1 DEPARTMENT OF HEALTH AND HUMAN SERVICES 

FOOD AND DRUG ADMINISTRATION 
CENTER FOR DRUG EVALUATION AND RESEARCH
DERMATOLOGIC AND OPHTHALMIC DRUGS ADVISORY COMMITTEE MEETING NO. 52

								OPEN SESSION
Thursday, June 29, 2000 10:00 a.m.
Holiday Inn Bethesda Versailles I 

8120 Wisconsin Avenue Bethesda, Maryland 

	2 PARTICIPANTS 
Lynn A. Drake, M.D., Chairperson 

Jaime Henriquez, Executive Secretary 
MEMBERS 
	Robert E. Jordan, M.D. 

O. Fred Miller III, M.D. Robert S. Stern, M.D.
SPECIAL GOVERNMENT EMPLOYEES 
Wilma F. Bergfeld, M.D. Joan P. Chesney, M.D. John J. DiGiovanna, M.D. 
James S. Kilpatrick, Jr., Ph.D. Joseph McGuire, M.D. 

Joel Mindel, M.D., Ph.D. Eduardo Tschen, M.D. William Rosenberg, M.D. 
GUEST SPEAKERS 
Roselyn E. Epps, M.D. Mervyn Elgart, M.D. 
Richard Steven Feldman, M.D., Ph.D. Lloyd E. King, Jr., M.D., Ph.D. Theodore Rosen, M.D. 

	Mary Spraker, M.D. 
FDA 
Jonathan K. Wilkin, M.D. Lois LaGrenade, M.D. Hon-Sum Ko, M.D. 

Markham C.Luke, M.D., Ph.D. Martin Okun, M.D., Ph.D. Susan Walker, M.D. 

		3 C O N T E N T S 

NDA 20-010 - Lotrisone (betamethasone diproprionate and clotrimazole) Lotion 
Schering-Plough, Inc. 

for Treatment of Tinea Pedis, Tinea Cruris and Tinea Corporis 

Call to Order and Welcome: Lynn A. Drake, M.D.		5 
Conflict of Interest Statement: Jaime Henriquez		5 
Overview of the Issues: Jonathan Wilkin, M.D.	10 
Presentations - FDA 
		Fixed Drug Products Combination Policy: 
			Antifungal Plus Corticosteroid for Tinea 
			Infections: Martin Okum, M.D., Ph.D.	11 
		NDA 20-010 Lotrisone Lotion: 
			Markham Luke, M.D., Ph.D.	63 
Review of Lotrisone Adverse Events: 1984-1999: 
			Lois LaGrenade, M.D., M.P.H.	67 
		Recap: Markham Luke, M.D., Ph.D.	76 
Presentations - Invited Experts 
		Perspectives on Topical Antifungal Therapy: 
			Theodore Rosen, M.D.	78 
Open Public Hearing			95 
Presentations - Invited Experts (Continued) 
		Tinea Incognito and Strong Topical Steroids: 
			Mervyn Elgart, M.D., Ph.D.	95 
		Use of Lotrisone in the United States: 
			Richard Steven Feldman, M.D.                      105 
Sponsor Presentation 
		Lotrisone Facts and Issues: Todd Plott, M.D.        135 
Question for the Committee                               166 

4 

		5 C O N T E N T S(Continued) 

NDA 20-996 - Dermex II (zinc oxinate) Ointment Dermex Pharmaceuticals, LLC 
for Treatment of Actinic Keratosis, Basal Cell Carcinoma 
				and Squamous Cell Carcinoma 

Conflict of Interest: Jaime Henriquez	223 
Introductory Remarks: Jonathan Wilkin, M.D.	224 
FDA Presentation 
		NDA 20-996 - Dermex (zinc oxinate) Ointment: 
			Hon-Sum Ko, M.D.	225 
Sponsor Presentation 
			Summary of Company: Frank Potestio, M.D.	232 
			Updating Committee on Dermex: Carl Hanson	236 
Committee Discussion	250 

			6 1		         P R O C E E D I N G S
	2		       Call to Order and Welcome 
	3		DR. DRAKE:  Good morning.  I am Lynn Drake from 
	4	the University of Oklahoma, currently, and, as of July 1, 
	5	from Harvard Medical School.  I would like to welcome you to 
	6	the fifty-second meeting of the Dermatologic and
	7	Ophthalmologic Drugs Advisory Committee for the Center for 
	8	Drug Evaluation and Research of the Food and Drug 
	9	Administration.  The date is June 29, 2000. 
10		The first thing I would like to do, before 
11	introductions, is make a primary introduction.  I would like
12	to introduce our new executive secretary, Jaime Henriquez. 
13		MR. HENRIQUEZ:  Welcome. 
14		     Conflict of Interest Statement 
15		MR. HENRIQUEZ:  The following is the conflict of 
16	interest statement.  The following announcement addresses

17	the issues of conflict of interest with regards to this 
18	meeting and is made a part of the record to preclude even 
19	the appearance of such at this meeting. 
20		Based on the submitted agenda and information 
21	provided by the participants, the agency has determined that
22	all reported interests in firms regulated by the Center for 
23	Drug Evaluation and Research present no potential for a 

24	conflict of interest at this meeting with the following 
25	exceptions. 

			7 1		In accordance with 18 USC 208-B, full waivers have
	2	been granted to Drs. Joel Mindel and Robert S. Stern.  
	3	Copies of these waiver statements may be obtained by 

	4	submitting a written request to the FDA's Freedom of 
	5	Information Office located in 12A-30 in the Parklawn 
	6	Building.

	7		In addition, we would like to disclose for the 
	8	record that Dr. Lynn Drake has interests which do not 
	9	constitute a financial interest within the meaning of 18 USC 
10	208-A but which could create the appearance of a conflict.  
11	The agency has determined, not withstanding these interests,
12	that the interests of the government and her participation 
13	outweigh the concerns that the integrity of the agency's 

14	programs and operations may be questioned. 
15		With respect to the FDA's invited guest, Drs. 
16	Stephen Feldman, Mervyn Elgart, Theodore Rosen and Mary

17	Spraker have reported interests which we believe should be 
18	made public to allow the participants to objectively 
19	evaluate their comments. 
20		Dr Elgart would like the disclose that he speaks 
21	for Vertex concerning Mentax.  Dr. Feldman would like to

22	disclose that his Department of Dermatology received a 
23	teaching grant from Ortho for Spectazole and a teaching 
24	grant for Allergan grant for Naftin Cream and research 

25	funding from Ortho from Spectazole Cream and NDA 21-026  His 

			8 1	department has also received similar research funding in the
	2	past from Glaxo for Oxistate. 
	3		Dr. Theodore Rosen would like to disclose that his 
	4	department received a grant from Vertex for a study of 
	5	Mentax.  Approximately six years ago, his department 
	6	received a grant from Allergan for a study of Naftin.  Dr.
	7	Rosen was an investigator on the study but received no 
	8	personal remunerations.  Dr. Rosen has also given talks 
	9	concerning Mentax for Vertex and received speakers fees from 
10	1998 through 2000.  In 1999, Dr. Rosen received an 
11	honorarium from Allergan for a lecture concerning Naftin.
12		Dr. Mary Spraker is an investigator on unrelated 
13	studies for both Schering and Glaxo.  In the event that the 
14	discussions involve any other products or firms not already 
15	on the agenda for which the FDA participants have a 
16	financial interest, the participants are aware of the need
17	to exclude themselves from such involvement and their 
18	exclusion will be noted for the record. 
19		With respect to all other participants, we ask, in 
20	the interest of fairness, that they address any current or 
21	previous financial involvements with any firms whose
22	products they may wish to comment upon. 
23		DR. DRAKE:  Thank you. 
24		The agenda is very busy this morning.  It is a 
25	very interesting agenda.  The first thing I would like to do 

			9 1	is introduce the panel.  I think most of us know each other
	2	but there may be some who don't and there also may be people 
	3	in our audience who would like to know who the participants 
	4	are. 
	5		I guess I would like to start from this side of 

	6	the table with the FDA folks and we will wander around the
	7	table.  Please identify yourself and your affiliation. 

	8		DR. LaGRENADE:  I am Lois LaGrenade with the 
	9	Office of Postmarket Drug Risk Assessment at the FDA.  I am 
10	a medical officer. 
11		DR. OKUN:  I am Marty Okun with the Division of
12	Dermatologic and Dental Drug Products, FDA. 
13		DR. LUKE:  Markham Luke with the FDA, Center for 
14	Drug Evaluation and Research, Dermatologic Division. 
15		DR. WILKIN:  Jonathan Wilkin, Division Director, 
16	Dermatologic and Dental Drug Products.
17		DR. MINDEL:  Joel Mindel, Mt. Sinai School of 
18	Medicine, Departments of Ophthalmology and Pharmacology. 
19		DR. McGUIRE:  Joe McGuire, Stanford, Dermatology 
20	and Pediatrics. 
21		DR. ROSENBERG:  Bill Rosenberg, Dermatology at the
22	University of Tennessee. 
23		DR. KILPATRICK:  Jim Kilpatrick, Biostatistics, 
24	Medical College of Virginia, Richmond, Virginia. 
25		DR. STERN:  Robert Stern, Dermatology at the Beth 

					10 1	Israel Deaconess Medical Center at Harvard Medical School.
	2		MR. HENRIQUEZ:  Jaime Henriquez, FDA. 
	3		DR. BERGFELD:  Wilma Bergfeld, Cleveland Clinic, 
	4	Departments of Dermatology and Pathology. 
	5		DR. JORDAN:  Bob Jordan, Dermatology, University 
	6	of Texas, Houston.
	7		DR. MILLER:  Fred Miller, Geisinger Medical 
	8	Center, Dermatology. 
	9		DR. DiGIOVANNA:  John DiGiovanna, Dermatology, 
10	Brown University and National Cancer Institute. 
11		DR. TSCHEN:  Eduardo Tschen, Dermatology,
12	University of New Mexico. 
13		DR. DRAKE:  This panel, just for the audience's 
14	pleasure, are our invited experts.  Please. 
15		DR. EPPS:  Roselyn Epps, Children's National 
16	Medical Center, Washington, D.C.
17		DR. ROSEN:  Ted Rosen, Department of Dermatology, 
18	Baylor College of Medicine, Houston. 
19		DR. FELDMAN:  Steve Feldman, Department of 
20	Dermatology and Pathology at Wake Forest University School 
21	of Medicine.
22		DR. KING:  Lloyd King, Vanderbilt University and 
23	Nashville V.A., Dermatology and Dermatopathology. 

24		DR. DRAKE:  I would like to thank all the 
25	committee and our experts for your time.  I also want to 

			11 1	thank the FDA for the very nice presentations, that we have

	2	received the documents ahead of time which is nice because 
	3	we have had an opportunity to review them and we look 
	4	forward to your presentations. 
	5		I guess we would like to start with Dr. Wilkin, 
	6	who is Chair of the Dermatologic and Opthalmologic Drugs
	7	Division.  Dr. Wilkin, would you give us an overview, 
	8	please, of what we discussing today. 
	9		         Overview of the Issues 
10		DR. WILKIN:  Thank you, Dr. Drake.  What we are 
11	going to be looking at later this morning is Lotrisone

12	Lotion which is currently under review as an NDA in our 
13	division.  You will hear the regulatory history of Lotrisone 
14	Lotion.  You will learn that it received an approvable 
15	letter in past.  I can tell you that the sponsor has met the 
16	conditions spelled out for approvability and so the intent
17	is, in the very near future, that I will be signing an 
18	approval letter for this product. 
19		This product is, of course, a line extension from 
20	the Lotrisone Cream which has been of interest in the 
21	literature to dermatologists and different comments have
22	been made.  We have invited guests to speak to some of those 
23	very specific Lotrisone-related issues. 
24		What we hope to hear from the committee and also 
25	from the guests is constructive suggestions for labeling 

			12 1	that might address some of these issues.
	2		Before we get into the very specific aspects of 
	3	this particular antifungal corticosteroid combination 
	4	product, we would first like to begin the morning session 

	5	with an overview of antifungal/corticosteroid combination 
	6	product policy and ways of thinking about the attributes of
	7	these products and how they might be labeled. 
	8		Again, in general, we will not be talking about a 
	9	specific product but I think those kinds of answers will 
10	then help inform the specific questions that will follow on 
11	this particular product.
12		DR. DRAKE:  Thank you very much. 
13		I think we will move, then, onto the main part of 
14	the program.  Dr. Okun, would you like to begin? 
15		          Presentations - FDA 
16		Fixed Drug Products Combination Policy:
17	    Antifungal Plus Corticosteroid for Tinea Infections 
18		DR. OKUN:  Good morning. 
19		[Slide.] 
20		As Dr. Wilkin indicated in his introduction, my 
21	purpose here is to present an overview of how the agency's
22	combination policy is applied to topical drug products 
23	containing an antifungal agent and a corticosteroid agent. 
24		[Slide.] 
25		First, I would like to define some symbols that 

			13 1	will be used in the presentation.  AF+CS refers to a fixed-
	2	drug combination topical drug product containing and 
	3	antifungal and a corticosteroid agent for treatment of tinea 
	4	infections.  AF refers to a topical drug product containing 
	5	an antifungal agent.  CS refers to a topic drug product 
	6	containing a corticosteroid agent.
	7		[Slide.] 
	8		21 CFR 300.50 spells out the informational needs 
	9	for approval of fixed combination prescription drugs.  Each 
10	component of the combination must be shown to make a 
11	contribution to the treatment effect.  The dosage of each
12	component is such that the combination is safe and effective 
13	for a patient population requiring combination therapy as 
14	defined in the labeling of the product. 
15		[Slide.] 
16		This slide describes the informational needs for
17	approval of an antifungal/corticosteroid combination drug 
18	product for treatment of tinea.  When I say tinea here and 
19	throughout this presentation, I am referring specifically to 
20	tinea pedis.  The agency view is that the treatment of tinea 
21	pedis is the highest hurdle for assessing efficacy of
22	antifungal agents and that treatment of tinea cruris is the 
23	appropriate disease model to assess local adverse events for 
24	safety. 
25		First a word about entry criteria for patients 

			14 1	enrolling in tinea pedis studies.  The patients must have
	2	the clinical signs and symptoms of tinea infection at 

	3	baseline.  They must have a positive KOH at baseline.  
	4	Fungus culture is collected at baseline and patients whose 
	5	culture turns out to be negative are subsequently excluded 
	6	from the efficacy analysis.
	7		Informational needs for approval are that the 
	8	contribution of the antifungal and of the corticosteroid 
	9	components be demonstrated, that the 
10	antifungal/corticosteroid combination be demonstrated to 
11	safe and effective for tinea infections and that the
12	population requiring combination therapy be identified. 
13		[Slide.] 
14		What are the potential benefits to patients with 
15	tinea of using an antifungal/corticosteroid combination 

16	product?  The antifungal component is going to treat the
17	infection with the point of cure occurring approximately 
18	five weeks after the start of treatment. 
19		The corticosteroid component will relieve the 
20	symptoms of infection early, usually about one week after 
21	the start of treatment.  The antifungal/corticosteroid

22	combination, then, relieves symptoms of infection early and 
23	treats the infection. 
24		[Slide.] 
25		In comparing the antifungal/corticosteroid 

			15 1	combination with the antifungal stand-alone product, an
	2	antifungal stand-alone product relieves the symptoms by the 
	3	point of cure as the infection is cured.  The antifungal 
	4	stand alone may provide some relief of symptoms early as the 
	5	infection begins to clear. 
	6		The only potential benefit of
	7	antifungal/corticosteroid combination, compared to 
	8	antifungal, is if the antifungal/corticosteroid combination 
	9	provides more symptomatic relief early. 
10		[Slide.] 
11		I am going to use the following abbreviations for
12	the rest of this talk on my slides: ROS to stand for relief 
13	of the signs and symptoms of tinea infection such as 
14	itching, erythema, scaling early in the treatment course; 

15	TTI referring to the treatment of tinea infection which 
16	includes mycologic cure and relief of signs and symptoms of
17	tinea infection, usually occurring late in the treatment 
18	course or post-treatment. 
19		[Slide.] 
20		To demonstrate the contribution of the 
21	corticosteroid component in antifungal/corticosteroid
22	combination products, the antifungal/corticosteroid 
23	combination must be shown to be superior to the antifungal 
24	stand alone in relief of symptoms early in the treatment 
25	course. 

			16 1		This condition applies regardless whether the
	2	corticosteroid stand alone is equivalent to the component 

	3	product with respect to the relief of symptoms or if the 
	4	corticosteroid stand alone is inferior to the component 
	5	product with respect to the relief of symptoms. 
	6		The experts on clinical-trial design here are
	7	probably blanching at the notion of demonstrating 

	8	equivalence in the clinical study.  In fact, the equals sign 
	9	is really a shorthand for demonstrating noninferiority 
10	within a prespecified confidence interval. 
11		Scenario No. 1 where the corticosteroid arm is
12	superior to the antifungal/corticosteroid combination with 
13	respect to the relief of symptoms is a scenario that I will 
14	discuss the ramifications of in a few minutes. 
15		[Slide.] 
16		To demonstrate the antifungal component in an
17	antifungal/corticosteroid combination, the combination must 
18	be shown superior to the corticosteroid-only arm in terms of 
19	the treatment of the tinea infection.  This condition 
20	applies regardless whether the antifungal is inferior to the 
21	component product with respect to tinea infection.
22		The ramifications of scenarios 2 and 3 where the 
23	antifungal arm is equivalent with respect to the combination 
24	for treatment of tinea infection or where the antifungal arm 
25	is superior to the combination arm with respect to treatment 

			17 1	of tinea infection will be discussed in just a few minutes.
	2		[Slide.] 
	3		Let's return to one of the previously identified 
	4	scenarios, Scenario No. 1.  To refresh our memories, in 
	5	Scenario No. 1, the combination product is demonstrated 
	6	superior to the antifungal arm with respect to the relief of
	7	symptoms which demonstrates the contribution of the 
	8	corticosteroid component.  Also, the combination product is 
	9	demonstrated superior to the corticosteroid-only arm with 
10	respect to the treatment of tinea infection; this 
11	demonstrates the contribution of the antifungal component.
12		What if the corticosteroid-only arm is superior to 
13	the combination product with respect to the relief of 
14	symptoms.  Under this scenario, the combination product has 
15	risks and benefits associated with its use.  The risk is 
16	that the antifungal component in the combination product is
17	impairing the early relief of signs and symptoms. 
18		The benefit is the antifungal component is 
19	providing treatment to the tinea infection.  Very obviously, 
20	in this scenario, the benefits of a combination product is 
21	outweighing its risks.
22		[Slide.] 
23		Let's consider Scenario No. 2.  Let's assume that 
24	the combination product is superior to the antifungal arm 

25	with respect to the relief of symptoms.  Again, this 

			18 1	demonstrates the corticosteroid contribution.  Let's assume

	2	the combination product is superior to the corticosteroid- 
	3	only arm.  This demonstrates the contribution of the 

	4	antifungal component in terms of treatment of tinea 
	5	infection. 
	6		Let's assume the combination product is equivalent
	7	to the antifungal stand-alone arm with respect to the 
	8	treatment of tinea infections.  Under these circumstances, 
	9	the question for your consideration is should such an 

10	antifungal/corticosteroid combination product with these 
11	properties be labeled for all tinea or should it be labeled
12	only for the more inflammatory tinea that warrants the use 
13	of an antiinflammatory treatment. 
14		[Slide.] 
15		Let's consider Scenario No. 3 now.  In this 
16	scenario, again the combination product is superior to the
17	antifungal with respect to the relief of symptoms, again 
18	demonstrating the corticosteroid contribution.  The 
19	combination product is superior to the corticosteroid arm 
20	with respect to the treatment of tinea infections, again 
21	demonstrating the contribution of the antifungal component.
22		What if the antifungal arm is superior to the 
23	combination arm with respect to the treatment of tinea 
24	infection?  Under these circumstances, combination product 
25	has risks and benefits associated with its use, the 

			19 1	principle risk being that the corticosteroid component is
	2	impairing the treatment of the tinea infection. 
	3		The benefit is that the corticosteroid component 
	4	is providing early relief of the signs and symptoms of 
	5	infection.  Under this scenario, only patients with 
	6	clinically significant symptoms at baseline could benefit
	7	from use of the combination product. 
	8		A question for your consideration is how could 

	9	labeling of such a product identify which patients could 
10	benefit from an antifungal/corticosteroid combination drug 
11	product with these properties.
12		[Slide.] 
13		I would like to turn now to a discussion of some 
14	aspects of the clinical-study design for 
15	antifungal/corticosteroid combination drug products.  The 
16	original paradigm that has been used for study of these
17	products is a three-arm or sometimes a four-arm study where 
18	the arms are antifungal plus corticosteroid combination, 

19	another arm being the antifungal stand alone, another arm 
20	being the corticosteroid stand alone, and, in some 
21	circumstances, a fourth arm being the vehicle for all the
22	other arms. 
23		There are some shortcomings of including a 
24	corticosteroid arm in a clinical study of treatment of tinea 
25	infections in that anecdotal experience and publications 

			20 1	suggest that the corticosteroid component may interfere with
	2	the host-immune response against a fungus. 
	3		[Slide.] 
	4		This leads us to wonder if we can reconsider 
	5	clinical-study design to fulfill the informational needs of 
	6	the combination policy without enrolling the study subjects

	7	in a corticosteroid stand-alone arm. 
	8		[Slide.] 
	9		A new paradigm under consideration is a three-arm 
10	study where the three arms are composed of antifungal plus 
11	corticosteroid combination, the antifungal stand alone and
12	the vehicle.  In this paradigm, if the combination is 
13	superior to the antifungal stand alone with respect to the 
14	relief of symptoms, this demonstrates the contribution of 
15	the corticosteroid component. 
16		If the combination product is superior to the
17	vehicle with respect to the treatment of tinea infection, 
18	this demonstrates the contribution of the antifungal 
19	component under the assumption that the corticosteroid is 
20	not contributing to the treatment of tinea infection. 
21		So we have demonstrated, under this paradigm, the

22	contribution of each component.  What information is lost by 
23	not having a corticosteroid stand-alone study arm? 
24		[Slide.] 
25		Under the three-armed study where there is a 

			21 1	combination arm, antifungal arm and vehicle study arm, in

	2	the absence of a corticosteroid study arm to demonstrate 
	3	antifungal contribution, the combination product must be 
	4	shown to be superior to the vehicle with respect to 
	5	treatment of tinea infection. 
	6		If the combination product is demonstrated to be

	7	superior to the vehicle with respect to relief of symptoms, 
	8	this may be due either to the contribution of the 
	9	corticosteroid component or to early antiinflammatory effect 
10	of the antifungal component or, potentially, both. 
11		For a sponsor to claim that the antifungal
12	component provides relief of symptoms early in treatment 
13	comparable to that of a corticosteroid component, the 
14	sponsor would have to demonstrate that the antifungal arm is 
15	equivalent to the corticosteroid arm with respect to the 

16	relief of symptoms and that the antifungal arm is superior
17	to the vehicle with respect to the relief of symptoms and 
18	that the corticosteroid arm is superior to the vehicle with 
19	relief of symptoms.  This claim is not possible without a 
20	corticosteroid stand-alone arm. 
21		A question for your consideration is whether the
22	knowledge obtained from including a corticosteroid arm 

23	compensates for the previously mentioned shortcomings of 
24	having a corticosteroid arm in a clinical trial for 
25	treatment of tinea infections. 

				22 1		This concludes my presentation.  Thank you.
	2		DR. DRAKE:  Thank you very much.  You did a great 
	3	job.  That is complex and you did it in a manner that all of 
	4	us understand.  Thank you. 
	5		DR. OKUN:  Thank you. 
	6		DR. DRAKE:  There has been a lot of thought gone
	7	into that presentation. 
	8		I would like to ask Dr. Wilkin, would you like to 
	9	consider these questions now?  Is this an appropriate time? 
10		DR. WILKIN:  I think it would be.  The questions 
11	that are limited to this.
12		DR. DRAKE:  The three questions he has? 

13		DR. WILKIN:  That's right; just to the 
14	antifungal/corticosteroid combination policy types of 
15	issues.  Yes. 
16		DR. DRAKE:  Let's consider the questions, then, at
17	this moment, since this is fresh in our mind, of just the 

18	policy issues, the three questions that were outlined.  I am 
19	going to pose the first question, then. 
20		The first question is, "Is the proposed set of 
21	decision rules for antifungal/corticosteroid combination
22	topical products acceptable for documenting the contribution 
23	of both components?"  That is the question. 
24		I would like to ask for a point of clarification.  
25	I have read it, but I think, for the whole committee's 

					23 1	benefit, the proposed set of decision rules we have before

	2	us or we been just given questions.  We don't really have 
	3	the proposed set on a slide yet. 
	4		Jon, is the proposed set of rules before us?  Do 
	5	you want to elucidate a little bit on those? 
	6		DR. WILKIN:  If you like, Dr. Okun has them in his
	7	slides. 
	8		DR. DRAKE:  Could we go back to the slides?  I 
	9	would like to go back so we are all talking the same set of 
10	rules. 
11		DR. OKUN:  I am just trying to think of which
12	would be the most appropriate slide. 
13		DR. DRAKE:  I think one of the questions that 

14	pertained to this was on Slides 13 and 15.  One of the 
15	things you wanted to know is the corticosteroid arm 
16	important for this.  That was Slides 13 and 15.
17		DR. OKUN:  Certainly, we can start with that.  If 
18	we consider the utility of the corticosteroid-only arm, 
19	let's go the Slide No. 15. 
20		[Slide.] 
21		This is the three-armed paradigm in which a
22	corticosteroid-only arm is excluded.  In this paradigm, for 
23	us to demonstrate the contribution of each component, again, 
24	there is the combination arm, the antifungal stand-alone arm 
25	and the vehicle arm.  The antifungal combination 

			24 1	corticosteroid arm must be demonstrated superior to the
	2	antifungal arm with respect the relief of symptoms. 
	3		I should mention, parenthetically, that implicit 
	4	in this is also that the antifungal/corticosteroid 
	5	combination arm is superior to the vehicle with respect to 
	6	the relief of symptoms.  In addition, the combination arm
	7	must be shown to be superior to the vehicle with respect to 
	8	the treatment of the tinea infections. 
	9		The latter demonstrates the contribution of the 
10	antifungal component.  So our Question No. 2c, "Is it 
11	sufficient that the corticosteroid does not reduce the
12	antifungal activity--"  Dr. Drake, what question are we on?  
13	I'm sorry. 
14		DR. DRAKE:  Let me back up.  Maybe I didn't make 
15	myself very clear.  On Question 1, one of the questions that 
16	I think probably everyone has is is the proposed set of
17	decision rules for this combination product acceptable for 
18	documenting the contribution of both components. 
19		I think we may be a little weak, at least from my 
20	personal perspective, on exactly what are the proposed set 
21	of rules which I don't think I actually know for sure

22	exactly what we are proposing.  Or is that what we are 
23	supposed to decide?  Do you want advice on what we would 
24	propose? 
25		DR. OKUN:  I think I can help you out. 

				25 1		DR. DRAKE:  Good.  I could use some help.
	2		DR. OKUN:  I apologize.  I should have made this a 
	3	little more explicitly clear.  Obviously, several decision 

	4	rules were bandied about in my presentation.  I wasn't very 
	5	explicit in terms of referring to which we were talking 
	6	about here.
	7		DR. DRAKE:  While you are looking, I am going to 
	8	take a couple of comments from the panel.  Dr. Stern? 
	9		DR. STERN:  One of the interesting things about 
10	these rules is that they are in the complete absence of any 
11	rules about risk.  Somehow, we have gotten into thinking a

12	lot about tinea pedis where the risk of these agents, except 
13	for what is in the rules, is probably minimal. 
14		But, in fact, these combination agents are used in 
15	a variety of other sites where there may be greater 
16	desirability to avoid corticosteroids where possible.  So,
17	if you are just looking at inflammation at eight days and 
18	fungal cure at 35 days, I am not sure that these rules can 
19	be generally applicable unless you have it as the caveat and 
20	in a site where you don't really care whether you are using 
21	steroids for a week or two.
22		That is the one thing that seemed to be a little 
23	bit absent from this discussion which I know is very much a 
24	concern for the specific agent we are going to be 
25	considering later. 

					26 1		DR. WILKIN:  I think the point is well taken.  I
	2	think actually your concern is incorporated into one of the 
	3	decision rules.  Perhaps, the best place, rather than the 
	4	slides where we would be looking at the individual rules, if 
	5	you look at this document that came to you, the Overview and 
	6	Questions, if you look at the top of--
	7		DR. DRAKE:  Jon, was this in the material that was 
	8	mailed out to us ahead, or is it in our packet today? 
	9		DR. WILKIN:  It is material that was mailed to 
10	you. 
11		DR. DRAKE:  It is in the mailed packet; okay. 
12	Let's just make sure we are on the right thing. 
13		DR. WILKIN:  It is under Tab 1. 
14		DR. STERN:  Are these the three, the last page of 
15	Tab 1. 
16		DR. WILKIN:  At the top.  It starts, in

17	parenthesis, if the antifungal is superior to the 
18	combination for antifungal activity, that could be 

19	anticipated for many products, and, antifungal is non- 
20	inferior, essentially non-different, from the combination 
21	for antiinflammatory activity, then the question is one
22	could approve the antifungal alone for all tinea regardless 
23	of the inflammatory component because, once again, the 
24	antifungal alone is superior to the combination for 
25	antifungal activity and the sponsor has not been able to 

			27 1	demonstrate a difference between the combination and the

	2	antifungal alone in treating the antiinflammatory part. 
	3		So that would be the first decision rule.  The 

	4	question is does that particular outcome and how we would go 
	5	with that.  So this would not be a combination product.  It 
	6	would be approval of the antifungal alone.
	7		DR. STERN:  But implicit in that, would you not 
	8	approve a combination product where the antifungal 
	9	component, in fact, gave you these results, superiority with 
10	respect to mycologic cure and equivalence with respect to 
11	antiinflammatory effect?
12		So the other side of the question is, it is clear 
13	here that the antifungal, assuming it beats placebo, would 
14	be indicated for all types of tinea.  It is clear to me that 
15	it would be.  But is the flip side if someone gives you 
16	agent A, that antifungal, and B, the corticosteroid and this
17	combination, these are the results of these trials the you 
18	say, "Sure, A is fine for all types of tinea but we are not 
19	going to approve the combination of A and B because you 

20	already have something that is, in fact, better in one 
21	metric and equal in the other metric, so no combination
22	agent." 

23		DR. WILKIN:  Yes; that is exactly what is intended 
24	by this.  That is what is intended by that decision. 
25		DR. STERN:  I think you should say then only the 

					28 1	AF would be approved because it doesn't say, "And we would
	2	reject the AF/CS combination." 
	3		DR. WILKIN:  Yes.  It does say, "Then approve AF 

	4	alone, the antifungal alone."  That is what the intent of 
	5	that was.  But you are right; we could have added in there, 
	6	"And reject the combination."
	7		DR. DRAKE:  I see some hands.  Dr. Rosenberg? 
	8		DR. ROSENBERG:  At the risk of wandering a little 
	9	bit, I feel I really want to make a few remarks about the 
10	one particular antifungal/corticosteroid combination, the  
11	Lotrisone, which is--
12		DR. DRAKE:  Bill, can I wait until we get to the 
13	section? 
14		DR. ROSENBERG:  Well, no; I want to talk in 
15	general.  It relates to the product we have seen. 
16		DR. DRAKE:  If you comment on general policy for
17	any product-- 
18		DR. ROSENBERG:  Yes; general policy. 
19		DR. DRAKE:  This, right now, is general policy on 
20	any product that might come before the FDA. 
21		DR. ROSENBERG:  Exactly; this is general policy.
22		DR. DRAKE:  Please. 

23		DR. ROSENBERG:  When the first of these products-- 
24	and I wanted to commend Dr. Wilkin and the agency for the 
25	format of this in which we look at the whole issue of 

					29 1	corticosteroid/antifungal combinations.
	2		DR. DRAKE:  I think that is very proper. 
	3		DR. ROSENBERG:  I think it is necessary that we do 
	4	that.  I recall when the first of these products was being 
	5	developed and when it was being reviewed and so forth, 
	6	different people were here at that time.  It had to meet
	7	very specific criteria.  It had a very active, good 
	8	antifungal, clotrimazole, and to add a corticosteroid to it 
	9	and meet the combination product requirements, it had to add 
10	a dimension. 
11		The dimension that was required was that the
12	inflammation--the clotrimazole was going to cure the fungal 
13	infection at a high rate, so why add something to it.  What 
14	was added was a high-potency corticosteroid in order to give 
15	more rapid symptomatic relief than could be achieved with 
16	the clotrimazole alone.
17		Now, the plain clotrimazole is quite good at 
18	providing symptomatic relief. 
19		DR. DRAKE:  Bill, can I get you off the product 
20	and get you back into generics? 
21		DR. ROSENBERG:  Okay; we will talk generically.
22		DR. DRAKE:  Yes, please. 
23		DR. ROSENBERG:  The antifungals we now have are 

24	quite good and people get better quite quickly and their 
25	symptoms go away quite quickly.  If you are going to 

			30 1	demonstrate that putting a corticosteroid into the product
	2	adds to it, you need a very good corticosteroid.  You need a 
	3	very good corticosteroid to make it go that much more 
	4	quickly. 
	5		So that is why we have very high-potency 
	6	corticosteroids added to antifungals, because if you had a
	7	lesser potency corticosteroid, it would be hard to catch up 
	8	with the good antiinflammatory of curing the fungus 
	9	infection. 
10		I submit that that may not be the right question.  
11	I think more to the point is that is there a really a
12	clinical need for such rapid relief of symptoms that we need 
13	to add a corticosteroid to a good antifungal.  I would 
14	submit that, no, there is not, really.  But I think there is 
15	a major and very important need for a reasonable treatment 
16	for red, scaly spots that might be fungus and might not be

17	fungus. 
18		In the real world, in managed care, where we have 
19	primary-care doctors, there is public policy towards OTC 
20	where possible, where even specialists who are on time 
21	categories of patient visits and laboratory fees, et cetera,
22	are trying to hold down costs, that there is a real place 
23	for something that would be a very good treatment for 
24	something that might be fungal but not necessarily so, in 
25	the hands of whatever person is treating it. 

			31 1		In fact, I submit that the product which is now
	2	there, the combination product, succeeds as it does not 
	3	because it provides more rapid symptomatic relief for bona 
	4	fide fungal tinea pedis but because it fills that need for a 
	5	combination corticosteroid/antifungal. 
	6		I submit that a better performance for that
	7	purpose, the combination, would be one with an antifungal 
	8	with a less strong corticosteroid, one that is suitable for 
	9	use in something that doesn't require a very powerful one, 
10	hydrocortisone, for instance. 
11		In fact, the old CIBA Viaform, if I may mention
12	it, hydrocortisone product which left because it couldn't 
13	meet the antifungal requirements--I remember the hearing.  I 
14	was involved in that.  The plain Viaform wasn't all that 

15	good for antifungal but it was a very good product.  Of 
16	course, it might have been fungal, it might have been
17	nummular, it might have been bacterial and it just might 
18	have been dermatitis.  In fact, I see it is back. 
19		So, we have, now, a public policy where most 
20	medical problems of this magnitude are being handled by 

21	primary-care physicians and many of them, again with public
22	policy in yesterday's New York Times at the OTC level where 
23	patients see that there is something round and itchy and 

24	they would like to buy something that would be helpful for 
25	it, and should be allowed to have something over the 

				32 1	counter.
	2		So this is a whole different set of questions.  I 
	3	think the present combination products are not being used 
	4	for--I think we are telling ourselves a story if we are 

	5	going to characterize these things on how rapidly they 
	6	relieve symptoms without interfering with the antifungal

	7	properties and if there are any side effects and so forth. 
	8		I think we have backed ourselves into a very 

	9	useful product that could be made better by making the 
10	regulatory aspect of it somewhat different. 
11		Thank you.
12		DR. ROSEN:  Lynn, can I make a comment? 
13		DR. DRAKE:  Please. 
14		DR. ROSEN:  I think more specifically to the 
15	question that is being asked right now, at least one of the 
16	questions that is posed to the panel, is whether you want

17	some approval from us or the panel whether to go from a 
18	four-arm to a three-arm in terms of how to determine the 
19	efficacy of antifungal, antifungal combination drugs. 

20		The one thing you are dropping out is the 
21	corticosteroid-only arm.  I think that is a major question
22	that you are asking.  While I think that that was not of 
23	significance, and I am going to address this later in my 

24	presentation so I won't elaborate, it wasn't of significance 
25	for some of the antifungal agents because there is actually 

			33 1	a hierarchy of inherent antiinflammatory activity for the
	2	antifungal drugs as stand alone. 
	3		It is really not an issue for the current one that 
	4	is going to be discussed later but there may be an issue for 
	5	some of the other antifungals which have come along 
	6	subsequently which have more inherent antiinflammatory
	7	properties. 
	8		The thing is a manufacturers probably will not 
	9	attempt to claim antiinflammatory activity equal to 
10	corticosteroid because the only way to verify that would be 
11	to continue with a corticosteroid-only arm.  But I don't
12	think the manufacturers are really going to go after that 
13	claim.  That is the first thing. 
14		The second thing is from a purely pragmatic 
15	standpoint, if you include the corticosteroid-only arm, then 
16	what you are doing is deliberately subjecting some number of
17	patients in a clinical study to application of 
18	corticosteroid to a fungal infection.  I seriously doubt 
19	that any clinician in the room would really want to do that 
20	to their patients. 
21		Now, intellectually, it might be nice to compare

22	corticosteroid-only to antifungal-only and that would allow 
23	the claim of the antifungal if, in fact, it were equal or 
24	better.  It would allow the claim of the antifungal to 
25	possess antiinflammatory properties equal to or better than 

			34 1	the corticosteroid.
	2		But I think nobody really would want to do that, 

	3	as a clinical investigator, to put corticosteroid-only on 
	4	known fungal infections because you have excluded negative 
	5	KOH and negative culture.  You are not putting it on 
	6	question-mark diagnoses.  You are putting it on patients who
	7	have a known fungal infection. 
	8		So I would be in favor, although it would be 
	9	intellectually interesting to compare corticosteroid and 

10	antifungal, I would be in favor of leaving your three-arm as 
11	you propose and dropping out the corticosteroid-only arm
12	unless or until some sponsor said, "I want to claim that my 
13	antifungal is as good as a steroid," and I don't think you 
14	will have many takers on that. 
15		Even though it may be true, that study could pose 
16	risks for the participants.  So I think your three-arm for

17	virtually everything you might get would be appropriate 
18	rather than the four-arm.  And that is your specific 
19	question and that would be my suggestion. 
20		DR. DRAKE:  I have three hands that I have noted; 
21	Bob Jordan, Wilma Bergfeld and John DiGiovanna, in that
22	order, please. 
23		DR. JORDAN:  I guess I come back to my comment 
24	earlier about the exclusion of patients who are KOH- 
25	negative.  The main reason, I think the way these products 

			35 1	are being used now, those are the very patients that are
	2	being subjected to these kinds of treatments. 
	3		As I mentioned before, very oftentimes, with very 
	4	inflammatory tinea, you may have a negative KOH.  You may 
	5	have a positive culture, but, again, it is this group of 
	6	patients that probably are being treated with this
	7	combination more than just the antifungal alone.  So I still 
	8	have a problem with that. 
	9		DR. DRAKE:  Bob, I just want to elucidate a little 
10	bit.  I want you to elucidate a little bit because everybody 
11	in the audience may not know exactly what you are referring
12	to about the inflammatory nature of an early patient and the 
13	enrollment criteria for study, and they may never get in one 
14	of these. 
15		Would you please comment on that for the benefit 
16	of the total audience?
17		DR. JORDAN:  Very oftentimes, in tinea, when it is 
18	very inflammatory, the KOH will be negative.  The culture 
19	may be negative for that matter because of other 
20	superimposed factors that are involved with the tinea.  I 

21	think by excluding that group of patients, those are the
22	very patients that are going to be treated with this 
23	combination anyway, it seems to me we are losing something 
24	in terms of the benefit, if there is a benefit, to these 
25	combination products. 

			36 1		DR. DRAKE:  Thank you.
	2		Dr. Bergfeld. 
	3		DR. BERGFELD:  I think there are many questions 
	4	that have been put upon the table but I would like to 
	5	address a couple of things that have been said.  First of 

	6	all, Dr. Rosen, I disagree with you that you don't need a
	7	corticosteroid arm because, if you heard from the FDA, they 
	8	stated that this was a tinea pedis, interdigital type.  
	9	There is very, very little risk to the patient if you were 
10	to do a corticosteroid arm in that particular group. 
11		I am sort of interested in the fact that tinea
12	pedis is sort of the gold standard for the site to be 
13	treated yet the application will be to the groin and to the 
14	trunk and maybe a small spot, or a very large area, which 
15	adds a dimension of risk.  But, as far as treating tinea 

16	pedis, there is very minimal risk to using a corticosteroid
17	arm. 
18		The other thing that I was interested in in the 
19	study design was if you are going to have a response to 

20	corticosteroids, and it was very nicely demonstrated that 
21	the response was in the first five days, and that the tinea
22	response, the fungal response and the fact the culture- 
23	negative was seen at the end of the treatment period which 
24	was stated to be 30-plus days. 
25		In the design, and I didn't see this but I suspect 

			37 1	it was done, was there a notation on clinical symptomatology
	2	in the first five days rather than the global which was, I 

	3	gathered, what was presented at the 30-day marker, because 
	4	the symptom response for corticosteroids, as stated by 

	5	everyone, is acute within the first week.  If the was 
	6	significantly improved, that would be a significant feature.
	7		DR. WILKIN:  The actual time of when the 
	8	antiinflammatory effects are assessed is somewhat up to the 
	9	sponsor to suggest.  What we don't like to see in phase III 
10	trials is where they will look at inflammatory signs and 

11	symptoms over several days and then come in and tell us,
12	"Well, the greatest difference was on Day 3 or 4 or 5," sort 
13	of after the fact and that was where the statistical 
14	difference is. 
15		So it is always nice if they have looked in a 
16	phase II kind of study where they have figured out when they
17	are going to see that difference and that they will, then, 
18	do the study in phase III where they will assess at the time 
19	that they anticipate the greatest delta between the 
20	corticosteroid-containing arms and the non-corticosteroid- 
21	containing arms for the inflammatory signs and symptoms.
22		DR. DRAKE:  John? 
23		DR. DiGIOVANNA:  I think a part of my comment has 
24	already been iterated, but I would just like to rephrase it 
25	a bit in that I think that this is labeled as a policy 

			38 1	document.  I think that a main issue that I see is if one
	2	were to appropriately look at when a wise use of these 
	3	compounds, this combination would be, it would be mostly for 
	4	individuals who have been excluded by the entry criteria 
	5	that you have listed. 
	6		Most dermatologists who get a positive KOH, or
	7	most dermatologists would do a KOH, in a suspected tinea if 
	8	it was inflammatory.  But I think there is enough 
	9	documentation to know that there are many of those, if not 
10	most of those, that would have a negative KOH and a negative 
11	culture.
12		Therefore, if you exclude those patients who are 
13	most inflammatory and most likely to be the ones to benefit 
14	from this, you have already set up a situation where the 

15	rest of the very nice logistic paradigm falls through. 
16		So what I would like to suggest is whether or not
17	there is a role for a redefinition of what the clinical 

18	circumstances, what the appropriate indication might be, 
19	for, as Dr. Rosenberg said, a red, scaly spot that is 
20	suspected of being a tinea. 
21		DR. DRAKE:  Dr. Wilkin?
22		DR. WILKIN:  Yes; if I could get some--it sounds 
23	like there is actually some convergence in Dr. Jordan, Dr. 
24	DiGiovanna and Dr. Rosenberg.  They are going into, I think, 
25	a very helpful area for us at the FDA to hear. 

			39 1		There is this group that really has not been
	2	identified in our previous studies that come to us that may 
	3	have some benefit from this kind of a product.  My question 
	4	back to the whole committee, but especially the three of 

	5	you, is do you envision that ultimately in the population 
	6	that will be analyzed statistically for outcomes that, at

	7	some time during the treatment, there will be a positive KOH 
	8	or a positive culture, or are you suggesting that really we 
	9	should have more of a reductive kind of approach to the 

10	indication and the indication should be "red and scaly?" 
11		DR. ROSENBERG:  If I could answer, I would say
12	absolutely.  I think there is a place for studies of red 

13	scaly things that might or might not be fungus, which comes 
14	up all the time in many, many offices and many, many 
15	households. 
16		I think the appropriate study would be to enlist
17	those kinds of people, just as they are, to do KOHs and do 
18	cultures to see how things turned out, but to treat them 

19	with these different arms and see, in fact, how the 
20	combination product versus the different single products did 
21	for the whole mass of them, those who turned out to have it
22	and those who turned out not to have it. 
23		One of the things we would be looking for would be 
24	if the combination did no harm and it got a few that 
25	wouldn't have been picked up by the other, then why not a 

			40 1	combination.  Certainly, the over-the-counter area of
	2	medicine includes such cough-cold--if we backed up and went 
	3	after the symptoms of redness and scaliness, then such a 
	4	product would make all kinds of sense, or similar products, 
	5	a nystatin, a hydrocortisone cream, a Viaform--back to 
	6	Mycolog 1.
	7		Those are things, though, that enjoyed great 
	8	popularity in a profession of doctors who are getting up 
	9	every day and trying to do the right thing for their 
10	patients.  I think, by being so rigid in terms of how we 

11	define these products, we have backed ourselves into the
12	same sort of a thing, but not the way we have intended. 
13		DR. DRAKE:  Jon? 

14		DR. WILKIN:  If I could just respond to that, not 
15	to the part about rigid but, actually, to the part about-- 
16	what I think the evidence has come in in the past and what
17	we have asked for on these kinds of products would allow us 
18	to say, yes; there is an antifungal contribution.  We have 
19	documented that, and also there is an antiinflammatory 
20	contribution and then taking that information that both of 
21	those have been demonstrated, then I could actually see a

22	translation into the clinical setting of reduction where, 
23	then, it is a reductive approach to the clinical problem but 
24	it is based on a fairly substantial database that says if it 
25	is fungus, it is going to be okay.  We have good outcomes 

			41 1	with this product.  And, if it is not, you are treating the
	2	inflammation anyway. 
	3		DR. DRAKE:  Rob? 
	4		DR. STERN:  As we are coming to convergence, I 
	5	hate to throw a random thought out there, but when we have 
	6	looked at these data, it seems that the antiinflammatory
	7	component from corticosteroids, if there is a benefit, is 
	8	early on, usually in the first five or seven days of what is 
	9	typically two- or three- or even four-week courses of 
10	therapy. 
11		So we have coupled two agents, one of which you
12	need to use for a number of weeks if there is fungus there 
13	for clearing and nonreoccurrance with an agent that you only 
14	want there for the first five or seven days because there is 
15	little or any evidence of additional benefit either 
16	practically or theoretically once you have gotten beyond
17	that point for these red, scaly, itchy things. 
18		So I guess my question, from a health perspective, 
19	given the wide variety of these very efficacious 
20	antifungals, why have these agents at all when you have 
21	unnecessary therapy for sometimes as much as 80 percent an
22	extra agent there.  You only need it for the first 
23	20 percent. 
24		It is not so difficult to have recommendations, in 
25	fact, that you use in certain situations, two agents when 

			42 1	there is ambiguity.  That is certainly something I do.  You
	2	use the appropriate antiinflammatory corticosteroid, 
	3	depending on its degree and the site, the appropriate one, 
	4	for three, five, seven or ten days and then, since you think 
	5	there might have been fungus there, you use the appropriate 
	6	antifungal agent for two, three or four weeks, depending on

	7	the site of the agent and the data for that. 
	8		So I guess I would like to go back and sort of 
	9	maybe take the radical position, are we missing the main 

10	boat about whether these agents are, in fact, useful enough 
11	in clinical practice, given the widely available, over-the-
12	counter antifungal agents that are highly efficacious for 
13	yeast and fungus and very inexpensive. 
14		Are we doing bad things rather than good things 
15	even considering them for approval because, in fact, their 
16	net clinical benefit, in terms of risk/benefit, is likely to
17	be small.  So maybe we should make one step back before we 
18	make rules. 
19		DR. DRAKE:  I want to apologize to the committee 
20	for kind of taking the prerogative here, but time is a 
21	little bit tight here.  I think this discussion has really
22	demonstrated how important something new in the last few 

23	years that the agency is doing, and that is addressing the 
24	policy issues. 
25		I saw them do policy with respect to 

			43 1	onychomycosis.  I saw you do policy with respect to
	2	psoriasis.  I think this is another major step in trying to 
	3	prospectively define the policy which is a benefit to 

	4	industry, a benefit to us and a benefit to everyone. 
	5		However, any time you get into policy, the 

	6	discussions become quite interesting and wonderful.  First
	7	of all, I want to compliment you for it and I want to 

	8	apologize to the agency for us kind of having a packed 
	9	agenda here and, as chairman, I want to get us done on time.  
10	But we would come back to it. 
11		Having said that, in the interest of time, what I

12	would like to do is kind of get a sense of the committee on 
13	your specific questions that you have asked us so we can go 
14	on to the invited presentations.  Time permitting, we may, 
15	then, revisit this later in the day.  Would that be 
16	acceptable?
17		I still don't understand Question 1, so I am going 
18	to skip it and come back to it.  But I think we do have a 
19	lot of understanding about Question 2b.  I am going to start 
20	there, and I am going to read it.  "Is the knowledge and 
21	corresponding labeling that allows the claim that
22	antifungals alone provide the antiinflammatory activity 

23	comparable to a corticosteroid a sufficient advance in 
24	public health to warrant a corticosteroid-only arm?" 

25		I don't know that we want to have a vote.  Do you 

				44 1	want just the sense of the committee, or do you want a vote
	2	on this?  How much information do you guys want?  Do you 
	3	want a sense so that you can have leeway to continue to 
	4	contemplate this or do you want to vote? 
	5		DR. WILKIN:  We would be pleased to have a vote on 
	6	this, but I should say that we always listen very carefully

	7	to all of the discussion leading up to the vote, so it is 
	8	not just the vote that we rely on. 
	9		DR. DRAKE:  I think it is clear that there are a 
10	lot of parameters that this committee has put on the table 
11	that are not being addressed, perhaps, in the traditional
12	way we do the studies.  We may be missing a big cohort of 
13	patients that would benefit from such a product. 
14		I wanted to ask Dr. Rosenberg a very quick 
15	question before we vote.  When you said red, scaly spots, 

16	did you mean that we would still try to identify a causative
17	agent such as mycology or would you just throw that out and 
18	base it totally on just red, scaly spots? 
19		DR. ROSENBERG:  Otherwise undiagnosed.  I think 
20	the study should be done at a primary-care level or a walk- 
21	in-clinic level.
22		DR. DRAKE:  I think that is a very important 
23	notion. 
24		DR. ROSENBERG:  That is where the people are, and 
25	that is where the prescriptions are written. 

				45 1		DR. DRAKE:  As a lot of things move to OTC, this
	2	becomes a more important notion because not everybody has 
	3	the expertise to do the KOHs or to interpret them properly.  
	4	So I think that is an important notion for FDA to please 
	5	think about when you work with industry and for industry who 
	6	is in the audience, I would strongly suggest that one of you
	7	perhaps capture this opportunity to answer some of these 
	8	questions which are clearly important to the committee 
	9	members. 
10		Now, back to Question 2b.  Yes?  Jim?  I knew I 
11	couldn't get straight to it.
12		DR. KILPATRICK:  I would like to ask the agency 
13	about "comparable to."  That speaks to equivalence which is 
14	difficult to establish, or do we simply mean not 
15	statistically different from which is a question of how 
16	large the sample is.  Jon?
17		DR. WILKIN:  We don't mean just simply not 
18	significantly different from, which always allows the type-2 
19	error.  No; we are interested in actually a formal analysis 
20	of equivalence.  Noninferiority is what we are looking for. 
21		DR. DRAKE:  So what we are talking about is how
22	many of us think that--does everybody understand the 
23	question on 2b?  I would like to ask for how many are in 

24	agreement with this Question 2b.  If you are voting yes, 
25	please raise your hand.  If you want a corticosteroid arm, 

				46 1	raise your hand, please.
	2		[Show of hands.] 
	3		DR. DRAKE:  Ten.  I think it is a unanimous vote. 
	4		DR. MINDEL:  I have a question.  How long is the 

	5	corticosteroid arm? 
	6		DR. DRAKE:  I think what we have seen, in this
	7	study, at least, was about eight days.  Jon, would you like 
	8	to address that? 
	9		DR. WILKIN:  I think Dr. Mindel has an important 
10	question.  One can build into protocols an ethical safety 
11	escape clause, if you will, that if these patients are
12	followed very closely and if it looks like there is 
13	deterioration, while one will not know which arm of the 
14	study they have gone into, that patient can be taken out of 
15	the study immediately and given standard therapy. 
16		DR. DRAKE:  Wilma?
17		DR. BERGFELD:  I am trying to grapple with all 
18	this as many of the panel members are, but I am looking at 
19	the reverse side of that and that is called the risk side.  
20	If, for instance, you were to apply this to a rash, 
21	clinically suspected to being tinea and it wasn't, what harm
22	would be done? 
23		Well, in reality, none, with how we give it.  If 
24	this was applied, this topical combination was applied, to 
25	something that was tinea and it also has a limitation of 

			47 1	duration of therapy, what harm would be done?
	2		The worst scenario I can see, and I did read some 
	3	of the information sent here, was that you might have some 

	4	thinning of the skin.  But, again, you have limitations of 
	5	time.  It is not a forever application.  It is two weeks, 
	6	four weeks, max, usually.
	7		So when we are talking about risk assessment, 

	8	which I know we will speak about later, no matter which way 
	9	you go with either product, the harm is rather minimal. 
10		DR. DRAKE:  One other thing they suggested in the 
11	data they presented us is that--I agree with you.  I think
12	the harm is rather minimal.  Besides the thinning skin, one 
13	other thing that was pointed out was that the 
14	corticosteroids may--by suppressing the inflammatory 

15	response, if it is tinea that is present, then there may be- 
16	-it may work less fast.  That is not good English, but it
17	may work not quite as quickly if it is on the tinea because 
18	you are getting a suppression of the host response from the 
19	corticosteroids. 
20		DR. BERGFELD:  But your studies would reflect 
21	that.
22		DR. DRAKE:  I think if the studies are designed 

23	properly, they would.  I think that is the issue.  That is 
24	the question they are asking us on policy that we need to 
25	make sure that these prospective studies are designed with 

			48 1	that information.
	2		Question 2c, I am going to go to next.  "Is it 
	3	sufficient that the corticosteroid does not reduce the 
	4	antifungal activity of the combination to label the product 
	5	for all tinea or should combination products containing 

	6	corticosteroids be labeled only for the more inflammatory
	7	tinea warranting antiinflammatory treatment?" 
	8		I think this is a key question and I think one of 
	9	the things they have asked to address, according to Dr. 

10	Wilkin's introductory statement.  It is not a question of 
11	whether this at least one upcoming product and, potentially
12	future products are approved, but do we want to tinker with 
13	labeling or do we want to make recommendations about 
14	labeling. 
15		Am I correct on that, Dr. Wilkin?  Please clarify. 
16		DR. WILKIN:  Yes, Dr. Drake, you are.  And 2a

17	actually helps this question in that we are asking about 
18	this, perhaps somewhat inelegant phrase, of "sufficiently 

19	inflamed tinea warranting a corticosteroid component," which 
20	is, then, captured again in 2c. 
21		We were hoping that you might first address this.
22		DR. DRAKE:  I would be happy to do so. 
23		DR. WILKIN:  Come up with maybe something better 
24	to put in labeling if you think this is an important 
25	consideration in the Indications Section of the labeling. 

				49 1		DR. DRAKE:  May we go to 2a instead.  I think that
	2	is a better order.  I am still avoiding 1 for the moment.  I 
	3	want you to know that. 
	4		Question 2a; "Can a distinction be made in 
	5	labeling between minimally inflamed tinea not requiring a 
	6	corticosteroid component and sufficiently inflamed tinea
	7	warranting a corticosteroid component and, if so, suggest 
	8	wording." 
	9		So the first question I would like to pose to the 
10	committee is can a distinction be made between minimally 
11	inflamed and sufficiently inflamed warranting a
12	corticosteroid.  First of all, I want to ask you to vote, 

13	can a distinction be made between that or do you want a 
14	little discussion beforehand because we have not discussed 
15	that at all. 
16		Dr. Bergfeld?
17		DR. BERGFELD:  We have never had great success in 
18	defining minimal to severe in any disease.  My preference 
19	would be inflamed versus noninflamed. 

20		DR. DRAKE:  Other comments?  All right; then let's 
21	vote.  Would the committee vote, please.  I want to vote on
22	the question, not on Wilma's comment.  I agree with your 

23	comment, actually, but I think we should do this. 
24		DR. STERN:  Are we interested in the presence of 
25	inflammation or are we interested in the presence of 

			50 1	inflammation and symptoms associated with inflammation,
	2	particular pruritus, in most cases, because most of the 
	3	tinea I see--I see a lot of tinea that is completely 
	4	asymptomatic but it is still pink and, therefore, 
	5	inflammatory but it doesn't need a corticosteroid because 
	6	they are not itchy.
	7		So I wonder if it should be a distinction between 
	8	inflammatory and symptomatic as the criteria versus not 
	9	meeting both of those criteria. 
10		DR. DRAKE:  I see a lot of heads nodding.  I would 
11	like just a sense.  This is not a vote.  I would like just a
12	sense of the committee about recommending linking 
13	inflammatory and symptomatic together versus inflammatory 
14	alone. 
15		How many would like to see the two words linked? 
16		[Show of hands.]
17		DR. DRAKE:  For the FDA, I think you see a sense 
18	of the committee that just pink doesn't cut it, that you 
19	need pink and itchy, or whatever. 
20		Now then, back to Question 2a.  That is a 
21	suggested labeling.  Now, with respect to Question 2a, and I
22	am going to try to help the committee get this simmered 
23	down, would the FDA be willing to accept inflammatory versus 
24	non-inflammatory?  Do you want me to address the issue just 
25	as the question says, "minimally versus more than minimal?" 

				51 1		Hearing no answer, what we are going to do is we

	2	are going to do it just the way the FDA did it.  I want a 
	3	sense of the committee.  First of all, can we distinguish, 
	4	do you think, and should the labeling distinguish, between 
	5	minimally inflamed and sufficiently inflamed?  Can we make 
	6	that distinction?
	7		All those who think we can make that distinction, 
	8	please raise your hand. 
	9		[One hand raised.] 
10		DR. DRAKE:  All those who think we cannot make 
11	that distinction, raise your hand.
12		[Show of hands.] 
13		DR. DRAKE:  John, comment? 
14		DR. DiGIOVANNA:  I think we can do it by the way 
15	Rob said we can do it. 
16		DR. STERN:  But not by that word alone.
17		DR. DiGIOVANNA:  By the presence of symptoms. 
18		DR. DRAKE:  I understand that, but we sort of 
19	backed into it.  I wanted the sense of the committee.  Now, 
20	I would entertain a suggestion from the committee, having 
21	done those two steps.  I would entertain, then, a motion so
22	that we can vote on it to provide some information to the 
23	committee regarding how we ought to phrase it. 
24		Rob? 
25		DR. STERN:  I would suggest that the labeling 

				52 1	should be distinguished between those agents which are just
	2	to treat tinea pedis and those agents which might be tested 
	3	for treating tinea pedis which has associated symptoms since 
	4	I think it is hard to have much tinea pedis without any 
	5	inflammation and recognize it except by culture and random 
	6	sampling.
	7		So I would say it is plain tinea pedis and tinea 
	8	pedis with associated symptoms as opposed to signs or 

	9	laboratory tests--associated inflammation, rather than 
10	symptoms. 
11		DR. DRAKE:  Symptomatic inflamed tinea?  Would you
12	accept that? 
13		DR. MILLER:  Symptomatology can be very varied 

14	also.  With some tinea pedis, you can have fissures and it 
15	is very painful and perhaps the corticosteroids are not 
16	going to play a role there.  So there might be some
17	obfuscation with just symptomatology. 
18		DR. STERN:  Can we think of anything but pruritus, 
19	I guess would be my question, that would be an indication 

20	for--probably pruritus is really the only one.  I don't 
21	think burning or pain, as you rightly suggest, are likely to
22	be corticosteroid-responsive aspects of-- 
23		DR. DRAKE:  So would you like to change the 
24	wording of your motion to read--to use the word "pruritus" 
25	instead of symptoms? 

					53 1		DR. STERN:  Can you think of other symptoms beyond
	2	pruritus that we are really thinking about with this that 
	3	would be reasons for using a corticosteroid? 
	4		DR. ROSENBERG:  I don't want to go over and over 
	5	again.  I think the reason for using a corticosteroid is 

	6	maybe it is just a patch of eczema and not fungus at all. 
	7	That is the reason for putting the corticosteroid on. 
	8		DR. DRAKE:  And it might not itch.  A patch of 
	9	eczema might not itch. 
10		DR. ROSENBERG:  It doesn't have to itch.  If you 
11	don't know what it is, that is what you do.
12		DR. DRAKE:  Then let's leave some leeway. 
13		DR. ROSENBERG:  If you will put in, "For use on 
14	rashes of unknown--dermatitis of unknown cause," then 
15	undiagnosed.  If you want to have a product for undiagnosed 
16	skin disease, it would fill a major societal need.
17		DR. DRAKE:  We will come back to that.  I want to 
18	stay on my questions. 
19		DR. ROSENBERG:  This would be a start. 

20		DR. DRAKE:  We will come back to that. 
21		Wilma?
22		DR. BERGFELD:  I would like to revisit the terms.  
23	I still think that symptomatic and inflamed might be the 

24	best term.  I disagree with my colleagues who say that it 
25	doesn't help when it is painful.  I think that pain is 

				54 1	related to inflammation and swelling and it does help that. 
	2	And it may even help fissures because they are involved with 
	3	swelling and inflammation. 
	4		DR. DRAKE:  Pain and itch are often very hard to 

	5	separate because those fibers run right next to each other 
	6	and they have shown the synapses jump.  So I think there is
	7	a legitimate argument probably not to separate them. 
	8		Fred, you had a comment? 
	9		DR. MILLER:  I guess I do.  I was just going to 
10	comment on Bill's comment about using this on red, scaly 
11	areas undiagnosed.  We are certainly going to have to change
12	the entire way we have been taught and we think about 
13	diagnosis and using combination therapy. 

14		When we look at these particular products--indeed, 
15	I don't know dermatologists that really are using them; it 
16	is mainly the non-dermatologists who are using the
17	combinations. 
18		DR. ROSENBERG:  I would just interject that the 

19	good non-dermatologists are using these.  The bad ones are 
20	giving them dose packs.  Let's put this all in perspective. 
21		DR. DRAKE:  Bill, as usual, you are about six
22	years ahead of the rest of us.  In the interest of time, I 
23	really do want to try to--Rob, can we say symptomatic? 
24		DR. STERN:  Yes. 
25		DR. DRAKE:  All in favor of that motion, please 

				55 1	raise your hand.
	2		[Show of hands.] 
	3		DR. DRAKE:  All opposed. 
	4		[No response.] 
	5		DR. DRAKE:  It passes.  I have done 2a.  Now, I am 
	6	going to go to 2c, please.  That is the one we read a minute
	7	ago.  "Is it sufficient that the corticosteroid does not 
	8	reduce the antifungal activity of the combination to label 
	9	the product for all tinea or should combination products 
10	containing corticosteroids be labeled only for the more 
11	inflammatory tinea warranting antiinflammatory treatment?"
12		It seems like we just answered that.  But we can 
13	vote on it.  Any comments on this motion? 
14		DR. BERGFELD:  I am going to bring back the issue 
15	of "no harm."  What harm would be if it was incorporated 
16	into the--a combination was used, a noninflammatory? 
17	Whether there is a need or not, what harm would there be? 
18		DR. STERN:  Wilma, would you be in favor of having 
19	class 2 steroids be over the counter?  I think if you are 
20	not in favor of that, then there is some potential for harm 
21	in these agents because, if there is no harm with their
22	potential use, a class 2 steroid as we are discussing here, 
23	then that would be grounds for it. 
24		I certainly think there is potential for harm with 
25	these agents used when they don't add additional benefit.  

			56 1	That is why I think the labeling should be restrictive to
	2	cases where there is, in fact, also some additional 
	3	potential benefit and, therefore, since it is hard for me to 
	4	believe, nor have I seen demonstration of additional benefit 
	5	of corticosteroids with an antifungal in the absence of 
	6	symptoms related to inflammation, I would say that we would
	7	take the more restrictive approach. 
	8		DR. BERGFELD:  I would agree with you in the fact 
	9	that it seems logical not to include an extra chemical when 
10	you don't need it.  The fact is this is still a prescription 
11	item and the fact is that the prescribed use is two to four
12	weeks, max six weeks.  That is the labeling. 
13		Now, one could approach the "no harm" part of it 
14	by the labeling if one desired. 
15		DR. DRAKE:  I think, though, that all of us have 
16	seen six weeks--I mean, if every doctor in the world stuck

17	strictly to the labeling religiously, it might be a 
18	different world.  But, in fact, I think we have to really 
19	seriously consider whether we want combinations used just 
20	willy-nilly, or whether we want to have some restricting 
21	labeling on it and try to encourage doctors to use it

22	appropriately instead of using it inappropriately. 
23		I think that is the issue, is that nobody is 
24	trying to deny access to this drug.  What we are trying to 
25	do is help the agency look at the labeling to try to 

				57 1	encourage better behavior and better compliance with the
	2	labeling. 
	3		So your choice with this motion, or with this 
	4	question, is whether you want to endorse the first half or 
	5	the second half.  The second half really calls for a little 
	6	more restrictive where it says you really shouldn't use
	7	corticosteroids.  The labeling will outline corticosteroids 
	8	for inflammatory, and not just tinea across the board, which 
	9	is the first half. 
10		So I am going to ask you to choose between the 

11	first and the second half of this question.  Everybody in
12	favor of the first half where you would just--all products 
13	for all tinea, please raise your hand. 
14		[No response.] 
15		DR. DRAKE:  All in favor of having the label--any 
16	product containing corticosteroids be labeled only for the
17	more inflammatory tinea warranting antiinflammatory 
18	treatment.  Please raise your hand. 
19		[Show of hands.] 
20		DR. DRAKE:  Once again, it is unanimous. 
21		So now we have answered every question except 1. 
22	We are back to my 1.  Maybe since we have had all this 

23	discussion, we can understand this a little better.  I think 
24	what we have just decided maybe is what this question is all 
25	about, wouldn't you say?  I think we have answered this 

			58 1	question because we have given you--by answering 2, we have
	2	actually answered 1.  Is everybody in agreement?  Does 
	3	anybody on the committee have a different opinion? 
	4		Bingo.  We are on time.  Wilma? 
	5		DR. BERGFELD:  I'm sorry.  I think that one 

	6	important statement has to be made and that is the fact
	7	that, for patient compliance, the need to get the patient 
	8	the information is probably the most important factor.  So 

	9	patient handouts regarding use need to accompany these kinds 
10	of products. 
11		DR. DRAKE:  That is a positive suggestion. 
12	Another positive suggestion I would like to make is I think 
13	this whole notion of the FDA addressing the policy issues--I 
14	said it earlier.  I can't tell you how important I think it 
15	is.  I think the things that Bill Rosenberg and others here 
16	today have put on the table--just like Eduardo and John and
17	Bob putting this business of improper enrollment or maybe 

18	improper exclusion in the inclusion criteria. 
19		I think Joe's question--well, you have asked 
20	questions earlier about other things, anyway.  I just think 
21	all the questions--I told you I would be the first one to do
22	it--I think all the questions that have come about here 
23	really are important and may warrant a longer session with 
24	more in-depth discussion and contemplation. 
25		I think getting the policy set prospectively is 

			59 1	really to everybody's benefit and I want to congratulate you
	2	for it. 
	3		Joel? 
	4		DR. MINDEL:  I would like to throw one other 
	5	question, whether all these steroid antifungal agents should 
	6	be limited to a five-day maximum use, because whether it is
	7	a fungus or not, it seems like that is the limit.  If it is 
	8	not a fungus, five days is enough.  If it is a fungus, then 
	9	you should switch, at that point, to an antifungal agent 
10	alone. 
11		The problem you get with a combination, the worst
12	pharmacologic, or one of the two worst pharmacologic 
13	reasons, for giving a combination, the first worst argument- 
14	-there are three.  But one of them is that you continue one 
15	of the drugs when you don't need it. 
16		I showed this to Jonathan and he said would I
17	bring it up, but the U.S. Pharmacopoeia, in talking about 

18	the clotrimazole and betamethasone topical combinations 
19	makes the recommendation in the U.S Pharmacopoeia's 

20	publication--it says, "During the first few days of 
21	treatment," they are recommending this, "or as along as
22	inflammation persists, after this time U.S.P. medical 

23	experts recommend the use of plain clotrimazole or other 
24	topical antifungal agents," and their experts also recommend 
25	a maximum of five days." 

			60 1		That seems to me a reasonable length of time.  It
	2	would cut out, I think, actually a lot of the considerations 
	3	that we have today.  If it came in a tube that was just a 
	4	five-day supply. 
	5		DR. DRAKE:  A dosing tube of five days.  
	6	Interesting.
	7		Bob? 
	8		DR. JORDAN:  I guess this is a paradox that I 
	9	think all of us are kind of wrestling with, at least I am, 
10	as a physician when I see patients like this.  Again, the 
11	way the studies were designed, with a positive KOH and
12	culture, my likelihood of using one of these agents, if I 

13	have got a positive KOH and culture, is pretty small. It is 
14	actually the patients that Bill Rosenberg has been talking 
15	about where there is a confusion between an eczema versus a 
16	tinea where they might have some benefit for the patient.
17		There may be a need to treat for longer than five 
18	days, but maybe Bill could comment on it.  Personally, 
19	though, if I have got a patient that I have seen and I have 
20	got a positive KOH and culture, I doubt that I would ever 
21	use an agent like this.
22		DR. DRAKE:  Bill? 

23		DR. ROSENBERG:  I think that is right.  To move up 
24	a notch from something on the skin, I don't know what it is, 
25	to--maybe it is nummular dermatitis, round, patchy 

			61 1	dermatitis, that can be confused with fungus frequently and
	2	can be hard to treat and which--the older books, the British 
	3	books, still, the new Rooks textbook still comes out for 
	4	Viaform corticosteroid combinations--require actually 
	5	persisting treatment. 
	6		So to the degree that we were going to have a
	7	product that was good for a fungus and good for nummular 
	8	eczema, and really no criticism of the person who couldn't 
	9	tell which it was, then I think the limitation on days 
10	starts to fall down. 
11		Rather, I think we should think about a product--
12	there is no harm in using any of these antifungals forever.  
13	They really don't do any harm.  I think the time limitation 
14	has to do with the corticosteroid and that relates to its 

15	category, whether it is a very strong one or a weaker one. 
16		A lovely product would be a hydrocortisone

17	combination with some appropriate antimicrobial.  The 
18	problem with that is if you are trying to make that product 
19	go through the hoop of bringing more rapid statistically 
20	significant relief of symptoms than the antimicrobial alone 
21	in a defined fungus infection, you are not going to get it.
22		So to get from here to there, we have to--you 
23	can't get from here to there the way the rules are now 
24	written. 
25		DR. DRAKE:  Joe.  That is the last comment before 

			62 1	we go on to the next section.
	2		DR. McGUIRE:  Okay; this is the last word. 
	3		DR. DRAKE:  You betcha.  From the expert.  It is 
	4	your final answer; right? 
	5		DR. McGUIRE:  I just wanted to point out that we 
	6	are shooting at two different products.  Bill wants
	7	something that is safe, that is going to be used in a 
	8	shotgun way by lots and lots of practitioners.  Our other 
	9	goal is to somehow limit and make this product safer in the 
10	market. 
11		Everyone sitting around the table realizes that

12	the use of these combination drugs is far more related to 
13	the practitioner than whether the KOH is positive.  Some 
14	people use the drugs.  Others, like Bob Jordan, rarely use 
15	the drug.  So we are marching off in two different 
16	directions.
17		DR. DRAKE:  We are, and we are going to march 

18	right back down the road here to where we need to be.  What 
19	I want to do is I would like to take this opportunity to 

20	welcome two additional experts who have come in late.  I 
21	suspect planes were late, if I had to guess; Dr. Merve
22	Elgart and Dr. Mary Spraker.  I would like you to identify 
23	yourselves, which I have just done, but give us your 
24	affiliation, please, for the record. 
25		DR. ELGART:  I am Dr. Elgart.  I am in private 

					63 1	practice.  I am Clinical Professor of Dermatology at George
	2	Washington University and my plane flew in from Alexandria.  
	3	I couldn't find a place to park. 
	4		DR. DRAKE:  Then I have a real question about your 
	5	watch. 
	6		DR. SPRAKER:  I am Dr. Mary Spraker.  I am a
	7	pediatric dermatologist on the faculty of Emory University 

	8	in Atlanta.  I came a day early because I wanted to be here 
	9	for the Lotrisone discussion because it is of interest to 
10	all of us in pediatric dermatology. 
11		DR. DRAKE:  Good.  Now then, we have three
12	presentations between now and the noon hour.  I don't know 
13	how much time each of you were given, but I know it wasn't 
14	more than fifteen minutes.  However, if you can do it in 

15	twelve minutes or so, that would be wonderful.  If you 
16	can't, that's fine.  We will run late.
17		Yes, Jon? 
18		DR. WILKIN:  Excuse me, Dr. Drake.  We still have 
19	Dr. Luke and Dr. LaGrenade to give the Lotrisone-- 
20		DR. DRAKE:  I can't believe I just did that.  Do 
21	you want to fire me?
22		DR. WILKIN:  No. 
23		DR. DRAKE:  I can be fired, you know. 
24		DR. WILKIN:  We're doing fine. 
25		DR. DRAKE:  We are not on time and that is why you 

			64 1	were trying to get my attention a minute ago.  Now we are in
	2	big trouble, you guys, time-wise.  That's okay.  It's worth 
	3	it.  Dr. Luke, would you please give us your presentation in 
	4	the manner in which you see fit. 
	5		      NDA 20-010 Lotrisone Lotion 
	6		DR. LUKE:  Hi.  Good morning.  I would like to
	7	discuss NDA 20-010, Lotrisone, betamethasone and 
	8	clotrimazole, Lotion. 
	9		[Slide.] 
10		Part of the evidence for effect of Lotrisone 
11	Lotion, NDA 20-010, is based on the effectiveness of the
12	combination of the two active components in Lotrisone Cream, 
13	a different NDA, NDA 18-827, submitted on December 23, 1982 
14	and approved in 1984. 
15		Lotrisone Lotion has the same active ingredients 
16	in the same concentrations and the same indication and
17	dosing regimen as Lotrisone Cream. 
18		[Slide.] 
19		The development program for Lotrisone Lotion, NDA 
20	20-010, formulation, the same concentration, again, is as 
21	follows: one parallel group comparison of active lotion and
22	vehicle in tinea pedis.  The tinea pedis is considered to be 
23	the higher efficacy hurdle, as Dr. Wilkin had stated 
24	earlier. 
25		A parallel group comparison of active lotion and 

				65 1	vehicle in tinea cruris.  Tinea cruris is the most sensitive
	2	for adverse drug reactions, as was previously stated.  
	3	Together, the two trials would allow interpolation for tinea 
	4	corporis, a separate indication. 
	5		In addition, a vasoconstrictor assay to compare 

	6	cream and lotion and confirm availability of corticosteroid
	7	was performed. 
	8		[Slide.] 
	9		NDA 20-101 for Lotrisone Lotion was originally 
10	submitted to FDA on August 31, 1989.  I would like to have 
11	you keep in mind that the studies were done over a decade
12	ago. 
13		[Slide.] 
14		Study No. 1 was conducted with Lotrisone Lotion 
15	versus vehicle.  This is a two-armed study for Lotrisone 

16	Lotion.  119 patients were included for safety.  93 of those
17	patients were included for efficacy.  The age group of the 
18	patients was ages 12 to	80.  Lotrisone Lotion was found more 
19	effective than vehicle in treatment of tinea pedis. 
20		[Slide.] 
21		Study No. 2 was a study on Lotrisone Lotion versus
22	vehicle in tinea cruris.  This, again, was a two-armed study 
23	for Lotrisone Lotion.  126 patients were included for 
24	safety, 120 patients included for efficacy.  The age group 
25	was 16 to 88.  Lotrisone Lotion was found more effective 

			66 1	than vehicle in the treatment of tinea cruris.
	2		[Slide.] 
	3		Again, from Study 2, 7 of the 63 subjects using 

	4	Lotrisone Lotion failed to complete the study all due to 
	5	lack of efficacy.  15 of 63 of the vehicle patients failed 
	6	to complete the study, again, all due to lack of efficacy. 
	7	Two patients in the Lotrisone group and one patient in the 

	8	vehicle group experienced dry skin during the study and that 
	9	was the major local side effect of the drug. 
10		[Slide.] 
11		A vasoconstrictor assay was submitted.  The date
12	was 1990.  The Lotrisone Lotion, the to-be-marketed product, 
13	from this data, appears to have comparable or lower 
14	blanching scores compared to Lotrisone Cream.  No confidence 
15	intervals were provided and no bracketing was done in this 
16	study with the lower strength topical corticosteroid; hence,
17	the submission of additional vasoconstrictor assay data by 
18	the sponsor. 
19		[Slide.] 
20		Two additional studies were performed and a 
21	different manner of presentation of the study was given
22	using a categorization of the subjects upon where they would 
23	fall, whether they would favor Lotrisone Cream, whether no 
24	difference was detected or whether they would favor 
25	Lotrisone Lotion.  The nonsignificant McNemar's test exact 

			67 1	p-values were shown.

	2		[Slide.] 
	3		To summarize, the combination 
	4	antifungal/corticosteroid was shown to be superior to 
	5	vehicle for antifungal effect.  Vasoconstrictor assays 

	6	showed that Lotrisone Lotion was comparable to Lotrisone
	7	Cream for corticosteroid effect.  The safety profile was 
	8	adequate to allow labeling for the population study. 
	9		A side note; this was the last NDA for which 

10	vasoconstrictor assays were used to determine inflammatory 
11	effect.
12		[Slide.] 
13		Based on information submitted, the agency 
14	determined that Lotrisone Lotion was approvable.  An 
15	approvable letter was sent to the Schering Corporation on 
16	July 31, 1991.  The issues for response were CFC issues and
17	a labeling update. 

18		[Slide.] 
19		On October 7, 1999, Schering Corporation submitted 
20	a response to the approval letter of July 31, 1991.  This 
21	and subsequent submissions responded adequately to the
22	issues brought forth in the 1991 letter. 
23		[Slide.] 
24		During the interim between 1991 and 1999, 
25	additional information regarding the Lotrisone drug product 

			68 1	emerged.
	2		[Slide.] 
	3		The first of these, I would like to propose, is 
	4	the Rosen and Elewski paper from 1995 in JAAD which proposed 
	5	the failure of clotrimazole betamethasone diproprionate 
	6	cream in treatment of Microsporum canis infections.
	7		[Slide.] 
	8		In 1996, there was a paper by Dr. Elgart which 
	9	appeared in Dermatologic Clinics describing the use of 

10	topical corticosteroids in the treatment of unrecognized 
11	dermatophyte infection, tinea incognito, which may lead to

12	non-cure.  Additionally, he discussed the use of combination 
13	antifungal corticosteroid drugs. 
14		[Slide.] 
15		In 1999, Fleischer and Feldman described a 

16	prescription of high-potency corticosteroid agents and
17	clotrimazole betamethasone diproprionate by pediatricians. 
18		At this point, I would like to introduce Dr. Lois 
19	LeGrenade from the Office of Postmarketing Drug Risk 
20	Assessment, or OPDRA for short.  She will describe a review 
21	of Lotrisone adverse events as has been reported.
22	       Review of Lotrisone Adverse Events: 1984-1999 
23		DR. LeGRENADE:  Good morning. 
24		[Slide.] 
25		I am going to summarize for you the results of a 

			69 1	review of Lotrisone adverse events reported to the agency
	2	from the time of approval to 1999. 
	3		[Slide.] 
	4		First a little background.  Lotrisone Cream was 
	5	approved in July of 1984.  It is a combination product 
	6	consisting of clotrimazole, which is a synthetic antifungal
	7	agent and betamethasone diproprionate which is a high- 
	8	potency topical steroid. 
	9		It is labeled for twice-daily use for two weeks 
10	duration for tinea cruris and tinea corporis and twice daily 
11	use for four weeks duration for tinea pedis.
12		[Slide.] 
13		The original 1984 label indicated that it was not 
14	to be used in children under the age of 12.  The Precaution 
15	Section of the label, Pediatric Use, contained the statement 
16	that "Safety and efficacy have not been established in
17	children under 12." 
18		In 1991, the label was strengthened with the 

19	addition of the words in the same section, "The use of 
20	Lotrisone in diaper dermatitis is not recommended." 
21		[Slide.]
22		The objective of our review was to compile a list 
23	of all the adverse events reported to the agency from the 
24	time of marketing to 1999.  Specifically, we were asked to 
25	focus on the following questions; were the adverse events 

			70 1	reported associated with the duration of treatment longer
	2	than indicated by the label and were adverse events reported 
	3	in the under-12 age group. 
	4		[Slide.] 
	5		In order to compile this review, we searched the 

	6	agency's Adverse Event Reporting System, AERS for short, for
	7	all adverse events reported to Lotrisone Cream in the time 
	8	period under review.  We also used commercially available 
	9	databases IMS Health and we used two of their databases 
10	which are available to the agency, NPA, National 
11	Prescription Audit.  We used this to estimate the total
12	numbers of prescriptions for Lotrisone over the period, and 
13	NDTI, National Disease and Therapeutic Index, to get the 

14	demographics of the patients for whom these prescriptions 
15	were written and the indications for use. 
16		[Slide.]
17		Just the next few slides, I will tell you a little 
18	bit about the databases that we used.  AERS is a 
19	computerized passive surveillance system into which all our 
20	adverse events reported to any drugs in the agency are 
21	entered.  It is a spontaneous system and that means that the
22	agency does not go out and solicit, actively solicit, 
23	adverse-event reports, but we rely on health-care 
24	practitioners, physicians, nurses, pharmacists and 
25	consumers, themselves, to report adverse events to us in the 

			71 1	agency either directly or though the company responsible for
	2	the drug.  It contains all adverse events reported from 1969 
	3	until the present time. 
	4		[Slide.] 
	5		The strengths of AERS is that it is a cost- 

	6	effective method of detecting rare adverse events.  Its
	7	limitations are that it is not comprehensive.  There is 

	8	substantial underreporting and it varies depending on the 
	9	type of adverse event, the seriousness of the adverse event, 
10	and whether it is a labeled or unlabeled adverse event. 
11		[Slide.]
12		It also has limitations in the fact that 
13	individual case reports are not always complete.  For 
14	example, we may lack information in the age of the case or 
15	on the gender of the case and other information may be 
16	missing from each report.
17		[Slide.] 
18		The IMS data that we have available or that we 

19	used for this review, National Disease and Therapeutic 
20	Index, or NDTI.  It is an ongoing survey of treatment 
21	practices and diseases at patient visits to office-based

22	medical practices in the Continental United States.  From 
23	that we got the demographics of the cases and indications 
24	for use. 
25		The National Prescription Audit, or NPA, provides 

			72 1	estimates of the total numbers of prescriptions written for
	2	drugs in the United States.  Its basis is an audit of retail 
	3	pharmacies including chain, independent, food stores and 
	4	mail-order pharmacies. 
	5		[Slide.] 
	6		Now to the results.  The total number of adverse
	7	events reported to the agency in association with Lotrisone 
	8	Cream use was 786.  The total number of cases was 330.  The 
	9	reason why the number of events exceeds the number of cases 
10	is because it is possible, and, indeed, it often happens, 

11	that a case may have more than one adverse event reported.
12		For those cases for whom we had information on 
13	gender, there were 151 females and 126 males.  This slide 
14	shows the number of Lotrisone adverse events reported by 
15	year.  You can see that there is a gradual rise from the 
16	time of marketing until the present time, then a decline
17	until the present time, with a peak in 1991 and again in 
18	1994. 
19		[Slide.] 
20		This slide shows the top ten adverse events 
21	reported with Lotrisone.  The first three are more or less

22	common to nearly all topical drugs reported to the agency.  
23	What I want you to focus on are that skin atrophy and skin 
24	striae are both in the top ten, and these are permanent 
25	conditions once they develop. 

			73 1		[Slide.]
	2		This slide shows the distribution of cases by age, 
	3	gender and duration of treatment.  But first I want to 
	4	explain how we defined our age categories.  For example, in 
	5	the first category, 0 to 1, 1 includes all cases who have 
	6	not reached their second birthday and is similarly applied
	7	down the categories. 
	8		We see that, in the first three categories, in the 
	9	0 to 1 age group, there were twelve cases of adverse events: 
10	2 to 6, 13; 7 to 12, 19; and, in all, in the 0 to 12 age 

11	group, there were 25 percent of all adverse events reported
12	to the agency for Lotrisone Cream. 
13		Additionally, we see on the far-right column that 
14	58 percent of patients in the 0 to 1 age group were treated 
15	for longer than two weeks, 38 percent in the 2 to 6, and 
16	32 percent in the 7 to 12 age group.
17		[Slide.] 
18		Looking at the pediatric adverse events by age 
19	group, in the 0 to 1 age group, there were nine patients 
20	treated for diaper dermatitis, nine of the twelve, making 
21	75 percent.  16.5 weeks was the mean duration of therapy. 
22	The median was six weeks and the range was 1 to 80 weeks. 
23	Seven of the nine cases of diaper dermatitis had a duration 
24	of therapy in excess of 2 weeks. 
25		[Slide.] 

			74 1		Also in the 0 to 1 age group, we had one case of
	2	growth retardation.  A male infant, aged 1 year and 4 
	3	months.  The indication for the prescription was diaper 
	4	dermatitis and he was treated for 27 weeks. 
	5		[Slide.] 
	6		There were three cases of skin atrophy in the 0 to
	7	1 age group as well.  Two of them were female.  All had, as 
	8	the indication for prescription, diaper dermatitis and all 
	9	were treated for longer than 2 weeks and one extreme case, 
10	80 weeks. 
11		[Slide.]
12		There was also one case of benign intracranial 
13	hypertension in this age group, a five-month-old infant, for 
14	whom other information was not forthcoming. 
15		[Slide.] 
16		In the 2 to 12 age group, there were 32 cases with
17	an equal gender distribution.  61 percent of these patients 
18	were treated for longer than two weeks with a mean of 

19	26 weeks, a median of 6 weeks and a range from 1 day to 
20	156 weeks. 
21		[Slide.]
22		The indications for treatment in this age group, 
23	the top three were tinea facei, tinea corporis and diaper 
24	dermatitis. 
25		[Slide.] 

			75 1		In the 2 to 12 age group, the most frequent
	2	adverse events were similar to that for the overall group.  
	3	We also see that there were three cases of atrophy of the 

	4	skin, two in patients who had tinea facei and, in both of 
	5	these patients, the duration of treatment was longer than 
	6	two weeks being 4 and 13 weeks respectively.
	7		[Slide.] 
	8		We also had clinically serious adverse events in 

	9	adults.  We had three patients with Cushing's syndrome.  We 
10	only had clinical information on one patient who was a 38- 
11	year-old female who was prescribed Lotrisone for a yeast
12	infection and whose duration of therapy was 5 years. 
13		[Slide.] 
14		Now we turn to the usage patterns which we got 
15	from IMS Health Data.  I must say, at this point, that we 
16	are using this at this presentation with permission from IMS
17	Health. 
18		[Slide.] 
19		The computerized NPA records only go back as far 
20	as 1993.  We can see that between the years 1993 and 1999, 
21	the estimated total number of prescriptions for Lotrisone

22	Cream rose from 4.3 million gradually to 5.1 million in 
23	1999. 
24		DR. DRAKE:  May I interrupt you for just one 
25	moment.  What is IMS Health? 

				76 1		DR. LeGRENADE:  IMS Health is a data vendor.  It

	2	used to stand for something but it no longer--the name is 
	3	now IMS Health. 
	4		DR. DRAKE:  Okay; so it is just a data bank. 
	5		DR. LeGRENADE:  Yes; it is just a data vendor. 
	6		DR. DRAKE:  Thank you.
	7		[Slide.] 
	8		DR. LeGRENADE:  This slide shows the total 
	9	Lotrisone prescriptions by age.  This we got from the NPA 
10	data.  We can see that 6.5 percent of all prescriptions 
11	written in the time period were for patients in the 0 to 1
12	age group, 6.8 in the 2 to 6 and 6.4 in the 7 to 12 age 
13	group-- 
14		[Slide.] 

15		--making for a total of nearly 20 percent of all 
16	prescriptions written in the time period in the United

17	States being written for children under the age of 12. 
18		[Slide.] 
19		This slide and the next few will show the top five 
20	diagnoses for which prescriptions of Lotrisone Cream were 

21	written.  For the non-physicians present, ICD-9 stands for
22	the ninth revision of the International Classification of 
23	Diseases which is a numerical coding system which 

24	facilitates the tracking of morbidity and morality data over 
25	time and worldwide. 

			77 1		We cans see from this data that prescriptions were
	2	written in the 0 to 1 age group for candidiasis and diaper 

	3	dermatitis in the top five in the 0 to 1 age group. 
	4		[Slide.] 
	5		In the 2 to 6 age group, the top five 
	6	prescriptions also included diaper dermatitis.
	7		[Slide.] 
	8		In the 7 to 12 age group, these are the top five 
	9	conditions.  They include non-fungal infections of alopecia 
10	and pityriasis rosea. 
11		[Slide.]
12		So we concluded from this review that Lotrisone 
13	Cream is widely used off-label.  It is used in children 

14	younger than 12 years old.  It is used for diaper 
15	dermatitis.  And it used for longer than two weeks.  Serious 
16	adverse events have been reported in association with this

17	off-label use and I must point out here that the actual 
18	numbers of events are likely to be much higher because of 
19	the substantial underreporting that I mentioned earlier. 
20		Thank you. 
21		DR. DRAKE:  Very nice.
22		Markham, do you have more? 
23		                 Recap 
24		DR. LUKE:  That would start on Slide 17. 
25		[Slide.] 

			78 1		I would like to recall what the agency has
	2	discussed.  Our indication for Lotrisone Lotion needs 
	3	clarification.  We would like the committee to discuss what 
	4	would be an appropriate indication for this NDA.  We have 
	5	put on the table inflamed tinea versus all tinea. 
	6		Additionally, we would like to address the issue
	7	of Microsporum canis indication which the sponsor has 
	8	proposed and I understand will be discussed.  Additionally, 
	9	we would like to discuss means for addressing off-label use 
10	of the Lotrisone Lotion and, perhaps, the Lotrisone Cream 
11	product as Dr. LeGrenade has discussed.
12		Specifically, we would like to discuss pediatric 
13	use, diaper dermatitis and duration of use. 
14		[Slide.] 
15		I would like to show you what the applicant has 
16	proposed as a Pediatric Use Section for Lotrisone Lotion,
17	NDA 20-010.  Pediatric use: Lotrisone Lotion is not 
18	recommended for use in children under 12 years of age as the 
19	safety and effectiveness have not been established in well- 
20	controlled clinical studies in pediatric patients under 
21	12 years; it is not to be used for diaper dermatitis.  It is
22	not to be used under the age of 12 and not to be used in 
23	diaper dermatitis. 
24		I understand we have guest speakers. 
25		DR. DRAKE:  Let me make sure I have my agenda 

				79 1	correct.  We will go through the whole presentation and we

	2	will do the questions last.  Is that satisfactory?  Fine. 
	3		I think we have time to at least start on our 
	4	invited presentations.  We are actually fine on time.  We 
	5	are okay because there is some time this afternoon which is 
	6	not committed that we can commit.  But I do believe we have
	7	time to at least do one of the presentations before lunch. 
	8		Dr. Rosen, about how long is your presentation? 
	9		DR. ROSEN:  It is an hour but, for you, I will do 
10	it in fifteen minute. 
11		DR. DRAKE:  You are a wonderful human being.  How
12	would you like to go right now 
13		DR. ROSEN:  Let's do it. 
14		    Presentations - Invited Experts 
15	         Perspectives on Topical Antifungal Therapy 
16		DR. ROSEN:  Good morning.
17		[Slide.] 
18		Dr. Wilkin asked me to give an academician- 
19	clinician view of the perspective of combination antifungal 
20	agents.  I want to make a few key points.  I have to lay 
21	some predicates for that.  I will try and do this very
22	quickly.  I have already told you where I am from. 
23		[Slide.] 
24		Of course, we are talking about superficial 
25	infections.  We are not talking about anything other than 

			80 1	that.  And we are primarily talking about dermatophytosis
	2	because that is what the indication is.  While I agree with 
	3	Dr. Rosenberg's comments that there may be some ambivalent, 
	4	ambiguous cases and we might need a nice, safe drug for 
	5	those cases, in fact, what we are talking about is a drug 
	6	that is approved and indicated for dermatophytosis.
	7		[Slide.] 
	8		I do want to point out that there are different 
	9	dermatophytes.  There are those that primarily affect 
10	humans, anthropophilic, those that primarily affect animals, 
11	zoophilic, and some that primarily are found in plants and
12	soil, the geophilic.  They are not all equivalent.  Just 
13	like spokes in a bicycle, they are not the same. 
14		[Slide.] 
15		I also want to point out that we are talking about 
16	different tineas.  When we were talking about the studies
17	where tinea pedis is sort of the gold standard, and I thank 
18	Dr. Bergfeld for disagreeing with me and pointing out that 
19	the risk may be low on the feet, in point of fact, we are 

20	also talking about an agent that is approved for tinea 
21	elsewhere.  That includes in the groin and on the body.
22		I would like to further point out that some of 
23	these are quite chronic, in fact.  Tinea cruris may be 
24	recurrent over many years or even an entire lifetime and 

25	that chronicity and that recurrence leads to the inescapable 

			81 1	possibility of repetitive clinical use despite the labeling
	2	being for short-term use as in two weeks. 
	3		If the patient has a tube and they have recurrence 
	4	of tinea cruris, crotch rot for those who are not 
	5	dermatologist or physicians, they will see fit, I am 
	6	certain, to use the drug over and over again.  So we are
	7	talking about apples and oranges.  Tinea pedis is not the 
	8	same thing, athlete's foot, as fungal infections elsewhere. 
	9		[Slide.] 
10		And then we have talked a little bit about finding 
11	fungi.  And for everything that is fungal, there is
12	something that looks an awful lot like it that isn't fungus.  
13	I am of the opinion that people should try and find fungus 
14	and that there are ways to find fungus. 
15		[Slide.] 
16		I am also of the opinion that most clinicians who

17	are adequately trained can find fungus, whether it is by KOH 
18	or culture or other methodology.  There are some cases, and 
19	this has already been discussed by the panel, and probably 
20	deserves additional discussion and maybe an entire other 

21	session, where one, despite repeated efforts and diligent
22	and proper efforts, cannot find fungus. 
23		By the same token, the fact that a drug may be 
24	used, not approved but used, in a "shotgun" fashion then 
25	sends a message that, perhaps, these endeavors are not 

			82 1	worthwhile at all to which I disagree.  I think the
	2	proposition should be that individuals, regardless of their 
	3	specialty and that includes primary care, should be trained 
	4	to adequately use the appropriate one of these techniques to 
	5	find fungi and to know what they are treating. 
	6		[Slide.]
	7		Granted, there are some that we can't find but I 
	8	think an effort should be made in every case and that using 
	9	a "shotgun" method of therapy really discourages appropriate 
10	investigation. 
11		Now, granted, if something is fungal and that is
12	what we are talking about, a drug that is approved for 
13	fungal infection, one has to make a choice of therapy.  
14	There are various factors that enter into that including the 
15	site of infection, the likely pathogen which we will get 
16	back to, what are the risks, the age and health of the
17	patient. 
18		[Slide.] 
19		There are two basic possibilities in algorithmic 
20	approach, either a topical or a systemic drug. 
21		[Slide.]
22		For some conditions, a systemic drug really is the 
23	drug of choice for most nail infections, for tinea capitis, 
24	for, of course, the deep or systemic fungal infections that 
25	involve the viscera and, possibly, for extremely extensive 

			83 1	superficial fungal infections.  What is extensive enough to
	2	warrant systemic therapy versus topical therapy I think 

	3	could be defined by the physician.  And then, for most 
	4	localized infections, topical therapy is certainly an 
	5	adequate form of treatment. 
	6		[Slide.]

	7		It would be nice to avoid the potential for side 
	8	effects, which I think are greater with oral medications, if 
	9	topical medication is used.  And so you avoid the potential 
10	for drug-drug interactions and serious adverse reactions 
11	such as hepatotoxicity, hematologic toxicity, taste
12	disturbance, skin rashes and so forth with systemic agents. 
13		[Slide.] 
14		I think it is important that we understand that 
15	antifungal agents--just as diseases are not the same, 
16	antifungal agents are not the same--and that clotrimazole is
17	not the same thing as econazole which is not the same thing 
18	as naftafine or butenafine or cyclic peroxolamine. 
19		They are different based on pharmacokinetics and 
20	pharmacodynamics.  Basically, what happens when you rub that 
21	cream on, where does it go, how long does it bind, how is it
22	ultimately metabolized and excreted and what does it best 

23	work for, what is the spectrum of antifungal activity.  
24	These do impact upon even topical agents. 
25		[Slide.] 

			84 1		I have listed all of these different aspects of
	2	topical antifungal mechanisms.  Each one of them has some 
	3	bearing on the use and the efficacy of the drug.  I am going 
	4	to go through them very quickly, but I am going to come back 
	5	to them at the very end. 
	6		For example, the various agents that we now have
	7	available, and I do think we need to keep in mind that 1984, 
	8	when the drug Lotrisone was first approved, is not 2000.  We 
	9	now have a large number of classes of drugs.  In 1984, all 
10	we had were the azole, the imidazole agents.  We now have 
11	allylamine, benzylamine, hydroxyperidone and there are
12	several other entirely new classes of antifungal drugs that 
13	are being worked on. 
14		They all have a different mechanism of action.  
15	While the end result resolution of the fungal disease is the 
16	same, the different mechanisms of action impact upon other
17	properties of these drugs and impact on which organisms the 
18	various classifications of drugs work best upon. 
19		Also, the impact on a laboratory granted property 
20	of the drugs whether they are fungistatic or fungicidal and 
21	without going into great length as to how that is
22	determined, it is a laboratory technique. 
23		[Slide.] 
24		Ultimately, the difference between fungistatic and 
25	fungicidal may not alter the ultimate results but, in fact, 

			85 1	fungicidal activity, those that have been demonstrated in
	2	vitro in a test tube to be fungicidal are generally 
	3	associated with more rapid resolution. 
	4		[Slide.] 
	5		Some drugs, antifungal drugs, bind to keratin, the 
	6	outermost dead portion of the skin, more than others do, and
	7	is that important?  Again, keratin biding, like fungistatic 
	8	or fungicidal, does not materially alter the ultimate result 
	9	that can be obtained but it is associated with reduced 
10	frequency of application in a shorter duration of therapy. 
11		As you notice, Lotrisone is approved for four
12	weeks for tinea pedis where some of the newer agents can be 
13	used for as short a duration as one week based, in part, 
14	because they bind to the site and can be used for shorter 
15	periods of time.  Ultimately, the resolution may be the same 
16	but there is a difference.
17		[Slide.] 
18		In vitro assays are very difficult to compare 
19	because there are varying techniques, varying methodologies, 
20	various parameters that are set up but basically, within any 
21	given technique, all the publications pretty much agree that
22	for the dermatophytes, the subject of this discussion, 
23	butenafine, terbinafine and naftifine generally have lower 
24	minimal inhibitory concentrations than the azoles. 
25		Does that mean that the azoles won't work?  Of 

			86 1	course, it does not.  But what it does mean is that, in some
	2	situations, this may be a disadvantage.  Again, we will get 
	3	back to that. 
	4		[Slide.] 
	5		To show you some quantitative data derived from a 
	6	variety of publications, and there is a degree of variation,
	7	again based upon the technique that was used to determine in 
	8	vitro minimal inhibitory concentrations which do not always 
	9	correlate with clinical use, but you can clearly see that 
10	the minimal inhibitory concentration for virtually all the 
11	imidazoles are higher than some of the newer agents when it
12	comes to dermatophytes. 
13		[Slide.] 
14		The opposite is true when it comes to Candida 
15	albicans. 
16		[Slide.]
17		Again, a lower MIC does not improve the achievable 
18	ultimate results but those agents for which a given organism 
19	is used that have a lower minimal inhibitory concentration 
20	generally will have more rapid symptomatic relief and 

21	shorter overall courses of therapy.  These are based on
22	comparison studies, head-to-head comparison studies where 
23	the azoles have been compared to some of the more new 
24	agents. 
25		Also, the lower MIC does become important not so 

			87 1	much for the anthropophilic fungi like Trichophyton rubrum

	2	or even many cases of Trichophyton mentagrophytes, but it 
	3	does become important for those organisms where the MIC is 
	4	at the absolute upper end of those MICs that have been 

	5	measured, mostly zoophilic and geophilic fungi, particularly 
	6	zoophilic, those that are acquired from animals.
	7		[Slide.] 
	8		So this brings me, with that predicate, to steroid 
	9	antifungal combination.  I think the rationales for use 

10	would be to treat both fungal infection and some form of 
11	eczema or red scaling spots, as some of you have called
12	this, when the diagnosis is uncertain. 

13		The steroid component, in theory, should aid in 
14	symptomatic resolution even if the disease is known to be 

15	fungal in nature.  These would be the two rationales for use 
16	of a steroid antifungal combination understanding that the

17	first rationale listed is not the one for which the drug 
18	under discussion is indicated nor approved. 
19		There is no indication nor approval for use of a 
20	combination agent for red scaly spots whose etiology is 

21	unknown.  I think that is a very good issue that has been
22	brought up and really warrants an entirely separate 
23	discussion and, perhaps, a charge to the sponsor if they 
24	should choose to seek that sort of indication. 
25		But, really, what we are talking about is the 

			88 1	second one where the steroid should aid in the symptomatic
	2	resolution when a disorder is known to be fungal. 
	3		[Slide.] 
	4		I have already said my prejudice, and I admit it, 
	5	that using this, in fact, to me discourages very careful 
	6	medical care because it says, "Use a combination.  It
	7	doesn't matter what it is; it should take care of it."  I am 
	8	of the opinion that our primary-care physicians as well as 

	9	dermatologists should be capable of looking for fungi and 
10	knowing what they are treating. 
11		There are potential side effects.  Those have
12	already been mentioned.  I will show, I think, one more 
13	slide along those lines.  But the other important point I 

14	want to make, based upon MICs, based upon fungistatic versus 
15	fungicidal activity based upon keratin binding and mechanism 
16	of action, all of those properties, at least the steroid
17	antifungal combination agent under discussion today, which 
18	may or may not apply to other agents with different 
19	antifungals because they are not all the same, may not work 
20	in those infections acquired from animals. 
21		[Slide.]
22		We have already been told about some of the 

23	potential for steroid-related adverse events.  Again, I 
24	agree that the likelihood on the foot is small, but do bear 
25	in mind the chronicity of use for recurrences if patients 

			89 1	have fungal infection involving the groin which may actually
	2	originate from the foot and even from the nails.  The 
	3	patient who has an agent that has worked once will use it 
	4	again without their physician's supervision. 
	5		That is a proviso.  It is a given.  It is common 
	6	sense and it happens.  So one has to be concerned about
	7	things like atrophy and striae in the groin.  That is in 
	8	adults and perhaps even more so in children. 
	9		I agree, again, a very elegant discussion about 
10	adverse events seriously underestimate the number of adverse 
11	events because this is a voluntary reporting system and not
12	everybody is going to report every adverse event. 
13		[Slide.] 
14		I also would like to point this out, that in the 
15	Year 2000, it is not the same as 1984, that some of the 

16	current antifungal agents have inherent antiinflammatory
17	properties. 
18		[Slide.] 
19		Without, again going into detail, and for time, 
20	suffice it to say that we have investigated this in an 
21	in vivo system in human beings--
22		[Slide.] 
23		--based upon the similarity of inflammatory 

24	mediators induced by ultraviolet exposure and fungal 
25	infection. 

			90 1		[Slide.]
	2		This is just an example.  You can see some red 
	3	dots and some minor red dots and no red dots. 
	4		[Slide.] 
	5		It is one of the patients in our studies which 
	6	showed that, of the antifungal agents as they are currently
	7	available for prescription--i.e., out of the tube, the 
	8	entire preparation--that, based upon measuring reduction in 
	9	erythema and inflammation, some of the newer agents are 
10	actually quite inflammatory in this in vivo system in human 
11	beings.
12		There have also been in vitro investigations and 
13	in vivo investigations in animals that support this data in 
14	human beings.  They are all very parallel.  My point in 

15	showing this is that if one of the predicates for using a 
16	steroid antifungal combination is that the steroid component
17	is important for reducing the inflammatory portion of a 

18	fungal infection, that, in point of fact, some of the 
19	currently available antifungals are quite good at reducing 
20	at inflammation by themselves. 
21		You have a protocol which you agreed to, at least
22	in theory, that may allow a sponsor to claim that 
23	inflammatory property, but it has already been shown in an 
24	informal, small study on human beings. 
25		[Slide.] 

			91 1		There are the references for that particular work.
	2		[Slide.] 
	3		Here is the bottom line and towards the end of my 
	4	discussion.  Because the current steroid antifungal product 
	5	under discussion utilizes an antifungal agent that has a 
	6	high MIC for some organisms, particularly the zoophilic
	7	ones, has a low keratin binding, is fungistatic rather than 
	8	fungicidal, there is a theoretical risk.  That is why there 
	9	may be some failures or some worsening of infection. 
10		You have been shown data to the effect that that 
11	can happen on occasion.  The reality is that most of the
12	time, this is not a clinical issue but it is an issue when 
13	certain organisms are involved. 
14		[Slide.] 
15		That relates to some of the patients that we 
16	reported in the paper that you have been given in advance. 
17	An individual who was diligently applying a steroid 
18	antifungal combination to tinea of her hand acquired from 
19	her new kitten.  By the way, I am not anti-kitten.  I have 
20	two cats, so I like them.  But this is what she was applying 
21	diligently, twice daily and her disorder getting worse
22	instead of better. 
23		[Slide.] 
24		In one week of applying a different antifungal 
25	agent which is keratin-binding, inflammatory and a lower MIC 

			92 1	for Microsporum canis, which is what she cultured, she was
	2	clear. 
	3		[Slide.] 
	4		Another patient who was diligently applying the 

	5	steroid antifungal combination in consideration today who 
	6	acquired Microsporum canis infection from a kitten that his
	7	wife had purchased who slept in the bed with them mostly on 
	8	him.  He cleared when this combination agent was stopped. 

	9		There are several other cases in the paper that 
10	you have. 
11		[Slide.]
12		The question might be put, well, why should this 
13	happen at all, because if you do in vitro testing, while 

14	there is a high MIC for Microsporum canis with clotrimazole, 
15	in point of fact, it is still within achievable ranges.  My 
16	suggestion is that it may be either.  It is at the upper

17	limits and, therefore, this is a marginally effective 
18	antifungal for this kind of organism, or the steroid 
19	component suppresses several of the five or six innate 

20	defense mechanisms that we use against fungal infection and 
21	that may impair the person's own contribution to clearing

22	the infection or some as yet undetermined combination of 
23	both of those events leading to failure with Microsporum 
24	canis infections, which I have reported and have seen more 
25	than just the cases reported. 

			93 1		But it is of some concern to me and I think it is
	2	based on the pharmacokinetics and pharmacodynamics of the 
	3	antifungal agent in this combination plus the steroid. 
	4		[Slide.] 
	5		We also know that steroid alone--you have 
	6	mentioned using a steroid-alone arm and chosen or
	7	recommended that that should be used.  Just keep in mind 
	8	that if you have a patient who has a known fungal infection 
	9	for which they are applying steroid alone, that that may be 
10	responsible for exacerbation of their disease. 
11		[Slide.]
12		While that may not be a serious problem on the 
13	foot, it may, certainly, be in the face, in the groin or in 
14	the trunk-- 
15		[Slide.] 
16		--as this patient who was diligently applying a
17	steroid given her for the diagnosis of eczema and her fungal 
18	infection was ever increasing. 
19		So we know that steroids, by themselves, while 
20	they may relieve some symptoms, ultimately may exacerbate 
21	the disorder.  You will hear more about that from one of the
22	other speakers. 
23		We know that if you combine a high-potency steroid 
24	with what I would consider to be a lower-potency antifungal 
25	agent under certain conditions, like with zoophilic fungi, 

			94 1	there are some potential problems.
	2		[Slide.] 
	3		Of course, everybody is concerned about cost.  The 
	4	highest cost of a drug is one that either doesn't work for 
	5	what it is given for or given for the wrong diagnosis.  I am 
	6	particularly concerned about failure to achieve the goal of
	7	therapy with a steroid antifungal combination when the 

	8	fungal infection is with an organism where there may be 
	9	problems with that agent. 
10		[Slide.] 
11		So, in conclusion, I think that there are
12	potential for adverse events.  There is clearly use beyond 
13	the label, both for age and indication.  Whether that is 
14	justifiable for indication is an entirely different 
15	discussion. 

16		There are cases which have exacerbated.  There are
17	cases which have failed to achieve the goal for which the 
18	drug was given which have been summarized for you from the 
19	agency and for which I have shown you several examples and 
20	published additional ones. 
21		I think that information should be considered when
22	you take up the issue of labeling for this extension of the 
23	product line. 
24		I apologize for the fact that my presentation is 
25	not before you.  I tried six different ways to send it.  

			95 1	Maybe that is another federal hearing.  It kept bouncing
	2	back from the FDA, "user unknown."  I tried to send it to 
	3	Mr. Henriquez. 
	4		But thank you very much for your kind attention.  
	5	I hope those remarks will be helpful. 
	6		DR. DRAKE:  Ted, those were very helpful.
	7		It is past the lunch hour, significant so.  So I 
	8	think we will recess.  We will reconvene promptly at 
	9	1 o'clock.  See you then. 
10		[Whereupon, at 12:15 p.m., the proceedings were 
11	recessed to be resumed at 1 o'clock p.m.] 

			96 1	         A F T E R N O O N   P R O C E E D I N G S
	2		                                       [1:05 p.m.] 
	3		DR. DRAKE:  I am going to reconvene our meeting.  
	4	The same rules as outlined earlier are in place. 
	5		I want to do one thing before we have our next two 
	6	presentations.  Posted in the agenda at 1 o'clock was the
	7	Open Public Hearing section of this meeting. 
	8		          Open Public Hearing 
	9		DR. DRAKE:  We had no requests in advance for time 
10	at the mike.  But I do want to make that opportunity 
11	available if anyone has a comment that they would like to
12	make at the mike from the audience. 
13		Seeing none, then I think we shall proceed, then, 
14	with our presentations.  We have two; Dr. Elgart and Dr. 
15	Feldman.  Dr. Elgart, would you please proceed? 
16	        Presentations - Invited Experts (Continued)
17	        Tinea Incognito and Strong Topical Steroids 
18		DR. ELGART:  Hi.  I am Dr. Elgart. 
19		[Slide.] 
20		I am going to review a little bit a paper which, I 
21	think, has now been placed in front of most of you that I
22	wrote on tinea incognito.  At the time I wrote it, I was at 
23	George Washington University.  I am now in private practice. 
24		[Slide.] 
25		The paper talks a lot about Majocchi's granuloma.  

			97 1	Majocchi's granuloma is really an infection by a
	2	dermatophyte; in other words, a fungus that is a superficial 
	3	type of fungus which loses its way and gets down deeper into 
	4	the skin.  Most of the dermatophyte infections are within 
	5	the keratin portion of the epidermis, but, in these 
	6	instances, the fungi get down, usually down a hair follicle,
	7	then rupture the hair follicle and produce an inflammatory 

	8	response down in the deeper epidermis and, indeed, in the 
	9	dermis. 
10		It usually produces a granulomatous response.  By 
11	this definition, I guess you would have to include not only
12	the dermatophyte infections but, also, Pityrosporum 
13	folliculitis you might consider a form of this disease. 
14		[Slide.] 
15		Dominico Majocchi was the first great Italian 

16	dermatologist.  In 1883, he described a strange kind of
17	fungus infection in the groin.  This was in the groin of 
18	fairly large Italian men built something like me who had a 
19	large panniculus and the panniculus folded over the groin, 
20	to some extent. 
21		So, when they would get a dermatophyte in that

22	area, there was no time at which that dermatophyte was 
23	exposed to the air because they were sitting and it was 

24	always macerated.  Because of this, the fungus was able to 
25	grow down into the follicles and produce a more inflammatory 

			98 1	disease.
	2		This was a curiosity until 1954.  J. Walter 
	3	Wilson, who wrote a wonderful textbook of mycology, gave a 
	4	paper when he was initiated into the ADA on Majocchi's 
	5	granuloma.  It turned out that the Majocchi's granuloma that 
	6	he was seeing was in young women who were shaving their
	7	legs.  They would start with the razor at their ankles and 
	8	work their way up. 
	9		Those who had fungus infections on their feet 

10	would pick up bits of fungus on the razor and then plant 
11	them along the way, producing a fungal folliculitis because
12	of the trauma produced by the razor. 
13		[Slide.] 

14		Here are some photographs of that type of disease.  
15	You can see small papular lesions-- 
16		[Slide.]
17		--and, in one instance here, pustular lesions from 
18	what had been a fungus infection that was on the surface and 
19	showed only the scaly lesions and now is developing more 
20	pustular problems. 

21		[Slide.]
22		Here is a biopsy of one of those to show a 
23	follicle in the center with this epidermis and dermis there- 
24	-a follicle in the center and then inflammatory reaction 
25	around it. 

			99 1		[Slide.]
	2		When you get down a little deeper, you can find 
	3	inflammatory responses, not a granuloma but there is a 
	4	fungal element in the center and there are polys around the 
	5	edge. 
	6		[Slide.]
	7		The fungus, in this instance, was Trichophyton 
	8	rubrum.  There are a fluffy top-- 
	9		[Slide.] 
10		--and the red backing and the birds-on-a-wire 
11	microconidia that one sees in Trichophyton rubrum.  But you
12	can get this from any of the dermatophyte infections given 
13	the right sequence of events. 
14		[Slide.] 
15		Okay; we know that in Italy, in the late 19th 
16	Century, this could be caused by occlusion and in America,
17	in the mid 20th Century, this could be caused by trauma and 
18	shaving.  What causes Majocchi's granuloma in the Year 2000? 
19		There are two things, immunocompromised patients, 
20	particularly, and in immunocompromised patients, they can 

21	have AIDs, they can have transplants, they can be
22	immunocompromised because of medications, cancer 

23	chemotherapy, oral steroids, azathioprine.  These are all 
24	patients who, before, say, 1980 probably would have died 
25	because we didn't have the ability to keep them alive. 

			100 1		But now we have people whose immune response to
	2	this organism is not the same and, therefore, the organism 

	3	is able to penetrate down deeper and cause some problems. 
	4		But the other cause that I see of Majocchi's 
	5	granuloma is topical steroids.  Class 1 and Class 2 topical 
	6	steroids place on dermatophyte infections can induce the
	7	penetration of the fungus down into the follicle to produce 
	8	this disease. 
	9		[Slide.] 
10		Here is just such a case.  There was an annular 
11	lesion.  You can just see the outlines of the pigmentation. 
12	The Lotrisone was used.  The lesion disappeared and then it 
13	keeps coming back in this one place.  They keep putting the 
14	Lotrisone on.  The surface disappears.  In other words, the 
15	scaling on the surface, or, really, the dermatophyte on the 
16	surface disappears, but there is still dermatophyte down
17	deep where the clotrimazole, the Lotrisone, can't penetrate 
18	and so it keeps coming back because it can't be reached. 
19		[Slide.] 
20		Majocchi's granuloma, you also have to 
21	Pityrosporum folliculitis, is probably part of this same
22	picture.  Pityrosporum has gotten more complicated because 
23	there has been work to separate the Pityrosporum that we 

24	used to think of as two organisms into, now, seven 
25	organisms.  It is uncertain whether one species is 

			101 1	responsible for more of this than the others.
	2		[Slide.] 
	3		But Pityrosporum folliculitis is certainly seen, 
	4	particular in AIDs patients, and it shows up as usually 
	5	noninflammatory follicular prominence lesions that look like 
	6	this.
	7		[Slide.] 
	8		Microscopically, one can see the Pityrosporum 
	9	yeast--these are yeast and not filamentous fungi--you can 

10	see the Gram-positive budding yeast within the follicle.  
11	Sometimes they rupture and sometimes they can cause
12	inflammation. 
13		[Slide.] 
14		Ofuji's syndrome is called eosinophilic 

15	folliculitis and it is another kind of folliculitis 
16	associated with immune-compromised patients.  In most

17	instances, the etiology of Ofuji's syndrome is unknown, but 
18	occasionally in Ofuji's syndrome, a fungus has occasionally 
19	been demonstrated. 

20		[Slide.] 
21		Indeed, some--this is a Gomori methenamine silver
22	stain showing fungal elements in one of those patients.  Of 
23	course, these patients do respond to systemic antifungals. 
24		[Slide.] 
25		Getting back to the Majocchi's granuloma that I am 

			102 1	seeing a lot of the office, strong topical steroids are
	2	being routinely.  They are used because we have a lot of 

	3	samples of them, for one thing, and for another, a lot of 
	4	the people who are handing them out don't have any 
	5	understanding as to what is strong, what is mid-level, what 
	6	is a weaker topical steroid
	7		Second of all, KOHs are not being done.  

	8	Sometimes, they are not being done because the CLIA 
	9	regulations get in the way and people don't want to have a 
10	lab.  Sometimes they are not done because people don't know, 
11	or don't want to know, how to do them.
12		If the patient is put on steroids and doesn't 

13	respond, then they are put on antifungals.  But, by that 
14	time, the fungus may have grown down the follicle and 

15	produced the folliculitis which the topical antifungal 
16	cannot reach and, therefore, you created a significant

17	problem by the way a lot of people take care of the these 
18	kinds of lesions. 

19		[Slide.] 
20		I didn't put up this slide to make fun of 
21	nondermatologists.  I put up this slide because when I was a
22	nondermatologist, back 40 years ago, I was a general medical 
23	officer in the service.  At that time, I didn't know 
24	anything about dermatology except I didn't want to look too 
25	stupid.  So I had a cream that I would put onto something.  

			103 1	If it worked, then I was a hero.  If I wasn't, it got
	2	referred to a dermatologist. 
	3		In those days, the cream of choice was Mycolog.  
	4	It had in it something that was a steroid and it was 
	5	antibacterial and it was antiyeast.  I didn't know the 
	6	difference between a yeast and a fungus at that point,
	7	anyway.  So that was the way I used the product. 
	8		Indeed, that is the way a lot of people are using 
	9	the products that we have today.  The nondermatologist often 
10	does not understand the difference between the potency of 

11	different steroids.  They rarely understand the difference
12	between the clinical presentations of yeast or fungus 

13	infections and often, even though there are specific 
14	differences that one can see clinically, they are not taught 
15	and they do not remember these differences when they see 
16	patients.  The nondermatologist may not recognize the

17	difference between eczematous conditions and tinea. 
18		So a lot of this is being done by the seat of 
19	their pants.  So they are using a medication which they 

20	think will take care of everything.  That is one of the ways 
21	that this drug gets used.
22		I am amused at how careful we are in our labeling, 
23	but I think a lot of people who are using this drug are not 
24	reading the label.  They are using the drug because they 

25	perceive it as cure all and, therefore, are using it in a 

			104 1	lot of situations where we might otherwise not wish them to
	2	use it. 
	3		[Slide.] 
	4		Steroid antifungal combinations are perceived as a 
	5	single treatment that will work for everything.  Of course, 
	6	this is not true.
	7		[Slide.] 
	8		In my day, Mycolog, the original Mycolog, 
	9	contained the things I talked about.  Mycolog 2 got rid of 
10	the neomycin and the other antibiotics.  And Lotrisone today 
11	is what gets used a great deal.
12		[Slide.] 
13		The other thing to remember is, as was said 
14	before, patients don't throw things away.  If you want to 

15	really frighten yourself, open your medicine cabinet and 
16	look in it because there things there from twenty years ago
17	that you are saving just in case you have a really bad pain 
18	and you need that codeine, or whatever. 
19		It is amazing what is in my medicine cabinet, and 
20	I try to be careful.  So patients save this stuff and then, 
21	when they get the groin inflammation again, they go back and
22	they use it over again.  Although prescribed for a limited 
23	amount of time, sometimes nondermatologists refill 
24	prescriptions that they should not refill and the drugs get 
25	used for longer periods and patients often continue to use 

			105 1	it.
	2		There is an old theory that if a little is good, 
	3	then a lot must be better and so they continue to do it. 
	4		[Slide.] 
	5		I also want to point out that a lot of people 
	6	don't do KOHs.  I always go back to Dick Dobson who gave a

	7	wonderful talk that I heard.  He said, "There are only two 
	8	times when you do a KOH.  One is when you suspect a fungus 
	9	and one is when you don't suspect a fungus." 

10		I think that is something I have been teaching for 
11	a long time.  I think it really does make diagnoses, and
12	most of the time it has been extraordinarily helpful to me 
13	in thinking about what I am dealing with. 
14		[Slide.] 
15		So the steroid antifungal combinations; usually 

16	the steroid isn't need for the dermatophyte to work.  The
17	steroid helps the symptoms of Candidiasis and, indeed, of 
18	some of the dermatophyte infections in the early stages.  
19	But, after a few days, the steroid is no longer needed and 
20	may be harmful. 
21		There are other products and, as Ted said, a
22	product such as cycloproxoleamine, and others, have other 
23	inflammatory effects which may be as strong as many of the 
24	steroids that we use. 

25		I think that we make a mistake, often, in medicine 

			106 1	where we put things in boxes.  "This is an antifungal." 
	2	That doesn't mean that it can't also be inflammatory or 
	3	antibacterial or anti-something else.  But we think of it as 
	4	an antifungal and, therefore, we don't think of it as doing 
	5	anything else.  It will do what it darn pleases and we have 
	6	got to find out what that is.  For cycloprox, it is also
	7	inflammatory. 
	8		[Slide.] 
	9		When you have Majocchi's granuloma, topical 

10	measures do not work.  You need systemic medications, 
11	griseofulvin and terbinafine or, if you are dealing with
12	yeast organisms, itraconazole, fluconazole, would be the 
13	drugs of choice. 
14		Thank you. 
15		DR. DRAKE:  Dr. Elgart, thank you for a very 
16	precise and informative presentation.
17		Dr. Feldman?  If any of you prefer, there is a 
18	podium and a mike there, if you prefer to stand at the 
19	podium.  It is clearly your preference. 
20		 Use of Lotrisone in the United States 
21		DR. FELDMAN:  Thank you for letting me speak
22	today. 
23		[Slide.] 

24		I am going to speak on the use of the combination 
25	of clotrimazole-betamethasone diproprionate in the United 

			107 1	States.
	2		[Slide.] 
	3		Most of what I am going to present today are data 
	4	that the federal government has collected through the 
	5	National Ambulatory Medical Care Survey.  I am going to talk 
	6	about the use of the clotrimazole-betamethasone product to
	7	treat fungal disease, its use in general and, in particular, 
	8	use by pediatricians and then, perhaps, a little bit about 
	9	diaper rash. 
10		[Slide.] 
11		The National Ambulatory Medical Care Survey is a

12	terrific resource for understanding outpatient practice of 
13	medicine in the United States.  It is performed by the 
14	National Center for Health Statistics.  They survey 35,000, 
15	give or take, office visits across the United States per 
16	year.
17		These are not hospital inpatients or government- 
18	employed physicians.  So it is a real terrific survey for 

19	looking at skin care which is practiced predominantly in the 
20	outpatient setting.  The survey has information on patient 
21	demographics, diagnoses and what medications are used, among
22	other things. 
23		[Slide.] 
24		Some details about the study are in the handout.  
25	I don't think we need to go into them now. 

			108 1		[Slide.]
	2		Regarding the treatment of common fungal 
	3	infections, one can use monotherapy or combination therapy.  
	4	I think there are three real common reasons why combination 
	5	therapy is used.  One is if there is inflammation that needs 
	6	treatment.  That is the one that we have spent a lot of time
	7	discussing. 
	8		But, as Dr. Rosenberg mentioned early, probably a 
	9	much more important reason is if you are unsure of the 
10	diagnosis.  Then a third reason that I don't think has been 
11	touched on quite so much is if you have no clue what is in

12	the combination and just happen to be using it because 
13	someone told you to. 

14		[Slide.] 
15		There are problems with combination therapy.  
16	There is increased cost to the medication.  We just heard

17	about reduced efficacy and we have also heard about reduced 
18	safety, adding the risk profile of the corticosteroid agent 
19	when, perhaps, there is no good reason to. 
20		[Slide.] 
21		This is just an example from my practice of
22	someone who developed a tinea incognito. 
23		[Slide.] 
24		The picture on the left is steroid atrophy.  The 
25	picture on the right is an example of cutaneous atrophy in 

			109 1	the groin area.  This patient was not treated with the
	2	Lotrisone product.  This was a patient treated with Elecon, 
	3	another high-potency topical steroid agent that is probably 
	4	misperceived by many people. 
	5		[Slide.] 
	6		We worry when these products are used in sensitive
	7	skin areas like the face or the groin area because the 
	8	penetration of steroid, as you can see, is much greater in 
	9	those areas than it would be on the foot. 
10		[Slide.] 
11		So the combination treatment I am going to talk

12	most about, of course, is the clotrimazole-betamethasone 
13	product. 
14		[Slide.] 
15		This box of samples was in my clinic.  One of the 
16	things I noticed about it is, on the cover, it says that it
17	is appropriate for use in jock itch without any statement 
18	about the length of time for which it could be used safely 

19	or the age range, at least not here on the cover of the box, 
20	for which it could be used safely. 
21		I think having a combination steroid antiinfective
22	product is a great idea for things like seborrheic 
23	dermatitis on the face where we know there is inflammation 
24	and an infective component for intertriginous eruptions 
25	where we think of inflammation and an infective component. 

			110 1		But the steroid that was chosen here is really not
	2	appropriate, at least for any kind of prolonged use on the 
	3	face or groin area and, perhaps, there is not enough effort 
	4	to make people aware of what the potency of that steroid is. 
	5		[Slide.] 
	6		We looked at visits in the United States in this
	7	National Ambulatory Medical Care Survey for common 
	8	superficial fungal infections.  What we found is that 
	9	dermatologists rarely prescribe betamethasone-clotrimazole 
10	when they make a diagnosis of a fungal infection.  So 

11	4 percent of visits where a dermatologist has made the
12	diagnosis of a superficial fungal infection, something like 
13	Lotrisone is prescribed. 
14		In contrast, the internists, over half the time 
15	they make the diagnosis of a common fungal infection, they 
16	are prescribing the combination of clotrimazole and
17	betamethasone diproprionate.  I suspect that rarely, if 
18	ever, it is because they are treating the inflammation.  I 
19	suspect that it is one of the two other reasons that we 
20	mentioned earlier, either that they are not sure of the 
21	diagnostic ability in making fungal infections or they just
22	don't know what is in the product. 
23		Family doctors, of course, less than internists.  
24	I think they have a better understanding of skin disease.  
25	And pediatricians use the combination even less than the 

			111 1	family doctors although, in a pediatric setting, there is
	2	probably much less reason to ever use the product. 
	3		[Slide.] 
	4		Given those data, we wanted to explore in more 
	5	detail how the combination clotrimazole-betamethasone 
	6	diproprionate is used by the different specialties.  So we
	7	looked, first, here at visits to family physicians.  We 
	8	looked at those visits that were for superficial fungal 
	9	infections based on ICD-9 coding. 
10		We also looked at when they made diagnoses of 
11	inflammatory disorders.
12		[Slide.] 
13		What we found is that the combination product is 
14	used for superficial infections but even more commonly when 
15	the family physician is making a diagnosis--I'm sorry; it is 
16	used when the infectious conditions are diagnosed as well
17	when inflammatory conditions are diagnosed, much less 
18	frequently so by dermatologists. 
19		[Slide.] 
20		As was mentioned earlier, looking at the diagnoses 
21	that are treated, inflammatory dermatosis, or the diagnosis
22	of an inflammatory disorder, is the most common time that 

23	this product is used but it is also commonly used for groin 
24	infections and for diaper dermatitis. 
25		[Slide.] 

			112 1		There was frequent use in patients age 0 to 4. 
	2	40 percent of all the topical steroids used by family 
	3	physicians, in the 0 to 4 age group, was the clotrimazole- 
	4	betamethasone diproprionate product.  For all ages, you can 
	5	see that genital, anal area and diaper-dermatitis eruptions 
	6	were common reasons for Lotrisone to be used.
	7		Interestingly, 23 percent of the visits at which a 
	8	family physician made a diagnosis of seborrheic dermatitis, 
	9	clotrimazole-betamethasone diproprionate was prescribed. 
10		[Slide.] 
11		Internists showed similar findings.  They don't

12	see that many pediatric patients, but three of their top 
13	five diagnoses were genital area eruptions that they were 
14	treating with the product. 
15		[Slide.] 
16		The data on pediatricians, in this National
17	Ambulatory Medical Care Survey, was analyzed for the years 
18	1990 through 1994.  These data are published. 
19		[Slide.] 
20		Pediatricians are very unlikely, in general, to 
21	use high-potency topical steroids.  I think there is a real
22	tendency, among pediatricians, to be very conservative in 
23	their use of topical steroids and to say away from the high 
24	and super-high potency class 1 and class 2 agents. 
25		[Slide.] 

			113 1		You can see here, for corticosteroid monotherapy,
	2	what pediatricians are using.  You can see they really tend 
	3	to stay away from the high-potency topical steroids.  It 
	4	turns out they use far more Lotrisone than the combination 
	5	of those two class 1 and class 2 steroid monotherapies. 
	6		I think that suggests, at least in part, that they
	7	don't realize what is in this drug. 
	8		[Slide.] 
	9		Of the diagnoses that they were treating, tinea 
10	corporis was the most common but dermatitis, I was very 
11	surprised to see how frequently well-baby visits were
12	associated with the use of Lotrisone. 
13		Let me just go back.  You can see the total use of 
14	Lotrisone over this time period is 700,000 prescriptions.  
15	Going back, the combination of high and super-high is about 
16	300,000, so there is much more Lotrisone than they are using
17	highs and super-highs. 
18		[Slide.] 
19		56 percent of the pediatric use of Lotrisone was 
20	in the 0 to 4 age group.  In that age group, well-baby visit 
21	was the most common diagnosis.  Dermatologists, at least in
22	this study period, did not prescribe Lotrisone to any child 
23	in the 0 to 4 age group. 
24		[Slide.] 
25		Of particular concern to me is the use of the 

			114 1	product in diaper rash in children.  I think there are
	2	plenty of other good treatments that are more effective, 

	3	less expensive and certainly less risky than to use this 
	4	product in kids. 
	5		[Slide.] 
	6		This just summarizes that pediatricians tend to be
	7	conservative.  Their use of Lotrisone seems excessive 
	8	compared to the use of other potent topical steroids.  I 
	9	think our take-home message from this was that they may be 
10	unaware of the steroid potency of Lotrisone and there could 
11	be strong efforts made to make pediatricians aware of the
12	potency. 
13		[Slide.] 
14		To further analyze this, we left the National 
15	Ambulatory Medical Care Survey for a minute.  A survey was 
16	done at the 1999 American Academy of Pediatrics meeting
17	where 106 pediatricians completed the survey.  These were 
18	all pediatricians who currently prescribed the product for 
19	at least some of their patients. 
20		[Slide.] 
21		This is the proportion of patients who are treated
22	with Lotrisone in various conditions.  You can see diaper 
23	dermatitis is treated--23 percent of patients with diaper 
24	dermatitis are treated with Lotrisone by these 
25	pediatricians. 

			115 1		[Slide.]
	2		This is interesting.  This is the proportion who 

	3	never prescribe Lotrisone for various conditions.  So about 
	4	40 percent of these pediatricians never prescribe Lotrisone 
	5	for diaper dermatitis meaning that 60 percent of the 
	6	pediatricians who prescribe Lotrisone prescribe it at least
	7	some of the time for diaper dermatitis. 
	8		[Slide.] 
	9		We thought that the primary reason pediatricians 
10	use Lotrisone despite the warnings would be that they did 
11	not realize what topical steroid was in it.  We asked them;
12	"What topical steroid do you think is in Lotrisone?"  Only 
13	18 percent recognized it to be a high-potency topical 
14	steroid. 
15		Unfortunately, there was no relationship to 
16	whether they knew it was a high-potency topical steroid and
17	how often they prescribed it to their patients for diaper 
18	rash. 
19		[Slide.] 
20		We also asked how often they used it in excess of 
21	the recommendations in the PDR.  25 percent of the time,
22	they were using in excess of the two weeks recommended for 
23	tinea cruris.  We didn't address diaper dermatitis here 

24	since Lotrisone is never appropriate for use in diaper 
25	dermatitis. 

			116 1		[Slide.]
	2		We addressed how diaper dermatitis, in general, is 
	3	treated looking at the National Ambulatory Medical Care 
	4	Survey data, looking at those visits that had an ICD-9 code 
	5	of 691.0 which is diaper dermatitis.  But we also included 
	6	balanitis, vulva vaginitis, intertrigo and candidiasis in
	7	patients under the age of 4. 
	8		[Slide.] 
	9		There were 8 million visits.  They were primarily 
10	to pediatricians and family physicians, very few to 
11	dermatologists.
12		[Slide.] 
13		The most common treatments were nystatin and 
14	clotrimazole No. 1 and 2, but then the combination products 
15	including triamcinolone and betamethasone diproprionate both 
16	which, I think, are probably too strong for any kind of
17	prolonged use in the diaper area. 
18		[Slide.] 
19		So, in summary, the clotrimazole-betamethasone 

20	diproprionate product is not the best treatment choice for 
21	either inflammation or for tinea infection if you know that
22	that is what you are dealing with.  It is most frequently 
23	used by non-dermatologists.  It is generally not being used 

24	to treat highly inflammatory tinea infections.  In fact, the 
25	use of it appears to be inconsistent with good medical 

			117 1	practice.
	2		DR. DRAKE:  Thank you very much. 
	3		They say the mark of a good speaker is being able 
	4	to present the information they want to present in a finite 
	5	period of time and have it understandable.  I want to say 
	6	that has been true of every single speaker we have had
	7	today.  I am really very impressed. 
	8		Right before we go to the sponsor presentation, I 
	9	would like to ask the panel; we have heard some-- 
10		DR. SPRAKER:  I was just raising my hand.  At some 
11	point, I would like to make some comments to follow up his
12	discussion but wherever it is appropriate. 
13		DR. DRAKE:  Please, Mary.  I just have a question 
14	but please let's hear your comments because you may answer 
15	it.  I am going to ask the panel if they have any questions 
16	for our group of experts before we go to the sponsor for a

17	few minutes. 
18		Dr. Spraker, please. 
19		DR. SPRAKER:  I would just like to give the panel 
20	a bit of historical perspective about the Lotrisone problem 
21	from the vantage point of the pediatric dermatologist. 
22	About ten years ago, at our Pediatric Society board 
23	meetings, there were discussions regarding the Lotrisone 

24	problem because we were hearing about striae that were 
25	induced in the diaper area and we were hearing from 

			118 1	pediatricians in our communities when we were asked, "Why
	2	are you using Lotrisone for treatment of diaper dermatitis?" 
	3	that the drug reps were going to the offices and telling 
	4	them about Lotrisone and implying, or the pediatricians were 
	5	getting the message, that Lotrisone was appropriate therapy. 
	6		So we were very concerned about this problem and a
	7	number of pediatric dermatologists actually went to Schering 
	8	to talk about the Lotrisone problem.  From those 
	9	discussions, a number of things were accomplished. 
10		The company agreed that it would no longer send 
11	the reps to the pediatricians' offices.  I don't recall the
12	details, but at least they weren't going to be talking about 
13	the use of Lotrisone in pediatric patients. 
14		The second thing that came out of these 
15	discussions was the company developed an education program 
16	for pediatricians regarding potency ranking of topical
17	steroids because all of us recognized that most 
18	pediatricians, and I think probably primary-care physicians, 
19	as you have said, Steve, really do not know that there is 
20	such a thing as a potency-ranking chart. 
21		They are aware that there are weak steroids,

22	medium ones and strong ones, but they really don't know 
23	anything about the different groups.  So there were, 
24	actually, I think, quite good educational materials that 
25	were prepared and distributed. 

			119 1		Many of us are educators for pediatricians and
	2	were often speaking at meetings to large groups of 
	3	pediatricians.  So, in that era, many of us, that was one of 
	4	the things that we would talk about, "What's New," or a 
	5	whole lecture on potency ranking of topical steroids, pros 

	6	and cons of topical steroids, when to use what, that type of
	7	thing. 
	8		So we had hoped that the Lotrisone problem had 
	9	been addressed and maybe solved.  So it was quite 
10	disturbing, then, to see these papers and this data 
11	presented which clearly show that we still have problems out
12	there. 
13		I guess I have several recommendations.  Some of 
14	them have been in your materials already.  I strongly feel 
15	that the box and the tube should state that the drug is not 
16	to be used in the diaper area because I think the mothers,
17	or the parents, will read that.  Even if we change the 
18	material, what is written in the package insert that is 
19	going to be in the PDR, you can't assume that the physician 
20	is necessarily going to see that. 
21		But parents read those things and they will come
22	back to the pediatrician and ask, "Why did you prescribe 

23	this when it clearly says this is not to be used?"  So I 
24	think that that might be a very effective vehicle for 
25	changing habits. 

			120 1		I also think that there should be a big black-box
	2	warning in the PDR that emphasizes, not just a statement but 
	3	a big black box, that, "This drug is not to be used for the 
	4	treatment of diaper dermatitis." 
	5		The side effects should be enumerated, not just a 
	6	one word, "Because of cutaneous atrophy," but we should list
	7	how many patients have been reported with cutaneous atrophy, 
	8	how many patients in these young age groups have had 
	9	problems with striae so physicians are given more 
10	information to work with. 
11		It is interesting to me that the PDR never states
12	what the potency ranking of a topical steroid is, as far as 
13	I know.  It hasn't been the custom, I guess.  You have to 
14	have your little chart.  Maybe that is something that, not 
15	at this meeting but at another level, but that that could be 
16	addressed so that routinely potency rankings are included in
17	topical steroid PDR information. 
18		I do agree that it would be a very good idea to 

19	send a letter to pediatricians and primary-care physicians 
20	just addressing the problem and the things that have been 
21	done to address the problem.
22		DR. DRAKE:  Thank you, Dr. Spraker. 
23		Dr. Epps? 
24		DR. EPPS:  I just have a few comments.  I agree 
25	with much of what has been presented today.  Certainly as a 

			121 1	board-certified pediatrician and dermatologist, I kind of
	2	get to see both sides of the coin.  As a pediatric 
	3	dermatologist at a referral center, I tend to see a rather 
	4	distinct population and those are the ones that are not 
	5	successful. 
	6		I would say that, certainly, the number of cases
	7	in which the drugs are ineffective or the drug--the response 
	8	was not good to therapy is vastly underreported.  The 

	9	majority of patients that I do see have had at least a 
10	little bit of Lotrisone applied. 
11		The reasons for that may numerous.  One, the
12	diagnosis was not made or it was incorrectly made.  Or it 
13	wasn't prescribed properly or it wasn't used properly.  

14	There are a lot of factors into why a particular medication 
15	didn't work. 
16		But, clearly, if patients are being treated for 16
17	weeks or 150 weeks or whatever, it wasn't appropriate and 
18	may not be working.  Also, as far as making the diagnosis, 
19	there are a lot of red, scaly spots, not only the tinea and 

20	eczema, but there is pityriasis and psoriasis, whatever, but 
21	there are a considerable number of other conditions that
22	were not seen and, certainly, Dr. Elgart elucidated nicely a 
23	problem with the class 2 steroid. 
24		In fact, yesterday, I had a patient who was using- 
25	-the child was two, had a spot on the face.  There was an 

			122 1	area of vasoconstriction on the cheek and the mother was
	2	told that it would "bring out the fungus" so that it could 

	3	be treated.  So there is a lot of misinformation out there. 
	4		In addition to the vasoconstriction, another side 
	5	effect--I am not sure the population that was tested on in 
	6	children, but another side effect that I do see sometimes is
	7	hypopigmentation.  I don't know whether people of color or 
	8	what types of skin were included in the study, but I do see 
	9	hypopigmentation not only on dark but also fair-skinned 

10	children, in patients.  That can persist long after and it 
11	takes a while to resolve.
12		So that may be another side effect which should be 
13	considered.  Although it is listed in the insert, it wasn't 
14	specifically addressed in the side effects.  It may have 
15	been in the "not otherwise specified," but it wasn't 
16	addressed more specifically, and maybe that needs some
17	attention. 
18		Additionally, as to the large number of 
19	prescriptions which seem to be increasing despite efforts of 
20	education and letters, which doesn't really necessarily 
21	relate to what our function is, but some of the HMO

22	insurance plan formularies will have two or three 
23	antifungal, nystatin, Lotrisone and maybe that is it. 
24		Anything else you prescribe is not covered.  
25	Sometimes, a pharmacist will also substitute what you 

			123 1	prescribe.  It is not even appropriate in all instances for
	2	what is being treated.  So that is a problem, also.  Clearly 
	3	it is probably beyond the panel, but that may be another 
	4	reason why things are going up, especially with some of the 
	5	formularies. 
	6		So I would strongly--if approved, certainly I
	7	would support some of the comments about avoiding the diaper 
	8	area.  Some patients are also being treated with Lotrisone 
	9	for tinea capitis, which is not working.  So it is not just 
10	the diaper area.  People are using it on the face.  People 
11	are using it on the scalp.  Clearly other modalities and
12	medications would be more appropriate. 
13		I guess I am from the school of "know what you are 
14	treating," and not applying something because, clearly, mom 
15	is going to call you every single day until it goes away.  
16	But if you apply the proper treatment, it will go away and
17	everyone will be much happier. 
18		DR. DRAKE:  Thank you.  Eduardo, and then Joe. 
19		DR. TSCHEN:  Since, I guess, we are discussing the 
20	proposal for labeling, I will propose that, just like the 

21	label has, "not for opthalmologic use," I would like to see
22	it say something about "not for use under occlusion," or 
23	"not for use in the diaper area." 
24		I think occlusion also is important because the 
25	axillas under the breast, the groin area, I guess just 

				124 1	because of the nature of how they are, is an area of
	2	occlusion.  So I think it should be clear, just like, "not 

	3	for ophthalmic use," "not for diaper-area use," and, "not 
	4	for use under occlusion," should be very clearly specified 
	5	in that. 
	6		Most of the cases I see of rosacea are due to this
	7	product.  Again, I don't think this product should be used 
	8	in the face.  So then we keep on adding different things in 
	9	there, but I think it should be very clear that I don't 
10	think this product should be used on the face, either. 
11		DR. DRAKE:  Joe, please?
12		DR. McGUIRE:  Mary, is there and indication in 

13	children to use Lotrisone?  Is there a pediatric indication? 
14		DR. SPRAKER:  In my opinion, the only time to use 
15	Lotrisone for anybody is in inflammatory tinea pedis and toe 
16	web infections.  It is very unusual for children to have

17	extremely inflammatory tinea pedis.  I don't think I have 
18	ever prescribed Lotrisone so I haven't found a need to use 
19	it for anything. 
20		DR. McGUIRE:  I have never used Lotrisone in a 
21	child.  I wonder if I am too old to learn or I am missing
22	something.  I wasn't asking you, Lynn. 

23		DR. DRAKE:  First I got called somebody's mom and 
24	then--John? 
25		DR. JORDAN:  I have a question for Dr. Epps.  You 

			125 1	raised a point that I found interesting with respect to
	2	hypopigmentation.  I wonder if you have, in your experience, 
	3	seen, in very inflammatory dermatophytes, if there is post- 
	4	inflammatory hypopigmentation and, in those situations, if 

	5	you do, do you ever use a steroid to minimize that? 
	6		DR. EPPS:  Generally speaking, I don't.  Even in
	7	inflammatory tinea, I don't usually--sometimes, you see 
	8	hyperpigmentation if it is truly inflammatory.  I don't see 
	9	the hypopigmentation.  That is usually when they keep using 
10	it after the medicine, but I don't really use Lotrisone 
11	either for the similar reasons.  I don't see much tinea
12	pedis in kids, mainly above there. 
13		Sometimes in some of the teenagers or they are a 
14	little bit older, but, even still, it is not that 
15	inflammatory.  As far as the pigmentation is concerned, no; 
16	I don't see that hypopigmentation.  Usually it is "hyper."

17		DR. DRAKE:  Lloyd, we haven't heard from you.  Dr. 
18	King; I don't know if you have much to say, but you have 
19	been awfully quiet down there. 
20		DR. KILPATRICK:  You oftentimes can't be beat upon 
21	if you don't open your mouth and prove that you don't have a
22	great thing to say.  My comments; we don't use it in 
23	children.  To the best of my knowledge, we have a pediatric 
24	dermatologist and the only time I can remember seeing it 
25	prescribed was inflammatory tinea pedis. 

			126 1		We do have a great experience of it inducing
	2	steroid acne, and so that would be my only comment.  I don't 
	3	know why, if you are going to ban it in one site which is 
	4	the groin in children, you would allow it on the face 
	5	either.  So I think that what I would propose is that you 

	6	increase the black-box labeling and make it very clear what
	7	the indications are. 
	8		If it is not on the tube, mama's won't read it.  
	9	If mama ain't happy, ain't nobody happy.  So they have come 
10	back to tell you. 
11		DR. DRAKE:  Other comments?  I have a question in
12	a minute, but anybody else from this expert panel?  Do you 
13	have other things to add?  I would like to ask a question.  
14	I was at Emory for a number of years with Earl Jones who is 
15	quite a famous mycologist and expert in this arena. 
16		Pursuant to the comments that were down here, how
17	difficult it is to identify, sometimes, fungal elements in 

18	inflammatory areas, and I hate to quote him because I may be 
19	quoting him wrong, but I wanted to give you a gestalt of 
20	what he taught us as young faculty.  Dr. Spraker, you were 
21	there, too, so maybe you can help me out on this.
22		I seem to recall, and I practice this way, that 
23	Earl always used to say, "You cannot find hyphal elements in 
24	the middle of an inflammatory mess.  You have to scrape at 
25	the edge."  But he would go ahead and say, "You must scrape 

			127 1	at the edge because the edge is where the living organisms

	2	are where they haven't been gobbled up by the inflammatory 
	3	process and you will find them at the edge." 
	4		I tend to use that all the time and I tend to 

	5	teach my residents that.  I usually find them.  Mary, I 
	6	would like you to comment first and then I would like some
	7	of our fungal experts here to comment on that particular 
	8	theory.  I don't know that we ever proved it by a study, 
	9	but--Dr. Spraker? 

10		DR. SPRAKER:  I learned that somewhere, and I am 
11	not sure where.  It could very well have been from Earl. 
12	Tomorrow, we are going to talking about diaper dermatitis 
13	and how difficult it is to diagnose Candida diaper 

14	dermatitis because KOHs are often negative.  Clinically, you 
15	know that the patient has to have Candida diaper dermatitis, 
16	and the KOH is only positive 30 percent of the time,
17	approximately, unless you go for a satellite pustule, and 
18	then I think it can be more likely to be positive. 
19		Again, I think it is because the host mounts such 
20	a wonderful inflammatory response by shedding off the 
21	stratum corneum.  By shedding off the stratum corneum, you
22	get rid of the organisms. 
23		Merve? 
24		DR. ELGART:  My recollection of what Earl did, and 
25	he had some beautiful things that he did while he was still 

			128 1	in the service, he took people who had not been exposed to
	2	fungus infections before, he called them "fungal virgins."  
	3	A wonderful comment. 
	4		But he would put a culture of material on in a 
	5	central spot and watch it.  The fungus would grow, but there 
	6	would be no inflammation for about week until cellular
	7	immunity appeared.  When cellular immunity appeared, then 

	8	there was a large inflammatory response, but the scale, by 
	9	that time, was a little beyond where the inflammation was 
10	and so the inflammation sort of had to catch up with it. 
11		Eventually, the inflammation would catch up with

12	it and everything would disappear, but there was still live 
13	fungus at the edge and that was work that he did, oh, 
14	probably in the mid-60's, I suspect. 
15		DR. DRAKE:  Yes; the work was done.  And he did 
16	teach you; you scrape at the advancing edge where there is
17	still normal, healthy tissue. 
18		Ted? 
19		DR. ROSEN:  There are several ways to find fungi, 
20	too, don't forget.  First of all, if it is inflammatory--we 
21	are all talking about inflammatory like we have the same

22	things in our mind which may not be true.  There is red.  
23	There is intense maceration without scale, interdigital.  
24	There may be huge blisters, centimeters of blisters on the 
25	bottom of the foot. 

			129 1		If you have bolus tinea, that is very
	2	inflammatory, very uncomfortable, but very easy to find 
	3	organisms by taking the blister roof and turning it upside 
	4	down and looking at the edge of the blister. 
	5		If you have intense maceration between the toes, 
	6	it is extremely difficult to have a positive KOH in those
	7	circumstances even at the edge but you will often have a 
	8	positive culture.  I understand that, in the current milieu, 
	9	cultures are expensive and many people are loathe to do them 
10	or the plan won't reimburse for them, et cetera. 
11		But it is not just the bedside, which would be the
12	ideal because it is cheap and it is quick, but culture also 
13	can determine when there is a fungus there even if KOH is 

14	negative.  So there are at least a couple of steps that 
15	could be taken. 
16		DR. JORDAN:  I don't know.  We seem to be tippy-
17	toeing around some issues here.  I want to ask the panel, 
18	and Mary you brought this up, the indication for this 
19	product being inflammatory tinea pedis.  I will ask this of 
20	the panel just to get an impression. 
21		If you have a patient and you have got a positive
22	KOH, you have got a positive culture, would you use this 

23	product over antifungals we have available to us now or some 
24	form of systemic therapy? 
25		DR. SPRAKER:  I wouldn't use the product because I 

			130 1	think the inflammatory response the host mounts might be
	2	good and beneficial, getting rid of more of that fungus.  
	3	That is my personal philosophy on it.  It is very difficult 
	4	to prove any of those things, however. 
	5		As a mother, I only had one child who had Candida 
	6	diaper dermatitis.  This is different but, in some ways, I
	7	think it is the same kind of issue.  When my son got a 
	8	florid case of Candida diaper dermatitis, I said, "Okay; I 

	9	am not going to add any topical steroids to this and I am 
10	just going to use the antifungal." 
11		A day later, I just couldn't stand it and I
12	smeared on some kind of topical steroid.  So I understand 
13	from a personal level the temptation and the need.  I think 
14	Kligman has shown with Candida that you can take dead 
15	Candida organisms and put them on skin and get an 
16	inflammatory reaction that induces cytokines, or something.

17		DR. ELGART:  It is an irritant contact dermatitis. 
18		DR. SPRAKER:  Merve is saying an irritant contact 
19	dermatitis.  So the inflammatory response to these fungal 

20	organisms is really quite interesting 
21		DR. ROSEN:  I am going to answer Bob's question
22	directly because, as you all know, or many of you know, I 

23	work in the VA.  Everybody has tinea pedis there, virtually, 
24	if you look.  Many of them are inflammatory, whether you 
25	want to talk about interdigital or bolus tinea on the bottom 

			131 1	of the foot.
	2		I wouldn't use this product, period.  If I were 

	3	going to use a topical antifungal, I would use one of the 
	4	newer ones, as I mentioned.  They have inflammatory effects.  
	5	They can be used at a much shorter time period and much less 
	6	frequently.  And then I would look at the nails because, in

	7	some cases of tinea pedis, if not many of them, the source 
	8	is really the nail and they require systemic therapy as 
	9	well. 
10		That is an additional point, but I, personally, 
11	would not.
12		DR. FELDMAN:  I would not, in this situation or in 
13	any other situation.  I think there is always a more potent 
14	antifungal, if I know it is an antifungal.  If I know it is 
15	inflammatory, I know there is a cheaper antifungal that is 
16	of the appropriate potency.  Even, as Bill was saying, if it
17	is the situation where it is not sure, then I would pick, as 
18	Dr. Stern said, an antifungal of the appropriate type along 
19	with an appropriate topical steroid. 
20		DR. ELGART:  I have to agree with the other 
21	members of the antifungal experts, but I think, also, what

22	we are dancing around a little bit is the fact that the 
23	indications on the label is not the way the product is used 
24	by the people who actually use it.  I think that is really 
25	where the problem lies is that the use is perceived to be 

					132 1	different by those who use it than by those who write
	2	regulations. 
	3		DR. DRAKE:  I don't feel a compelling need to use 
	4	up all of our time, but I do want to make sure that 
	5	everybody is heard from for this panel with questions.  So I 
	6	am going to poll my panel as well as the FDA.  I am just
	7	going to go around and ask if there are any further 
	8	questions you have for our panel of experts. 
	9		Eduardo? 
10		DR. TSCHEN:  No. 

11		DR. DRAKE:  John?
12		DR. DiGIOVANNA:  No. 
13		DR. DRAKE:  Fred? 

14		DR. MILLER:  No. 
15		DR. DRAKE:  Bob? 
16		DR. JORDAN:  No.

17		DR. DRAKE:  Wilma? 
18		DR. BERGFELD:  No. 

19		DR. DRAKE:  Dr. Chesney?  Welcome back. 
20		DR. CHESNEY:  Thank you.  How well has Lotrisone 
21	been studied in children?  Do we have a lot of data on its
22	use in children?  Is it being used without any data? 
23		DR. DRAKE:  Actually, one of the things we might 
24	do--I'm sorry, during the presentation from the FDA--they 
25	gave a good one.  There is a little bit in there that might 

				133 1	be helpful but, in addition, does somebody want to try to
	2	summarize that for her?  There is a presentation in there on 
	3	how much it is used, and the AEs. 
	4		DR. STERN:  To answer your question, we are not 

	5	aware of many controlled studies, if that is what you mean 
	6	by study, as opposed to studying the frequency of use for

	7	which there are data that we have heard about.  But, in 
	8	terms of how well it works in comparison to either placebo 
	9	or other agents in children. 
10		Have there been any NDAs or anything?  That is 
11	what you meant, essentially, or clinical studies in children
12	of this agent versus other agents in things that are 
13	excluded from the label earlier on, the '84 or whatever, 
14	that would should know about? 
15		DR. WILKIN:  Not in the recent NDA submission, if 
16	your question is is it in the recent submission.  If there
17	are any studies at all, you will hear from the sponsor and 
18	that would be a chance to have a query directed-- 
19		DR. DRAKE:  Dr. Stern?  Questions? 
20		DR. STERN:  No. 

21		DR. DRAKE:  Jim?
22		DR. KILPATRICK:  No. 
23		DR. DRAKE:  Bill? 

24		DR. ROSENBERG:  No. 
25		DR. DRAKE:  Joe? 

					134 1		DR. McGUIRE:  Lynn, sometime, I would like to hear
	2	from the panel if anyone thinks that the combination is 
	3	indicated in children.  If we think that it is not indicated 
	4	in children, then that should be made clear in labeling. 
	5		DR. DRAKE:  I am going to put that down.  Would 
	6	you please bring that back up again when we get to
	7	discussing the questions because we are going to get into 
	8	specifics on the labels. 
	9		DR. McGUIRE:  Just give me an opportunity. 
10		DR. DRAKE:  Absolutely.  All you have to do is 
11	raise your hand, pal.
12		Jonathan and Markham, any questions for the panel? 
13		DR. WILKIN:  No. 
14		DR. DRAKE:  I certainly do thank you.  Let's move, 
15	then, to the next section.  Now that the sponsor has heard 
16	all the concerns, maybe you can help elucidate and give us
17	some additional information.  I believe Dr. Todd Plott is 
18	going to present for the sponsor. 
19		One of the advantages of getting all these 
20	questions on the table ahead of time is this gives you a 
21	nice opportunity to respond and address any of these issues. 
22	I invite you to do so.  During the discussion period, I will 
23	also invite you to respond because we do want to hear from 
24	you.  You are kind of at the end here. 
25		DR. PLOTT:  I will try to answer the questions and 

				135 1	give you time for questions after the presentation.
	2		DR. DRAKE:  Great.  Thank you. 
	3		DR. PLOTT:  I am like a shrimp on the grill. 

	4		DR. DRAKE:  I had to think you were probably 
	5	feeling that way.  But I think this is a good opportunity 
	6	for us to exchange information and that is what this is all
	7	about. 
	8		DR. PLOTT:  I agree. 
	9		DR. DRAKE:  So please feel free to answer 
10	questions and address this even if it is not part of your 
11	presentation.
12		DR. PLOTT:  If I could make a comment.  I think 

13	that it is unfortunate that non-dermatologists are not part 
14	of your panel to provide their perspective because, as you 
15	have heard, many of the experts or panelists do not use the 
16	product, so it would not be an experience that is common to
17	them, a rationale that they use in their everyday practice.  
18	They have mentioned other non-dermatology specialties that 
19	may use it more than dermatologists. 
20		It could also be important to get that 
21	perspective, I would suggest.
22		DR. DRAKE:  Just so you will know.  There has been 
23	a little effort to do that.  Dr. Spraker and Dr. Epps and 

24	Dr. Chesney are all three board-certified pediatricians so 
25	at least--but you are absolutely right.  You are an 

			136 1	internist, Lloyd, but you don't practice internal medicine. 
	2		So you are right.  We don't have a practicing 
	3	internal-medicine person or a practicing family-practice.  I 
	4	think it is a very valid counterpoint. 
	5		          Sponsor Presentation 
	6		DR. PLOTT:  Let me introduce myself.  My name is
	7	Todd Plott.  I am the Director of Antiinfectives and 
	8	Dermatology at the Schering-Plough Research Institute. 
	9		[Slide.] 
10		I would like to begin by giving you some facts 
11	about Lotrisone and to first reference where this
12	information comes from because I think it is very important. 
13		What we have done in this presentation is to take 
14	the same database that was presented earlier by a member of 
15	the agency and to use the same database in preparing our 

16	slides.  We have used the package that was mailed to you,
17	the briefing package, in the preparation so that the 

18	information that we are all talking about is the same. 
19	But it is different than the information that Dr. Feldman 
20	has referenced. 

21		[Slide.]
22		So, with that understanding, I will move through 
23	this first slide quite quickly because I think that most of 
24	us agree on tinea infections as being an infection of not 
25	only organisms but this disease also involves an 

			137 1	inflammatory response.
	2		Commonly, within clinical trials, we look at 
	3	erythema, which is redness, and pruritus, which is itching, 
	4	and then scale.  These are the symptoms that are most 
	5	commonly used.  This disease often occurs in adults, but it 
	6	can also occur in children.
	7		[Slide.] 
	8		Lotrisone has been mentioned as a combination 
	9	product of clotrimazole and betamethasone.  It is important 
10	to point out that the potency of the corticosteroid here is 
11	a high-potency product and not a super-potent product as
12	indicated in your package. 
13		It is a product that involves the combination of 
14	two active ingredients that are currently on the market; 
15	one, Lotrimin and the other Diprosone, and that the 
16	rationale for this combination is that you would be able to
17	provide a treatment for the fungal infection which achieving 
18	an early inflammatory clinical response and resolution of 
19	the signs and symptoms. 
20		We have seen that mentioned in other 
21	presentations.
22		[Slide.] 
23		The justification for the combination Lotrisone 

24	Cream was first provided in three clinical studies in tinea 
25	cruris, tinea pedis and tinea corporis.  This is based on 

			138 1	mycologic response and that response of the combination

	2	using the new math that we have been introduced to this 
	3	morning. 
	4		That combination, with the combination, was at 
	5	least as effective as the antifungal alone.  In most cases, 
	6	the combination was statistical more effective than
	7	corticosteroid when we are talking about a mycologic 
	8	response. 
	9		Looking at the early inflammatory efficacy, the 
10	combination product was statistical superior in each one of 
11	these indications to the single-agent antifungal alone.  So
12	this demonstrated the benefit of the combination in the 
13	treatment of tinea infections. 
14		[Slide.] 
15		What is important to point out; it has been 
16	mentioned that there may be treatment failures as a common
17	problem with this particular product.  In our clinical 

18	studies where we know what the diagnosis was and we know 
19	that patients were followed at least as closely as they 

20	could be and treatment compliance was what it is supposed to 
21	be labeled as, the number of patients that experienced
22	treatment failure was twice as many in the Lotrimin in the 
23	single-agent antifungal group and three times that as in the 
24	Diprosone group. 
25		So there is really a lower number of patients who 

				139 1	were discontinued from our clinical trials as treatment
	2	failures in Lotrisone as in its ingredients. 
	3		DR. ROSENBERG:  What were the diagnoses, Todd?  
	4	Who were those patients? 
	5		DR. PLOTT:  These are patients from our clinical 
	6	trials, our three clinical trials combined; tinea pedis
	7	patients, tinea cruris, tinea corporis patients. 
	8		DR. ROSENBERG:  Thank you. 
	9		DR. PLOTT:  And the number of patients studied in 
10	each group.  The studies that were done originally for the 
11	cream had the two components in the arm.  They didn't just

12	pick and choose. 
13		[Slide.] 

14		DR. PLOTT:  Moving to the lotion; now, the lotion 
15	formulation has demonstrated efficacy both mycologically and 
16	with early inflammatory response against the placebo.  In
17	addition to that, the corticosteroid potency has been 
18	demonstrated to be comparable to the cream formulation in 
19	the vasoconstrictor assay. 
20		In conclusion, I would like to point out that 
21	inflammation is really a very important and an integral part
22	of the tinea infections and that the disease is effectively 
23	being treated by the combination product, and we have shown 
24	that in clinical trials. 
25		The cream has established mycologic and early 

			140 1	efficacy response over its individual components in
	2	controlled clinical trials.  The Lotrisone Lotion has shown 
	3	inflammatory, antifungal activity and similar inflammatory 
	4	potency as the cream in clinical trials.  The lotion, 
	5	therefore, should be labeled the same as a cream. 
	6		[Slide.]
	7		I would like to shift gears a little bit now.  I 
	8	have covered the efficacy.  I would like to dwell on the 
	9	safety of Lotrisone Cream in clinical practice and give you 
10	an historical perspective for what the safety has been with 
11	this particular product.
12		I think some advantages of coming from the 
13	sponsor's point of view, this is obviously a product that we 
14	are very interested in and we track it very closely.  We 
15	follow adverse events.  I am notified every time there is an 
16	adverse event.  I get that report on my desk.
17		[Slide.] 
18		This product has been in clinical use for sixteen 
19	years.  Each year, there are 3.25 million patients treated 
20	with Lotrisone, a tremendous number when we talk about 
21	dermatology practice.
22		DR. KILPATRICK:  Excuse me; where was that number 
23	from, for example?  How do you know that 3.25 million 
24	patients are treated each year? 
25		DR. PLOTT:  We know from the sales of product that 

					141 1	we sell.  We know how many tubes go out the door and we
	2	know, on an average, how many patients it takes to use a 
	3	tube.  For example, 1.6 prescriptions will be given to one 
	4	particular patient. 
	5		DR. KILPATRICK:  That is what I was getting at.  
	6	You don't actually have the--
	7		DR. PLOTT:  That is the ratio of prescriptions to 
	8	cases. 
	9		DR. KILPATRICK:  That is an assumption. 
10		DR. PLOTT:  No, sir.  We know how many tubes walk 
11	out the door.
12		DR. KILPATRICK:  I know you know how many tubes 

13	walk out the door, but you don't know--I am a statistician 
14	and I am quibbling.  I appreciate that, but patients are 
15	different from tubes is the point that I am making. 
16		DR. PLOTT:  I am saying that conversion is 1.6.
17		DR. KILPATRICK:  I am saying there is some 
18	variation in that. 
19		DR. PLOTT:  That is an average. 
20		DR. KILPATRICK:  Exactly.  That average may be 
21	inaccurate.  I am just questioning the apparent specificity
22	of your figures. 
23		DR. PLOTT:  That is across the sample of 
24	62 million prescriptions.  So I would say the confidence 
25	intervals are narrowing so that would could make a 

				142 1	generalization.
	2		62 million prescriptions have been written since 
	3	1985 and 315, according to the agency's numbers, and we 
	4	concur with the adverse-event numbers that you have 
	5	presented.  The package that was sent out was a little 
	6	different than the numbers that were presented today but,
	7	generally speaking, these numbers are correct. 
	8		What is important to point out here, I think, is 
	9	that this means that there are eight cases of adverse events 
10	reported in every 1 million patients that have been treated.  
11	The annual number of adverse events reported has declined
12	since the labeling was changed in the early 1990s as well as 
13	the clinical-trial and clinical-use data, more important 
14	than the clinical-trial, supports the use of the product as 
15	safe and effective as it is labeled 
16		DR. ROSEN:  May I interrupt you one second?  315

17	unduplicated adverse events; so that is not a patient who 
18	has two different adverse events or the same patient.  These 
19	are distinct units; this person had this-- 
20		DR. PLOTT:  This number comes from what was 
21	delivered to you in your FDA briefing book.
22		DR. ROSEN:  Would you comment, however, about 

23	unreported adverse events.  Most physicians, that I know, 
24	unless the adverse event is significant in terms of life- 
25	threatening won't take the time to fill out these forms or 

				143 1	won't call the FDA.  In our VA hospital, we can't even get

	2	them to pick up the phone and call the pharmacy service. 
	3		I don't have a number and you don't have a number.  
	4	Nobody has a number but, just in general, could you make a 
	5	generic comment about the possibility that there are adverse 
	6	events including atrophy, failure, worsening, that are not
	7	reported at all, and do you have any handle on that or any 
	8	way to estimate that at all? 
	9		DR. PLOTT:  I think the presentation that was made 
10	previously by the postmarketing group mentioned the 
11	variation and the weaknesses of this particular type of
12	data.  I can't tell you about adverse events that are not 
13	reported.  I prefer to stand on data, what I know. 
14		DR. DRAKE:  I am going to take the Chairman's 
15	prerogative and say please, let's let Dr. Plott finish his 
16	presentation and please save your questions for the end
17	because he deserves an uninterrupted time.  I don't want him 
18	to feel under attack.  I want him to be responsive and have 
19	an opportunity to present his case, and then we will ask 
20	questions that are pertinent once you are done. 
21		Dr. Plott, please continue.
22		DR. PLOTT:  Thank you. Let's go to the next slide.  
23	I think I have covered what I wish to here. 
24		[Slide.] 
25		I would like to point out the current trends in 

			144 1	clinical practice today as of 1999 for is the last full year
	2	that we have data for, which is 82 percent of all Lotrisone 
	3	Cream prescriptions went to patients that were over 12 year 
	4	old which is the appropriate age population. 
	5		For the patients where there were prescriptions 
	6	written under 12 years of age, which is not labeled, the
	7	number of prescriptions is declining.  In fact, in 1999, 
	8	17.9 percent of all Lotrisone prescriptions were for 
	9	children under the age of 12 years old and 1.4 percent, 
10	again, of all Lotrisone prescriptions were for diaper rash.  
11		In 1999, the tracking data suggests that there
12	were just over 600,000 cases of diaper rash treated.  Of all 
13	the diaper rash, 2.9 percent, or 18,000 cases, were treated 
14	with Lotrisone. 
15		[Slide.] 
16		So that you have an idea for the diaper rash
17	picture which I think is the most important disease process 
18	that we are really talking about here today, non-antifungal 
19	treatments were used in 34 percent of cases.  A topical 
20	steroid was given in 8 percent of these cases.  Mycolog, a 
21	product that Dr. Elgart mentioned, a combination product
22	that is only generally available generically, was used in 15 
23	percent of cases.  Lotrisone was used in 3 percent of cases. 
24		I would propose to the committee that the general 
25	guidelines that were discussed early this morning are very 

			145 1	important not only for this product but for other products
	2	as well.  In diaper dermatitis, that is important.  The use 
	3	in diaper dermatitis has declined.  It has declined between 
	4	50 and 60 percent over the last ten years or so. 
	5		[Slide.] 
	6		Much of this decline has been in the under-1-year-
	7	old age group where there has been about a 75 percent 
	8	decline from 1992. 

	9		[Slide.] 
10		Adverse events in the under-12-year-old age group 
11	are certainly a concern for us.  Any use in underage
12	patients is inappropriate.  It appears that these patients 
13	would be more frequently at risk if this product is used in 
14	an inappropriate condition like diaper rash, or if it is 
15	used for an extended period of time, 16 weeks. 
16		The mean treatment period for the patients that
17	were in the briefing book was 16 weeks.  That is four 
18	months.  That is much too long for any patient to be on a 
19	product like this and not to be reevaluated by their 
20	physician. 
21		Physicians recognize the benefit and manage the

22	risk of Lotrisone.  That is probably why there is such use 
23	in this population.  Physicians understand, because they 
24	have been educated.  They know that they can't use this 

25	product for a long duration of time.  They know they should 

			146 1	not be using it in the underage populations.
	2		[Slide.] 
	3		In fact, I would like to point out some very 
	4	important information that was not in your briefing packet 
	5	that probably should have been, and that is the current 
	6	label for Lotrisone.  The package insert and the information
	7	that you have is the older label. 
	8		In May of this year, the label was changed.  It is 
	9	a more prominent label for Lotrisone Cream and we have been 
10	proposing the same labeling for the lotion.  Let me point 
11	out what that label says because, like most physicians, I
12	typically don't read labels. 
13		In two places, the Indication and Use Section, and 
14	in the Pediatric Use Section, it is bolded and in all 
15	capitals, "Not to be used under the age of 12 and not to be 
16	used in diaper dermatitis."  I don't know how more clear it
17	could be; two places, bolded and all capitals on the label. 
18		In fact, if you look at the label, in the Dosage 
19	and Administration Section, it says, "The use of Lotrisone 
20	Cream for longer than four weeks is not recommended."  That 
21	should be a clue; right?  "The Lotrisone Cream should be

22	discontinued of the condition persists after two weeks in 
23	corporis and cruris and after four weeks in tinea pedis.  
24	Lotrisone Cream should not be used with occlusive 
25	dressings."  It says that in the label today. 

			147 1		In the Information to Patients, we are trying to

	2	communicate to people.  "Notify physician if there is no 
	3	improvement in one week in tinea cruris and tinea corporis 
	4	and in two weeks for tinea pedis."  There is a clue; see 

	5	your physician if you are not getting any better in short 
	6	period of time.
	7		"In the groin area, use the medicine for two weeks 
	8	only."  No matter what you have got; two weeks only.  
	9	Schering has an ongoing effort to try to educate all 
10	physicians, especially about the appropriate ages where this 
11	product should be used and the duration of treatment and
12	what the appropriate conditions should be. 
13		We agree with the agency and we support augmenting 
14	our educational efforts to the pediatrician where we believe 
15	that it is going to do the most good in eliminating diaper 
16	dermatitis usage.

17		[Slide.] 
18		Schering supports expediting reports of adverse 
19	events in patients that are under the age of 12-years-old.  

20	That is something we agree with.  That is easy enough to do.  
21		[Slide.]
22		Lotrisone Lotion should be labeled consistent with 
23	the current cream labeling.  The product is safe and 
24	effective when it is used as it is currently being labeled 

25	today.  We believe that that current label needs time to 

				148 1	take effect and see an impact that was just implemented in
	2	May 2000. 
	3		But Schering will continue to reinforce the 
	4	appropriate use of this product as it is labeled. 
	5		Thank you for your listening.  I would be glad to 
	6	answer any questions.
	7		DR. DRAKE:  I am going to recognize Dr. Wilkin 
	8	first since "he da boss." 
	9		Todd, while I am waiting on Jonathan, I just want 
10	to thank you for a presentation that, I think, answered some 
11	questions before they got fired at you.
12		DR. PLOTT:  Good.  Thank you. 
13		DR. DRAKE:  I also want to compliment you because 
14	Dr. Spraker, who doesn't use your product on kids, said that 
15	you guys were responsive to their initiative to you when 
16	they went to see you.  So I think that is also very
17	positive.  I think this is an example where, if we work 
18	together, we can accomplish the goals that we want and that 
19	is the benefit of our patients. 
20		So I want to thank you for the company's efforts 
21	and being responsive to the concerns of the dermatologic and
22	pediatric communities. 
23		DR. PLOTT:  Thank you. 
24		DR. DRAKE:  I think that is positive and I think 
25	your presentation shows it.  One slide you did not have I 

				149 1	wanted to make sure the panel--I was impressed with this--
	2	maybe I was looking down or something, but the linear 
	3	decrease in the use of Lotrisone in those under one year old 
	4	declined 75 percent from 1992.  That is pretty impressive.  
	5	And that was before your new label this May; right? 
	6		DR. PLOTT:  That's right.  I don't think that we
	7	have seen the impact on the decline in prescriptions in this 
	8	age group yet because it has only been implemented since 
	9	May. 
10		DR. DRAKE:  What I want to do now--Dr. Wilkin? 
11		DR. WILKIN:  I would just mention that we prepared
12	the document before the time that Dr. Plott indicates that 
13	they submitted this material about the cream labeling.  So 
14	it is true that was not in here. 
15		DR. DRAKE:  Okay; so that is positive.  Now, let's 
16	have some questions.  Dr. Stern?
17		DR. STERN:  I have a number of questions.  Let me 
18	start with the one that I think is most important.  Would 
19	the company be amenable, rather than to changing the label, 
20	to, in fact, as has been suggested, to put on every box and 
21	every tube the same warning about, "Do not use in persons
22	under 12?" 
23		If we are trying to effect change, that is the way 
24	to effect change and not in the label since we are talking 
25	about 600,000 to a million people or tubes a year, depending 

			150 1	on whose estimates you use of inappropriate utilization.  To
	2	me, a lot of it has to do with risk and benefit.  I think we 
	3	have firmly established that this is an agent that does not 
	4	have huge therapeutic advantages over other agents. 
	5		It is not treating a life-threatening condition 
	6	and, therefore, we have to look at less-than-optimal use,
	7	perhaps, more critically than we would in an agent that, in 
	8	fact, has some unique therapeutic properties.  So when there 
	9	are 600,000 to a million inappropriate uses a year and it 

10	seems everyone agrees that that inappropriate use is pretty 
11	easy to stamp out without much loss of benefit by direct

12	labeling of the product and its container, how does the 
13	company feel about being really proactive and not just doing 
14	labeling but, in fact, labeling the product, per se, the 
15	thing in the mother's or the father's hands? 
16		DR. PLOTT:  My response to that is that just in
17	May have we revised this labeling, as I have indicated, that 
18	we have not see an impact on what that labeling change can 
19	do.  Second is that, while there is inappropriate usage, as 
20	physicians, these physicians feel that they understand the 
21	risk and the benefit of this particular product and they are
22	willing to take that risk because they know of the benefit. 
23		The jeopardy that we put ourselves into in  

24	aggressively labeling this product is that we can get 
25	between the patient and the physician in that relationship. 

			151 1		DR. STERN:  I think that there were data presented
	2	earlier that, in fact, the learned intermediaries who are 
	3	principally prescribing this in the under-12 have a very low 
	4	prevalence of knowledge about the potency of the steroid 
	5	which is actually the issue here. 
	6		So there is an information gap.  I guess, again,
	7	to me, it is risk and benefit.  When you have a product that 
	8	so far I have not heard anything that this is something with 
	9	a unique therapeutic advantage, as opposed to being 
10	effective and safe when used as labeled, and you have a 
11	problem that involves hundreds of thousands to a million
12	persons a year, it seems to me that you want to take direct 
13	steps and not wait and see what the trends will be in two or 
14	three years. 
15		The only loss in doing that is really a loss of 
16	sales.  The gains in doing that is that is how you can

17	substantially--most individuals would believe that that 
18	would be the action most likely to change the use of this 
19	drug because--for all the reasons we have heard all day 
20	today. 

21		So if you can really do something, why not do it? 
22	I understand it is going to cost you 20 percent of your 

23	market.  But it is the 20 percent you are committed to 
24	getting rid of, according to what your label is.  So why not 
25	do it? 

				152 1		DR. PLOTT:  We have really gone further than
	2	simply putting a label or something on the box which is to 

	3	go further to educate the physician.  Writing something on 
	4	the tube may not change the prescribing habits.  It is going 
	5	to be the education of the physician and, in this case, 
	6	specifically, the pediatrician that is going to be
	7	different. 
	8		DR. STERN:  I just had one other comment. 
	9		DR. DRAKE:  Go ahead.  Then I am going to go the 
10	rest of the panel. 
11		DR. STERN:  As you know, or as you may know, I
12	have had some interest in spontaneous adverse-drug-reaction 
13	reporting over the last 25 years or so, or 20 years or so-- 
14		DR. ROSENBERG:  30. 
15		DR. STERN:  No; that's him.  I will say 25 for me.  
16	But, in all seriousness, the whole focus on spontaneous
17	reporting is basically unusual and serious, usually 
18	together.  In looking at the numerators you have, I think 
19	you can only look at them in context. 
20		I guess the context I would ask, because for not 
21	very serious reactions, it is product dependent, usage
22	dependent, age-group dependent and company dependent.  So I 
23	guess I would ask what are the rates per million tubes of 

24	reactions of this degree that are reported for the 
25	comparable two parts of this agent?  How many ADRs did you 

				153 1	have for Lotrimin compared to the number of sales you have
	2	had?  How many have you had for Diprosone over a comparable 
	3	period--not Diproline but Diprosone--so we can get some idea 
	4	about what the signal is in your system for agents that are 
	5	at least both topical and, in fact, are the components? 
	6		Do you have those data?
	7		DR. PLOTT:  I do not have that data here.  I can 

	8	point to what we experienced in our clinical trials which 
	9	was previously presented by a member of the agency.  The 
10	adverse-event profile in the clinical trials was very 

11	comparable and it was low.  But, obviously, we didn't have a
12	million patients in the clinical trial. 
13		We have looked at, some time ago, adverse events 
14	compared to Mycolog which is a similar combination.  Our 

15	adverse-event rate was approximately half of what has been 
16	reported in the early 1990s for Mycolog.  We were not able
17	to get that data updated, however. 
18		DR. DRAKE:  I am going to go to John and then 
19	Wilma. 

20		DR. DiGIOVANNA:  Actually, I have two comments.  I 
21	think they are on the opposite side of the coin.  The first
22	is that I just wanted a point of clarification.  By 
23	labeling, we are really talking about what is in that little 
24	piece of paper in the box that the patients don't get.  We 
25	are not talking about labeling the box or labeling the tube. 

					154 1		I think Fred and I were a little unclear about

	2	that.  It would be of interest, I think, for me to see 
	3	exactly what the tube and the box, the new version of it, 
	4	looks like and whether or not there--and I guess this is 

	5	really Rob's issue again--whether or not there is something 
	6	that can be placed on the label to indicate to the parent.

	7		DR. PLOTT:  I have a copy of the new labeling. 
	8		DR. DiGIOVANNA:  My second point was-- 
	9		DR. DRAKE:  Excuse me.  Can I have the committee's 
10	attention all in one area?  Dr. Stern? 
11		DR. KILPATRICK:  We are being chastised.
12		DR. STERN:  We are number crunchers.  I'm sorry. 
13		DR. DRAKE:  That's all right.  I know you number 
14	crunchers.  I am not going to let you sit together again. 

15		DR. DiGIOVANNA:  So all of this really is the 
16	package insert.  The box and the tube have none of this.

17		The second is that the first point that Todd made, 
18	I think, really struck a cord because it recognized, to me, 
19	that I am extremely biased in this area.  One of the points 
20	I made over lunch is that I probably think that the chair of 
21	my derm department would want to take back my residency
22	certification for board certification if I actually 
23	prescribed this compound because he was one of the people 

24	who was extremely adamant against the use of combination 
25	products. 

			155 1		I think most dermatologists tend to feel that we
	2	treat specifically because we are trained to do that.  I 
	3	really would be interested in hearing the opinions of 
	4	people, if there are such people, who really do favor this 
	5	product because I don't think we have heard that. 
	6		DR. DRAKE:  I think that was Dr. Plott's initial
	7	comment to us, that there is a whole body of experience out 
	8	there that do use this product and like it.  Perhaps, we are 
	9	missing something. 
10		DR. ROSENBERG:  If we are going to have a general 
11	discussion, I would like to take that point of view.
12		DR. DRAKE:  Take it.  And then I am going to call 
13	on Wilma. 
14		DR. ROSENBERG:  I think one of the things that we 
15	just have to recognize, that caught me by surprise but I 

16	have thought about it, is the number of tubes of Lotrisone
17	which are coded on well-baby visit.  Let's stop and think 

18	what has happened.  That baby has been there for a checkup.  
19	That baby has had a visit scheduled.  It has been weighed.  
20	It has been looked at.  It has been put on the growth curve.  
21	The mother has talked about how it is growing.
22		Her own concerns have been answered.  And, on the 
23	way out, "How about this redness on Ginger's bottom?"  This 
24	does not call for a referral to a dermatologist.  It does 

25	not call for a KOH.  It does not call for a new code or an 

			156 1	upcode.  It calls for something that can be given that is
	2	going to be useful. 
	3		The sad thing is there is nothing--the combination 
	4	rules that FDA is constrained by, have kept off the market 
	5	what this pediatrician ought to be able to write for, or to 
	6	suggest, something like Lotrisone/Baby, which would be the
	7	clotrimazole with half percent hydrocortisone. 
	8		It would meet that need.  I have had, personally, 
	9	a lot of experience at the Rx to OTC interface.  It used to 
10	be one was one and one was the other, like night and day.  
11	But, you know, there is night and day but there is dawn and
12	dusk and there is a lot of blurring. 
13		When it come to patients, there are diagnoses, but 
14	then there is, "No, we don't need a diagnosis.  It will 

15	straighten itself out, but in the meantime."  I think we 
16	have got to rethink, as the practice of medicine is
17	changing, so that more conditions are being treated by 
18	people themselves and more conditions are being treated at 
19	the primary-care level. 
20		We have to rethink the kinds of--what the 

21	diagnoses are and move some medical diagnoses towards
22	symptomatic kinds of things and allow the kind of product 
23	that we would have--I would write that prescription a lot if 
24	it were available and I imagine a lot of people would, too. 
25		DR. DRAKE:  I am to do Wilma, and then I have Joe.  

				157 1	I haven't forgotten your question.  When I come to you--

	2	well, in a minute, we are going to really discuss it.  I 
	3	haven't forgotten you. 
	4		DR. BERGFELD:  Bill, I have to agree with you.  I 
	5	think you have said this before this morning and early this 
	6	afternoon.  But I think that our responsibility here today

	7	is to look at a labeling issue on a prescription item that 
	8	is already out there with a request for another vehicle. 
	9		So I am going to direct my questions to that, if 
10	you don't mind.  I think, as I understand it, the lotion has 
11	a better effect on the side of health vasoconstrictive rate;
12	is that correct?  It is not as vasoconstrictive as the 
13	cream? 
14		DR. PLOTT:  In the vasoconstrictor, it was 
15	comparable. 
16		DR. BERGFELD:  Comparable?  I thought the numbers
17	were slightly lower. 
18		DR. PLOTT:  I believe the numbers that were shown 
19	earlier were maybe very minimally, but probably, I think, 

20	not statistically significantly different. 
21		DR. BERGFELD:  Thank you for clearing that up.  So
22	the studies that you presented on the cream and then you 
23	allowed to actually lap over to the lotion demonstrate that 
24	we don't have to repeat all the testing with the lotion as 
25	long as it has some efficacy that is equal as against 

			158 1	placebo.  You did a little bit of an abbreviation of your
	2	study. 
	3		That is the first question.  What we are doing is 
	4	looking at another vehicle which has, perhaps, a little 
	5	different elegance to it and, perhaps, a little different 
	6	patient satisfaction for uses as you described.
	7		The second question, and it is a brief question, 

	8	is I am not understanding why 12 years old was chosen if we 
	9	are talking about children. 
10		DR. PLOTT:  That is what our label limits-- 
11		DR. BERGFELD:  I know what your label limits--but
12	why did you chose 12?  Why not 14 or 15?  If we are talking 
13	skin and we are talking bones, the epiphyses are not closed 
14	until they are out a little older than that, 12.  What is 
15	the basis of that? 
16		DR. PLOTT:  Unfortunately, that decision was
17	probably made sometime before my time.  However, I think 
18	that 12-year-old was probably not selected based on 

19	physiology but rather more classical age limitations. 
20		DR. BERGFELD:  It looks like it just was chosen.   
21	The last thing I would like to say is that I think that you
22	have heard from all of us that we would like, in dealing 

23	with the label, that the label not only appear on the tube 
24	but there be some patient inserts that would be 
25	automatically given by the pharmacist to the purchaser;-- 

			159 1	namely, probably the mother--so that they may have that
	2	information at hand about the adverse events. 
	3		DR. DRAKE:  What I am going to do here in a 

	4	minute, Todd, is let you sit down.  I don't want you 
	5	standing while we are getting into the discussion phase and 
	6	we are tottering on that.
	7		Joe, do you have a question for Dr. Plott, or is 
	8	it a comment? 
	9		DR. McGUIRE:  It is a comment that I would like 
10	for you to address.  There are linked assumptions in this 
11	business.  The first assumption is that if you print it in
12	the PI, they will read.  The second assumption is that, if 

13	they read, they will comprehend.  The third assumption is if 
14	they comprehend, they will change behavior. 
15		DR. DRAKE:  You have been sitting next to Bill 
16	Rosenberg.
17		DR. McGUIRE:  That was not my funny line.  If I 
18	can get the panel serious again.  It seems to me that all of 
19	these assumptions are flawed.  The question of putting 
20	something in bold on the label and on the tube I think is an 
21	important one because very few of my families ever report to
22	me anything about disturbing information in the PI. 
23		So I think information--what is the point?  The 

24	point is that a lot of information is lost in the package 
25	insert.  I think it is paramount to put it on the tube and 

				160 1	on the box.
	2		The second comment, and I will stop, is that I am 
	3	very uncomfortable about using Diprosone or Lotrisone on 
	4	genital or inguinal skin.  I simply don't use those products 
	5	in that location.  I would hope that you would rethink the 

	6	application of the product in whatever age group in genital
	7	or inguinal skin. 
	8		That's it.  Thank you. 
	9		DR. DRAKE:  I want to make sure that anything 
10	else, now, is a question for Dr. Plott and then we will get 
11	into the discussion phase.  Dr. Chesney and then Ted.

12		DR. CHESNEY:  Have you studied Lotrisone in 
13	children under 12 at all?  Have you done any trials using it 
14	in children? 
15		DR. PLOTT:  The answer is that no; we have not 

16	conducted trials in children under 12.  Our clinical trials
17	included children up to age 12.  There is, however, 
18	information in the literature on children younger than 12 
19	and use in children younger than that. 
20		We have summarized that information and that 
21	information has been discussed with the agency.
22		DR. CHESNEY:  I would certainly urge you to do 
23	those studies.  I think it would put you way ahead.  But 
24	just one other comment-- 
25		DR. PLOTT:  Let me comment there because I think 

					161 1	if you do studies in children under 12 but then you say that
	2	you should not use the product in that area, you are really 
	3	in a Catch 22.  How do you say, "Don't use it, but these are 
	4	the studies."  It is a difficult position for a sponsor to 
	5	be in. 
	6		DR. CHESNEY:  That was my next suggestion. 
	7	Parents are extremely sophisticated these days.  They get on 
	8	the web.  They come in office.  They already know 
	9	everything.  In most cases, they know more than we do.  I 
10	would urge not only labeling on the box and on the tube 
11	because, ultimately, they are the best advocate, but I would
12	also urge that you say, number one, this has not been 

13	studied in children under 12 and that is why it is not 
14	recommended-- 
15		DR. PLOTT:  It says that. 

16		DR. DRAKE:  It says that.
17		DR. CHESNEY:  And, number two, what are side 
18	effects, not on the label but, again, a special insert for 
19	parents or on the box.  What are the side effects?  Just to 
20	say there are side effects is a very general term, but if 
21	they knew specifically what it might do, I think they would
22	be very-- 
23		DR. PLOTT:  The side effects are mentioned, and 
24	mentioned in the label.  I would say that that labeling is 
25	in every box that goes out and is available to be read.  I 

				162 1	don't have data on how many patients are going to read tubes
	2	more than they read labels. 
	3		DR. CHESNEY:  Again, I would just like to echo 

	4	what I have heard from so many people.  None of us reads 
	5	labels. 
	6		DR. PLOTT:  Do we read tubes?
	7		DR. CHESNEY:  They are too long.  They are too 
	8	detailed.  I am sure parents don't read the labels. 
	9		DR. DRAKE:  Ted and then--just questions.  And 
10	then Mary. 
11		DR. ROSEN:  I would like to get back to mycology
12	for just one second.  Not seeing many children in the VA 
13	hospital--in our wisdom, they don't serve in the armed 
14	forces, yet--what I have published and what I have seen 
15	personally in adults have been failures not in the common 
16	organisms for pedis, cruris or corporis, which would be T.
17	rubrum, then T. mentag next, but in the animal-acquired 

18	predominantly Microsporum canis.  That is what I wrote about 
19	and that is what I have seen. 
20		My suspicion is that the initial indication, the 
21	initial labeling, was based upon in vitro data showing the

22	clotrimazole by itself is sufficient, in vitro, to handle 
23	Microsporum canis.  But it may be that this combination, in 
24	practice, may be less than optimal. 
25		My suspicion is that, in your initial clinical 

			163 1	trials, the overwhelming number of patients were T. rubrum,
	2	maybe some T. mentag and very few Microsporum canis which is 
	3	where I have seen failure. 
	4		Do you have any plans to address that or can you 
	5	address that or can you tell me if the company is at all 
	6	concerned about that?
	7		DR. PLOTT:  Specifically regarding Microsporum 
	8	canis, the agency correctly points out in our lotion 
	9	clinical trials, there were no patients treated with the 
10	lotion active ingredient with Microsporum canis.  It was 
11	unfortunate, however, there were two patients in the lotion
12	clinical trials that did have that organism. 
13		They happened to be randomized to placebo, of 
14	course.  So there is no experience with Microsporum canis.  
15	However, it is something that is more common in tinea 
16	corporis than tinea pedis which was studied and tinea cruris
17	which was studied.  So we didn't study the disease entity.  
18	We were not asked to do that where it might be more commonly 
19	found. 
20		That is the data that exists.  I think that we are 
21	in discussions about the remainder of the labeling and other
22	issues regarding the lotion.  That is likely to be one of 

23	the discussions that we have with the agency. 
24		DR. DRAKE:  Mary? 
25		DR. SPRAKER:  Todd, I think we all here in this 

			164 1	room in agreement that we would like to see the drug used as
	2	it is labeled.  You indicated, in your presentation, that 

	3	your company would like to reinforce among physicians the 
	4	use as labeled.  What concrete suggestions do you have of 
	5	reinforcing that, or educating primary-care physicians 
	6	further?

	7		DR. PLOTT:  We believe that the type of usage that 
	8	we are most concerned about is in the area of the 
	9	pediatrician where there are several things.  It is under 
10	age of 12 where we are not labeled.  It is diaper dermatitis 
11	or diaper rash where we clearly state, "Do not use this."
12		The pediatrician is the most likely person to see 
13	that patient.  For example, the well-baby visit kind of 
14	thing.  We think that education of the pediatrician probably 
15	needs to be augmented.  Ways that we can do that are in our 
16	ongoing efforts where we are trying to educate physicians,

17	all physicians, not to use it, but specifically target 
18	pediatricians, by our sales reps by also in direct-mail 
19	campaigns, focusing on physicians that are writing this 
20	prescription and communicating with them. 
21		DR. DRAKE:  That is really good.  I am glad you
22	asked that because I think it helps us get our attention 

23	back on--it helps us when we address the labeling.  But our 
24	duty, our job, here today is to talk about labeling and get 
25	to the questions which I am going to do as soon as Bill 

				165 1	Rosenberg asks his last question.
	2		DR. ROSENBERG:  I want to ask about labeling.  
	3	Have you had an opportunity to look at the computer- 
	4	generated printed little story that is being generated at 
	5	the various major drug stores when this is now being 
	6	dispensed.  My experience is pharmacists tell patients more
	7	than I want them to know about the side effects of the 
	8	prescriptions I write. 
	9		Have they picked up on it?  Is that coming out 
10	now, and so forth? 
11		DR. PLOTT:  That type of information that is
12	handed out should be picked up out of the current labeling 
13	with the bolded print as we have indicated here.  
14	Unfortunately, that is variable depending on the pharmacy 
15	where you get your prescription filled.  But we would expect 
16	that that is becoming more common where that is done.
17		DR. ROSENBERG:  It's getting to be that there are 
18	not that many drugstores.  They are all big chains. 

19		DR. DRAKE:  I am going to ask if there are 
20	questions from people who have not spoken. 
21		Eduardo?
22		DR. TSCHEN:  No. 

23		DR. DRAKE:  John? 
24		DR. DiGIOVANNA:  No. 
25		DR. DRAKE:  Fred? 

					166 1		DR. MILLER:  No.

	2		DR. DRAKE:  Bob? 
	3		DR. JORDAN:  No. 

	4		DR. DRAKE:  Wilma? 
	5		DR. BERGFELD:  No.  Any more?  Rob? 
	6		DR. STERN:  No.
	7		DR. DRAKE:  Jim? 
	8		DR. KILPATRICK:  I simply want to compliment you 
	9	in keeping your cool under all of this barrage. 
10		DR. PLOTT:  Thank you. 
11		DR. DRAKE:  That was very nice.  I agree.
12		Bill? 
13		DR. ROSENBERG:  Nothing. 
14		DR. DRAKE:  Joe? 
15		DR. McGUIRE:  Nothing. 
16		DR. DRAKE:  Joel.
17		DR. MINDEL:  No. 
18		DR. DRAKE:  Jon?  No questions? 
19		I would invite you to stay because we may call 
20	upon you as we get into the discussion.  So thank you, Dr. 
21	Plott.  You did a great job.  We appreciate it.  I agree

22	with your comment about being a little skewered, but we like 
23	you anyway and we appreciate all Schering does for us for 
24	our patients.  So we are just trying to help you here to 
25	make the labeling a little better, or maybe reign it in just 

			167 1	a touch, as they would say in the South; "Let's just reign
	2	it in just a touch." 
	3		      Questions for the Committee 
	4		DR. DRAKE:  We are going to go to the questions 
	5	right now.  We have six questions to answer and we have 
	6	about forty-five minutes to do it in.  So I think, with your
	7	permission, we could start unless somebody feels the need to 
	8	discuss something. 
	9		Joe, I haven't forgotten you.  Before we start the 
10	questions, I am going to bring up your question you asked a 
11	long time ago because we are on the discussion phase.  I
12	think, before we hit Question 1, I would like Joe to restate 
13	his question because he wanted a sense from this committee.  
14	What was that again, Joe? 
15		DR. McGUIRE:  I just wanted to get some idea from 
16	the committee, realizing that it is a very special group of
17	physicians and does not represent other specialties and 
18	generalists.  But I would like to know if any of the 
19	committee use the product. 
20		DR. STERN:  I hate to say it, but I do; usually 

21	just the samples but, for example, when someone has got tons
22	of lichenification in an intertriginous area, I will give 
23	them enough for three or five days if I have some samples.  
24	If someone has LSC right around the ankle and has tinea 
25	pedis, I will use it down there.  I will give them a choice 

				168 1	between using two things or this, usually as a starter.
	2		I often do combinations empirically by writing two 
	3	scripts, but if I have some Lotrisone samples, I admit, I am 
	4	a sinner. 
	5		DR. McGUIRE:  I wasn't putting that litmus test on 
	6	it.  I just wanted to get some idea of what the frequency of
	7	use is. 
	8		DR. DRAKE:  Does anybody use it very often?  I 
	9	think we are not the primary users. 
10		DR. ROSENBERG:  I ought to be pointed out that I 
11	think at least a couple of years ago, Lotrisone outsold all
12	other topical antifungals combined--all other topical 
13	antifungals combined, a few years.  Todd is nodding.  So 
14	there really is a need for a product like this. 

15		DR. DRAKE:  Todd, what did you say? 
16		DR. PLOTT:  That is still true that it outsells
17	all other single-agent antifungals combined. 
18		DR. DRAKE:  So people like it.  I am going to say 
19	this, too.  I am a big believer in treating what you know 
20	you are treating.  I think you ought to have a diagnosis 

21	before you treat.  I can just see my old chief.  I see my
22	chief shaking his head at me a little bit.  But, in most 
23	instances, I like that. 
24		On the other hand, there is something else you 
25	taught me and that is that patients are empirically smart 

			169 1	and if something works, they use it.  And, if they don't
	2	like it, they let their doctors know and it doesn't get used 
	3	again.  So the fact that so many people are using this tells 
	4	us something, I think, in one form or another. 
	5		I don't have any magic answers.  I would ask you 

	6	to keep that balance as we go through the discussion.  There
	7	is a balance.  There are a lot of people who like this drug 
	8	and I don't think all the doctors and all the patients who 
	9	use it are dummies.  There are a lot of people using it for 
10	some reason. 
11		On the other hand, we have a set of different
12	concerns so I want to keep a balance as we move through the 
13	questions.  And our task here is not to approve or 

14	disapprove this product.  Our task here is to look 
15	specifically at the labeling to see if there are ways we can 
16	refine it and help to address our concerns, or the concerns
17	that I have heard raised by this committee that, frankly, as 
18	I gather, shared by the company, also. 
19		So, with that, I think what we will do is we will 
20	start the questions and try to go through them.  Question 1 
21	is what would be appropriate indications for Lotrisone
22	Lotion. 
23		Jon, may I ask you a question?  Does the committee 
24	have an option of saying the same as the Lotrisone Cream or 
25	the same as the Lotrisone Cream with these changes?  Would 

					170 1	you give us some guidance on this?
	2		DR. WILKIN:  Sure.  At the end, we are going to 
	3	ask the question, everything that you recommend for the 
	4	lotion, does that also apply to the cream. 
	5		DR. DRAKE:  That is what I wanted to ask you. 
	6		DR. WILKIN:  What would be the appropriate
	7	indication, in part, is to address the aspect of, I think, 
	8	how you have described it as symptomatic inflammatory tinea.  
	9	I think you have addressed this in part, but, of course, you 
10	can rethink that now that you are thinking about a-- 
11		DR. DRAKE:  Do we want symptomatic inflammatory
12	tinea. 
13		DR. WILKIN:  Do you want those sorts of things.  

14	Currently, you will find that the labeling is for tinea and 
15	then it describes the different areas, pedis cruris, pedis 
16	corporis.  The question is is there a need to modify that. 
17	In this case, it would be somewhat restrictive, restricting 
18	it to symptomatic inflammatory tinea, or any other phrase. 
19		But the question is not meant to be limited to 

20	that.  It is based on all that you have heard, you have 
21	recommendations, in general, related to the indication.
22		DR. DRAKE:  So why don't we start with some 
23	generic comments then.  I think, from our previous 

24	discussion on the first question, what would be appropriate 
25	indications for Lotrisone Lotion, clearly inflammatory 

			171 1	symptomatic tinea.
	2		DR. STERN:  But the other thing that came up this 
	3	morning is that in virtually all of the studies that have 
	4	been done of these combinations agents, it is in first five 
	5	or eight days.  So the question is should the indication be 
	6	for symptomatic inflammatory tinea for up to eight days use

	7	with the recommendation that, for continued usage, just a 
	8	monotherapy be continued. 
	9		Like I say, I use this agent actually often for 
10	three or four or five days in exactly that setting and am 
11	very comfortable with it.  But I don't use it for 30 days
12	because there is no advantage for the last 22 of them. 

13		DR. DRAKE:  What I am going to do, then--I have 
14	the same trouble with Question No. 1 that I did last time.  
15	It is very broad.  I think if we go through some of the 

16	other questions and then come back to Question 1, we will
17	have about answered it. 
18		So I would like to go to Question 2 for the 
19	moment.  If you look at Question 2, it is--possible wording 
20	for including in labeling may be--let's get the committee to 
21	respond to this--"minimally inflamed tinea pedis, corporis

22	and cruris not requiring a corticosteroid component may be 
23	effectively treated with a topical antifungal drug product 
24	not containing corticosteroid." 
25		DR. WILKIN:  Dr. Drake, actually that was 

					172 1	misnumbered.  It should have been 1a because it is really a
	2	subset of the first one. 
	3		DR. DRAKE:  That is what I was thinking, it is a 
	4	subset.  This is not Question 2.  This is 1a. 
	5		DR. STERN:  That is an awful long way to say, 
	6	"Don't use it in minimally inflamed."  I think short,
	7	positive statements; "Use it here."  "Don't use it there." 
	8		DR. WILKIN:  Again, the wording that you looked at 
	9	earlier and suggested symptomatic inflammatory.  We are 
10	revisiting the same issue in a different-- 
11		DR. DRAKE:  I think the answer here should be
12	symptomatic inflammatory.  That is what we spent a lot of 

13	time getting a general policy for and the committee was 
14	unanimous on that.  Do I hear any dissension from the 

15	committee, clearly for 1 and 1a, at least in part, to just 
16	have us say symptomatic inflammatory tinea.
17		DR. DiGIOVANNA:  It is not dissent.  It is maybe 
18	clarification. 
19		DR. DRAKE:  Fine.  Clarify. 
20		DR. DiGIOVANNA:  We had a discussion earlier as to 
21	whether the symptoms were from the tinea, whether the
22	symptoms were from the inflammation because lots of times 
23	there is some itching or what not. 
24		Do we want to say, "In tinea with inflammation 
25	sufficient to cause symptoms?" 

					173 1		DR. DRAKE:  I would like to have you take that
	2	under advisement, Jon, you and your group because that is 
	3	wordsmithing.  Would you just take that under advisement as 
	4	to how you think it is the most clearly presented.  The 
	5	concept is the same.  It is just wordsmithing. 
	6		Does somebody else have anything?  Wilma?
	7		DR. BERGFELD:  I think it might be appropriate to 
	8	consider, in addition to this, and that is what Rob had 
	9	suggested, is q question of limiting it in time of therapy, 
10	as to one week, two weeks or whatever would be decided upon. 
11		The second part of that is what we speak of for

12	the lotion should be true of the cream because they are so 
13	similar in their biological activity. 
14		DR. WILKIN:  If I could respond to that.  The 

15	database we have is for the time period as listed in the 
16	dosage and administration section of the labeling.  If we
17	somehow cut that shorter, we really would not have a 
18	database to know what the antifungal efficacy would be in 
19	that circumstance. 

20		DR. DRAKE:  You have already got your timelines in 
21	there, basically.
22		DR. WILKIN:  Yes. 
23		DR. DRAKE:  With those represented to us and, 
24	unless we see a need for change, then we probably should not 
25	mess with that because that means we have to go back and 

			174 1	redress the whole issue.
	2		DR. MINDEL:  With regard to the cream and the 
	3	lotion having the same labeling or the argument for it, if 

	4	you look in the PDR for different manufacturers' products 
	5	containing the same ingredients, the labeling, especially 
	6	the older labeling, may be quite dissimilar.  So you don't
	7	have to have the same--that argument has limited merit. 

	8		I think, in this case, I want to emphasize that.  
	9	The other is that we can all learn from our mistakes.  So it 
10	doesn't have to be a very cogent argument that the lotion 
11	and the cream have to be labeled the same way.  I would like
12	to argue against--who is going to know?  The patients?  Is 
13	the patient going to pick up the cream labeling and the 
14	lotion labeling and say-- 
15		DR. DRAKE:  Jon, I would like you to address that. 
16		DR. WILKIN:  I think maybe a more specific version
17	or question would be actually two parts; give us what you 

18	think would be really good labeling for the lotion which is 
19	the product under consideration and then we would like your 
20	sense as to whether you think those would also be useful 
21	items to incorporate into the labeling for the cream.
22		Now, in this particular circumstance, we are 
23	talking about what we think of as a line extension.  A line 
24	extension is a different vehicle for the same active 
25	ingredient or ingredients, the same concentration, the same 

				175 1	population, the same duration of usage, so are many relevant
	2	similarities between the two products and what they are 
	3	intended for.  Labeling probably ought to have some relevant 
	4	similarities also. 
	5		DR. DRAKE:  Would the audiovisual folks turn up 

	6	these lights?  Every time I look to my left, it is dreary. 
	7	That sort of signifies nap time.  Maybe I am just getting 

	8	old and not seeing good, but I would like some light on the 
	9	subject.  I would like to see Dr. Epps, for example.  I 
10	would like to see Ted. 
11		Thank you.  I feel like I have gone out in the

12	sunshine.  Sorry to digress with such a mundane thing.  
13	John, question? 
14		DR. FELDMAN:  I have a question for Dr. Wilkin.  
15	If we would recommend specific labeling for the lotion, 

16	would you then ask that the cream labeling be changed to
17	meet that?  Is that my understanding of what you were 
18	saying? 
19		DR. WILKIN:  Yes. 

20		DR. DRAKE:  Basically, for everybody, so you will 
21	know, we are sort of answering--at this moment, we are sort
22	of beginning to answer Question 5.  So we have kind of 
23	wandered into Question 5 here.  But that is okay because if 
24	we answer it now, we don't have to do it later. 
25		DR. WILKIN:  The answer was yes. 

					176 1		DR. DRAKE:  The answer was yes.  So let's go ahead
	2	and answer Question 5.  Or do you want to get the labeling 

	3	for the lotion first and then decide if that is appropriate 
	4	for the cream. 
	5		DR. DiGIOVANNA:  I have a suggestion on the 
	6	labeling.  I think the labeling is great.  It just needs to
	7	be moved to the outside.  I think we have all agreed to 
	8	that, outside the package. 
	9		DR. ELGART:  We are taught early in our 
10	dermatology careers that the base makes a difference, that 
11	steroid ointments are more potent than steroid creams. 

12	Steroid creams are more potent than steroid lotions.  We 
13	know here that the vasoconstrictor assay shows that this 

14	product is not as significant a steroid in a lotion form as 
15	it is in a cream form. 
16		DR. DRAKE:  No, wait.  They are equivalent.
17		DR. ELGART:  They are equivalent, but the numbers 
18	are a little less--not statistically equivalent, I know. 
19		DR. DRAKE:  They were basically equivalent. 
20		DR. ELGART:  So I think that we may want to make 
21	some change for the vehicle.
22		DR. DRAKE:  I think the only way we would want to 
23	make--I appreciate your concern but, in fact, the major 

24	issue there would be the vasoconstriction and it is the 
25	same.  So I think we would have to have some justification 

					177 1	for making them totally different.  I don't mind considering
	2	that but I would like to have a justification that would 
	3	make sense. 
	4		Wilma? 
	5		DR. BERGFELD:  I would like to put on the table 
	6	the consideration of a restriction in the labeling for use
	7	in the groin and, possibly, the face. 
	8		DR. DRAKE:  Keep that thought because I don't want 
	9	to get on the restrictions just yet.  I want to look at-- 

10		DR. BERGFELD:  No; it would be in the labeling. 
11		DR. DRAKE:  So you want it in all the labeling. 
12	Okay; I'm with you.  Sorry.  I got it. 
13		I made whole list as you guys were talking about 
14	restrictions.  I can tell you here is what came down the 

15	list was diaper dermatitis, groin dermatitis, breast, belly,  
16	face and underocclusion.  So, I made a list in the earlier
17	questions and comments.  So it would quite a list of 
18	exclusions if you want to get into exclusions. 
19		Jon, how do you feel about exclusions versus 
20	inclusions? 
21		DR. WILKIN:  Of course, one of the exclusions that
22	you have mentioned, the groin, seems incompatible with a 
23	tinea cruris. 
24		DR. DRAKE:  That's right.  But I am just saying 

25	this is a list that had fallen out on the table.  Isn't it 

			178 1	true that if people would use these products according to

	2	the defined indications, which is five days--two weeks; 
	3	right?  Two weeks in the groin?  Does that give anybody 

	4	indigestion?  If people would live with the labeling as it 
	5	is, could you use this product for two weeks in the groin 
	6	without getting into trouble?  Why don't I just get a straw
	7	poll on that? 
	8		DR. McGUIRE:  It is presumptuous for us to think 
	9	that we can limit the duration of treatment.  I don't know 

10	where patients get the drug but, if they start with a potent 
11	steroid and they like it, they get it.  And they get it from
12	me once. 
13		DR. DRAKE:  That is true with every drug, Joe.  I 
14	don't know a single drug out here that is not abused.  I 

15	can't tell you one single dermatologic drug that is not 
16	abused by people, by doctors particularly and by patients

17	secondarily.  Joe, Merve Elgart said it very nicely, what is 
18	in the medicine cabinet. 
19		As a matter of fact, half the stuff is used for 

20	people that it wasn't even given to.  It was given to your 
21	cousin or your brother or your next-door-neighbor or your
22	brother-in-law.  We can't control behavior totally. 
23		What we are dealing with today is what is in the 
24	label.  The label says two weeks in the groin.  If that is 
25	acceptable, we have covered that issue.  Is there anybody 

					179 1	who doesn't think that two weeks is acceptable in the groin? 
	2		Let's get a straw poll on that.  I would like a 
	3	straw poll because the labeling right now for groin 
	4	restricts it to two weeks, no longer. 
	5		DR. DiGIOVANNA:  May I ask a question? 
	6		DR. DRAKE:  John.
	7		DR. DiGIOVANNA:  Were there not studies done that 
	8	documented it was safe and effective and that has been 
	9	declared. 
10		DR. DRAKE:  It has already been done.  It has 

11	already been documented that it is safe and effective.
12		DR. DiGIOVANNA:  So you are asking us if our 
13	subjective feelings are different than that. 
14		DR. DRAKE:  No; I guess I am asking if anybody 

15	feels strongly enough to ask the agency to look for a change 
16	in labeling for something that has already been proven safe
17	and effective for that time period.  In other words, we are 
18	trying to make a labeling better.  We can't enforce human 

19	behavior. 
20		What I am asking the committee to be is pragmatic.  
21	Please step away from your gestalt and your own personal

22	prejudices and look at this in an objective manner.  Is 
23	there anybody at this table who says a patient is going to 
24	be harmed by using this, is it safe and effective in the 

25	groin for two weeks?  If there is, then you need to tell me 

			180 1	and you need to defend it, but the data suggest that it is
	2	for that time period. 
	3		Joel? 
	4		DR. MINDEL:  The labeling, as it now exists, has a 
	5	lot of messages in it.  One of them says, "Clinical 
	6	improvement with relief of erythema and pruritus usually
	7	occurs within three to five days of treatment."  You could 

	8	pick and choose the four weeks, the eight weeks here, the 
	9	this and that, but this is a combination drug.  One of the 
10	ingredients is only--I haven't heard an argument that it 
11	really is needed or useful or helpful beyond, say, a period
12	of eight days, probably five days is maximum. 
13		That, I think, bothers a lot of people sitting 
14	here at the table.  I would like to see the labeling 
15	improved so that it restricts the length of the use of the 
16	drug.

17		DR. DRAKE:  So you could stretch the length of the 
18	use of the drug? 
19		DR. MINDEL:  Limit. 
20		DR. DRAKE:  But it is limited to two weeks.  So, 
21	Joel, what I want us to keep in mind is the labeling already
22	says it is limited to two weeks.  I think modifying the 
23	labeling is one thing.  Changing the parameters for efficacy 
24	is another.  This drug has already been proved safe and 
25	efficacious for that period of time. 

				181 1		I think the stronger issue here is defining what
	2	it is used for, perhaps.  But I hate for us to go into this 
	3	trying to change the safety and efficacy things because I 
	4	think Dr. Wilkin, in his opening statement, says the company 
	5	already has a letter that it is proven safe and effective 
	6	for the time parameters as outlined in the previous studies.
	7		That is not our charge today.  We may feel that 
	8	way, but that is not our charge. 
	9		DR. CHESNEY:  I was just going to add to that that 
10	I don't think you can change that without doing the studies 
11	that demonstrate it.
12		DR. DRAKE:  That's right.  And that is not our 
13	task today. 
14		Bob? 
15		DR. JORDAN:  it took me a while to find the two 
16	weeks but it is in here.  I just wonder if, as a precaution,
17	this could be bolded. 
18		DR. DRAKE:  Dr. Plott, just a suggestion for 
19	future reference; it might have been very helpful for this 
20	committee if you had had a blown-up diagram of the current 
21	labeling for every committee member so we would know how the
22	drug is currently labeled.  You can see we are grappling 
23	with trying to find it.  Just a suggestion, if this comes up 
24	again.  I may not be here but please-- 
25		DR. STERN:  I think there are two issues.  One is 

			182 1	what is the right labeling and the second is what is the
	2	right way to get the message across so that, in fact, there 
	3	will be a substantially higher compliance with the labeling 
	4	between information to the learned intermediaries and to the 
	5	consumers. 
	6		So I think the labeling is not so much the issue

	7	as how should those rules be made apparent and operational 
	8	in terms of the entire gestalt of education, packaging, et 
	9	cetera, et cetera. 
10		DR. DRAKE:  I have a suggestion how I am going to 
11	proceed, then, as chairman because we could get bogged down
12	in this forever.  The opinions are all over the place.  I 
13	want to have us vote on each question as defined to us by 
14	the agency because these are the questions they wanted 
15	answered. 
16		And then, following that, if we have additional

17	suggestions and comments or guidance things that we could 
18	propose to them, I would like us to do that also.  Would 
19	that be satisfactory, Dr. Wilkin, to you guys, because you 
20	always take into account what we say. 
21		So let us address your questions as requested and
22	then we shall add any additional suggestions and 
23	recommendations that haven't already been offered.  
24	Reasonable?  Okay. 

25		I think Question 1 has been answered by the policy 

				183 1	discussion we had early on.  Question 2, I am going to ask
	2	you--1a: thank you, Wilma--remember Question 2 has been 
	3	changed to 1a.  The thing I am going to ask you to vote on 
	4	is this wording acceptable to you.  Forget the second 
	5	paragraph there.  I want to talk about just, "Minimally 

	6	inflamed tinea pedis, corporis and cruris not requiring a
	7	corticosteroid component may be effectively treated with a 
	8	topical antifungal drug product not containing 
	9	corticosteroid." 
10		Yes; question, Joe? 
11		DR. McGUIRE:  I think the thought is good.  The
12	sentence needs a lot of surgery.  It just sort of tumbles 
13	over itself. 
14		DR. DRAKE:  It is awkward, isn't it?  It is an 
15	awkward sentence; yes. 
16		DR. WILKIN:  Actually, I thought you had just

17	addressed this.  This was where we got the response of 
18	symptomatic inflammatory and then Dr. DiGiovanna gave a 
19	rearrangement of those words-- 
20		DR. DRAKE:  And I said we were going to let you 
21	wordsmith it.
22		DR. WILKIN:  And we are going to-- 

23		DR. DRAKE:  Thank you, because I already said does 
24	the committee approve it and everybody did.  Thank you, Jon.  
25	Let's go to Question	3.  Question 3 is, "Should Microsporum 

			184 1	canis be deleted from the list of dematophytes for which
	2	Lotrisone Lotion is indicated pending phase IV studies to 
	3	demonstrate clinical efficacy in the treatment of M. canis?" 
	4		Comments?  Let me just ask a question.  How many 

	5	of you say yes.  The vote would be yes versus no.  How many 
	6	of you want to vote yes on this?
	7		DR. BERGFELD:  Is it in the list of the--is it 
	8	there? 
	9		DR. JORDAN:  It is here.  I can see Microsporum 
10	canis. 
11		DR. DRAKE:  It is already in there.  Bob, thank
12	you for having that in front of us.  That is very helpful. 
13		DR. JORDAN:  I have really got to magnify to see 
14	it. 
15		DR. DRAKE:  That is why I suggested to Todd that 
16	the next time you give us a big thing.  But it is there.  It
17	is already in there as an inclusion; right--that is 
18	indicated for the treatment of M. canis.  Our job here, 

19	today, is do we want to keep it in there or do we want to 
20	delete it. 
21		The question from the agency is do we want to
22	delete it from the list of dermatophytes for which Lotrisone 
23	Lotion is indicated, pending phase IV studies.  Other 
24	comments or questions? 
25		All in favor?  Anybody who wants to vote yes to 

				185 1	delete M. canis, pending phase IV, please raise your hand. 
	2		[Show of hands.] 
	3		DR. DRAKE:  Eight.  It passes. 
	4		DR. ROSEN:  Lynn, can I make a comment about that? 
	5		DR. DRAKE:  Yes. 
	6		DR. ROSEN:  Remember that you are already
	7	concerned about the labeling and the assumptions that 
	8	physicians will read the label, understand the label and act 
	9	appropriately.  I would suggest to the voting panel that you 
10	consider something about labeling, "Caution should be used 
11	in those dermatophyte infections suspected to be acquired

12	from animals," because I have a feeling that some of the 
13	prescribing physicians wouldn't know the difference between 
14	Microsporum canis and Superman. 
15		This may not mean much to them.  They must 
16	understand that this is animal-acquired fungus somewhere in
17	common language, somewhere in the labeling, not "Don't do 
18	it," but, "Caution." 

19		DR. DRAKE:  That is a suggestion for the agency to 
20	take under advisement please. 
21		I am going to move to Question 4.  "Is the
22	labeling for pediatric use of Lotrisone Lotion as proposed 
23	by the sponsor sufficient?"  That, and correct me if I am 

24	wrong, says basically it should not be used for dermatitis 
25	and it should not be used in those under age 12.  That is 

			186 1	the current labeling; is that correct?   It says, "Should
	2	not be used for diaper dermatitis or under age 12." 
	3		Is that sufficient?  Let's ask that.  Or, the next 
	4	part of the question, "Should the label be further 
	5	strengthened; i.e., via alternative language, additional 
	6	statements in the Warnings or Contraindication Section and
	7	placement of warnings on the product tube, itself?" 
	8		That is a big one.  Fred? 
	9		DR. JORDAN:  Actually, I am just going to be 
10	reiterating, I think, what has already been said but when we 
11	talk about an educational process and you are going to reach
12	physicians, so many people slip through the cracks.  It is 
13	impossible to have an ongoing campaign where you truly get 
14	everyone. 
15		New physicians come on board.  People are not 
16	there when the process takes place.  People don't read the
17	literature that comes through.  The one thing that we have 
18	gotten from this is that this is not approved for pediatric 
19	patients and it should not be used in children under the age 
20	of 12.  We have heard that plea, I think, from the expert 
21	panel.
22		The only place it is really going to have any 

23	effect is on the tube, itself, "Not to be used in children."  
24	And then parents will see it and they will certainly bring 
25	it to the attention of the physician. 

				187 1		DR. DRAKE:  We have certainly heard that around
	2	the table today.  other comments? 
	3		DR. McGUIRE:  I would include box. 
	4		DR. DRAKE:  A black box? 
	5		DR. McGUIRE:  No.  On the box and the tube. 
	6		DR. DRAKE:  Oh; on the box and on the tube.  I am

	7	certainly hearing a consensus.  Maybe I could kind of take 
	8	this backwards.  Can we take the last part of this question 
	9	first? 
10		DR. STERN:  Why don't we have a motion. 
11		DR. DRAKE:  Please.
12		DR. STERN:  I move that we recommend to the FDA 
13	that it be clearly indicated on the container and the tube 
14	or bottle that use under age 12 and for diaper dermatitis 
15	are contraindicated in lay terms. 
16		DR. DRAKE:  Is there a second to that motion?
17		[Second.] 
18		DR. DRAKE:  Is there discussion on that motion?  
19	Bill? 
20		DR. ROSENBERG:  Perhaps an amendment that could 
21	say, "See Lotrisone/Baby for such use."
22		DR. DRAKE:  Is there a second to that amendment?  
23	No? 
24		DR. KING:  Part of why you don't speak up is you 

25	try to get the sense of it.  My sense is, having worked with 

			188 1	the federal government for a long time, that regulations

	2	have the force of law.  When you deal with law, you deal 
	3	with lawyers, having recent experience. 
	4		So what you are really talking about is if a 
	5	pediatrician writes a prescription for this, inadvertently 
	6	or whatever, then they are going to be held to standard
	7	practice and sued.  So, in a contrary observation, I have 
	8	noticed that when we deal with research people from China 
	9	and all around the world, in our laboratory, when we have 

10	skill and crossbones on there, they don't read, but they can 
11	see that and they know exactly that is poison.
12		So I guess my question is how can you get across 
13	the information in a visual way not depending upon English 
14	as a primary language.  If you have an X through there--I 

15	was trying to draw a diagram of what a diaper would look 
16	like and put an X through it but I couldn't quite get there.
17		It seems to me that the question is how are you 
18	going to get that because, in our experience, creams get 

19	handed around from mother, father, across the back door, 
20	shared.  So I think if it is not on the tube, itself, 
21	without a skull and crossbones on the chemical thing, you
22	are going to just pass it around anyway.  Nobody is going to 
23	read that label.  That is just wasted. 
24		DR. DRAKE:  Lloyd, you have brought up two 
25	separate points, both which are important.  One is that 

				189 1	words are inadequate; you need a picture.
	2		DR. KING:  Absolutely; highway signs. 
	3		DR. DRAKE:  The second thing you brought up that 
	4	is equally important is on our zeal here today to try to 
	5	make this language sterner, even Mary Spraker, our pediatric 
	6	dermatologist--what is the matter?
	7		DR. STERN:  Sterner? 
	8		DR. DRAKE:  Excuse me; no pun intended.  My 
	9	meetings are never boring, Rob.  You have to say that.  You 
10	guys haven't been taking a nap down there today. 
11		I want to go back to Mary Spraker's comment.  Even
12	in the best of times, knowing the best of information, when 
13	it is your eight-month-old son screaming because he is 
14	miserable, you may, in fact, decide that, in this particular 
15	instance, for a day or two, it is appropriate and useful in 
16	this particular situation.
17		We, as physicians, have always had the ability to 
18	use something if, in our best judgment, we thought it was 
19	appropriate.  What my question is is do we want to be 
20	absolute in this and fix it so that nobody can ever use this 
21	for any reason and take that decision-making power away from
22	the physician or do we want to try to word this in a softer 
23	manner. 
24		When I was writing guidelines of care for 
25	dermatology, we tried to write it so that we gave the best 

				190 1	recommendations and advice we could give, but we tried never
	2	to restrict the physician's ability to make an independent 

	3	decision about what is best for their patient based upon a 
	4	government regulation. 
	5		Now, if somebody's life is at stake, then we may 
	6	want to be that absolute.  On the other hand, I think we
	7	want to be very careful, as we set this policy today, that 
	8	we don't restrict a physician's ability to make an 
	9	independent decision regarding their patient and what is in 
10	their patient's best interest. 
11		There is a difference between education and
12	mandated forbiddance. 
13		DR. KILPATRICK:  Madame Chair, we are not setting 
14	policy. 
15		DR. DRAKE:  We are if we vote this. 
16		DR. STERN:  The company has already, in the
17	Lotrisone Cream, actually said it better and, in fact, it 
18	was on the slides as well, "Not to be used under the age of 

19	12 and not to be used in diaper dermatitis."  Plain English.  
20	Bold type. 
21		In fact, my original question is--
22		DR. DRAKE:  I hate it when you are right. 

23		DR. STERN:  So, therefore, all of the legal 
24	implications are already here because this is the official 
25	document.  Everything else is window dressing, as I 

			191 1	understand it with the FDA.
	2		DR. DRAKE:  But, does this mean anybody who uses 
	3	it goes to jail? 
	4		DR. KILPATRICK:  Madame chair, Rob is not only 
	5	right but he is also stern. 
	6		DR. CHESNEY:  I think there is a difference
	7	between contraindicated and should not be used.  
	8	Contraindicated suggests fear and damage.  Although we have 
	9	evidence for that, I think the vast majority of the time, 

10	there is no side effect of this.  So I think "Should not be 
11	used" is good, but I still would think about the caveat,
12	"Because it has not been studied in children." 
13		We use a lot of drugs in pediatrics, as you all 
14	know.  We have to talk to the parents and say, "This is not 
15	indicated but it is only because it hasn't been studied.  
16	And these are my reasons for thinking that this is a drug
17	that we should use anyway." 
18		DR. DRAKE:  That is a very nice way of softening 
19	it so that it still leaves that independent choice to the 
20	physician and yet tells them not to do it.  I would like to 
21	ask, from the other pediatricians in the room, what is your
22	reaction to that? 
23		Dr. Epps? 
24		DR. EPPS:  I agree.  Most of the drugs in the PDR 
25	haven't been tested, necessarily, in kids under 12.  But we 

			192 1	use them, and it is my understanding from the rules, that if
	2	it is approved and, of course, there is compassionate use 

	3	and reasons and indications to use it in children and in 
	4	other situations.  So those are instances when it occurs. 
	5		DR. DRAKE:  Dr. Spraker? 
	6		DR. SPRAKER:  I have been sitting here thinking
	7	about the pediatrician who induces striae and then goes to 
	8	court.  I was thinking about that actually before Lloyd 
	9	mentioned it.  It seems to me that we don't want that kind 
10	of difficulty.  That is what Schering is talking about.  
11	They don't want to be in the middle between the physician
12	and the indication. 

13		But I was wondering if we could say, "Not intended 
14	for use in diaper dermatitis." 
15		DR. EPPS:  "Not recommended." 
16		DR. SPRAKER:  And because of those reasons.  It
17	already says, "Do not."  I understand that. 
18		DR. STERN:  This label without the actions to 

19	protect it is exactly what puts the physician in danger.  
20	Here we have all agreed that here is a piece of information 
21	that the members of the committee were not aware of, let

22	alone the practicing pediatrician, that protects Schering 
23	from suit. 
24		They have told us, as a learned intermediaries, 
25	not to do it.  So the way to protect the physicians, once 

			193 1	something like this is in the label, is to make sure there
	2	is every level of protection so that an unintended use is 
	3	less likely to occur. 
	4		As long as this is here, anything that we don't do 
	5	to get information to every level along the use chain is, in 
	6	fact, putting every pediatrician with greater risk.  This is
	7	basically liability proof from a company's point of view and 
	8	a slam dunk from a lawyer's point of view with the kind of 

	9	information system as has been pointed out by my much older 
10	colleague that is unlikely to be translated into changes in 
11	behavior.
12		DR. DRAKE:  Can I do something for just a moment 
13	because we have drifted from the motion.  We can come back 
14	to discuss the changes in the wording but the motion, as I 
15	understand it, is to take whatever wording we end up with 
16	and add it to the tube and the box.
17		Can we vote on that and get that out of the way 
18	and then go back to wordsmithing again?  Is everybody in 

19	this room in favor of putting whatever wording is finalized 
20	by the agency on the box and the tube.  I would like you to 
21	vote yea or nay on that.
22		How many are in favor of putting said language on 
23	the box and tube? 
24		[Show of hands.] 
25		DR. KILPATRICK:  Madame Chair, I am a literalist.  

				194 1	We would have to have a very large tube to put all this
	2	wording on.  So, amended, I agree with the sense of this 
	3	wording, but not this wording. 
	4		DR. DRAKE:  I think you have got a valid point.  I 
	5	can't believe where I am on this.  I called for the vote.  
	6	It is already voted and passed, so your comments--
	7		DR. KILPATRICK:  Will be considered. 
	8		DR. STERN:  We just said appropriate warning. 

	9		DR. DRAKE:  So it still can be done.  Jim, the 
10	motion has passed.  The motion was appropriate wording, 
11	whatever we end up with, so the agency can then finesse that
12	down so that it does fit on the box.  The sense of the 

13	committee, and the motion of the committee, is that a 
14	warning be put in the box and on the tube of some sort. 

15		Does that satisfy the agency?  Are you guys okay 
16	with that?
17		DR. WILKIN:  Yes. 
18		DR. DRAKE:  I am sorry we were not more specific.  
19	Your comment is good.  It should have just come in a little 
20	earlier because it is valid.  I am certain Todd is over 

21	there dying, thinking, "Oh; my gosh, I have got to put
22	twenty-five things on the tube."  And you can't.  But I 
23	think you can work with that if that is where the agency 
24	goes. 
25		Remember, we are only advisory to the agency.  

				195 1	They may make a different decision altogether.
	2		DR. PLOTT:  I was just going to say, we don't mind 
	3	making a bigger tube. 
	4		DR. DRAKE:  True marketing over there. 
	5		I want to go back--I guess it is sufficient, since 
	6	some of us want to weaken it--I didn't really want to weaken
	7	it.  I just wanted to add a softening such as Dr. Chesney's 
	8	suggestion. 
	9		DR. EPPS:  The other issue is it is a class 2 

10	steroid.  So if you want to use a steroid, use something 
11	else.  Don't use it.  I think that is what the company is
12	saying, "Not to be used under the age of 12 and not in 

13	diaper dermatitis."  If you want to use a steroid, don't use 
14	a class 2 steroid there.  Use something else. 
15		DR. DRAKE:  That is a positive suggestion, but 
16	that doesn't really address the label.  You can't say on the
17	label, "Use something else."  No company is going to go for 
18	that.  "We want you to use another product." 
19		DR. BERGFELD:  Hearing the concerns of everyone, 
20	in the PDR information, package information, under the 
21	discussion of the corticosteroid, is it appropriate, or is

22	it possible, to place there that it is a class 2 steroid? 
23		DR. WILKIN:  The idea of describing it as a 
24	class 2 steroid implies that we have some evidence from a 
25	vasoconstrictor study in which we have bracketed the 

			196 1	vasoconstrictor response by that of known potency
	2	preparations.  It hasn't been bracketed, is the key. 
	3		DR. BERGFELD:  I would suggest that, if it was 

	4	possible to do and, again, something to take back to the 
	5	agency, that, under the discussion that is paragraphed on 
	6	the second side of this first page, it might be helpful to
	7	those who would read it to know what class of steroid they 
	8	actually have. 
	9		DR. ROSENBERG:  I have a lot of patients if they 
10	read that would say they want a class 1 steroid. 
11		DR. DRAKE:  Dr. Wilkin, I want to go back to Dr.
12	Chesney's comment.  I tell you, I am still concerned.  I 
13	know the company is very happy with saying this is 

14	absolutely don't use it because you will die, but there are 
15	a lot of physicians out there using it and, in some 
16	instances, it is in their best judgement for the benefit of
17	their patient. 
18		Is there anybody on this committee besides me and 
19	Dr. Chesney who would like to add this language here that 
20	was actually in our packet where it says the reason we are 
21	adding this language is because it has not been established
22	in well-controlled clinical studies in the pediatric 
23	patients under 12. 
24		Would anybody besides the two of us like to see 
25	that language added? 

				197 1		DR. DiGIOVANNA:  I see two issues.  I see that
	2	addresses the fact that it hasn't been studied and it 
	3	softens it, which I feel fine about.  It doesn't really 
	4	address the side-effects issue as much. 
	5		Part of the reason that I feel you are making an 
	6	appropriate point is because we are not hearing, as Todd
	7	mentioned, from the people who like this drug. 
	8		DR. DRAKE:  That's right. 
	9		DR. DiGIOVANNA:  I clearly have been biased 
10	against it.  So I am wondering if we are not missing 
11	information from people who do use it and use it
12	appropriately.  I think what you are suggesting is that, by 
13	us coming out and recommending a blanket condemnation of it 
14	in that age group, we are really condemning it and not 
15	hearing from the people who appear to think it is effective. 
16		DR. McGUIRE:  John, the other side of what you
17	just said is that many of us sitting around the table have 
18	seen the children who have been treated inappropriately and 
19	who have atrophy, who have ecchymoses.  We see them after 

20	they are three months, six months, twelve months into 
21	treatment.
22		They got their drug somehow.  We don't know how.  
23	But we are the ones who have seen the bad effects. 
24		DR. DiGIOVANNA:  I have also seen those, and that 
25	was the first part of my question, that saying that it 

				198 1	hasn't been studied doesn't address the side effects.
	2		DR. DRAKE:  Those people are already in violation 
	3	of the label.  If you used it for two weeks, like it said, 
	4	it might not happen. 
	5		DR. McGUIRE:  No.  I was addressing John's issue 
	6	with the bias of this group.  I think we are biased for a
	7	reason. 
	8		DR. DiGIOVANNA:  I agree.  I am biased for the 
	9	same reason. 
10		DR. McGUIRE:  We are the ones to whom those 
11	children come.
12		DR. DiGIOVANNA:  But that doesn't change the fact 
13	that we are not hearing from the people who apparently have 
14	a different bias and we are apparently recommending labeling 
15	that prevents them from doing what they apparently consider 
16	effective.  And I don't know how many of those 62 million

17	prescriptions were used by pediatricians who felt that it 
18	was very, very effective and were basically coming up with 
19	an imprimatur that says, "This can't be used in that age 
20	group." 
21		And we are not saying because it hasn't been
22	studied.  We are merely saying it can't be done. 

23		DR. DRAKE:  It can't be used.  Dr. Chesney?  And I 
24	am going to ask Lloyd to comment. 
25		DR. CHESNEY:  I had wanted to make this point 

			199 1	before that if there were any way to put an insert, and
	2	somebody else had mentioned that, in the box for the parents 
	3	explaining what the side effects are--one thing that I 

	4	haven't heard any of you mention but that I have seen 
	5	personally, being in infectious disease, is babies, when 
	6	they have severe Herpes simplex infections of the diaper
	7	area can look like a diaper dermatitis. 

	8		This is obviously strongly contraindicated.  So, 
	9	as an advocate for infants, I would like to put as much 

10	information out there as possible for pediatricians who I 
11	think you are all quite correct, don't know what category of
12	steroid this is and don't always know about these side 

13	effects, although most of us understand the scarring. 
14		But if there were something, again, to put in the 
15	box or on the label, "Hasn't been studied; side effects that 
16	should be considered are the following."  I also appreciate
17	your comment about the physician who has to go to court 
18	because of striae, but something to say that infant skin is 
19	different from adult skin and we don't know all the side 

20	effects.  Some other wording that also explains what the 
21	side effects are is going to be educational for everyone.
22		DR. KILPATRICK:  Lynn, may I add to that? 
23		DR. DRAKE:  Yes, Jim. 
24		DR. KILPATRICK:  Coming back to the label as 

25	distributed, information for patients, unfortunately, comes 

			200 1	at a break of a page, but there is a list of seven items
	2	there that I think are very important.  I would like to see 
	3	those incorporated with Dr. Chesney's suggestion and put in 
	4	quite separately because, at the moment now, they disappear. 
	5		I know I am off the question. 
	6		DR. DRAKE:  No; that's fine.  That is an important
	7	comment.  Lloyd, and then Dr. Epps.  Fred, you have been 

	8	awful quiet.  And Bob.  You guys have been quiet down at 
	9	this end.  Maybe I am not looking this way.  Holler at me, 
10	would you? 
11		DR. KING:  My comment is quite simple.  Having sat
12	on the academic side and also on the VA side, it becomes 

13	clear to me that, in the land of the rare, the rare is 
14	common.  What we are not hearing is what the pediatricians 
15	and other people, internists, are doing.  So if you have a 
16	product that is beneficial to a lot of people and then, all
17	of a sudden, you are restricted to that one population which 
18	is likely to see you, it then gets to be population 
19	genetics. 
20		My mother almost died twice in Vanderbilt Hospital 
21	because she was allergic to aspirin.  One could conclude
22	that aspirin should be banned because it causes reaction.  
23	We have people allergic to water.  You can take this ad 
24	nauseam but it seems to me the fundamental problem, as I see 
25	it, is what is the greater good and what is a physician to 

			201 1	do when facing this kind of process.
	2		If we are going to make a decision on the group of 
	3	physicians who use this a lot more than dermatologists, I 
	4	think we have to have some input.  And then, the reverse of 
	5	that is that if we are going to make these kinds of things, 
	6	they really do have the force of law, whether you say so or
	7	not, because, in the State of Tennessee, whatever it says on 
	8	the PDR and the insert is actually what the lawyers look up, 
	9	and they sue you for injecting a triamcinolone, et cetera, 
10	et cetera, because it is written there. 
11		So I think putting it on the label and let the
12	mothers and fathers decide even if they can't read English 
13	would be a best solution.  Short of that, putting something 
14	on the tube where you don't have to read English at all and 
15	have somebody else look at it is the best solution as far as 
16	I can see.
17		DR. DRAKE:  Dr. Epps? 
18		DR. EPPS:  Briefly.  Certainly, we are not hearing 
19	both sides, necessarily.  I do see some of the ineffective 
20	cases.  I guess it is hard to do clinical trials and 
21	controlled studies when people are using it on something
22	that is not diagnosed.  There are a lot of people who use it 
23	and they don't necessarily have a diagnosis so it is kind of 
24	difficult to sort that out when another drug or something 

25	else would take care of it just as easily, I guess, whether 

				202 1	it is fungal or dermatitis or whatever.
	2		DR. DRAKE:  Fred? 
	3		DR. MILLER:  This is just a point of information.  
	4	How costly is this preparation, when we talk about cost 
	5	effectiveness? 
	6		DR. STERN:  Correct me if I am wrong, it is about,
	7	average wholesale price is $1.50 or so a gram in a 30-gram 

	8	tube.  $45.00 average wholesale price for this 30-gram tube 
	9	plus or minus $6.00.  Is that about right?  So, it ain't 
10	cheap. 
11		DR. MILLER:  So I think this is the point.  Again,
12	if we don't need the preparation, if, indeed, it is not a 
13	tinea and would respond to a lesser steroid, what should be 
14	used as we are trying to economize. 
15		DR. DRAKE:  I am going to go back to my question 
16	to the committee.  Do you want to let stand this absolute,

17	"Thou shalt not ever use this ever in any circumstances," or 
18	do you want to put a modifier on there, "Because it hasn't 
19	been studied." 
20		I guess I am still very concerned.  I am with 
21	Lloyd.  I apologize.  As a committee chair, I am supposed to
22	be just a facilitator and I promise I am going to quit after 
23	this, but I would like a sense of the committee as to where 
24	you are on this issue because it may be just three of us.  
25	It may be just Lloyd, Dr. Chesney and myself. 

				203 1		But I would like to have you give a sense of the
	2	committee to the agency where you would like them to explore 
	3	a method of not sending people to the courtroom or being 
	4	forbidden to use something when they might see a particular 
	5	need for it at a particular time for a short period of time. 
	6		DR. STERN:  So you are asking also about the
	7	label, then, which already has that very direct-- 
	8		DR. DRAKE:  It already has it but I think we 
	9	certainly have the right to suggest that, perhaps, a 
10	modifier be put on there because I don't like to see any 
11	drug ever restricted from a physician being able to use it
12	in any patient. 
13		DR. KILPATRICK:  Madame Chair, we are in a 
14	"Catch 22" because we don't want to recommend a weakening of 
15	the language. 
16		DR. DRAKE:  But this is an absolute forbiddance. 
17	I don't think at any time a drug should be absolutely 
18	forbidden to a physician to use if they think that 
19	particular drug is going to help that particular patient.  
20	We have been protected by law on that for years. 
21		I quit.  I am not going to say any more.  John? 

22	And then I am going to call for a sense of the committee so 
23	we don't dwell on this anymore. 
24		DR. DiGIOVANNA:  I tend to agree with you and I 
25	wonder where this wording came from.  I get the 

			204 1	understanding that this is a new wording and that it is a
	2	response--I get the sense it is a response from Schering to 
	3	the adverse events that have been reported. 
	4		I agree with you that, while I don't personally 
	5	use the drug, I don't personally like the drug, I think it 
	6	is abused, clearly, there are physicians who find it useful. 
	7	I agree with you, we should carefully think if we are going 
	8	to be extreme in what is said and going to put our force of 
	9	rule or force of numbers behind it, then we should feel, 
10	certainly, that it is true. 
11		While I think that, in most situations, it should
12	not be used in children, I think, depending on how sternly 
13	that is stated is something that should be given 
14	consideration.  Now that I have said that tersely, Dr. 
15	Stern. 
16		DR. JORDAN:  It is interesting.  If you read the
17	indications and usage of this product, it is for the topical 
18	treatment of the following dermal infections; tinea pedis, 
19	cruris, tinea corporis due to organisms.  Of course, this is 
20	probably not where it is used. 
21		But then, again, I think maybe to solve this
22	problem, they do have verbiage here that the lotion is "not 
23	recommended" rather than "not used."  Maybe that would be 

24	more appropriate for the physicians that use it for some of 
25	these other purposes. 

				205 1		DR. DRAKE:  I would like to ask the sense of the
	2	committee because we could debate this all night.  Please; I 
	3	am going to ask the sense of the committee on the question.  
	4	I am not going to word it because I want to leave it up to 
	5	the FDA to take the sense of the committee, but I would like 
	6	to know the members of this committee who feel that,
	7	perhaps, there shouldn't be an absolute ban but some thought 
	8	be given into providing language that allows a physician to 
	9	use it in certain instances only but without--I am going to 
10	ask for the sense of the committee now. 
11		I want to know who is in favor of putting some

12	kind of a modifier on there so that somebody is not in 
13	trouble if they choose to use this product.  Please raise 
14	your hand if you are in favor of that. 
15		[Show of hands.] 
16		DR. DRAKE:  So you have got ten.  John, so that at
17	least helps you.  I think the committee does not think this 
18	product should not be widely used or even routinely used on 
19	the pediatric population, and certainly diaper dermatitis.  
20	However, none of us want to put it in such hard language 

21	that no physician would feel comfortable using it if they
22	thought there was a need or be beneficial to one of their 
23	patients. 
24		DR. MINDEL:  Not none. 
25		DR. DRAKE:  Yes? 

					206 1		DR. MINDEL:  I voted against.
	2		DR. DRAKE:  How many are against it?  I'm sorry.  
	3	I forgot.  How many are against? 
	4		[Show of hands.] 
	5		DR. DRAKE:  Two are against.  So it is 10 to 2. 

	6		DR. BERGFELD:  Can we have some discussion of why
	7	we are against? 
	8		DR. DRAKE:  Yes. 
	9		DR. BERGFELD:  The reason I voted against it is 
10	because, under question 3, I have here-- 
11		DR. DRAKE:  But those are not the questions we are
12	using today, Wilma.  Those were old in the book.  They are 
13	not the questions we are using. 
14		DR. BERGFELD:  The point of fact is the sponsor 
15	proposed a pediatric-use labeling.  Is that not the same? 
16		DR. DRAKE:  There were some documents that were

17	removed from the packets earlier and then Wilma got a late 
18	packet.  That is a late packet and that is not what is 

19	before us.  The questions that are before us are on this 
20	document right here. 
21		Is there anything anybody else wants to add to
22	Question 4?  I am going to go to Question 5.  I am trying to 
23	get us done halfway on time here. 
24		Question 5 is, "Should the pediatric section, in 
25	addition to other labeling sections for Lotrisone Cream be 

				207 1	changed to mirror labeling for Lotrisone Lotion as discussed
	2	in the above question?"  That is sort of what we discussed 
	3	earlier, should there be any difference. 
	4		I would like the committee to vote on this.  If 
	5	there is discussion, fine.  If not, I would entertain a 
	6	motion.
	7		DR. ROSENBERG:  Make them the same. 
	8		DR. DRAKE:  Is that seconded? 
	9		[Second.] 
10		DR. DRAKE:  All in favor, please raise your hands. 
11		[Show of hands.]
12		DR. DRAKE:  Bingo. 
13		Question 6, "Does the committee have 
14	recommendations regarding additional ways," now this is 
15	where you can get into some information that you have been 
16	on the table a lot for the committee.  We have about ten
17	minutes before break.  "Does the committee have 
18	recommendations regarding additional ways to address the use 
19	of products containing superpotent topical corticosteroids 
20	in children and infants?" 
21		Jon?
22		DR. WILKIN:  If we could amend that to instead of 
23	saying "superpotent," just, "at the higher end." 
24		DR. DRAKE:  Okay; saying, "higher-end topical 
25	corticosteroids."  Now is the time for you guys to give all 

			208 1	your very good ideas that we have heard here.
	2		DR. ROSENBERG:  I make a motion that the agency 
	3	consider a baby product with half percent hydrocortisone in 
	4	it. 
	5		DR. DRAKE:  Just a second, Bill.  May I ask a 
	6	point of order.  Is it up to the agency to consider it or is
	7	it up to a company to present it to the agency? 
	8		DR. WILKIN:  Well, you know, if a sponsor presents 
	9	us anything, we will consider it.  I think he is encouraging 
10	a sponsor to consider-- 
11		DR. ROSENBERG:  It is sort of like "Field of
12	Dreams."  If you approve it, the companies will come, I 
13	think. 
14		DR. WILKIN:  I will say to that, we will promise 
15	to consider it. 
16		DR. PLOTT:  I think that the clinical-trial data
17	has to support the rationale for using a combination 
18	product.  Historically, I have personally been involved with 
19	another combination product which did not come to the market 
20	because it could not meet that justification. 
21		I think the problem with having a lower potency
22	topical steroid probably has something to do with being able 
23	to meet the requirements of a combination product, not that 
24	the utility would not be appreciated, simply it does not 
25	meet the hurdle that is necessary. 

			209 1		DR. DRAKE:  Then, Bill, that makes your motion
	2	appropriate because what we are hearing from Todd is that 
	3	even if they wanted to, there are rules in place that would 
	4	preclude that.  So, do you want to make a motion that the 
	5	agency consider some new rules or additional rules.  I see 
	6	Jon is reaching for the mike.
	7		DR. WILKIN:  I am not sure exactly what Dr. 
	8	Plott's product seemed, in their minds, to fail to meet some 
	9	sort of endpoint.  I would say that when we think about 
10	antifungal corticosteroid combination products, we are 
11	really looking for the antiinflammatory aspect.  The sponsor
12	can select the time from phase II trials where they think 

13	they are going to have the greatest delta, and they can end 
14	up powering it to where they--if there is an effect, I think 
15	they can achieve that effect. 
16		DR. DRAKE:  Bill?
17		DR. ROSENBERG:  I don't want to preempt this, but 
18	I think we are really talking realistically.  Let's back up.  
19	The word you used earlier, Jonathan, I forget what it was 

20	but it was very good.  Let's back up on the entry-level 
21	criteria for the study.  Let's envision the real world
22	settings in which these products are used which are in 

23	primary-care settings, often as, by the way, where we don't 
24	need to upgrade and add cost and so forth, "Do you think 
25	this might be a ringworm?  What should we do?" 

			210 1		Let's do a study with those kinds of patients, not
	2	in dermatologists' offices.  Let's do it in offices where 
	3	they have no CLIA certificate and where they don't do a KOH, 
	4	and let's let the doctors put these different armed, coded 
	5	products on those kinds of walk-in patients and see how the 
	6	combination, the lesser combination, would do as compared to
	7	a plain Lotrisone. 
	8		I bet it would do a lot better because I bet 
	9	80 percent are not fungus of the ones who get it.  But these 
10	are the ones that the doctors who are seeing these patients, 
11	and appropriately seeing these patients.  This is the way
12	the system should work. 
13		If these doctors think this may be a fungus, and 
14	would take part in this kind of a trial, I think you could 
15	do it with data and you could show that, perhaps, the 

16	combination has utility and efficacy over anyone of the
17	single agents. 
18		DR. WILKIN:  If I could respond to that.  I think 
19	it is a philosophical approach to what is the kind of 
20	information one wants from the phase III trials.  I would 
21	argue that if you can differentiate the patient, if you can

22	actually figure out what is the cause of the redness and the 
23	scale, that you actually have a better database. 
24		If it turns out that the product would work for 
25	both a tinea and also for an eczematous condition that 

				211 1	doesn't have tinea, then I think it would be from a much
	2	more informed position that the physician who would choose 
	3	to use this without doing the KOH and the culture, they 
	4	would have the certainty that it would work in both 
	5	circumstances. 
	6		DR. DRAKE:  We have five minutes left.  I want to
	7	make sure we get everything in that we want to, so, please, 
	8	for the panel, try to keep your suggestions concise.  I see 
	9	Dr. Chesney, John, Joe and Mary.  Mary, is yours pertinent 
10	for right at the moment? 
11		DR. SPRAKER:  Any time.
12		DR. DRAKE:  Dr. Chesney, John, Joe and Mary. 
13		DR. CHESNEY:  Just a comment.  I don't know if you 
14	are all aware that the NIH has funded eight to ten pediatric 
15	pharmacokinetic research units across the country now, and 
16	they are in fact, right now, looking at an antifungal
17	Fortinia.  They are requiring a mycological diagnosis and 
18	coming up with some very, very interesting information. 
19		So the mechanism is there for doing these studies 
20	in children.  You don't even have to go to primary-care 
21	offices.  These are very sophisticated pediatric
22	pharmacokineticists and physicians who are totally set up to 
23	do these studies now. 
24		DR. DRAKE:  John? 
25		DR. DiGIOVANNA:  I would respectfully like to 

			212 1	disagree with Dr. Rosenberg, for the first time, in that I
	2	believe it was Senator Moynihan who coined the phrase, 
	3	something about the dumbing down of medicine.  I think that 
	4	the fact that we have come to a point where there are people 
	5	who are using less sophisticated, less accurate, techniques 
	6	for larger percentages of the population doesn't necessarily
	7	empower us to go ahead and try to develop less active, less 
	8	dangerous, medications to fit that need. 
	9		I think that if we had a medication that was 

10	really great for all diseases, maybe we would all have to 
11	find another specialty and that would be fine.  But I do
12	think that, while if a medication is useful, it should be 
13	available, I don't know that the best course is to go and 

14	try to find medications which are effective when the best, 
15	most sophisticated techniques we have are simply on 
16	available or not useful.
17		DR. DRAKE:  Joe? 
18		DR. McGUIRE:  Two brief ones.  First, I am sure 
19	the sponsor is already planning to put out a "Dear Doctor" 
20	letter that would contain the changes that you now have in 
21	the product information sheet.  Unfortunately, I think that
22	is going to have to go to all pediatricians, which is a big 
23	mailing. 

24		The second item, which is something that I believe 
25	the agency has to think about, is that we have left out a 

				213 1	very large part of the population which is the geriatric
	2	group who have pruritus of the scrotum, pruritus of the 
	3	anus, pruritus of the vulva.  They get this product and they 
	4	use it over and over again. 
	5		I hardly ever use class 1 or class 2 steroids in 
	6	older people, whatever "older" means.  I will talk to Rob
	7	later.  But they get very atrophic very, very quickly. 
	8		DR. DRAKE:  I think that is a wonderful comment, 
	9	Joe.  Thank you for bringing us back to what we are supposed 
10	to be doing and that is giving suggestions to the agency. 
11		Mary?
12		DR. SPRAKER:  Would the committee like to 
13	recommend to FDA that the sponsor be asked to present a 
14	specific plan to the agency regarding how to further educate 
15	pediatricians about the problems associated with 
16	inappropriate Lotrisone use?
17		DR. DRAKE:  How does the committee feel about 
18	that?  Would you like to have the sponsor present a formal 
19	plan to the agency?  Let's get a sense of the committee.  

20	How many would like to do that, raise your hand. 
21		[Show of hands.]
22		DR. DRAKE:  That is sort of like voting for 
23	Motherhood and Apple Pie.  Todd, I don't think that is too 
24	restrictive. 
25		DR. BERGFELD:  I think that it is too limited, 

					214 1	just to pediatricians.  I mean, if you looked at the
	2	statistics, the family-practice docs and the internists were 
	3	really the high users.  So I think that has to be a very 
	4	large program of education.  Pediatricians could be focused 
	5	because we are dealing with wee ones and we are all 
	6	sympathetic to that, but there is a larger population at
	7	risk. 
	8		DR. KILPATRICK:  Madame Chairman, may I add to 
	9	that also. 
10		DR. DRAKE:  Yes. 
11		DR. KILPATRICK:  On the handout that we were given
12	by the agency, there is a suggestion for postmarketing 
13	surveillance.  It may be that the two could be combined in 
14	some way so we know who is doing what. 
15		DR. DRAKE:  That is a very good suggestion.  Jim, 
16	you just earned your keep today.
17		DR. KILPATRICK:  I earned my $33.00. 
18		DR. DRAKE:  You did.  That is a very good 
19	suggestion.  I like that a lot. 
20		John? 
21		DR. DiGIOVANNA:  There is a little bit of a
22	conflicting statement here.  If you are going to label that 
23	it shouldn't be used at all in children under 12, why would 
24	Schering want to have it sent at all to pediatricians. 
25		DR. DRAKE:  We have just suggested that labeling 

			215 1	be modified just a tad.
	2		DR. McGUIRE:  Because that is a group whose 
	3	practice is going to be modified the most, and they need to 
	4	know. 
	5		DR. DRAKE:  Would the committee like to have the 
	6	FDA report back to us in some future meeting about what
	7	Schering is doing to address these concerns?  No?  Okay.  
	8	Oh; yes?  How many would like to have a follow up on this:  
	9	Raise your hand. 
10		[Show of hands.] 
11		DR. KILPATRICK:  By E-mail.
12		DR. DRAKE:  By E-mail.  We would like to have 

13	something, Dr. Wilkin.  The committee would love to learn 
14	what Schering has got in mind to further this educational 
15	program. 
16		I have one suggestion.  I think that the

17	information that has been presented here today, particularly 
18	by Dr. La Grenade, I think that kind of stuff is really 
19	interesting.  I think the whole thing should be presented.  
20	I would certainly encourage anybody at this table, or the 

21	FDA, themselves, or Schering, to think about getting this
22	written up so that it appears in multiple journals. 
23		People still look at their journals so I would 
24	strongly think about publishing it in journals in different 
25	capacities. 

			216 1		I am going to do one last thing.  I am going to
	2	ask each member of the committee what ideas they might have 
	3	plus I am going to go back and hit you guys.  Give me your 

	4	best idea for the committee. 
	5		Eduardo; what is the best idea you have got to 
	6	make this better?
	7		DR. TSCHEN:  I think there are two things; the 
	8	information in the package and in the tube as well as the 

	9	education to the physicians who are going to be prescribing 
10	it.  I think the drug rep is a big source of information to 
11	most of the clinicians.  I think it is an incredibly good

12	source of information for most of the clinicians who are 
13	practicing in this field. 

14		DR. DRAKE:  John? 
15		DR. DiGIOVANNA:  I think one point that has been 
16	made and I think would be very useful with respect to
17	Question 6 is including information about the specific known 
18	adverse events in a way that is clear for people using it 

19	and the parents of infants using it so that they are aware 
20	of the differences in the risks in children and adults with 
21	respect to the adverse events which have been observed,
22	mainly atrophy and striae. 

23		DR. DRAKE:  Fred? 
24		DR. MILLER:  I would just echo what they said but, 
25	again, I would say that I don't think that the educational 

				217 1	process can reach everyone.  I just think there are too many
	2	lacunae and people will slip through.  So it needs to be, 
	3	again, the label on the tube. 
	4		DR. DRAKE:  Bob? 
	5		DR. JORDAN:  I agree with labeling the tube and 
	6	the box, particularly when it comes to the pediatric group. 
	7	But I think one point maybe the sponsor should understand, 

	8	we are all not very comfortable with the strength of this 
	9	corticosteroid in this product. 
10		I would like to see something, at least some 
11	statement, as to the strength of this.
12		DR. DRAKE:  And the side effects from it. 
13		Yes? 
14		DR. BERGFELD:  I have only a brief addition.  In 
15	the product information piece, as one reads through it, for 
16	the division of the component active ingredients, I am not

17	hit by anything that I should be particularly worried about.  
18	As stated, in dermatology, we are very worried about skin 

19	atrophy and striae.  In some way, I would like that brought 
20	out in this piece as well as in the patient information. 
21		DR. DRAKE:  Dr. Chesney?
22		DR. CHESNEY:  Pediatricians need to be educated 
23	but please be sure to include family practitioners in any 
24	"Dear John" letter because they also treat many, many 
25	children. 

				218 1		DR. DRAKE:  And internists, because they take care
	2	of the elderly, the geriatrics. 
	3		Rob? 
	4		DR. STERN:  Nothing to add. 
	5		DR. DRAKE:  What?  Jim. 
	6		DR. KILPATRICK:  Some of you may not realize, but

	7	the FDA does not pay for overtime.  I have earned my keep 
	8	today, so I have no other comments. 
	9		DR. DRAKE:  Bill? 
10		DR. ROSENBERG:  I have a recommendation for the 
11	Chair.  I know that the Chair spent her year on Capitol Hill
12	on the Senate side with Bob Dole, but I think adoption of 
13	the House policy of allowing members to come back and talk 

14	into the microphone under special orders when everybody else 
15	has gone home would be useful.  That would help some of us. 
16		DR. DRAKE:  When everybody else has gone home?

17		DR. ROSENBERG:  Yes; that is my suggestion. 
18		DR. DRAKE:  I have instituted this policy of 

19	really forcing all the members to talk because, sometimes, 
20	one or two members talk and nobody else does.  But I have 
21	tried to force everybody to talk.  We have been a little bit
22	restricted on time, but I agree with you.  I think these 
23	committees have so many good ideas. 
24		Joe? 
25		DR. McGUIRE:  Thanks, Lynn.  I have said what I 

				219 1	wanted to say.
	2		DR. DRAKE:  Joel? 
	3		DR. MINDEL:  I hate to be serious again. 
	4		DR. DRAKE:  That's okay. 
	5		DR. MINDEL:  But the studies on which this present 
	6	drug is based were done twelve years ago.  The drug on which
	7	we are saying we have to have the duplicate labeling was 
	8	done twelve years ago with the present modification. 
	9		I would like to see this new drug limited to a 
10	seven- or eight-day labeling maximum use, period. 
11		DR. DRAKE:  Okay; that is a thoughtful suggestion.
12		Now, you experts have had a chance to think.  Dr. 
13	Epps? 
14		DR. EPPS:  One recommendation for wording may be 
15	two separate sentences such as, "Not to be used in diaper 

16	dermatitis due to striae and whatever side effects."  And
17	the second one, "Not recommended under the age of 12." 
18		DR. DRAKE:  Ted? 
19		DR. ROSEN:  I have nothing further to add.  I 

20	think you all have heard the same recommendations multiple 
21	times.  They are all good ones.
22		DR. DRAKE:  Steve? 
23		DR. FELDMAN:  We talked about this drug has been 
24	proven safe.  Safety, in small trials, doesn't really tell 
25	you about safety for less common events.  It is clear from 

			220 1	the postmarketing data there have been a lot of adverse
	2	events.  That could be listed under adverse reactions much 
	3	more prominently. 
	4		Again, it raises the issue--I don't think we 

	5	should say that this drug has been proven safe.  On the 
	6	contrary, the postmarketing data has shown that there are
	7	adverse events reaction with this drug with the labeling 
	8	that has been out there limiting its use. 
	9		So I think the committee should feel really 

10	comfortable making decisions that say the labeling needs to 
11	be strengthened or its use should be curtailed in some way. 
12	I think it was an excellent point that was brought up that 
13	the new product really has not been shown to add anything 
14	over existing product and even the old product that was out 

15	there hasn't really been shown to add anything over existing 
16	products.
17		I think the idea of comparing the numerator and 

18	denominator of the adverse-event profile of Lotrisone to 
19	Diprosone would be very important because if you did find 

20	that the adverse events are much more common with Lotrisone, 
21	when you know that the drug is equally potent in terms of
22	its steroid effects, then you would really say that 
23	something is going on with the marketing of the product or 
24	the use of the product that is of serious concern given the 
25	risk/benefit ratio. 

				221 1		DR. DRAKE:  Mary?
	2		DR. SPRAKER:  Echoing Wilma.  When you read the 
	3	package insert, there is a word or two about the adverse 
	4	events.  I think a whole paragraph on the problem in 
	5	children, how many children have been seen with striae, the 
	6	adverse reports that have been reported would help emphasize
	7	and give the practicing physician more information go to on. 
	8		DR. DRAKE:  I think you earlier even said about a 
	9	black box.  We never got back to that, but they might want 
10	to consider that. 
11		DR. DRAKE:  Mark?
12		DR. ELGART:  As I sit here listening to this, I 

13	think that probably 20, maybe more, percent of my practice 
14	is off-label use of drugs.  I think that most of us do that.  
15	I think that no matter how aggressive we are on the label, 
16	we cannot, as you have said, restrict totally the use of
17	these medications. 
18		That is probably good.  You can lead a horse to 

19	water but you can't make him drink.  You can lead a family 
20	practitioner to what the right way to use this is but, if he 
21	wants to use it another way, he may be right, for him.
22		So I think that we can't be too obstructionist in 
23	the way that we put this material out. 
24		DR. DRAKE:  Lloyd? 
25		DR. KING:  Actually, I am struck by how visual we 

			222 1	are and, in the coming of the E-commerce area, I am struck
	2	by the pharmaceutical industry is becoming worldwide.  If we 
	3	can develop symbols for smiley faces and all this for the 
	4	computer, a shorthand for "I'm happy," "I'm sad," would it 
	5	not be a challenge like developing international signs for a 
	6	roadway, for bathrooms, et cetera, if we could come up with

	7	some kind of symbolic language that says, "Don't use this," 
	8	with an X mark, some improvement on the skull and 
	9	crossbones. 
10		So I think the challenge is people are visual.  
11	They are not going to read all these things if they are
12	illiterate.  But they see a skull and crossbones, they get 
13	the message.  So I think we could take a lead from E- 

14	commerce and say smiley faces.  These things may be the 
15	challenge of the future. 
16		May I ask a question from all the folks from the
17	agency.  Do you have what you want?  Do you have what you 
18	need from us at this point? 
19		DR. WILKIN:  Yes.  I would like to thank the 

20	sponsor, Dr. Plott, for his presentation, the invited 
21	guests, experts who presented and the committee who
22	deliberated in great depth over these, I think, difficult 
23	questions because they had both scientific aspects and they 
24	also had societal values imbedded. 
25		Let it be said that dermatologists considered 

				223 1	their colleagues in other specialties.  We heard that
	2	message as well.  I would thank you, Dr. Drake.  We got very 
	3	good information which we will take back and think about.  
	4	We heard the charge.  We will report back. 
	5		DR. DRAKE:  I, too, want to thank the sponsor.  I 
	6	want to point out there are lots of people in the audience

	7	here today who have antifungal products and what not.  I 
	8	think you have heard a lot of very positive suggestions.  
	9	Bill, "Tinea/Baby?"  What was it?  I don't remember.  But 

10	you have heard a lot of position suggestions.  Please don't 
11	let us stop you from developing something new.  It is always
12	good for our patients. 
13		Now, we have kind of run over.  I am going to have 
14	a seven-minute break.  I am going to reconvene at 4 o'clock 
15	because, if we don't, we won't get out of here and it is not 
16	fair to the next company.  So I want to reconvene at 4:00.
17		[Break.] 
18	       NDA 20-966 - Dermex II (zinc oxinate) Ointment 
19		         Dermex Pharmaceuticals 
20	  For Treatment of Actinic Keratosis, Basal Cell Carcinoma 
21		      and Squamous Cell Carcinoma
22		DR. DRAKE:  We are reconvened.  The last thing on 
23	our agenda today is the open session.  Mr. Henriquez, would 
24	you please do the conflict of interest statements. 
25		     Conflict of Interest Statement 

			224 1		MR. HENRIQUEZ:  The following announcement
	2	addresses the issues of conflict of interest with regards to 
	3	this meeting and is made a part of the record to preclude 
	4	even the appearance of such at this meeting. 
	5		Based on the submitted agenda and information 
	6	provided by the participants, the agency has determined that
	7	all reported interests in firms regulated by the Center for 
	8	Drug Evaluation and Research present no potential for a 
	9	conflict of interest at this meeting when evaluated against 
10	the agenda. 
11		We would, however, like to disclose for the record
12	that Dr. Lynn Drake has interests which would not constitute 
13	a financial interest within the meaning of 18 USC 208-A but 
14	which could create the appearance of a conflict.  The agency 
15	has determined, not withstanding these interests, that the 
16	interests of the government and her participation outweigh
17	the concerns that the integrity of the agency's programs and 
18	operations may be questioned. 
19		With respect to the FDA's invited guest, Dr. 

20	Stephen Feldman, Dr. Theodore Rosen and Dr. Mary Spraker 
21	have reported interests which we believe should be made
22	public to allow the participants to objectively evaluate 
23	their comments. 
24		Dr. Feldman would like to disclose that his 

25	department has a grant with Dermex for a pending NDA.  Dr. 

			225 1	Theodore Rosen would like to disclose that approximately six
	2	years ago, his department received a grant from Allergan for 
	3	a study of Naftin.  Dr. Rosen was an investigator on the 
	4	study but received no personal remunerations.  In 1999, Dr. 
	5	Rosen received an honorarium from Allergan for a lecture 
	6	concerning Naftin.
	7		Dr. Mary Spraker would like to disclose that she 
	8	is a speaker for Dermex' Distinguished Lecture Program.  Dr. 
	9	Spraker's talks to do involve speaking about any of Dermex' 
10	products.  In the event that the discussions involve any 

11	other products or firms not already on the agenda for which
12	the FDA participants have a financial interest, the 
13	participants are aware of the need to exclude themselves 
14	from such involvement and their exclusion will be noted for 
15	the record. 
16		With respect to all other participants, we ask, in
17	the interest of fairness, that they address any current or 
18	previous financial involvements with any firms whose 
19	products they may wish to comment upon. 
20		DR. DRAKE:  Thank you. 
21		Dr. Wilkin?
22		          Introductory Remarks 
23		DR. WILKIN:  This afternoon, we will consider the 
24	zinc oxinate ointment product.  Dr. Ko will give the agency 
25	presentation.  At the end, what we are interested in does 

			226 1	the committee have comments.  We actually have no specific
	2	questions to give to the committee.  I think it will be 
	3	explanatory after Dr. Coe's presentation. 
	4		DR. DRAKE:  I guess the first presenter is the FDA 
	5	and that is Dr. Hon-Sum Ko. 
	6		            FDA Presentation
	7	         NDA 20-996 Dermex (zinc oxinate) Ointment 
	8		DR. KO:  Thank you, Madame Chairman. 
	9		[Slide.] 
10		My presentation will be on NDA 20-996 from Dermex 
11	Pharmaceuticals.
12		[Slide.] 
13		They have a product called zinc oxinate which is a 
14	chelate of zinc chloride with 8-hydroxyquinoline in an 
15	ointment base.  Now, its active ingredient is said to be at 
16	least, in part, a metal-ligand complex formed by the
17	reaction of 1 mole of zinc chloride with 2 moles of 8- 
18	hydroxyquinoline in situ during the manufacturer of the drug 
19	product. 
20		As well, the sponsor states that an excess of zinc 
21	ion is needed for its activity.
22		[Slide.] 
23		Zinc chloride has been used in Mohs surgery as a 
24	fixative.  It is also available for nutrition 
25	supplementation when diluted.  For 8-hydroxyquinoline, it is 

			227 1	used as a chelating agent, for example, in nuclear medicine
	2	to chelate indium, radioactive indium.  It also has 
	3	antibacterial properties and so it may be used in some 
	4	topical products. 
	5		[Slide.] 
	6		The proposed indications for this NDA has changed
	7	with time.  When the NDA was first submitted in March, 1998, 
	8	six indications were requested; squamous-cell carcinoma, 

	9	basal-cell carcinoma, actinic keratoses, Kaposi's sarcoma 
10	and also genital warts and verruca warts. 
11		When a resubmission was given to the agency in
12	September of 1999, only three indications were sought.  

13	These were squamous-cell carcinoma, basal-cell carcinoma and 
14	actinic keratoses. 
15		[Slide.] 
16		In the submission of 1999, a clinical protocol was
17	provided.  It is included in your briefing package in 
18	Attachment 1. 
19		[Slide.] 
20		Basically, the protocol involves having patients 
21	biopsied to verify the diagnosis and have photographs before
22	and after treatment.  There were two phases in the study.  A 
23	patient may be given 8-hydroxyquinoline or zinc chloride or 
24	vehicle in the blind phase which is followed by an open 
25	phase with the Dermex product. 

				228 1		Up to three applications may be given.  And then,
	2	as mentioned, there would be a post-treatment biopsy. 
	3		[Slide.] 
	4		We are going into a summary discussion of the 
	5	clinical data. 
	6		[Slide.]
	7		This table provides the material that we have 
	8	received from the sponsor for the three indications; actinic 
	9	keratoses, basal-cell carcinoma and squamous-cell carcinoma.  
10	There were descriptions of ten patients of actinic keratoses 
11	in 1998 and one more in 1999.  Basal-cell carcinoma, we had

12	fourteen patients in 1998 and eight in	1999.  There was one 
13	squamous-cell carcinoma description in	1999. 
14		In both submissions, the same photographic cases 
15	were presented.  There were five of them.  They are also 
16	present in the sponsor's package which I think you have with
17	you right now. 
18		[Slide.] 
19		I am going into just a very brief discussion of 
20	the clinical data of the 1999 cases.  These were more 
21	representative and were presented in greater detail as there
22	was also histological information. 
23		There was one case of actinic keratoses in a 60- 
24	year-old Caucasian female having multiple lesions on the 

25	face.  Treatment with the product resulted in necrosis after 

			229 1	the application.
	2		[Slide.] 
	3		For basal-cell carcinoma, eight cases were 
	4	reported in the 1999 submission with seven males and one 

	5	female.  The age range was between 42 and 81.  There were 
	6	seven Caucasians and one black.  These patients had disease
	7	duration lasting between six months to 30 years.  The 

	8	lesions were almost all in the head and neck area except one 
	9	which was in the right hand. 
10		Serial histological specimens showed that four out 
11	of the eight patients showed no tumor on the last follow-up
12	biopsy after treatment. 
13		DR. ROSEN:  Can I interrupt you a second.  Does 
14	that mean that the other four out of eight did have tumor on 
15	the last biopsy submitted? 
16		DR. KO:  Yes.
17		[Slide.] 
18		The third indication is squamous-cell carcinoma.  
19	There was one case report of a 72-year-old Caucasian male 
20	having skin ulceration over the cheek.  Serial histology 
21	still showed presence of squamous-cell carcinoma at the last
22	biopsy. 
23		[Slide.] 
24		There is limitation of the efficacy data because, 
25	really, the data is regarded as anecdotal.  The investigator 

			230 1	for the submission in 1999, his qualifications have not been
	2	verified.  The endpoints have not been clear-cut, defined, a 
	3	priori and there are issues on study design including 
	4	randomization and blinding which have been problematic. 
	5		The sponsor did also present some animal data 
	6	apart from the human data.  However, these are not
	7	appropriate to support a human indication. 
	8		[Slide.] 
	9		Concerning the safety data, the cases presented in 
10	1999 did not, really, provide any safety information to 

11	support the adverse-reactions section of the label which
12	lists a number of possible side effects including burning, 
13	inflammatory response, contact dermatitis, increased 

14	sensitivity to sunlight, itching, oozing, soreness, 
15	darkening of the skin and scaling. 
16		[Slide.]
17		In your package, under Appendix 1, you have the 
18	regulations concerning adequate and well-controlled studies.  
19	This slide is really just a summary of what the agency 
20	regards as adequate and well-controlled studies to support 
21	indications in an NDA.
22		The student needs to have clear-cut objectives and 
23	a summary of methods of analysis.  It should be properly 
24	designed to allow valid comparison with proper control.  It 
25	needs to have good subject-selection criteria to assure that 

			231 1	programs actually have the disease or condition to be
	2	studied. 
	3		Methods of assigning patients to the treatment 
	4	would minimize bias such as by randomization with or without 
	5	stratification.  There should be measures to minimize bias 
	6	on the part of subjects, observers and in the data analysis. 
	7	The evaluate of response needs to be clearly defined and 
	8	reliable and there should be adequate analysis of the 
	9	results of the drug effects. 
10		[Slide.] 
11		This slide shows the regulatory history of this

12	application.  The original submission in March of 1998 was 
13	not fileable because of deficiencies.  Subsequent to this, 
14	the applicant requested conference with the agency and this 
15	was held.  The application submitted new material in 1999 
16	and requested the agency to file the application for review.

17		Despite deficiencies, the regulations to allow the 
18	agency to file the application.  So this was filed and 
19	reviewed. 
20		[Slide.] 
21		The clinical biostatistical review showed the

22	following deficiencies.  The application lacks proper 
23	format, content and information on compliance with IRB 
24	regulations.  There were no adequate and well-controlled 

25	studies to support safety or efficacy of the Dermex product 

			232 1	in the treatment of the requested indications, actinic
	2	keratoses, basal-cell carcinoma and squamous-cell carcinoma. 
	3		[Slide.] 
	4		Other review disciplines also found deficiencies 
	5	with the application.  The chemistry, manufacturing and 
	6	control team noted that this NDA lacks specifications such

	7	as quality attributes, analytical methods and acceptance 
	8	criteria for starting materials, active pharmaceutical 

	9	ingredient or drug substance or proposed finished drug 
10	product. 
11		Without the analytical controls, the identity,
12	strength, quality and purity of the drug product cannot be 
13	ascertained.  It also lacks stability data to support the 
14	expiration date and data to evaluate differences in 
15	formulations between batches used for the clinical studies 
16	and the proposed to-be-marketed drug product.
17		[Slide.] 
18		There are also issues of the manufacturing 

19	microbiology part because this NDA does not provide a 
20	statement indicating whether the product is sterile or non- 
21	sterile.  If it is sterile, then information on the
22	sterilization process validation data needs to be provided. 
23		If non-sterile, then it would need microbial 

24	limits-testing methodology and corresponding acceptance 
25	criteria or scientific rationale for lack of this testing. 

			233 1	Also, if it is non-sterile, then there would be a need to
	2	provide a preservative, if any, its effectiveness validation 
	3	data or demonstrating that the antimicrobial properties are 
	4	inherent in the non-preserved product. 
	5		Also, if it is non-sterile, it needs 
	6	microbiological stability data.
	7		[Slide.] 
	8		Pharmacology, toxicology discipline issues relate 
	9	to the lack, in this NDA, of in vitro and preclinical animal 
10	data routinely collected to help identify potential 
11	toxicities of the product, or studies that can help bridging
12	existing data on individual components of the Dermex 
13	product. 
14		[Slide.] 
15		Because of these deficiencies in the application, 
16	it really precludes approval of this application.  The
17	agency brings this to the committee to see whether you have 
18	any recommendations. 
19		DR. DRAKE:  In the interest of time, would it be 
20	worthwhile to hear from the sponsor immediately and then we 
21	can kind of address or comments all together.
22		Dr. Potestio, welcome.  Please proceed. 
23		          Sponsor Presentation 

24		           Summary of Company 
25		DR. POTESTIO:  My main purpose here is to 

			234 1	introduce our company.  Our company is an extremely small
	2	company.  It consists of three people.  The first one, Dr. 
	3	Russell Jordan who did all the formulation for this drug, is 
	4	home, extremely sick.  He is in heart failure, terminal 
	5	stages of hepatitis C, uncontrollable diabetes and nephrosis 
	6	and his doctor, as you can obviously tell, has kept him at
	7	home. 
	8		Our second member of this is Mr. Carl Hanson who 
	9	is a registered pharmacist who is compounding our 
10	medications and presenting this to the FDA.  He has also 
11	been in research with Abbott Laboratories.  I am a retired,
12	board-certified obstetrician-gynecologist.  The reason that 
13	I am retired is because I lost my right eye back in 1998 due 
14	the retinal detachment. 
15		The reason this company was formed was originally 
16	not because of the skin-cancer cure that we have but because
17	of the fact that my wife came down with a right upper- 
18	quadrant pain, and we buried her five-and-a-half weeks 
19	later.  The next day after she had her pain, we brought her 
20	in to the internist who did not discover any gall stones but 
21	a wild-growing pancreatic cancer.
22		She underwent bypass surgery to avoid obstruction 
23	and was put on 5FU for chemotherapy.  Everybody in the 
24	hospital at that particular time knew that 5FU caused severe 
25	nausea and vomiting except our learned oncologist.  I quit 

			235 1	being a doctor and became a husband and looked all over for
	2	any kind of cure and called all the pharmaceutical companies 
	3	to see if they had anything.  They had nothing. 
	4		Finally, the name of Russ Jordan came up and the 
	5	reason I knew Russ Jordan was because he did oncology and 
	6	research all his life.  When I first met him, he was at
	7	National Jewish working in immunology at that particular 
	8	time.  I took care of his wife and daughters while I was in 
	9	private practice. 
10		I called Russ and told him what my problem was and 
11	he formulated some oral medication, the lowest possible dose
12	to give to my wife.  With this medication, ladies and 

13	gentlemen, she had no nausea, no vomiting and no side 
14	effects. 
15		In spite of the fact that it was the lowest 
16	possible dose and she only took it for two weeks before she
17	died of pulmonary edema, the tumor began to recede.  Two 
18	months later, after her death, he called me up.  We had 

19	lunch and he discussed starting a pharmaceutical company.  
20	He had done all of his work through a Dr. Marie Gonzalez in 
21	the Free Clinic of Mexico where they had treated at least
22	over 100 skin cancers. 
23		Every one of the skin cancers was first diagnosed 
24	by biopsy, treated, post-op biopsy to verify it and at least 
25	a five- to ten-year follow up to make sure it didn't recur.  

			236 1	The controls were usually the same person as they had
	2	multiple lesions. 
	3		We started the company, but my main purpose was 
	4	not the skin.  My main purpose was the oral as I knew he had 
	5	a cure for breast cancer, lung cancer and GI cancer, from 

	6	what I could see.  But we needed a lot of money and a lot
	7	more research to bring it on the market. 
	8		So we decided to start crawling before we started 
	9	walking and came out with our skin-cancer product.  Ladies 
10	and gentlemen, I have used this product.  It is totally 
11	different than what I just heard a few minutes ago from the
12	previous speaker.  Every time I have used this product, I 
13	have seen virtually no side effects.  I have seen the tumor 

14	disappear after only one application and a short follow up.  
15	I have seen no recurrence. 
16		There is going to be one out of every five humans
17	in this world that is going to come down with cancer of the 
18	skin.  Ladies and gentlemen, we do have a drug that needs to 
19	be out there that does work.  It is most unfortunate that 
20	this drug is in the hands of a small pharmaceutical company 
21	with limited money.  But we will bring it on the market with
22	the blessing of the FDA as we do not want to go herbal 
23	because skin cancer is too serious of a disease to put in 
24	the hands of the lay people and it should be in the hands of 
25	the professionals who know what they are treating and how 

			237 1	they are treating it.
	2		Thank you so much. 
	3		DR. DRAKE:  Thank you. 
	4		Mr. Hanson? 
	5		    Updating the Committee on Dermex 
	6		MR. HANSON:  I will try to make this a brief as
	7	possible.  You have the handouts.  One thing I would like to 
	8	correct and ask Dr. Ko--you said the animal studies did not 
	9	pertain to the human cancer cells; is that correct?   I want 
10	to ask you that now. 
11		DR. KO:  I didn't say that.
12		MR. HANSON:  I think you did.  You said that 

13	animal studies did not pertain--squamous cell in the cow 
14	does pertain to the human.  A hundred studies were done.  
15	They were included in the filing that we made.  I just 
16	wanted to make that correction.
17		A lot of the deficiencies that are in there for 
18	the analytical part of it, we have limited funds.  We are a 
19	small company.  So we did not start with the manufacturing 
20	entity until March when we found out that it was in the 
21	final stages for this advisory committee.
22		At the time, I called for an inspection.  We have 

23	received an inspection.  All of the supposed deficiencies on 
24	the analytical has been addressed.  The microbial problem is 
25	taken care of.  We have hired and contracted a microbial-- 

			238 1	actually, Nelson Laboratories in Utah is going to do our
	2	microbial work. 
	3		We have installed a pure pharmaceutic water 
	4	system.  We have the machinery now.  The analytical part was 
	5	not done before because, in my experience in manufacturing 

	6	from Abbott and from my own compounding, I have 48 years of
	7	experience in pharmacy. 
	8		We did not start any of the analytical work 
	9	because it was a moot thing because I was doing a mortar- 
10	and-pestle up to that time.  We have an ANDA in place for 

11	the equine horse which we are waiting the final approval on. 
12	We also have an IND in for the squamous-cell cow.  We are 
13	working on the dog.  We have 44 indications for the dog.  It 
14	sounds like kind of an overall type thing. 
15		If there are not any more questions on that, I 
16	would like to get on with the handout, if I could.  I will
17	briefly go through that. 
18		I inclosed a letter that I wrote to this Mr. 
19	Castle.  I informed Dr. Jonathan Wilkin that there was a lot 
20	of dysfunctional letters and correspondence that evolved 

21	after we were notified that we were going to be before the
22	advisory committee.  I had eight phone calls in to one 
23	gentlemen with no answer.  I would hope that the FDA would 
24	treat small companies better than we were treated at this 
25	time. 

			239 1		The treatment that we received from Dr. Wilkin's

	2	division was exemplary.  I want to comment and thank Dr. 
	3	Wilkin and also Mary Jean.  At one point, I had no idea of 
	4	the language needed or what was needed and I told Mary Jean 
	5	at one point that, "I am a farm boy who came to town on a 

	6	load of turnips and fell off."  At that point, she was very
	7	gracious. 
	8		Let's go to the archival information.  The 
	9	original application was for more indications but Dr. Jordan 
10	had a tremendous amount of valuable clinical work in his 
11	office.  His office was inundated with twenty to thirty feet
12	of water at the same time that Colorado State University 
13	lost their library.  We lost a tremendous amount of 
14	information. 
15		But it was our decision, at that time, to go ahead 
16	with what we could salvage at that time and work from there. 
17	So we do have some information on the--quite a bit on the 

18	warts, but it seemed like a moot thing to do that at this 
19	time, to cloud the issue.  Kaposi's sarcoma, he had many, 
20	many cases.  We were able to salvage one which was not 
21	applicable at this time.

22		If you will notice, we limited down to the three.  
23	The reason, now, also, I am putting this in the archival, we 
24	asked, at this time, for the accelerated approval with 
25	expedited review.  Expedited review is an executive order 

			240 1	asking that, due to small companies with limited assets,
	2	that they expedite the review which Dr. Wilkin and his staff 
	3	did 
	4		The accelerated approval, the reason we placed it 
	5	there is that it would remain in postmarket clinical 

	6	studies.  In other words, we didn't feel that we had a
	7	complete case to file, but we placed ourselves in that 

	8	position so that it would be under the direction and the 
	9	guidelines of a protocol that would be substantial to 
10	substantiate the work that has been done. 
11		We also realized at this time, we were trying to
12	seek more clinical help.  I know there are quite a few 
13	dermatologists here, but I was appalled.  We approached four 
14	very prominent dermatologists in Denver.  Each one of them 
15	gave the same response.  One was a good friend of Dr. 
16	Potestio's.  The response that he got from his friend was,
17	"Frank, we have two rooms going with surgical procedures 
18	that we average $2,000 to $3,000 from.  Why should I get a 
19	product on the market that might eliminate my surgery?" 
20		I am sorry about that, but we did make a very good 
21	effort to try to set up a clinical study in Denver which is
22	a good place for it, but we came against a brick wall. 
23		We did give the reasons why we thought it should 
24	be an expedited marketing position.  It provides a very 

25	meaningful advantage over the existing treatment which is 

			241 1	surgical excision, radiation and electrodissection.
	2		I will go through these very fast.  They are kind 
	3	of mundane.  Demonstrates reliability and effectiveness in 
	4	the following.  The supportive evidence is covered by 
	5	Subpart E.  Procedures; complies within the scope of serious 
	6	and life-threatening criteria, which we discussed with a
	7	member of the division in 1997 and 1998.  We confirmed it.  
	8	We complied with the fact that it had to be within the six 

	9	months previous to a filing. 
10		I don't see any mention of this in any of the 
11	correspondence we received.  Supporting evidence should
12	provide the effect of a surrogate endpoint for Dermex.  

13	Distribution and use will be restricted during the specified 
14	time administered by the FDA, Dermex II will comply with-- 
15	anyway.  We had decided on this protocol that we will comply 
16	with the protocol in a postmarketing condition in a very,

17	very strict sense and limit the marketing very rigidly. 
18		We actually have found and have made the first 
19	approach to Kaiser.  I am a consultant for geriatrics with 
20	Kaiser at the present time, part-time.  We found that, 

21	basically, economically--you can see No. 7 is economic
22	importance. 
23		HMOs and Medicare are trying to save money.  This 
24	product will save a tremendous amount of money for Medicare 
25	and for HMOs.  We have found great favor in approaching some 

			242 1	of the HMOs, particularly Kaiser.  They are not in the
	2	position of trying to do surgery to make money.  I am sorry 
	3	to have to make that statement, but I have been in the 
	4	medical profession for more years than I care to talk about. 
	5		Information available reveals that there is no 
	6	other chemical treatment available for the indicated
	7	illnesses.  Highly selective.  We have data here from a Sir 
	8	Alpert which I am going to include in there.  Sir Alpert 
	9	started working with chelation as far back as 1930, 1940 and 
10	1950. 
11		Chelation is not a chemical reaction, as
12	purported.  It is actually a claw where the two chemicals 
13	come together, which brings me to the point that one is 8- 
14	hydroxyquinoline which is not under any prescription 
15	control.  Zinc is definitely not.  We have two entities here 
16	that are not under any control at the present time by
17	prescription. 
18		Dr. Jordan has accumulated sufficient evidence in 
19	treating topical Kaposi's sarcoma.  We are going to pursue 
20	this more aggressively in postmarket clinical studies.  I 
21	tried to eliminate a lot of the information that we have. 
22	Bridging from the information that we provided, which they 
23	said was not done for toxicology and pharmacology, I believe 
24	we sufficiently gave enough information which, according to 
25	the CFRs that I studied, were allowed, if it has been used 

			243 1	previously, either component has been used previously, in a
	2	manner that would pertain internally or externally.  Both of 
	3	these products meet that. 
	4		I put in there selected toxicity mainly to show 
	5	you that 8-hydroxyquinoline has been used and it is in most 
	6	of the USPs and formularies around the world.  Diaper
	7	dermatitis; I know I listened to a lot of discussion this 
	8	day on Lotrisone.  I think there was some opposition.  I 
	9	would make one suggestion at this time.  If you want to know 
10	what the pharmacist is going to on labeling, you should talk 
11	to a pharmacist.
12		Effective oxyquinoline ointment on diaper 
13	dermatitis, when you consider the amount of area on a child, 
14	on a baby, what, 25, 30 percent of the body area is 
15	buttocks, so it was used on that.  Activity with some of the 
16	things here.  We have potential amebocide for 8-
17	hydroxyquinoline.  The thing was brought up about a 
18	preservative.  The original talks that Dr. Jordan had with 
19	the division was to use eucerin which has nickel in it which 
20	actually interferes with the zinc and would replace it.  So 
21	we went to a plasty-base, which is Squibb's original
22	product. 
23		We have antibacterial, antifungal, activity for 

24	the oxine.  That is the next page, 11, I think it is.  I 
25	don't have my pages numbered here.  There is sufficient 

			244 1	evidence.  We tried to highlight most of it so that you
	2	could just review it. 
	3		Indium 111 is a very important one for us because 
	4	I did work on the IND for--I was a nuclear pharmacist and I 
	5	worked on the IND with indium 111 with a Dr. Klingan-Smith.  
	6	This actually is an isotopic follow through the body of 8-
	7	hydroxyquinoline.  If you look under mechanism of action and 
	8	effect, labeling of leukocyte, which we did within the cell, 
	9	the radioactive indium dissociates from oxyquinoline and 

10	becomes firmly attached to the cytoplasm components while 
11	the nonradioactive oxyquinoline is released by the cell.

12		They also established, in these studies, the fact 
13	that carcinogenicity, you go to the other page, here, is, 
14	"Although earlier studies suggested oxyquinoline might have 
15	carcinogenic potential, recent studies have not shown the 
16	carcinogenic effect in rats and mice given oxyquinoline in
17	feed concentrations of 1500 or 3000 parts per million." 

18		"Indium 111 is excreted in breast milk," and such 
19	like that, which we did find. 
20		Toxicology and carcinogenesis studies of 8- 
21	hydroxyquinoline; profound.  We have got survival of dosed
22	male and female rats and mice in two-year studies comparable 
23	to that of the corresponding controls, the high-dose rats 
24	and mice of each sex exhibited slight decreases in mean body 
25	weight and decreased feed consumption. 

			245 1		"In vitro, 8-hydroxyquinoline did not induce

	2	either unscheduled DNA synthesis in rat hepatocytes or 
	3	transformation--""  "An audit of the experimental data for 
	4	these carcinogenesis studies on 8-hydroxyquinoline was 
	5	conducted.  No data discrepancies were found."  I rushed 
	6	that.
	7		Let's go on to zinc.  Zinc oxide has been 

	8	preferred--when my wife and I were raising our nine 
	9	children, we used zinc oxide and didn't have any Lotrisone.  
10	We also used calcium and zinc undecylenate with very good 
11	success, a product called Keldicine.
12		We have got oral zinc.  Strength usually available 
13	for zinc chloride, we have got zinc gluconate, but it is 
14	zinc, 1.4 milligrams of elemental goes down to 60 milligrams 
15	of elemental zinc.  Canada has 10 to 50.  I was told I had a 
16	high PSA and they recommended that I take zinc orally.  I am
17	taking 30 milligrams a day.  Zinc chloride has been used in 
18	an injection form, no apparent problems. 
19		Zinc-chloride mouthwash on plaque and zinc levels 
20	on surface enamels.  That is pretty self explanatory.  Zinc 
21	chloride paste for the debridement of chronic leg ulcers.  I
22	think that is self-explanatory. 
23		Zinc chloride spray--magnesium hydroxide ointment.  
24	This spray was used, and I don't think I highlighted that, 
25	but it was used in the incision and OB procedures, 

			246 1	vaginally.
	2		Does zinc really cure common cold?  Zinc has been 
	3	profoundly taken internally as lozenges and whatever have 
	4	you.  Zinc deficiencies.  Okay; on a chelate, the worst 
	5	possible scenario is that the chelate releases the zinc.  So 
	6	what do we have in the pharmacokinetic range?  We have zinc
	7	and we have 8-hydroxyquinoline. 
	8		8-hydroxyquinoline and zinc, as a chelate oxine, 

	9	is very stable.  Sir Alpert did about five years of work on 
10	stability and, as far as the stability of the product goes, 
11	we did confer and provide mathematical constants for the
12	chelation. 
13		Chelation, I might address.  I just received--I 
14	have two friends of mine that are pharmaceutical chemists.  
15	They are professors, Ph.D.s at the University of Idaho.  

16	Both of these people have been working on a good assay.
17		The assay for the chelate is very hard to do 
18	because it is non-ionic.  You can't draw it out.  So the 

19	best possible way is to break it up and bring it out so you 
20	don't have--then, you don't have a good assay.  But we have 
21	found a way to analyze a chelate which we are now working on
22	and will have in place. 
23		By the way, our inspection, we gave a deadline of 
24	September 1 to have all of the problems solved and we are 
25	well on the way.  We have got about 50 percent of them done 

			247 1	already.
	2		Zinc, the super mineral.  Self-explanatory.  Okay; 
	3	we have got, important in wound healing, zinc.  The element 
	4	also functions as an antioxidant.  Helpful in treatment of 
	5	acne.  Hastens healing of peptic ulcers. 
	6		What diseases are associated with zinc?  They have
	7	got pig studies and whatever there.  Zinc's little-known tie 
	8	to immunity.  Zinc, an unsung mineral.  This, by the way, is 
	9	one-tenth of the information references that we gave to the 
10	division.  Zinc and the common cold.  Zinc in plasma.  I am 
11	not going to spend any time with these.  I think they are
12	pretty--zinc deficiency. 
13		What we have here is we have a product that is 
14	made of two components that are not under the direct 
15	division of the FDA, if I may be corrected on that, Dr. 
16	Wilkin?  8-hydroxyquinoline was used in baby oil for many
17	years.  I don't know if many of you are familiar with that.  
18	8-hydroxyquinoline is not in bagbone.  Many pediatricians 

19	are writing bagbone for diaper rash.  I call them back and 
20	tell them not to use it, it has too much phenol in it. 

21		We then put in Dr. Jordan's curriculum vitae to
22	establish the fact that here is a man that did these 
23	clinical studies in Mexico, at that time under the protocol 
24	set by the FDA which is not the same as it is today.  But he 
25	did comply with them. 

				248 1		You can see that he was in charge of research at
	2	many places.  He has a Ph.D. in microbiology and virology 
	3	from the University of Michigan.  We could not establish--he 
	4	is very ill.  Only his wife and the physicians at this time 
	5	are able to confer with him, but it kind of establishes the 
	6	fact that here is a man of very high quality.  As a matter
	7	or fact, he worked for Kettering, Charles Kettering  
	8	Institute.  He was director of that. 
	9		Let's go on and--are we running out of time? 
10		DR. DRAKE:  Mr. Hanson, we are very appreciative-- 
11		MR. HANSON:  Could I go through the slides?  I
12	don't want to seem abrupt, but I will be.  To give a whole 
13	day on Lotrisone and then give us about twenty minutes to 

14	give a presentation on a very viable product--I would like 
15	ten more minutes. 
16		DR. DRAKE:  May I finish, though.
17		MR. HANSON:  Sure. 
18		DR. DRAKE:  Just so you know, the company, the 
19	sponsor's portion was thirty minutes and they were held to 
20	that.  So your thirty minutes is up but we would happy to 
21	give you a few more minutes to go through the pictures.

22		DR. DRAKE:  I will skip and go to the--all right; 
23	I'll tell you what.  Let's go to the pictures.  All of the 
24	advisory committee has the pictures? 
25		DR. KILPATRICK:  Sir, would it not be more 

			249 1	advantageous to you and your colleagues if you could get
	2	some of the reactions of members of the committee to what 

	3	you presented and what we have in front of us rather than 
	4	spending the time taking us through things-- 
	5		MR. HANSON:  Could I show the slides? 
	6		DR. KILPATRICK:  I am not the chair, but--
	7		DR. DRAKE:  Number one, the agency said that they 
	8	are not going to approve it as it stands now.  We are very 
	9	appreciative that you gentlemen have brought this forward.  
10	I think it is wonderful that three people have made this 
11	gallant effort to start a company and do it on your own.  It
12	is very admirable. 
13		By the way, Dr. Potestio, I want to tell you how 
14	sorry we are about your wife and about the tragedies that 
15	led you into this, but thank goodness you are using it for 
16	something very positive.
17		So we are very grateful that you brought this 
18	forward.  I really admire you guys for doing this.  It is 
19	really important that people--America is founded on 
20	individual people doing something or trying to do something 
21	great.  My question to you, and I am happy to use the time
22	either way, is we can spend the next twenty-five minutes, 

23	which you have--which you don't have but the whole committee 
24	has--trying to help you maybe be successful by giving you 
25	some strong or good advice. 

			250 1		Or we are happy to go through the pictures.  But I
	2	honestly believe that, if I was in your position, this group 
	3	is the one that is going to approve it.  Maybe you would 
	4	like to hear from this committee on how to do your job more 
	5	effectively so that you can move forward. 
	6		MR. HANSON:  All right.  At this time, I would
	7	like to make another statement.  Dr. Jordan, at one of his 
	8	last visits, said that if we have too much problem, let's 
	9	just go herbal.  We have a product that we have made, I have 
10	made and compounded herbally, that we have used on animals, 
11	squamous-cell on cows' eyes.  It is a totally herbal
12	product. 
13		We are in a position to go ahead and manufacture 
14	that but we are trying to keep this under the auspices and 
15	the guidance and the protection of the medical profession.  
16	If this was released, organically chelated zinc for skin
17	care, it would be horrendous.  It is something that we just 
18	want.  Our patent does state that we do have that ability, 
19	and we do have that ability. 
20		So I would like to make that statement at this 
21	time.
22		DR. DRAKE:  Thank you.  I think now what I would 
23	like to do is, again, thank you for coming forward and thank 
24	you for your efforts.  I think this entrepreneurialism is 
25	wonderful. 

			251 1		          Committee Discussion
	2		Now, I would like to turn it back to the committee 
	3	and ask the committee to give you some suggestions.  I would 
	4	like the committee to be helpful.  I would like to start 
	5	with Jim and then Rob. 
	6		DR. KILPATRICK:  You haven't met members of the

	7	committee, sir, but you should know that I am a medical 
	8	statistician from the Medical College of Virginia in 
	9	Richmond, Virginia.  I have been there for thirty-five 
10	years.  I have been involved in collaborative research all 
11	that period.
12		I am currently collaborating with residents in 
13	orthopedics.  I have been forced to tell them something 

14	which I think may be applicable to this situation.  In real 
15	estate, there are three major factors in buying a piece of 
16	real estate; location, location, location.  I have used that
17	as an example to tell my students who are working with me 
18	there are three major factors in research; focus, focus, 

19	focus. 
20		What I have heard is that you and your colleagues 
21	strongly believe that you have a safe and effective product. 
22	What I would suggest, very humbly, sir, is that you pick out 
23	the one aspect that you think is most easily demonstrable-- 
24	the one aspect that is most easily demonstrable--and, if you 
25	want FDA approval, take that particular aspect through the 

					252 1	phase I, phase II, phase III protocols that you have heard
	2	from the rest of us. 
	3		This is my contribution to where I think you have 
	4	to go. 
	5		MR. HANSON:  Thank you very much, Doctor. 
	6		DR. DRAKE:  Dr. Stern?
	7		DR. STERN:  I had a question and, perhaps, a 
	8	suggestion.  Since we just received this, there may be this 
	9	material, but it wasn't clear to me in either presentation 
10	about the status of human studies, committee review, IRB 
11	review for the various protocols that have involved humans. 
12	Certainly, it is my impression that the only information 

13	gathered with appropriate approval of the Human Studies 
14	Protection Committee can be, in fact, even entertained by 
15	the FDA. 
16		DR. DRAKE:  Dr. Wilkin?
17		DR. WILKIN:  There are not IRBs exactly 
18	everywhere.  Europe has a somewhat different system.  It is 
19	the Declaration of Helsinki. 
20		DR. STERN:  Right; but some sort of protection. 
21		DR. WILKIN:  Yes.  It is in our regs that that is
22	to be an important component of the information that comes 
23	to us.  Now, the IRB regs, I think, go back to possibly 
24	1978, 1979, something like that.  Sometimes, there are data 
25	that precede those.  We are not excluded from considering 

					253 1	that.
	2		If we have a product that is out there that was 
	3	studied under questionable circumstances but it is for a 
	4	life-threatening kind of situation, it is something that we 
	5	would think about, looking at the data; yes. 
	6		DR. STERN:  But is it not helpful to an
	7	investigator to review their protocol with the Committee for 
	8	the Protection of Human Subjects? 
	9		DR. WILKIN:  Oh; it is expected that there will be 
10	either the IRB, Declaration of Helsinki and that there will 
11	be consent form.
12		DR. STERN:  Informed consent. 
13		DR. WILKIN:  Yes. 
14		DR. DRAKE:  Dr. Bergfeld. 
15		DR. BERGFELD:  I would like to make a few 
16	statements.  First of all, I laud you at your attempts to
17	coming forward with a nonsurgical approach to skin cancers 
18	and, perhaps, others.  I think that the clinical photographs 
19	that we have all been looking at are very nicely presented.  
20	One, we can see what has happened. 
21		I think that the loss of your databank due to

22	flood is a major insult to your credibility in moving 
23	forward.  I think that you have a great need to somehow 

24	associate yourselves with someone or some company that has 
25	more funds than you do to allow you to go forward with the 

				254 1	studies because I think this would be a worthwhile new
	2	therapy for us in medicine. 
	3		I wouldn't want to be discouraging here because 
	4	you have presented us a very unique idea and a very unique 
	5	product.  We have had some experience with the old Mohs 
	6	technique with the zinc chloride as well and we do know, in
	7	dermatology at least, that this was a very effective therapy 
	8	and now currently being used for melanoma. 
	9		I had leaned over to Dr. Jordan here to ask him if 
10	there had been any clinical studies on Dr. Mohs' cases and I 
11	don't believe there have been.  They never came for review
12	by anyone. 
13		DR. DRAKE:  So we are a step ahead.  They at least 
14	came. 
15		DR. BERGFELD:  You have come.  So I think that 
16	gathering up some information, putting it together a little
17	bit tighter, focusing and perhaps getting one of other 
18	colleagues over here interested in what you have had to say, 
19	might allow you to go forward. 
20		DR. DRAKE:  Other comments? 
21		MR. HANSON:  If I could make a statement right
22	here.  Dr. Jordan did have clinical studies that he did in 
23	Mexico on malignant melanoma.  He did have excellent 
24	results. 
25		DR. DRAKE:  Dr. DiGiovanna? 

			255 1		DR. DiGIOVANNA:  Just a point of clarification. 
	2	On page 42, it says that Dr. Jordan is an M.D., Ph.D.  He is 
	3	the one who did the clinical studies? 
	4		MR. HANSON:  We could not verify that.  Due to his 
	5	illness, we could not make proper contact so we sent a 
	6	letter back to Dr. Wilkin and his division saying that we

	7	could only verify his Ph.D. at this time.  So I want to 
	8	clarify that.  We have clarified that--someone assumed that 
	9	he did have an M.D.  There was evidence that he did, but we 
10	could not authenticate it. 
11		So I sent a letter to Dr. Wilkin and Mary Jean. 
12	You did get that letter?  Yes; thank you.  That is a good 
13	point. 
14		DR. DRAKE:  Other comments from committee?  Dr. 
15	King? 
16		DR. KING:  I just had a simple question.  It kind

17	of threw me off looking at the data, and I didn't look at it 
18	very much.  I was trying to figure out what the difference 

19	was between using zinc as a fixative and, say, formaldehyde.  
20	It wasn't clear to me you were fixing the tumor or the 

21	process in the skin and then there is surgical removal
22	because it is almost like repeating so-called Mohs surgery 
23	where you fix it and then cut it out, because when I was 
24	looking at the animal, the cow data, or maybe it was the 
25	Yorkie, it looked like you had fixed it with zinc and then 

				256 1	you had gone back and repeatedly cut it out.
	2		I guess I am having trouble with what is the exact 
	3	protocol. 
	4		MR. HANSON:  Mode of action? 
	5		DR. KING:  No, no; I know what the mode of action 
	6	is in one sense.  It is a fixative.  So you use it for
	7	electron microscopy.  What I was asking is what is the 
	8	protocol?  Is it zinc chloride fixative and zinc 
	9	interactions and then you cut it out or you just put it on 
10	there like another chemical Effudex and seeing what happens. 
11		The protocol is the problem; I don't know what you
12	are doing, actually. 
13		MR. HANSON:  I see.  With the Yorkie, he actually 
14	put it on, but he was having trouble getting it to stay on 
15	with the dog.  It was such a large fibrosarcoma.  So he 
16	called and actually what he did was he put it in an

17	ointment, which is kind of crude.  Anyway, he made a 
18	solution out of it and injected the fibrosarcoma. 
19		DR. KING:  That would be a version of injecting 
20	formaldehyde or formalin and fixation.  It looks to me like 
21	you are doing chemical fixation and then debriding it.  That
22	is a different issue.  That is why I was asking you is it 
23	just topical and watch what happens with no scarring or is 
24	it doing surgical removal after fixation? 
25		MR. HANSON:  No; it wasn't.  Actually, the 

			257 1	debriding that he made was due to--the healthy tissue was
	2	actually interfering with his work so he had to debride it 
	3	to continue on with the topical application.  But the 
	4	topical application was the final--I see what your point is. 
	5		DR. KING:  I am just having trouble.  Rubbing on 
	6	the cream is different from rubbing on the cream and then
	7	cutting it out.  I never saw a tumor get out of formalin if 
	8	it was adequately excised. 
	9		MR. HANSON:  It is kind of interesting.  Go ahead, 
10	Dr. Drake, if you want to make some other comments. 
11		DR. DRAKE:  I think Wilma hit the nail on the
12	head.  I think everybody in dermatology would be very 
13	enthusiastic and eager to have a nonsurgical approach to 
14	skin cancer, or for any other cancer, for that matter.  But, 
15	clearly, this is an area in which there is a great demand.  
16	I couldn't support Rob Stern any more by saying that it
17	really needs to be focused. 
18		Finally, I think you need to get--whether you 

19	approach some venture capital folks, or maybe somebody in 
20	this audience that has a company might have an idea to 

21	partner with you, but I think, conceptually, you need a
22	partner of some sort so that you can do the necessary work 
23	that is credible and scientifically valid so that the agency 
24	and this committee can consider it seriously. 
25		But, in terms of concept of needing a nonsurgical 

					258 1	approach, that would be very interesting to this committee.

	2		MR. HANSON:  I have some of the product that we 
	3	have made.  This was sent for a chemical analysis, by the 
	4	way.  You can see it is kind of a yucky green.  I am going 
	5	to do something here in a minute.  This actually only 
	6	attacks cancer cells.  I just put some on my skin and there
	7	is no reaction.  I am going to eat it.  Isn't that neat?  
	8	Call 911, would you? 
	9		DR. DRAKE:  Mr. Hanson, you know what I am going 

10	to do now so that we can use our time wisely, I am going to 
11	poll the panel and ask the panel to each person give you
12	their single best idea, including you guys. 
13		MR. HANSON:  That would be great. 
14		DR. DRAKE:  Let each member of the panel, much as 
15	we did with Schering, I want to ask the panel members to 

16	each give them their one best idea on how to be helpful to
17	you.  I am going to ask the panel to be original.  If it has 
18	already been said, think of something new. 
19		Eduardo. 
20		DR. TSCHEN:  An interesting idea.  I think more 

21	formal clinical trials will be a great idea, formal clinical
22	studies. 
23		DR. DiGIOVANNA:  I am not that original.  I have 
24	to agree with Wilma.  I think partnering with someone who 
25	has extensive knowledge in formal trials would be helpful. 

					259 1		DR. MILLER:  The FDA has listed the things that

	2	need to be complied with with the NDA, so each of those 
	3	items would have to be complied with before you would be 
	4	able to go forward. 

	5		MR. HANSON:  We are addressing those aggressively.  
	6	Yes.
	7		DR. JORDAN:  I think the notion to focus this, 

	8	maybe just pick one of these tumors, like basal-cell, and 
	9	focus in on those studies, but do them well. 
10		DR. DRAKE:  That is an excellent idea; do just one 
11	tumor.  Wilma, go ahead.  You are not off the hook.
12		DR. BERGFELD:  Because I am an entrepreneur-like 
13	therapist, I would say that I would hope that you would go 
14	forward.  It sounds very interesting to me. 
15		MR. HANSON:  We will.  We are, aggressively. 
16		DR. DRAKE:  Dr. Stern?
17		DR. STERN:  I think I made my suggestion.  I think 
18	it will also help to be in contact with an institutional 
19	review board and Protection of Human Subjects. 
20		MR. HANSON:  Thank you. 
21		DR. DRAKE:  Jim?
22		DR. KILPATRICK:  Again, three words; focus, focus, 
23	focus. 
24		DR. STERN:  Very good. 
25		DR. DRAKE:  Actually, I gave Rob credit for that, 

				260 1	but it was you.  You are exactly right.  I'm sorry.  Sorry,
	2	Jim.  You are the one that had that good idea. 
	3		DR. STERN:  Dr. Kilpatrick just says what I think. 
	4		DR. DRAKE:  Bill? 
	5		DR. ROSENBERG:  I just think you have to realize 

	6	that, over the years, individuals have come forward and said
	7	this or that would cure cancer.  There are people with 

	8	cancer who will turn anywhere for help.  Now, with skin 
	9	cancer, we have treatments that work.  I think to suggest 
10	that we are going to be able to treat to people until we 
11	know so is wrong.
12		So I think the studies need to be done with people 
13	who understand that--either people or animals.  I think 
14	starting with animals makes more sense.  It is easier to get 
15	permission to study cancer in animals.  I think if you were 
16	to work with a veterinary group or an academic veterinary
17	group and see if you can cure skin cancer in animals, I 
18	think the world would beat a path to your door. 
19		But I think you must be very cautious, or more 
20	than cautious.  I think you just must realize that there are 
21	too many people who have cancer and are too upset and too
22	sad who can't just think that somebody has got a cure for 
23	it.  You don't want to be in that category. 
24		MR. HANSON:  I agree with you wholeheartedly.  Too 
25	many of my friends have beaten the path to Mexico to look 

				261 1	for the wonder drug.  When you say there are treatments for
	2	it, are you talking about the excisions?  There is no 
	3	topical--I think Effudex is no longer recommended for any 
	4	type of skin cancer, actinic keratoses. 
	5		DR. ROSENBERG:  There is actually something that 
	6	is being studied now.
	7		DR. DRAKE:  I don't want to go there.  I would 

	8	like to continue, please, because we are getting close to 
	9	adjournment hour and I would like to call on Joe.  We are 
10	going to do this other table, too.  So, Joe? 
11		DR. McGUIRE:  You have a concept and you have a

12	product and you are frustrated because people are skeptical.  
13	That is the way it is going to be until the information is 
14	presented in a way that someone other than you can 
15	understand it.  It is very hard for me to understand your 
16	data, here.
17		I think you need to sit down with some friendly 

18	but smart person and ask them how to get your data in shape 
19	so that it is interpretable by someone else.  This was a lot 
20	of work but it is also very difficult for an outsider to 
21	understand.
22		DR. DRAKE:  Joel? 
23		DR. MINDEL:  Nothing.  Thank you. 
24		DR. DRAKE:  Jon?  I want to go back down here.  
25	Dr. Epps? 

			262 1		DR. EPPS:  Once you have your protocols and your
	2	process together, have as many subjects as you can and also 
	3	some controls. 
	4		MR. HANSON:  The control, by the way, was done by 
	5	Dr. Jordan down there.  He used the same patient.  One of 
	6	those photos was the cheek.  That was a surveyor that was in
	7	Mexico.  He put the separate components on other lesions 
	8	that this man had and the base and used that type of 
	9	control.  In other words, the same immune system, the same 
10	person, persons.  That was his control. 
11		DR. DRAKE:  Mr. Hanson, what I want to say is you
12	are using--another thing, if you are going to come before 

13	this committee again, I think you have to have credible 
14	people.  We don't even know, and you don't even know, what 
15	credentials Dr. Jordan has, or Mr. Jordan, or whatever he 
16	is.

17		I think you really have to go back and look at the 
18	credibility of your work because the outside world is not 
19	going to buy in until they understand who is doing the work.  
20	By controls, I guess I would like to elucidate a little bit.  
21	By controls is, you may treat a tumor with this product and

22	then you go back and remove it by an excisional method, the 
23	traditional way, and look at it histologically and see if 
24	the tumor is all gone. 

25		So that is what I am thinking of.  When I think of 

			263 1	controls, I want to make sure that the tumor is gone and
	2	that this product will do the job. 
	3		MR. HANSON:  Yes; I do 
	4		DR. ROSEN:  Not only focus, focus, focus, but 
	5	data, data, data.  It is not only the quality of data but 
	6	the quantity of data.  There is more than one method of
	7	treating skin cancer now, not only excision.  Effudex is 
	8	still used in actinic keratoses.  Superficial multicentered 
	9	basal-cell, intralesional interferon.  There are immune- 

10	modifier-response drugs that are being studied now for the 
11	treatment of skin cancer.
12		You will have to have data that is in comparable 
13	quantity to perform comparably so that you show that your 
14	product is equally good to the other options but has an 
15	advantage of no surgery, smaller recuperation time, better 
16	cosmetic outcome or something.  But you have to have a

17	quantity of data that will be comparable to the other 
18	methods that are available. 
19		I would also echo one of the other comments on the 
20	other side of the room.  Human data is, A, hard to come by 
21	and it is risky and requires institutional review board. 

22	Having lost a pet to a very aggressive sarcoma, you could 
23	easily, probably more easily, partner with a veterinary 
24	academic group and do a world of good for treating animal 

25	tumors.  You are held to somewhat less stringent standards, 

				264 1	if you wanted to start there and at least prove the

	2	viability of your product in one group of mammals. 
	3		MR. HANSON:  Thank you. 
	4		DR. DRAKE:  Steve? 
	5		DR. FELDMAN:  I feel more comfortable if the 
	6	studies were clearly blinded as well as controlled.
	7		MR. HANSON:  Thank you. 
	8		DR. DRAKE:  Lloyd? 
	9		DR. KING:  It has been my experience in life the 
10	great idea whose time has not come is a failure.  It 
11	oftentimes fails because it is not presented in a way that
12	users, or the people who need to concept, understand.  So I 
13	think you are going to have to do the focus and set up this 
14	in a way--you have got to speak English to English and 
15	French to French. 
16		This is, so far, more a testimonial and not in the
17	usual format.  So I think you have a great idea.  You are 
18	just not convincing because you are speaking French to 
19	English folks. 
20		DR. DRAKE:  With that, the hour is getting quite 
21	late.  What I want to do is I want to thank you, Mr. Hanson,
22	and you, Dr. Potestio, for coming and, once again, warmly 
23	welcome you to the world of investigation.  I hope our 
24	comments have been helpful. 
25		With that, I would like, then, to-- 

					265 1		MR. HANSON:  If I could take a minute and thank
	2	the advisory committee for their patience with us and good 
	3	advice. 
	4		DR. DRAKE:  We wish you great success. 
	5		MR. HANSON:  We are going to market this.  Thank 
	6	you.
	7		DR. DRAKE:  Dr. Wilkin? 
	8		DR. WILKIN:  Dr. Drake, we thank the invited 
	9	guests, the experts, the sponsor for their earnest 
10	presentation, the members of the committee and you, the 
11	Chair, for the comments.  They have been helpful for us. 
12	They were directed at the sponsor, but they were helpful for 
13	us to hear as well.  Thank you. 
14		DR. DRAKE:  Is there any further business to come 
15	before this committee?  We stand in recess until tomorrow. 
16		[Whereupon, at 5:15, the proceedings were recessed
17	to be resumed at 8:30 a.m., Friday, June 30, 2000.] 
18				    - - -