1
DEPARTMENT OF HEALTH AND HUMAN
SERVICES
FOOD AND DRUG
ADMINISTRATION
CENTER FOR DRUG EVALUATION AND
RESEARCH
JOINT SESSION WITH THE
NONPRESCRIPTION AND
DERMATOLOGIC DRUGS
ADVISORY COMMITTEE
VOLUME II
Thursday, March 24,
2004
8:00 a.m.
Hilton Washington DC
North
620 Perry Parkway
Gaithersburg, Maryland
2
P A R T I C I P A N T S
Alastair Wood, M.D., Chair, NDAC
Teresa A. Watkins, R.Ph., Executive
Secretary
Committee Members:
Michael C. Alfano, DMD, Ph.D. (Industry
Representative)
Terrence F. Blaschke, M.D.
Ernest B. Clyburn, M.D.
Frank F. Davidoff, M.D.
Jack E. Fincham, Ph.D.
Sonia Patten, Ph.D. (Consumer
Representative)
Wayne R. Snodgrass, M.D., Ph.D.
Robert E. Taylor, M.D., Ph.D., FACP, FCP
Mary E. Tinetti, M.D.
Government Employyee Consultants
(Voting):
Michael E. Bigby, M.D.
Sharon S. Raimer, M.D.
Eileen W. Ringel, M.D.
Jimmy D. Schmidt, M.D.
Robert B. Skinner, Jr., M.D.
Thomas R. Ten Have, Ph.D.
Elizabeth S. Whitmore, M.D.
Michael G. Wilkerson, M.D.
SGE Consultants (Voting):
Patricia Chesney, M.D.
Roselyn Epps, M.D.
Robert M. Nelson, M.D.
Victor Santana, M.D.
Federal Employee Consultants (Voting)
Constantine Stratakis, M.D.
Donald R. Mattison, M.D.
FDA Participants:
Charles Ganley, M.D.
Curtis Rosebraugh, M.D., MPH
Jonathan Wilkin, M.D.
3
C O N T E N T S
Call to Order and Introduction:
Alastair Wood, M.D. 4
Conflict of Interest Statement,
LCDR Teresa A. Watkins, R.Ph 7
Introduction:
Charles Ganley, M.D. 11
FDA Presentations:
OTC Dermatologic Topical Corticosteroids:
Mike Koenig, Ph.D. 16
Rx Topical Corticosteroids: HPA Axis Suppression
and Cutaneous Effects:
Denise Cook, Ph.D. 32
Lessons Learned from Growth Studies with
Orally
Inhaled and Intranasal
Corticosteroids:
Stephen Wilson, Dr. P.H., CAPT
USPHS 77
HPA Axis Suppression Studies: Conduct,
Utility
and Pediatric Considerations:
Markham Luke, M.D. 92
Questions from the Committee and
Committee
Discussion 106
Open Public Hearing:
Jerry Roth 181
Charles H. Ellis, M.D. 189
Valentine J. Ellis, MBA 197
Michael Paranzino 206
Sandra Read, M.D. 211
Luz Fonacier, M.D. 219
Questions to the Committee and Committee
Discussion 236
4
P R O C E E D I N G S
Call to Order and
Introductions
DR. WOOD: If everybody could take their
seats and let's begin by going around the
table and
have everybody introduce themselves. Why don't we
start with Mike.
DR. ALFANO: Good morning.
I am Mike
Alfano, New York University. I am the industry
liaison to NDAC.
DR. FINCHAM: Good morning.
I am Jack
Fincham, an NDAC member, and I am a
Professor of
Pharmacy and Public Health at the
University of
Georgia.
DR. RAIMER: Good morning. I am Sharon
Raimer, in Dermatology, University of
Texas.
DR. TINETTI: I am Mary Tinetti, Internal
Medicine, Geriatrics at Yale.
DR. RINGEL: Eileen Ringel, Dermatologist,
Waterville, Maine.
DR. CLYBURN: I am Ben Clyburn, Internal
Medicine, Medical University of South
Carolina in
Charleston.
DR. SANTANA: Good morning.
I am Victor
Santana.
I am a pediatric hematologist/oncologist
at St. Jude Children's Research Hospital
in
5
Memphis, Tennessee.
DR. SKINNER: I am Bob Skinner from the
University of Tennessee at Memphis. I am a
dermatologist.
DR. PATTEN: I am Sonia Patten. I am the
consumer representative on NDAC. I am an
anthropologist on faculty at Macalister
College in
St. Paul, Minnesota.
DR. DAVIDOFF: I am Frank Davidoff. I am
the Emeritus Editor of Annals of Internal
Medicine.
I am an internist although I started life
as an
endocrinologist, and I am a member NDAC.
DR. BIGBY: Michael Bigby, a dermatologist
at Beth Israel Deaconess Medical Center
and Harvard
Medical School.
LCDR WATKINS: I am Teresa Watkins. I am
the Executive Secretary with the advisors
and
consultant staff.
DR. NELSON: Robert Nelson, Pediatric
6
Critical Care Medicine at Children's
Hospital,
Philadelphia, and the University of
Pennsylvania.
DR. SNODGRASS: Wayne Snodgrass,
pediatrician, University of Texas Medical
Branch.
DR. MATTISON: Don Mattison, National
Institute of Child Health and Human
Development.
DR. SCHMIDT: Jimmy Schmidt, Houston,
Texas, dermatologist.
DR. EPPS: Roselyn Epps, Chief, Pediatric
Dermatology, Children's National Medical
Center,
Washington, D.C.
DR. CHESNEY: Joan Chesney, Pediatric
Infectious Diseases at the University of
Tennessee
at
Memphis and Academic Programs at St. Jude
Children's Research Hospital.
DR. TAYLOR: Robert Taylor, internist and
clinical pharmacologist, Howard
University,
Washington.
DR. WILKERSON: Michael Wilkerson,
University of Oklahoma, Tulsa Branch,
Assistant
Professor, Clinical, and dermatologist.
DR. BLASCHKE: Terry Blaschke, internist,
7
clinical pharmacologist, Stanford.
DR. WILKIN: Jonathan Wilkin, Director,
Division of Dermatologic and Dental Drug
Products,
FDA.
DR. ROSEBRAUGH: Curt Rosebraugh, Deputy
Director, OTC, FDA.
DR. GANLEY:
Charley Ganley, Director of
OTC.
DR. WOOD: I am Alastair Wood. I am an
internist, Professor of Medicine,
Associate Dean at
Vanderbilt. There has probably never been a
committee with so many people from
Tennessee on it,
I don't think.
Teresa, why don't you read the
Conflict of
Interest Statement.
Conflict of Interest
Statement
LCDR WATKINS: The following announcement
addresses the issue of conflict of
interest and is
made part of the record to preclude even
the
appearance of such at this meeting.
Based on the submitted agenda
and all
financial interests reported by the
Committee
8
participants, it has been determined that
all
interests in firms regulated by the
Center for Drug
Evaluation and Research present no
potential for an
appearance of a conflict of interest at
this
meeting with the following exceptions.
In accordance with 18 U.S.C.
Section
208(b)(3), full waivers have been granted
to the
following participants. Please note that all
interests are in firms that could
potentially be
affected by the committee's discussions.
Dr. Michael Wilkerson for
activities on
Speakers Bureaus for three firms. He receives less
than $10,001 per year, per firm.
Dr. Robert Skinner for a patent licensed
to a firm that could potentially be
affected by the
committee's discussion. He has received no
royalties at this time. Also, for his Speakers
Bureaus activities for two firms, he receives
less
than $10,001 per year, per firm.
Dr. Patricia Chesney for stock
in six
firms.
One stock is valued at less than $5,001,
one stock is valued between $5,001 to
$25,000,
9
three stocks are valued between $25,001
and
$50,000, and one stock is valued greater
than
$100,000.
Dr. Thomas Ten Have for stock
valued
between $25,001 to $50,000.
Dr. Victor Santana for stock in two firms.
These stocks are worth between $5,001 and
$25,000
each.
Dr. Sharon Raimer for two
grants that are
valued at less than $100,000 per firm,
per year.
Also, for stock in three firms, each
stock is
currently valued between $5,001 and
$25,000.
Dr. Sonia Patten is an unpaid
volunteer
member of the Sumasil Foundation Board of
Directors. The Foundation owns stock interest in
two firms. One stock is currently valued between
$25,001 and $50,000 and the other stock
is
currently valued between $5,001 and
$25,000.
We would also like to disclose
that Dr.
Terrence Blaschke owns stock in a firm,
valued from
$5,001 to $25,000. A waiver under 18 U.S.C.
208(b)(3) is not required because the de
minimis
10
exemption 2640.202(b)(2) applies.
A copy of the waiver statements
may be
obtained by submitting a written request
to the
Agency's Freedom of Information Office,
Room 12A-30
of the Parklawn building.
In the event that the
discussions involve
any other products or firms not already
on the
agenda for which an FDA participant has a
financial
interest, the participants are aware of
the need to
exclude themselves from such involvement
and their
exclusion will be note for the record.
In addition, we would also like to
note
that Dr. Michael Alfano is participating
in this
meeting as a non-voting industry
representative,
acting on behalf of regulated
industry. Dr.
Alfano's role on this committee is to
represent
industry interests in general, and not
any one
particular company. Dr. Alfano is Dean of the
College of Dentistry, New York
University.
With respect to all other
participants, we
ask in the interest of fairness that they
address
any current or previous financial
involvement with
11
any firm whose products they may wish to
comment
upon.
Thank you.
DR. WOOD: Thanks a lot.
Our first speaker is Charley
Ganley.
Charley.
Introduction
DR. GANLEY: Good morning.
I would just
like to start by thanking all the members
for
participating in this meeting. I would also like
to thank the advisors and consultant
staff for all
the hard work they do in putting these
meetings
together, it is always difficult to get
two
different committees together, and last
but not
least, the staff of the Dermatologic and
OTC
Divisions who have put together the
presentations.
[Slide.]
We are here today to discuss
the safety
data necessary to consider a switch of
dermatologic
topical corticosteroids from prescription
to OTC
status.
[Slide.]
The FDA presentations will
cover the
regulatory history of OTC hydrocortisone,
the
assessment of safety for current
prescription
12
dermatologic topical corticosteroids
products, an
assessment of safety effects for other
categories
of steroid products, and testing for HPA
axis
suppression.
[Slide.]
Now, low potency dermatologic
topical
corticosteroids are currently available
OTC, and
the only product that you will hear in
the next
talk is hydrocortisone. Its purpose is for the
symptomatic treatment of certain skin
conditions,
and there is a limitation on the duration
of use.
Over the last year or so,
several
manufacturers have expressed an interest
in
switching some dermatologic topical
corticosteroids
from prescription to OTC, asking for
similar type
claims, and also for durations of use.
[Slide.]
Now, in your background
package, we
included a list of the various potencies
of topical
13
steroids, and there is quite a difference
in the
potency of prescription dermatologic
topical
steroids, and potency impacts on efficacy
and
safety of these products.
The main issue for the
discussion today is
the safety in the OTC setting. The question really
is where do we draw the line between safe
versus
unsafe products in this category for OTC
use.
[Slide.]
Can all dermatologic topical
steroids be
used safely OTC? Well, some highly potent products
used for extended periods or in large
amounts may
pose a significant risk for developing a serious
adverse event.
At least in the OTC setting,
limiting the
duration of use through labeling may be
effective
for the majority of users. There will, however, be
a minority of consumers who will use
large amounts
and for durations that exceed label
recommendations.
I think in part of the open
public
session, you will hear a little bit of
information
14
of
what possible percentage of consumers that may
be.
[Slide.]
So, what are the safety
concerns? We have
divided them up into the systemic effects
and local
effects, and within the systemic effects,
we divide
them further into HPA axis suppression,
which is in
this case where an exogenous steroid
causes the
body to stop making corticosteroid, and
in stress
situations, it could lead to acute
adrenal crisis
which would be life-threatening.
This can occur with weeks of
use and the
use of the OTC product may be unknown to
a health
provider who has to treat someone who
comes into
the emergency room in this situation.
The other systemic effects are essentially
Cushing's syndrome, which could be
osteoporosis,
truncal obesity, growth suppression, and
hypertension, it goes on and on, and the
severity
may be related to the daily dose and the
duration
of therapy.
The local effects during the
course of the
15
presentations today, that will also be
reviewed.
[Slide.]
Now, you may not be able to see
this very
well.
I printed out one page, but this is one of
the schematics that we are going to work
with
today, and what we have done is we have
created a
hierarchy of what we think the importance
of these
various potential safety issues are.
Starting at the top is HPA axis
suppression. The second one is other systemic
effects, and the third is local
effects. You will
see the way the questions are presented
will also
follow this course.
I don't want to go into great
detail with
this now, but during the course of the
discussion
and prior to some of the questioning
maybe later
this afternoon, we can go through this in
a little
more detail.
Right now I am going to turn it
over to
Michael Koenig, who is going to talk a
little bit
about the regulatory history of
hydrocortisone.
FDA Presentations
OTC Dermatologic Topical
Corticosteroids
[Slide.]
DR. KOENIG: Good morning.
I am Michael
16
Koenig, an interdisciplinary scientist in
the
Division of Over-the-Counter Drug
Products.
Over the next 15 minutes, I
will be
providing you with information about the
only
dermatologic topical steroids that are
available
over the counter, hydrocortisone and
hydrocortisone
acetate.
Because hydrocortisone and
hydrocortisone
acetate are functionally the same thing,
for the
rest of this presentation, I will simply
refer to
the two corticosteroids as hydrocortisone.
[Slide.]
This presentation is divided
into three
parts.
First, I will describe the OTC monograph
system under which these OTC
corticosteroids are
regulated. Second, I will review the regulatory
history of hydrocortisone. Third, I will show you
the current labeling of hydrocortisone
products if
they are in compliance with the
monograph.
[Slide.]
I would like to begin by just
especially
for members of the Dermatologic and
Ophthalmic
Drugs Committee to review the way OTC
drugs are
regulated. All OTC drugs are regulated by one of
two means, either under an NDA, or a new
drug
17
application, or under the monograph
system.
New drugs applications, or
NDAs, are
prepared by a drug manufacturer for a
specific
product, a specific drug product, and all
of the
review of this information and things
related to
the review are kept strictly
confidential.
Neither of the OTC
corticosteroids that I
will be talking about are regulated under
NDAs.
Instead, they are regulated under the
monograph
system, and this differs because under
the
monograph, monographs deal with specific
active
ingredients rather than drug products,
and I will
show you how that plays out in just a
minute.
In contrast to the NDAs, the
information
included in the monograph is a very
public process.
The monographs are published in the
Federal
18
Register, and FDA actively solicits
feedback from
the public at every step of the process.
[Slide.]
So the OTC monographs came
about with the
initiation of the OTC drug review back in
1972. At
that time, there were over 200,000
different drug
products available OTC, and it was really
impractical to think that we could review
the
safety and effectiveness of all 200,000
of these
drug products.
So, since they were made up of
about 700
active ingredients, it was determined
that the
active ingredients should be studied for
safety and
effectiveness rather than the products
themselves.
Again, this is a key difference between
monographs
and drugs marketed under an NDA.
Of the 700 active ingredients, these
were
classified into 26 different therapeutic
categories
for further review.
[Slide.]
The initial review as by an
Advisory
Review Panel. This was made up of outside
experts,
19
outside FDA experts in that particular
therapeutic
category.
There were 7 voting members, but in may
respects, it was somewhat analogous to
the Advisory
Committee.
These panel members looked at
each of the
active ingredients and determined whether
they were
Category I or GRASE, Generally Recognized
as Safe
and Effective; Category II, not GRASE; or
Category
III, insufficient data to determine
whether or not
the ingredients were safe and effective
for their
intended use.
[Slide.]
The recommendations of the
Advisory
Committee were published in the Federal
Register as
an Advanced Notice of Proposed
Rulemaking, or ANPR.
[Slide.]
FDA's first position on the
ingredients in
the different categories were made public
in a
proposed rule. This followed solicitation of
comments from the public, and as I said,
resulted
in the publication of a proposed rule,
also known
as a Tentative Final Monograph, I have
abbreviated
20
here as TFM.
[Slide.]
The last step in the monograph
process is
the development of a Final Rule, and that
follows
input of comments from the public again,
as well as
any new data that is relevant to generate
this
Final Rule or Final Monograph, which I
have
abbreviated FM.
[Slide.]
I would like to now speak
specifically
about the regulatory history of
hydrocortisone.
[Slide.]
This low potency topic
corticosteroid was
introduced into the U.S. market as a
prescription
drug in 1952. Four years later, in 1956, a Citizen
Petition was submitted requesting that
hydrocortisone be switched from
prescription to
OTC.
The switch was rejected in 1957
for two
reasons:
first, there was a failure to demonstrate
that consumers could safety self-medicate
using
hydrocortisone; and, second, it was felt
that more
21
testing was needed on absorption of
hydrocortisone
through the skin. In other words, there was a
concern about systemic effects, much as
we will be
talking about today.
Hydrocortisone was included
with other
ingredients classified as external
analgesics in a
review by the Topical Analgesics Panel,
which met
between 1973 and 1978.
[Slide.]
The findings of the panel and the
preliminary regulations were published in
1979 and
the Advanced Notice of Proposed
Rulemaking or ANPR.
Among other things, the panel did
consider whether
hydrocortisone had any adverse local
effects, and
noted that there was a noticeable lack of
adverse
local effects.
The striae and telangiectasia
that were
characteristic of more potent fluorinated
corticosteroids were not generally found
with
hydrocortisone or hydrocortisone acetate. Dr.
Cook, who will follow my presentation,
will be
showing you some pictures of that and
discussing
22
this is a little bit more detail.
Pustular eruptions and crusting
were
reported in one case of a person who was
using
hydrocortisone, but was it turns out
attributed to
a secondary infection and the scratching
of the
secondary infection, and treatment with
an
antibiotic resolved the issue while the
person
continued to use hydrocortisone. So, again, a lack
of local adverse effects.
[Slide.]
Also, in the ANPR, the fact
that there was
a lack of systemic effects was
published. Several
experiments look at percutaneous
absorption.
People used carbon-14 hydrocortisone, in
one case
tritiated hydrocortisone, and did not see
any
significant absorption through the skin.
Other measures of systemic
effects were
eosinophil count, there was no depression
in
eosinophil count in three or four studies
that were
presented in the ANPR. Urinary levels of
17-hydroxysteroids and 17-ketosteroids
were not
increased as you would expect if there
were a
23
significant systemic effect.
Blood glucose levels were
unchanged, as
was
the serum sodium level, and plasma cortisol did
increase as expected or predicted in
response to
insulin stress.
[Slide.]
Insulin stress tests back in
the '70s was
a major test for HPA axis function. It is no
longer the current standard, but one
report that
you will see in the ANPR, which
incidentally is
included in your background package, was
a study by
Munro and Clift, which published in 1973.
This is in Tab 5 of your
background
package, published in the British Journal
of
Dermatology. These investigators looked at 40
patients with chronic skin disease,
eczema,
psoriasis, who had been using
corticosteroids for
prolonged periods, I believe is in the
title.
Ninety-five percent or 38 of the 40 had
been using
corticosteroids for more than 10 months.
In fact, they were using a
variety of
corticosteroids, betamethasone, and some
others.
24
Ten of these 40 included among the
combination of
corticosteroids they had been using 1
percent
hydrocortisone acetate.
All 10 of those 10 subjects had
a normal
insulin stress response, and, in fact, 37
of the 40
enrollees in the study had a normal
insulin stress
response.
Of the 3 that did not, 2 had occlusion
over extensive areas of the body, and 2
had an
exceptionally large dose of
corticosteroid.
[Slide.]
Now, the panel also reported
that one of
the items that they had received was a
review of
the literature covering the period 1952
to 1973
about the serious adverse events that had
occurred.
The report was based on some 12,000
subjects in 90
different clinical studies, and in those
12,000
subjects, there were only 3 reports of
serious
adverse events.
One of these was 1960 report of
temporary
growth retardation in a 5 1/2-year-old
male, who
was having 1 percent hydrocortisone
applied for 16
months.
In 1962, there was a report of temporary
25
growth retardation in an infant, who also
had 1
percent hydrocortisone applied twice
daily for 6
months, and this was--that says total
body--whole
body and unction was what the report says
in the
ANPR.
In 1966, there was a rapid gain in body
weight in a 3-week-old infant male, who
was only
using 0.25 percent hydrocortisone 3 times
a day for
8 1/2 days, but over a very large
coverage 2,100
mg/m2 body surface area.
So, all in all, that panel
considered this
a very favorable response, only 3 out of
over
12,000 subjects had any serious adverse
events with
hydrocortisone.
[Slide.]
The panel recommendations in
the ANPR were
that hydrocortisone and hydrocortisone
acetate
should be considered GRASE over a
concentration
range of 0.25 to 0.5 percent. Remember GRASE is
generally recognized as safe and
effective.
The panel also has some recommendations
for labeling, and since I will be showing
you
26
labeling in the third part of the talk, I
just
wanted to let you see how this labeling
developed
as the monograph developed.
The panel felt that the
indication should
be or the use of hydrocortisone should be
temporary
relief of minor skin irritations,
itching, and
rashes due to a variety of different
conditions,
and we will get into that when we look at
the
labeling.
The panel also felt that among
several
warnings should be these two, which are
relevant to
today's discussion I think. One is that consumers
should stop use if the condition worsened
or lasted
more than 7 days, so there was a time
limit put on
the use of hydrocortisone.
The other warning I wanted to
mention was
the one that it should not be used on
children
under 2 years of age. In fact, these two
warnings
were included on all external analgesic
active
ingredients, but they are directly
relevant to some
of some of the discussion you will be
having later
I
think.
Finally, the panel felt that
under
Directions should be a direction to apply
this to
the affected area essentially only, not
more than 3
27
to
4 times a day.
[Slide.]
FDA's position was made public
in the
Tentative Final Monograph, TFM, which
published a
little over 3 years later in 1983. FDA agreed that
the concentration range specified by the
panel was
appropriate, that 0.25 to 0.5 percent
hydrocortisone should be considered
GRASE, safe and
effective, and FDA did make some labeling
modifications.
Among those was the focus of
the
indication on antipruritic aspects of
hydrocortisone, so instead of temporary
relief of
skin irritations, itching, and rash, it
became
temporary relief of itching associated
with skin
irritation and rashes due to a variety of
conditions, and hydrocortisone is today,
that is
the only indication, antipruritic.
Additionally, to the stop use
condition,
28
FDA added the clause, "Stop use if
condition
worsens or last more than 7 days or if
symptoms
clear up and occur again within a few
days."
[Slide.]
The Tentative Final Monograph
was amended
in 1990 in response to a Citizen Petition
which
requested an increase in dosage strength
to a
maximum of 1 percent from remember the
previous 0.5
percent.
This amended TFM included an
extensive
data and literature review mostly
centered around
the use of 1 percent hydrocortisone, and
ultimately
considered the higher concentration of 1
percent to
be GRASE for OTC use.
Additionally, there were some
labeling
modifications. Under Do Not Use was added, "Do not
use
any other hydrocortisone product when using the
product you are using," and "Do
not use this for
the treatment of diaper rash," which
is still on
the labeling, and this is largely due to
the
occlusive nature of a diaper.
[Slide.]
What about the Final Monograph,
the last
step?
It is pending. We are working on
it. We
have found that manufacturers are
generally
29
complying with the Tentative Final
Monograph and
the amended TFM. I will show you that in some
labeling in just a minute.
We are continuing our review of
data
submitted by manufacturers, as well as in
the
literature.
[Slide.]
In light of today's discussion,
I just
wanted to point out some of the
literature that we
have been reviewing. This table represents 5
studies that have been conducted since
the ANPR
published in 1979. All of these studies were in
children, and all of these used the
modern standard
ACTH stimulation to measure HPA axis
function.
ACTH, as Dr. Cook will go into
a little
bit more detail on this, ACTH is
adrenocorticotropic hormone. This is released from
the anterior pituitary and stimulates
release of
cortisol from the adrenal glands. That is the P
30
and the A, adrenal glands in the HPA
axis.
So, by looking at the amount of
cortisol
released in response to a known amount of
ACTH, or
in a more practical sense, some synthetic
analogue
of ACTH, you can tell whether the HPA
axis is
functioning properly.
In all of these studies, at
hydrocortisone
concentrations ranging from 1 percent to
a maximum
of 2.5 percent, and with durations of
treatment
ranging from 2 weeks or 14 days up to
just under 18
years, the HPA axis was found to be
functioning
normally in response to hydrocortisone.
[Slide.]
I would now like to look at the
current
labeling of hydrocortisone in this third
part of
the talk.
[Slide.]
Since 1999, OTC products should
be
conforming to the Drug Facts labeling
standard.
This is what the hydrocortisone labeling
should
look like if it's in compliance with the
monograph,
and there are three things I would just
like to
31
point out to you. We have been discussing the
development of the monograph through the
various
stages, and I wanted to show you how that
looks in
the labeling.
So, under Uses, you see the
indication,
temporarily relieves itching associated
with minor
skin irritations, inflammation and rashes
due to a
variety of conditions, and the number of
conditions
that may be causing the itching has
increased over
the years with each new monograph
publication.
[Slide.]
Also, under Warnings, this is
very much as
it appeared in the TFM, the Tentative
Final
Monograph's "Stop use and ask a
doctor if the
symptoms persist for more than 7 days or
clear up
and occur again within a few days."
[Slide.]
And under Directions,
"Apply to affected
area not more than 3 to 4 times a day,
children
under 2 years of age, do not use."
[Slide.]
This is labeling that is taken
off of a
32
currently marketed OTC product, and I
just wanted
to show you that again, manufacturers are
very much
in compliance with the monograph
standards.
So, in this labeling under
Uses, we see
the
same thing, "temporarily relieves itching of
minor skin irritations, inflammation and
rashes."
[Slide.]
Under Warnings, "Stop use
and ask a doctor
if symptoms persist for more than 7
days."
[Slide.]
Under Directions, the same two
that I just
mentioned.
I would like to thank you for
your
attention and I will be followed by Dr.
Denise Cook
of the Division of Dermatologic and
Dental Drug
Products.
Denise will be talking about
prescription topical corticosteroids.
Thank you.
Rx Topical Corticosteroids:
HPA Axis
Suppression and Cutaneous
Effects
[Slide.]
DR. COOK: Good morning.
Good morning to
33
the respective chairs of the respective
advisory
committees that are here, also to the
advisory
committee members, to my FDA colleagues,
and people
in the audience.
I am Denise Cook. I am a dermatologist in
the Division of Dermatology and Dental
Drug
products.
[Slide.]
Today, I will be speaking to
you on
prescription topical corticosteroids, the
HPA axis
suppression, and cutaneous effects.
The majority of the
presentation will be
on the systemic effect of the HPA axis
and the
suppression, and the FDA's experience
with. I will
be presenting trial data from approved
drug
products, the resultant labeling
changes. I will
also give a postmarketing summary of
adverse events
as it relates to the HPA axis suppression
that we
have in our database.
But first I will give you a
background to
the talk, so that you can follow it
probably a
little bit later. I will talk about the
34
classification of topical
corticosteroids, give you
a synopsis of the cosyntropin stimulation
test and
how it is performed, and also give you an
evolution
of interpretation of normal HPA axis
function as it
has been done over the years at the FDA.
I will give you background also
on class
labeling for topical corticosteroids and
how that
developed, and the cutaneous adverse
events from
topical corticosteroid use.
[Slide.]
The topical corticosteroids are
divided
into seven classes. Although the FDA does not
purport this classification, it is widely
used in
the dermatologic community.
Class I consists of superpotent
topical
corticosteroids, Class II high potency,
Class III
through VI are mid-potency with Class III
being
closer, of course, to the high potency,
and Class
VI being close to the low potency of
Class VII.
It is usually determined by a
vasoconstrictor assay where the topical
corticosteroids placed on the cutaneous
surface,
35
and blanching or vasoconstriction is
determined
relative to the other corticosteroid.
[Slide.]
The cosyntropin stimulation
test, which is
the test that I will be discussing in the
bulk of
the studies that you are going to hear
about today,
is used to assess the function of the end
organ,
the adrenal gland, in the
hypothalamic-pituitary
adrenal axis.
In the case of topical
corticosteroids, it
is assessing an exogenous unwanted
treatment
effect.
What is usually done is the
cosyntropin is
given at 0.125 mg or 0.25 mg depending on
age
and/or body weight, and it is
administered
intravenously at baseline and at the end
of
treatment.
Blood is then drawn for serum
cortisol
values at 30 minutes and sometimes 60
minutes post
stimulation. Then, the interpretation of the
results determines a normal or abnormal
response.
[Slide.]
The evolution of the
interpretation of the
normal function of the HPA axis at the
FDA has
undergone many revisions. First, in 1985, a.m.
36
serum cortisol, then urinary corticoid
concentrations were used to determine whether
you
had normal function of your HPA axis
after
treatment with topical corticosteroids.
Then, in 1996, the cosyntropin
stimulation
test was employed. At that time, a 30-minute post
stimulation serum cortisol had to be
greater than
20 mcg/dL. Also, if the pre-stimulation serum
cortisol was already greater than 20
mcg/dL, then,
you needed to have at least a 6 increment
change
from pre-stimulation to post-stimulation
in order
to be considered to have a normal
response.
In 1999, the FDA went to a
single
criterion to determine normal function of
your HPA
axis.
That was a 30-minute post-stimulation serum
cortisol greater than 18 mcg/dL.
[Slide.]
In 2001, it was decided that if
we were
going to use cosyntropin to determine
normal
37
function of hormonal therapy HPA axis,
then, the
label should be followed as it is
currently
written, that is, that the control plasma
cortisol
level should exceed 5 mcg/100 mL. The
30-minute
level should show an increment of at least
7
mcg/100 mL, and the 30-minute level
should exceed
18 mcg/100 mL.
Currently, in 2004, there had
been a lot
of work in the FDA with endocrinologists
and also
members in the Division of Dermatology to
determine
that we need to go back to a single
criterion for
HPA axis function and determining it from
the
cosyntropin test. Therefore, at the present time,
we only use a 30-minute level, and that
serum
cortisol level should exceed 18 mcg/100
mL.
[Slide.]
Now, class labeling for
prescription
topical corticosteroids went into effect
in 1990,
and I am going to give you a little
background on
one of the factors that propelled this
into being.
This class labeling talks about
the
effects on the HPA axis, effects on
glucose
38
metabolism, development of Cushing's
syndrome,
effects on growth, and effects on
intracranial
pressure.
[Slide.]
Two studies have propelled this
into
being.
There were two open-label trials with
Temovate Ointment. In Trial 1, there were 6 adult
patients with psoriasis who applied 7
grams/day to
30 percent of their body surface area for
7 days.
ACTH stimulation was performed
at baseline
and 2 post-treatment a.m. cortisols were
taken.
They found that 50 percent of the
patients
exhibited decreases in cortisol
production.
[Slide.]
In the second trial, the
objective was to
determine the largest dose over a 7-day
period that
would not cause significant suppression
of the
adrenal gland.
Three doses were used - 7
grams/day, 3.5
grams/day, and 2.0 grams/day.
Suppression in this trial was
determined
by an A.M. plasma cortisol and urinary
corticoid
39
concentrations.
It was interesting, it was
found that none
of the psoriatic patients suppressed at
7.0
grams/day or even at 3.5 grams/day, but
doses as
low as 2.0 grams/day caused marked
suppression of
cortisol secretion in patients with
atopic
dermatitis. We can possibly presume that this may
be because they may have had a higher
compromise in
the epidermis.
DR. WOOD: What were the numbers in that
study?
DR. COOK: I don't know the numbers. You
mean like exactly what the serum cortisol
levels
were?
DR. WOOD: The number of patients.
DR. COOK: The number of patients, I don't
have that either. This was 1985, and this is taken
out of the label. But I would suspect that they
were small, because in the current
studies that we
have, the numbers are small, they are not
huge
numbers.
[Slide.]
So, this led to a Temovate
label in 1985
that stated in the Precautions, it is a
highly
potent topical corticosteroid that has
been shown
40
to suppress the HPA axis at doses as low
as 2
grams/day. As you note here, it is a Class I
steroid in the superpotent category.
Under Pediatric Use, it was
determined
that it should not be used in children
under 12
years of age, at least it is not
recommended.
[Slide.]
So, now we will move on to the
actual
class label that was generated.
[Slide.]
In the Precautions Section, it
states that
systemic absorption of topical
corticosteroids can
produce reversible
hypothalamic-pituitary-adrenal
axis suppression with the potential for
glucocorticoid insufficiency after
withdrawal from
treatment.
Manifestations of Cushing's
syndrome,
hyperglycemia, and glucosuria can also be
produced
in some patients by systemic absorption
of topical
41
corticosteroids while on treatment.
[Slide.]
It goes on to say that patients
applying a
potent topical steroid to a large surface
area or
to areas under occlusion should be
evaluated
periodically for evidence of HPA axis
suppression.
This may be done by using the ACTH
stimulation, AM
plasma cortisol, and urinary free
cortisol tests.
[Slide.]
If HPA axis suppression is
noted, an
attempt should be made to withdraw the
drug, to
reduce the frequency of application, or
to
substitute a less potent steroid.
Recovery of HPA
axis function is generally prompt upon
discontinuation of topical
corticosteroids.
Infrequently, signs and symptoms of
glucocorticosteroid insufficiency may
occur
requiring supplemental systemic
corticosteroids.
[Slide.]
The class label also addressed
pediatric
use in the Pediatric Use Section of the
label.
[Slide.]
Currently, this is what is
there if there
haven't been any tests done on pediatric
patients,
but as you shall see in the studies that
I will
42
present, since the advent of FDAMA, we
have been
able to get studies in pediatric
patients, so some
of this has been modified in the
respective labels.
Safety and effectiveness in
children and
infants have not been established. Because of a
higher ratio of skin surface area to body
mass,
children are at a greater risk than
adults of HPA
axis suppression when they are treated
with topical
corticosteroids.
They are therefore also at
greater risk of
glucocorticosteroid insufficiency after
withdrawal
of treatment and of Cushing's syndrome
while on
treatment.
[Slide.]
HPA axis suppression, Cushing's
syndrome,
linear growth retardation, delayed weight
gain, and
intracranial hypertension have been
reported in
pediatric patients receiving topical
corticosteroids.
Manifestations of adrenal suppression
in
pediatric patients include low plasma
cortisol
levels to an absence of response to ACTH
stimulation. Manifestations of intracranial
hypertension include bulging fontanelles,
headaches, and bilateral papilledema.
43
[Slide.]
Now, we are going to move on to
the bulk
of the presentation, which is going to be
about the
prescription topical corticosteroid data
and its
relationship with HPA axis suppression.
I am going to speak about 10
drug
products.
There are 8 topical corticosteroid
products, 2 topical combination drug
products.
[Slide.]
Just to give you those, I am going
to
speak about Dermatop, which is a
mid-potency
steroid; Cutivate Cream, another
mid-potency
topical corticosteroid; Diprolene AF
Cream, which
is a high potency steroid.
You might want to look in Tab 2, I think
it is, of your background package. It has that
44
classification that I spoke of earlier,
the high
potency steroids being in Class II.
Diprosone Ointment, a high
potency
steroid; Diprosone Cream and Lotion, both
in the
mid-potency category; Clobex Lotion, a
superpotent
steroid; and Temovate E Cream. Both of these are
clobetasol propionate.
There will be 11 studies that I
am going
to discuss. The ages of these patients were from 3
months to adult. These are all open-label trials,
and they all use the cosyntropin
stimulation test
to determine the function of the HPA
axis.
[Slide.]
Dermatop is a Class V steroid
near the
bottom part of the mid-potency topical
corticosteroids. It was approved in May 1996. We
are going to discuss a pediatric atopic
dermatitis
trial.
[Slide.]
There were 59 patients enrolled
and there
were 2 targeted populations. The patients were
between 1 month and 2 years and also
between 2 and
45
12 years.
There were 10 patients who were less
than 2 years old and 49 patients were
greater than
or equal to 2 years of age.
[Slide.]
They had to use the medication
over
greater than 20 percent of the body
surface area.
I mean they had to have atopic dermatitis
to that
amount of cutaneous surface, and use it
twice daily
for 21 consecutive days.
Again, we used the cosyntropin
stimulation
test. It was administered at baseline and
at day
22.
In this trial, patients who were greater than
or equal to 15 kilograms received a
higher dose of
0.25 mg IV, those less than 15 kg
received 0.125 mg
IV.
[Slide.]
The criteria in this study was
the adrenal
response to ACTH at 30 and 60
minutes. Here, the
post-stimulation serum cortisol had to be
greater
than 20 mcg/dL, and if the pre-stimulation
serum
cortisol level was already greater than
20, then,
an incremental increase of greater than 6
mcg/dL in
46
the serum cortisol was required.
[Slide.]
There were 3 patients according
to the
protocol criteria who were
suppressed. Two
patients, 1 an 18-month-old, had a peak
response of
a 5 mcg/dL change from baseline, 1
patient had a
post-stimulation cortisol value actually
decreased
from baseline.
At that time, the Agency agreed
with an
outside endocrinologist that since these
3 patients
had a post-stimulation response that was
already
greater than 20 mcg/dL, although they
didn't have
that required incremental rise, that they
should
not be considered suppressed.
So, this led to the current
label that
reads for this drug, that "none of
the 59 patients
showed evidence of HPA axis
suppression."
[Slide.]
The next drug is Cutivate
Cream, which is
also a Class V steroid, was approved in
June 1999.
We are going to look at another atopic
dermatitis
trial in pediatric patients.
[Slide.]
There were 43 evaluable
patients with
moderate to severe atopic dermatitis; 29
of the
47
patients were 3 months to 2 years of age,
and 24
patients were 3 years to 5 years old.
[Slide.]
The criteria for entry into the
study was
that they had to have at least a 35
percent body
surface area involvement, and I will tell
you in
all of these studies, we were looking for
maximum
use conditions, so you could get your
worst case
scenario.
They applied the medication
twice a day
for 3 to 4 weeks. Patients up to 2 years were
limited to 120 grams/week, and patients 3
to 5
years of age were limited to 180
grams/week.
[Slide.]
Looking at body surface area
improvement
over time to show the response to the
medication,
23 of the patients, or 50 percent, had a
decrease
of 50 percent by 2 weeks, and 9 had a
decrease of
50 percent by 3 weeks, and 9 percent of
the
48
patients had a 50 percent decrease by 4
weeks.
[Slide.]
The cosyntropin was
administered at
baseline and end of treatment, and in
this study,
they used age, younger age group was
given a lower
dose than the older age group.
[Slide.]
Here, a normal response was a
serum
cortisol level that exceeded 18 mcg/dL at
30
minutes post-stimulation.
[Slide.]
Two the patients out of the 43
patients
experienced adrenal suppression. One was a
5-year-old who actually had 95 percent
body surface
area involvement, used the drug for 4
weeks, used
561 grams, and his pre-stimulation, as
you see
here, pre-treatment value was 33.9 after
stimulation, and yet it fell to 11.8, but in
follow-up he recovered at 19.8 with his
serum
cortisol.
The other patient was a
2-year-old who had
the minimum amount of body surface area
involvement
49
of 35 percent. His duration of treatment was for 5
weeks.
He used 176.5 grams, and his end-treatment
post-stimulation serum cortisol was 9.4.
Unfortunately, we don't know whether he
recovered
or not because he was lost to follow-up
and the
investigator did make an honest effort to
try to
track this child down.
[Slide.]
But this led to labeling
changes for
Cutivate Cream, which stated that
children as young
at 3 months of age for up to 4 weeks of
use could
use the medication, and appropriate
sections of the
label were updated.
[Slide.]
Now, I am going to talk about 4
or 5
betamethasone propionate products. They were all
approved in 2001, and when I say approved
in 2001,
I mean the pediatric part of the label
was changed.
Their supplement for safety was changed,
because,
of course, they have been on the market a
lot
longer than just 2001.
One is Diprolene AF Cream,
which is a
50
Class II steroid; Diprosone Ointment,
another Class
II steroid; Diprosone Cream, a Class III
steroid;
Diprosone Lotion, which is mid-potency,
but the
lower end of the mid-potency, and that
will be
significant when you see the study
results of this
drug, of Diprosone Lotion.
Then, I am going to speak of the 2
combination products, Lotrisone Cream and
Lotion.
[Slide.]
The criteria for a normal HPA
axis
response in all of these studies was that
we would
follow the cosyntropin label, that the
failure of
any one of three criteria would indicate
suppression of the HPA axis, and
stimulation should
occur at baseline and end of treatment.
[Slide.]
So, the criteria for the
30-minute
post-stimulation, the three criteria that
they
needed to meet to have a normal response,
is that
the control plasma cortisol level should
exceed 5
mcg/100 mL, the 30-minute cortisol level
should
show an increment of at least 7 mcg/100
mL above
51
the basal level, and the 30-minute level
should
exceed 18 mcg/100 mL, and a failure of
any one of
those three would indicate suppression.
[Slide.]
So, with Diprolene AF Cream,
there were 60
evaluable patients. They ranged in age from 1 to
12 years with atopic dermatitis. They had a mean
body surface area involvement of 58 percent. They
used the study drug twice a day for 2 to
3 weeks,
and that depended upon whether their
disease
cleared or not.
If they cleared within 2 weeks,
they were
allowed to stop and then be tested at
that point.
If they needed 3 weeks, they could use if
for 3
weeks.
They were limited to 45 grams per week.
[Slide.]
The results of the cosyntropin
stimulation
showed that 19 out of 60 or 32 percent of
these
patients showed evidence of HPA axis
suppression.
I won't go through all of these, but if
you just
took the criterion that we look at now,
which is
greater than 18 mcg/dL, 58 percent of the
patients
52
had suppression.
[Slide.]
If you look at suppression by
age group,
it appeared that a larger percentage of
patients
suppressed as the age decreased.
Looking at recovery of normal HPA axis
suppression, unfortunately, all the
patients were
not retested. We would have liked to have all of
them retested, but 4 patients were
retested 2 weeks
post-treatment, and 3 of the 4 recovered
normal
function of their HPA axis.
[Slide.]
We tried to do a statistical
analysis in
the development of HPA axis suppression
with each
drug.
With Diprolene AF, there was no correlation
between amount of drug used, body weight,
age or
sex, and the incidence of adrenal gland
suppression.
The statistical relationship
did exist
between body surface area and risk of HPA
axis
suppression such that for an increase of
1 percent
body surface area involved, the risk of
HPA axis
53
suppression increased 4.4 percent with a
p value of
less than 0.01.
[Slide.]
This led to a label change for
Diprolene
AF Cream, such that it was restricted to
patients
13 years and older, and appropriate
information was
included in other sections of the label.
[Slide.]
Diprosone Ointment. That study had 53
evaluable patients with atopic
dermatitis. The age
range was 6 months to 12 years. The medication
again was applied twice a day for 2 to 3
weeks.
The mean body surface area involved was
58 percent.
DR. WOOD: Can we just go back to that
last slide? The one with the 1 percent
BSA
involved.
DR. COOK: Excuse me.
Which one?
DR. WOOD: The last slide, the slide
before that, Slide 39. That is clearly key. Is
that really right? I mean does that mean that a 20
percent, that is linear throughout the
thing, so
going from 1 percent to 21 percent would
mean 88
54
percent of people had HPA
suppression? That
doesn't seem to make much sense to me.
DR. COOK: Well, you will have to talk to
our statistician.
DR. WOOD: All right.
Fair enough. Go
on.
DR. COOK: Let's see, I have figure out
where I left off. I think I was here, at Diprosone
Ointment and getting ready to tell you
the patient
that suppressed.
There were 28 percent of
patients who
showed evidence of HPA axis suppression
when given
the cosyntropin stimulation test, and
here again,
if we just looked at the criterion of
less than 18,
of those who weren't able to exceed 18,
53 percent
of the patients had a post-stimulation
plasma
cortisol value that would suggest
suppression.
[Slide.]
Again, if you looked at
suppression by
age, for this drug, again, there was a
higher
proportion of patients who suppressed, the
younger
the patients were.
[Slide.]
In the statistical analysis
here in the
development of HPA axis suppression,
these
55
statisticians didn't find a statistically
significant effect for drug usage, for
percent of
body surface area involved, for weight,
or for age.
It did show that for some
reason, a higher
proportion of males than females developed
HPA axis
suppression using this drug.
[Slide.]
In testing patients for
recovery, 2 of the
15 patients were retested and 100 percent
recovered
at 2 weeks.
[Slide.]
This led to a label change
similar to
Diprolene AF Cream in which an age
restriction was
added that patients should be 13 years of
age or
old, and appropriate parts of the label
were
updated with the clinical data.
[Slide.]
Diprosone Cream studied 43
evaluable
patients with atopic dermatitis. They ranged in
56
age from 2 to 12 years. Here, the mean body
surface area involvement was 40 percent.
Again,
they applied the medication twice a day
for 2 to 3
weeks.
[Slide.]
In this study, 23 percent of
the patients
showed evidence of adrenal suppression
using the
Cortrosyn label with all three criteria
and a
failure of one.
If you look again at a
post-stimulation
value that was less than 18, 50 percent
of patients
showed evidence of adrenal suppression.
[Slide.]
In this study, you can't quite
see the
value here. Starting here with 14 percent of
patients 9 to 12 years of age showed
evidence of
suppression. As you march down again, the
percentages went up, but here,
interestingly, which
will show you the dilemma that we all are
in, in
determining just what is going to make
someone
suppressed, what are the risk factors
here, none of
the infants in this study showed evidence
of
57
adrenal suppression.
[Slide.]
Again, with the statistical
analysis for
this particular drug, in these patients,
there was
no statistically significant effect for
number of
days treated, for weight, or for age.
However, there was a
statistical
significance found for mean amount of
drug usee -
81 grams in those who suppressed versus
37 grams in
those that did not.
There was a numerically higher
percent of
body surface area involvement in those
who
suppressed, and numerically, more males
developed
suppression.
[Slide.]
When looking at recovery of HPA
axis
function with Diprosone Cream, 2 out the
10
patients were retested, and 50 percent, 1
out of
the 2, recovered function at 2 weeks.
[Slide.]
Here again, the label was changed to add
and age restriction to 13 years or older,
and
58
appropriate portions of the label were
updated.
[Slide.]
Now, Diprosone Lotion, I will
remind you
again is a Class V steroid, so just like
two
classes above the lowest potency of
topical
corticosteroid.
Here, they had 15 evaluable
patients with
atopic dermatitis. They ranged in age from 6 to 12
years old. The mean body surface area involvement
was 45 percent. They applied the medication twice
a day for 2 to 3 weeks.
[Slide.]
This was a very interesting
study. Eleven
of the 15 patients or 73 percent of the
patients
showed evidence of HPA axis
suppression. If we
look at just getting a serum cortisol
value that
exceeded 18 mcg/dL, 91 percent of the
patients
failed to do that.
[Slide.]
Although this study was
supposed to enroll
infants, it was felt that with such a
high degree
of HPA axis suppression, the proportion
of patients
59
6 to 12 years of age, that no patients
were
enrolled in the lower age group. This brought up
the issue that possibly it is not only
the chemical
moiety that might produce HPA axis
suppression, but
since it is coming from the skin, it may
involve
the vehicle in which the chemical moiety
is in.
In this instance, the lotion,
it may
somehow with the chemical moiety quicker
from the
skin into the systemic circulation, and
thereby
cause more HPA axis suppression. So, in other
words, vehicle may play a role also in
determining
that systemic effect.
[Slide.]
When looking at the statistical
analysis
in the development of HPA axis
suppression, it was
a numerical analysis. The subjects exhibiting HPA
axis suppression used the larger mean
amount of
drug.
They had a slightly higher percent of BSA
involvement.
They had lower mean weights at
visit 1,
lower mean weights at visit 4, but the
difference
with respect to age and days of
treatment, at least
60
from a statistical point of view, were
minuscule.
[Slide.]
Looking at recovery of HPA axis
function
with Diprosone Lotion, it's good to
report that 67
percent of the patients who were retested
recovered
their HPA axis function at 2 weeks.
[Slide.]
So, the labeling change for
Diprosone
Lotion was that an age restriction was
added to 13
years and older, and appropriate sections
of the
label again were updated.
[Slide.]
Just to look at the four
betamethasone
products together, again, you see that
the three
here, Cream, Ointment, and Cream, all
seemed to
suppress somewhat where in the same
range. When
you got down to the lotion, you had a
much, much
higher percentage of patients who
experienced HPA
suppression. Again, it may have to do with the
vehicle, if there is an absorption
enhancer in it
or other factors.
[Slide.]
Lotrisone Cream is the other
betamethasone
product that I am going to speak
about. It is a
combination product of betamethasone
dipropionate
61
with Lotrimin Cream. It is indicated for the
treatment of tinea pedis and tinea
cruris, so we
did a study in both of those.
Both studies were in the
adolescent
population, 12 to 16 years. Medication was applied
twice daily. The study duration for tinea pedis
was 4 weeks and for tinea cruris was 2
weeks.
[Slide.]
Here, we also have some
surprising
results.
Seventeen out of 43 or 39.5 percent of
patients demonstrated adrenal suppression
in the
tinea pedis study, and we might not have
actually
expected that given that the stratum
corneum of the
feet is somewhat thick, but it might also
be
teenagers wear sox and tennis shoes all
day long,
and
that might also cause more occlusion and
absorption of the drug product.
In tinea cruris, there were
47.1 percent
who demonstrated adrenal suppression, and
this is
62
also is an area where you may have some
natural
occlusion, increasing absorption.
[Slide.]
So, this led to some labeling
changes for
Lotrisone Cream and Lotion. The Indication Section
was
expanded, it added an age restriction to
patients 17 years and older. It also recommended
that effective treatment may be obtained
without
the use of a corticosteroid for
non-inflammatory
tinea infections. Then, other appropriate sections
of the label were updated with clinical
information.
DR. FINCHAM: Dr. Cook, may I interrupt
for a second and just ask a question
about the data
sets that you are reporting on?
DR. COOK:
Sure.
DR. FINCHAM: Is this Phase IV data that
is provided by sponsors, that then the
Agency has
acted on to change the label?
DR. COOK: No.
Most of this was done in
response to what we call "pediatric
written
requests," which is part of the FDA
Modernization
63
Act.
So, we could either ask them to do the
studies--I mean all of this was
post-approval, but
I don't know if we actually call it Phase
IV--we
could either ask them to do the studies
or they
could propose the study to us, but we
would have to
then issue them the pediatric written
request which
would allow them to do the studies. That is sort
of a quick summary.
[Slide.]
Now, this steroid, Clobex
Lotion, was
actually approved in 2003, and this
actually was
part of their NDA, and was not a Phase
IV. At that
time, we were able to ask for and get
trials in
pediatric patients if we needed it.
These trials, atopic dermatitis
and for
psoriasis, were done in both pediatric
and adult
patients.
[Slide.]
There were 3 studies involving
Clobex
Lotion, 2 adult studies, 1 in psoriasis
and one in
atopic dermatitis, and 1 pediatric study,
ages 12
to 17 years in atopic dermatitis.
In all of the studies, there
was a
comparator drug, Temovate E Cream, which
is also
clobetasol propionate, so the same
chemical moiety
64
in a different vehicle. As I say here, it is a
Class I steroid.
[Slide.]
The construct of the HPA axis
evaluation
for this study went back to the 3
criteria, and
that is because the actual NDA and
construct of the
study was done prior to our criterion of
just 1,
because it was approved in 2003, so the
studies
were done prior to that.
[Slide.]
In the adolescent study, there
were 24
evaluable patients, 14 were treated with
Clobex
Lotion and 10 were treated with Temovate
E Cream.
They all had moderate to severe
atopic
dermatitis. They had to have a body
surface area
involvement of at least 20 percent. The medication
was applied twice a day for 2 weeks, and
there was
a 50-gram/week limit, and a lot of this
at the time
was driven by the fact that Temovate E
Cream, that
65
is how it's labeled.
[Slide.]
It was found that 9 of the 14 or 64
percent of subjects treated with Clobex
Lotion were
suppressed versus 20 percent of subjects
treated
with Temovate E Cream, again suggesting
that the
vehicle may have something to do with the
amount of
drug that gets into the systemic
circulation.
[Slide.]
In the statistical analysis the
mean
percent body surface area treated was
higher for
patients that had adrenal suppression,
32.8 percent
versus 27.7 for the Clobex Lotion and 35
percent
versus 25.3 percent for the Temovate E
Cream.
[Slide.]
When retested, 1 of the 4
patients treated
with Clobex Lotion remained suppressed
after 2
weeks, and 1 of the patients, which was
the only 1,
that was suppressed with Temovate E Cream
recovered.
[Slide.]
In the adult study, there were
18
66
evaluable patients, 9 were treated with
Clobex
Lotion and 9 with Temovate E. They all again had
moderate to severe atopic
dermatitis. The mean
body surface area treated was
approximately the
same for both drug products. They applied it twice
a day for 2 weeks, again with a
50-gram/week limit.
[Slide.]
Here, 56 percent of the
patients treated
with Clobex Lotion suppressed and 44
percent with
the
Temovate E Cream suppressed.
[Slide.]
When looking at recovery for
these 2
products, 1 of the 3 patients retested
failed to
recover function 7 days post-treatment
with the
Clobex Lotion, and 2 out of 2 patients on
Temovate
E Cream recovered their function 7 days
afterwards.
[Slide.]
Finally, in the adult study,
moderate to
severe plaque psoriasis , there were 20
evaluable
patients, 10 in each arm. Again, the mean body
surface area treated for both was
approximately the
same.
The medication was applied twice a day here
67
for 4 weeks, and there was again a 50-gram/week
limit.
[Slide.]
Eighty percent of the patients
treated
with Clobex Lotion suppressed and 30
percent with
Temovate E Cream suppressed. One of the 2 subjects
retested with Clobex Lotion remained
suppressed
after 8 days, and none of the 3 subjects
on
Temovate E Cream unfortunately were
retested.
[Slide.]
So, the indication for Clobex
Lotion, when
it was approved based on these results,
was that it
would be restricted to patients 18 years
of age or
older.
It could be used for two consecutive weeks
not to exceed 50 grams/week.
For moderate or severe
psoriasis, for
localized lesions less than 10 percent
body surface
area involvement, that an additional 2
weeks of
treatment, the lotion could be used. Appropriate
other sections of the label were updated.
[Slide.]
Now, I am going to shift gears
from our
68
trial data and look at a postmarketing
summary of
HPA axis suppression across all topical
corticosteroids since the induction of
the AERS
database, which is one of our sources
since 1969,
and also from medical literature case
reports.
[Slide.]
I will just give you a
background on the
Adverse Event Reporting System. It is a
spontaneous, voluntary surveillance
system. It is
voluntary reporting by health care
professionals
and consumers, but it requires mandatory
reporting
by manufacturers.
There are approximately 3
million reports
in the database. Again, the database originated in
1969.
It contains human drug and therapeutic
biologic reports. The exception is it doesn't have
vaccines.
The quality of the reports are
variable
and they are often incomplete, so you
have to keep
that in mind. It is also subject to
under-reporting, the true numerator is
not known,
and duplicate reporting does occur.
[Slide.]
There have been 94 cases
reported spanning
3
decades, 65 adult cases and 29 pediatric cases.
69
The gamut of manifestations had been
adrenal
insufficiency, Cushing's syndrome, and
growth
retardation.
[Slide.]
In the 29 pediatric patients,
and some of
these overlap within same patients, 11
were with
adrenal insufficiency, 17 with Cushing's
syndrome,
and there are 13 with growth retardation.
The ages ranged from 6 weeks to 15 years
with the mean being 5 years. The duration of use
was 22 days to 7.5 years with a mean of
20.8
months.
Fifty-five percent of these patients
received medication for 3 months or
longer. There
were varied indications, but 34 percent
in the
pediatric population were using topical
corticosteroids for diaper rash.
Betamethasone containing,
clobetasol, and
mometasone products were implicated most
often with
34 percent using high-potency topical
70
corticosteroids.
In these 29 pediatric patients
who had
evidence of some type of HPA axis
compromise, it
resulted in 14 hospitalizations and 2
deaths. The
latter were from Cushing's syndrome or
complications thereof.
[Slide.]
In the adult cases, there were
65, 46 with
adrenal insufficiency and suppression, 32
with
Cushing's syndrome.
The age range was from 19 years
to 74
years, with the mean age being 47.4
years. The
duration of use 7 days to 12.0 years, and
the mean
use was 35.6 months.
Forty-six percent of the patients received
the medication for 3 months or
longer. Again,
there were varied indications, but 51
percent used
topical steroids for psoriasis. Again,
betamethasone containing and clobetasol
products
were implicated most often, with 61
percent using
high potency topical corticosteroids.
These cases resulted in 34
71
hospitalizations and 2 deaths, and the
deaths were
attributed in part of the adrenal event.
[Slide.]
So, the postmarketing reports,
just in
summary, the common factors were that
most of the
AEs occurred in the following settings:
Prolonged use of the topical
corticosteroid, use of a superpotent
topical
corticosteroid, use of multiple topical
corticosteroid products or concomitant
use with
other corticosteroid formulations like
inhaled or
systemic, and also use of excessive
amount or
possible inappropriate use of the topical
corticosteroid product.
[Slide.]
In summary of the data for the
HPA axis
suppression, HPA axis suppression does
occur with
the use of topical corticosteroids.
The adrenal suppression is not
limited to
the superpotent class of topical
corticosteroids.
High BSA involvement and amount
of drug
used appear to be risk factors for HPA
axis
72
suppression.
[Slide.]
The type of vehicle may
contribute to the
extent of absorption of the active
chemical moiety.
The suppression appears in most
cases to
be reversible upon cessation of drug
usage.
Long-term use of topical
corticosteroids,
particularly high potency ones, can lead
to serious
morbidity and even death.
[Slide.]
Now, we are going to move on to
cutaneous
safety. We will first speak about the
known
cutaneous adverse events, and then we
will just
address here briefly the question of
cutaneous
malignancy as it might relate to topical
corticosteroids, if at all.
[Slide.]
Now, the adverse events
associated with
topical corticosteroid use include
atrophy of the
skin, telangiectasia, striae, erythema of
the face,
steroid rosacea, hypopigmentation,
infection, and
retarded wound healing.
[Slide.]
Because pictures speak a
thousand words, I
am going to give you a pictorial
presentation of
73
these adverse events.
[Slide.]
This is a photo of cutaneous
atrophy. It
is not the best photo, but here you can
appreciate
a little bit of thinning of the skin and
some
shininess to the cutaneous surface.
[Slide.]
Here, we have
telangiectasia. You can see
the very fine blood vessels coursing here
through
this person's chin.
[Slide.]
This is a picture of striae,
probably
long-standing.
[Slide.]
Another picture of striae,
maybe a little
more of acute onset in nature.
[Slide.]
This is a picture of facial
erythema.
[Slide.]
Another of facial erythema.
[Slide.]
This is a picture of steroid
rosacea where
someone was applying topical
corticosteroids and
had a flare of the disease. Certainly, here, the
potency of the topical corticosteroid
would have to
74
be weaned down, and then the rosacea,
which is the
underlying disease, had to be treated
appropriately.
[Slide.]
This is a picture of
hypopigmentation from
topical corticosteroid use.
[Slide.]
Other adverse effects that can
happen.
Topical corticosteroids placed on certain
infections, for example, tinea
infections, may
exacerbate them. Topical corticosteroids placed on
open or surgical wounds will retard
healing. Use
of topical corticosteroids in the
periorbital area
may cause an increase in intraocular
pressure.
[Slide.]
Now, as far as cutaneous
malignancy, we
75
will look at the postmarketing reports
out of the
same system that I was speaking about
prior, the
AERS database, and there are 2 reports as
of
February 5, 2005, that spans all the way
back to
1969.
One was a 7-month-old male with
a history
of mastocytoma, and he reported or
someone reported
cancer several months after
discontinuation of
clobetasol. The patient actually used fluticasone
for a short while, and then used
clobetasol
propionate for 1 week, stopped for 1
week, and then
started to reapply for another week, but
developed
cutaneous atrophy, and the medication was
stopped,
and then several months later, the report
came that
he developed skin cancer.
The second case is a female of
unknown age
who used betamethasone cream for
psoriasis and then
reported "what started as psoriasis
became cancer".
So, from this we can say that
the AERS
data do not suggest a compelling safety
signal for
malignancy formation with the use of
topical
corticosteroids.
[Slide.]
So, as far as cutaneous adverse
events,
corticosteroid-induced adverse events can
be early
76
or late event. It depends on the potency of the
drug and the duration of use. It depends on the
site of application. Occlusion at the
site may
increase the risk.
Corticosteroid-induced adverse events may
resolve slowly or they may not resolve at
all.
[Slide.]
So, in conclusion, HPA axis
suppression
can occur with short-term use of topical
corticosteroids. HPA axis suppression can occur
with even mid-potency topical
steroids. It can
occur as early as two weeks of continuous
therapy.
[Slide.]
The suppression that occurs is
usually
reversible. The interrelationship between
body
surface area, amount of drug used, and
potency of
the medication is complex as it relates
to the
development of HPA axis suppression.
Long-term use and/or misuse of
topical
77
corticosteroids, particularly those of
high
potency, can lead to serious medical
complications
and death.
[Slide.]
The cutaneous adverse events
can be
related to both duration of use and
potency of
topical corticosteroid use. It can occur with
short-term or long-term use.
Resolution of these cutaneous
adverse
events is possible with some, but not all
of them.
There also is no firm evidence
to date to
link cutaneous malignancy with the use of
topical
corticosteroids.
Thank you for your attention
for this
presentation.
Next, we will have Dr Stephen Wilson. He
is in the Division of Biometrics II. He will speak
on lessons learned from growth studies
with orally
inhaled and intranasal corticosteroids.
Lessons Learned from Growth Studies
with Orally
Inhaled and Intranasal
Corticosteroids
DR. WILSON: Gray Gaithersburg morning to
78
you.
It is my pleasure to be here
this morning
substituting for Peter Starke. I think that I was
elected for this job because I am the
only one that
was around when they did the class
labeling
advisory committee in 1998, but we have
had some
lessons that we have learned from that
advisory
committee in dealing with growth studies
for orally
inhaled and intranasal corticosteroids,
and I would
like to share some of those with you in
the short
amount of time that we have.
[Slide.]
Specifically, we have been
charged with
providing you with somewhat of a
background of why
we do these studies within our area for
intranasal
and orally-inhaled corticosteroids, and
then talk
about what these growth studies are.
In particular, we are going to
focus on
what we call longitudinal growth studies,
which are
fairly long-term growth studies. Then, we will
talk about some of the design issues with
these
studies and the regulatory history that sort
of
79
brought us to this moment in terms of the
science.
I will provide with the results
from some
of the studies that we have seen within
the
Division.
When I say "we," I mean the Division of
Pulmonary and Allergy Drug Products.
[Slide.]
So, why do we perform growth
studies? I
think that looking at it from our
perspective,
growth is an indicator of systemic
exposure and of
the potential to cause systemic toxicity.
Growth suppression is a
well-known side
effect of systemic corticosteroid
use. It has a
class effect. We view it as a class effect, that
all CS given in sufficiently high doses
will
produce growth effects. It is thought to be a
direct effect on the bone, and may also
act through
secondary mediators and hormones.
We believe that growth is the most
sensitive indicator of systemic effect
within our
review environment because we have seen
growth
effects in the absence of effects from
HPA axis
studies by cosyntropin stimulation.
[Slide.]
There are basically two types
of studies
that are presented to us by
sponsors. One goes by
80
the name of knemometry, and the other is
the
longitudinal or long-term growth studies.
Sponsors have done knemometry
studies.
These are generally short-term studies,
so it is
attractive in the sense that they can be
done
rather quickly, and there are a number of
methodological issues. They can essentially be
done in only a few centers.
The consistency of results has
been
puzzling and a little bit problematic to
us as a
regulatory agency, because we don't
always see the
same kinds of results coming out, and we
view these
as primarily a research tool.
So, focusing on longitudinal
growth
studies, these are growth studies
designed to
measure growth velocity over a 1-year treatment
period, so this is a long treatment
period.
The patient population has to
be carefully
selected because this is a patient
population that
81
needs to have the treatment, but we also
need--and
you will see in a minute--we also need to
be able
to run a concurrent control, so some on
corticosteroids and others using other
kinds of
medications.
[Slide.]
What is the population that we look at in
these growth studies? These two CDC charts are
provided primarily to show you where we
consider
growth to be fairly linear.
For one thing, it is very
difficult to get
growth measurements in the youngest
children, zero
to 2 years old. By 2, you are able to get
the
stadiometry measurements, and the growth
is fairly
linear, until you get up to puberty,
about 9 to 11
years old depending on sex.
So, this is the focus of these
growth
studies that are provided to us by the
sponsors.
[Slide.]
So, what are these growth
studies, what do
they look like? Basically, it is fairly
straightforward. It's serial stadiometry. There
82
is a baseline period of about 3 months in
which we
measure growth, baseline growth.
Then, there is an on-treatment
period and
then another follow-up of 3 months. There was a
guidance that was developed following the
advisory
committee that I mentioned in 2001, and
it is still
available on the website, so you can see
some of
the details of what we are suggesting.
[Slide.]
So, longitudinal growth
studies. As I
said, they are technically difficult to
perform.
They require relatively large numbers of
children.
In fact, in the guidance that we provide,
we say
that ideally, they would have almost 125
children
in each of the treatment groups. So, you
can see
they are quite a bit larger than the
studies we
have been looking at.
They require a long baseline and treatment
period, and the measurement and
compliance issues
are very difficult, in other words, you
have got to
keep children on these studies for a long
time,
working with parents and providing
treatment.
There are also statistical
issues in terms
of when the data has been provided to
us. This is
what I think probably sponsors have the
most
83
problem with is we are not looking at these as
superiority trials or even equivalence or
non-inferiority trials. It is just too difficult
to make a judgment as to what the delta
or the
difference that you are looking at would
be.
So, we essentially are
presuming that
there is a growth effect from these
drugs, and we
are designing them to best characterize
that
effect, so this is a little bit
different, and that
means that you have to have the proper
size, you
have to conduct the studies
appropriately, and that
is what we are going to be reviewing if
we are
going to describe what your study has
done in the
label.
So, the size of the growth
effect that is
clinically relevant is unknown or not
fully known.
That is what our presumption is.
[Slide.]
So, how did we get here? Actually, there
84
is some OTC history here. In 1996-97, there were
two longitudinal growth studies done to
better
characterize the systemic risks prior to
consideration of taking beclomethasone
dipropionate
nasal spray over-the-counter.
So, in other words, the company
was
developing, wanted to go OTC, had these
growth
studies going, and when the results of
these growth
studies became available, it was
recognized that
there was a growth effect that hadn't
been shown in
the other kinds of tests.
Then, at that same time, the
number of
other companies who were doing growth
studies also
came in and demonstrated this same kind
of effect.
So, 1998, we held a Joint
Pulmonary-Allergy and Metabolic-Endocrine
Advisory
Committee, which ended up recommending a
class
labeling for all orally inhaled and
intranasal
corticosteroids, and we ended up also
implementing
that recommendation.
[Slide.]
So, what did that label end up
looking
85
like?
Well, in the General Use and Pediatric Use
Subsections, we essentially said orally
inhaled/intranasal corticosteroids may
cause a
reduction in growth velocity in pediatric
patients.
Also, in the Pediatric Use
Section, we
noted that growth effect may occur in the
absence
of
laboratory evidence of
hypothalamic-pituitary-adrenal axis
suppression,
potential for treatment
"catch-up" growth has not
been addressed, and basically, our advice
to the
physician was to titrate to the lowest
effective
dose for each patient and monitor growth
routinely.
If reported, cases of growth
suppression
should be noted in the Advise Reactions
Section.
So, basically, in terms of this
being a
class labeling, we would only note
certain kinds of
growth suppression if it was being
reported to our
systems.
[Slide.]
So, how did this original study
look, the
one that we were looking at for the
advisory
committee?
Intranasal beclomethasone
basically was a
randomized, double-blind,
placebo-controlled,
parallel group, prospective, one-year
study.
86
The age groups of the children,
they were
children with allergic rhinitis being
treated by
intranasal corticosteroids, ages from 6
to 9.5
years.
Basically, the same size study groups, and
you just had a placebo against the intranasal
corticosteroid, about 50 in each group.
[Slide.]
Now, the results showed that
the growth
rate centimeters/year on the BDP
treatment group
was 5.1 versus a placebo of 5.8, or a
difference or
a
delta of minus 0.7. So, that was the
extent of
the depression that we saw for that one
year.
Now, this was a statistically
significant
difference based on the prespecified
analysis, and
it was an unexpected result, but
basically, we were
comparing mean annual growth rates.
In the same study, however,
these same
children were tested, and there was no
significant
differences observed between treatment
groups by
87
mean basal cortisol or ACTH-stimulated
plasma
cortisol levels.
[Slide.]
I wanted to make sure to
include this
slide.
This is again these same patients, and
looking at those charts that you saw
earlier, the
growth charts, these are the results of
the
patients based on where they fell on
those charts
after a year.
I can remember the
endocrinologist, Sol
Malozowski, was extremely interested in
thinking
about what it meant. Even though we were looking
at mean data, in other words, there was a
sense of
a minus 0.7 that I showed you, we were
also looking
obviously, and very concerned about, how
the
children as individuals or groups fell
within these
two groups.
So, the mean data as expressed
in
percentage within growth rate percentiles
is
displayed here, so you can see something
like 22
versus 4 in placebo or less than 3
percent in terms
of the average growth., and that was true
88
throughout, so this is the mean data
expressed
another way.
[Slide.]
We also looked at some other
intranasal
drugs, and these are the data that came
in later.
You notice, as oftentimes happens, this
was
actually the largest difference that we
saw was on
the first one, and the intranasal drugs
that came
in afterwards, budesonide and
fluticasone, also
showed some growth depression. Mometasone,
however, as you can note, did not show.
[Slide.]
The orally inhaled drugs tended
to show
more growth suppression, BDP, for
example, minus 2
versus the 0.7 that you saw before. This slide
also indicates that this is a study that
was done,
and you had some of those younger
children, so you
tended to see a lot more variability in
the
estimate, so the recommendations in the
guidance
became, you know, you had to have these
older
children that you could measure, because
a lot of
these included recumbent measurements,
and those
89
are difficult measurements to make.
Another thing here is that
there is some
kind of apparent dose effect from a
company that
did try to test two doses. So, we had all of this
data available to us in trying to make
these
determinations.
[Slide.]
So, the issues. These are indeed
difficult studies to perform if you are
thinking
about doing one of these studies. They are also
difficult studies to review. Now, if you
are in a
regulatory setting, so basically, you are
taking
what the company has given you as
evidence, and you
are making some assessment of that.
If a company has, for example,
if there
are a lot of subjects that have dropped
out, you
have to worry a lot about missing data,
and you
have to worry about if they haven't
measured them
carefully over time, in other words,
there are some
sort of glitches in the measurement, they
then make
decisions as to how they are going to
analyze that
data, so then as a reviewer, you have to
respond to
90
that, so these are difficult studies.
Growth studies are not designed
to
evaluate obviously the reversibility of
the HPA
axis effects or changes greater than a
year. So,
although we do measure for another 3
months after
the study, we do not try to see whether
or not this
would be long term.
A lot of these patients, a lot
of these
children are going to be on the drug for
a lot
longer than 1 year.
We have not identified a
clinically
relevant effect size, and that means that
we all
sit around a number of time, on a number
of
occasions, saying how could we pin down
what the
effect size is, so that maybe we could
look at
non-inferiority trial, but everybody said
that
basically, it is not acceptable or there
is no
clinically relevant effect size on that
mean value.
[Slide.]
So, conclusions. We use growth studies as
a stand-alone measure. We believe that they are a
sensitive indicator of systemic effects,
and we
91
think of this because sometimes the HPA
axis and
the growth study results are discordant,
they don't
agree with each other.
We take them as a surrogate for
systemic
exposure and potential to cause systemic
toxicity.
So, we are looking at children, these are
people
that are going to need these drugs, but
we also
take them with the notion that this is a
sentinel,
this is something that is going to tell
us is this
drug going to have effects more
generally.
We believe that results are
applicable to
all age groups. Obviously, you can't study growth
in 20- to 25-year-olds. We also feel that the
class effect labeling, when you look at
the class
effect labeling, we state, as I stated
earlier, all
orally inhaled and intranasal
corticosteroids have
this effect.
As these studies come in to us
from
companies, we review them and we
determine whether
or not this is information that is going
to help
the
physician. This is information we need
to put
into the label.
Sometimes we put what the
company has
offered, and other times we feel that we
are not as
sure that the results of the study are as
reliable
92
as we would like them to be.
[Slide.]
Again, there is reference
Division of
Pulmonary and Allergy Drug Products.
I can't believe that I actually
finished
early, but I look forward to any
questions you
might have.
Thank you.
The next presenter is Dr.
Markham Luke.
HPA Axis Suppression Studies:
Conduct,
Utility, and Pediatric Considerations
DR. LUKE: Good morning, Dr. Wood, members
of the Committee, ladies and gentlemen in
the
audience.
[Slide.]
Today, I am going to speak on
topical
corticosteroids and testing for adrenal
suppression
in the context of potential Rx to OTC
switch.
[Slide.]
This is a brief outline of my
talk.
First, I am going to speak a little bit
about the
various systemic effects that have been
seen with
topical corticosteroids and some which
have not
been seen.
We are also going to discuss
specifically
93
the hypothalamic pituitary adrenal axis
testing,
what tests are available to look at HPA,
and more
specifically, we are going to focus in on
cosyntropin stimulation testing, look at
what our
current testing recommendations, how we are
trying
to standardize the testing, and we are
going to
discuss how precise an estimate would we
need for
adrenal suppression potential for OTC.
[Slide.]
Now, as Dr. Cook and Dr. Wilson
have
stated, prescription corticosteroids have
systemic
effects which we evaluate during drug
development.
[Slide.]
Now, I would like to separate
these out
into those areas where specific studies
have not
been required for dermatologic topical
94
corticosteroids. These include sodium retention on
mineralocorticoid effect, glucose
tolerance, growth
suppression, osteoporosis, and what we do
look at,
which is HPA axis suppression.
With regard to sodium
retention, they are
receptor-specific effects and they may be
less
concerned with glucocorticoids. I am going to go a
little bit into that.
Regarding glucose tolerance and
growth
suppression, data available for glucose
tolerance
from clinical studies, the growth
suppression
studies, as Dr. Wilson has discussed, is
technically challenging and is difficult
to perform
and to review.
Further, for osteoporosis, the
same could
be said for that. It is difficult to have these
topical corticosteroids used for the long
term.
The patients wax and wane with their
disease, so
the application of the topical
corticosteroid can
increase and decrease, plus the strength
of the
corticosteroid may vary during the
conduct of a
year-long study, so there is the
potential for
95
change in dose and potency, which again
leads to
inconsistent and very challenging
evaluation of any
data that would be obtained from such a
study.
Regarding HPA axis suppression,
we will
get into that a little bit more.
[Slide.]
This is a table of the relative
potencies
for various steroids with a cortisol at
1.0 and
there are two references in the package
that was
given to the Committee regarding
this. This table
is excerpted from those references.
As you can see, the two
examples of
topical corticosteroids given in this
table are
triamcinolone and betamethasone. Both of those
have a higher affinity or a higher
relative potency
regarding glucocorticoid effect but a
lower
mineralocorticoid effect. This can be contrasted
to aldosterone which has a much higher
mineralocorticoid effect as compared to
glucocorticoid effect.
(Slide.)
This is a schematic diagram of
the HPA
96
axis.
We have been talking a lot about the HPA
axis. Regarding specifically what
it is, we have
the hypothalamus. This is
a schematic
representation, again; the pituitary,
anterior
pituitary, and what their effects are on
adrenals.
This is a neural, hormonal axis
and is
important for the human response to
stress. Humans
respond to stress by producing ACTH which
then
causes cortisol rises. F stands for cortisol here
in this diagram. If there is a failure to mount
such a response, it can lead to a
hypotension and
cardiovascular collapse.
Now, this failure to mount may
not be
easily clinically recognizable so
attributing cause
and effect may be difficult with regards
to adrenal
suppression in the clinical setting.
The ACTH here, in general,
causes a rise
in the cortisol. However, with constant exposure
to exogenous corticosteroids, it has been
thought
that there is a down-regulation of
receptors here
and here which may lead to
decrease-ability of the
adrenals to then respond and produce
cortisol.
(Slide.)
With that, we get into HPA axis
testing.
(Slide.)
97
There are two classes of tests,
basic
classes; the basal testing, which is done
with
basal plasma levels and 24-hour urine
cortisol
levels.
These are thought to be less useful in
measuring an adrenal response to stress
than
dynamic testing where you try to
stimulate the
adrenals to cause a response and you
measure the
magnitude of that response.
(Slide.)
There are various dynamic tests
of HPA
axis function. Earlier, it was mentioned, the
insulin tolerance test which is an older
test.
When you administer insulin, you cause a
hypoglycemic event. It then results in a potent
stress stimulus for the adrenal glands.
Now, these subjects, when you
administer
insulin, you need very close subject
monitoring.
It is thought that this test, as it is
currently
done, produces undue risk to the subject
and,
98
therefore, the agency does not recommend
this as a
test for HPA axis function.
The cosyntropin, or ACTH amino
acids 1 to
24, test is available in higher or lower
concentrations. The higher dose is the labeled
dose for cosyntropin. Lower dose studies vary and
there is no standardization regarding how
much of a
rise in cortisol you need with lower dose
and the
timing of the rise is not
standardized. So the
lower test is still experimental at this
time and
if one is to use it, there should be
discussion
with the Agency regarding how it is used.
For higher dose testing, we
will discuss
that in just a moment. There is also a
corticotropin-releasing hormone test, the
CRH test.
This also is experimental and not widely
available.
(Slide.)
The higher dose cosyntropin
test is the
most commonly used test to evaluate for
adrenal
suppression. The procedure is to administer a
superphysiologic dose. It is currently labeled for
IV or IM use of 125 micrograms if the
patient is
99
less than 3 years of age or 250
micrograms if the
patient is 3 years or older. The serum or plasma
cortisol concentrations are measured
before and 30
minutes after the cosyntropin
administration.
(Slide.)
The advantages of this test are
that it is
simple, it is fast and relatively
inexpensive. It
is an outpatient test and it takes
approximately 30
minutes to do. There are some limitations. It is
not the most sensitive test. It can be equated to
being a physiologic hammer. I mean you are giving
a very high dose of what is equivalent to
ACTH to
cause the adrenals to respond. So the
sensitivity
may have some concern.
(Slide.)
The criteria for a normal
response in
Cortrosyn, according to label and the
30-minute
test is as follows: The control of basal cortisol
level should be greater than 5
mcg/dL. At 30
minutes, after administering the
Cortrosyn, there
should be at least a 7 mcg/dL rise above
basal--the
incremental cortisol rise, that is--and
the
100
30-minute level should exceed 18 mcg/dL.
However, we note that basal
cortisol
levels vary throughout the day and the
higher the
basal level, the lower the incremental
cortisol
rise.
So, for regulatory purposes and for drug
development, it is thought that normal
response of
peak cortisol level of greater than 18
mcg/dL 30
minutes after giving Cortrosyn should be
sufficient
as the test for adrenal suppression.
(Slide.)
With that, we segue to what are current
testing recommendations for adrenal
suppression.
[Slide.]
There was an Advisory Committee
on October
29th of 2003, and there was some
discussion about
the HPA axis test, Joint Committee
discussion. It
was discussed that higher dose
cosyntropin test is
a sufficient determinant of HPA axis
function with
regard to prescription topical
corticosteroids.
A greater than 18 mcg/dL or 500
nM/L
post-stimulation cortisol level at 30
minutes is
equivalent to that subject being not
suppressed.
101
It was also discussed at that Advisory
Committee
where data was presented on reversibility, and
you
saw the reversibility data, we have very
little of
that.
We need follow-up for reversibility when we
do these studies.
[Slide.]
It was a pediatric meeting, so
there was
discussion about the pediatric
cohorts. The
pediatric population was divided into 4
cohorts
here.
Sequential testing was usually done for
these studies with the older patients
first, but at
this Advisory Committee it was discussed
that
potentially concurrent testing can be
done if the
safety of the patients can be
assured. The
rationale for that is to obtain more data
regarding
the adrenal suppression in each of these
cohorts.
[Slide.]
Additional recommendations from
the Agency
are as follows: the 60-minute cortisol is not
recommended. The standardization for a 60-minute
level is poor, and the results can vary
somewhat
from one, 60-minute test to another
60-minute test.
Testing less than 4 weeks apart
is not
recommended. Administering the ACTH or Cortrosyn
start to leave an impression on the
adrenals and
102
there may be effects on later response
especially
when the tests are done closer than 4
weeks apart.
There is a need to monitor the
local
cutaneous adverse events during the
conduct of this
study.
Finally, it is important to
note when
interpreting these studies that the
percent of
patient suppressed, not the mean cortisol
levels is
important. Mean levels may mask individual
patients, so if someone were to present data
on
mean levels, ask them what the percent of
patients
suppressed was.
[Slide.]
Finally, we note Dr. Cook's
presentation,
the body surface area involved can vary
from atopic
dermatitis, at least 30 percent body
surface area
is needed, for psoriasis, at least 25
percent body
surface area involvement for these
patients, and
these are maximally involved diseased
patients.
It is also important to note that patients
who enter the study should not be adrenal
suppressed, so there should be testing
for adrenal
suppression prior to exposing them to
corticosteroid to make sure they are not
suppressed
at baseline. Often these patients will have come
103
into a study having been on other
corticosteroids
for a protracted length of time because
of their
significant disease.
[Slide.]
The last part of this talk, we
are going
to discuss a little bit about what
precision do we
need for OTC use of corticosteroids.
[Slide.]
For topical corticosteroids
drugs to be
used in an OTC setting, how acceptable is
HPA axis
suppression, and how many subjects need
to be
evaluated to rule out
corticosteroid-induced
adrenal suppression for an OTC product if
this is
one of the tests that is going to be
used?
[Slide.]
Here is an exercise I would
like to pose
104
to you.
If we had 30 subjects and we treated them
all
with topical corticosteroids for 4 weeks, and
we noted those 30 subjects, zero had
cosyntropin
stimulation test indicative of adrenal
suppression,
that is, the rate was zero out of 30.
The question arises with what
risk, if
any, of adrenal suppression induced by
topical
corticosteroids might these results be
compatible,
is it zero risk? I would like to propose that it
is not.
[Slide.]
Zero out of 30 subjects rules
out, with 95
percent confidence, a greater than 10
percent
chance for adrenal suppression to occur
in the
global population. This is a statistical concept,
and there is a paper in the package that
was handed
out
discussing the rule of 3's, and this is one way
to look at this.
The sample size determines the
extent we
can rule out adrenal suppression in the
global
population with zero subjects suppressed.
[Slide.]
With that, we can go to this
table on
sample size effect on the upper
confidence interval
to just go over and give an example. Say we have
105
10
subjects and we had zero of those 10 subjects
suppressed.
Well, that would rule out with
a 95
percent confidence interval no greater
than 26
percent adrenal suppression. Whereas, if we double
the number and go to 20 subjects, we can
increase
that upper confidence interval to 14
percent.
To get to really small
percentage numbers
for upper adverse event occurrences, we
need larger
sample sizes. So, the greater the number of
patients you have, the more assuredly you
can be of
that zero that you see for that study, if
the study
does give you zero.
[Slide.]
So, the question asked for the
Committee:
Cosyntropin stimulation studies are used
to inform
labeling for prescription products with
regard to
potential for adrenal suppression.
If the cosyntropin stimulation
studies are
106
to be used for OTC products, how many
subjects are
needed for those studies, that is, what
is the
level of tolerance for adrenal
suppression for an
OTC drug product?
That is it for my portion of
the talk.
Thank you.
DR. WOOD: Okay, great.
It is exactly 10
o'clock, so let's take a break for 10
minutes and
be back ready to start again at ten past
10:00, and
we will go straight to the questions for
the
speakers, and then pass on to the
questions for the
Committee at that point.
[Break.]
Questions from the
Committee and
Committee Discussion
DR. WOOD: So we have heard all the
presentations. Let's open the session for the
Committee to question the speakers. Terry?
DR. BLASCHKE: I have a technical
question, I think for Dr. Luke. In your
presentation, you indicated that the
cosyntropic
administration could be IV or IM. I am just
107
wondering how many of the subjects, for
example, in
the studies that we were presented
actually got the
cosyntropin IM and do we know whether there
is more
variability or sensitivity, differences
in
sensitivity, when the cosyntropin is
administrated
IM versus IV.
DR. LUKE: As far as I know, there are no
comparisons in the literature between IM
and IV
use.
For pediatric studies, it is often more
convenient to do an IV study rather than
an IM
study simply because of the pain
threshold of those
patients.
You can insert a cannula and inject the
cosyntropin and also withdraw blood from
the same
cannula afterwards and so there is only
one stick.
When you go to do the IM, it
may be due to
access difficulties that one would resort
to an IM.
Regarding whether one should do IM or IV,
I think
it is important to be consistent
throughout each
study as to what route you choose to
administer the
cosyntropin. But, as far as I know, there are no
studies to compare the two routes.
DR. BLASCHKE: I suspect it is not done
108
consistently because I suspect that it
really does
relate to ease of access of a vein in a
small child
and so forth. We know that there are a lot of
compounds that, when they are
administered IM,
depending on where, et cetera, that the
absorption
and the absorption rate is quite
different for IM,
obviously, than IV.
It sounds like, as you say, there is no
comparative data so maybe no answer to
the
question.
DR. WOOD: Dr. Snodgrass.
DR. SNODGRASS: Are there any standards
required for the timing of the test, 8:00
a.m., for
example, and knowledge about their sleep
patterns
for the circadian rhythm aspects?
DR. LUKE: Because of the circadian
rhythm, it is thought that a standard
time might be
helpful but keep it close within. It is often
difficult to do a study where you have
all the
patients done at the same time. So there is some
variability allowed for it.
Just to go back, also, to the
IM versus IV
109
concern.
Of note, the lower cosyntropin
stimulation test, the lower dose, there
have been
concerns raised about the peptide
sticking to
tubing, so that may be a concern raised
if you are
performing lower dose cosyntropin
testing.
DR. WOOD: Dr. Epps.
DR. EPPS: My questions actually are for
Dr. Wilson. Is that okay?
DR. WOOD: Sure.
We are taking questions
for all of the last speakers.
DR. EPPS: Okay.
The growth charts, the
CDC growth charts, were those based on
the standard
growth charts that are used or are they
updated and
different?
DR. WILSON: Those are the standard growth
charts that everybody sees and are
available from
the government.
DR. EPPS: The reason I ask is that--I
thought it was my understanding that they
were
standardized on a group of cohorts in Kansas
in the
'50s or '60s or something and that is why
I
wondered if they had been updated at all.
DR. WILSON: That is a good question. I
don't know. I mean we kept looking for whatever
the most current was. We recommend the most
110
current.
These are trials in which we have
comparators and are randomized. So we have all
those kinds of things taken care of.
But you are right. We pondered a lot
about the growth charts and what they
really meant
for individuals. As you were looking at those
percentage breakdowns, that is where it
becomes
more important probably.
DR. EPPS:
Also, my question was do the
kids recover. You were taking about growth
velocity which is different from overall
growth
potential and whether--you know, kids
accelerate
and decelerate and, really, the lines are
kind of
percentiles or averages. So that was one question
I had, whether the velocity--I guess, the
long
term.
DR. WILSON: The long term. Again,
sponsors have presented to us, and there
have been
a few studies done on trying to assess
whether
111
there are some long-term effects. But those are
even more difficult to do than these
annual
studies.
I think that the assumption has
always
been, and Gene, you could correct me if I
am wrong,
that a lot of this will be
recovered. We have
never looked at ultimate height. Companies, of
course, are always saying this. They want to have
that in their label that this isn't going
to affect
it.
This is Gene Sullivan from the
Division.
DR. SULLIVAN: Hi. I
am a pulmonologist
in the Pulmonary Division. I think what you are
getting at is part of the reason why the
slide said
we don't know the clinical
significance. We can
measure what happens in that year, what
happens
when you stop the drug, is there catch-up
growth,
is the full adult height affected? Those are
still, we consider, unknown.
DR. EPPS: To follow up that, what about
children who have asthma or are on these
medications? Is their velocity different from
112
normal?
In other words, sometimes growth is
affected just by having chronic disease.
DR. WILSON: By the disease itself. But
these pediatric studies, for a number of
reasons
including ethical considerations, are
done in
children with the disease. So the studies of
orally inhaled corticosteroids are done
in children
who need the medications. So the comparison is the
placebo group versus the active treatment
should
take that out of the picture.
DR. EPPS: Certainly, breathing comes
first.
Now, my last question is, for
any of these
studies with inhaled and intranasal
steroids, did
any of them also have atopic
dermatitis? They
usually run together, so you might have
topical
steroids and intranasal and inhaled
steroids all
working together, and would that affect
their
growth, as well
DR. SULLIVAN: I can't say categorically
because I don't know these studies, each
one, that
well, but I presume that almost all of
them would
113
have excluded concomitant use of other
corticosteroids.
DR. WOOD: Dr. Bigby.
DR. BIGBY: I have actually four
questions. The first one actually is a
philosophical question both for the FDA
and for the
people here on the panel. If one of these classes
of topical corticosteroids has been shown
to
produce HPA axis suppression, would we
not
recommend it for OTC approval? That is the
philosophical question.
DR. WOOD: That is the question we are
going to address in the discussion on the
questions, so I guess right now let's
just confine
our questions to the last set of
speakers, so we
can let them off the hook.
DR. BIGBY: The second question is has an
ingredient ever gone backwards from being OTC
to by
prescription? What I am really asking is, if we
make a mistake, can we go backwards?
[Laughter.]
DR. WOOD: I will answer for them, because
114
they won't. Not without a huge amount of
difficulty is the answer. It is much harder to get
something off the market than it is to
not approve
it to go on.
DR. BIGBY:
Lastly, other than
hydrocortisone, is there any foreign
country
experience with an OTC more potent
topical
corticosteroid?
DR. KOENIG: I am sorry, I thought about
looking at that, but I did not, so I
can't say.
Does anyone in the audience
know?
DR. GANLEY: We have some industry folks
here, they may know that answer.
DR. WOOD: Let's move on then.
Dr. Davidoff.
DR. DAVIDOFF: Yes, I would like to shift
away from the HPA for a moment back to
bones, but
bones at the other end of the age
spectrum, because
as you hit around my age, there is
obviously the
problem of osteoporosis, and I understand
that it
is difficult to study osteoporosis, but
that is
such a huge public health and medical
problem, I
115
wonder if there are any data on potent
corticosteroid dermatologic preparation's
effect on
bone density in the older age group. However
preliminary or partial or whatever, I
would think
that any hints as to that potential
toxicity would
be extremely important.
DR. WILKIN: Well, I think we are limited
somewhat in looking at the long-term
safety with
topical corticosteroids, because the
conditions
that they treat, the dermatologic
conditions wax
and wane significantly.
It is not like with the pulmonary
inhalers
where a child may be expected to be using
a product
for very long periods of time. The situation for
dermatologic conditions is that often
things will
resolve, and maybe moisturizers alone,
and then
when things begin to come back, it's a
high
potency.
Then, as it gets under control, it goes
to a medium potency corticosteroid, so it
would be
difficult in that setting to say which
corticosteroid actually led to it.
So, that is the reason why I
don't think
116
we have that in a regulatory environment,
but
someone could look at a more general
question in an
academic environment I suppose, just, you
know,
would the use of mid- to potent, but not
specific
products consistently over a long period
of time,
would those people be at risk.
DR. DAVIDOFF: Yes, exactly.
I mean I
didn't expect that you would necessarily
have it as
part of the regulatory process, but
whether you
have looked or anyone has looked into
literature
specifically on that question.
Mary, do you have any idea from
the
geriatric literature?
DR. TINETTI: I am not aware of any with
the topical. Certainly with systemic, it's a major
issue.
DR. GANLEY: I just want to add something
here.
I think in some of the presentations, that
this growth suppression is really a
surrogate for a
possible systemic effect even when you
would not
have HPA axis suppression.
That is how I think the
Pulmonary Division
117
has looked at it, is that if it causes
growth
suppression in kids, you could assume
that in an
adult, it could potentially cause this.
I did a lot of literature
search, and I
think other folks did, trying to, in Pub
Med,
attach topical corticosteroids with
osteoporosis,
and you just don't get a lot of hits from
it. So,
I don't think there is data, but our
assumption is
that, in this setting, that growth
suppression is a
surrogate for other things.
Now, the dose-response may be
different,
but we don't have the data to really
answer that.
DR. WOOD: When we get to the questions, I
guess, the question you are trying to get
at is
would a topical steroid go OTC if it had
systemic
effects, and the specific targets you
have
illustrated it with are ones that are
easily
measured.
Is that fair? Okay.
DR. GANLEY: I think Dr. Luke pointed out,
and Jon has just mentioned it, with the
topical
corticosteroids, it is much more
difficult to
conduct a long-term study because of the
variation
118
in dose, the waxing and waning of the
disease, and
so forth.
DR. WOOD: Dr. Whitmore.
DR. WHITMORE: I think one other thing
that is most disturbing is in the betamethasone
dipropionate studies looking at growth
suppression,
the 49 individuals, none of them showed
any
suppression, any adrenal suppression.
I am presuming the same type of
testing
was done as was done in the steroid
patients. So,
from that presumption, you can step from
there and
say there probably is some effect on
growth in our
patients who are having HPA suppression
with their
topical steroids.
It is a different marker
obviously, but it
seems like if that is occurring in those
patients
with the inhalers, they are not getting
HPA
suppression. We are getting HPA suppression in our
patients with the topical steroids. I would
presume there is some bone effect, some
growth
effect if used long term.
Was the testing that was done,
the
119
cosyntropin testing in those 49
patients? That was
for Dr. Wilson, I am sorry.
DR. WILSON: It wasn't the same test as I
understand it.
DR. WHITMORE: Oh, it was not?
DR. WILSON: No.
Markham has some more
details on it. Unfortunately, I was looking
yesterday, trying to find out all of the
data from
that test for this committee, but was not
able to
locate the original. It's a different test.
DR. WHITMORE: So, we can't make any
assumptions about that, I presume.
Dr. Cook, I have a question for
you. In
the pediatric testing that was done for
the
steroids, excluding clobetasol, you
didn't have any
adult testing for HPA suppression with
those same
steroids.
I am presuming that the only
HPA
suppression was that we found in our
brown book
here in terms of testing in adults, so it
is pretty
much lacking. The only reason they did that was to
go back to get pediatric approval.
Is there any reason to presume
that if
someone is 13 years of age and has the
same body
surface area of involvement, they are not
going to
120
get the same HPA suppression?
So, the companies that make the
pediatric
products that were doing the testing in
pediatric
patients, after they found HPA
suppression with
their products, they came back to the
labeling
saying 13 years of age or older. Is there any
reason to presume that HPA suppression is
any
different in a 13 through 100-year-old
individual?
It just is concerning.
DR. COOK: Yes, I see your point because
the other, meaning 13-year-olds who are
fully
developed, just as adults, and I don't
think it is
to say that HPA axis suppression would
not occur in
adults.
It is just that we didn't have the exact
data to be able to put that in labeling.
DR. WHITMORE: Has the FDA considered
asking the companies to go back and study
adults
with any of these things?
DR. WHITMORE: Didn't you propose a
121
hierarchical sort of structure? At least that was
the way I heard it, that it would be
easiest to do
HPA suppression in adults, so you would
start with
adults.
If that was positive, you would stop
there, right?
DR. COOK: I think for newer drugs, like
Clobex, because we have all this data,
you know, it
started with adults, and we also could
ask for
children.
For some of those products that I
discussed there, have been on the market
for many,
many years, and I don't know that there
is any
regulation that could make the companies
go back
and look specifically at adults.
The reason that we were able to
do that
for pediatric patients is because we got
a new
regulation that said we need more safety
information in pediatric patients.
Now, in some of the older tests
that were
done, like looking at a.m. serum cortisol
levels
when the drug products first came out,
that is how
they looked at HPA axis suppression back
then.
That was certainly in adults
and did, you
122
know, propagate the class labeling that said
that
you can get HPA axis suppression in
adults, because
the Temovate was done in adults and in
children--well, it is done in adults,
adults with
atopic dermatitis and adults with psoriasis.
DR. WHITMORE: One last comment. With the
inhalant steroids, they oftentimes will
look at
markers of bone metabolism as opposed to
looking
for evidence of osteoporosis. So, you can look at
urinary calcium to creatinine ratios, you
can look
at PTH, so there are things you can look
at to see
if there is evidence for decreased
calcium
absorption or excretion, and things like
that.
DR. WOOD: Dr. Ringel.
DR. RINGEL: I was struck by the
difference between the cosyntropin test
and the
tests that were originally done on
hydrocortisone
to justify its approval as an
over-the-counter
drug. I think it was Dr. Malkinson who
did
radiolabeling of hydrocortisone and showed that it
was not absorbed, which seems very
different from
the cosyntropin test.
As I was reading the
preparatory material
that was sent, I was struck by the fact
that 95
percent specificity of the test was 57
percent
123
sensitive, and I guess I wanted to
explore that,
because I am want to make sure I really
understand
what this test can and can't do. I am a
dermatologist, I am not an
endocrinologist, and I
just want to make sure I understand the
test.
Correct me if I am wrong. It is a test of
chronic effects of corticosteroids, so
that you are
looking for adrenal atrophy, you are
looking for
the adrenal gland not to be able to
respond to ACTH
stress, which means to me that this test
does not
mean that the steroid is not absorbed, it
doesn't
mean that you have excluded the fact that
the
pituitary may be insensitive to the
cortisol, in
other words, that it may just not be able
to
respond with its own ACTH.
And it doesn't mean that let's
say you
have an increase in cortisol after the
ACTH test,
it doesn't mean that that increase in
cortisol is
necessarily going to be sufficient for a
particular
124
stress.
It other words, maybe the person should
have responded with an even greater
cortisol
increase for that level of ACTH
stimulation.
I guess what I am trying to do
is explore
the limits of what we are really testing
with
cosyntropin, and making sure this is
really an
appropriate test and it is going to pick
up people
whose pituitaries are suppressed.
DR. WOOD: Don't all rush to answer that.
DR. LUKE: We do have an endocrinologist
on the panel who can help us with some of
those
answers, I think. The test, as we have
discussed,
having 18 or less of post-stimulation was
thought
to be a sufficient indicator that that
patient
would be suppressed.
Now, as far as how much more of
a rise
would you need for other stressors, I
think the 18
was thought to be sufficient for most
stressors.
DR. RINGEL: Do you know what the
sensitivity was?
DR. LUKE: Of the test?
DR. RINGEL: Yes.
DR. LUKE: Dr. Stratakis, do you want to
address that?
DR. STRATAKIS: The cosyntropin test is a
125
screening test for the diagnosis of
adrenocortical
insufficiency. Therefore, as a screening test, it
has a good specificity, a very good
specificity.
You can set out the specificity wherever
you want,
and it has a low sensitivity, of course,
and that
is how we use it.
With the 18 as the cutoff, it
has a
sensitivity of about 70 percent, a
specificity of
about 95 to 100 percent, so it is very
good in
detecting the patient who is adrenocortical
insufficient. It is not very good at identifying
all the patients that have adrenocortical
insufficiency, it misses about 30 percent
of them.
What I wanted to say is that a
limiting
step in the recovery of the HPA axis
after
adrenocortical suppression--and this has
been shown
in a couple of studies, that are very
good
studies--is the cortical trough, in other
words,
the pituitary cell. It is not the adrenal.
There is actually a very good paper that
was published about 10 years ago about
that, and it
is clear that it is the cortical
trough. So, when
we are suppressing by endogenous steroids
or
exogenous steroids, the HPA axis, all we
are doing
is we are suppressing the cortical trough
cell of
126
the pituitary and, to some extent, the
CRH-producing neurons of the
hypothalamus.
We are not doing anything to the adrenals
or this has not been shown convincingly I
should
say.
We don't really know whether we are doing
anything to the adrenal cortex.
Up to recently it wasn't even
known, and
to
this day it is not known with certainty, that
the glucocorticoid receptor is expressed
in normal
adrenal cortex. I believe it is. In some of our
experimental data, it seems that it is,
but at very
low levels.
The other point is that since the
rate-limiting step is the cortical
trough, then,
the question is how long does it take to
develop
adrenocortical atrophy in response to
suppression,
127
and that varies a lot from individual to
individual, but on average, we consider
that time
to be approximately two weeks,
approximately two
weeks.
I was surprised to see that in
some of the
studies with the mid-potency steroids,
you have
levels, we have levels of response to the
ACTH stim
test down to about 9 or 10, which
actually, if I
look back at my patients with endogenous
Cushing's,
it is something that we get about 6
months of so of
recovery time after a pituitary
tumor-producing
ACTH is excised.
So, this is quite significant
general
atrophy, and since the test if not very
sensitive,
you would consider that as the tip of the
iceberg,
that you are really missing a lot of
patients that
have developed moderate adrenocortical
atrophy, and
you have no way of picking up those that
have
moderate cortical trough cell suppression
in other
words.
DR. WOOD: So, what would be your estimate
of the number you are missing, 30
percent, is that
128
what you said?
DR. STRATAKIS: The sensitivity is about
70 percent, so I would say about 30
percent.
DR. WOOD: Jack.
DR. FINCHAM: This is just an observation
in the context of what we are going to be
discussing this afternoon as far as how
these
products may be used by consumers in an
OTC
setting, a nonprescription setting.
I was struck by Dr. Cook's
presentation of
a couple of instances where we saw an
effect, and I
would assume that these are controlled
situations
where the individuals had some limits on
what they
could obtain and how they could obtain
it, but in
the 5-year-old subject that was detailed
in Slide
31, 95 percent body surface area, but
there was an
ounce a day being used, which is an
enormous amount
of product.
For the 2-year-old, it was an
ounce a
week, and in the Diprosone study, it was
an ounce a
week.
I was just struck. Were there
controls, Dr.
Cook, on oral systemic agents that
perhaps would
129
have been used? Were there strict limits on this
being only topical application?
DR. COOK: Yes, since they were patients
with atopic dermatitis and they weren't
supposed to
be on any other medications that would
affect the
outcome of the study.
DR. FINCHAM: I guess the observation is
that was an enormous amount of product
being used
even in a controlled setting, and we can
only
presume what might happen or might not
happen in an
uncontrolled over-the-counter setting,
whether it
be worse or better, but it just struck me
as an
amount that was being used.
DR. COOK: In the 5-year-old, I believe
that the parent continued to use the
medication
even when the patient was getting better
over that
same amount of body surface area, and
even though
you would think that the integument would
not have
been as compromised as time went on. Somehow there
was a lot of absorption, but when you
look at the
smaller child, didn't use quite as much,
but still
HPA axis suppression.
DR. WOOD: Dr. Stratakis, before we go on
to the next question, I guess, none of
the
presenters actually told us why we care
about HPA
130
suppression that I can remember, and
maybe we
should just, for the record, say
something about
for everybody's benefit why we care, or
what are
the consequences of having your HPA axis
suppressed
particularly in response to stress or
surgery or if
you end up in a road accident or
whatever. Just
very briefly.
DR. STRATAKIS: The reason we care is
because HPA axis suppression can lead to
sudden
death.
In fact, there was a recent study that
looked at the long-term morbidity and
mortality of
patients with panhypopituitarism, and the
single
most frequent cause of death in this
long-term
status was, in fact, the absence of ACTH
secretion
by the pituitary, adrenocortical
insufficiency, in
other words, so sudden death.
DR. WOOD: So, showing up in an emergency
room and not being recognized as having a
failure
of your stress response may be bad for
you is the
131
point we are getting at here.
DR. STRATAKIS: Right.
In fact, one would
like to go back to the studies where I
think in one
of the studies, there were two deaths that
were
recorded as Cushing's, I mean do you know
what the
cause of death was, because Cushing's
doesn't
actually kill you.
DR. COOK: Right.
No, it could have been
complications thereof, it didn't really
say.
DR. WOOD: Dr. Patten.
DR. PATTEN: I have a question about the
HPA suppression retests. It appears to me that the
longest time lapse to retest was 14 days
in these
studies that Dr. Cook summarize for us.
My question is this. Does this imply that
if recovery has not happened by 14 days,
it is
unlike to ever happen, or is after 14
days, is that
simply unknown territory?
DR. COOK: I would have to say that the
studies are really inadequate to answer
that
question.
First of all, we didn't have all of the
patients retested like we would have
liked, and
132
then once we got the studies, for some
reason, when
patients failed to respond, they weren't
retested
again.
Those are certainly things that we are
trying to address in future studies,
especially
now, we don't even want them retested
until they
have been out at least 4 weeks because of
the
possible influences of the results on
continuously
re-stimulating the adrenal gland.
Unfortunately, we don't have
the answer to
that.
DR. WOOD:
Dr. Nelson.
DR. NELSON: I would like to make some
observations on the data that Dr. Cook
presented
and invite comments to just see if I am
getting it
right.
This is just looking at what I
see as 9
pediatric studies that you
presented. If you look
at it by class, there is a 27 percent
incidence,
ignoring the differences in methods of
adrenal
suppression.
If you scan it, in terms of
potency, it
looks to me like there may be an effect
based on
133
potency, but not being a statistician and
just
doing it quickly, it is difficult to say,
but you
would assume then that the incidence of
impact on
growth philosophy would be higher than 27
percent
given the data presented about the
sensitivity of
that finding.
Then, the other question is
whether there
is a threshold and most of these studies
are all in
class, sort of I guess Class II and
above, so you
can't ask the question whether there is a
threshold
effect somewhere in terms of Class I.
What I just did reflects my
biases that
since almost all studies that are submitted
are
usually for efficacy and other
indications, that
you can only see a safety signal if you
do a
meta-analysis, but I guess my question is
I presume
if you had done that, you would have
presented that
data.
I am curious, am I off the mark
here, or
is this an appropriate way for me, in my
sort of
rough non-statistician approach, of
thinking about
this data in the pediatric studies.
DR. WILKIN: I think the answer is yes.
It was very complex, isn't that your
point, that
basically looking in the individual
studies, the
134
denominators are small, and that you
really ought
to look across classes, and I think we
take your
point that we might learn something more
about the
class if we grouped these sorts of things
together?
But there are some difficulties
with that,
and I think something maybe we didn't
stress enough
is that at any one given time over the
last 20
years, we have been consistent at least
for 6
months in how we think about topical
corticosteroids, but we have really
changed
radically from the beginning, you know,
paleoregulatory 20 years ago, I am not
sure exactly
what kind of studies were done for HPA
axis
suppression.
Then, when we looked, we looked
at
endpoints that were serum cortisol. There was no
Cortrosyn stimulation. Then, subsequent
to that, we
looked at perhaps more stringent
criteria. We
looked at what is in the Cortrosyn
labeling, which
135
gives 3 criteria, and would identify more
subjects
as being positive than what we are now
looking at
today given the benefit from the
endocrinologists
telling us that they only use the single
criterion
in their practice.
So, just how we look at it has
changed
radically over time. Also, over time we have been
able to, now armed with PREA, the
Pediatric
Research Equity Act, we are now able to
ask for
much more data that we have gotten in the
past.
So, I think one of the great
difficulties
is there is enormous heterogeneity in the
data sets
and the conduct of the studies in each of
these
classes.
DR. NELSON: If I could just make one
comment in response, all of the pediatric
studies,
it looked to me the only difference in
the
stimulation testing was whether you
picked the
threshold alone versus the rate of rise,
and if you
drop out the rate of rise and just pick
threshold,
you are still going to end up around 20
percent
overall incidence among all these
studies.
So, since that is since 1999 or
1998, so I
guess I would encourage you to look at
the
pediatric studies. I think there is probably
136
enough homogeneity that you could draw
some
conclusions from those studies, if you
grouped them
as
a class or did it by potency.
DR. WILKIN: I take your point on the
pediatric patient being a better sentinel
population in which to look for this
particular
event.
I think one of the things that we have
learned is that while we can make some
correlations
and say that, in general, a higher body
surface
area, longer use, younger age, more
severe disease,
these things tend to correlate with the
finding of
HPA axis suppression.
In point of fact, in any one
study, we may
see an adult who has a very small body
surface area
involvement who suppresses, a child who
has a much
larger body surface area involved, and
not suppress
with this.
So, it is certainly not a
mathematically
precise kind of outcome.
DR. WOOD: The reason we have all these
pediatric studies is sort of an
experiment in
commerce.
I mean we happens that we got these
studies because of the Pediatric Rule
that people
came in to you to get an indication. It's not so
much that there is some specific reason
to
137
investigate children here except for the
commercial
reason.
There might be reasons, as
well, but that
wasn't why it was done, right?
DR. WILKIN: Well, no, I mean that isn't
the reason for PREA being enacted
certainly, but I
can say within our Division, we
recognized that
atopic dermatitis was primarily a
pediatric
disease, and so even before PREA, our
Division was
asking for pediatric studies.
DR. WOOD: Right, but if someone came in
for an OTC indication, which is what we
are looking
at, they wouldn't necessarily have had to
have
done--let me ask it s a question--they
wouldn't
necessarily have had to have done a
pediatric
study, right?
DR. WILKIN: I would agree with that.
DR. WOOD: Dr. Chesney.
DR. CHESNEY: Thank you.
I think my
question is along the lines of Dr.
Whitmore's
earlier, and it is for Dr. Cook. In Slides 55 and
58,
this is looking at Diprosone Lotion. The
suppression was 80 percent for the 9- to
12-year
group, and yet it was approved for 13
years and
older, and I was curious, that it wasn't
approved
138
for adults, and at that time there was no
data on
13 and older, and I don't know of any
reason to
think that a 13-year-old is different
than a
12-year-old.
So, I guess my question was why
was it
approved for 13 and older instead of
perhaps
adults, only given that there wasn't any
information for the 12- to 18-year-old.
DR. COOK: All I can say is that that was
the cutoff that was chosen. I mean your point is
well taken. I mean it could have just said don't
use this product at all because, you
know, by the
time you are 12, you may be near adult
size, but I
139
guess there are some 12-year-olds who are
still
prepubertal or whatever. That was where the study
was taken to, so that was the age cutoff
there.
DR. WOOD: Dr. Taylor.
DR. TAYLOR: My question is really for Dr.
Luke. In his Slide No. 4, when he talked
about
systemic effects, indicating that HPA
axis
suppression is the only one that had
really been
studied well, I was concerned about
glucose
tolerance and sodium retention although I
recognize
with these drugs, sodium retention is
going to be
minimal since they lack significant
mineralocorticoid effects.
But what about in effects on
glucose
tolerance, is there any data to suggest
that
topical steroids might alter glucose
tolerance in
susceptible individuals, for example, in
diabetics?
DR. LUKE: When these products are used
under a physician's care, you would
expect that
those patients would have some
monitoring.
DR. TAYLOR: That is my point, though.
DR. LUKE: The class labels for the
140
corticosteroids do include discussion
about glucose
tolerance and the sodium retention and
mineralocorticoid effect, so when these
prescription products are being used, it
is thought
that those are things that would fall
under the
rubric of a physician-patient discussion
of
examination.
DR. TAYLOR: So, what is the Agency's
position in terms of when the physician
is no
longer there, what is the Agency's remedy
for
ensuring that this growing population of
diabetics,
for example, have some guidance other
than just the
label on the box?
DR. LUKE: I think when you go to the
history of hydrocortisone, there was
discussion in
that monograph about mineralocorticoid
effects, and
it was found that there was no studies
that showed
that hydrocortisone had a
mineralocorticoid effect.
DR. WOOD: My sense of what we are trying
to do, though, is this. What we are trying to
decide is what is the most sensitive test
for
systemic effect of these drugs, and at
what level
141
would you put a barrier up to a
demonstration of a
systemic effect that would preclude OTC
marketing.
So, I guess maybe we should
turn the
question to Dr. Stratakis. I mean what is the most
reasonable, sensitive, and doable test
for systemic
effects of steroids administered by any
route?
DR. STRATAKIS: Well, having said all the
caveats of the ACTH stim test, I still
think that
the ACTH stim test satisfies all the
criteria you
just mentioned, the big response of
cortisol of 30
minutes to 250 micrograms of
synacthen. I mean
it's still the most doable, the easiest
to
interpret, you can do it anytime of the
day, you
can do it IM, you can do it IV, and it
has a
sensitivity of around 70 percent with
specificity
of 95 percent, you can't get in any other
test.
DR. WOOD: So, to address Dr. Taylor's
question, would you expect to see people
who had
elevation in blood glucose who did not
demonstrate
suppression of HPA axis?
DR. STRATAKIS: That would have glucose
intolerance?
DR. WOOD: Right.
DR. STRATAKIS: Especially if they are
predisposed to that? Oh, yes.
I think it is the
142
same thing that we see with growth. Growth is a
very sensitive index of the systemic
effect of
glucocorticoids, and yet you don't see
abnormal
ACTH stim tests in these patients, so I
agree, but
at this point there is no good test to
identify
these individuals.
DR. TAYLOR: So, the point is that the HPA
stim test is not a good surrogate for the
variety
of systemic effects that one is likely to
see.
DR. STRATAKIS:
I agree with that
statement except that there is nothing
else.
DR. WOOD: Charley.
DR. GANLEY: Let me just tough on that and
just think about it. We would be asking the same
questions if we did this test in 25
diabetics and
saw no effect on glucose tolerance, would
we write
a label that says it has no effect on
glucose
tolerance.
I would be a little
uncomfortable in that
143
the labeling for the physician is that
you are
treating the individual, so there may be
patients
that are much more sensitive than others.
Well, to carry that over into
the OTC
setting there may be always that patient
out there,
well, how do you address that. Well, you would try
to address it through labeling, so anyone
who is
diabetic should talk to their doctor, for
example,
before using this product.
Then, you get into the issue,
well, does
that have the impact that you want, is
the person
going to follow that advice. So, I am not sure
that having that data in front of me
would make me
feel better about being at OTC if it
showed that it
didn't have an effect, because I couldn't
absolutely be sure that maybe there is
someone out
there, so you err on the side of caution
and you
label it as such.
I think we will get into that
discussion a
little more about some of these systemic
effects of
whether--and if you look at the options,
one is
that you just label for them, because the
outcome
144
isn't as critical as death with a stress
situation
when there is HPA axis suppression.
DR. WOOD: Frank, do you want to engage in
this?
DR. DAVIDOFF: Yes. I
had a somewhat
related question because we are hearing that
the
HPA axis assessment using the cosyntropin
test has
a sensitivity of about 70 percent, but
that implies
that there is a gold standard of some
sort, and I
was curious what gold standard it is
being measured
against.
But the related point I wanted
to make was
that the results of this test are clearly
a
surrogate measure, and admittedly, if you
don't
want to hang around until people have experienced
the ultimate criterion of suppression,
which is to
die because of adrenal insufficiency, so
you have
to use the surrogate measure, but that
does get to
the question of what is the sort of
intermediate
gold standard short of death that is used
on the
basis of which you can say it is a
sensitivity of
70 percent.
DR. STRATAKIS: The gold standard for the
diagnosis of adrenocortical insufficiency
has
always been the insulin tolerance test,
the ITT, so
145
hypoglycemia induced by insulin is the
gold
standard except that you can't do it in
the
clinical setting, it is unsafe today.
We have to realize that ACTH stim test
is
a sensitive screening test, is a good
screening
test, not a sensitive screening test, and
it was
designed to prevent exactly the adverse
event that
we all want to avoid, sudden death in the
setting
of undiagnosed adrenocortical
insufficiency.
It was not designed to pick up
mild
glucose intolerance. It was not designed to pick
up growth suppression effects, it was not
designed
to pick up all these other--blood
pressure
elevation perhaps, and so on.
So, that is what this test was
designed
for and that is what it is good for.
DR. WOOD: Dr. Mattison.
DR. MATTISON: To follow up on that, what
do we know about age-related differences
in adrenal
146
suppression with exogenous
corticosteroids? Then,
I would like to follow up with a comment
after
that.
DR. STRATAKIS: Well, I am a pediatrician,
so I haven't reviewed the literature
recently.
What I can tell you as a researcher in
the
glucocorticoid field, is that as we grow
older, we
have generally a lower sensitivity of the
HPA axis,
of the central part of the HPA axis. We tend to
have slightly high cortisol secretion,
and the ACTH
levels are, in turn, higher in older
individuals.
Now, why do we say we have a
lower
sensitivity? Because you actually need, as a
result of what I just said, of this
epidemiologic
data, you seem to need higher ACTH levels
to
maintain normal or slightly higher
cortisol levels.
The other thing that we need to
realize
is-- which I like the question about the
pediatric
studies being a good index of perhaps
what is going
on--is that as we grow older, the HPA
axis, the
central part of the HPA axis is very
sensitive to
almost everything we have.
So, if you have a mild
autoimmune disease,
for example, if you suffer from chronic
fatigue,
you present at this meeting at 6 o'clock
in the
147
morning, or if you travel a lot, your HPA
axis
suffers from all that, and that has an
effect on
the sensitivity of the cortical trough,
we know
that.
So, how to interpret the ACTH
stim test in
older adults will be different from how
to
interpret the HPA stim test in kids,
where all
these other factors are simply not
present.
DR. CLYBURN: I just more had a comment
going to the New England Journal article
in here
talking about critical care, and
following up with
Dr. Ringel's comment and questions
earlier about
sensitivity and severity of illness, they
actually
talk about if an increase of less than 9
mcg/dL in
Cortrosyn stim is, in two references,
associated
with a higher risk of death, so I mean it
does
matter which population and the severity
of illness
that we are dealing with.
The other question is for the
FDA. I
148
think I know the answer, but we saw the
data with
Lotrisone, if clotrimazole and
betamethasone are
over-the-counter, there is nothing to
preclude the
combination being sold from what I
understand. Is
that the case?
DR. WILKIN: I would think that were it
over-the-counter, it would still need to
have the
same duration of treatment for the
primary
indication, which would be tinea pedis,
and that
that might be a different duration than
what we are
talking about today, which is limited at
7 days, I
believe, with the monograph. So, I think there
might be a distinction.
DR. WOOD: Dr. Mattison, I forgot to go
back to you for your comment, sorry.
DR. MATTISON: I wanted to follow up on
Dr. Nelson's and Dr. Wilkin's comments
about how I
understand the data that has been
presented, and I
am a little bit frustrated because my
sense of the
data leaves me with a lot of uncertainty
about the
dose or structure-response relationships,
and
relationships with therapeutic efficacy,
that is to
149
say, the structure or dose required to
produce a
therapeutic effect and the adverse events
that
might be produced.
So, if I could just share my
sort of
thinking about this to see whether I have
got it
right or wrong. You indicated that as we go from
the less to the stronger potent
compounds, there
appears to be greater efficacy, but
roughly
proportional or something like that
safety hazard,
and that in addition, as either dose or
surface
area or duration of treatment increases,
efficacy
increases, but concomitantly, safety
concerns
increase, as well, but there are a range
of other
factors that are poorly understood
including what
is in the medium that is used to put the
drug on
the skin and age-related effects and
others.
So, I am sort of hard pressed
to come to
some kind of a concrete description of
this
safety-efficacy balance that we are
trying to
achieve in other than just sort of
general terms.
Am I missing something, or is
that kind of
the state of what we understand or what
is
150
understood?
DR. WILKIN: I guess I would make one
point, which is that I think the way you
describe
this, you would present the moiety as
having a
potency, but it is actually the product
that has
the potency which can be determined in
substantial
part by the vehicle.
The vehicle may have a
penetration
enhancer.
Not all of the active ingredient may
actually be in solution, only that which
is in
solution participates in the
concentration gradient
which drives it across the barrier, which
is the
stratum corneum, so we don't really think
of it in
terms of the moiety. We think about it as the
product itself.
But the other things that you
said, I
think are quite true. These are sort of rough
guidelines on what might actually get
more systemic
exposure, greater body surface area,
under-occlusion, all of these sorts of
things.
I think that maybe we didn't
make the
point that, you know, one can look at
what we
151
provide in the professional labeling for
the
prescription product and maybe interpret
it in too
precise a manner, because I don't really
think that
is what the ultimate intent is.
I don't think the denominators
are large
enough and that we really know all of the
degrees
of freedom in the suppression model, all
the
different aspects, that we have really
solid
labeling that says at 35 percent body
surface area,
in a child who weighs X amount, who
applies this
amount of cream, we are never going to
have that.
We see people that are actually out of
order, when you think you have got the
order of the
factors, some people suppress when you
would
expect, and others suppress when you
don't.
So, we have taken this as a very
rough way
of looking, and then how we use it, I
think one of
our most recent labels was the--was it
Clobex
Lotion?
I think in there, I think it gives the
notion of what we do.
We said the product was
approved I believe
for 18 years of age and above, but we
don't say
152
under Contraindication that it is
contraindicated.
I think we have in there, in the
Indication
Section, it is not recommended, but that
gives I
think the physician the kind of
information, if
they really read through the Indication
Section,
the notion that it is much better in the
18 and
over, and the younger the child, the more
one
really needs to think about this, but at
the end of
the day, this is never going to be
mathematically
precise.
I think that is one of our great
difficulties.
DR. WOOD: Jon, I am always impressed by
how
subtly you think we interpret these labels.
I
don't think any of us ever understand
that kind of
subtlety.
Let me take Dr. Skinner next.
DR. SKINNER: I just had a question about
labeling.
I was struck in Dr. Ganley's lecture
about low potency, Slide 4, use of OTC
hydrocortisone, and he had used limits
into 1 week.
Later on when they actually showed the
labeling
warning, "Stop use if condition
worsens or lasts
153
greater than 7 days."
Certainly, atopics from 3
months to
whatever, 12 years of age, hydrocortisone
1 percent
ointment and cream are rubbed on 2 and 3
times a
day for years at a time, so it seems a
little
different than what the labeling actually
says.
In fact, if you are managing
atopics and
they do well in hydrocortisone 1 percent
ointment,
it is great, you know, come back in 3
months or
whatever, in fact, even on 2.5 percent
ointment.
So, I was surprised to see the label says
7 days.
DR. WOOD: Well, that was my point to Jon.
Dr. Alfano.
DR. ALFANO: Growth suppression mediated
by malnutrition is coupled with sort of a
spectrum
of other functional deficits - the immune
function,
the salivary gland development, sexual
maturation,
and the like, some of which are permanent. In
other words, when you restore nutrients,
the
deficits stay.
In corticosteroid-mediated
growth
suppression, are any of those other
factors
154
identified?
DR. WOOD: Dr. Stratakis.
DR. STRATAKIS: Are you asking whether the
growth suppression is permanent or are
you asking
whether there is additional effects on
these
patients that have--
DR. ALFANO: I am asking related effects.
In other words, there is critical periods
in
development, if the animal isn't growing
properly
at that time, there are functional
deficits which
persist into adulthood.
DR. STRATAKIS: In the studies that have
been done, no, to my knowledge, there is
nothing
that seems to be associated with growth
suppression.
Let me just say one thing about
the
permanence or not. I can tell you from endogenous
Cushing's syndrome, from patients that
have either
adrenal tumors or pituitary tumors in
childhood,
there is a long-term effect on growth.
These
patients seem to end up about 1 to 1.5
times
deviation shorter than controls that are
age and
155
gender matched.
So, there is a permanent effect
on growth
in patients that have been exposed to
consistently
high cortisol levels from adrenal or
pituitary
tumors.
DR. WOOD: Dr. Whitmore.
DR. WHITMORE: May I just ask, if you were
to look at a large population of
patients, what
dose of prednisone would result in a 20
percent
incidence of HPA suppression, oral
prednisone?
DR. STRATAKIS: Well, the equivalent, in a
70-kilo adult, with replacement dose of
hydrocortisone that I consider proper
replacement
is
about 20, 25 milligrams of hydrocortisone a day,
and the equivalent for that in prednisone
would be
7.5 milligrams.
So, I would say that any
prednisone that
is given consistently every day, that is
higher
than 10 or 15 milligrams a day, would
result in
suppression.
DR. WHITMORE: So, kind of what we are
saying here, with 30 percent of patients
showing
156
HPA suppression, that is like having
somebody on
prednisone at a higher dose than 7.5 or
so for an
adult.
I mean my point here is the
fact that is
like having somebody on oral prednisone
every day
with this evidence for HPA suppression,
is this
worse than 5 milligrams of prednisone
every day? I
mean it looks like it.
DR. WOOD: You have to be careful. I mean
clinical pharmacologists, the amount you
get into
the systemic circulation may differ if
you give it
orally and some of it is metabolized
pre-systemically, and so on.
DR. WHITMORE: We are still looking at the
end result, though.
DR. WOOD: I know, so it won't just be
concentration, it won't just be dose
dependent,
because you may get a higher
concentration in the
blood, but you are right in terms of
effect.
DR. STRATAKIS: To add to that, remember
what I said earlier, that a limiting
level to
suppression is the cortical trough. So, the
157
cortical trough is not regulated in a
steady way.
It is regulated in a pulsatile manner,
and it
receives input from many sources.
So, the amount of
glucocorticoids that the
cortical trough sees is just one of the
sources
where the cell receives input from to
determine
ACTH production. So, it is not one and one.
DR. WHITMORE: One of the issues in safety
with the steroids the way we use them, we
use them
bid, so we get a.m. and p.m. dosing,
which you
never do with oral prednisone unless
there is a
reason to produce more suppression, so
that is one
thing.
Only one of the steroids, I
think just
Elocon has the FDA approval of once daily
dosing,
and for the most part, the other topical
steroids
have not been tested 1 qd versus bid.
So, if the pharmaceuticals are
interested
in looking at possibly lesser
suppression, applying
a.m. 1 dose versus bid, would be
something to think
about if they are doing HPA suppression
studies
anyway, just to look at that, and even
the thought
158
of qod dosing with superpotent steroids
in terms of
affecting HPA suppression.
Just one more comment and that
is about
carcinogenesis. We received a notice from the FDA
that Lachydrin was changing their label
in terms of
use on sun- exposed areas because of
concerns about
using it on sun-exposed areas, and I
think that
probably relates to carcinogenesis, but
the other
concern about topical steroids going
over-the-counter is looking at
carcinogenesis.
So application of topical
steroids
producing immune suppression or contact
hypersensitivity suppression, and also
the thought
of suppression of "rejection"
of tumor antigens and
things like that.
The idea of having this go
over-the-counter with not really knowing
if topical
steroid application on a regular basis to
the face
might increase the risk of skin cancer,
and we are
almost indicating that now with the
Lachydrin
warning.
I am not quite sure how to take
the
159
Lachydrin warning, but with the question
about
Protopic and Elidel and Lachydrin, I
think you also
have to start addressing the idea of
corticosteroids and increased risk of
skin cancer
with corticosteroid use on a chronic
basis and
UV-induced skin cancers.
DR. WOOD: Dr. Ringel.
DR. RINGEL: I have two questions. The
first is kind of this simple-minded idea
that I
have, which is so simple-minded that it
must be
wrong, but I was wondering if Dr.
Stratakis could
tell me why.
Why can't you take 100 people,
half of
whom are on steroids and half of whom are
on
placebo, measure their ACTH before and
then during
the treatment, and if it looks like there
is less
ACTH in the treated versus the placebo,
then, you
know that they are being suppressed and
that's the
end of it. Why doesn't that work?
DR. STRATAKIS: Well, that's a simple
question. The ACTH is secreted in a
pulsatile
fashion, so you can't do ACTH
measurements, single
160
ACTH measurements, and see whether a
patient is
suppressed or not.
What you have to do, if you
want to do
that, would be to really do either
12-hour sampling
or 24-hour sampling every 20
minutes. Then, there
are statistical ways of analyzing these
12-hour/24-hour data that will look at
how the
cortical trough has behaved, but that is
a
complicated study and quite expensive.
DR. RINGEL: Thank you, I appreciate it.
I knew it was too easy to be true.
Just one other quick
question. Are we
interested here in only chronic HPA
suppression, or
are we also clinically interested in
acute HPA
suppression?
In other words, if somebody has
been on
steroids for a week and then gets in a
traffic
accident, are they going to--I mean my
impression
is that people would not, in the ICU,
then give
them supplementary corticosteroids.
Is acute HPA suppression really
not that
important, do you need to have the
adrenal atrophy
161
for us to be concerned about it?
DR. WOOD: I think we have had the answer,
but go ahead and tell us again.
DR. STRATAKIS: I think what we are asking
here is whether, in a stress situation, a
patient
will have adequate cortisol
secretion. That is all
we are asking. We said that, on average, it takes
about 14 days or so to atrophy the
adrenal, but
that also is quite variable between
individuals, so
I don't know--
DR. WOOD: But the hypothalamic
pituitary--
DR. STRATAKIS: Oh, absolutely.
DR. WOOD: That is the key point that
needs to be put across, so I mean there
is two
different dynamic things going on. One is the
suppression of the pituitary and
hypothalamus, and
then there is the consequence of that,
which is the
adrenal atrophy, and one occurs first.
DR. STRATAKIS: But what leads to that--so
there is sort of a gap here--what leads
to that is
not the absence of ACTH, what leads to
that is the
162
absence of glucocorticoids.
So, really, the question is
whether these
patients will have adequate cortisol
secretion in a
stress situation, because there are many
other
factors that regulate cortisol secretion,
it is not
just ACTH. There is a problem there, but that is
what they have to deal with.
DR. RINGEL: If you have been taking
corticosteroids, will your ACTH respond
appropriately to stress, or increase
appropriately?
DR. STRATAKIS: Most likely not.
DR. WOOD: Jimmy.
DR. SCHMIDT: I am glad to follow you, Dr.
Ringel, from Maine, because there was the
funniest
cartoon last Sunday in Doonesbury where
the
minister was calling to check on the snow
plow and
he got the exact times, and then, he
said, "How is
the weather in Calcutta?" He said, "I don't have
any windows here."
The reason I bring this up is I
think
globalization is a real important thing,
and I want
to just comment on something that Dr.
Bigby asked
163
about, about what is going on in other
countries.
In preparation for this trip, I
excerpted
an article from the Lancet about a
Chinese woman
who developed Cushing's from taking a
vitamin pill
that had prednisone in it. I just want to read the
last paragraph of this. There is a reference in a
British medical journal by Shuster about
over-the-counter sale of topical
corticosteroids,
which I apologize, but I didn't excerpt
it to
bring.
But essentially what it says is
guidelines
for over-the-counter steroid availability
vary
between countries. Iatrogenic Cushing's syndrome
from topical steroids is well known, and
major
debates on the pros and cons of
over-the-counter
topical steroids have been carried out in
developed
countries.
Although systemic steroids
should be
unavailable without a doctor's
prescription, such
restriction is difficult to achieve in
developing
countries.
In a study from Brazil, clients
were able
164
to buy 65 percent of prescription-only
systemic
steroids that they require for the
treatment of
arthritis.
Then, it just goes on. It says that this
particular patient epitomizes the
nefarious effects
of unregulated over-the-counter steroids.
Then, I want to make one more
comment. I
am sort of a paleodermatologist, having
been in
practice for a while, and the way it was
recommended, we used to, and this is my
bible for
topical steroids, it is Topical Skin
Therapeutics
by Polano is the way we used to do this
was
patients who were treated with large
amounts of
topical steroids may be monitored in the
following
way:
Estimation of the 9:00 a.m.
serum cortisol
every 14 days, as long as the level is 6
mcg/mL or
more, 100 mL, the treatment may be
continued. If
the level is lower than that, then, your
test must
be performed for the synacthen test.
As long as this test shows a
normal
response, continuation of the treatment
is safe; if
165
abnormal, the topical steroid treatment
should be
stopped, and then they talk about backing
them up
with some prednisone.
So, I throw that out for the
group.
DR. WOOD: Okay.
Mary.
DR. TINETTI: I wanted a clarification
from the FDA, if you will, how you
decided on the
cutoff for a positive test for the
cosyntropin,
because I want to differ a little bit
with Dr.
Stratakis. Usually, with a screening test, we
maximize sensitivity.
We don't mind if there is a few
false
positives and usually one would not sort
of pick
for something as serious as this, where
it's a
surrogate for all the systemic effects,
wouldn't
pick a cutoff that gave you a 70 percent
sensitivity, therefore, lose 30 percent
at the
expense of a 95 percent.
I am sort of curious, with that
in mind,
why you made the switch to really an 18
versus the
20, because one way to deal with this
problem would
be to have a more stringent cutoff for a
positive
166
test, and that would sort of deal with
some of the
concerns we have here, particularly as we
are
saying already, it is a surrogate for a
lot of
other outcomes that we are particularly
interested
in.
I just sort of wondered what the
reasoning
was.
DR. WOOD: You mean a less stringent, so
that you would catch the--
DR. TINETTI: Less stringent, so that you
would want a higher result of the test,
and why
they made the switch from 20 to 18, for
instance.
DR. STRATAKIS: This was taken in the
context of the whole test. I mean you have a
minimum body surface area of application
which is
fairly large, I mean 35 percent, 30
percent,
greater that 30 percent body surface area.
You are exposing those patients
to fairly
large amounts of topical corticosteroid.
DR. WOOD: I don't think that is what she
is asking. Go ahead, Mary.
DR. TINETTI: What I am asking is that we
167
heard from Dr. Stratakis that the present
measure,
I presume that is based on 18, is only 70
percent
sensitive, so therefore we miss 30
percent of the
people.
One way to deal with that is to
require a
test to have at least, for instance, to
20
milligrams, so I am not talking about how
much
surface area, et cetera, I am just talking
about
how you define a positive or a negative
response to
the cosyntropin.
DR. STRATAKIS: This has been looked at.
We will increase a little bit the number
of false
positives, but that is again not in the
setting of
topical corticosteroids, this in
endocrine
literature.
So, what has to happen here is
that
essentially, a cutoff from the endocrine
literature
on how you pick up patient with
adrenocortical
insufficiency has been applied in that
setting, and
it may not be the appropriate cutoff.
DR. WOOD: It is important to emphasize,
endocrinologists, we use it clinically
for a
168
different purpose from what is it is
being used for
here.
DR. STRATAKIS: Absolutely.
DR. WOOD: You have always got the other
option of extending it to other tests if
you are
still unsure or if you think the diagnostic
situation is unclear. Mary's point I think is that
that is not the situation you are in with
a
regulatory--
DR. STRATAKIS: The proper idea of testing
the test here would be to apply the gold
standard
that we use in endocrinology, for
example, in
central adrenocortical insufficiency,
studies have
compared the ACTH stim test with the ITT,
the
insulin tolerance test in the setting of
central
adrenocortical insufficiency, but, to my
knowledge,
this has not been done in long-term
application of
corticosteroids, local corticosteroids,
again, do
the ITT, do the ACTH stim test, and then
compare
the two.
DR. WOOD: But I guess one response to
Mary's question would be that would tend
to force
169
you further down this chart that we have
I guess.
DR. TINETTI: Right.
It would seem
logical that if we want to maximize
safety, the
other alternative would be to, in the
absence of
that information, would be to require a
higher
response.
That would be another simple response
barring all that other information,
because I think
we all agree that we are maximizing
safety.
DR. WOOD: Frank.
DR. DAVIDOFF: I wanted to get back to Dr.
Whitmore's question about the dose
equivalence,
because I think it is important to recognize
that
in glucocorticoid therapeutics, it isn't
just the
dose, it's the timing of the dose, and
that the
kind of long sustained input of steroid
into the
systemic circulation that is more likely
to happen
with putting it on your skin, is going to
mimic
Cushing's syndrome abnormality in the
sense of
cortisol being around when there should
be a trough
in the blood level, so that even a
smaller dose is
likely to be more suppressive because of
the long
sustained activity.
DR. WOOD: Dr. Wilkerson.
DR. WILKERSON: Just some observations.
Either we are standing on the head of the
giant or
170
this is a tempest in a teapot, and
unfortunately, I
don't feel like we have the database to
really
understand this.
Just some observations. When we have
hormonal patches of one sort or another
which
literally have micrograms of product that
exert
significant hormonal influences on the
body of
similar sterol-based molecule.
So it is no surprise that our
topical
steroids are doing this, we have all had
a
trivialization I think of topical therapy
over the
years by tradition or whatever that we
have not
considered these things to be
significant, but the
data that we have seen presented today I
think
certainly begs the question that maybe we
really
are standing on the head of the giant and
we don't
even realize the events that occur around
us, we
don't recognize because of lack of the
prepared
mind to recognize these events.
I think if we all go back to
our practices
and start looking for these things, I bet
we start
seeing more instances of effects and
particularly
the things that we are concerned about as
far as
osteoporosis and hypertension and glucose
intolerance.
171
I mean there are times that we
literally,
as dermatologists, coat our patients with
topical
steroids with the knowledge and with that
yes, we
know that we are exerting a systemic
effect there,
but I don't think that knowledge extends
many times
out into general practitioners, and it
certainly
doesn't extend to the public as a whole
in terms of
their misuse of these products.
I think we need a lot more
information
personally about the pharmacology and the
pharmacodynamics of these products before
we go any
further with this issue.
DR. WOOD: And I suspect, just to extend
what you are saying, most emergency room
doctors or
anesthesiologists don't take a history of
topical
steroid use before they--
DR. WILKERSON: Nobody.
I have had the
unfortunate or fortunate experience of
having seen
a patient within the last 6 months who
was using a
very small amount of
clobetasol-containing product
that had been given to her by another
physician,
and the only reason I dug into this, she
had
significant cutaneous atrophy in the
areas of
application, but she had also noticed
extension to
other areas of the body.
172
We did the appropriate screening test, and
she was using less than 50 grams a month
of product
and receiving significant suppression, so
it is out
there, it happens, and I think it
probably happens
with a variety of preparations, not just
that
preparation, but I think we just don't
know the
pharmacodynamics, we don't know the
pharmacogenetics or genomics of this
either at all.
I mean what is the difference
in
metabolism of different people or
particular
steroids.
We sort of make an assumption that they
are the same, and I don't see any reason
why they
would be, and that may explain part of
the
173
differences that we see in these studies.
It may be nothing more than
rates of
hydrolysis and metabolism, and certainly
that makes
some people not affected, it makes other
people
probably severely affected by some of
these
potential side effects.
DR. WOOD: Dr. Santana.
DR. SANTANA: I want to get back to this
issue of age-related differences in the
test
results and what this data means.
Can you clarify for me, when
you addressed
the question earlier, I think the
discussion went
to the side of the adults, but I didn't
hear a
discussion whether age-related
differences in this
testing and whether this value of 18 applies
across
all pediatric age groups, that is, are we
under- or
overdiagnosing based on this test?
I think that is going to be
critical
because if these products become
over-the-counter,
they are going to be used in a large
pediatric
population, because that is what they are
indicated
for pharmacologically, for atopic
dermatitis.
Can you clarify that for me, is
that test
really applicable across all age groups
in terms of
the value of 18?
174
DR. STRATAKIS: Yes, it is.
DR. WOOD: Any other questions? Yes,
Wayne.
DR. SNODGRASS: I have two questions. One
is does the FDA have any plans to request
or
require studies that demonstrate a dose
threshold
for ACTH suppression for topical
products?
Secondly, what is the error
rate, if it's
known, or any estimate of it, of the
general
population for misuse of OTC topical
products?
DR. GANLEY: I will address the latter
question and Jon can address the first
question.
We don't have a lot of data per se, but I
think one
of
the presentations during the open session
provides some survey data and also
purchase data,
and it will give you a sense mainly based
on
purchasing of how many people would use
these
chronically, so then that I think would address
your question.
DR. WOOD: In the absence of any other
questions, I think what we will do is we
will take
a break--I am sorry, Charley.
DR. GANLEY: We have one more question.
Jon had to finish the first question.
DR. WOOD: I beg your pardon.
175
DR. WILKIN: I think the question was will
FDA be looking for a way to find out what
the
threshold dose of a topical product might
be.
Again, because of all the degrees of
freedom in the
model, I just think it's incredibly
difficult to
say that, you know, 22 grams used in a
child of a
certain age, I just think really that it
doesn't
allow that kind of--
DR. SNODGRASS: What I was getting at,
that is a different study design. In other words,
you really could find a
dose-response. If you had
more than one dose, you could find a
dose-response
for the effect you are looking at, and
you could
set your a priori criteria 1 in 100 or
whatever to
be suppressed, and that would give much
more
information than we currently have
product by
176
product.
DR. WOOD: Although it would be difficult
to conceive of an over-the-counter
product being
over the counter in which even a high end
showed
suppression, it would seem to me. I mean the
complexity of that label would be pretty
tough, I
think.
DR. SNODGRASS: Well, I think if you did
it, you know, it depends on what dose you
have got.
If you have got a test right now that is
30 percent
insensitive, once you get beyond, look at
the table
we have got here, and beyond 100 in yours
arms, I
think you might begin to find some
numbers there.
I realize it would be much more
expensive,
more complex, and all that, to do that
type of
studies.
DR. WILKIN: Well, actually, the way the
study is conducted, I realize there is
this
sensitivity issue, and I think Dr.
Tinetti's
comment that if we altered the criterion,
we could
tinker with the sensitivity, but also
think about
the context in which we are doing these
studies. We
177
are looking at the extreme upper end of
body
surface area involvement although Dr.
Wilkerson
mentioned that from time to time,
dermatologists
will give patients topicals to cover most
of the
body, I am not sure that that is the
usual rule.
I think it might be unlikely in an
OTC
setting if the container size is
small. So, the
testing circumstance is really geared
towards
maximum, really provocative, looking to
see if,
under these extreme conditions, that HPA
axis
suppression can occur.
DR. WOOD: Dr. Mattison, did you want to
say something? No?
Okay. Charley.
DR. GANLEY: I just want a clarification
on this sensitivity issue. Maybe I misheard you,
that your sense was for something that
would be
clinically significant leading to
possible death,
the test is fairly good. It is not a 30 percent
sensitivity or we don't know that.
If you have someone that is
suppressed,
this test is actually pretty good to pick
it up in
terms of putting them in a situation that
if they
178
were stressed.
DR. STRATAKIS: Well, that is the
specificity. It will pick up all the patients that
have severe adrenocortical insufficiency.
DR. GANLEY: Right, and that is the
population that we are interested in is
the person
who is going to come into an emergency
room, who is
in a stress situation, who could die from
it. It
is actually pretty good to pick those
folks up.
DR. STRATAKIS: Well, if you want to
comment on that, but I mean basically,
with the
criterion of 18, we have a fairly low
rate of false
positives and acceptable rate of false
negatives.
DR. TINETTI: Right.
The way it says now
is that if you do have a positive test,
you are
pretty darn sure you are going to be in
trouble,
but if you have a negative test, i.e.,
you pass
this test, you still have a 30 percent
chance of
having difficulty. That was the point that I was
trying to make.
DR. STRATAKIS: Actually, you can read
studies that say as good as 85 percent,
and you can
179
see studies that say as low as 68 percent
I think.
DR. TINETTI: So, it's a little bit eye in
the beholder of how many people you are
willing to
miss not to overestimate, so for
something like
mortality, you probably want to have a
sensitivity
of as close to 100 percent as possible,
realizing
you will have a lot of false positives.
DR. STRATAKIS: Because of your
specificity.
DR. TINETTI: The cutoff now minimizes
false negatives, but maximizes false
positives.
DR. WOOD: Terry.
DR. BLASCHKE: I just wanted to make note
of the fact that when we are talking
about safety
issues, we are not just talking about
adrenal
insufficiency, we are actually talking
also the
fact that this is picking up excess
corticoid in
the body, and all of the comments that
have been
made already about the possible effects
on glucose
metabolism, on bones, growth, et cetera,
are also
not to be overlooked as important
consequences of
absorption of the more potent
corticosteroids.
DR. WOOD: Immunosuppression, as well.
In the absence of any other
questions,
let's take a break now for lunch and plan
to be
180
back here at 12:30.
For the audience before they
all rush out,
we will start immediately with the public
comment
session.
You have all got your numbers, so we will
be starting with No. 1 obviously and
moving on from
there.
Thanks a lot.
[Whereupon, at 11:30 a.m., the
proceedings
were recessed, to be resumed at 12:30
p.m.]
181
A F T E R N O O N P R O C E E DI N G S
[1:00 p.m.]
Open Public Hearing
DR. WOOD: We are going to do the public
comment period. All the people who have requested
time in the public comment period have
got a
number, and I will call you up by number.
You have 10 minutes to present
and we will
strictly enforce the 10-minute rule. At the end of
the
10 minutes, the microphone will go dead and
only your lips will be moving.
Let's get started with No. 1.
MR. ROTH: I am Jerry Roth. I am
president and owner of Hill
Dermaceuticals. I was
present at the last Advisory Committee
meeting on
pediatric corticosteroids for
pediatrics. I
recognize some of the panel members from
the last
one, so I hope I don't bore you here
because I am
presenting this information.
I remember Dr. Chesney said you are
supposed to say if anybody paid your way
here. I
paid my own way, so as I said before, I
am one of
182
the dinosaurs left in this industry.
First of all, in presenting
this data, it
is not our intention in any way, shape,
or form to
want our product Derma-Smoothe/FS to be
nonprescription. It is a prescription and we
intend it to stay that way, but we felt
that this
is giving you a little bit of data that
you have
not maybe heard earlier today.
[Slide.]
First of all, Derma-Smoothe/FS
contains
0.01 percent fluocinolone acetonide in a
peanut oil
base
It is considered a low to medium potency
corticosteroid, and I wanted to present
HPA axis
suppression studies that were done in
patients 2 to
12 years of age.
You have heard a lot today
about vehicles
and I think that this will give you once
again a
little bit additional evidence.
[Slide.]
This is a multi-center,
open-label safety
study. What you haven't heard yet is this
was done
in patients with greater than 50 percent
body
183
involvement.
The dosage, it was also brought
up that
everything was once a day. The dosage on this was
twice daily for a period of 4 weeks. The criteria
was evaluation with the cosyntropin
stimulation
test.
Derma-Smoothe/FS was one of the
first
drugs that was studied for safety and
efficacy, the
Rules, as have been mentioned, have
changed since
that time, and you will see that Day 1,
prior to
the first treatment, and at the end of
treatment we
had a pre-stimulation cortisol level and
then
immediate followed by stimulation, and
then the
post-stimulation cortisol level was at 60
minutes.
At that time, the protocol or
the Agency
only request cosyntropin tests. It wasn't
differentiated between 60 minutes and 30
minutes at
that time.
[Slide.]
The population that I want you
to
recognize is that 18 of the patients had
greater
than 75 percent body involvement, and 16
had 50 to
184
75
body involvement. We calculated the
amount of
drug by what was returned, and the
average drug use
per day was about 9.5 plus or minus 4.7
mL/day.
Now, this is important because there is
something,
vehicles and drug exposure.
[Slide.]
Just to remind those who aren't
physicians, regarding body surface area,
when you
are talking about this much, 50 to 75, or
75, you
are talking about the chest, front and
back, legs,
front and back, arms, a substantial
area. Once
again, I believe this is the only drug
that had
been tested with that level besides
hydrocortisone
of that amount of body surface.
[Slide.]
Before the treatment, prior to
treatment,
now we did averages because this is a
public
hearing, each of the data individually is
on file
with the Agency, and this was approved,
so each
individual case report form is on file.
Anyway, the average pre-stimulation was
11.63.
At 60 minutes, it was 26.82, the doubling
185
which you should see.
[Slide.]
After 4 weeks of treatment,
there was very
little change, 11.26, and after
post-stimulation,
it was 25.06. Of the 34 patients, there was not
one that experience any adrenal
suppression.
[Slide.]
The exposure we feel is very
important.
Derma-Smoothe/FS is a 4-ounce
container. Within
this container, there is 12 mg of
fluocinolone.
You will see that the average patient,
the 4
ounces, 118 mL, lasted 12 days. The patient was
exposed to not more than 1 mg of
fluocinolone per
day.
On the basis, which is the generally accepted
percent of absorption of 1 to 2 percent,
that is an
infinitesimal amount that is absorbed.
What is important is this is an
oil
vehicle, the spreadability is great. This
particular cream is 60 grams, and there
are 60 mg
of corticosteroid in this cream. To cover a vast
majority of the body, it would require a
lot more
cream to do this than of this oil, so you
may use
186
quite a bit more of the cream. I think that was
brought out earlier.
So, therefore, vehicles are
important and
possibly does have substantial amount
regarding
safety data.
[Slide.]
In conclusion, after 4 weeks of
daily
application of Derma-Smoothe/FS ,
involving 50 to
90 percent of the body surface area,
there was no
change in the morning baseline value of
the
cortisol, nor did it affect the cortisol
stimulation of ACTH.
You might wonder, well, if
there is so
little amount of steroid does it work,
with this
small amount on the body, after 4 weeks,
60 percent
of the patients showed excellent or 75 to
100
percent improvement.
Would you like to ask me any
questions
especially on the amount of surface? I think, just
to follow up, Dr. Wilkin has said that
the tests
are becoming a bit more
sophisticated. We are
ready to commence down to 3 months with
this
187
product in greater than 30 percent of the
body
area, and we will be following, I think
there was a
question if you have any adrenal
suppression, will
you be following those patients. In that protocol,
we will be. We don't expect any, but we will test
until we have data.
Second of all, once again,
there was also
a statement that companies often just do
this
because they are required. That is some of the
case, but in any cases it is not, and in
this case,
it is not. It was our request to do these.
Yes, sir.
DR. WOOD: Dr. Nelson has a question for
you.
DR. NELSON: I was told it had better be a
good one, hopefully, it is. You had mentioned in
passing that it is generally accepted
that 1 to 2
percent of corticosteroids are absorbed
topically.
I was just wondering what is the data and
how
generally accepted is that?
MR. ROTH: That is in the Textbook of
Corticosteroids, I believe it is by Dr.
Howard
188
Mayback. That is a generally accepted
textbook.
DR. NELSON: For all corticosteroids?
MR. ROTH: I believe, yes, on topically
applied, yes. That is why the amount that you are
exposed to is quite substantial.
DR. WHITMORE: I don't know that that
applies to all corticosteroids. I think
hydrocortisone versus the others--
DR. WOOD: Let's hold all of our questions
to all of the speakers at the end,
otherwise, we
will take forever to do this. Let's go through all
the speakers and then we will take
questions for
them at the end.
MR. ROTH: I can quote out of
the textbook
if you would like.
DR. WOOD: Teresa has handed me a
late-breaking statement that I need to
read.
Both the Food and Drug
Administration and
the public believe in a transparent
process for
information gathering and
decisionmaking. To
ensure such transparency at the open
public hearing
session of the Advisory Committee
meeting, the FDA
189
believes that it is important to
understand the
context of an individual's presentation.
For this reason, FDA encourages
you, the
open public hearing speaker, at the
beginning of
your written or oral statement to advise
the
committee of any financial relationship
that you
may have with any sponsor or products.
For example, this financial
information
may include the sponsor's payment of your
travel,
lodging, or other expenses in connection
with your
attendance at the meeting.
Likewise, the FDA encourages
you at the
beginning of your statement to advise the
committee
if you do not have any such financial
relationships. If you choose not to address this
issue of financial relationships at the
beginning
of your statement, it will not preclude
you from
speaking.
Speaker No. 2.
DR. CHARLES ELLIS: Thank you very much.
I am pleased to be here to speak on
patterns of use
of OTC topical hydrocortisone. Thank you for
190
allowing me this opportunity.
[Slide.]
I am Charles Ellis. I am Professor of
Dermatology at the University of Michigan
Medical
School.
I am also Chief of Dermatology at the Ann
Arbor Veterans Affairs Medical Center.
[Slide.]
Here are my disclosures for my
talk today.
[Slide.]
I am thrilled to be able to be
here to
present our research which is in press
and will
soon be published in the peer-reviewed
Journal of
the American Academy of Dermatology. Our research
is entitled, "Consumers
appropriately self-treat
based on labeling for over-the-counter
hydrocortisone."
[Slide.]
First, I am going to tell you
the results
of our research and then I will give you
the
details.
So, what has our research shown
about the
use of topical hydrocortisone in the
United States?
191
The reported use is largely consistent
with the OTC
monograph label.
The percentage of use in
accordance with
the label is similar for both adults and
children.
Over-the-counter hydrocortisone
is used
primarily for brief periods of treatment
of
apparently minor conditions.
[Slide.]
By way of background, you have
heard that
hydrocortisone has been available over
the counter
since 1979, and in the 1 percent concentration
since 1990.
The OTC label is designed for
safe use,
and compliance with the label implies
that there be
a low risk of adverse effects, however,
we found no
published data on how OTC hydrocortisone
is being
used in the population.
[Slide.]
So, our research objective was
indeed to
look at real world user behavior, and we
did this
with a telephone survey which was performed
by a
company called Synovate through one of
their
192
regular national telephone surveys. We had them
ask questions about the usage of
over-the-counter
hydrocortisone.
This is as reported by the
adult users in
the family when we called them. This also included
these adults' reports on the use in their
children.
They gave us the reason for using the
hydrocortisone, the daily frequency of
use, and the
duration of use. We evaluated their responses for
consistency with the labeling.
[Slide.]
This was one with a random
digit-dialing
to over 64,000 households although about
55,000 of
them didn't answer the phone, so that is
the
problem of caller ID, I think. In the end, we
achieved 2,000 adult respondents who
actually
completed the survey.
Of these respondents, 396 adults
reported
using over-the-counter hydrocortisone in
the last 6
months; 168 households reported treating
a child
with OTC hydrocortisone in the last 6
months.
[Slide.]
So, our analysis undertook a weighting
to
represent the U.S. demographics in the
2002
National Health Interview Survey. Limitation of
193
this work is that it is based on
self-reports. Of
course, we couldn't go into everybody's
house to
see what they were actually doing, so we
relied on
what they told us in answer to our
questions.
The strengths of the study
includes that
it was open-ended questioning, so we
didn't use
terms right off the label, and the
respondents
didn't have the label in front of them,
so this
avoided biasing them to give us answers
that they
might think that we wanted to hear.
Also, when we came to the
children, we
asked about the youngest child at home
who used
over-the-counter hydrocortisone, the
youngest one
who used it, and we picked the youngest
one because
we felt that that person might be at most
risk for
adverse effects.
[Slide.]
You have seen this prototypical
over-the-counter hydrocortisone label
from the
194
monograph. It talks about the uses for temporarily
relieving itching of minor skin
irritations and
inflammation, and rashes due to a number
of
conditions. It is for age 2 and over.
Frequency is maximum 3 to 4
times daily.
It is for external use only, not for use
in diaper
rash.
Avoid contact with the eyes, and the
duration for up to 7 days on the
labeling, and we
inquired on these points in an open-ended
fashion.
If you look at the overall
compliance with
the label, 73 percent of adults and 72
percent of
the children that adults reported on, in
fact, were
completely consistent with the
labeling. A smaller
percentage, about 20 percent, were not
acting in
consistency with the label for 1 reason,
and a much
smaller percentage were not consistent
for 2 or 3
reasons.
By far and away the most common
situation
that we found was that they couldn't give
us an
answer of why they were using it that was
specifically listed on the label. So, we are going
to look at the people who were not
consistent with
195
the label and try to understand exactly
what was
going on.
[Slide.]
So, we asked, "The last
time you used an
over-the-counter hydrocortisone product,
what were
you using that product to
treat?" Eighty-three
percent of adults, the reports were 86
percent of
children were consistent with the label,
but you
can see down here is this hatched bar,
there were
other situations that we couldn't code as
being
consistent. Most of these actually were indeed
called Other, they were vague responses
or no
condition was reported, and in a few
children, they
used the term "cracking skin."
So, some of these in this
hatched bar may,
in fact be consistent with the label, but
the
respondent was unable to actually verbalize
it in
that way.
"Cracking skin" could well be eczema,
for example.
About 2 percent were using it
for cuts and
approximately the same percentage were
using it for
what they described as fungus, arthritis,
acne, or
196
diaper rash.
[Slide.]
Now, we asked, "Think
about your youngest
child who has used over-the-counter
hydrocortisone
in the last 6 months. How old is that child?" In
93 percent of reported uses on the
youngest child,
the age of the child was 2 years or
older, which is
consistent with the labeling.
So, here we have the age across
this way,
and the cumulative percentage reporting
this way,
and the dash line is the non-consistent
use with
the label. However, 81 percent of the adults who
told us about these children, 81 percent
of them
said they had discussed the use of
hydrocortisone
with a doctor in this group.
[Slide.]
So, then, we asked, "The
last time you
used an over-the-counter hydrocortisone
product,
how many days in a row did you use the
hydrocortisone?" For 92 percent of adults and for
94 percent of children, they were treated
for 7 or
fewer days, again showing here the
duration of use,
197
cumulative responses, and then this
segment here,
the smaller segment here are the people
who were
not consistent with the labeling. The median use
was for 3 days.
[Slide.]
And we asked, "And how many times per day
did you use the hydrocortisone
product?" And 98
percent of adults and 97 percent of
children, they
used it 4 or fewer applications per
day. Again,
the number of applications and the cumulative
reporting, up to 98 percent, roughly 97,
98
percent, and the median use was 2
applications per
day.
[Slide.]
So, in conclusion, the reported
use of an
over-the-counter topical corticosteroid
is largely
consistent with the label for conditions
treated
and for frequency and duration of use.
Thank you.
DR. WOOD: The next speaker is also called
Ellis, and it's Valentine Ellis.
MS. ELLIS: Thank you for your time. My
198
name is Valentine Ellis and I am here
today to
present the patterns of household
purchase behavior
in the OTC hydrocortisone category.
In way of disclosures, I am
actually not
related in any way to Dr. Ellis, we only
met a week
or two ago. I am a full-time employee with
GlaxoSmithKline Consumer Healthcare, and
I work as
a consumer research manager there, so the
majority
of my work is done behind consumer
behavior
analysis and consumer insights.
I am formerly an employee of
A.C. Nielsen.
I will be talking about them a little in
the
methodology where I worked as home scan
specialist
and specifically on this research
project, which is
why I was asked to present it to you
today by my
team.
[Slide.]
The research objectives at the
time we
undertook this study were to understand
purchase
behaviors in the OTC hydrocortisone
category among
U.S. households. The basic underlying assumptions
that we use in research on the consumer
side is
199
that the household data is a proxy for
annual
household usage, and this information
that I am
providing today is likely an
overestimation because
we are reporting against 100 percent of
purchases,
which does not necessarily mean people
use 100
percent of the product that they bring
into their
household.
[Slide.]
Methodologically, AC Nielsen is
a
supplier, a commercial supplier of
research data.
Most people are familiar with the AC
Nielsen TV
ratings, but they do have another arm
which
captures, maintains, and reports data for
all the
products that are out in the world today
that we
purchase and use at home.
We are using data from their
household
panel, which at the time of the study had
55,000
households enrolled. It is demographically and
geographically balanced to the U.S.
Census.
The panelists agreed to scan
all of the
products that they purchased with UPC bar
codes
regardless of where they purchase it,
provided that
200
they use it for personal consumption.
This is a pretty accurate
reporting
system.
These people scan via an in-home bar code
scanner, which you can see this little
lady here
using, everything, so in a sense, they
are blindly
reporting their purchases, they are not
paying
attention to the frequency with which
they scan
these products, and they transmit the
data back to
Nielsen once a week.
They are incented for
consistent
reporting, so Nielsen provides them with
a
non-biasing points redeemable type
program, because
they don't want to in any way bias a
product that a
person would purchase or how they would
necessarily
use it once they get it into their home.
Most of the panelists stay within the
panel, and there is actually about an 80
percent
retention rate year on year.
[Slide.]
The custom analysis that we
undertook was
to take AC Nielsen's hydrocortisone
reported
category, which is over the counter. It includes
201
all of the brands we have listed here,
all of the,
you know half-percent, 1 percent
ointments, creams.
Most of the sizes I believe that are out
in retail
today would be half-ounce, 1 ounce, and 2
ounces.
[Slide.]
The time period that we looked
at was 52
weeks ending October 19, 2002, and the
primary
measures that we looked at were buying
households
and buy rate in both ounces and purchase
frequency.
The sample of the data was any
household
that had scanned a hydrocortisone product
at least
once during the 52-week time period, and
the
advantage of a custom analysis is it
allows us to
take the total buyer group and break it
down into
both households with children and
households
without children, children at this point
being
defined as any household under 18.
These are mutually exclusive
buyer groups,
so the value of these two groups of
households will
add up to the sum total of total buying
households.
[Slide.]
Some of the advantages of this
methodology
202
are that the ongoing electronic purchase
of actual
behavior provides us with a pretty
objective and
accurate measure of purchasing across the
household, but at the same time, there
are
limitations to this data what we want to
be
perfectly clear about. This tells us about
household level purchasing.
We can't link it from this
particular data
set to who in the household is using the
product or
necessarily how they are using it in
terms of
frequency, duration, or condition. We just know
that this household has made so many
purchases and
we know that volume is actually going
into these
different groups of people.
[Slide.]
Our key findings were that
annual
household purchasing of OTC
hydrocortisone products
is reasonably limited. About 13 percent of total
U.S. households purchase at least one
product per
year.
Of those 13 percent of buying households, 75
percent of them purchase only once, 90
percent of
them purchase 5 ounces or less per year.
We have also discovered that
households
with children actually buy less volume
per year
than households without children, despite
the fact
203
that there are significantly more people
in that
household.
[Slide.]
A little detail on that, the
data that we
have just presented in the key
findings. Again,
you see that 13 percent of the households
purchase
OTC hydrocortisone, and that is the
little red pie
sliver.
When we look at the household
composition
of those 13 percent of households, what
we see is
that 34 percent of the buying households
did have
children, and 66 percent did not. This number is
consistent with the U.S. demographic
breakdown of
households with and without children.
[Slide.]
We also look at the households
in total,
and of the buying households, 75 percent of
them
make only 1 purchase per year, 92 percent
of them
over the course of the year make 3
purchases or
204
less.
[Slide.]
This chart demonstrates the
cumulative
percentage of households going up the
bar, across
the volume that is actually purchased
during the
course of the year.
If you look at the black bar in
the
center, that is our total households, all
of them,
and what it tells us is that 90 percent
of the
households purchase 5 ounces or less per
year of
OTC hydrocortisone.
Then, the red bar, which is on
top, that
is our households with children under
18. It
cumulates or builds a little quicker,
which is why
it is above the black bar, and what it
tells us is
that 85 percent of households with
children
purchase 3 ounces or less per year, and
94 percent
buy 5 ounces or less per year.
[Slide.]
Looking at it from a
consolidated
perspective, the gold bars on the left
tell you the
percent of buying households the buyer
group
205
represents, and then the blue bar on the
right
tells you proportionately how much volume
they
contribute to the total volume purchased.
What we see is households with
children,
while they represent 34 percent of the
buyer
groups, are really only contributing
about 26
percent of the total volume purchases,
and this is
because the average buy rate in
households with
children is about 1.9 ounces a year,
while it is
2.8 for the households that do not have
children.
[Slide.]
The conclusions we reached from
this data
was again that annual household
purchasing of OTC
hydrocortisone products is limited. It is not a
large--well, it is a large group of
people, but it
is only 13 percent of the
population. They
purchase infrequently with 75 percent of
them
purchasing only once, and for the most
part, they
purchase, 90 percent of them, 5 ounces or
less.
We see lower purchase volumes
in
households with children, despite the
fact that we
have twice as many people in them, and
then based
206
on
the amounts of product that we see purchased,
excessive use of the OTC topical
corticosteroids is
probably not an issue, and, in fact,
would lead us
to believe that people are using it much
they way
they have told us in Dr. Ellis' usage
survey.
That is it.
DR. WOOD: Thanks very much.
Let's go back to Speaker No. 2,
who has
now shown up, Mr. Paranzino.
MR. PARANZINO: Thanks very much for
accommodating my late arrival, I
appreciate it.
My name is Michael Paranzino, I
am with
Psoriasis Cure Now, which is a patient
advocacy
group.
I have no conflicts either personally or
through Psoriasis Cure Now with any
content
involved today.
Our written statement is
available on the
web at psoriasiscurenow.org, and I will
just make a
couple points briefly.
First, thank you for holding
this hearing.
While not two psoriasis cases are alike,
one thing
that unites just about all 6.5 million
Americans
207
with psoriasis is that we use a lot of
topical
steroids, one or many over the years.
As I noted in my written
statement, I took
a quick look at a popular list of topical
steroids,
and I have been prescribed at least 15
over the
last two decades, and that is the way, as
many of
the dermatologists in this room now, you
try one,
then you try another, then you flip back,
and then
you try another, so we do know topical
steroids.
It is very important to us.
We believe that some of the
topical
steroids that are currently
prescription-only can
be used safely and effectively by
psoriasis
patients over the counter. Most psoriasis patients
are actively involved in treating their
skin
symptoms.
They are also actively interested in
minimizing the medications they use, so
they are
very cognizant of overuse.
Now, that said, we do have some
concerns,
and one of them is every rule has its
exceptions,
and we still come across psoriasis patients
who use
what might be considered excessive either
through
208
duration or extent over the body topical
steroids
over a period of time, and only later
come to
realize that there could be side effects to
that.
But we think that can be dealt with
through better
education, maybe through labeling. There is also
some education that needs to be done
still we
believe with dermatologists, because
there is a
wide range of strategies that are
employed by
dermatologists in prescribing topical
steroids. I
am not speaking anecdotally, not in terms
of
studies, but I have talked to a lot of
patients
over the years, and some doctors, every
time they
prescribe a topical steroid, they peel
off the
preprinted chart, they circle the one
they are
giving you, and they say this is where
your topical
steroid falls in the mild to strong, this
is where
it falls.
Other just write the prescription, they
are busy, they move on.
Just last month, someone came
to me and
said they went in for what turned out to
be
psoriasis on the leg. A quick appointment with a
dermatologist, walked away with a
Temovate
209
prescription, and they said to me,
"But it's a mild
one, because it's 0.05
percent." I said, well,
according to this chart I am looking at,
you can't
just go by the percentage, because, well,
as you
all know, but we are lay people, so it's
a common
mistake that can be made. But again that can be
dealt with through better education.
I did want to address children
just for a
moment, because it is particularly tough
for
parents trying to treat children with
psoriasis,
and some actually try to avoid topical
steroid use
in children, but it is becoming more and
more
complex just with the FDA's actions in
recent days
with Protopic and Elidel, there are some
children
with psoriasis and some adults using
those
off-label for psoriasis specifically to
avoid
steroid use, and now they hear some
warnings about
potential cancers.
So, it is very tough for a
parent to weigh
the costs and benefits between UV light
and Dovonex
and steroids, Protopic, Elidel,
systemics,
biologics, anything that can be done in
terms of
210
educating, if there is a scientific
consensus on
what a child should do, it has to reach
the
patients better.
Finally, I hope you would use
your
influence with your colleagues downtown
and closer
to Washington and Bethesda and encourage
more
research on psoriasis. The challenges that parents
face and all psoriasis patients face
underscores
the need for additional treatments. Psoriasis has
been underfunded woefully for the last 10
years at
least at NIH, and NIH funding is up 99
percent
after inflation in the last 10 years,
psoriasis
funding is down 8 percent. It is hard to go down
in the environment over the last 10
years, and you
folks can help change that.
So, thank you again for the
hearing. It
is very important to psoriasis patients,
and I
appreciate the time to fit me in even
though I am
late.
Thanks.
DR. WOOD: Thank you.
The next speaker is Dr. Sandra
Read.
DR. READ: Good afternoon, Mr. Chairman,
distinguished members of the Committee
and
colleagues. Thank you for letting me be here. My
211
name is Dr. Sandra Read, and I am
appearing on
behalf of the American Academy of
Dermatology
Association.
Thank you for allowing me a few
minutes to
share with you safety concerns on an
important
matter to me, to my patients, to doctors
in
America, as well as to the Academy,
regarding
changing topical corticosteroids to
over-the-counter status.
In the spirit of full
disclosure, I do not
conduct any research for pharmaceutical
companies.
I am on the Speakers' Bureau for a
company that
manufactures a high potency steroid
cream.
However, I have not been in contact with
this
company regarding this testimony.
I have been in the practice of
medicine
for 30 years, more than 20 of those in
the private
practice of Dermatology in the District
of
Columbia.
I serve on the clinical faculty of
212
Georgetown University, and I have been
lecturing on
Pediatric Dermatology there for more than
10 years.
I have been prescribing topical
corticosteroids since my training days,
and they
are an integral part of my therapeutic
armamentarium. Over the years, I have developed
not only an appreciation of their
usefulness, but
also a respect, a very healthy respect
for the
potential abuse of these agents. I urge the
Committee not to be lulled by their route
of
administration. These are powerful external agents
that can have serious internal and
external side
effects.
Treating patients of all ages
with topical
steroids is a mainstay of many of our
dermatological practices. They are potent
medications and, when used properly, they
offer
relief to suffering patients and enables
them to
lead comfortable and normal lives.
Used improperly, however, these
medications can cause great harm and that
is why
the American Academy of Dermatology is opposed
to
213
the proposal to make these medications
available
OTC.
I have done a random survey of
100 of my
patients' charts. Of these 100 patients, I
prescribed topical steroid creams in
36. Of these
prescriptions, 16 percent were super
potent, 36
percent were mid-strength, and 50 percent
were low
potency.
Some patients received more than 2
prescription for different
strengths. As the last
speaker pointed out, this can sometimes
be very
confusing to patients on how to use. However, the
usefulness of these agents is reinforced
by the
figures of my practice. I cannot do without
topical steroid creams, neither can my
patients.
However, I have seen too often
the results
of abuse of these agents. Cutaneous adverse
effects include thinning and
discoloration of the
skin, telangiectasias, and striae, permanent
stretch marks.
These side effects can be
permanent and
disfiguring and last a lifetime. Pediatric
patients, our youngest patients are
especially
214
vulnerable to these adverse events. In fact, I use
a picture frequently of one of pediatric
patients
who was treated with a topical steroid
cream, on
whose inappropriately was left with thin
skin, with
hypopigmentation, and
telangiectasias. The medical
students at Georgetown tell me they never
forget
this picture.
I have seen patients have
access to these
treatments and misuse them for
non-steroid
responsive dermatoses, such as tinea,
scabies, and
even skin cancers. Now, we all know that
this
delays diagnosis and obscures diagnosis,
but it can
also worsen disease, as we all know, in
topical
ringworm and fungus.
I have seen, and so have
dermatologists in
this room seen, the inappropriate use of
in
steroids of body folds in genital
regions. In
these areas, increased absorption rapidly
intensifies and produces the cutaneous
side effects
we are talking about, and, of course, one
cannot
ignore the augmented potency that is
delivered by
these creams when applied under
occlusion. Mild
215
creams become strong creams, strong
creams become
even stronger under occlusion.
This can happen, of course, by
accident
with patients using these creams on their
own and
unsupervised. Now, not only are cutaneous
adverse
events accelerated and magnified, but the
risks of
systemic absorption and all of its
complications
are well known to the members of this
committee.
The medical literature is rich
with
studies providing the direct link between
topical
steroid creams and hypothalamic pituitary
adrenal
axis suppression, growth suppression in
children,
and the adverse effects on the skin that
I have
just discussed.
It is only with close
monitoring of our
patients who present with adverse treatments
and
reactions that physicians are able to
prevent and
monitor for these dangerous clinical
diseases and
side effects.
I note to you that if you
remove the
physician from this equation, you would
be
effectively removing a very important
safeguard and
216
protection for patients, and that is our
primary
duty as doctors.
By changing the status of these
pharmaceuticals from prescription to
over-the-counter, the FDA would
effectively be
turning over the practice of medicine to
patients.
As well informed as patients can be, I do
not
believe that they should be
self-diagnosing or
self-treating symptoms with medications
that can
have potential for such serious side
effects.
The danger of pediatric
patients being
treated with over-the-counter steroids should
be
consider by this committee
seriously. As parents
search for relief for their children
bothered by
eczema and other skin diseases and their
symptoms,
it would not be unheard of for them to
use a
topical steroid cream incorrectly, such
as too
often, using too much in an application,
or
applying it to too large of an area
and/or too
long.
Pediatric patients have a
higher risk of
systemic absorption, which can lead to
their growth
217
suppression because of their higher ratio
of
surface area to body volume.
The FDA itself has expressed
concern that
patients do not understand the risks of
hypothalamic-pituitary-adrenal axis
suppression
when using steroid creams. Therefore, the risk of
doctors missing a diagnosis of HPA
suppression in
pediatric patients when the parents fail
to inform
them is a real risk of topical steroid
use.
This Advisory Committee is
being tasked
with determining at what point the risk
of HPA axis
suppression and other adverse effects
outweighs the
benefit of making these treatments more
available
to the public.
I believe that there is no
acceptable
point at which those of us in the medical
community
should allow our patients to not only
self-diagnose, but also to self-treat at
any level
of skin disease.
The complications that can
arise, ranging
from mild to severe, as I have told you,
should
exclude automatically the expansion of
OTC status
218
to topical steroid creams. Our patients are not
qualified to make these kinds of medical
determinations, nor should we be asking
them to
make these determinations.
I ask you, what is the rush to
change the
prescription status? I ask you, what is the
marginal benefit to the consumer for
stronger
over-the-counter creams? There is no overwhelming
need and there is no clear benefit in
making these
treatments more accessible. The goal here should
be patient safety first and
foremost. That is our
duty as doctors.
Given the FDA's increased focus
on drug
safety, I believe that changing the
status of these
treatments will have the opposite effect
on the
public sentiment than what is intended by
this
committee.
Patients will not be more
satisfied
because these treatments have been made
available
over-the-counter. In fact, I believe that their
satisfaction will diminish, as will their
trust in
the medical community and in the FDA once
they
219
become aware of the severe side effects
associated
with the incorrect use of these agents.
Topical corticosteroids play an
important
role in the treatment of patients with
skin disease
and have improved the lives of countless
patients.
Please do not make their suffering worse
by allow
them the opportunity to diagnose or
misdiagnose and
mistreat their conditions. These are being
effectively treated by countless
physicians each
and every day.
The American Academy of
Dermatology urges
this advisory committee not to make these
powerful
medications available over-the-counter to
the
public.
I think you for this
opportunity and your
time. Have a good day.
DR. WOOD: Thank you very much.
Could we have Speaker No. 6.
DR. FONACIER: Good afternoon. I am Dr.
Luz Fonacier and I represent the American
College
of Allergy, Asthma, and Immunology.
I do not represent any industry
in this
220
meeting.
I am the chair of the Dermatologic
Allergy Committee of the American College
of
Allergy, Asthma, and Immunology, and the
Secretary
of the Food, Drug, Dermatologic, Allergy
and
Anaphylaxis Committee of the American
Academy of
Allergy, Asthma, and Immunology.
I head the section of Allergy
at Winthrop
University Hospital in New York, and am
Associate
Professor of Medicine in SUNY of Stony
Brook.
Thank you for allowing us to be
represented in this hearing. The allergists use
steroids in every shape and form for
asthma,
allergic rhinitis, and atopic dermatitis. Unlike
the ENT who uses the nasal steroids, the
pulmonologists for inhaled, the
dermatologists for
topical corticosteroids, we use all of
them.
Many of our patients use
topical,
intranasal, and inhaled corticosteroids
together or
separately. The concern of the American College of
Allergy, Asthma, and Immunology is
twofold, the
cutaneous use of topical corticosteroids
for eczema
especially for the less than 2 years of
age for
221
which nor many drugs are approved, and
the
translation of this to intranasal and
inhaled
corticosteroids.
For the cutaneous
corticosteroids, neither
systemic nor local side effects are easily
recognizable. The sensitivity of the cosyntropin
stimulation test, the cortisol level,
which are
lower than what we would want them to
be. The
growth velocity, osteoporosis, even adrenal
insufficiency are not recognized unless
specialized
testing is done.
Much of the discussion this
morning was on
the systemic effects of topical
corticosteroids,
but local side effects could be
disfiguring, as
well.
Skin atrophy, facial erythema,
telangiectasia are not easily
recognizable, at
least not until the irreversible stage of
the
striae.
There is low reporting of side
effects and
difficulty of monitoring is a big
concern. There
is also increasing incidence of allergic
contact
dermatitis to topical corticosteroids
probably due
222
to greater awareness, expanding market of
the
corticosteroids, and improved testing
procedure.
There are many reasons for
potential abuse
or misuse of over-the-counter
corticosteroids. Mid
and high potency steroids are going to be
more
effective than low potency. In fact, it was
brought up this morning that 1 percent
hydrocortisone, whose label says not to
use more
than 7 day, is actually being used years
and years
for chronic atopic dermatitis even in
children less
than 2.
Because of decreased efficacy,
there is
potential for prolonged use and thus
increasing
absorption and side effects, more so for
over-the-counter. Because the only topical
corticosteroids approved for less than 2
years of
age, is fluticasone, and that is more
than 3 months
of age, and this is a prescription, the
obvious
option for patients, especially those who
are
concerned of drug costs or don't have
medical
plans, is over-the-counter topical steroids.
Also, with the proposed black
box warning
223
for pimecrolimus and tacrolimus, there is
anticipated an increased shift to topical
corticosteroids. If more potent ones are
over-the-counter, in chronic eczema and
atopic
dermatitis, there may be increased
off-label use,
that is, more than 7 days and under
occlusion.
Other important issues that we
are
concerned about in over-the-counter
topical
corticosteroids are inappropriately
linked,
trivialization of what over-the-counter
is, that
is, the perception that over-the-counter
is safe,
credibility of advertising, appropriate
labeling,
and differences in vehicle that increase
absorption.
Note, that it is the Diprosone
Lotion
which may be alcohol based that showed
more HPA
axis suppression, and in the tacrolimus
and
pimecrolimus study, it is the study on
ethanol that
showed increased absorption of the drug.
The second major concern of the
allergists
is how this issue will translate to
intranasal and
inhaled corticosteroids for asthma and
allergic
224
rhinitis patients. We would not like to
see
difficulty in access of the medication,
unnecessary
panic or concern of the use of
corticosteroids in
potentially life-threatening disease such
as
asthma, nor suboptimal treatment. But at the same
time, would like to be able to monitor
our
patients, not only in terms of efficacy,
but most
importantly the safety.
Thus, as the representative of
the
American College of Allergy, Asthma, and
Immunology, until safer steroids are
available,
more sensitive tests can be used, better
monitoring
can be done, and more studies are
conducted, we
would like the current prescription
cutaneous,
intranasal and inhaled corticosteroids to
remain
prescription.
Again, in behalf of the
American College
of Allergy and Immunology, I thank you
for this
opportunity.
DR. WOOD: Thank you very much.
Are there any really pressing
questions
from the Committee for the public forum
speakers?
225
Yes.
DR. BIGBY: I just have one question for
Valentine Ellis. How many households are there in
the U.S., the total number of households?
MS. ELLIS: Right now there are about 113
million households in the total U.S.
DR. BIGBY: Thank you.
DR. WOOD: Any other questions? Yes, Jon.
DR. WILKIN: If I could ask Dr. Ellis if
he discerned why patients stopped using
the topical
corticosteroids over-the-counter, you have
that
they used it for 7 day or no more than 7
days for
the most part, I think it was, no more
than
something like 5 percent used it beyond
that, but
was that because they ran out of product,
or it no
longer seemed to work, or it actually did
work? I
mean did you get that piece out?
DR. ELLIS: Jonathan, that is very good
question. We did not delve into that in
this
survey.
The only answer I could say is that much
of the use was for insect bites and other
trivial
issues, and I am sure that explains part
of it,
226
part of the short-term use for 3 days of median
usage, so that would be my
interpretation, but we
didn't ask that specific question, and
that would
be a good one to ask at a future date.
DR. WILKIN: So, it is fair to say that
their, in large part, use is consistent
with
labeling, but not absolutely proven that
it was
driven by labeling?
DR. ELLIS: I don't know how I would
answer that specifically. Again, we asked them
questions, the type of question that I
showed you,
and then we later coded the responses to
determine
if they were consistent with the
labeling, so we
found that, by and large, people do
follow the
label, and we presume they are reading it
and that
is why they are following the label.
DR. WOOD: Let me just follow up on that.
I am intrigued by your confidence in
that. If you
look at Slide 12, 10 percent of the
children were
under 2, and how do you square that with
the label?
You need to look at that slide in the
context of
the way you framed the question.
You said, "Think about
your youngest child
who has used over-the-counter
hydrocortisone in the
last 6 months. How old is that child?"
227
Well, if that child is now 2
1/2, that
child was under 2 when they were using it
if they
were taking it 6 months ago, so if you
assume it
was averaged over 3 months, that brings
that up to
about 10 percent. That seems to me pretty high if
you think that the label is being
followed.
DR. ELLIS: Well, that is a qualitative
statement, I take your point. You know, we
think--I don't know--again that is a
qualitative
statement to determine whether 10 percent
is too
high or too low. I can tell you that of the people
who were at the time that we asked the
question
under 2 years old, so I take your point
that there
is a 6-month variation in here, but in
that 7
percent of children, in 81 percent of
those
children, the family had discussed it
with a
doctor, had discussed the use of
hydrocortisone
with a doctor, so that is somewhat reassuring
to me
on that point.
DR. WOOD: And more than 20 percent were
under 3, so again adding 6 months, we are
well over
that.
That is a pretty high number it seems to me,
wouldn't you think?
DR. ELLIS: You are assuming now that
everybody who is less than 4 is less than
2.
228
DR. WOOD: I am looking at your slide, and
if you put in 3, the vertical line from 3
is above
20 percent, and that is not adding in the
6 month
issue.
That seems to me pretty high.
Anyway,
okay.
DR. ELLIS: When you said 10 percent, I
would go with you on 10 percent. I think 20
percent is tipping it the other
direction.
DR. WOOD: The slide shows under 3 is over
20 percent without making any adjustment.
DR. ELLIS: Right, but the labeling says
under 2.
DR. WOOD: I understand, but I doubt that
there is a huge difference between a
2-year-old and
a 3-year-old that would give us
that. I mean that
says that almost 25 percent of the
product is being
229
used in under 3-year-olds. That is pretty scary.
Okay. Any other questions? Charley.
DR. GANLEY: Just to follow up on your
point, Alastair, I think it is important
to
understand that in that case, 81 percent
talked to
a physician or were guided by a
physician. I think
one of the difficulties that we have in
looking at
data like this is when people fall
outside the
labeling, well, why did they do that, and
we often
don't understand that.
It is very legitimate to talk
to a
physician, in fact, there is 3 or 4
warnings about
talking to a pharmacist, physician, or
someone else
either before taking it or after taking,
or if this
happened, you should do this.
So, to suggest that because we
have this
data that someone is buying 3 percent or
buying 7
tubes or more per year, that that is
somehow bad.
Well, maybe there is a physician
directing them to
do that.
So, I think that is what you
factor into
that is how does that fit into the
equation here.
DR. WOOD: Okay.
Dr. Mattison.
DR. MATTISON: Sort of taking a look at
the data from the other end, both of your
data sets
230
seem consistent in suggesting that 5
percent of the
kids used either more than 5 ounces a
year or for 7
or more days. So, from the other end of the data,
that seems like a fairly large group of
children
that are exposed for a long period of
time or to a
potentially large volume or dose.
DR. WOOD: Mary.
DR. TINETTI: My question is for the two
Academy people. You are operating on the
assumption that the fallback is that all
these
families and people have access to
dermatologists
or
allergists, and what is your stance on the 40
million people in this country who are
uninsured
and probably twice that are underinsured,
probably
will not have access to dermatologists,
and how do
they sort of fit into your equation of
the benefits
and harms for conditions such as atopic
dermatitis?
DR. FONACIER: I feel that those that have
mild eczema may use the 1 percent or the
0.5
231
percent hydrocortisone, but once you
start going to
moderate to severe atopic dermatitis,
which is a
really chronic disease, these patients
should be
under the care of a dermatologist or an
allergist,
and once the higher potency
corticosteroids are put
over the counter, they will access that.
DR. TINETTI: My question to you is those
people who don't have the insurance to
pay for
dermatologists, does the Academy demand
or require
that dermatologists see people who aren't
able to
afford the care? I understand that the perfect
position would be that they see a
dermatologist,
but for those who financially can't, what
is the
position of the Academy?
DR. FONACIER: Well, I represent American
College of Allergy and Immunology. You are talking
about the global health care issue here
for people
who would have the disease and have no
access to
care.
I would think that would be a Medicaid issue
of some sort. I don't know whether the American
College of Allergy would have a position
on that.
DR. WOOD: Dr. Santana.
DR. SANTANA: Following up on this issue
that was discussed a few minutes ago, of
pediatric
usage and looking at numbers, I want to
follow up
232
on that.
Do any of the two consumer surveys have
data that could help us investigate that
the
product was bought for an adult, but was
used on a
child, that they elected to use it on a
child
although the primary indication for
buying it was
for an adult?
MS. ELLIS: From the purchase perspective,
I can tell you we don't have that in this
particular data set, but it is something
we could
potentially follow up on and
discover. The
panelists, they tend to work more so on a
forward
going basis when they do that kind of
analysis,
but, yes, that is something that could
ultimately
be determined.
Just to be clear, just because
we see 5
ounces of product going into a household
with a
child, doesn't necessarily mean that the
child is
using it.
The data would indicate to us that
because there is no increased consumption
in a
233
household with a child, even though we
are seeing
disproportionately increased numbers of
bodies in
the household, we can't necessarily make
the leap
of faith that they are transferring
product usage
to a child without further analysis, a
little
different than what we undertook here.
DR. WOOD: Dr. Patten.
DR. PATTEN: Yes, I have a question for
Valentine Ellis. This is a question about the
children under 2 years of age. Do you know what
percentage of all households surveyed had
children
under 2 years of age?
MS. ELLIS: Yes, I do know that. I have
it probably in the back of the room.
DR. PATTEN: So, then we can figure out,
of those at risk, shall we say, what
percentage
actually were treated.
DR. WOOD: No, because they are different
surveys.
MS. ELLIS: I can't tell you if the child
was treated. I can tell you how much product the
household purchased, but I don't know
from the data
234
set that we have who in the household the
product
was used on.
DR. PATTEN: So, I guess I am thinking
about the other data set, the other Ellis, Dr
Ellis.
DR. ELLIS: That is a very good question.
I am not sure I can answer it
specifically because
you see we asked the adult in the family
to think
about the children in the family, and we
asked
think of the youngest child who actually
used the
hydrocortisone.
So, we were skewing out data
purposely
toward younger children, but I cannot
tell you--I
am sure that in the census data, there
probably are
these figures, but I don't know what
percentage of
households in the U.S. actually have a
child under
2.
I mean I am sure it can be looked up, but I
don't know the answer.
DR. PATTEN: It would have been really
good to also ask how old is the youngest
child in
your family, in addition to what is the
youngest
child that actually is treated. That way, we would
235
know.
I mean for all we know, 100 percent of
children under 2 years of age in your
survey were
being treated with this.
DR. ELLIS: Well, it is probably not the
case, though, because we asked the person
to think
about the youngest child who actually was
using
hydrocortisone.
DR. PATTEN: Right.
DR. ELLIS: And that turned out to be, if
you are interested in children under 2,
it was,
depending on how you averaged the data
point, but
least clearly, 7 percent were under 2 and
were
using hydrocortisone, and the family had
consulted
with a physician in about 80 percent of
those
situations.
DR. PATTEN: Right, I understand that.
DR. ELLIS: But I don't know if there were
children who were 6 who were using it,
and there
was also a children under 2 in that
family who
wasn't using hydrocortisone. I mean it must be
that there were such situations, but we
did not ask
that.
As you can imagine, with
surveys, after a
few questions, you are pretty tired of
answering
questions.
236
Thank you.
DR. WOOD: We have spent an hour on the
public comment period. I would like to thank the
public speakers for their time and their
attention
to our questions.
Let's move on to the discussion of the
questions and the Committee discussion.
Jack.
Questions to the Committee and
Committee Discussion
DR. FINCHAM: Alastair, over the break at
noon, I did as much as I could to find
out what the
environment is elsewhere, and I could
only have
time to do Canada, the UK, Australia, and
New
Zealand as far as what products are
available.
As far as I could tell, the
only
over-the-counter product in the class that
is
available is hydrocortisone. For example,
in New
Zealand, there is a limit on half a
percent
strength of hydrocortisone in a 30 gram
or less
237
container. There is nasal fluticasone available,
but it is not topical, and it is in a
class, at
least in New Zealand, there is 4 classes
of drugs.
There is prescription,
pharmacist only,
pharmacy only, and general sale, and it is
for
pharmacy only, so it is just like it is
in the
United States, but none of the other more
potent
agents that could determine were
available
over-the-counter anywhere else, at least
in those.
DR. WOOD: So, none of these are available
in the UK or Canada either. Okay, good.
Dr.
Nelson.
DR. NELSON: My impression of a lot of the
questions that we were asking our public
speakers,
which are difficult to answer, and I am
trying to
get a handle on this, is what is the
population
exposure for this product, and if that is
high, and
I am getting numbers that are in the
million, you
know, taking the number of households,
you assume 2
adults per household, which I realize is
probably
not correct, et cetera, you get a big
number, and
then the answer to the 10 percent
question is 10
238
percent of a big number is a big number,
too.
So, I guess I would say I am
not terribly
reassured by the fact that 90 percent
might be
using it on label, and even if the
labeling needs
to be improved, frankly, I find it
confusing as a
physician to keep track as a
non-dermatologist of
all of these different concentrations and
what I
should or shouldn't use, because I can
prescribe it
to myself, which I sometimes do, and it
takes me a
long time to figure out what to do.
The thought of someone going up
to a
countertop without my training and
figuring it out
is a little bit beyond me absent better
labeling.
I guess that's an editorial comment, but
I guess
the 10 percent sounds to me like a big
number, as
well.
I share your concern on that, that I heard
earlier.
DR. WOOD: Mike.
DR. ALFANO: I apologize, Alastair, for
not bringing this up this morning, but I
actually
didn't learn it until the lunch
break. In the
charge to the Committee, the Agency
indicated that
239
companies are potentially proffering more
potent
corticosteroids to go
over-the-counter. In my
mind, that said this could potentially be
revolutionary, I have got Class III in my
mind, I
don't really know.
But at the break, I learned
that one of
them is actually a Class VI, which is
classified as
mild, so that leads to the following
question. In
the AERS data that was presented by Dr.
Cook, I
understand there was a meeting in October
of 2003,
at which Dr. Karowski reviewed the AERS
data by
class, and in October of 2003, there was
not a
single serious adverse event leading to
Class VI
corticosteroid, and my question is has
that changed
in the year and a half since.
DR. KAROWSKI: In our update, we
didn't
find any of our additional cases had
involved
agents that were--
DR. WOOD: Could you identify yourself for
the transcriptionist.
DR. KAROWSKI: I am sorry.
Claudia
Karowski with the Division of Drug Risk
Evaluation
240
in the Office of Drug Safety. So, even in the
adult patients, they were all with the
more potent
corticosteroids. There was one case with Aclovate,
but that was also used in combination
with another
topical steroid.
DR. ALFANO: Thank you.
DR. WOOD: Frank.
DR. DAVIDOFF: I am having some
extrapolation problems here. One revolves around
the Dr. Ellis study, which I am having
difficulty
extrapolating from his data to the
general
population since he really only sampled 3
percent
of his potential population, so I think
it is a bit
of a stretch to generalize his
conclusions to the
rest of the population.
In effect, that study doesn't
help me
understand the appropriateness of use of
hydrocortisone more generally, but that
consideration is really secondary to my
other
concern, which is about what indications
are being
considered for the high potency steroids
if they
were to go over-the-counter.
Hydrocortisone is clearly being
used or is
approved under the monograph for--or
perhaps NDA,
whatever--as an acute, purely symptomatic
use, but
241
it sounds to me as though the high-potency
steroids, if they were to go
over-the-counter,
would be labeled and approved for more
chronic use
for actual therapy.
Maybe I am misunderstanding the
issue, but
we haven't heard a lot about what the
indications
would be or what the labeling would be,
and it
seems to me to try to extrapolate from
hydrocortisone with its very limited
intention for
us to the high-potency steroids, which
are not only
a different pharmacological class, but a
whole
different medical class, I am having
great
difficulty deciding how to extrapolate
from one to
the other.
Could somebody perhaps let us
know what is
being requested or what is the intention
in terms
of the prescribed indications and
duration of
therapy?
DR. GANLEY: I think there was no specific
242
indications other than what is already
available
for hydrocortisone, and that is not
atypical. I
don't think it's any different than when
other
drugs come over-the-counter. If there is a
heartburn indication when the H2 blockers
came
over-the-counter, they pretty much got
the same
labeling that a monograph antacid
treatment
received.
So, I think if that is as
holdup, you
ought to put it into that context. I think the one
thing that when you do look at the
current
labeling, where it has conditions that are
chronic
conditions, it almost is encouraging some
people to
do that, and I think that is a valid
thing that we
would have to look at if we were going to
put more
potent products on the market, because it
does have
the term psoriasis and things like that.
DR. DAVIDOFF: But if I may follow up on
that, it sounds like, then, that what is
being
proposed is to go after a flea with an
elephant
gun.
I mean to relieve an itch with a high-potency
steroid, I don't understand what the
request is.
DR. GANLEY: Let me just challenge you on
that a little bit, and I think you are
taking away
from people, allowing people to make
decisions. If
243
someone goes out and has a case of poison
ivy, and
with all due respect to the
dermatologists, it is
not easy to get an appointment with you
folks. In
personal experience, it's at least a
3-month wait
for family members.
But if someone chooses to use a
topical
over-the-counter product, and they choose
hydrocortisone, or if they choose a more
potent,
should they not be allowed to make that
choice? If
it doesn't work, they are not likely to
purchase it
again.
If it does work, they will have a future
reference that this worked the last time
I had
poison ivy. You are not allowing them to
make that
decision.
That is why I have a
difficulty. We have
all these other products out there where
there is
probably 6 or 8 antihistamines
over-the-counter,
but we don't have the same questions
about those.
So, I am having a very difficult time
understanding
244
that part of the equation as to why
should someone
not be allowed to make that choice.
DR. DAVIDOFF: But I think, if I
may, the
reason is that these--possibly--is that
these are
very potent, potentially very toxic
drugs. It is
not the same as just buying
hydrocortisone.
DR. GANLEY: Again, I think the issue here
was the safety of it. We recognize that these more
potent products present more--you know,
they could
lead to bigger problems. Otherwise, we
would have
just been putting these out there, and
one of the
speakers who suggested that we are
rushing to a
decision here, we haven't had one out on
the market
in the last 20 years, and I am very
encouraged that
we are actually--
DR. WOOD: We are rushing to a decision
here, we have planes to catch.
DR. GANLEY: Yes.
DR. WOOD: I would remind you, though,
Charley, that, you know, I seem to recall
the
antihistamine meeting, and the same cast
of
characters showed up to tell us we
shouldn't do
245
that as well. Isn't that right? Okay.
Jon.
DR. WILKIN: It is a fine point, but when
we are talking about more potent, I think
we at FDA
are talking more potent than the
currently approved
OTS hydrocortisone products. We are not thinking
about the more potent of all the current
Rx
products.
DR. WOOD: Dr. Epps.
DR. EPPS: I am going to comment and then
I have a question. One thing that is rather second
nature to a lot of dermatologists, but
not
necessarily to others, is the classes of
topical
steroids, even within hydrocortisone can
be very
different. There is hydrocortisone acetate,
butyrate and valerate, and they can vary
from Class
IV to Class VII, so some are
prescription, some are
not prescription, and just as several of
our
speakers have said, some people confuse
the
percentage as being their strength. Some
people
think hydrocortisone valerate 0.2 percent
is weaker
than hydrocortisone 2.5 percent, when
that is not,
246
in fact, the case.
There is some confusion out
there, and
different medications are put on the
incorrect
areas, which would be my concern as a
pediatric
dermatologist who certainly defend for
the little
people who cannot vote and cannot speak
for
themselves.
As far as application, of
course, the ones
who are getting the diaper rashes under
2, and, of
course, there are some seniors and some
nursing
home patients that we become concerned
about as
being applied on a moist area under
occlusion in
the diaper, and that is where your
absorption
occurs, that is where the side effects
occur,
whether it be stria or telangiectasias or
absorption, but that is where the
dermatitis
occurs.
That is one major concern that
we are
having, also people under 2 cannot
express to you
that they feel bad, that they feel
fatigued, that
they are having side effects that you may be
experiencing from HPA axis for an older
person or
247
child can do that.
One question someone asked, who
treats the
people if you don't have a dermatologist,
people in
emergency rooms, doctors treat them,
pediatricians,
family practitioners, nurse
practitioners. They
are often the first line, and as a
pediatric
dermatologist, if things don't respond,
they end up
in my office.
Is there any data--I guess my
question--at
other meetings, they have had express
script data
regarding a number of steroid
prescriptions and
ages for particular steroids, is any of
that data
available? Maybe that would help some people who
have questions about how many
prescriptions are
written, but there has been data
presented
previously. I don't know if any of that is handy.
DR. WOOD: While somebody is looking for
that, Dr. Wilkerson.
DR. WILKERSON: A couple of points of
clarification from the Agency. Are we--or Mr.
Chairman--are we actually talking about,
are we
deciding today that 1 percent
hydrocortisone is
248
safe?
DR. WOOD: No. At
least my impression is
that what we are deciding here is the
questions
that are listed on the table, which is
focused on
what one would need to do to demonstrate
that a
future application by a sponsor that
their drug was
safe to go over-the-counter.
DR. WILKERSON: But by extrapolation, if
one assumes we are making an assumption
in the room
that 1 percent hydrocortisone is safe,
has it been
subjected to the same criteria that we
are now
being asked to determine if these are
appropriate
criteria.
I can almost bet you that if I
cover your
body with 1 percent hydrocortisone cream
twice a
day for the next two weeks, I bet I can
suppress
your HPA axis unless somebody has
evidence to the
contrary, my point is I have not seen
that
presented today in terms of what is--we
are blanket
approving or passing on 1 percent
hydrocortisone in
any quantity to be safe, and that just
doesn't pass
the smell test, and if that doesn't pass
the smell
249
test, then, why do we go on to more
potent topical
steroids of which we don't have a metric
that we
even know the validation of right
now. If we don't
know the validation, the metric of 1
percent
hydrocortisone, what is the--
DR. KOENIG: I have two large boxes of
data from the meetings regarding the 1
percent
hydrocortisone, and the amended TFM that
came out
in 1990 addressed that specifically. I don't know
if I included that in the background
package, I
guess not, but there was extensive data
and
literature reviews, and it was determined
to be
safe and effective by FDA.
DR. WILKERSON: In what quantities and
what ages and what application rates?
DR. KOENIG: Well, it's OTC, so it follows
the labeling that is in the
monograph. That would
be children over 2, and it is restricted
to people
over the age of 2 years old and no more
than 3 to 4
times a day.
DR. WILKERSON: By these questions, we are
being asked to determine what is an
acceptable
250
level of HPA axis suppression, which is
directly
related to the volume, quantity,
condition of the
patient in whom it is being applied
to. How can we
do that if we don't even have a standard
for the--
DR. WOOD: Let me try and focus the
question.
I think the question you are asking is
has there been HPA axis suppression tests
for
topical hydrocortisone, right?
DR. WILKERSON: Right, and in what
quantities.
DR. WOOD: Let's hear if there is an
answer.
Do we have an answer to that in the two
boxes of data?
DR. KOENIG: We have HPA axis suppression
tests with 1 percent showing no evidence
of
suppression using the ACTH stim test,
actually,
cosyntropin.
DR. WILKERSON: But what quantity, what
percent body surface area, what age
groups, all
those things?
DR. KOENIG: It varies.
The ones that I
showed were all in children ranging in
age from I
251
guess 2, 2.5 year mean, median 2.5 years
up to I
think 14, and the body surface areas
ranged in the
five studies I presented from I think the
smallest
was about 30 percent up to over 50
percent of body
surface area.
DR. WILKERSON: Okay.
Well, I mean that
is a start for our metric then.
DR. WOOD: So, the answer to the question
is yes, there have been studies, and, no,
they
didn't show HPA suppression.
DR. KOENIG: They have, right.
DR. WOOD: Any other questions? Yes.
DR. RAIMER: Just a comment. If the FDA
is
looking at putting Class VI steroids
over-the-counter, I just want to remind
folks that
our ability to class steroids is so crude
still. I
mean what we do is basically the
vasoconstrictor
assay, which is running the cream on the
skin and
then coming back and measuring how big an
area of
blanching you get.
That is the best we have, and
that is
terribly crude. We have already seen today that
252
something that is considered a Class V,
which is
still considered really fairly mild,
caused HPA
suppression in 73 percent of older
children, not
even younger children.
So, I think we have to be
careful at being
too confident that things that are Class
VI really
all that mild. We just don't have a good way to
actually classify steroids, and it's
according to
strength at this point in time.
DR. WOOD: Dr. Skinner.
DR. SKINNER: I think in the idea of can
the public diagnose and treat themselves
with
strong topical steroids, you have to look
at
Lotrisone, which was kind of promoted as
is it
fungus, is it dermatitis, who cares, you
know, this
will take care of it.
So, how well did the family
practice
doctors and internists do with that? I know
dermatologists have seen a whole lot
problems with
that, African-American babies that had
white diaper
areas, stria, things like that, so this
is doctors
not being able to do it too well, so how
well in
253
the next step can the public do?
DR. WOOD: Dr. Nelson.
DR. NELSON: I guess I just want to keep
two questions distinct in my mind. One is whether
there is serious adverse events when used
within
the label that might be considered for
over-the-counter and limiting similar to
hydrocortisone versus what is the risk
when you
increase the potency of the particular
medication
you use for that 10 percent who is not
using it
within the confines of that label.
All the data we saw this
morning is
presented in a way that would not be
labeled for
over-the-counter use. It is 2 to 3 weeks, et
cetera.
To some extent, that is a question that we
have not been presented any data to be
able to
answer, because none of the studies of
the more
potent agents have been done on 7 days or
less of
treatment, so we are trying to
extrapolate on top
of extrapolations, which is fairly
difficult.
DR. WOOD: Right.
The issue here in that
context is there an over-the-counter
indication in
254
which there would be a reasonable
assumption that
people will not follow the label
precisely. I mean
maybe they will, and that is different
from an Rx
situation. So, that is part of the context for
this discussion, I think.
Dr. Bigby.
DR. BIGBY: I would just like to make two
comments and sort of expand on what Dr.
Raimer
said.
The first one is about this sort of
Stoughton vasoconstrictor assay. This test has
really not been without controversy. In fact, it
was the subject of an FDA panel regarding
generic
topical corticosteroids, and Stoughton
published an
article claiming that generics were not
biologically equivalent to enervators
based on the
vasoconstrictor assay.
The fallout from that paper was
that if
you take the same product and test it on
different
people on different days, you will often
get a very
different assay result and as much as a
two-class
difference in the product. So, I think it
really is
an inexact thing.
If you look at the table that
was provided
in Tab 1, in general, ointments are more
potent
than creams, which are more potent than
lotions,
255
but Aristocort Cream, which is 0.1
percent
triamcinolone is listed as being a Class
VI,
whereas, Kenalog Lotion, same product as
a lotion,
which I think all of us would agree
should be less
potent, is classified as a Class V, and
there are
many, many examples of this sort of
thing.
The second one was, you know, I
am very
familiar with Rule of 3, so if there are
no adverse
events in 20 patients, you put 3 over the
number
exposed, and that will give you the upper
95
percent confidence interval.
The other side of that is,
though, if you
have a very small study and you do detect
a signal,
it usually implies that there are, in
fact, going
to be a significant number of adverse
events, and
if you look at what was provided in Tab
9, in that
what was called Group 2 was included
betamethasone
valerate at 0.025 percent and
fluocinolone at 0.006
percent, and 1 out of the 17 of these
people tested
256
had HPA axis suppression, so already in
the lowest
group that we can consider, you already
have a
signal that you have HPA axis
suppression.
So, I mean I think that the
onus really is
on showing some really good proof that
these things
are safe, not at what level we need to
detect a
signal, because we have already detected
a signal.
DR. WOOD: Dr. Ringel.
DR. RINGEL: Two comments.
The first is
that we have talked about vehicles, and
one thing
that is important to remember is that the
monograph
process, the way it was described to me
today, it
is the drug that will be approved, and
not the
vehicle, so if we approve betamethasone
valerate,
we don't know what kind of enhanced
vehicle the
generic companies will compound it in,
and it feels
as if we would lose control over the
product that
is being used by our patients.
DR. WOOD: In fairness, though, and I
don't want to cut you off here, but that
is not
what we are approving today. I mean we are
addressing issues of HPA axis
suppression. Am I
257
right, Charley?
DR. GANLEY: It's that, but these are
products that are marketed under NDAs,
and they
would be marketed under NDAs, so their
formulations
are already set, whether it is an NDA or
an ANDA.
DR. WOOD: You mean they can't come in
with--
DR. GANLEY: They can't go into the
monograph.
DR. RINGEL: Okay.
DR. GANLEY: They would remain NDAs, they
would still have the same reporting
requirements as
all the others. Whatever hurdles you would set
today with regard to safety would apply
to a
company coming in with a specific product
saying we
want this to go OTC, whether it's a Class
I or a
Class 6, but this is the hurdles that you
have to
get over, that's it.
So, I don't want you to get
locked up in
all the formulation issues, because that,
I don't
know if it is an issue right now.
DR. WOOD: Do you want to respond to this,
258
John?
DR. WILKIN: If I could just comment on
the vaso, two members of the panel
mentioned the
vasoconstrictor assay. I can say on the new drug
side, and that is what we are talking
about today,
is that we have never used
vasoconstrictor data as
a surrogate for efficacy or safety, and
that is
really not part of that flow chart that
was
presented to this group.
DR. WOOD: Charley again.
DR. GANLEY: There was a question about
use of prescription products, and we do
have some
claims information.
DR. RINGEL: I did have one other quick
comment.
DR. WOOD: Go on and finish.
DR. RINGEL: I think that generalizing
about the use of other corticosteroids
based on
hydrocortisone may be not very accurate
either. I
think one reason that people don't use
much
hydrocortisone frankly is it doesn't work
very
well.
I think they stop it because it is not doing
259
anything in many cases.
I have no trouble getting my
psoriatic
patients to stop using
hydrocortisone. I have
enormous trouble getting my psoriatic
patients to
stop using clobetasol, because one they
get their
hands on it, and they realize that it's
doing
something, they don't want to let
go. I think the
better the product, the more abuse you
are going to
see.
DR. WOOD: Go ahead.
DR. MOENY: David Moeny from the Office of
Drug Safety. I did conduct an analysis of advanced
PCS claims data. This would just cover
prescription products, it doesn't cover very
much
OTC products.
We did find that the younger
the patient,
the lower the potency, and the smaller
the tube
that is dispensed to the patient. For instance,
basically, under age 16, greater than 80,
85
percent were dispensed of a low to medium
potency
product at 30 grams or less. Use is kind of
typically where you would expect to see
that in
260
that age group.
Does that answer the question?
DR. WOOD: It was Dr. Nelson who asked the
question, right?
DR. NELSON: What are the numbers, the
total numbers of prescriptions out of
curiosity?
DR. MOENY:
Prescription claims per year
were over 4 million.
DR. WOOD: Dr. Whitmore.
DR. WHITMORE: I think what disturbs me
about this is that the first
consideration probably
should be the ends that we are coming to,
and the
ends being patients being able to
correctly
diagnose and treat themselves.
If we could establish that that
is going
to be the case, then, I think you can
step back and
look at the other issues, but until you
can
establish that, I don't think you can
tell
pharmaceuticals that they have any
grounds to stand
on in terms of getting these
over-the-counter.
Surely, there are patients who
know
exactly what they have and they are
patients who
261
have already seen a dermatologist, been
taught how
to use things, who could efficiently
probably get
over-the-counter products like this, but
you are
going to have a great number of patients
who have
no idea what they are doing in terms of
they don't
know what their skin disease is. It may be a skin
cancer, it may be a fungus, it may be,
you know,
whatever, who are going to be using these
products,
and until somebody can establish for us
that
patients can diagnose themselves, I would
say that
the currently prescription products
should never go
over-the-counter.
DR. WOOD: Are there any new points that
any Committee members want to bring up,
that have
not been ventilated before? Okay.
In that case, let's move on, in
the
absence of hearing any, let's move on to
the
questions, and there is a preamble which
I will
read.
Companies are interested in the
potential
marketing of OTC topical corticosteroids
that are
more potent than the hydrocortisone
products
262
currently on the market.
Current OTC corticosteroids
labeling
limits use to approximately 7 days,
however, a
minority of consumers may exceed the
labeled
duration.
Safety concerns include systemic effects
and local effects. Of the systemic effects,
potential adrenal suppression is the most
concerning followed by Cushing-like
effects.
Please discuss the questions
below in
regards to developing a possible paradigm
to
evaluate the safety of topical
corticosteroid
products, and if I can find it again,
Charley or
somebody passed out the sheet, which I
can't lay my
hands on right now, but it is here, the
flow
diagram, yes, this one, the flow diagram
that
Charley passed out.
I guess that is sort of is the
basis for
the decisionmaking process.
So, let's go to the first
question.
If any subject has HPA axis suppression
with ACTH testing under maximal use
conditions,
does that preclude OTC marketing of that
263
dermatologic topical corticosteroid
product?
Is there discussion on
this? Yes.
DR. NELSON: I wouldn't mind a
clarification of what the phrase
"maximal use
conditions" means. Is that use as anticipated
under what might be an OTC label, or is
that misuse
as anticipated within the population who
would be
potentially buying this off of the
counter?
DR. WOOD: Well, my view would be the
latter, but I think the FDA may be
reluctant to say
that.
DR. WILKIN: The idea is maybe rather than
maximal use, a provocative test to see if
under
extreme conditions, it could occur.
DR. WOOD: Go ahead.
DR. BIGBY: I would just like to remind
the panel that the test being used to
detect HPA
axis suppression has a sensitivity of 70
percent,
so, even if the number is zero, you are
missing or
you are potentially missing 30 percent of
people
who are suppressed.
DR. WOOD: So, what you would suggest for
264
the sensitivity?
DR. BIGBY: My whole suggestion has been
stated, I mean that is the test that we
have, and
that is the question we are being asked,
but it has
a sensitivity of 70 percent.
DR. WOOD: Well, there is the Tinetti
modification of the test, widely
described in the
last two hours. I mean we could increase the
sensitivity by going up in the
requirement.
I mean I don't think we want to
do that
here, because none of us have a sense of
where that
number comes, but what Mary--I don't want
to put
words in Mary's mouth--but I think what
Mary was
suggesting was that you would increase
the height
of the bar and that that would bring that
sensitivity up substantially, and without
knowing
where that number is, you would be
reluctant to set
it, but that is probably there in data
somewhere.
Wayne.
DR. SNODGRASS: This Question 1, the way I
am reading it is I am being asked to
comment on
sort of a risk issue, a risk
consideration, and the
265
way it is worded is if any subject
has--and it goes
on--I am looking for any subject out of
what number
tested.
DR. WOOD: That's Question 2.
DR. SNODGRASS: All right.
DR. WOOD: So, the first one is an
absolute, and then the second one is out
of what
sample size. That is my reading of it, right?
Okay.
Yes, Ben.
DR. CLYBURN: The only thing I was going
to comment is that even with a relatively
insensitive test, and for secondary
adrenal
insufficiency, I think the numbers were
57 to 60
percent, there is still significant HPA
suppression
in the tests that we have already seen
presented
today, so we do have the smoke, so to
speak.
DR. WOOD: Dr. Wilkerson.
DR. WILKERSON: I went back to my point,
what is this maximal, I mean are we going
to apply
this to 60 percent body surface area, are
we going
to apply it to the back of the hand? I mean that
266
is what is going to determine for most of
these
drugs whether they pass the test or not.
If I put clobetasol on the back
of my hand
only, I am probably not going to suppress
my HPA
axis, but if I put it over 30 percent of
my body
surface, I am probably going to.
DR. GANLEY: The question was just
answered.
It is following the extreme provocative
test that is already required for
prescriptions,
where it is two weeks and covering 30
percent or
more, Jon, of the body? That is the extreme.
DR. WILKERSON: Okay.
DR. WILKIN: And I should add "involved
skin," in other words, not normal
skin, but skin
where the area has been compromised.
DR. WILKERSON: So, 30 percent involved
twice a day involved area.
DR. WILKIN: Well, maximal use, if the
corticosteroid is actually approved for 3
times a
day or 4 times a day, it would be at the
maximum
frequency, maximum duration, maximum
amount to be
applied, and the body surface area of
approximately
267
30 or 35 is the minimum.
DR. WILKERSON: I think that is a
reasonable pattern of potential overuse
for
over-the-counter.
DR. WOOD: Any other comments, questions?
No. Okay.
Then, let's vote on this. If
any subject has HPA axis suppression, and
does that
preclude marketing, so I guess if the
answer is
Yes, that means that precludes
marketing. Right?
Okay.
Let's start with Jack.
DR. FINCHAM: No.
DR. RAIMER: Yes.
DR. TINETTI: No.
DR. RINGEL: Yes.
DR. WHITMORE: No.
DR. CLYBURN: No.
DR. SANTANA: Yes.
DR. SKINNER: Yes.
DR. PATTEN: Yes.
DR. TEN HAVE: Yes.
DR. DAVIDOFF: No.
DR. BIGBY: Yes.
DR. WOOD: Yes.
DR. NELSON: Yes.
268
DR. SNODGRASS: Yes.
DR. MATTISON: Yes.
DR. SCHMIDT: Yes.
DR. EPPS: Yes.
DR. CHESNEY: Yes.
DR. TAYLOR: Yes.
DR. WILKERSON: Yes.
DR. STRATAKIS: Yes.
DR. BLASCHKE: Yes.
DR. WOOD: Okay.
Four No and the rest are
Yes.
The next question addresses the
issue we
just discussed. It is an attempt to sort of
address I guess from two directions, but
not
including Dr. Bigby's although I think we
probably
would want to add--
DR. ROSEBRAUGH: Alastair, the people that
said No, it might be of interest to the
Agency to
know, you know, one of the ways to look
at how to
269
draw the bar on safety was HPA axis
suppression, so
the people that said No, I would be
interested to
know how they would draw the bar then to
decide
what potency, what strength that they
would allow
over-the-counter and what sort of safety
thing they
want to look at.
DR. WOOD: So the people who voted No, we
are interested in knowing what, if
anything I
guess, you would use to distinguish it,
and we will
start, and I am going around the
room. Let's take
in the order they are on this list.
Frank.
DR. DAVIDOFF: Well, as I understood the
question, it was whether there is the
existence of
any potential to preclude its use
over-the-counter.
DR. WOOD: Not any potential.
DR. DAVIDOFF: Potential, right.
DR. WOOD: No, not potential, any actual.
DR. DAVIDOFF: Potential or actual, it
seems to me.
DR. WOOD: The question is actual, it is
not potential.
DR. DAVIDOFF: Okay.
The existence of
actual could be one case out of a
million. That,
to me, is not an appropriate--
270
DR. WOOD: That is Question 2.
DR. ROSEBRAUGH: Let me clarify it. If we
do sort of something similar to what they
do on the
prescription side, your second question
is how many
people do you test, but we have it number
of
subjects that we test, we run HPA
suppression tests
like we typically do on the prescription
side. If
any of those people suppress, does that
mean that
it would not be a product that could go
OTC?
That is the question, and so
the people
that said Yes, that means that that is
where they
draw the bar at. So, the people that said No, I
just wonder how you draw the bar.
DR. DAVIDOFF: Well, that's the next
question, I haven't gotten to that. All I was
trying to say is--
DR. WOOD: Frank, I think that is not the
next question. I mean the next question might be
answered by the Committee that they only
needed to
271
do 10 people, for example. I am not suggesting
that will be, but if that was the
question and you
found one, your answer was that that
would not
preclude its marketing.
DR. CLYBURN: I was going to say, I went
the same line of thought that if any
subject, so
theoretically, there could be one subject
who would
be suppressed, and you would look at it
out of a
large number, and say that that was
probably an
acceptable rate, whereas, I could have
easily gone
the other way had I said even the change
here, does
the
potential for suppression, it depends on how
much potential. That was in our original
packet,
the original question.
DR. ROSEBRAUGH: Well, let me just try to
clarify for the panel then. A sponsor brings a
package in to us. They have run the test
however we
decide by 2, it's Question 2, however
many numbers
we say you need to run it, and one of
them have
suppressed on that test, does that mean
that that
drug should not go OTC. That is what the question
is supposed to mean.
DR. DAVIDOFF: May I finish my answer,
because I haven't had a chance? I have been cut
off four times.
272
Even if they brought in data
showing zero,
and their sample was 100, we still know
that there
is the potential. The point that I am trying to
make about why I voted was that there are
any
number of drugs that are on the market
over-the-counter including things like
acetaminophen, which can rot your liver,
and does
regularly in this country. That does not preclude
its utility and its acceptance for use
over-the-counter.
Using the same reasoning, I
couldn't a
priori vote that the actual occurrence of
HPA
suppression, on its own merits, would be
enough, by
itself, to preclude over-the-counter
marketing.
DR. WHITMORE: I second what Dr. Davidoff
said, and there are other reasons why I
would not
let it go over-the-counter, but not this.
DR. WOOD: Say that again.
DR. WHITMORE: I second what Dr. Davidoff
273
said, and if there were 1 in 100 or even
zero in a
100, well, let's say a positive, there
was 1
positive, because you said any positive,
so if
there were any positives, 1 in 50 even,
that would
not be my reason for not allowing this to
go
over-the-counter. I have other reasons, but not
that.
DR. WOOD: Ben.
DR. CLYBURN: Just echoing what I said
before on what Dr. Davidoff said.
DR. WOOD: Mary.
DR. TINETTI: I agree with Dr. Davidoff.
DR. WOOD: Jack.
DR. FINCHAM: I think I am the fourth and
final one.
DR. WOOD: You are the fifth and final one
now that we--
DR. FINCHAM: That's a great question, and
I guess I answered it in the context that
Dr.
Davidoff talked about relative to other
products
that are available over-the-counter. There are
geriatric patients that have GI bleeds
that die
274
weekly because of NSAID use or aspirin
use, so I
think it is a risk-benefit assessment.
That is a long answer to a
short question,
but that is what I was looking at was in
the
context of everything else that's
available.
DR. WOOD: Then, let's go to Question 2.
The number of subjects evaluated provides
for the
confidence in ruling out HPA axis
suppression at a
desired upper limit. With a 95 confidence
limit,
what is the greatest rate of HPA axis
suppression
to be ruled out?
The question really here
relates to the
sample size, and I guess we could add to
that, if
Dr. Bigby agrees, and Mary, that part of
that could
also include whether there should be some
increased
sensitivity for the test. Is that reasonable,
Mary?
Okay. So, we would review this
with an
increased sensitivity. Okay.
Discussion?
DR. TINETTI: Are we limited to the
numbers on this?
DR. WOOD: I don't see why we should be.
Dr. Nelson.
DR. NELSON: A question for the
endocrinologists perhaps. Of those individuals who
275
would be suppressed, what is the percent
risk of
sudden death in those individuals? We talked about
that is what we fear, but if you took 100
patients
who were suppressed from whatever steroid
administration, how many of them would
necessarily
suffer that fate?
DR. STRATAKIS: I wouldn't have the answer
to this question, because when we talk
about
suppression here, we define it by the
criterion of
18, and for the people that have died in
emergency
rooms and under other circumstances of
stress, that
were insufficient, nobody has been able to
go back
and regulate the sudden death with the
actual
stimulated peak values.
DR. WOOD: I am not sure that they are
using this just for sudden death. I mean they are
using this as a surrogate for other evidence
of
corticosteroid--
DR. STRATAKIS: Well, he is asking
276
specifically about that.
DR. WOOD: I understand, but my sense
is--and this can be addressed to the
FDA--that we
are using HPA suppression as a means, a
quality to
measure of systemic corticosteroid
excess, you
know, Cushing's, glucose intolerance that
Dr.
Taylor talked about, and all the other things,
and
that is one way to get at that.
DR. STRATAKIS: That is Question No. 3.
DR. GANLEY: I guess there is a sense that
of the people who come to an emergency room
or are
admitted to a hospital with the diagnosis
of
adrenal suppression or symptomatic
because they are
on known steroids, what percentage of
them die?
That is one question.
But again I think the thing is
that
apparently there is a lot of people out
there that
are on chronic steroids topically and
orally that
are just going along and perking along
and do fine
until they get into a stress situation,
so what is
the risk of getting into a stress
situation, too?
It is fraction of a fraction.
DR. WOOD: But it is not possible to
answer that question.
DR. STRATAKIS: Except that perhaps the
277
best way to answer that question would
be--and I
just thought about something, and I used
the
example before--of patients with
panhypopituitarism
who, by definition, have cortisol
responses to ACTH
of
zero.
So, these patients, if you look
at the
studies I mentioned before, you look at
lifetime
risk of death, as I mentioned before,
death from
adrenal cortical insufficiency was the
number one
cause of death in these patients.
DR. WOOD: And these are patients who
carry the diagnosis with them at all
times.
DR. STRATAKIS: Correct.
This is lifetime
risk of a patient that has a cortisol
value of
zero, an endogenous cortisol value of
zero in
response of ACTH, lifetime risk of sudden
death
being the highest reason for mortality in
these
patients.
DR. WOOD: But I mean most of these
278
patients have a bracelet, and so on. These are
different from people who are taking--
DR. STRATAKIS: Correct.
So, there are
factors, I guess, that would increase
mortality in
our population.
DR. WOOD: Dr. Epps.
DR. EPPS: Just a comment, I guess.
Hydrocortisone has been around for 50
years, we
have good experience with that. That is all the
atopics had for many, many years. Some of the
newer ones have been around 20 years,
perhaps 10
years.
We don't have as much information about
them on a large area, but there is a
large
experience with hydrocortisone.
We don't know about the newer
ones, and
that is really what we are talking about,
the ones
we really don't know.
DR. WOOD: Any other comments on this
question?
Yes, Dr. Bigby.
DR. BIGBY: I actually apologize for
keeping going back to this. If roughly 30 percent
of the patients who have this test may be
giving
279
false negative numbers, the actual
numbers of the
upper adverse event rate in this table
are actually
10 times what is printed here.
DR. EPPS: I agree with what he says and
also that suppression is under-recognized
and
under-diagnosed, so that some of those
cases are
being missed, too, you know, the patient
is not
getting better, we don't really know why,
on and
on.
I mean this would be more of an acute
situation rather than probably in the
outpatient
situation, but that is true.
DR. GANLEY: Could I just get
clarification? I am not sure what you are saying
is 10 times. If you have 10 people and it's zero,
10 times 26 is not 260 percent. I don't know what
the number is, but I don't know if it's
10 times.
DR. BIGBY: That is true for the very low
numbers, but if you go to 100, for
example, you
know, it is 3 divided by 100 or 3
percent, but
there may be 30 people who gave you a
false
negative result, so it is really 33 out
of 100, not
3 out of 100.
DR. GANLEY: But you could increase your
sample size by a certain amount.
DR. WOOD: One.
280
DR. TINETTI: It would only be one extra,
so it would be 4 percent rather than 3
percent.
DR. WOOD: It would be 30 percent of 3,
not 30 percent of 100. So, it would be 4, not 3,
but the point is still the same.
Dr. Skinner.
DR. SKINNER: Until this morning I really
had never thought about the idea of
people rolling
into trauma units of emergency rooms on
topical
steroids and dying because of that. So, we don't
know what that problem is, how big it
is. Now, we
are talking about multiplying that
problem by
something if potent topical steroids go
over-the-counter.
It is hard to make these
decisions not
knowing what that multiplier is. If it's no
problem, then, multiplying it probably
isn't a
problem.
If it's a pretty good problem, then, you
know.
I guess that data is never going to be
281
known, but I think that certainly weighs
in how you
think about this.
DR. WOOD: Dr. Nelson.
DR. NELSON: My concern here is and I
don't fully understand how you monitor
the safety
of
over-the-counter drugs. Certainly, the
Adverse
Event Reporting System--
DR. WOOD: This is not to monitor the
safety, this is to determine--
DR. NELSON: I understand that, but there
is a relationship between how many people
you put
in the initial trials versus the ultimate
safety of
the drug.
We have taken things off the market
because things have occurred at a much
lower
incidence than 0.3 percent in the first
1,000.
So, I am not confident that
what we do for
drug approvals in non-over-the-counters
in fact is
sufficient, and I find myself going back
and forth
around that issue, you know, how much do
you do in
the first part, then, what do you do
post-marketing
to monitor it, and my confidence would be
assured
if I thought we had a decent
post-marketing system.
282
Otherwise, you end up increasing the
pre-marketing
number quite high to where you keep
things off of
the market.
That is where I find it a
little bit
difficult to put a number on a
pre-marketing study.
DR. GANLEY: For these drugs, the
reporting requirements are no different
than
prescription, so the question is, is the
reporting
different for OTCs versus
prescription. I mean we
know the prescription adverse events are
not
reported as well as we would like.
DR. NELSON: That answer is both are poor.
DR. GANLEY: Both are poor, but there is
mandatory requirements to reporting from
a
company's point of view for an NDA
product.
DR. WOOD: But OTC is unlikely to be
better.
DR. GANLEY: I would agree with that.
DR. WOOD: Mike.
DR. ALFANO: This will be more meaningful
to the people from NDAC who were here
yesterday,
because yesterday we were dealing with a
surrogate
283
test also, and we killed it basically
because there
was no link to a specific meaningful
clinical
endpoint.
So, we have another surrogate
test for
adrenal sufficiency, the HPA suppression
test
today, and we are embracing it, and yet
it is not
linked, as we have learned, to a specific
clinical
endpoint.
Certainly, there is a suspicion as there
was yesterday that there is a linkage
there, but
there is no way to directly link it.
So, that concerns me a bit that
for some
reason, a very analogous situation is
viewed
differently today than it was
yesterday. Then, if
you look at the AERS database, and for
Class VI and
VII, real world experience, there is not
a single
serious adverse event reported in the
entire
database of several million reports.
So, there seems to be an
inconsistency in
the way at least NDAC has acted over the
last two
days.
Admittedly, different situations, different
tests, different degrees of potential
negative
outcomes, but in principle, we are
valuing this
284
particular test higher than we valued
yesterday's.
DR. WOOD: I am not sure I agree. I mean
this is like a blood culture for yesterday's
analogy.
I mean this is a diagnostic test for a
disease, and this is the diagnostic test
for
cortisol excess in the systemic
circulation, used
to diagnose Cushing's, used to diagnose
HPA
suppression in vivo. I mean that is different from
sampling bugs on the hand.
This is the test that if you
walked into a
hospital in this country today, and
somebody said I
believe you have got adrenal suppression,
the test
that would be done to do that is--
DR. ALFANO: I understand the subtlety,
Alastair, I really do. It is just that when
pressed to define what that means in
terms of
severe outcomes, to suppress who is
positive in
this test, we have not been able to
relate it to
anything, and that is parallel to
yesterday.
DR. WOOD: I think the question that was
asked was sudden death to which it was
difficult to
give an answer. We know a lot about the morbidity
285
associated with HPA suppression and with
Cushing's.
I don't think these are the same at all,
and I
think it would be misleading if we left
people with
the
impression the only bad thing that happens to
you from HPA suppression is dying in the
emergency
room because somebody didn't give you
steroids, I
mean it is substantially worse than that.
DR. STRATAKIS: I agree.
I think it is
misleading to say that--I voted Yes to
this, the
first question because I think that there
is a high
risk of having patients dying in the
emergency room
because of adrenocortical insufficiency
after they
have used OTCs. I don't think that is the case. I
think that the risk of that happening is
extraordinarily low, but I am concerned
about the
patients that we are missing that have
some degree
of adrenocortical axis suppression, that
have many
other systemic effects that we cannot, or
at this
point we don't know how to measure them.
DR. ALFANO: Again, just trying to link to
the real world, we saw 60 events in over
50 years
of availability, at least of
hydrocortisone, and I
286
don't know how many millions of doses
were applied,
so I am just trying to--
DR. WOOD: But we see very few events with
digoxin, too.
DR. STRATAKIS: What were the 60 events?
DR. WOOD: All drugs have very small
number of events in AERS, so digoxin,
which is the
largest cause of adverse events in
hospitals, and
warfarin, don't have a proportional
number of
events in AERS database even though, in
hospital-based drug safety studies, they
are the
most frequent causes of adverse events.
So, I mean I think you have to
be careful
about it.
The largest reporting rate occurs in the
first few months of a drug's marketing.
Dr. Whitmore.
DR. WHITMORE: I need to preface this and
again say that I am not for approval of
these going
OTC, but what I would say is that 20 or
30 percent
of our patients who are using the higher
potency
steroids are having this HPA suppression,
which we
are not doing anything about, and
hopefully, if we
287
are seeing them on a regular basis, which
may be
regular or less regular, we would pick up
if they
had any clinical symptoms of adrenal
insufficiency.
But I would have to add to that
this is
happening all the time, and there is
nothing that
is being done about it, so I don't know
if it makes
it any different whether it
over-the-counter or by
prescription, still nothing is being done
about it,
and
maybe we should be doing something different.
Again, I have to reiterate I
don't think
they should be OTC for a different
reason.
DR. WOOD: That is Dr. Alfano's point, as
well, actually.
Dr. Chesney.
DR. CHESNEY: In response to the AERS
database, I think many physicians don't
report
known side effects, so they may be seeing
striae
and they may be seeing a lot of other
things, but
they wouldn't report them as an adverse
event
because it's a well-described
complication.
So, I think the fact that there
aren't
many reports doesn't convince me. I think the
288
other thing that we have said over and
over again,
which is we have no idea of how many
patients who
are immunosuppressed because they have
had topical
steroids come in with sudden death, and
nobody
thinks to ask them, nobody looks for it,
so I just
wanted to make that point again.
DR. WOOD: Any other comments? All right.
Are we ready to take this question?
Are we going to give an
answer--I guess
what we need is an answer, and Mary is
not here, so
maybe we can do it without having to come
up with
other numbers, but her question was do we
have to
stick to these numbers, and I guess the
answer is
no, but you want us to give a number,
right? All
right.
So, pick a number.
DR. BLASCHKE: I will pick a number. I
would pick 100.
DR. STRATAKIS: 1,000.
DR. WILKERSON: 1,000.
DR. TAYLOR: I would pick 100.
DR. CHESNEY: I haven't a clue how to
answer this, I really don't, so I am
going to say
289
10.
DR. EPPS: Greater than 1,000.
DR. SCHMIDT: 50.
DR. MATTISON: 1,000.
DR. SNODGRASS: 1,000.
DR. NELSON: 1,000 or greater.
DR. WOOD: 1,000.
DR. BIGBY: Can you come back to me?
DR. WOOD: No, now is your moment. Now is
your moment.
DR. BIGBY: I would say greater than
1,000, and then the other thing I would
say is that
we already have a signal in the lowest
class in
drugs that we can consider, 1 out of 17,
so I don't
know why we are giving a number.
DR. CHESNEY: I agree.
That is why I
didn't know how to answer it.
DR. DAVIDOFF: I would say at least 1,000.
DR. TEN HAVE: 1,000.
DR. PATTEN: 1,000.
DR. SKINNER: 1,000.
DR. SANTANA: At least 1,000.
DR. CLYBURN: At least 1,000.
DR. WHITMORE: 100.
DR. RINGEL: I don't even want to have 3
290
out of 1,000 people running around with
HPA
suppression without any monitoring, so it
is going
to be greater than 1,000.
DR. TINETTI: Greater than 1,000.
DR. RAIMER: 1,000.
DR. FINCHAM: 1,000.
DR. WOOD: Let's go on to Question 3.
Beyond HPA axis suppression, are there
any other
safety concerns that would not permit OTC
marketing
of a dermatologic topical corticosteroid?
I guess you would mean that in
the context
of the absence of HPA suppression in
whatever the
number was you decided on, correct? Okay.
So, what we are looking for
here are
safety concerns that would for some
reason not have
been picked up with HPA suppression in
that screen.
Any comments? Yes, Dr. Nelson.
DR. NELSON: I think to bring up the
growth velocity as a pediatrician. I think one of
291
my concerns would be if it is relatively
unsupervised, the duration may exceed
reasonable
duration, and the issue of reversibility
may not
then occur.
I mean a lot of that would be
reversible
if you stopped it and doing it
unsupervised just
leaves that as an open-ended question, so
growth
velocity is of concern to me.
DR. WOOD: Any other comments?
DR. SCHMIDT: One of the things we haven't
mentioned is we are seeing a lot of
contact
dermatitis from the topical steroids, and
I don't
know how much of a safety problem that is
unless
you have a severe contact dermatitis that
gets
infected.
I am going to pass this article on from
Contact Dermatitis, that it gives the
percentages
of the different contact dermatitis with
topical
corticosteroids, but that is something
that I would
consider is severe contact dermatitis
from some of
these things.
DR. WOOD: Any other comments? Yes.
DR. WILKERSON: I think from a pure public
292
health standpoint, the elderly
population, bone
mineral density loss, declining levels of
vitamin D
levels in the population, thinning skin,
probably
increased percutaneous absorption, that
BMD is a
significant public health concern with
use of large
amounts of topical steroids.
DR. SANTANA: This is my interpretation of
safety in a very broad sense, but as I
commented to
a colleague recently, you know, the issue
for me
for OTC products is the ability of the
individual
to self-diagnose and make a diagnosis
that is
consistent with the indication for which
they are
using the product.
So, to me, it is a safety risk
if people
are not educated to use the product for
which it is
indicated, and they are buying it on
their own
unsupervised. To me, that is a safety risk.
DR. WOOD: Dr. Taylor.
DR. TAYLOR: I still would like to see
some data on the diabetes issue and
particularly
those individuals who have brittle
diabetes,
insulin dependent.
DR. WOOD: Any other comments? Yes.
DR. MATTISON: I also have some concern
about blood pressure control especially
in the
293
context of hypertension in the context of
increasing incidence of obesity in the
United
States.
So, that is an issue that I would be
concerned about.
DR. SCHMIDT: One other thing that has
been mentioned is the use of concomitant
nasal
steroids or even oral steroids with this,
you know,
a potentiating effect.
DR. WOOD: Other comments? Okay.
I guess
that is all we need on that really. We don't need
a vote, or do we want a yes/no vote? Okay.
We
want a yes/no vote.
So, the yes/no vote is
what? Are there
other safety concerns that would not
permit OTC
marketing of a dermatologic topical
corticosteroid?
In the absence of HPA axis suppression
you mean,
right?
Okay.
DR. GANLEY: To find out just what were
those concerns, so I am not sure--do you
need a
294
vote, Jon? No.
DR. WOOD: No vote?
Good.
Would labeling, for example,
warnings for
the
systemic effects other than HPA axis
suppression be an acceptable regulatory
path in
lieu of testing for the other systemic
effects, for
example, growth hormone suppression,
osteoporosis?
Comments? Yes.
DR. MATTISON: I am concerned that we are
good enough at risk communication to be
able to
effectively transmit complex information
about
growth or other non-HPA axis impacts to
the diverse
populations of parents that might be
using these on
their children.
So, I guess I would have to see
the labels
and understand how effective they were in
testing
before I would be willing to be
comfortable with
that approach.
DR. WOOD:
And labeling has been
extraordinarily unsuccessful in
prescription drugs,
at least in my view, so I am not at all
confident
we would be very successful.
DR. GANLEY: That is because you are
dealing with a population, that is the
population
you are dealing with in a prescription--
295
DR. WOOD: I understand that. It is these
damn doctors, right? Okay. Dr. Epps.
DR. EPPS: On many of the prescription
drugs, there already is discussion of
growth
suppression on the insert. Some read it, some
don't.
DR. WOOD: Dr. Whitmore.
DR. WHITMORE: I would say absolutely not
in terms of relying on patients to detect
these
things that we have to have very
sensitive testing
to detect? Absolutely not.
DR. WOOD: Sorry, say that again.
DR. WHITMORE: I mean you can't bypass
this by saying you are going to put in
the patient
information package your child may have
growth
suppression, watch for this. We have to use
extremely sensitive testing to be able to
pick up
that.
I mean how can you tell a parent that, to be
watching for--or an adult--to be watching
for
296
osteoporosis? Well, when they get their DEXA, they
are told they have osteoporosis, they
will know.
DR. WOOD: Beware of fractures, right?
DR. GANLEY: Can I just interject here?
The thought process here I think was what
do you do
with the tests that you ask for, and we think
about
that all the time, does it help us make a
regulatory decision.
So, let's just say for the sake
of
discussion that we could do growth
suppression,
which you have already heard would be
very hard to
do
with the dermatologic condition.
So, then, you think about,
well, if I did
the test and it came out and showed
growth
suppression, does that mean I could
convey that in
the labeling with some accuracy, or does it
mean
that this is a no-go for this drug,
because it did
that.
Now, if it's just a label
issue, well, I
don't need the test to write a label,
because I can
say, and you heard the pulmonologists
say, that
there is a lack of certainty. They make an
297
assumption that there is growth
suppression, so if
you do make that assumption, is it okay
to convey
that?
Again, this is for the situation where
people are misusing the product, not for
the actual
use of the product.
DR. WHITMORE: Well, essentially, what you
would be doing is just making a
disclaimer, that
you may have growth suppression, you may
have
osteoporosis when you use this if you put
that on
the label.
DR. GANLEY: You already have that on the
prescription labels. They don't check for
osteoporosis, they don't check for growth
suppression. You already have that. Are you
applying a different standard, that's
all.
DR. WHITMORE: Well, it seems like we are
for the HPA suppression, but what I would
say is
maybe we should readdress that in terms
of the
prescription medications and what testing
is
required for approval of prescription
topical
steroids.
DR. EPPS: And the difference is the
supervision that's involved, over-the-counter
versus prescription. You are talking about doing
298
it unsupervised, over-the-counter.
DR. GANLEY: No, what we are doing is
saying if you use this for extended
periods of
time, it could lead to these things. If you go to
the store and buy a nonsteroidal
anti-inflammatory,
acetaminophen, aspirin, antihistamines,
it has all
these disclaimers on it already, if you
do these
bad things, so that is what we are asking
here.
DR. EPPS: But even under customary,
regular use, there are occasions when we
are seeing
suppression.
DR. WOOD: Let me try and resolve this. I
think if we break the question down into
two parts,
it might help people to focus their
discussion.
The question, which maybe we went over 3
too
quickly, is are there other things that
would
preclude the drug being marketed
over-the-counter,
other adverse events.
For those who felt there were
not other
299
adverse events that would preclude the
drug being
marketed over-the-counter, then, would
labeling be
sufficient, would there be a way to label
the drug
to explain that carefully enough to
people. Is
that sort of a fair summary,
Charley? Yes.
DR. GANLEY: I think so.
DR. WOOD:
We didn't get on Teresa's list
here growth suppression, right? All right.
Does
that help?
DR. WHITMORE: I guess as you are saying,
we don't really have to answer No. 4
because we
have already said, in No. 3, there are a
host of
different reasons why this shouldn't be
approved
based on side effects.
DR. WOOD: We didn't a host, we said four
things.
Actually, if there are more, Teresa is
trying--
DR. WHITMORE: Oh, absolutely. I didn't
speak up because I thought we had already
been
through all these, but all of the
cutaneous side
effects, telangiectasias--
DR. WOOD: Wait, wait.
If there are
300
people who didn't get a fair hearing on
3, let's go
back to that. Teresa has the following things
down:
diabetes, hypertension, osteoporosis, and
growth suppression.
Are there other--let's be clear
what we
are saying--we are not asking for an
encyclopedic
list of every potential side effect of
topical
steroids here, we are asking for side
effects that
would preclude them being marketed, and
as Charley
said, there are lots of side effects
associated
with lots of drugs that are marketed
over-the-counter including renal failure,
hepatic
failure, and so on.
So, we are asking for show
stoppers
essentially.
DR. WHITMORE: Can I continue?
DR. WOOD: Sure.
DR. WHITMORE: Increased ocular pressure,
glaucoma, potentially cataracts. Other things
would be steroid-induced acne, which I
have seen
before, with mid-potency topical steroids
used for
6 months on the face, coming in with this
301
horrendous acne from eruption that takes
months and
months and months to get rid of.
I think each one of those
potential
systemic side effects that we have
already talked
about are very important, and we don't
have enough
data to even know how important they may
be.
DR. WOOD: So, before Mike has a stroke
here, how would a company perform a study
that
would exclude these things? I mean if we are
specifying show-stopping issues, then, by
definition, they would have to be looked
for before
the drug could go OTC.
I am not arguing with you, I am
just
getting a sense of where we put that
bar. So, how
would you, for instance--
DR. WHITMORE: Well, in terms of we were
talking before about osteoporosis.
DR. WOOD: I was thinking of the acne.
How would they exclude acne?
DR. WHITMORE: There definitely is--well,
for one thing, those mid-potency steroids
should
never be used on the face, but they are.
DR. WOOD: So, that would see to be
Charley's labeling issue, I guess. Do you see what
I am saying? I am trying to make a distinction
302
between the ones that set a bar that
would preclude
marketing, which would require some kind
of
investigation first, and ones that are
warnings
that would require labeling, "Don't
use it on the
face."
DR. WHITMORE: Further investigation in
terms of use on the eyelids, they could
label it as
such that it can't be used on the eyelids
or,
instead, they would have to do a study
where they
applied it to eyelids and come up with a
number of
induced increased intraocular pressure,
and things
like that.
I think these side effects are
things that
we, as dermatologists, look for every
time a
patient comes back, and if these things
are not
looked for, they are going to be
missed. So, I
would say--I am kind of back to that ends
again--and saying that diagnosis and
treatment,
ongoing treatment, should not be done by
a patient,
303
and so to give the pharmaceutical
recommendation
about testing is difficult.
DR. WOOD: Jon, do you want to say
something?
DR. WILKIN: It might be helpful,
especially as the different panel members
are
weighing in on this, it would be helpful
to know
what you do when you prescribe Class I
and Class
II, the really upper end potency products
to your
patients.
I mean do you have a scheduled time
when
they go to the ophthalmologist to look
for eye
pressure, for cataracts, you know, how
often does
one test glucose tolerance, checking
blood
pressures, things like that.
Just to remind everyone, we are not
talking about Class I and Class II
products
imminently going over-the-counter. We are really
thinking that Class VI would be the
target zone of
candidates, not necessarily ones that are
sure to
go over, so much, much less potent than
the Class
I/Class II, and if you could give us an
idea of
304
what you routinely do for the patients
maybe at the
upper end, that would be helpful.
DR. WHITMORE: I would just say in terms
of seeing an ophthalmologist for an eye
pressure
check, if they were using clobetasol on
their
elbows, I would not do that, so it
depends totally
on where you using whatever product is
you are
using.
You take a pill, it goes in your stomach,
and it's affecting your whole body, but
we are
talking about application of topical
products that
are site specific and potentially side
effect site
specific, too, so it is very difficult to
outline a
whole program of that, and that is why
dermatologists train for the period of
time they
train.
So, to answer your question,
you would
have to give me a specific body area of
treatment
and a potency of a topical steroid for me
to answer
the question about how they should be
monitored.
DR. WILKIN: Well, how about brittle
diabetes or blood pressure control, under
what
circumstances do you routinely say look
for glucose
305
intolerance in patients who are using
topical
corticosteroids in your practice?
DR. WHITMORE: I don't normally do that.
Most patients who have diabetes are
monitoring
their blood sugars on a regular basis, so
I think
that takes care of that issue if indeed
there is
enough systemic absorption to affect
their glucose
metabolism for that answer.
I don't have a regular program,
I don't
have a regular protocol that I talk to
them about
hypertension with topical steroid use.
DR. STRATAKIS: On the list of things that
we didn't add before, I just would like
to add
local and systemic immunosuppression and
obesity,
weight gain.
DR. WOOD: Other comments? Let me weigh
in on this, as well, then. i have a concern I
guess about just producing a laundry list
of known
side effects of steroids and making
that--and I am
not advocating for potent steroids to go
over-the-counter, but as a principle, I
have a
concern about creating a laundry list of
side
306
effects from a drug and saying any drug
that
produces these known side effects of
these drugs
cannot go over-the-counter.
That is not to say that I am
advocating
for them to go over-the-counter, but that
seems to
me a dangerous sort of step. I mean, for example,
if the risks of glaucoma are from
applying them to
the eyelids, then, you don't do a study
to test,
applying them to the eyelids to show that
you don't
get glaucoma, you label them to say don't
apply to
the eyelids.
I want to try and make that
distinction
somehow, so that we don't just go down,
and we are
now halfway down the page, to say that we
know, for
example, that drugs that produce excess
systemic
cortisol or any systemic increase in
corticosteroids are going to produce
obesity.
DR. STRATAKIS: But weight gain is a real
complication of any steroid.
DR. WOOD: I understand.
The implication
of saying that this is a show stopper
means you
either have to go look for it before the
drug and
307
be marketed over-the-counter. I mean you would
have to do a study, we need to get a
chart out like
this again and say how many people do we
need to
study to exclude obesity in people who
are getting
the drug applied.
I mean I think the Committee
needs to be
clear on the implications of sort of just
getting
our pocket Hippocrates out or whatever
and listing
the side effects of topical steroids and
saying if
any one of these occurs with any one of
these
drugs, it can't go over-the-counter
because that's
a self-fulfilling prophecy.
DR. STRATAKIS: I agree with you the
Committee needs to be consistent. You can't
suggest that you look for diabetes and
not say the
obvious, that you need to look for weight
gain.
DR. WOOD: Dr. Nelson has been very
patient here.
DR. NELSON: I want to comment on growth
velocity. Let me just make a couple of
quick
distinctions. In my mind, there is a difference
between what can be seen and unseen. I mean I
308
can't see osteoporosis. I can weigh myself in the
morning and see if I am gaining weight,
and have
that on a label that tells me if I am
gaining
weight, go see a doctor or some other
approach, so
I am less concerned about the cutaneous.
What bothers me about growth
velocity is
that is also something that is unseen,
and my
understanding from a lot of the pediatric
studies
in other product areas, is you can see
growth
velocity in a 3-month trial. You don't need to
wait for years, that as long as it's in a
population that can stand up and you can
get decent
measurements, and I would probably, as
sort of a
general principle, say if there is any
topical
steroid that had demonstrated systemic
effects on
almost any measurement, I wouldn't make
that
over-the-counter.
But to me, if you demonstrated
growth
velocity changes under your maximal use
conditions,
I would exclude that from going
over-the-counter
personally.
DR. GANLEY: But I think, I don't know if
309
the pulmonologists have any comments on
that, but I
think that there is a certain inaccuracy
and then
to being able to accurately estimate
whether there
is a reduction in growth velocity or not,
and so it
gets back into that situation of what are
the
numbers that you are talking about here.
DR. NELSON: But that is why it's a
randomized trial, and that's why it falls
out on
both sides, and it has been demonstrated
in small
enough trials under the Pediatric
Exclusivity Rule
and pediatric trials have been conducted
that you
have decreased growth velocity.
I think, just as a factual
question, I
think it is technically doable. If it isn't, I
would be open to hear that argument, but
I know in
some other studies, it is technically
doable.
DR. STRATAKIS: I just wanted to say that
growth velocity measurements are
inaccurate when
they are measured below 6 months. I mean that is
the thinking between pediatric
endocrinologists
anyway.
I guess the setting is
different when you
310
have groups of patients, though, on
medication, and
you record a 3-month effect, so there is
a
difference between a trial where you are
in a
controlled setting, you measure growth
velocity in
two groups of patients, and a control
group, or a
control group and a group of patients,
and when you
assess growth velocity in an individual
child, it
is when you say that 6-month growth
velocity
measurements and lower are not accurate,
we mean
about the individual child.
DR. NELSON: Just to be clear, I think the
trials are generally in 6, 7, and
8-year-old
patients and it is controlled. I am just
suggesting that a trial could be designed
to do
growth velocity within a short period of
time, so
it's feasible, and if that demonstrated,
I would
personally then exclude that from OTC on
the
principle of a systemic effect.
DR. WOOD: Terry.
DR. BLASCHKE: I think this sort of a more
general comment. I think that a lot of the
dermatology members of this meeting are
311
disadvantaged by not knowing what the
NDAC people
are familiar with, and that is that there
needs to
be an actual use simulated study to find
out
whether people, in fact, do understand
the label,
and if that were ever to come then to
this
committee for determination of
over-the-counter, if
it was discovered that 20 percent of the
people
were not going to dermatologists with serious
conditions, but instead were using a
stronger or
more potent steroid, it wouldn't get
approved.
I mean they could submit the
data, but I
don't think that the FDA would approve
that. So, I
think a lot of the worry that I am
hearing around
the table probably would be obviated if
the actual
use study demonstrated that, in fact,
because the
hydrocortisone is not very effective, as
somebody
stated, and more potent steroids are
effective for
these minor conditions, and that is, in
fact, what
they were being used for
over-the-counter, we
wouldn't have all of these concerns about
these
long-term side effects.
So, it really is important to
understand
312
that there would be a study that would
actually
demonstrate that the label was good, that
it was
understood by the people purchasing it in
the
pharmacy, and I think it would be much
easier to
make a judgment about whether or not, as
Jon is
saying, a slightly more potent steroid
might be
useful over-the-counter.
DR. WOOD: Dr. Taylor.
DR. TAYLOR: I want to get back to what
Dr. Wood commented on in terms of
bringing some
balance to our decisions. I think we want to come
up with recommendations for the Agency
that will be
helpful.
We can't just categorically say no
because we have got this laundry list.
There are other ways that you
can limit
exposure, for example, you can have only
a certain
class available over-the-counter, you can
have
certain formulations that could be approved. You
could have amounts.
I think our assumption is most
of the
discussions that patients would have
unlimited
access to as much of the product as they
want. In
313
reality, if you look at most of the drugs
that have
gone over-the-counter, the package only
has 4 or 5
of the tablets in there, for
example. So, there
are ways that you can get around some of
the
exposure issues rather than just saying
no, you
can't have it.
DR. WOOD: Dr. Wilkerson.
DR. WILKERSON: What I just want to say is
I think, as dermatologists, this has been
an
eye-opening experience for me today to
see the
degree of HPA axis suppression that was
presented
by Dr. Cook.
When we are looking at 40 and
50 percent
axis, if you queried most dermatologists,
yes, we
are aware obviously that this could happen,
but we
would probably put it in the range of
less than 1
percent in our mind of a clinical risk,
and I think
this, to me, speaks stronger than any
other issue
before us today, that not only do we have
an issue
as far as these drugs going
over-the-counter, but
we have a safety signal or an issue of
the
prescription use of these products that
is not
314
being addressed back to the professional
body that
uses these materials the most, that being
dermatologists and primary physicians.
When we are seeing these levels
of
suppression, this is the first time I
have seen
this material, and I suspect most of us
in the room
that are dermatologists have not seen it
either,
and I think this is the biggest safety
signal to
come out of this entire meeting.
It is not so much the question
of do these
drugs go over-the-counter, which is
pretty
obviously should not right now, but what
are we
going to do about clinical application of
these
materials.
DR. WOOD: Dr. Schmidt.
DR. SCHMIDT: I think we have always known
this, you know, that these strong topical
steroids
have done stuff even again I get my old
proto
textbook and it says in adults, 100 grams
a week of
topical steroids in Class I, III under
occlusion,
or 45 grams of clobetasol without
occlusion may be
used, but then they say, but over that
you are
315
going to have problems.
It is just that to me, a lot of
this will
affect the adrenal-pituitary axis, and
even given
prednisone, you affect the
adrenal-pituitary axis,
but then it snaps back into place
normally in most
patients, so to me, I wonder whether we
are setting
the bar too high, you know, with some of
these
things, and I tend to agree that if these
things do
go over-the-counter, there is ways that
you can
limit.
I remember when I was a
resident, I lived
in a house that was almost falling over,
and
several of the neighbors had kids with
atopic
eczema, and these people were not, you
know,
probably like me, weren't the most
sophisticated
people in the world, and they would have
their
little tube of 5-gram triamcinolone in a
little
box, you know, that they used very
sparingly.
So, I think we need to give the
American
public some credit for not just taking
this stuff
and rubbing it in their eyes or eating it
or
anything like that. I think, I don't know, I have
316
got some real questions that some of
these things,
we have always known it, but we do it
anyway, but
then we stop and do pulse therapy.
As far as the clinical aspect
of this
thing, I don't think I have ever seen
glaucoma, you
know, from putting steroids in people's
eyes, I
don't think I have ever heard of it. I mean maybe
it occurs and it is reported in the
literature, and
I have been in practice 32 years, I have
never seen
anybody get fat with topical steroids.
DR. WOOD: Let me stand up.
[Laughter.]
DR. SCHMIDT: Thank you.
No, mine is from
the cookie.
DR. WOOD: I am sitting here too long.
DR. SCHMIDT: I just think clinically, we
need to kind of mellow out.
DR. WOOD: Okay.
Mellowing out, Dr. Epps.
DR. EPPS: Thank you.
That being said,
the truth of the matter is once it's
over-the-counter, it's available for any
age, in
any amount, on any part of the body, and
not
317
everyone is as sophisticated. You have got to
think about the lowest common
denominator. Not
everybody is going to read every warning
on every
box.
Literally, it is equivalent to you can buy it
as you could buy lotion, you can buy as
much as you
want, put it anywhere you want, on any
age person
that you want to put it on.
Certainly, there is a question,
and I
understand his question about whether or
not it is
clinically significant, but those patients we
are
monitoring very carefully.
DR. WOOD: Let's return and let's focus
the question. We are on Question 4. Would
labeling for the systemic effects other
than HPA
axis suppression be an acceptable regulatory
path
in lieu of testing for the other systemic
effects?
Are there any other comments on
that, that
we have not heard? Yes, Dr. Chesney.
DR. CHESNEY: I wanted to weigh in with
Dr. Whitmore and Dr. Nelson on the issue
of
labeling for growth suppression. I think growth
suppression has been well documented with
these
318
drugs, and I think it is very serious,
and I think
labeling is not adequate to warn the
public about
that, because it is not something you can
see, as
Dr. Whitmore said, and I think as Dr.
Nelson said,
it is a reason that these drugs should
not go
over-the-counter, and I just wanted to
weigh in on
that.
DR. WOOD: Any other comments specifically
on labeling? Dr. Bigby?
No, not on labeling?
Hang on, I will get to you in a second.
Any other comments on labeling? Mike.
DR. ALFANO: It's a labeling comment, and
it goes back to Dr. Ellis' report where
upwards of
90 percent of the current product is used
on label.
I think the Chair made a comment about
this
relative to Rx compliance with label.
I mean this is right up there,
in fact,
probably exceeds many Rx drugs. So, in terms of
the ability of this particular label to
convey
something meaningful to the population,
it seems to
have done that, presumably similar
labeling would
be developed and similar in-use testing
would
319
confirm that if something else were to
come on the
market, it would be equally
efficacious. Nothing
stops a mother from taking her
prescription drug
and putting it on her baby's butt.
DR. BIGBY: But the thing that is wrong
with that logic is you are making the
assumption
that it is being used on label because of
the
label.
It may be being used that way because it
didn't work. I mean you are making the assumption
that just because people used it for less
than 7
days, it is because they read the label and
paid
attention to that, and there is no
evidence of that
whatsoever.
DR. ALFANO: That is only length of use.
DR. WOOD: Hang on, if I can just
intercede here. That's the point Terry
Blaschke was
trying to make earlier on for the benefit
of the
panel members who have not seen this
reviewed.
That will be tested before a drug could
go
over-the-counter, so, in other words, a
sponsor
would have to come in with an actual use
study and
a label comprehension study that
demonstrated that
320
the label was understood by them and that
in a
quasi-operational fashion were able to
operationalize the content of the label.
I am not necessarily arguing
that. Mike,
sorry.
DR. ALFANO: That was going to be my point
and also that study related, not just to
duration
of use, but what it was used on, and for
the most
part, it was used on the right
conditions.
DR. WOOD: Dr. Ringel.
DR. RINGEL: I guess I have sort of
collected comments here. One quick one is about
the labeling issue, that people will use
what makes
them feel good, and you can test that
they
comprehend it and that the label is
clear, but you
can't test to make sure that they are
really going
to do what they read on the label. If they feel
bad, and the cream makes them feel good,
they will
continue to use it, at least that is my
experience
in my clinical practice.
DR. WOOD: It doesn't sound like a bad
thing actually, does it?
DR. RINGEL: Yes, if there are side
effects.
Let me go back to Dr. Wilkin's question,
which was what do you do in your office
practice,
321
dermatologists, to monitor people, and I
can only
tell you what I do, and you make me kind
of guilty
sitting here, you know, thinking about
everything
we have heard today and I really do, and
clearly it
is not enough what I do do.
If I have somebody on
high-potency
steroids for a long time, over a long
portion of
their body, I really do do a cortisol
test. I know
it is not a great test to do, but I do
it, and
every once in a while somebody is low and
I try to
do something about it.
When you see people, and I
think that most
of the dermatologists, maybe they don't
think that
they do this, but I really think they do
this, you
see somebody with diabetes and it is not
going
well, and you are giving them the
clobetasol, I
think, huh, maybe I shouldn't be giving
them so
much clobetasol, or somebody who is
having, you
know, their osteoporosis is getting worse
and
322
worse, and I am giving them clobetasol, I
go
through the same thing in my mind, maybe
this is
not a great idea.
Then, I start to fight with
people, say,
well, you shouldn't use this much, and
they say,
well, they want to use it because nothing
else
works, and I am always fighting with
people, I am
always trying to take it away, and they
are always
trying to get a little bit more from me,
and that
is not going to happen if it's
over-the-counter.
The other thing is that for me,
this whole
experience has been a sort of an NGE,
kind of a
neurosis generating event. I mean I am going to be
in my office and people are going to be
wanting me
to give them more steroids and I am going
to be
say, oh, my gosh, they are going to get
pituitary
suppression, and I mean what it makes me
think is
maybe we need to rethink what we are
doing by
prescription, not that we need therefore
to just go
ahead and make it over-the-counter.
I mean Denise gave us such
convincing
evidence that there really can be a
problem, I was
323
convinced. I really think that you did a great
job, and I saw no evidence presented by
the FDA
today that this is not a problem, so how
can I then
go ahead and say fine, make it over the
counter.
I need to see some evidence
first from the
FDA or someone that it is not a problem,
and that's
it.
DR. WOOD: Jack.
DR. FINCHAM: Well, we are all over the
map, so bear with me, but I think we have
got--
DR. WOOD: Labeling.
DR. FINCHAM: I know, bear with me,
please, I am with you. We have a formal health
care system and an informal system, and
if we
assume just because we prescribe a
therapy, that it
is only going to be used by that
individual, we are
really wrong, because when this gets out
in the
system, regardless of whether it is
prescribed for
somebody or not, it is used by anybody,
they share
it.
Jimmy, I think eloquently
talked about why
we need to have something available to
let people
324
make informed decisions, and you use the
labeling
to try to do the best that you can to
help people
make informed decisions, but if it is
going to be
misused, it is going to be misused
whether it is a
prescription product or whether it's an
over-the-counter product, whether there
is a
board-certified dermatologist involved or
not, and
I just think you have to give people the
benefit of
the doubt, give them a chance, label it
appropriately, and go from there.
DR. WOOD:
I have a personal comment on
that, as well. Although I don't believe that
labeling actually works, I certainly
would not want
to leave the impression that people
should have to
do studies to exclude all these other
effects
before the drug could be submitted for
OTC use. It
is unfortunate perhaps the way this is
worded, but
i would rephrase it to say should they
have to
exclude all these other lists that Teresa
has here,
and I think the answer to that is no in
my view.
Dr. Nelson. Labeling?
DR. NELSON: Yes, on labeling. What we
325
are not being asked is how many people
would need
to be able to follow the label if, in
fact, the
label constrained the use far enough
below the
maximal use conditions--
DR. WOOD: That is the question that would
come up for NDAC.
DR. NELSON: I understand, so all I am
saying is that what we are answering in a
sense is
both questions, and that is part of the
confusion,
to what extent, if it's zero out of 1,000
in
maximal use, well, if then everybody
could follow
the label, that becomes a very different
question,
and that may be part of the difficulty.
We are conflating it, and not
separating
those two things.
DR. WOOD: Do we want to vote on this?
Okay.
Let's start with Jack. Would labeling be
an acceptable regulatory pathway, so Yes
would mean
it would be acceptable.
DR. FINCHAM: Yes.
DR. RAIMER: I am going to say no.
DR. RINGEL:
No.
DR. WHITMORE: No.
DR. CLYBURN: Yes.
326
DR. SKINNER: No.
DR. PATTEN: Yes.
DR. TEN HAVE: No.
DR. DAVIDOFF: No.
DR. BIGBY: No.
DR. WOOD: Yes.
DR. NELSON: With your indulgence, no for
some, such as growth velocity, yes for
others, such
as cutaneous manifestations.
DR. SNODGRASS: No.
DR. MATTISON: No.
DR. SCHMIDT: Yes.
DR. EPPS: No.
DR. TAYLOR: Yes.
DR. WILKERSON: No.
DR. STRATAKIS: No.
DR. BLASCHKE: Without belaboring it any
longer, I will say yes.
DR. WOOD: All right.
Question No. 5.
327
With regard to dermatologic local
cutaneous
effects, at what level of severity do
risks
outweigh the benefits of topical
corticosteroid use
in an OTC setting?
Dr. Bigby.
DR. BIGBY: This question is actually
directed to Jon. It seems to me that the simplest
question to ask is should the more potent
topical
corticosteroids be considered for
over-the-counter
use, period, as opposed to--I mean why
didn't you
ask us that question?
DR. WILKIN: Well, I guess because we were
interested in the answer to that
question.
[Laughter.]
DR. WOOD: Thank you.
Next question.
DR. WILKIN: The point about at what level
of severity of local cutaneous effects,
because I
mean you might have mild erythema, on the
other
hand, you might have really severe
atrophy, and we
were asking for something that would
qualitative or
quantitative from the Committee, where they
thought
something that had the potential to do X
or Y, or
328
whatever, that those are the products
that should
not go over-the-counter.
DR. WOOD: Let's hear from the
dermatologist first on this. They are the people
who should be able to answer this best.
Dr. Whitmore.
DR. WILKIN: Stria, telangiectasias, acne
eruptions.
DR. WOOD: Dr. Wilkerson.
DR. WILKERSON: I think certainly in
blacks, the hypopigmentation issue is
big. I just
wanted to add that every good sermon has
three
points and every good advisory committee
has five
questions, so that is the answer to Dr.
Bigby's
question.
DR. WOOD: Dr. Schmidt.
DR. SCHMIDT: I think the most important
one is stria because it is something that
is
permanent. You know, the rest of these things
resolve with time and then the other
thing, and I
don't want to belabor this, but I really
think that
contact dermatitis, you know, to some of
these
329
things, you know, I think that if
something induced
contact dermatitis in a lot of patients,
I think I
would consider not having that either.
DR. WOOD: Any other comments?
DR. RAIMER: I think sometimes atrophy can
be permanent, too, especially in an older
person,
so I think stria or severe atrophy that
doesn't
resolve.
DR. WOOD: Dr. Skinner.
DR. SKINNER: I was thinking some of this
probably could be done with good
labeling. It
would just be so restrictive, you know,
don't use
it on the face, don't use it in the
axilla, don't
use it in the antecubital popliteal
fossa, don't
use it in the groin. You know, with that I think
you could avoid most of the trouble with
the
cutaneous effects.
DR. WOOD: Any other comments? Yes, Dr.
Nelson.
DR. NELSON: As a non-dermatologist, what
would strike me as most important here is
reversibility, and not necessarily
severity. If
330
something could appear as severe, but if
it's
reversible when stopped by the individual
who is
using it, that is much different than if
it could
be mild, but then be reversible, so I
think it's
the reversibility.
If I think of myself as a
consumer buying
it, I see it, I stop it, I would want it
to go
away, would be the key rather than how
severe it
might look for that period of time.
DR. WOOD: Any other comments? Yes, Dr.
Epps.
DR. EPPS: I should also mention
hypertrichosis, which some people get,
too.
DR. WOOD: Any other comments? All right.
We are through, ten past 3:00, guys. Thanks a lot.
DR. FINCHAM: Alastair, thank you for
shepherding us today through all
this. Nicely
done.
[Whereupon, the meeting was
concluded at
3:10 p.m.]
- - -