective.  So again, no correlation between stratum corneum concentration and clinical efficacy.
		Next slide.  Now this is the Temovate data, Temovate cream and Temovate emollient cream.  It shows a DPK difference, but Glaxo reports comparable clinical efficacy between Temovate cream and Temovate-E cream, and there is no difference in vasoconstriction on these two products when tested on 30 subjects.  Labeling classified both products as super high potency, and this is there in the PDR.
		The difference in DPK between these products may be due to issues such as:  18-69 percent of the applied dose was recovered in the stratum corneum in this study may represent unabsorbed drug and questions the validity of the study.
		Spreading of the emollient cream beyond application site diminishes the amount recovered.  So validation is very important.
		Let us look at many of the corticosteroid products.  Diprosone lotion, Diprolene ointment gave same stratum corneum concentrations, but everyone knows that Diprosone lotion is a weak mid-potent formulation, where Diprolene ointment is a high potency formulation.  So again no correlation.
		Two to 11 strips had about 40-93 percent of the drug.  So again, questions related to the contamination of the strips.  Next.
		So future:  What we request is we should take a staged approach, whichever the method we select. The critical parameters of the method should be identified, evaluated and formally validated.
		Proposed surrogate needs to be demonstrated to be relevant to the target site.  DPK results must correlate to clinical outcomes.  DPK then to be tested in specific therapeutic classes, different target sites, and different delivery systems, and should be blinded, multi-center study, not one center -- multi-center study.
		The dose should be two to three milligrams, and data from these studies must include mass balance.  
		Clinical studies:  Again, relationship between stratum corneum concentration and systemic exposure has to be shown.  Dr. Rougier showed it in rodents, but we want to see that this exists in human beings for different drugs having different physicochemical properties, again normal versus diseased, different body sites.  That has to be evaluated.  Next, please.
		So in conclusion, DPK is a research tool that has not been validated or shown to be correlated to clinical efficacy and systemic safety.
		We in PhRMA wish to participate on any expert panel or committee for this topic that is established by both Advisory Committees.  Thank you very much.
		ACTING CHAIRMAN DRAKE:  Thank you so much, and again thank you for the extra minutes.  A very nice presentation.  
		I would like to invite Deborah -- is it Miran? -- from the Generic Pharmaceuticals Association to present, and you asked for five minutes.
		MS. MIRAN:  Thank you very much.  I don't have data, and I don't have slides, and I will probably be less than five minutes.
		ACTING CHAIRMAN DRAKE:  You get better every minute.
		MS. MIRAN:  The GPhA or the Generic Pharmaceutical Association would like to take this opportunity to make a brief statement, and we thank you for this.
		We have supported, and continue to support, the issuance of this guidance as a means to demonstrate bioequivalence in topically applied generic dermatologic drug products.
		GPhA well recognizes the role and the purpose of both the innovator discovery based industry and the generic industry, which provides lower cost, quality alternatives.  Both segments can and should peacefully coexist, and I wish to reiterate that there is only one standard of quality for review and approval for both generics and innovators.
		Regarding DPK, we have been patient, persistent and diligent in facing the issues and answering the scientific questions about the use of DPK as a measure of bioequivalence.  This work, as has been mentioned, has effectively been ongoing for more than ten years, and a vast amount of data have been generated by both the industry, the agency, and academic institutions.
		These data have been reviewed carefully by experts around the world.  These studies have been designed to look at equivalence between test and reference products, correlations between clinical results and DPK results in both bioinequivalent and bioequivalent situations.
		Every time the Joint Advisory Committees have met and concluded that this is a potential or promising assay for BA/BE determinations, the agency, the industry and academia has responded with more studies and more data.  These data have been presented to this group, and as today and in the past and as we have heard from Lynn, there is more to come.
		In our opinion, these data support the use of this technique as a means to detect differences between "two like products" and to establish equivalence between test and reference products.
		Presently, the generic industry continues to only have two choices for developing ANDAs and registering topically delivered generic alternatives.  These choices, unfortunately, are (1) not to develop at all, and not to make available the generic alternative or (2) to conduct and extensive and expensive full scale clinical efficacy trial to determine equivalence.
		In our opinion, this approach is inconsistent with FDA's whole objective of reduction of regulatory burden and exposure to patients.  
		FDA and CDER continue to evolve into and support a risk based approach to assessing regulatory requirements, so long as they are based on sound science.  
		As we were reminded throughout this week of Advisory Committee meetings, there is never a no-risk environment, but we believe that the DPK and its use in evaluating bioequivalence has reached the minimal risk category, as Dr. Shah stated earlier.
		Remember, too, that the statute does not require that generics reestablish efficacy.  This has been proven.  Waxman-Hatch, by definition, assumes that efficacy and safety will be proven through the link that the bioequivalency study provides.
		In conclusion, we believe that DPK is determined by the current evidence and that the draft guidance, after two and a half years in review, should be finalized and implemented.  Thank you.
		ACTING CHAIRMAN DRAKE:  Thank you.  Then there is one last public comment from the American Academy of Dermatology, Cheryl Hayden.  Oh, there she is behind the post where I couldn't see you.  You are so little.  There we go.  Again, five minutes.
		MS. HAYDEN:  Oh, I'll be less than that.  My name is Cheryl Hayden.  I am the Assistant Director of Federal Affairs at the American Academy of Dermatology, and I would like to thank Dr. Drake and the members of the Committee for the ability of the Academy to present the fifth time our reservations with the guidance document for establishing bioavailability and bioequivalence using skin tape stripping.
		The Academy has on a number of occasions expressed our reservations with this document.  I am just going to briefly summarize Dr. Scher's statement.
		Our concerns mainly have to do with the fact that there is no testing done on diseased skin, that patients with eczema, psoriasis, etcetera, will not be done well by this method.
		We are also concerned that the method in and of itself has flaws, including the inability to assess whether or not the drug that is in the furrows of the skin has, in fact, been absorbed into or through the stratum corneum.
		In addition to diseased skin, we are also concerned that the guidance document fails to note that it would require testing on skin in the elderly and in children, which also has its own unique qualities.
		Finally, we have also anecdotally heard problems from some of our members.  This issue has been discussed at our task force, our FDA Therapeutics Task Force.  Some members have tried to replicate the process as described in the guidance document and have had some difficulty.  So we wanted to bring that to your attention as well.  Thank you.
		ACTING CHAIRMAN DRAKE:  Ms. Hayden, thank you.  I want to thank all of those individuals who took their time from their busy schedules to present from the interested public at this meeting.  It is very important, and although I have joked about the time, I can't tell you how important your input is, and I would encourage you at any future hearings to please do this.
		For those of you who want to be taken most seriously, be sure you try to give us something in writing ahead of time, because that helps the Committee then have an opportunity to review it before we hear it the first time.  It carries much more weight, but I do want to thank you.
		At this point, what I would like to do now is open it back up to the Committee.  Dr. Stern?
		DR. STERN:  Just to get things going, because this is my sense of what's happened, I guess I would like to move that the Committee recommend withdrawal of this guidance document with the instruction that in future DPK guidance documents, at least in the next ones that come forward, that they be limited to specific therapeutic classes; because, to me, the utility of this may well vary substantially according to therapeutic class of the topical agent.
		A global one is, from my perspective, a long way from ready for prime time.  So I think this global guidance document should be withdrawn, and I certainly think looking at it on a therapeutic class basis -- there may be some classes where it's very useful.
		ACTING CHAIRMAN DRAKE:  Is there a second?
		DR. KING:  Second.
		ACTING CHAIRMAN DRAKE:  Okay.  The motion has been made and seconded that this guidance document be withdrawn, with the -- and I haven't forgotten you.  I'll certainly allow the discussion period.
		Let me just restate the motion, please, so I make sure I have it correctly:  That the guidance document be withdrawn, with the instruction that, when it is re-presented, that it is done so with therapeutic classification structure in place.  Is that an accurate summary?  Okay.  That's the motion.
		Open for discussion, and it's been seconded, and Dr. Hussain.
		DR. HUSSAIN:  Just a point of clarification, ma'am.  I think the purpose of this meeting was not to call for a vote.  We requested this meeting primarily to discuss the issues and bring the new members up to date on the topic.
		We would like to reconvene the Joint Committee meeting with all the data.  We did not present any of the data here, and the purpose of the meeting was not to call for a decision at this point.
		ACTING CHAIRMAN DRAKE:  Okay.  I think that may have -- Dr. Stern, I don't want to speak for you, but in one of the presentations it talked about perhaps the guidance document -- a recommendation being withdrawn.
		I don't know that this is a vote.  What I would like to do then, taking your comments into consideration, which I certainly have healthy respect for the purpose of this meeting, but I also have a healthy respect for the sense of the Committee -- would it be reasonable -- Let me just ask, would it be reasonable, instead of this being a motion, to take it as a sense of the Committee, so to provide you with some guidance?  Would that be acceptable?  John?
		DR. WILKIN:  Actually --
		ACTING CHAIRMAN DRAKE:  Dr. Stern says only if we have punch ballots with curlicues or whatever they are called.  So --
		DR. WILKIN:  Okay.  Then I guess we figure out whether they are dimpled.
		ACTING CHAIRMAN DRAKE:  We need to know if they are dimpled or pregnant or whatever, but other than that, we are fine.  Yes.  Go ahead.
		DR. WILKIN:  You have to understand what our views were in coming to the group.  If we really thought that we were coming to the group where we were going to get an up-down kind of recommendation or any sort of specific recommendation, I really think we probably might have deferred the meeting until we had the additional data that are coming in, that we certainly would have given a lot more data and informational pieces.
		You would have had a much thicker guidance -- not guidance, but briefing document, so you could pour over these sorts of things.  
		Really, the intent today was not for the up-down or for any sort of aspect like that.  It was really for those who are conducting these kinds of studies, for those of us who are working together at the FDA to think about the informational needs and how they might be achieved, to get some thinking along those lines.
		ACTING CHAIRMAN DRAKE:  I understand.  Rob?
		DR. STERN:  Can I then -- Given that, can I make a suggestion that at 12:25 we take a straw poll to suggest whether, as individuals, we feel this document is what I would call ready for prime time or not ready for prime time, and a second question would be whether we think -- if we don't think it's ready for prime time as it is currently given, whether we think it might be closer to being ready for prime time and application if it were done on a therapeutic class basis rather than as a global document.
		So that's really more the issue of how we feel about it and advice and not really voting, but would that be more in the spirit of today?
		DR. WILKIN:  Actually, to my own personal sense of fairness, it really wouldn't.  I mean, to be honest.  My sense is that, had we been thinking that there would be a vote or a recommendation or even something informal as a straw vote at the end, that really we would have had a longer meeting. 
		We would have presented more data.  It would have been a much more thorough discussion.  My own sense of fairness is that that really doesn't --
		DR. STERN:  Then I withdraw my motion.
		ACTING CHAIRMAN DRAKE:  Rob, are you withdrawing your motion then?  Withdraw the second?  Dr. Mindel?
		DR. MINDEL:  The other side of this, though, Jonathan -- this is the third time that we have spent considerable time on this subject, and the only new information that was presented was on two slides, one of -- that one of the corticosteroid, and the other was a study in progress.
		It seems that some people are beating a dead horse, and I don't -- You know, I think that enough is enough.  So I would like to call on the Chairwoman to use her prerogative as a Chairwoman to have a vote.
		ACTING CHAIRMAN DRAKE:  I would like a little more discussion.  I thank you.  And I have three lawyers lined up.  
		DR. DiGIOVANNI:  I'm always good for a little discussion.  I also had a sense that the politics of this had moved more forward than we had actually been given enough information to deal with.
		I think that, when I read this, my sense was that this was a work that had been presented as President without the vote being counted, and the votes that I recollect from the prior meetings was that there were many questions that hadn't been answered.
		Some of them are quite obvious questions:  How much of the topical preparations are left in the crevices and clefts? You know, that may be an obvious one.  There are others that may be more or less substantial:  What are the various endpoints, certainly, as Rob had mentioned?
		I think for dermatologists to look at the skin as one homogeneous group, it just doesn't seem to work that way.  So without looking at different classes of drugs and addressing them specifically and coming up with some more scientific sense of addressing this, my gestalt was the same as Rob's.  This is sort of being shoved down our throats almost further ahead than the information that we have been able to digest.
		So I think the sense of the discussion is that there are some very focused questions that should be addressed before the term paper is submitted next time.
		ACTING CHAIRMAN DRAKE:  Dr. Hussain?
		DR. HUSSAIN:  I think I second that, in the sense, if you really look at the advice we sought, I think -- If you look at my slides, the questions I posed to the Committee is how do we redirect our research focus so that when we come back to this Committee with the data, that would essentially address some of those concerns.
		I laid out a means of approaching it, and I didn't get any feedback on the questions I sort of posed to the Committee.
		ACTING CHAIRMAN DRAKE:  I am going to take the prerogative of the Chairman here for just a moment -- or Chairwoman.  I think that -- I do feel that -- Here is what I am going to do, as we will not take a vote, but I am going to poll this committee one by one and ask for their opinion, and I am going to ask you to give your opinion in two sentences or less without a long explanation.  But you want our opinion, and I think there are some members we haven't heard from, and I would like to make sure everybody gets included.
		I want to just go around the room asking for your gestalt on the subject.  John?
		DR. WILKIN:  One of the aspects that we realized in coming to the group is that there are members here around the table today from the Pharmaceutical Sciences Advisory Committee and from the Dermatologic and Ophthalmic Drugs Advisory Committee who have not heard this DPK presented at a committee discussion before.
		So one of the key objectives was to give with this new group -- bring everyone sort of up to speed as to what some of the concerns are, and to describe informationally not the dataset that we have but what is --
		ACTING CHAIRMAN DRAKE:  Needed.
		DR. WILKIN:  -- literally in the oven, that is being worked on right now, and it is with the intent that when that dataset arrive that it will come back to the Joint Committee and then that's the day that, you know, gets the kind of discussion that you are describing.  But our intent, really, was more keeping the awareness and sort of giving a brief and a half-day kind of update.
		ACTING CHAIRMAN DRAKE:  John, I think we really appreciate -- and I want the Committee to correct me if I am wrong, but I am going to try to state for the Committee from what I've heard, that we're going back to the notion that, yes, a noninvasive measure that is cheap, fast and expensive is needed and useful and important, and we commend Dr. Shah, Dr. Hussain and you, Dr. Wilkin, for trying to make this happen.
		We have heard this before.  I've been on other committees.  There isn't anybody at this table, in my opinion, that doesn't think that's an important next step.  Am I correct on that?
		Secondly, I do not believe that this committee has had the evidence presented today that would allow them to validate this as the way to go forward.  There are serious, serious and substantial concerns about what we have heard today, and I think, if you did hold a vote, it would not be to move forward in this direction.
		So I think you are hearing serious reservations from this group about what we've heard.  Is that also a correct statement?
		All right.  The third statement that I think I -- and this may be my own personal opinion -- I love the fact that you've had this combined meeting, because it has allowed the pharmacologists to get together with the clinicians and try to share information, which is extraordinarily important, because that's how best decisions are made, is by having a sharing of information.
		Without sharing of information, frequently you get bad decisions, and then bad outcomes.  So I want to commend the FDA personally for bringing us altogether, because I've had great fun meeting some of our colleagues who actually know more about areas under the curves than I'll ever know.  But it's important.
		If we don't have that kind of information -- and I hope it's as important to you to learn what we as clinicians face.  But I think it's a sense from all groups that we are not at that point yet.  Is that a correct assumption, and do we like this joint meeting?  So everybody likes the joint meeting.  All right.  So that's the third summary.
		The fourth summary is I want to make sure, at least from my perspective, that this information sharing in no way implies that we have given the okay or the go-ahead for the forwarding of this document with the kind of information we have.  
		In other words, I don't want this to be used on a slide in the future to say we met and liked it, because I think you've heard we've met, and we are uncomfortable at this point, and that we need more information.  Is that a fair assumption?  Okay.
		So I think that is my -- As a chairman, that is my prerogative in where we are, and I think that probably I can't -- We've asked this before.  I asked it once as a member of this committee when we had this.  
		To come into a meeting with two things not happening, not having all the studies and information before us is a mistake.  I understand some of it is not ready, but there is some stuff that's been done that was not in our packet.
		So I would beg of you to make sure the committee gets all that information ahead of time, not only from the FDA but from all the audience here who has a vested interest in the outcomes.  Please give us your work ahead of time, and the back-up documentation, because we may not like wading through all of it, but I'll assure you, you have a conscientious committee here who will wade through it, and we will try to come to some rational recommendations that ultimately benefit the end users, the patients.  That's our goal here, as I understand it.
		Now then, having said that, I probably talked too much.  But I wanted to try to synthesize and condense what we have heard.  Now I do want to take this moment to call on two people at this table who I have not heard them open their mouth, and I want to know if you have any additions or comments to what has already been said or what I've said.  And Dr. Bloom, you are one.
		DR. BLOOM:  This is the first I ever heard of all this information.  So it's kind of hard to just suck it in.  The other thing, I am concerned of the need for a validation of analytical methodology.  Meanwhile, these studies are being performed.  So it's kind of like there is no balance.
		My concern is you first have to validate an analytical methodology, and then go ahead and do the particular studies.  This is a concern of mine, because maybe the data might be influenced just because of that particular aspect.  That's one of them.
		The other one, I got concerns of maybe information that I don't have, for example, if it is taking into account the possibility that the active ingredients are being intercalated into proteins, although here on the follicles -- So I don't know that information.  That might be influencing the bioavailability studies that might be taken into account.
		So basically I am trying to get all the information and try to figure out the outcomes.  So that's my perspective.  There's other aspects about this skin stripping that needs to be validated, and the pressure that should be applied, the area that should be taken into account, the need to spread the emulsion.  
		All those little, bitty details may make a big influence in the bioavailability studies and bioequivalence studies in terms of just the concentration to be estimated.
		ACTING CHAIRMAN DRAKE:  Do you see why I make everybody speak?  What you've just said makes so much sense.  Thank you.  
		Dr. Boehlert, would you please contribute?
		DR. BOEHLERT:  Yes.  I am concerned that we are extrapolating a small database, what I've seen from the data presented today, to a larger population.  I have listened to the combinations, different skin types, different disease states, and I am not sure we have enough data or I have seen enough data to make that extrapolation.  That is always a concern of mine.
		The other thing that I would bring up that I think Dr. Wilkin addressed to some extent is that Q1 and Q2, in and of themselves, may not be enough to distinguish products.
		They do not get into the physical state of the active ingredient.  Particle size is critical in dermatological products.  I have had experience with developing dermatological products and seen them to be very different based on just the physical state of the active ingredient, and that is not addressed in Q1 and Q2.  You can have the same ingredients at the same concentration and different particle size.
		So there are other issues here that we need to look at.
		ACTING CHAIRMAN DRAKE:  Thank you very much.  Again, validating my notion that everybody needs to comment, because you bring different perspectives to the table that all of us need to hear about.
		With that, I am going to just quickly track around the table, asking for any additional comments.  Please, I am going to suggest we don't repeat, but that we, in one sentence, summarize.
		Right before I start that, Dr. Shah, you have a comment?
		DR. SHAH:  Yes.  I just had a comment on what Judy indicated, and that's true.  Q1 and Q2 by itself is not enough, but along with that we also have the physical, chemical characterization of the product.  
		We also have the in vitro drug release, which is similar to the dissolution that's a part of the requirement, and also the particle size of the active ingredients.
		All this put together is going to be the total body of evidence for the bioequivalence.
		ACTING CHAIRMAN DRAKE:  Okay.  Dr. Lamborn?
		DR. LAMBORN:  I think that I share a number of the concerns that have been expressed before. There were some of the questions that I posed that I think at the next time we come back it would be very helpful if they were clarified, both in terms of the basis currently now in bioequivalence and also the intent of the guidance, and also to reiterate what others have said.  
		The next time through, it would be very helpful if we are presenting new data to make sure that we had the background that led us to truly understand what the trials are that are being done, potentially the protocol as a document, not necessarily spend the time during the meeting but prior to it so that we can bring out questions.
		ACTING CHAIRMAN DRAKE:  I think, instead of presenting that stuff here, in view of limited time, if we have it ahead of time, then you don't have to present the protocol.  We will know the protocol, but then we can ask questions.  So that's a real strong recommendation you are hearing, particularly from your Chairman.
		Dr. Tang?
		DR. TANG:  For the purpose of showing bioequivalence, my suggestion to the future researchers:  You go from -- to the therapeutic area, therapeutic classes where you have -- antifungal, and go to another therapeutic classes.  This validation should only be done by therapeutic classes.
		ACTING CHAIRMAN DRAKE:  By therapeutic.  Okay, Dr. Mindel?
		DR. MINDEL:  I look forward to the fourth presentation of this subject.
		ACTING CHAIRMAN DRAKE:  That's right.  Listen, I have a great graph I want you to put on the agenda.  Jaime, I have this wonderful thing I want to talk about to start the meeting about dead horses, and I want to be sure that you remind me, because I want to present it.  
		It was just presented at the Harvard Business School by a very famous leader, John Kotter, and I'm going to share it with this group about "dead horses"  before the next meeting.  Okay?  Can I have permission to do that?  It's fun.
		Okay, go ahead.  Sorry.  All right, Jaime, do you have a comment on all this?  Okay.  Dr. Abel?
		DR. ABEL:  I agree with all the comments of the Chairperson, and I think there is a great unmet need for the generic drug industry here, and we need to come up with some methodology.
		I do question the methodology here, and I think the major concern is that the bioequivalence does not equal bioavailability in the disease state.  Perhaps we need to investigate other possible technologies.  I have no background in the imaging techniques, but maybe there is a completely new methodology or involving MR or imaging that might play a role here.
		Thank you very much, and I agree that we need to review all materials ahead of time.
		ACTING CHAIRMAN DRAKE:  Dr. Jordan, you haven't said very much today.  So --
		DR. JORDAN:  Oh, I said a few things.  I'm being very pensive.  Actually, I have not heard the prior presentation.  So this is my first time, but I get a sense that people are tiring a little of it.
		I do think this is very difficult, at least for me, and not having seen any of this ahead of time.  To be really sure this is some kind of a standardized procedure that could be used to evaluate these kinds of studies, I think it would have been nice to see some of the studies done on generic versus pediatric, the skin types, to really be sure this is something that could be applied to this kind of methodology.
		ACTING CHAIRMAN DRAKE:  Dr. DiGiovanni.
		DR. DiGIOVANNI:  I have no further comment.
		ACTING CHAIRMAN DRAKE:  Dr. Stern?
		DR. STERN:  I think this is something that we need to think about as not one methodology fits all, but by therapeutic class.  I also think, in addition to thinking about the scientific rationale for the application of this to a given therapeutic class, also think about the extent to which equivalency is clinically important for a therapeutic class.
		ACTING CHAIRMAN DRAKE:  Dr. Lim?
		DR. LIM:  I have expressed my concerns before about using a one-time application of in vitro method for an in vivo clinical response, and I have no further comments beyond that.
		ACTING CHAIRMAN DRAKE:  Dr. King?
		DR. KING:  This has been a useful, informative meeting.  However, I am not convinced that the DPK and related studies should be the only criteria that you evaluate for proof of concept, and suggest, as Dr. Abel did, we need newer methods and another evaluation before we go forward -- new methods, and this is not going to fly.
		ACTING CHAIRMAN DRAKE:  Okay, thank you.  New methods is not -- Without something different, yes.  Okay.  Dr. Miller.
		DR. MILLER:  I think that we should remember that this is just a draft, and you know, it can be changed.  I think Jonathan very eloquently in his presentation raised most of the issues that we've discussed, and he did say there are different therapeutic classes.
		I think it's apparent now that there is the ongoing study with Tretinoin, and we'll be looking for those data when they are available, and then I think from that, there will have to be more similar studies using different therapeutic classes and different age groups.
		So I think that the whole thing has to be extended, and we are still in the very nascent stage of all of this, but I think it is still a draft.  Certainly, DPK cannot replace clinical trials at this time.
		ACTING CHAIRMAN DRAKE:  Okay.  So I want to -- I think one additional comment that comes from your Chairperson then, based upon this final roundtable, is that without the clinical correlation that this will be, in fact, a very difficult option for us to support as a committee, keeping in mind that we are totally and completely advisory.  But we all want to head toward the same goal.
		Again, I want to commend Dr. Shah, Dr. Hussain, Dr. Wilkin for moving us along.  I also want to reiterate, though, that perhaps the next time would be a real good time to have a lot of this data in front of us ahead of time so that we can come to some kind of closure or at least some kind of recommendation.
		I get the sense from the committee that we have heard it many times, and it's probably time to -- I mean, this may not be the best way to do it.  I don't know.  But if we don't have data to support it, I think we should -- I guess what I'm trying to say is I would encourage you to not only look at this.  
		The concept is so important of having noninvasive measures that I would encourage you to look at any other alternatives and other options that might be called into play at this point, particularly with all the new technologies out there today.  I mean, there's so many new technologies.
		You might even think about offering an RFP or a solicitation or however you do that -- far be it from me to suggest that, but you know, if you canvas the different universities, different pharmaceutical companies, different generic houses, I suspect there's techniques and tools out there that could be brought into play, and with a little bit of support might be developed.
		I'll give you one example at my own institution.  I do know that there is a way now of screening genetically some new drug compounds, and that has been patented and licensed now, and several companies have licensed that as a screening tool.
		I mean, there's just so many new techniques and tools out there that I would really encourage you to do some kind of very vigorous and aggressive looking about to see what else is out there, because you are exactly right on the concept.
		You are exactly right to try to get something that is not invasive and cheaper and more efficient.  So my hat is off to you for working in this very difficult area.
		I want to -- Before I shut down, I want to make sure that I thank, particularly, Jaime Henriquez and his staff for another great meeting.  You guys do such a good job.  Thanks, Jaime.
		(Applause.)
		ACTING CHAIRMAN DRAKE:  I want to thank all of my committee members for coming, as big time in your day and your week.  I want to thank our audiovisual folks.  As usual, good job, guys.  Mikes, good job.  And thank you.
		Before I close the meeting, are there any additional comments?  Yes, Dr. Hussain?
		DR. HUSSAIN:  Ma'am, I had requested a few minutes to answer Dr. Lamborn's question, but I did not.
		ACTING CHAIRMAN DRAKE:  Shoot.
		DR. HUSSAIN:  I requested that Dale Conner do that on my behalf.
		ACTING CHAIRMAN DRAKE:  You did, and I forgot, and I apologize.  Would it be more useful to do it now or would it be more useful to do it the next meeting?  May I ask that question?
		DR. HUSSAIN:  We could close with that comment.
		ACTING CHAIRMAN DRAKE:  You want to close with this?  Please go ahead, and I apologize for forgetting.  I usually make notes, and I didn't -- because it was during break, and I didn't make a note.
		DR. CONNER:  Since I've only had probably 15 or 20 minutes and I wasn't preparing to talk --
		ACTING CHAIRMAN DRAKE:  That's okay.  I'm only going to give you four minutes anyway.  
		DR. CONNER:  Just a few comments, you know, probably not in a very logical order.  If I had two or three more minutes to prepare, I might have gotten --
		ACTING CHAIRMAN DRAKE:  You will have it at the next meeting, for certain, but give us some closing thoughts.  This is important.
		DR. CONNER:  First off, I think we've addressed the fact of what we're after with bioequivalence in approving a generic product.  I've been in many, many, many discussions like this, and some of them with simply internal FDA people, and the discussion always gets to the point where people become confused and mix up BA and BE, and they mix up proving efficacy of a product or a drug substance versus simply formulation comparisons.
		What we are really after with generic drugs is doing a formulation comparison, and it's a much, much simpler question than BA or clinical efficacy of the primary product.  All we are trying to do is form a bridge between this other formulation and the one where we have already done extensive testing and proved, hopefully to everyone's satisfaction, that it works, and that it's safe within known quantities.
		So I mean, that's important to always keep in mind.  The bioequivalence testing we do, no matter what it is, is always an artificial situation.  You look at any of the generic drugs we do, and I would even, you know, parenthetically say that even the clinical studies we do to prove efficacy are artificial.
		So we are always doing some technique.  Since this is -- You know, despite what anyone says, this is a very simple question, is does this product deliver that same active drug substance, make it available to the body and presumably eventually to the site of activity in the same manner as the original product, which has the extensive testing.  
		That's really a very -- much more simple question than does it work?  Is it by itself an effective product?  We're connecting everything with that very narrow bridge to the original product.  
		So that's point one, and you really always have to keep that in mind, because people become confused when they talk about clinical trials, about inherent safety and efficacy, proving it all over again for that new product, and that's really not the point of a generic, and that's not the rules that we operate under.
		A few other comments:  Someone brought up a lot earlier the fact that, well, the clinical differences, you know, that I see between these different products aren't all that great; yet you are showing big effects on DPK, and that really says that DPK is probably a little bit -- a lot more discriminating.
		Perhaps the danger of this, if we answer all the other questions, is it's going to be overly discriminating.  It is going to perhaps knock out products that are fairly close together, because it simply says there's a difference here, but that difference may not mean anything, you know, in clinical settings.
		So in effect, we may have something that actually knocks out products that might ordinarily work exactly the same way in the clinical setting.  But rom a regulator's standpoint, I'd rather deal with that than with something that underdiscriminates.
		Finally, and I'll finish up, the part about the sensitivity of clinical versus the kinetic way of doing things -- You will have to remember that clinical and pharmacodynamics operate on a sigmoidal dose response curve.
		So you can be -- You know, at very low doses you can see next to no effect.  You get to a part where you increase dose or exposure.  You get to kind of a steep, almost linear portion.  Then finally you get up to a part where you have a plateau.  Even if you increase the dose by considerable amounts, you don't really see any difference in effect.
		Unfortunately, most of these drugs are kind of in the upper part of the dose response curve.  So even increasing the dose by significant amounts really doesn't give you that big of -- big or any difference between the products.
		One thing, when you look at pharmacodynamics or clinical effects, and to do a very discerning study on those, you really have to make sure you are in that steep part or else the test really has no ability to differentiate between products, even if they are very, very different.
		That's something you always have to keep in mind when you look at clinical or pharmacodynamic effects; whereas, kinetics usually in most cases are very linear.  You know, twice the dose will give you twice the amount of drug presence.  I mean, that's something to always keep in mind.
		ACTING CHAIRMAN DRAKE:  Thank you very much.  I appreciate that clarification, and that's actually very good, considering you just had a few minutes to think about it.  Thank you so much.
		DR. CONNER:  I've done this before.  
		ACTING CHAIRMAN DRAKE:  I suspect you have, yes.  Thank you so much.  Dr. Hussain, thank you.  That's helpful.
		Anything else before the committee?  Again, thank you guys from the FDA for continuing to think about this important subject.  
		The meeting is adjourned.
		(Whereupon, the foregoing matter went off the record at 12:28 p.m.)