1

 

                DEPARTMENT OF HEALTH AND HUMAN SERVICES

 

                      FOOD AND DRUG ADMINISTRATION

 

                CENTER FOR DRUG EVALUATION AND RESEARCH

 

 

 

 

 

 

 

 

 

 

                         JOINT SESSION WITH THE

 

                 NONPRESCRIPTION AND DERMATOLOGIC DRUGS

 

                           ADVISORY COMMITTEE

 

 

                               VOLUME II

 

 

 

 

 

 

 

 

 

 

 

 

                        Thursday, March 24, 2004

 

                               8:00 a.m.

 

 

 

 

 

 

 

 

                       Hilton Washington DC North

                           620 Perry Parkway

                         Gaithersburg, Maryland

                                                                 2

 

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

 

      Alastair Wood, M.D., Chair, NDAC

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

 

      Committee Members:

 

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

        Representative)

      Terrence F. Blaschke, M.D.

      Ernest B. Clyburn, M.D.

      Frank F. Davidoff, M.D.

      Jack E. Fincham, Ph.D.

      Sonia Patten, Ph.D. (Consumer Representative)

      Wayne R. Snodgrass, M.D., Ph.D.

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

      Mary E. Tinetti, M.D.

 

      Government Employyee Consultants (Voting):

 

      Michael E. Bigby, M.D.

      Sharon S. Raimer, M.D.

      Eileen W. Ringel, M.D.

      Jimmy D. Schmidt, M.D.

      Robert B. Skinner, Jr., M.D.

      Thomas R. Ten Have, Ph.D.

      Elizabeth S. Whitmore, M.D.

      Michael G. Wilkerson, M.D.

      SGE Consultants (Voting):

 

      Patricia Chesney, M.D.

      Roselyn Epps, M.D.

      Robert M. Nelson, M.D.

      Victor Santana, M.D.

 

      Federal Employee Consultants (Voting)

 

      Constantine Stratakis, M.D.

      Donald R. Mattison, M.D.

 

      FDA Participants:

 

      Charles Ganley, M.D.

      Curtis Rosebraugh, M.D., MPH

      Jonathan Wilkin, M.D.

                                                                 3

 

                            C O N T E N T S

 

      Call to Order and Introduction:

         Alastair Wood, M.D.                                     4

 

      Conflict of Interest Statement,

         LCDR Teresa A. Watkins, R.Ph                            7

 

      Introduction:

                Charles Ganley, M.D.                            11

 

      FDA Presentations:

      OTC Dermatologic Topical Corticosteroids:

                Mike Koenig, Ph.D.                              16

 

      Rx Topical Corticosteroids: HPA Axis Suppression

         and Cutaneous Effects:

                Denise Cook, Ph.D.                              32

 

      Lessons Learned from Growth Studies with Orally

         Inhaled and Intranasal Corticosteroids:

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

 

      HPA Axis Suppression Studies: Conduct, Utility

         and Pediatric Considerations:

                Markham Luke, M.D.                              92

 

      Questions from the Committee and Committee

      Discussion                                               106

 

      Open Public Hearing:

                Jerry Roth                                     181

                Charles H. Ellis, M.D.                         189

                Valentine J. Ellis, MBA                        197

                Michael Paranzino                              206

                Sandra Read, M.D.                              211

                Luz Fonacier, M.D.                             219

 

      Questions to the Committee and Committee

         Discussion                                            236

 

                                                                 4

 

                         P R O C E E D I N G S

 

                    Call to Order and Introductions

 

                DR. WOOD:  If everybody could take their

 

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

 

      have everybody introduce themselves.  Why don't we

 

      start with Mike.

 

                DR. ALFANO:  Good morning.  I am Mike

 

      Alfano, New York University.  I am the industry

 

      liaison to NDAC.

 

                DR. FINCHAM:  Good morning.  I am Jack

 

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

 

      Pharmacy and Public Health at the University of

 

      Georgia.

 

                DR. RAIMER:  Good morning.  I am Sharon

 

      Raimer, in Dermatology, University of Texas.

 

                DR. TINETTI:  I am Mary Tinetti, Internal

 

      Medicine, Geriatrics at Yale.

 

                DR. RINGEL:  Eileen Ringel, Dermatologist,

 

      Waterville, Maine.

 

                DR. CLYBURN:  I am Ben Clyburn, Internal

 

      Medicine, Medical University of South Carolina in

 

      Charleston.

 

                DR. SANTANA:  Good morning.  I am Victor

 

      Santana.  I am a pediatric hematologist/oncologist

 

      at St. Jude Children's Research Hospital in

 

                                                                 5

 

      Memphis, Tennessee.

 

                DR. SKINNER:  I am Bob Skinner from the

 

      University of Tennessee at Memphis.  I am a

 

      dermatologist.

 

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

 

      consumer representative on NDAC.  I am an

 

      anthropologist on faculty at Macalister College in

 

      St. Paul, Minnesota.

 

                DR. DAVIDOFF:  I am Frank Davidoff.  I am

 

      the Emeritus Editor of Annals of Internal Medicine.

 

      I am an internist although I started life as an

 

      endocrinologist, and I am a member NDAC.

 

                DR. BIGBY:  Michael Bigby, a dermatologist

 

      at Beth Israel Deaconess Medical Center and Harvard

 

      Medical School.

 

                LCDR WATKINS:  I am Teresa Watkins.  I am

 

      the Executive Secretary with the advisors and

 

      consultant staff.

 

                DR. NELSON:  Robert Nelson, Pediatric

 

                                                                 6

 

      Critical Care Medicine at Children's Hospital,

 

      Philadelphia, and the University of Pennsylvania.

 

                DR. SNODGRASS:  Wayne Snodgrass,

 

      pediatrician, University of Texas Medical Branch.

 

                DR. MATTISON:  Don Mattison, National

 

      Institute of Child Health and Human Development.

 

                DR. SCHMIDT:  Jimmy Schmidt, Houston,

 

      Texas, dermatologist.

 

                DR. EPPS:  Roselyn Epps, Chief, Pediatric

 

      Dermatology, Children's National Medical Center,

 

      Washington, D.C.

 

                DR. CHESNEY:  Joan Chesney, Pediatric

 

      Infectious Diseases at the University of Tennessee

 

      at Memphis and Academic Programs at St. Jude

 

      Children's Research Hospital.

 

                DR. TAYLOR:  Robert Taylor, internist and

 

      clinical pharmacologist, Howard University,

 

      Washington.

 

                DR. WILKERSON:  Michael Wilkerson,

 

      University of Oklahoma, Tulsa Branch, Assistant

 

      Professor, Clinical, and dermatologist.

 

                DR. BLASCHKE:  Terry Blaschke, internist,

 

                                                                 7

 

      clinical pharmacologist, Stanford.

 

                DR. WILKIN:  Jonathan Wilkin, Director,

 

      Division of Dermatologic and Dental Drug Products,

 

      FDA.

 

                DR. ROSEBRAUGH:  Curt Rosebraugh, Deputy

 

      Director, OTC, FDA.

 

                DR. GANLEY:  Charley Ganley, Director of

 

      OTC.

 

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

 

      internist, Professor of Medicine, Associate Dean at

 

      Vanderbilt.  There has probably never been a

 

      committee with so many people from Tennessee on it,

 

      I don't think.

 

                Teresa, why don't you read the Conflict of

 

      Interest Statement.

 

                     Conflict of Interest Statement

 

                LCDR WATKINS:  The following announcement

 

      addresses the issue of conflict of interest and is

 

      made part of the record to preclude even the

 

      appearance of such at this meeting.

 

                Based on the submitted agenda and all

 

      financial interests reported by the Committee

 

                                                                 8

 

      participants, it has been determined that all

 

      interests in firms regulated by the Center for Drug

 

      Evaluation and Research present no potential for an

 

      appearance of a conflict of interest at this

 

      meeting with the following exceptions.

 

                In accordance with 18 U.S.C. Section

 

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

 

      following participants.  Please note that all

 

      interests are in firms that could potentially be

 

      affected by the committee's discussions.

 

                Dr. Michael Wilkerson for activities on

 

      Speakers Bureaus for three firms.  He receives less

 

      than $10,001 per year, per firm.

 

                Dr. Robert Skinner for a patent licensed

 

      to a firm that could potentially be affected by the

 

      committee's discussion.  He has received no

 

      royalties at this time.  Also, for his Speakers

 

      Bureaus activities for two firms, he receives less

 

      than $10,001 per year, per firm.

 

                Dr. Patricia Chesney for stock in six

 

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

 

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

 

                                                                 9

 

      three stocks are valued between $25,001 and

 

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

 

      $100,000.

 

                Dr. Thomas Ten Have for stock valued

 

      between $25,001 to $50,000.

 

                Dr. Victor Santana for stock in two firms.

 

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

 

      each.

 

                Dr. Sharon Raimer for two grants that are

 

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

 

      Also, for stock in three firms, each stock is

 

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

 

                Dr. Sonia Patten is an unpaid volunteer

 

      member of the Sumasil Foundation Board of

 

      Directors.  The Foundation owns stock interest in

 

      two firms.  One stock is currently valued between

 

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

 

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

 

                We would also like to disclose that Dr.

 

      Terrence Blaschke owns stock in a firm, valued from

 

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

 

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

 

                                                                10

 

      exemption 2640.202(b)(2) applies.

 

                A copy of the waiver statements may be

 

      obtained by submitting a written request to the

 

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

 

      of the Parklawn building.

 

                In the event that the discussions involve

 

      any other products or firms not already on the

 

      agenda for which an FDA participant has a financial

 

      interest, the participants are aware of the need to

 

      exclude themselves from such involvement and their

 

      exclusion will be note for the record.

 

                In addition, we would also like to note

 

      that Dr. Michael Alfano is participating in this

 

      meeting as a non-voting industry representative,

 

      acting on behalf of regulated industry.  Dr.

 

      Alfano's role on this committee is to represent

 

      industry interests in general, and not any one

 

      particular company.  Dr. Alfano is Dean of the

 

      College of Dentistry, New York University.

 

                With respect to all other participants, we

 

      ask in the interest of fairness that they address

 

      any current or previous financial involvement with

 

                                                                11

 

      any firm whose products they may wish to comment

 

      upon.

 

                Thank you.

 

                DR. WOOD:  Thanks a lot.

 

                Our first speaker is Charley Ganley.

 

      Charley.

 

                              Introduction

 

                DR. GANLEY:  Good morning.  I would just

 

      like to start by thanking all the members for

 

      participating in this meeting.  I would also like

 

      to thank the advisors and consultant staff for all

 

      the hard work they do in putting these meetings

 

      together, it is always difficult to get two

 

      different committees together, and last but not

 

      least, the staff of the Dermatologic and OTC

 

      Divisions who have put together the presentations.

 

                [Slide.]

 

                We are here today to discuss the safety

 

      data necessary to consider a switch of dermatologic

 

      topical corticosteroids from prescription to OTC

 

      status.

 

                [Slide.]

 

                The FDA presentations will cover the

 

      regulatory history of OTC hydrocortisone, the

 

      assessment of safety for current prescription

 

                                                                12

 

      dermatologic topical corticosteroids products, an

 

      assessment of safety effects for other categories

 

      of steroid products, and testing for HPA axis

 

      suppression.

 

                [Slide.]

 

                Now, low potency dermatologic topical

 

      corticosteroids are currently available OTC, and

 

      the only product that you will hear in the next

 

      talk is hydrocortisone.  Its purpose is for the

 

      symptomatic treatment of certain skin conditions,

 

      and there is a limitation on the duration of use.

 

                Over the last year or so, several

 

      manufacturers have expressed an interest in

 

      switching some dermatologic topical corticosteroids

 

      from prescription to OTC, asking for similar type

 

      claims, and also for durations of use.

 

                [Slide.]

 

                Now, in your background package, we

 

      included a list of the various potencies of topical

 

                                                                13

 

      steroids, and there is quite a difference in the

 

      potency of prescription dermatologic topical

 

      steroids, and potency impacts on efficacy and

 

      safety of these products.

 

                The main issue for the discussion today is

 

      the safety in the OTC setting.  The question really

 

      is where do we draw the line between safe versus

 

      unsafe products in this category for OTC use.

 

                [Slide.]

 

                Can all dermatologic topical steroids be

 

      used safely OTC?  Well, some highly potent products

 

      used for extended periods or in large amounts may

 

      pose a significant risk for developing a serious

 

      adverse event.

 

                At least in the OTC setting, limiting the

 

      duration of use through labeling may be effective

 

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

 

      a minority of consumers who will use large amounts

 

      and for durations that exceed label

 

      recommendations.

 

                I think in part of the open public

 

      session, you will hear a little bit of information

 

                                                                14

 

      of what possible percentage of consumers that may

 

      be.

 

                [Slide.]

 

                So, what are the safety concerns?  We have

 

      divided them up into the systemic effects and local

 

      effects, and within the systemic effects, we divide

 

      them further into HPA axis suppression, which is in

 

      this case where an exogenous steroid causes the

 

      body to stop making corticosteroid, and in stress

 

      situations, it could lead to acute adrenal crisis

 

      which would be life-threatening.

 

                This can occur with weeks of use and the

 

      use of the OTC product may be unknown to a health

 

      provider who has to treat someone who comes into

 

      the emergency room in this situation.

 

                The other systemic effects are essentially

 

      Cushing's syndrome, which could be osteoporosis,

 

      truncal obesity, growth suppression, and

 

      hypertension, it goes on and on, and the severity

 

      may be related to the daily dose and the duration

 

      of therapy.

 

                The local effects during the course of the

 

                                                                15

 

      presentations today, that will also be reviewed.

 

                [Slide.]

 

                Now, you may not be able to see this very

 

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

 

      the schematics that we are going to work with

 

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

 

      hierarchy of what we think the importance of these

 

      various potential safety issues are.

 

                Starting at the top is HPA axis

 

      suppression.  The second one is other systemic

 

      effects, and the third is local effects.  You will

 

      see the way the questions are presented will also

 

      follow this course.

 

                I don't want to go into great detail with

 

      this now, but during the course of the discussion

 

      and prior to some of the questioning maybe later

 

      this afternoon, we can go through this in a little

 

      more detail.

 

                Right now I am going to turn it over to

 

      Michael Koenig, who is going to talk a little bit

 

      about the regulatory history of hydrocortisone.

 

                           FDA Presentations

 

                OTC Dermatologic Topical Corticosteroids

 

                [Slide.]

 

                DR. KOENIG:  Good morning.  I am Michael

 

                                                                16

 

      Koenig, an interdisciplinary scientist in the

 

      Division of Over-the-Counter Drug Products.

 

                Over the next 15 minutes, I will be

 

      providing you with information about the only

 

      dermatologic topical steroids that are available

 

      over the counter, hydrocortisone and hydrocortisone

 

      acetate.

 

                Because hydrocortisone and hydrocortisone

 

      acetate are functionally the same thing, for the

 

      rest of this presentation, I will simply refer to

 

      the two corticosteroids as hydrocortisone.

 

                [Slide.]

 

                This presentation is divided into three

 

      parts.  First, I will describe the OTC monograph

 

      system under which these OTC corticosteroids are

 

      regulated.  Second, I will review the regulatory

 

      history of hydrocortisone.  Third, I will show you

 

      the current labeling of hydrocortisone products if

 

      they are in compliance with the monograph.

 

                [Slide.]

 

                I would like to begin by just especially

 

      for members of the Dermatologic and Ophthalmic

 

      Drugs Committee to review the way OTC drugs are

 

      regulated.  All OTC drugs are regulated by one of

 

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

 

                                                                17

 

      application, or under the monograph system.

 

                New drugs applications, or NDAs, are

 

      prepared by a drug manufacturer for a specific

 

      product, a specific drug product, and all of the

 

      review of this information and things related to

 

      the review are kept strictly confidential.

 

                Neither of the OTC corticosteroids that I

 

      will be talking about are regulated under NDAs.

 

      Instead, they are regulated under the monograph

 

      system, and this differs because under the

 

      monograph, monographs deal with specific active

 

      ingredients rather than drug products, and I will

 

      show you how that plays out in just a minute.

 

                In contrast to the NDAs, the information

 

      included in the monograph is a very public process.

 

      The monographs are published in the Federal

 

                                                                18

 

      Register, and FDA actively solicits feedback from

 

      the public at every step of the process.

 

                [Slide.]

 

                So the OTC monographs came about with the

 

      initiation of the OTC drug review back in 1972.  At

 

      that time, there were over 200,000 different drug

 

      products available OTC, and it was really

 

      impractical to think that we could review the

 

      safety and effectiveness of all 200,000 of these

 

      drug products.

 

                So, since they were made up of about 700

 

      active ingredients, it was determined that the

 

      active ingredients should be studied for safety and

 

      effectiveness rather than the products themselves.

 

      Again, this is a key difference between monographs

 

      and drugs marketed under an NDA.

 

                Of the 700 active ingredients, these were

 

      classified into 26 different therapeutic categories

 

      for further review.

 

                [Slide.]

 

                The initial review as by an Advisory

 

      Review Panel. This was made up of outside experts,

 

                                                                19

 

      outside FDA experts in that particular therapeutic

 

      category.  There were 7 voting members, but in may

 

      respects, it was somewhat analogous to the Advisory

 

      Committee.

 

                These panel members looked at each of the

 

      active ingredients and determined whether they were

 

      Category I or GRASE, Generally Recognized as Safe

 

      and Effective; Category II, not GRASE; or Category

 

      III, insufficient data to determine whether or not

 

      the ingredients were safe and effective for their

 

      intended use.

 

                [Slide.]

 

                The recommendations of the Advisory

 

      Committee were published in the Federal Register as

 

      an Advanced Notice of Proposed Rulemaking, or ANPR.

 

                [Slide.]

 

                FDA's first position on the ingredients in

 

      the different categories were made public in a

 

      proposed rule.  This followed solicitation of

 

      comments from the public, and as I said, resulted

 

      in the publication of a proposed rule, also known

 

      as a Tentative Final Monograph, I have abbreviated

 

                                                                20

 

      here as TFM.

 

                [Slide.]

 

                The last step in the monograph process is

 

      the development of a Final Rule, and that follows

 

      input of comments from the public again, as well as

 

      any new data that is relevant to generate this

 

      Final Rule or Final Monograph, which I have

 

      abbreviated FM.

 

                [Slide.]

 

                I would like to now speak specifically

 

      about the regulatory history of hydrocortisone.

 

                [Slide.]

 

                This low potency topic corticosteroid was

 

      introduced into the U.S. market as a prescription

 

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

 

      Petition was submitted requesting that

 

      hydrocortisone be switched from prescription to

 

      OTC.

 

                The switch was rejected in 1957 for two

 

      reasons:  first, there was a failure to demonstrate

 

      that consumers could safety self-medicate using

 

      hydrocortisone; and, second, it was felt that more

 

                                                                21

 

      testing was needed on absorption of hydrocortisone

 

      through the skin.  In other words, there was a

 

      concern about systemic effects, much as we will be

 

      talking about today.

 

                Hydrocortisone was included with other

 

      ingredients classified as external analgesics in a

 

      review by the Topical Analgesics Panel, which met

 

      between 1973 and 1978.

 

                [Slide.]

 

                The findings of the panel and the

 

      preliminary regulations were published in 1979 and

 

      the Advanced Notice of Proposed Rulemaking or ANPR.

 

      Among other things, the panel did consider whether

 

      hydrocortisone had any adverse local effects, and

 

      noted that there was a noticeable lack of adverse

 

      local effects.

 

                The striae and telangiectasia that were

 

      characteristic of more potent fluorinated

 

      corticosteroids were not generally found with

 

      hydrocortisone or hydrocortisone acetate.  Dr.

 

      Cook, who will follow my presentation, will be

 

      showing you some pictures of that and discussing

 

                                                                22

 

      this is a little bit more detail.

 

                Pustular eruptions and crusting were

 

      reported in one case of a person who was using

 

      hydrocortisone, but was it turns out attributed to

 

      a secondary infection and the scratching of the

 

      secondary infection, and treatment with an

 

      antibiotic resolved the issue while the person

 

      continued to use hydrocortisone.  So, again, a lack

 

      of local adverse effects.

 

                [Slide.]

 

                Also, in the ANPR, the fact that there was

 

      a lack of systemic effects was published.  Several

 

      experiments look at percutaneous absorption.

 

      People used carbon-14 hydrocortisone, in one case

 

      tritiated hydrocortisone, and did not see any

 

      significant absorption through the skin.

 

                Other measures of systemic effects were

 

      eosinophil count, there was no depression in

 

      eosinophil count in three or four studies that were

 

      presented in the ANPR.  Urinary levels of

 

      17-hydroxysteroids and 17-ketosteroids were not

 

      increased as you would expect if there were a

 

                                                                23

 

      significant systemic effect.

 

                Blood glucose levels were unchanged, as

 

      was the serum sodium level, and plasma cortisol did

 

      increase as expected or predicted in response to

 

      insulin stress.

 

                [Slide.]

 

                Insulin stress tests back in the '70s was

 

      a major test for HPA axis function.  It is no

 

      longer the current standard, but one report that

 

      you will see in the ANPR, which incidentally is

 

      included in your background package, was a study by

 

      Munro and Clift, which published in 1973.

 

                This is in Tab 5 of your background

 

      package, published in the British Journal of

 

      Dermatology.  These investigators looked at 40

 

      patients with chronic skin disease, eczema,

 

      psoriasis, who had been using corticosteroids for

 

      prolonged periods, I believe is in the title.

 

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

 

      corticosteroids for more than 10 months.

 

                In fact, they were using a variety of

 

      corticosteroids, betamethasone, and some others. 

 

                                                                24

 

      Ten of these 40 included among the combination of

 

      corticosteroids they had been using 1 percent

 

      hydrocortisone acetate.

 

                All 10 of those 10 subjects had a normal

 

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

 

      enrollees in the study had a normal insulin stress

 

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

 

      over extensive areas of the body, and 2 had an

 

      exceptionally large dose of corticosteroid.

 

                [Slide.]

 

                Now, the panel also reported that one of

 

      the items that they had received was a review of

 

      the literature covering the period 1952 to 1973

 

      about the serious adverse events that had occurred.

 

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

 

      different clinical studies, and in those 12,000

 

      subjects, there were only 3 reports of serious

 

      adverse events.

 

                One of these was 1960 report of temporary

 

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

 

      was having 1 percent hydrocortisone applied for 16

 

      months.  In 1962, there was a report of temporary

 

                                                                25

 

      growth retardation in an infant, who also had 1

 

      percent hydrocortisone applied twice daily for 6

 

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

 

      body and unction was what the report says in the

 

      ANPR.

 

                In 1966, there was a rapid gain in body

 

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

 

      using 0.25 percent hydrocortisone 3 times a day for

 

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

 

      mg/m2 body surface area.

 

                So, all in all, that panel considered this

 

      a very favorable response, only 3 out of over

 

      12,000 subjects had any serious adverse events with

 

      hydrocortisone.

 

                [Slide.]

 

                The panel recommendations in the ANPR were

 

      that hydrocortisone and hydrocortisone acetate

 

      should be considered GRASE over a concentration

 

      range of 0.25 to 0.5 percent.  Remember GRASE is

 

      generally recognized as safe and effective.

 

                The panel also has some recommendations

 

      for labeling, and since I will be showing you

 

                                                                26

 

      labeling in the third part of the talk, I just

 

      wanted to let you see how this labeling developed

 

      as the monograph developed.

 

                The panel felt that the indication should

 

      be or the use of hydrocortisone should be temporary

 

      relief of minor skin irritations, itching, and

 

      rashes due to a variety of different conditions,

 

      and we will get into that when we look at the

 

      labeling.

 

                The panel also felt that among several

 

      warnings should be these two, which are relevant to

 

      today's discussion I think.  One is that consumers

 

      should stop use if the condition worsened or lasted

 

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

 

      the use of hydrocortisone.

 

                The other warning I wanted to mention was

 

      the one that it should not be used on children

 

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

 

      were included on all external analgesic active

 

      ingredients, but they are directly relevant to some

 

      of some of the discussion you will be having later

 

      I think.

 

                Finally, the panel felt that under

 

      Directions should be a direction to apply this to

 

      the affected area essentially only, not more than 3

 

                                                                27

 

      to 4 times a day.

 

                [Slide.]

 

                FDA's position was made public in the

 

      Tentative Final Monograph, TFM, which published a

 

      little over 3 years later in 1983.  FDA agreed that

 

      the concentration range specified by the panel was

 

      appropriate, that 0.25 to 0.5 percent

 

      hydrocortisone should be considered GRASE, safe and

 

      effective, and FDA did make some labeling

 

      modifications.

 

                Among those was the focus of the

 

      indication on antipruritic aspects of

 

      hydrocortisone, so instead of temporary relief of

 

      skin irritations, itching, and rash, it became

 

      temporary relief of itching associated with skin

 

      irritation and rashes due to a variety of

 

      conditions, and hydrocortisone is today, that is

 

      the only indication, antipruritic.

 

                Additionally, to the stop use condition,

 

                                                                28

 

      FDA added the clause, "Stop use if condition

 

      worsens or last more than 7 days or if symptoms

 

      clear up and occur again within a few days."

 

                [Slide.]

 

                The Tentative Final Monograph was amended

 

      in 1990 in response to a Citizen Petition which

 

      requested an increase in dosage strength to a

 

      maximum of 1 percent from remember the previous 0.5

 

      percent.

 

                This amended TFM included an extensive

 

      data and literature review mostly centered around

 

      the use of 1 percent hydrocortisone, and ultimately

 

      considered the higher concentration of 1 percent to

 

      be GRASE for OTC use.

 

                Additionally, there were some labeling

 

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

 

      use any other hydrocortisone product when using the

 

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

 

      the treatment of diaper rash," which is still on

 

      the labeling, and this is largely due to the

 

      occlusive nature of a diaper.

 

                [Slide.]

 

                What about the Final Monograph, the last

 

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

 

      have found that manufacturers are generally

 

                                                                29

 

      complying with the Tentative Final Monograph and

 

      the amended TFM.  I will show you that in some

 

      labeling in just a minute.

 

                We are continuing our review of data

 

      submitted by manufacturers, as well as in the

 

      literature.

 

                [Slide.]

 

                In light of today's discussion, I just

 

      wanted to point out some of the literature that we

 

      have been reviewing.  This table represents 5

 

      studies that have been conducted since the ANPR

 

      published in 1979.  All of these studies were in

 

      children, and all of these used the modern standard

 

      ACTH stimulation to measure HPA axis function.

 

                ACTH, as Dr. Cook will go into a little

 

      bit more detail on this, ACTH is

 

      adrenocorticotropic hormone.  This is released from

 

      the anterior pituitary and stimulates release of

 

      cortisol from the adrenal glands.  That is the P

 

                                                                30

 

      and the A, adrenal glands in the HPA axis.

 

                So, by looking at the amount of cortisol

 

      released in response to a known amount of ACTH, or

 

      in a more practical sense, some synthetic analogue

 

      of ACTH, you can tell whether the HPA axis is

 

      functioning properly.

 

                In all of these studies, at hydrocortisone

 

      concentrations ranging from 1 percent to a maximum

 

      of 2.5 percent, and with durations of treatment

 

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

 

      years, the HPA axis was found to be functioning

 

      normally in response to hydrocortisone.

 

                [Slide.]

 

                I would now like to look at the current

 

      labeling of hydrocortisone in this third part of

 

      the talk.

 

                [Slide.]

 

                Since 1999, OTC products should be

 

      conforming to the Drug Facts labeling standard.

 

      This is what the hydrocortisone labeling should

 

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

 

      and there are three things I would just like to

 

                                                                31

 

      point out to you.  We have been discussing the

 

      development of the monograph through the various

 

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

 

      the labeling.

 

                So, under Uses, you see the indication,

 

      temporarily relieves itching associated with minor

 

      skin irritations, inflammation and rashes due to a

 

      variety of conditions, and the number of conditions

 

      that may be causing the itching has increased over

 

      the years with each new monograph publication.

 

                [Slide.]

 

                Also, under Warnings, this is very much as

 

      it appeared in the TFM, the Tentative Final

 

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

 

      symptoms persist for more than 7 days or clear up

 

      and occur again within a few days."

 

                [Slide.]

 

                And under Directions, "Apply to affected

 

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

 

      under 2 years of age, do not use."

 

                [Slide.]

 

                This is labeling that is taken off of a

 

                                                                32

 

      currently marketed OTC product, and I just wanted

 

      to show you that again, manufacturers are very much

 

      in compliance with the monograph standards.

 

                So, in this labeling under Uses, we see

 

      the same thing, "temporarily relieves itching of

 

      minor skin irritations, inflammation and rashes."

 

                [Slide.]

 

                Under Warnings, "Stop use and ask a doctor

 

      if symptoms persist for more than 7 days."

 

                [Slide.]

 

                Under Directions, the same two that I just

 

      mentioned.

 

                I would like to thank you for your

 

      attention and I will be followed by Dr. Denise Cook

 

      of the Division of Dermatologic and Dental Drug

 

      Products.  Denise will be talking about

 

      prescription topical corticosteroids.

 

                Thank you.

 

                  Rx Topical Corticosteroids: HPA Axis

 

                   Suppression and Cutaneous Effects

 

                [Slide.]

 

                DR. COOK:  Good morning.  Good morning to

 

                                                                33

 

      the respective chairs of the respective advisory

 

      committees that are here, also to the advisory

 

      committee members, to my FDA colleagues, and people

 

      in the audience.

 

                I am Denise Cook.  I am a dermatologist in

 

      the Division of Dermatology and Dental Drug

 

      products.

 

                [Slide.]

 

                Today, I will be speaking to you on

 

      prescription topical corticosteroids, the HPA axis

 

      suppression, and cutaneous effects.

 

                The majority of the presentation will be

 

      on the systemic effect of the HPA axis and the

 

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

 

      be presenting trial data from approved drug

 

      products, the resultant labeling changes.  I will

 

      also give a postmarketing summary of adverse events

 

      as it relates to the HPA axis suppression that we

 

      have in our database.

 

                But first I will give you a background to

 

      the talk, so that you can follow it probably a

 

      little bit later. I will talk about the

 

                                                                34

 

      classification of topical corticosteroids, give you

 

      a synopsis of the cosyntropin stimulation test and

 

      how it is performed, and also give you an evolution

 

      of interpretation of normal HPA axis function as it

 

      has been done over the years at the FDA.

 

                I will give you background also on class

 

      labeling for topical corticosteroids and how that

 

      developed, and the cutaneous adverse events from

 

      topical corticosteroid use.

 

                [Slide.]

 

                The topical corticosteroids are divided

 

      into seven classes.  Although the FDA does not

 

      purport this classification, it is widely used in

 

      the dermatologic community.

 

                Class I consists of superpotent topical

 

      corticosteroids, Class II high potency, Class III

 

      through VI are mid-potency with Class III being

 

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

 

      VI being close to the low potency of Class VII.

 

                It is usually determined by a

 

      vasoconstrictor assay where the topical

 

      corticosteroids placed on the cutaneous surface,

 

                                                                35

 

      and blanching or vasoconstriction is determined

 

      relative to the other corticosteroid.

 

                [Slide.]

 

                The cosyntropin stimulation test, which is

 

      the test that I will be discussing in the bulk of

 

      the studies that you are going to hear about today,

 

      is used to assess the function of the end organ,

 

      the adrenal gland, in the hypothalamic-pituitary

 

      adrenal axis.

 

                In the case of topical corticosteroids, it

 

      is assessing an exogenous unwanted treatment

 

      effect.

 

                What is usually done is the cosyntropin is

 

      given at 0.125 mg or 0.25 mg depending on age

 

      and/or body weight, and it is administered

 

      intravenously at baseline and at the end of

 

      treatment.

 

                Blood is then drawn for serum cortisol

 

      values at 30 minutes and sometimes 60 minutes post

 

      stimulation.  Then, the interpretation of the

 

      results determines a normal or abnormal response.

 

                [Slide.]

 

                The evolution of the interpretation of the

 

      normal function of the HPA axis at the FDA has

 

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

 

                                                                36

 

      serum cortisol, then urinary corticoid

 

      concentrations were used to determine whether you

 

      had normal function of your HPA axis after

 

      treatment with topical corticosteroids.

 

                Then, in 1996, the cosyntropin stimulation

 

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

 

      stimulation serum cortisol had to be greater than

 

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

 

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

 

      you needed to have at least a 6 increment change

 

      from pre-stimulation to post-stimulation in order

 

      to be considered to have a normal response.

 

                In 1999, the FDA went to a single

 

      criterion to determine normal function of your HPA

 

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

 

      cortisol greater than 18 mcg/dL.

 

                [Slide.]

 

                In 2001, it was decided that if we were

 

      going to use cosyntropin to determine normal

 

                                                                37

 

      function of hormonal therapy HPA axis, then, the

 

      label should be followed as it is currently

 

      written, that is, that the control plasma cortisol

 

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

 

      level should show an increment of at least 7

 

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

 

      18 mcg/100 mL.

 

                Currently, in 2004, there had been a lot

 

      of work in the FDA with endocrinologists and also

 

      members in the Division of Dermatology to determine

 

      that we need to go back to a single criterion for

 

      HPA axis function and determining it from the

 

      cosyntropin test.  Therefore, at the present time,

 

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

 

      cortisol level should exceed 18 mcg/100 mL.

 

                [Slide.]

 

                Now, class labeling for prescription

 

      topical corticosteroids went into effect in 1990,

 

      and I am going to give you a little background on

 

      one of the factors that propelled this into being.

 

                This class labeling talks about the

 

      effects on the HPA axis, effects on glucose

 

                                                                38

 

      metabolism, development of Cushing's syndrome,

 

      effects on growth, and effects on intracranial

 

      pressure.

 

                [Slide.]

 

                Two studies have propelled this into

 

      being.  There were two open-label trials with

 

      Temovate Ointment.  In Trial 1, there were 6 adult

 

      patients with psoriasis who applied 7 grams/day to

 

      30 percent of their body surface area for 7 days.

 

                ACTH stimulation was performed at baseline

 

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

 

      They found that 50 percent of the patients

 

      exhibited decreases in cortisol production.

 

                [Slide.]

 

                In the second trial, the objective was to

 

      determine the largest dose over a 7-day period that

 

      would not cause significant suppression of the

 

      adrenal gland.

 

                Three doses were used - 7 grams/day, 3.5

 

      grams/day, and 2.0 grams/day.

 

                Suppression in this trial was determined

 

      by an A.M. plasma cortisol and urinary corticoid

 

                                                                39

 

      concentrations.

 

                It was interesting, it was found that none

 

      of the psoriatic patients suppressed at 7.0

 

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

 

      low as 2.0 grams/day caused marked suppression of

 

      cortisol secretion in patients with atopic

 

      dermatitis.  We can possibly presume that this may

 

      be because they may have had a higher compromise in

 

      the epidermis.

 

                DR. WOOD:  What were the numbers in that

 

      study?

 

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

 

      mean like exactly what the serum cortisol levels

 

      were?

 

                DR. WOOD:  The number of patients.

 

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

 

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

 

      out of the label.  But I would suspect that they

 

      were small, because in the current studies that we

 

      have, the numbers are small, they are not huge

 

      numbers.

 

                [Slide.]

 

                So, this led to a Temovate label in 1985

 

      that stated in the Precautions, it is a highly

 

      potent topical corticosteroid that has been shown

 

                                                                40

 

      to suppress the HPA axis at doses as low as 2

 

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

 

      steroid in the superpotent category.

 

                Under Pediatric Use, it was determined

 

      that it should not be used in children under 12

 

      years of age, at least it is not recommended.

 

                [Slide.]

 

                So, now we will move on to the actual

 

      class label that was generated.

 

                [Slide.]

 

                In the Precautions Section, it states that

 

      systemic absorption of topical corticosteroids can

 

      produce reversible hypothalamic-pituitary-adrenal

 

      axis suppression with the potential for

 

      glucocorticoid insufficiency after withdrawal from

 

      treatment.

 

                Manifestations of Cushing's syndrome,

 

      hyperglycemia, and glucosuria can also be produced

 

      in some patients by systemic absorption of topical

 

                                                                41

 

      corticosteroids while on treatment.

 

                [Slide.]

 

                It goes on to say that patients applying a

 

      potent topical steroid to a large surface area or

 

      to areas under occlusion should be evaluated

 

      periodically for evidence of HPA axis suppression.

 

      This may be done by using the ACTH stimulation, AM

 

      plasma cortisol, and urinary free cortisol tests.

 

                [Slide.]

 

                If HPA axis suppression is noted, an

 

      attempt should be made to withdraw the drug, to

 

      reduce the frequency of application, or to

 

      substitute a less potent steroid. Recovery of HPA

 

      axis function is generally prompt upon

 

      discontinuation of topical corticosteroids.

 

                Infrequently, signs and symptoms of

 

      glucocorticosteroid insufficiency may occur

 

      requiring supplemental systemic corticosteroids.

 

                [Slide.]

 

                The class label also addressed pediatric

 

      use in the Pediatric Use Section of the label.

 

                [Slide.]

 

                Currently, this is what is there if there

 

      haven't been any tests done on pediatric patients,

 

      but as you shall see in the studies that I will

 

                                                                42

 

      present, since the advent of FDAMA, we have been

 

      able to get studies in pediatric patients, so some

 

      of this has been modified in the respective labels.

 

                Safety and effectiveness in children and

 

      infants have not been established.  Because of a

 

      higher ratio of skin surface area to body mass,

 

      children are at a greater risk than adults of HPA

 

      axis suppression when they are treated with topical

 

      corticosteroids.

 

                They are therefore also at greater risk of

 

      glucocorticosteroid insufficiency after withdrawal

 

      of treatment and of Cushing's syndrome while on

 

      treatment.

 

                [Slide.]

 

                HPA axis suppression, Cushing's syndrome,

 

      linear growth retardation, delayed weight gain, and

 

      intracranial hypertension have been reported in

 

      pediatric patients receiving topical

 

      corticosteroids.

 

                Manifestations of adrenal suppression in

 

      pediatric patients include low plasma cortisol

 

      levels to an absence of response to ACTH

 

      stimulation.  Manifestations of intracranial

 

      hypertension include bulging fontanelles,

 

      headaches, and bilateral papilledema.

 

                                                                43

 

                [Slide.]

 

                Now, we are going to move on to the bulk

 

      of the presentation, which is going to be about the

 

      prescription topical corticosteroid data and its

 

      relationship with HPA axis suppression.

 

                I am going to speak about 10 drug

 

      products.  There are 8 topical corticosteroid

 

      products, 2 topical combination drug products.

 

                [Slide.]

 

                Just to give you those, I am going to

 

      speak about Dermatop, which is a mid-potency

 

      steroid; Cutivate Cream, another mid-potency

 

      topical corticosteroid; Diprolene AF Cream, which

 

      is a high potency steroid.

 

                You might want to look in Tab 2, I think

 

      it is, of your background package.  It has that

 

                                                                44

 

      classification that I spoke of earlier, the high

 

      potency steroids being in Class II.

 

                Diprosone Ointment, a high potency

 

      steroid; Diprosone Cream and Lotion, both in the

 

      mid-potency category; Clobex Lotion, a superpotent

 

      steroid; and Temovate E Cream.  Both of these are

 

      clobetasol propionate.

 

                There will be 11 studies that I am going

 

      to discuss.  The ages of these patients were from 3

 

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

 

      and they all use the cosyntropin stimulation test

 

      to determine the function of the HPA axis.

 

                [Slide.]

 

                Dermatop is a Class V steroid near the

 

      bottom part of the mid-potency topical

 

      corticosteroids.  It was approved in May 1996.  We

 

      are going to discuss a pediatric atopic dermatitis

 

      trial.

 

                [Slide.]

 

                There were 59 patients enrolled and there

 

      were 2 targeted populations.  The patients were

 

      between 1 month and 2 years and also between 2 and

 

                                                                45

 

      12 years.  There were 10 patients who were less

 

      than 2 years old and 49 patients were greater than

 

      or equal to 2 years of age.

 

                [Slide.]

 

                They had to use the medication over

 

      greater than 20 percent of the body surface area.

 

      I mean they had to have atopic dermatitis to that

 

      amount of cutaneous surface, and use it twice daily

 

      for 21 consecutive days.

 

                Again, we used the cosyntropin stimulation

 

      test. It was administered at baseline and at day

 

      22.  In this trial, patients who were greater than

 

      or equal to 15 kilograms received a higher dose of

 

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

 

      IV.

 

                [Slide.]

 

                The criteria in this study was the adrenal

 

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

 

      post-stimulation serum cortisol had to be greater

 

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

 

      cortisol level was already greater than 20, then,

 

      an incremental increase of greater than 6 mcg/dL in

 

                                                                46

 

      the serum cortisol was required.

 

                [Slide.]

 

                There were 3 patients according to the

 

      protocol criteria who were suppressed.  Two

 

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

 

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

 

      post-stimulation cortisol value actually decreased

 

      from baseline.

 

                At that time, the Agency agreed with an

 

      outside endocrinologist that since these 3 patients

 

      had a post-stimulation response that was already

 

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

 

      that required incremental rise, that they should

 

      not be considered suppressed.

 

                So, this led to the current label that

 

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

 

      showed evidence of HPA axis suppression."

 

                [Slide.]

 

                The next drug is Cutivate Cream, which is

 

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

 

      We are going to look at another atopic dermatitis

 

      trial in pediatric patients.

 

                [Slide.]

 

                There were 43 evaluable patients with

 

      moderate to severe atopic dermatitis; 29 of the

 

                                                                47

 

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

 

      patients were 3 years to 5 years old.

 

                [Slide.]

 

                The criteria for entry into the study was

 

      that they had to have at least a 35 percent body

 

      surface area involvement, and I will tell you in

 

      all of these studies, we were looking for maximum

 

      use conditions, so you could get your worst case

 

      scenario.

 

                They applied the medication twice a day

 

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

 

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

 

      years of age were limited to 180 grams/week.

 

                [Slide.]

 

                Looking at body surface area improvement

 

      over time to show the response to the medication,

 

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

 

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

 

      50 percent by 3 weeks, and 9 percent of the

 

                                                                48

 

      patients had a 50 percent decrease by 4 weeks.

 

                [Slide.]

 

                The cosyntropin was administered at

 

      baseline and end of treatment, and in this study,

 

      they used age, younger age group was given a lower

 

      dose than the older age group.

 

                [Slide.]

 

                Here, a normal response was a serum

 

      cortisol level that exceeded 18 mcg/dL at 30

 

      minutes post-stimulation.

 

                [Slide.]

 

                Two the patients out of the 43 patients

 

      experienced adrenal suppression.  One was a

 

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

 

      area involvement, used the drug for 4 weeks, used

 

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

 

      here, pre-treatment value was 33.9 after

 

      stimulation, and yet it fell to 11.8, but in

 

      follow-up he recovered at 19.8 with his serum

 

      cortisol.

 

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

 

      the minimum amount of body surface area involvement

 

                                                                49

 

      of 35 percent.  His duration of treatment was for 5

 

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

 

      post-stimulation serum cortisol was 9.4.

 

      Unfortunately, we don't know whether he recovered

 

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

 

      investigator did make an honest effort to try to

 

      track this child down.

 

                [Slide.]

 

                But this led to labeling changes for

 

      Cutivate Cream, which stated that children as young

 

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

 

      use the medication, and appropriate sections of the

 

      label were updated.

 

                [Slide.]

 

                Now, I am going to talk about 4 or 5

 

      betamethasone propionate products.  They were all

 

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

 

      I mean the pediatric part of the label was changed.

 

      Their supplement for safety was changed, because,

 

      of course, they have been on the market a lot

 

      longer than just 2001.

 

                One is Diprolene AF Cream, which is a

 

                                                                50

 

      Class II steroid; Diprosone Ointment, another Class

 

      II steroid; Diprosone Cream, a Class III steroid;

 

      Diprosone Lotion, which is mid-potency, but the

 

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

 

      significant when you see the study results of this

 

      drug, of Diprosone Lotion.

 

                Then, I am going to speak of the 2

 

      combination products, Lotrisone Cream and Lotion.

 

                [Slide.]

 

                The criteria for a normal HPA axis

 

      response in all of these studies was that we would

 

      follow the cosyntropin label, that the failure of

 

      any one of three criteria would indicate

 

      suppression of the HPA axis, and stimulation should

 

      occur at baseline and end of treatment.

 

                [Slide.]

 

                So, the criteria for the 30-minute

 

      post-stimulation, the three criteria that they

 

      needed to meet to have a normal response, is that

 

      the control plasma cortisol level should exceed 5

 

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

 

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

 

                                                                51

 

      the basal level, and the 30-minute level should

 

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

 

      those three would indicate suppression.

 

                [Slide.]

 

                So, with Diprolene AF Cream, there were 60

 

      evaluable patients.  They ranged in age from 1 to

 

      12 years with atopic dermatitis.  They had a mean

 

      body surface area involvement of 58 percent.  They

 

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

 

      and that depended upon whether their disease

 

      cleared or not.

 

                If they cleared within 2 weeks, they were

 

      allowed to stop and then be tested at that point.

 

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

 

      weeks.  They were limited to 45 grams per week.

 

                [Slide.]

 

                The results of the cosyntropin stimulation

 

      showed that 19 out of 60 or 32 percent of these

 

      patients showed evidence of HPA axis suppression.

 

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

 

      took the criterion that we look at now, which is

 

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

 

                                                                52

 

      had suppression.

 

                [Slide.]

 

                If you look at suppression by age group,

 

      it appeared that a larger percentage of patients

 

      suppressed as the age decreased.

 

                Looking at recovery of normal HPA axis

 

      suppression, unfortunately, all the patients were

 

      not retested.  We would have liked to have all of

 

      them retested, but 4 patients were retested 2 weeks

 

      post-treatment, and 3 of the 4 recovered normal

 

      function of their HPA axis.

 

                [Slide.]

 

                We tried to do a statistical analysis in

 

      the development of HPA axis suppression with each

 

      drug.  With Diprolene AF, there was no correlation

 

      between amount of drug used, body weight, age or

 

      sex, and the incidence of adrenal gland

 

      suppression.

 

                The statistical relationship did exist

 

      between body surface area and risk of HPA axis

 

      suppression such that for an increase of 1 percent

 

      body surface area involved, the risk of HPA axis

 

                                                                53

 

      suppression increased 4.4 percent with a p value of

 

      less than 0.01.

 

                [Slide.]

 

                This led to a label change for Diprolene

 

      AF Cream, such that it was restricted to patients

 

      13 years and older, and appropriate information was

 

      included in other sections of the label.

 

                [Slide.]

 

                Diprosone Ointment.  That study had 53

 

      evaluable patients with atopic dermatitis.  The age

 

      range was 6 months to 12 years.  The medication

 

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

 

      The mean body surface area involved was 58 percent.

 

                DR. WOOD:  Can we just go back to that

 

      last slide? The one with the 1 percent BSA

 

      involved.

 

                DR. COOK:  Excuse me.  Which one?

 

                DR. WOOD:  The last slide, the slide

 

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

 

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

 

      percent, that is linear throughout the thing, so

 

      going from 1 percent to 21 percent would mean 88

 

                                                                54

 

      percent of people had HPA suppression?  That

 

      doesn't seem to make much sense to me.

 

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

 

      our statistician.

 

                DR. WOOD:  All right.  Fair enough.  Go

 

      on.

 

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

 

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

 

      Ointment and getting ready to tell you the patient

 

      that suppressed.

 

                There were 28 percent of patients who

 

      showed evidence of HPA axis suppression when given

 

      the cosyntropin stimulation test, and here again,

 

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

 

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

 

      of the patients had a post-stimulation plasma

 

      cortisol value that would suggest suppression.

 

                [Slide.]

 

                Again, if you looked at suppression by

 

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

 

      proportion of patients who suppressed, the younger

 

      the patients were.

 

                [Slide.]

 

                In the statistical analysis here in the

 

      development of HPA axis suppression, these

 

                                                                55

 

      statisticians didn't find a statistically

 

      significant effect for drug usage, for percent of

 

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

 

                It did show that for some reason, a higher

 

      proportion of males than females developed HPA axis

 

      suppression using this drug.

 

                [Slide.]

 

                In testing patients for recovery, 2 of the

 

      15 patients were retested and 100 percent recovered

 

      at 2 weeks.

 

                [Slide.]

 

                This led to a label change similar to

 

      Diprolene AF Cream in which an age restriction was

 

      added that patients should be 13 years of age or

 

      old, and appropriate parts of the label were

 

      updated with the clinical data.

 

                [Slide.]

 

                Diprosone Cream studied 43 evaluable

 

      patients with atopic dermatitis.  They ranged in

 

                                                                56

 

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

 

      surface area involvement was 40 percent. Again,

 

      they applied the medication twice a day for 2 to 3

 

      weeks.

 

                [Slide.]

 

                In this study, 23 percent of the patients

 

      showed evidence of adrenal suppression using the

 

      Cortrosyn label with all three criteria and a

 

      failure of one.

 

                If you look again at a post-stimulation

 

      value that was less than 18, 50 percent of patients

 

      showed evidence of adrenal suppression.

 

                [Slide.]

 

                In this study, you can't quite see the

 

      value here.  Starting here with 14 percent of

 

      patients 9 to 12 years of age showed evidence of

 

      suppression.  As you march down again, the

 

      percentages went up, but here, interestingly, which

 

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

 

      determining just what is going to make someone

 

      suppressed, what are the risk factors here, none of

 

      the infants in this study showed evidence of

 

                                                                57

 

      adrenal suppression.

 

                [Slide.]

 

                Again, with the statistical analysis for

 

      this particular drug, in these patients, there was

 

      no statistically significant effect for number of

 

      days treated, for weight, or for age.

 

                However, there was a statistical

 

      significance found for mean amount of drug usee -

 

      81 grams in those who suppressed versus 37 grams in

 

      those that did not.

 

                There was a numerically higher percent of

 

      body surface area involvement in those who

 

      suppressed, and numerically, more males developed

 

      suppression.

 

                [Slide.]

 

                When looking at recovery of HPA axis

 

      function with Diprosone Cream, 2 out the 10

 

      patients were retested, and 50 percent, 1 out of

 

      the 2, recovered function at 2 weeks.

 

                [Slide.]

 

                Here again, the label was changed to add

 

      and age restriction to 13 years or older, and

 

                                                                58

 

      appropriate portions of the label were updated.

 

                [Slide.]

 

                Now, Diprosone Lotion, I will remind you

 

      again is a Class V steroid, so just like two

 

      classes above the lowest potency of topical

 

      corticosteroid.

 

                Here, they had 15 evaluable patients with

 

      atopic dermatitis.  They ranged in age from 6 to 12

 

      years old.  The mean body surface area involvement

 

      was 45 percent.  They applied the medication twice

 

      a day for 2 to 3 weeks.

 

                [Slide.]

 

                This was a very interesting study.  Eleven

 

      of the 15 patients or 73 percent of the patients

 

      showed evidence of HPA axis suppression.  If we

 

      look at just getting a serum cortisol value that

 

      exceeded 18 mcg/dL, 91 percent of the patients

 

      failed to do that.

 

                [Slide.]

 

                Although this study was supposed to enroll

 

      infants, it was felt that with such a high degree

 

      of HPA axis suppression, the proportion of patients

 

                                                                59

 

      6 to 12 years of age, that no patients were

 

      enrolled in the lower age group.  This brought up

 

      the issue that possibly it is not only the chemical

 

      moiety that might produce HPA axis suppression, but

 

      since it is coming from the skin, it may involve

 

      the vehicle in which the chemical moiety is in.

 

                In this instance, the lotion, it may

 

      somehow with the chemical moiety quicker from the

 

      skin into the systemic circulation, and thereby

 

      cause more HPA axis suppression.  So, in other

 

      words, vehicle may play a role also in determining

 

      that systemic effect.

 

                [Slide.]

 

                When looking at the statistical analysis

 

      in the development of HPA axis suppression, it was

 

      a numerical analysis.  The subjects exhibiting HPA

 

      axis suppression used the larger mean amount of

 

      drug.  They had a slightly higher percent of BSA

 

      involvement.

 

                They had lower mean weights at visit 1,

 

      lower mean weights at visit 4, but the difference

 

      with respect to age and days of treatment, at least

 

                                                                60

 

      from a statistical point of view, were minuscule.

 

                [Slide.]

 

                Looking at recovery of HPA axis function

 

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

 

      percent of the patients who were retested recovered

 

      their HPA axis function at 2 weeks.

 

                [Slide.]

 

                So, the labeling change for Diprosone

 

      Lotion was that an age restriction was added to 13

 

      years and older, and appropriate sections of the

 

      label again were updated.

 

                [Slide.]

 

                Just to look at the four betamethasone

 

      products together, again, you see that the three

 

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

 

      suppress somewhat where in the same range.  When

 

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

 

      higher percentage of patients who experienced HPA

 

      suppression.  Again, it may have to do with the

 

      vehicle, if there is an absorption enhancer in it

 

      or other factors.

 

                [Slide.]

 

                Lotrisone Cream is the other betamethasone

 

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

 

      combination product of betamethasone dipropionate

 

                                                                61

 

      with Lotrimin Cream.  It is indicated for the

 

      treatment of tinea pedis and tinea cruris, so we

 

      did a study in both of those.

 

                Both studies were in the adolescent

 

      population, 12 to 16 years.  Medication was applied

 

      twice daily.  The study duration for tinea pedis

 

      was 4 weeks and for tinea cruris was 2 weeks.

 

                [Slide.]

 

                Here, we also have some surprising

 

      results.  Seventeen out of 43 or 39.5 percent of

 

      patients demonstrated adrenal suppression in the

 

      tinea pedis study, and we might not have actually

 

      expected that given that the stratum corneum of the

 

      feet is somewhat thick, but it might also be

 

      teenagers wear sox and tennis shoes all day long,

 

      and that might also cause more occlusion and

 

      absorption of the drug product.

 

                In tinea cruris, there were 47.1 percent

 

      who demonstrated adrenal suppression, and this is

 

                                                                62

 

      also is an area where you may have some natural

 

      occlusion, increasing absorption.

 

                [Slide.]

 

                So, this led to some labeling changes for

 

      Lotrisone Cream and Lotion.  The Indication Section

 

      was expanded, it added an age restriction to

 

      patients 17 years and older.  It also recommended

 

      that effective treatment may be obtained without

 

      the use of a corticosteroid for non-inflammatory

 

      tinea infections.  Then, other appropriate sections

 

      of the label were updated with clinical

 

      information.

 

                DR. FINCHAM:  Dr. Cook, may I interrupt

 

      for a second and just ask a question about the data

 

      sets that you are reporting on?

 

                DR. COOK:  Sure.

 

                DR. FINCHAM:  Is this Phase IV data that

 

      is provided by sponsors, that then the Agency has

 

      acted on to change the label?

 

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

 

      response to what we call "pediatric written

 

      requests," which is part of the FDA Modernization

 

                                                                63

 

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

 

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

 

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

 

      could either ask them to do the studies or they

 

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

 

      then issue them the pediatric written request which

 

      would allow them to do the studies.  That is sort

 

      of a quick summary.

 

                [Slide.]

 

                Now, this steroid, Clobex Lotion, was

 

      actually approved in 2003, and this actually was

 

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

 

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

 

      pediatric patients if we needed it.

 

                These trials, atopic dermatitis and for

 

      psoriasis, were done in both pediatric and adult

 

      patients.

 

                [Slide.]

 

                There were 3 studies involving Clobex

 

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

 

      atopic dermatitis, and 1 pediatric study, ages 12

 

      to 17 years in atopic dermatitis.

 

                In all of the studies, there was a

 

      comparator drug, Temovate E Cream, which is also

 

      clobetasol propionate, so the same chemical moiety

 

                                                                64

 

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

 

      Class I steroid.

 

                [Slide.]

 

                The construct of the HPA axis evaluation

 

      for this study went back to the 3 criteria, and

 

      that is because the actual NDA and construct of the

 

      study was done prior to our criterion of just 1,

 

      because it was approved in 2003, so the studies

 

      were done prior to that.

 

                [Slide.]

 

                In the adolescent study, there were 24

 

      evaluable patients, 14 were treated with Clobex

 

      Lotion and 10 were treated with Temovate E Cream.

 

                They all had moderate to severe atopic

 

      dermatitis. They had to have a body surface area

 

      involvement of at least 20 percent.  The medication

 

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

 

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

 

      was driven by the fact that Temovate E Cream, that

 

                                                                65

 

      is how it's labeled.

 

                [Slide.]

 

                It was found that 9 of the 14 or 64

 

      percent of subjects treated with Clobex Lotion were

 

      suppressed versus 20 percent of subjects treated

 

      with Temovate E Cream, again suggesting that the

 

      vehicle may have something to do with the amount of

 

      drug that gets into the systemic circulation.

 

                [Slide.]

 

                In the statistical analysis the mean

 

      percent body surface area treated was higher for

 

      patients that had adrenal suppression, 32.8 percent

 

      versus 27.7 for the Clobex Lotion and 35 percent

 

      versus 25.3 percent for the Temovate E Cream.

 

                [Slide.]

 

                When retested, 1 of the 4 patients treated

 

      with Clobex Lotion remained suppressed after 2

 

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

 

      that was suppressed with Temovate E Cream

 

      recovered.

 

                [Slide.]

 

                In the adult study, there were 18

 

                                                                66

 

      evaluable patients, 9 were treated with Clobex

 

      Lotion and 9 with Temovate E.  They all again had

 

      moderate to severe atopic dermatitis.  The mean

 

      body surface area treated was approximately the

 

      same for both drug products.  They applied it twice

 

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

 

                [Slide.]

 

                Here, 56 percent of the patients treated

 

      with Clobex Lotion suppressed and 44 percent with

 

      the Temovate E Cream suppressed.

 

                [Slide.]

 

                When looking at recovery for these 2

 

      products, 1 of the 3 patients retested failed to

 

      recover function 7 days post-treatment with the

 

      Clobex Lotion, and 2 out of 2 patients on Temovate

 

      E Cream recovered their function 7 days afterwards.

 

                [Slide.]

 

                Finally, in the adult study, moderate to

 

      severe plaque psoriasis , there were 20 evaluable

 

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

 

      surface area treated for both was approximately the

 

      same.  The medication was applied twice a day here

 

                                                                67

 

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

 

      limit.

 

                [Slide.]

 

                Eighty percent of the patients treated

 

      with Clobex Lotion suppressed and 30 percent with

 

      Temovate E Cream suppressed.  One of the 2 subjects

 

      retested with Clobex Lotion remained suppressed

 

      after 8 days, and none of the 3 subjects on

 

      Temovate E Cream unfortunately were retested.

 

                [Slide.]

 

                So, the indication for Clobex Lotion, when

 

      it was approved based on these results, was that it

 

      would be restricted to patients 18 years of age or

 

      older.  It could be used for two consecutive weeks

 

      not to exceed 50 grams/week.

 

                For moderate or severe psoriasis, for

 

      localized lesions less than 10 percent body surface

 

      area involvement, that an additional 2 weeks of

 

      treatment, the lotion could be used.  Appropriate

 

      other sections of the label were updated.

 

                [Slide.]

 

                Now, I am going to shift gears from our

 

                                                                68

 

      trial data and look at a postmarketing summary of

 

      HPA axis suppression across all topical

 

      corticosteroids since the induction of the AERS

 

      database, which is one of our sources since 1969,

 

      and also from medical literature case reports.

 

                [Slide.]

 

                I will just give you a background on the

 

      Adverse Event Reporting System.  It is a

 

      spontaneous, voluntary surveillance system.  It is

 

      voluntary reporting by health care professionals

 

      and consumers, but it requires mandatory reporting

 

      by manufacturers.

 

                There are approximately 3 million reports

 

      in the database.  Again, the database originated in

 

      1969.  It contains human drug and therapeutic

 

      biologic reports.  The exception is it doesn't have

 

      vaccines.

 

                The quality of the reports are variable

 

      and they are often incomplete, so you have to keep

 

      that in mind.  It is also subject to

 

      under-reporting, the true numerator is not known,

 

      and duplicate reporting does occur.

 

                [Slide.]

 

                There have been 94 cases reported spanning

 

      3 decades, 65 adult cases and 29 pediatric cases.

 

                                                                69

 

      The gamut of manifestations had been adrenal

 

      insufficiency, Cushing's syndrome, and growth

 

      retardation.

 

                [Slide.]

 

                In the 29 pediatric patients, and some of

 

      these overlap within same patients, 11 were with

 

      adrenal insufficiency, 17 with Cushing's syndrome,

 

      and there are 13 with growth retardation.

 

                The ages ranged from 6 weeks to 15 years

 

      with the mean being 5 years.  The duration of use

 

      was 22 days to 7.5 years with a mean of 20.8

 

      months.  Fifty-five percent of these patients

 

      received medication for 3 months or longer. There

 

      were varied indications, but 34 percent in the

 

      pediatric population were using topical

 

      corticosteroids for diaper rash.

 

                Betamethasone containing, clobetasol, and

 

      mometasone products were implicated most often with

 

      34 percent using high-potency topical

 

                                                                70

 

      corticosteroids.

 

                In these 29 pediatric patients who had

 

      evidence of some type of HPA axis compromise, it

 

      resulted in 14 hospitalizations and 2 deaths.  The

 

      latter were from Cushing's syndrome or

 

      complications thereof.

 

                [Slide.]

 

                In the adult cases, there were 65, 46 with

 

      adrenal insufficiency and suppression, 32 with

 

      Cushing's syndrome.

 

                The age range was from 19 years to 74

 

      years, with the mean age being 47.4 years.  The

 

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

 

      use was 35.6 months.

 

                Forty-six percent of the patients received

 

      the medication for 3 months or longer.  Again,

 

      there were varied indications, but 51 percent used

 

      topical steroids for psoriasis.  Again,

 

      betamethasone containing and clobetasol products

 

      were implicated most often, with 61 percent using

 

      high potency topical corticosteroids.

 

                These cases resulted in 34

 

                                                                71

 

      hospitalizations and 2 deaths, and the deaths were

 

      attributed in part of the adrenal event.

 

                [Slide.]

 

                So, the postmarketing reports, just in

 

      summary, the common factors were that most of the

 

      AEs occurred in the following settings:

 

                Prolonged use of the topical

 

      corticosteroid, use of a superpotent topical

 

      corticosteroid, use of multiple topical

 

      corticosteroid products or concomitant use with

 

      other corticosteroid formulations like inhaled or

 

      systemic, and also use of excessive amount or

 

      possible inappropriate use of the topical

 

      corticosteroid product.

 

                [Slide.]

 

                In summary of the data for the HPA axis

 

      suppression, HPA axis suppression does occur with

 

      the use of topical corticosteroids.

 

                The adrenal suppression is not limited to

 

      the superpotent class of topical corticosteroids.

 

                High BSA involvement and amount of drug

 

      used appear to be risk factors for HPA axis

 

                                                                72

 

      suppression.

 

                [Slide.]

 

                The type of vehicle may contribute to the

 

      extent of absorption of the active chemical moiety.

 

                The suppression appears in most cases to

 

      be reversible upon cessation of drug usage.

 

                Long-term use of topical corticosteroids,

 

      particularly high potency ones, can lead to serious

 

      morbidity and even death.

 

                [Slide.]

 

                Now, we are going to move on to cutaneous

 

      safety. We will first speak about the known

 

      cutaneous adverse events, and then we will just

 

      address here briefly the question of cutaneous

 

      malignancy as it might relate to topical

 

      corticosteroids, if at all.

 

                [Slide.]

 

                Now, the adverse events associated with

 

      topical corticosteroid use include atrophy of the

 

      skin, telangiectasia, striae, erythema of the face,

 

      steroid rosacea, hypopigmentation, infection, and

 

      retarded wound healing.

 

                [Slide.]

 

                Because pictures speak a thousand words, I

 

      am going to give you a pictorial presentation of

 

                                                                73

 

      these adverse events.

 

                [Slide.]

 

                This is a photo of cutaneous atrophy.  It

 

      is not the best photo, but here you can appreciate

 

      a little bit of thinning of the skin and some

 

      shininess to the cutaneous surface.

 

                [Slide.]

 

                Here, we have telangiectasia.  You can see

 

      the very fine blood vessels coursing here through

 

      this person's chin.

 

                [Slide.]

 

                This is a picture of striae, probably

 

      long-standing.

 

                [Slide.]

 

                Another picture of striae, maybe a little

 

      more of acute onset in nature.

 

                [Slide.]

 

                This is a picture of facial erythema.

 

                [Slide.]

 

                Another of facial erythema.

 

                [Slide.]

 

                This is a picture of steroid rosacea where

 

      someone was applying topical corticosteroids and

 

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

 

      potency of the topical corticosteroid would have to

 

                                                                74

 

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

 

      underlying disease, had to be treated

 

      appropriately.

 

                [Slide.]

 

                This is a picture of hypopigmentation from

 

      topical corticosteroid use.

 

                [Slide.]

 

                Other adverse effects that can happen.

 

      Topical corticosteroids placed on certain

 

      infections, for example, tinea infections, may

 

      exacerbate them.  Topical corticosteroids placed on

 

      open or surgical wounds will retard healing.  Use

 

      of topical corticosteroids in the periorbital area

 

      may cause an increase in intraocular pressure.

 

                [Slide.]

 

                Now, as far as cutaneous malignancy, we

 

                                                                75

 

      will look at the postmarketing reports out of the

 

      same system that I was speaking about prior, the

 

      AERS database, and there are 2 reports as of

 

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

 

      1969.

 

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

 

      of mastocytoma, and he reported or someone reported

 

      cancer several months after discontinuation of

 

      clobetasol.  The patient actually used fluticasone

 

      for a short while, and then used clobetasol

 

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

 

      started to reapply for another week, but developed

 

      cutaneous atrophy, and the medication was stopped,

 

      and then several months later, the report came that

 

      he developed skin cancer.

 

                The second case is a female of unknown age

 

      who used betamethasone cream for psoriasis and then

 

      reported "what started as psoriasis became cancer".

 

                So, from this we can say that the AERS

 

      data do not suggest a compelling safety signal for

 

      malignancy formation with the use of topical

 

      corticosteroids.

 

                [Slide.]

 

                So, as far as cutaneous adverse events,

 

      corticosteroid-induced adverse events can be early

 

                                                                76

 

      or late event.  It depends on the potency of the

 

      drug and the duration of use.  It depends on the

 

      site of application. Occlusion at the site may

 

      increase the risk.

 

                 Corticosteroid-induced adverse events may

 

      resolve slowly or they may not resolve at all.

 

                [Slide.]

 

                So, in conclusion, HPA axis suppression

 

      can occur with short-term use of topical

 

      corticosteroids.  HPA axis suppression can occur

 

      with even mid-potency topical steroids.  It can

 

      occur as early as two weeks of continuous therapy.

 

                [Slide.]

 

                The suppression that occurs is usually

 

      reversible. The interrelationship between body

 

      surface area, amount of drug used, and potency of

 

      the medication is complex as it relates to the

 

      development of HPA axis suppression.

 

                Long-term use and/or misuse of topical

 

                                                                77

 

      corticosteroids, particularly those of high

 

      potency, can lead to serious medical complications

 

      and death.

 

                [Slide.]

 

                The cutaneous adverse events can be

 

      related to both duration of use and potency of

 

      topical corticosteroid use.  It can occur with

 

      short-term or long-term use.

 

                Resolution of these cutaneous adverse

 

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

 

                There also is no firm evidence to date to

 

      link cutaneous malignancy with the use of topical

 

      corticosteroids.

 

                Thank you for your attention for this

 

      presentation.

 

                Next, we will have Dr  Stephen Wilson.  He

 

      is in the Division of Biometrics II.  He will speak

 

      on lessons learned from growth studies with orally

 

      inhaled and intranasal corticosteroids.

 

            Lessons Learned from Growth Studies with Orally

 

                 Inhaled and Intranasal Corticosteroids

 

                DR. WILSON:  Gray Gaithersburg morning to

 

                                                                78

 

      you.

 

                It is my pleasure to be here this morning

 

      substituting for Peter Starke.  I think that I was

 

      elected for this job because I am the only one that

 

      was around when they did the class labeling

 

      advisory committee in 1998, but we have had some

 

      lessons that we have learned from that advisory

 

      committee in dealing with growth studies for orally

 

      inhaled and intranasal corticosteroids, and I would

 

      like to share some of those with you in the short

 

      amount of time that we have.

 

                [Slide.]

 

                Specifically, we have been charged with

 

      providing you with somewhat of a background of why

 

      we do these studies within our area for intranasal

 

      and orally-inhaled corticosteroids, and then talk

 

      about what these growth studies are.

 

                In particular, we are going to focus on

 

      what we call longitudinal growth studies, which are

 

      fairly long-term growth studies.  Then, we will

 

      talk about some of the design issues with these

 

      studies and the regulatory history that sort of

 

                                                                79

 

      brought us to this moment in terms of the science.

 

                I will provide with the results from some

 

      of the studies that we have seen within the

 

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

 

      Pulmonary and Allergy Drug Products.

 

                [Slide.]

 

                So, why do we perform growth studies?  I

 

      think that looking at it from our perspective,

 

      growth is an indicator of systemic exposure and of

 

      the potential to cause systemic toxicity.

 

                Growth suppression is a well-known side

 

      effect of systemic corticosteroid use.  It has a

 

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

 

      all CS given in sufficiently high doses will

 

      produce growth effects.  It is thought to be a

 

      direct effect on the bone, and may also act through

 

      secondary mediators and hormones.

 

                We believe that growth is the most

 

      sensitive indicator of systemic effect within our

 

      review environment because we have seen growth

 

      effects in the absence of effects from HPA axis

 

      studies by cosyntropin stimulation.

 

                [Slide.]

 

                There are basically two types of studies

 

      that are presented to us by sponsors.  One goes by

 

                                                                80

 

      the name of knemometry, and the other is the

 

      longitudinal or long-term growth studies.

 

                Sponsors have done knemometry studies.

 

      These are generally short-term studies, so it is

 

      attractive in the sense that they can be done

 

      rather quickly, and there are a number of

 

      methodological issues.  They can essentially be

 

      done in only a few centers.

 

                The consistency of results has been

 

      puzzling and a little bit problematic to us as a

 

      regulatory agency, because we don't always see the

 

      same kinds of results coming out, and we view these

 

      as primarily a research tool.

 

                So, focusing on longitudinal growth

 

      studies, these are growth studies designed to

 

      measure growth velocity over a 1-year treatment

 

      period, so this is a long treatment period.

 

                The patient population has to be carefully

 

      selected because this is a patient population that

 

                                                                81

 

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

 

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

 

      to run a concurrent control, so some on

 

      corticosteroids and others using other kinds of

 

      medications.

 

                [Slide.]

 

                What is the population that we look at in

 

      these growth studies?  These two CDC charts are

 

      provided primarily to show you where we consider

 

      growth to be fairly linear.

 

                For one thing, it is very difficult to get

 

      growth measurements in the youngest children, zero

 

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

 

      stadiometry measurements, and the growth is fairly

 

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

 

      years old depending on sex.

 

                So, this is the focus of these growth

 

      studies that are provided to us by the sponsors.

 

                [Slide.]

 

                So, what are these growth studies, what do

 

      they look like?  Basically, it is fairly

 

      straightforward.  It's serial stadiometry.  There

 

                                                                82

 

      is a baseline period of about 3 months in which we

 

      measure growth, baseline growth.

 

                Then, there is an on-treatment period and

 

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

 

      guidance that was developed following the advisory

 

      committee that I mentioned in 2001, and it is still

 

      available on the website, so you can see some of

 

      the details of what we are suggesting.

 

                [Slide.]

 

                So, longitudinal growth studies.  As I

 

      said, they are technically difficult to perform.

 

      They require relatively large numbers of children.

 

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

 

      that ideally, they would have almost 125 children

 

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

 

      they are quite a bit larger than the studies we

 

      have been looking at.

 

                They require a long baseline and treatment

 

      period, and the measurement and compliance issues

 

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

 

      keep children on these studies for a long time,

 

      working with parents and providing treatment.

 

                There are also statistical issues in terms

 

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

 

      what I think probably sponsors have the most

 

                                                                83

 

      problem with is we are not looking at these as

 

      superiority trials or even equivalence or

 

      non-inferiority trials.  It is just too difficult

 

      to make a judgment as to what the delta or the

 

      difference that you are looking at would be.

 

                So, we essentially are presuming that

 

      there is a growth effect from these drugs, and we

 

      are designing them to best characterize that

 

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

 

      means that you have to have the proper size, you

 

      have to conduct the studies appropriately, and that

 

      is what we are going to be reviewing if we are

 

      going to describe what your study has done in the

 

      label.

 

                So, the size of the growth effect that is

 

      clinically relevant is unknown or not fully known.

 

      That is what our presumption is.

 

                [Slide.]

 

                So, how did we get here?  Actually, there

 

                                                                84

 

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

 

      two longitudinal growth studies done to better

 

      characterize the systemic risks prior to

 

      consideration of taking beclomethasone dipropionate

 

      nasal spray over-the-counter.

 

                So, in other words, the company was

 

      developing, wanted to go OTC, had these growth

 

      studies going, and when the results of these growth

 

      studies became available, it was recognized that

 

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

 

      the other kinds of tests.

 

                Then, at that same time, the number of

 

      other companies who were doing growth studies also

 

      came in and demonstrated this same kind of effect.

 

                So, 1998, we held a Joint

 

      Pulmonary-Allergy and Metabolic-Endocrine Advisory

 

      Committee, which ended up recommending a class

 

      labeling for all orally inhaled and intranasal

 

      corticosteroids, and we ended up also implementing

 

      that recommendation.

 

                [Slide.]

 

                So, what did that label end up looking

 

                                                                85

 

      like?  Well, in the General Use and Pediatric Use

 

      Subsections, we essentially said orally

 

      inhaled/intranasal corticosteroids may cause a

 

      reduction in growth velocity in pediatric patients.

 

                Also, in the Pediatric Use Section, we

 

      noted that growth effect may occur in the absence

 

      of laboratory evidence of

 

      hypothalamic-pituitary-adrenal axis suppression,

 

      potential for treatment "catch-up" growth has not

 

      been addressed, and basically, our advice to the

 

      physician was to titrate to the lowest effective

 

      dose for each patient and monitor growth routinely.

 

                If reported, cases of growth suppression

 

      should be noted in the Advise Reactions Section.

 

                So, basically, in terms of this being a

 

      class labeling, we would only note certain kinds of

 

      growth suppression if it was being reported to our

 

      systems.

 

                [Slide.]

 

                So, how did this original study look, the

 

      one that we were looking at for the advisory

 

      committee?

 

                Intranasal beclomethasone basically was a

 

      randomized, double-blind, placebo-controlled,

 

      parallel group, prospective, one-year study.

 

                                                                86

 

                The age groups of the children, they were

 

      children with allergic rhinitis being treated by

 

      intranasal corticosteroids, ages from 6 to 9.5

 

      years.  Basically, the same size study groups, and

 

      you just had a placebo against the intranasal

 

      corticosteroid, about 50 in each group.

 

                [Slide.]

 

                Now, the results showed that the growth

 

      rate centimeters/year on the BDP treatment group

 

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

 

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

 

      the depression that we saw for that one year.

 

                Now, this was a statistically significant

 

      difference based on the prespecified analysis, and

 

      it was an unexpected result, but basically, we were

 

      comparing mean annual growth rates.

 

                In the same study, however, these same

 

      children were tested, and there was no significant

 

      differences observed between treatment groups by

 

                                                                87

 

      mean basal cortisol or ACTH-stimulated plasma

 

      cortisol levels.

 

                [Slide.]

 

                I wanted to make sure to include this

 

      slide.  This is again these same patients, and

 

      looking at those charts that you saw earlier, the

 

      growth charts, these are the results of the

 

      patients based on where they fell on those charts

 

      after a year.

 

                I can remember the endocrinologist, Sol

 

      Malozowski, was extremely interested in thinking

 

      about what it meant.  Even though we were looking

 

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

 

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

 

      obviously, and very concerned about, how the

 

      children as individuals or groups fell within these

 

      two groups.

 

                So, the mean data as expressed in

 

      percentage within growth rate percentiles is

 

      displayed here, so you can see something like 22

 

      versus 4 in placebo or less than 3 percent in terms

 

      of the average growth., and that was true

 

                                                                88

 

      throughout, so this is the mean data expressed

 

      another way.

 

                [Slide.]

 

                We also looked at some other intranasal

 

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

 

      You notice, as oftentimes happens, this was

 

      actually the largest difference that we saw was on

 

      the first one, and the intranasal drugs that came

 

      in afterwards, budesonide and fluticasone, also

 

      showed some growth depression.  Mometasone,

 

      however, as you can note, did not show.

 

                [Slide.]

 

                The orally inhaled drugs tended to show

 

      more growth suppression, BDP, for example, minus 2

 

      versus the 0.7 that you saw before.  This slide

 

      also indicates that this is a study that was done,

 

      and you had some of those younger children, so you

 

      tended to see a lot more variability in the

 

      estimate, so the recommendations in the guidance

 

      became, you know, you had to have these older

 

      children that you could measure, because a lot of

 

      these included recumbent measurements, and those

 

                                                                89

 

      are difficult measurements to make.

 

                Another thing here is that there is some

 

      kind of apparent dose effect from a company that

 

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

 

      data available to us in trying to make these

 

      determinations.

 

                [Slide.]

 

                So, the issues.  These are indeed

 

      difficult studies to perform if you are thinking

 

      about doing one of these studies.  They are also

 

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

 

      regulatory setting, so basically, you are taking

 

      what the company has given you as evidence, and you

 

      are making some assessment of that.

 

                If a company has, for example, if there

 

      are a lot of subjects that have dropped out, you

 

      have to worry a lot about missing data, and you

 

      have to worry about if they haven't measured them

 

      carefully over time, in other words, there are some

 

      sort of glitches in the measurement, they then make

 

      decisions as to how they are going to analyze that

 

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

 

                                                                90

 

      that, so these are difficult studies.

 

                Growth studies are not designed to

 

      evaluate obviously the reversibility of the HPA

 

      axis effects or changes greater than a year.  So,

 

      although we do measure for another 3 months after

 

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

 

      would be long term.

 

                A lot of these patients, a lot of these

 

      children are going to be on the drug for a lot

 

      longer than 1 year.

 

                We have not identified a clinically

 

      relevant effect size, and that means that we all

 

      sit around a number of time, on a number of

 

      occasions, saying how could we pin down what the

 

      effect size is, so that maybe we could look at

 

      non-inferiority trial, but everybody said that

 

      basically, it is not acceptable or there is no

 

      clinically relevant effect size on that mean value.

 

                [Slide.]

 

                So, conclusions.  We use growth studies as

 

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

 

      sensitive indicator of systemic effects, and we

 

                                                                91

 

      think of this because sometimes the HPA axis and

 

      the growth study results are discordant, they don't

 

      agree with each other.

 

                We take them as a surrogate for systemic

 

      exposure and potential to cause systemic toxicity.

 

      So, we are looking at children, these are people

 

      that are going to need these drugs, but we also

 

      take them with the notion that this is a sentinel,

 

      this is something that is going to tell us is this

 

      drug going to have effects more generally.

 

                We believe that results are applicable to

 

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

 

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

 

      class effect labeling, when you look at the class

 

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

 

      orally inhaled and intranasal corticosteroids have

 

      this effect.

 

                As these studies come in to us from

 

      companies, we review them and we determine whether

 

      or not this is information that is going to help

 

      the physician.  This is information we need to put

 

      into the label.

 

                Sometimes we put what the company has

 

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

 

      sure that the results of the study are as reliable

 

                                                                92

 

      as we would like them to be.

 

                [Slide.]

 

                Again, there is reference Division of

 

      Pulmonary and Allergy Drug Products.

 

                I can't believe that I actually finished

 

      early, but I look forward to any questions you

 

      might have.

 

                Thank you.

 

                The next presenter is Dr. Markham Luke.

 

                 HPA Axis Suppression Studies: Conduct,

 

                 Utility, and Pediatric Considerations

 

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

 

      of the Committee, ladies and gentlemen in the

 

      audience.

 

                [Slide.]

 

                Today, I am going to speak on topical

 

      corticosteroids and testing for adrenal suppression

 

      in the context of potential Rx to OTC switch.

 

                [Slide.]

 

                This is a brief outline of my talk.

 

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

 

      various systemic effects that have been seen with

 

      topical corticosteroids and some which have not

 

      been seen.

 

                We are also going to discuss specifically

 

                                                                93

 

      the hypothalamic pituitary adrenal axis testing,

 

      what tests are available to look at HPA, and more

 

      specifically, we are going to focus in on

 

      cosyntropin stimulation testing, look at what our

 

      current testing recommendations, how we are trying

 

      to standardize the testing, and we are going to

 

      discuss how precise an estimate would we need for

 

      adrenal suppression potential for OTC.

 

                [Slide.]

 

                Now, as Dr. Cook and Dr. Wilson have

 

      stated, prescription corticosteroids have systemic

 

      effects which we evaluate during drug development.

 

                [Slide.]

 

                Now, I would like to separate these out

 

      into those areas where specific studies have not

 

      been required for dermatologic topical

 

                                                                94

 

      corticosteroids.  These include sodium retention on

 

      mineralocorticoid effect, glucose tolerance, growth

 

      suppression, osteoporosis, and what we do look at,

 

      which is HPA axis suppression.

 

                With regard to sodium retention, they are

 

      receptor-specific effects and they may be less

 

      concerned with glucocorticoids.  I am going to go a

 

      little bit into that.

 

                Regarding glucose tolerance and growth

 

      suppression, data available for glucose tolerance

 

      from clinical studies, the growth suppression

 

      studies, as Dr. Wilson has discussed, is

 

      technically challenging and is difficult to perform

 

      and to review.

 

                Further, for osteoporosis, the same could

 

      be said for that.  It is difficult to have these

 

      topical corticosteroids used for the long term.

 

      The patients wax and wane with their disease, so

 

      the application of the topical corticosteroid can

 

      increase and decrease, plus the strength of the

 

      corticosteroid may vary during the conduct of a

 

      year-long study, so there is the potential for

 

                                                                95

 

      change in dose and potency, which again leads to

 

      inconsistent and very challenging evaluation of any

 

      data that would be obtained from such a study.

 

                Regarding HPA axis suppression, we will

 

      get into that a little bit more.

 

                [Slide.]

 

                This is a table of the relative potencies

 

      for various steroids with a cortisol at 1.0 and

 

      there are two references in the package that was

 

      given to the Committee regarding this.  This table

 

      is excerpted from those references.

 

                As you can see, the two examples of

 

      topical corticosteroids given in this table are

 

      triamcinolone and betamethasone.  Both of those

 

      have a higher affinity or a higher relative potency

 

      regarding glucocorticoid effect but a lower

 

      mineralocorticoid effect.  This can be contrasted

 

      to aldosterone which has a much higher

 

      mineralocorticoid effect as compared to

 

      glucocorticoid effect.

 

                (Slide.)

 

                This is a schematic diagram of the HPA

 

                                                                96

 

      axis.  We have been talking a lot about the HPA

 

      axis.  Regarding specifically what it is, we have

 

      the hypothalamus.  This is  a schematic

 

      representation, again; the pituitary, anterior

 

      pituitary, and what their effects are on adrenals.

 

                This is a neural, hormonal axis and is

 

      important for the human response to stress.  Humans

 

      respond to stress by producing ACTH which then

 

      causes cortisol rises.  F stands for cortisol here

 

      in this diagram.  If there is a failure to mount

 

      such a response, it can lead to a hypotension and

 

      cardiovascular collapse.

 

                Now, this failure to mount may not be

 

      easily clinically recognizable so attributing cause

 

      and effect may be difficult with regards to adrenal

 

      suppression in the clinical setting.

 

                The ACTH here, in general, causes a rise

 

      in the cortisol.  However, with constant exposure

 

      to exogenous corticosteroids, it has been thought

 

      that there is a down-regulation of receptors here

 

      and here which may lead to decrease-ability of the

 

      adrenals to then respond and produce cortisol.

 

                (Slide.)

 

                With that, we get into HPA axis testing.

 

                (Slide.)

 

                                                                97

 

                There are two classes of tests, basic

 

      classes; the basal testing, which is done with

 

      basal plasma levels and 24-hour urine cortisol

 

      levels.  These are thought to be less useful in

 

      measuring an adrenal response to stress than

 

      dynamic testing where you try to stimulate the

 

      adrenals to cause a response and you measure the

 

      magnitude of that response.

 

                (Slide.)

 

                There are various dynamic tests of HPA

 

      axis function.  Earlier, it was mentioned, the

 

      insulin tolerance test which is an older test.

 

      When you administer insulin, you cause a

 

      hypoglycemic event.  It then results in a potent

 

      stress stimulus for the adrenal glands.

 

                Now, these subjects, when you administer

 

      insulin, you need very close subject monitoring.

 

      It is thought that this test, as it is currently

 

      done, produces undue risk to the subject and,

 

                                                                98

 

      therefore, the agency does not recommend this as a

 

      test for HPA axis function.

 

                The cosyntropin, or ACTH amino acids 1 to

 

      24, test is available in higher or lower

 

      concentrations.  The higher dose is the labeled

 

      dose for cosyntropin.  Lower dose studies vary and

 

      there is no standardization regarding how much of a

 

      rise in cortisol you need with lower dose and the

 

      timing of the rise is not standardized.  So the

 

      lower test is still experimental at this time and

 

      if one is to use it, there should be discussion

 

      with the Agency regarding how it is used.

 

                For higher dose testing, we will discuss

 

      that in just a moment.  There is also a

 

      corticotropin-releasing hormone test, the CRH test.

 

      This also is experimental and not widely available.

 

                (Slide.)

 

                The higher dose cosyntropin test is the

 

      most commonly used test to evaluate for adrenal

 

      suppression.  The procedure is to administer a

 

      superphysiologic dose.  It is currently labeled for

 

      IV or IM use of 125 micrograms if the patient is

 

                                                                99

 

      less than 3 years of age or 250 micrograms if the

 

      patient is 3 years or older.  The serum or plasma

 

      cortisol concentrations are measured before and 30

 

      minutes after the cosyntropin administration.

 

                (Slide.)

 

                The advantages of this test are that it is

 

      simple, it is fast and relatively inexpensive.  It

 

      is an outpatient test and it takes approximately 30

 

      minutes to do.  There are some limitations.  It is

 

      not the most sensitive test.  It can be equated to

 

      being a physiologic hammer.  I mean you are giving

 

      a very high dose of what is equivalent to ACTH to

 

      cause the adrenals to respond. So the sensitivity

 

      may have some concern.

 

                (Slide.)

 

                The criteria for a normal response in

 

      Cortrosyn, according to label and the 30-minute

 

      test is as follows:  The control of basal cortisol

 

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

 

      minutes, after administering the Cortrosyn, there

 

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

 

      incremental cortisol rise, that is--and the

 

                                                               100

 

      30-minute level should exceed 18 mcg/dL.

 

                However, we note that basal cortisol

 

      levels vary throughout the day and the higher the

 

      basal level, the lower the incremental cortisol

 

      rise.  So, for regulatory purposes and for drug

 

      development, it is thought that normal response of

 

      peak cortisol level of greater than 18 mcg/dL 30

 

      minutes after giving Cortrosyn should be sufficient

 

      as the test for adrenal suppression.

 

                (Slide.)

 

                With that, we segue to what are current

 

      testing recommendations for adrenal suppression.

 

                [Slide.]

 

                There was an Advisory Committee on October

 

      29th of 2003, and there was some discussion about

 

      the HPA axis test, Joint Committee discussion.  It

 

      was discussed that higher dose cosyntropin test is

 

      a sufficient determinant of HPA axis function with

 

      regard to prescription topical corticosteroids.

 

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

 

      post-stimulation cortisol level at 30 minutes is

 

      equivalent to that subject being not suppressed. 

 

                                                               101

 

      It was also discussed at that Advisory Committee

 

      where data was presented on reversibility, and you

 

      saw the reversibility data, we have very little of

 

      that.  We need follow-up for reversibility when we

 

      do these studies.

 

                [Slide.]

 

                It was a pediatric meeting, so there was

 

      discussion about the pediatric cohorts.  The

 

      pediatric population was divided into 4 cohorts

 

      here.  Sequential testing was usually done for

 

      these studies with the older patients first, but at

 

      this Advisory Committee it was discussed that

 

      potentially concurrent testing can be done if the

 

      safety of the patients can be assured.  The

 

      rationale for that is to obtain more data regarding

 

      the adrenal suppression in each of these cohorts.

 

                [Slide.]

 

                Additional recommendations from the Agency

 

      are as follows:  the 60-minute cortisol is not

 

      recommended.  The standardization for a 60-minute

 

      level is poor, and the results can vary somewhat

 

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

 

                Testing less than 4 weeks apart is not

 

      recommended.  Administering the ACTH or Cortrosyn

 

      start to leave an impression on the adrenals and

 

                                                               102

 

      there may be effects on later response especially

 

      when the tests are done closer than 4 weeks apart.

 

                There is a need to monitor the local

 

      cutaneous adverse events during the conduct of this

 

      study.

 

                Finally, it is important to note when

 

      interpreting these studies that the percent of

 

      patient suppressed, not the mean cortisol levels is

 

      important.  Mean levels may mask individual

 

      patients, so if someone were to present data on

 

      mean levels, ask them what the percent of patients

 

      suppressed was.

 

                [Slide.]

 

                Finally, we note Dr. Cook's presentation,

 

      the body surface area involved can vary from atopic

 

      dermatitis, at least 30 percent body surface area

 

      is needed, for psoriasis, at least 25 percent body

 

      surface area involvement for these patients, and

 

      these are maximally involved diseased patients.

 

                It is also important to note that patients

 

      who enter the study should not be adrenal

 

      suppressed, so there should be testing for adrenal

 

      suppression prior to exposing them to

 

      corticosteroid to make sure they are not suppressed

 

      at baseline.  Often these patients will have come

 

                                                               103

 

      into a study having been on other corticosteroids

 

      for a protracted length of time because of their

 

      significant disease.

 

                [Slide.]

 

                The last part of this talk, we are going

 

      to discuss a little bit about what precision do we

 

      need for OTC use of corticosteroids.

 

                [Slide.]

 

                For topical corticosteroids drugs to be

 

      used in an OTC setting, how acceptable is HPA axis

 

      suppression, and how many subjects need to be

 

      evaluated to rule out corticosteroid-induced

 

      adrenal suppression for an OTC product if this is

 

      one of the tests that is going to be used?

 

                [Slide.]

 

                Here is an exercise I would like to pose

 

                                                               104

 

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

 

      all with topical corticosteroids for 4 weeks, and

 

      we noted those 30 subjects, zero had cosyntropin

 

      stimulation test indicative of adrenal suppression,

 

      that is, the rate was zero out of 30.

 

                The question arises with what risk, if

 

      any, of adrenal suppression induced by topical

 

      corticosteroids might these results be compatible,

 

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

 

      is not.

 

                [Slide.]

 

                Zero out of 30 subjects rules out, with 95

 

      percent confidence, a greater than 10 percent

 

      chance for adrenal suppression to occur in the

 

      global population.  This is a statistical concept,

 

      and there is a paper in the package that was handed

 

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

 

      to look at this.

 

                The sample size determines the extent we

 

      can rule out adrenal suppression in the global

 

      population with zero subjects suppressed.

 

                [Slide.]

 

                With that, we can go to this table on

 

      sample size effect on the upper confidence interval

 

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

 

                                                               105

 

      10 subjects and we had zero of those 10 subjects

 

      suppressed.

 

                Well, that would rule out with a 95

 

      percent confidence interval no greater than 26

 

      percent adrenal suppression.  Whereas, if we double

 

      the number and go to 20 subjects, we can increase

 

      that upper confidence interval to 14 percent.

 

                To get to really small percentage numbers

 

      for upper adverse event occurrences, we need larger

 

      sample sizes.  So, the greater the number of

 

      patients you have, the more assuredly you can be of

 

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

 

      does give you zero.

 

                [Slide.]

 

                So, the question asked for the Committee:

 

      Cosyntropin stimulation studies are used to inform

 

      labeling for prescription products with regard to

 

      potential for adrenal suppression.

 

                If the cosyntropin stimulation studies are

 

                                                               106

 

      to be used for OTC products, how many subjects are

 

      needed for those studies, that is, what is the

 

      level of tolerance for adrenal suppression for an

 

      OTC drug product?

 

                That is it for my portion of the talk.

 

      Thank you.

 

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

 

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

 

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

 

      we will go straight to the questions for the

 

      speakers, and then pass on to the questions for the

 

      Committee at that point.

 

                [Break.]

 

                    Questions from the Committee and

 

                          Committee Discussion

 

                DR. WOOD:  So we have heard all the

 

      presentations.  Let's open the session for the

 

      Committee to question the speakers.  Terry?

 

                DR. BLASCHKE:  I have a technical

 

      question, I think for Dr. Luke.  In your

 

      presentation, you indicated that the cosyntropic

 

      administration could be IV or IM.  I am just

 

                                                               107

 

      wondering how many of the subjects, for example, in

 

      the studies that we were presented actually got the

 

      cosyntropin IM and do we know whether there is more

 

      variability or sensitivity, differences in

 

      sensitivity, when the cosyntropin is administrated

 

      IM versus IV.

 

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

 

      comparisons in the literature between IM and IV

 

      use.  For pediatric studies, it is often more

 

      convenient to do an IV study rather than an IM

 

      study simply because of the pain threshold of those

 

      patients.  You can insert a cannula and inject the

 

      cosyntropin and also withdraw blood from the same

 

      cannula afterwards and so there is only one stick.

 

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

 

      access difficulties that one would resort to an IM.

 

      Regarding whether one should do IM or IV, I think

 

      it is important to be consistent throughout each

 

      study as to what route you choose to administer the

 

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

 

      studies to compare the two routes.

 

                DR. BLASCHKE:  I suspect it is not done

 

                                                               108

 

      consistently because I suspect that it really does

 

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

 

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

 

      compounds that, when they are administered IM,

 

      depending on where, et cetera, that the absorption

 

      and the absorption rate is quite different for IM,

 

      obviously, than IV.

 

                It sounds like, as you say, there is no

 

      comparative data so maybe no answer to the

 

      question.

 

                DR. WOOD:  Dr. Snodgrass.

 

                DR. SNODGRASS:  Are there any standards

 

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

 

      example, and knowledge about their sleep patterns

 

      for the circadian rhythm aspects?

 

                DR. LUKE:  Because of the circadian

 

      rhythm, it is thought that a standard time might be

 

      helpful but keep it close within.  It is often

 

      difficult to do a study where you have all the

 

      patients done at the same time.  So there is some

 

      variability allowed for it.

 

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

 

                                                               109

 

      concern.  Of note, the lower cosyntropin

 

      stimulation test, the lower dose, there have been

 

      concerns raised about the peptide sticking to

 

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

 

      performing lower dose cosyntropin testing.

 

                DR. WOOD:  Dr. Epps.

 

                DR. EPPS:  My questions actually are for

 

      Dr. Wilson.  Is that okay?

 

                DR. WOOD:  Sure.  We are taking questions

 

      for all of the last speakers.

 

                DR. EPPS:  Okay.  The growth charts, the

 

      CDC growth charts, were those based on the standard

 

      growth charts that are used or are they updated and

 

      different?

 

                DR. WILSON:  Those are the standard growth

 

      charts that everybody sees and are available from

 

      the government.

 

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

 

      thought it was my understanding that they were

 

      standardized on a group of cohorts in Kansas in the

 

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

 

      wondered if they had been updated at all.

 

                DR. WILSON:  That is a good question.  I

 

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

 

      the most current was.  We recommend the most

 

                                                               110

 

      current.  These are trials in which we have

 

      comparators and are randomized.  So we have all

 

      those kinds of things taken care of.

 

                But you are right.  We pondered a lot

 

      about the growth charts and what they really meant

 

      for individuals.  As you were looking at those

 

      percentage breakdowns, that is where it becomes

 

      more important probably.

 

                DR. EPPS:  Also, my question was do the

 

      kids recover.  You were taking about growth

 

      velocity which is different from overall growth

 

      potential and whether--you know, kids accelerate

 

      and decelerate and, really, the lines are kind of

 

      percentiles or averages.  So that was one question

 

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

 

      term.

 

                DR. WILSON:  The long term.  Again,

 

      sponsors have presented to us, and there have been

 

      a few studies done on trying to assess whether

 

                                                               111

 

      there are some long-term effects.  But those are

 

      even more difficult to do than these annual

 

      studies.

 

                I think that the assumption has always

 

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

 

      that a lot of this will be recovered.  We have

 

      never looked at ultimate height.  Companies, of

 

      course, are always saying this.  They want to have

 

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

 

      it.

 

                This is Gene Sullivan from the Division.

 

                DR. SULLIVAN:  Hi.  I am a pulmonologist

 

      in the Pulmonary Division.  I think what you are

 

      getting at is part of the reason why the slide said

 

      we don't know the clinical significance.  We can

 

      measure what happens in that year, what happens

 

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

 

      is the full adult height affected?  Those are

 

      still, we consider, unknown.

 

                DR. EPPS:  To follow up that, what about

 

      children who have asthma or are on these

 

      medications?  Is their velocity different from

 

                                                               112

 

      normal?  In other words, sometimes growth is

 

      affected just by having chronic disease.

 

                DR. WILSON:  By the disease itself.  But

 

      these pediatric studies, for a number of reasons

 

      including ethical considerations, are done in

 

      children with the disease.  So the studies of

 

      orally inhaled corticosteroids are done in children

 

      who need the medications.  So the comparison is the

 

      placebo group versus the active treatment should

 

      take that out of the picture.

 

                DR. EPPS:  Certainly, breathing comes

 

      first.

 

                Now, my last question is, for any of these

 

      studies with inhaled and intranasal steroids, did

 

      any of them also have atopic dermatitis?  They

 

      usually run together, so you might have topical

 

      steroids and intranasal and inhaled steroids all

 

      working together, and would that affect their

 

      growth, as well

 

                DR. SULLIVAN:  I can't say categorically

 

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

 

      well, but I presume that almost all of them would

 

                                                               113

 

      have excluded concomitant use of other

 

      corticosteroids.

 

                DR. WOOD:  Dr. Bigby.

 

                DR. BIGBY:  I have actually four

 

      questions.  The first one actually is a

 

      philosophical question both for the FDA and for the

 

      people here on the panel.  If one of these classes

 

      of topical corticosteroids has been shown to

 

      produce HPA axis suppression, would we not

 

      recommend it for OTC approval?  That is the

 

      philosophical question.

 

                DR. WOOD:  That is the question we are

 

      going to address in the discussion on the

 

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

 

      our questions to the last set of speakers, so we

 

      can let them off the hook.

 

                DR. BIGBY:  The second question is has an

 

      ingredient ever gone backwards from being OTC to by

 

      prescription?  What I am really asking is, if we

 

      make a mistake, can we go backwards?

 

                [Laughter.]

 

                DR. WOOD:  I will answer for them, because

 

                                                               114

 

      they won't.  Not without a huge amount of

 

      difficulty is the answer.  It is much harder to get

 

      something off the market than it is to not approve

 

      it to go on.

 

                DR. BIGBY:  Lastly, other than

 

      hydrocortisone, is there any foreign country

 

      experience with an OTC more potent topical

 

      corticosteroid?

 

                DR. KOENIG:  I am sorry, I thought about

 

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

 

                Does anyone in the audience know?

 

                DR. GANLEY:  We have some industry folks

 

      here, they may know that answer.

 

                DR. WOOD:  Let's move on then.

 

                Dr. Davidoff.

 

                DR. DAVIDOFF:  Yes, I would like to shift

 

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

 

      bones at the other end of the age spectrum, because

 

      as you hit around my age, there is obviously the

 

      problem of osteoporosis, and I understand that it

 

      is difficult to study osteoporosis, but that is

 

      such a huge public health and medical problem, I

 

                                                               115

 

      wonder if there are any data on potent

 

      corticosteroid dermatologic preparation's effect on

 

      bone density in the older age group.  However

 

      preliminary or partial or whatever, I would think

 

      that any hints as to that potential toxicity would

 

      be extremely important.

 

                DR. WILKIN:  Well, I think we are limited

 

      somewhat in looking at the long-term safety with

 

      topical corticosteroids, because the conditions

 

      that they treat, the dermatologic conditions wax

 

      and wane significantly.

 

                It is not like with the pulmonary inhalers

 

      where a child may be expected to be using a product

 

      for very long periods of time.  The situation for

 

      dermatologic conditions is that often things will

 

      resolve, and maybe moisturizers alone, and then

 

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

 

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

 

      to a medium potency corticosteroid, so it would be

 

      difficult in that setting to say which

 

      corticosteroid actually led to it.

 

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

 

                                                               116

 

      we have that in a regulatory environment, but

 

      someone could look at a more general question in an

 

      academic environment I suppose, just, you know,

 

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

 

      products consistently over a long period of time,

 

      would those people be at risk.

 

                DR. DAVIDOFF:  Yes, exactly.  I mean I

 

      didn't expect that you would necessarily have it as

 

      part of the regulatory process, but whether you

 

      have looked or anyone has looked into literature

 

      specifically on that question.

 

                Mary, do you have any idea from the

 

      geriatric literature?

 

                DR. TINETTI:  I am not aware of any with

 

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

 

      issue.

 

                DR. GANLEY:  I just want to add something

 

      here.  I think in some of the presentations, that

 

      this growth suppression is really a surrogate for a

 

      possible systemic effect even when you would not

 

      have HPA axis suppression.

 

                That is how I think the Pulmonary Division

 

                                                               117

 

      has looked at it, is that if it causes growth

 

      suppression in kids, you could assume that in an

 

      adult, it could potentially cause this.

 

                I did a lot of literature search, and I

 

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

 

      attach topical corticosteroids with osteoporosis,

 

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

 

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

 

      that, in this setting, that growth suppression is a

 

      surrogate for other things.

 

                Now, the dose-response may be different,

 

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

 

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

 

      guess, the question you are trying to get at is

 

      would a topical steroid go OTC if it had systemic

 

      effects, and the specific targets you have

 

      illustrated it with are ones that are easily

 

      measured.  Is that fair?  Okay.

 

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

 

      and Jon has just mentioned it, with the topical

 

      corticosteroids, it is much more difficult to

 

      conduct a long-term study because of the variation

 

                                                               118

 

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

 

      so forth.

 

                DR. WOOD:  Dr. Whitmore.

 

                DR. WHITMORE:  I think one other thing

 

      that is most disturbing is in the betamethasone

 

      dipropionate studies looking at growth suppression,

 

      the 49 individuals, none of them showed any

 

      suppression, any adrenal suppression.

 

                I am presuming the same type of testing

 

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

 

      from that presumption, you can step from there and

 

      say there probably is some effect on growth in our

 

      patients who are having HPA suppression with their

 

      topical steroids.

 

                It is a different marker obviously, but it

 

      seems like if that is occurring in those patients

 

      with the inhalers, they are not getting HPA

 

      suppression.  We are getting HPA suppression in our

 

      patients with the topical steroids.  I would

 

      presume there is some bone effect, some growth

 

      effect if used long term.

 

                Was the testing that was done, the

 

                                                               119

 

      cosyntropin testing in those 49 patients?  That was

 

      for Dr. Wilson, I am sorry.

 

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

 

      understand it.

 

                DR. WHITMORE:  Oh, it was not?

 

                DR. WILSON:  No.  Markham has some more

 

      details on it.  Unfortunately, I was looking

 

      yesterday, trying to find out all of the data from

 

      that test for this committee, but was not able to

 

      locate the original.  It's a different test.

 

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

 

      assumptions about that, I presume.

 

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

 

      the pediatric testing that was done for the

 

      steroids, excluding clobetasol, you didn't have any

 

      adult testing for HPA suppression with those same

 

      steroids.

 

                I am presuming that the only HPA

 

      suppression was that we found in our brown book

 

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

 

      much lacking.  The only reason they did that was to

 

      go back to get pediatric approval.

 

                Is there any reason to presume that if

 

      someone is 13 years of age and has the same body

 

      surface area of involvement, they are not going to

 

                                                               120

 

      get the same HPA suppression?

 

                So, the companies that make the pediatric

 

      products that were doing the testing in pediatric

 

      patients, after they found HPA suppression with

 

      their products, they came back to the labeling

 

      saying 13 years of age or older.  Is there any

 

      reason to presume that HPA suppression is any

 

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

 

      It just is concerning.

 

                DR. COOK:  Yes, I see your point because

 

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

 

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

 

      to say that HPA axis suppression would not occur in

 

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

 

      data to be able to put that in labeling.

 

                DR. WHITMORE:  Has the FDA considered

 

      asking the companies to go back and study adults

 

      with any of these things?

 

                DR. WHITMORE:  Didn't you propose a

 

                                                               121

 

      hierarchical sort of structure?  At least that was

 

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

 

      HPA suppression in adults, so you would start with

 

      adults.  If that was positive, you would stop

 

      there, right?

 

                DR. COOK:  I think for newer drugs, like

 

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

 

      started with adults, and we also could ask for

 

      children.  For some of those products that I

 

      discussed there, have been on the market for many,

 

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

 

      regulation that could make the companies go back

 

      and look specifically at adults.

 

                The reason that we were able to do that

 

      for pediatric patients is because we got a new

 

      regulation that said we need more safety

 

      information in pediatric patients.

 

                Now, in some of the older tests that were

 

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

 

      when the drug products first came out, that is how

 

      they looked at HPA axis suppression back then.

 

                That was certainly in adults and did, you

 

                                                               122

 

      know, propagate the class labeling that said that

 

      you can get HPA axis suppression in adults, because

 

      the Temovate was done in adults and in

 

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

 

      atopic dermatitis and adults with psoriasis.

 

                DR. WHITMORE:  One last comment.  With the

 

      inhalant steroids, they oftentimes will look at

 

      markers of bone metabolism as opposed to looking

 

      for evidence of osteoporosis.  So, you can look at

 

      urinary calcium to creatinine ratios, you can look

 

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

 

      if there is evidence for decreased calcium

 

      absorption or excretion, and things like that.

 

                DR. WOOD:  Dr. Ringel.

 

                DR. RINGEL:  I was struck by the

 

      difference between the cosyntropin test and the

 

      tests that were originally done on hydrocortisone

 

      to justify its approval as an over-the-counter

 

      drug. I think it was Dr. Malkinson who did

 

      radiolabeling of hydrocortisone and showed that it

 

      was not absorbed, which seems very different from

 

      the cosyntropin test.

 

                As I was reading the preparatory material

 

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

 

      percent specificity of the test was 57 percent

 

                                                               123

 

      sensitive, and I guess I wanted to explore that,

 

      because I am want to make sure I really understand

 

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

 

      dermatologist, I am not an endocrinologist, and I

 

      just want to make sure I understand the test.

 

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

 

      chronic effects of corticosteroids, so that you are

 

      looking for adrenal atrophy, you are looking for

 

      the adrenal gland not to be able to respond to ACTH

 

      stress, which means to me that this test does not

 

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

 

      mean that you have excluded the fact that the

 

      pituitary may be insensitive to the cortisol, in

 

      other words, that it may just not be able to

 

      respond with its own ACTH.

 

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

 

      have an increase in cortisol after the ACTH test,

 

      it doesn't mean that that increase in cortisol is

 

      necessarily going to be sufficient for a particular

 

                                                               124

 

      stress.  It other words, maybe the person should

 

      have responded with an even greater cortisol

 

      increase for that level of ACTH stimulation.

 

                I guess what I am trying to do is explore

 

      the limits of what we are really testing with

 

      cosyntropin, and making sure this is really an

 

      appropriate test and it is going to pick up people

 

      whose pituitaries are suppressed.

 

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

 

                DR. LUKE:  We do have an endocrinologist

 

      on the panel who can help us with some of those

 

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

 

      having 18 or less of post-stimulation was thought

 

      to be a sufficient indicator that that patient

 

      would be suppressed.

 

                Now, as far as how much more of a rise

 

      would you need for other stressors, I think the 18

 

      was thought to be sufficient for most stressors.

 

                DR. RINGEL:  Do you know what the

 

      sensitivity was?

 

                DR. LUKE:  Of the test?

 

                DR. RINGEL:  Yes.

 

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

 

      address that?

 

                DR. STRATAKIS:  The cosyntropin test is a

 

                                                               125

 

      screening test for the diagnosis of adrenocortical

 

      insufficiency.  Therefore, as a screening test, it

 

      has a good specificity, a very good specificity.

 

      You can set out the specificity wherever you want,

 

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

 

      is how we use it.

 

                With the 18 as the cutoff, it has a

 

      sensitivity of about 70 percent, a specificity of

 

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

 

      detecting the patient who is adrenocortical

 

      insufficient.  It is not very good at identifying

 

      all the patients that have adrenocortical

 

      insufficiency, it misses about 30 percent of them.

 

                What I wanted to say is that a limiting

 

      step in the recovery of the HPA axis after

 

      adrenocortical suppression--and this has been shown

 

      in a couple of studies, that are very good

 

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

 

      the pituitary cell.  It is not the adrenal.

 

                There is actually a very good paper that

 

      was published about 10 years ago about that, and it

 

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

 

      we are suppressing by endogenous steroids or

 

      exogenous steroids, the HPA axis, all we are doing

 

      is we are suppressing the cortical trough cell of

 

                                                               126

 

      the pituitary and, to some extent, the

 

      CRH-producing neurons of the hypothalamus.

 

                We are not doing anything to the adrenals

 

      or this has not been shown convincingly I should

 

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

 

      anything to the adrenal cortex.

 

                Up to recently it wasn't even known, and

 

      to this day it is not known with certainty, that

 

      the glucocorticoid receptor is expressed in normal

 

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

 

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

 

      low levels.

 

                The other point is that since the

 

      rate-limiting step is the cortical trough, then,

 

      the question is how long does it take to develop

 

      adrenocortical atrophy in response to suppression,

 

                                                               127

 

      and that varies a lot from individual to

 

      individual, but on average, we consider that time

 

      to be approximately two weeks, approximately two

 

      weeks.

 

                I was surprised to see that in some of the

 

      studies with the mid-potency steroids, you have

 

      levels, we have levels of response to the ACTH stim

 

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

 

      look back at my patients with endogenous Cushing's,

 

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

 

      recovery time after a pituitary tumor-producing

 

      ACTH is excised.

 

                So, this is quite significant general

 

      atrophy, and since the test if not very sensitive,

 

      you would consider that as the tip of the iceberg,

 

      that you are really missing a lot of patients that

 

      have developed moderate adrenocortical atrophy, and

 

      you have no way of picking up those that have

 

      moderate cortical trough cell suppression in other

 

      words.

 

                DR. WOOD:  So, what would be your estimate

 

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

 

                                                               128

 

      what you said?

 

                DR. STRATAKIS:  The sensitivity is about

 

      70 percent, so I would say about 30 percent.

 

                DR. WOOD:  Jack.

 

                DR. FINCHAM:  This is just an observation

 

      in the context of what we are going to be

 

      discussing this afternoon as far as how these

 

      products may be used by consumers in an OTC

 

      setting, a nonprescription setting.

 

                I was struck by Dr. Cook's presentation of

 

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

 

      would assume that these are controlled situations

 

      where the individuals had some limits on what they

 

      could obtain and how they could obtain it, but in

 

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

 

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

 

      ounce a day being used, which is an enormous amount

 

      of product.

 

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

 

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

 

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

 

      Cook, on oral systemic agents that perhaps would

 

                                                               129

 

      have been used?  Were there strict limits on this

 

      being only topical application?

 

                DR. COOK:  Yes, since they were patients

 

      with atopic dermatitis and they weren't supposed to

 

      be on any other medications that would affect the

 

      outcome of the study.

 

                DR. FINCHAM:  I guess the observation is

 

      that was an enormous amount of product being used

 

      even in a controlled setting, and we can only

 

      presume what might happen or might not happen in an

 

      uncontrolled over-the-counter setting, whether it

 

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

 

      amount that was being used.

 

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

 

      that the parent continued to use the medication

 

      even when the patient was getting better over that

 

      same amount of body surface area, and even though

 

      you would think that the integument would not have

 

      been as compromised as time went on.  Somehow there

 

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

 

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

 

      HPA axis suppression.

 

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

 

      to the next question, I guess, none of the

 

      presenters actually told us why we care about HPA

 

                                                               130

 

      suppression that I can remember, and maybe we

 

      should just, for the record, say something about

 

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

 

      the consequences of having your HPA axis suppressed

 

      particularly in response to stress or surgery or if

 

      you end up in a road accident or whatever.  Just

 

      very briefly.

 

                DR. STRATAKIS:  The reason we care is

 

      because HPA axis suppression can lead to sudden

 

      death.  In fact, there was a recent study that

 

      looked at the long-term morbidity and mortality of

 

      patients with panhypopituitarism, and the single

 

      most frequent cause of death in this long-term

 

      status was, in fact, the absence of ACTH secretion

 

      by the pituitary, adrenocortical insufficiency, in

 

      other words, so sudden death.

 

                DR. WOOD:  So, showing up in an emergency

 

      room and not being recognized as having a failure

 

      of your stress response may be bad for you is the

 

                                                               131

 

      point we are getting at here.

 

                DR. STRATAKIS:  Right.  In fact, one would

 

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

 

      of the studies, there were two deaths that were

 

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

 

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

 

      actually kill you.

 

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

 

      complications thereof, it didn't really say.

 

                DR. WOOD:  Dr. Patten.

 

                DR. PATTEN:  I have a question about the

 

      HPA suppression retests.  It appears to me that the

 

      longest time lapse to retest was 14 days in these

 

      studies that Dr. Cook summarize for us.

 

                My question is this.  Does this imply that

 

      if recovery has not happened by 14 days, it is

 

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

 

      simply unknown territory?

 

                DR. COOK:  I would have to say that the

 

      studies are really inadequate to answer that

 

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

 

      patients retested like we would have liked, and

 

                                                               132

 

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

 

      patients failed to respond, they weren't retested

 

      again.  Those are certainly things that we are

 

      trying to address in future studies, especially

 

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

 

      have been out at least 4 weeks because of the

 

      possible influences of the results on continuously

 

      re-stimulating the adrenal gland.

 

                Unfortunately, we don't have the answer to

 

      that.

 

                DR. WOOD:  Dr. Nelson.

 

                DR. NELSON:  I would like to make some

 

      observations on the data that Dr. Cook presented

 

      and invite comments to just see if I am getting it

 

      right.

 

                This is just looking at what I see as 9

 

      pediatric studies that you presented.  If you look

 

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

 

      ignoring the differences in methods of adrenal

 

      suppression.

 

                If you scan it, in terms of potency, it

 

      looks to me like there may be an effect based on

 

                                                               133

 

      potency, but not being a statistician and just

 

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

 

      would assume then that the incidence of impact on

 

      growth philosophy would be higher than 27 percent

 

      given the data presented about the sensitivity of

 

      that finding.

 

                Then, the other question is whether there

 

      is a threshold and most of these studies are all in

 

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

 

      can't ask the question whether there is a threshold

 

      effect somewhere in terms of Class I.

 

                What I just did reflects my biases that

 

      since almost all studies that are submitted are

 

      usually for efficacy and other indications, that

 

      you can only see a safety signal if you do a

 

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

 

      if you had done that, you would have presented that

 

      data.

 

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

 

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

 

      rough non-statistician approach, of thinking about

 

      this data in the pediatric studies.

 

                DR. WILKIN:  I think the answer is yes.

 

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

 

      basically looking in the individual studies, the

 

                                                               134

 

      denominators are small, and that you really ought

 

      to look across classes, and I think we take your

 

      point that we might learn something more about the

 

      class if we grouped these sorts of things together?

 

                But there are some difficulties with that,

 

      and I think something maybe we didn't stress enough

 

      is that at any one given time over the last 20

 

      years, we have been consistent at least for 6

 

      months in how we think about topical

 

      corticosteroids, but we have really changed

 

      radically from the beginning, you know,

 

      paleoregulatory 20 years ago, I am not sure exactly

 

      what kind of studies were done for HPA axis

 

      suppression.

 

                Then, when we looked, we looked at

 

      endpoints that were serum cortisol.  There was no

 

      Cortrosyn stimulation. Then, subsequent to that, we

 

      looked at perhaps more stringent criteria.  We

 

      looked at what is in the Cortrosyn labeling, which

 

                                                               135

 

      gives 3 criteria, and would identify more subjects

 

      as being positive than what we are now looking at

 

      today given the benefit from the endocrinologists

 

      telling us that they only use the single criterion

 

      in their practice.

 

                So, just how we look at it has changed

 

      radically over time.  Also, over time we have been

 

      able to, now armed with PREA, the Pediatric

 

      Research Equity Act, we are now able to ask for

 

      much more data that we have gotten in the past.

 

                So, I think one of the great difficulties

 

      is there is enormous heterogeneity in the data sets

 

      and the conduct of the studies in each of these

 

      classes.

 

                DR. NELSON:  If I could just make one

 

      comment in response, all of the pediatric studies,

 

      it looked to me the only difference in the

 

      stimulation testing was whether you picked the

 

      threshold alone versus the rate of rise, and if you

 

      drop out the rate of rise and just pick threshold,

 

      you are still going to end up around 20 percent

 

      overall incidence among all these studies.

 

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

 

      guess I would encourage you to look at the

 

      pediatric studies.  I think there is probably

 

                                                               136

 

      enough homogeneity that you could draw some

 

      conclusions from those studies, if you grouped them

 

      as a class or did it by potency.

 

                DR. WILKIN:  I take your point on the

 

      pediatric patient being a better sentinel

 

      population in which to look for this particular

 

      event.  I think one of the things that we have

 

      learned is that while we can make some correlations

 

      and say that, in general, a higher body surface

 

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

 

      these things tend to correlate with the finding of

 

      HPA axis suppression.

 

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

 

      see an adult who has a very small body surface area

 

      involvement who suppresses, a child who has a much

 

      larger body surface area involved, and not suppress

 

      with this.

 

                So, it is certainly not a mathematically

 

      precise kind of outcome.

 

                DR. WOOD:  The reason we have all these

 

      pediatric studies is sort of an experiment in

 

      commerce.  I mean we happens that we got these

 

      studies because of the Pediatric Rule that people

 

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

 

      much that there is some specific reason to

 

                                                               137

 

      investigate children here except for the commercial

 

      reason.

 

                There might be reasons, as well, but that

 

      wasn't why it was done, right?

 

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

 

      the reason for PREA being enacted certainly, but I

 

      can say within our Division, we recognized that

 

      atopic dermatitis was primarily a pediatric

 

      disease, and so even before PREA, our Division was

 

      asking for pediatric studies.

 

                DR. WOOD:  Right, but if someone came in

 

      for an OTC indication, which is what we are looking

 

      at, they wouldn't necessarily have had to have

 

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

 

      necessarily have had to have done a pediatric

 

      study, right?

 

                DR. WILKIN:  I would agree with that.

 

                DR. WOOD:  Dr. Chesney.

 

                DR. CHESNEY:  Thank you.  I think my

 

      question is along the lines of Dr. Whitmore's

 

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

 

      58, this is looking at Diprosone Lotion.  The

 

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

 

      group, and yet it was approved for 13 years and

 

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

 

                                                               138

 

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

 

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

 

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

 

      12-year-old.

 

                So, I guess my question was why was it

 

      approved for 13 and older instead of perhaps

 

      adults, only given that there wasn't any

 

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

 

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

 

      the cutoff that was chosen.  I mean your point is

 

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

 

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

 

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

 

                                                               139

 

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

 

      prepubertal or whatever.  That was where the study

 

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

 

                DR. WOOD:  Dr. Taylor.

 

                DR. TAYLOR:  My question is really for Dr.

 

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

 

      systemic effects, indicating that HPA axis

 

      suppression is the only one that had really been

 

      studied well, I was concerned about glucose

 

      tolerance and sodium retention although I recognize

 

      with these drugs, sodium retention is going to be

 

      minimal since they lack significant

 

      mineralocorticoid effects.

 

                But what about in effects on glucose

 

      tolerance, is there any data to suggest that

 

      topical steroids might alter glucose tolerance in

 

      susceptible individuals, for example, in diabetics?

 

                DR. LUKE:  When these products are used

 

      under a physician's care, you would expect that

 

      those patients would have some monitoring.

 

                DR. TAYLOR:  That is my point, though.

 

                DR. LUKE:  The class labels for the

 

                                                               140

 

      corticosteroids do include discussion about glucose

 

      tolerance and the sodium retention and

 

      mineralocorticoid effect, so when these

 

      prescription products are being used, it is thought

 

      that those are things that would fall under the

 

      rubric of a physician-patient discussion of

 

      examination.

 

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

 

      position in terms of when the physician is no

 

      longer there, what is the Agency's remedy for

 

      ensuring that this growing population of diabetics,

 

      for example, have some guidance other than just the

 

      label on the box?

 

                DR. LUKE:  I think when you go to the

 

      history of hydrocortisone, there was discussion in

 

      that monograph about mineralocorticoid effects, and

 

      it was found that there was no studies that showed

 

      that hydrocortisone had a mineralocorticoid effect.

 

                DR. WOOD:  My sense of what we are trying

 

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

 

      decide is what is the most sensitive test for

 

      systemic effect of these drugs, and at what level

 

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      would you put a barrier up to a demonstration of a

 

      systemic effect that would preclude OTC marketing.

 

                So, I guess maybe we should turn the

 

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

 

      reasonable, sensitive, and doable test for systemic

 

      effects of steroids administered by any route?

 

                DR. STRATAKIS:  Well, having said all the

 

      caveats of the ACTH stim test, I still think that

 

      the ACTH stim test satisfies all the criteria you

 

      just mentioned, the big response of cortisol of 30

 

      minutes to 250 micrograms of synacthen.  I mean

 

      it's still the most doable, the easiest to

 

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

 

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

 

      sensitivity of around 70 percent with specificity

 

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

 

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

 

      question, would you expect to see people who had

 

      elevation in blood glucose who did not demonstrate

 

      suppression of HPA axis?

 

                DR. STRATAKIS:  That would have glucose

 

      intolerance?

 

                DR. WOOD:  Right.

 

                DR. STRATAKIS:  Especially if they are

 

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

 

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      same thing that we see with growth.  Growth is a

 

      very sensitive index of the systemic effect of

 

      glucocorticoids, and yet you don't see abnormal

 

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

 

      at this point there is no good test to identify

 

      these individuals.

 

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

 

      stim test is not a good surrogate for the variety

 

      of systemic effects that one is likely to see.

 

                DR. STRATAKIS:  I agree with that

 

      statement except that there is nothing else.

 

                DR. WOOD:  Charley.

 

                DR. GANLEY:  Let me just tough on that and

 

      just think about it.  We would be asking the same

 

      questions if we did this test in 25 diabetics and

 

      saw no effect on glucose tolerance, would we write

 

      a label that says it has no effect on glucose

 

      tolerance.

 

                I would be a little uncomfortable in that

 

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      the labeling for the physician is that you are

 

      treating the individual, so there may be patients

 

      that are much more sensitive than others.

 

                Well, to carry that over into the OTC

 

      setting there may be always that patient out there,

 

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

 

      to address it through labeling, so anyone who is

 

      diabetic should talk to their doctor, for example,

 

      before using this product.

 

                Then, you get into the issue, well, does

 

      that have the impact that you want, is the person

 

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

 

      that having that data in front of me would make me

 

      feel better about being at OTC if it showed that it

 

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

 

      absolutely be sure that maybe there is someone out

 

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

 

      label it as such.

 

                I think we will get into that discussion a

 

      little more about some of these systemic effects of

 

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

 

      that you just label for them, because the outcome

 

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      isn't as critical as death with a stress situation

 

      when there is HPA axis suppression.

 

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

 

      this?

 

                DR. DAVIDOFF:  Yes.  I had a somewhat

 

      related question because we are hearing that the

 

      HPA axis assessment using the cosyntropin test has

 

      a sensitivity of about 70 percent, but that implies

 

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

 

      was curious what gold standard it is being measured

 

      against.

 

                But the related point I wanted to make was

 

      that the results of this test are clearly a

 

      surrogate measure, and admittedly, if you don't

 

      want to hang around until people have experienced

 

      the ultimate criterion of suppression, which is to

 

      die because of adrenal insufficiency, so you have

 

      to use the surrogate measure, but that does get to

 

      the question of what is the sort of intermediate

 

      gold standard short of death that is used on the

 

      basis of which you can say it is a sensitivity of

 

      70 percent.

&n