FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

PEDIATRIC ADVISORY SUBCOMMITTEE

OF THE

ANTI-INFECTIVE DRUGS ADVISORY COMMITTEE

8:06 a.m.

Wednesday, October 29, 2003

The Ballrooms

The Hilton Hotel

620 Perry Parkway

Gaithersburg, Maryland

ATTENDEES

ANTI-INFECTIVE DRUGS ADVISORY COMMITTEE MEMBERS: (Voting)

STEVEN E. EBERT, PHARM.D.

Department of Pharmacy

Meriter Hospital

202 South Park Street

Madison, Wisconsin 53715

MARY GLODE, M.D.

Professor of Pediatrics

The Children\'s Hospital of Denver

University of Colorado Health Sciences Center

1056 East 19th Avenue (B158)

Denver, Colorado 80218

DERMATOLOGIC AND OPHTHALMIC DRUGS ADVISORY COMMITTEE MEMBERS: (Voting)

ROSELYN EPPS, M.D.

Chief, Division of Dermatology

Children\'s National Medical Center

SHARON RAIMER, M.D.

University of Texas Medical Branch

THOMAS TEN HAVE, PH.D.

Department of Biostatistics and

Clinical Epidemiology

University of Pennsylvania School of Medicine

SPECIAL GOVERNMENT EMPLOYEES-CONSULTANTS: (Voting)

ELIZABETH ANDREWS, M.D.

Vice President

RTI Health Solutions

PATRICIA CHESNEY, M.D., Meeting Chair

Professor of Pediatrics

University of Tennessee College of Medicine

DAVID DANFORD, M.D.

Associate Professor of Pediatrics

University of Nebraska Medical Center

ATTENDEES (Continued)

SPECIAL GOVERNMENT EMPLOYEES-CONSULTANTS: (Voting)

(Continued)

ROBERT FINK, M.D.

Chairman, Department of Allergy and Pulmonary Medicine

Children\'s National Medical Center

NORMAN FOST, M.D., M.P.H.

University of Wisconsin Hospital

RICHARD GORMAN, M.D., FAAP

Pediatrician

Pediatric Partners

Ellicott City, Maryland

VICTOR SANTANA, M.D.

Associate Professor

Dependent of Hematology/Oncology

St. Jude\'s Children\'s Research Hospital

BRUCE SCHNEIDER, M.D.

Associate Professor for Clinical Research

Association of American Medical Colleges

FEDERAL EMPLOYEES: (Voting)

DON MATTISON, M.D.

National Institute of Child Health and

Human Development, NIH

CONSTANTINE STRATAKIS, M.D.

National Institute of Child Health and

Human Development, NIH

BENJAMIN WILFOND, M.D.

Bioethics Research Section

National Institutes of Health

ATTENDEES (Continued)

FOOD AND DRUG ADMINISTRATION STAFF:

SHAAVHREE BUCKMAN, M.D.

DENISE COOK, M.D.

SOLOMON IYASU, M.D.

CLAUDIA KARWOSKI, PHARM.D.

BEVERLY LINDSAY, M.D.

DIANNE MURPHY, M.D.

BINDI NIKHAR, M.D.

THOMAS PEREZ, R.PH., M.P.H., Executive Secretary

JEAN TEMECK, M.D.

ANNE TRONTELL, M.D.

JONATHAN WILKIN, M.D.

ALSO PRESENT:

JERRY ROTH

C O N T E N T S

CLINICAL RISK MANAGEMENT OF HPA AXIS SUPPRESSION

IN CHILDREN WITH ATOPIC DERMATITIS

BEING TREATED WITH TOPICAL CORTICOSTEROIDS

\* \* \*

AGENDA ITEM PAGE

CALL TO ORDER AND INTRODUCTIONS

By Dr. Joan Chesney 7

MEETING STATEMENT

By Mr. Thomas Perez 11

OPENING COMMENTS

By Dr. Dianne Murphy 13

By Dr. Jonathan Wilkin 15

ATOPIC DERMATITIS: ITS CLINICAL COURSE

AND THERAPEUTIC OPTIONS

By Dr. Bindi Nikhar 18

OVERVIEW OF HPA AXIS SUPPRESSION

By Dr. Jean Temeck 30

FDA EXPERIENCE: TOPICAL CORTICOSTEROIDS

AND HPA AXIS SUPPRESSION

By Dr. Denise Cook 46

POST-MARKETING ADVERSE EVENT REPORTS

By Dr. Claudia Karwoski 69

QUESTIONS TO THE SPEAKERS 79

FRAMEWORK FOR RISK ASSESSMENT AND

MANAGEMENT

By Dr. Anne Trontell 106

QUESTIONS TO THE SPEAKER 124

OPEN PUBLIC HEARING PRESENTATION

By Mr. Jerry Roth 147

PRESENTATION OF QUESTIONS TO THE COMMITTEE

By Dr. Dianne Murphy 156

DISCUSSION OF QUESTIONS 157

C O N T E N T S (Continued)

SECTION 17, BEST PHARMACEUTICALS FOR CHILDREN ACT

ADVERSE EVENT REPORTING

\* \* \*

AGENDA ITEM PAGE

MEETING STATEMENT

By Mr. Thomas Perez 235

ADVERSE EVENT REPORTS PER

SECTION 17 OF BPCA

By Dr. Solomon Iyasu 240

By Dr. ShaAvhree Buckman 252

OPEN PUBLIC HEARING 258

P R O C E E D I N G S

(8:06 a.m.)

DR. CHESNEY: I think we are ready to begin. My name is Joan Chesney, and
good morning. I would like to welcome the committee members, the
consultants, the guests, and the members of the FDA.

Just briefly, today and tomorrow we will be reviewing two classes of
drugs which have been approved for use in the treatment of atopic eczema
topically: the topical corticosteroids and the topical
immunosuppressants which inhibit the enzyme calcineurin.

Even with topical use often, when used inappropriately, the
corticosteroids can cause suppression of the hypothalamic-pituitary axis
and the immunosuppressants have been associated with lymphoproliferative
disorders when given orally to patients and with lymphoma and follicular
cell thyroid adenomas in rodents when given orally, and mouse
photocarcinogenicity studies have been associated with cutaneous
malignancies.

We are being asked today and tomorrow to provide feedback to the FDA
regarding two specific issues. Number one, what are the specific risks
of each event associated with each drug? And secondly, how should risk
management programs be conducted for, number one, the prevention of HPA
suppression with corticosteroids and, number two, with the topical
immunosuppressants, how to design long-term registry programs to
evaluate the potential cancer risk from exposure to these topical
immunosuppressants?

As always, the FDA has provided us with excellent written materials to
review and superb consultants to assist us with the discussion of these
two questions.

If we could now turn to the introduction of the individual introductions
of the people at the table, and I guess we\'ll start with Dianne.

DR. MURPHY: I\'m Dianne Murphy and I\'m the Office Director for the
Office of Pediatric Therapeutics and also for the Office of
Counter-terrorism and Pediatric Drug Development.

DR. WILKIN: I\'m Jonathan Wilkin, Director of the Division of
Dermatologic and Dental Drug Products.

DR. TRONTELL: I\'m Anne Trontell, the Deputy Director of the Office of
Drug Safety in the Center for Drugs.

DR. DANFORD: I\'m David Danford, a pediatric cardiologist at the
University of Nebraska Medical Center and Creighton University School of
Medicine in Omaha and a member of the subcommittee.

DR. SANTANA: Good morning. I\'m Victor Santana. I\'m a pediatric
hematologist/oncologist at St. Jude\'s Children\'s Research Hospital in
Memphis, Tennessee.

DR. GLODE: I\'m Mimi Glode. I\'m a member of the subcommittee. My
background is pediatric infectious disease, and I work at Children\'s
Hospital, University of Colorado School of Medicine in Denver.

DR. EPPS: I\'m Dr. Roselyn Epps, the Chief of the Division of
Dermatology at Children\'s National Medical Center, Washington, D.C.

DR. FOST: Norm Fost, Professor of Pediatrics, general pediatrician, and
Director of the Bioethics Program at the University of Wisconsin.

DR. CHESNEY: I\'m Joan Chesney. My field is infectious diseases, and
I\'m at the University of Tennessee in Memphis and St. Jude Children\'s
Research Hospital.

MR. PEREZ: I am Tom Perez, Executive Secretary to this meeting.

DR. EBERT: I\'m Steve Ebert. I\'m a pharmacist in infectious diseases at
Meriter Hospital and Professor of Pharmacy at the University of
Wisconsin, Madison.

DR. GORMAN: I\'m Rich Gorman. I\'m engaged in the private practice of
general pediatrics in Ellicott City, Maryland and a member of the
subcommittee.

DR. SCHNEIDER: I\'m Bruce Schneider. I\'m Associate Vice President for
Clinical Research at the Association of American Medical Colleges in
Washington, D.C. I\'m a clinical endocrinologist, formerly a medical
officer at FDA, and before that Professor of Medicine at Albert Einstein
College of Medicine in New York.

DR. FINK: Bob Fink, pediatric pulmonologist at Children\'s Medical
Center in Dayton, Ohio, and Professor of Pediatrics at Wright State
University.

DR. TEN HAVE: Tom Ten Have, Professor of Biostatistics, University of
Pennsylvania, and member of the Dermatology Advisory Committee.

DR. ANDREWS: I\'m Elizabeth Andrews. I\'m a pharmacoepidemiologist. I\'m
Vice President of RTI Health Solutions at Research Triangle Institute in
North Carolina.

DR. RAIMER: I\'m Sharon Raimer. I\'m a pediatric dermatologist from the
University of Texas in Galveston, Texas.

DR. WILFOND: I\'m Ben Wilfond. I\'m a pediatric pulmonologist with the
Department of Clinical Bioethics at the NIH and also with the National
Human Genome Research Institute.

DR. MATTISON: Don Mattison. I\'m at NICHD. My clinical training is in
obstetrics.

DR. CHESNEY: Thank you.

Next on the agenda is the meeting statement by Tom Perez, our Executive
Secretary.

MR. PEREZ: Thank you.

The following announcement addresses the issue of conflict of interest
with respect to this meeting and is made a part of the record to
preclude even the appearance of such at the meeting.

The subcommittee will discuss the risk assessment and possible risk
management strategies for hypothalamic-pituitary-adrenal axis
suppression in children who are treated for skin disorders with topical
corticosteroids.

The topic of today\'s meeting is an issue of broad applicability. Unlike
issues before a committee in which a particular product is discussed,
issues of broader applicability involve many industrial sponsors and
academic institutions.

All special government employees have been screened for their financial
interests as they may apply to the general topics at hand. Because there
have been reported interests in pharmaceutical companies, the Food and
Drug Administration has granted a general matters waiver to Dr. Richard
Gorman, which permits him to participate in today\'s discussions.

A copy of the waiver statement may be obtained by submitting a written
request to the agency\'s Freedom of Information Office, room 12A-30 of
the Parklawn Building.

Because general topics impact so many institutions, it is not prudent to
recite all potential conflicts of interest as they apply to each member
and consultant. FDA acknowledges that there may be potential conflicts
of interest, but because of the general nature of the discussion before
the committee, these potential conflicts are mitigated.

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 noted for the record.

With respect to all other participants, we ask in the interest of
fairness that they address any current or previous financial involvement
with any firm whose product they may wish to comment upon.

Thank you.

DR. CHESNEY: Thank you.

Our first speakers, who will make opening comments, are Dr. Dianne
Murphy and Dr. Wilkin. Dr. Murphy is the Director of the Office of
Counter-terrorism and Pediatrics and the Director of the Office of
Pediatric Therapeutics. Dr. Wilkin is the Director of the Division of
Dermatologic and Dental Drug Products of the FDA. They will be providing
us with an introduction and overview.

DR. MURPHY: Good morning and welcome to the lousy weather we have in
what should be a glorious autumn, but unfortunately you will mostly be
locked up in this room with us. So I guess it doesn\'t matter as much.

But we are delighted to have the committee meet and help advise us. We
have combined the elements of our Pediatric Advisory Subcommittee and
members of the Dermatology Advisory Committee, and we look forward to
your recommendations to us today.

The good news is that we are bringing these questions to you today
because we have conducted trials in children. We had this information
brought to us because we asked for these studies to be done. The
information, some of it or much of it, is the result of trials that were
conducted in response to a written request which the FDA sent to
sponsors, and if sponsors respond to these written requests and conduct
the trials as we have asked them to do, they are awarded additional
marketing exclusivity. This has been a tremendous motivator for the
conduct of trials in children, which have been very necessary because,
as we all know, the products are being used anyway. So like all things,
once you get information, being mostly scientists here, it just tends to
generate more questions, and that is exactly what has happened here.

You will hear over the next two days about two different classes of
products that are used in diseases that can be serious, not
life-threatening, but for which children need options. So these
products, over the next two days, are linked. They are linked because
they\'re treating similar diseases. They are linked because they\'re
topicals, and they\'re linked because they, again, bring forth questions
from the studies that have been conducted. And they\'re particularly
linked ‑‑ and I think this is going to be the challenge to you over the
next two days ‑‑ because they are, in essence, options for parents and
children and physicians. If one can\'t use one, one may need to use the
other. Yet, what we are asking you to help us with is how do we
appropriately advise the people who are both prescribing these products
and the parents who are using them when we are not able to clearly
delineate the level of risk. That is really what you\'re going to
struggle with over the next two days.

You are going to hear what we think the risk is, but not only what
additional studies do we need, but how are we going to develop a risk
management program that will not, in essence, limit options and yet
clearly inform so that the selection of the product will be that it will
be used in the safest manner until we are better informed about what the
true risk is. As I said, you will also be asked questions about how to
help us identify additional studies that might define this risk. So
it\'s, I think, a very difficult task that you have in the next two
days.

You\'re going to hear about risk management programs that we have and
various approaches to risk management, but I think the real quandary to
you is we\'re asking you to help us say when we don\'t have an absolute
certainty on the risk, it is not completely defined, how do we best
manage these risk management programs.

Thank you and we look forward to your discussion.

DR. CHESNEY: Dr. Wilkin?

DR. WILKIN: I\'d be happy to make my very brief comments from here. I\'d
like to first echo Dr. Murphy\'s welcome.

I\'d like to point out that we have pediatric dermatologic reviewers in
our Division of Dermatologic and Dental Drug Products who will be
looking forward to how the committee responds to the questions later in
this day, but I would like to point out that they spend a lot of time
looking over the transcripts for the entire meeting because what you say
and discuss in each section is actually just as meaningful as specific
fill-in-the-blank answers that come later in the day.

Dr. Murphy has given an overview of both days. I would like to say just
a couple of words about what we\'ll think about today.

Topical corticosteroids have really been the workhorse for many
dermatoses. Most dermatoses are, in fact, inflammatory and many of the
dermatoses in children are inflammatory and respond to topical
corticosteroids. There has been a lot of success and advantage from this
group of products over the last four decades.

We have recognized for many years the potential for adrenal suppression
with some of the topical corticosteroids, especially when used over
larger body surface areas and in smaller children with a somewhat larger
surface-to-volume ratio, and there may be some additional factors also
in the younger children.

It\'s a difficult area to really think about. There is some uncertainty.
There aren\'t many post-marketing reports of adverse events. On the
other hand, we have substantial evidence for adrenal suppression with
the testing that Dr. Murphy has described that we have been able to
obtain from the different products during product development. I think
by first principles, the agency has gotten to the stage where we believe
that there are certain things we need to say in labeling about risk
management, and we\'ll share with you where we are on this. But we\'re
looking for the committee and for the experts to give us advice on are
we where we need to be.

Again, adrenal suppression is silent. It\'s like hypertension or
osteoporosis. I think the usually statement about osteoporosis is the
first warning sign is there isn\'t any. It\'s a fracture. And that my be
the case with adrenal suppression. It\'s either hidden from view until
there is sepsis or some major traumatic event or it\'s really not
detected.

Alvin Feinstein, who coined a lot of words, is the Yale clinical
epidemiologist. One word that probably should have gotten picked up more
and didn\'t was he used the word \"lanthanic\" for these kinds of
conditions. It comes from Greek lanthanos, hidden from view, or
lanthanine, to escape notice. You may recall from chemistry the
lanthanide series of elements, the rare earth elements, the ones that
were very difficult to detect. I think that\'s what we\'re talking
about, a lanthanic kind of condition in Feinstein\'s terminology.

So, again, there is this kind of uncertainty and we would like to share
this uncertainty, the first principles, how we\'ve been thinking about
it, how we\'ve been crafting our statements for risk management, and get
the sense of the committee, are we on target, are there other things we
need to do.

Thank you.

DR. MURPHY: We depend on Jonathan to give us a new word.

(Laughter.)

DR. CHESNEY: I was thinking of laudanum. There must be a derivative
there somewhere.

Our first formal presentation is by Dr. Nikhar, and Dr. Nikhar is a
medical officer with the Division of Dermatologic and Dental Drug
Products and a board certified pediatrician. She will present an
overview of atopic dermatitis, its clinical course and therapeutic
options.

DR. NIKHAR: Good morning. My talk this morning covers atopic dermatitis,
its clinical course and therapeutic options.

Starting off with a brief introduction, atopic dermatitis is a chronic
inflammatory disease of the skin, primarily seen in the pediatric age
group. It is characterized by dry skin, pruritus, erythema, edema,
scaling, excoriations, oozing, and lichenification. However, dry skin
and pruritus are invariably present all stages of the disease. It is a
multi-faceted disease showing increasing prevalence and rising costs,
and together with asthma and allergic rhinitis, it forms part of the
atopic triad.

Going on to epidemiology, currently about 10 to 20 percent of children
in industrialized countries develop atopic dermatitis, and for reasons
that are unclear, this number seems to be increasing. Environmental
factors such as urbanization and development may be contributory
factors. It is commoner in higher socioeconomic groups and in children
from smaller families. The overall clearance is about 50 to 60 percent
and 80 percent of children with severe disease continue to have lifelong
exacerbations.

Considering morbidity, it has an impact on the quality of life at all
ages, and this is due to psychological problems from visible skin
lesions due to stigmatization, the itch-scratch cycle that is aggravated
during flare-ups, sleeplessness, lack of concentration at school or
work, and distress over repeated treatments, time involved, and
financial costs.

Atopic dermatitis can cause a considerable drain on financial resources
of patients and health services. The costs increase with disease
severity and they\'re highest in the first few years, after which
there\'s a decrease indicating a learning effect in the treatment of
patients. And while the FDA does not consider pharmacoeconomic issues in
drug approvals, we do recognize that cost is an important factor in drug
availability.

Going on to clinical manifestations, atopic dermatitis is a condition of
early infancy and in 50 to 75 percent of cases, the age of onset is 6
months or younger. A clearance rate of 60 percent is expected by age 16.
However, relapses can occur in adulthood. A worse prognosis is indicated
by severe childhood disease, early onset, concomitant or family history
of asthma or allergic rhinitis, and a biparental history of atopy.

There are three main age-related stages. Dry skin and pruritus are
associated with all stages. The skin barrier function is decreased and
this may lead to increased absorption of topically applied treatments.
However, this usually improves with adequate treatment.

The infantile phase is from 0 to 2 years of age. The onset can be around
3 months of age, and under 6 months, the face and scalp are commonly
involved, while at an older age, the limb folds and hands may be
involved. Red, scaly, crusted, weeping patches with excoriations may be
seen on both cheeks and extensor surfaces of extremities, and typically
the course is chronically relapsing and remitting.

These pictures, courtesy of the University of Erlangen, illustrates the
features just described. The infant on the left has typical facial and
upper chest involvement and probably has a body surface area involvement
of about 20 to 25 percent, while the infant on the right has facial and
extensor surface involvement as is again typical in this age group and
probably has a body surface area involvement of about 30 to 35 percent.

The childhood phase is from 2 to 12 years of age. Here papular areas in
flexural regions are common, and in areas of chronic involvement,
persistent rubbing and scratching lead to lichenified plaques and
excoriations.

The adult phase is from puberty onwards, and here flexural lichenified
eczema with facial involvement in periorbital regions may be seen. The
upper trunk, shoulders, and scalp may be affected, with chronic
remissions and exacerbations.

In this picture, this young child shows flexural involvement, which is
again typical of this age group, and probably has a body surface area
involvement of about 35 to 40 percent.

The first picture on the left shows lichenification which is seen in
areas of chronic involvement. The picture on the right on the top shows
periorbital involvement. The young man on the left in the picture on the
bottom shows impetigo, which is a complication that may be seen with
atopic dermatitis, while the picture on the right shows typical flexural
involvement.

The following are some of the reported immunological features of atopic
dermatitis. There is increased IgE production with specific IgE to
multiple antigens, increased basophil spontaneous histamine release,
decreased CD8 suppressor/cytotoxic number and function, an increased
expression of CD23 on mononuclear cells, chronic macrophage activation
with increased secretion of granulocyte macrophage colony-stimulating
factor, PGE2, and interleukin 10, an expansion of interleukin 4 and 5
secreting Th2-like cells and decreased numbers of
interferon-gamma-secreting Th1-like cells.

The diagnosis of atopic dermatitis requires the presence of three or
more major and three or more minor criteria, as defined by Hanifin and
Rajka, which is a commonly used method. The major criteria include
pruritus, lichenification, chronic or chronically relapsing course, and
personal or family history of atopy. There are 23 minor criteria that
have not been mentioned in this presentation.

As far as the management of atopic dermatitis, there is no single ideal
treatment available. Each patient should have a flexible plan tailored
for their need taking into account the severity of the illness, the
resources available, the compliance of the patient, and so on.

Dietary history is important, but dietary manipulation remains
controversial. Infants are most likely to benefit from this, in which
case their nutritional status should be closely monitored.

Family education is important regarding atopic dermatitis and its
clinical course, while measures to reduce exposure to allergens such as
house dust mites, animals, and clothing should be discussed.

Going on to general treatment guidelines, moisturizers are the
cornerstone of therapy in atopic dermatitis. Their frequent use,
together with avoidance of drying bathing products, is important because
atopic dermatitis is often accompanied by dry skin. Creams, ointments,
or lotions can be used depending on individual needs.

Itch control is another important aspect. It can be a very distressing
symptom leading to skin breakdown, infections, and lack of skin healing.
Oral antihistamines, often of the sedating variety, are used to try and
break the itch-scratch cycle.

Patients with extensive atopic dermatitis are often colonized with
Staph. aureus. A course of oral antibiotics, plus or minus topical
antibiotics, may be needed for lichenified, excoriated lesions not
responding to treatment. Viral infections, for example, warts, eczema
herpeticum, may be seen in these patients and should be appropriately
managed.

The selection of treatment depends upon the disease severity, the age,
the compliance, the efficacy and safety data, and treatment costs.

The following ‑‑ that is, the first three ‑‑ are some of the
prescription treatment options available. Topical corticosteroids are
currently the mainstay of first-line therapy of atopic dermatitis and
will be discussed further. Topical immunosuppressants. This group of
calcineurin inhibitors has been introduced as second-line therapy for
treatment of atopic dermatitis and will also be discussed. Systemic
corticosteroids are useful for severe, acute cases of atopic dermatitis.
However, chronic use can lead to serious side effects and they should be
used with caution.

The following are then the off-label and other treatment options
available.

Photochemotherapy has been tried mainly in adults.

Cyclosporin was the first in the class of immunosuppressants to be
introduced for recalcitrant atopic dermatitis. However, it can lead to
serious systemic side effects such as hypertension, renal toxicity, and
a propensity for malignant tumors, and this has limited its use.

Azathioprine, thymopentin, and interferon-gamma therapy have all been
tried.

Traditional Chinese medicine has also been tried. However, liver
function abnormalities and interstitial renal fibrosis has limited its
use.

Gamma-linoleic acid in the form of evening primrose oil has also been
tried.

Now going on to review topical corticosteroids. These were first
introduced in the 1950s and are currently the mainstay of prescription
therapy for atopic dermatitis. They are safe and effective when used as
recommended. The weakest steroid that will keep the eczema under control
should be used, and potent steroids should be used in short pulses,
generally about 2 to 3 weeks.

The following are some of the factors to consider when prescribing
topical corticosteroids. First, the type of preparation, that is, the
base and the potency. The base can be an ointment, cream, emulsion, gel,
or lotion, and this is important because that can affect the efficacy.
The potency is classified from group I, which is the most potent, to
group VII, which is the least potent.

Second, acute or chronic eczema.

Third, the age of the child. More potent steroids should be avoided in
younger children.

Then the site to be treated, for example, the face and scalp need
special attention in choosing potency of steroids.

Next, the extent of eczema. A higher body surface area involvement would
lead to increased absorption.

And lastly, the method of application. For example, steroids used under
occlusion would lead to increased absorption.

As far as the mechanism of action of topical corticosteroids, there are
three effects.

The first is the anti-inflammatory effect. Topical corticosteroids
affect inflammatory cells, chemical mediators, and tissue responses
which are all responsible for cutaneous inflammation.

Second, the antiproliferative effects. Topical corticosteroids may
reduce mitotic activity in the epidermis leading to flattening of the
basal cell layer and thinning of the stratum corneum and granulosum.

And thirdly, the atrophogenic effects. Topical corticosteroids can
promote atrophy of the dermis through inhibition of fibroblast
proliferation, migration, chemotaxis, and protein synthesis.

Now considering the systemic effects of topical corticosteroids. If a
topical corticosteroid is absorbed percutaneously in significant
quantities, it can cause systemic adverse effects similar to
systemically administered corticosteroids. And this is discussed under
adverse effects, and so the adverse effects can result from the drug
substance or the vehicle which can potentiate problems.

The following are some of the systemic adverse effects of topical
corticosteroids. Suppression of hypothalamic-pituitary-adrenal axis,
atrogenic Cushing\'s syndrome, growth retardation in infants and
children. And these effects are usually associated with a large body
surface area use of potent topical corticosteroids and will be discussed
further in the next presentation by Dr. Temeck.

The following are some of the risk factors for systemic adverse effects.
Young age, especially infants and children, liver and renal disease, the
amount of steroid applied, the extent of skin disease treated, the
frequency of application, the length of treatment, the potency of drug,
and the use of occlusion. It is not established whether catch-up growth
in children will occur when steroids are discontinued.

These are the local side effects of topical corticosteroids. Epidermal
atrophy leading to wrinkled skin with prominent vasculature,
pseudoscars, striae, or purpura; steroid dependence or rebound; glaucoma
and cataracts; and an increased susceptibility to bacterial, fungal and
viral infections.

Now going on to the next class of drugs, topical immunosuppressants,
these will be discussed in brief today and in further detail tomorrow.
This is the newest pharmacological class for atopic dermatitis. These
drugs were introduced in this decade. They have a direct
immunosuppressive action in diseases with an immunological basis. There
are two currently FDA-approved products: tacrolimus, FK506, the trade
name being Protopic; and pimecrolimus, SDZ ASM 981, the trade name being
Elidel.

Now reviewing their background. Protopic ointment was approved in
December of 2000. There are two strengths available. The .03 percent
ointment was approved for children 2 to 15 years of age, while the .1
percent ointment was approved for adults. The indication in both age
groups is short and intermittent long-term therapy of patients with
moderate to severe atopic dermatitis.

Systemic tacrolimus, or Prograf, was first introduced for prevention of
allograft rejection and is now used in kidney, liver, and heart
transplantation.

Elidel cream 1 percent was approved in December of 2001. It is indicated
for patients 2 years of age and older for short and intermittent
long-term therapy in the treatment of mild to moderate atopic
dermatitis. Both drugs were not approved for use in children less than 2
years of age. And systemic absorption can take place in both adult and
pediatric age groups from the topical application of both drugs.

And further, pediatric patients enrolled in clinical studies of
tacrolimus and pimecrolimus had an increased frequency of certain
adverse events, for example, viral infections compared to vehicle, and
currently the effects of topical immunosuppressants on the developing
immune system are unknown.

Thus, the indication for use, as mentioned, is second-line therapy in
the treatment of atopic dermatitis. Both Protopic and Elidel are
indicated for patients in whom the use of alternative, conventional
therapies are deemed inadvisable because of potential risks or in the
treatment of patients who are not adequately responsive to or are
intolerant of alternative, conventional therapies.

Lastly, I wish to acknowledge Diepgen, Yihune, et al., and the
Dermatology Online Atlas for the pictures used in this presentation. And
that brings me to the end.

DR. CHESNEY: Thank you very much.

I understand we\'ll have time for asking questions of the speakers after
our next three speakers.

Next, Dr. Jean Temeck, who is a medical officer in the Division of
Pediatric Drug Development and a board certified pediatrician and
pediatric endocrinologist, will present an overview of the
hypothalamic-pituitary-adrenal axis suppression secondary to the use of
topical corticosteroids.

DR. TEMECK: Good morning and welcome. Thank you all for coming today to
help us sort out some very difficult issues.

The topic of my presentation is hypothalamic-pituitary-adrenal axis
suppression following topical corticosteroid administration. I\'m going
to be covering the following topics in this presentation: the regulation
of glucocorticoid secretion, the spectrum of hormonal effects of
exogenous glucocorticoids on the HPA axis, the spectrum of clinical
manifestations of adrenal insufficiency, the importance of diagnosing
it, the tests which are used to diagnose it, and the risk factors for
HPA axis suppression.

This slide depicts the regulation of glucocorticoid secretion. The
hypothalamus secretes corticotropin-releasing hormone, or CRH, which
stimulates the pituitary gland to synthesize and secrete ACTH. The ACTH,
in turn, stimulates the adrenal gland to synthesize and secrete
cortisol. As cortisol levels rise, they suppress the secretion of ACTH
and CRH.

Exogenous glucocorticoids may have variable effects on the HPA axis.
They may not suppress the HPA axis at all or they may suppress the
secretion of ACTH and CRH, and this is termed secondary or central
adrenal insufficiency.

The degree of this suppression is variable. It may be mild or partial or
it may be complete. If suppression is mild or if it is short-term, only
the pituitary ACTH response to stress may be impaired. Both the basal
ACTH and cortisol levels may be normal, as well as the adrenal cortisol
response to stress. If suppression is severe or prolonged, then adrenal
cortical atrophy may occur, and in this circumstance, the basal cortisol
levels are low and the entire HPA axis is suppressed.

The clinical manifestations of adrenal insufficiency are variable. Some
patients are asymptomatic but their HPA axis is suppressed by hormonal
testing. This hormonal suppression is not just an abnormal laboratory
finding. It is clinically relevant because when the HPA axis is
suppressed, the patient is at risk for an acute adrenal crisis during
periods of stress. Other patients with adrenal insufficiency may be
symptomatic and the symptoms are generally nonspecific and subtle, such
as weakness, lethargy, or decrease in appetite, and they may be
insidious in onset. Other patients with adrenal insufficiency may
present with an acute adrenal crisis, and this is generally triggered by
stress, stress of a febrile illness, for example, trauma or surgery. It
is characterized by fever, severe hypotension and shock which may
progress to coma and death unless the patient is treated emergently with
supplemental glucocorticoids.

This slide reinforces the concept that all patients with HPA axis
suppression, regardless of whether they have symptoms or not, are at
risk for an acute adrenal crisis during periods of stress.

The true prevalence of glucocorticoid-induced adrenal insufficiency is
unknown, and this may be because of several factors. One, there may be
lack of clinical suspicion. There may be failure to recognize that
topical corticosteroids are systemically absorbed, and therefore they
can cause HPA axis suppression. In addition, because the signs and
symptoms of adrenal insufficiency are so subtle and nonspecific,
clinical suspicion is not aroused and therefore diagnostic testing is
not performed or attribution is made to other causes.

For example, if a child with HPA axis suppression secondary to topical
corticosteroid use for atopic dermatitis sustains major trauma from a
car accident, the ensuing shock may be attributed solely to the car
accident without recognizing the contribution of the adrenal
insufficiency to the shock.

Another reason that the true prevalence is not known is if the period of
suppression induced by the steroids is short so that the short period of
suppression goes undetected.

Finally, if a hormonal test with low sensitivity is used for diagnosis,
one may get a false negative test result and therefore the adrenal
insufficiency is not diagnosed.

Identifying patients with adrenal insufficiency even if it is mild, is
important because these patients are at risk for life-threatening
hypotension during periods of stress, and the condition is totally
preventable if supplemental glucocorticoids are administered before or
early in the course of the stress.

The following slides will describe the tests that are available to make
the diagnosis. Basically there are two types of tests which are
available: the basal hormonal tests and also the dynamic tests.

The dynamic tests fall into two groups: those which test the integrity
of the adrenal gland only and those which test the integrity of the
entire HPA axis.

There are two basal hormonal tests which are available for diagnosis:
the plasma cortisol level and either single or multiple measurements may
be obtained; and also the 24-hour urinary free cortisol test.

Plasma cortisol levels are only helpful if the level is either very low
or very high. For example, a level cutoff usually used is less than 3
micrograms per deciliter, which is drawn early in the morning around
8:00 a.m., that is soon after the peak cortisol surge occurs, or if the
level is very high, greater than or equal to 20 micrograms per
deciliter, and that can be obtained at any time of day. Unfortunately,
measurements of plasma cortisol usually fall between these two extremes,
and therefore they are not diagnostic.

Likewise, the 24-hour urinary free cortisol level is often
non-diagnostic because normal individuals may have low cortisol
excretion rates and also there may be difficulty in obtaining a complete
24-hour urine, especially in infants.

Due to the low sensitivity of these basal tests, most patients do
require dynamic testing for diagnosis. And the advantage of the dynamic
testing is that it provides information regarding the function, the
reserve capacity, and hence the ability of the adrenal gland or of the
entire HPA axis to respond to stress.

There are four dynamic tests which are available to make this diagnosis.
Two of these tests, the high-dose and the low-dose cosyntropin
stimulation tests, assess only the ability of the adrenal gland to
respond to exogenous ACTH. The other two tests, the insulin tolerance
test and the CRH test, assess the ability of the entire HPA axis to
respond to stress.

This concept can be described graphically. With the cosyntropin tests,
exogenous ACTH is administered and this stimulates the adrenal gland to
release cortisol. So the cosyntropin test directly assesses the ability
of the adrenal gland to release cortisol.

With the CRH test, exogenous CRH is administered and this directly
stimulates the pituitary gland to release ACTH.

With the insulin tolerance test, one administers insulin and then
subsequently you get a hypoglycemia. The hypoglycemia is a potent stress
stimulus for the release of both CRH and ACTH. So then you can see that
the ITT and the CRH tests directly assess the ability of the pituitary
gland or also of the hypothalamus to release ACTH and CRH, respectively.

Remember that secondary adrenal insufficiency, secondary to exogenous
glucocorticoid administration, means that the pituitary ACTH reserve
capacity is impaired. As I just pointed out, the ITT and the CRH tests
directly assess pituitary ACTH reserve, and therefore these tests are
very sensitive for diagnosing secondary adrenal insufficiency.

The cosyntropin stimulation test will also be sensitive for diagnosing
secondary adrenal insufficiency if it is chronic or longstanding. The
chronic ACTH deficiency leads to adrenal gland atrophy and this is the
basis for an abnormal cosyntropin test. However, if the ACTH deficiency
is of recent onset, then adrenal gland atrophy may not have had time to
develop and therefore the cosyntropin test will be normal although
secondary adrenal insufficiency is present.

Likewise, if the ACTH deficiency is mild, there may be sufficient
secretion of ACTH to prevent involution of the adrenal gland. So then
again the cosyntropin test will be normal although secondary adrenal
insufficiency is present.

Therefore, if secondary adrenal insufficiency is of mild or recent
onset, the cosyntropin stimulation test may yield a false negative
result, and additional testing may be needed in such circumstances if
the patient is symptomatic or if there is a high index of suspicion of
adrenal insufficiency.

The next few slides will describe each of these four dynamic tests which
are available to diagnose adrenal insufficiency.

The high-dose cosyntropin test is the one that is most commonly used to
make this diagnosis. A supraphysiologic dose of synthetic ACTH is
administered either IV or IM. The cosyntropin label states that this
dose is usually 250 micrograms, but that a dose of 125 micrograms may be
sufficient in a child who is 2 years of age or younger. Serum cortisol
levels are obtained at baseline and at the completion of the test. The
advantage of this test is that it is simple, fast, and inexpensive. It
can be performed at any time of day as an outpatient and you can
complete the test in an hour or less.

The cosyntropin label refers to both the 30-minute cosyntropin
stimulation test, as well as the 60-minute test. Since as you will hear
from Dr. Denise Cook\'s talk that the clinical studies that were
performed generally use the 30-minute test, it\'s the 30-minute test
that we will predominantly focus on now.

There is controversy regarding the criteria that should be used to
define a normal cortisol response. The cosyntropin label mentions three
criteria. A basal cortisol level should be greater than 5 micrograms per
deciliter. The peak cortisol level should be greater than 18 micrograms
per deciliter, and the increment, which is the difference between the
baseline cortisol and the peak cortisol levels, should be greater than
or equal to 7 micrograms per deciliter. However, the label does specify
that since this test can be performed at any time of day and since it is
only the peak level which is not dependent on the time of day, the peak
cortisol level is sufficient in and of itself to make the diagnosis of
adrenal insufficiency.

I would also like to mention that use of the increment may be
problematic because the increment is inversely proportional to the basal
cortisol level, so that the higher the basal cortisol level, the lower
the increment. Therefore, most endocrinologist use a peak cortisol level
of greater than 18 micrograms per deciliter to denote a normal response
to the 30-minute test.

The disadvantage of this test has already been mentioned. You can get a
false negative test when the secondary adrenal insufficiency is mild or
is of recent onset. Additional testing may be needed if the patient is
symptomatic or there is a high index of suspicion of adrenal
insufficiency.

The next test for discussion is the low-dose cosyntropin stimulation
test. This is a newer test, and a physiologic dose of ACTH, either 0.5
microgram per meter squared or in other circumstances 1 microgram per
meter squared ‑‑ those are some of the ACTH doses which have been used
as reported in the literature in children ‑‑ is administered
intravenously, and then blood samples are obtained at baseline for
cortisol measurement and then serially post ACTH administration. Because
such a low dose of ACTH is being administered in this test and ACTH has
a very short half-life, this test requires frequent, carefully timed
blood sampling because you do not want to miss the peak cortisol
response.

Some have reported that this is a more sensitive test than the high-dose
test to detect mild secondary adrenal insufficiency because you are
administering a physiologic dose of ACTH and therefore only mobilizing
the cortisol that is available in the immediate release pool. However,
results of studies on this issue have been conflicting.

In addition, there is no standard method of performance for this test
either with regard to the dose of ACTH that should be administered or
the frequency or the timing of the blood samples post ACTH
administration.

In addition, this low dose of ACTH is not commercially available, and
therefore dilutional errors can occur. There can be variability in the
amount of the ACTH that is administered from test to test, and there is
at least one report of adherence of part of the ACTH to the plastic
tubing of the vein delivery set.

This slide compares the low-dose to the high-dose ACTH test. Again, with
the low-dose test, this dose is not commercially available, but the 250
microgram dose is. Low-dose, you\'re administering a physiologic ACTH
dose; with the high-dose test, you\'re administering a supraphysiologic
dose. The low-dose test, as we said, requires frequent, carefully timed
venous sampling, while with the high-dose test, only a single cortisol
level needs to be obtained at the end of the test and it does not have
to be precisely timed. While there is no consensus on method of
performance of the low-dose test, the method of performance with the
high-dose test has been standardized. And while with the high-dose test
there is no consensus regarding what constitutes a normal cortisol
response, with the high-dose test, it is generally accepted that a peak
cortisol level greater than 18 micrograms per deciliter with a 30-minute
test constitutes a normal response. So as you can see, on balance, the
high-dose test offers a number of advantages over the low-dose test.

The next two slides will describe the insulin tolerance test. As we
mentioned before, hypoglycemia is a potent stress stimulator for the
release of CRH and ACTH. This test involves administration of
intravenous insulin after an overnight fast. Plasma cortisol and glucose
levels are obtained before and at 30, 45, 60, and 90 minutes post
insulin administration. A normal response is a peak cortisol level of
greater than 18 to 20 micrograms per deciliter at 60 to 90 minutes post
insulin administration, with a concomitant serum glucose level of less
than 40 milligrams per deciliter.

Although this test provides a direct and definitive assessment of HPA
axis integrity, it is a very high-risk test, and there has been
significant neurologic morbidity and also mortality has been reported
with conduct of this test in children. Therefore, this test is rarely,
if ever, used. Safer diagnostic alternatives are available.

The next three slides will discuss the CRH test. This test is a newer
test, and as we said, the physiologic basis for this test is that CRH
stimulates the release of ACTH and hence of cortisol.

A 1 microgram per kilogram dose of CRH is administered intravenously,
and plasma ACTH and cortisol levels are measured periodically for 90 to
180 minutes post CRH administration. This test has been used to
differentiate primary from secondary from tertiary adrenal
insufficiency. With primary adrenal insufficiency, basal ACTH levels are
high, and they increase with CRH administration but cortisol levels do
not. Both secondary and tertiary adrenal insufficiency are characterized
by low levels of ACTH basally. With secondary adrenal insufficiency, you
get a flat response to CRH administration, while with tertiary adrenal
insufficiency, you get an exaggerated ACTH response to CRH. However, I
would like to point out that the distinction between secondary and
tertiary adrenal insufficiency is not important here because we\'re
talking about adrenal insufficiency secondary to exogenous
glucocorticoid administration.

The advantages of this test are several. The CRH test provides a direct
and definitive assessment of HPA axis integrity. There are also reports
that the CRH test has equivalent diagnostic value to the insulin
tolerance test, but unlike the insulin tolerance test, the CRH test is
safe and it can be conducted as an outpatient.

There are a number of disadvantages to this test. First, it is expensive
and it does require performance of multiple blood samples. There may be
errors in blood collection and storage, and this is because ACTH has a
short half-life. It\'s readily inactivated by proteases so that when
you\'re collecting the samples for ACTH, you have to collect them in
pre-chilled containers and then the specimen should be kept frozen to
minus 20 degrees Centigrade until ready for assay.

In addition, the normal responses of ACTH on cortisol are
laboratory-dependent, and so there is no consensus regarding what
constitutes a normal response.

Also, FDA has not approved the CRH test as a diagnostic for adrenal
insufficiency. It has only approved it for the use of the differential
diagnosis of Cushing\'s syndrome, whether the ACTH hypersecretion is
from the pituitary or from an ectopic source.

Additional studies are needed to confirm the usefulness of this test as
a diagnostic for adrenal insufficiency.

We\'ll now discuss risk factors for HPA axis suppression. Again, to
remind you, there is individual susceptibility. HPA axis suppression is
variable as is time to recovery. Therefore, the diagnosis of adrenal
insufficiency does require performance of hormonal testing.

Nevertheless, there are a number of risk factors that may influence the
development and the degree of HPA axis suppression. Certainly the higher
the potency of the steroid used and the longer the half-life, the
greater the risk of suppression. Also, the vehicle or base used, that
is, whether the preparation is a cream, a lotion, or an ointment, may
also be an influencing factor, and Dr. Cook will discuss this in her
talk.

The greater the extent of absorption, the greater the risk of
suppression. Absorption of topical corticosteroids is increased by thin
stratum corneum such as found in the face in the intertriginous areas.
Absorption is also enhanced in areas of heat and moisture, such as found
in the intertriginous areas. And likewise, absorption is greater when
the steroid is applied to abraded or inflamed skin as opposed to if you
had an intact skin barrier.

Also, the greater the amount of steroid used, the greater the risk of
suppression. With topical corticosteroids, the dose administered is a
function of the concentration of the steroid in the base vehicle and the
percent of skin surface area that is covered. We know that infants are
particularly susceptible or vulnerable to HPA axis suppression. It\'s
postulated that this is due to the higher ratio of skin surface area to
body mass.

In addition, the longer the contact time of the steroid with the skin,
the greater the risk of suppression.

The cumulative dose is a function of the dosing interval and the
duration of treatment. The more frequent the application, the less the
chance of HPA axis recovery between applications so that continuous
application would be expected to be more suppressive than intermittent
application.

With regard to duration of treatment, if a topical steroid is used for,
let\'s say, a week or 2 or less, one would anticipate less chance of
suppression and if it did occur, there would be more rapid recovery.

These next three slides will summarize the main points of this
presentation.

First topical corticosteroids are systemically absorbed and therefore
they may cause secondary adrenal insufficiency.

The symptoms of adrenal insufficiency may be subtle and nonspecific, and
therefore the diagnosis may not be suspected clinically or attribution
is made to other causes.

Patients with secondary adrenal insufficiency are at risk for an acute
adrenal crisis regardless of the degree of suppression or the presence
of symptoms. An acute adrenal crisis is preventable if supplemental
glucocorticoids are administered before or early in the course of
stress.

Although risk factors for HPA axis suppression may be present,
individual susceptibility is variable.

Hormonal testing is required for the diagnosis, and basal hormonal tests
are often nondiagnostic. Therefore, the majority of the patients do
require dynamic hormonal testing.

Dynamic tests of HPA axis integrity are more sensitive for the diagnosis
of mild or recent onset secondary adrenal insufficiency than are tests
which measure only adrenocortical reserve.

A negative cosyntropin test may warrant additional testing, particularly
if the patient is symptomatic or if there is a high index of suspicion
of secondary adrenal insufficiency.

When HPA axis suppression is diagnosed, treatment should follow standard
medical practice and the patient should be followed to document full
recovery of the axis.

Thank you.

DR. CHESNEY: Thank you very much.

Our next speaker is Dr. Denise Cook, who is also a medical officer and
board certified pediatrician in the Division of Dermatologic and Dental
Drug Products. She will present data on HPA axis suppression from the
clinical studies for various topical corticosteroid drug products.

DR. COOK: Thank you. I\'d just like to make one correction. I\'m a board
certified internist and dermatologist, although I\'d love to claim to be
in the field of pediatrics also.

DR. CHESNEY: We\'re glad to have you join us even if name only.

(Laughter.)

DR. COOK: With that, good morning, everyone.

I\'m going to speak today on topical corticosteroids and HPA axis
suppression. This presentation will outline the history of where the FDA
has been and where we are presently as it relates to HPA axis
suppression and the use of topical corticosteroids. I\'ll examine the
history of labeling as it relates to systemic safety and topical
corticosteroids. I will briefly speak about the regulation and
legislation relevant to this topic. The large majority of the talk will
focus on specific drug products data. Information presented will come
from labels and trials to help us examine the relationship between
topical corticosteroid use and HPA axis suppression. Since this is a
Pediatric Advisory Committee meeting, the main focus of the talk will be
on pediatric patients.

As mentioned by Dr. Nikhar, topical corticosteroids were first
introduced in the 1950s and have been the mainstay of treatment of
atopic dermatitis for approximately half a century.

Before I get started, for understanding I will briefly mention the
classification of these drug products. Topical corticosteroids are
divided into seven classes. Class I is the superpotent topical steroid
of which Temovate is the drug most known. Class II is the high potency
topical corticosteroids. Class III through VI are mid-potency, and those
steroids are divided into high mid-potency and low mid-potency. And
Class VII is the low potency for which hydrocortisone acetate is the
prototype.

The classes are determined by a vasoconstrictor assay in which caucasian
patients are used and medication is applied to the skin with bracketing
of known drug products, and then the amount of blanching is determined
as compared to products in certain classes. And that\'s how the class is
determined for that particular drug product.

I am going to begin with a label dated in the early 1970s as a 30-year
history should suffice to show the progression of labeling.

Lidex gel is a class II high potency topical steroid that was approved
in 1971. At that time, the safety information in labels was very brief,
and it stated in the precaution section, if extensive areas are treated,
the possibility exists of increased systemic absorption and suitable
precautions should be taken.

In the 1980s, labels become somewhat more sophisticated. The safety
update information was expanded. In the precaution section for Temovate
cream and ointment, which was approved in 1985, it stated: Temovate is a
highly potent topical corticosteroid that has been shown to suppress the
HPA axis at doses as low as 2 grams per day. A pediatric use section was
now in the labels, and it stated that use of Temovate cream and ointment
in children under 12 years of age is not recommended.

The claims in the label were supported by the following two trials.
These trial were done with Temovate ointment and they were open-label
trials.

Trial 1, there were 6 adult patients with psoriasis who applied the
medication to 30 percent of their body surface area for 7 days at a dose
of 7 grams per day. In this trial, the ACTH stimulation test was
performed at baseline and two post-treatment AM cortisols were obtained.
They found in this study that 3 of the 6 patients, or 50 percent of the
patients, exhibited decreases in cortisol production.

The second trial objective was to determine the largest dose that could
be used over a 7-day period that would not cause significant suppression
of the adrenal gland. Three doses were used: 7 grams per day, 3.5 grams
per day, and 2 grams per day. Suppression in this trial was determined
not by the cosyntropin stimulation test, but by just determining the
basal AM plasma cortisol levels and urinary corticoid concentrations.
It\'s interesting that none of the psoriasis patients suppressed, but at
doses as low as 2 grams per day, marked suppression of cortisol
secretion occurred in patients with atopic dermatitis. That led to the
label that I discussed earlier.

Now that we had documentation of HPA axis suppression, class labeling
was adopted for topical corticosteroids in 1990. It primarily affected
the precaution section and the pediatric use section. I will go over
each of these sections.

First, the precaution section. In the general part of the label it
stated, 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 corticosteroids while on treatment.

It went 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.

Further, it stated: 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 glucocorticoid insufficiency may
occur requiring supplemental systemic corticosteroids.

The pediatric use section also had an update and was part of this
topical class labeling. If no trials had been performed in pediatric
patients, which was usually the case at the time, then the statement
\"safety and effectiveness in children and infants have not been
established\" was used. 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.

Further, it stated: 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.

One regulation and two pieces of legislation improved the agency\'s
ability to examine safety of new and existing drug products in the
pediatric population, and I will speak briefly about them. The first one
was the Pediatric Rule in 1994. The second one was section 111 of the
Food and Drug Administration Modernization Act approved in 1997, and the
final one was the Best Pharmaceuticals for Children Act passed in 2002.

In the Pediatric Rule, it allowed for extrapolation of adult efficacy
data to pediatric patients, when appropriate, plus additional safety,
PK, and/or dose-ranging studies in the targeted pediatric population.

Section 111 of FDAMA introduced the written request where sponsors are
offered 6 months of exclusivity for their chemical moiety if they fairly
respond to the agency\'s request for pediatric studies.

The Best Pharmaceuticals for Children Act had several important edicts,
two of which are relevant to this talk. It establishes additional
mechanisms for the study of both on-patent and off-patent drugs.
Pediatric supplements are now priority reviews.

The following portion of the talk will examine individual drug products
and the trials that were undertaken in an attempt to provide additional
safety data regarding their use. So I hope you had a healthy dose of
caffeine as we delve into all of this data.

(Laughter.)

DR. COOK: There are 10 drug products that we\'re going to speak about,
although more have been done. Eight are topical corticosteroid products,
and two that I will speak about are combination drug products. Eleven
studies will be discussed. The patients ages range from 3 months to
adult, and all of the studies evaluating the function of
hypothalamic-pituitary-adrenal axis were open-label studies.

As mentioned earlier by Dr. Temeck, the cosyntropin stimulation test is
the most frequently used to assess adrenal function. As you will note,
varying criteria over the years have been used by the agency to define
adrenal gland suppression via this test. We are currently in the process
of drafting a consistent approach to the evaluation of HPA axis
suppression.

The first drug that I\'m going to speak about is Dermatop, a class V
steroid that was approved in 1996, and a pediatric atopic dermatitis
trial was performed. In this trial, there were 59 pediatric patients
enrolled, and there were two targeted populations. Patients between 1
month and 2 years and patients between 2 years and 12 years of age. 10
patients were less than 2 years old. 49 patients were greater than or
equal to 2 years old.

The treatment criteria for this trial was that greater than 20 percent
of the body surface area had to be involved, patients had to use the
drug twice daily for 21 consecutive days. In this trial, it did not
matter if the patient\'s skin disease had cleared. They continued to use
the drug for 21 consecutive days.

The ACTH stimulation test was used. Cosyntropin was administered at
baseline and day 22. Patients who were greater than 15 kilograms
received .25 milligram IV, and patients less than 15 kilograms received
0.125 milligram IV. This happens to be the case for all of the studies
except the Cutivate study in which they divided the dose according to
age.

The criteria per protocol for a normal adrenal response to ACTH
stimulation at 30 and 60 minutes was that the post-stimulation serum
cortisol had to be greater than 20 micrograms per deciliter. Also, if
the pre-stimulation serum cortisol level was already greater than 20
micrograms per deciliter, then an incremental increase greater than 6
micrograms per deciliter in serum cortisol was required.

The outcome was that 3 patients according to the protocol criteria were
suppressed. 2 patients, 1 an 18-month-old, had a peak response of 5
micrograms per deciliter change from baseline. 1 patient had a
post-stimulation cortisol value that actually decreased after
stimulation.

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 micrograms per deciliter, although they didn\'t have the
required incremental rise, they would not be suppressed. This led to the
current label for Dermatop which reads that none of the 59 patients
showed evidence of HPA axis suppression.

The next drug is Cutivate cream which is also a class V steroid. It was
approved June 17th, 1999. When I talk about approval, I am not speaking
about the approval of the drug product itself, but the approval of the
pediatric supplement that came into the agency.

There was a pediatric atopic dermatitis and psoriasis trial. However, in
the trial only patients with atopic dermatitis were studied. There were
43 patients who were evaluable, all with moderate to severe atopic
dermatitis. When I say evaluable, that means that at baseline the
patients did not show any evidence of adrenal suppression on cosyntropin
stimulation.

29 of the patients were 3 months to 2 years old, and 14 patients were 3
years to 5 years old.

The treatment criteria for this trial was that at least 35 percent of
the body surface area would be involved and treated. There would be
twice-a-day application for 3 to 4 weeks. In this trial, patients were
required to use the drug continuously for 3 weeks. If they continued to
have disease at that point, they could use an additional week of drug
product. Patients up to 2 years of age were limited to 120 grams per
week, and patients 3 to 5 years of age were limited to 180 grams per
week.

I just want to put into perspective about using the drug for the
required 3 weeks even if the disease had cleared. In this study, there
were 46 patients who were enrolled, and 23 of the patients, or 50
percent, had a decrease of body surface area improvement of 50 percent
by 2 weeks. 20 percent had a decrease of 50 percent BSA involvement by 3
weeks, and 9 percent had a 50 percent decrease of BSA involvement by 4
weeks. So this kind of shows that most of the patients still had some
evidence of disease throughout the trial.

The cosyntropin stimulation test was used. The test was administered at
baseline and end of treatment, and again, in this trial the younger age
group had the smaller dose and the older age group had the larger dose.

A normal response in this trial was a serum cortisol level greater than
18 micrograms per deciliter at 30 minutes post stimulation.

2 out of the 43 patients experienced adrenal suppression. 1 was a
5-year-old who had 95 body surface area, and over the course of the
trial improved to about 26 percent BSA involvement, used the drug for 4
weeks, used 561 grams, as mom continued to apply the drug to 95 percent
BSA, although the requirement was just 35 percent BSA. You can see that
the post-stimulation cortisol was 11.8. However, 2 weeks after treatment
when there was no medication used, the patient recovered with a
post-stimulation of 19.8.

The second child was a 2-year-old who only had 35 percent BSA
involvement, used a much smaller amount of drug over 5 weeks, 176.5
grams, and was suppressed at the end of treatment with a serum cortisol
of 9.4 micrograms per deciliter. Unfortunately, he was lost to
follow-up, although several attempts were made to locate the patient, so
we don\'t know about that patient\'s recovery.

This led to a labeling change for Cutivate cream where the indication
stated that children as young as 3 months of age could use the drug for
up to 4 weeks, and safety update information was included in the
precaution section\'s general and pediatric use sections.

The next group of drugs that I\'m going to speak about are the
betamethasone propionate drugs approved in 2001. These drugs range in
class potency from a class II steroid high potency to a class V steroid.
Lotrisone cream and lotion will also be discussed here because it also
includes betamethasone propionate.

The betamethasones heralded, with extra divisional input, an internal
change in policy regarding what constitutes HPA axis suppression using
cosyntropin stimulation. That included that now for normal HPA axis
response, we must follow the Cortrosyn label, and failure of any one of
three criteria would indicate suppression of the HPA axis. Stimulation
should also occur at baseline and end of treatment in any future trials.

Those criteria at the 30-minute post-stimulation, which you have heard
earlier, are that the control plasma cortisol level should exceed 5
micrograms per 100 milliliters. The 30-minute level should show an
increment of at least 7 micrograms per 100 milliliters above the basal
level. The 30-minute level should also exceed 18 micrograms per 100
milliliters.

The first drug I\'m going to speak about is Diprolene AF cream. In this
trial, there were 60 evaluable patients, ages 1 to 12 years, with
moderate to severe atopic dermatitis. The mean body surface area
involved was 58 percent. Patients in these studies used the drug per the
product label. They used the study drug twice a day for 2 to 3 weeks,
and they were limited to 45 grams per week. Again, they used it for 2
weeks, and if they needed an additional third week because there was
still significant disease present, they used it for 3 weeks. So the test
could either occur at the 2-week point or at the 3-week point.

In this study, 32 percent of these patients showed evidence of HPA axis
suppression. Of the 19 patients who suppressed, 11, or 58 percent, had a
post-stimulation plasma cortisol value of less than 18 micrograms per
deciliter. 6 patients failed to have an incremental change of at least 7
micrograms per deciliter, and 11 percent had a pre-stimulation cortisol
less than 5 micrograms per deciliter. I should also mention that most of
the cosyntropin testing was done in the morning, AM, 8 o\'clock.

Now, if we look at suppression by age group in Diprolene AF cream, we
will find that the younger the patient was, the greater the proportion
of subjects who suppressed. For example, in the 9-year to 12-year group,
17 percent of patients suppressed, and in the infant group, 3 months to
1 year, 50 percent of the patients suppressed.

Regarding recovery of normal HPA axis function, 4 patients were retested
2 weeks post treatment, and 3 of the 4 recovered normal function of the
HPA axis.

Now, the statistical analysis in the development of HPA axis suppression
for Diprolene AF showed there was no correlation between amount of drug
used, body weight, age, or sex and the incidence of adrenal gland
suppression. There was a statistical relationship between body surface
area and risk of HPA axis suppression such that for an increase of 1
percent BSA involved, risk of HPA axis suppression increased by 4.4
percent, and that should be p is less than 0.01. This latter statistical
fact, in the absence of a correlation with amount of study medication
used, may be related to the increased BSA to body mass ratio in young
children and infants.

This study led to a labeling change for Diprolene AF cream such that the
cream was restricted to patients who were 13 years of age and older, and
clinical safety information was updated in the appropriate sections of
the label.

The next drug is Diprosone ointment. In this study there were 53
evaluable patients with atopic dermatitis. Their age range was 6 months
to 12 years old. Medication again was applied twice a day for 2 to 3
weeks, and there was a mean body surface area involvement of 58 percent.

In this study, 28 percent of patients showed evidence of HPA axis
suppression. Of those 15 patients who suppressed, 53 percent had a
post-stimulation plasma cortisol value of less than 18, and 47 percent
failed to have an incremental change of at least 7 micrograms per
deciliter.

If we look at this drug at suppression by age group, we will see the
same thing. The younger the patient, the greater the proportion of
subjects that experienced suppression, ranging from 17 percent in the
9-year to 12-year-old group to 36 percent in the infant group.

The statistical analysis, however, did not show a significant effect for
drug usage percent BSA involvement, weight, or age. However, there was a
higher proportion of males than females who developed HPA axis
suppression.

In the recovery of HPA axis function, there were 2 of 15 patients who
were suppressed that were retested, and there was 100 percent recovery
at 2 weeks.

A labeling change for Diprosone ointment also added an age restriction
of 13 years and older, and clinical safety information was updated in
the clinical pharmacology, the precautions, general and pediatric use
sections of the label.

Diprosone cream had 43 evaluable patients with atopic dermatitis in its
trial. The age range was 1 year to 12 years old. The mean body surface
area involvement was 40 percent. The medication was applied twice a day
for 2 to 3 weeks.

In the Diprosone cream trial, 23 percent of patients showed evidence of
adrenal suppression. Of those 10 patients, 50 percent had a
post-stimulation plasma cortisol value of less than 18 micrograms per
deciliter. 30 percent failed to have an incremental change of at least 7
micrograms per deciliter, and 2 of the 10 patients had a pre-stimulation
cortisol less than 5 micrograms per deciliter. In all of these trials,
there were some patients who failed actually on more than one criterion.

If we look at HPA axis suppression by age in this study, there again was
a progression the younger that the patient was, except in this trial,
for some reason, no infant suppressed.

The statistical analysis did not show a statistically significant effect
for number of days treated, weight, or age.

There was a statistical significance found for this particular drug
product in the mean amount of drug used. Those who suppressed used 81
grams versus 37 grams in those who did not suppress.

There was a numerically higher percent of body surface area involvement
in those who suppressed, and numerically more males developed
suppression.

In the recovery of HPA axis function, 2 of 10 patients were retested,
and 1 of the 2 patients recovered HPA axis function at 2 weeks.

The labeling change for Diprosone cream was also the same in the
indication where age restriction of 13 years and older was placed.
Clinical safety information was updated in the appropriate sections of
the label.

The last solitary betamethasone propionate product that I will speak
about is Diprosone lotion. In this trial, pediatric patients were to be
enrolled in a step-wise fashion beginning with the oldest age group. If
significant suppression was not observed, then progressively younger age
groups could be enrolled. This is a class V corticosteroid. There were
15 evaluable patients with atopic dermatitis. The age range was 6 to 12
years old. The mean body surface area involvement was 45 percent. The
medication was applied twice a day for 2 to 3 weeks.

In this trial, 73 percent of patients showed evidence of HPA axis
suppression, and of those 11 patients who suppressed, 91 percent had a
post-stimulation plasma cortisol value less than 18 micrograms per
deciliter. And 1 of the 11 patients failed to have an incremental change
of at least 7 micrograms per deciliter.

When you look at suppression by age group, you see, because there was
such a high percentage of patients who developed adrenal suppression,
there were no patients less than 6 years of age who were enrolled in the
study.

When you do a numerical analysis ‑‑ we only did a numerical analysis
because the numbers were so small ‑‑ it showed that subjects exhibiting
HPA axis suppression had a larger mean amount of drug used, had a
slightly higher percent of body surface area involved, had lower mean
weights at visit 1 and 4, but the differences with respect to age and
days of treatment were minuscule.

In recovery of HPA axis function with Diprosone lotion, there were 6 of
the 11 patients retested, and 67 percent recovered their HPA axis
function at 2 weeks.

This led to a label change for Diprosone lotion where the age
restriction was of 13 years and older and the appropriate clinical
safety information was updated in the label.

Now, if you look at a comparison of HPA axis suppression criteria of the
betamethasone dipropionates, whether you use all three criteria as per
the label or whether you just use greater than 18 micrograms per
deciliter, you will see that the Diprolene AF cream, the Diprosone
ointment, and the Diprosone cream all tended to clutter around the same
ball park in their ability to suppress the adrenal gland. However,
Diprosone lotion stands out by itself with a high rate of suppression.
This led us to believe that the actual vehicle in which the chemical
moiety is in may play a role in the amount of absorption into the
systemic circulation of the chemical moiety.

Lotrisone cream is the last betamethasone diproprionate product that I
will speak about. This also includes clotrimazole and is approved for
the treatment of dermatophytosis. The two studies were a tinea pedis
study and a tinea cruris study. Both studies were in the adolescent
population, ages 12 to 16 years. The medication was applied twice daily.
In the tinea pedis study, it was applied for 4 weeks. In the tinea
cruris study, it was applied for 2 weeks.

In this study, 39.5 percent of patients demonstrated adrenal suppression
in the tinea pedis study and 47 percent demonstrated adrenal suppression
in the tinea cruris study.

This led to a label change for Lotrisone cream and also for lotion by
extension of the betamethasone lotion study that was done which showed
significant suppression. An expanded indication section was developed.
It added an age restriction to only patients 17 years and older. It also
recommended that effective treatment may be obtained without the use of
a corticosteroid for noninflammatory tinea infections. They updated
safety information in the appropriate sections of the label.

The last drug product that I will speak about are the clobetasol
propionate products. These are class I steroids, the superpotent
steroids. I will speak about Clobex lotion and Temovate E cream.

This was done under Clobex lotion. There were three studies, two adult
studies, one in psoriasis and one in atopic dermatitis. There was one
pediatric study, ages 12 to 17, in atopic dermatitis.

The construct of the HPA axis evaluation was the control plasma cortisol
levels should exceed 5. The 30-minute level should show an increment of
at least 7 micrograms, and the 30-minute level should exceed 18
micrograms per 100 milliliters.

In these trials, however, there were some exceptions. The plasma
cortisol levels were drawn at 60 minutes post stimulation. In the adult
studies, subjects were stimulated with cosyntropin weekly.

In the adolescent study, there were 24 evaluable patients, 14 treated
with Clobex lotion and 10 treated with Temovate E cream. They had
moderate to severe atopic dermatitis. They had to have at least 20
percent body surface area involvement. Medication was applied twice a
day for 2 weeks. There was a 50 gram per week limit. This is because the
trial had to follow the Temovate E labeling.

In this trial, HPA axis suppression was noted in 64 percent of the
subjects treated with Clobex lotion as compared to 20 percent of the
subjects treated with Temovate E cream, again suggesting that the
vehicle, which is a lotion, may play a role in the absorption of the
chemical moiety into the systemic circulation.

In the statistical analysis the mean percent body surface area treated
was higher for patients with adrenal suppression, 32 percent versus 27
for Clobex lotion and 35 percent versus 25 for Temovate E cream.

In the recovery of HPA axis function, 1 of the 4 patients retested, who
were treated with Clobex lotion, remained suppressed after 2 weeks. The
1 patient who was retested with Temovate E cream recovered.

In one of the adult studies, there were 18 evaluable patients, 9 in each
arm, moderate to severe atopic dermatitis. Their mean body surface area
treated was approximately the same for both drugs. Medication was
applied twice a day for 2 weeks, and there was a 50 gram per week limit.

In this trial, 56 percent of the subjects treated with Clobex lotion
suppressed, and 44 percent of the subjects treated with Temovate E cream
suppressed.

Of the patients who were retested, 1 out of the 3 patients on Clobex
lotion failed to recover function 7 days post treatment. Both patients
who were retested on Temovate E cream recovered function 7 days post
treatment.

In the final adult study, there were 20 evaluable patients, 10 treated
with Clobex lotion and 10 treated with Temovate E cream. The patients
had moderate to severe plaque psoriasis. They had approximately the same
body surface area treated, 16.2 percent for Clobex lotion and 17.9
percent for Temovate E cream. Here the medication was applied twice a
day for 4 weeks. Temovate E allows for 4-week treatment to small areas
of body surface area involvement in psoriasis. The gram limit again is
50 grams per week.

In this study, 80 percent of the subjects treated with Clobex lotion
suppressed compared to 30 percent of subjects with Temovate E cream.

In the recovery of their HPA axis function, 1 of the 2 patients treated
with Clobex lotion remained suppressed after 8 days. None of the
patients on Temovate E cream were retested.

The label for Clobex lotion that was developed stated the drug would be
restricted to patients 18 years or older. It could be used for 2
consecutive weeks, not to exceed 50 grams per week. Moderate or severe
psoriasis for localized lesions less than 10 percent body surface area
could be treated an additional 2 weeks. And safety information was
included in the indications and usage, in the precautions, general and
pediatric use, and in the dosage and administration sections.

In summary, just a few salient points. HPA axis suppression does occur
with the use of topical corticosteroids. The adrenal suppression is not
limited to the superpotent class of topical corticosteroids. 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.

In conclusion, there has been progress in acquiring safety information
in the pediatric age group for the use of topical corticosteroids as it
relates to systemic safety, in particular, the function of the HPA axis.
The Pediatric Rule of 1994, section 111 of FDAMA, and the Best
Pharmaceuticals for Children Act have certainly spurred this process in
obtaining information for specific drug products to aid healthcare
professionals in their risk-benefit analysis. Yet, there are more
questions that remain to be answered and hopefully will be answered by
this committee today.

Thank you.

DR. CHESNEY: Thank you very much for presenting a lot of technical
information in a way that kept us all alert. We had enough coffee.

Our final formal presentation of the morning is by Claudia Karwoski, who
is a safety evaluator team leader with the Division of Drug Risk
Evaluation in the Office of Drug Safety, and she will present the
adverse event reports of HPA axis suppression among children treated
with topical corticosteroids.

DR. KARWOSKI: Good morning. I\'ll first provide an overview of AERS,
including its strengths and limitations. I\'ll touch upon the potency
classification system for the topical corticosteroids, and then I\'ll
discuss the methods for case selection, the results of our evaluation of
the cases, and finally provide an overall summary of our findings.

The Adverse Event Reporting System is a spontaneous, voluntary
surveillance system of adverse events for U.S.-marketed products.
Reporting by healthcare professionals and consumers is voluntary.
Reporting by manufacturers is mandatory.

There are currently about 3 million reports in the database. It dates
back to 1969 with the implementation of the Spontaneous Reporting
System. SRS was replaced in November of \'97 with AERS. At that time,
all the reports were migrated from SRS into AERS. AERS contains reports
for all human drug and therapeutic biologic reports except for the
vaccines, which is a separate database.

Spontaneous reporting systems such as AERS have several limitations. The
quality of the reports are variable and often incomplete. Because
reporting is voluntary, AERS is subject to under-reporting and therefore
the true numerator of adverse events for a specific product is unknown.
Reporting biases exist. An example is increased reporting that often
occurs following publicity of a safety issue.

Although we often use drug usage data to estimate exposure, the exact
denominator or number of patients exposed to a product is unknown. And
because we don\'t know the true numerator or denominator, we cannot use
spontaneous reports to determine incidence of an adverse event.

Duplicate reporting also occurs and matching duplicates can be difficult
particularly when the information is incomplete.

Despite its limitations, AERS does have several strengths. It allows for
early detection of events not seen in clinical trials. It is especially
useful for detecting serious rare events such as hepatic failure or
aplastic anemia. Often one or more well-documented reports can trigger
further evaluation. And a case series evaluation may aid in identifying
adverse event trends such as events that occur when a product is used
for a specific indication or in a specific patient population such as
children or the elderly. And lastly, AERS is relatively inexpensive
compared to alternative surveillance strategies.

The topical steroids are classified by potency, and you\'ve seen this
slide before. Generally the class I includes the most potent and VII
includes the least potent. The characteristics of the concentration of
the product, as well as the vehicle, will influence the potency, and the
potency is determined by the drug\'s ability to induce vasoconstriction.

We searched AERS for all adverse events reported for the topical
steroids in children from 0 to 16 years of age. This was done in 2001 to
provide an overall safety review of these products in that population.
We also searched AERS and the medical literature for case reports of
adrenal suppression, Cushing\'s syndrome, and growth retardation in
children.

This graph depicts the leading adverse events as a percentage of all
adverse events in children treated with topical steroids. The most
commonly reported events are local irritation and application site
reaction, which represents about 27 percent of all adverse events. This
is followed by lack of effect, skin discoloration, and skin atrophy,
which represent about 12 to 13 percent of adverse events. Among the top
events are Cushing\'s syndrome, adrenal suppression, and growth
retardation.

Our search for cases of adrenal suppression, Cushing\'s syndrome, and
growth retardation identified 24 total cases in AERS and the published
literature. We excluded two because one turned out not to be an event of
interest and in the other the use of a topical corticosteroid was
reported. Of the remaining 22 cases, 8 reported adrenal suppression, 13
reported Cushing\'s syndrome, and 10 reported growth retardation. Some
of the cases reported more than one of these events, and six were
published in the literature.

The children\'s ages ranged from about 6 weeks to 15 years of age and
the median age was 3.

9 of the adverse events occurred in pediatric patients younger than 3
years and 5 occurred in infants. There were over twice as many reports
in males than females.

And the duration of therapy ranged from 22 days to 7 years. In 7 cases,
use of the topical corticosteroids continued for over a year, and it\'s
only clear in 1 of the 7 reports that the use was intermittent.

Slightly more than half of the cases are foreign, and these reports span
just over 20 years, with the first being reported in the literature in
1980.

10 patients were hospitalized and 2 patients with Cushing\'s syndrome
died. 1 death was secondary to respiratory infection, and the
circumstances in the second death were not provided.

A variety of indications were reported. 7 reported being treated for
atopic dermatitis or eczema. In 6 cases the children received topical
steroids to treat diaper rash and 2 were being treated for hair loss.

The site of application includes the diaper area in 7 cases. 2 reported
the use of a topical steroid to the entire body, and 3 reported use in
more than one location on the body.

Clobetasol, mometasone, and betamethasone-containing products were the
most frequently implicated. In 4 cases, the patient was treated with
more than one topical corticosteroid product.

The patients presented with one or more of the following. 12 patients
presented with weight gain or other Cushingoid features. 10 presented
with growth retardation. 1 infant presented with acute adrenal
insufficiency after a possible acute illness, and 1 child presented with
skin striae and depigmentation.

I\'ll now present select cases that provided laboratory evidence of
adrenal suppression. The first is of a 4-month-old boy who presented
with accelerated weight gain, obesity, and diaper dermatitis that was
unresponsive to topical corticosteroids. At 2 months of age, he was
prescribed hydrocortisone which was to be administered three to four
times daily for a week. This was continued by his mother and she
additionally used clobetasol. A total of eight tubes of hydrocortisone
and six tubes of clobetasol were used within a 2-month frame.

On presentation, his laboratory evaluation included decreased levels of
ACTH, cortisol, and 24-hour urinary free cortisol. A low-dose
cosyntropin test showed no increase in cortisol levels. His parents were
instructed to reduce the frequency of the applications to prevent
adrenal crisis. After 2 months, a low-dose ACTH test was repeated and
showed a significant cortisol response.

The second case involves a 4-and-a-half month old who presented with a
history of increased weight and body fat. It was discovered that his
mother had been applying clobetasol for diaper rash for over
2-and-a-half months. The infant had received approximately 8 to 10
25-gram tubes within that time frame. His morning and evening cortisol
levels were low. He was discharged on physiologic oral replacement with
hydrocortisone. At his 2-month physician visit, an ACTH stimulation test
showed continued suppression. A normal response was seen after 6 months,
at which time his hydrocortisone was tapered and eventually
discontinued.

The third case is of a 1-year-old male infant who was brought to a baby
clinic with a history of sudden increase in weight and increasing fat
deposits. It was discovered that his mother had used approximately seven
tubes of clobetasol for diaper rash for over 2 months. His serum
cortisol was low. He was placed on physiologic oral replacement with
hydrocortisone. An ACTH stimulation test 2 months later showed a serum
cortisol of 2.8, 20, and 23 before, 30 and 60 minutes after ACTH
injection. Hydrocortisone was tapered and stopped. On subsequent visits,
his Cushingoid features gradually improved and his weight decreased to a
normal range.

The fourth case involves an 11-year-old male with an 8-year history of
atopic dermatitis who developed Cushing\'s syndrome and adrenal
suppression secondary to long-term whole-body application of a topical
betamethasone-containing product. He presented with amnesia, somnolence,
moon face, and low height and obesity. His serum cortisol was low and he
had a low ACTH level. A rapid ACTH test showed adrenal suppression. He
had concomitantly received betamethasone-containing tablets at some
point in his treatment. However, the dates of administration and
duration were not provided. Upon discontinuing his topical steroids,
neurological status improved. His cortisol levels and ACTH test 5 months
later were normal.

The last case I\'ll present involves a child who was hospitalized at 15
months of age with Cushing\'s syndrome. He developed an Abken rash at 5
months of age and was prescribed clobetasol cream. Treatment was
continued without medical supervision for the next 10 months. The
parents noticed an increased weight and hypertrichosis for 3 months
before his admission. On exam, he was found to be Cushingoid. His
morning and evening cortisol levels were low. Following discontinuation
of clobetasol, the morning cortisol rose to 2.9 micrograms per deciliter
after 12 days and 14.2 after 17 days. A synacthen test was performed 3
weeks after he initially presented, which showed an increase in cortisol
response 30 and 60 minutes after an injection. 2 months after initial
presentation, he was well, with a decrease in body weight. His
examination was unremarkable except for some mild Cushingoid features.

The factors affecting absorption of topical steroids are multifactorial
and one or more of these factors were present in many of our cases. One
factor is the size of the area being treated. In two cases the topical
steroid was used or applied to the entire body, and three cases reported
application in more than one location on the body.

Longer duration of treatment is another factor. The duration of
treatment was 3 months or longer in 11 cases and over a year in 7 cases.

Increased penetration can occur with the use of occlusive dressings. An
occlusion of a topical steroid by a diaper occurred in 7 cases.

Small children are at increased risk of topical steroid absorption
because they have a higher ratio of skin surface to body weight. 40
percent of our cases were in children less than 3 and 5 were in infants.

The site of application may have been a factor in some cases.
Penetration of the steroid is related to the thickness of the stratum
corneum and the vascular supply to the area. The are regional
differences in absorption and the diaper area, which was the site of
application in seven cases, has a greater absorption relative to other
sites such as the arms and legs. There was also one case where the
product was applied to second degree burns which were devoid of
epidermis.

Other contributing factors were present in some cases. 15 reported the
use of a superpotent or a potent topical corticosteroid product. In four
cases, more than one topical corticosteroid product was used
simultaneously, and in four cases use of a topical corticosteroid
product occurred without medical supervision. Two reported concomitant
or prior use of a systemic corticosteroid product.

In summary, there are a small number of post-marketing cases of adrenal
suppression, Cushing\'s syndrome, and growth retardation given their
long marketing history and probable large exposures. This is probably
due in part to under-reporting which is a known limitation of
spontaneous reporting systems. And as Dr. Temeck had alluded to earlier,
there may be a lack of suspicion, including a failure to recognize that
topical corticosteroids may be systemically absorbed; an assumption that
the adrenal suppression is unusual and therefore routine testing is not
done; and that the signs and symptoms may be subtle and nonspecific,
therefore attributed to other causes.

DR. CHESNEY: Thank you very much, Dr. Karwoski.

We have 15 minutes on the agenda now for questions from the committee
and the consultants for the speakers. Dr. Fink.

DR. FINK: I had several questions. One was how often is decreased growth
velocity associated with adrenal suppression, or is that known? Because
obviously a clinical marker of adrenal suppression would be much easier
to use in reality than just laboratory assessment.

DR. CHESNEY: Were you addressing anyone in particular?

DR. FINK: No. Anyone who has data.

DR. TEMECK: Certainly growth suppression would be associated with
chronic use of steroids, and we\'re talking here basically about
short-term use. The cases, therefore, that Dr. Karwoski was referring to
regard misuse of the products because these are really basically labeled
for 4 weeks or less. So you would not really expect to see an effect on
growth as opposed, for example, if you were treating an asthmatic
patient with an inhaled steroid and you would need a long period of
treatment, then you would start to see the growth suppression.

DR. FINK: Actually that leads into my second question which is, is
anything known about the interaction of topical corticosteroids with
inhaled corticosteroids or pulse oral steroid therapy since in these
atopic individuals, many of them will have concomitant asthmatic
symptoms with chronic low-dose inhaled corticosteroid and will that
potentiate the intermittent use of topicals?

DR. TEMECK: You\'re asking if the patient is on multiple topical inhaled
systemic. Yes, you would certainly expect a potentiation of effect.

DR. CHESNEY: Dr. Gorman?

DR. GORMAN: I have another general question which is at the risk of
making my nephrology and hematology friends upset because I\'ll mangle
their data. Do we have any idea how much adrenal suppression is
necessary before clinical symptomatology becomes available? In the
hematological world, you can use a lot of your particular clotting
factors before you see any abnormality in clotting on a clinical basis.
Do we have such data? Can you lose 20 percent of your reaction and still
have no problems or 40 percent or 80 percent?

DR. TEMECK: Yes. I mean, it\'s very variable. You can have some patients
that may not have as much suppression as another patient and yet they
will have symptoms. So there\'s no specific cutoff value, if you will,
of degree of suppression that is associated with symptoms that I\'m
aware of, unless Dr. Stratakis or Dr. Schneider have information to the
contrary.

DR. SCHNEIDER: If I could comment on that. That question might apply
more aptly to primary adrenal insufficiency in which there is loss of
mineralocorticoid function and patients are much more susceptible to
shock and hyperkalemia and so on.

The manifestations of pure secondary glucocorticoid insufficiency are
really more protein and may be much more subtle, which is really part of
the problem. It\'s very hard to characterize degree of loss in terms of
percent loss of adrenal function in secondary adrenal insufficiency, as
well as loss of ACTH function. So I think it\'s a difficult question.

DR. STRATAKIS: I agree. This is also the problem with defining the
cutoff criterion for the peak stimulation value. Although most people
agree that 18 micrograms is what the cutoff criterion should be, at the
NIH we usually use anything above 16 as an indication of adequate
stimulation. Other people might say that normal is only above 20. So 18
is a nice compromise, but there\'s no good data as to whether 18 is the
actual normal value.

DR. GORMAN: If I can be forgiven a follow-up question. So 18 or 20 or 16
was picked because it\'s a statistical number that meets some criteria,
or does it have a biological analog that\'s measurable?

DR. STRATAKIS: There are simply no good studies addressing this
particular question. It\'s clinical experience from about 30 years of
use of this test now that have defined 18 as the criterion. But as I
said, it\'s a compromise really.

DR. CHESNEY: Dr. Danford.

DR. DANFORD: To follow up on that question about the stimulation test, I
have some concerns about whether stimulation testing is valid in the
very young infant. I\'m picturing how this test is being done. Taking
your standard 18-month-old and hauling them off and trying a few times
to get some blood or maybe starting a heparin lock might be a stress in
itself and may have either predictable or unpredictable effects on
either the changes in cortisol levels you will get or in baseline or
response.

I wonder, have control studies been done of normal individuals of that
age, performed in the way that these tests might have been done in
testing of the dermatologic products to show that this test tells us
anything in this group performed in that way?

DR. TEMECK: Yes. I think that there is a significant amount of published
data with performance of the cosyntropin test in infants. Certainly if
they\'re going to be stressed, you will expect, therefore, a higher
basal cortisol level than you would if you did the test in an unstressed
individual. And just the fact that they can elevate their cortisol
level, if you have a basal level of 18 or 20, which you can very well
get in a crying infant, that certainly is evidence that the patient does
not have axis suppression. So, therefore, there are standards in that
age group with regard to performance of this test, so it\'s not really
problematic doing this test in young infants. We have sufficient
normative data.

I don\'t know if Dr. Stratakis or Dr. Schneider want to add to that.

DR. CHESNEY: Dr. Stratakis.

DR. STRATAKIS: I\'m glad you made the comment. There is an additional
factor here that the adrenal cortex does not assume its normal adult
configuration until the end of the first year of life. So we really
don\'t know what the effect of an ACTH stimulation test would be in an
incompletely developed adult adrenal cortex. So the adrenal cortex
during fetal development has the fetal zone which normally involutes by
the end of the first year of life. So unlike mouse, for example,
there\'s continued development of the fetal adrenal cortex into the
adult adrenal cortex for the first year of life. It finishes by 18
months or so.

So we really don\'t know. There are really no good studies on addressing
what ACTH does to cortisol secretion in a continuously developing
adrenal cortex and on an involuting fetal adrenal cortex. We certainly
don\'t know what the effects are of exogenous steroids on a developing
adrenal cortex.

DR. CHESNEY: Dr. Glode, did you have a question?

DR. GLODE: I did. I just wanted to ask Dr. Temeck if you thought there
was any possibility of identifying a surrogate marker that would be
easier to measure than the stimulation test. I wondered about if you had
someone of these drugs for 3 or 4 weeks, that you could monitor, that
would say it\'s being absorbed and this is the surrogate marker for
suppression like a total lymphocyte count or a total eosinophil count or
a CD4 or CD8 or something. Is there anything that anybody has looked at
that might just be ‑‑

DR. TEMECK: I\'m not aware of a surrogate marker.

DR. SCHNEIDER: I can just say as an endocrinologist, I\'m not either
aware. The best tests are the biochemical tests that we have, and I
think that they\'re pretty good. We know a lot about them and what they
correlate with at this point.

DR. GLODE: But it just seems that they would be potentially more
cumbersome to use. I\'m in infectious disease. If we have someone on an
antibiotic for 4 weeks, we do a weekly CBC, a weekly BUN, creatinine, a
urinalysis and that\'s our markers for interstitial nephritis and bone
marrow maturation arrest, and they\'re easy to measure and it\'s a
simple blood test. It\'s just nice to have instead. The stimulation test
is pretty. It can\'t be done in the dermatologist office, for example, I
don\'t think. Or is it?

DR. SCHNEIDER: It could be done in the dermatologist\'s office.

DR. GLODE: Oh, is it done in a dermatologist\'s office?

DR. SCHNEIDER: An ACTH stim test can done practically anywhere at any
time of the day, and so that\'s of great usefulness. Of course, also the
cortisol assay is excellent at this point. So we have a lot of data in
support of it.

The question is, what do we do with the information? Whom do we test and
so on? This will come out later in the discussion.

DR. TEMECK: Just to add to that, you could do a simple 8:00 a.m. basal
cortisol level and certainly, as I said, if it\'s elevated, then you\'re
okay. You don\'t have to do a dynamic test like the cosyntropin test.
But unfortunately, many times that\'s not the case.

I don\'t know. Dr. Stratakis, did you want to add further to the
response to this question?

DR. STRATAKIS: No. I think the comment was appropriate.

DR. TEMECK: It\'s adequately covered?

DR. STRATAKIS: Yes.

DR. CHESNEY: I have Dr. Epps and Dr. Santana, and then I had a question.

DR. EPPS: One quick comment. Dermatologists aren\'t going to do
stimulation tests.

(Laughter.)

DR. EPPS: My questions were regarding the adverse event reporting. Some
of the adverse events can occur regardless of the medication. For
example, hypopigmentation can be post-inflammatory. Some people have
stinging or redness regardless of what is applied. Even bath water can
make you sting. So I guess my question ‑‑ two of them. One is regarding
is there any estimation of the real numbers that really are due to the
medications.

I think the cases that were presented clearly were secondary to
inappropriate use. I think the ages were inappropriate, the amount of
medication was inappropriate. The body surface area, the location. I
wasn\'t really surprised that side effects could have occurred with
those extreme cases. But a lot of the other ones are hard to determine
because the underlying condition can result in stinging and redness and
some of the things that were reported.

Also, is there a way to differentiate when things are reported as an
adverse event whether it\'s due to the medication or the use, or is that
broken down?

DR. KARWOSKI: I think your first question was could we tell exactly how
many reports there actually are. No, I don\'t think so. It\'s been
estimated that the FDA receives somewhere between 1 to 30 percent of
adverse event reports, but there\'s just really no way of knowing what
we\'re receiving. I think what we do have is probably the worst cases
where there was clear recognition of symptoms.

As far as causality goes, we can never be totally clear that it was
attributable to the actual product. It becomes even less clear when
there are confounding factors such as use of systemic products, but for
many of the cases, I think it was relatively clear that it the use of
the topical steroid, and as you stated, it was an overuse or misuse of
the products in these cases.

DR. CHESNEY: Dr. Santana.

DR. SANTANA: I have two questions for you, Dr. Temeck, and Dr. Cook can
help me. It appeared to me in looking at the data that was presented on
the pediatric studies, that the majority of patients recovered HPA
function when these products were used in the quasi-acute setting, that
is, for a defined period of time of 3 or 4 weeks. But I think in reality
we know that these products are used repeatedly in many patients who
have exacerbations over long periods of time. So is there any data on
the incremental risk of suppression with intermittent chronic use?
That\'s one question.

And then the second question is, when do you test for the first time?
These patients were all tested within 3 to 4 weeks, but I got no sense,
based on the data. If you could give us some indication of when would be
an appropriate recommendation to test these patients.

DR. COOK: I\'ll answer the second question first. That\'s probably why
we\'re having the advisory committee meeting.

(Laughter.)

DR. COOK: Because that is a question about when is the appropriate time
to test these patients who obviously have a chronic remitting and
relapsing disease.

In the second question where I think you ‑‑ remind me of the second
question.

DR. SANTANA: Is there an incremental suppression risk when you do
repeated therapy intermittently over months or over years?

DR. COOK: We don\'t have data for that. These are the trials that we
were able to convince the sponsors to do on a short-term basis. But we
do actually have a question as to what does happen even with chronic
intermittent suppression of the adrenal gland. Is it a problem? We
don\'t really know. Dr. Temeck was stating how you need long-term use
before you get actual growth suppression with adrenal suppression to get
growth suppression, and the question is, is there a problem and can you
get growth suppression over long-term intermittent use of topical
corticosteroids for years? And we just don\'t have that answer.

DR. CHESNEY: Dr. Wilkin.

DR. WILKIN: Dr. Cook may actually have more information on this. But
it\'s been my recollection in the data sets that have come to our
division that we always like the HPA axis suppression tests done during
drug development on the higher body surface area children, and as a
consequence those kids are very likely to have had their atopic
dermatitis for a substantial period of time. It\'s not uncommon for us
to see kids who at baseline, that is, before they actually get treated
with the corticosteroid that\'s being tested, that they\'re already
suppressed. They have the signals of suppression at baseline. So I think
we have some hint of that, but we have nothing very quantitative that we
could say after X number of months of intermittent use.

DR. CHESNEY: Good point.

Dr. Wilfond.

DR. WILFOND: I have two questions that are related to sort of a
benefit-risk ratio. We\'ve been focusing mostly on risks, and I have a
couple questions about benefits.

My first question really has to do with whether or not ‑‑ it\'s part of
a dermatologic question ‑‑ early and aggressive use of some drug could
actually change the course of atopic dermatitis, in particular, whether
there\'s any additional efficacy even from systemic steroids in that
regard.

My second question, which is more of a labeling question, is that in the
more recent products that have been labeled to be fairly restrictive of
being only used in adults or older children, is the purpose of that
because it\'s believed that it\'s not appropriate to use that in young
children or just that there\'s an interest in not having the companies
aggressively marketing that for young children? I\'m not clear about
that.

DR. CHESNEY: Dr. Wilkin.

DR. WILKIN: I\'ll pick up on your second question. That\'s right. We\'ve
really tried to achieve some balance in labeling. What we\'ve done in
the indications section is we will say something like indicated for age
13 and above. That\'s not the same thing as contraindicated in 12 and
under. And then there will be the pediatrics use section and
precautions, and it will describe the material that you\'ve seen
generally in our labeling that speaks to HPA axis suppression. Because
we recognize that dermatologists and pediatricians and other clinicians
from time to time will make wise clinical choices to use these products
outside of the 13 to above. So I think we\'re trying to hit a fine line
on that.

DR. MURPHY: Let me just say that you brought up a subject which is very
difficult because the one thing you do not want to do is to de facto
give an indication when you don\'t want to give an indication. In
pediatrics, we are constantly in this balancing act. If you talk to our
marketing people and other policy people, we shouldn\'t be putting
anything in the label if they don\'t have any indication. In other
words, we haven\'t proved it\'s safe and efficacious.

There are times when we say it\'s been proven to be efficacious but here
are the restrictions because of the safety issue. There are other times
when it has not been proven to be efficacious. We know people are using
it, and we\'re trying to put safety information in there.

There are a variety of situations that arise, but you don\'t want to be
giving the indication because you\'re putting information in the label.
That\'s the problem. Yet, at the same time, you\'re trying to achieve
that communication of what the safety issues are. So it is often very
difficult to balance that.

DR. CHESNEY: I think Dr. Fost wanted to comment on the same issue and,
Dr. Andrews, I think maybe you had your hand up.

DR. FOST: Well, a couple questions on the same issue. First, I\'d be
interested in hearing from the dermatologists how much of this problem
is due to inappropriate use of the more potent steroids. That is, is
that sort of the general practice now not among obviously excellent
dermatologists but among pediatricians or others who are taking care of
these children? Is there an overuse of the more potent classes?

Second, what do we know about the marketing, particularly CME
activities, and distribution of samples that\'s pushing that? That is,
how much of this problem is due to inappropriate use of excessively
potent steroids? How many of these children could be well cared for with
less potent uses and how much of that is being driven by CME or other
marketing efforts?

DR. CHESNEY: No one wants to answer that.

(Laughter.)

DR. RAIMER: I will. I think that the pediatricians are almost overly
cautious with topical steroids, so I don\'t think it\'s the
pediatricians who are using the high potency steroids. If you look at
the reports, several of these are foreign reports, and one of them where
steroids are more available over the counter. Mothers can get them and
use them inappropriately. So dermatologists I don\'t think are using
high or super potent steroids in young children very often, and I don\'t
think it\'s the pediatricians. So I don\'t think it\'s being done
terribly often in the United States, frankly.

DR. COOK: I\'ll just make a quick comment just from the study data that
was presented. I just want to make the point that it\'s not all super
potent topical corticosteroids. As I pointed out, there are steroids in
class V that also can cause significant adrenal suppression.

In these studies, at least ‑‑ I can\'t speak for how people practice ‑‑
most of the topical corticosteroids are going to be used for 1 to 2
weeks, 2 weeks to 3 weeks. In the studies, most of them were used for 2
weeks. I tried to point out that children still had some disease left
for some of the drugs that were used because these weren\'t efficacy
studies, of course. They still had some evidence of adrenal suppression
with appropriate use of a topical corticosteroid.

So the question is not just those who we know the drug is being abused,
and that answer is very easy. It\'s what do we do with those who are
using it appropriately and are getting intermittently suppressed.

DR. CHESNEY: Dr. Andrews, and then I think Dr. Schneider has his hand
up, and then Dr. Gorman. Dr. Andrews.

DR. ANDREWS: My question is really in follow-up to the question about
what do we know about actual use patterns for these drugs? Evidently
they are used repeatedly. And what do we know about recovery of adrenal
function following repeat suppression? And maybe we don\'t know it for
these particular drugs, but I wonder if there are some analogies from
patients with inhaled steroids for asthma. It may be a question for Dr.
Schneider.

DR. SCHNEIDER: I\'d just like to make a comment. If you look at this
quantitatively, it seems to me that if you\'re giving, let\'s say, 50
grams of a preparation which is .something percent active ingredient,
but if it\'s a very highly potent steroid, you\'re giving maybe several
hundred milligrams of that steroid over a small period of time. Now, we
really don\'t know what percent of that material gets systemically
absorbed in patients with active skin diseases. We suspect, of course,
that it\'s higher than in patients who have intact skin. If you just
sort of look at this quantitatively, much of this suppression of the HPA
axis is entirely predictable on the basis of the pharmacokinetics. For
example, you can suppress the entire axis with a milligram of
dexamethasone given by mouth at night. It\'s a common dex suppression
test. So that it\'s not surprising to me that there is this degree of
HPA axis suppression as evidenced biochemically. Of course, our task
later on will be to figure out what to do about this and how to label
for it. But it\'s clear that there is a high prevalence of axis
suppression, and it seems to me that this is quite predictable and it
shouldn\'t be surprising.

I had one question and that has to do with the language used to describe
recovery. I see over and over and over again in these labels, in general
HPA axis suppression recovers promptly. I see the word \"promptly\" over
and over and over again and with data, 2 out of 3 recovered, 1 out of 4
recovered or didn\'t recover and so on.

What this really means, of course, is that the patients recovered
responsiveness to exogenous ACTH 1 to 24 stimulation. That doesn\'t mean
that the entire axis has recovered, and it certainly doesn\'t mean that
the patient would respond appropriately to stress. Has anyone looked at
that? Has anyone done further examinations of patients who have
recovered to 1 to 24 stimulation to see if they can respond to material
pollen or ITT?

DR. COOK: I\'m not aware of any such studies. In these studies, they
were just required to follow the patients out until they had an
appropriate response to cosyntropin. Actually the data, as I showed it,
we really didn\'t get all of the patients retested either due to lost to
follow-up or a discrepancy in the criterion of what really constituted
adrenal suppression. So that\'s what we have.

DR. SCHNEIDER: So accordingly, these patients would still be vulnerable
during stress of surgery or accidents or whatever, at least according to
generally acceptable practice in the adult population.

DR. COOK: If they have a normal response to ACTH, then you would assume
that they could respond appropriately.

DR. SCHNEIDER: You can\'t assume that in all patients.

DR. COOK: Therein lies the problem.

DR. SCHNEIDER: Right.

DR. CHESNEY: Dr. Gorman, Dr. Ten Have, Dr. Fink and myself have
questions, but I don\'t know that we answered Dr. Andrews\' question
which I think was what about recovery after repeated insults, another
example of which would be asthma. Does anybody have an answer to that?
Dr. Fink.

DR. FINK: Well, with asthma, it\'s definitely clear that with repeated
pulses of oral steroids, if they are closer together than 4 to 6 weeks,
you will get a cumulative effect on adrenal suppression, but that\'s
really oral corticosteroids with a 4- to 6-week break. It\'s less clear
with inhaled corticosteroids.

DR. CHESNEY: So you do get a cumulative suppression. I mean, you\'re not
just suppressed with each episode, but each one is additive to an
overall suppression?

DR. FINK: You\'re more likely to see suppression in a child who\'s had
multiple courses of oral corticosteroids separated by less than 4 to 6
weeks. Probably once you get beyond about 8 weeks, you\'re safe or you
appear to be clinically safe.

DR. CHESNEY: Dr. Gorman.

DR. GORMAN: This is a question to the FDA. The classification of
steroids in my simple clinical head deals with how effective are. And
now I know they\'re generated by this vasoconstrictive test. Is there
any consideration being given to creating another scale of the risks or
the TPA suppression? Because the data showed pretty elegantly this
morning that the classes of steroids don\'t correlate with their TPA
suppression. So there may need to be a new rating of steroids, topically
or orally, that deal with what their risk of suppression is as well as
their potential for efficacy.

DR. WILKIN: Well, if we could achieve that, I think it would truly be
wonderful. I think one of the difficulties ‑‑ and maybe I should just
speak to the classification. It really isn\'t a classification about the
corticosteroid moiety. It\'s really about the product because you can
have an individual moiety that can be in a different class based on its
concentration or the vehicle in which it is presented. Because there is
so much noise in extracting this signal of HPA axis suppression, I would
think that there would really have to be a whole series of head-to-head
studies literally of steroid A versus steroid B to really figure out
what the groupings might be.

You have seen the numbers. Many of the HPA axis suppression testing are
in numbers that are sufficiently small that the confidence intervals are
somewhat difficult for us to say this has a precise eventual risk
estimate at 4 weeks of, say, 40 percent of the population is going to be
suppressed. We have the confidence interval problem plus we have a lot
of different body surface areas of involvement, different frequencies of
use. I think the quantitative aspects of this ‑‑ it would be nice if we
could do that. I just think it\'s close to insurmountable unless we had
really large numbers and head-to-head studies.

DR. CHESNEY: Dr. Ten Have?

DR. TEN HAVE: I have two epidemiological questions, one for Dr. Cook
regarding whether or not we can use the age trend data to provide us any
hints of any long-term effects of cumulative use of corticosteroids. I
noticed you had consistent downward trends across age, and if these
post-infant children are using steroids cumulatively, would you expect
an increase across age if there was a long-term cumulative effect?

DR. COOK: I\'m not sure I know the answer to that. Even though in the
betamethasones, it showed that there was an increased proportion of
children who became suppressed the younger they were ‑‑ so I guess the
natural progression is you would think that there may be some effect
over time in those children ‑‑ it didn\'t seem to be the case for all of
the drugs. That\'s part of our problem. When we saw the statistical
analysis, it also didn\'t necessarily bear it out.

DR. MURPHY: Just to follow up on that, I think the thing that is
interesting is when you look at the data for the tinea pedis. These are
adolescents. Of course, you had the lotion issue that you need to
consider, but we felt we had some confounding information here, that
certainly in one area it looks like you have this trend, but overall,
when you look at this data, we didn\'t feel as comfortable that you
could make those sort assessments.

DR. CHESNEY: Dr. Ten Have, you had another question.

DR. TEN HAVE: Yes. I\'m sorry. I didn\'t quite understand your answer.
In adolescents there\'s a ‑‑

DR. MURPHY: There was a high percentage of suppression, yes, a 60
percent I believe in one of the slides. Denise, is that right? 47, yes.
So, again, when you took that adolescent group and looked at it, you got
a different type of answer. There are other issues there, but I\'m just
saying it didn\'t look quite as clear as it did with the one product.

DR. TEN HAVE: Thank you.

The second question I had was for Dr. Karwoski. I\'m wondering if we can
get anything from the ‑‑ even though we had a small sample of reports of
adverse events in terms of adrenal suppression, in that registry data we
had, I think it was, about 42 cases, but the timing of those reports was
interesting in table 10 where you had data going all the way back to
1980 with I believe 2 cases in 1980 and \'81 and then the real cluster
of cases starting in 1995, about, prior to the introduction of the AERS
reporting system. I\'m wondering if we can get anything from that in
terms of whether or not there\'s a corresponding increase in
corticosteroid use for atopic dermatitis.

DR. KARWOSKI: Unfortunately, we didn\'t actually look at the drug use
data, so we didn\'t actually look at trends over time. But we do know
that reporting has increased over time, so that could account for just
the increased number of reports that we\'ve gotten after 1985 or
whenever it was.

DR. CHESNEY: I think Dr. Mattison was next on our list.

DR. MATTISON: Two questions. I think the first may have already been
answered. I\'m confused about actual use by age and given especially
that the products are available both over the counter and by
prescription.

But the second thing that I\'d appreciate some information on is
efficacy. When we talk about characterizing risk, it\'s also helpful, I
think, to understand efficacy and benefit. So if there could be some
description of that, and perhaps that will come in the discussion of
risk and benefit later in the day.

DR. COOK: Well, on the issue of efficacy, I think topical
corticosteroids have shown over the decades that they\'re quite
efficacious in treating atopic dermatitis. As far as the potency of the
drug, according to the vasoconstrictor assay, as far as efficacy, I
think that you can rely on that scale and the amount of efficacy you\'re
going to get for a given severity of the disease. Like the class V
lotion product, for example, is not as efficacious in moderate to severe
atopic dermatitis as, say, clobetasol which is in class I. That may have
something to do with the fact that the chemical moiety doesn\'t stay in
the epidermis as long and somehow gets into the systemic circulation.
That has been a thought since we got this new data. But the drugs are
highly efficacious in treating atopic dermatitis over short periods of
time in getting the disease under control.

DR. CHESNEY: I think we\'ll plan to take a break in 5 minutes. So I have
two more people on the list. Dr. Schneider and Dr. Wilfond.

DR. SCHNEIDER: I may have missed this, but have you redone the
statistics, the correlation statistics, using the single criterion of
18? And do the data look any different at all or any cleaner or not?

DR. COOK: Well, I only looked at it for the betamethasone products. I
showed that chart there. Even though we used three criteria, I looked at
the 18, and as you saw, it was pretty consistent with using the three
criteria. And if you look through each one, I tried to point out even
though that the failure of one would do it, most of the ones who
suppressed did have a cortisol level that was less than 18.

DR. CHESNEY: Dr. Wilfond.

DR. WILFOND: I also have a question for Dr. Cook that\'s related to what
Dr. Mattison asked also. It\'s not so much efficacy only but just the
efficacy-risk balance. I just want to clarify. I\'m assuming that the
reason why these drugs are used is that even though there are side
effects, it\'s viewed that the benefits far outweigh the side effects in
some circumstances. Like in chemotherapy there are horrible side
effects, but we still think it\'s appropriate to use them because the
benefits are substantial and necessary. That\'s why I just want to
clarify that because this may be less of an issue if we actually think
that these are really necessary interventions.

DR. COOK: Well, yes. I don\'t think we\'re here to advocate that topical
corticosteroids not be used in atopic dermatitis. It\'s just that we
discovered that something else is going on and we\'re trying to get a
handle on what\'s the best way to make physicians and the public aware
that there is this potential and that there may be a need for something
to be done on the short term.

DR. CHESNEY: Dr. Wilkin.

DR. WILKIN: Yes, I agree with Dr. Cook\'s response and would just add to
it. Of course, these topical corticosteroids are not curing. They\'re
suppressing. I think there\'s a lot of information especially in the
dermatologic literature and the guidelines that the AAD, the American
Academy of Dermatology, has.

The goal of therapy is to treat early and, if there\'s a lot of
inflammation, to use something towards the upper end of potency to
achieve control, and then fairly rapidly move to things that are lower
down or even drop off the corticosteroid list and maybe go with
moisturizers. A dermatologist doesn\'t just offer corticosteroids to the
patient with atopic dermatitis. They talk about the soaps that they\'re
using and a variety of other things, the humidity in the bedroom, which
is where one spends one-third of the time as a child.

So I think that yes, it really does fit very well with a good
risk-benefit calculus. These products are really safe and efficacious
when used appropriately.

DR. CHESNEY: One last question before the break. Dr. Ebert.

DR. EBERT: I think you kind of touched on my question which is it
appears that when these agents are used, they are used in a fixed dose
and in a fixed frequency throughout the course. Is there ever the
determination that you might want to use these drugs similar to what you
might do with a systemic steroid in a more aggressive manner early and
then taper and use it, say, as a once-a-day administration over a longer
period of time, whether that might be a means to reduce some of the
effect that you\'re seeing on the HPA axis.

DR. WILKIN: Well, there are actually two committee members that are in
the trenches and actually do these sorts of things, and they probably
want to comment. But certainly that point of view is well established in
the dermatologic literature, that one wants to get on top of the
situation promptly, so it\'s treat as soon as possible. Sometimes that
means even giving a patient an early clinic visit or some other
arrangement to ensure prompt treatment.

DR. CHESNEY: I think we will take a 15-minute break now, and if
everybody could reconvene at 11 o\'clock, we\'ll move on to the second
part of the morning\'s program.

(Recess.)

DR. CHESNEY: Our next speaker is Dr. Anne Trontell. Dr. Trontell is the
Deputy Director of the FDA Office of Drug Safety. She\'s a pediatrician
and an epidemiologist with experience working at the CDC and HCFA/CMS.
She will present a framework for risk assessment and management.

DR. TRONTELL: Good morning. I\'m going to be giving what might be
lightly termed some risk management 101. This will really reflect FDA\'s
experience to date with risk management programs across a broad array of
drug products. I\'ll also be touching upon the risk management practices
that are currently under development within the agency.

It should come as no surprise that FDA has been involved in risk
management for many years. We simply haven\'t been using that term. As
part of our approval of drug products, we weigh risks relative to
benefits.

It was in 1999 when the FDA Commissioner issued the Report on Managing
the Risks of Medical Products, that the term \"risk management\" came
into widespread use within the agency.

It was under PDUFA3 that FDA\'s role in risk management became
formalized when the agency was called upon to develop three interrelated
guidances for industry on risk management and to do so by September 30th
next year. The topics for these three guidances included pre-marketing
risk assessment, post-marketing risk assessment through
pharmacovigilance or pharmacoepidemiology, and the third, risk
management per se. In that capacity, I\'m privileged to serve as the
chair of the joint working group between the Center for Drugs and the
Center for Biologics to develop that guidance, and some of my remarks
will be based upon some of that work.

FDA developed some preliminary concepts about risk management for each
of these three topic areas and published them and then presented them in
a public forum in April of this year. This was as concept papers and the
opportunity was used to solicit comments at that meeting and
subsequently. Based upon those concept papers and the commentary that
was received, FDA expects to issue draft guidances later this fall.

In this presentation, I\'m going to focus on FDA\'s experience with risk
management in a wide variety of drug products. I will draw upon some of
the concepts that were articulated in the concept paper entitled Risk
Management Programs, but I need to remind you that as such I\'m talking
about a snapshot of what is truly a very rapidly evolving field and
approach to drug safety.

The Risk Management Programs concept paper focuses on risk minimization
efforts. These efforts were termed risk management programs in the
concept paper issued in the spring. The risks that we discussed and the
minimization efforts are, in fact, identified using practices outlined
in the other two concept papers dealing with risk assessment in the
pre-marketing and in the post-marketing arena.

The concept paper indicates and reminds all that safety in some sense is
relative, that when FDA determines that a product is safe and effective,
it means that the beneficial actions outweigh the likelihood of harmful
or undesirable side effects and shouldn\'t be construed to mean that
risks are absent.

Turning now to some of the definitions that we established in the
concept paper on risk management programs, we defined them as being
strategic safety efforts that involve an effort to reduce risk and
having at least one or more risk reduction goals and the use of one or
more interventions, sometimes called tools, other than the package
insert to reduce risk. The package insert may be known to you by many
different names, sometimes called the PI or the professional labeling,
sometimes known as the FDA-approved labeling. This has really been the
cornerstone of industry and the FDA in speaking to clinicians and to the
public about the safe and effective use of drug products. These were
considered not to be risk management programs per se.

To define the goals of a risk management program, the concept paper
stated that these would be tailored to the specific risk concerns and
that they would describe the ideal product use scenario or the desired
end result of the risk management program. Borrowing from the management
literature, you might use a term such as a \"vision statement\" to refer
to it where you would look for the optimal drug use scenario. Examples
probably are better illustrative than the definitions. In the case of
thalidomide, a known teratogen, one goal might be stated as no fetal
exposures, or for the drug product clozapine, no agranulocytosis.

The concept paper attempted to address when a risk management program
might be appropriate. It said certainly in terms of timing, that this
could occur at any point in the product\'s life cycle when a risk
reduction need emerged. So it could occur pre-marketing or
post-marketing. This could be done at the initiation of the drug company
or upon FDA\'s suggestion. The language stated in the concept paper was:
\"when the number or severity of a product\'s risks appears to undermine
the magnitude of benefits in an important segment of actual or potential
users.\"

The challenges, however, to determine exactly when that point might
occur ‑‑ and the concept paper indicated this was a complex task. There
is clearly no simple formula that will compare risks to benefits. These
are measured in different units and there are different types, so that
the best FDA could state, at least in the concept paper, was that they
anticipated that this would be a matter of case-by-case judgments done
jointly by the drug company/sponsor, as well as FDA, on whether or not a
risk management should be developed, submitted, or implemented.

We did state, however, in our concept paper that our mainstay of risk
communication, the package insert, would probably suffice for the vast
majority of products, so that formal risk management programs are, in
fact, things that we expect to apply to a limited number of drug
products.

To define risk management program tools a little further, these were
defined as processes or systems intended to enhance the safe use of a
product by reducing risk, and the choice of tools would be influenced by
the severity, reversibility, or rate of the risk that was being avoided.

I\'ll now turn to some discussion of FDA\'s experience in various types
of tools which we\'ve put into three broad categories with probably some
fuzzy boundaries, the first being education and outreach; the second,
so-called guiding systems, which I\'ll elaborate upon; and the third
category being restricted access programs.

Education and outreach, as defined in a risk management program context
in this concept paper published to date describes those efforts again
that go beyond the package insert that\'s traditionally used. These
might, for example, entail the mailing of Dear Healthcare Practitioner
letters or other public notices of risks. It could include training
programs or continuing education and may, in fact, use various forms of
patient-oriented labeling, such as medication guides and patient package
inserts, which I\'ll now elaborate upon.

Medication guides are one form of FDA-approved patient labeling
regulated since 1999 under the federal regulation described here.
Medication guides are distinctive in that they are required to be
dispensed with each prescription to a patient, most commonly by the
pharmacist, but this can also be done by the physician.

These were intended primarily for outpatient drug products that could
pose serious and significant public health concerns, and at the time
that this authorization was passed, it was anticipated that about 5 or
10 products a year might fall into this category.

There are now approximately 13 medication guide texts concerning again
approximately 22 products. It depends on if you\'re a lumper or a
splitter in your counting. The risks that they cover are wide. They
include but are not limited to hepatotoxicity, teratogenicity, abuse and
diversion, or overdose.

The text of this slide may not be well legible, but this lists the 13
broad categories. I have a second slide that lists those where pediatric
safety or exposure concerns were part of the contents of the medication
guide or in some instances some of the motivating reasons for their
being written. The committee has been given a copy of a sample
medication guide which they may wish to refer to since I\'m going to
walk through some of the specifics of it in a minute.

Back to the medication guides requirements. Since this is to be used in
a judicious manner, three triggering criteria were set forth in federal
regulation, at least one of which needed to be met, the first being that
patient labeling in fact could make a difference in preventing the
occurrence of serious adverse events. The second was that there might,
in fact, be serious risks relative to benefits about which a patient
should be informed in terms of making an informed decision about whether
to initiate or continue use of that product. And the third criterion was
instances where patient adherence to the directions for use of the
product were considered crucial to the product\'s effectiveness for a
serious or life-threatening condition. And the medication guide
regulations in fact go so far as to describe the content areas and
format for this material, as well as even the font size that should be
employed.

I\'ll go through this quickly. If you wish to refer to the example,
please do. Basically the medication guide follows something known to
many of us who use the internet, the frequently asked questions format.
So after describing the title, brand name, and established name, it
starts with a bolded topic sentence saying, well, what is the most
important information I should know about this product. This is
typically the section of the medication guide that describes the health
concern that in fact prompted the medication guide being issued.

Subsequent sections will talk about what is the drug where we typically
then take the indications and disease states that are associated with
that drug product and describe them in lay terms.

Contraindications are again expressed in lay language in the section
that says who should not take the drug product.

Then a subsequent section, how should I take the drug, is where dosing
instructions are typically found.

Precautions or special population concerns are addressed in the section
which says what should I avoid while taking the drug product.

Side effects and general information on safe and effective use are also
included.

Another form of FDA-approved patient labeling is patient package
inserts. These, in the case of estrogen-containing products, are in fact
required to be distributed, under a different federal regulation. In
some instances, these patient package inserts are being used as the
basis for the brief summary in direct-to-consumer advertisements, and in
that case again, they\'re subject to our oversight under regulation.

These days, in fact, the distinction between patient package inserts and
medication guides may be somewhat artificial. Many of the patient
package inserts now in fact follow the medication guide. That\'s the
agency\'s recommendation since we know that has been generally well
accepted, and we would like to promote consistency in FDA-approved
patient labeling.

In instances were products are packaged in unit-of-use packaging with
the PPI included, these may operate quite similarly to medication guides
in that each patient would receive one with every prescription. But just
to be quite clear, the distinction really relates to this requirement on
whether or not the product needs to be accompanied by this patient
information. Medication guides are required. PPIs are optional with the
exception of the estrogen products.

The other thing to bear in mind, if generic products exist or are
anticipated, the requirements for a medication guide readily transfer to
the generic products from the innovator.

Turning now to the second broad category of tools, those that may guide
prescribing, dispensing and use. The purpose of these tools are really
to assist individuals in following what are considered to be appropriate
prescribing and use practices. Alternatively stated, they\'re really
designed to make it difficult for individuals to forget important safety
processes or precautions. A variety of reminders or prompts may be used
in these systems, as we\'ve described them.

One example may include patient agreements where a patient is given
information about the product, its risks, and the patient signs that to
assure communication and education has occurred. In some instances,
practitioner certification has been required. In other instances,
special conditions have been attached to the dispensing of the product
or in some instances the packaging. Packaging may be constrained in a
certain way. There may be a limitation on the supply allowed at any one
time or refills may be barred for certain products. In some instances,
certain pharmacy checking mechanisms have been put into place to assure
that appropriate prescribing is done, and I\'ll give you a few examples
that may make this clearer.

Lindane may be a useful example of special packaging. Earlier this year,
this product\'s labeling was modified, and at that time the volume that
was available to any patient was reduced to being either 1 or 2 ounce
aliquots. This was done out of concern for seizures and deaths that had
been reported to the agency on occasions where individuals had used this
product excessively or reapplied it.

Some additional guiding systems were used with Lindane. The package
insert, the cornerstone of risk management for the agency, was in fact
revised to include a boxed warning about its second-line use and about
concerns for its reuse, as well as highlighting the risk to children and
to individuals of low body weight. A medication guide was issued for
Lindane, and that\'s in fact the example we\'ve provided to the
committee. It instructs about the risks and how to use the product
appropriately.

Also the FDA issued a public health advisory to make these changes
salient to practitioners and to patients.

Two other products with guiding systems are alosetron and isotretinoin.
Very broadly stated, each of these have a patient agreement that\'s to
be signed, and in each instance, the physician is asked to attest to
having either necessary knowledge to prescribe the product or test the
patient. This attestation is the mechanism whereby that clinician
obtains stickers which are then placed on the prescription itself. Those
stickers are to be used to indicate in fact that, depending on the
product, the physician has the necessary expertise or has made the
appropriate decisions in selecting the patient for this therapy, or in
some instances, that the physician has done the appropriate testing to
make sure the product is being safely used.

When the patient takes these prescriptions to the pharmacist, the
pharmacist is asked to check for the presence of this sticker to make
sure in fact that all the safe conditions of prescribing have been
followed.

Turning now to the last category of tools, at least as we have
categorized them, they are those that we call restricted access systems.
These are systems that link drug product access to compliance with risk
management program elements. And for those of you who know the drug
product clozapine, a pharmacist is not allowed to dispense that to a
patient unless in fact they\'re presented with a CBC indicating an
adequate white count. The moniker for that is \"no blood, no drug.\"

In these restricted access programs, typically prescribing and
dispensing is limited to a select population of clinicians and
pharmacists. In some instances they require documentation of safe use
conditions as in the case of clozapine producing a laboratory test
result before the product can be dispensed to the patient.

An example of a restricted access program is the drug product
thalidomide, which has the system for a thalidomide education and
prescribing safety, abbreviated STEPS. I\'m presenting only a portion of
what\'s a complex system, but just to hit some of the key features, this
product thalidomide is only shipped to registered pharmacists and those
pharmacists are only to dispense thalidomide to patients who are
registered and who have prescriptions from registered physicians. There
is a central authorization process where information is centrally placed
from both the provider and from the patient to assure that the woman is
not pregnant at the time that she receives her prescription.

Turning back to our concept paper, FDA set forth several considerations
to industry and to itself in terms of how tools might be selected or put
together in a risk management program. One important consideration was
to seek input from stakeholders on the feasibility and acceptability of
tools that are proposed for use. So this would certainly, at a minimum,
include prescribers, pharmacists, patients, and third-party payors, as
well as probably many others.

The FDA also stated the value of seeking consistency and using risk
management tools that were already in existence and had documented
acceptance, the idea being we wanted to avoid confusion and burden on
the medical system by creating numerous customized programs.

FDA also stated value in using tools that had been documented to be
effective in the past either in a similar drug product or in a similarly
related health objective.

Public comments to FDA were generally supportive. We were reminded of
the importance of preserving patient access to benefits in the
discussion of risks, and also again asked to be sure to seek to avoid
confusion and burden to the medical care sector and to pharmacy practice
by creating multiple customized programs.

FDA in its concept paper had one additional important point that it
feels is a substantial departure from its practices to date which was
the importance of measuring the effectiveness of a risk management
program as developed, and that was to assure in fact that the program is
effective and that its tools add value in achieving its stated goals. To
that end, FDA recommendedm wherever possiblem to look at the health
outcomes of interest to see if in fact there\'s a change in their
occurrence or to go to the next best available surrogate for that health
outcome. The intent of gathering information on the effectiveness of
programs was to allow modification of these programs, perhaps either to
make them more stringent or more lenient, as the case may call for based
upon the data.

Evaluation can take many forms. I won\'t elaborate on that here. There
is some overlap with other concept papers, in particular, the one
addressing pharmacovigilance and pharmacoepidemiology, if evaluation is
to take some form of active surveillance for outcomes or adverse events.

So let me summarize our experience to date with risk management programs
at FDA and as we are developing guidance on this topic. Risk management
programs are intended in FDA\'s mind to be applied sparingly and are
intended to be used to minimize identified drug risks. These risk
management programs should be goal-oriented and should use tools that
are commensurate with the risks and benefits of the products, and that
any program, if instituted, should consider evaluation to assure
effectiveness in achieving its stated goals.

Let me give you again a quick digest of the three broad categories of
tools that I\'ve presented, the first category being education and
outreach. It probably comes as no surprise to many of you education and
outreach can take many forms. There can be general information or highly
targeted information. This has been applied to many drugs, probably more
than we would be able to count in terms of the amount of information
that has been issued in the form of brochures. Certainly over the years,
the agency and drug company/sponsors have issued many Dear Healthcare
Practitioner letters.

This category of tools based on our feedback and experience is perceived
by many to be limited in terms of how intrusive they are upon
conventional prescribing, dispensing, and use of drug products. Data on
the effectiveness of these educational interventions are in fact
limited, and some data that have been collected to look at changes in
physician behavior in response to Dear Healthcare Practitioner letters
and labeling changes have, in fact, shown quite mixed results in terms
of limited or small changes in response to these forms of education.

The second category of tools, what I abbreviated as guiding systems, are
used on a more limited number of products. I can\'t give you an exact
number, but we\'re probably talking tens or twenties of products. These
are perceived to be somewhat moderately intrusive on conventional
prescribing, dispensing, and use. To date, we actually don\'t have
within the agency any evidence on the effectiveness of these programs,
but evaluations are in fact planned for the two drug products with
sticker programs that I described to you in my presentation.

Turning to the last category of restricted access systems which in the
definition I used really have a very tight linkage between release of
the product and compliance with risk management processes, we in fact
have probably the smallest number of drug products that fall in this
category. My count is about six or seven products. These have to date
largely been applied for products where the condition has limited
therapeutic alternatives and where in fact may be limited options for
those people, and the products themselves in fact pose significant
risks. As such, the user populations for this very restricted category
of drug products is typically small. These systems, not surprisingly,
are perceived as being the most restrictive on prescribing, dispensing,
and use. The name in fact tells you they do restrict access.

Those systems that register all the components, patients, providers,
pharmacists, in fact give us some of the best data that we have in terms
of effectiveness, and it is encouraging the data that the agency has
received do support their effectiveness in risk minimization, again
within these very specialized populations to which they\'ve been
applied. But there is other information as well that suggests that the
imposition of such systems may, in fact, limit product uptake or slow
product uptake or in some instances may lead to substitution of
alternative drug products, sometimes with unintended consequences if
those substitutions may themselves impose risks.

This committee will be considering today and tomorrow, as Dr. Murphy
indicated, two broad categories of drug products that are often used for
the same indication, and decisions made in fact relative to one class of
drug products may have impacts on how that other class of drug products
is also used.

Thank you.

DR. CHESNEY: Thank you very much.

Are there questions for Dr. Trontell while she\'s still at the podium?

(No response.)

DR. CHESNEY: I have one. You mentioned early on that the real challenges
to determine when the need for an RMP is appropriate. Could you give us
maybe just a little bit of the thought process behind when you decided
that you had to put restricted access on that very small number of
drugs? It seems intuitively obvious, but there must have been a whole
process behind doing this for thalidomide, say, or the other five drugs.

DR. TRONTELL: It\'s sometimes difficult to talk about our rationale
because the agency truthfully is learning in the process of executing
these programs and there is some history of time over which those
restricted access programs have been developed.

My own interpretation, which won\'t necessarily reflect the historical
record, is that again these have been instances where the agency may
have, in some instances, felt it had little choice in terms of approving
the drug product without some severe restrictions because of the
magnitude of the public health risk that was seen. In the case of
clozapine, the rate of agranulocytosis in clinical trials was in fact
quite high. So the concern was that this product represented a
meaningful therapeutic alternative for patients who might have been
refractory to other forms of antipsychotic therapy. So it was approved
with conditions around the manner in which it would be used. It had
second-line use and this attempted to look at the rate of
agranulocytosis.

I think probably the next major significant restricted distribution
system to come out of the agency was the one involving thalidomide where
clearly there\'s a long history and very high concern about the risk of
pregnancy exposures to that drug product. In fact, that system and its
clarity in terms of its goals informed some of our decisions and
thinking about the concept paper. The goal was very clearly articulated
with that product given its history of previous use that they wanted to
design a system that would avoid, at all possible costs, the risk of
fetal exposures in recognition, however, that there was a strong cry
within the medical community for this product for certain indications.

So they\'ve tended to be decided by the agency on a case-by-case basis.
In fact, we still are largely making these decisions on a case-by-case
basis, and sometimes the particular benefits and risks, as they\'re
interpreted in different areas of the agency, may have slightly
different emphases placed.

So that\'s as close as I can come to a rationale. These are products
that you might think you wouldn\'t approve if you didn\'t have a very
compelling reason to put them on the market.

DR. CHESNEY: Any other questions for Dr. Trontell? Dr. Danford.

DR. DANFORD: The discussion of risk management that you just gave us
focuses a great deal on the risks of bad events coming from use of a
product, and the more aggressive you get with the restriction of the
use, the more likely you are to uncover the risks of not being able to
effectively treat the disease you\'re trying to approach in the first
place. It looks to me as though the monitoring for the effectiveness of
your risk management focuses on just looking at the minimization of the
risks caused by the drug and it might be blind to the risks we encounter
by restricting use of the drug to people who might benefit from it.

Is there an effective way to monitor the reduction of benefits that
might occur with the implementation of risk management, which I think is
probably harder than looking for the risks of the use of the drug in the
first place?

DR. TRONTELL: That\'s an excellent question. I had anticipated your
asking about unintended consequences, but on the benefits arena, I know
certainly in the instances of some drug products, the agency certainly
hears from patient groups and clinicians when drug products in the worst
case scenario are withdrawn from availability. That\'s really a case
where we have the most obvious loss of potential benefits as well as of
potential risks.

In terms of systematically accounting for benefits lost, I actually
don\'t think we have stated an explicit process for that. In the case of
the drug product alosetron, that product\'s reintroduction into the
marketplace was in part in recognition of the benefits of that
product\'s use prior to its temporary withdrawal from the patient
community and probably an increased recognition on the part of the
agency about symptomatic disease having profound impacts on daily
functioning.

So I think we would rely on information volunteered to us, but in terms
of looking at benefits foresworn, I think that\'s a much more
challenging thing to address.

DR. CHESNEY: Questions for any of the other speakers? Dr. Fink.

DR. FINK: This is really more a comment than a question. Earlier it was
stated that it was thought that the AERS database contained the severe
reactions. My concern would be that with HPA axis suppression, it is so
far below the clinical radar screen that I\'m not sure that it\'s
adequate to say that the database really reflects severe reactions.

Thinking about it, I consult frequently in the ICU. Topical products are
typically not asked for in the medication history by physicians in
practice. They are not included in ICU databases such as Apache. And the
critical question that would have to be looked at is does topical use of
steroids predispose children or adults to increased ICU admissions. And
I don\'t think that can be done easily retrospectively. Yet that is
really the key issue because without that data, we really don\'t have a
handle on the risk. You have data that says here\'s what we can measure
with a clinical test that would not be easy to implement on a wide scale
basis, and we don\'t really know whether this risk is clinically
significant and causing significant harm to patients in an unrecognized
manner.

DR. CHESNEY: I think certainly that\'s one of the points Dr. Cummins
made to me on the phone call that we routinely have to discuss the
content of the meeting, is that we really don\'t know. For example, how
many children come in with bad RSV and we incidentally notice that they
have eczema, but really don\'t make that association. Certainly I\'ve
had patients several years ago come in and say they were on Protopic,
and I said, what is that? I\'ve never heard of that. So as a
non-dermatologist, I think we routinely, even people in academic medical
centers, don\'t pay any attention to topical medication.

Dr. Fost.

DR. FOST: Yes, I think that is at the core issue. I mean, we have all
these very scary numbers of high incidence of HPA suppression, but we
have no idea whether that\'s just bad numbers or really a clinical
problem. But I\'m wondering how hard it is to study that
retrospectively. If you went to a database like Kaiser which must have
thousands if not tens of thousands of kids on topical steroids and could
also tell you how many had herniorrhaphies or were admitted to ICUs and
so on, I wonder if it wouldn\'t be possible to do a retrospective study
and get at least a preliminary handle on it.

DR. MURPHY: Joan, I had a question for Dr. Gorman before we get to the
questions later. One of the important issues which you all have
discussed is we really don\'t know what the risk is. The simple way of
putting it is we don\'t have bodies saying this adrenal axis suppression
related to this product is why this is happening. We just don\'t have
that. We have facts. We all know adrenal axis suppression is bad. We
know what you\'re supposed to do if you diagnose it, but the whole point
that is being put forth today is that we think that people may not be
asking the right questions and how do we find out what the real risk is.
That\'s really the crux of the question. But to get to the real risk,
some of it is the use, both appropriate and misuse, of products.

I wanted to ask Dr. Gorman to say something because having been in
charge of a large ambulatory care setting for pediatrics, I am concerned
about as much as people try to counsel and appropriately define use of
products, what his perception of some of the issues are with use of
these products because despite all the efforts of the physician, we
don\'t always control what happens with that product once it leaves our
pen onto the pad. So I\'d like Dr. Gorman to make some comments along
that line.

DR. GORMAN: I guess this is because I practice in a trench like my
dermatology colleagues that sit around the table.

You used an analogy at the end. I just finished reading three books that
examine the history of the world, one through salt. Salt has determined
the history of the world. And the second one was olives determined the
history of the world. And the third is codfish determined the history of
the world. They all make very convincing arguments. I often wondered
whether the prescription pad has determined the history of the world,
but I haven\'t seen that book yet.

I think there\'s a lot of different factors that sort of intersect in
how people use medicine. One of it is how available it is. So we try to
control that with prescription versus nonprescription. But this class of
medicines that we\'re discussing is available both ways. So I think
sales numbers become important.

There\'s another factor, at least in the \"velvet valley\" of Ellicott
City that I practice in. It\'s the quest for perfection. And the quest
for perfection in the dermatology world I think is very explicit. People
don\'t want wrinkles. So they use the wrinkle cream, and now they use
Botox, the first biological weapon developed, but now we\'re using it to
take care of wrinkles in people\'s skin. Accutane was developed for
severe nodular cystic acne, if I\'ve got the label correct, but now if
you have two zits and you\'re 45 years old, you go to your dermatologist
or your internist and you ask for a prescription. I know now you\'ve got
a sticker system, but there\'s this quest for perfection.

When a mother looks at their baby\'s bottom and sees redness, they put
goop on it.

(Laughter.)

DR. GORMAN: Now, they put goop on it that I prescribe. They put goop on
it that they get over the counter. We had a presentation this morning
that says genetics has something to do with this. So atopic kids come
from atopic parents, so they use the goop that I give them and then they
give this stuff that they\'ve been given themselves. They add that to
the stuff that they get over the counter.

These agents, as Dr. Fink says are not thought about by clinicians. I
think really carefully ‑‑ and I check the chart before I refill a
prescription on one of my attention deficit medicines. I never look at
the chart before I refill WestCort or Lotrimin or Lotrisone. I had data
presented this morning ‑‑ that\'s something I don\'t even think about
doing when a 17-year-old with athlete\'s foot calls me about giving them
a prescription for athlete\'s foot medicine may, in fact, have some
significant risk for these kids. It\'s not over-the-counter, but it\'s a
non-physician visit, so it\'s not going to be captured in a lot of the
databases that we use because I\'m going to prescribe that with a phone
call. I suspect I\'m not alone in that particular prescribing pattern.

I\'m trying to think about clinical ways that I\'ve seen steroid
overuse. I have never, fortunately, made the diagnosis after I\'ve
admitted someone to the ICU. But there have been many times when I\'ve
had discussions in my office mainly under the diaper area of this is
atopy. I\'m sorry. This is now disease caused by our medication, not
disease that was there before where their skin becomes atrophic. This
thinness and redness and purpura that you\'re seeing is because of the
medicine you\'ve been using and not because of the disease that started
it.

So I don\'t think this is as simple as I am a well-trained pediatrician
and I prescribe appropriately. I think there\'s a lot of other themes
that come in, and I suspect parents are using these medicines because of
their perceived safety and their very generous availability in the home.
These things never go bad. As long as you can squeeze it out of the
tube, you\'re going to use it. I know you put an expiration date on it,
but they never go bad.

(Laughter.)

DR. GORMAN: And parents don\'t throw this stuff out.

I don\'t think there\'s an epidemic that\'s clinically significant to
the point where you don\'t respond to shock out there. I think we might
have seen that. But I think there\'s an epidemic of use of these agents
in ways that we don\'t understand.

There\'s one piece of data. A fellow did a research study where he
wanted to count the number of ointments or salves that were put on a
baby by the age of 4 months, and the average number was 27. This has
been a long time since I looked at that data, just the number stunned
me. That means one new stuff every 3 days gets put on a kid, a baby, who
we think of as safe. I don\'t remember the data whether they were
prescription or not.

DR. MURPHY: And I always look to Dr. Gorman to give me a fact I never
had before. Thank you.

(Laughter.)

DR. CHESNEY: Dr. Wilkin has his hand up but Dr. Epps has read another
book on the history of the world and she wanted to discuss that with
you.

DR. EPPS: Well, not that much detail certainly.

One was a question I guess briefly for Dr. Cook. Are fluorinated topical
steroids still considered to be more of a problem than non-fluorinated?

DR. WILKIN: There are corticosteroids that typically have fluorine or
one of the other halogens at the 9 alpha carbon, and what that does is
it is slower to metabolize and so it lingers longer at the active site
and it becomes more potent that way. But the pharmaceutical companies
have been very good at figuring out other ways of adding potency to the
basic steroid nucleus by esterifying, putting some long chain thing onto
the carbon 17 or carbon 20 or carbon 21.

Actually that\'s one of the points I wanted to make back to Dr. Gorman.
The hydrocortisone that is in the class VII, which is the only one that
really is over the counter, is substantially different from the
hydrocortisones that are in those higher classes because they\'re not
truly hydrocortisone. They are esters of hydrocortisone, hydrocortisone
valerate, hydrocortisone butyrate. Once again, if you esterify the
steroid nucleus, that\'s a way to make it more potent independent of
adding halogens to the 9 alpha or some other site.

I think Dr. Gorman, Dr. Fost, and others have touched on one of the key
pieces we would like to hear back from the committee today. Everyone has
been up-front I think from FDA in conveying that there\'s a lot of
uncertainty here that we\'re saying with you our inference structure on
why we think it might be prudent in the short term, in the absence of
having definitive information, that we do have some kind of risk
management. We\'d like to know from you if that inference structure is
reasonable and if the risk management approaches that you\'ve seen
embedded in labeling, if they seem to be somehow appropriate. And I
think we\'ve heard of some examples of maybe ways where we can go and
explore and find out is there really a problem out there.

But our fundamental concern is that we see a substantial amount of
signals for adrenal suppression during drug development, and that\'s the
only time we would see that, when we ask for it and get it
prospectively. This is again one of those lanthanic conditions where
there are no signs or symptoms. Our thought is that a patient may have
to have some additional event, major trauma or sepsis, for this to
become clinically important.

My first year after medical school was not as a dermatologist. I was a
first year resident in obstetrics and gynecology, and I know that year I
didn\'t ask about topical products in the pre-op list. My wife is an
anesthesiologist so I have contact with a small number of
anesthesiologists, and none of them routinely ask for topical products.
They do ask for injectables in addition to oral products.

My thought is all of the signs and symptoms one would see in the setting
of sepsis or major trauma you could ascribe to the sepsis or the trauma.
This is really something that requires a high index of suspicion.

So I like the comment that we may need to go with one of these
controlled third party groups where the outpatient care and the
emergency inpatient care might somehow get into the same system and
maybe that\'s the source. But if there are any other suggestions on how
we may actually tease out whether there is a signal, we would be very
grateful in hearing that.

DR. FOST: Wouldn\'t Kaiser have a complete database of all prescribed
topicals?

DR. EPPS: Not everybody stays in the system.

DR. FOST: You\'d have enough that you could do a case control study of
children who are on topicals, and there must have been a large number of
them who come in for anesthesia or for surgery or for trauma other
things and look at outcomes.

DR. EPPS: It\'s better than most, but certainly I\'m not participating
in Kaiser and a lot of people pay to get what they want if they can\'t
get it from Kaiser, especially in dermatology. They may have one
dermatologist for a huge region, and so if they don\'t achieve
satisfaction, then they opt out. That is one thing that people will pay
for is dermatology services. If you can\'t get it within your HMO or
your plan, then you go to who your friend goes to or your mom says.

DR. TRONTELL: I can speak a little bit. The Kaiser system in California,
which operates more in the closed model, staff model HMO, may in fact
give you the opportunity to look at drug exposures and outcomes. The
issue would have to be clarity on the outcome you want to look at. You
might be able to look grossly at issues like ICU admissions relative to
RSV, for instance. You might also consider prospective forms of data
collection where you may want to capture even a random cortisol in
situations of sepsis and trauma, where typically lines are being placed
and bloods are being drawn. Again, this is more in the nature of an
investigation to try and assess the impact of it. But the challenge in
observational data is many factors that might lead an individual to an
ICU still may not be well captured by the data systems that we have in
place.

DR. CHESNEY: Dr. Schneider.

DR. SCHNEIDER: Yes, just to step back a moment. The way I look at this
is that after the data that we heard this morning, we know that a
substantial proportion of patients exposed to these drugs are in a
situation which I would consider to be at risk, that is, that they have
abnormal Cortrosyn stimulation tests. The clinical manifestations of
that situation ‑‑ that is a precarious situation. We know that if that
continues down the road, patients will get into trouble one way or
another. We also know from adverse event reports, of course, there is a
small number of patients who have either had adrenal insufficiency or
frank Cushing\'s syndrome associated with the use of these agents and
that apparently the adverse events were reversible on withdrawing the
drug. We don\'t know in that situation if it continues for a little
while, there are other adverse events not all that serious that are
associated with this sort of intermediate situation, and that may be
psychological changes. No one has brought up osteoporosis, for example,
which can occur rapidly in children exposed to steroids and so on.

We do know that down the road some people will be at extreme risk. We
know that patients who are admitted to ICUs who cannot mount an adequate
ACTH and cortisol response endogenously don\'t do as well. So we know
that there will be a small number of patients who will be at risk or
will actually develop these serious adverse events or death.

I don\'t know how well one could do a formal study to examine this, and
given what we know now about the effects of systemic steroids ‑‑ and I
really don\'t see much difference here. I take a more quantitative view
of this. I think we have a good idea clinically what the risks are. We
know that these patients are now at risk after 3 or 4 weeks, and if it
continues, they will be more at risk. If you stop it, probably most of
them, if not all, will recover, and no one will wind up in the ICU.

DR. CHESNEY: Dr. Gorman and then Dr. Fink.

DR. GORMAN: This is responding to the question of suggested ways to look
at this. It can be looked for as a confounding variable for
hospitalizations in ongoing clinical trials, knowing that I just
probably broke four FDA regulations. But I can think of several recently
approved drugs that hospitalization was one of the outcomes to prove
efficacy and perhaps it could be looked for as a confounder whether or
not they use topical steroids.

DR. CHESNEY: Dr. Fink.

DR. FINK: It seems like if we look at risk management programs, one
concern I would have is obviously education about this is potentially
beneficial, but it also strikes me that education about this problem is
also potentially very harmful in that if this is widely publicized, you
may see the medical community reacting to this with the sense that
anytime a child who\'s on topical steroids has a cold or an illness,
they get put on systemic steroids to cover them for the risk of HPA axis
suppression. So you could have an RMP program that actually increased
the risk of the side effect you\'re trying to avoid because of the way
physicians would tend to react.

And it really is an issue of perceived risk. If I have an asthmatic
who\'s been on systemic steroids in the last 6 months, I always get
called by an anesthesiologist before anesthesia even though, if it\'s 4
months ago, there\'s really no risk. You rarely get called for other
things. So I think it is an issue of perceived risk, but I am concerned
that an intervention here, particularly education, unless it is really
well done, could actually increase the risk of children being exposed to
adrenal suppression by an inappropriate response to the educational
program.

DR. CHESNEY: Dr. Trontell.

DR. TRONTELL: I think those are very legitimate concerns and it gets at
the difficult area of unintended consequences. How do you know what you
don\'t know in advance? Some of the stakeholder input that I alluded to
in the selection of tools in fact ‑‑ the concept paper, in fact,
suggests that you may try pretesting, particularly in the educational
arena. Again, there are challenges in trying to assess what people learn
versus what they do. But it may be possible to try and get some
assessment before you send out a message whether or not that message
might be misperceived.

DR. CHESNEY: Dr. Andrews.

DR. ANDREWS: I had a couple of comments back to the question can you
study this association between exposure and outcome. As an
epidemiologist I\'m always looking to use an electronic database where
the data are already existing rather than go out and do a very elaborate
study. In this particular case, the use of a database like a Kaiser is
very appealing if you could identify the outcome well and if the outcome
is frequent enough. So I think you could do that in terms of identifying
the outcomes.

Exposure is the difficult part. Because people tend to use these drugs
not just within 3 months or a week of when they\'re prescribed, and they
may have been prescribed to another family member, one might broaden
your scope in looking at a fairly long period of time before the
outcome, as well as looking at all family members who might have
received a prescription. But I think you would also have to supplement
that data collection with an interview with a parent to find out what
they actually used before the outcome.

DR. CHESNEY: Dr. Fink.

DR. FINK: In terms of risk management programs, the list you had was
good. The one that occurs to me that I did not see on the list is
liaisons with professional organizations to encourage them to have
increased drug information into their recertification and certification
exams. As someone who recertifies in pediatrics and pediatric
pulmonology and serving on this committee, I\'m almost amazed at the
lack of drug-related questions on board exams. One mechanism ‑‑ if more
questions about drug reactions or drug toxicity were put into
professional recertification exams, it would force physicians to raise
their interest in that subject because I think the average practitioner
gets most of their information from the detail person and probably does
not read the package insert before they prescribe a drug.

DR. TRONTELL: That\'s an excellent suggestion. I didn\'t mean to imply
that the tools that I listed were, by any means, exhaustive. I think in
some instances the agency has worked very well in cooperation with
professional societies. It\'s an excellent suggestion.

DR. MURPHY: Actually I think we\'ve mentioned this to the peds committee
before. We\'ve been working with the American Academy of Pediatrics to
make, as part of their recertification, a certain number of drug-related
‑‑ new labels basically that deal with changes that have occurred that
we all know that your bedtime reading is not the PDR and nowadays,
particularly for some of the older products that we\'re looking at or
being studied, won\'t be in there at all anyway. But the changes that
are occurring to labels because of these studies, both from dosing and
safety, you\'re lucky if you get one or two. We\'ve got 60 new labels
now. So I think it really is a matter of having to have possibly
multiple approaches.

DR. CHESNEY: We have one more question and then I think we probably need
to break for lunch so that we still have a half hour. There are one or
two people signed up for the open public hearing, and we want to have
lots of time to have open discussion on Dr. Murphy\'s questions. So, Dr.
Glode, would you like the last question or comment before lunch?

DR. GLODE: Thank you. It\'s a comment I guess and a short question for
Dr. Cook. So it\'s just in the studies that you reviewed, again without
a calculator present, it looked like there were about 57 children less
than 2 who have been studied in the 10 or 11 studies you presented. So
that\'s just to point out the scarcity of data in young infants with
diaper rashes.

Secondly, I just had a question about study design in most of these
studies, because of the 100 and some ‑‑ I added up to 113 individuals
studied who were suppressed, had evidence of suppression ‑‑ only about
26 of those were retested. So were the protocols to retest? And so why
did 75 percent of the people get lost to follow-up or refuse to be
retested? Or was it not part of the study design?

DR. COOK: Well, no, it was part of the study design that patients who
showed evidence of HPA axis suppression at end of treatment should be
retested. The problem actually came in the definition of what was HPA
axis suppression according to the sponsor versus the agency. So for that
reason, there were some patients who by our definition were suppressed
and not considered suppressed by the investigator and therefore the test
didn\'t occur. In a few there were some that were like lost to
follow-up. So that\'s why there\'s somewhat a paucity of data there.

DR. CHESNEY: Thank you.

Tom tells me that there is an area in the dining room that\'s been set
aside for the committee and consultants to eat. I think we need to
reconvene in an hour at 1 o\'clock for the open public hearing. Thank
you.

(Whereupon, at 12:03 p.m., the committee was recessed, to reconvene at
1:00 p.m., this same day.)

AFTERNOON SESSION

(1:03 p.m.)

DR. CHESNEY: I think we\'re ready for the afternoon session, if
everybody could take their seats please.

This is the beginning of the open public hearing, and the FDA has a new
policy which I will read, or a new statement which needs to be read
before public hearings.

Both the Food and Drug Administration and the public believe in a
transparent process for information-gathering and decision-making. To
ensure such transparency at the open public hearing session of the
advisory committee meeting, the FDA believes that it is important to
understand the context of an individual\'s presentation.

For this reason, the 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
company or any group that is likely to be impacted by the topic of this
meeting.

For example, the financial information may include a company\'s or a
group\'s payment of your travel, lodging or other expenses in connection
with your attendance at the meeting. Likewise 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.

Is there anybody who would like to speak at our open public hearing? Is
there a Mr. Jerry Roth here?

MR. ROTH: Thank you. My name is Jerry Roth. I am President and owner of
Hill Dermaceuticals, which in today\'s society makes me a dinosaur in
the sense of, so to speak, the side effects stop here.

During today I wanted to let you know that every corticosteroid possibly
will not fall into the side effect range of what you\'ve seen this
morning. There were three things that have been mentioned by every
speaker and that is the body surface area, the vehicle, and the volume
of use or the amount exposed to. And I hoped that some of these
questions would get answered in the safety data that I\'m going to
present. I will make it very brief since we\'ve been here long, and I\'m
not used to sitting still this long myself.

First of all, Derma-Smoothe/FS is a fluocinolone acetonide in a peanut
oil vehicle. We conducted two independent studies for the treatment of
atopic dermatitis in ages 2 to 12, and I want you to understand that the
criteria for atopic dermatitis was greater than 50 percent body
involvement. The data that I\'m about to show has been approved by the
dermatology branch of the Food and Drug Administration.

I might add that you had a pre-conference document and it mentioned
fluocinolone acetonide topical oil. It\'s ages 6 to 12. Since that time,
it has been approved for ages 2 to 12.

The study design as an open-label safety study. Once again, the patient
criteria was moderate to severe atopic dermatitis involving greater than
50 percent of the body. The dosage was twice a day application to the
diseased skin for continuous treatment for 4 weeks. The criteria is what
you have heard all day, the cosyntropin ACTH stimulation test and the
serum cortisol levels both baseline and post stimulation.

The study design was prior to day 1 and day 29 the pre-stimulation serum
cortisol level was assessed, immediately followed by stimulation with
cosyntropin, and then the post-stimulation cortisol level was taken
after 60 minutes.

The total population was 34 patients. There\'s a typo in your
pre-packet. You had 33. It was 34 patients.

But 18 patients had a body involvement of greater than 75 percent of the
body. 16 additional patients were involved. The body surface area was 50
to 75 percent.

The other question that we\'ll get answered is the amount of volume of
use and the amount exposed. The average patient used in the 30-day ‑‑ in
the 4-week ‑‑ or 29-day level was 9.5 milliliters and I will come back
to that in just a minute.

But the baseline cortisol levels did not change from day 1 to day 29.
The p value in the first study was .6. The p value in the second study,
.376. When you increased or did the stimulation, the increment was no
difference from day 20 ‑‑ statistical difference between day 1 and day
29.

Just for those who are not physicians, we\'re talking about a
considerable amount of body surface area, your chest, back, front of
your legs, back of your legs, arms, and so forth. So once again, I want
to point out that it is a significant body surface area.

Study 1, just to review. The baseline from day 1 and 21 on the cortisol
levels ‑‑ or to 29 was not statistically significant. It was .6. The
increment increase in cortisol after stimulation of day 1 and after 4
weeks was not significantly different either.

Study 2 showed pretty much the same. There was not statistical
difference from day 1 to day 29 in their cortisol levels as well as the
increment increase.

I mentioned drug exposure. Each patient was dispensed ‑‑ and it\'s been
brought up by several of the advisory committee today. Each patient was
dispensed a 4 ounce bottle and the average usage was 9.5 milliliters.
Now, within this 4 ounce bottle, there are 12 milligrams of
fluocinolone. That means that the average patient had exposure of no
more than 1 milligram of fluocinolone, and that is not much. I mean,
that\'s infinitesimal compared to what you\'ve seen and the amount of
usage in the studies that have been presented today.

The conclusion, of course, 4 weeks, twice daily application of
Derma-Smoothe/FS, or fluocinolone acetonide in peanut oil, to diseased
skin involving 50 to 90 percent of the body surface area, there was no
change in the morning baseline value of plasma cortisol, nor did it
affect the cortisol stimulation by the administration of ACTH.

It has been asked several times in here this morning about efficacy, and
very briefly, these patients, the 34 patients, greater than 60 percent,
actually 67 percent, 23 patients had a 75 to 100 percent improvement.

I want to thank you. I know you\'ve heard a lot of data today. If there
are any questions, I would certainly ‑‑

DR. CHESNEY: Any questions for Mr. Roth? Dr. Fink.

DR. FINK: Yes. Analysis of pooled data would hide potentially outliers
who had adrenal suppression. Did any of the subjects in either study
show evidence of adrenal suppression?

MR. ROTH: Not one patient showed adrenal suppression. I should have said
that in the beginning

DR. CHESNEY: Dr. Stratakis.

DR. STRATAKIS: The question I have is again with regard to the test that
you used to assess adrenal suppression. So I think it was very nicely
put forward this morning that baseline cortisol values are not a good
test to assess adrenal suppression. I think that this is evident from
your numbers. In one of your studies anyway, you have a baseline value
of 10.73 as the average and then you have a standard deviation of 5.1
with a mean value of cortisol of 10.73?

MR. ROTH: That was the range. I think that the accepted standard here
and what the agency requires for a test is the baseline cortisol and
stimulation before the study. I believe Dr. Wilkin had mentioned that
there\'s not one of these patients that haven\'t been treated before. At
this time, that is the best that the agency has. I\'m only comparing my
data to the same test standards that what you\'ve seen this morning.

DR. STRATAKIS: Do you have the numbers of the ACTH stimulated values?

MR. ROTH: Yes. I believe they\'re on your chart. Is it not? The
increment is on there.

DR. STRATAKIS: This is the increment.

MR. ROTH: Yes, the increment.

DR. STRATAKIS: The actual number.

MR. ROTH: The actual increment, yes.

DR. STRATAKIS: The actual peak ‑‑

MR. ROTH: It more than doubled on each of those patients, and I believe
at 60 minutes the standard range is a double, and I believe that each of
those, the increment wasn\'t more than doubled in each of the patients
after the stimulation.

DR. STRATAKIS: Thank you.

DR. SCHNEIDER: Obviously, these results are a little bit at variance
with what we\'ve heard earlier. Let me ask you first. The total amount
of steroid that the patient was exposed to during this 29-day period was
1 milligram?

MR. ROTH: Per day.

DR. SCHNEIDER: It was 1 milligram per day.

MR. ROTH: Per day. Once again, fluocinolone is considered a light to mid
potency and this vehicle is possibly less because the vasoconstriction
is even less than what this same active would be in something else. If
you put this amount in an ointment or cream, the amount exposed would be
many times more than that 1 milligram to cover the same body surface
area.

DR. SCHNEIDER: You mean the amount that was applied.

MR. ROTH: Right. In other words, being in a peanut oil base, you have
spreadability. That\'s why the average ‑‑ and we calculated each bottle
returned ‑‑ was 1 milligram per day. If this same corticosteroid may
have been in an ointment or something, you would have to apply a lot
more to cover the same amount of surface. Therefore you would be exposed
to far more than possibly the 1 milligram per day. It may take three
tubes or four tubes.

DR. SCHNEIDER: Do you have any information on differential absorption?
For example, if you put the material in peanut oil, is it absorbed less
through the skin?

MR. ROTH: Well, we don\'t get much absorption. This the product on the
market in a peanut oil. We didn\'t do it just for this study. It was
previously on the market. It was done. I can\'t tell you that if you put
it in plain mineral oil, it\'s going to be any different, but the
product was approved way before we did these studies. The product was
initially approved in 1988 and it was also approved under a different
thing for scalp psoriasis. This has been on the market. It wasn\'t that
we put it in the peanut oil just to check for this study. The vehicle is
an NDA and because of the vehicle, it is an NDA drug not a generic
equivalent.

DR. SCHNEIDER: I mean, your contention is since the efficacy was the
same that you achieved this equal efficacy with less total skin exposure
than if you put it in a cream or a lotion and, in addition, that you may
also have less systemic absorption.

MR. ROTH: I\'m not telling you that this works better than the cream.

DR. SCHNEIDER: Well, you don\'t have a head-to-head trial.

MR. ROTH: Okay.

DR. SCHNEIDER: But the response was certainly within the range of what
we heard earlier for other drugs.

MR. ROTH: Yes. The response was, yes, and that\'s always been the case.
Efficacy studies were done. This was done as an efficacy approval and
efficacy was done at many centers for efficacy results besides these 34
patients. This was approved as an efficacy study. Once again, we showed
that oil sometimes ‑‑ it has been mentioned many times in here today
regarding hydration or whatever, and there have certainly been many
studies done on peanut oil with hydration. So that\'s not our claim in
the label though.

DR. SCHNEIDER: Thank you.

MR. ROTH: Okay.

DR. CHESNEY: Dr. Ebert.

DR. EBERT: Your figure of 1 to 2 percent absorption is based on what ‑‑

MR. ROTH: That was the general accepted, I believe, in the textbook of
corticosteroids by Dr. Maybach. I believe that that\'s their accepted of
what is absorbed through the skin. That I believe is a range. I don\'t
think that\'s amount. However, with just 1 milligram you certainly have
room for a lot more. That 1-2 percent, of course, is higher for more
exposure, volume of steroids.

DR. CHESNEY: Dr. Wilkin.

DR. WILKIN: Yes. We in the review division for this product were not
made aware of the content of this particular presentation in the open
public section, and so I would say that we\'re in the position of
extreme neutrality in terms of the data and the conduct of the trial. We
just simply didn\'t prepare. Had we known and if this is an important
thing to discuss, we could have reviewed this efficacy supplement, but
we did not realize this was going to be discussed.

DR. CHESNEY: Any other comments, questions?

(No response.)

DR. CHESNEY: Thank you very much.

MR. ROTH: Thank you very much for your time.

DR. CHESNEY: Is there anybody else who wanted to speak in the open
public hearing?

(No response.)

DR. CHESNEY: Dr. Murphy is going to give us the questions for our
deliberation for the afternoon.

DR. MURPHY: Can somebody put the slides up for the questions?

We\'re going to give you first two questions that are slow balls and
then we\'ll get a little harder here. Okay?

(Laughter.)

DR. MURPHY: The first question really has to do with a drug development
approach, and it starts out with the statement which is clinical studies
of pediatric patients using topical corticosteroids have demonstrated
HPA axis suppression during the ACTH stimulation test. I think everyone
agrees with that statement.

The next question is, is the cosyntropin test performed during drug
development sufficient to determine the risk of potentially
life-threatening adrenal suppression? And if one has other
recommendations, are there additional specific tests that the
subcommittee would recommend to measure this risk that we would ask
sponsors to perform? That\'s not on this slide, but basically as part of
the drug development process. The division is asking in their approach
to having these products developed for use in children, is this the best
test that we should be using and are there any additional specific tests
that we should be asking for.

DR. CHESNEY: Do you want discussion on question 1 and then we\'ll come
to question 2?

DR. MURPHY: I\'d like to. I think once we go to question 3, we may be
here for a while. So I wanted to try and address these individually
first.

DR. CHESNEY: And we have a total of three questions. Correct? Three
questions total?

DR. MURPHY: Yes. Well, there are three questions, but question 3 is ‑‑
no. Somebody said three pages. No. It\'s two pages.

(Laughter.)

DR. CHESNEY: I\'m trying to make a rough allotment of time. We give 5
minutes to question 1 and then a half hour for each of the others.

So question 1. Any comments as Dr. Murphy has presented it and as we see
it on our handout and on the screen? Dr. Fink.

DR. FINK: I guess the only question is, is there any data available
looking at multiple applications of the cosyntropin assay on the same
day? Because the clinically relevant issue is does the patient respond
appropriately to stress. An impaired adrenal gland may respond to the
first supraphysiologic dose of cosyntropin, but if you hit it again 2
hours later, would you see an impaired response that you did not see
with the initial stimulation? Or can you count on it responding
reliably?

DR. MURPHY: I am going to ask for all endocrinologists in the room to
please respond to that.

DR. SCHNEIDER: Actually the adrenal gland is impaired because the
pituitary is impaired. So the answer to that is really it won\'t be
impaired. In fact, it will be better. There used to be a thing called
the long-term cosyntropin test where you would either drip it in or give
it every 8 hours or whatever. This was before ACTH assays were available
or reliable, and this would distinguish primary from secondary adrenal
insufficiency. So if you take somebody with secondary adrenal
insufficiency, and even if they have had a lousy response at the
beginning, as you keep hitting them with exogenous ACTH, the gland will
wake up, and normally that will take about a day or two. We have a lot
of data on that, and the answer is if you have an impaired gland through
secondary adrenal insufficiency, repeated stimulation will only improve
cortisol responsiveness.

DR. FINK: Over a short period of time?

DR. SCHNEIDER: Over 24 to 48 hours. I was actually forced to do some of
these tests when I was an intern, and it can distinguish the two.

DR. CHESNEY: Dr. Murphy, it occurs to me there are two questions here.
One is, is the cosyntropin test sufficient to determine the risk of
potentially life-threatening adrenal suppression and I think many of us
would be dependent on our endocrine colleagues.

But the other part of the question is should the FDA ask sponsors to do
this in future studies of topical corticosteroids?

DR. MURPHY: The second part of the question is if the answer is that we
need additional tests, then would you recommend that we ask sponsors to
do these during their conduct of trials, when they\'re looking at the
efficacy, to assess safety side of the question.

DR. CHESNEY: Dr. Fost.

DR. FOST: I\'m having a little trouble with the phrase
\"life-threatening\" because from what we\'ve heard, I don\'t know if
there\'s any ‑‑ I don\'t know what the risk of life-threatening is. My
impression is it\'s pretty low, but we don\'t know. We talked about ways
of getting at that.

So I would feel more comfortable if you phrased the question is the
cosyntropin test sufficient to determine the risk of adrenal
suppression. My impression is from what I\'ve heard ‑‑ I\'m no
endocrinologist ‑‑ it\'s a pretty good screening test. It\'s not perfect
because of the other elements of the axis, but weighing costs and
benefits of assessing the whole axis, not to mention stress to the
children who would be in these studies, it strikes me as a reasonable
screening test for a problem whose clinical significance we don\'t know
anyway. It\'s not the ideal test, but it strikes me as a reasonable,
middle-ground sort of test to see if there\'s any effect at all.

DR. MURPHY: So your answer is that as far as looking at the adrenal
response, you think it\'s an adequate test. That\'s what we\'re asking.

DR. FOST: That\'s my impression.

DR. MURPHY: That\'s what we\'re asking. You\'re going to the latter
part, the part we really have a hard time defining and brought to the
committee. You\'re correct for sort of taking that out of this part of
the question.

DR. CHESNEY: Dr. Stratakis.

DR. STRATAKIS: I agree with what was said, that this is the best
screening test we have so far.

I think we have to also agree, however, on how to use the results of the
ACTH stimulation test. In other words, we have to agree on whether the
18 micrograms per deciliter is what we are going to use as the criterion
for adrenocortical insufficiency.

There are really not good studies looking at the increment. There are
not good studies looking at the baseline value. Although I agree that
baseline values and increments can be used in the overall assessment of
a test, we think we should prioritize on what we use, if we\'re going to
use it as a screening test, as the best value for that test.

I think that if I were to order, what I would use for this test as a
screening test, would be first the peak value, and I would compromise
with 18 micrograms per deciliter, which I think is reasonable based on
the data that we have so far, number one. Then between the other two,
increment and baseline, I would use increment second. And baseline ‑‑
I\'m not even sure that I would look at it. I don\'t know whether it
should be actually one of the criteria.

DR. CHESNEY: Dr. Wilkin.

DR. WILKIN: I would just like to say that we have that as an action item
that we\'re following up on. We\'re going to get specific discussion
from experts on exactly what criteria to use with the Cortrosyn testing.
We didn\'t see that as actually a specific question that we would
discuss today. I think there are other experts, in addition to some who
are here today, that will help us on that.

DR. MURPHY: We appreciate the comment. It\'s just that we didn\'t want
the committee to get bogged down into that very specific which criteria
to use because we are doing additional work on that because we thought
could be an extensive discussion unto itself. So it was really using the
criteria that had been discussed, does the committee feel that this is
an adequate test.

DR. CHESNEY: Would anybody recommend any other specific tests? Dr.
Schneider and then Dr. Stratakis.

DR. SCHNEIDER: I\'d just like to sort of mix these two things together
and make the observation that during drug development, there are early
parts and there are late parts of drug development because you asked the
question relating to drug development, to what we can learn during this
process. There is, or there should be, in the development of a drug an
early period in which there is intensive PK/PD studies, and then a later
part where there are what are usually termed population based PK/PD. We
have a larger population.

During this intensive phase I think sponsors have the opportunity to
study the absorption of the drug itself perhaps in a clinical research
center environment and to do some more sophisticated PD studies such as,
for example, looking at the timed cortisol levels or the time to ACTH
levels or the peaks or whatever to get some idea of how big a problem
this is with a new molecular entity. Remember, whether it\'s an inhaled
steroid or a dermatological steroid, the drug is being developed because
it will exert its effect locally and the systemic effects will be
minimized. So here\'s a time during development when there is a really
great opportunity to get what we would term intensive PK/PD data. In
that regard, there are other tests that can be used such as, for
example, a temporal profiling of cortisol levels or even cortisol
production rates or ACTH levels or whatever. But clearly you couldn\'t
do this with 200 people.

Later on in my opinion, the Cortrosyn stimulation test is really the
best screening test that we have. In my opinion, the single peak value
of 18 or 20 micrograms per deciliter outweighs the others. The increment
I don\'t think is quite as reliable simply because it\'s inversely
proportionate to the baseline level.

So I think one really should distinguish these essentially two broad
phases of drug development. And early in development you do have the
opportunity to get some really good information. If it turns out, for
example, that the drug is really absorbed systemically by whatever
analytical method you have and that furthermore it has a pharmacodynamic
effect, then you\'ve really learned a lot and I think a warning light
should go off and you might really look at some of these issues
subsequent in development. I know that this came up in our deliberations
over inhaled steroids, the same thing. Having said all of that, that
would be my answer regarding drug development.

Is the test performed during drug development sufficient to determine
the risk of life-threatening adrenal suppression? Again, not absolutely.
It can give you some indication but there will always be exceptions and
there will always be people whose adrenals will respond but whose
hypothalamic-pituitary units will not respond adequately to stress. On a
population and a clinical level, it\'s I think the best that we can do
today.

DR. CHESNEY: Dr. Stratakis.

DR. STRATAKIS: I agree with the statements by Dr. Schneider.

I just wanted to add another dimension. When we talk about these
compounds, we haven\'t addressed at all the mineralocorticoid effects
that some of the compounds may have. I guess I need some help here
whether fluorinated compounds have more mineralocorticoid effects than
one would anticipate from the usual hydrocortisone esters that we have
been using. So the question is whether other measures like blood
pressure, for example, and other mineralocorticoid effects should be
used. I\'m asking this more as a question to the pharmaceutical
development people here.

With regard to any other tests, other than the blood pressure, which I
would like more help with with regard to the mineralocorticoid effects,
obviously this morning we talked about the CRH stimulation test. The CRH
stimulation test, in theory at least, is a better test than the ACTH
stimulation test. However, at this point, because the data are not out
there, we can\'t use those tests. I think we are addressing this issue
in question 3, but in the future, more studies ought to be done
employing the use of the CRH test in the evaluation of secondary
adrenocortical insufficiency, and at least again in theory it may be
more practical than ACTH and also more applicable in all situations of
secondary adrenocortical insufficiency because as it was pointed out, if
you do an ACTH stimulation test within the first couple of days, you
won\'t pick up secondary adrenocortical insufficiency.

So any light on the fluorinated compounds and whether mineralocorticoid
effects would be screened more carefully?

DR. WILKIN: I can\'t really comment on halogenated versus
non-halogenated. But we take your point about considering the blood
pressure and mineralocorticoid effects and we\'ll have those discussions
with sponsors.

DR. CHESNEY: Have we answered question 1?

DR. MURPHY: Yes, thank you. I think basically I took a consensus that
the cosyntropin test with the three criteria to be ranked later is
adequate, that there are some other things that we can look at, both
earlier in development on smaller numbers of patients and enrich the
database to inform us more about the behavior of the product, and also
to answer if there are any other mineralocorticoid type of activities.
So I think that\'s the consensus I took out of what was said.

There\'s another hand.

DR. SCHNEIDER: Just a question. Does this question include what\'s
appropriate in labeling for the tests that are recommended?

DR. MURPHY: No.

DR. CHESNEY: Dr. Fink has the last word here.

DR. FINK: I guess I would feel comfortable accepting this as a bronze
standard, but if you want a gold standard, you need to get adult
volunteers who you bleed into shock and see what their response is.

(Laughter.)

DR. FINK: But the real issue here is if you go with a standard and you
say that we want to develop a risk management program, the fact that
you\'ve documented some HPA axis suppression may not have a big impact
on practitioners. They may say this is just a biological observation,
and if you don\'t tie it to clinical outcomes, it doesn\'t necessarily
move me to make a lot of change in my practice.

DR. MURPHY: I think that that is the crux of really the third question
of what are we going to do while we don\'t have the final answer.

Next question. The questions are a little different on those slides than
they are in what I have in my hand. Nothing like keeping us on our toes
here.

Just basically I\'m saying this for the recorder here. The younger
pediatric patients have a larger surface area to mass ratio when
compared to adults and may be at greater risk of higher systemic
exposure to topically applied drugs. A statement of fact.

Because of this, the FDA has usually requested the sponsor conduct
suppression studies in older groups first. If there is no evidence of
suppression, to proceed in sequentially younger patients until all
groups have been studied or until there is evidence of significant
suppression. This is too a statement of fact.

Given the data from clinical trials that were presented today, does the
subcommittee recommend continuing this sequential testing or should the
testing be performed concurrently?

We ask you this question because we have had objections to doing it the
way we do it, and it has had consequences for some product development.
So we\'re asking what the committee thinks about this approach.

DR. CHESNEY: Dr. Gorman.

DR. GORMAN: I think dose-ranging studies is something the agency
probably has a wealth of experience with. I think using the age
criteria, of marching down the age criteria is certainly one way to do
it to protect the youngest patients. And other way to do it would be to
test them for the suppression more frequently after smaller doses of the
drug either by changing the amount of surface area that could be treated
or the duration of treatment. There are a lot of ways to do dose-ranging
studies that I don\'t think would necessarily dictate the age
march-down, that would perhaps satisfy the sponsor and company, as well
as the agency, as well as protecting human subjects as they go through
this research process.

DR. CHESNEY: Dr. Santana.

DR. SANTANA: I would actually state that I think in this scenario in
which we have some data, although limited, that the studies should be
done concurrently. When I looked at the numbers that Dr. Cook presented,
1 out of every 6 patients in those series were under 2 years of age. So
it\'s already happening. These patients are getting the therapy. So I
think we should be studying them concurrently. We shouldn\'t restrict it
to the older age groups first because we already have some evidence in
those older age groups that it is occurring in frequency between 30 to
50 percent of the patients have some sort of suppression. So we have
some indication that occurs in the older age group. Why not extend it
concurrently to the younger age group in which potentially it could be
more problematic? Because I heard Constantine say over there that he was
concerned that the adrenal is not as mature in the younger age groups,
et cetera. I think we need that information early not later.

DR. CHESNEY: Dr. Danford and then Dr. Epps.

DR. DANFORD: I think the answer to this question hinges not in a small
amount on the meaning of the word \"significant\" when it\'s used in the
phrase \"evidence of significant suppression.\" Significant might mean a
statistically detectable level or significant might mean evidence of
some potentially life-threatening problem. I guess I need to know which
of these we\'re looking at or if we can even tell. I might be inclined
to allow a laboratory abnormality to occur in a large proportion of
patients in whom I would use a drug like this if I knew that the risk of
a clinically recognized bad outcome was extraordinarily low, but I\'m
not sure we have that with the suppression test.

Are you asking about detectable suppression on the test or are you
asking about risks of bad outcomes?

DR. MURPHY: We\'re asking about the test. If you look at the next part
of this, it might make it a little ‑‑ we\'re trying not to prejudge what
you\'re going to say so that\'s why we divided it out.

If you\'re doing sequential testing and you\'re telling them we want the
results of the older age group before we go into the next age group,
that means that a priori you should have some criteria at which you\'re
going to say don\'t go into the lower age group. So if we are going to
continue to do this, what is the committee\'s thought again for the test
itself, not for the clinical outcome, at which you should say you should
no longer go into the younger age group? But it sounds like the
committee was beginning to say they didn\'t even think that we needed to
do this sequentially.

Again, if you do it sequentially and you have criteria for just the test
that ‑‑ I\'ll just pick a number here ‑‑ 50 percent ‑‑ when you got to
the 5- and 6-year-old, that 50 percent of the children suppressed, then
should you, therefore, go into the next age group? That doesn\'t mean
you won\'t go. It just means we don\'t want you doing that trial until
we know the results of what the suppression is in the older ones. You
may want to put in a safety parameter. You may want to consent them
differently. There\'s just a different process. So that\'s what we were
saying.

Right now we\'re telling them that they have to do it sequentially. Do
you agree that that\'s correct? And if you do do it sequentially, then
what would be your criteria for saying before you just go on to the next
lower age group, you need to have more safety parameters in place or
reconsenting or whatever? That\'s really the question in its totality.

DR. FINK: Is this in the context of preclinical, i.e., before the drug
is released for marketing?

DR. MURPHY: Yes. Again, that\'s why I was emphasizing this is in the
drug development process.

It could be out there for some other indication, but it\'s being tested
for kids for the indication under study. So it\'s not been approved for
that for children yet.

DR. CHESNEY: Three people: Dr. Epps, then Dr. Stratakis, and Dr. Fost.

DR. EPPS: I would recommend sequential testing continue. As someone who
sees pediatric dermatology patients, there are certain seasons of the
year when my entire practice could be atopic dermatitis. Those of us who
treat these kids prescribe topical steroids and other immune modulators
all day every day. There are some medications under which certain ages I
don\'t use, and certainly just like clobetasol or whatever aren\'t
recommended below certain age groups and some of the immune modulators
aren\'t recommended below age 2 because of side effects, I think if you
march down, you pick up certain problems that can certainly be amplified
in younger age groups. Some of these smaller kids can\'t tell you I feel
bad, I\'m dizzy, I\'m whatever. They\'re so busy itching and having
other issues.

But I would continue sequential testing. I tend to err on the side ‑‑
may be more conservative for safety but I think it\'s worth knowing. I
know it would be a little bit more burdensome to industry as far as
testing is concerned, but I wouldn\'t want to just throw it open and
then everybody under the age of 5 has horrible problems when you could
pick that up earlier.

DR. CHESNEY: Dr. Stratakis, Dr. Fost, and Dr. Wilfond.

DR. STRATAKIS: First of all, I would like to ask myself a clarification
of the question. When you mean sequentially, what are the age groups
that you are thinking of testing sequentially? So are you dividing the
groups in post-pubertal, pubertal, pre-pubertal, toddlers, and infants,
or what exactly are the age groups that you\'re thinking of? Then I
would like to make a clarification and a comment on that.

DR. COOK: Well, in the studies that we did where you saw the
differential, they were divided 9 to 12 and 6 years and then 2 to 5 and
then infants. However, in some studies we came to the conclusion that
there probably isn\'t a lot of difference in patients 12 on up to 18. So
they\'re usually grouped together, and then the younger children, and
then the infants.

I will say that those studies that you saw were supposed to all have
been sequential and it didn\'t quite happen that way. In one respect, I
think it was probably good that it didn\'t happen that way or we would
not have had any data on the infants and the younger children. Actually
in one study, no infants suppressed. I don\'t know why, but some of the
older children did. So I think sometimes assumptions can\'t be made.

DR. STRATAKIS: So I\'m in favor of concurrent testing because the 0 to 2
adrenocortical development of zona fasciculata, which is the organ of
interest here ‑‑ this is the zona that produces cortisol. It is during
this first 24 months of life that zona fasciculata forms, and during
this time, the fetal zone involutes. We have no data as to what the
proper ACTH response of the fetal zone and then the young, newly formed
zona fasciculata cells ACTH responses are. We really don\'t know that. I
would favor concurrent testing with ACTH cautiously for these patients.
I also would favor an extreme control of administration of these
compounds in this particular age group.

Now, after the age of 2, until about puberty or until the onset of
puberty, the only changes that take place in the adrenal is the
development of the androgen production by zona reticularis. I suspect
that this may have something to do to ACTH responses, in particular with
androgen production, but I don\'t know whether it has any effect on
cortisol production. I think that that can be done concurrently or
sequentially, but it only makes sense to study these other groups and
subdivide them in only two age groups. So from 2 to pre-puberty, 8 or 9,
and then from 8 or 9 and up would be peri-pubertal and post-pubertal.

DR. CHESNEY: Thank you.

Dr. Fost, then Dr. Wilfond, then Dr. Ebert.

DR. FOST: I\'m just trying to understand the current practice. The
description says if there is no evidence of suppression, you proceed
sequentially to younger children until all these groups have been
studied. If there is evidence of suppression in adults, do you stop
there and just assume that the children also will suppress, or do you
continue to test anyway?

DR. COOK: Usually there is some defined criterion. With most studies, at
that time it was if you found 10 percent suppression. Usually in our
safety studies, we suggest to the sponsor that if you find significant
safety issues in adults, we can extrapolate downward, but we don\'t
extrapolate upward. So if they want to get the indication in children,
for example, then they need to study the lowest age group until they
come to a safety problem.

DR. FOST: So if they do first studies in adults and they find
substantial suppression, by whatever your criterion is ‑‑ let\'s say 50
percent or something ‑‑ do you then assume that you have at least that
amount of trouble in children, or do you require them to ‑‑

DR. COOK: That\'s what we have assumed in the past.

DR. FOST: So you only go down when there are negative results or not
worrisome results.

DR. COOK: Or not worrisome results. Unless they want to start a little
lower, if they\'re starting with a pediatric age group, say, 12 to 18.

DR. CHESNEY: Dr. Wilfond.

DR. WILFOND: Norm\'s question actually has made me want to ask a second
question in addition to the first one I was going to ask.

So the new question is it seems to me that even if you did see some
evidence of a safety issue, if there was a clinical reason why the drug
might still have use and importance in children, you might still want to
consider studying it. Is that correct or not correct from your
perspective?

DR. WILKIN: Well, once again, I think this is an inference that we
thought we were willing to make. If it turns out we have 25 adults and
23 of them suppressed, then the question is what will we learn from
studying smaller patients. I think one could safely assume that they\'re
likely to suppress as much as the adults because again, the Cortrosyn
test is, we\'ve already heard, described as the bronze standard. Then I
think Dr. Ten Have could speak to the smallish kinds of numbers that
we\'re seeing in our series. We\'re really not talking about point
estimates that are very useful in labeling with the enormous confidence
intervals. I think what we\'re really getting out of numbers like 25
subjects is, is there any chance of adrenal suppression? Is it
plausible? Is it very likely? I mean, it\'s sort of rough
semi-quantitative sorts of things when we\'re down at this numerical
level. I don\'t know. You may want to ‑‑

DR. TEN HAVE: Yes, a quick comment on that. In light of the small
numbers in each of those separate studies, sort of a pseudo
meta-analysis across studies to see if you have any sort of consistency
with such wide confidence intervals, consistency in my mind is the best
you can get in terms of evidence in favor of a trend. It sounds like you
don\'t have consistency across the different studies. A couple show
downward trends and a couple show high immunosuppression rates for the
older age groups. So I think it\'s a mixed bag.

DR. CHESNEY: Dr. Wilfond, I don\'t think you were finished. Then we have
Drs. Ebert, Fink, and Fost.

DR. WILFOND: Well, actually your answer is helpful as I begin my second
question. First, I have a comment. I could imagine a situation where we
were talking about the use of systemic steroids for a period of 6 or 8
weeks where we were highly confident that it would cause adrenal
suppression, but depending upon why we\'re using it, we might still
think that a study was worthwhile in children because we were interested
in assessing the efficacy as well as the safety.

Which brings me to the main point I want to get to in favor of possibly
concurrent testing, which is it appears that the greatest risks of
adrenal suppression is when it\'s undiagnosed, undocumented, and
something happens. Therefore, I think the risks of this are probably
much higher in the clinical setting than in a research setting if there
was an important scientific question to be asked because those risks
could be minimized. So it seems to me that what I would want to know
about whether we do concurrent is whether there was a belief that there
was an important scientific question to be asked by enrolling children
in that study. If it was, I think it might make sense to do that.

DR. CHESNEY: Dr. Ebert?

DR. EBERT: Regarding that, I think I favor the concurrent testing mainly
because I haven\'t really heard a lot of compelling information that the
younger children who did see suppression really had any adverse events
if they were followed up over a longer period of time.

The other thing I\'d just be interested hearing some comments from the
endocrinologists is whether we should place a little bit greater
emphasis on those who did show suppression and who showed sustained
suppression as opposed to just a one-time suppression and then they
regained their adrenal reactivity. The numbers that you talked about
were so small because of differences of opinion in who was really
suppressed versus who wasn\'t, I think that\'s a fairly fertile area for
continued study.

DR. CHESNEY: Dr. Fink and then Dr. Fost.

DR. FINK: I guess I\'m relatively neutral about concurrent or sequential
testing. But I guess what I would ask the agency, I believe you have
four options. You cannot approve the drug. You can label it as having no
indication below a given age. You can label it as not recommended, or
you can label it as contraindicated. It would appear, if we\'re going to
use HPA axis suppression, then you may want to establish percentages for
each of those. I have no idea what those percentages should be, but I do
think it is different to label a drug as no indication, not recommended,
or contraindicated, and if you can establish those break points, it
would seem to be the appropriate approach.

DR. CHESNEY: Dr. Fost.

DR. FOST: I have two comments.

I\'m not following the rationale for concurrent testing. That is, if
adults suppress, the assumption is that children will suppress also. It
seems to me a reasonable assumption. Therefore, we can spare a lot of
children from having suppression studies because many of these new
products are going to suppress in adults, and if they do, there\'s no
need to test children. If they don\'t, then you need to go, but why not
reduce the number of children? So I\'m not following what the virtue of
concurrent testing is, what it adds.

Second, to go to the second half of your question of what percent of
suppression would be worrisome, 1 percent, 5 percent, 50 percent, that
seems to me inextricably connected with the question we asked this
morning of how severe is the outcome. If the outcome was death, if 1 in
1,000 children died or 1 in 100 from topical corticosteroids, then it
would be extremely important to know about it, but if there are no
deaths and if there\'s no really serious adverse events, then you\'d use
a much higher cutoff, a much higher threshold because it\'s a less
worrisome problem.

I realize we don\'t know the answer to that, but I guess, if anything,
it just highlights the importance of trying to get some handle on it,
recognizing it\'s difficult to study. But you\'re being asked to make
this decision in a vacuum without knowing whether you\'re dealing with a
very severe adverse event or relatively trivial or nonexistent. I just
don\'t know.

DR. SANTANA: Can I comment on that?

DR. CHESNEY: Dr. Santana.

DR. SANTANA: Since I was a proponent for concurrent testing, my answer
would be that maybe the assumption is incorrect. Maybe the assumption
that what you\'re seeing in adults readily translates to the
particularly younger age groups is incorrect. And I got a sense from
some of the data that was presented this morning, albeit the numbers are
very small and we take them with a grain of salt, is that there may be
differences. Some of the younger children were not being suppressed, and
I didn\'t quite understand whether that was a numbers phenomenon or a
testing phenomenon. But the assumption that they\'re the same I\'m not
convinced of. Therefore, that would be an argument to suggest that they
should be concurrently tested.

The second argument is what was being discussed on the other side of the
table, that is, that I think maturationally they\'re different and so
the outcome of the bad results of the test potentially could predict
what that bad adverse event would be, whether it be that the younger
children, because they\'re suppressed, will be at greater risk of
developing worsening problems. I don\'t know that either, but the
suggestion that there are maturational effects in the gland would
suggest that there may be some differences that we need to explore. So
for those two reasons, I would advocate that we do need to do concurrent
testing.

DR. FOST: But the hypothesis would have to be then that there would be a
situation in which there\'s a topical steroid that causes significant
suppression in adults but doesn\'t cause any suppression in children and
would therefore be labeled, be really careful in adults, but use it at
will in infants and children.

DR. SANTANA: No.

DR. FOST: We\'re hypothesizing, one, that there would be a product that
would cause no worrisome suppression in children, even though it does in
adults.

DR. SANTANA: The argument is there is no good data and the absence of
data is just as bad as bad data.

DR. FOST: Right, but the only reason to test the children in the
presence of suppression in adults is because of the possibility that you
may get a different outcome, and the only different outcome there could
be is no suppression. So the reason for testing in children is to avoid
a situation in which we\'d have a product ‑‑ the scenario that you\'re
worried about is that we would have a product that should be used in
children but should not be used in adults or should be used with great
caution in adults but it can be used without any caution in children.
That seems to be implausible.

DR. CHESNEY: Dr. Gorman, then Dr. Stratakis, and then Dr. Fink.

DR. GORMAN: I think as a pediatrician, we often focus on the drugs that
children have more trouble with than adults, but there\'s another group
of drugs that children have much less trouble with or are handled very
differently. I think of acetaminophen. If I give somebody who\'s over 18
a fairly large dose, I can be pretty confident that I\'m going to cause
them liver failure. And yet when you look at children under 6 who have
taken huge doses acutely, there doesn\'t seem to be much toxicity at
all. Gentamicin, which we use in adults, we have to use 4 to 17 times as
much in children, depending on their age. I think there is an argument
that children may handle this differently, and I\'d echo Dr. Santana\'s
argument that what we don\'t know we don\'t know, and I would test to
find that out.

Does it put some children at risk? Yes, it does. But it puts a few
children at risk, to echo Dr. Wilfond\'s argument, rather than putting
many children at risk after it gets out. If you put a topical steroid on
the market, it will be used in children. It just will be. Somebody will
use it because whatever else they\'ve tried hasn\'t worked or some
parent will use it. So I think we should know what the risk is. Whether
it gets tested concurrently or in a dose-ranging study or sequentially I
don\'t think is the issue. I think the issue is it does need to be
studied because if you would have told me before today\'s meeting that
lotions get better absorbed than ointments, I would have told you I was
skeptical. But now I have data that shows me that my prejudice was
incorrect.

DR. CHESNEY: Dr. Stratakis.

DR. STRATAKIS: The implication of what we said earlier, that there\'s a
developmental difference in adrenocortical responses is not that we
would allow something that would be dangerous for adults to be given to
a child, although that might happen in some medications. But as I said
earlier, I would have other concerns about what the effects of this
would be on the adrenal cortex, in other words, that in this particular
group of patients, like the infants, for example, the ACTH test may not
be the best way of assessing what the damage is, if there is damage.
That\'s why I said from the very beginning that there\'s a need for
other markers to look at in certain groups. I think we will only find
that out by doing concurrent testing and seeing what\'s going on in the
various groups.

DR. CHESNEY: Dr. Fink.

DR. FINK: I think in terms of answering Dr. Fost\'s question, to some
degree it also relates to the package labeling, that if 20 percent of
adults showed suppression and you said that was acceptable but it was 50
percent of children and 90 percent of infants, you then might want a
package label that says this drug is absolutely contraindicated in
infants. And that\'s important information to me as a practicing
physician because contraindicated is different than not recommended, and
I think establishing a threshold there could be important.

DR. MURPHY: Joan, let me see if I can summarize what\'s been said. It
sounds like the committee wants children to be studied, that we don\'t
know what we don\'t know, and that the more data we get, the more
confused we\'re getting here. I\'m going to try to construct what ‑‑
I\'m trying to take it out of what\'s been said. There might still be a
reason to do some of it sequentially, maybe the much older down to 2 or
whatever, and then if you saw a very high rate or a high rate, whatever
one wishes to define ‑‑ if you don\'t do it sequentially and you go into
a study and you\'re enrolling hundreds, you may not get the kind of
follow-up and testing. While if you knew you had an issue in this older
age group, you are going to take the assertion, I think, that it\'s
going to occur, until proven otherwise, in the lower age group.
Therefore, you might actually want to modify that study so you have more
intense follow-up, more intense sampling, other testing that you might
want to do in the lower age group.

Does that tend to synthesize the majority of what I\'ve been hearing
around the table, or not?

DR. SANTANA: I would argue that if that\'s your study design, it\'s
going to be flawed because your different populations are going to be
observed differently and with different intent. So if you don\'t define
up front how all populations, independent of age are evaluated or
monitored or followed and have the same testing, then you will wind up,
for example, detecting that it\'s 50 percent in the older age groups, 90
percent in the younger age group, but you detected 90 percent in the
younger age group because your testing was much different. It was more
intense. It was quantitatively and qualitatively different.

So I think you\'ve got to be careful with that. If you start saying
we\'re going to do the study this way ‑‑ and then we always do that in
clinical research. We start a study one way and we modify it as we learn
as we go through. That\'s the beauty of it. But I think you have to be
careful because if you start saying that if you make an observation in
the older age group and now you\'re going to treat the younger age group
differently in terms of the observations that you do, you may be
detecting different things. And I\'m not sure that would be helpful.

DR. MURPHY: I\'m not saying you change the criteria for the diagnosis of
adrenal axis suppression. I\'m not saying that. I\'m saying you use the
same criteria. And you can do this prospectively so that if you reach a
certain point, you then have additional data that you would collect, and
particularly I think you would want to ‑‑ actually you would have liked
to have had it for all, but you may enhance the follow-up for testing to
make sure that the patients revert back.

DR. CHESNEY: Dianne, can I ask you, what other drug populations is this
kind of sequential testing used in? For example, we would never use it
for otitis media. We would never use it for meningitis. We would never
use it for a whole lot of other drugs. We would almost first test them
in children. So why is this different? Why was it even initially
designed differently to be sequential from old to young? And what other
drugs ‑‑

DR. MURPHY: Well, just two comments. One, the diseases you named are
mostly pediatric diseases, so you study them in children. So you
designed them mostly based on the pediatric population.

I think the issue here is that it\'s a safety design issue. We do know
‑‑ and I\'m trying to think off the top of my head what other products
this would be, but we do know that we have products in which a couple of
things happen. Actually it\'s happened so much that we were in the
situation we\'re in now with products not getting studied at all in
kids. You have a safety signal and the division may have decided not to
study the product at all, not just not sequentially but not at all,
which we know the problems with that. You don\'t even need to raise your
hand. We know. It\'s out there. It\'s going to be used in kids. Okay?

Or there is a safety issue. And this is actually something we do have to
do at times where because the population that got studied was not as
robust ‑‑ it\'s a serious, life-threatening disease or limited options
‑‑ you need to get the product out there. There may be other parameters
you heard for follow-up or additional studies ‑‑ you are not going to go
into that pediatric population until you have additional data that you
can then design a better trial for children because you had such limited
information when you began. So it tends to be more on the safety side
that this tends to happen.

I don\'t know if anybody from FDA wants to enhance.

DR. CHESNEY: I could argue that atopic eczema was a pediatric disease
too. In this setting, it seems to be a separate issue.

But what are other examples of drugs that are used where you go down
sequentially from the older groups?

DR. MURPHY: I was trying to think of them.

DR. SANTANA: Wasn\'t that done in some of the HIV trials?

DR. MURPHY: I was going to say HIV. That was the area that really
actually changed a lot of pediatric testing because that\'s what they
were doing. Products weren\'t getting studied in kids.

DR. FINK: It\'s true for 98 percent of all asthma drugs. They are always
studied in the adult population above 18 before they move into pediatric
trials.

DR. SANTANA: We were talking about the designation of the different
pediatric age groups and moving from the older to the next younger age
group.

DR. FINK: Right, and that\'s what happened to the asthma ‑‑

DR. SANTANA: HIV was the model that kind of presented this.

DR. MURPHY: But I do want to make an amendment to the HIV statement.
Once we started studying products for HIV in the pediatric population,
actually the pediatric population became the predominant database in
some applications. So it just has happened. And there are certain
products where they may study them first in adults before they decide
whether they want ‑‑ because, remember, sometimes these are completely
new molecular entities, and people really don\'t know that much about
them. Particularly when you get into the very young kids, back to some
of the older reasons, they can\'t articulate some of the things that you
wish to assess. So they want to have a better understanding, if they can
obtain that, before they move into the younger population.

DR. CHESNEY: Dr. Gorman.

DR. GORMAN: I just want to amplify Dr. Chesney\'s comment, which is
these are pediatric diseases. Well, excuse me. Some of them are. Atopic
dermatitis and eczema are pediatric diseases, and it\'s only because you
survived long enough to get into adulthood that they then become adult
diseases. But they start in our age population, and I think they should
be studied in our age population. Psoriasis I will give to the adult
dermatologists. But these diseases are our diseases.

I would think that pharmaceutical companies might consider wanting to
try their agents on the uninitiated patient, in other words, so the
signal to noise ratio for both the therapeutic effect, as well as the
potential risks of therapy, would be the cleanest as opposed to people
who have been previously pretreated with other therapeutic options.

DR. CHESNEY: Dr. Schneider and then Dr. Fink.

DR. SCHNEIDER: Well, clearly the drugs will have to be studied in the
population that they\'re intended for. So they\'ll have to be studied in
pediatrics.

The question is whether to do sequential testing or not. Part of the
answer, as I see it, is what is the risk to any patient during this
test. This is a very circumscribed period. It\'s 2 weeks, 3 weeks, 4
weeks. Presumably they\'re being monitored. And even if there is HPA
axis suppression, hopefully they\'ll be monitored until their not
suppressed, or they\'ll be followed appropriately. So if there is zero
risk to these kids ‑‑ if ‑‑ then concurrent testing is probably okay. I
mean, you\'re going to have to do it anyway, so it would be okay.

But let\'s say there isn\'t zero risk. From the data I heard this
morning, there are always one or two people who remain suppressed and
they\'re either lost to follow-up or Lord knows what happened to them,
and we don\'t know. Furthermore, very little kids are very much more
vulnerable to the effects of a subtle problem. I feel lousy. I\'m sort
of dragging my feet and so on and so forth. And they can\'t really
complain the way older kids can. So they are more vulnerable.

So now you have an ethical problem because you have a disease for which
there are already 11 different fluorinated steroids, and the efficacy
seems to be the same. And along comes a 12th fluorinated steroid, and
unless it\'s in ‑‑ I don\'t know ‑‑ peanut oil or something where there
may be some claim that it\'s less systemically available, it\'s the
umpteenth drug. So now you have a child with an illness which is serious
but not life-threatening for which there are other drugs that will be
presumably equally efficacious that are already on the market who is now
going to participate in a clinical trial of a new molecular entity. Will
there be an ethical problem there? In my opinion there is if there is an
ongoing risk.

DR. CHESNEY: Dr. Fink, then Dr. Fost.

DR. FINK: It would appear to me that the critical question here is can
you rely on atopic dermatitis in adults as having the same underlying
pathophysiology as it does in children and younger, in infants, because
if the pathophysiology is similar enough to be predictive, then I would
maintain that the Helsinki Agreement would mandate sequential testing.
If the pathophysiology of the disease is different, then you could
justify concurrent testing, but if the pathophysiology, as it is in
asthma, is deemed to be the same, it would be considered unethical to do
pediatric trials before you\'ve completed the adult trials.

DR. CHESNEY: Dr. Fost.

DR. FOST: If the subtle clinical effects that Dr. Schneider refers to
were being studied as part of the evaluation process, then that would be
a strong argument for concurrent testing, but since the only thing
that\'s going to be monitored is the simple laboratory value, I mean,
you\'re right. It may be that these laboratory values have other effects
besides death or serious adverse events, but since no one is studying
them, I don\'t know what it is.

I am persuaded by Dr. Fink\'s suggestion, though, that the incidence of
suppression might be much higher as you go down and might lead to a
difference between warning, education versus prohibition, if you had a
markedly different incidence of suppression.

DR. CHESNEY: Dr. Wilkin.

DR. WILKIN: If I could just comment on some inferences that we have been
willing to make. First of all, corticosteroids are somewhat unique in
the indication. Most indications are for signs, symptoms, specific
syndromes, diseases. It has a self-referential indication.
Corticosteroids are indicated for corticosteroid-responsive dermatoses.
I mean, this is paleo-regulatory. I don\'t know how ancient this really
is.

(Laughter.)

DR. WILKIN: But I think it gets back to the question we heard. Can we
assume that atopic dermatitis in adults is the same as it is in
children? I\'m not sure we actually have to decide that to take efficacy
data from adults which could tells us about corticosteroid
responsiveness, if you will, and then also combine that with data from
children.

What we\'ve been willing to do with the corticosteroids in atopic
dermatitis is efficacy can be demonstrated in adults and we\'re willing
to extrapolate efficacy downward. But in general, we have wanted to
extrapolate safety, if we\'re going to do that, upwards. So if it\'s
very safe in the youngest children with large body surface area
involvement, then we have been more willing to extrapolate to adults.

I mention this because there are limited resources, and it does affect
ultimately the price of drugs. I think if you think about how the word
\"elegance\" is used in organic chemistry, the organic chemists talk
about an elegant synthesis as one where you have the fewest number of
starting sorts of things, the fewest number of steps, and you get the
highest yield. Mathematicians use the term \"elegance.\" They talk about
an elegant proof, which is the fewest logical steps that really make the
case.

I think we could argue for regulatory elegance. I mean, it\'s not a way
to minimize burden for industry per se. It\'s really trying to find the
data set that is both necessary and sufficient. And that\'s what the
spirit of our question is. What is really necessary and what is
sufficient for us to label these products?

DR. CHESNEY: Dr. Wilfond.

DR. WILFOND: Yes. I appreciate your comment. One of my thoughts about
that is it would certainly never be enough just to include children
because you won\'t learn anything unless the data is then reported for
that particular subgroup. Certainly I\'ve seen in many asthma studies
where they will include people from ages of 15 and above or 12 and above
and not report a particular pediatric subgroup. So even though children
have been included, the readers of the journals never actually learn
anything special about the children. So I think one of the things that
will be critical, if children were included, is that we would have the
data reported back for that population specifically.

DR. COOK: We do usually ask for subgroup analysis for a specific age
group.

DR. WILFOND: Great.

DR. CHESNEY: Dr. Epps.

DR. EPPS: Though I do favor more sequential testing, if you were to get
a certain percentage of adults that had a side effect, it would be hard
to convince my IRB that it should be tested in children. So that\'s a
consideration too as far as testing is concerned.

I would also have a hard time recruiting if I said, well, we\'ve tested
this in adults and we\'ve had a lot of complications, but we want to
test your child. So that needs to be taken into consideration.

DR. CHESNEY: Dr. Glode.

DR. GLODE: Just a comment from the world of vaccines and related to the
necessary and sufficient issue. In general, for vaccine development, it
did proceed sequentially. I guess one could have argued the ethics of
giving an H. flu B vaccine to adults who had very minimal risk of
disease from that organism because of their natural immunity. But it was
a safety issue because it was vaccines that were going to be used
universally and recommended for millions of children every year.

So, I mean, necessary and sufficient. 57 children less than 2 cannot be
used in the same sentence with necessary or sufficient for a product
that might be used in ‑‑ I have no idea. Somebody has to tell me how
many millions of prescriptions are marketed every year for these drugs.
But if the prevalence of the disease is as represented this morning,
then that\'s a lot of people using it. So I sure wouldn\'t have thought
57 2-year-olds was anywhere near enough to be talking about using that
drug in that population. I favor sequential.

DR. CHESNEY: Maybe a way to summarize this, it sounds like nobody is
against sequential, and I think many of us feel strongly that it should
be tested in children unless there\'s a very, very real reason when you
get to some point not to continue.

But I\'m also very persuaded by Dr. Fink\'s comment and Dr. Gorman\'s
that unless some study is done in children and it can be explicitly
stated that this is contraindicated, it will be used uniformly, and then
we\'re right back as if we had done nothing. So I think most of us would
say sequential was okay, but at some point we want to be sure that it\'s
looked at in children so that some statement about whether it\'s
contraindicated or not could be made.

I don\'t know if I\'m expressing that well. If somebody else would like
to summarize it better.

DR. FOST: If you think they all should be tested in children regardless,
then what\'s the point of sequential?

DR. CHESNEY: Well, no. Dr. Murphy I thought made a good argument that if
you have danger signs in the adults or the older children, you might
test it differently in the younger children, not that the test would be
different, but that your consent might be different. I think that\'s
what I heard you say.

DR. MURPHY: Or you could prospectively design a trial so that at a
certain critical definition that you would have a different type of
follow-up, you would do more intensive type of follow-up and maybe for
testing to make sure that they revert. That was, again, focusing more on
the safety part of it because that\'s really what we\'re trying to get
at here since the division is willing to extrapolate the efficacy.

DR. CHESNEY: Dr. Glode and Dr. Danford.

DR. GLODE: I need an ethicist here to comment on whether we have a moral
obligation. The example that comes to my mind is the fluoroquinolones at
least initially contraindicated in children, not based on giving it to
children a subset and proving it is extremely harmful. Right? I mean,
based on animal data. And then people said, but they\'re such good
drugs. Can\'t we study them very carefully, et cetera? So that happened.

But I would have a problem saying now let\'s find a subset of children
because we think this is dangerous in children, but we want to establish
it so we can get the contraindication instead of the \"has not been
studied.\" Isn\'t that an ethical problem or not?

DR. CHESNEY: Well, we\'ll find out from the ethicist, but for me ‑‑ what
do I know about ethics? But for me, the test itself is not dangerous. In
other words, the 2 to 4 weeks of testing. I don\'t see that as being
dangerous. I see the continued used, when we don\'t know what the bottom
line is, and the use totally untested is much more dangerous to me than
exposing a small number under very controlled circumstances with
everybody well informed and so on.

DR. TEN HAVE: Excuse me. Are we going to be able to answer that question
with the types of studies that were currently done, the short, follow-up
studies to look at long-term use to answer your question? Is that
question going to be answered?

DR. CHESNEY: With what I just proposed or with what\'s going on
currently?

DR. TEN HAVE: What\'s being done currently with the types of clinical
trials that are currently being done in adults.

DR. FOST: You\'re asking whether there may be long-term toxicities that
we\'ll never know about.

DR. TEN HAVE: Yes, and the question you asked. I think everybody is
concerned about long-term use and less concerned about the short-term
use that the current studies are addressing.

DR. CHESNEY: What I was addressing was simply the short-term, 2- to
4-week. If that shows 90 percent of children ages 2 to 4 years are
suppressed, then I am anxious about recommending that for use whether
it\'s just acute or whether it\'s a chronic issue. Does that answer?

The ethicist, please.

DR. FOST: Well, I think your point you said well, Joan, that it would be
problematic to do that if what you were asking the parents to expose
their children to was something that was life-threatening or could cause
serious disability or severe pain or something. But what we\'re talking
about is 2 weeks of something with a few blood samples. I don\'t think
we\'re asking parents to volunteer their kids for something that\'s so
onerous. It almost meets minimal risk criteria. It would be problematic
if that were not the case.

DR. CHESNEY: Dr. Wilkin.

DR. WILKIN: I heard the word \"contraindication\" used on several
occasions, and 201.57(c) of the Code of Federal Regulations actually
describes what goes in different sections of labeling. Things that might
be a potential risk and perhaps from animal data, that would be more of
a precaution. A contraindication is something that would be expected for
most people. It\'s been seen in humans. In general, our labeling does
conform to those kinds of standards. I do understand you can find
labeling for specific products that may not completely be consistent
with that, but at least that\'s the way we\'re supposed to go with it.

Having said that, what we\'ve usually done with the adrenal suppression
data set is trim the indication. In the indication section, we have said
indicated for ages, and then whatever age at which we didn\'t see much
suppression, that age and above. So that\'s generally how we\'ve
operated with this. Then in the precautions section and the pediatric
use section, that\'s where we\'ve laid out the data for the children and
the adults or whichever age groups.

DR. CHESNEY: Dr. Schneider.

DR. SCHNEIDER: I will just make a comment that whether one does
sequential testing or concurrent testing, in my opinion with the data
that I saw this morning, these controlled studies need to have tighter
control. There were patients who were lost to follow-up. There were
people with adrenal suppression and we don\'t know the answer to what
happened to them. So I don\'t think this is as simple an issue as
you\'re going to study 15 kids or 50 kids or whatever for 2 weeks and at
the end of 2 weeks, we\'ll know what happened to all 50 of them. At the
end of 6 weeks, we\'ll know what happened to all 50 of them. In the real
world, this obviously isn\'t happening.

Although ultimately the drug should be studied in this population, I\'m
concerned that ethically I think it\'s mandatory to get the information
on adults and in older children first before going on to these studies
and also fixing the protocol if you can.

DR. CHESNEY: Dr. Murphy, have we answered question 2?

DR. MURPHY: As best as I think we can.

(Laughter.)

DR. CHESNEY: Thank you.

DR. MURPHY: Now, before we go to the third question, I want to just
reiterate a little bit what has been said throughout the day. What we
are asking you here ‑‑ we\'re going to go through a couple of facts,
restate the facts and a premise, and then ask you to help us with the
risk management program ‑‑ is in essence, in the state of knowledge that
presently exists in which we have a known laboratory test which we know
has potential severe adverse outcomes if one has adrenal axis
suppression and one has a stress and one doesn\'t get treated and one
has maintained that suppression ‑‑ we have those facts, but we also have
the fact that we don\'t know how this is playing out clinically, and I
think we tried to make that clear. From our adverse event reporting,
we\'ve seen a couple of cases where there\'s been clear results of
overuse and misuse and suppression. But we really don\'t have, for the
millions of prescriptions that are out there and have been issued and
are being used, a clear idea of what the clinical outcome is of the use
of these products with this ongoing suppression because we do know that
the products are not always used as directed and we do know that most of
the kids, though we didn\'t have the long-term follow-up that we\'d
like, appeared to revert to normal responses, as far as their adrenal is
concerned. So we\'re in this state of knowledge which is we really
don\'t know the clinical state of how many children are having bad
outcomes because of the suppression.

In that state that we are in, we\'re asking you, should we do anything
else? The options are do nothing. Wait until we get additional studies,
information, data. We have a better handle on it. Or implement some sort
of program. So that\'s really what this third question is about.

Let\'s go through the facts. The facts are that there are only a few
post-marketing cases of adrenal suppression in patients using topical
corticosteroids. That\'s what you heard this morning. The AERS reporting
system and what we\'ve been able to glean from other literature.

Fact two. Data from clinical studies has consistently demonstrated that
a percentage of pediatric patients using topical corticosteroids under
the maximal labeled use conditions will experience adrenal suppression.
This suppression is most likely transient in nature ‑‑ and you
understand the limitations of this statement ‑‑ and related to extent of
exposure.

Fact three. Patients with a post-ACTH stimulation cortisol level of less
than 18 micrograms per deciliter by cosyntropin stimulation testing
require corticosteroid replacement at stress doses if they experience
trauma, sepsis, or are challenged with any other cause of physiologic
stress.

The premise is it may not be recognized that the clinical course of
patients who have undergone trauma, sepsis, or major surgery is
complicated by adrenal suppression for underlying topical corticosteroid
use and hence this adverse event may go unrecognized and under-reported.

Given the above information, does the subcommittee think this represents
a clinically significant or relevant concern for pediatric patients
exposed to topical corticosteroids? If yes, should any additional risk
management action be taken? Please discuss which risk management
approaches below you think would be appropriate and why if you answer
yes.

And we\'ve listed ‑‑ I\'m not going to read them all off. How many is
it? 10? Yes, 10 different actions that are part of a risk management
program. We unfortunately have them on two different slides. But it
begins with do nothing more but get additional studies and then to such
things as the FDA is very good at, putting in boxed warnings, limiting
it to certain age groups, which we\'ve done, recommendations against use
in certain age groups, which is slightly different, and then into these
areas of actual contraindicating, then into the things that are really
the risk management program issues. So it\'s do nothing, get more
studies, do what the FDA usually does in labeling, do something more to
our labeling, or include also additional risk management programs, as
you\'ve heard about this morning, if I could sort of lump them for you.

DR. CHESNEY: Dr. Santana.

DR. SANTANA: Dianne, can I ask you a question of clarification? Are
these 10 points a graded system that the agency uses kind of
generically, or are they just all out there?

DR. MURPHY: Well, we tried to do that. Like at the bottom, you\'ve got
education programs for providers. That would not be considered as more
intrusive than the medication guide. So it isn\'t completely in priority
of activity.

DR. CHESNEY: Dr. Epps, Dr. Ebert, and Dr. Glode.

DR. EPPS: As far as suppression is concerned, it may be under-reported
and unrecognized. So therefore that\'s where additional studies would
come into play. The agency will be happy to know that parents do read
inserts in packages and everything given out by the pharmacies, and they
will say, I\'m not comfortable with this medication. I\'m not
comfortable with this. So, therefore, before putting that there, I would
study it so that they don\'t become unnecessarily alarmed by the use of
topical steroids because in most cases it\'s well tolerated. It\'s used
sparingly. That\'s our mantra, sparing use of a topical steroid.

I think education programs for those in the ER and anesthesiologists and
people who are doing procedures is reasonable, although emphasizing that
we don\'t have exact numbers and we don\'t know exactly the extent and
certainly additional studies are ongoing.

But as far as boxed warnings and packaging and giving out with every
description, I probably wouldn\'t do that at this time.

DR. FOST: Because you\'re worried about alarming people?

DR. EPPS: Yes. We use topical steroids all the time every day, and
certainly ‑‑ knock wood ‑‑ I don\'t know that I\'ve had anybody with
suppression. Maybe they\'re out there or maybe that\'s part of the lack
of recognition, but I\'m certainly more comfortable with that as opposed
to oral steroids. I don\'t use that very often at all, under certain
circumstances. So if you\'re using just a small amount and they get
better and you have proper follow-up, a lot of those problems that we
were having described don\'t necessarily occur, and people with severe
atopic dermatitis ‑‑ there are always those outliers who need more
medication, who need stronger medication or have extensive body surface
area, but you follow them. You follow them very carefully and you wean
them down and you use the medication so they don\'t crash. Honestly,
they probably do have some suppression, but they don\'t necessarily
manifest the fever and feeling poorly and the hypotension or whatever.
But they need to be followed. You don\'t send them out with refills for
a year. Some of the side effects we\'ve been hearing about, someone used
it for 10 months in the diaper area. Was someone not following them? I
mean, I wouldn\'t give someone refills that they could fill, you know,
clobetasol 8 times in 2 months. That\'s not going to happen. Sometimes
that\'s insurance motivated too. If someone is calling you back for
refills, you say, well, if you\'ve already used up your refills, you
need to come in and we need to look at it and talk about it because
either it\'s not being used properly or it\'s not helping. So I think
there are some management issues. But I don\'t think we need necessarily
to alarm people or parents or physicians even about a problem that we
really can\'t quantify.

DR. CHESNEY: Dr. Ebert.

DR. EBERT: Just a question for clarification. Are these strategies
strategies that would be applied to the class of compounds or products
as a whole, or would we be identifying certain high risk products within
the group and targeting those specifically?

DR. WILKIN: I think it\'s unlikely that we would be thinking of these
with the hydrocortisone that\'s over the counter. It\'s really intended
for the upper end products where we see signals of suppression. That was
the intent.

DR. CHESNEY: Dr. Fost and then Dr. Wilfond. Oh, I\'m sorry. Dr. Glode is
first.

DR. GLODE: Thanks. Just under the category of additional studies, it\'s
really a question for the dermatologists here, the issue of clarifying
the population. I would like to see studies done ‑‑ but maybe this is
impossible especially with the sequential model ‑‑ in steroid-naive
patients or at least be very certain about when the last time it was
used and have some criteria that has not seen steroids for 2 months or 3
months or something prior to entry into the study.

But my question for the dermatologists is the chronic intermittent use
issue. So presuming you are referred the patients with the more
recalcitrant atopic dermatitis that you\'re treating, on average how
many times in a year might you use topical steroids on a given child
with significant atopic dermatitis? Three or four times or once? Is
there chronic intermittent use? Would it be frequent?

DR. RAIMER: There is chronic intermittent use. I think most of us try
not to use anything that\'s mid-strength or stronger longer than 2 to 3
weeks at a time, and then you\'d like to give them a rest period. But
often with very chronic severe disease, you do that multiple times
during the year. In other children you don\'t. You do it once or twice.
It depends on the severity of the disease and the chronicity of the
disease. But it\'s frequent that we give them multiple courses during
the year.

DR. GLODE: So I think that\'s an additional study, the chronic
intermittent population studied to see what their axis looks like.

DR. CHESNEY: Dr. Fost and then Dr. Wilfond.

DR. FOST: Well, a couple of things to summarize my view on this list.
Good ethics starts with good facts, and this is a classic in trying to
base policy on inadequate information, namely the clinical relevance of
this laboratory measurement. So any policy you come up with is going to
be suspect because it\'s just not data-based. I don\'t consider the
laboratory evidence sufficient. So the first point, additional studies,
to me is the most important thing. Get the NIH interested in this or
somebody who can do those studies.

Second, all the things on the list that have to do with education seems
to be desirable. I agree with Dr. Epps, we don\'t want to have bad
education or alarming education or misrepresented education. But all
these things about boxed labels and patient package inserts, physician
education, physician label stuff and so on all seems to me desirable,
namely to mainly put this red flag out there if used to excess, if used
for more than X number of weeks or without your doctor\'s advice. There
are potential life-threatening dangers. It seems to me all that would be
to the good to discourage inappropriate use of it.

Third, on the indication and contraindication use, it seems to me
desirable to do what you can to have these more potent classes used as a
last resort, that is, to have the indication say this is indicated when
milder topical steroids fail. Now, I heard there is some argument
against that, that the sooner you clear it up, the better, and there may
be a less good clinical outcome if you try to march up the ladder of
potency. I haven\'t heard quite enough about that to be sure. So if
there\'s a strong argument for starting with the bomb, then that would
undermine what I just said.

But if that\'s not clear ‑‑ I\'ve heard different comments from
different experts around the table about whether there\'s overuse of the
potent steroids, whether they\'re really being overly prescribed for
children who might do very well with less potent. So I\'m not sure what
the facts are there, but if the facts are that that\'s true, then it
seems to me the recommendation should be you don\'t use a nuclear weapon
when a fly swatter will do.

I think that sums up my comments.

DR. CHESNEY: Dr. Wilfond.

DR. WILFOND: I just want to reiterate two of the points that Norm just
made. But with regard to the additional studies, I think again it\'s not
just additional studies prior to approval, but really what Norm was
talking about earlier today, the idea of the Kaiser study of lots of
people to see what the clinical outcome is. I think that\'s the sort of
study that\'s needed. It\'s not typically what a particular sponsor
would do in a new drug application. So it really would require some
other way of getting that study done, but I think that\'s really
critical.

With regard to the issue of indication, I agree it does depend upon when
it\'s necessary, but I want to return to a point that I made before.
It\'s my understanding that part of the issue of considering something
an indication is that if it\'s an indication, then there\'s the
opportunity for direct to physician marketing of that indication by the
sponsor. I think that\'s where I would have to the greatest concern
about inappropriate use because I\'ve certainly seen in my own practice
of pulmonology pediatricians doing things in response to what\'s
available such as Obenix that makes no clinical sense, but all the
pediatricians are doing it because it\'s marketed. There there are no
issues of side effects, but I would worry about it if the drug we were
talking about was likely to have side effects.

DR. CHESNEY: Dr. Fink.

DR. FINK: I think I would agree with the agency and say yes to this. In
terms of education, there is part of me that says this justifies a boxed
warning about HPA axis suppression because I think anything less than a
boxed warning won\'t really get physician attention. I wouldn\'t go
beyond saying HPA axis suppression, but if you feel HPA axis suppression
is a major side effect, then the data that was presented here today
would pretty clearly, I think, justify a boxed warning about it.

But I think the devil is also in the details. I think there should be a
patient package insert, but a patient package insert that says, use the
least amount, use it for the least period of time, and be sure to inform
your physician that you\'re using this medication on your child or
yourself in a condition of stress or if an accident occurs, or if
they\'re very sick, is different than a patient package insert that
might say, it causes adrenal suppression. I\'m not sure a patient
package insert would even have to mention adrenal suppression. It could
just talk about proper use of the drug and making sure you inform your
physician that you\'re using this drug. Some of it is sort of
overlapping, and the real issue is how it\'s implemented.

DR. CHESNEY: Dr. Stratakis.

DR. STRATAKIS: I think it is very important that in the letter provided
to the healthcare providers that some sort of a disclaimer that we are,
in fact, doing additional studies to see what that value of 18
micrograms per deciliter in response to the Cortrosyn test means. That
is very important. I wanted to bring back something that Dr. Fink had
said earlier this morning, that we don\'t want to try to prevent a
problem by creating another problem, which is giving these patients
extraordinary amounts of glucocorticoids to treat a laboratory value. 18
micrograms per deciliter at this point is a laboratory value.

Then to extend this fear a little bit further, we don\'t really know
what stress doses of glucocorticoids are. If you look in the literature
and try to find out what is being used for stress doses for
glucocorticoids, that\'s quite arbitrary. I know this is outside the
scope of this presentation, but I\'m just emphasizing the need for that
disclaimer that, yes, there is a risk for suppression based on that 18
micrograms per deciliter value, but additional studies are ongoing to
define what exactly that means.

DR. CHESNEY: Dr. Epps.

DR. EPPS: Thank you.

Well, certainly I think education or knowledge can be very powerful.
I\'m not an intensivist, but the diagnosis you don\'t think about is the
one you miss. If you have a kid who\'s not getting better and somebody
is using potent steroids and doesn\'t think about it and they\'re
suppressed, maybe that\'s an issue.

Certainly in dermatology and pediatric dermatology, we have people we
work with such as the preacher who gives advice about medication and the
aunt who gives a medication and grandma and the health food store,
they\'ve got some kind of remedy for it. There are lots of things that
people put on skin to treat eczema and atopic dermatitis from other
people\'s recommendations. So usually ‑‑ certainly myself and some of my
colleagues ‑‑ we always do a thorough medication evaluation. What are
your home remedies? What do you get from the health food store? What do
you get from your doctor? What do you get from your friend? Because
usually people aren\'t using just what you give them. They\'re using
other things too.

DR. CHESNEY: Dr. Schneider.

DR. SCHNEIDER: It seems to me that we do have a lot of information. In
fact, I\'ve learned a lot today listening to all of these data and these
results. We do know that these drugs get systemically absorbed. We know
that they not only can suppress the HPA axis, but they can cause
Cushing\'s syndrome in a small number of patients and hypoglycemia and
so on and so forth. And we know that perhaps as many as 20, 30 percent
of people who take these drugs have evidence of a systemic effect
manifest biochemically, but still a systemic effect after just a few
weeks of therapy.

We also know a lot about the natural history of this. We know that, for
example, if this practice continues to 6 weeks and 8 weeks and 10 weeks,
there will be more systemic effects, and the patients will be more at
risk.

So the trick is to change the level of warning without really changing
practice that much. In other words, if a patient really needs the
medication, by all means give it to the patient, but the physician
should understand that this is not a 100 percent risk-free practice and
that this is not just some bizarre laboratory problem, but that
diligence is required.

Really oftentimes, at least in general medical practice and endocrine
practice with patients on systemic steroids where there\'s a recognized
risk, that diligence is enough. It doesn\'t mean that we\'re spraying
everybody with tons of steroids. Even if we treat them presumptively
during stress with a couple of hundred milligrams of hydrocortisone
given for a day or two, I don\'t know of any terrible adverse effect of
doing that, of being overly cautious.

In my opinion, the labels that I have seen that I read through do not
adequately warn about this. I don\'t think that they give a serious
enough impression about this problem. You read about 1 or 2 percent of
the material is absorbed through intact rat skin and maybe 1 percent
through intact human skin and so on and so forth. We have no idea how
much is absorbed across diseased human skin. There\'s this constantly
recurring phrase about prompt recovery, which I really can\'t buy, given
the data that we\'ve seen. So I think that the label needs some work.

In addition, some of the suggested laboratory tests in the label I think
are just outmoded and wouldn\'t be used. For example, using a 24-hour
urine cortisol to screen for this. That\'s not what the test was even
developed for, let alone this. You can have a normal 24-hour urine
cortisol and be really suppressed. So that really should be taken out of
the label.

The basal levels of cortisol one can argue about, and perhaps it\'s all
right if it\'s over 13 or 14 in the morning spontaneously and maybe not
all right if it\'s under 3 or something like that. But basically I think
that part of the label also needs to be addressed.

But I think that the major tone of the label is not serious enough in
addressing this problem in my opinion.

DR. CHESNEY: I was going to take the chair\'s prerogative and weigh in
myself unless Tom makes me ask others first.

I\'ve also learned a great deal today. I never take a topical therapy
history. It\'s so you got steroids. Now let\'s worry about why you\'re
so sick with RSV or why you happen to have meningitis. So what I\'ve
learned is to take a history of topical steroid use: how long have you
been using it, how long has your aunt been giving it to you to use even
though I didn\'t give it to you to use? It didn\'t occur to me until we
addressed this issue that I should be thinking stress steroids, which
doesn\'t mean I\'m going to give them probably ever without consulting
my endocrinologist, but I will consult the endocrinologist now and say
this child has been on them for 10 months and now has West Nile fever.
What about that? What do I do about that?

I think bringing it to the attention of parents that ‑‑ and I agree we
don\'t know. We don\'t know the significance of this. We do know that
inappropriate use has led to some complications, but making it apparent
to them.

But then the last point is that whatever we do with the label in the
box, that\'s not where it\'s at. Most of us never read those. The
patients never read those, or not very often and don\'t know how to
interpret because they\'re rats and dogs and birds and stuff. And I\'m
not putting anything down. It\'s just that I think that some of the
other alternatives that were presented to us today by Dr. Trontell
should be pursued. It has to be something that is brought immediately or
soon to everybody\'s attention, including the parents. And I don\'t
think it has to be alarmist. I think it just has to say we\'ve gained
new information because we now study drugs in children, and this is just
something to be aware of.

So I think Dr. Fink was next.

DR. FINK: In terms of additional studies, one that might help lend some
clarity to this would be to actually look at an ICU study of drawing
serum cortisol levels on admission and looking at history of prior
topical steroid use with the premise that if someone is in this ICU, has
already gotten there and is obviously pretty stressed, if they have low
levels of serum cortisol, they probably need to be treated with stressed
doses. But how often that occurs would also come out of that data
because the one thing that bothers me a little bit is in the intensive
care unit, nearly every study of super-systemic steroid doses, whether
it\'s for treating sepsis or treating ARDS, has failed to show clinical
benefit, and I sure don\'t want to encourage intensivists to just start
using more steroids on random patients. But I think a well-designed
study to look at serum cortisol levels in the stress situation,
particularly in those patients who have a history of topical steroid
use, might be very illustrative.

DR. CHESNEY: Other comments? Would you also like ideas for studies, or
do you have more than enough of those?

DR. MURPHY: We always like ideas for studies. We got a couple good
suggestions here. I\'m still hearing a balanced opinion that giving
information out to the patients is not the way to go, that maybe we need
to first give information out to the healthcare providers. I\'m still
not clear on the message here as to whether we need to do ‑‑

DR. FOST: I thought the only disagreement was what information to give
to patients. It\'s not whether. I mean, not give overly alarming, not
mention cortisol levels. I mean, the practical stuff: don\'t use this
more than X number of weeks without your doctor\'s prescription.

DR. MURPHY: But a lot of that is already in the label. Right? So I think
what we\'re saying is what Dr. Schneider said, that some of this is
already in the label. So are you suggesting ‑‑

DR. FOST: I\'m talking about patient handouts.

DR. MURPHY: That\'s what I\'m trying to get at. There are different
mechanisms that we have to go through, as you heard.

DR. FOST: I think almost everyone agreed that a patient handout that
gives them practical information, number one, about misuse and, number
two, if your child is sick or ‑‑

DR. MURPHY: Because I didn\'t hear that. That\'s what I want to make
sure ‑‑

DR. FOST: We\'re all nodding our heads.

DR. MURPHY: ‑‑ that the committee wants a patient handout.

DR. FOST: Yes.

DR. MURPHY: Okay, because I thought you said the patients do read them
but then you didn\'t want to worry them. But now I\'m hearing we do want
to give it to them and we want to just make sure that it\'s not
alarming, it simply states some facts, and make sure they know to tell
people about their topical steroid use.

DR. CHESNEY: Just to bring it to your attention or this may not have
been ‑‑ I think the label in the box they just don\'t read. So unless
the provider explicitly states it ‑‑ and many of us as providers didn\'t
really think or weren\'t paying enough attention to this issue. So I
think the providers need to hear it separately from the label and the
patients need to hear it separately from the provider.

DR. MURPHY: And the other thing I want to make sure of is that what
you\'re saying is you are favoring a patient package insert, not a
medication guide. One is mandatory, the other isn\'t. Most of them now,
as Dr. Trontell said, tend to follow this very helpful question and
answer approach. Maybe we need more discussion on that whether it\'s to
be a PPI or a medication guide. Again, you heard what the usual use of
the medication guides is for. So just to clarify which way the committee
is suggesting.

DR. CHESNEY: I note Dr. Gorman wants to speak.

That has been the puzzle for me because the Lindane medication guide you
gave us is very clear, and I haven\'t seen some of that information
anywhere else. I mean, putting the cream under your nails. I never saw
that before. That\'s extremely good information. And I\'ve written
articles about scabies, which doesn\'t say much for my articles I guess.

(Laughter.)

DR. CHESNEY: It was very thorough. I thought that was really excellent.

On the other hand, is this alarmist if we do that? The other part of me
has said, well, maybe we should just put it in the box.

Dr. Gorman.

DR. GORMAN: I think the focus of what I would hope would be a patient
package piece of information and not the mandated, got to be given out,
is that just because it just goes on your skin doesn\'t mean it doesn\'t
have effects on the rest of your body because I think that would apply
for a lot of dermatological products besides just steroids. It would
then focus on the fact that this has systemic effects ‑‑ excuse me ‑‑
has potential systemic effects. You might make it as a class. You could
put it in creams and ointments and maybe not be so fearful.

Steroids in their various forms and formulations are probably the most
widely used drugs certainly that we use or certainly the most often
chronically used drugs between asthma and atopic dermatitis and certain
other viral infectious diseases where they help the symptoms if not the
disease process.

They\'re certainly the drug that pediatricians get sued successfully the
most on. If you\'re going to sue a pediatrician for malpractice,
they\'re going to lose on steroids rather than on any other drug.

So these are drugs that I think the community out there knows about.

I\'d like to amplify on Dr. Epps. There\'s a fair amount of steroid
phobia out there already. I would hate to see that magnified and then
prevent people from using what is generally an effective medicine, and
while its safety may be in some doubt, it\'s very effective for the
diseases we use it for.

DR. CHESNEY: Dr. Andrews.

DR. ANDREWS: Well, I think education is always a good thing, and
education of patients, parents, and physicians, including physicians who
will be treating patients and perhaps not asking about history of
topical steroid use. It\'s a good thing.

I worry a lot about making policy without data, and we don\'t have
clinical data to support this surrogate endpoint. So I worry about
precedent if we moved in the direction of a mandatory medication guide
when the other medication guides that are out there are for very
well-documented, serious risks.

I also think about what are some other hypothetical risks in other
patient populations and in pediatric populations that we\'re not warning
about, and would there be some unintended consequences and scaring of
people against very important medications to actions that may be more
harmful.

So I would go in the direction of some kind of patient education, not a
mandatory medication guide.

DR. CHESNEY: Dr. Fink.

DR. FINK: I think we have to be a little careful because it worries me a
little bit as a pulmonologist who deals with asthma. If an inhaled
corticosteroid at the clinically appropriate dose caused adrenal
suppression in 20 to 40 percent of patients with chronic use, it would
never get approved for marketing. I\'m not sure what the risk of HPA
axis suppression is, but in many other areas or arenas it is accepted as
a significant risk of something and 20 to 40 percent occurrence would be
considered unacceptable for a new drug.

DR. FOST: Doesn\'t that have to do with the chronicity of use as
compared with these patients?

DR. FINK: Well, it\'s used chronically but it would still be considered
unacceptable if you got that side effect.

DR. FOST: There\'s a difference between HPA suppression for a few weeks
several times out of the year as compared with an asthma patient who is
on it all the time.

DR. FINK: Yes, except many of these steroids do get used quite
chronically in the moderately severe to severe atopics.

DR. SCHNEIDER: Could I ask a question? It wouldn\'t be approved for use
given the fact that there are other agents that don\'t ‑‑ if you didn\'t
have the other, of course, it wouldn\'t be. But if you didn\'t have the
other agents, it might be approved for use, as would be systemic
steroids where you\'d have 100 percent suppression.

Also just a comment. I don\'t see this exactly as a surrogate basically.
This is part of the pathophysiology of a sequence of events that will
lead to X down the road. And it probably won\'t if the drug is used
appropriately. Even if it sort of, kind of does, if there\'s appropriate
consciousness-raising among the physicians and other healthcare
providers, then steps can be taken. But there must be a way to educate
the public, starting with the physicians, without stopping the
appropriate use of these drugs.

DR. CHESNEY: Dr. Fink and then Dr. Glode.

DR. FINK: I guess a question maybe for the endocrinologists. Coming
again from pediatric pulmonary, it\'s known that inhaled corticosteroids
at clinical doses that are acceptable and do not cause HPA axis
suppression over long periods of time do contribute to calcium loss and
some osteoporosis. They do contribute to cataracts. Is there any reason
to suspect that prolonged use, even if intermittent, of topical steroids
wouldn\'t be related to some of these same issues that we have studied
or investigated?

DR. SCHNEIDER: No. I think that basically a steroid is a steroid. It\'s
action is fairly well defined by its receptor affinity and which
receptor it occupies. I think that the dose response for bone effects
and growth and loss of calcium is shifted to the left actually,
surprisingly, of that of HPA axis. So I think there\'s no reason to
believe.

DR. FINK: Which would make then the finding of HPA axis suppression
indicative of other potential side effects with intermittent chronic
use.

DR. SCHNEIDER: Absolutely. It just indicates to me that the material is
getting absorbed and it\'s acting.

DR. FINK: Therefore, the risk is higher. To me that becomes then a
significant ‑‑

DR. SCHNEIDER: It\'s mitigated only by the fact that it\'s used ‑‑ or
the hope that it\'s used intermittently and appropriately.

DR. FINK: I think that is very different than how I think 99 percent of
physicians view topical steroids. If you said do they cause osteoporosis
with chronic use or risk of cataracts, people would say no.

DR. SCHNEIDER: Nobody has studied it. We just don\'t have the data. But
if it gets absorbed and if it works as it does ‑‑ one steroid is like
another steroid; one glucocorticoid is like another glucocorticoid.

DR. CHESNEY: Dr. Glode.

DR. GLODE: Again, following up on that issue then in the want of sort of
consistency from everybody\'s standpoint, for oral corticosteroids then
is there a boxed warning and is there a medication guide, et cetera, or
not? I mean, it would be sort of inconsistent to do it for a topical if
you didn\'t do it for oral. I just don\'t know.

DR. SCHNEIDER: I don\'t recall. The difference is with the appropriate
use of an oral corticosteroid, there is the expectation that it\'s going
to have predictable systemic effects. These drugs are developed and in
fact marketed ‑‑ by these drugs, I mean any locally active, the inhaled
ones or whatever ‑‑ on the basis of having a specific local effect, at
the same time minimizing systemic effects. The warning is needed not
because they\'re more dangerous but because people are just unaware of
these effects. I think the warning is needed.

DR. CHESNEY: Dr. Raimer.

DR. RAIMER: I was just going to point out that we\'re throwing around
these 30 to 40 percent figures, and that\'s for class II steroids, which
are not recommended for kids under 12 anyway. When we look back at
prednicarbate, basically none of the kids on that were suppressed, and
fluticasone was only 2 to 3 percent. So the ones that are actually
approved for use in children, it\'s very low. So we might want to look
at what we\'re labeling. We might want to label the stronger steroids
differently than we do the weaker steroids.

DR. CHESNEY: Dr. Wilkin.

DR. WILKIN: I think Dr. Schneider has made the point on several
occasions, and I\'d just like probably a highly reductive reiteration.
So one of the key messages to our group is that the topical delivery is
the part that isn\'t getting through to clinicians, anesthesiologists,
internists, folks in emergency rooms, perhaps even pediatricians and
dermatologists that topically applied products can have systemic
effects. That seems to be a theme that would go beyond corticosteroids
that we need to think about for some of our other products as well.

DR. CHESNEY: Dr. Murphy, are we finished with question 3, or another
step?

DR. MURPHY: I\'m probably going to be sorry I asked this, but I\'ll go
ahead because tomorrow you\'re going to be talking about long-term
studies. And it\'s been brought up a number of times today, additional
studies. As you will hear, long-term studies are extraordinarily
difficult. They get very confounded, et cetera. I would like to hear a
little more about how you think we\'re going to address this issue
clinically besides in the conduct of the drug development process, what
we\'ve already discussed. How are we going to delineate any potential
other longer-term outcomes in the population that is using this
recurrently multiple times over their lifetime? If anyone has any
thoughts on that. It\'s a very difficult area.

DR. CHESNEY: Dr. Andrews, then Dr. Fost.

DR. ANDREWS: Well, it seems like we need more information on steroids in
general since they\'re widely used in kids, and we don\'t have a good
handle on the dose-response issue going from topical to oral around a
number of endpoints, including cataract and bone effects.

One possible opportunity is to use the upcoming National Children\'s
Study which will be following 100,000 children from before birth to age
21. If there\'s sufficient use in 100,000 children, one could learn
quite a lot.

DR. CHESNEY: Dr. Fost.

DR. FOST: Yes, just repeating I think what Ben said earlier, that I
don\'t see pharmaceutical companies as being able to carry out these
studies as a condition of approval. It seems to me these are for NIH and
the Children\'s Study and other agencies or entities that do
epidemiologic research.

I think there are many possibilities, many different studies that could
be done that would not be all that difficult or expensive to pull off. I
mean, rather than the ICU model that Bob suggests, which strikes me as
troublesome because of all the confounding of ICU patients, if 20
percent of kids who are on these, just go to a large healthcare system
and look at elective surgery or look at just hernias, and look at
complication rates, post-op hospitalization rates. It seems to me
there\'s a simpler way of looking at risk of exposure to trauma and
stress in kids on steroids versus not.

DR. EPPS: I don\'t know whether there\'s an NHANES study going on right
now. I think there have been at least two. But if some dermatologic
questions were included regarding atopic dermatitis, that might be
really helpful.

DR. CHESNEY: Dr. Stratakis.

DR. STRATAKIS: In long-term studies, one should also look again at
what\'s happening to adrenocortical function as the child grows into
adulthood. So questions like, for example, what happens to adrenarche,
which occurs between the ages of 5 and 7, in these kids that are
repeated users of local steroids, what happens to them with puberty,
what happens to reproductive function. Are these kids that are exposed
to chronic local steroids or inhaled steroids or whatever at risk for
perhaps an increased risk of polycystic ovarian syndrome when they
become adolescents? I\'m just throwing out one question. I can\'t think
of a direct effect, but I can think of many indirect effects. So
long-term studies should look at all these variables, including the
mineralocorticoid effects that I mentioned earlier.

DR. CHESNEY: I wonder if it necessarily has to be that long-term. If you
have a child with moderate to severe eczema who is using four or five or
six different applications in the first year of life, it seems like you
could get a fair bit of information just from studying those children
over a 1-year period, and that might be within the bailiwick of the
sponsor.

DR. STRATAKIS: But this would be intermediate effects. This would be
between short-term and long-term. They would be referring to bone
mineral density perhaps, growth rate, and things like that.

I\'m also concerned about the very long-term effects.

DR. CHESNEY: No. I agree. I\'m just thinking of something that might be
a little more doable in the immediate future.

Dr. Fink and then Dr. Ten Have.

DR. FINK: Just a brief comment, again going back to the asthma model,
which I think is fairly appropriate. One of the difficulties of doing
long-term studies is people are going to bring up the fact that any
chronic inflammatory disease, including one of the skin, potentially
affects growth and bone mineralization. So if you have a patient who is
short, the question is are they shorter because of their eczema or
because of the steroids used to treat it. And that\'s not a trivial
question. It\'s been confounding in asthma where untreated asthma
clearly can affect growth, and I think there\'s no question untreated
eczema when it\'s moderately severe also can affect linear growth. So
you may be looking at the lesser of evils rather than measuring a direct
effect.

DR. TEN HAVE: Just regarding designs and gold standard designs, I think
there is a precedent in the asthma world in terms of post-marketing
randomized studies of safety of salmeterol. Glaxo SmithKline just
finished a big 70,000 ‑‑

DR. FINK: 26,000.

DR. TEN HAVE: ‑‑ 26,000 subject study. I believe the original sample
size was 70,000 and they couldn\'t finish it. But it ended up with sort
of a controversial result.

But there is a precedent there for randomizing patients to two
treatments to look at safety issues. Of course, it\'s a shorter-term
safety issue there, but in terms of Dr. Chesney\'s 1-year follow-up,
that is feasible from that point of view, but not necessarily longer
term, though.

DR. CHESNEY: Dr. Fink.

DR. FINK: I was just going to say the SMART trial that he\'s referring
to, which some people now are calling the stupid trial ‑‑

(Laughter.)

DR. FINK: ‑‑ was not actually a safety trial. It was a trial to try and
establish that a long-acting beta agent could be used as a primary
controller for the treatment of asthma, and it turned out that the
intervention group had excess deaths compared to placebo.

DR. TEN HAVE: I was actually on the DSMB. It was a safety trial. The
original hypothesis was whether or not adverse event rates were the same
in both groups. That was what the power was based on.

DR. MURPHY: Okay. It was very helpful. We did get some very clear
instructions as to where we need some additional information.

Anne, did you have any questions for the committee?

DR. TRONTELL: No.

DR. MURPHY: Thank you all very much.

DR. CHESNEY: Thank you, Dr. Murphy, and I guess this concludes the first
half of the issues that have to do with agents for eczema.

We will take a 15-minute break and reconvene at 3:25, and that\'s just
for the committee. Is that correct? Or everybody who is here?

MR. PEREZ: Everybody who is here.

DR. CHESNEY: Everybody who is here. If we could reconvene at 3:25
please.

(Recess.)

DR. CHESNEY: I think we should reconvene, if everybody could find their
seats please.

Because this is a separate part of today\'s meeting, the Executive
Secretary has to read the meeting statement. So we\'ll start with that
first.

MR. PEREZ: The following announcement addresses the issue of conflict of
interest with regard to this meeting and is made a part of the record to
preclude even the appearance of such at this meeting.

Based on the submitted agenda for the meeting and all financial
interests reported by the subcommittee 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. 208(b)(3), Dr. Robert Fink has been granted
a waiver for his membership on speaker bureaus for a sponsor and a
competitor on unrelated matters. He receives fees of less than \$5,001
per year from one firm and over \$10,001 from the other.

Dr. Benjamin Wilfond has been granted a waiver for his consulting for a
competitor on unrelated matters. His fees are less than \$10,001.

Dr. Joan Chesney has been granted a waiver for her ownership of stock in
a sponsor and competitor. The stock values are between \$50,001 to
\$100,000 and \$5,001 to \$25,000.

Dr. Elizabeth Andrews has been granted a waiver for her consulting for
two competitors as part of her employment on unrelated matters. Fees to
her employer are less than \$10,001.

A copy of these waiver statements may be obtained by submitting a
written request to the agency\'s Freedom of Information Office, room
12A-30 of the Parklawn Building.

In addition, Drs. Benjamin Wilfond, Victor Santana, and Sharon Raimer
have been granted waivers under 21 U.S.C. 355(n)(4), an amendment of
section 505 of the Food and Drug Administration Modernization Act, for
ownership of stock valued between \$5,001 and \$25,000. Because these
stock interests fall below the de minimis exemption allowed under 5
C.F.R. 2640.202(b)(2), waivers under 18 U.S.C. 208 are not required.

Further, we would like to disclose that Dr. Elizabeth Andrews has been
recused from participating in today\'s discussions concerning Serzone
and Busulfex.

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 noted for the record.

With respect to all other participants, we ask in the interest of
fairness that they address any current or previous financial involvement
with any firm whose product they may wish to comment upon.

Thank you.

DR. CHESNEY: Thank you, Tom.

Dr. Murphy has somebody she would like to introduce to the committee.

DR. MURPHY: Yes. Dr. Sara Goldkind, would you stand up please? It\'s
with great pleasure to introduce the Office of Pediatric Therapeutics
board certified internist who is our ethicist that we have brought on
board in the last month. She basically, as I said, is an internist who
has a clinical fellowship in ethics, has been providing consultation and
policy opinions in the last couple of years. I\'m not going to go
through all of her background. And she has a masters degree with a focus
on comparative religious ethics and religion and public policy.

Her job with the Office of Pediatric Therapeutics, as you know, is
mandated by the Best Pharmaceuticals for Children Act that that office
have an ethicist on board. She\'ll be working with us on our subpart D
activities, also on the consultations inter-center, and is our liaison
with NIH and a number of the other federal activities in the area deal
with ethical issues. So we\'re delighted to have her, and we want to
make sure you at least recognize the face and knew the name.

I have one other housekeeping activity. Sorry, Joan. I forgot to tell
you I need to do this. Before we move into the presentation by Dr. Iyasu
and the division on the product safety update on the products that have
been granted exclusivity, I needed to tell the committee that there is a
product that was to be ‑‑ its due date was for this meeting. Let\'s put
it that way. And to bring your attention to an FDA talk paper that was
released this week in case you did not see that. The talk paper is that
FDA issues public health advisory reports of suicidality in pediatric
patients being treated with antidepressant medications for major
depressive disorder. I wanted you to know that FDA ‑‑ I\'m going to read
from this just so you\'ll know why we\'re moving some of these products
to the next meeting that will occur in February.

FDA has completed a preliminary review of reports for eight
antidepressant drugs ‑‑ I\'m not going to list them all ‑‑ all studied
under the pediatric exclusivity provisions of FDAMA. We note to date
that the data do not clearly establish an association between the use of
these drugs and increased suicidal thoughts or actions by pediatric
patients. Nevertheless, it is not possible at this point to rule out an
increased risk of these adverse events for any of these drugs, including
Paxil, which was the subject of an FDA talk paper on June 19th, 2003.

Because of this issue, we are deferring review of any of the products in
this class until February, of which I hope many of you have already been
notified about the date of February 2nd, those of you on the Pediatric
Advisory Subcommittee. In order to promote a public discussion of the
data and pertinent regulatory actions, FDA has scheduled a meeting on
February 2nd, 2004 before the Psychopharmacologic Drugs Advisory
committee and the Pediatric Subcommittee of the Anti-Infective Drug
Advisory Committee. So that is information to you why we may not be
presenting products in this area that may have ‑‑ indicate that we
should be discussing them because we will be delaying that until
February.

That is all the housekeeping that I needed to do. Thank you very much.

DR. CHESNEY: Thank you, and we look forward to working with Dr.
Goldkind.

Next we will hear the report of adverse event monitoring for drugs
granted exclusivity under BPCA to be presented by Dr. Solomon Iyasu and
Dr. ShaAvhree Buckman. Drs. Iyasu and Buckman are both with the Division
of Pediatric Drug Development. Dr. Iyasu has provided us with a written
review of 1-year post pediatric exclusivity post-marketing adverse
events. Today they will highlight the findings described in that report.

DR. IYASU: Good afternoon. As you recall, BPCA mandates that FDA monitor
adverse event reports for a period of 1 year after exclusivity is
granted. Today we will report adverse events for six drugs that have
been given exclusivity. These six drugs are busulfan, losartan,
tamoxifen, nefazodone, cetirizine, and quinapril. I will report on the
first four drugs, and then Dr. ShaAvhree Buckman will present on the
last two drugs.

I think it may be helpful to review the sources that we used to monitor
adverse event reports. The data source for the adverse event reports is
the AERS database, which has been earlier described. It is comprised of
spontaneous and voluntary system post-marketing adverse event reports
that come to FDA either from consumers, from health professionals, and
also from manufacturers to a large extent.

As with all spontaneous reporting systems, it has several important
limitations that should be reviewed again. Under-reporting, as earlier
discussed, is a huge issue, and also reporting biases are inherent in
this system. As an example, duration of time a drug has been on the
market or publicity about a certain adverse event may influence the
reporting rates for certain adverse events with drugs. Often the quality
of the reports is variable, and perhaps the most important limitation is
the inability to calculate true exposure risk or make causal inferences
between an adverse event and an exposure to a drug.

I\'ll also try to review some of the data sources for the frequency of
medication use in pediatric patients. FDA uses various data sources.

The National Prescription Audit Plus measures prescriptions dispensed
from retail pharmacies and can also provide national estimates which are
projected from this database. Its chief limitation is that it does not
provide estimates by patient demographics, such as age and gender. So it
gives you just the total prescriptions dispensed.

The National Disease and Therapeutic Index is a continuing survey of
office-based physicians and measures mentions of medications during
patient visits to these office settings. While data are available by
patient demographics, the small sample size can make the national data
estimates very unstable. This is often problematic when use of a drug is
uncommon, as is often the case in the pediatric population.

AdvancePCS is a prescription claims database from a large pharmacy
benefit management company and covers about 50 million patients and
processes about 300 million prescriptions annually. An important
limitation is that the data cannot be projected to make national
estimates. However, we do see that data does come from all 50 states. It
has a reasonable approximation of the distribution or frequency of drug
use, although there\'s no methodology really to have a national
estimate.

The Premier database collects inpatient drug use from 400 acute,
short-stay, non-federal hospitals. While a projection methodology is
available from this database, it\'s only accurate selectively and needs
to be interpreted with caution for newly marketed drugs. Another
limitation is that there\'s no linkage between a drug and the diagnosis
for which a particular drug may have been used. It also does not collect
information on treatments administered in hospital outpatient clinics.

Let me now turn to the actual reports of adverse events for each of the
drugs. The first drug is busulfan which is an antitumor drug marketed by
ESP Pharma. It\'s approved as a conditioning regimen in combination with
cyclophosphamide prior to allogenic hematopoietic progenitor cell
transplantation in chronic myelogenous leukemia. In children, the
effectiveness of busulfan in the treatment of CML has not been
specifically studied. An open-label, uncontrolled study evaluated the
pharmacokinetics of busulfan in 24 patients as part of a conditioned
regimen administered prior to hematopoietic progenitor cell
transplantation for a variety of malignant hematologic and nonmalignant
disease. Based on the results of this study, a suggested dosing
guideline in pediatric patients is included in the label.

Now, turning to the frequency of use of this medication from the
databases that we looked at, there was no outpatient busulfan use that
was noted. However, inpatient pediatric use from the Premier database,
was estimated to be about 10 percent of all inpatient busulfan use in
2000 and about 4.9 percent in 2002. However, these data represent a very
small number of discharges.

During the 1-year post exclusivity period, there were a total of 103
adult and pediatric adverse event reports. After a manual review of all
these reports, there were 9 unduplicated or unique pediatric adverse
event reports that were identified. 3 of the 9 reports were pediatric
deaths. None of the events, including the pediatric deaths, could be
attributed to busulfan use. All reports involved also multiple drug use
and complex medical conditions. Therefore, the reported events could not
be attributed to busulfan use.

Just to summarize, in terms of the 3 deaths, there were clear causes
that are unrelated to the drug. One was an interstitial pneumonia, a
labeled event for another drug; an acute heart failure, a labeled event
for a co-suspect drug which is cyclophosphamide; and an acute cardiac
arrest due to aspiration. And we could not attribute any of this to
busulfan use.

If there are any questions on this drug, I would open it for discussion.
Otherwise, I\'ll move to the next drug.

DR. FOST: Dr. Iyasu, the slide that says it accounted for 10 percent of
inpatient pediatric use, you mean 10 percent of its use was inpatients?

DR. IYASU: No. Of all the mentions in inpatient settings, 10 percent was
in inpatients. So if you look at the numbers, it was based on very small
number of discharges because it\'s really based from the discharges.

DR. FOST: So of all the children who got busulfan, 10 percent of them
got it as an inpatient. Is that what that means?

DR. IYASU: No. Of all in patient use of that particular drug ‑‑

DR. FOST: 10 percent was in children.

DR. IYASU: ‑‑ 10 percent was in children.

DR. SANTANA: Kind of following up on that, the number of pediatric
transplants hasn\'t gone down. If anything, they\'ve gone up
arithmetically in any time period that you looked at. So I\'m having a
little bit of difficulty because it reflects under-reporting if one year
it was 10 percent and the other year represented half of that, whereas
the number of transplants have been going up. So there\'s a problem with
the numbers. That may be related to under-reporting, I grant you that.
But that raised a red flag because we\'re not doing less transplants,
we\'re doing more transplants. It could be that they\'re also going up
faster too. That may be true.

But that was going to be my next question is. Is there any database that
specifically looks at pediatric hospitals because part of the problem is
the data is derived from large sets of many different hospitals, of
which pediatrics is variable depending which hospital you choose.

DR. IYASU: Right. At present there is another database also which
collects information from about 29 children\'s hospitals, and these are
not probability samples of hospitals and we cannot really make national
projections. They are very limited and data from that source also
corroborates the finding in terms of very limited use. I don\'t have any
data on whether there\'s an increasing trend in transplant or not, so I
can\'t comment on that unless there\'s someone from the division who can
comment on this.

The next drug is losartan, which is an antihypertensive agent marketed
by Merck. It\'s approved for use in the treatment of hypertension with
left ventricular hypertrophy and also for the treatment of nephropathy
in patients with type II diabetes and a history of hypertension. There
are no specific approved pediatric indications.

The losartan label contains a boxed warning against use during pregnancy
because of its potential to cause injury and death to the developing
fetus. This is not restricted to this particular drug but to the class
of drugs which are the ACE inhibitors and the different sartans which
are in this class. Losartan has a pregnancy category C designation in
the first trimester and a designation of D in the second and third
trimester.

Again, looking at the use data according to the NPA, the total dispensed
prescriptions seem to be increasing. The prescriptions dispensed were
higher for Cozaar than for Hyzaar. Hyzaar, just to remind you, is a
combination of losartan and hydrochlorothiazide. The pediatric specialty
accounted for about 54,000 of the prescriptions in the year 2002. There
was a total of about 16 million prescriptions for this medication in the
same year, which means including adults and pediatric patients.

Pediatric use estimates during visits to office-based physicians
represented approximately 1 percent of all losartan mentions in these
settings. In pediatric patients, cardiomyopathy and essential
hypertension were the two diagnoses most often associated with losartan
use in the office settings.

Data from the AdvancePCS suggest that prescriptions for Cozaar increased
slightly while they remained stable for Hyzaar. However, the percent of
pediatric prescriptions were extremely small to really make any
conclusions about the trends.

Looking at the adverse events, AERS contained a total of 298 adverse
event reports during the 1 year post exclusivity period. A majority of
these reports were from foreign sources. A manual review of these
reports revealed 5 unduplicated and unique pediatric reports. 4 of the 5
were maternal exposures or in utero exposures. The remaining 1 report
was due to an accidental ingestion by a 2-year-old. 2 of the 5 patients
died. In one, the fetus was exposed in utero and an elective abortion
was performed because of exposure during pregnancy. In the second
pediatric death, an accidental ingestion and overdose of losartan was
involved and the patient died.

All of the adverse events were covered in the label and therefore are
expected based on the label. So there were no unlabeled events that were
unexpected events observed during the 1 year post exclusivity period.
But I must remind you, as I said earlier, that there\'s a boxed warning
against use during pregnancy and therefore there\'s an adequate warning.
Maybe it\'s not being heeded.

Are there any questions on this drug?

DR. GORMAN: Was the accidental ingestion that led to the death a single
moiety? Was that the only agent ingested?

DR. IYASU: As far as I know, that was the only agent that was ingested
and it was prescribed for an adult.

Did you have additional information? Beverly actually did the review, so
she might have additional information.

DR. LINDSAY: Yes. This was a 2-year-old who ingested his grandparents\'
medication. So it was multiple medications, not only just losartan.

DR. IYASU: Thanks for that correction, Beverly.

Any other questions?

(No response.)

DR. IYASU: The next drug is tamoxifen. Tamoxifen is a nonsteroidal
antiestrogen marketed by AstraZeneca. In adults, it\'s approved for the
treatment of breast cancer in women and men and it\'s also used to
reduce the incidence of breast cancer in high-risk women.

The label contains data from a single, uncontrolled multi-center
clinical trial of the treatment of girls age 2 to 10 with
McCune-Albright syndrome and precocious puberty. The safety and efficacy
of tamoxifen has not been studied beyond 1 year of therapy. However, an
increase in the mean uterine volume was noted during the 1-year
treatment, but no causal relationship could be established with the
drug. In adults, it has to be noted that an increase in the incidence of
adenocarcinoma and uterine sarcoma has been noted and therefore
continued monitoring of McCune-Albright patients treated with tamoxifen
is recommended in the label.

Now, turning to the use data, total prescriptions dispensed for
tamoxifen amounted to 4.3 million in 2002. However, the pediatric
specialty was responsible for only 8,000 prescriptions during the same
year and for about 5,000 prescriptions during January to May of 2003.

Tamoxifen mentions during patient visits to office-based physicians
represented less than 1 percent of total use. Pediatric use appears to
be primarily in the adolescent subgroup of 12- to 16-year-olds. The
diagnosis associated with its use appears to be exclusively for
malignant neoplasm of the brain. It doesn\'t mean that it was not used
for the other indication. It just means that we could not adequately
project the data. If was less than a certain minimum number, then you
can\'t really make any kind of projections.

During the 1 year post exclusivity period, we received a total of 369
adverse event reports for mostly adults, but we did not find any
pediatric adverse event reports in the AERS database during the year. So
there is nothing to say really about this drug right now in terms of
adverse events for the year. It\'s good news I guess that we did not get
any.

DR. SANTANA: No. The other interpretation is that the majority of the
brain tumor patients, pediatric patients, that are getting this drug,
it\'s being used in the setting of multiple recurrent disease, so
they\'re all dying from their primary disease.

DR. IYASU: That\'s possible too. Thank you.

The last drug I will discuss is nefazodone. Nefazodone is an
antidepressant marketed by Bristol-Myers. In adults, it\'s approved for
the treatment of MDD. There are no approved pediatric indications for
use.

Nefazodone has been associated with life-threatening hepatic toxicity,
and in 2001 a boxed warning was added to the label. This is the relevant
safety labeling I just wanted to mention.

Turning to drug use data, it shows that both pediatric and adult
prescriptions for nefazodone declined between 1999 and 2003, largely
fueled by concerns about its potential for liver toxicity. Nefazodone is
one of the least prescribed antidepressants in pediatric patients. Since
exclusivity was granted, nefazodone use has declined by more than half
in pediatric patients and by one-third in adults. In pediatric patients,
a diagnosis associated with its use were personality disorders,
depressive disorder, and infantile autism.

Turning to the adverse event reports for this particular drug, we
received a total of 173 reports, adult and pediatric, during the year
after exclusivity was granted. Of these, 3 reports were in pediatric
patients. All the pediatric events were noted as serious events. There
were no pediatric deaths.

The first report is a congenital hand malformation in an infant born to
a mother who was taking nefazodone along with multiple medications, some
of which have the potential to cause birth defects. Nefazodone, as you
know, has pregnancy category designation C. The reported event in this
case could not be solely attributed to nefazodone.

The second report is a potential arrhythmia and agitation in a
3-year-old with an accidental ingestion of about 14 tablets of
nefazodone. The patient\'s symptoms resolved after an induced emesis.

The last patient was a biopsy-proven Crohn\'s disease and sclerosing
cholangitis in a patient who was taking nefazodone for depression and
also taking multiple other medications. Her liver function tests did not
begin to normalize until the fourth month following discontinuation of
nefazodone. By 1 year, all liver function tests were normal. Concomitant
medications with known liver toxicity included mercaptopurine and
sulfasalazine. The contribution in this case of nefazodone alone to this
adverse event was difficult to assess.

So there were only three reports of adverse events for this particular
drug.

Are there any questions before I turn the podium over to Dr. Buckman?

(No response.)

DR. IYASU: Thank you very much. ShaAvhree Buckman, Dr. Buckman, will be
presenting on the last two drugs.

DR. BUCKMAN: Good afternoon.

The next drug that we will be discussing is cetirizine, or Zyrtec. This
is an anti-allergic drug which is marketed by Pfizer. It\'s indicated in
the treatment of allergic rhinitis, both seasonal and perennial, and
chronic idiopathic urticaria. It is approved for use in adults, as well
as in children down to the age of 6 months.

According to NPAPlus, the total dispensed prescriptions for cetirizine
are increasing in all age groups from 9.3 million in 1998 to 25.7
million in 2002. In the pediatric specialty, about 4 million
prescriptions were dispensed in 2002.

According to the NDTI database, during the first quarter of 2003,
approximately one-half of the mentions for cetirizine were for pediatric
patients, and approximately one-quarter of the mentions for cetirizine
was with pseudoephedrine were for pediatric patients.

The adverse event reports for cetirizine during the 1 year post
exclusivity period totaled 253 reports in both adults and children. 141
of those reports were from the U.S. and 112 were from international
sources. There were 43 unduplicated pediatric reports. There were no
pediatric deaths. 15 of the top 20 adverse events were unlabeled.

This slide summarizes 43 of the unduplicated reports in pediatric
patients. It\'s important to note that the underlined adverse events are
currently unlabeled. The most common adverse event that was seen during
this 1 year post exclusivity period was medication errors. In 8 of 9
case, there was confusion between Zantac syrup and Zyrtec syrup, and in
1 case there was confusion between Zyrtec and Zoloft. The FDA is
currently discussing how to best address these issues.

There were 7 psychiatric events that included aggressive behavior,
agitation, and hallucinations. There were 5 seizures, 3 episodes of
somnolence, 3 allergic reactions, 3 cases of congenital anomalies, 3
episodes of liver injury which were described as either elevated
transaminases or hepatitis. There were 2 cases of renal impairment with
associated acute renal failure or IgA nephropathy.

In the \"other\" category, there were 8 additional cases, 1 case of
each: accidental overdose, hearing loss, hyperglycemia,
hypogammaglobulinemia, pancreatitis, supraventricular tachycardia,
tachypnea of the newborn, and vertigo.

One of the other concerning adverse events that was noted was
hallucinations. In a review conducted in March of 2001 by the Office of
Drug Safety, there was the suggestion of a probable linkage between the
use of cetirizine and the incidence of this adverse event. During the 1
year post exclusivity period for cetirizine, there were two reported
cases of hallucinations. One was in a 3-year-old male who was reportedly
taking concomitant medications, and another was in an 8-year-old female
who also was reportedly taking other medications. The temporal nature of
when these other medications were administered was not clear in those
case report forms. In both cases, however, the condition abated when
cetirizine was discontinued.

Before proceeding on to the next drug, are there any questions?

(No response.)

DR. BUCKMAN: The next drug we\'ll discus ‑‑

DR. CHESNEY: I have a question.

DR. BUCKMAN: Yes.

DR. CHESNEY: I just wanted to be sure I understood. There was confusion
with Zantac and Zyrtec syrup.

DR. BUCKMAN: Yes.

DR. CHESNEY: Are the underlying side effects clearly related to the drug
you discussed or could they be related to Zantac?

DR. CHESNEY: As far as the medication errors, it was clear that those
were due to patients that were dispensed the wrong medication and
usually it was a pharmacy error that was noted. In the cases where there
were non-underlined adverse events, those were clearly due to Zyrtec,
the medication that was administered.

DR. EPPS: Just a comment. Your number of cetirizine for 2003 actually
could be higher if it weren\'t for some insurance company policies. Now,
they\'re demanding, oh, you have to document 30 days\' worth of
loratadine or whatever before we will give you Zyrtec. So the numbers
could have actually been higher.

DR. BUCKMAN: That\'s very true.

Any other comments or questions?

(No response.)

DR. BUCKMAN: The next drug that we will discuss is quinapril, or
Accupril. This is an antihypertensive drug. It\'s marketed by
Parke-Davis. It is indicated in the treatment of hypertension and as
adjunctive therapy for heart failure in adults. There are no approved
pediatric indications.

According to NPAPlus, the total dispensed prescriptions for quinapril
were 10 million in 1998 and 15.7 million in 2002. Pediatric use
constitutes less than 1 percent of total prescriptions dispensed.

According to NDTI, the proportion of pediatric use was less than 1
percent of the total population of quinapril mentions during visits to
office-based physicians.

The adverse event reports for quinapril during the 1 year post
exclusivity period totaled 198 reports. 114 were from the United States
and 84 were from international sources. There was one unduplicated
pediatric report of a serious adverse event. This was described as a
congenital anomaly associated with maternal use. In particular, a
1-day-old female was born with a heart malformation after maternal
exposure to quinapril. Salbutamol was also reported as a concomitant
medication taken by the mother.

Quinapril is extensively labeled regarding use during pregnancy and
fetal exposure risks. So this was a report that was addressed in the
current labeling for that drug.

Are there any questions regarding quinapril?

(No response.)

DR. BUCKMAN: In conclusion, we have provided you with information on six
drugs which have obtained pediatric exclusivity. The inherent
limitations of the adverse event reporting system make attribution of
adverse events due to drug use particularly challenging. The FDA will
continue its routine monitoring of adverse events in all populations,
and we would like to thank the Office of Drug Safety, as well as the
Office of Counter-Terrorism and Pediatric Drug Development for their
assistance in compiling information for this report. Thank you.

DR. CHESNEY: Thank you both very much for that.

DR. SANTANA: Joan, I have a question. Has the agency noticed for these
six drugs, once the sponsor has achieved exclusivity, a change in more
usage pattern and is that reflective in terms of the adverse reporting
patterns? Is there any way to monitor that, or do you know?

DR. MURPHY: Because the product is granted exclusivity because of
studies they submitted in hopes of getting a new indication usually in
which one would expect the use would go up, I\'m not sure what one would
make out of that except that you would expect that the use would go up.

DR. SANTANA: What I was leading to is how does one normalize the adverse
event data if the denominator is changing?

DR. MURPHY: That\'s one of the problems. As you will hear, one of the
problems with AERS is that every time there\'s a newspaper report or
some increased publicity, then you tend to get an increased reporting
from not only healthcare providers but also patients, more reporting
from patients.

DR. CHESNEY: We have time allotted now for an open public hearing. Is
there anybody here who would like to speak in the open hearing?

(No response.)

DR. CHESNEY: I guess not.

Let me ask Tom if there are any housekeeping issues, and we start
tomorrow at 8 o\'clock. Is that correct? Do you have anything else?

MR. PEREZ: Yes, that is correct.

I just wanted to clarify one thing since the next meeting has been
mentioned. That will be more than a one-day meeting. We don\'t know what
additional topics will be discussed. I just didn\'t want any confusion
because I know we have three days allotted for that meeting. It\'s not
just the one day. Thank you.

DR. CHESNEY: Anything else, Dr. Murphy, before we adjourn?

DR. MURPHY: I wanted to thank everybody. It\'s been a very helpful day.
We appreciate it very much.

DR. CHESNEY: Thank you all and we\'ll see you again tomorrow morning at
8 o\'clock.

(Whereupon, at 4:07 p.m., the committee was recessed, to reconvene at
8:00 a.m., Thursday, October 30, 2003.)