DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH
JOINT SESSION WITH THE
NONPRESCRIPTION AND DERMATOLOGIC DRUGS
Thursday, March 24, 2004
Hilton Washington DC North
620 Perry Parkway
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
Michael C. Alfano, DMD, Ph.D. (Industry
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.
Charles Ganley, M.D.
Curtis Rosebraugh, M.D., MPH
Jonathan Wilkin, M.D.
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
Charles Ganley, M.D. 11
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
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
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
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,
DR. CLYBURN: I am Ben Clyburn, Internal
Medicine, Medical University of South Carolina in
DR. SANTANA: Good morning. I am Victor
Santana. I am a pediatric hematologist/oncologist
at St. Jude Children's Research Hospital
DR. SKINNER: I am Bob Skinner from the
University of Tennessee at Memphis. I am a
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
LCDR WATKINS: I am Teresa Watkins. I am
the Executive Secretary with the advisors and
DR. NELSON: Robert Nelson, Pediatric
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,
DR. EPPS: Roselyn Epps, Chief, Pediatric
Dermatology, Children's National Medical Center,
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,
DR. WILKERSON: Michael Wilkerson,
University of Oklahoma, Tulsa Branch, Assistant
Professor, Clinical, and dermatologist.
DR. BLASCHKE: Terry Blaschke, internist,
clinical pharmacologist, Stanford.
DR. WILKIN: Jonathan Wilkin, Director,
Division of Dermatologic and Dental Drug Products,
DR. ROSEBRAUGH: Curt Rosebraugh, Deputy
Director, OTC, FDA.
DR. GANLEY: Charley Ganley, Director of
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
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
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
three stocks are valued between $25,001 and
$50,000, and one stock is valued greater than
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
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
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
any firm whose products they may wish to comment
DR. WOOD: Thanks a lot.
Our first speaker is Charley Ganley.
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.
We are here today to discuss the safety
data necessary to consider a switch of dermatologic
topical corticosteroids from prescription to OTC
The FDA presentations will cover the
regulatory history of OTC hydrocortisone, the
assessment of safety for current
dermatologic topical corticosteroids products, an
assessment of safety effects for other categories
of steroid products, and testing for HPA axis
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.
Now, in your background package, we
included a list of the various potencies
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.
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
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
I think in part of the open public
session, you will hear a little bit of
of what possible percentage of consumers that may
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
The local effects during the
course of the
presentations today, that will also be reviewed.
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
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.
OTC Dermatologic Topical Corticosteroids
DR. KOENIG: Good morning.
I am Michael
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
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.
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.
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
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
Register, and FDA actively solicits feedback from
the public at every step of the process.
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
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.
The initial review as by an Advisory
Review Panel. This was made up of outside
outside FDA experts in that particular therapeutic
category. There were 7 voting members, but in may
respects, it was somewhat analogous to the Advisory
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
The recommendations of the Advisory
Committee were published in the Federal Register as
an Advanced Notice of Proposed Rulemaking, or ANPR.
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
here as TFM.
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
I would like to now speak specifically
about the regulatory history of hydrocortisone.
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
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
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.
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
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
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.
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
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 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
Ten of these 40 included among the combination of
corticosteroids they had been using 1 percent
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.
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
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
In 1962, there was a report of temporary
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
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
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
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
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
Finally, the panel felt that under
Directions should be a direction to apply this to
the affected area essentially only, not
more than 3
to 4 times a day.
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
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
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."
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
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.
What about the Final Monograph, the last
step? It is pending. We are working on it. We
have found that manufacturers are
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
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
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
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.
I would now like to look at the current
labeling of hydrocortisone in this third part of
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
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
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.
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."
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."
This is labeling that is taken
off of a
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."
Under Warnings, "Stop use and ask a doctor
if symptoms persist for more than 7 days."
Under Directions, the same two that I just
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.
Rx Topical Corticosteroids: HPA Axis
Suppression and Cutaneous Effects
DR. COOK: Good morning.
Good morning to
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
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
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.
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
and blanching or vasoconstriction is determined
relative to the other corticosteroid.
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
In the case of topical corticosteroids, it
is assessing an exogenous unwanted treatment
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
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.
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.
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.
In 2001, it was decided that if we were
going to use cosyntropin to determine
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.
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
metabolism, development of Cushing's syndrome,
effects on growth, and effects on intracranial
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.
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
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
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
DR. WOOD: What were the numbers in that
DR. COOK: I don't know the numbers. You
mean like exactly what the serum cortisol levels
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
So, this led to a Temovate label in 1985
that stated in the Precautions, it is a highly
potent topical corticosteroid that has
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.
So, now we will move on to the actual
class label that was generated.
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
Manifestations of Cushing's syndrome,
hyperglycemia, and glucosuria can also be produced
in some patients by systemic absorption
corticosteroids while on treatment.
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.
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.
The class label also addressed pediatric
use in the Pediatric Use Section of the label.
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
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
They are therefore also at greater risk of
glucocorticosteroid insufficiency after withdrawal
of treatment and of Cushing's syndrome while on
HPA axis suppression, Cushing's syndrome,
linear growth retardation, delayed weight gain, and
intracranial hypertension have been reported in
pediatric patients receiving topical
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.
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.
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
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
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.
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
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
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.
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
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
the serum cortisol was required.
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
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."
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.
There were 43 evaluable patients with
moderate to severe atopic dermatitis; 29
patients were 3 months to 2 years of age, and 24
patients were 3 years to 5 years old.
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
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.
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
patients had a 50 percent decrease by 4 weeks.
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.
Here, a normal response was a serum
cortisol level that exceeded 18 mcg/dL at 30
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
The other patient was a 2-year-old who had
the minimum amount of body surface area
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.
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.
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
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.
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.
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
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.
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.
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
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.
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
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
suppression increased 4.4 percent with a p value of
less than 0.01.
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.
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
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
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
DR. WOOD: All right. Fair enough. Go
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
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.
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.
In the statistical analysis here in the
development of HPA axis suppression,
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.
In testing patients for recovery, 2 of the
15 patients were retested and 100 percent recovered
at 2 weeks.
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.
Diprosone Cream studied 43 evaluable
patients with atopic dermatitis. They ranged in
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
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.
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
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
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.
Here again, the label was changed to add
and age restriction to 13 years or older,
appropriate portions of the label were updated.
Now, Diprosone Lotion, I will remind you
again is a Class V steroid, so just like two
classes above the lowest potency of topical
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.
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.
Although this study was supposed to enroll
infants, it was felt that with such a high degree
of HPA axis suppression, the proportion
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.
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
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
from a statistical point of view, were minuscule.
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.
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.
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.
Lotrisone Cream is the other betamethasone
product that I am going to speak about. It is a
combination product of betamethasone
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.
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
also is an area where you may have some natural
occlusion, increasing absorption.
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
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
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.
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
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
in a different vehicle. As I say here, it is a
Class I steroid.
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.
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
is how it's labeled.
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.
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.
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
In the adult study, there were
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.
Here, 56 percent of the patients treated
with Clobex Lotion suppressed and 44 percent with
the Temovate E Cream suppressed.
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.
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
The medication was applied twice a day here
for 4 weeks, and there was again a 50-gram/week
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.
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.
Now, I am going to shift gears
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.
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
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
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.
There have been 94 cases reported spanning
decades, 65 adult cases and 29 pediatric cases.
The gamut of manifestations had been adrenal
insufficiency, Cushing's syndrome, and growth
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
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
In the adult cases, there were 65, 46 with
adrenal insufficiency and suppression, 32 with
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
hospitalizations and 2 deaths, and the deaths were
attributed in part of the adrenal event.
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
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
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.
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.
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.
Because pictures speak a thousand words, I
am going to give you a pictorial
these adverse events.
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.
Here, we have telangiectasia. You can see
the very fine blood vessels coursing here through
this person's chin.
This is a picture of striae, probably
Another picture of striae, maybe a little
more of acute onset in nature.
This is a picture of facial erythema.
Another of facial erythema.
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
be weaned down, and then the rosacea, which is the
underlying disease, had to be treated
This is a picture of hypopigmentation from
topical corticosteroid use.
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.
Now, as far as cutaneous
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
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
So, as far as cutaneous adverse events,
corticosteroid-induced adverse events can
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.
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.
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
corticosteroids, particularly those of high
potency, can lead to serious medical complications
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
Thank you for your attention for this
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
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.
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
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.
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.
There are basically two types of studies
that are presented to us by
sponsors. One goes by
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
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
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.
So, what are these growth studies, what do
they look like? Basically, it is fairly
straightforward. It's serial stadiometry. There
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.
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
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
So, the size of the growth effect that is
clinically relevant is unknown or not fully known.
That is what our presumption is.
So, how did we get here? Actually, there
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
So, what did that label end up
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
So, how did this original study look, the
one that we were looking at for the advisory
Intranasal beclomethasone basically was a
randomized, double-blind, placebo-controlled,
parallel group, prospective, one-year
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.
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
mean basal cortisol or ACTH-stimulated plasma
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
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
throughout, so this is the mean data expressed
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.
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,
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
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
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.
So, conclusions. We use growth studies as
a stand-alone measure. We believe that they are a
sensitive indicator of systemic effects,
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
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
as we would like them to be.
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
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
Today, I am going to speak on topical
corticosteroids and testing for adrenal suppression
in the context of potential Rx to OTC switch.
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
We are also going to discuss
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.
Now, as Dr. Cook and Dr. Wilson have
stated, prescription corticosteroids have systemic
effects which we evaluate during drug development.
Now, I would like to separate these out
into those areas where specific studies have not
been required for dermatologic topical
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
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.
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
This is a schematic diagram of
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
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.
With that, we get into HPA axis testing.
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.
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
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.
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
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.
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.
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
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.
With that, we segue to what are current
testing recommendations for adrenal suppression.
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
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.
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.
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
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
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
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
into a study having been on other corticosteroids
for a protracted length of time because of their
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.
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?
Here is an exercise I would
like to pose
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
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.
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
10 subjects and we had zero of those 10 subjects
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.
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
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.
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.
Questions from the Committee and
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
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
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
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
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
DR. WILSON: Those are the standard growth
charts that everybody sees and are available from
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
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
DR. WILSON: The long term. Again,
sponsors have presented to us, and there have been
a few studies done on trying to assess
there are some long-term effects. But those are
even more difficult to do than these annual
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
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
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
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
have excluded concomitant use of other
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
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?
DR. WOOD: I will answer for them, because
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
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: 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
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
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
DR. TINETTI: I am not aware of any with
the topical. Certainly with systemic, it's a major
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
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
in dose, the waxing and waning of the disease, and
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
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,
cosyntropin testing in those 49 patients? That was
for Dr. Wilson, I am sorry.
DR. WILSON: It wasn't the same test as I
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
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
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
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
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
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
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
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
DR. LUKE: Of the test?
DR. RINGEL: Yes.
DR. LUKE: Dr. Stratakis, do you want to
DR. STRATAKIS: The cosyntropin test is a
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
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
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
and that varies a lot from individual to
individual, but on average, we consider that time
to be approximately two weeks, approximately two
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
DR. WOOD: So, what would be your estimate
of the number you are missing, 30
percent, is that
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
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
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
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
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
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
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
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
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
If you scan it, in terms of potency, it
looks to me like there may be an effect
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
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
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
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
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
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
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
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
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
investigate children here except for the commercial
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
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
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
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
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
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
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
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
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
DR. WOOD: Right.
DR. STRATAKIS: Especially if they are
predisposed to that? Oh, yes.
I think it is the
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
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
I would be a little
uncomfortable in that
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
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
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
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