1

DEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

JOINT SESSION WITH THE

NONPRESCRIPTION AND DERMATOLOGIC DRUGS

ADVISORY COMMITTEE

VOLUME II

Thursday, March 24, 2004

8:00 a.m.

Hilton Washington DC North

620 Perry Parkway

Gaithersburg, Maryland

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P A R T I C I P A N T S

Alastair Wood, M.D., Chair, NDAC

Teresa A. Watkins, R.Ph., Executive Secretary

Committee Members:

Michael C. Alfano, DMD, Ph.D. (Industry

Representative)

Terrence F. Blaschke, M.D.

Ernest B. Clyburn, M.D.

Frank F. Davidoff, M.D.

Jack E. Fincham, Ph.D.

Sonia Patten, Ph.D. (Consumer Representative)

Wayne R. Snodgrass, M.D., Ph.D.

Robert E. Taylor, M.D., Ph.D., FACP, FCP

Mary E. Tinetti, M.D.

Government Employyee Consultants (Voting):

Michael E. Bigby, M.D.

Sharon S. Raimer, M.D.

Eileen W. Ringel, M.D.

Jimmy D. Schmidt, M.D.

Robert B. Skinner, Jr., M.D.

Thomas R. Ten Have, Ph.D.

Elizabeth S. Whitmore, M.D.

Michael G. Wilkerson, M.D.

SGE Consultants (Voting):

Patricia Chesney, M.D.

Roselyn Epps, M.D.

Robert M. Nelson, M.D.

Victor Santana, M.D.

Federal Employee Consultants (Voting)

Constantine Stratakis, M.D.

Donald R. Mattison, M.D.

FDA Participants:

Charles Ganley, M.D.

Curtis Rosebraugh, M.D., MPH

Jonathan Wilkin, M.D.

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C O N T E N T S

Call to Order and Introduction:

Alastair Wood, M.D. 4

Conflict of Interest Statement,

LCDR Teresa A. Watkins, R.Ph 7

Introduction:

Charles Ganley, M.D. 11

FDA Presentations:

OTC Dermatologic Topical Corticosteroids:

Mike Koenig, Ph.D. 16

Rx Topical Corticosteroids: HPA Axis Suppression

and Cutaneous Effects:

Denise Cook, Ph.D. 32

Lessons Learned from Growth Studies with Orally

Inhaled and Intranasal Corticosteroids:

Stephen Wilson, Dr. P.H., CAPT USPHS 77

HPA Axis Suppression Studies: Conduct, Utility

and Pediatric Considerations:

Markham Luke, M.D. 92

Questions from the Committee and Committee

Discussion 106

Open Public Hearing:

Jerry Roth 181

Charles H. Ellis, M.D. 189

Valentine J. Ellis, MBA 197

Michael Paranzino 206

Sandra Read, M.D. 211

Luz Fonacier, M.D. 219

Questions to the Committee and Committee

Discussion 236

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P R O C E E D I N G S

Call to Order and Introductions

DR. WOOD: If everybody could take their

seats and let\'s begin by going around the table and

have everybody introduce themselves. Why don\'t we

start with Mike.

DR. ALFANO: Good morning. I am Mike

Alfano, New York University. I am the industry

liaison to NDAC.

DR. FINCHAM: Good morning. I am Jack

Fincham, an NDAC member, and I am a Professor of

Pharmacy and Public Health at the University of

Georgia.

DR. RAIMER: Good morning. I am Sharon

Raimer, in Dermatology, University of Texas.

DR. TINETTI: I am Mary Tinetti, Internal

Medicine, Geriatrics at Yale.

DR. RINGEL: Eileen Ringel, Dermatologist,

Waterville, Maine.

DR. CLYBURN: I am Ben Clyburn, Internal

Medicine, Medical University of South Carolina in

Charleston.

DR. SANTANA: Good morning. I am Victor

Santana. I am a pediatric hematologist/oncologist

at St. Jude Children\'s Research Hospital in

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Memphis, Tennessee.

DR. SKINNER: I am Bob Skinner from the

University of Tennessee at Memphis. I am a

dermatologist.

DR. PATTEN: I am Sonia Patten. I am the

consumer representative on NDAC. I am an

anthropologist on faculty at Macalister College in

St. Paul, Minnesota.

DR. DAVIDOFF: I am Frank Davidoff. I am

the Emeritus Editor of Annals of Internal Medicine.

I am an internist although I started life as an

endocrinologist, and I am a member NDAC.

DR. BIGBY: Michael Bigby, a dermatologist

at Beth Israel Deaconess Medical Center and Harvard

Medical School.

LCDR WATKINS: I am Teresa Watkins. I am

the Executive Secretary with the advisors and

consultant staff.

DR. NELSON: Robert Nelson, Pediatric

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Critical Care Medicine at Children\'s Hospital,

Philadelphia, and the University of Pennsylvania.

DR. SNODGRASS: Wayne Snodgrass,

pediatrician, University of Texas Medical Branch.

DR. MATTISON: Don Mattison, National

Institute of Child Health and Human Development.

DR. SCHMIDT: Jimmy Schmidt, Houston,

Texas, dermatologist.

DR. EPPS: Roselyn Epps, Chief, Pediatric

Dermatology, Children\'s National Medical Center,

Washington, D.C.

DR. CHESNEY: Joan Chesney, Pediatric

Infectious Diseases at the University of Tennessee

at Memphis and Academic Programs at St. Jude

Children\'s Research Hospital.

DR. TAYLOR: Robert Taylor, internist and

clinical pharmacologist, Howard University,

Washington.

DR. WILKERSON: Michael Wilkerson,

University of Oklahoma, Tulsa Branch, Assistant

Professor, Clinical, and dermatologist.

DR. BLASCHKE: Terry Blaschke, internist,

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clinical pharmacologist, Stanford.

DR. WILKIN: Jonathan Wilkin, Director,

Division of Dermatologic and Dental Drug Products,

FDA.

DR. ROSEBRAUGH: Curt Rosebraugh, Deputy

Director, OTC, FDA.

DR. GANLEY: Charley Ganley, Director of

OTC.

DR. WOOD: I am Alastair Wood. I am an

internist, Professor of Medicine, Associate Dean at

Vanderbilt. There has probably never been a

committee with so many people from Tennessee on it,

I don\'t think.

Teresa, why don\'t you read the Conflict of

Interest Statement.

Conflict of Interest Statement

LCDR WATKINS: The following announcement

addresses the issue of conflict of interest and is

made part of the record to preclude even the

appearance of such at this meeting.

Based on the submitted agenda and all

financial interests reported by the Committee

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participants, it has been determined that all

interests in firms regulated by the Center for Drug

Evaluation and Research present no potential for an

appearance of a conflict of interest at this

meeting with the following exceptions.

In accordance with 18 U.S.C. Section

208(b)(3), full waivers have been granted to the

following participants. Please note that all

interests are in firms that could potentially be

affected by the committee\'s discussions.

Dr. Michael Wilkerson for activities on

Speakers Bureaus for three firms. He receives less

than \$10,001 per year, per firm.

Dr. Robert Skinner for a patent licensed

to a firm that could potentially be affected by the

committee\'s discussion. He has received no

royalties at this time. Also, for his Speakers

Bureaus activities for two firms, he receives less

than \$10,001 per year, per firm.

Dr. Patricia Chesney for stock in six

firms. One stock is valued at less than \$5,001,

one stock is valued between \$5,001 to \$25,000,

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three stocks are valued between \$25,001 and

\$50,000, and one stock is valued greater than

\$100,000.

Dr. Thomas Ten Have for stock valued

between \$25,001 to \$50,000.

Dr. Victor Santana for stock in two firms.

These stocks are worth between \$5,001 and \$25,000

each.

Dr. Sharon Raimer for two grants that are

valued at less than \$100,000 per firm, per year.

Also, for stock in three firms, each stock is

currently valued between \$5,001 and \$25,000.

Dr. Sonia Patten is an unpaid volunteer

member of the Sumasil Foundation Board of

Directors. The Foundation owns stock interest in

two firms. One stock is currently valued between

\$25,001 and \$50,000 and the other stock is

currently valued between \$5,001 and \$25,000.

We would also like to disclose that Dr.

Terrence Blaschke owns stock in a firm, valued from

\$5,001 to \$25,000. A waiver under 18 U.S.C.

208(b)(3) is not required because the de minimis

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exemption 2640.202(b)(2) applies.

A copy of the waiver statements may be

obtained by submitting a written request to the

Agency\'s Freedom of Information Office, Room 12A-30

of the Parklawn building.

In the event that the discussions involve

any other products or firms not already on the

agenda for which an FDA participant has a financial

interest, the participants are aware of the need to

exclude themselves from such involvement and their

exclusion will be note for the record.

In addition, we would also like to note

that Dr. Michael Alfano is participating in this

meeting as a non-voting industry representative,

acting on behalf of regulated industry. Dr.

Alfano\'s role on this committee is to represent

industry interests in general, and not any one

particular company. Dr. Alfano is Dean of the

College of Dentistry, New York University.

With respect to all other participants, we

ask in the interest of fairness that they address

any current or previous financial involvement with

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any firm whose products they may wish to comment

upon.

Thank you.

DR. WOOD: Thanks a lot.

Our first speaker is Charley Ganley.

Charley.

Introduction

DR. GANLEY: Good morning. I would just

like to start by thanking all the members for

participating in this meeting. I would also like

to thank the advisors and consultant staff for all

the hard work they do in putting these meetings

together, it is always difficult to get two

different committees together, and last but not

least, the staff of the Dermatologic and OTC

Divisions who have put together the presentations.

\[Slide.\]

We are here today to discuss the safety

data necessary to consider a switch of dermatologic

topical corticosteroids from prescription to OTC

status.

\[Slide.\]

The FDA presentations will cover the

regulatory history of OTC hydrocortisone, the

assessment of safety for current prescription

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dermatologic topical corticosteroids products, an

assessment of safety effects for other categories

of steroid products, and testing for HPA axis

suppression.

\[Slide.\]

Now, low potency dermatologic topical

corticosteroids are currently available OTC, and

the only product that you will hear in the next

talk is hydrocortisone. Its purpose is for the

symptomatic treatment of certain skin conditions,

and there is a limitation on the duration of use.

Over the last year or so, several

manufacturers have expressed an interest in

switching some dermatologic topical corticosteroids

from prescription to OTC, asking for similar type

claims, and also for durations of use.

\[Slide.\]

Now, in your background package, we

included a list of the various potencies of topical

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steroids, and there is quite a difference in the

potency of prescription dermatologic topical

steroids, and potency impacts on efficacy and

safety of these products.

The main issue for the discussion today is

the safety in the OTC setting. The question really

is where do we draw the line between safe versus

unsafe products in this category for OTC use.

\[Slide.\]

Can all dermatologic topical steroids be

used safely OTC? Well, some highly potent products

used for extended periods or in large amounts may

pose a significant risk for developing a serious

adverse event.

At least in the OTC setting, limiting the

duration of use through labeling may be effective

for the majority of users. There will, however, be

a minority of consumers who will use large amounts

and for durations that exceed label

recommendations.

I think in part of the open public

session, you will hear a little bit of information

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of what possible percentage of consumers that may

be.

\[Slide.\]

So, what are the safety concerns? We have

divided them up into the systemic effects and local

effects, and within the systemic effects, we divide

them further into HPA axis suppression, which is in

this case where an exogenous steroid causes the

body to stop making corticosteroid, and in stress

situations, it could lead to acute adrenal crisis

which would be life-threatening.

This can occur with weeks of use and the

use of the OTC product may be unknown to a health

provider who has to treat someone who comes into

the emergency room in this situation.

The other systemic effects are essentially

Cushing\'s syndrome, which could be osteoporosis,

truncal obesity, growth suppression, and

hypertension, it goes on and on, and the severity

may be related to the daily dose and the duration

of therapy.

The local effects during the course of the

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presentations today, that will also be reviewed.

\[Slide.\]

Now, you may not be able to see this very

well. I printed out one page, but this is one of

the schematics that we are going to work with

today, and what we have done is we have created a

hierarchy of what we think the importance of these

various potential safety issues are.

Starting at the top is HPA axis

suppression. The second one is other systemic

effects, and the third is local effects. You will

see the way the questions are presented will also

follow this course.

I don\'t want to go into great detail with

this now, but during the course of the discussion

and prior to some of the questioning maybe later

this afternoon, we can go through this in a little

more detail.

Right now I am going to turn it over to

Michael Koenig, who is going to talk a little bit

about the regulatory history of hydrocortisone.

FDA Presentations

OTC Dermatologic Topical Corticosteroids

\[Slide.\]

DR. KOENIG: Good morning. I am Michael

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Koenig, an interdisciplinary scientist in the

Division of Over-the-Counter Drug Products.

Over the next 15 minutes, I will be

providing you with information about the only

dermatologic topical steroids that are available

over the counter, hydrocortisone and hydrocortisone

acetate.

Because hydrocortisone and hydrocortisone

acetate are functionally the same thing, for the

rest of this presentation, I will simply refer to

the two corticosteroids as hydrocortisone.

\[Slide.\]

This presentation is divided into three

parts. First, I will describe the OTC monograph

system under which these OTC corticosteroids are

regulated. Second, I will review the regulatory

history of hydrocortisone. Third, I will show you

the current labeling of hydrocortisone products if

they are in compliance with the monograph.

\[Slide.\]

I would like to begin by just especially

for members of the Dermatologic and Ophthalmic

Drugs Committee to review the way OTC drugs are

regulated. All OTC drugs are regulated by one of

two means, either under an NDA, or a new drug

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application, or under the monograph system.

New drugs applications, or NDAs, are

prepared by a drug manufacturer for a specific

product, a specific drug product, and all of the

review of this information and things related to

the review are kept strictly confidential.

Neither of the OTC corticosteroids that I

will be talking about are regulated under NDAs.

Instead, they are regulated under the monograph

system, and this differs because under the

monograph, monographs deal with specific active

ingredients rather than drug products, and I will

show you how that plays out in just a minute.

In contrast to the NDAs, the information

included in the monograph is a very public process.

The monographs are published in the Federal

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Register, and FDA actively solicits feedback from

the public at every step of the process.

\[Slide.\]

So the OTC monographs came about with the

initiation of the OTC drug review back in 1972. At

that time, there were over 200,000 different drug

products available OTC, and it was really

impractical to think that we could review the

safety and effectiveness of all 200,000 of these

drug products.

So, since they were made up of about 700

active ingredients, it was determined that the

active ingredients should be studied for safety and

effectiveness rather than the products themselves.

Again, this is a key difference between monographs

and drugs marketed under an NDA.

Of the 700 active ingredients, these were

classified into 26 different therapeutic categories

for further review.

\[Slide.\]

The initial review as by an Advisory

Review Panel. This was made up of outside experts,

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outside FDA experts in that particular therapeutic

category. There were 7 voting members, but in may

respects, it was somewhat analogous to the Advisory

Committee.

These panel members looked at each of the

active ingredients and determined whether they were

Category I or GRASE, Generally Recognized as Safe

and Effective; Category II, not GRASE; or Category

III, insufficient data to determine whether or not

the ingredients were safe and effective for their

intended use.

\[Slide.\]

The recommendations of the Advisory

Committee were published in the Federal Register as

an Advanced Notice of Proposed Rulemaking, or ANPR.

\[Slide.\]

FDA\'s first position on the ingredients in

the different categories were made public in a

proposed rule. This followed solicitation of

comments from the public, and as I said, resulted

in the publication of a proposed rule, also known

as a Tentative Final Monograph, I have abbreviated

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here as TFM.

\[Slide.\]

The last step in the monograph process is

the development of a Final Rule, and that follows

input of comments from the public again, as well as

any new data that is relevant to generate this

Final Rule or Final Monograph, which I have

abbreviated FM.

\[Slide.\]

I would like to now speak specifically

about the regulatory history of hydrocortisone.

\[Slide.\]

This low potency topic corticosteroid was

introduced into the U.S. market as a prescription

drug in 1952. Four years later, in 1956, a Citizen

Petition was submitted requesting that

hydrocortisone be switched from prescription to

OTC.

The switch was rejected in 1957 for two

reasons: first, there was a failure to demonstrate

that consumers could safety self-medicate using

hydrocortisone; and, second, it was felt that more

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testing was needed on absorption of hydrocortisone

through the skin. In other words, there was a

concern about systemic effects, much as we will be

talking about today.

Hydrocortisone was included with other

ingredients classified as external analgesics in a

review by the Topical Analgesics Panel, which met

between 1973 and 1978.

\[Slide.\]

The findings of the panel and the

preliminary regulations were published in 1979 and

the Advanced Notice of Proposed Rulemaking or ANPR.

Among other things, the panel did consider whether

hydrocortisone had any adverse local effects, and

noted that there was a noticeable lack of adverse

local effects.

The striae and telangiectasia that were

characteristic of more potent fluorinated

corticosteroids were not generally found with

hydrocortisone or hydrocortisone acetate. Dr.

Cook, who will follow my presentation, will be

showing you some pictures of that and discussing

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this is a little bit more detail.

Pustular eruptions and crusting were

reported in one case of a person who was using

hydrocortisone, but was it turns out attributed to

a secondary infection and the scratching of the

secondary infection, and treatment with an

antibiotic resolved the issue while the person

continued to use hydrocortisone. So, again, a lack

of local adverse effects.

\[Slide.\]

Also, in the ANPR, the fact that there was

a lack of systemic effects was published. Several

experiments look at percutaneous absorption.

People used carbon-14 hydrocortisone, in one case

tritiated hydrocortisone, and did not see any

significant absorption through the skin.

Other measures of systemic effects were

eosinophil count, there was no depression in

eosinophil count in three or four studies that were

presented in the ANPR. Urinary levels of

17-hydroxysteroids and 17-ketosteroids were not

increased as you would expect if there were a

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significant systemic effect.

Blood glucose levels were unchanged, as

was the serum sodium level, and plasma cortisol did

increase as expected or predicted in response to

insulin stress.

\[Slide.\]

Insulin stress tests back in the \'70s was

a major test for HPA axis function. It is no

longer the current standard, but one report that

you will see in the ANPR, which incidentally is

included in your background package, was a study by

Munro and Clift, which published in 1973.

This is in Tab 5 of your background

package, published in the British Journal of

Dermatology. These investigators looked at 40

patients with chronic skin disease, eczema,

psoriasis, who had been using corticosteroids for

prolonged periods, I believe is in the title.

Ninety-five percent or 38 of the 40 had been using

corticosteroids for more than 10 months.

In fact, they were using a variety of

corticosteroids, betamethasone, and some others.

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Ten of these 40 included among the combination of

corticosteroids they had been using 1 percent

hydrocortisone acetate.

All 10 of those 10 subjects had a normal

insulin stress response, and, in fact, 37 of the 40

enrollees in the study had a normal insulin stress

response. Of the 3 that did not, 2 had occlusion

over extensive areas of the body, and 2 had an

exceptionally large dose of corticosteroid.

\[Slide.\]

Now, the panel also reported that one of

the items that they had received was a review of

the literature covering the period 1952 to 1973

about the serious adverse events that had occurred.

The report was based on some 12,000 subjects in 90

different clinical studies, and in those 12,000

subjects, there were only 3 reports of serious

adverse events.

One of these was 1960 report of temporary

growth retardation in a 5 1/2-year-old male, who

was having 1 percent hydrocortisone applied for 16

months. In 1962, there was a report of temporary

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growth retardation in an infant, who also had 1

percent hydrocortisone applied twice daily for 6

months, and this was\--that says total body\--whole

body and unction was what the report says in the

ANPR.

In 1966, there was a rapid gain in body

weight in a 3-week-old infant male, who was only

using 0.25 percent hydrocortisone 3 times a day for

8 1/2 days, but over a very large coverage 2,100

mg/m2 body surface area.

So, all in all, that panel considered this

a very favorable response, only 3 out of over

12,000 subjects had any serious adverse events with

hydrocortisone.

\[Slide.\]

The panel recommendations in the ANPR were

that hydrocortisone and hydrocortisone acetate

should be considered GRASE over a concentration

range of 0.25 to 0.5 percent. Remember GRASE is

generally recognized as safe and effective.

The panel also has some recommendations

for labeling, and since I will be showing you

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labeling in the third part of the talk, I just

wanted to let you see how this labeling developed

as the monograph developed.

The panel felt that the indication should

be or the use of hydrocortisone should be temporary

relief of minor skin irritations, itching, and

rashes due to a variety of different conditions,

and we will get into that when we look at the

labeling.

The panel also felt that among several

warnings should be these two, which are relevant to

today\'s discussion I think. One is that consumers

should stop use if the condition worsened or lasted

more than 7 days, so there was a time limit put on

the use of hydrocortisone.

The other warning I wanted to mention was

the one that it should not be used on children

under 2 years of age. In fact, these two warnings

were included on all external analgesic active

ingredients, but they are directly relevant to some

of some of the discussion you will be having later

I think.

Finally, the panel felt that under

Directions should be a direction to apply this to

the affected area essentially only, not more than 3

27

to 4 times a day.

\[Slide.\]

FDA\'s position was made public in the

Tentative Final Monograph, TFM, which published a

little over 3 years later in 1983. FDA agreed that

the concentration range specified by the panel was

appropriate, that 0.25 to 0.5 percent

hydrocortisone should be considered GRASE, safe and

effective, and FDA did make some labeling

modifications.

Among those was the focus of the

indication on antipruritic aspects of

hydrocortisone, so instead of temporary relief of

skin irritations, itching, and rash, it became

temporary relief of itching associated with skin

irritation and rashes due to a variety of

conditions, and hydrocortisone is today, that is

the only indication, antipruritic.

Additionally, to the stop use condition,

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FDA added the clause, \"Stop use if condition

worsens or last more than 7 days or if symptoms

clear up and occur again within a few days.\"

\[Slide.\]

The Tentative Final Monograph was amended

in 1990 in response to a Citizen Petition which

requested an increase in dosage strength to a

maximum of 1 percent from remember the previous 0.5

percent.

This amended TFM included an extensive

data and literature review mostly centered around

the use of 1 percent hydrocortisone, and ultimately

considered the higher concentration of 1 percent to

be GRASE for OTC use.

Additionally, there were some labeling

modifications. Under Do Not Use was added, \"Do not

use any other hydrocortisone product when using the

product you are using,\" and \"Do not use this for

the treatment of diaper rash,\" which is still on

the labeling, and this is largely due to the

occlusive nature of a diaper.

\[Slide.\]

What about the Final Monograph, the last

step? It is pending. We are working on it. We

have found that manufacturers are generally

29

complying with the Tentative Final Monograph and

the amended TFM. I will show you that in some

labeling in just a minute.

We are continuing our review of data

submitted by manufacturers, as well as in the

literature.

\[Slide.\]

In light of today\'s discussion, I just

wanted to point out some of the literature that we

have been reviewing. This table represents 5

studies that have been conducted since the ANPR

published in 1979. All of these studies were in

children, and all of these used the modern standard

ACTH stimulation to measure HPA axis function.

ACTH, as Dr. Cook will go into a little

bit more detail on this, ACTH is

adrenocorticotropic hormone. This is released from

the anterior pituitary and stimulates release of

cortisol from the adrenal glands. That is the P

30

and the A, adrenal glands in the HPA axis.

So, by looking at the amount of cortisol

released in response to a known amount of ACTH, or

in a more practical sense, some synthetic analogue

of ACTH, you can tell whether the HPA axis is

functioning properly.

In all of these studies, at hydrocortisone

concentrations ranging from 1 percent to a maximum

of 2.5 percent, and with durations of treatment

ranging from 2 weeks or 14 days up to just under 18

years, the HPA axis was found to be functioning

normally in response to hydrocortisone.

\[Slide.\]

I would now like to look at the current

labeling of hydrocortisone in this third part of

the talk.

\[Slide.\]

Since 1999, OTC products should be

conforming to the Drug Facts labeling standard.

This is what the hydrocortisone labeling should

look like if it\'s in compliance with the monograph,

and there are three things I would just like to

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point out to you. We have been discussing the

development of the monograph through the various

stages, and I wanted to show you how that looks in

the labeling.

So, under Uses, you see the indication,

temporarily relieves itching associated with minor

skin irritations, inflammation and rashes due to a

variety of conditions, and the number of conditions

that may be causing the itching has increased over

the years with each new monograph publication.

\[Slide.\]

Also, under Warnings, this is very much as

it appeared in the TFM, the Tentative Final

Monograph\'s \"Stop use and ask a doctor if the

symptoms persist for more than 7 days or clear up

and occur again within a few days.\"

\[Slide.\]

And under Directions, \"Apply to affected

area not more than 3 to 4 times a day, children

under 2 years of age, do not use.\"

\[Slide.\]

This is labeling that is taken off of a

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currently marketed OTC product, and I just wanted

to show you that again, manufacturers are very much

in compliance with the monograph standards.

So, in this labeling under Uses, we see

the same thing, \"temporarily relieves itching of

minor skin irritations, inflammation and rashes.\"

\[Slide.\]

Under Warnings, \"Stop use and ask a doctor

if symptoms persist for more than 7 days.\"

\[Slide.\]

Under Directions, the same two that I just

mentioned.

I would like to thank you for your

attention and I will be followed by Dr. Denise Cook

of the Division of Dermatologic and Dental Drug

Products. Denise will be talking about

prescription topical corticosteroids.

Thank you.

Rx Topical Corticosteroids: HPA Axis

Suppression and Cutaneous Effects

\[Slide.\]

DR. COOK: Good morning. Good morning to

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the respective chairs of the respective advisory

committees that are here, also to the advisory

committee members, to my FDA colleagues, and people

in the audience.

I am Denise Cook. I am a dermatologist in

the Division of Dermatology and Dental Drug

products.

\[Slide.\]

Today, I will be speaking to you on

prescription topical corticosteroids, the HPA axis

suppression, and cutaneous effects.

The majority of the presentation will be

on the systemic effect of the HPA axis and the

suppression, and the FDA\'s experience with. I will

be presenting trial data from approved drug

products, the resultant labeling changes. I will

also give a postmarketing summary of adverse events

as it relates to the HPA axis suppression that we

have in our database.

But first I will give you a background to

the talk, so that you can follow it probably a

little bit later. I will talk about the

34

classification of topical corticosteroids, give you

a synopsis of the cosyntropin stimulation test and

how it is performed, and also give you an evolution

of interpretation of normal HPA axis function as it

has been done over the years at the FDA.

I will give you background also on class

labeling for topical corticosteroids and how that

developed, and the cutaneous adverse events from

topical corticosteroid use.

\[Slide.\]

The topical corticosteroids are divided

into seven classes. Although the FDA does not

purport this classification, it is widely used in

the dermatologic community.

Class I consists of superpotent topical

corticosteroids, Class II high potency, Class III

through VI are mid-potency with Class III being

closer, of course, to the high potency, and Class

VI being close to the low potency of Class VII.

It is usually determined by a

vasoconstrictor assay where the topical

corticosteroids placed on the cutaneous surface,

35

and blanching or vasoconstriction is determined

relative to the other corticosteroid.

\[Slide.\]

The cosyntropin stimulation test, which is

the test that I will be discussing in the bulk of

the studies that you are going to hear about today,

is used to assess the function of the end organ,

the adrenal gland, in the hypothalamic-pituitary

adrenal axis.

In the case of topical corticosteroids, it

is assessing an exogenous unwanted treatment

effect.

What is usually done is the cosyntropin is

given at 0.125 mg or 0.25 mg depending on age

and/or body weight, and it is administered

intravenously at baseline and at the end of

treatment.

Blood is then drawn for serum cortisol

values at 30 minutes and sometimes 60 minutes post

stimulation. Then, the interpretation of the

results determines a normal or abnormal response.

\[Slide.\]

The evolution of the interpretation of the

normal function of the HPA axis at the FDA has

undergone many revisions. First, in 1985, a.m.

36

serum cortisol, then urinary corticoid

concentrations were used to determine whether you

had normal function of your HPA axis after

treatment with topical corticosteroids.

Then, in 1996, the cosyntropin stimulation

test was employed. At that time, a 30-minute post

stimulation serum cortisol had to be greater than

20 mcg/dL. Also, if the pre-stimulation serum

cortisol was already greater than 20 mcg/dL, then,

you needed to have at least a 6 increment change

from pre-stimulation to post-stimulation in order

to be considered to have a normal response.

In 1999, the FDA went to a single

criterion to determine normal function of your HPA

axis. That was a 30-minute post-stimulation serum

cortisol greater than 18 mcg/dL.

\[Slide.\]

In 2001, it was decided that if we were

going to use cosyntropin to determine normal

37

function of hormonal therapy HPA axis, then, the

label should be followed as it is currently

written, that is, that the control plasma cortisol

level should exceed 5 mcg/100 mL. The 30-minute

level should show an increment of at least 7

mcg/100 mL, and the 30-minute level should exceed

18 mcg/100 mL.

Currently, in 2004, there had been a lot

of work in the FDA with endocrinologists and also

members in the Division of Dermatology to determine

that we need to go back to a single criterion for

HPA axis function and determining it from the

cosyntropin test. Therefore, at the present time,

we only use a 30-minute level, and that serum

cortisol level should exceed 18 mcg/100 mL.

\[Slide.\]

Now, class labeling for prescription

topical corticosteroids went into effect in 1990,

and I am going to give you a little background on

one of the factors that propelled this into being.

This class labeling talks about the

effects on the HPA axis, effects on glucose

38

metabolism, development of Cushing\'s syndrome,

effects on growth, and effects on intracranial

pressure.

\[Slide.\]

Two studies have propelled this into

being. There were two open-label trials with

Temovate Ointment. In Trial 1, there were 6 adult

patients with psoriasis who applied 7 grams/day to

30 percent of their body surface area for 7 days.

ACTH stimulation was performed at baseline

and 2 post-treatment a.m. cortisols were taken.

They found that 50 percent of the patients

exhibited decreases in cortisol production.

\[Slide.\]

In the second trial, the objective was to

determine the largest dose over a 7-day period that

would not cause significant suppression of the

adrenal gland.

Three doses were used - 7 grams/day, 3.5

grams/day, and 2.0 grams/day.

Suppression in this trial was determined

by an A.M. plasma cortisol and urinary corticoid

39

concentrations.

It was interesting, it was found that none

of the psoriatic patients suppressed at 7.0

grams/day or even at 3.5 grams/day, but doses as

low as 2.0 grams/day caused marked suppression of

cortisol secretion in patients with atopic

dermatitis. We can possibly presume that this may

be because they may have had a higher compromise in

the epidermis.

DR. WOOD: What were the numbers in that

study?

DR. COOK: I don\'t know the numbers. You

mean like exactly what the serum cortisol levels

were?

DR. WOOD: The number of patients.

DR. COOK: The number of patients, I don\'t

have that either. This was 1985, and this is taken

out of the label. But I would suspect that they

were small, because in the current studies that we

have, the numbers are small, they are not huge

numbers.

\[Slide.\]

So, this led to a Temovate label in 1985

that stated in the Precautions, it is a highly

potent topical corticosteroid that has been shown

40

to suppress the HPA axis at doses as low as 2

grams/day. As you note here, it is a Class I

steroid in the superpotent category.

Under Pediatric Use, it was determined

that it should not be used in children under 12

years of age, at least it is not recommended.

\[Slide.\]

So, now we will move on to the actual

class label that was generated.

\[Slide.\]

In the Precautions Section, it states that

systemic absorption of topical corticosteroids can

produce reversible hypothalamic-pituitary-adrenal

axis suppression with the potential for

glucocorticoid insufficiency after withdrawal from

treatment.

Manifestations of Cushing\'s syndrome,

hyperglycemia, and glucosuria can also be produced

in some patients by systemic absorption of topical

41

corticosteroids while on treatment.

\[Slide.\]

It goes on to say that patients applying a

potent topical steroid to a large surface area or

to areas under occlusion should be evaluated

periodically for evidence of HPA axis suppression.

This may be done by using the ACTH stimulation, AM

plasma cortisol, and urinary free cortisol tests.

\[Slide.\]

If HPA axis suppression is noted, an

attempt should be made to withdraw the drug, to

reduce the frequency of application, or to

substitute a less potent steroid. Recovery of HPA

axis function is generally prompt upon

discontinuation of topical corticosteroids.

Infrequently, signs and symptoms of

glucocorticosteroid insufficiency may occur

requiring supplemental systemic corticosteroids.

\[Slide.\]

The class label also addressed pediatric

use in the Pediatric Use Section of the label.

\[Slide.\]

Currently, this is what is there if there

haven\'t been any tests done on pediatric patients,

but as you shall see in the studies that I will

42

present, since the advent of FDAMA, we have been

able to get studies in pediatric patients, so some

of this has been modified in the respective labels.

Safety and effectiveness in children and

infants have not been established. Because of a

higher ratio of skin surface area to body mass,

children are at a greater risk than adults of HPA

axis suppression when they are treated with topical

corticosteroids.

They are therefore also at greater risk of

glucocorticosteroid insufficiency after withdrawal

of treatment and of Cushing\'s syndrome while on

treatment.

\[Slide.\]

HPA axis suppression, Cushing\'s syndrome,

linear growth retardation, delayed weight gain, and

intracranial hypertension have been reported in

pediatric patients receiving topical

corticosteroids.

Manifestations of adrenal suppression in

pediatric patients include low plasma cortisol

levels to an absence of response to ACTH

stimulation. Manifestations of intracranial

hypertension include bulging fontanelles,

headaches, and bilateral papilledema.

43

\[Slide.\]

Now, we are going to move on to the bulk

of the presentation, which is going to be about the

prescription topical corticosteroid data and its

relationship with HPA axis suppression.

I am going to speak about 10 drug

products. There are 8 topical corticosteroid

products, 2 topical combination drug products.

\[Slide.\]

Just to give you those, I am going to

speak about Dermatop, which is a mid-potency

steroid; Cutivate Cream, another mid-potency

topical corticosteroid; Diprolene AF Cream, which

is a high potency steroid.

You might want to look in Tab 2, I think

it is, of your background package. It has that

44

classification that I spoke of earlier, the high

potency steroids being in Class II.

Diprosone Ointment, a high potency

steroid; Diprosone Cream and Lotion, both in the

mid-potency category; Clobex Lotion, a superpotent

steroid; and Temovate E Cream. Both of these are

clobetasol propionate.

There will be 11 studies that I am going

to discuss. The ages of these patients were from 3

months to adult. These are all open-label trials,

and they all use the cosyntropin stimulation test

to determine the function of the HPA axis.

\[Slide.\]

Dermatop is a Class V steroid near the

bottom part of the mid-potency topical

corticosteroids. It was approved in May 1996. We

are going to discuss a pediatric atopic dermatitis

trial.

\[Slide.\]

There were 59 patients enrolled and there

were 2 targeted populations. The patients were

between 1 month and 2 years and also between 2 and

45

12 years. There were 10 patients who were less

than 2 years old and 49 patients were greater than

or equal to 2 years of age.

\[Slide.\]

They had to use the medication over

greater than 20 percent of the body surface area.

I mean they had to have atopic dermatitis to that

amount of cutaneous surface, and use it twice daily

for 21 consecutive days.

Again, we used the cosyntropin stimulation

test. It was administered at baseline and at day

22\. In this trial, patients who were greater than

or equal to 15 kilograms received a higher dose of

0.25 mg IV, those less than 15 kg received 0.125 mg

IV\.

\[Slide.\]

The criteria in this study was the adrenal

response to ACTH at 30 and 60 minutes. Here, the

post-stimulation serum cortisol had to be greater

than 20 mcg/dL, and if the pre-stimulation serum

cortisol level was already greater than 20, then,

an incremental increase of greater than 6 mcg/dL in

46

the serum cortisol was required.

\[Slide.\]

There were 3 patients according to the

protocol criteria who were suppressed. Two

patients, 1 an 18-month-old, had a peak response of

a 5 mcg/dL change from baseline, 1 patient had a

post-stimulation cortisol value actually decreased

from baseline.

At that time, the Agency agreed with an

outside endocrinologist that since these 3 patients

had a post-stimulation response that was already

greater than 20 mcg/dL, although they didn\'t have

that required incremental rise, that they should

not be considered suppressed.

So, this led to the current label that

reads for this drug, that \"none of the 59 patients

showed evidence of HPA axis suppression.\"

\[Slide.\]

The next drug is Cutivate Cream, which is

also a Class V steroid, was approved in June 1999.

We are going to look at another atopic dermatitis

trial in pediatric patients.

\[Slide.\]

There were 43 evaluable patients with

moderate to severe atopic dermatitis; 29 of the

47

patients were 3 months to 2 years of age, and 24

patients were 3 years to 5 years old.

\[Slide.\]

The criteria for entry into the study was

that they had to have at least a 35 percent body

surface area involvement, and I will tell you in

all of these studies, we were looking for maximum

use conditions, so you could get your worst case

scenario.

They applied the medication twice a day

for 3 to 4 weeks. Patients up to 2 years were

limited to 120 grams/week, and patients 3 to 5

years of age were limited to 180 grams/week.

\[Slide.\]

Looking at body surface area improvement

over time to show the response to the medication,

23 of the patients, or 50 percent, had a decrease

of 50 percent by 2 weeks, and 9 had a decrease of

50 percent by 3 weeks, and 9 percent of the

48

patients had a 50 percent decrease by 4 weeks.

\[Slide.\]

The cosyntropin was administered at

baseline and end of treatment, and in this study,

they used age, younger age group was given a lower

dose than the older age group.

\[Slide.\]

Here, a normal response was a serum

cortisol level that exceeded 18 mcg/dL at 30

minutes post-stimulation.

\[Slide.\]

Two the patients out of the 43 patients

experienced adrenal suppression. One was a

5-year-old who actually had 95 percent body surface

area involvement, used the drug for 4 weeks, used

561 grams, and his pre-stimulation, as you see

here, pre-treatment value was 33.9 after

stimulation, and yet it fell to 11.8, but in

follow-up he recovered at 19.8 with his serum

cortisol.

The other patient was a 2-year-old who had

the minimum amount of body surface area involvement

49

of 35 percent. His duration of treatment was for 5

weeks. He used 176.5 grams, and his end-treatment

post-stimulation serum cortisol was 9.4.

Unfortunately, we don\'t know whether he recovered

or not because he was lost to follow-up and the

investigator did make an honest effort to try to

track this child down.

\[Slide.\]

But this led to labeling changes for

Cutivate Cream, which stated that children as young

at 3 months of age for up to 4 weeks of use could

use the medication, and appropriate sections of the

label were updated.

\[Slide.\]

Now, I am going to talk about 4 or 5

betamethasone propionate products. They were all

approved in 2001, and when I say approved in 2001,

I mean the pediatric part of the label was changed.

Their supplement for safety was changed, because,

of course, they have been on the market a lot

longer than just 2001.

One is Diprolene AF Cream, which is a

50

Class II steroid; Diprosone Ointment, another Class

II steroid; Diprosone Cream, a Class III steroid;

Diprosone Lotion, which is mid-potency, but the

lower end of the mid-potency, and that will be

significant when you see the study results of this

drug, of Diprosone Lotion.

Then, I am going to speak of the 2

combination products, Lotrisone Cream and Lotion.

\[Slide.\]

The criteria for a normal HPA axis

response in all of these studies was that we would

follow the cosyntropin label, that the failure of

any one of three criteria would indicate

suppression of the HPA axis, and stimulation should

occur at baseline and end of treatment.

\[Slide.\]

So, the criteria for the 30-minute

post-stimulation, the three criteria that they

needed to meet to have a normal response, is that

the control plasma cortisol level should exceed 5

mcg/100 mL, the 30-minute cortisol level should

show an increment of at least 7 mcg/100 mL above

51

the basal level, and the 30-minute level should

exceed 18 mcg/100 mL, and a failure of any one of

those three would indicate suppression.

\[Slide.\]

So, with Diprolene AF Cream, there were 60

evaluable patients. They ranged in age from 1 to

12 years with atopic dermatitis. They had a mean

body surface area involvement of 58 percent. They

used the study drug twice a day for 2 to 3 weeks,

and that depended upon whether their disease

cleared or not.

If they cleared within 2 weeks, they were

allowed to stop and then be tested at that point.

If they needed 3 weeks, they could use if for 3

weeks. They were limited to 45 grams per week.

\[Slide.\]

The results of the cosyntropin stimulation

showed that 19 out of 60 or 32 percent of these

patients showed evidence of HPA axis suppression.

I won\'t go through all of these, but if you just

took the criterion that we look at now, which is

greater than 18 mcg/dL, 58 percent of the patients

52

had suppression.

\[Slide.\]

If you look at suppression by age group,

it appeared that a larger percentage of patients

suppressed as the age decreased.

Looking at recovery of normal HPA axis

suppression, unfortunately, all the patients were

not retested. We would have liked to have all of

them retested, but 4 patients were retested 2 weeks

post-treatment, and 3 of the 4 recovered normal

function of their HPA axis.

\[Slide.\]

We tried to do a statistical analysis in

the development of HPA axis suppression with each

drug. With Diprolene AF, there was no correlation

between amount of drug used, body weight, age or

sex, and the incidence of adrenal gland

suppression.

The statistical relationship did exist

between body surface area and risk of HPA axis

suppression such that for an increase of 1 percent

body surface area involved, the risk of HPA axis

53

suppression increased 4.4 percent with a p value of

less than 0.01.

\[Slide.\]

This led to a label change for Diprolene

AF Cream, such that it was restricted to patients

13 years and older, and appropriate information was

included in other sections of the label.

\[Slide.\]

Diprosone Ointment. That study had 53

evaluable patients with atopic dermatitis. The age

range was 6 months to 12 years. The medication

again was applied twice a day for 2 to 3 weeks.

The mean body surface area involved was 58 percent.

DR. WOOD: Can we just go back to that

last slide? The one with the 1 percent BSA

involved.

DR. COOK: Excuse me. Which one?

DR. WOOD: The last slide, the slide

before that, Slide 39. That is clearly key. Is

that really right? I mean does that mean that a 20

percent, that is linear throughout the thing, so

going from 1 percent to 21 percent would mean 88

54

percent of people had HPA suppression? That

doesn\'t seem to make much sense to me.

DR. COOK: Well, you will have to talk to

our statistician.

DR. WOOD: All right. Fair enough. Go

on.

DR. COOK: Let\'s see, I have figure out

where I left off. I think I was here, at Diprosone

Ointment and getting ready to tell you the patient

that suppressed.

There were 28 percent of patients who

showed evidence of HPA axis suppression when given

the cosyntropin stimulation test, and here again,

if we just looked at the criterion of less than 18,

of those who weren\'t able to exceed 18, 53 percent

of the patients had a post-stimulation plasma

cortisol value that would suggest suppression.

\[Slide.\]

Again, if you looked at suppression by

age, for this drug, again, there was a higher

proportion of patients who suppressed, the younger

the patients were.

\[Slide.\]

In the statistical analysis here in the

development of HPA axis suppression, these

55

statisticians didn\'t find a statistically

significant effect for drug usage, for percent of

body surface area involved, for weight, or for age.

It did show that for some reason, a higher

proportion of males than females developed HPA axis

suppression using this drug.

\[Slide.\]

In testing patients for recovery, 2 of the

15 patients were retested and 100 percent recovered

at 2 weeks.

\[Slide.\]

This led to a label change similar to

Diprolene AF Cream in which an age restriction was

added that patients should be 13 years of age or

old, and appropriate parts of the label were

updated with the clinical data.

\[Slide.\]

Diprosone Cream studied 43 evaluable

patients with atopic dermatitis. They ranged in

56

age from 2 to 12 years. Here, the mean body

surface area involvement was 40 percent. Again,

they applied the medication twice a day for 2 to 3

weeks.

\[Slide.\]

In this study, 23 percent of the patients

showed evidence of adrenal suppression using the

Cortrosyn label with all three criteria and a

failure of one.

If you look again at a post-stimulation

value that was less than 18, 50 percent of patients

showed evidence of adrenal suppression.

\[Slide.\]

In this study, you can\'t quite see the

value here. Starting here with 14 percent of

patients 9 to 12 years of age showed evidence of

suppression. As you march down again, the

percentages went up, but here, interestingly, which

will show you the dilemma that we all are in, in

determining just what is going to make someone

suppressed, what are the risk factors here, none of

the infants in this study showed evidence of

57

adrenal suppression.

\[Slide.\]

Again, with the statistical analysis for

this particular drug, in these patients, there was

no statistically significant effect for number of

days treated, for weight, or for age.

However, there was a statistical

significance found for mean amount of drug usee -

81 grams in those who suppressed versus 37 grams in

those that did not.

There was a numerically higher percent of

body surface area involvement in those who

suppressed, and numerically, more males developed

suppression.

\[Slide.\]

When looking at recovery of HPA axis

function with Diprosone Cream, 2 out the 10

patients were retested, and 50 percent, 1 out of

the 2, recovered function at 2 weeks.

\[Slide.\]

Here again, the label was changed to add

and age restriction to 13 years or older, and

58

appropriate portions of the label were updated.

\[Slide.\]

Now, Diprosone Lotion, I will remind you

again is a Class V steroid, so just like two

classes above the lowest potency of topical

corticosteroid.

Here, they had 15 evaluable patients with

atopic dermatitis. They ranged in age from 6 to 12

years old. The mean body surface area involvement

was 45 percent. They applied the medication twice

a day for 2 to 3 weeks.

\[Slide.\]

This was a very interesting study. Eleven

of the 15 patients or 73 percent of the patients

showed evidence of HPA axis suppression. If we

look at just getting a serum cortisol value that

exceeded 18 mcg/dL, 91 percent of the patients

failed to do that.

\[Slide.\]

Although this study was supposed to enroll

infants, it was felt that with such a high degree

of HPA axis suppression, the proportion of patients

59

6 to 12 years of age, that no patients were

enrolled in the lower age group. This brought up

the issue that possibly it is not only the chemical

moiety that might produce HPA axis suppression, but

since it is coming from the skin, it may involve

the vehicle in which the chemical moiety is in.

In this instance, the lotion, it may

somehow with the chemical moiety quicker from the

skin into the systemic circulation, and thereby

cause more HPA axis suppression. So, in other

words, vehicle may play a role also in determining

that systemic effect.

\[Slide.\]

When looking at the statistical analysis

in the development of HPA axis suppression, it was

a numerical analysis. The subjects exhibiting HPA

axis suppression used the larger mean amount of

drug. They had a slightly higher percent of BSA

involvement.

They had lower mean weights at visit 1,

lower mean weights at visit 4, but the difference

with respect to age and days of treatment, at least

60

from a statistical point of view, were minuscule.

\[Slide.\]

Looking at recovery of HPA axis function

with Diprosone Lotion, it\'s good to report that 67

percent of the patients who were retested recovered

their HPA axis function at 2 weeks.

\[Slide.\]

So, the labeling change for Diprosone

Lotion was that an age restriction was added to 13

years and older, and appropriate sections of the

label again were updated.

\[Slide.\]

Just to look at the four betamethasone

products together, again, you see that the three

here, Cream, Ointment, and Cream, all seemed to

suppress somewhat where in the same range. When

you got down to the lotion, you had a much, much

higher percentage of patients who experienced HPA

suppression. Again, it may have to do with the

vehicle, if there is an absorption enhancer in it

or other factors.

\[Slide.\]

Lotrisone Cream is the other betamethasone

product that I am going to speak about. It is a

combination product of betamethasone dipropionate

61

with Lotrimin Cream. It is indicated for the

treatment of tinea pedis and tinea cruris, so we

did a study in both of those.

Both studies were in the adolescent

population, 12 to 16 years. Medication was applied

twice daily. The study duration for tinea pedis

was 4 weeks and for tinea cruris was 2 weeks.

\[Slide.\]

Here, we also have some surprising

results. Seventeen out of 43 or 39.5 percent of

patients demonstrated adrenal suppression in the

tinea pedis study, and we might not have actually

expected that given that the stratum corneum of the

feet is somewhat thick, but it might also be

teenagers wear sox and tennis shoes all day long,

and that might also cause more occlusion and

absorption of the drug product.

In tinea cruris, there were 47.1 percent

who demonstrated adrenal suppression, and this is

62

also is an area where you may have some natural

occlusion, increasing absorption.

\[Slide.\]

So, this led to some labeling changes for

Lotrisone Cream and Lotion. The Indication Section

was expanded, it added an age restriction to

patients 17 years and older. It also recommended

that effective treatment may be obtained without

the use of a corticosteroid for non-inflammatory

tinea infections. Then, other appropriate sections

of the label were updated with clinical

information.

DR. FINCHAM: Dr. Cook, may I interrupt

for a second and just ask a question about the data

sets that you are reporting on?

DR. COOK: Sure.

DR. FINCHAM: Is this Phase IV data that

is provided by sponsors, that then the Agency has

acted on to change the label?

DR. COOK: No. Most of this was done in

response to what we call \"pediatric written

requests,\" which is part of the FDA Modernization

63

Act. So, we could either ask them to do the

studies\--I mean all of this was post-approval, but

I don\'t know if we actually call it Phase IV\--we

could either ask them to do the studies or they

could propose the study to us, but we would have to

then issue them the pediatric written request which

would allow them to do the studies. That is sort

of a quick summary.

\[Slide.\]

Now, this steroid, Clobex Lotion, was

actually approved in 2003, and this actually was

part of their NDA, and was not a Phase IV. At that

time, we were able to ask for and get trials in

pediatric patients if we needed it.

These trials, atopic dermatitis and for

psoriasis, were done in both pediatric and adult

patients.

\[Slide.\]

There were 3 studies involving Clobex

Lotion, 2 adult studies, 1 in psoriasis and one in

atopic dermatitis, and 1 pediatric study, ages 12

to 17 years in atopic dermatitis.

In all of the studies, there was a

comparator drug, Temovate E Cream, which is also

clobetasol propionate, so the same chemical moiety

64

in a different vehicle. As I say here, it is a

Class I steroid.

\[Slide.\]

The construct of the HPA axis evaluation

for this study went back to the 3 criteria, and

that is because the actual NDA and construct of the

study was done prior to our criterion of just 1,

because it was approved in 2003, so the studies

were done prior to that.

\[Slide.\]

In the adolescent study, there were 24

evaluable patients, 14 were treated with Clobex

Lotion and 10 were treated with Temovate E Cream.

They all had moderate to severe atopic

dermatitis. They had to have a body surface area

involvement of at least 20 percent. The medication

was applied twice a day for 2 weeks, and there was

a 50-gram/week limit, and a lot of this at the time

was driven by the fact that Temovate E Cream, that

65

is how it\'s labeled.

\[Slide.\]

It was found that 9 of the 14 or 64

percent of subjects treated with Clobex Lotion were

suppressed versus 20 percent of subjects treated

with Temovate E Cream, again suggesting that the

vehicle may have something to do with the amount of

drug that gets into the systemic circulation.

\[Slide.\]

In the statistical analysis the mean

percent body surface area treated was higher for

patients that had adrenal suppression, 32.8 percent

versus 27.7 for the Clobex Lotion and 35 percent

versus 25.3 percent for the Temovate E Cream.

\[Slide.\]

When retested, 1 of the 4 patients treated

with Clobex Lotion remained suppressed after 2

weeks, and 1 of the patients, which was the only 1,

that was suppressed with Temovate E Cream

recovered.

\[Slide.\]

In the adult study, there were 18

66

evaluable patients, 9 were treated with Clobex

Lotion and 9 with Temovate E. They all again had

moderate to severe atopic dermatitis. The mean

body surface area treated was approximately the

same for both drug products. They applied it twice

a day for 2 weeks, again with a 50-gram/week limit.

\[Slide.\]

Here, 56 percent of the patients treated

with Clobex Lotion suppressed and 44 percent with

the Temovate E Cream suppressed.

\[Slide.\]

When looking at recovery for these 2

products, 1 of the 3 patients retested failed to

recover function 7 days post-treatment with the

Clobex Lotion, and 2 out of 2 patients on Temovate

E Cream recovered their function 7 days afterwards.

\[Slide.\]

Finally, in the adult study, moderate to

severe plaque psoriasis , there were 20 evaluable

patients, 10 in each arm. Again, the mean body

surface area treated for both was approximately the

same. The medication was applied twice a day here

67

for 4 weeks, and there was again a 50-gram/week

limit.

\[Slide.\]

Eighty percent of the patients treated

with Clobex Lotion suppressed and 30 percent with

Temovate E Cream suppressed. One of the 2 subjects

retested with Clobex Lotion remained suppressed

after 8 days, and none of the 3 subjects on

Temovate E Cream unfortunately were retested.

\[Slide.\]

So, the indication for Clobex Lotion, when

it was approved based on these results, was that it

would be restricted to patients 18 years of age or

older. It could be used for two consecutive weeks

not to exceed 50 grams/week.

For moderate or severe psoriasis, for

localized lesions less than 10 percent body surface

area involvement, that an additional 2 weeks of

treatment, the lotion could be used. Appropriate

other sections of the label were updated.

\[Slide.\]

Now, I am going to shift gears from our

68

trial data and look at a postmarketing summary of

HPA axis suppression across all topical

corticosteroids since the induction of the AERS

database, which is one of our sources since 1969,

and also from medical literature case reports.

\[Slide.\]

I will just give you a background on the

Adverse Event Reporting System. It is a

spontaneous, voluntary surveillance system. It is

voluntary reporting by health care professionals

and consumers, but it requires mandatory reporting

by manufacturers.

There are approximately 3 million reports

in the database. Again, the database originated in

1969\. It contains human drug and therapeutic

biologic reports. The exception is it doesn\'t have

vaccines.

The quality of the reports are variable

and they are often incomplete, so you have to keep

that in mind. It is also subject to

under-reporting, the true numerator is not known,

and duplicate reporting does occur.

\[Slide.\]

There have been 94 cases reported spanning

3 decades, 65 adult cases and 29 pediatric cases.

69

The gamut of manifestations had been adrenal

insufficiency, Cushing\'s syndrome, and growth

retardation.

\[Slide.\]

In the 29 pediatric patients, and some of

these overlap within same patients, 11 were with

adrenal insufficiency, 17 with Cushing\'s syndrome,

and there are 13 with growth retardation.

The ages ranged from 6 weeks to 15 years

with the mean being 5 years. The duration of use

was 22 days to 7.5 years with a mean of 20.8

months. Fifty-five percent of these patients

received medication for 3 months or longer. There

were varied indications, but 34 percent in the

pediatric population were using topical

corticosteroids for diaper rash.

Betamethasone containing, clobetasol, and

mometasone products were implicated most often with

34 percent using high-potency topical

70

corticosteroids.

In these 29 pediatric patients who had

evidence of some type of HPA axis compromise, it

resulted in 14 hospitalizations and 2 deaths. The

latter were from Cushing\'s syndrome or

complications thereof.

\[Slide.\]

In the adult cases, there were 65, 46 with

adrenal insufficiency and suppression, 32 with

Cushing\'s syndrome.

The age range was from 19 years to 74

years, with the mean age being 47.4 years. The

duration of use 7 days to 12.0 years, and the mean

use was 35.6 months.

Forty-six percent of the patients received

the medication for 3 months or longer. Again,

there were varied indications, but 51 percent used

topical steroids for psoriasis. Again,

betamethasone containing and clobetasol products

were implicated most often, with 61 percent using

high potency topical corticosteroids.

These cases resulted in 34

71

hospitalizations and 2 deaths, and the deaths were

attributed in part of the adrenal event.

\[Slide.\]

So, the postmarketing reports, just in

summary, the common factors were that most of the

AEs occurred in the following settings:

Prolonged use of the topical

corticosteroid, use of a superpotent topical

corticosteroid, use of multiple topical

corticosteroid products or concomitant use with

other corticosteroid formulations like inhaled or

systemic, and also use of excessive amount or

possible inappropriate use of the topical

corticosteroid product.

\[Slide.\]

In summary of the data for the HPA axis

suppression, HPA axis suppression does occur with

the use of topical corticosteroids.

The adrenal suppression is not limited to

the superpotent class of topical corticosteroids.

High BSA involvement and amount of drug

used appear to be risk factors for HPA axis

72

suppression.

\[Slide.\]

The type of vehicle may contribute to the

extent of absorption of the active chemical moiety.

The suppression appears in most cases to

be reversible upon cessation of drug usage.

Long-term use of topical corticosteroids,

particularly high potency ones, can lead to serious

morbidity and even death.

\[Slide.\]

Now, we are going to move on to cutaneous

safety. We will first speak about the known

cutaneous adverse events, and then we will just

address here briefly the question of cutaneous

malignancy as it might relate to topical

corticosteroids, if at all.

\[Slide.\]

Now, the adverse events associated with

topical corticosteroid use include atrophy of the

skin, telangiectasia, striae, erythema of the face,

steroid rosacea, hypopigmentation, infection, and

retarded wound healing.

\[Slide.\]

Because pictures speak a thousand words, I

am going to give you a pictorial presentation of

73

these adverse events.

\[Slide.\]

This is a photo of cutaneous atrophy. It

is not the best photo, but here you can appreciate

a little bit of thinning of the skin and some

shininess to the cutaneous surface.

\[Slide.\]

Here, we have telangiectasia. You can see

the very fine blood vessels coursing here through

this person\'s chin.

\[Slide.\]

This is a picture of striae, probably

long-standing.

\[Slide.\]

Another picture of striae, maybe a little

more of acute onset in nature.

\[Slide.\]

This is a picture of facial erythema.

\[Slide.\]

Another of facial erythema.

\[Slide.\]

This is a picture of steroid rosacea where

someone was applying topical corticosteroids and

had a flare of the disease. Certainly, here, the

potency of the topical corticosteroid would have to

74

be weaned down, and then the rosacea, which is the

underlying disease, had to be treated

appropriately.

\[Slide.\]

This is a picture of hypopigmentation from

topical corticosteroid use.

\[Slide.\]

Other adverse effects that can happen.

Topical corticosteroids placed on certain

infections, for example, tinea infections, may

exacerbate them. Topical corticosteroids placed on

open or surgical wounds will retard healing. Use

of topical corticosteroids in the periorbital area

may cause an increase in intraocular pressure.

\[Slide.\]

Now, as far as cutaneous malignancy, we

75

will look at the postmarketing reports out of the

same system that I was speaking about prior, the

AERS database, and there are 2 reports as of

February 5, 2005, that spans all the way back to

1969\.

One was a 7-month-old male with a history

of mastocytoma, and he reported or someone reported

cancer several months after discontinuation of

clobetasol. The patient actually used fluticasone

for a short while, and then used clobetasol

propionate for 1 week, stopped for 1 week, and then

started to reapply for another week, but developed

cutaneous atrophy, and the medication was stopped,

and then several months later, the report came that

he developed skin cancer.

The second case is a female of unknown age

who used betamethasone cream for psoriasis and then

reported \"what started as psoriasis became cancer\".

So, from this we can say that the AERS

data do not suggest a compelling safety signal for

malignancy formation with the use of topical

corticosteroids.

\[Slide.\]

So, as far as cutaneous adverse events,

corticosteroid-induced adverse events can be early

76

or late event. It depends on the potency of the

drug and the duration of use. It depends on the

site of application. Occlusion at the site may

increase the risk.

Corticosteroid-induced adverse events may

resolve slowly or they may not resolve at all.

\[Slide.\]

So, in conclusion, HPA axis suppression

can occur with short-term use of topical

corticosteroids. HPA axis suppression can occur

with even mid-potency topical steroids. It can

occur as early as two weeks of continuous therapy.

\[Slide.\]

The suppression that occurs is usually

reversible. The interrelationship between body

surface area, amount of drug used, and potency of

the medication is complex as it relates to the

development of HPA axis suppression.

Long-term use and/or misuse of topical

77

corticosteroids, particularly those of high

potency, can lead to serious medical complications

and death.

\[Slide.\]

The cutaneous adverse events can be

related to both duration of use and potency of

topical corticosteroid use. It can occur with

short-term or long-term use.

Resolution of these cutaneous adverse

events is possible with some, but not all of them.

There also is no firm evidence to date to

link cutaneous malignancy with the use of topical

corticosteroids.

Thank you for your attention for this

presentation.

Next, we will have Dr Stephen Wilson. He

is in the Division of Biometrics II. He will speak

on lessons learned from growth studies with orally

inhaled and intranasal corticosteroids.

Lessons Learned from Growth Studies with Orally

Inhaled and Intranasal Corticosteroids

DR. WILSON: Gray Gaithersburg morning to

78

you.

It is my pleasure to be here this morning

substituting for Peter Starke. I think that I was

elected for this job because I am the only one that

was around when they did the class labeling

advisory committee in 1998, but we have had some

lessons that we have learned from that advisory

committee in dealing with growth studies for orally

inhaled and intranasal corticosteroids, and I would

like to share some of those with you in the short

amount of time that we have.

\[Slide.\]

Specifically, we have been charged with

providing you with somewhat of a background of why

we do these studies within our area for intranasal

and orally-inhaled corticosteroids, and then talk

about what these growth studies are.

In particular, we are going to focus on

what we call longitudinal growth studies, which are

fairly long-term growth studies. Then, we will

talk about some of the design issues with these

studies and the regulatory history that sort of

79

brought us to this moment in terms of the science.

I will provide with the results from some

of the studies that we have seen within the

Division. When I say \"we,\" I mean the Division of

Pulmonary and Allergy Drug Products.

\[Slide.\]

So, why do we perform growth studies? I

think that looking at it from our perspective,

growth is an indicator of systemic exposure and of

the potential to cause systemic toxicity.

Growth suppression is a well-known side

effect of systemic corticosteroid use. It has a

class effect. We view it as a class effect, that

all CS given in sufficiently high doses will

produce growth effects. It is thought to be a

direct effect on the bone, and may also act through

secondary mediators and hormones.

We believe that growth is the most

sensitive indicator of systemic effect within our

review environment because we have seen growth

effects in the absence of effects from HPA axis

studies by cosyntropin stimulation.

\[Slide.\]

There are basically two types of studies

that are presented to us by sponsors. One goes by

80

the name of knemometry, and the other is the

longitudinal or long-term growth studies.

Sponsors have done knemometry studies.

These are generally short-term studies, so it is

attractive in the sense that they can be done

rather quickly, and there are a number of

methodological issues. They can essentially be

done in only a few centers.

The consistency of results has been

puzzling and a little bit problematic to us as a

regulatory agency, because we don\'t always see the

same kinds of results coming out, and we view these

as primarily a research tool.

So, focusing on longitudinal growth

studies, these are growth studies designed to

measure growth velocity over a 1-year treatment

period, so this is a long treatment period.

The patient population has to be carefully

selected because this is a patient population that

81

needs to have the treatment, but we also need\--and

you will see in a minute\--we also need to be able

to run a concurrent control, so some on

corticosteroids and others using other kinds of

medications.

\[Slide.\]

What is the population that we look at in

these growth studies? These two CDC charts are

provided primarily to show you where we consider

growth to be fairly linear.

For one thing, it is very difficult to get

growth measurements in the youngest children, zero

to 2 years old. By 2, you are able to get the

stadiometry measurements, and the growth is fairly

linear, until you get up to puberty, about 9 to 11

years old depending on sex.

So, this is the focus of these growth

studies that are provided to us by the sponsors.

\[Slide.\]

So, what are these growth studies, what do

they look like? Basically, it is fairly

straightforward. It\'s serial stadiometry. There

82

is a baseline period of about 3 months in which we

measure growth, baseline growth.

Then, there is an on-treatment period and

then another follow-up of 3 months. There was a

guidance that was developed following the advisory

committee that I mentioned in 2001, and it is still

available on the website, so you can see some of

the details of what we are suggesting.

\[Slide.\]

So, longitudinal growth studies. As I

said, they are technically difficult to perform.

They require relatively large numbers of children.

In fact, in the guidance that we provide, we say

that ideally, they would have almost 125 children

in each of the treatment groups. So, you can see

they are quite a bit larger than the studies we

have been looking at.

They require a long baseline and treatment

period, and the measurement and compliance issues

are very difficult, in other words, you have got to

keep children on these studies for a long time,

working with parents and providing treatment.

There are also statistical issues in terms

of when the data has been provided to us. This is

what I think probably sponsors have the most

83

problem with is we are not looking at these as

superiority trials or even equivalence or

non-inferiority trials. It is just too difficult

to make a judgment as to what the delta or the

difference that you are looking at would be.

So, we essentially are presuming that

there is a growth effect from these drugs, and we

are designing them to best characterize that

effect, so this is a little bit different, and that

means that you have to have the proper size, you

have to conduct the studies appropriately, and that

is what we are going to be reviewing if we are

going to describe what your study has done in the

label.

So, the size of the growth effect that is

clinically relevant is unknown or not fully known.

That is what our presumption is.

\[Slide.\]

So, how did we get here? Actually, there

84

is some OTC history here. In 1996-97, there were

two longitudinal growth studies done to better

characterize the systemic risks prior to

consideration of taking beclomethasone dipropionate

nasal spray over-the-counter.

So, in other words, the company was

developing, wanted to go OTC, had these growth

studies going, and when the results of these growth

studies became available, it was recognized that

there was a growth effect that hadn\'t been shown in

the other kinds of tests.

Then, at that same time, the number of

other companies who were doing growth studies also

came in and demonstrated this same kind of effect.

So, 1998, we held a Joint

Pulmonary-Allergy and Metabolic-Endocrine Advisory

Committee, which ended up recommending a class

labeling for all orally inhaled and intranasal

corticosteroids, and we ended up also implementing

that recommendation.

\[Slide.\]

So, what did that label end up looking

85

like? Well, in the General Use and Pediatric Use

Subsections, we essentially said orally

inhaled/intranasal corticosteroids may cause a

reduction in growth velocity in pediatric patients.

Also, in the Pediatric Use Section, we

noted that growth effect may occur in the absence

of laboratory evidence of

hypothalamic-pituitary-adrenal axis suppression,

potential for treatment \"catch-up\" growth has not

been addressed, and basically, our advice to the

physician was to titrate to the lowest effective

dose for each patient and monitor growth routinely.

If reported, cases of growth suppression

should be noted in the Advise Reactions Section.

So, basically, in terms of this being a

class labeling, we would only note certain kinds of

growth suppression if it was being reported to our

systems.

\[Slide.\]

So, how did this original study look, the

one that we were looking at for the advisory

committee?

Intranasal beclomethasone basically was a

randomized, double-blind, placebo-controlled,

parallel group, prospective, one-year study.

86

The age groups of the children, they were

children with allergic rhinitis being treated by

intranasal corticosteroids, ages from 6 to 9.5

years. Basically, the same size study groups, and

you just had a placebo against the intranasal

corticosteroid, about 50 in each group.

\[Slide.\]

Now, the results showed that the growth

rate centimeters/year on the BDP treatment group

was 5.1 versus a placebo of 5.8, or a difference or

a delta of minus 0.7. So, that was the extent of

the depression that we saw for that one year.

Now, this was a statistically significant

difference based on the prespecified analysis, and

it was an unexpected result, but basically, we were

comparing mean annual growth rates.

In the same study, however, these same

children were tested, and there was no significant

differences observed between treatment groups by

87

mean basal cortisol or ACTH-stimulated plasma

cortisol levels.

\[Slide.\]

I wanted to make sure to include this

slide. This is again these same patients, and

looking at those charts that you saw earlier, the

growth charts, these are the results of the

patients based on where they fell on those charts

after a year.

I can remember the endocrinologist, Sol

Malozowski, was extremely interested in thinking

about what it meant. Even though we were looking

at mean data, in other words, there was a sense of

a minus 0.7 that I showed you, we were also looking

obviously, and very concerned about, how the

children as individuals or groups fell within these

two groups.

So, the mean data as expressed in

percentage within growth rate percentiles is

displayed here, so you can see something like 22

versus 4 in placebo or less than 3 percent in terms

of the average growth., and that was true

88

throughout, so this is the mean data expressed

another way.

\[Slide.\]

We also looked at some other intranasal

drugs, and these are the data that came in later.

You notice, as oftentimes happens, this was

actually the largest difference that we saw was on

the first one, and the intranasal drugs that came

in afterwards, budesonide and fluticasone, also

showed some growth depression. Mometasone,

however, as you can note, did not show.

\[Slide.\]

The orally inhaled drugs tended to show

more growth suppression, BDP, for example, minus 2

versus the 0.7 that you saw before. This slide

also indicates that this is a study that was done,

and you had some of those younger children, so you

tended to see a lot more variability in the

estimate, so the recommendations in the guidance

became, you know, you had to have these older

children that you could measure, because a lot of

these included recumbent measurements, and those

89

are difficult measurements to make.

Another thing here is that there is some

kind of apparent dose effect from a company that

did try to test two doses. So, we had all of this

data available to us in trying to make these

determinations.

\[Slide.\]

So, the issues. These are indeed

difficult studies to perform if you are thinking

about doing one of these studies. They are also

difficult studies to review. Now, if you are in a

regulatory setting, so basically, you are taking

what the company has given you as evidence, and you

are making some assessment of that.

If a company has, for example, if there

are a lot of subjects that have dropped out, you

have to worry a lot about missing data, and you

have to worry about if they haven\'t measured them

carefully over time, in other words, there are some

sort of glitches in the measurement, they then make

decisions as to how they are going to analyze that

data, so then as a reviewer, you have to respond to

90

that, so these are difficult studies.

Growth studies are not designed to

evaluate obviously the reversibility of the HPA

axis effects or changes greater than a year. So,

although we do measure for another 3 months after

the study, we do not try to see whether or not this

would be long term.

A lot of these patients, a lot of these

children are going to be on the drug for a lot

longer than 1 year.

We have not identified a clinically

relevant effect size, and that means that we all

sit around a number of time, on a number of

occasions, saying how could we pin down what the

effect size is, so that maybe we could look at

non-inferiority trial, but everybody said that

basically, it is not acceptable or there is no

clinically relevant effect size on that mean value.

\[Slide.\]

So, conclusions. We use growth studies as

a stand-alone measure. We believe that they are a

sensitive indicator of systemic effects, and we

91

think of this because sometimes the HPA axis and

the growth study results are discordant, they don\'t

agree with each other.

We take them as a surrogate for systemic

exposure and potential to cause systemic toxicity.

So, we are looking at children, these are people

that are going to need these drugs, but we also

take them with the notion that this is a sentinel,

this is something that is going to tell us is this

drug going to have effects more generally.

We believe that results are applicable to

all age groups. Obviously, you can\'t study growth

in 20- to 25-year-olds. We also feel that the

class effect labeling, when you look at the class

effect labeling, we state, as I stated earlier, all

orally inhaled and intranasal corticosteroids have

this effect.

As these studies come in to us from

companies, we review them and we determine whether

or not this is information that is going to help

the physician. This is information we need to put

into the label.

Sometimes we put what the company has

offered, and other times we feel that we are not as

sure that the results of the study are as reliable

92

as we would like them to be.

\[Slide.\]

Again, there is reference Division of

Pulmonary and Allergy Drug Products.

I can\'t believe that I actually finished

early, but I look forward to any questions you

might have.

Thank you.

The next presenter is Dr. Markham Luke.

HPA Axis Suppression Studies: Conduct,

Utility, and Pediatric Considerations

DR. LUKE: Good morning, Dr. Wood, members

of the Committee, ladies and gentlemen in the

audience.

\[Slide.\]

Today, I am going to speak on topical

corticosteroids and testing for adrenal suppression

in the context of potential Rx to OTC switch.

\[Slide.\]

This is a brief outline of my talk.

First, I am going to speak a little bit about the

various systemic effects that have been seen with

topical corticosteroids and some which have not

been seen.

We are also going to discuss specifically

93

the hypothalamic pituitary adrenal axis testing,

what tests are available to look at HPA, and more

specifically, we are going to focus in on

cosyntropin stimulation testing, look at what our

current testing recommendations, how we are trying

to standardize the testing, and we are going to

discuss how precise an estimate would we need for

adrenal suppression potential for OTC.

\[Slide.\]

Now, as Dr. Cook and Dr. Wilson have

stated, prescription corticosteroids have systemic

effects which we evaluate during drug development.

\[Slide.\]

Now, I would like to separate these out

into those areas where specific studies have not

been required for dermatologic topical

94

corticosteroids. These include sodium retention on

mineralocorticoid effect, glucose tolerance, growth

suppression, osteoporosis, and what we do look at,

which is HPA axis suppression.

With regard to sodium retention, they are

receptor-specific effects and they may be less

concerned with glucocorticoids. I am going to go a

little bit into that.

Regarding glucose tolerance and growth

suppression, data available for glucose tolerance

from clinical studies, the growth suppression

studies, as Dr. Wilson has discussed, is

technically challenging and is difficult to perform

and to review.

Further, for osteoporosis, the same could

be said for that. It is difficult to have these

topical corticosteroids used for the long term.

The patients wax and wane with their disease, so

the application of the topical corticosteroid can

increase and decrease, plus the strength of the

corticosteroid may vary during the conduct of a

year-long study, so there is the potential for

95

change in dose and potency, which again leads to

inconsistent and very challenging evaluation of any

data that would be obtained from such a study.

Regarding HPA axis suppression, we will

get into that a little bit more.

\[Slide.\]

This is a table of the relative potencies

for various steroids with a cortisol at 1.0 and

there are two references in the package that was

given to the Committee regarding this. This table

is excerpted from those references.

As you can see, the two examples of

topical corticosteroids given in this table are

triamcinolone and betamethasone. Both of those

have a higher affinity or a higher relative potency

regarding glucocorticoid effect but a lower

mineralocorticoid effect. This can be contrasted

to aldosterone which has a much higher

mineralocorticoid effect as compared to

glucocorticoid effect.

(Slide.)

This is a schematic diagram of the HPA

96

axis. We have been talking a lot about the HPA

axis. Regarding specifically what it is, we have

the hypothalamus. This is a schematic

representation, again; the pituitary, anterior

pituitary, and what their effects are on adrenals.

This is a neural, hormonal axis and is

important for the human response to stress. Humans

respond to stress by producing ACTH which then

causes cortisol rises. F stands for cortisol here

in this diagram. If there is a failure to mount

such a response, it can lead to a hypotension and

cardiovascular collapse.

Now, this failure to mount may not be

easily clinically recognizable so attributing cause

and effect may be difficult with regards to adrenal

suppression in the clinical setting.

The ACTH here, in general, causes a rise

in the cortisol. However, with constant exposure

to exogenous corticosteroids, it has been thought

that there is a down-regulation of receptors here

and here which may lead to decrease-ability of the

adrenals to then respond and produce cortisol.

(Slide.)

With that, we get into HPA axis testing.

(Slide.)

97

There are two classes of tests, basic

classes; the basal testing, which is done with

basal plasma levels and 24-hour urine cortisol

levels. These are thought to be less useful in

measuring an adrenal response to stress than

dynamic testing where you try to stimulate the

adrenals to cause a response and you measure the

magnitude of that response.

(Slide.)

There are various dynamic tests of HPA

axis function. Earlier, it was mentioned, the

insulin tolerance test which is an older test.

When you administer insulin, you cause a

hypoglycemic event. It then results in a potent

stress stimulus for the adrenal glands.

Now, these subjects, when you administer

insulin, you need very close subject monitoring.

It is thought that this test, as it is currently

done, produces undue risk to the subject and,

98

therefore, the agency does not recommend this as a

test for HPA axis function.

The cosyntropin, or ACTH amino acids 1 to

24, test is available in higher or lower

concentrations. The higher dose is the labeled

dose for cosyntropin. Lower dose studies vary and

there is no standardization regarding how much of a

rise in cortisol you need with lower dose and the

timing of the rise is not standardized. So the

lower test is still experimental at this time and

if one is to use it, there should be discussion

with the Agency regarding how it is used.

For higher dose testing, we will discuss

that in just a moment. There is also a

corticotropin-releasing hormone test, the CRH test.

This also is experimental and not widely available.

(Slide.)

The higher dose cosyntropin test is the

most commonly used test to evaluate for adrenal

suppression. The procedure is to administer a

superphysiologic dose. It is currently labeled for

IV or IM use of 125 micrograms if the patient is

99

less than 3 years of age or 250 micrograms if the

patient is 3 years or older. The serum or plasma

cortisol concentrations are measured before and 30

minutes after the cosyntropin administration.

(Slide.)

The advantages of this test are that it is

simple, it is fast and relatively inexpensive. It

is an outpatient test and it takes approximately 30

minutes to do. There are some limitations. It is

not the most sensitive test. It can be equated to

being a physiologic hammer. I mean you are giving

a very high dose of what is equivalent to ACTH to

cause the adrenals to respond. So the sensitivity

may have some concern.

(Slide.)

The criteria for a normal response in

Cortrosyn, according to label and the 30-minute

test is as follows: The control of basal cortisol

level should be greater than 5 mcg/dL. At 30

minutes, after administering the Cortrosyn, there

should be at least a 7 mcg/dL rise above basal\--the

incremental cortisol rise, that is\--and the

100

30-minute level should exceed 18 mcg/dL.

However, we note that basal cortisol

levels vary throughout the day and the higher the

basal level, the lower the incremental cortisol

rise. So, for regulatory purposes and for drug

development, it is thought that normal response of

peak cortisol level of greater than 18 mcg/dL 30

minutes after giving Cortrosyn should be sufficient

as the test for adrenal suppression.

(Slide.)

With that, we segue to what are current

testing recommendations for adrenal suppression.

\[Slide.\]

There was an Advisory Committee on October

29th of 2003, and there was some discussion about

the HPA axis test, Joint Committee discussion. It

was discussed that higher dose cosyntropin test is

a sufficient determinant of HPA axis function with

regard to prescription topical corticosteroids.

A greater than 18 mcg/dL or 500 nM/L

post-stimulation cortisol level at 30 minutes is

equivalent to that subject being not suppressed.

101

It was also discussed at that Advisory Committee

where data was presented on reversibility, and you

saw the reversibility data, we have very little of

that. We need follow-up for reversibility when we

do these studies.

\[Slide.\]

It was a pediatric meeting, so there was

discussion about the pediatric cohorts. The

pediatric population was divided into 4 cohorts

here. Sequential testing was usually done for

these studies with the older patients first, but at

this Advisory Committee it was discussed that

potentially concurrent testing can be done if the

safety of the patients can be assured. The

rationale for that is to obtain more data regarding

the adrenal suppression in each of these cohorts.

\[Slide.\]

Additional recommendations from the Agency

are as follows: the 60-minute cortisol is not

recommended. The standardization for a 60-minute

level is poor, and the results can vary somewhat

from one, 60-minute test to another 60-minute test.

Testing less than 4 weeks apart is not

recommended. Administering the ACTH or Cortrosyn

start to leave an impression on the adrenals and

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there may be effects on later response especially

when the tests are done closer than 4 weeks apart.

There is a need to monitor the local

cutaneous adverse events during the conduct of this

study.

Finally, it is important to note when

interpreting these studies that the percent of

patient suppressed, not the mean cortisol levels is

important. Mean levels may mask individual

patients, so if someone were to present data on

mean levels, ask them what the percent of patients

suppressed was.

\[Slide.\]

Finally, we note Dr. Cook\'s presentation,

the body surface area involved can vary from atopic

dermatitis, at least 30 percent body surface area

is needed, for psoriasis, at least 25 percent body

surface area involvement for these patients, and

these are maximally involved diseased patients.

It is also important to note that patients

who enter the study should not be adrenal

suppressed, so there should be testing for adrenal

suppression prior to exposing them to

corticosteroid to make sure they are not suppressed

at baseline. Often these patients will have come

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into a study having been on other corticosteroids

for a protracted length of time because of their

significant disease.

\[Slide.\]

The last part of this talk, we are going

to discuss a little bit about what precision do we

need for OTC use of corticosteroids.

\[Slide.\]

For topical corticosteroids drugs to be

used in an OTC setting, how acceptable is HPA axis

suppression, and how many subjects need to be

evaluated to rule out corticosteroid-induced

adrenal suppression for an OTC product if this is

one of the tests that is going to be used?

\[Slide.\]

Here is an exercise I would like to pose

104

to you. If we had 30 subjects and we treated them

all with topical corticosteroids for 4 weeks, and

we noted those 30 subjects, zero had cosyntropin

stimulation test indicative of adrenal suppression,

that is, the rate was zero out of 30.

The question arises with what risk, if

any, of adrenal suppression induced by topical

corticosteroids might these results be compatible,

is it zero risk? I would like to propose that it

is not.

\[Slide.\]

Zero out of 30 subjects rules out, with 95

percent confidence, a greater than 10 percent

chance for adrenal suppression to occur in the

global population. This is a statistical concept,

and there is a paper in the package that was handed

out discussing the rule of 3\'s, and this is one way

to look at this.

The sample size determines the extent we

can rule out adrenal suppression in the global

population with zero subjects suppressed.

\[Slide.\]

With that, we can go to this table on

sample size effect on the upper confidence interval

to just go over and give an example. Say we have

105

10 subjects and we had zero of those 10 subjects

suppressed.

Well, that would rule out with a 95

percent confidence interval no greater than 26

percent adrenal suppression. Whereas, if we double

the number and go to 20 subjects, we can increase

that upper confidence interval to 14 percent.

To get to really small percentage numbers

for upper adverse event occurrences, we need larger

sample sizes. So, the greater the number of

patients you have, the more assuredly you can be of

that zero that you see for that study, if the study

does give you zero.

\[Slide.\]

So, the question asked for the Committee:

Cosyntropin stimulation studies are used to inform

labeling for prescription products with regard to

potential for adrenal suppression.

If the cosyntropin stimulation studies are

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to be used for OTC products, how many subjects are

needed for those studies, that is, what is the

level of tolerance for adrenal suppression for an

OTC drug product?

That is it for my portion of the talk.

Thank you.

DR. WOOD: Okay, great. It is exactly 10

o\'clock, so let\'s take a break for 10 minutes and

be back ready to start again at ten past 10:00, and

we will go straight to the questions for the

speakers, and then pass on to the questions for the

Committee at that point.

\[Break.\]

Questions from the Committee and

Committee Discussion

DR. WOOD: So we have heard all the

presentations. Let\'s open the session for the

Committee to question the speakers. Terry?

DR. BLASCHKE: I have a technical

question, I think for Dr. Luke. In your

presentation, you indicated that the cosyntropic

administration could be IV or IM. I am just

107

wondering how many of the subjects, for example, in

the studies that we were presented actually got the

cosyntropin IM and do we know whether there is more

variability or sensitivity, differences in

sensitivity, when the cosyntropin is administrated

IM versus IV.

DR. LUKE: As far as I know, there are no

comparisons in the literature between IM and IV

use. For pediatric studies, it is often more

convenient to do an IV study rather than an IM

study simply because of the pain threshold of those

patients. You can insert a cannula and inject the

cosyntropin and also withdraw blood from the same

cannula afterwards and so there is only one stick.

When you go to do the IM, it may be due to

access difficulties that one would resort to an IM.

Regarding whether one should do IM or IV, I think

it is important to be consistent throughout each

study as to what route you choose to administer the

cosyntropin. But, as far as I know, there are no

studies to compare the two routes.

DR. BLASCHKE: I suspect it is not done

108

consistently because I suspect that it really does

relate to ease of access of a vein in a small child

and so forth. We know that there are a lot of

compounds that, when they are administered IM,

depending on where, et cetera, that the absorption

and the absorption rate is quite different for IM,

obviously, than IV.

It sounds like, as you say, there is no

comparative data so maybe no answer to the

question.

DR. WOOD: Dr. Snodgrass.

DR. SNODGRASS: Are there any standards

required for the timing of the test, 8:00 a.m., for

example, and knowledge about their sleep patterns

for the circadian rhythm aspects?

DR. LUKE: Because of the circadian

rhythm, it is thought that a standard time might be

helpful but keep it close within. It is often

difficult to do a study where you have all the

patients done at the same time. So there is some

variability allowed for it.

Just to go back, also, to the IM versus IV

109

concern. Of note, the lower cosyntropin

stimulation test, the lower dose, there have been

concerns raised about the peptide sticking to

tubing, so that may be a concern raised if you are

performing lower dose cosyntropin testing.

DR. WOOD: Dr. Epps.

DR. EPPS: My questions actually are for

Dr. Wilson. Is that okay?

DR. WOOD: Sure. We are taking questions

for all of the last speakers.

DR. EPPS: Okay. The growth charts, the

CDC growth charts, were those based on the standard

growth charts that are used or are they updated and

different?

DR. WILSON: Those are the standard growth

charts that everybody sees and are available from

the government.

DR. EPPS: The reason I ask is that\--I

thought it was my understanding that they were

standardized on a group of cohorts in Kansas in the

\'50s or \'60s or something and that is why I

wondered if they had been updated at all.

DR. WILSON: That is a good question. I

don\'t know. I mean we kept looking for whatever

the most current was. We recommend the most

110

current. These are trials in which we have

comparators and are randomized. So we have all

those kinds of things taken care of.

But you are right. We pondered a lot

about the growth charts and what they really meant

for individuals. As you were looking at those

percentage breakdowns, that is where it becomes

more important probably.

DR. EPPS: Also, my question was do the

kids recover. You were taking about growth

velocity which is different from overall growth

potential and whether\--you know, kids accelerate

and decelerate and, really, the lines are kind of

percentiles or averages. So that was one question

I had, whether the velocity\--I guess, the long

term.

DR. WILSON: The long term. Again,

sponsors have presented to us, and there have been

a few studies done on trying to assess whether

111

there are some long-term effects. But those are

even more difficult to do than these annual

studies.

I think that the assumption has always

been, and Gene, you could correct me if I am wrong,

that a lot of this will be recovered. We have

never looked at ultimate height. Companies, of

course, are always saying this. They want to have

that in their label that this isn\'t going to affect

it.

This is Gene Sullivan from the Division.

DR. SULLIVAN: Hi. I am a pulmonologist

in the Pulmonary Division. I think what you are

getting at is part of the reason why the slide said

we don\'t know the clinical significance. We can

measure what happens in that year, what happens

when you stop the drug, is there catch-up growth,

is the full adult height affected? Those are

still, we consider, unknown.

DR. EPPS: To follow up that, what about

children who have asthma or are on these

medications? Is their velocity different from

112

normal? In other words, sometimes growth is

affected just by having chronic disease.

DR. WILSON: By the disease itself. But

these pediatric studies, for a number of reasons

including ethical considerations, are done in

children with the disease. So the studies of

orally inhaled corticosteroids are done in children

who need the medications. So the comparison is the

placebo group versus the active treatment should

take that out of the picture.

DR. EPPS: Certainly, breathing comes

first.

Now, my last question is, for any of these

studies with inhaled and intranasal steroids, did

any of them also have atopic dermatitis? They

usually run together, so you might have topical

steroids and intranasal and inhaled steroids all

working together, and would that affect their

growth, as well

DR. SULLIVAN: I can\'t say categorically

because I don\'t know these studies, each one, that

well, but I presume that almost all of them would

113

have excluded concomitant use of other

corticosteroids.

DR. WOOD: Dr. Bigby.

DR. BIGBY: I have actually four

questions. The first one actually is a

philosophical question both for the FDA and for the

people here on the panel. If one of these classes

of topical corticosteroids has been shown to

produce HPA axis suppression, would we not

recommend it for OTC approval? That is the

philosophical question.

DR. WOOD: That is the question we are

going to address in the discussion on the

questions, so I guess right now let\'s just confine

our questions to the last set of speakers, so we

can let them off the hook.

DR. BIGBY: The second question is has an

ingredient ever gone backwards from being OTC to by

prescription? What I am really asking is, if we

make a mistake, can we go backwards?

\[Laughter.\]

DR. WOOD: I will answer for them, because

114

they won\'t. Not without a huge amount of

difficulty is the answer. It is much harder to get

something off the market than it is to not approve

it to go on.

DR. BIGBY: Lastly, other than

hydrocortisone, is there any foreign country

experience with an OTC more potent topical

corticosteroid?

DR. KOENIG: I am sorry, I thought about

looking at that, but I did not, so I can\'t say.

Does anyone in the audience know?

DR. GANLEY: We have some industry folks

here, they may know that answer.

DR. WOOD: Let\'s move on then.

Dr. Davidoff.

DR. DAVIDOFF: Yes, I would like to shift

away from the HPA for a moment back to bones, but

bones at the other end of the age spectrum, because

as you hit around my age, there is obviously the

problem of osteoporosis, and I understand that it

is difficult to study osteoporosis, but that is

such a huge public health and medical problem, I

115

wonder if there are any data on potent

corticosteroid dermatologic preparation\'s effect on

bone density in the older age group. However

preliminary or partial or whatever, I would think

that any hints as to that potential toxicity would

be extremely important.

DR. WILKIN: Well, I think we are limited

somewhat in looking at the long-term safety with

topical corticosteroids, because the conditions

that they treat, the dermatologic conditions wax

and wane significantly.

It is not like with the pulmonary inhalers

where a child may be expected to be using a product

for very long periods of time. The situation for

dermatologic conditions is that often things will

resolve, and maybe moisturizers alone, and then

when things begin to come back, it\'s a high

potency. Then, as it gets under control, it goes

to a medium potency corticosteroid, so it would be

difficult in that setting to say which

corticosteroid actually led to it.

So, that is the reason why I don\'t think

116

we have that in a regulatory environment, but

someone could look at a more general question in an

academic environment I suppose, just, you know,

would the use of mid- to potent, but not specific

products consistently over a long period of time,

would those people be at risk.

DR. DAVIDOFF: Yes, exactly. I mean I

didn\'t expect that you would necessarily have it as

part of the regulatory process, but whether you

have looked or anyone has looked into literature

specifically on that question.

Mary, do you have any idea from the

geriatric literature?

DR. TINETTI: I am not aware of any with

the topical. Certainly with systemic, it\'s a major

issue.

DR. GANLEY: I just want to add something

here. I think in some of the presentations, that

this growth suppression is really a surrogate for a

possible systemic effect even when you would not

have HPA axis suppression.

That is how I think the Pulmonary Division

117

has looked at it, is that if it causes growth

suppression in kids, you could assume that in an

adult, it could potentially cause this.

I did a lot of literature search, and I

think other folks did, trying to, in Pub Med,

attach topical corticosteroids with osteoporosis,

and you just don\'t get a lot of hits from it. So,

I don\'t think there is data, but our assumption is

that, in this setting, that growth suppression is a

surrogate for other things.

Now, the dose-response may be different,

but we don\'t have the data to really answer that.

DR. WOOD: When we get to the questions, I

guess, the question you are trying to get at is

would a topical steroid go OTC if it had systemic

effects, and the specific targets you have

illustrated it with are ones that are easily

measured. Is that fair? Okay.

DR. GANLEY: I think Dr. Luke pointed out,

and Jon has just mentioned it, with the topical

corticosteroids, it is much more difficult to

conduct a long-term study because of the variation

118

in dose, the waxing and waning of the disease, and

so forth.

DR. WOOD: Dr. Whitmore.

DR. WHITMORE: I think one other thing

that is most disturbing is in the betamethasone

dipropionate studies looking at growth suppression,

the 49 individuals, none of them showed any

suppression, any adrenal suppression.

I am presuming the same type of testing

was done as was done in the steroid patients. So,

from that presumption, you can step from there and

say there probably is some effect on growth in our

patients who are having HPA suppression with their

topical steroids.

It is a different marker obviously, but it

seems like if that is occurring in those patients

with the inhalers, they are not getting HPA

suppression. We are getting HPA suppression in our

patients with the topical steroids. I would

presume there is some bone effect, some growth

effect if used long term.

Was the testing that was done, the

119

cosyntropin testing in those 49 patients? That was

for Dr. Wilson, I am sorry.

DR. WILSON: It wasn\'t the same test as I

understand it.

DR. WHITMORE: Oh, it was not?

DR. WILSON: No. Markham has some more

details on it. Unfortunately, I was looking

yesterday, trying to find out all of the data from

that test for this committee, but was not able to

locate the original. It\'s a different test.

DR. WHITMORE: So, we can\'t make any

assumptions about that, I presume.

Dr. Cook, I have a question for you. In

the pediatric testing that was done for the

steroids, excluding clobetasol, you didn\'t have any

adult testing for HPA suppression with those same

steroids.

I am presuming that the only HPA

suppression was that we found in our brown book

here in terms of testing in adults, so it is pretty

much lacking. The only reason they did that was to

go back to get pediatric approval.

Is there any reason to presume that if

someone is 13 years of age and has the same body

surface area of involvement, they are not going to

120

get the same HPA suppression?

So, the companies that make the pediatric

products that were doing the testing in pediatric

patients, after they found HPA suppression with

their products, they came back to the labeling

saying 13 years of age or older. Is there any

reason to presume that HPA suppression is any

different in a 13 through 100-year-old individual?

It just is concerning.

DR. COOK: Yes, I see your point because

the other, meaning 13-year-olds who are fully

developed, just as adults, and I don\'t think it is

to say that HPA axis suppression would not occur in

adults. It is just that we didn\'t have the exact

data to be able to put that in labeling.

DR. WHITMORE: Has the FDA considered

asking the companies to go back and study adults

with any of these things?

DR. WHITMORE: Didn\'t you propose a

121

hierarchical sort of structure? At least that was

the way I heard it, that it would be easiest to do

HPA suppression in adults, so you would start with

adults. If that was positive, you would stop

there, right?

DR. COOK: I think for newer drugs, like

Clobex, because we have all this data, you know, it

started with adults, and we also could ask for

children. For some of those products that I

discussed there, have been on the market for many,

many years, and I don\'t know that there is any

regulation that could make the companies go back

and look specifically at adults.

The reason that we were able to do that

for pediatric patients is because we got a new

regulation that said we need more safety

information in pediatric patients.

Now, in some of the older tests that were

done, like looking at a.m. serum cortisol levels

when the drug products first came out, that is how

they looked at HPA axis suppression back then.

That was certainly in adults and did, you

122

know, propagate the class labeling that said that

you can get HPA axis suppression in adults, because

the Temovate was done in adults and in

children\--well, it is done in adults, adults with

atopic dermatitis and adults with psoriasis.

DR. WHITMORE: One last comment. With the

inhalant steroids, they oftentimes will look at

markers of bone metabolism as opposed to looking

for evidence of osteoporosis. So, you can look at

urinary calcium to creatinine ratios, you can look

at PTH, so there are things you can look at to see

if there is evidence for decreased calcium

absorption or excretion, and things like that.

DR. WOOD: Dr. Ringel.

DR. RINGEL: I was struck by the

difference between the cosyntropin test and the

tests that were originally done on hydrocortisone

to justify its approval as an over-the-counter

drug. I think it was Dr. Malkinson who did

radiolabeling of hydrocortisone and showed that it

was not absorbed, which seems very different from

the cosyntropin test.

As I was reading the preparatory material

that was sent, I was struck by the fact that 95

percent specificity of the test was 57 percent

123

sensitive, and I guess I wanted to explore that,

because I am want to make sure I really understand

what this test can and can\'t do. I am a

dermatologist, I am not an endocrinologist, and I

just want to make sure I understand the test.

Correct me if I am wrong. It is a test of

chronic effects of corticosteroids, so that you are

looking for adrenal atrophy, you are looking for

the adrenal gland not to be able to respond to ACTH

stress, which means to me that this test does not

mean that the steroid is not absorbed, it doesn\'t

mean that you have excluded the fact that the

pituitary may be insensitive to the cortisol, in

other words, that it may just not be able to

respond with its own ACTH.

And it doesn\'t mean that let\'s say you

have an increase in cortisol after the ACTH test,

it doesn\'t mean that that increase in cortisol is

necessarily going to be sufficient for a particular

124

stress. It other words, maybe the person should

have responded with an even greater cortisol

increase for that level of ACTH stimulation.

I guess what I am trying to do is explore

the limits of what we are really testing with

cosyntropin, and making sure this is really an

appropriate test and it is going to pick up people

whose pituitaries are suppressed.

DR. WOOD: Don\'t all rush to answer that.

DR. LUKE: We do have an endocrinologist

on the panel who can help us with some of those

answers, I think. The test, as we have discussed,

having 18 or less of post-stimulation was thought

to be a sufficient indicator that that patient

would be suppressed.

Now, as far as how much more of a rise

would you need for other stressors, I think the 18

was thought to be sufficient for most stressors.

DR. RINGEL: Do you know what the

sensitivity was?

DR. LUKE: Of the test?

DR. RINGEL: Yes.

DR. LUKE: Dr. Stratakis, do you want to

address that?

DR. STRATAKIS: The cosyntropin test is a

125

screening test for the diagnosis of adrenocortical

insufficiency. Therefore, as a screening test, it

has a good specificity, a very good specificity.

You can set out the specificity wherever you want,

and it has a low sensitivity, of course, and that

is how we use it.

With the 18 as the cutoff, it has a

sensitivity of about 70 percent, a specificity of

about 95 to 100 percent, so it is very good in

detecting the patient who is adrenocortical

insufficient. It is not very good at identifying

all the patients that have adrenocortical

insufficiency, it misses about 30 percent of them.

What I wanted to say is that a limiting

step in the recovery of the HPA axis after

adrenocortical suppression\--and this has been shown

in a couple of studies, that are very good

studies\--is the cortical trough, in other words,

the pituitary cell. It is not the adrenal.

There is actually a very good paper that

was published about 10 years ago about that, and it

is clear that it is the cortical trough. So, when

we are suppressing by endogenous steroids or

exogenous steroids, the HPA axis, all we are doing

is we are suppressing the cortical trough cell of

126

the pituitary and, to some extent, the

CRH-producing neurons of the hypothalamus.

We are not doing anything to the adrenals

or this has not been shown convincingly I should

say. We don\'t really know whether we are doing

anything to the adrenal cortex.

Up to recently it wasn\'t even known, and

to this day it is not known with certainty, that

the glucocorticoid receptor is expressed in normal

adrenal cortex. I believe it is. In some of our

experimental data, it seems that it is, but at very

low levels.

The other point is that since the

rate-limiting step is the cortical trough, then,

the question is how long does it take to develop

adrenocortical atrophy in response to suppression,

127

and that varies a lot from individual to

individual, but on average, we consider that time

to be approximately two weeks, approximately two

weeks.

I was surprised to see that in some of the

studies with the mid-potency steroids, you have

levels, we have levels of response to the ACTH stim

test down to about 9 or 10, which actually, if I

look back at my patients with endogenous Cushing\'s,

it is something that we get about 6 months of so of

recovery time after a pituitary tumor-producing

ACTH is excised.

So, this is quite significant general

atrophy, and since the test if not very sensitive,

you would consider that as the tip of the iceberg,

that you are really missing a lot of patients that

have developed moderate adrenocortical atrophy, and

you have no way of picking up those that have

moderate cortical trough cell suppression in other

words.

DR. WOOD: So, what would be your estimate

of the number you are missing, 30 percent, is that

128

what you said?

DR. STRATAKIS: The sensitivity is about

70 percent, so I would say about 30 percent.

DR. WOOD: Jack.

DR. FINCHAM: This is just an observation

in the context of what we are going to be

discussing this afternoon as far as how these

products may be used by consumers in an OTC

setting, a nonprescription setting.

I was struck by Dr. Cook\'s presentation of

a couple of instances where we saw an effect, and I

would assume that these are controlled situations

where the individuals had some limits on what they

could obtain and how they could obtain it, but in

the 5-year-old subject that was detailed in Slide

31, 95 percent body surface area, but there was an

ounce a day being used, which is an enormous amount

of product.

For the 2-year-old, it was an ounce a

week, and in the Diprosone study, it was an ounce a

week. I was just struck. Were there controls, Dr.

Cook, on oral systemic agents that perhaps would

129

have been used? Were there strict limits on this

being only topical application?

DR. COOK: Yes, since they were patients

with atopic dermatitis and they weren\'t supposed to

be on any other medications that would affect the

outcome of the study.

DR. FINCHAM: I guess the observation is

that was an enormous amount of product being used

even in a controlled setting, and we can only

presume what might happen or might not happen in an

uncontrolled over-the-counter setting, whether it

be worse or better, but it just struck me as an

amount that was being used.

DR. COOK: In the 5-year-old, I believe

that the parent continued to use the medication

even when the patient was getting better over that

same amount of body surface area, and even though

you would think that the integument would not have

been as compromised as time went on. Somehow there

was a lot of absorption, but when you look at the

smaller child, didn\'t use quite as much, but still

HPA axis suppression.

DR. WOOD: Dr. Stratakis, before we go on

to the next question, I guess, none of the

presenters actually told us why we care about HPA

130

suppression that I can remember, and maybe we

should just, for the record, say something about

for everybody\'s benefit why we care, or what are

the consequences of having your HPA axis suppressed

particularly in response to stress or surgery or if

you end up in a road accident or whatever. Just

very briefly.

DR. STRATAKIS: The reason we care is

because HPA axis suppression can lead to sudden

death. In fact, there was a recent study that

looked at the long-term morbidity and mortality of

patients with panhypopituitarism, and the single

most frequent cause of death in this long-term

status was, in fact, the absence of ACTH secretion

by the pituitary, adrenocortical insufficiency, in

other words, so sudden death.

DR. WOOD: So, showing up in an emergency

room and not being recognized as having a failure

of your stress response may be bad for you is the

131

point we are getting at here.

DR. STRATAKIS: Right. In fact, one would

like to go back to the studies where I think in one

of the studies, there were two deaths that were

recorded as Cushing\'s, I mean do you know what the

cause of death was, because Cushing\'s doesn\'t

actually kill you.

DR. COOK: Right. No, it could have been

complications thereof, it didn\'t really say.

DR. WOOD: Dr. Patten.

DR. PATTEN: I have a question about the

HPA suppression retests. It appears to me that the

longest time lapse to retest was 14 days in these

studies that Dr. Cook summarize for us.

My question is this. Does this imply that

if recovery has not happened by 14 days, it is

unlike to ever happen, or is after 14 days, is that

simply unknown territory?

DR. COOK: I would have to say that the

studies are really inadequate to answer that

question. First of all, we didn\'t have all of the

patients retested like we would have liked, and

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then once we got the studies, for some reason, when

patients failed to respond, they weren\'t retested

again. Those are certainly things that we are

trying to address in future studies, especially

now, we don\'t even want them retested until they

have been out at least 4 weeks because of the

possible influences of the results on continuously

re-stimulating the adrenal gland.

Unfortunately, we don\'t have the answer to

that.

DR. WOOD: Dr. Nelson.

DR. NELSON: I would like to make some

observations on the data that Dr. Cook presented

and invite comments to just see if I am getting it

right.

This is just looking at what I see as 9

pediatric studies that you presented. If you look

at it by class, there is a 27 percent incidence,

ignoring the differences in methods of adrenal

suppression.

If you scan it, in terms of potency, it

looks to me like there may be an effect based on

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potency, but not being a statistician and just

doing it quickly, it is difficult to say, but you

would assume then that the incidence of impact on

growth philosophy would be higher than 27 percent

given the data presented about the sensitivity of

that finding.

Then, the other question is whether there

is a threshold and most of these studies are all in

class, sort of I guess Class II and above, so you

can\'t ask the question whether there is a threshold

effect somewhere in terms of Class I.

What I just did reflects my biases that

since almost all studies that are submitted are

usually for efficacy and other indications, that

you can only see a safety signal if you do a

meta-analysis, but I guess my question is I presume

if you had done that, you would have presented that

data.

I am curious, am I off the mark here, or

is this an appropriate way for me, in my sort of

rough non-statistician approach, of thinking about

this data in the pediatric studies.

DR. WILKIN: I think the answer is yes.

It was very complex, isn\'t that your point, that

basically looking in the individual studies, the

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denominators are small, and that you really ought

to look across classes, and I think we take your

point that we might learn something more about the

class if we grouped these sorts of things together?

But there are some difficulties with that,

and I think something maybe we didn\'t stress enough

is that at any one given time over the last 20

years, we have been consistent at least for 6

months in how we think about topical

corticosteroids, but we have really changed

radically from the beginning, you know,

paleoregulatory 20 years ago, I am not sure exactly

what kind of studies were done for HPA axis

suppression.

Then, when we looked, we looked at

endpoints that were serum cortisol. There was no

Cortrosyn stimulation. Then, subsequent to that, we

looked at perhaps more stringent criteria. We

looked at what is in the Cortrosyn labeling, which

135

gives 3 criteria, and would identify more subjects

as being positive than what we are now looking at

today given the benefit from the endocrinologists

telling us that they only use the single criterion

in their practice.

So, just how we look at it has changed

radically over time. Also, over time we have been

able to, now armed with PREA, the Pediatric

Research Equity Act, we are now able to ask for

much more data that we have gotten in the past.

So, I think one of the great difficulties

is there is enormous heterogeneity in the data sets

and the conduct of the studies in each of these

classes.

DR. NELSON: If I could just make one

comment in response, all of the pediatric studies,

it looked to me the only difference in the

stimulation testing was whether you picked the

threshold alone versus the rate of rise, and if you

drop out the rate of rise and just pick threshold,

you are still going to end up around 20 percent

overall incidence among all these studies.

So, since that is since 1999 or 1998, so I

guess I would encourage you to look at the

pediatric studies. I think there is probably

136

enough homogeneity that you could draw some

conclusions from those studies, if you grouped them

as a class or did it by potency.

DR. WILKIN: I take your point on the

pediatric patient being a better sentinel

population in which to look for this particular

event. I think one of the things that we have

learned is that while we can make some correlations

and say that, in general, a higher body surface

area, longer use, younger age, more severe disease,

these things tend to correlate with the finding of

HPA axis suppression.

In point of fact, in any one study, we may

see an adult who has a very small body surface area

involvement who suppresses, a child who has a much

larger body surface area involved, and not suppress

with this.

So, it is certainly not a mathematically

precise kind of outcome.

DR. WOOD: The reason we have all these

pediatric studies is sort of an experiment in

commerce. I mean we happens that we got these

studies because of the Pediatric Rule that people

came in to you to get an indication. It\'s not so

much that there is some specific reason to

137

investigate children here except for the commercial

reason.

There might be reasons, as well, but that

wasn\'t why it was done, right?

DR. WILKIN: Well, no, I mean that isn\'t

the reason for PREA being enacted certainly, but I

can say within our Division, we recognized that

atopic dermatitis was primarily a pediatric

disease, and so even before PREA, our Division was

asking for pediatric studies.

DR. WOOD: Right, but if someone came in

for an OTC indication, which is what we are looking

at, they wouldn\'t necessarily have had to have

done\--let me ask it s a question\--they wouldn\'t

necessarily have had to have done a pediatric

study, right?

DR. WILKIN: I would agree with that.

DR. WOOD: Dr. Chesney.

DR. CHESNEY: Thank you. I think my

question is along the lines of Dr. Whitmore\'s

earlier, and it is for Dr. Cook. In Slides 55 and

58, this is looking at Diprosone Lotion. The

suppression was 80 percent for the 9- to 12-year

group, and yet it was approved for 13 years and

older, and I was curious, that it wasn\'t approved

138

for adults, and at that time there was no data on

13 and older, and I don\'t know of any reason to

think that a 13-year-old is different than a

12-year-old.

So, I guess my question was why was it

approved for 13 and older instead of perhaps

adults, only given that there wasn\'t any

information for the 12- to 18-year-old.

DR. COOK: All I can say is that that was

the cutoff that was chosen. I mean your point is

well taken. I mean it could have just said don\'t

use this product at all because, you know, by the

time you are 12, you may be near adult size, but I

139

guess there are some 12-year-olds who are still

prepubertal or whatever. That was where the study

was taken to, so that was the age cutoff there.

DR. WOOD: Dr. Taylor.

DR. TAYLOR: My question is really for Dr.

Luke. In his Slide No. 4, when he talked about

systemic effects, indicating that HPA axis

suppression is the only one that had really been

studied well, I was concerned about glucose

tolerance and sodium retention although I recognize

with these drugs, sodium retention is going to be

minimal since they lack significant

mineralocorticoid effects.

But what about in effects on glucose

tolerance, is there any data to suggest that

topical steroids might alter glucose tolerance in

susceptible individuals, for example, in diabetics?

DR. LUKE: When these products are used

under a physician\'s care, you would expect that

those patients would have some monitoring.

DR. TAYLOR: That is my point, though.

DR. LUKE: The class labels for the

140

corticosteroids do include discussion about glucose

tolerance and the sodium retention and

mineralocorticoid effect, so when these

prescription products are being used, it is thought

that those are things that would fall under the

rubric of a physician-patient discussion of

examination.

DR. TAYLOR: So, what is the Agency\'s

position in terms of when the physician is no

longer there, what is the Agency\'s remedy for

ensuring that this growing population of diabetics,

for example, have some guidance other than just the

label on the box?

DR. LUKE: I think when you go to the

history of hydrocortisone, there was discussion in

that monograph about mineralocorticoid effects, and

it was found that there was no studies that showed

that hydrocortisone had a mineralocorticoid effect.

DR. WOOD: My sense of what we are trying

to do, though, is this. What we are trying to

decide is what is the most sensitive test for

systemic effect of these drugs, and at what level

141

would you put a barrier up to a demonstration of a

systemic effect that would preclude OTC marketing.

So, I guess maybe we should turn the

question to Dr. Stratakis. I mean what is the most

reasonable, sensitive, and doable test for systemic

effects of steroids administered by any route?

DR. STRATAKIS: Well, having said all the

caveats of the ACTH stim test, I still think that

the ACTH stim test satisfies all the criteria you

just mentioned, the big response of cortisol of 30

minutes to 250 micrograms of synacthen. I mean

it\'s still the most doable, the easiest to

interpret, you can do it anytime of the day, you

can do it IM, you can do it IV, and it has a

sensitivity of around 70 percent with specificity

of 95 percent, you can\'t get in any other test.

DR. WOOD: So, to address Dr. Taylor\'s

question, would you expect to see people who had

elevation in blood glucose who did not demonstrate

suppression of HPA axis?

DR. STRATAKIS: That would have glucose

intolerance?

DR. WOOD: Right.

DR. STRATAKIS: Especially if they are

predisposed to that? Oh, yes. I think it is the

142

same thing that we see with growth. Growth is a

very sensitive index of the systemic effect of

glucocorticoids, and yet you don\'t see abnormal

ACTH stim tests in these patients, so I agree, but

at this point there is no good test to identify

these individuals.

DR. TAYLOR: So, the point is that the HPA

stim test is not a good surrogate for the variety

of systemic effects that one is likely to see.

DR. STRATAKIS: I agree with that

statement except that there is nothing else.

DR. WOOD: Charley.

DR. GANLEY: Let me just tough on that and

just think about it. We would be asking the same

questions if we did this test in 25 diabetics and

saw no effect on glucose tolerance, would we write

a label that says it has no effect on glucose

tolerance.

I would be a little uncomfortable in that

143

the labeling for the physician is that you are

treating the individual, so there may be patients

that are much more sensitive than others.

Well, to carry that over into the OTC

setting there may be always that patient out there,

well, how do you address that. Well, you would try

to address it through labeling, so anyone who is

diabetic should talk to their doctor, for example,

before using this product.

Then, you get into the issue, well, does

that have the impact that you want, is the person

going to follow that advice. So, I am not sure

that having that data in front of me would make me

feel better about being at OTC if it showed that it

didn\'t have an effect, because I couldn\'t

absolutely be sure that maybe there is someone out

there, so you err on the side of caution and you

label it as such.

I think we will get into that discussion a

little more about some of these systemic effects of

whether\--and if you look at the options, one is

that you just label for them, because the outcome

144

isn\'t as critical as death with a stress situation

when there is HPA axis suppression.

DR. WOOD: Frank, do you want to engage in

this?

DR. DAVIDOFF: Yes. I had a somewhat

related question because we are hearing that the

HPA axis assessment using the cosyntropin test has

a sensitivity of about 70 percent, but that implies

that there is a gold standard of some sort, and I

was curious what gold standard it is being measured

against.

But the related point I wanted to make was

that the results of this test are clearly a

surrogate measure, and admittedly, if you don\'t

want to hang around until people have experienced

the ultimate criterion of suppression, which is to

die because of adrenal insufficiency, so you have

to use the surrogate measure, but that does get to

the question of what is the sort of intermediate

gold standard short of death that is used on the

basis of which you can say it is a sensitivity of

70 percent.

DR. STRATAKIS: The gold standard for the

diagnosis of adrenocortical insufficiency has

always been the insulin tolerance test, the ITT, so

145

hypoglycemia induced by insulin is the gold

standard except that you can\'t do it in the

clinical setting, it is unsafe today.

We have to realize that ACTH stim test is

a sensitive screening test, is a good screening

test, not a sensitive screening test, and it was

designed to prevent exactly the adverse event that

we all want to avoid, sudden death in the setting

of undiagnosed adrenocortical insufficiency.

It was not designed to pick up mild

glucose intolerance. It was not designed to pick

up growth suppression effects, it was not designed

to pick up all these other\--blood pressure

elevation perhaps, and so on.

So, that is what this test was designed

for and that is what it is good for.

DR. WOOD: Dr. Mattison.

DR. MATTISON: To follow up on that, what

do we know about age-related differences in adrenal

146

suppression with exogenous corticosteroids? Then,

I would like to follow up with a comment after

that.

DR. STRATAKIS: Well, I am a pediatrician,

so I haven\'t reviewed the literature recently.

What I can tell you as a researcher in the

glucocorticoid field, is that as we grow older, we

have generally a lower sensitivity of the HPA axis,

of the central part of the HPA axis. We tend to

have slightly high cortisol secretion, and the ACTH

levels are, in turn, higher in older individuals.

Now, why do we say we have a lower

sensitivity? Because you actually need, as a

result of what I just said, of this epidemiologic

data, you seem to need higher ACTH levels to

maintain normal or slightly higher cortisol levels.

The other thing that we need to realize

is\-- which I like the question about the pediatric

studies being a good index of perhaps what is going

on\--is that as we grow older, the HPA axis, the

central part of the HPA axis is very sensitive to

almost everything we have.

So, if you have a mild autoimmune disease,

for example, if you suffer from chronic fatigue,

you present at this meeting at 6 o\'clock in the

147

morning, or if you travel a lot, your HPA axis

suffers from all that, and that has an effect on

the sensitivity of the cortical trough, we know

that.

So, how to interpret the ACTH stim test in

older adults will be different from how to

interpret the HPA stim test in kids, where all

these other factors are simply not present.

DR. CLYBURN: I just more had a comment

going to the New England Journal article in here

talking about critical care, and following up with

Dr. Ringel\'s comment and questions earlier about

sensitivity and severity of illness, they actually

talk about if an increase of less than 9 mcg/dL in

Cortrosyn stim is, in two references, associated

with a higher risk of death, so I mean it does

matter which population and the severity of illness

that we are dealing with.

The other question is for the FDA. I

148

think I know the answer, but we saw the data with

Lotrisone, if clotrimazole and betamethasone are

over-the-counter, there is nothing to preclude the

combination being sold from what I understand. Is

that the case?

DR. WILKIN: I would think that were it

over-the-counter, it would still need to have the

same duration of treatment for the primary

indication, which would be tinea pedis, and that

that might be a different duration than what we are

talking about today, which is limited at 7 days, I

believe, with the monograph. So, I think there

might be a distinction.

DR. WOOD: Dr. Mattison, I forgot to go

back to you for your comment, sorry.

DR. MATTISON: I wanted to follow up on

Dr. Nelson\'s and Dr. Wilkin\'s comments about how I

understand the data that has been presented, and I

am a little bit frustrated because my sense of the

data leaves me with a lot of uncertainty about the

dose or structure-response relationships, and

relationships with therapeutic efficacy, that is to

149

say, the structure or dose required to produce a

therapeutic effect and the adverse events that

might be produced.

So, if I could just share my sort of

thinking about this to see whether I have got it

right or wrong. You indicated that as we go from

the less to the stronger potent compounds, there

appears to be greater efficacy, but roughly

proportional or something like that safety hazard,

and that in addition, as either dose or surface

area or duration of treatment increases, efficacy

increases, but concomitantly, safety concerns

increase, as well, but there are a range of other

factors that are poorly understood including what

is in the medium that is used to put the drug on

the skin and age-related effects and others.

So, I am sort of hard pressed to come to

some kind of a concrete description of this

safety-efficacy balance that we are trying to

achieve in other than just sort of general terms.

Am I missing something, or is that kind of

the state of what we understand or what is

150

understood?

DR. WILKIN: I guess I would make one

point, which is that I think the way you describe

this, you would present the moiety as having a

potency, but it is actually the product that has

the potency which can be determined in substantial

part by the vehicle.

The vehicle may have a penetration

enhancer. Not all of the active ingredient may

actually be in solution, only that which is in

solution participates in the concentration gradient

which drives it across the barrier, which is the

stratum corneum, so we don\'t really think of it in

terms of the moiety. We think about it as the

product itself.

But the other things that you said, I

think are quite true. These are sort of rough

guidelines on what might actually get more systemic

exposure, greater body surface area,

under-occlusion, all of these sorts of things.

I think that maybe we didn\'t make the

point that, you know, one can look at what we

151

provide in the professional labeling for the

prescription product and maybe interpret it in too

precise a manner, because I don\'t really think that

is what the ultimate intent is.

I don\'t think the denominators are large

enough and that we really know all of the degrees

of freedom in the suppression model, all the

different aspects, that we have really solid

labeling that says at 35 percent body surface area,

in a child who weighs X amount, who applies this

amount of cream, we are never going to have that.

We see people that are actually out of

order, when you think you have got the order of the

factors, some people suppress when you would

expect, and others suppress when you don\'t.

So, we have taken this as a very rough way

of looking, and then how we use it, I think one of

our most recent labels was the\--was it Clobex

Lotion? I think in there, I think it gives the

notion of what we do.

We said the product was approved I believe

for 18 years of age and above, but we don\'t say

152

under Contraindication that it is contraindicated.

I think we have in there, in the Indication

Section, it is not recommended, but that gives I

think the physician the kind of information, if

they really read through the Indication Section,

the notion that it is much better in the 18 and

over, and the younger the child, the more one

really needs to think about this, but at the end of

the day, this is never going to be mathematically

precise. I think that is one of our great

difficulties.

DR. WOOD: Jon, I am always impressed by

how subtly you think we interpret these labels. I

don\'t think any of us ever understand that kind of

subtlety.

Let me take Dr. Skinner next.

DR. SKINNER: I just had a question about

labeling. I was struck in Dr. Ganley\'s lecture

about low potency, Slide 4, use of OTC

hydrocortisone, and he had used limits into 1 week.

Later on when they actually showed the labeling

warning, \"Stop use if condition worsens or lasts

153

greater than 7 days.\"

Certainly, atopics from 3 months to

whatever, 12 years of age, hydrocortisone 1 percent

ointment and cream are rubbed on 2 and 3 times a

day for years at a time, so it seems a little

different than what the labeling actually says.

In fact, if you are managing atopics and

they do well in hydrocortisone 1 percent ointment,

it is great, you know, come back in 3 months or

whatever, in fact, even on 2.5 percent ointment.

So, I was surprised to see the label says 7 days.

DR. WOOD: Well, that was my point to Jon.

Dr. Alfano.

DR. ALFANO: Growth suppression mediated

by malnutrition is coupled with sort of a spectrum

of other functional deficits - the immune function,

the salivary gland development, sexual maturation,

and the like, some of which are permanent. In

other words, when you restore nutrients, the

deficits stay.

In corticosteroid-mediated growth

suppression, are any of those other factors

154

identified?

DR. WOOD: Dr. Stratakis.

DR. STRATAKIS: Are you asking whether the

growth suppression is permanent or are you asking

whether there is additional effects on these

patients that have\--

DR. ALFANO: I am asking related effects.

In other words, there is critical periods in

development, if the animal isn\'t growing properly

at that time, there are functional deficits which

persist into adulthood.

DR. STRATAKIS: In the studies that have

been done, no, to my knowledge, there is nothing

that seems to be associated with growth

suppression.

Let me just say one thing about the

permanence or not. I can tell you from endogenous

Cushing\'s syndrome, from patients that have either

adrenal tumors or pituitary tumors in childhood,

there is a long-term effect on growth. These

patients seem to end up about 1 to 1.5 times

deviation shorter than controls that are age and

155

gender matched.

So, there is a permanent effect on growth

in patients that have been exposed to consistently

high cortisol levels from adrenal or pituitary

tumors.

DR. WOOD: Dr. Whitmore.

DR. WHITMORE: May I just ask, if you were

to look at a large population of patients, what

dose of prednisone would result in a 20 percent

incidence of HPA suppression, oral prednisone?

DR. STRATAKIS: Well, the equivalent, in a

70-kilo adult, with replacement dose of

hydrocortisone that I consider proper replacement

is about 20, 25 milligrams of hydrocortisone a day,

and the equivalent for that in prednisone would be

7.5 milligrams.

So, I would say that any prednisone that

is given consistently every day, that is higher

than 10 or 15 milligrams a day, would result in

suppression.

DR. WHITMORE: So, kind of what we are

saying here, with 30 percent of patients showing

156

HPA suppression, that is like having somebody on

prednisone at a higher dose than 7.5 or so for an

adult.

I mean my point here is the fact that is

like having somebody on oral prednisone every day

with this evidence for HPA suppression, is this

worse than 5 milligrams of prednisone every day? I

mean it looks like it.

DR. WOOD: You have to be careful. I mean

clinical pharmacologists, the amount you get into

the systemic circulation may differ if you give it

orally and some of it is metabolized

pre-systemically, and so on.

DR. WHITMORE: We are still looking at the

end result, though.

DR. WOOD: I know, so it won\'t just be

concentration, it won\'t just be dose dependent,

because you may get a higher concentration in the

blood, but you are right in terms of effect.

DR. STRATAKIS: To add to that, remember

what I said earlier, that a limiting level to

suppression is the cortical trough. So, the

157

cortical trough is not regulated in a steady way.

It is regulated in a pulsatile manner, and it

receives input from many sources.

So, the amount of glucocorticoids that the

cortical trough sees is just one of the sources

where the cell receives input from to determine

ACTH production. So, it is not one and one.

DR. WHITMORE: One of the issues in safety

with the steroids the way we use them, we use them

bid, so we get a.m. and p.m. dosing, which you

never do with oral prednisone unless there is a

reason to produce more suppression, so that is one

thing.

Only one of the steroids, I think just

Elocon has the FDA approval of once daily dosing,

and for the most part, the other topical steroids

have not been tested 1 qd versus bid.

So, if the pharmaceuticals are interested

in looking at possibly lesser suppression, applying

a.m. 1 dose versus bid, would be something to think

about if they are doing HPA suppression studies

anyway, just to look at that, and even the thought

158

of qod dosing with superpotent steroids in terms of

affecting HPA suppression.

Just one more comment and that is about

carcinogenesis. We received a notice from the FDA

that Lachydrin was changing their label in terms of

use on sun- exposed areas because of concerns about

using it on sun-exposed areas, and I think that

probably relates to carcinogenesis, but the other

concern about topical steroids going

over-the-counter is looking at carcinogenesis.

So application of topical steroids

producing immune suppression or contact

hypersensitivity suppression, and also the thought

of suppression of \"rejection\" of tumor antigens and

things like that.

The idea of having this go

over-the-counter with not really knowing if topical

steroid application on a regular basis to the face

might increase the risk of skin cancer, and we are

almost indicating that now with the Lachydrin

warning.

I am not quite sure how to take the

159

Lachydrin warning, but with the question about

Protopic and Elidel and Lachydrin, I think you also

have to start addressing the idea of

corticosteroids and increased risk of skin cancer

with corticosteroid use on a chronic basis and

UV-induced skin cancers.

DR. WOOD: Dr. Ringel.

DR. RINGEL: I have two questions. The

first is kind of this simple-minded idea that I

have, which is so simple-minded that it must be

wrong, but I was wondering if Dr. Stratakis could

tell me why.

Why can\'t you take 100 people, half of

whom are on steroids and half of whom are on

placebo, measure their ACTH before and then during

the treatment, and if it looks like there is less

ACTH in the treated versus the placebo, then, you

know that they are being suppressed and that\'s the

end of it. Why doesn\'t that work?

DR. STRATAKIS: Well, that\'s a simple

question. The ACTH is secreted in a pulsatile

fashion, so you can\'t do ACTH measurements, single

160

ACTH measurements, and see whether a patient is

suppressed or not.

What you have to do, if you want to do

that, would be to really do either 12-hour sampling

or 24-hour sampling every 20 minutes. Then, there

are statistical ways of analyzing these

12-hour/24-hour data that will look at how the

cortical trough has behaved, but that is a

complicated study and quite expensive.

DR. RINGEL: Thank you, I appreciate it.

I knew it was too easy to be true.

Just one other quick question. Are we

interested here in only chronic HPA suppression, or

are we also clinically interested in acute HPA

suppression?

In other words, if somebody has been on

steroids for a week and then gets in a traffic

accident, are they going to\--I mean my impression

is that people would not, in the ICU, then give

them supplementary corticosteroids.

Is acute HPA suppression really not that

important, do you need to have the adrenal atrophy

161

for us to be concerned about it?

DR. WOOD: I think we have had the answer,

but go ahead and tell us again.

DR. STRATAKIS: I think what we are asking

here is whether, in a stress situation, a patient

will have adequate cortisol secretion. That is all

we are asking. We said that, on average, it takes

about 14 days or so to atrophy the adrenal, but

that also is quite variable between individuals, so

I don\'t know\--

DR. WOOD: But the hypothalamic

pituitary\--

DR. STRATAKIS: Oh, absolutely.

DR. WOOD: That is the key point that

needs to be put across, so I mean there is two

different dynamic things going on. One is the

suppression of the pituitary and hypothalamus, and

then there is the consequence of that, which is the

adrenal atrophy, and one occurs first.

DR. STRATAKIS: But what leads to that\--so

there is sort of a gap here\--what leads to that is

not the absence of ACTH, what leads to that is the

162

absence of glucocorticoids.

So, really, the question is whether these

patients will have adequate cortisol secretion in a

stress situation, because there are many other

factors that regulate cortisol secretion, it is not

just ACTH. There is a problem there, but that is

what they have to deal with.

DR. RINGEL: If you have been taking

corticosteroids, will your ACTH respond

appropriately to stress, or increase appropriately?

DR. STRATAKIS: Most likely not.

DR. WOOD: Jimmy.

DR. SCHMIDT: I am glad to follow you, Dr.

Ringel, from Maine, because there was the funniest

cartoon last Sunday in Doonesbury where the

minister was calling to check on the snow plow and

he got the exact times, and then, he said, \"How is

the weather in Calcutta?\" He said, \"I don\'t have

any windows here.\"

The reason I bring this up is I think

globalization is a real important thing, and I want

to just comment on something that Dr. Bigby asked

163

about, about what is going on in other countries.

In preparation for this trip, I excerpted

an article from the Lancet about a Chinese woman

who developed Cushing\'s from taking a vitamin pill

that had prednisone in it. I just want to read the

last paragraph of this. There is a reference in a

British medical journal by Shuster about

over-the-counter sale of topical corticosteroids,

which I apologize, but I didn\'t excerpt it to

bring.

But essentially what it says is guidelines

for over-the-counter steroid availability vary

between countries. Iatrogenic Cushing\'s syndrome

from topical steroids is well known, and major

debates on the pros and cons of over-the-counter

topical steroids have been carried out in developed

countries.

Although systemic steroids should be

unavailable without a doctor\'s prescription, such

restriction is difficult to achieve in developing

countries.

In a study from Brazil, clients were able

164

to buy 65 percent of prescription-only systemic

steroids that they require for the treatment of

arthritis.

Then, it just goes on. It says that this

particular patient epitomizes the nefarious effects

of unregulated over-the-counter steroids.

Then, I want to make one more comment. I

am sort of a paleodermatologist, having been in

practice for a while, and the way it was

recommended, we used to, and this is my bible for

topical steroids, it is Topical Skin Therapeutics

by Polano is the way we used to do this was

patients who were treated with large amounts of

topical steroids may be monitored in the following

way:

Estimation of the 9:00 a.m. serum cortisol

every 14 days, as long as the level is 6 mcg/mL or

more, 100 mL, the treatment may be continued. If

the level is lower than that, then, your test must

be performed for the synacthen test.

As long as this test shows a normal

response, continuation of the treatment is safe; if

165

abnormal, the topical steroid treatment should be

stopped, and then they talk about backing them up

with some prednisone.

So, I throw that out for the group.

DR. WOOD: Okay. Mary.

DR. TINETTI: I wanted a clarification

from the FDA, if you will, how you decided on the

cutoff for a positive test for the cosyntropin,

because I want to differ a little bit with Dr.

Stratakis. Usually, with a screening test, we

maximize sensitivity.

We don\'t mind if there is a few false

positives and usually one would not sort of pick

for something as serious as this, where it\'s a

surrogate for all the systemic effects, wouldn\'t

pick a cutoff that gave you a 70 percent

sensitivity, therefore, lose 30 percent at the

expense of a 95 percent.

I am sort of curious, with that in mind,

why you made the switch to really an 18 versus the

20, because one way to deal with this problem would

be to have a more stringent cutoff for a positive

166

test, and that would sort of deal with some of the

concerns we have here, particularly as we are

saying already, it is a surrogate for a lot of

other outcomes that we are particularly interested

in.

I just sort of wondered what the reasoning

was.

DR. WOOD: You mean a less stringent, so

that you would catch the\--

DR. TINETTI: Less stringent, so that you

would want a higher result of the test, and why

they made the switch from 20 to 18, for instance.

DR. STRATAKIS: This was taken in the

context of the whole test. I mean you have a

minimum body surface area of application which is

fairly large, I mean 35 percent, 30 percent,

greater that 30 percent body surface area.

You are exposing those patients to fairly

large amounts of topical corticosteroid.

DR. WOOD: I don\'t think that is what she

is asking. Go ahead, Mary.

DR. TINETTI: What I am asking is that we

167

heard from Dr. Stratakis that the present measure,

I presume that is based on 18, is only 70 percent

sensitive, so therefore we miss 30 percent of the

people.

One way to deal with that is to require a

test to have at least, for instance, to 20

milligrams, so I am not talking about how much

surface area, et cetera, I am just talking about

how you define a positive or a negative response to

the cosyntropin.

DR. STRATAKIS: This has been looked at.

We will increase a little bit the number of false

positives, but that is again not in the setting of

topical corticosteroids, this in endocrine

literature.

So, what has to happen here is that

essentially, a cutoff from the endocrine literature

on how you pick up patient with adrenocortical

insufficiency has been applied in that setting, and

it may not be the appropriate cutoff.

DR. WOOD: It is important to emphasize,

endocrinologists, we use it clinically for a

168

different purpose from what is it is being used for

here.

DR. STRATAKIS: Absolutely.

DR. WOOD: You have always got the other

option of extending it to other tests if you are

still unsure or if you think the diagnostic

situation is unclear. Mary\'s point I think is that

that is not the situation you are in with a

regulatory\--

DR. STRATAKIS: The proper idea of testing

the test here would be to apply the gold standard

that we use in endocrinology, for example, in

central adrenocortical insufficiency, studies have

compared the ACTH stim test with the ITT, the

insulin tolerance test in the setting of central

adrenocortical insufficiency, but, to my knowledge,

this has not been done in long-term application of

corticosteroids, local corticosteroids, again, do

the ITT, do the ACTH stim test, and then compare

the two.

DR. WOOD: But I guess one response to

Mary\'s question would be that would tend to force

169

you further down this chart that we have I guess.

DR. TINETTI: Right. It would seem

logical that if we want to maximize safety, the

other alternative would be to, in the absence of

that information, would be to require a higher

response. That would be another simple response

barring all that other information, because I think

we all agree that we are maximizing safety.

DR. WOOD: Frank.

DR. DAVIDOFF: I wanted to get back to Dr.

Whitmore\'s question about the dose equivalence,

because I think it is important to recognize that

in glucocorticoid therapeutics, it isn\'t just the

dose, it\'s the timing of the dose, and that the

kind of long sustained input of steroid into the

systemic circulation that is more likely to happen

with putting it on your skin, is going to mimic

Cushing\'s syndrome abnormality in the sense of

cortisol being around when there should be a trough

in the blood level, so that even a smaller dose is

likely to be more suppressive because of the long

sustained activity.

DR. WOOD: Dr. Wilkerson.

DR. WILKERSON: Just some observations.

Either we are standing on the head of the giant or

170

this is a tempest in a teapot, and unfortunately, I

don\'t feel like we have the database to really

understand this.

Just some observations. When we have

hormonal patches of one sort or another which

literally have micrograms of product that exert

significant hormonal influences on the body of

similar sterol-based molecule.

So it is no surprise that our topical

steroids are doing this, we have all had a

trivialization I think of topical therapy over the

years by tradition or whatever that we have not

considered these things to be significant, but the

data that we have seen presented today I think

certainly begs the question that maybe we really

are standing on the head of the giant and we don\'t

even realize the events that occur around us, we

don\'t recognize because of lack of the prepared

mind to recognize these events.

I think if we all go back to our practices

and start looking for these things, I bet we start

seeing more instances of effects and particularly

the things that we are concerned about as far as

osteoporosis and hypertension and glucose

intolerance.

171

I mean there are times that we literally,

as dermatologists, coat our patients with topical

steroids with the knowledge and with that yes, we

know that we are exerting a systemic effect there,

but I don\'t think that knowledge extends many times

out into general practitioners, and it certainly

doesn\'t extend to the public as a whole in terms of

their misuse of these products.

I think we need a lot more information

personally about the pharmacology and the

pharmacodynamics of these products before we go any

further with this issue.

DR. WOOD: And I suspect, just to extend

what you are saying, most emergency room doctors or

anesthesiologists don\'t take a history of topical

steroid use before they\--

DR. WILKERSON: Nobody. I have had the

unfortunate or fortunate experience of having seen

a patient within the last 6 months who was using a

very small amount of clobetasol-containing product

that had been given to her by another physician,

and the only reason I dug into this, she had

significant cutaneous atrophy in the areas of

application, but she had also noticed extension to

other areas of the body.

172

We did the appropriate screening test, and

she was using less than 50 grams a month of product

and receiving significant suppression, so it is out

there, it happens, and I think it probably happens

with a variety of preparations, not just that

preparation, but I think we just don\'t know the

pharmacodynamics, we don\'t know the

pharmacogenetics or genomics of this either at all.

I mean what is the difference in

metabolism of different people or particular

steroids. We sort of make an assumption that they

are the same, and I don\'t see any reason why they

would be, and that may explain part of the

173

differences that we see in these studies.

It may be nothing more than rates of

hydrolysis and metabolism, and certainly that makes

some people not affected, it makes other people

probably severely affected by some of these

potential side effects.

DR. WOOD: Dr. Santana.

DR. SANTANA: I want to get back to this

issue of age-related differences in the test

results and what this data means.

Can you clarify for me, when you addressed

the question earlier, I think the discussion went

to the side of the adults, but I didn\'t hear a

discussion whether age-related differences in this

testing and whether this value of 18 applies across

all pediatric age groups, that is, are we under- or

overdiagnosing based on this test?

I think that is going to be critical

because if these products become over-the-counter,

they are going to be used in a large pediatric

population, because that is what they are indicated

for pharmacologically, for atopic dermatitis.

Can you clarify that for me, is that test

really applicable across all age groups in terms of

the value of 18?

174

DR. STRATAKIS: Yes, it is.

DR. WOOD: Any other questions? Yes,

Wayne.

DR. SNODGRASS: I have two questions. One

is does the FDA have any plans to request or

require studies that demonstrate a dose threshold

for ACTH suppression for topical products?

Secondly, what is the error rate, if it\'s

known, or any estimate of it, of the general

population for misuse of OTC topical products?

DR. GANLEY: I will address the latter

question and Jon can address the first question.

We don\'t have a lot of data per se, but I think one

of the presentations during the open session

provides some survey data and also purchase data,

and it will give you a sense mainly based on

purchasing of how many people would use these

chronically, so then that I think would address

your question.

DR. WOOD: In the absence of any other

questions, I think what we will do is we will take

a break\--I am sorry, Charley.

DR. GANLEY: We have one more question.

Jon had to finish the first question.

DR. WOOD: I beg your pardon.

175

DR. WILKIN: I think the question was will

FDA be looking for a way to find out what the

threshold dose of a topical product might be.

Again, because of all the degrees of freedom in the

model, I just think it\'s incredibly difficult to

say that, you know, 22 grams used in a child of a

certain age, I just think really that it doesn\'t

allow that kind of\--

DR. SNODGRASS: What I was getting at,

that is a different study design. In other words,

you really could find a dose-response. If you had

more than one dose, you could find a dose-response

for the effect you are looking at, and you could

set your a priori criteria 1 in 100 or whatever to

be suppressed, and that would give much more

information than we currently have product by

176

product.

DR. WOOD: Although it would be difficult

to conceive of an over-the-counter product being

over the counter in which even a high end showed

suppression, it would seem to me. I mean the

complexity of that label would be pretty tough, I

think.

DR. SNODGRASS: Well, I think if you did

it, you know, it depends on what dose you have got.

If you have got a test right now that is 30 percent

insensitive, once you get beyond, look at the table

we have got here, and beyond 100 in yours arms, I

think you might begin to find some numbers there.

I realize it would be much more expensive,

more complex, and all that, to do that type of

studies.

DR. WILKIN: Well, actually, the way the

study is conducted, I realize there is this

sensitivity issue, and I think Dr. Tinetti\'s

comment that if we altered the criterion, we could

tinker with the sensitivity, but also think about

the context in which we are doing these studies. We

177

are looking at the extreme upper end of body

surface area involvement although Dr. Wilkerson

mentioned that from time to time, dermatologists

will give patients topicals to cover most of the

body, I am not sure that that is the usual rule.

I think it might be unlikely in an OTC

setting if the container size is small. So, the

testing circumstance is really geared towards

maximum, really provocative, looking to see if,

under these extreme conditions, that HPA axis

suppression can occur.

DR. WOOD: Dr. Mattison, did you want to

say something? No? Okay. Charley.

DR. GANLEY: I just want a clarification

on this sensitivity issue. Maybe I misheard you,

that your sense was for something that would be

clinically significant leading to possible death,

the test is fairly good. It is not a 30 percent

sensitivity or we don\'t know that.

If you have someone that is suppressed,

this test is actually pretty good to pick it up in

terms of putting them in a situation that if they

178

were stressed.

DR. STRATAKIS: Well, that is the

specificity. It will pick up all the patients that

have severe adrenocortical insufficiency.

DR. GANLEY: Right, and that is the

population that we are interested in is the person

who is going to come into an emergency room, who is

in a stress situation, who could die from it. It

is actually pretty good to pick those folks up.

DR. STRATAKIS: Well, if you want to

comment on that, but I mean basically, with the

criterion of 18, we have a fairly low rate of false

positives and acceptable rate of false negatives.

DR. TINETTI: Right. The way it says now

is that if you do have a positive test, you are

pretty darn sure you are going to be in trouble,

but if you have a negative test, i.e., you pass

this test, you still have a 30 percent chance of

having difficulty. That was the point that I was

trying to make.

DR. STRATAKIS: Actually, you can read

studies that say as good as 85 percent, and you can

179

see studies that say as low as 68 percent I think.

DR. TINETTI: So, it\'s a little bit eye in

the beholder of how many people you are willing to

miss not to overestimate, so for something like

mortality, you probably want to have a sensitivity

of as close to 100 percent as possible, realizing

you will have a lot of false positives.

DR. STRATAKIS: Because of your

specificity.

DR. TINETTI: The cutoff now minimizes

false negatives, but maximizes false positives.

DR. WOOD: Terry.

DR. BLASCHKE: I just wanted to make note

of the fact that when we are talking about safety

issues, we are not just talking about adrenal

insufficiency, we are actually talking also the

fact that this is picking up excess corticoid in

the body, and all of the comments that have been

made already about the possible effects on glucose

metabolism, on bones, growth, et cetera, are also

not to be overlooked as important consequences of

absorption of the more potent corticosteroids.

DR. WOOD: Immunosuppression, as well.

In the absence of any other questions,

let\'s take a break now for lunch and plan to be

180

back here at 12:30.

For the audience before they all rush out,

we will start immediately with the public comment

session. You have all got your numbers, so we will

be starting with No. 1 obviously and moving on from

there.

Thanks a lot.

\[Whereupon, at 11:30 a.m., the proceedings

were recessed, to be resumed at 12:30 p.m.\]

181

A F T E R N O O N P R O C E E DI N G S

\[1:00 p.m.\]

Open Public Hearing

DR. WOOD: We are going to do the public

comment period. All the people who have requested

time in the public comment period have got a

number, and I will call you up by number.

You have 10 minutes to present and we will

strictly enforce the 10-minute rule. At the end of

the 10 minutes, the microphone will go dead and

only your lips will be moving.

Let\'s get started with No. 1.

MR. ROTH: I am Jerry Roth. I am

president and owner of Hill Dermaceuticals. I was

present at the last Advisory Committee meeting on

pediatric corticosteroids for pediatrics. I

recognize some of the panel members from the last

one, so I hope I don\'t bore you here because I am

presenting this information.

I remember Dr. Chesney said you are

supposed to say if anybody paid your way here. I

paid my own way, so as I said before, I am one of

182

the dinosaurs left in this industry.

First of all, in presenting this data, it

is not our intention in any way, shape, or form to

want our product Derma-Smoothe/FS to be

nonprescription. It is a prescription and we

intend it to stay that way, but we felt that this

is giving you a little bit of data that you have

not maybe heard earlier today.

\[Slide.\]

First of all, Derma-Smoothe/FS contains

0.01 percent fluocinolone acetonide in a peanut oil

base It is considered a low to medium potency

corticosteroid, and I wanted to present HPA axis

suppression studies that were done in patients 2 to

12 years of age.

You have heard a lot today about vehicles

and I think that this will give you once again a

little bit additional evidence.

\[Slide.\]

This is a multi-center, open-label safety

study. What you haven\'t heard yet is this was done

in patients with greater than 50 percent body

183

involvement.

The dosage, it was also brought up that

everything was once a day. The dosage on this was

twice daily for a period of 4 weeks. The criteria

was evaluation with the cosyntropin stimulation

test.

Derma-Smoothe/FS was one of the first

drugs that was studied for safety and efficacy, the

Rules, as have been mentioned, have changed since

that time, and you will see that Day 1, prior to

the first treatment, and at the end of treatment we

had a pre-stimulation cortisol level and then

immediate followed by stimulation, and then the

post-stimulation cortisol level was at 60 minutes.

At that time, the protocol or the Agency

only request cosyntropin tests. It wasn\'t

differentiated between 60 minutes and 30 minutes at

that time.

\[Slide.\]

The population that I want you to

recognize is that 18 of the patients had greater

than 75 percent body involvement, and 16 had 50 to

184

75 body involvement. We calculated the amount of

drug by what was returned, and the average drug use

per day was about 9.5 plus or minus 4.7 mL/day.

Now, this is important because there is something,

vehicles and drug exposure.

\[Slide.\]

Just to remind those who aren\'t

physicians, regarding body surface area, when you

are talking about this much, 50 to 75, or 75, you

are talking about the chest, front and back, legs,

front and back, arms, a substantial area. Once

again, I believe this is the only drug that had

been tested with that level besides hydrocortisone

of that amount of body surface.

\[Slide.\]

Before the treatment, prior to treatment,

now we did averages because this is a public

hearing, each of the data individually is on file

with the Agency, and this was approved, so each

individual case report form is on file.

Anyway, the average pre-stimulation was

11.63. At 60 minutes, it was 26.82, the doubling

185

which you should see.

\[Slide.\]

After 4 weeks of treatment, there was very

little change, 11.26, and after post-stimulation,

it was 25.06. Of the 34 patients, there was not

one that experience any adrenal suppression.

\[Slide.\]

The exposure we feel is very important.

Derma-Smoothe/FS is a 4-ounce container. Within

this container, there is 12 mg of fluocinolone.

You will see that the average patient, the 4

ounces, 118 mL, lasted 12 days. The patient was

exposed to not more than 1 mg of fluocinolone per

day. On the basis, which is the generally accepted

percent of absorption of 1 to 2 percent, that is an

infinitesimal amount that is absorbed.

What is important is this is an oil

vehicle, the spreadability is great. This

particular cream is 60 grams, and there are 60 mg

of corticosteroid in this cream. To cover a vast

majority of the body, it would require a lot more

cream to do this than of this oil, so you may use

186

quite a bit more of the cream. I think that was

brought out earlier.

So, therefore, vehicles are important and

possibly does have substantial amount regarding

safety data.

\[Slide.\]

In conclusion, after 4 weeks of daily

application of Derma-Smoothe/FS , involving 50 to

90 percent of the body surface area, there was no

change in the morning baseline value of the

cortisol, nor did it affect the cortisol

stimulation of ACTH.

You might wonder, well, if there is so

little amount of steroid does it work, with this

small amount on the body, after 4 weeks, 60 percent

of the patients showed excellent or 75 to 100

percent improvement.

Would you like to ask me any questions

especially on the amount of surface? I think, just

to follow up, Dr. Wilkin has said that the tests

are becoming a bit more sophisticated. We are

ready to commence down to 3 months with this

187

product in greater than 30 percent of the body

area, and we will be following, I think there was a

question if you have any adrenal suppression, will

you be following those patients. In that protocol,

we will be. We don\'t expect any, but we will test

until we have data.

Second of all, once again, there was also

a statement that companies often just do this

because they are required. That is some of the

case, but in any cases it is not, and in this case,

it is not. It was our request to do these.

Yes, sir.

DR. WOOD: Dr. Nelson has a question for

you.

DR. NELSON: I was told it had better be a

good one, hopefully, it is. You had mentioned in

passing that it is generally accepted that 1 to 2

percent of corticosteroids are absorbed topically.

I was just wondering what is the data and how

generally accepted is that?

MR. ROTH: That is in the Textbook of

Corticosteroids, I believe it is by Dr. Howard

188

Mayback. That is a generally accepted textbook.

DR. NELSON: For all corticosteroids?

MR. ROTH: I believe, yes, on topically

applied, yes. That is why the amount that you are

exposed to is quite substantial.

DR. WHITMORE: I don\'t know that that

applies to all corticosteroids. I think

hydrocortisone versus the others\--

DR. WOOD: Let\'s hold all of our questions

to all of the speakers at the end, otherwise, we

will take forever to do this. Let\'s go through all

the speakers and then we will take questions for

them at the end.

MR. ROTH: I can quote out of the textbook

if you would like.

DR. WOOD: Teresa has handed me a

late-breaking statement that I need to read.

Both the Food and Drug Administration and

the public believe in a transparent process for

information gathering and decisionmaking. To

ensure such transparency at the open public hearing

session of the Advisory Committee meeting, the FDA

189

believes that it is important to understand the

context of an individual\'s presentation.

For this reason, FDA encourages you, the

open public hearing speaker, at the beginning of

your written or oral statement to advise the

committee of any financial relationship that you

may have with any sponsor or products.

For example, this financial information

may include the sponsor\'s payment of your travel,

lodging, or other expenses in connection with your

attendance at the meeting.

Likewise, the FDA encourages you at the

beginning of your statement to advise the committee

if you do not have any such financial

relationships. If you choose not to address this

issue of financial relationships at the beginning

of your statement, it will not preclude you from

speaking.

Speaker No. 2.

DR. CHARLES ELLIS: Thank you very much.

I am pleased to be here to speak on patterns of use

of OTC topical hydrocortisone. Thank you for

190

allowing me this opportunity.

\[Slide.\]

I am Charles Ellis. I am Professor of

Dermatology at the University of Michigan Medical

School. I am also Chief of Dermatology at the Ann

Arbor Veterans Affairs Medical Center.

\[Slide.\]

Here are my disclosures for my talk today.

\[Slide.\]

I am thrilled to be able to be here to

present our research which is in press and will

soon be published in the peer-reviewed Journal of

the American Academy of Dermatology. Our research

is entitled, \"Consumers appropriately self-treat

based on labeling for over-the-counter

hydrocortisone.\"

\[Slide.\]

First, I am going to tell you the results

of our research and then I will give you the

details.

So, what has our research shown about the

use of topical hydrocortisone in the United States?

191

The reported use is largely consistent with the OTC

monograph label.

The percentage of use in accordance with

the label is similar for both adults and children.

Over-the-counter hydrocortisone is used

primarily for brief periods of treatment of

apparently minor conditions.

\[Slide.\]

By way of background, you have heard that

hydrocortisone has been available over the counter

since 1979, and in the 1 percent concentration

since 1990.

The OTC label is designed for safe use,

and compliance with the label implies that there be

a low risk of adverse effects, however, we found no

published data on how OTC hydrocortisone is being

used in the population.

\[Slide.\]

So, our research objective was indeed to

look at real world user behavior, and we did this

with a telephone survey which was performed by a

company called Synovate through one of their

192

regular national telephone surveys. We had them

ask questions about the usage of over-the-counter

hydrocortisone.

This is as reported by the adult users in

the family when we called them. This also included

these adults\' reports on the use in their children.

They gave us the reason for using the

hydrocortisone, the daily frequency of use, and the

duration of use. We evaluated their responses for

consistency with the labeling.

\[Slide.\]

This was one with a random digit-dialing

to over 64,000 households although about 55,000 of

them didn\'t answer the phone, so that is the

problem of caller ID, I think. In the end, we

achieved 2,000 adult respondents who actually

completed the survey.

Of these respondents, 396 adults reported

using over-the-counter hydrocortisone in the last 6

months; 168 households reported treating a child

with OTC hydrocortisone in the last 6 months.

\[Slide.\]

So, our analysis undertook a weighting to

represent the U.S. demographics in the 2002

National Health Interview Survey. Limitation of

193

this work is that it is based on self-reports. Of

course, we couldn\'t go into everybody\'s house to

see what they were actually doing, so we relied on

what they told us in answer to our questions.

The strengths of the study includes that

it was open-ended questioning, so we didn\'t use

terms right off the label, and the respondents

didn\'t have the label in front of them, so this

avoided biasing them to give us answers that they

might think that we wanted to hear.

Also, when we came to the children, we

asked about the youngest child at home who used

over-the-counter hydrocortisone, the youngest one

who used it, and we picked the youngest one because

we felt that that person might be at most risk for

adverse effects.

\[Slide.\]

You have seen this prototypical

over-the-counter hydrocortisone label from the

194

monograph. It talks about the uses for temporarily

relieving itching of minor skin irritations and

inflammation, and rashes due to a number of

conditions. It is for age 2 and over.

Frequency is maximum 3 to 4 times daily.

It is for external use only, not for use in diaper

rash. Avoid contact with the eyes, and the

duration for up to 7 days on the labeling, and we

inquired on these points in an open-ended fashion.

If you look at the overall compliance with

the label, 73 percent of adults and 72 percent of

the children that adults reported on, in fact, were

completely consistent with the labeling. A smaller

percentage, about 20 percent, were not acting in

consistency with the label for 1 reason, and a much

smaller percentage were not consistent for 2 or 3

reasons.

By far and away the most common situation

that we found was that they couldn\'t give us an

answer of why they were using it that was

specifically listed on the label. So, we are going

to look at the people who were not consistent with

195

the label and try to understand exactly what was

going on.

\[Slide.\]

So, we asked, \"The last time you used an

over-the-counter hydrocortisone product, what were

you using that product to treat?\" Eighty-three

percent of adults, the reports were 86 percent of

children were consistent with the label, but you

can see down here is this hatched bar, there were

other situations that we couldn\'t code as being

consistent. Most of these actually were indeed

called Other, they were vague responses or no

condition was reported, and in a few children, they

used the term \"cracking skin.\"

So, some of these in this hatched bar may,

in fact be consistent with the label, but the

respondent was unable to actually verbalize it in

that way. \"Cracking skin\" could well be eczema,

for example.

About 2 percent were using it for cuts and

approximately the same percentage were using it for

what they described as fungus, arthritis, acne, or

196

diaper rash.

\[Slide.\]

Now, we asked, \"Think about your youngest

child who has used over-the-counter hydrocortisone

in the last 6 months. How old is that child?\" In

93 percent of reported uses on the youngest child,

the age of the child was 2 years or older, which is

consistent with the labeling.

So, here we have the age across this way,

and the cumulative percentage reporting this way,

and the dash line is the non-consistent use with

the label. However, 81 percent of the adults who

told us about these children, 81 percent of them

said they had discussed the use of hydrocortisone

with a doctor in this group.

\[Slide.\]

So, then, we asked, \"The last time you

used an over-the-counter hydrocortisone product,

how many days in a row did you use the

hydrocortisone?\" For 92 percent of adults and for

94 percent of children, they were treated for 7 or

fewer days, again showing here the duration of use,

197

cumulative responses, and then this segment here,

the smaller segment here are the people who were

not consistent with the labeling. The median use

was for 3 days.

\[Slide.\]

And we asked, \"And how many times per day

did you use the hydrocortisone product?\" And 98

percent of adults and 97 percent of children, they

used it 4 or fewer applications per day. Again,

the number of applications and the cumulative

reporting, up to 98 percent, roughly 97, 98

percent, and the median use was 2 applications per

day.

\[Slide.\]

So, in conclusion, the reported use of an

over-the-counter topical corticosteroid is largely

consistent with the label for conditions treated

and for frequency and duration of use.

Thank you.

DR. WOOD: The next speaker is also called

Ellis, and it\'s Valentine Ellis.

MS. ELLIS: Thank you for your time. My

198

name is Valentine Ellis and I am here today to

present the patterns of household purchase behavior

in the OTC hydrocortisone category.

In way of disclosures, I am actually not

related in any way to Dr. Ellis, we only met a week

or two ago. I am a full-time employee with

GlaxoSmithKline Consumer Healthcare, and I work as

a consumer research manager there, so the majority

of my work is done behind consumer behavior

analysis and consumer insights.

I am formerly an employee of A.C. Nielsen.

I will be talking about them a little in the

methodology where I worked as home scan specialist

and specifically on this research project, which is

why I was asked to present it to you today by my

team.

\[Slide.\]

The research objectives at the time we

undertook this study were to understand purchase

behaviors in the OTC hydrocortisone category among

U.S. households. The basic underlying assumptions

that we use in research on the consumer side is

199

that the household data is a proxy for annual

household usage, and this information that I am

providing today is likely an overestimation because

we are reporting against 100 percent of purchases,

which does not necessarily mean people use 100

percent of the product that they bring into their

household.

\[Slide.\]

Methodologically, AC Nielsen is a

supplier, a commercial supplier of research data.

Most people are familiar with the AC Nielsen TV

ratings, but they do have another arm which

captures, maintains, and reports data for all the

products that are out in the world today that we

purchase and use at home.

We are using data from their household

panel, which at the time of the study had 55,000

households enrolled. It is demographically and

geographically balanced to the U.S. Census.

The panelists agreed to scan all of the

products that they purchased with UPC bar codes

regardless of where they purchase it, provided that

200

they use it for personal consumption.

This is a pretty accurate reporting

system. These people scan via an in-home bar code

scanner, which you can see this little lady here

using, everything, so in a sense, they are blindly

reporting their purchases, they are not paying

attention to the frequency with which they scan

these products, and they transmit the data back to

Nielsen once a week.

They are incented for consistent

reporting, so Nielsen provides them with a

non-biasing points redeemable type program, because

they don\'t want to in any way bias a product that a

person would purchase or how they would necessarily

use it once they get it into their home.

Most of the panelists stay within the

panel, and there is actually about an 80 percent

retention rate year on year.

\[Slide.\]

The custom analysis that we undertook was

to take AC Nielsen\'s hydrocortisone reported

category, which is over the counter. It includes

201

all of the brands we have listed here, all of the,

you know half-percent, 1 percent ointments, creams.

Most of the sizes I believe that are out in retail

today would be half-ounce, 1 ounce, and 2 ounces.

\[Slide.\]

The time period that we looked at was 52

weeks ending October 19, 2002, and the primary

measures that we looked at were buying households

and buy rate in both ounces and purchase frequency.

The sample of the data was any household

that had scanned a hydrocortisone product at least

once during the 52-week time period, and the

advantage of a custom analysis is it allows us to

take the total buyer group and break it down into

both households with children and households

without children, children at this point being

defined as any household under 18.

These are mutually exclusive buyer groups,

so the value of these two groups of households will

add up to the sum total of total buying households.

\[Slide.\]

Some of the advantages of this methodology

202

are that the ongoing electronic purchase of actual

behavior provides us with a pretty objective and

accurate measure of purchasing across the

household, but at the same time, there are

limitations to this data what we want to be

perfectly clear about. This tells us about

household level purchasing.

We can\'t link it from this particular data

set to who in the household is using the product or

necessarily how they are using it in terms of

frequency, duration, or condition. We just know

that this household has made so many purchases and

we know that volume is actually going into these

different groups of people.

\[Slide.\]

Our key findings were that annual

household purchasing of OTC hydrocortisone products

is reasonably limited. About 13 percent of total

U.S. households purchase at least one product per

year. Of those 13 percent of buying households, 75

percent of them purchase only once, 90 percent of

them purchase 5 ounces or less per year.

We have also discovered that households

with children actually buy less volume per year

than households without children, despite the fact

203

that there are significantly more people in that

household.

\[Slide.\]

A little detail on that, the data that we

have just presented in the key findings. Again,

you see that 13 percent of the households purchase

OTC hydrocortisone, and that is the little red pie

sliver.

When we look at the household composition

of those 13 percent of households, what we see is

that 34 percent of the buying households did have

children, and 66 percent did not. This number is

consistent with the U.S. demographic breakdown of

households with and without children.

\[Slide.\]

We also look at the households in total,

and of the buying households, 75 percent of them

make only 1 purchase per year, 92 percent of them

over the course of the year make 3 purchases or

204

less.

\[Slide.\]

This chart demonstrates the cumulative

percentage of households going up the bar, across

the volume that is actually purchased during the

course of the year.

If you look at the black bar in the

center, that is our total households, all of them,

and what it tells us is that 90 percent of the

households purchase 5 ounces or less per year of

OTC hydrocortisone.

Then, the red bar, which is on top, that

is our households with children under 18. It

cumulates or builds a little quicker, which is why

it is above the black bar, and what it tells us is

that 85 percent of households with children

purchase 3 ounces or less per year, and 94 percent

buy 5 ounces or less per year.

\[Slide.\]

Looking at it from a consolidated

perspective, the gold bars on the left tell you the

percent of buying households the buyer group

205

represents, and then the blue bar on the right

tells you proportionately how much volume they

contribute to the total volume purchased.

What we see is households with children,

while they represent 34 percent of the buyer

groups, are really only contributing about 26

percent of the total volume purchases, and this is

because the average buy rate in households with

children is about 1.9 ounces a year, while it is

2.8 for the households that do not have children.

\[Slide.\]

The conclusions we reached from this data

was again that annual household purchasing of OTC

hydrocortisone products is limited. It is not a

large\--well, it is a large group of people, but it

is only 13 percent of the population. They

purchase infrequently with 75 percent of them

purchasing only once, and for the most part, they

purchase, 90 percent of them, 5 ounces or less.

We see lower purchase volumes in

households with children, despite the fact that we

have twice as many people in them, and then based

206

on the amounts of product that we see purchased,

excessive use of the OTC topical corticosteroids is

probably not an issue, and, in fact, would lead us

to believe that people are using it much they way

they have told us in Dr. Ellis\' usage survey.

That is it.

DR. WOOD: Thanks very much.

Let\'s go back to Speaker No. 2, who has

now shown up, Mr. Paranzino.

MR. PARANZINO: Thanks very much for

accommodating my late arrival, I appreciate it.

My name is Michael Paranzino, I am with

Psoriasis Cure Now, which is a patient advocacy

group. I have no conflicts either personally or

through Psoriasis Cure Now with any content

involved today.

Our written statement is available on the

web at psoriasiscurenow.org, and I will just make a

couple points briefly.

First, thank you for holding this hearing.

While not two psoriasis cases are alike, one thing

that unites just about all 6.5 million Americans

207

with psoriasis is that we use a lot of topical

steroids, one or many over the years.

As I noted in my written statement, I took

a quick look at a popular list of topical steroids,

and I have been prescribed at least 15 over the

last two decades, and that is the way, as many of

the dermatologists in this room now, you try one,

then you try another, then you flip back, and then

you try another, so we do know topical steroids.

It is very important to us.

We believe that some of the topical

steroids that are currently prescription-only can

be used safely and effectively by psoriasis

patients over the counter. Most psoriasis patients

are actively involved in treating their skin

symptoms. They are also actively interested in

minimizing the medications they use, so they are

very cognizant of overuse.

Now, that said, we do have some concerns,

and one of them is every rule has its exceptions,

and we still come across psoriasis patients who use

what might be considered excessive either through

208

duration or extent over the body topical steroids

over a period of time, and only later come to

realize that there could be side effects to that.

But we think that can be dealt with through better

education, maybe through labeling. There is also

some education that needs to be done still we

believe with dermatologists, because there is a

wide range of strategies that are employed by

dermatologists in prescribing topical steroids. I

am not speaking anecdotally, not in terms of

studies, but I have talked to a lot of patients

over the years, and some doctors, every time they

prescribe a topical steroid, they peel off the

preprinted chart, they circle the one they are

giving you, and they say this is where your topical

steroid falls in the mild to strong, this is where

it falls. Other just write the prescription, they

are busy, they move on.

Just last month, someone came to me and

said they went in for what turned out to be

psoriasis on the leg. A quick appointment with a

dermatologist, walked away with a Temovate

209

prescription, and they said to me, \"But it\'s a mild

one, because it\'s 0.05 percent.\" I said, well,

according to this chart I am looking at, you can\'t

just go by the percentage, because, well, as you

all know, but we are lay people, so it\'s a common

mistake that can be made. But again that can be

dealt with through better education.

I did want to address children just for a

moment, because it is particularly tough for

parents trying to treat children with psoriasis,

and some actually try to avoid topical steroid use

in children, but it is becoming more and more

complex just with the FDA\'s actions in recent days

with Protopic and Elidel, there are some children

with psoriasis and some adults using those

off-label for psoriasis specifically to avoid

steroid use, and now they hear some warnings about

potential cancers.

So, it is very tough for a parent to weigh

the costs and benefits between UV light and Dovonex

and steroids, Protopic, Elidel, systemics,

biologics, anything that can be done in terms of

210

educating, if there is a scientific consensus on

what a child should do, it has to reach the

patients better.

Finally, I hope you would use your

influence with your colleagues downtown and closer

to Washington and Bethesda and encourage more

research on psoriasis. The challenges that parents

face and all psoriasis patients face underscores

the need for additional treatments. Psoriasis has

been underfunded woefully for the last 10 years at

least at NIH, and NIH funding is up 99 percent

after inflation in the last 10 years, psoriasis

funding is down 8 percent. It is hard to go down

in the environment over the last 10 years, and you

folks can help change that.

So, thank you again for the hearing. It

is very important to psoriasis patients, and I

appreciate the time to fit me in even though I am

late.

Thanks.

DR. WOOD: Thank you.

The next speaker is Dr. Sandra Read.

DR. READ: Good afternoon, Mr. Chairman,

distinguished members of the Committee and

colleagues. Thank you for letting me be here. My

211

name is Dr. Sandra Read, and I am appearing on

behalf of the American Academy of Dermatology

Association.

Thank you for allowing me a few minutes to

share with you safety concerns on an important

matter to me, to my patients, to doctors in

America, as well as to the Academy, regarding

changing topical corticosteroids to

over-the-counter status.

In the spirit of full disclosure, I do not

conduct any research for pharmaceutical companies.

I am on the Speakers\' Bureau for a company that

manufactures a high potency steroid cream.

However, I have not been in contact with this

company regarding this testimony.

I have been in the practice of medicine

for 30 years, more than 20 of those in the private

practice of Dermatology in the District of

Columbia. I serve on the clinical faculty of

212

Georgetown University, and I have been lecturing on

Pediatric Dermatology there for more than 10 years.

I have been prescribing topical

corticosteroids since my training days, and they

are an integral part of my therapeutic

armamentarium. Over the years, I have developed

not only an appreciation of their usefulness, but

also a respect, a very healthy respect for the

potential abuse of these agents. I urge the

Committee not to be lulled by their route of

administration. These are powerful external agents

that can have serious internal and external side

effects.

Treating patients of all ages with topical

steroids is a mainstay of many of our

dermatological practices. They are potent

medications and, when used properly, they offer

relief to suffering patients and enables them to

lead comfortable and normal lives.

Used improperly, however, these

medications can cause great harm and that is why

the American Academy of Dermatology is opposed to

213

the proposal to make these medications available

OTC.

I have done a random survey of 100 of my

patients\' charts. Of these 100 patients, I

prescribed topical steroid creams in 36. Of these

prescriptions, 16 percent were super potent, 36

percent were mid-strength, and 50 percent were low

potency. Some patients received more than 2

prescription for different strengths. As the last

speaker pointed out, this can sometimes be very

confusing to patients on how to use. However, the

usefulness of these agents is reinforced by the

figures of my practice. I cannot do without

topical steroid creams, neither can my patients.

However, I have seen too often the results

of abuse of these agents. Cutaneous adverse

effects include thinning and discoloration of the

skin, telangiectasias, and striae, permanent

stretch marks.

These side effects can be permanent and

disfiguring and last a lifetime. Pediatric

patients, our youngest patients are especially

214

vulnerable to these adverse events. In fact, I use

a picture frequently of one of pediatric patients

who was treated with a topical steroid cream, on

whose inappropriately was left with thin skin, with

hypopigmentation, and telangiectasias. The medical

students at Georgetown tell me they never forget

this picture.

I have seen patients have access to these

treatments and misuse them for non-steroid

responsive dermatoses, such as tinea, scabies, and

even skin cancers. Now, we all know that this

delays diagnosis and obscures diagnosis, but it can

also worsen disease, as we all know, in topical

ringworm and fungus.

I have seen, and so have dermatologists in

this room seen, the inappropriate use of in

steroids of body folds in genital regions. In

these areas, increased absorption rapidly

intensifies and produces the cutaneous side effects

we are talking about, and, of course, one cannot

ignore the augmented potency that is delivered by

these creams when applied under occlusion. Mild

215

creams become strong creams, strong creams become

even stronger under occlusion.

This can happen, of course, by accident

with patients using these creams on their own and

unsupervised. Now, not only are cutaneous adverse

events accelerated and magnified, but the risks of

systemic absorption and all of its complications

are well known to the members of this committee.

The medical literature is rich with

studies providing the direct link between topical

steroid creams and hypothalamic pituitary adrenal

axis suppression, growth suppression in children,

and the adverse effects on the skin that I have

just discussed.

It is only with close monitoring of our

patients who present with adverse treatments and

reactions that physicians are able to prevent and

monitor for these dangerous clinical diseases and

side effects.

I note to you that if you remove the

physician from this equation, you would be

effectively removing a very important safeguard and

216

protection for patients, and that is our primary

duty as doctors.

By changing the status of these

pharmaceuticals from prescription to

over-the-counter, the FDA would effectively be

turning over the practice of medicine to patients.

As well informed as patients can be, I do not

believe that they should be self-diagnosing or

self-treating symptoms with medications that can

have potential for such serious side effects.

The danger of pediatric patients being

treated with over-the-counter steroids should be

consider by this committee seriously. As parents

search for relief for their children bothered by

eczema and other skin diseases and their symptoms,

it would not be unheard of for them to use a

topical steroid cream incorrectly, such as too

often, using too much in an application, or

applying it to too large of an area and/or too

long.

Pediatric patients have a higher risk of

systemic absorption, which can lead to their growth

217

suppression because of their higher ratio of

surface area to body volume.

The FDA itself has expressed concern that

patients do not understand the risks of

hypothalamic-pituitary-adrenal axis suppression

when using steroid creams. Therefore, the risk of

doctors missing a diagnosis of HPA suppression in

pediatric patients when the parents fail to inform

them is a real risk of topical steroid use.

This Advisory Committee is being tasked

with determining at what point the risk of HPA axis

suppression and other adverse effects outweighs the

benefit of making these treatments more available

to the public.

I believe that there is no acceptable

point at which those of us in the medical community

should allow our patients to not only

self-diagnose, but also to self-treat at any level

of skin disease.

The complications that can arise, ranging

from mild to severe, as I have told you, should

exclude automatically the expansion of OTC status

218

to topical steroid creams. Our patients are not

qualified to make these kinds of medical

determinations, nor should we be asking them to

make these determinations.

I ask you, what is the rush to change the

prescription status? I ask you, what is the

marginal benefit to the consumer for stronger

over-the-counter creams? There is no overwhelming

need and there is no clear benefit in making these

treatments more accessible. The goal here should

be patient safety first and foremost. That is our

duty as doctors.

Given the FDA\'s increased focus on drug

safety, I believe that changing the status of these

treatments will have the opposite effect on the

public sentiment than what is intended by this

committee.

Patients will not be more satisfied

because these treatments have been made available

over-the-counter. In fact, I believe that their

satisfaction will diminish, as will their trust in

the medical community and in the FDA once they

219

become aware of the severe side effects associated

with the incorrect use of these agents.

Topical corticosteroids play an important

role in the treatment of patients with skin disease

and have improved the lives of countless patients.

Please do not make their suffering worse by allow

them the opportunity to diagnose or misdiagnose and

mistreat their conditions. These are being

effectively treated by countless physicians each

and every day.

The American Academy of Dermatology urges

this advisory committee not to make these powerful

medications available over-the-counter to the

public.

I think you for this opportunity and your

time. Have a good day.

DR. WOOD: Thank you very much.

Could we have Speaker No. 6.

DR. FONACIER: Good afternoon. I am Dr.

Luz Fonacier and I represent the American College

of Allergy, Asthma, and Immunology.

I do not represent any industry in this

220

meeting. I am the chair of the Dermatologic

Allergy Committee of the American College of

Allergy, Asthma, and Immunology, and the Secretary

of the Food, Drug, Dermatologic, Allergy and

Anaphylaxis Committee of the American Academy of

Allergy, Asthma, and Immunology.

I head the section of Allergy at Winthrop

University Hospital in New York, and am Associate

Professor of Medicine in SUNY of Stony Brook.

Thank you for allowing us to be

represented in this hearing. The allergists use

steroids in every shape and form for asthma,

allergic rhinitis, and atopic dermatitis. Unlike

the ENT who uses the nasal steroids, the

pulmonologists for inhaled, the dermatologists for

topical corticosteroids, we use all of them.

Many of our patients use topical,

intranasal, and inhaled corticosteroids together or

separately. The concern of the American College of

Allergy, Asthma, and Immunology is twofold, the

cutaneous use of topical corticosteroids for eczema

especially for the less than 2 years of age for

221

which nor many drugs are approved, and the

translation of this to intranasal and inhaled

corticosteroids.

For the cutaneous corticosteroids, neither

systemic nor local side effects are easily

recognizable. The sensitivity of the cosyntropin

stimulation test, the cortisol level, which are

lower than what we would want them to be. The

growth velocity, osteoporosis, even adrenal

insufficiency are not recognized unless specialized

testing is done.

Much of the discussion this morning was on

the systemic effects of topical corticosteroids,

but local side effects could be disfiguring, as

well. Skin atrophy, facial erythema,

telangiectasia are not easily recognizable, at

least not until the irreversible stage of the

striae.

There is low reporting of side effects and

difficulty of monitoring is a big concern. There

is also increasing incidence of allergic contact

dermatitis to topical corticosteroids probably due

222

to greater awareness, expanding market of the

corticosteroids, and improved testing procedure.

There are many reasons for potential abuse

or misuse of over-the-counter corticosteroids. Mid

and high potency steroids are going to be more

effective than low potency. In fact, it was

brought up this morning that 1 percent

hydrocortisone, whose label says not to use more

than 7 day, is actually being used years and years

for chronic atopic dermatitis even in children less

than 2.

Because of decreased efficacy, there is

potential for prolonged use and thus increasing

absorption and side effects, more so for

over-the-counter. Because the only topical

corticosteroids approved for less than 2 years of

age, is fluticasone, and that is more than 3 months

of age, and this is a prescription, the obvious

option for patients, especially those who are

concerned of drug costs or don\'t have medical

plans, is over-the-counter topical steroids.

Also, with the proposed black box warning

223

for pimecrolimus and tacrolimus, there is

anticipated an increased shift to topical

corticosteroids. If more potent ones are

over-the-counter, in chronic eczema and atopic

dermatitis, there may be increased off-label use,

that is, more than 7 days and under occlusion.

Other important issues that we are

concerned about in over-the-counter topical

corticosteroids are inappropriately linked,

trivialization of what over-the-counter is, that

is, the perception that over-the-counter is safe,

credibility of advertising, appropriate labeling,

and differences in vehicle that increase

absorption.

Note, that it is the Diprosone Lotion

which may be alcohol based that showed more HPA

axis suppression, and in the tacrolimus and

pimecrolimus study, it is the study on ethanol that

showed increased absorption of the drug.

The second major concern of the allergists

is how this issue will translate to intranasal and

inhaled corticosteroids for asthma and allergic

224

rhinitis patients. We would not like to see

difficulty in access of the medication, unnecessary

panic or concern of the use of corticosteroids in

potentially life-threatening disease such as

asthma, nor suboptimal treatment. But at the same

time, would like to be able to monitor our

patients, not only in terms of efficacy, but most

importantly the safety.

Thus, as the representative of the

American College of Allergy, Asthma, and

Immunology, until safer steroids are available,

more sensitive tests can be used, better monitoring

can be done, and more studies are conducted, we

would like the current prescription cutaneous,

intranasal and inhaled corticosteroids to remain

prescription.

Again, in behalf of the American College

of Allergy and Immunology, I thank you for this

opportunity.

DR. WOOD: Thank you very much.

Are there any really pressing questions

from the Committee for the public forum speakers?

225

Yes.

DR. BIGBY: I just have one question for

Valentine Ellis. How many households are there in

the U.S., the total number of households?

MS. ELLIS: Right now there are about 113

million households in the total U.S.

DR. BIGBY: Thank you.

DR. WOOD: Any other questions? Yes, Jon.

DR. WILKIN: If I could ask Dr. Ellis if

he discerned why patients stopped using the topical

corticosteroids over-the-counter, you have that

they used it for 7 day or no more than 7 days for

the most part, I think it was, no more than

something like 5 percent used it beyond that, but

was that because they ran out of product, or it no

longer seemed to work, or it actually did work? I

mean did you get that piece out?

DR. ELLIS: Jonathan, that is very good

question. We did not delve into that in this

survey. The only answer I could say is that much

of the use was for insect bites and other trivial

issues, and I am sure that explains part of it,

226

part of the short-term use for 3 days of median

usage, so that would be my interpretation, but we

didn\'t ask that specific question, and that would

be a good one to ask at a future date.

DR. WILKIN: So, it is fair to say that

their, in large part, use is consistent with

labeling, but not absolutely proven that it was

driven by labeling?

DR. ELLIS: I don\'t know how I would

answer that specifically. Again, we asked them

questions, the type of question that I showed you,

and then we later coded the responses to determine

if they were consistent with the labeling, so we

found that, by and large, people do follow the

label, and we presume they are reading it and that

is why they are following the label.

DR. WOOD: Let me just follow up on that.

I am intrigued by your confidence in that. If you

look at Slide 12, 10 percent of the children were

under 2, and how do you square that with the label?

You need to look at that slide in the context of

the way you framed the question.

You said, \"Think about your youngest child

who has used over-the-counter hydrocortisone in the

last 6 months. How old is that child?\"

227

Well, if that child is now 2 1/2, that

child was under 2 when they were using it if they

were taking it 6 months ago, so if you assume it

was averaged over 3 months, that brings that up to

about 10 percent. That seems to me pretty high if

you think that the label is being followed.

DR. ELLIS: Well, that is a qualitative

statement, I take your point. You know, we

think\--I don\'t know\--again that is a qualitative

statement to determine whether 10 percent is too

high or too low. I can tell you that of the people

who were at the time that we asked the question

under 2 years old, so I take your point that there

is a 6-month variation in here, but in that 7

percent of children, in 81 percent of those

children, the family had discussed it with a

doctor, had discussed the use of hydrocortisone

with a doctor, so that is somewhat reassuring to me

on that point.

DR. WOOD: And more than 20 percent were

under 3, so again adding 6 months, we are well over

that. That is a pretty high number it seems to me,

wouldn\'t you think?

DR. ELLIS: You are assuming now that

everybody who is less than 4 is less than 2.

228

DR. WOOD: I am looking at your slide, and

if you put in 3, the vertical line from 3 is above

20 percent, and that is not adding in the 6 month

issue. That seems to me pretty high. Anyway,

okay.

DR. ELLIS: When you said 10 percent, I

would go with you on 10 percent. I think 20

percent is tipping it the other direction.

DR. WOOD: The slide shows under 3 is over

20 percent without making any adjustment.

DR. ELLIS: Right, but the labeling says

under 2.

DR. WOOD: I understand, but I doubt that

there is a huge difference between a 2-year-old and

a 3-year-old that would give us that. I mean that

says that almost 25 percent of the product is being

229

used in under 3-year-olds. That is pretty scary.

Okay. Any other questions? Charley.

DR. GANLEY: Just to follow up on your

point, Alastair, I think it is important to

understand that in that case, 81 percent talked to

a physician or were guided by a physician. I think

one of the difficulties that we have in looking at

data like this is when people fall outside the

labeling, well, why did they do that, and we often

don\'t understand that.

It is very legitimate to talk to a

physician, in fact, there is 3 or 4 warnings about

talking to a pharmacist, physician, or someone else

either before taking it or after taking, or if this

happened, you should do this.

So, to suggest that because we have this

data that someone is buying 3 percent or buying 7

tubes or more per year, that that is somehow bad.

Well, maybe there is a physician directing them to

do that.

So, I think that is what you factor into

that is how does that fit into the equation here.

DR. WOOD: Okay. Dr. Mattison.

DR. MATTISON: Sort of taking a look at

the data from the other end, both of your data sets

230

seem consistent in suggesting that 5 percent of the

kids used either more than 5 ounces a year or for 7

or more days. So, from the other end of the data,

that seems like a fairly large group of children

that are exposed for a long period of time or to a

potentially large volume or dose.

DR. WOOD: Mary.

DR. TINETTI: My question is for the two

Academy people. You are operating on the

assumption that the fallback is that all these

families and people have access to dermatologists

or allergists, and what is your stance on the 40

million people in this country who are uninsured

and probably twice that are underinsured, probably

will not have access to dermatologists, and how do

they sort of fit into your equation of the benefits

and harms for conditions such as atopic dermatitis?

DR. FONACIER: I feel that those that have

mild eczema may use the 1 percent or the 0.5

231

percent hydrocortisone, but once you start going to

moderate to severe atopic dermatitis, which is a

really chronic disease, these patients should be

under the care of a dermatologist or an allergist,

and once the higher potency corticosteroids are put

over the counter, they will access that.

DR. TINETTI: My question to you is those

people who don\'t have the insurance to pay for

dermatologists, does the Academy demand or require

that dermatologists see people who aren\'t able to

afford the care? I understand that the perfect

position would be that they see a dermatologist,

but for those who financially can\'t, what is the

position of the Academy?

DR. FONACIER: Well, I represent American

College of Allergy and Immunology. You are talking

about the global health care issue here for people

who would have the disease and have no access to

care. I would think that would be a Medicaid issue

of some sort. I don\'t know whether the American

College of Allergy would have a position on that.

DR. WOOD: Dr. Santana.

DR. SANTANA: Following up on this issue

that was discussed a few minutes ago, of pediatric

usage and looking at numbers, I want to follow up

232

on that. Do any of the two consumer surveys have

data that could help us investigate that the

product was bought for an adult, but was used on a

child, that they elected to use it on a child

although the primary indication for buying it was

for an adult?

MS. ELLIS: From the purchase perspective,

I can tell you we don\'t have that in this

particular data set, but it is something we could

potentially follow up on and discover. The

panelists, they tend to work more so on a forward

going basis when they do that kind of analysis,

but, yes, that is something that could ultimately

be determined.

Just to be clear, just because we see 5

ounces of product going into a household with a

child, doesn\'t necessarily mean that the child is

using it. The data would indicate to us that

because there is no increased consumption in a

233

household with a child, even though we are seeing

disproportionately increased numbers of bodies in

the household, we can\'t necessarily make the leap

of faith that they are transferring product usage

to a child without further analysis, a little

different than what we undertook here.

DR. WOOD: Dr. Patten.

DR. PATTEN: Yes, I have a question for

Valentine Ellis. This is a question about the

children under 2 years of age. Do you know what

percentage of all households surveyed had children

under 2 years of age?

MS. ELLIS: Yes, I do know that. I have

it probably in the back of the room.

DR. PATTEN: So, then we can figure out,

of those at risk, shall we say, what percentage

actually were treated.

DR. WOOD: No, because they are different

surveys.

MS. ELLIS: I can\'t tell you if the child

was treated. I can tell you how much product the

household purchased, but I don\'t know from the data

234

set that we have who in the household the product

was used on.

DR. PATTEN: So, I guess I am thinking

about the other data set, the other Ellis, Dr

Ellis.

DR. ELLIS: That is a very good question.

I am not sure I can answer it specifically because

you see we asked the adult in the family to think

about the children in the family, and we asked

think of the youngest child who actually used the

hydrocortisone.

So, we were skewing out data purposely

toward younger children, but I cannot tell you\--I

am sure that in the census data, there probably are

these figures, but I don\'t know what percentage of

households in the U.S. actually have a child under

2\. I mean I am sure it can be looked up, but I

don\'t know the answer.

DR. PATTEN: It would have been really

good to also ask how old is the youngest child in

your family, in addition to what is the youngest

child that actually is treated. That way, we would

235

know. I mean for all we know, 100 percent of

children under 2 years of age in your survey were

being treated with this.

DR. ELLIS: Well, it is probably not the

case, though, because we asked the person to think

about the youngest child who actually was using

hydrocortisone.

DR. PATTEN: Right.

DR. ELLIS: And that turned out to be, if

you are interested in children under 2, it was,

depending on how you averaged the data point, but

least clearly, 7 percent were under 2 and were

using hydrocortisone, and the family had consulted

with a physician in about 80 percent of those

situations.

DR. PATTEN: Right, I understand that.

DR. ELLIS: But I don\'t know if there were

children who were 6 who were using it, and there

was also a children under 2 in that family who

wasn\'t using hydrocortisone. I mean it must be

that there were such situations, but we did not ask

that.

As you can imagine, with surveys, after a

few questions, you are pretty tired of answering

questions.

236

Thank you.

DR. WOOD: We have spent an hour on the

public comment period. I would like to thank the

public speakers for their time and their attention

to our questions.

Let\'s move on to the discussion of the

questions and the Committee discussion.

Jack.

Questions to the Committee and Committee Discussion

DR. FINCHAM: Alastair, over the break at

noon, I did as much as I could to find out what the

environment is elsewhere, and I could only have

time to do Canada, the UK, Australia, and New

Zealand as far as what products are available.

As far as I could tell, the only

over-the-counter product in the class that is

available is hydrocortisone. For example, in New

Zealand, there is a limit on half a percent

strength of hydrocortisone in a 30 gram or less

237

container. There is nasal fluticasone available,

but it is not topical, and it is in a class, at

least in New Zealand, there is 4 classes of drugs.

There is prescription, pharmacist only,

pharmacy only, and general sale, and it is for

pharmacy only, so it is just like it is in the

United States, but none of the other more potent

agents that could determine were available

over-the-counter anywhere else, at least in those.

DR. WOOD: So, none of these are available

in the UK or Canada either. Okay, good. Dr.

Nelson.

DR. NELSON: My impression of a lot of the

questions that we were asking our public speakers,

which are difficult to answer, and I am trying to

get a handle on this, is what is the population

exposure for this product, and if that is high, and

I am getting numbers that are in the million, you

know, taking the number of households, you assume 2

adults per household, which I realize is probably

not correct, et cetera, you get a big number, and

then the answer to the 10 percent question is 10

238

percent of a big number is a big number, too.

So, I guess I would say I am not terribly

reassured by the fact that 90 percent might be

using it on label, and even if the labeling needs

to be improved, frankly, I find it confusing as a

physician to keep track as a non-dermatologist of

all of these different concentrations and what I

should or shouldn\'t use, because I can prescribe it

to myself, which I sometimes do, and it takes me a

long time to figure out what to do.

The thought of someone going up to a

countertop without my training and figuring it out

is a little bit beyond me absent better labeling.

I guess that\'s an editorial comment, but I guess

the 10 percent sounds to me like a big number, as

well. I share your concern on that, that I heard

earlier.

DR. WOOD: Mike.

DR. ALFANO: I apologize, Alastair, for

not bringing this up this morning, but I actually

didn\'t learn it until the lunch break. In the

charge to the Committee, the Agency indicated that

239

companies are potentially proffering more potent

corticosteroids to go over-the-counter. In my

mind, that said this could potentially be

revolutionary, I have got Class III in my mind, I

don\'t really know.

But at the break, I learned that one of

them is actually a Class VI, which is classified as

mild, so that leads to the following question. In

the AERS data that was presented by Dr. Cook, I

understand there was a meeting in October of 2003,

at which Dr. Karowski reviewed the AERS data by

class, and in October of 2003, there was not a

single serious adverse event leading to Class VI

corticosteroid, and my question is has that changed

in the year and a half since.

DR. KAROWSKI: In our update, we didn\'t

find any of our additional cases had involved

agents that were\--

DR. WOOD: Could you identify yourself for

the transcriptionist.

DR. KAROWSKI: I am sorry. Claudia

Karowski with the Division of Drug Risk Evaluation

240

in the Office of Drug Safety. So, even in the

adult patients, they were all with the more potent

corticosteroids. There was one case with Aclovate,

but that was also used in combination with another

topical steroid.

DR. ALFANO: Thank you.

DR. WOOD: Frank.

DR. DAVIDOFF: I am having some

extrapolation problems here. One revolves around

the Dr. Ellis study, which I am having difficulty

extrapolating from his data to the general

population since he really only sampled 3 percent

of his potential population, so I think it is a bit

of a stretch to generalize his conclusions to the

rest of the population.

In effect, that study doesn\'t help me

understand the appropriateness of use of

hydrocortisone more generally, but that

consideration is really secondary to my other

concern, which is about what indications are being

considered for the high potency steroids if they

were to go over-the-counter.

Hydrocortisone is clearly being used or is

approved under the monograph for\--or perhaps NDA,

whatever\--as an acute, purely symptomatic use, but

241

it sounds to me as though the high-potency

steroids, if they were to go over-the-counter,

would be labeled and approved for more chronic use

for actual therapy.

Maybe I am misunderstanding the issue, but

we haven\'t heard a lot about what the indications

would be or what the labeling would be, and it

seems to me to try to extrapolate from

hydrocortisone with its very limited intention for

us to the high-potency steroids, which are not only

a different pharmacological class, but a whole

different medical class, I am having great

difficulty deciding how to extrapolate from one to

the other.

Could somebody perhaps let us know what is

being requested or what is the intention in terms

of the prescribed indications and duration of

therapy?

DR. GANLEY: I think there was no specific

242

indications other than what is already available

for hydrocortisone, and that is not atypical. I

don\'t think it\'s any different than when other

drugs come over-the-counter. If there is a

heartburn indication when the H2 blockers came

over-the-counter, they pretty much got the same

labeling that a monograph antacid treatment

received.

So, I think if that is as holdup, you

ought to put it into that context. I think the one

thing that when you do look at the current

labeling, where it has conditions that are chronic

conditions, it almost is encouraging some people to

do that, and I think that is a valid thing that we

would have to look at if we were going to put more

potent products on the market, because it does have

the term psoriasis and things like that.

DR. DAVIDOFF: But if I may follow up on

that, it sounds like, then, that what is being

proposed is to go after a flea with an elephant

gun. I mean to relieve an itch with a high-potency

steroid, I don\'t understand what the request is.

DR. GANLEY: Let me just challenge you on

that a little bit, and I think you are taking away

from people, allowing people to make decisions. If

243

someone goes out and has a case of poison ivy, and

with all due respect to the dermatologists, it is

not easy to get an appointment with you folks. In

personal experience, it\'s at least a 3-month wait

for family members.

But if someone chooses to use a topical

over-the-counter product, and they choose

hydrocortisone, or if they choose a more potent,

should they not be allowed to make that choice? If

it doesn\'t work, they are not likely to purchase it

again. If it does work, they will have a future

reference that this worked the last time I had

poison ivy. You are not allowing them to make that

decision.

That is why I have a difficulty. We have

all these other products out there where there is

probably 6 or 8 antihistamines over-the-counter,

but we don\'t have the same questions about those.

So, I am having a very difficult time understanding

244

that part of the equation as to why should someone

not be allowed to make that choice.

DR. DAVIDOFF: But I think, if I may, the

reason is that these\--possibly\--is that these are

very potent, potentially very toxic drugs. It is

not the same as just buying hydrocortisone.

DR. GANLEY: Again, I think the issue here

was the safety of it. We recognize that these more

potent products present more\--you know, they could

lead to bigger problems. Otherwise, we would have

just been putting these out there, and one of the

speakers who suggested that we are rushing to a

decision here, we haven\'t had one out on the market

in the last 20 years, and I am very encouraged that

we are actually\--

DR. WOOD: We are rushing to a decision

here, we have planes to catch.

DR. GANLEY: Yes.

DR. WOOD: I would remind you, though,

Charley, that, you know, I seem to recall the

antihistamine meeting, and the same cast of

characters showed up to tell us we shouldn\'t do

245

that as well. Isn\'t that right? Okay.

Jon.

DR. WILKIN: It is a fine point, but when

we are talking about more potent, I think we at FDA

are talking more potent than the currently approved

OTS hydrocortisone products. We are not thinking

about the more potent of all the current Rx

products.

DR. WOOD: Dr. Epps.

DR. EPPS: I am going to comment and then

I have a question. One thing that is rather second

nature to a lot of dermatologists, but not

necessarily to others, is the classes of topical

steroids, even within hydrocortisone can be very

different. There is hydrocortisone acetate,

butyrate and valerate, and they can vary from Class

IV to Class VII, so some are prescription, some are

not prescription, and just as several of our

speakers have said, some people confuse the

percentage as being their strength. Some people

think hydrocortisone valerate 0.2 percent is weaker

than hydrocortisone 2.5 percent, when that is not,

246

in fact, the case.

There is some confusion out there, and

different medications are put on the incorrect

areas, which would be my concern as a pediatric

dermatologist who certainly defend for the little

people who cannot vote and cannot speak for

themselves.

As far as application, of course, the ones

who are getting the diaper rashes under 2, and, of

course, there are some seniors and some nursing

home patients that we become concerned about as

being applied on a moist area under occlusion in

the diaper, and that is where your absorption

occurs, that is where the side effects occur,

whether it be stria or telangiectasias or

absorption, but that is where the dermatitis

occurs.

That is one major concern that we are

having, also people under 2 cannot express to you

that they feel bad, that they feel fatigued, that

they are having side effects that you may be

experiencing from HPA axis for an older person or

247

child can do that.

One question someone asked, who treats the

people if you don\'t have a dermatologist, people in

emergency rooms, doctors treat them, pediatricians,

family practitioners, nurse practitioners. They

are often the first line, and as a pediatric

dermatologist, if things don\'t respond, they end up

in my office.

Is there any data\--I guess my question\--at

other meetings, they have had express script data

regarding a number of steroid prescriptions and

ages for particular steroids, is any of that data

available? Maybe that would help some people who

have questions about how many prescriptions are

written, but there has been data presented

previously. I don\'t know if any of that is handy.

DR. WOOD: While somebody is looking for

that, Dr. Wilkerson.

DR. WILKERSON: A couple of points of

clarification from the Agency. Are we\--or Mr.

Chairman\--are we actually talking about, are we

deciding today that 1 percent hydrocortisone is

248

safe?

DR. WOOD: No. At least my impression is

that what we are deciding here is the questions

that are listed on the table, which is focused on

what one would need to do to demonstrate that a

future application by a sponsor that their drug was

safe to go over-the-counter.

DR. WILKERSON: But by extrapolation, if

one assumes we are making an assumption in the room

that 1 percent hydrocortisone is safe, has it been

subjected to the same criteria that we are now

being asked to determine if these are appropriate

criteria.

I can almost bet you that if I cover your

body with 1 percent hydrocortisone cream twice a

day for the next two weeks, I bet I can suppress

your HPA axis unless somebody has evidence to the

contrary, my point is I have not seen that

presented today in terms of what is\--we are blanket

approving or passing on 1 percent hydrocortisone in

any quantity to be safe, and that just doesn\'t pass

the smell test, and if that doesn\'t pass the smell

249

test, then, why do we go on to more potent topical

steroids of which we don\'t have a metric that we

even know the validation of right now. If we don\'t

know the validation, the metric of 1 percent

hydrocortisone, what is the\--

DR. KOENIG: I have two large boxes of

data from the meetings regarding the 1 percent

hydrocortisone, and the amended TFM that came out

in 1990 addressed that specifically. I don\'t know

if I included that in the background package, I

guess not, but there was extensive data and

literature reviews, and it was determined to be

safe and effective by FDA.

DR. WILKERSON: In what quantities and

what ages and what application rates?

DR. KOENIG: Well, it\'s OTC, so it follows

the labeling that is in the monograph. That would

be children over 2, and it is restricted to people

over the age of 2 years old and no more than 3 to 4

times a day.

DR. WILKERSON: By these questions, we are

being asked to determine what is an acceptable

250

level of HPA axis suppression, which is directly

related to the volume, quantity, condition of the

patient in whom it is being applied to. How can we

do that if we don\'t even have a standard for the\--

DR. WOOD: Let me try and focus the

question. I think the question you are asking is

has there been HPA axis suppression tests for

topical hydrocortisone, right?

DR. WILKERSON: Right, and in what

quantities.

DR. WOOD: Let\'s hear if there is an

answer. Do we have an answer to that in the two

boxes of data?

DR. KOENIG: We have HPA axis suppression

tests with 1 percent showing no evidence of

suppression using the ACTH stim test, actually,

cosyntropin.

DR. WILKERSON: But what quantity, what

percent body surface area, what age groups, all

those things?

DR. KOENIG: It varies. The ones that I

showed were all in children ranging in age from I

251

guess 2, 2.5 year mean, median 2.5 years up to I

think 14, and the body surface areas ranged in the

five studies I presented from I think the smallest

was about 30 percent up to over 50 percent of body

surface area.

DR. WILKERSON: Okay. Well, I mean that

is a start for our metric then.

DR. WOOD: So, the answer to the question

is yes, there have been studies, and, no, they

didn\'t show HPA suppression.

DR. KOENIG: They have, right.

DR. WOOD: Any other questions? Yes.

DR. RAIMER: Just a comment. If the FDA

is looking at putting Class VI steroids

over-the-counter, I just want to remind folks that

our ability to class steroids is so crude still. I

mean what we do is basically the vasoconstrictor

assay, which is running the cream on the skin and

then coming back and measuring how big an area of

blanching you get.

That is the best we have, and that is

terribly crude. We have already seen today that

252

something that is considered a Class V, which is

still considered really fairly mild, caused HPA

suppression in 73 percent of older children, not

even younger children.

So, I think we have to be careful at being

too confident that things that are Class VI really

all that mild. We just don\'t have a good way to

actually classify steroids, and it\'s according to

strength at this point in time.

DR. WOOD: Dr. Skinner.

DR. SKINNER: I think in the idea of can

the public diagnose and treat themselves with

strong topical steroids, you have to look at

Lotrisone, which was kind of promoted as is it

fungus, is it dermatitis, who cares, you know, this

will take care of it.

So, how well did the family practice

doctors and internists do with that? I know

dermatologists have seen a whole lot problems with

that, African-American babies that had white diaper

areas, stria, things like that, so this is doctors

not being able to do it too well, so how well in

253

the next step can the public do?

DR. WOOD: Dr. Nelson.

DR. NELSON: I guess I just want to keep

two questions distinct in my mind. One is whether

there is serious adverse events when used within

the label that might be considered for

over-the-counter and limiting similar to

hydrocortisone versus what is the risk when you

increase the potency of the particular medication

you use for that 10 percent who is not using it

within the confines of that label.

All the data we saw this morning is

presented in a way that would not be labeled for

over-the-counter use. It is 2 to 3 weeks, et

cetera. To some extent, that is a question that we

have not been presented any data to be able to

answer, because none of the studies of the more

potent agents have been done on 7 days or less of

treatment, so we are trying to extrapolate on top

of extrapolations, which is fairly difficult.

DR. WOOD: Right. The issue here in that

context is there an over-the-counter indication in

254

which there would be a reasonable assumption that

people will not follow the label precisely. I mean

maybe they will, and that is different from an Rx

situation. So, that is part of the context for

this discussion, I think.

Dr. Bigby.

DR. BIGBY: I would just like to make two

comments and sort of expand on what Dr. Raimer

said. The first one is about this sort of

Stoughton vasoconstrictor assay. This test has

really not been without controversy. In fact, it

was the subject of an FDA panel regarding generic

topical corticosteroids, and Stoughton published an

article claiming that generics were not

biologically equivalent to enervators based on the

vasoconstrictor assay.

The fallout from that paper was that if

you take the same product and test it on different

people on different days, you will often get a very

different assay result and as much as a two-class

difference in the product. So, I think it really is

an inexact thing.

If you look at the table that was provided

in Tab 1, in general, ointments are more potent

than creams, which are more potent than lotions,

255

but Aristocort Cream, which is 0.1 percent

triamcinolone is listed as being a Class VI,

whereas, Kenalog Lotion, same product as a lotion,

which I think all of us would agree should be less

potent, is classified as a Class V, and there are

many, many examples of this sort of thing.

The second one was, you know, I am very

familiar with Rule of 3, so if there are no adverse

events in 20 patients, you put 3 over the number

exposed, and that will give you the upper 95

percent confidence interval.

The other side of that is, though, if you

have a very small study and you do detect a signal,

it usually implies that there are, in fact, going

to be a significant number of adverse events, and

if you look at what was provided in Tab 9, in that

what was called Group 2 was included betamethasone

valerate at 0.025 percent and fluocinolone at 0.006

percent, and 1 out of the 17 of these people tested

256

had HPA axis suppression, so already in the lowest

group that we can consider, you already have a

signal that you have HPA axis suppression.

So, I mean I think that the onus really is

on showing some really good proof that these things

are safe, not at what level we need to detect a

signal, because we have already detected a signal.

DR. WOOD: Dr. Ringel.

DR. RINGEL: Two comments. The first is

that we have talked about vehicles, and one thing

that is important to remember is that the monograph

process, the way it was described to me today, it

is the drug that will be approved, and not the

vehicle, so if we approve betamethasone valerate,

we don\'t know what kind of enhanced vehicle the

generic companies will compound it in, and it feels

as if we would lose control over the product that

is being used by our patients.

DR. WOOD: In fairness, though, and I

don\'t want to cut you off here, but that is not

what we are approving today. I mean we are

addressing issues of HPA axis suppression. Am I

257

right, Charley?

DR. GANLEY: It\'s that, but these are

products that are marketed under NDAs, and they

would be marketed under NDAs, so their formulations

are already set, whether it is an NDA or an ANDA.

DR. WOOD: You mean they can\'t come in

with\--

DR. GANLEY: They can\'t go into the

monograph.

DR. RINGEL: Okay.

DR. GANLEY: They would remain NDAs, they

would still have the same reporting requirements as

all the others. Whatever hurdles you would set

today with regard to safety would apply to a

company coming in with a specific product saying we

want this to go OTC, whether it\'s a Class I or a

Class 6, but this is the hurdles that you have to

get over, that\'s it.

So, I don\'t want you to get locked up in

all the formulation issues, because that, I don\'t

know if it is an issue right now.

DR. WOOD: Do you want to respond to this,

258

John?

DR. WILKIN: If I could just comment on

the vaso, two members of the panel mentioned the

vasoconstrictor assay. I can say on the new drug

side, and that is what we are talking about today,

is that we have never used vasoconstrictor data as

a surrogate for efficacy or safety, and that is

really not part of that flow chart that was

presented to this group.

DR. WOOD: Charley again.

DR. GANLEY: There was a question about

use of prescription products, and we do have some

claims information.

DR. RINGEL: I did have one other quick

comment.

DR. WOOD: Go on and finish.

DR. RINGEL: I think that generalizing

about the use of other corticosteroids based on

hydrocortisone may be not very accurate either. I

think one reason that people don\'t use much

hydrocortisone frankly is it doesn\'t work very

well. I think they stop it because it is not doing

259

anything in many cases.

I have no trouble getting my psoriatic

patients to stop using hydrocortisone. I have

enormous trouble getting my psoriatic patients to

stop using clobetasol, because one they get their

hands on it, and they realize that it\'s doing

something, they don\'t want to let go. I think the

better the product, the more abuse you are going to

see.

DR. WOOD: Go ahead.

DR. MOENY: David Moeny from the Office of

Drug Safety. I did conduct an analysis of advanced

PCS claims data. This would just cover

prescription products, it doesn\'t cover very much

OTC products.

We did find that the younger the patient,

the lower the potency, and the smaller the tube

that is dispensed to the patient. For instance,

basically, under age 16, greater than 80, 85

percent were dispensed of a low to medium potency

product at 30 grams or less. Use is kind of

typically where you would expect to see that in

260

that age group.

Does that answer the question?

DR. WOOD: It was Dr. Nelson who asked the

question, right?

DR. NELSON: What are the numbers, the

total numbers of prescriptions out of curiosity?

DR. MOENY: Prescription claims per year

were over 4 million.

DR. WOOD: Dr. Whitmore.

DR. WHITMORE: I think what disturbs me

about this is that the first consideration probably

should be the ends that we are coming to, and the

ends being patients being able to correctly

diagnose and treat themselves.

If we could establish that that is going

to be the case, then, I think you can step back and

look at the other issues, but until you can

establish that, I don\'t think you can tell

pharmaceuticals that they have any grounds to stand

on in terms of getting these over-the-counter.

Surely, there are patients who know

exactly what they have and they are patients who

261

have already seen a dermatologist, been taught how

to use things, who could efficiently probably get

over-the-counter products like this, but you are

going to have a great number of patients who have

no idea what they are doing in terms of they don\'t

know what their skin disease is. It may be a skin

cancer, it may be a fungus, it may be, you know,

whatever, who are going to be using these products,

and until somebody can establish for us that

patients can diagnose themselves, I would say that

the currently prescription products should never go

over-the-counter.

DR. WOOD: Are there any new points that

any Committee members want to bring up, that have

not been ventilated before? Okay.

In that case, let\'s move on, in the

absence of hearing any, let\'s move on to the

questions, and there is a preamble which I will

read.

Companies are interested in the potential

marketing of OTC topical corticosteroids that are

more potent than the hydrocortisone products

262

currently on the market.

Current OTC corticosteroids labeling

limits use to approximately 7 days, however, a

minority of consumers may exceed the labeled

duration. Safety concerns include systemic effects

and local effects. Of the systemic effects,

potential adrenal suppression is the most

concerning followed by Cushing-like effects.

Please discuss the questions below in

regards to developing a possible paradigm to

evaluate the safety of topical corticosteroid

products, and if I can find it again, Charley or

somebody passed out the sheet, which I can\'t lay my

hands on right now, but it is here, the flow

diagram, yes, this one, the flow diagram that

Charley passed out.

I guess that is sort of is the basis for

the decisionmaking process.

So, let\'s go to the first question.

If any subject has HPA axis suppression

with ACTH testing under maximal use conditions,

does that preclude OTC marketing of that

263

dermatologic topical corticosteroid product?

Is there discussion on this? Yes.

DR. NELSON: I wouldn\'t mind a

clarification of what the phrase \"maximal use

conditions\" means. Is that use as anticipated

under what might be an OTC label, or is that misuse

as anticipated within the population who would be

potentially buying this off of the counter?

DR. WOOD: Well, my view would be the

latter, but I think the FDA may be reluctant to say

that.

DR. WILKIN: The idea is maybe rather than

maximal use, a provocative test to see if under

extreme conditions, it could occur.

DR. WOOD: Go ahead.

DR. BIGBY: I would just like to remind

the panel that the test being used to detect HPA

axis suppression has a sensitivity of 70 percent,

so, even if the number is zero, you are missing or

you are potentially missing 30 percent of people

who are suppressed.

DR. WOOD: So, what you would suggest for

264

the sensitivity?

DR. BIGBY: My whole suggestion has been

stated, I mean that is the test that we have, and

that is the question we are being asked, but it has

a sensitivity of 70 percent.

DR. WOOD: Well, there is the Tinetti

modification of the test, widely described in the

last two hours. I mean we could increase the

sensitivity by going up in the requirement.

I mean I don\'t think we want to do that

here, because none of us have a sense of where that

number comes, but what Mary\--I don\'t want to put

words in Mary\'s mouth\--but I think what Mary was

suggesting was that you would increase the height

of the bar and that that would bring that

sensitivity up substantially, and without knowing

where that number is, you would be reluctant to set

it, but that is probably there in data somewhere.

Wayne.

DR. SNODGRASS: This Question 1, the way I

am reading it is I am being asked to comment on

sort of a risk issue, a risk consideration, and the

265

way it is worded is if any subject has\--and it goes

on\--I am looking for any subject out of what number

tested.

DR. WOOD: That\'s Question 2.

DR. SNODGRASS: All right.

DR. WOOD: So, the first one is an

absolute, and then the second one is out of what

sample size. That is my reading of it, right?

Okay.

Yes, Ben.

DR. CLYBURN: The only thing I was going

to comment is that even with a relatively

insensitive test, and for secondary adrenal

insufficiency, I think the numbers were 57 to 60

percent, there is still significant HPA suppression

in the tests that we have already seen presented

today, so we do have the smoke, so to speak.

DR. WOOD: Dr. Wilkerson.

DR. WILKERSON: I went back to my point,

what is this maximal, I mean are we going to apply

this to 60 percent body surface area, are we going

to apply it to the back of the hand? I mean that

266

is what is going to determine for most of these

drugs whether they pass the test or not.

If I put clobetasol on the back of my hand

only, I am probably not going to suppress my HPA

axis, but if I put it over 30 percent of my body

surface, I am probably going to.

DR. GANLEY: The question was just

answered. It is following the extreme provocative

test that is already required for prescriptions,

where it is two weeks and covering 30 percent or

more, Jon, of the body? That is the extreme.

DR. WILKERSON: Okay.

DR. WILKIN: And I should add \"involved

skin,\" in other words, not normal skin, but skin

where the area has been compromised.

DR. WILKERSON: So, 30 percent involved

twice a day involved area.

DR. WILKIN: Well, maximal use, if the

corticosteroid is actually approved for 3 times a

day or 4 times a day, it would be at the maximum

frequency, maximum duration, maximum amount to be

applied, and the body surface area of approximately

267

30 or 35 is the minimum.

DR. WILKERSON: I think that is a

reasonable pattern of potential overuse for

over-the-counter.

DR. WOOD: Any other comments, questions?

No. Okay. Then, let\'s vote on this. If

any subject has HPA axis suppression, and does that

preclude marketing, so I guess if the answer is

Yes, that means that precludes marketing. Right?

Okay.

Let\'s start with Jack.

DR. FINCHAM: No.

DR. RAIMER: Yes.

DR. TINETTI: No.

DR. RINGEL: Yes.

DR. WHITMORE: No.

DR. CLYBURN: No.

DR. SANTANA: Yes.

DR. SKINNER: Yes.

DR. PATTEN: Yes.

DR. TEN HAVE: Yes.

DR. DAVIDOFF: No.

DR. BIGBY: Yes.

DR. WOOD: Yes.

DR. NELSON: Yes.

268

DR. SNODGRASS: Yes.

DR. MATTISON: Yes.

DR. SCHMIDT: Yes.

DR. EPPS: Yes.

DR. CHESNEY: Yes.

DR. TAYLOR: Yes.

DR. WILKERSON: Yes.

DR. STRATAKIS: Yes.

DR. BLASCHKE: Yes.

DR. WOOD: Okay. Four No and the rest are

Yes.

The next question addresses the issue we

just discussed. It is an attempt to sort of

address I guess from two directions, but not

including Dr. Bigby\'s although I think we probably

would want to add\--

DR. ROSEBRAUGH: Alastair, the people that

said No, it might be of interest to the Agency to

know, you know, one of the ways to look at how to

269

draw the bar on safety was HPA axis suppression, so

the people that said No, I would be interested to

know how they would draw the bar then to decide

what potency, what strength that they would allow

over-the-counter and what sort of safety thing they

want to look at.

DR. WOOD: So the people who voted No, we

are interested in knowing what, if anything I

guess, you would use to distinguish it, and we will

start, and I am going around the room. Let\'s take

in the order they are on this list.

Frank.

DR. DAVIDOFF: Well, as I understood the

question, it was whether there is the existence of

any potential to preclude its use over-the-counter.

DR. WOOD: Not any potential.

DR. DAVIDOFF: Potential, right.

DR. WOOD: No, not potential, any actual.

DR. DAVIDOFF: Potential or actual, it

seems to me.

DR. WOOD: The question is actual, it is

not potential.

DR. DAVIDOFF: Okay. The existence of

actual could be one case out of a million. That,

to me, is not an appropriate\--

270

DR. WOOD: That is Question 2.

DR. ROSEBRAUGH: Let me clarify it. If we

do sort of something similar to what they do on the

prescription side, your second question is how many

people do you test, but we have it number of

subjects that we test, we run HPA suppression tests

like we typically do on the prescription side. If

any of those people suppress, does that mean that

it would not be a product that could go OTC?

That is the question, and so the people

that said Yes, that means that that is where they

draw the bar at. So, the people that said No, I

just wonder how you draw the bar.

DR. DAVIDOFF: Well, that\'s the next

question, I haven\'t gotten to that. All I was

trying to say is\--

DR. WOOD: Frank, I think that is not the

next question. I mean the next question might be

answered by the Committee that they only needed to

271

do 10 people, for example. I am not suggesting

that will be, but if that was the question and you

found one, your answer was that that would not

preclude its marketing.

DR. CLYBURN: I was going to say, I went

the same line of thought that if any subject, so

theoretically, there could be one subject who would

be suppressed, and you would look at it out of a

large number, and say that that was probably an

acceptable rate, whereas, I could have easily gone

the other way had I said even the change here, does

the potential for suppression, it depends on how

much potential. That was in our original packet,

the original question.

DR. ROSEBRAUGH: Well, let me just try to

clarify for the panel then. A sponsor brings a

package in to us. They have run the test however we

decide by 2, it\'s Question 2, however many numbers

we say you need to run it, and one of them have

suppressed on that test, does that mean that that

drug should not go OTC. That is what the question

is supposed to mean.

DR. DAVIDOFF: May I finish my answer,

because I haven\'t had a chance? I have been cut

off four times.

272

Even if they brought in data showing zero,

and their sample was 100, we still know that there

is the potential. The point that I am trying to

make about why I voted was that there are any

number of drugs that are on the market

over-the-counter including things like

acetaminophen, which can rot your liver, and does

regularly in this country. That does not preclude

its utility and its acceptance for use

over-the-counter.

Using the same reasoning, I couldn\'t a

priori vote that the actual occurrence of HPA

suppression, on its own merits, would be enough, by

itself, to preclude over-the-counter marketing.

DR. WHITMORE: I second what Dr. Davidoff

said, and there are other reasons why I would not

let it go over-the-counter, but not this.

DR. WOOD: Say that again.

DR. WHITMORE: I second what Dr. Davidoff

273

said, and if there were 1 in 100 or even zero in a

100, well, let\'s say a positive, there was 1

positive, because you said any positive, so if

there were any positives, 1 in 50 even, that would

not be my reason for not allowing this to go

over-the-counter. I have other reasons, but not

that.

DR. WOOD: Ben.

DR. CLYBURN: Just echoing what I said

before on what Dr. Davidoff said.

DR. WOOD: Mary.

DR. TINETTI: I agree with Dr. Davidoff.

DR. WOOD: Jack.

DR. FINCHAM: I think I am the fourth and

final one.

DR. WOOD: You are the fifth and final one

now that we\--

DR. FINCHAM: That\'s a great question, and

I guess I answered it in the context that Dr.

Davidoff talked about relative to other products

that are available over-the-counter. There are

geriatric patients that have GI bleeds that die

274

weekly because of NSAID use or aspirin use, so I

think it is a risk-benefit assessment.

That is a long answer to a short question,

but that is what I was looking at was in the

context of everything else that\'s available.

DR. WOOD: Then, let\'s go to Question 2.

The number of subjects evaluated provides for the

confidence in ruling out HPA axis suppression at a

desired upper limit. With a 95 confidence limit,

what is the greatest rate of HPA axis suppression

to be ruled out?

The question really here relates to the

sample size, and I guess we could add to that, if

Dr. Bigby agrees, and Mary, that part of that could

also include whether there should be some increased

sensitivity for the test. Is that reasonable,

Mary? Okay. So, we would review this with an

increased sensitivity. Okay.

Discussion?

DR. TINETTI: Are we limited to the

numbers on this?

DR. WOOD: I don\'t see why we should be.

Dr. Nelson.

DR. NELSON: A question for the

endocrinologists perhaps. Of those individuals who

275

would be suppressed, what is the percent risk of

sudden death in those individuals? We talked about

that is what we fear, but if you took 100 patients

who were suppressed from whatever steroid

administration, how many of them would necessarily

suffer that fate?

DR. STRATAKIS: I wouldn\'t have the answer

to this question, because when we talk about

suppression here, we define it by the criterion of

18, and for the people that have died in emergency

rooms and under other circumstances of stress, that

were insufficient, nobody has been able to go back

and regulate the sudden death with the actual

stimulated peak values.

DR. WOOD: I am not sure that they are

using this just for sudden death. I mean they are

using this as a surrogate for other evidence of

corticosteroid\--

DR. STRATAKIS: Well, he is asking

276

specifically about that.

DR. WOOD: I understand, but my sense

is\--and this can be addressed to the FDA\--that we

are using HPA suppression as a means, a quality to

measure of systemic corticosteroid excess, you

know, Cushing\'s, glucose intolerance that Dr.

Taylor talked about, and all the other things, and

that is one way to get at that.

DR. STRATAKIS: That is Question No. 3.

DR. GANLEY: I guess there is a sense that

of the people who come to an emergency room or are

admitted to a hospital with the diagnosis of

adrenal suppression or symptomatic because they are

on known steroids, what percentage of them die?

That is one question.

But again I think the thing is that

apparently there is a lot of people out there that

are on chronic steroids topically and orally that

are just going along and perking along and do fine

until they get into a stress situation, so what is

the risk of getting into a stress situation, too?

It is fraction of a fraction.

DR. WOOD: But it is not possible to

answer that question.

DR. STRATAKIS: Except that perhaps the

277

best way to answer that question would be\--and I

just thought about something, and I used the

example before\--of patients with panhypopituitarism

who, by definition, have cortisol responses to ACTH

of zero.

So, these patients, if you look at the

studies I mentioned before, you look at lifetime

risk of death, as I mentioned before, death from

adrenal cortical insufficiency was the number one

cause of death in these patients.

DR. WOOD: And these are patients who

carry the diagnosis with them at all times.

DR. STRATAKIS: Correct. This is lifetime

risk of a patient that has a cortisol value of

zero, an endogenous cortisol value of zero in

response of ACTH, lifetime risk of sudden death

being the highest reason for mortality in these

patients.

DR. WOOD: But I mean most of these

278

patients have a bracelet, and so on. These are

different from people who are taking\--

DR. STRATAKIS: Correct. So, there are

factors, I guess, that would increase mortality in

our population.

DR. WOOD: Dr. Epps.

DR. EPPS: Just a comment, I guess.

Hydrocortisone has been around for 50 years, we

have good experience with that. That is all the

atopics had for many, many years. Some of the

newer ones have been around 20 years, perhaps 10

years. We don\'t have as much information about

them on a large area, but there is a large

experience with hydrocortisone.

We don\'t know about the newer ones, and

that is really what we are talking about, the ones

we really don\'t know.

DR. WOOD: Any other comments on this

question? Yes, Dr. Bigby.

DR. BIGBY: I actually apologize for

keeping going back to this. If roughly 30 percent

of the patients who have this test may be giving

279

false negative numbers, the actual numbers of the

upper adverse event rate in this table are actually

10 times what is printed here.

DR. EPPS: I agree with what he says and

also that suppression is under-recognized and

under-diagnosed, so that some of those cases are

being missed, too, you know, the patient is not

getting better, we don\'t really know why, on and

on. I mean this would be more of an acute

situation rather than probably in the outpatient

situation, but that is true.

DR. GANLEY: Could I just get

clarification? I am not sure what you are saying

is 10 times. If you have 10 people and it\'s zero,

10 times 26 is not 260 percent. I don\'t know what

the number is, but I don\'t know if it\'s 10 times.

DR. BIGBY: That is true for the very low

numbers, but if you go to 100, for example, you

know, it is 3 divided by 100 or 3 percent, but

there may be 30 people who gave you a false

negative result, so it is really 33 out of 100, not

3 out of 100.

DR. GANLEY: But you could increase your

sample size by a certain amount.

DR. WOOD: One.

280

DR. TINETTI: It would only be one extra,

so it would be 4 percent rather than 3 percent.

DR. WOOD: It would be 30 percent of 3,

not 30 percent of 100. So, it would be 4, not 3,

but the point is still the same.

Dr. Skinner.

DR. SKINNER: Until this morning I really

had never thought about the idea of people rolling

into trauma units of emergency rooms on topical

steroids and dying because of that. So, we don\'t

know what that problem is, how big it is. Now, we

are talking about multiplying that problem by

something if potent topical steroids go

over-the-counter.

It is hard to make these decisions not

knowing what that multiplier is. If it\'s no

problem, then, multiplying it probably isn\'t a

problem. If it\'s a pretty good problem, then, you

know. I guess that data is never going to be

281

known, but I think that certainly weighs in how you

think about this.

DR. WOOD: Dr. Nelson.

DR. NELSON: My concern here is and I

don\'t fully understand how you monitor the safety

of over-the-counter drugs. Certainly, the Adverse

Event Reporting System\--

DR. WOOD: This is not to monitor the

safety, this is to determine\--

DR. NELSON: I understand that, but there

is a relationship between how many people you put

in the initial trials versus the ultimate safety of

the drug. We have taken things off the market

because things have occurred at a much lower

incidence than 0.3 percent in the first 1,000.

So, I am not confident that what we do for

drug approvals in non-over-the-counters in fact is

sufficient, and I find myself going back and forth

around that issue, you know, how much do you do in

the first part, then, what do you do post-marketing

to monitor it, and my confidence would be assured

if I thought we had a decent post-marketing system.

282

Otherwise, you end up increasing the pre-marketing

number quite high to where you keep things off of

the market.

That is where I find it a little bit

difficult to put a number on a pre-marketing study.

DR. GANLEY: For these drugs, the

reporting requirements are no different than

prescription, so the question is, is the reporting

different for OTCs versus prescription. I mean we

know the prescription adverse events are not

reported as well as we would like.

DR. NELSON: That answer is both are poor.

DR. GANLEY: Both are poor, but there is

mandatory requirements to reporting from a

company\'s point of view for an NDA product.

DR. WOOD: But OTC is unlikely to be

better.

DR. GANLEY: I would agree with that.

DR. WOOD: Mike.

DR. ALFANO: This will be more meaningful

to the people from NDAC who were here yesterday,

because yesterday we were dealing with a surrogate

283

test also, and we killed it basically because there

was no link to a specific meaningful clinical

endpoint.

So, we have another surrogate test for

adrenal sufficiency, the HPA suppression test

today, and we are embracing it, and yet it is not

linked, as we have learned, to a specific clinical

endpoint. Certainly, there is a suspicion as there

was yesterday that there is a linkage there, but

there is no way to directly link it.

So, that concerns me a bit that for some

reason, a very analogous situation is viewed

differently today than it was yesterday. Then, if

you look at the AERS database, and for Class VI and

VII, real world experience, there is not a single

serious adverse event reported in the entire

database of several million reports.

So, there seems to be an inconsistency in

the way at least NDAC has acted over the last two

days. Admittedly, different situations, different

tests, different degrees of potential negative

outcomes, but in principle, we are valuing this

284

particular test higher than we valued yesterday\'s.

DR. WOOD: I am not sure I agree. I mean

this is like a blood culture for yesterday\'s

analogy. I mean this is a diagnostic test for a

disease, and this is the diagnostic test for

cortisol excess in the systemic circulation, used

to diagnose Cushing\'s, used to diagnose HPA

suppression in vivo. I mean that is different from

sampling bugs on the hand.

This is the test that if you walked into a

hospital in this country today, and somebody said I

believe you have got adrenal suppression, the test

that would be done to do that is\--

DR. ALFANO: I understand the subtlety,

Alastair, I really do. It is just that when

pressed to define what that means in terms of

severe outcomes, to suppress who is positive in

this test, we have not been able to relate it to

anything, and that is parallel to yesterday.

DR. WOOD: I think the question that was

asked was sudden death to which it was difficult to

give an answer. We know a lot about the morbidity

285

associated with HPA suppression and with Cushing\'s.

I don\'t think these are the same at all, and I

think it would be misleading if we left people with

the impression the only bad thing that happens to

you from HPA suppression is dying in the emergency

room because somebody didn\'t give you steroids, I

mean it is substantially worse than that.

DR. STRATAKIS: I agree. I think it is

misleading to say that\--I voted Yes to this, the

first question because I think that there is a high

risk of having patients dying in the emergency room

because of adrenocortical insufficiency after they

have used OTCs. I don\'t think that is the case. I

think that the risk of that happening is

extraordinarily low, but I am concerned about the

patients that we are missing that have some degree

of adrenocortical axis suppression, that have many

other systemic effects that we cannot, or at this

point we don\'t know how to measure them.

DR. ALFANO: Again, just trying to link to

the real world, we saw 60 events in over 50 years

of availability, at least of hydrocortisone, and I

286

don\'t know how many millions of doses were applied,

so I am just trying to\--

DR. WOOD: But we see very few events with

digoxin, too.

DR. STRATAKIS: What were the 60 events?

DR. WOOD: All drugs have very small

number of events in AERS, so digoxin, which is the

largest cause of adverse events in hospitals, and

warfarin, don\'t have a proportional number of

events in AERS database even though, in

hospital-based drug safety studies, they are the

most frequent causes of adverse events.

So, I mean I think you have to be careful

about it. The largest reporting rate occurs in the

first few months of a drug\'s marketing.

Dr. Whitmore.

DR. WHITMORE: I need to preface this and

again say that I am not for approval of these going

OTC, but what I would say is that 20 or 30 percent

of our patients who are using the higher potency

steroids are having this HPA suppression, which we

are not doing anything about, and hopefully, if we

287

are seeing them on a regular basis, which may be

regular or less regular, we would pick up if they

had any clinical symptoms of adrenal insufficiency.

But I would have to add to that this is

happening all the time, and there is nothing that

is being done about it, so I don\'t know if it makes

it any different whether it over-the-counter or by

prescription, still nothing is being done about it,

and maybe we should be doing something different.

Again, I have to reiterate I don\'t think

they should be OTC for a different reason.

DR. WOOD: That is Dr. Alfano\'s point, as

well, actually.

Dr. Chesney.

DR. CHESNEY: In response to the AERS

database, I think many physicians don\'t report

known side effects, so they may be seeing striae

and they may be seeing a lot of other things, but

they wouldn\'t report them as an adverse event

because it\'s a well-described complication.

So, I think the fact that there aren\'t

many reports doesn\'t convince me. I think the

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other thing that we have said over and over again,

which is we have no idea of how many patients who

are immunosuppressed because they have had topical

steroids come in with sudden death, and nobody

thinks to ask them, nobody looks for it, so I just

wanted to make that point again.

DR. WOOD: Any other comments? All right.

Are we ready to take this question?

Are we going to give an answer\--I guess

what we need is an answer, and Mary is not here, so

maybe we can do it without having to come up with

other numbers, but her question was do we have to

stick to these numbers, and I guess the answer is

no, but you want us to give a number, right? All

right. So, pick a number.

DR. BLASCHKE: I will pick a number. I

would pick 100.

DR. STRATAKIS: 1,000.

DR. WILKERSON: 1,000.

DR. TAYLOR: I would pick 100.

DR. CHESNEY: I haven\'t a clue how to

answer this, I really don\'t, so I am going to say

289

10\.

DR. EPPS: Greater than 1,000.

DR. SCHMIDT: 50.

DR. MATTISON: 1,000.

DR. SNODGRASS: 1,000.

DR. NELSON: 1,000 or greater.

DR. WOOD: 1,000.

DR. BIGBY: Can you come back to me?

DR. WOOD: No, now is your moment. Now is

your moment.

DR. BIGBY: I would say greater than

1,000, and then the other thing I would say is that

we already have a signal in the lowest class in

drugs that we can consider, 1 out of 17, so I don\'t

know why we are giving a number.

DR. CHESNEY: I agree. That is why I

didn\'t know how to answer it.

DR. DAVIDOFF: I would say at least 1,000.

DR. TEN HAVE: 1,000.

DR. PATTEN: 1,000.

DR. SKINNER: 1,000.

DR. SANTANA: At least 1,000.

DR. CLYBURN: At least 1,000.

DR. WHITMORE: 100.

DR. RINGEL: I don\'t even want to have 3

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out of 1,000 people running around with HPA

suppression without any monitoring, so it is going

to be greater than 1,000.

DR. TINETTI: Greater than 1,000.

DR. RAIMER: 1,000.

DR. FINCHAM: 1,000.

DR. WOOD: Let\'s go on to Question 3.

Beyond HPA axis suppression, are there any other

safety concerns that would not permit OTC marketing

of a dermatologic topical corticosteroid?

I guess you would mean that in the context

of the absence of HPA suppression in whatever the

number was you decided on, correct? Okay.

So, what we are looking for here are

safety concerns that would for some reason not have

been picked up with HPA suppression in that screen.

Any comments? Yes, Dr. Nelson.

DR. NELSON: I think to bring up the

growth velocity as a pediatrician. I think one of

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my concerns would be if it is relatively

unsupervised, the duration may exceed reasonable

duration, and the issue of reversibility may not

then occur.

I mean a lot of that would be reversible

if you stopped it and doing it unsupervised just

leaves that as an open-ended question, so growth

velocity is of concern to me.

DR. WOOD: Any other comments?

DR. SCHMIDT: One of the things we haven\'t

mentioned is we are seeing a lot of contact

dermatitis from the topical steroids, and I don\'t

know how much of a safety problem that is unless

you have a severe contact dermatitis that gets

infected. I am going to pass this article on from

Contact Dermatitis, that it gives the percentages

of the different contact dermatitis with topical

corticosteroids, but that is something that I would

consider is severe contact dermatitis from some of

these things.

DR. WOOD: Any other comments? Yes.

DR. WILKERSON: I think from a pure public

292

health standpoint, the elderly population, bone

mineral density loss, declining levels of vitamin D

levels in the population, thinning skin, probably

increased percutaneous absorption, that BMD is a

significant public health concern with use of large

amounts of topical steroids.

DR. SANTANA: This is my interpretation of

safety in a very broad sense, but as I commented to

a colleague recently, you know, the issue for me

for OTC products is the ability of the individual

to self-diagnose and make a diagnosis that is

consistent with the indication for which they are

using the product.

So, to me, it is a safety risk if people

are not educated to use the product for which it is

indicated, and they are buying it on their own

unsupervised. To me, that is a safety risk.

DR. WOOD: Dr. Taylor.

DR. TAYLOR: I still would like to see

some data on the diabetes issue and particularly

those individuals who have brittle diabetes,

insulin dependent.

DR. WOOD: Any other comments? Yes.

DR. MATTISON: I also have some concern

about blood pressure control especially in the

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context of hypertension in the context of

increasing incidence of obesity in the United

States. So, that is an issue that I would be

concerned about.

DR. SCHMIDT: One other thing that has

been mentioned is the use of concomitant nasal

steroids or even oral steroids with this, you know,

a potentiating effect.

DR. WOOD: Other comments? Okay. I guess

that is all we need on that really. We don\'t need

a vote, or do we want a yes/no vote? Okay. We

want a yes/no vote.

So, the yes/no vote is what? Are there

other safety concerns that would not permit OTC

marketing of a dermatologic topical corticosteroid?

In the absence of HPA axis suppression you mean,

right? Okay.

DR. GANLEY: To find out just what were

those concerns, so I am not sure\--do you need a

294

vote, Jon? No.

DR. WOOD: No vote? Good.

Would labeling, for example, warnings for

the systemic effects other than HPA axis

suppression be an acceptable regulatory path in

lieu of testing for the other systemic effects, for

example, growth hormone suppression, osteoporosis?

Comments? Yes.

DR. MATTISON: I am concerned that we are

good enough at risk communication to be able to

effectively transmit complex information about

growth or other non-HPA axis impacts to the diverse

populations of parents that might be using these on

their children.

So, I guess I would have to see the labels

and understand how effective they were in testing

before I would be willing to be comfortable with

that approach.

DR. WOOD: And labeling has been

extraordinarily unsuccessful in prescription drugs,

at least in my view, so I am not at all confident

we would be very successful.

DR. GANLEY: That is because you are

dealing with a population, that is the population

you are dealing with in a prescription\--

295

DR. WOOD: I understand that. It is these

damn doctors, right? Okay. Dr. Epps.

DR. EPPS: On many of the prescription

drugs, there already is discussion of growth

suppression on the insert. Some read it, some

don\'t.

DR. WOOD: Dr. Whitmore.

DR. WHITMORE: I would say absolutely not

in terms of relying on patients to detect these

things that we have to have very sensitive testing

to detect? Absolutely not.

DR. WOOD: Sorry, say that again.

DR. WHITMORE: I mean you can\'t bypass

this by saying you are going to put in the patient

information package your child may have growth

suppression, watch for this. We have to use

extremely sensitive testing to be able to pick up

that. I mean how can you tell a parent that, to be

watching for\--or an adult\--to be watching for

296

osteoporosis? Well, when they get their DEXA, they

are told they have osteoporosis, they will know.

DR. WOOD: Beware of fractures, right?

DR. GANLEY: Can I just interject here?

The thought process here I think was what do you do

with the tests that you ask for, and we think about

that all the time, does it help us make a

regulatory decision.

So, let\'s just say for the sake of

discussion that we could do growth suppression,

which you have already heard would be very hard to

do with the dermatologic condition.

So, then, you think about, well, if I did

the test and it came out and showed growth

suppression, does that mean I could convey that in

the labeling with some accuracy, or does it mean

that this is a no-go for this drug, because it did

that.

Now, if it\'s just a label issue, well, I

don\'t need the test to write a label, because I can

say, and you heard the pulmonologists say, that

there is a lack of certainty. They make an

297

assumption that there is growth suppression, so if

you do make that assumption, is it okay to convey

that?

Again, this is for the situation where

people are misusing the product, not for the actual

use of the product.

DR. WHITMORE: Well, essentially, what you

would be doing is just making a disclaimer, that

you may have growth suppression, you may have

osteoporosis when you use this if you put that on

the label.

DR. GANLEY: You already have that on the

prescription labels. They don\'t check for

osteoporosis, they don\'t check for growth

suppression. You already have that. Are you

applying a different standard, that\'s all.

DR. WHITMORE: Well, it seems like we are

for the HPA suppression, but what I would say is

maybe we should readdress that in terms of the

prescription medications and what testing is

required for approval of prescription topical

steroids.

DR. EPPS: And the difference is the

supervision that\'s involved, over-the-counter

versus prescription. You are talking about doing

298

it unsupervised, over-the-counter.

DR. GANLEY: No, what we are doing is

saying if you use this for extended periods of

time, it could lead to these things. If you go to

the store and buy a nonsteroidal anti-inflammatory,

acetaminophen, aspirin, antihistamines, it has all

these disclaimers on it already, if you do these

bad things, so that is what we are asking here.

DR. EPPS: But even under customary,

regular use, there are occasions when we are seeing

suppression.

DR. WOOD: Let me try and resolve this. I

think if we break the question down into two parts,

it might help people to focus their discussion.

The question, which maybe we went over 3 too

quickly, is are there other things that would

preclude the drug being marketed over-the-counter,

other adverse events.

For those who felt there were not other

299

adverse events that would preclude the drug being

marketed over-the-counter, then, would labeling be

sufficient, would there be a way to label the drug

to explain that carefully enough to people. Is

that sort of a fair summary, Charley? Yes.

DR. GANLEY: I think so.

DR. WOOD: We didn\'t get on Teresa\'s list

here growth suppression, right? All right. Does

that help?

DR. WHITMORE: I guess as you are saying,

we don\'t really have to answer No. 4 because we

have already said, in No. 3, there are a host of

different reasons why this shouldn\'t be approved

based on side effects.

DR. WOOD: We didn\'t a host, we said four

things. Actually, if there are more, Teresa is

trying\--

DR. WHITMORE: Oh, absolutely. I didn\'t

speak up because I thought we had already been

through all these, but all of the cutaneous side

effects, telangiectasias\--

DR. WOOD: Wait, wait. If there are

300

people who didn\'t get a fair hearing on 3, let\'s go

back to that. Teresa has the following things

down: diabetes, hypertension, osteoporosis, and

growth suppression.

Are there other\--let\'s be clear what we

are saying\--we are not asking for an encyclopedic

list of every potential side effect of topical

steroids here, we are asking for side effects that

would preclude them being marketed, and as Charley

said, there are lots of side effects associated

with lots of drugs that are marketed

over-the-counter including renal failure, hepatic

failure, and so on.

So, we are asking for show stoppers

essentially.

DR. WHITMORE: Can I continue?

DR. WOOD: Sure.

DR. WHITMORE: Increased ocular pressure,

glaucoma, potentially cataracts. Other things

would be steroid-induced acne, which I have seen

before, with mid-potency topical steroids used for

6 months on the face, coming in with this

301

horrendous acne from eruption that takes months and

months and months to get rid of.

I think each one of those potential

systemic side effects that we have already talked

about are very important, and we don\'t have enough

data to even know how important they may be.

DR. WOOD: So, before Mike has a stroke

here, how would a company perform a study that

would exclude these things? I mean if we are

specifying show-stopping issues, then, by

definition, they would have to be looked for before

the drug could go OTC.

I am not arguing with you, I am just

getting a sense of where we put that bar. So, how

would you, for instance\--

DR. WHITMORE: Well, in terms of we were

talking before about osteoporosis.

DR. WOOD: I was thinking of the acne.

How would they exclude acne?

DR. WHITMORE: There definitely is\--well,

for one thing, those mid-potency steroids should

never be used on the face, but they are.

DR. WOOD: So, that would see to be

Charley\'s labeling issue, I guess. Do you see what

I am saying? I am trying to make a distinction

302

between the ones that set a bar that would preclude

marketing, which would require some kind of

investigation first, and ones that are warnings

that would require labeling, \"Don\'t use it on the

face.\"

DR. WHITMORE: Further investigation in

terms of use on the eyelids, they could label it as

such that it can\'t be used on the eyelids or,

instead, they would have to do a study where they

applied it to eyelids and come up with a number of

induced increased intraocular pressure, and things

like that.

I think these side effects are things that

we, as dermatologists, look for every time a

patient comes back, and if these things are not

looked for, they are going to be missed. So, I

would say\--I am kind of back to that ends

again\--and saying that diagnosis and treatment,

ongoing treatment, should not be done by a patient,

303

and so to give the pharmaceutical recommendation

about testing is difficult.

DR. WOOD: Jon, do you want to say

something?

DR. WILKIN: It might be helpful,

especially as the different panel members are

weighing in on this, it would be helpful to know

what you do when you prescribe Class I and Class

II, the really upper end potency products to your

patients.

I mean do you have a scheduled time when

they go to the ophthalmologist to look for eye

pressure, for cataracts, you know, how often does

one test glucose tolerance, checking blood

pressures, things like that.

Just to remind everyone, we are not

talking about Class I and Class II products

imminently going over-the-counter. We are really

thinking that Class VI would be the target zone of

candidates, not necessarily ones that are sure to

go over, so much, much less potent than the Class

I/Class II, and if you could give us an idea of

304

what you routinely do for the patients maybe at the

upper end, that would be helpful.

DR. WHITMORE: I would just say in terms

of seeing an ophthalmologist for an eye pressure

check, if they were using clobetasol on their

elbows, I would not do that, so it depends totally

on where you using whatever product is you are

using. You take a pill, it goes in your stomach,

and it\'s affecting your whole body, but we are

talking about application of topical products that

are site specific and potentially side effect site

specific, too, so it is very difficult to outline a

whole program of that, and that is why

dermatologists train for the period of time they

train.

So, to answer your question, you would

have to give me a specific body area of treatment

and a potency of a topical steroid for me to answer

the question about how they should be monitored.

DR. WILKIN: Well, how about brittle

diabetes or blood pressure control, under what

circumstances do you routinely say look for glucose

305

intolerance in patients who are using topical

corticosteroids in your practice?

DR. WHITMORE: I don\'t normally do that.

Most patients who have diabetes are monitoring

their blood sugars on a regular basis, so I think

that takes care of that issue if indeed there is

enough systemic absorption to affect their glucose

metabolism for that answer.

I don\'t have a regular program, I don\'t

have a regular protocol that I talk to them about

hypertension with topical steroid use.

DR. STRATAKIS: On the list of things that

we didn\'t add before, I just would like to add

local and systemic immunosuppression and obesity,

weight gain.

DR. WOOD: Other comments? Let me weigh

in on this, as well, then. i have a concern I

guess about just producing a laundry list of known

side effects of steroids and making that\--and I am

not advocating for potent steroids to go

over-the-counter, but as a principle, I have a

concern about creating a laundry list of side

306

effects from a drug and saying any drug that

produces these known side effects of these drugs

cannot go over-the-counter.

That is not to say that I am advocating

for them to go over-the-counter, but that seems to

me a dangerous sort of step. I mean, for example,

if the risks of glaucoma are from applying them to

the eyelids, then, you don\'t do a study to test,

applying them to the eyelids to show that you don\'t

get glaucoma, you label them to say don\'t apply to

the eyelids.

I want to try and make that distinction

somehow, so that we don\'t just go down, and we are

now halfway down the page, to say that we know, for

example, that drugs that produce excess systemic

cortisol or any systemic increase in

corticosteroids are going to produce obesity.

DR. STRATAKIS: But weight gain is a real

complication of any steroid.

DR. WOOD: I understand. The implication

of saying that this is a show stopper means you

either have to go look for it before the drug and

307

be marketed over-the-counter. I mean you would

have to do a study, we need to get a chart out like

this again and say how many people do we need to

study to exclude obesity in people who are getting

the drug applied.

I mean I think the Committee needs to be

clear on the implications of sort of just getting

our pocket Hippocrates out or whatever and listing

the side effects of topical steroids and saying if

any one of these occurs with any one of these

drugs, it can\'t go over-the-counter because that\'s

a self-fulfilling prophecy.

DR. STRATAKIS: I agree with you the

Committee needs to be consistent. You can\'t

suggest that you look for diabetes and not say the

obvious, that you need to look for weight gain.

DR. WOOD: Dr. Nelson has been very

patient here.

DR. NELSON: I want to comment on growth

velocity. Let me just make a couple of quick

distinctions. In my mind, there is a difference

between what can be seen and unseen. I mean I

308

can\'t see osteoporosis. I can weigh myself in the

morning and see if I am gaining weight, and have

that on a label that tells me if I am gaining

weight, go see a doctor or some other approach, so

I am less concerned about the cutaneous.

What bothers me about growth velocity is

that is also something that is unseen, and my

understanding from a lot of the pediatric studies

in other product areas, is you can see growth

velocity in a 3-month trial. You don\'t need to

wait for years, that as long as it\'s in a

population that can stand up and you can get decent

measurements, and I would probably, as sort of a

general principle, say if there is any topical

steroid that had demonstrated systemic effects on

almost any measurement, I wouldn\'t make that

over-the-counter.

But to me, if you demonstrated growth

velocity changes under your maximal use conditions,

I would exclude that from going over-the-counter

personally.

DR. GANLEY: But I think, I don\'t know if

309

the pulmonologists have any comments on that, but I

think that there is a certain inaccuracy and then

to being able to accurately estimate whether there

is a reduction in growth velocity or not, and so it

gets back into that situation of what are the

numbers that you are talking about here.

DR. NELSON: But that is why it\'s a

randomized trial, and that\'s why it falls out on

both sides, and it has been demonstrated in small

enough trials under the Pediatric Exclusivity Rule

and pediatric trials have been conducted that you

have decreased growth velocity.

I think, just as a factual question, I

think it is technically doable. If it isn\'t, I

would be open to hear that argument, but I know in

some other studies, it is technically doable.

DR. STRATAKIS: I just wanted to say that

growth velocity measurements are inaccurate when

they are measured below 6 months. I mean that is

the thinking between pediatric endocrinologists

anyway.

I guess the setting is different when you

310

have groups of patients, though, on medication, and

you record a 3-month effect, so there is a

difference between a trial where you are in a

controlled setting, you measure growth velocity in

two groups of patients, and a control group, or a

control group and a group of patients, and when you

assess growth velocity in an individual child, it

is when you say that 6-month growth velocity

measurements and lower are not accurate, we mean

about the individual child.

DR. NELSON: Just to be clear, I think the

trials are generally in 6, 7, and 8-year-old

patients and it is controlled. I am just

suggesting that a trial could be designed to do

growth velocity within a short period of time, so

it\'s feasible, and if that demonstrated, I would

personally then exclude that from OTC on the

principle of a systemic effect.

DR. WOOD: Terry.

DR. BLASCHKE: I think this sort of a more

general comment. I think that a lot of the

dermatology members of this meeting are

311

disadvantaged by not knowing what the NDAC people

are familiar with, and that is that there needs to

be an actual use simulated study to find out

whether people, in fact, do understand the label,

and if that were ever to come then to this

committee for determination of over-the-counter, if

it was discovered that 20 percent of the people

were not going to dermatologists with serious

conditions, but instead were using a stronger or

more potent steroid, it wouldn\'t get approved.

I mean they could submit the data, but I

don\'t think that the FDA would approve that. So, I

think a lot of the worry that I am hearing around

the table probably would be obviated if the actual

use study demonstrated that, in fact, because the

hydrocortisone is not very effective, as somebody

stated, and more potent steroids are effective for

these minor conditions, and that is, in fact, what

they were being used for over-the-counter, we

wouldn\'t have all of these concerns about these

long-term side effects.

So, it really is important to understand

312

that there would be a study that would actually

demonstrate that the label was good, that it was

understood by the people purchasing it in the

pharmacy, and I think it would be much easier to

make a judgment about whether or not, as Jon is

saying, a slightly more potent steroid might be

useful over-the-counter.

DR. WOOD: Dr. Taylor.

DR. TAYLOR: I want to get back to what

Dr. Wood commented on in terms of bringing some

balance to our decisions. I think we want to come

up with recommendations for the Agency that will be

helpful. We can\'t just categorically say no

because we have got this laundry list.

There are other ways that you can limit

exposure, for example, you can have only a certain

class available over-the-counter, you can have

certain formulations that could be approved. You

could have amounts.

I think our assumption is most of the

discussions that patients would have unlimited

access to as much of the product as they want. In

313

reality, if you look at most of the drugs that have

gone over-the-counter, the package only has 4 or 5

of the tablets in there, for example. So, there

are ways that you can get around some of the

exposure issues rather than just saying no, you

can\'t have it.

DR. WOOD: Dr. Wilkerson.

DR. WILKERSON: What I just want to say is

I think, as dermatologists, this has been an

eye-opening experience for me today to see the

degree of HPA axis suppression that was presented

by Dr. Cook.

When we are looking at 40 and 50 percent

axis, if you queried most dermatologists, yes, we

are aware obviously that this could happen, but we

would probably put it in the range of less than 1

percent in our mind of a clinical risk, and I think

this, to me, speaks stronger than any other issue

before us today, that not only do we have an issue

as far as these drugs going over-the-counter, but

we have a safety signal or an issue of the

prescription use of these products that is not

314

being addressed back to the professional body that

uses these materials the most, that being

dermatologists and primary physicians.

When we are seeing these levels of

suppression, this is the first time I have seen

this material, and I suspect most of us in the room

that are dermatologists have not seen it either,

and I think this is the biggest safety signal to

come out of this entire meeting.

It is not so much the question of do these

drugs go over-the-counter, which is pretty

obviously should not right now, but what are we

going to do about clinical application of these

materials.

DR. WOOD: Dr. Schmidt.

DR. SCHMIDT: I think we have always known

this, you know, that these strong topical steroids

have done stuff even again I get my old proto

textbook and it says in adults, 100 grams a week of

topical steroids in Class I, III under occlusion,

or 45 grams of clobetasol without occlusion may be

used, but then they say, but over that you are

315

going to have problems.

It is just that to me, a lot of this will

affect the adrenal-pituitary axis, and even given

prednisone, you affect the adrenal-pituitary axis,

but then it snaps back into place normally in most

patients, so to me, I wonder whether we are setting

the bar too high, you know, with some of these

things, and I tend to agree that if these things do

go over-the-counter, there is ways that you can

limit.

I remember when I was a resident, I lived

in a house that was almost falling over, and

several of the neighbors had kids with atopic

eczema, and these people were not, you know,

probably like me, weren\'t the most sophisticated

people in the world, and they would have their

little tube of 5-gram triamcinolone in a little

box, you know, that they used very sparingly.

So, I think we need to give the American

public some credit for not just taking this stuff

and rubbing it in their eyes or eating it or

anything like that. I think, I don\'t know, I have

316

got some real questions that some of these things,

we have always known it, but we do it anyway, but

then we stop and do pulse therapy.

As far as the clinical aspect of this

thing, I don\'t think I have ever seen glaucoma, you

know, from putting steroids in people\'s eyes, I

don\'t think I have ever heard of it. I mean maybe

it occurs and it is reported in the literature, and

I have been in practice 32 years, I have never seen

anybody get fat with topical steroids.

DR. WOOD: Let me stand up.

\[Laughter.\]

DR. SCHMIDT: Thank you. No, mine is from

the cookie.

DR. WOOD: I am sitting here too long.

DR. SCHMIDT: I just think clinically, we

need to kind of mellow out.

DR. WOOD: Okay. Mellowing out, Dr. Epps.

DR. EPPS: Thank you. That being said,

the truth of the matter is once it\'s

over-the-counter, it\'s available for any age, in

any amount, on any part of the body, and not

317

everyone is as sophisticated. You have got to

think about the lowest common denominator. Not

everybody is going to read every warning on every

box. Literally, it is equivalent to you can buy it

as you could buy lotion, you can buy as much as you

want, put it anywhere you want, on any age person

that you want to put it on.

Certainly, there is a question, and I

understand his question about whether or not it is

clinically significant, but those patients we are

monitoring very carefully.

DR. WOOD: Let\'s return and let\'s focus

the question. We are on Question 4. Would

labeling for the systemic effects other than HPA

axis suppression be an acceptable regulatory path

in lieu of testing for the other systemic effects?

Are there any other comments on that, that

we have not heard? Yes, Dr. Chesney.

DR. CHESNEY: I wanted to weigh in with

Dr. Whitmore and Dr. Nelson on the issue of

labeling for growth suppression. I think growth

suppression has been well documented with these

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drugs, and I think it is very serious, and I think

labeling is not adequate to warn the public about

that, because it is not something you can see, as

Dr. Whitmore said, and I think as Dr. Nelson said,

it is a reason that these drugs should not go

over-the-counter, and I just wanted to weigh in on

that.

DR. WOOD: Any other comments specifically

on labeling? Dr. Bigby? No, not on labeling?

Hang on, I will get to you in a second.

Any other comments on labeling? Mike.

DR. ALFANO: It\'s a labeling comment, and

it goes back to Dr. Ellis\' report where upwards of

90 percent of the current product is used on label.

I think the Chair made a comment about this

relative to Rx compliance with label.

I mean this is right up there, in fact,

probably exceeds many Rx drugs. So, in terms of

the ability of this particular label to convey

something meaningful to the population, it seems to

have done that, presumably similar labeling would

be developed and similar in-use testing would

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confirm that if something else were to come on the

market, it would be equally efficacious. Nothing

stops a mother from taking her prescription drug

and putting it on her baby\'s butt.

DR. BIGBY: But the thing that is wrong

with that logic is you are making the assumption

that it is being used on label because of the

label. It may be being used that way because it

didn\'t work. I mean you are making the assumption

that just because people used it for less than 7

days, it is because they read the label and paid

attention to that, and there is no evidence of that

whatsoever.

DR. ALFANO: That is only length of use.

DR. WOOD: Hang on, if I can just

intercede here. That\'s the point Terry Blaschke was

trying to make earlier on for the benefit of the

panel members who have not seen this reviewed.

That will be tested before a drug could go

over-the-counter, so, in other words, a sponsor

would have to come in with an actual use study and

a label comprehension study that demonstrated that

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the label was understood by them and that in a

quasi-operational fashion were able to

operationalize the content of the label.

I am not necessarily arguing that. Mike,

sorry.

DR. ALFANO: That was going to be my point

and also that study related, not just to duration

of use, but what it was used on, and for the most

part, it was used on the right conditions.

DR. WOOD: Dr. Ringel.

DR. RINGEL: I guess I have sort of

collected comments here. One quick one is about

the labeling issue, that people will use what makes

them feel good, and you can test that they

comprehend it and that the label is clear, but you

can\'t test to make sure that they are really going

to do what they read on the label. If they feel

bad, and the cream makes them feel good, they will

continue to use it, at least that is my experience

in my clinical practice.

DR. WOOD: It doesn\'t sound like a bad

thing actually, does it?

DR. RINGEL: Yes, if there are side

effects. Let me go back to Dr. Wilkin\'s question,

which was what do you do in your office practice,

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dermatologists, to monitor people, and I can only

tell you what I do, and you make me kind of guilty

sitting here, you know, thinking about everything

we have heard today and I really do, and clearly it

is not enough what I do do.

If I have somebody on high-potency

steroids for a long time, over a long portion of

their body, I really do do a cortisol test. I know

it is not a great test to do, but I do it, and

every once in a while somebody is low and I try to

do something about it.

When you see people, and I think that most

of the dermatologists, maybe they don\'t think that

they do this, but I really think they do this, you

see somebody with diabetes and it is not going

well, and you are giving them the clobetasol, I

think, huh, maybe I shouldn\'t be giving them so

much clobetasol, or somebody who is having, you

know, their osteoporosis is getting worse and

322

worse, and I am giving them clobetasol, I go

through the same thing in my mind, maybe this is

not a great idea.

Then, I start to fight with people, say,

well, you shouldn\'t use this much, and they say,

well, they want to use it because nothing else

works, and I am always fighting with people, I am

always trying to take it away, and they are always

trying to get a little bit more from me, and that

is not going to happen if it\'s over-the-counter.

The other thing is that for me, this whole

experience has been a sort of an NGE, kind of a

neurosis generating event. I mean I am going to be

in my office and people are going to be wanting me

to give them more steroids and I am going to be

say, oh, my gosh, they are going to get pituitary

suppression, and I mean what it makes me think is

maybe we need to rethink what we are doing by

prescription, not that we need therefore to just go

ahead and make it over-the-counter.

I mean Denise gave us such convincing

evidence that there really can be a problem, I was

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convinced. I really think that you did a great

job, and I saw no evidence presented by the FDA

today that this is not a problem, so how can I then

go ahead and say fine, make it over the counter.

I need to see some evidence first from the

FDA or someone that it is not a problem, and that\'s

it.

DR. WOOD: Jack.

DR. FINCHAM: Well, we are all over the

map, so bear with me, but I think we have got\--

DR. WOOD: Labeling.

DR. FINCHAM: I know, bear with me,

please, I am with you. We have a formal health

care system and an informal system, and if we

assume just because we prescribe a therapy, that it

is only going to be used by that individual, we are

really wrong, because when this gets out in the

system, regardless of whether it is prescribed for

somebody or not, it is used by anybody, they share

it.

Jimmy, I think eloquently talked about why

we need to have something available to let people

324

make informed decisions, and you use the labeling

to try to do the best that you can to help people

make informed decisions, but if it is going to be

misused, it is going to be misused whether it is a

prescription product or whether it\'s an

over-the-counter product, whether there is a

board-certified dermatologist involved or not, and

I just think you have to give people the benefit of

the doubt, give them a chance, label it

appropriately, and go from there.

DR. WOOD: I have a personal comment on

that, as well. Although I don\'t believe that

labeling actually works, I certainly would not want

to leave the impression that people should have to

do studies to exclude all these other effects

before the drug could be submitted for OTC use. It

is unfortunate perhaps the way this is worded, but

i would rephrase it to say should they have to

exclude all these other lists that Teresa has here,

and I think the answer to that is no in my view.

Dr. Nelson. Labeling?

DR. NELSON: Yes, on labeling. What we

325

are not being asked is how many people would need

to be able to follow the label if, in fact, the

label constrained the use far enough below the

maximal use conditions\--

DR. WOOD: That is the question that would

come up for NDAC.

DR. NELSON: I understand, so all I am

saying is that what we are answering in a sense is

both questions, and that is part of the confusion,

to what extent, if it\'s zero out of 1,000 in

maximal use, well, if then everybody could follow

the label, that becomes a very different question,

and that may be part of the difficulty.

We are conflating it, and not separating

those two things.

DR. WOOD: Do we want to vote on this?

Okay.

Let\'s start with Jack. Would labeling be

an acceptable regulatory pathway, so Yes would mean

it would be acceptable.

DR. FINCHAM: Yes.

DR. RAIMER: I am going to say no.

DR. RINGEL: No.

DR. WHITMORE: No.

DR. CLYBURN: Yes.

326

DR. SKINNER: No.

DR. PATTEN: Yes.

DR. TEN HAVE: No.

DR. DAVIDOFF: No.

DR. BIGBY: No.

DR. WOOD: Yes.

DR. NELSON: With your indulgence, no for

some, such as growth velocity, yes for others, such

as cutaneous manifestations.

DR. SNODGRASS: No.

DR. MATTISON: No.

DR. SCHMIDT: Yes.

DR. EPPS: No.

DR. TAYLOR: Yes.

DR. WILKERSON: No.

DR. STRATAKIS: No.

DR. BLASCHKE: Without belaboring it any

longer, I will say yes.

DR. WOOD: All right. Question No. 5.

327

With regard to dermatologic local cutaneous

effects, at what level of severity do risks

outweigh the benefits of topical corticosteroid use

in an OTC setting?

Dr. Bigby.

DR. BIGBY: This question is actually

directed to Jon. It seems to me that the simplest

question to ask is should the more potent topical

corticosteroids be considered for over-the-counter

use, period, as opposed to\--I mean why didn\'t you

ask us that question?

DR. WILKIN: Well, I guess because we were

interested in the answer to that question.

\[Laughter.\]

DR. WOOD: Thank you. Next question.

DR. WILKIN: The point about at what level

of severity of local cutaneous effects, because I

mean you might have mild erythema, on the other

hand, you might have really severe atrophy, and we

were asking for something that would qualitative or

quantitative from the Committee, where they thought

something that had the potential to do X or Y, or

328

whatever, that those are the products that should

not go over-the-counter.

DR. WOOD: Let\'s hear from the

dermatologist first on this. They are the people

who should be able to answer this best.

Dr. Whitmore.

DR. WILKIN: Stria, telangiectasias, acne

eruptions.

DR. WOOD: Dr. Wilkerson.

DR. WILKERSON: I think certainly in

blacks, the hypopigmentation issue is big. I just

wanted to add that every good sermon has three

points and every good advisory committee has five

questions, so that is the answer to Dr. Bigby\'s

question.

DR. WOOD: Dr. Schmidt.

DR. SCHMIDT: I think the most important

one is stria because it is something that is

permanent. You know, the rest of these things

resolve with time and then the other thing, and I

don\'t want to belabor this, but I really think that

contact dermatitis, you know, to some of these

329

things, you know, I think that if something induced

contact dermatitis in a lot of patients, I think I

would consider not having that either.

DR. WOOD: Any other comments?

DR. RAIMER: I think sometimes atrophy can

be permanent, too, especially in an older person,

so I think stria or severe atrophy that doesn\'t

resolve.

DR. WOOD: Dr. Skinner.

DR. SKINNER: I was thinking some of this

probably could be done with good labeling. It

would just be so restrictive, you know, don\'t use

it on the face, don\'t use it in the axilla, don\'t

use it in the antecubital popliteal fossa, don\'t

use it in the groin. You know, with that I think

you could avoid most of the trouble with the

cutaneous effects.

DR. WOOD: Any other comments? Yes, Dr.

Nelson.

DR. NELSON: As a non-dermatologist, what

would strike me as most important here is

reversibility, and not necessarily severity. If

330

something could appear as severe, but if it\'s

reversible when stopped by the individual who is

using it, that is much different than if it could

be mild, but then be reversible, so I think it\'s

the reversibility.

If I think of myself as a consumer buying

it, I see it, I stop it, I would want it to go

away, would be the key rather than how severe it

might look for that period of time.

DR. WOOD: Any other comments? Yes, Dr.

Epps.

DR. EPPS: I should also mention

hypertrichosis, which some people get, too.

DR. WOOD: Any other comments? All right.

We are through, ten past 3:00, guys. Thanks a lot.

DR. FINCHAM: Alastair, thank you for

shepherding us today through all this. Nicely

done.

\[Whereupon, the meeting was concluded at

3:10 p.m.\]

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