FOOD AND DRUG ADMINISTRATION













                         JOINT SESSION WITH THE




                           ADVISORY COMMITTEE



                               VOLUME II













                        Thursday, March 24, 2004


                               8:00 a.m.









                       Hilton Washington DC North

                           620 Perry Parkway

                         Gaithersburg, Maryland



                        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


      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.



                            C O N T E N T S


      Call to Order and Introduction:

         Alastair Wood, M.D.                                     4


      Conflict of Interest Statement,

         LCDR Teresa A. Watkins, R.Ph                            7



                Charles Ganley, M.D.                            11


      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




                         P R O C E E D I N G S


                    Call to Order and Introductions


                DR. WOOD:  If everybody could take their


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


      have everybody introduce themselves.  Why don't we


      start with Mike.


                DR. ALFANO:  Good morning.  I am Mike


      Alfano, New York University.  I am the industry


      liaison to NDAC.


                DR. FINCHAM:  Good morning.  I am Jack


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


      Pharmacy and Public Health at the University of




                DR. RAIMER:  Good morning.  I am Sharon


      Raimer, in Dermatology, University of Texas.


                DR. TINETTI:  I am Mary Tinetti, Internal


      Medicine, Geriatrics at Yale.


                DR. RINGEL:  Eileen Ringel, Dermatologist,


      Waterville, Maine.


                DR. CLYBURN:  I am Ben Clyburn, Internal


      Medicine, Medical University of South Carolina in




                DR. SANTANA:  Good morning.  I am Victor


      Santana.  I am a pediatric hematologist/oncologist


      at St. Jude Children's Research Hospital in




      Memphis, Tennessee.


                DR. SKINNER:  I am Bob Skinner from the


      University of Tennessee at Memphis.  I am a




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


      consumer representative on NDAC.  I am an


      anthropologist on faculty at Macalister College in


      St. Paul, Minnesota.


                DR. DAVIDOFF:  I am Frank Davidoff.  I am


      the Emeritus Editor of Annals of Internal Medicine.


      I am an internist although I started life as an


      endocrinologist, and I am a member NDAC.


                DR. BIGBY:  Michael Bigby, a dermatologist


      at Beth Israel Deaconess Medical Center and Harvard


      Medical School.


                LCDR WATKINS:  I am Teresa Watkins.  I am


      the Executive Secretary with the advisors and


      consultant staff.


                DR. NELSON:  Robert Nelson, Pediatric




      Critical Care Medicine at Children's Hospital,


      Philadelphia, and the University of Pennsylvania.


                DR. SNODGRASS:  Wayne Snodgrass,


      pediatrician, University of Texas Medical Branch.


                DR. MATTISON:  Don Mattison, National


      Institute of Child Health and Human Development.


                DR. SCHMIDT:  Jimmy Schmidt, Houston,


      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,




                DR. WILKERSON:  Michael Wilkerson,


      University of Oklahoma, Tulsa Branch, Assistant


      Professor, Clinical, and dermatologist.


                DR. BLASCHKE:  Terry Blaschke, internist,




      clinical pharmacologist, Stanford.


                DR. WILKIN:  Jonathan Wilkin, Director,


      Division of Dermatologic and Dental Drug Products,




                DR. ROSEBRAUGH:  Curt Rosebraugh, Deputy


      Director, OTC, FDA.


                DR. GANLEY:  Charley Ganley, Director of




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


      internist, Professor of Medicine, Associate Dean at


      Vanderbilt.  There has probably never been a


      committee with so many people from Tennessee on it,


      I don't think.


                Teresa, why don't you read the Conflict of


      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




      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,




      three stocks are valued between $25,001 and


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




                Dr. Thomas Ten Have for stock valued


      between $25,001 to $50,000.


                Dr. Victor Santana for stock in two firms.


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




                Dr. Sharon Raimer for two grants that are


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


      Also, for stock in three firms, each stock is


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


                Dr. Sonia Patten is an unpaid volunteer


      member of the Sumasil Foundation Board of


      Directors.  The Foundation owns stock interest in


      two firms.  One stock is currently valued between


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


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


                We would also like to disclose that Dr.


      Terrence Blaschke owns stock in a firm, valued from


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


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




      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




      any firm whose products they may wish to comment




                Thank you.


                DR. WOOD:  Thanks a lot.


                Our first speaker is Charley Ganley.






                DR. GANLEY:  Good morning.  I would just


      like to start by thanking all the members for


      participating in this meeting.  I would also like


      to thank the advisors and consultant staff for all


      the hard work they do in putting these meetings


      together, it is always difficult to get two


      different committees together, and last but not


      least, the staff of the Dermatologic and OTC


      Divisions who have put together the presentations.




                We are here today to discuss the safety


      data necessary to consider a switch of dermatologic


      topical corticosteroids from prescription to OTC






                The FDA presentations will cover the


      regulatory history of OTC hydrocortisone, the


      assessment of safety for current prescription




      dermatologic topical corticosteroids products, an


      assessment of safety effects for other categories


      of steroid products, and testing for HPA axis






                Now, low potency dermatologic topical


      corticosteroids are currently available OTC, and


      the only product that you will hear in the next


      talk is hydrocortisone.  Its purpose is for the


      symptomatic treatment of certain skin conditions,


      and there is a limitation on the duration of use.


                Over the last year or so, several


      manufacturers have expressed an interest in


      switching some dermatologic topical corticosteroids


      from prescription to OTC, asking for similar type


      claims, and also for durations of use.




                Now, in your background package, we


      included a list of the various potencies of topical




      steroids, and there is quite a difference in the


      potency of prescription dermatologic topical


      steroids, and potency impacts on efficacy and


      safety of these products.


                The main issue for the discussion today is


      the safety in the OTC setting.  The question really


      is where do we draw the line between safe versus


      unsafe products in this category for OTC use.




                Can all dermatologic topical steroids be


      used safely OTC?  Well, some highly potent products


      used for extended periods or in large amounts may


      pose a significant risk for developing a serious


      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




                I think in part of the open public


      session, you will hear a little bit of information




      of what possible percentage of consumers that may






                So, what are the safety concerns?  We have


      divided them up into the systemic effects and local


      effects, and within the systemic effects, we divide


      them further into HPA axis suppression, which is in


      this case where an exogenous steroid causes the


      body to stop making corticosteroid, and in stress


      situations, it could lead to acute adrenal crisis


      which would be life-threatening.


                This can occur with weeks of use and the


      use of the OTC product may be unknown to a health


      provider who has to treat someone who comes into


      the emergency room in this situation.


                The other systemic effects are essentially


      Cushing's syndrome, which could be osteoporosis,


      truncal obesity, growth suppression, and


      hypertension, it goes on and on, and the severity


      may be related to the daily dose and the duration


      of therapy.


                The local effects during the course of the




      presentations today, that will also be reviewed.




                Now, you may not be able to see this very


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


      the schematics that we are going to work with


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


      hierarchy of what we think the importance of these


      various potential safety issues are.


                Starting at the top is HPA axis


      suppression.  The second one is other systemic


      effects, and the third is local effects.  You will


      see the way the questions are presented will also


      follow this course.


                I don't want to go into great detail with


      this now, but during the course of the discussion


      and prior to some of the questioning maybe later


      this afternoon, we can go through this in a little


      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




                DR. KOENIG:  Good morning.  I am Michael




      Koenig, an interdisciplinary scientist in the


      Division of Over-the-Counter Drug Products.


                Over the next 15 minutes, I will be


      providing you with information about the only


      dermatologic topical steroids that are available


      over the counter, hydrocortisone and hydrocortisone




                Because hydrocortisone and hydrocortisone


      acetate are functionally the same thing, for the


      rest of this presentation, I will simply refer to


      the two corticosteroids as hydrocortisone.




                This presentation is divided into three


      parts.  First, I will describe the OTC monograph


      system under which these OTC corticosteroids are


      regulated.  Second, I will review the regulatory


      history of hydrocortisone.  Third, I will show you


      the current labeling of hydrocortisone products if


      they are in compliance with the monograph.




                I would like to begin by just especially


      for members of the Dermatologic and Ophthalmic


      Drugs Committee to review the way OTC drugs are


      regulated.  All OTC drugs are regulated by one of


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




      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




      Register, and FDA actively solicits feedback from


      the public at every step of the process.




                So the OTC monographs came about with the


      initiation of the OTC drug review back in 1972.  At


      that time, there were over 200,000 different drug


      products available OTC, and it was really


      impractical to think that we could review the


      safety and effectiveness of all 200,000 of these


      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.




                The initial review as by an Advisory


      Review Panel. This was made up of outside experts,




      outside FDA experts in that particular therapeutic


      category.  There were 7 voting members, but in may


      respects, it was somewhat analogous to the Advisory




                These panel members looked at each of the


      active ingredients and determined whether they were


      Category I or GRASE, Generally Recognized as Safe


      and Effective; Category II, not GRASE; or Category


      III, insufficient data to determine whether or not


      the ingredients were safe and effective for their


      intended use.




                The recommendations of the Advisory


      Committee were published in the Federal Register as


      an Advanced Notice of Proposed Rulemaking, or ANPR.




                FDA's first position on the ingredients in


      the different categories were made public in a


      proposed rule.  This followed solicitation of


      comments from the public, and as I said, resulted


      in the publication of a proposed rule, also known


      as a Tentative Final Monograph, I have abbreviated




      here as TFM.




                The last step in the monograph process is


      the development of a Final Rule, and that follows


      input of comments from the public again, as well as


      any new data that is relevant to generate this


      Final Rule or Final Monograph, which I have


      abbreviated FM.




                I would like to now speak specifically


      about the regulatory history of hydrocortisone.




                This low potency topic corticosteroid was


      introduced into the U.S. market as a prescription


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


      Petition was submitted requesting that


      hydrocortisone be switched from prescription to




                The switch was rejected in 1957 for two


      reasons:  first, there was a failure to demonstrate


      that consumers could safety self-medicate using


      hydrocortisone; and, second, it was felt that more




      testing was needed on absorption of hydrocortisone


      through the skin.  In other words, there was a


      concern about systemic effects, much as we will be


      talking about today.


                Hydrocortisone was included with other


      ingredients classified as external analgesics in a


      review by the Topical Analgesics Panel, which met


      between 1973 and 1978.




                The findings of the panel and the


      preliminary regulations were published in 1979 and


      the Advanced Notice of Proposed Rulemaking or ANPR.


      Among other things, the panel did consider whether


      hydrocortisone had any adverse local effects, and


      noted that there was a noticeable lack of adverse


      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




      this is a little bit more detail.


                Pustular eruptions and crusting were


      reported in one case of a person who was using


      hydrocortisone, but was it turns out attributed to


      a secondary infection and the scratching of the


      secondary infection, and treatment with an


      antibiotic resolved the issue while the person


      continued to use hydrocortisone.  So, again, a lack


      of local adverse effects.




                Also, in the ANPR, the fact that there was


      a lack of systemic effects was published.  Several


      experiments look at percutaneous absorption.


      People used carbon-14 hydrocortisone, in one case


      tritiated hydrocortisone, and did not see any


      significant absorption through the skin.


                Other measures of systemic effects were


      eosinophil count, there was no depression in


      eosinophil count in three or four studies that were


      presented in the ANPR.  Urinary levels of


      17-hydroxysteroids and 17-ketosteroids were not


      increased as you would expect if there were a




      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.




                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. 




      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.




                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




      growth retardation in an infant, who also had 1


      percent hydrocortisone applied twice daily for 6


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


      body and unction was what the report says in the




                In 1966, there was a rapid gain in body


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


      using 0.25 percent hydrocortisone 3 times a day for


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


      mg/m2 body surface area.


                So, all in all, that panel considered this


      a very favorable response, only 3 out of over


      12,000 subjects had any serious adverse events with






                The panel recommendations in the ANPR were


      that hydrocortisone and hydrocortisone acetate


      should be considered GRASE over a concentration


      range of 0.25 to 0.5 percent.  Remember GRASE is


      generally recognized as safe and effective.


                The panel also has some recommendations


      for labeling, and since I will be showing you




      labeling in the third part of the talk, I just


      wanted to let you see how this labeling developed


      as the monograph developed.


                The panel felt that the indication should


      be or the use of hydrocortisone should be temporary


      relief of minor skin irritations, itching, and


      rashes due to a variety of different conditions,


      and we will get into that when we look at the




                The panel also felt that among several


      warnings should be these two, which are relevant to


      today's discussion I think.  One is that consumers


      should stop use if the condition worsened or lasted


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


      the use of hydrocortisone.


                The other warning I wanted to mention was


      the one that it should not be used on children


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


      were included on all external analgesic active


      ingredients, but they are directly relevant to some


      of some of the discussion you will be having later


      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




      to 4 times a day.




                FDA's position was made public in the


      Tentative Final Monograph, TFM, which published a


      little over 3 years later in 1983.  FDA agreed that


      the concentration range specified by the panel was


      appropriate, that 0.25 to 0.5 percent


      hydrocortisone should be considered GRASE, safe and


      effective, and FDA did make some labeling




                Among those was the focus of the


      indication on antipruritic aspects of


      hydrocortisone, so instead of temporary relief of


      skin irritations, itching, and rash, it became


      temporary relief of itching associated with skin


      irritation and rashes due to a variety of


      conditions, and hydrocortisone is today, that is


      the only indication, antipruritic.


                Additionally, to the stop use condition,




      FDA added the clause, "Stop use if condition


      worsens or last more than 7 days or if symptoms


      clear up and occur again within a few days."




                The Tentative Final Monograph was amended


      in 1990 in response to a Citizen Petition which


      requested an increase in dosage strength to a


      maximum of 1 percent from remember the previous 0.5




                This amended TFM included an extensive


      data and literature review mostly centered around


      the use of 1 percent hydrocortisone, and ultimately


      considered the higher concentration of 1 percent to


      be GRASE for OTC use.


                Additionally, there were some labeling


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


      use any other hydrocortisone product when using the


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


      the treatment of diaper rash," which is still on


      the labeling, and this is largely due to the


      occlusive nature of a diaper.




                What about the Final Monograph, the last


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


      have found that manufacturers are generally




      complying with the Tentative Final Monograph and


      the amended TFM.  I will show you that in some


      labeling in just a minute.


                We are continuing our review of data


      submitted by manufacturers, as well as in the






                In light of today's discussion, I just


      wanted to point out some of the literature that we


      have been reviewing.  This table represents 5


      studies that have been conducted since the ANPR


      published in 1979.  All of these studies were in


      children, and all of these used the modern standard


      ACTH stimulation to measure HPA axis function.


                ACTH, as Dr. Cook will go into a little


      bit more detail on this, ACTH is


      adrenocorticotropic hormone.  This is released from


      the anterior pituitary and stimulates release of


      cortisol from the adrenal glands.  That is the P




      and the A, adrenal glands in the HPA axis.


                So, by looking at the amount of cortisol


      released in response to a known amount of ACTH, or


      in a more practical sense, some synthetic analogue


      of ACTH, you can tell whether the HPA axis is


      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.




                I would now like to look at the current


      labeling of hydrocortisone in this third part of


      the talk.




                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




      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.




                Also, under Warnings, this is very much as


      it appeared in the TFM, the Tentative Final


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


      symptoms persist for more than 7 days or clear up


      and occur again within a few days."




                And under Directions, "Apply to affected


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


      under 2 years of age, do not use."




                This is labeling that is taken off of a




      currently marketed OTC product, and I just wanted


      to show you that again, manufacturers are very much


      in compliance with the monograph standards.


                So, in this labeling under Uses, we see


      the same thing, "temporarily relieves itching of


      minor skin irritations, inflammation and rashes."




                Under Warnings, "Stop use and ask a doctor


      if symptoms persist for more than 7 days."




                Under Directions, the same two that I just




                I would like to thank you for your


      attention and I will be followed by Dr. Denise Cook


      of the Division of Dermatologic and Dental Drug


      Products.  Denise will be talking about


      prescription topical corticosteroids.


                Thank you.


                  Rx Topical Corticosteroids: HPA Axis


                   Suppression and Cutaneous Effects




                DR. COOK:  Good morning.  Good morning to




      the respective chairs of the respective advisory


      committees that are here, also to the advisory


      committee members, to my FDA colleagues, and people


      in the audience.


                I am Denise Cook.  I am a dermatologist in


      the Division of Dermatology and Dental Drug






                Today, I will be speaking to you on


      prescription topical corticosteroids, the HPA axis


      suppression, and cutaneous effects.


                The majority of the presentation will be


      on the systemic effect of the HPA axis and the


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


      be presenting trial data from approved drug


      products, the resultant labeling changes.  I will


      also give a postmarketing summary of adverse events


      as it relates to the HPA axis suppression that we


      have in our database.


                But first I will give you a background to


      the talk, so that you can follow it probably a


      little bit later. I will talk about the




      classification of topical corticosteroids, give you


      a synopsis of the cosyntropin stimulation test and


      how it is performed, and also give you an evolution


      of interpretation of normal HPA axis function as it


      has been done over the years at the FDA.


                I will give you background also on class


      labeling for topical corticosteroids and how that


      developed, and the cutaneous adverse events from


      topical corticosteroid use.




                The topical corticosteroids are divided


      into seven classes.  Although the FDA does not


      purport this classification, it is widely used in


      the dermatologic community.


                Class I consists of superpotent topical


      corticosteroids, Class II high potency, Class III


      through VI are mid-potency with Class III being


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


      VI being close to the low potency of Class VII.


                It is usually determined by a


      vasoconstrictor assay where the topical


      corticosteroids placed on the cutaneous surface,




      and blanching or vasoconstriction is determined


      relative to the other corticosteroid.




                The cosyntropin stimulation test, which is


      the test that I will be discussing in the bulk of


      the studies that you are going to hear about today,


      is used to assess the function of the end organ,


      the adrenal gland, in the hypothalamic-pituitary


      adrenal axis.


                In the case of topical corticosteroids, it


      is assessing an exogenous unwanted treatment




                What is usually done is the cosyntropin is


      given at 0.125 mg or 0.25 mg depending on age


      and/or body weight, and it is administered


      intravenously at baseline and at the end of




                Blood is then drawn for serum cortisol


      values at 30 minutes and sometimes 60 minutes post


      stimulation.  Then, the interpretation of the


      results determines a normal or abnormal response.




                The evolution of the interpretation of the


      normal function of the HPA axis at the FDA has


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




      serum cortisol, then urinary corticoid


      concentrations were used to determine whether you


      had normal function of your HPA axis after


      treatment with topical corticosteroids.


                Then, in 1996, the cosyntropin stimulation


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


      stimulation serum cortisol had to be greater than


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


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


      you needed to have at least a 6 increment change


      from pre-stimulation to post-stimulation in order


      to be considered to have a normal response.


                In 1999, the FDA went to a single


      criterion to determine normal function of your HPA


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


      cortisol greater than 18 mcg/dL.




                In 2001, it was decided that if we were


      going to use cosyntropin to determine normal




      function of hormonal therapy HPA axis, then, the


      label should be followed as it is currently


      written, that is, that the control plasma cortisol


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


      level should show an increment of at least 7


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


      18 mcg/100 mL.


                Currently, in 2004, there had been a lot


      of work in the FDA with endocrinologists and also


      members in the Division of Dermatology to determine


      that we need to go back to a single criterion for


      HPA axis function and determining it from the


      cosyntropin test.  Therefore, at the present time,


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


      cortisol level should exceed 18 mcg/100 mL.




                Now, class labeling for prescription


      topical corticosteroids went into effect in 1990,


      and I am going to give you a little background on


      one of the factors that propelled this into being.


                This class labeling talks about the


      effects on the HPA axis, effects on glucose




      metabolism, development of Cushing's syndrome,


      effects on growth, and effects on intracranial






                Two studies have propelled this into


      being.  There were two open-label trials with


      Temovate Ointment.  In Trial 1, there were 6 adult


      patients with psoriasis who applied 7 grams/day to


      30 percent of their body surface area for 7 days.


                ACTH stimulation was performed at baseline


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


      They found that 50 percent of the patients


      exhibited decreases in cortisol production.




                In the second trial, the objective was to


      determine the largest dose over a 7-day period that


      would not cause significant suppression of the


      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






                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




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


      mean like exactly what the serum cortisol levels




                DR. WOOD:  The number of patients.


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


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


      out of the label.  But I would suspect that they


      were small, because in the current studies that we


      have, the numbers are small, they are not huge






                So, this led to a Temovate label in 1985


      that stated in the Precautions, it is a highly


      potent topical corticosteroid that has been shown




      to suppress the HPA axis at doses as low as 2


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


      steroid in the superpotent category.


                Under Pediatric Use, it was determined


      that it should not be used in children under 12


      years of age, at least it is not recommended.




                So, now we will move on to the actual


      class label that was generated.




                In the Precautions Section, it states that


      systemic absorption of topical corticosteroids can


      produce reversible hypothalamic-pituitary-adrenal


      axis suppression with the potential for


      glucocorticoid insufficiency after withdrawal from




                Manifestations of Cushing's syndrome,


      hyperglycemia, and glucosuria can also be produced


      in some patients by systemic absorption of topical




      corticosteroids while on treatment.




                It goes on to say that patients applying a


      potent topical steroid to a large surface area or


      to areas under occlusion should be evaluated


      periodically for evidence of HPA axis suppression.


      This may be done by using the ACTH stimulation, AM


      plasma cortisol, and urinary free cortisol tests.




                If HPA axis suppression is noted, an


      attempt should be made to withdraw the drug, to


      reduce the frequency of application, or to


      substitute a less potent steroid. Recovery of HPA


      axis function is generally prompt upon


      discontinuation of topical corticosteroids.


                Infrequently, signs and symptoms of


      glucocorticosteroid insufficiency may occur


      requiring supplemental systemic corticosteroids.




                The class label also addressed pediatric


      use in the Pediatric Use Section of the label.




                Currently, this is what is there if there


      haven't been any tests done on pediatric patients,


      but as you shall see in the studies that I will




      present, since the advent of FDAMA, we have been


      able to get studies in pediatric patients, so some


      of this has been modified in the respective labels.


                Safety and effectiveness in children and


      infants have not been established.  Because of a


      higher ratio of skin surface area to body mass,


      children are at a greater risk than adults of HPA


      axis suppression when they are treated with topical




                They are therefore also at greater risk of


      glucocorticosteroid insufficiency after withdrawal


      of treatment and of Cushing's syndrome while on






                HPA axis suppression, Cushing's syndrome,


      linear growth retardation, delayed weight gain, and


      intracranial hypertension have been reported in


      pediatric patients receiving topical




                Manifestations of adrenal suppression in


      pediatric patients include low plasma cortisol


      levels to an absence of response to ACTH


      stimulation.  Manifestations of intracranial


      hypertension include bulging fontanelles,


      headaches, and bilateral papilledema.






                Now, we are going to move on to the bulk


      of the presentation, which is going to be about the


      prescription topical corticosteroid data and its


      relationship with HPA axis suppression.


                I am going to speak about 10 drug


      products.  There are 8 topical corticosteroid


      products, 2 topical combination drug products.




                Just to give you those, I am going to


      speak about Dermatop, which is a mid-potency


      steroid; Cutivate Cream, another mid-potency


      topical corticosteroid; Diprolene AF Cream, which


      is a high potency steroid.


                You might want to look in Tab 2, I think


      it is, of your background package.  It has that




      classification that I spoke of earlier, the high


      potency steroids being in Class II.


                Diprosone Ointment, a high potency


      steroid; Diprosone Cream and Lotion, both in the


      mid-potency category; Clobex Lotion, a superpotent


      steroid; and Temovate E Cream.  Both of these are


      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.




                Dermatop is a Class V steroid near the


      bottom part of the mid-potency topical


      corticosteroids.  It was approved in May 1996.  We


      are going to discuss a pediatric atopic dermatitis






                There were 59 patients enrolled and there


      were 2 targeted populations.  The patients were


      between 1 month and 2 years and also between 2 and




      12 years.  There were 10 patients who were less


      than 2 years old and 49 patients were greater than


      or equal to 2 years of age.




                They had to use the medication over


      greater than 20 percent of the body surface area.


      I mean they had to have atopic dermatitis to that


      amount of cutaneous surface, and use it twice daily


      for 21 consecutive days.


                Again, we used the cosyntropin stimulation


      test. It was administered at baseline and at day


      22.  In this trial, patients who were greater than


      or equal to 15 kilograms received a higher dose of


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






                The criteria in this study was the adrenal


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


      post-stimulation serum cortisol had to be greater


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


      cortisol level was already greater than 20, then,


      an incremental increase of greater than 6 mcg/dL in




      the serum cortisol was required.




                There were 3 patients according to the


      protocol criteria who were suppressed.  Two


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


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


      post-stimulation cortisol value actually decreased


      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."




                The next drug is Cutivate Cream, which is


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


      We are going to look at another atopic dermatitis


      trial in pediatric patients.




                There were 43 evaluable patients with


      moderate to severe atopic dermatitis; 29 of the




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


      patients were 3 years to 5 years old.




                The criteria for entry into the study was


      that they had to have at least a 35 percent body


      surface area involvement, and I will tell you in


      all of these studies, we were looking for maximum


      use conditions, so you could get your worst case




                They applied the medication twice a day


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


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


      years of age were limited to 180 grams/week.




                Looking at body surface area improvement


      over time to show the response to the medication,


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


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


      50 percent by 3 weeks, and 9 percent of the




      patients had a 50 percent decrease by 4 weeks.




                The cosyntropin was administered at


      baseline and end of treatment, and in this study,


      they used age, younger age group was given a lower


      dose than the older age group.




                Here, a normal response was a serum


      cortisol level that exceeded 18 mcg/dL at 30


      minutes post-stimulation.




                Two the patients out of the 43 patients


      experienced adrenal suppression.  One was a


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


      area involvement, used the drug for 4 weeks, used


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


      here, pre-treatment value was 33.9 after


      stimulation, and yet it fell to 11.8, but in


      follow-up he recovered at 19.8 with his serum




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


      the minimum amount of body surface area involvement




      of 35 percent.  His duration of treatment was for 5


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


      post-stimulation serum cortisol was 9.4.


      Unfortunately, we don't know whether he recovered


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


      investigator did make an honest effort to try to


      track this child down.




                But this led to labeling changes for


      Cutivate Cream, which stated that children as young


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


      use the medication, and appropriate sections of the


      label were updated.




                Now, I am going to talk about 4 or 5


      betamethasone propionate products.  They were all


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


      I mean the pediatric part of the label was changed.


      Their supplement for safety was changed, because,


      of course, they have been on the market a lot


      longer than just 2001.


                One is Diprolene AF Cream, which is a




      Class II steroid; Diprosone Ointment, another Class


      II steroid; Diprosone Cream, a Class III steroid;


      Diprosone Lotion, which is mid-potency, but the


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


      significant when you see the study results of this


      drug, of Diprosone Lotion.


                Then, I am going to speak of the 2


      combination products, Lotrisone Cream and Lotion.




                The criteria for a normal HPA axis


      response in all of these studies was that we would


      follow the cosyntropin label, that the failure of


      any one of three criteria would indicate


      suppression of the HPA axis, and stimulation should


      occur at baseline and end of treatment.




                So, the criteria for the 30-minute


      post-stimulation, the three criteria that they


      needed to meet to have a normal response, is that


      the control plasma cortisol level should exceed 5


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


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




      the basal level, and the 30-minute level should


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


      those three would indicate suppression.




                So, with Diprolene AF Cream, there were 60


      evaluable patients.  They ranged in age from 1 to


      12 years with atopic dermatitis.  They had a mean


      body surface area involvement of 58 percent.  They


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


      and that depended upon whether their disease


      cleared or not.


                If they cleared within 2 weeks, they were


      allowed to stop and then be tested at that point.


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


      weeks.  They were limited to 45 grams per week.




                The results of the cosyntropin stimulation


      showed that 19 out of 60 or 32 percent of these


      patients showed evidence of HPA axis suppression.


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


      took the criterion that we look at now, which is


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




      had suppression.




                If you look at suppression by age group,


      it appeared that a larger percentage of patients


      suppressed as the age decreased.


                Looking at recovery of normal HPA axis


      suppression, unfortunately, all the patients were


      not retested.  We would have liked to have all of


      them retested, but 4 patients were retested 2 weeks


      post-treatment, and 3 of the 4 recovered normal


      function of their HPA axis.




                We tried to do a statistical analysis in


      the development of HPA axis suppression with each


      drug.  With Diprolene AF, there was no correlation


      between amount of drug used, body weight, age or


      sex, and the incidence of adrenal gland




                The statistical relationship did exist


      between body surface area and risk of HPA axis


      suppression such that for an increase of 1 percent


      body surface area involved, the risk of HPA axis




      suppression increased 4.4 percent with a p value of


      less than 0.01.




                This led to a label change for Diprolene


      AF Cream, such that it was restricted to patients


      13 years and older, and appropriate information was


      included in other sections of the label.




                Diprosone Ointment.  That study had 53


      evaluable patients with atopic dermatitis.  The age


      range was 6 months to 12 years.  The medication


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


      The mean body surface area involved was 58 percent.


                DR. WOOD:  Can we just go back to that


      last slide? The one with the 1 percent BSA




                DR. COOK:  Excuse me.  Which one?


                DR. WOOD:  The last slide, the slide


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


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


      percent, that is linear throughout the thing, so


      going from 1 percent to 21 percent would mean 88




      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




                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.




                Again, if you looked at suppression by


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


      proportion of patients who suppressed, the younger


      the patients were.




                In the statistical analysis here in the


      development of HPA axis suppression, these




      statisticians didn't find a statistically


      significant effect for drug usage, for percent of


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


                It did show that for some reason, a higher


      proportion of males than females developed HPA axis


      suppression using this drug.




                In testing patients for recovery, 2 of the


      15 patients were retested and 100 percent recovered


      at 2 weeks.




                This led to a label change similar to


      Diprolene AF Cream in which an age restriction was


      added that patients should be 13 years of age or


      old, and appropriate parts of the label were


      updated with the clinical data.




                Diprosone Cream studied 43 evaluable


      patients with atopic dermatitis.  They ranged in




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


      surface area involvement was 40 percent. Again,


      they applied the medication twice a day for 2 to 3






                In this study, 23 percent of the patients


      showed evidence of adrenal suppression using the


      Cortrosyn label with all three criteria and a


      failure of one.


                If you look again at a post-stimulation


      value that was less than 18, 50 percent of patients


      showed evidence of adrenal suppression.




                In this study, you can't quite see the


      value here.  Starting here with 14 percent of


      patients 9 to 12 years of age showed evidence of


      suppression.  As you march down again, the


      percentages went up, but here, interestingly, which


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


      determining just what is going to make someone


      suppressed, what are the risk factors here, none of


      the infants in this study showed evidence of




      adrenal suppression.




                Again, with the statistical analysis for


      this particular drug, in these patients, there was


      no statistically significant effect for number of


      days treated, for weight, or for age.


                However, there was a statistical


      significance found for mean amount of drug usee -


      81 grams in those who suppressed versus 37 grams in


      those that did not.


                There was a numerically higher percent of


      body surface area involvement in those who


      suppressed, and numerically, more males developed






                When looking at recovery of HPA axis


      function with Diprosone Cream, 2 out the 10


      patients were retested, and 50 percent, 1 out of


      the 2, recovered function at 2 weeks.




                Here again, the label was changed to add


      and age restriction to 13 years or older, and




      appropriate portions of the label were updated.




                Now, Diprosone Lotion, I will remind you


      again is a Class V steroid, so just like two


      classes above the lowest potency of topical




                Here, they had 15 evaluable patients with


      atopic dermatitis.  They ranged in age from 6 to 12


      years old.  The mean body surface area involvement


      was 45 percent.  They applied the medication twice


      a day for 2 to 3 weeks.




                This was a very interesting study.  Eleven


      of the 15 patients or 73 percent of the patients


      showed evidence of HPA axis suppression.  If we


      look at just getting a serum cortisol value that


      exceeded 18 mcg/dL, 91 percent of the patients


      failed to do that.




                Although this study was supposed to enroll


      infants, it was felt that with such a high degree


      of HPA axis suppression, the proportion of patients




      6 to 12 years of age, that no patients were


      enrolled in the lower age group.  This brought up


      the issue that possibly it is not only the chemical


      moiety that might produce HPA axis suppression, but


      since it is coming from the skin, it may involve


      the vehicle in which the chemical moiety is in.


                In this instance, the lotion, it may


      somehow with the chemical moiety quicker from the


      skin into the systemic circulation, and thereby


      cause more HPA axis suppression.  So, in other


      words, vehicle may play a role also in determining


      that systemic effect.




                When looking at the statistical analysis


      in the development of HPA axis suppression, it was


      a numerical analysis.  The subjects exhibiting HPA


      axis suppression used the larger mean amount of


      drug.  They had a slightly higher percent of BSA




                They had lower mean weights at visit 1,


      lower mean weights at visit 4, but the difference


      with respect to age and days of treatment, at least




      from a statistical point of view, were minuscule.




                Looking at recovery of HPA axis function


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


      percent of the patients who were retested recovered


      their HPA axis function at 2 weeks.




                So, the labeling change for Diprosone


      Lotion was that an age restriction was added to 13


      years and older, and appropriate sections of the


      label again were updated.




                Just to look at the four betamethasone


      products together, again, you see that the three


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


      suppress somewhat where in the same range.  When


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


      higher percentage of patients who experienced HPA


      suppression.  Again, it may have to do with the


      vehicle, if there is an absorption enhancer in it


      or other factors.




                Lotrisone Cream is the other betamethasone


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


      combination product of betamethasone dipropionate




      with Lotrimin Cream.  It is indicated for the


      treatment of tinea pedis and tinea cruris, so we


      did a study in both of those.


                Both studies were in the adolescent


      population, 12 to 16 years.  Medication was applied


      twice daily.  The study duration for tinea pedis


      was 4 weeks and for tinea cruris was 2 weeks.




                Here, we also have some surprising


      results.  Seventeen out of 43 or 39.5 percent of


      patients demonstrated adrenal suppression in the


      tinea pedis study, and we might not have actually


      expected that given that the stratum corneum of the


      feet is somewhat thick, but it might also be


      teenagers wear sox and tennis shoes all day long,


      and that might also cause more occlusion and


      absorption of the drug product.


                In tinea cruris, there were 47.1 percent


      who demonstrated adrenal suppression, and this is




      also is an area where you may have some natural


      occlusion, increasing absorption.




                So, this led to some labeling changes for


      Lotrisone Cream and Lotion.  The Indication Section


      was expanded, it added an age restriction to


      patients 17 years and older.  It also recommended


      that effective treatment may be obtained without


      the use of a corticosteroid for non-inflammatory


      tinea infections.  Then, other appropriate sections


      of the label were updated with clinical




                DR. FINCHAM:  Dr. Cook, may I interrupt


      for a second and just ask a question about the data


      sets that you are reporting on?


                DR. COOK:  Sure.


                DR. FINCHAM:  Is this Phase IV data that


      is provided by sponsors, that then the Agency has


      acted on to change the label?


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


      response to what we call "pediatric written


      requests," which is part of the FDA Modernization




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


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


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


      could either ask them to do the studies or they


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


      then issue them the pediatric written request which


      would allow them to do the studies.  That is sort


      of a quick summary.




                Now, this steroid, Clobex Lotion, was


      actually approved in 2003, and this actually was


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


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


      pediatric patients if we needed it.


                These trials, atopic dermatitis and for


      psoriasis, were done in both pediatric and adult






                There were 3 studies involving Clobex


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


      atopic dermatitis, and 1 pediatric study, ages 12


      to 17 years in atopic dermatitis.


                In all of the studies, there was a


      comparator drug, Temovate E Cream, which is also


      clobetasol propionate, so the same chemical moiety




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


      Class I steroid.




                The construct of the HPA axis evaluation


      for this study went back to the 3 criteria, and


      that is because the actual NDA and construct of the


      study was done prior to our criterion of just 1,


      because it was approved in 2003, so the studies


      were done prior to that.




                In the adolescent study, there were 24


      evaluable patients, 14 were treated with Clobex


      Lotion and 10 were treated with Temovate E Cream.


                They all had moderate to severe atopic


      dermatitis. They had to have a body surface area


      involvement of at least 20 percent.  The medication


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


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


      was driven by the fact that Temovate E Cream, that




      is how it's labeled.




                It was found that 9 of the 14 or 64


      percent of subjects treated with Clobex Lotion were


      suppressed versus 20 percent of subjects treated


      with Temovate E Cream, again suggesting that the


      vehicle may have something to do with the amount of


      drug that gets into the systemic circulation.




                In the statistical analysis the mean


      percent body surface area treated was higher for


      patients that had adrenal suppression, 32.8 percent


      versus 27.7 for the Clobex Lotion and 35 percent


      versus 25.3 percent for the Temovate E Cream.




                When retested, 1 of the 4 patients treated


      with Clobex Lotion remained suppressed after 2


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


      that was suppressed with Temovate E Cream






                In the adult study, there were 18




      evaluable patients, 9 were treated with Clobex


      Lotion and 9 with Temovate E.  They all again had


      moderate to severe atopic dermatitis.  The mean


      body surface area treated was approximately the


      same for both drug products.  They applied it twice


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




                Here, 56 percent of the patients treated


      with Clobex Lotion suppressed and 44 percent with


      the Temovate E Cream suppressed.




                When looking at recovery for these 2


      products, 1 of the 3 patients retested failed to


      recover function 7 days post-treatment with the


      Clobex Lotion, and 2 out of 2 patients on Temovate


      E Cream recovered their function 7 days afterwards.




                Finally, in the adult study, moderate to


      severe plaque psoriasis , there were 20 evaluable


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


      surface area treated for both was approximately the


      same.  The medication was applied twice a day here




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






                Eighty percent of the patients treated


      with Clobex Lotion suppressed and 30 percent with


      Temovate E Cream suppressed.  One of the 2 subjects


      retested with Clobex Lotion remained suppressed


      after 8 days, and none of the 3 subjects on


      Temovate E Cream unfortunately were retested.




                So, the indication for Clobex Lotion, when


      it was approved based on these results, was that it


      would be restricted to patients 18 years of age or


      older.  It could be used for two consecutive weeks


      not to exceed 50 grams/week.


                For moderate or severe psoriasis, for


      localized lesions less than 10 percent body surface


      area involvement, that an additional 2 weeks of


      treatment, the lotion could be used.  Appropriate


      other sections of the label were updated.




                Now, I am going to shift gears from our




      trial data and look at a postmarketing summary of


      HPA axis suppression across all topical


      corticosteroids since the induction of the AERS


      database, which is one of our sources since 1969,


      and also from medical literature case reports.




                I will just give you a background on the


      Adverse Event Reporting System.  It is a


      spontaneous, voluntary surveillance system.  It is


      voluntary reporting by health care professionals


      and consumers, but it requires mandatory reporting


      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




                The quality of the reports are variable


      and they are often incomplete, so you have to keep


      that in mind.  It is also subject to


      under-reporting, the true numerator is not known,


      and duplicate reporting does occur.




                There have been 94 cases reported spanning


      3 decades, 65 adult cases and 29 pediatric cases.




      The gamut of manifestations had been adrenal


      insufficiency, Cushing's syndrome, and growth






                In the 29 pediatric patients, and some of


      these overlap within same patients, 11 were with


      adrenal insufficiency, 17 with Cushing's syndrome,


      and there are 13 with growth retardation.


                The ages ranged from 6 weeks to 15 years


      with the mean being 5 years.  The duration of use


      was 22 days to 7.5 years with a mean of 20.8


      months.  Fifty-five percent of these patients


      received medication for 3 months or longer. There


      were varied indications, but 34 percent in the


      pediatric population were using topical


      corticosteroids for diaper rash.


                Betamethasone containing, clobetasol, and


      mometasone products were implicated most often with


      34 percent using high-potency topical






                In these 29 pediatric patients who had


      evidence of some type of HPA axis compromise, it


      resulted in 14 hospitalizations and 2 deaths.  The


      latter were from Cushing's syndrome or


      complications thereof.




                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




      hospitalizations and 2 deaths, and the deaths were


      attributed in part of the adrenal event.




                So, the postmarketing reports, just in


      summary, the common factors were that most of the


      AEs occurred in the following settings:


                Prolonged use of the topical


      corticosteroid, use of a superpotent topical


      corticosteroid, use of multiple topical


      corticosteroid products or concomitant use with


      other corticosteroid formulations like inhaled or


      systemic, and also use of excessive amount or


      possible inappropriate use of the topical


      corticosteroid product.




                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








                The type of vehicle may contribute to the


      extent of absorption of the active chemical moiety.


                The suppression appears in most cases to


      be reversible upon cessation of drug usage.


                Long-term use of topical corticosteroids,


      particularly high potency ones, can lead to serious


      morbidity and even death.




                Now, we are going to move on to cutaneous


      safety. We will first speak about the known


      cutaneous adverse events, and then we will just


      address here briefly the question of cutaneous


      malignancy as it might relate to topical


      corticosteroids, if at all.




                Now, the adverse events associated with


      topical corticosteroid use include atrophy of the


      skin, telangiectasia, striae, erythema of the face,


      steroid rosacea, hypopigmentation, infection, and


      retarded wound healing.




                Because pictures speak a thousand words, I


      am going to give you a pictorial presentation of




      these adverse events.




                This is a photo of cutaneous atrophy.  It


      is not the best photo, but here you can appreciate


      a little bit of thinning of the skin and some


      shininess to the cutaneous surface.




                Here, we have telangiectasia.  You can see


      the very fine blood vessels coursing here through


      this person's chin.




                This is a picture of striae, probably






                Another picture of striae, maybe a little


      more of acute onset in nature.




                This is a picture of facial erythema.




                Another of facial erythema.




                This is a picture of steroid rosacea where


      someone was applying topical corticosteroids and


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


      potency of the topical corticosteroid would have to




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


      underlying disease, had to be treated






                This is a picture of hypopigmentation from


      topical corticosteroid use.




                Other adverse effects that can happen.


      Topical corticosteroids placed on certain


      infections, for example, tinea infections, may


      exacerbate them.  Topical corticosteroids placed on


      open or surgical wounds will retard healing.  Use


      of topical corticosteroids in the periorbital area


      may cause an increase in intraocular pressure.




                Now, as far as cutaneous malignancy, we




      will look at the postmarketing reports out of the


      same system that I was speaking about prior, the


      AERS database, and there are 2 reports as of


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




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


      of mastocytoma, and he reported or someone reported


      cancer several months after discontinuation of


      clobetasol.  The patient actually used fluticasone


      for a short while, and then used clobetasol


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


      started to reapply for another week, but developed


      cutaneous atrophy, and the medication was stopped,


      and then several months later, the report came that


      he developed skin cancer.


                The second case is a female of unknown age


      who used betamethasone cream for psoriasis and then


      reported "what started as psoriasis became cancer".


                So, from this we can say that the AERS


      data do not suggest a compelling safety signal for


      malignancy formation with the use of topical






                So, as far as cutaneous adverse events,


      corticosteroid-induced adverse events can be early




      or late event.  It depends on the potency of the


      drug and the duration of use.  It depends on the


      site of application. Occlusion at the site may


      increase the risk.


                 Corticosteroid-induced adverse events may


      resolve slowly or they may not resolve at all.




                So, in conclusion, HPA axis suppression


      can occur with short-term use of topical


      corticosteroids.  HPA axis suppression can occur


      with even mid-potency topical steroids.  It can


      occur as early as two weeks of continuous therapy.




                The suppression that occurs is usually


      reversible. The interrelationship between body


      surface area, amount of drug used, and potency of


      the medication is complex as it relates to the


      development of HPA axis suppression.


                Long-term use and/or misuse of topical




      corticosteroids, particularly those of high


      potency, can lead to serious medical complications


      and death.




                The cutaneous adverse events can be


      related to both duration of use and potency of


      topical corticosteroid use.  It can occur with


      short-term or long-term use.


                Resolution of these cutaneous adverse


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


                There also is no firm evidence to date to


      link cutaneous malignancy with the use of topical




                Thank you for your attention for this




                Next, we will have Dr  Stephen Wilson.  He


      is in the Division of Biometrics II.  He will speak


      on lessons learned from growth studies with orally


      inhaled and intranasal corticosteroids.


            Lessons Learned from Growth Studies with Orally


                 Inhaled and Intranasal Corticosteroids


                DR. WILSON:  Gray Gaithersburg morning to






                It is my pleasure to be here this morning


      substituting for Peter Starke.  I think that I was


      elected for this job because I am the only one that


      was around when they did the class labeling


      advisory committee in 1998, but we have had some


      lessons that we have learned from that advisory


      committee in dealing with growth studies for orally


      inhaled and intranasal corticosteroids, and I would


      like to share some of those with you in the short


      amount of time that we have.




                Specifically, we have been charged with


      providing you with somewhat of a background of why


      we do these studies within our area for intranasal


      and orally-inhaled corticosteroids, and then talk


      about what these growth studies are.


                In particular, we are going to focus on


      what we call longitudinal growth studies, which are


      fairly long-term growth studies.  Then, we will


      talk about some of the design issues with these


      studies and the regulatory history that sort of




      brought us to this moment in terms of the science.


                I will provide with the results from some


      of the studies that we have seen within the


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


      Pulmonary and Allergy Drug Products.




                So, why do we perform growth studies?  I


      think that looking at it from our perspective,


      growth is an indicator of systemic exposure and of


      the potential to cause systemic toxicity.


                Growth suppression is a well-known side


      effect of systemic corticosteroid use.  It has a


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


      all CS given in sufficiently high doses will


      produce growth effects.  It is thought to be a


      direct effect on the bone, and may also act through


      secondary mediators and hormones.


                We believe that growth is the most


      sensitive indicator of systemic effect within our


      review environment because we have seen growth


      effects in the absence of effects from HPA axis


      studies by cosyntropin stimulation.




                There are basically two types of studies


      that are presented to us by sponsors.  One goes by




      the name of knemometry, and the other is the


      longitudinal or long-term growth studies.


                Sponsors have done knemometry studies.


      These are generally short-term studies, so it is


      attractive in the sense that they can be done


      rather quickly, and there are a number of


      methodological issues.  They can essentially be


      done in only a few centers.


                The consistency of results has been


      puzzling and a little bit problematic to us as a


      regulatory agency, because we don't always see the


      same kinds of results coming out, and we view these


      as primarily a research tool.


                So, focusing on longitudinal growth


      studies, these are growth studies designed to


      measure growth velocity over a 1-year treatment


      period, so this is a long treatment period.


                The patient population has to be carefully


      selected because this is a patient population that




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


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


      to run a concurrent control, so some on


      corticosteroids and others using other kinds of






                What is the population that we look at in


      these growth studies?  These two CDC charts are


      provided primarily to show you where we consider


      growth to be fairly linear.


                For one thing, it is very difficult to get


      growth measurements in the youngest children, zero


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


      stadiometry measurements, and the growth is fairly


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


      years old depending on sex.


                So, this is the focus of these growth


      studies that are provided to us by the sponsors.




                So, what are these growth studies, what do


      they look like?  Basically, it is fairly


      straightforward.  It's serial stadiometry.  There




      is a baseline period of about 3 months in which we


      measure growth, baseline growth.


                Then, there is an on-treatment period and


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


      guidance that was developed following the advisory


      committee that I mentioned in 2001, and it is still


      available on the website, so you can see some of


      the details of what we are suggesting.




                So, longitudinal growth studies.  As I


      said, they are technically difficult to perform.


      They require relatively large numbers of children.


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


      that ideally, they would have almost 125 children


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


      they are quite a bit larger than the studies we


      have been looking at.


                They require a long baseline and treatment


      period, and the measurement and compliance issues


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


      keep children on these studies for a long time,


      working with parents and providing treatment.


                There are also statistical issues in terms


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


      what I think probably sponsors have the most




      problem with is we are not looking at these as


      superiority trials or even equivalence or


      non-inferiority trials.  It is just too difficult


      to make a judgment as to what the delta or the


      difference that you are looking at would be.


                So, we essentially are presuming that


      there is a growth effect from these drugs, and we


      are designing them to best characterize that


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


      means that you have to have the proper size, you


      have to conduct the studies appropriately, and that


      is what we are going to be reviewing if we are


      going to describe what your study has done in the




                So, the size of the growth effect that is


      clinically relevant is unknown or not fully known.


      That is what our presumption is.




                So, how did we get here?  Actually, there




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


      two longitudinal growth studies done to better


      characterize the systemic risks prior to


      consideration of taking beclomethasone dipropionate


      nasal spray over-the-counter.


                So, in other words, the company was


      developing, wanted to go OTC, had these growth


      studies going, and when the results of these growth


      studies became available, it was recognized that


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


      the other kinds of tests.


                Then, at that same time, the number of


      other companies who were doing growth studies also


      came in and demonstrated this same kind of effect.


                So, 1998, we held a Joint


      Pulmonary-Allergy and Metabolic-Endocrine Advisory


      Committee, which ended up recommending a class


      labeling for all orally inhaled and intranasal


      corticosteroids, and we ended up also implementing


      that recommendation.




                So, what did that label end up looking




      like?  Well, in the General Use and Pediatric Use


      Subsections, we essentially said orally


      inhaled/intranasal corticosteroids may cause a


      reduction in growth velocity in pediatric patients.


                Also, in the Pediatric Use Section, we


      noted that growth effect may occur in the absence


      of laboratory evidence of


      hypothalamic-pituitary-adrenal axis suppression,


      potential for treatment "catch-up" growth has not


      been addressed, and basically, our advice to the


      physician was to titrate to the lowest effective


      dose for each patient and monitor growth routinely.


                If reported, cases of growth suppression


      should be noted in the Advise Reactions Section.


                So, basically, in terms of this being a


      class labeling, we would only note certain kinds of


      growth suppression if it was being reported to our






                So, how did this original study look, the


      one that we were looking at for the advisory




                Intranasal beclomethasone basically was a


      randomized, double-blind, placebo-controlled,


      parallel group, prospective, one-year study.




                The age groups of the children, they were


      children with allergic rhinitis being treated by


      intranasal corticosteroids, ages from 6 to 9.5


      years.  Basically, the same size study groups, and


      you just had a placebo against the intranasal


      corticosteroid, about 50 in each group.




                Now, the results showed that the growth


      rate centimeters/year on the BDP treatment group


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


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


      the depression that we saw for that one year.


                Now, this was a statistically significant


      difference based on the prespecified analysis, and


      it was an unexpected result, but basically, we were


      comparing mean annual growth rates.


                In the same study, however, these same


      children were tested, and there was no significant


      differences observed between treatment groups by




      mean basal cortisol or ACTH-stimulated plasma


      cortisol levels.




                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




      throughout, so this is the mean data expressed


      another way.




                We also looked at some other intranasal


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


      You notice, as oftentimes happens, this was


      actually the largest difference that we saw was on


      the first one, and the intranasal drugs that came


      in afterwards, budesonide and fluticasone, also


      showed some growth depression.  Mometasone,


      however, as you can note, did not show.




                The orally inhaled drugs tended to show


      more growth suppression, BDP, for example, minus 2


      versus the 0.7 that you saw before.  This slide


      also indicates that this is a study that was done,


      and you had some of those younger children, so you


      tended to see a lot more variability in the


      estimate, so the recommendations in the guidance


      became, you know, you had to have these older


      children that you could measure, because a lot of


      these included recumbent measurements, and those




      are difficult measurements to make.


                Another thing here is that there is some


      kind of apparent dose effect from a company that


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


      data available to us in trying to make these






                So, the issues.  These are indeed


      difficult studies to perform if you are thinking


      about doing one of these studies.  They are also


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


      regulatory setting, so basically, you are taking


      what the company has given you as evidence, and you


      are making some assessment of that.


                If a company has, for example, if there


      are a lot of subjects that have dropped out, you


      have to worry a lot about missing data, and you


      have to worry about if they haven't measured them


      carefully over time, in other words, there are some


      sort of glitches in the measurement, they then make


      decisions as to how they are going to analyze that


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




      that, so these are difficult studies.


                Growth studies are not designed to


      evaluate obviously the reversibility of the HPA


      axis effects or changes greater than a year.  So,


      although we do measure for another 3 months after


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


      would be long term.


                A lot of these patients, a lot of these


      children are going to be on the drug for a lot


      longer than 1 year.


                We have not identified a clinically


      relevant effect size, and that means that we all


      sit around a number of time, on a number of


      occasions, saying how could we pin down what the


      effect size is, so that maybe we could look at


      non-inferiority trial, but everybody said that


      basically, it is not acceptable or there is no


      clinically relevant effect size on that mean value.




                So, conclusions.  We use growth studies as


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


      sensitive indicator of systemic effects, and we




      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




      as we would like them to be.




                Again, there is reference Division of


      Pulmonary and Allergy Drug Products.


                I can't believe that I actually finished


      early, but I look forward to any questions you


      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






                Today, I am going to speak on topical


      corticosteroids and testing for adrenal suppression


      in the context of potential Rx to OTC switch.




                This is a brief outline of my talk.


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


      various systemic effects that have been seen with


      topical corticosteroids and some which have not


      been seen.


                We are also going to discuss specifically




      the hypothalamic pituitary adrenal axis testing,


      what tests are available to look at HPA, and more


      specifically, we are going to focus in on


      cosyntropin stimulation testing, look at what our


      current testing recommendations, how we are trying


      to standardize the testing, and we are going to


      discuss how precise an estimate would we need for


      adrenal suppression potential for OTC.




                Now, as Dr. Cook and Dr. Wilson have


      stated, prescription corticosteroids have systemic


      effects which we evaluate during drug development.




                Now, I would like to separate these out


      into those areas where specific studies have not


      been required for dermatologic topical




      corticosteroids.  These include sodium retention on


      mineralocorticoid effect, glucose tolerance, growth


      suppression, osteoporosis, and what we do look at,


      which is HPA axis suppression.


                With regard to sodium retention, they are


      receptor-specific effects and they may be less


      concerned with glucocorticoids.  I am going to go a


      little bit into that.


                Regarding glucose tolerance and growth


      suppression, data available for glucose tolerance


      from clinical studies, the growth suppression


      studies, as Dr. Wilson has discussed, is


      technically challenging and is difficult to perform


      and to review.


                Further, for osteoporosis, the same could


      be said for that.  It is difficult to have these


      topical corticosteroids used for the long term.


      The patients wax and wane with their disease, so


      the application of the topical corticosteroid can


      increase and decrease, plus the strength of the


      corticosteroid may vary during the conduct of a


      year-long study, so there is the potential for




      change in dose and potency, which again leads to


      inconsistent and very challenging evaluation of any


      data that would be obtained from such a study.


                Regarding HPA axis suppression, we will


      get into that a little bit more.




                This is a table of the relative potencies


      for various steroids with a cortisol at 1.0 and


      there are two references in the package that was


      given to the Committee regarding this.  This table


      is excerpted from those references.


                As you can see, the two examples of


      topical corticosteroids given in this table are


      triamcinolone and betamethasone.  Both of those


      have a higher affinity or a higher relative potency


      regarding glucocorticoid effect but a lower


      mineralocorticoid effect.  This can be contrasted


      to aldosterone which has a much higher


      mineralocorticoid effect as compared to


      glucocorticoid effect.




                This is a schematic diagram of the HPA




      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.




                With that, we get into HPA axis testing.






                There are two classes of tests, basic


      classes; the basal testing, which is done with


      basal plasma levels and 24-hour urine cortisol


      levels.  These are thought to be less useful in


      measuring an adrenal response to stress than


      dynamic testing where you try to stimulate the


      adrenals to cause a response and you measure the


      magnitude of that response.




                There are various dynamic tests of HPA


      axis function.  Earlier, it was mentioned, the


      insulin tolerance test which is an older test.


      When you administer insulin, you cause a


      hypoglycemic event.  It then results in a potent


      stress stimulus for the adrenal glands.


                Now, these subjects, when you administer


      insulin, you need very close subject monitoring.


      It is thought that this test, as it is currently


      done, produces undue risk to the subject and,




      therefore, the agency does not recommend this as a


      test for HPA axis function.


                The cosyntropin, or ACTH amino acids 1 to


      24, test is available in higher or lower


      concentrations.  The higher dose is the labeled


      dose for cosyntropin.  Lower dose studies vary and


      there is no standardization regarding how much of a


      rise in cortisol you need with lower dose and the


      timing of the rise is not standardized.  So the


      lower test is still experimental at this time and


      if one is to use it, there should be discussion


      with the Agency regarding how it is used.


                For higher dose testing, we will discuss


      that in just a moment.  There is also a


      corticotropin-releasing hormone test, the CRH test.


      This also is experimental and not widely available.




                The higher dose cosyntropin test is the


      most commonly used test to evaluate for adrenal


      suppression.  The procedure is to administer a


      superphysiologic dose.  It is currently labeled for


      IV or IM use of 125 micrograms if the patient is




      less than 3 years of age or 250 micrograms if the


      patient is 3 years or older.  The serum or plasma


      cortisol concentrations are measured before and 30


      minutes after the cosyntropin administration.




                The advantages of this test are that it is


      simple, it is fast and relatively inexpensive.  It


      is an outpatient test and it takes approximately 30


      minutes to do.  There are some limitations.  It is


      not the most sensitive test.  It can be equated to


      being a physiologic hammer.  I mean you are giving


      a very high dose of what is equivalent to ACTH to


      cause the adrenals to respond. So the sensitivity


      may have some concern.




                The criteria for a normal response in


      Cortrosyn, according to label and the 30-minute


      test is as follows:  The control of basal cortisol


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


      minutes, after administering the Cortrosyn, there


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


      incremental cortisol rise, that is--and the




      30-minute level should exceed 18 mcg/dL.


                However, we note that basal cortisol


      levels vary throughout the day and the higher the


      basal level, the lower the incremental cortisol


      rise.  So, for regulatory purposes and for drug


      development, it is thought that normal response of


      peak cortisol level of greater than 18 mcg/dL 30


      minutes after giving Cortrosyn should be sufficient


      as the test for adrenal suppression.




                With that, we segue to what are current


      testing recommendations for adrenal suppression.




                There was an Advisory Committee on October


      29th of 2003, and there was some discussion about


      the HPA axis test, Joint Committee discussion.  It


      was discussed that higher dose cosyntropin test is


      a sufficient determinant of HPA axis function with


      regard to prescription topical corticosteroids.


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


      post-stimulation cortisol level at 30 minutes is


      equivalent to that subject being not suppressed. 




      It was also discussed at that Advisory Committee


      where data was presented on reversibility, and you


      saw the reversibility data, we have very little of


      that.  We need follow-up for reversibility when we


      do these studies.




                It was a pediatric meeting, so there was


      discussion about the pediatric cohorts.  The


      pediatric population was divided into 4 cohorts


      here.  Sequential testing was usually done for


      these studies with the older patients first, but at


      this Advisory Committee it was discussed that


      potentially concurrent testing can be done if the


      safety of the patients can be assured.  The


      rationale for that is to obtain more data regarding


      the adrenal suppression in each of these cohorts.




                Additional recommendations from the Agency


      are as follows:  the 60-minute cortisol is not


      recommended.  The standardization for a 60-minute


      level is poor, and the results can vary somewhat


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


                Testing less than 4 weeks apart is not


      recommended.  Administering the ACTH or Cortrosyn


      start to leave an impression on the adrenals and




      there may be effects on later response especially


      when the tests are done closer than 4 weeks apart.


                There is a need to monitor the local


      cutaneous adverse events during the conduct of this




                Finally, it is important to note when


      interpreting these studies that the percent of


      patient suppressed, not the mean cortisol levels is


      important.  Mean levels may mask individual


      patients, so if someone were to present data on


      mean levels, ask them what the percent of patients


      suppressed was.




                Finally, we note Dr. Cook's presentation,


      the body surface area involved can vary from atopic


      dermatitis, at least 30 percent body surface area


      is needed, for psoriasis, at least 25 percent body


      surface area involvement for these patients, and


      these are maximally involved diseased patients.


                It is also important to note that patients


      who enter the study should not be adrenal


      suppressed, so there should be testing for adrenal


      suppression prior to exposing them to


      corticosteroid to make sure they are not suppressed


      at baseline.  Often these patients will have come




      into a study having been on other corticosteroids


      for a protracted length of time because of their


      significant disease.




                The last part of this talk, we are going


      to discuss a little bit about what precision do we


      need for OTC use of corticosteroids.




                For topical corticosteroids drugs to be


      used in an OTC setting, how acceptable is HPA axis


      suppression, and how many subjects need to be


      evaluated to rule out corticosteroid-induced


      adrenal suppression for an OTC product if this is


      one of the tests that is going to be used?




                Here is an exercise I would like to pose




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


      all with topical corticosteroids for 4 weeks, and


      we noted those 30 subjects, zero had cosyntropin


      stimulation test indicative of adrenal suppression,


      that is, the rate was zero out of 30.


                The question arises with what risk, if


      any, of adrenal suppression induced by topical


      corticosteroids might these results be compatible,


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


      is not.




                Zero out of 30 subjects rules out, with 95


      percent confidence, a greater than 10 percent


      chance for adrenal suppression to occur in the


      global population.  This is a statistical concept,


      and there is a paper in the package that was handed


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


      to look at this.


                The sample size determines the extent we


      can rule out adrenal suppression in the global


      population with zero subjects suppressed.




                With that, we can go to this table on


      sample size effect on the upper confidence interval


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




      10 subjects and we had zero of those 10 subjects




                Well, that would rule out with a 95


      percent confidence interval no greater than 26


      percent adrenal suppression.  Whereas, if we double


      the number and go to 20 subjects, we can increase


      that upper confidence interval to 14 percent.


                To get to really small percentage numbers


      for upper adverse event occurrences, we need larger


      sample sizes.  So, the greater the number of


      patients you have, the more assuredly you can be of


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


      does give you zero.




                So, the question asked for the Committee:


      Cosyntropin stimulation studies are used to inform


      labeling for prescription products with regard to


      potential for adrenal suppression.


                If the cosyntropin stimulation studies are




      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.




                    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




      wondering how many of the subjects, for example, in


      the studies that we were presented actually got the


      cosyntropin IM and do we know whether there is more


      variability or sensitivity, differences in


      sensitivity, when the cosyntropin is administrated


      IM versus IV.


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


      comparisons in the literature between IM and IV


      use.  For pediatric studies, it is often more


      convenient to do an IV study rather than an IM


      study simply because of the pain threshold of those


      patients.  You can insert a cannula and inject the


      cosyntropin and also withdraw blood from the same


      cannula afterwards and so there is only one stick.


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


      access difficulties that one would resort to an IM.


      Regarding whether one should do IM or IV, I think


      it is important to be consistent throughout each


      study as to what route you choose to administer the


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


      studies to compare the two routes.


                DR. BLASCHKE:  I suspect it is not done




      consistently because I suspect that it really does


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


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


      compounds that, when they are administered IM,


      depending on where, et cetera, that the absorption


      and the absorption rate is quite different for IM,


      obviously, than IV.


                It sounds like, as you say, there is no


      comparative data so maybe no answer to the




                DR. WOOD:  Dr. Snodgrass.


                DR. SNODGRASS:  Are there any standards


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


      example, and knowledge about their sleep patterns


      for the circadian rhythm aspects?


                DR. LUKE:  Because of the circadian


      rhythm, it is thought that a standard time might be


      helpful but keep it close within.  It is often


      difficult to do a study where you have all the


      patients done at the same time.  So there is some


      variability allowed for it.


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




      concern.  Of note, the lower cosyntropin


      stimulation test, the lower dose, there have been


      concerns raised about the peptide sticking to


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


      performing lower dose cosyntropin testing.


                DR. WOOD:  Dr. Epps.


                DR. EPPS:  My questions actually are for


      Dr. Wilson.  Is that okay?


                DR. WOOD:  Sure.  We are taking questions


      for all of the last speakers.


                DR. EPPS:  Okay.  The growth charts, the


      CDC growth charts, were those based on the standard


      growth charts that are used or are they updated and




                DR. WILSON:  Those are the standard growth


      charts that everybody sees and are available from


      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




      current.  These are trials in which we have


      comparators and are randomized.  So we have all


      those kinds of things taken care of.


                But you are right.  We pondered a lot


      about the growth charts and what they really meant


      for individuals.  As you were looking at those


      percentage breakdowns, that is where it becomes


      more important probably.


                DR. EPPS:  Also, my question was do the


      kids recover.  You were taking about growth


      velocity which is different from overall growth


      potential and whether--you know, kids accelerate


      and decelerate and, really, the lines are kind of


      percentiles or averages.  So that was one question


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




                DR. WILSON:  The long term.  Again,


      sponsors have presented to us, and there have been


      a few studies done on trying to assess whether




      there are some long-term effects.  But those are


      even more difficult to do than these annual




                I think that the assumption has always


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


      that a lot of this will be recovered.  We have


      never looked at ultimate height.  Companies, of


      course, are always saying this.  They want to have


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




                This is Gene Sullivan from the Division.


                DR. SULLIVAN:  Hi.  I am a pulmonologist


      in the Pulmonary Division.  I think what you are


      getting at is part of the reason why the slide said


      we don't know the clinical significance.  We can


      measure what happens in that year, what happens


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


      is the full adult height affected?  Those are


      still, we consider, unknown.


                DR. EPPS:  To follow up that, what about


      children who have asthma or are on these


      medications?  Is their velocity different from




      normal?  In other words, sometimes growth is


      affected just by having chronic disease.


                DR. WILSON:  By the disease itself.  But


      these pediatric studies, for a number of reasons


      including ethical considerations, are done in


      children with the disease.  So the studies of


      orally inhaled corticosteroids are done in children


      who need the medications.  So the comparison is the


      placebo group versus the active treatment should


      take that out of the picture.


                DR. EPPS:  Certainly, breathing comes




                Now, my last question is, for any of these


      studies with inhaled and intranasal steroids, did


      any of them also have atopic dermatitis?  They


      usually run together, so you might have topical


      steroids and intranasal and inhaled steroids all


      working together, and would that affect their


      growth, as well


                DR. SULLIVAN:  I can't say categorically


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


      well, but I presume that almost all of them would




      have excluded concomitant use of other




                DR. WOOD:  Dr. Bigby.


                DR. BIGBY:  I have actually four


      questions.  The first one actually is a


      philosophical question both for the FDA and for the


      people here on the panel.  If one of these classes


      of topical corticosteroids has been shown to


      produce HPA axis suppression, would we not


      recommend it for OTC approval?  That is the


      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?




                DR. WOOD:  I will answer for them, because




      they won't.  Not without a huge amount of


      difficulty is the answer.  It is much harder to get


      something off the market than it is to not approve


      it to go on.


                DR. BIGBY:  Lastly, other than


      hydrocortisone, is there any foreign country


      experience with an OTC more potent topical




                DR. KOENIG:  I am sorry, I thought about


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


                Does anyone in the audience know?


                DR. GANLEY:  We have some industry folks


      here, they may know that answer.


                DR. WOOD:  Let's move on then.


                Dr. Davidoff.


                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




      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




      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




                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




      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




      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




      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




                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




      get the same HPA suppression?


                So, the companies that make the pediatric


      products that were doing the testing in pediatric


      patients, after they found HPA suppression with


      their products, they came back to the labeling


      saying 13 years of age or older.  Is there any


      reason to presume that HPA suppression is any


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


      It just is concerning.


                DR. COOK:  Yes, I see your point because


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


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


      to say that HPA axis suppression would not occur in


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


      data to be able to put that in labeling.


                DR. WHITMORE:  Has the FDA considered


      asking the companies to go back and study adults


      with any of these things?


                DR. WHITMORE:  Didn't you propose a




      hierarchical sort of structure?  At least that was


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


      HPA suppression in adults, so you would start with


      adults.  If that was positive, you would stop


      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




      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




      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




      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




      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




      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,




      and that varies a lot from individual to


      individual, but on average, we consider that time


      to be approximately two weeks, approximately two




                I was surprised to see that in some of the


      studies with the mid-potency steroids, you have


      levels, we have levels of response to the ACTH stim


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


      look back at my patients with endogenous Cushing's,


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


      recovery time after a pituitary tumor-producing


      ACTH is excised.


                So, this is quite significant general


      atrophy, and since the test if not very sensitive,


      you would consider that as the tip of the iceberg,


      that you are really missing a lot of patients that


      have developed moderate adrenocortical atrophy, and


      you have no way of picking up those that have


      moderate cortical trough cell suppression in other




                DR. WOOD:  So, what would be your estimate


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




      what you said?


                DR. STRATAKIS:  The sensitivity is about


      70 percent, so I would say about 30 percent.


                DR. WOOD:  Jack.


                DR. FINCHAM:  This is just an observation


      in the context of what we are going to be


      discussing this afternoon as far as how these


      products may be used by consumers in an OTC


      setting, a nonprescription setting.


                I was struck by Dr. Cook's presentation of


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


      would assume that these are controlled situations


      where the individuals had some limits on what they


      could obtain and how they could obtain it, but in


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


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


      ounce a day being used, which is an enormous amount


      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




      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




      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




      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




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


      patients failed to respond, they weren't retested


      again.  Those are certainly things that we are


      trying to address in future studies, especially


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


      have been out at least 4 weeks because of the


      possible influences of the results on continuously


      re-stimulating the adrenal gland.


                Unfortunately, we don't have the answer to




                DR. WOOD:  Dr. Nelson.


                DR. NELSON:  I would like to make some


      observations on the data that Dr. Cook presented


      and invite comments to just see if I am getting it




                This is just looking at what I see as 9


      pediatric studies that you presented.  If you look


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


      ignoring the differences in methods of adrenal




                If you scan it, in terms of potency, it


      looks to me like there may be an effect based on




      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




                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




      denominators are small, and that you really ought


      to look across classes, and I think we take your


      point that we might learn something more about the


      class if we grouped these sorts of things together?


                But there are some difficulties with that,


      and I think something maybe we didn't stress enough


      is that at any one given time over the last 20


      years, we have been consistent at least for 6


      months in how we think about topical


      corticosteroids, but we have really changed


      radically from the beginning, you know,


      paleoregulatory 20 years ago, I am not sure exactly


      what kind of studies were done for HPA axis




                Then, when we looked, we looked at


      endpoints that were serum cortisol.  There was no


      Cortrosyn stimulation. Then, subsequent to that, we


      looked at perhaps more stringent criteria.  We


      looked at what is in the Cortrosyn labeling, which




      gives 3 criteria, and would identify more subjects


      as being positive than what we are now looking at


      today given the benefit from the endocrinologists


      telling us that they only use the single criterion


      in their practice.


                So, just how we look at it has changed


      radically over time.  Also, over time we have been


      able to, now armed with PREA, the Pediatric


      Research Equity Act, we are now able to ask for


      much more data that we have gotten in the past.


                So, I think one of the great difficulties


      is there is enormous heterogeneity in the data sets


      and the conduct of the studies in each of these




                DR. NELSON:  If I could just make one


      comment in response, all of the pediatric studies,


      it looked to me the only difference in the


      stimulation testing was whether you picked the


      threshold alone versus the rate of rise, and if you


      drop out the rate of rise and just pick threshold,


      you are still going to end up around 20 percent


      overall incidence among all these studies.


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


      guess I would encourage you to look at the


      pediatric studies.  I think there is probably




      enough homogeneity that you could draw some


      conclusions from those studies, if you grouped them


      as a class or did it by potency.


                DR. WILKIN:  I take your point on the


      pediatric patient being a better sentinel


      population in which to look for this particular


      event.  I think one of the things that we have


      learned is that while we can make some correlations


      and say that, in general, a higher body surface


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


      these things tend to correlate with the finding of


      HPA axis suppression.


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


      see an adult who has a very small body surface area


      involvement who suppresses, a child who has a much


      larger body surface area involved, and not suppress


      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




      investigate children here except for the commercial




                There might be reasons, as well, but that


      wasn't why it was done, right?


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


      the reason for PREA being enacted certainly, but I


      can say within our Division, we recognized that


      atopic dermatitis was primarily a pediatric


      disease, and so even before PREA, our Division was


      asking for pediatric studies.


                DR. WOOD:  Right, but if someone came in


      for an OTC indication, which is what we are looking


      at, they wouldn't necessarily have had to have


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


      necessarily have had to have done a pediatric


      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




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


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


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




                So, I guess my question was why was it


      approved for 13 and older instead of perhaps


      adults, only given that there wasn't any


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


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


      the cutoff that was chosen.  I mean your point is


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


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


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




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


      prepubertal or whatever.  That was where the study


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


                DR. WOOD:  Dr. Taylor.


                DR. TAYLOR:  My question is really for Dr.


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


      systemic effects, indicating that HPA axis


      suppression is the only one that had really been


      studied well, I was concerned about glucose


      tolerance and sodium retention although I recognize


      with these drugs, sodium retention is going to be


      minimal since they lack significant


      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




      corticosteroids do include discussion about glucose


      tolerance and the sodium retention and


      mineralocorticoid effect, so when these


      prescription products are being used, it is thought


      that those are things that would fall under the


      rubric of a physician-patient discussion of




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


      position in terms of when the physician is no


      longer there, what is the Agency's remedy for


      ensuring that this growing population of diabetics,


      for example, have some guidance other than just the


      label on the box?


                DR. LUKE:  I think when you go to the


      history of hydrocortisone, there was discussion in


      that monograph about mineralocorticoid effects, and


      it was found that there was no studies that showed


      that hydrocortisone had a mineralocorticoid effect.


                DR. WOOD:  My sense of what we are trying


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


      decide is what is the most sensitive test for


      systemic effect of these drugs, and at what level




      would you put a barrier up to a demonstration of a


      systemic effect that would preclude OTC marketing.


                So, I guess maybe we should turn the


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


      reasonable, sensitive, and doable test for systemic


      effects of steroids administered by any route?


                DR. STRATAKIS:  Well, having said all the


      caveats of the ACTH stim test, I still think that


      the ACTH stim test satisfies all the criteria you


      just mentioned, the big response of cortisol of 30


      minutes to 250 micrograms of synacthen.  I mean


      it's still the most doable, the easiest to


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


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


      sensitivity of around 70 percent with specificity


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


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


      question, would you expect to see people who had


      elevation in blood glucose who did not demonstrate


      suppression of HPA axis?


                DR. STRATAKIS:  That would have glucose




                DR. WOOD:  Right.


                DR. STRATAKIS:  Especially if they are


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




      same thing that we see with growth.  Growth is a


      very sensitive index of the systemic effect of


      glucocorticoids, and yet you don't see abnormal


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


      at this point there is no good test to identify


      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




                I would be a little uncomfortable in that




      the labeling for the physician is that you are


      treating the individual, so there may be patients


      that are much more sensitive than others.


                Well, to carry that over into the OTC


      setting there may be always that patient out there,


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


      to address it through labeling, so anyone who is


      diabetic should talk to their doctor, for example,


      before using this product.


                Then, you get into the issue, well, does


      that have the impact that you want, is the person


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


      that having that data in front of me would make me


      feel better about being at OTC if it showed that it


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


      absolutely be sure that maybe there is someone out


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


      label it as such.


                I think we will get into that discussion a


      little more about some of these systemic effects of


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


      that you just label for them, because the outcome




      isn't as critical as death with a stress situation


      when there is HPA axis suppression.


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




                DR. DAVIDOFF:  Yes.  I had a somewhat


      related question because we are hearing that the


      HPA axis assessment using the cosyntropin test has


      a sensitivity of about 70 percent, but that implies


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


      was curious what gold standard it is being measured




                But the related point I wanted to make was


      that the results of this test are clearly a


      surrogate measure, and admittedly, if you don't


      want to hang around until people have experienced


      the ultimate criterion of suppression, which is to


      die because of adrenal insufficiency, so you have


      to use the surrogate measure, but that does get to


      the question of what is the sort of intermediate


      gold standard short of death that is used on the


      basis of which you can say it is a sensitivity of


      70 percent.