Rx Topical Corticosteroids and Testing for Adrenal Suppression by ijm13762

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									Rx Topical Corticosteroids and
     Testing for Adrenal
        Suppression

        Markham C. Luke, M.D., Ph.D.
          Lead Medical Officer, FDA
   Division of Dermatologic and Dental Drug
                   Products
  Joint NDAC/DODAC Advisory Committee Meeting
  March 24, 2005
                         Outline of Talk
1) Rx Topical Corticosteroids: Systemic
   Effects
2) HPA axis testing
  a) Tests available
  b) Cosyntropin stimulation testing
3) Current testing recommendations
4) How precise an estimate of adrenal
   suppression potential is needed for OTC?
   Joint NDAC/DODAC Advisory Committee Meeting
   March 24, 2005                                2
Rx Corticosteroids: Systemic
          Effects




Joint NDAC/DODAC Advisory Committee Meeting
March 24, 2005
                      Systemic Effects
• Sodium Retention (mineralocorticoid effect)
• Glucose Tolerance
• Growth Suppression
  – Long term studies are difficult
      • Change in Dose and Potency
• Osteoporosis

• HPA Axis Suppression

   Joint NDAC/DODAC Advisory Committee Meeting
   March 24, 2005                                4
                    Relative Potency
                               Glucocorticoid   Mineralocorticoid

   Cortisol                              1.0          1.0
  Cortisone                              0.8          0.8
  Prednisone                              4           <0.1
Triamcinolone                             5           <0.1
Betamethasone                            25            0
Dexamethasone                            25            0
 Aldosterone                            0.25          500


 Joint NDAC/DODAC Advisory Committee Meeting
 March 24, 2005                                                     5
  What is the Hypothalamic,
Pituitary, Adrenal (HPA) axis?




                                              CRH = Corticotropin Releasing
Joint NDAC/DODAC Advisory Committee Meeting     AVP = Arginine Vasopressin
March 24, 2005                                                                6
                                               ACTH = Adrenocorticotropin
                                                               F = Cortisol
                HPA Axis Testing




Joint NDAC/DODAC Advisory Committee Meeting
March 24, 2005
        Basal vs. Dynamic Testing
• Basal testing
  – Basal plasma and 24 hour urine cortisol

• Dynamic testing
  – Adrenal response to stress




   Joint NDAC/DODAC Advisory Committee Meeting
   March 24, 2005                                8
  Dynamic Tests of HPA Axis
          Function
• Insulin Tolerance Test
    Causes hypoglycemia - a potent stress stimulus for
     the adrenal glands.
    Need very close subject monitoring
    Undue risk to the subject
• Cosyntropin (ACTH1-24) Test
    • Higher (as labeled) Dose
    • Lower Dose
• Corticotropin Releasing Hormone Test (CRH)
    Experimental
 Joint NDAC/DODAC Advisory Committee Meeting
 March 24, 2005                                           9
         Higher Dose Cosyntropin Test

• Most commonly used test to evaluate for adrenal
  suppression

• Procedure:
   – Administer supraphysiologic dose (currently
     labeled) of cosyntropin, IV or IM:
      • 125 μg if less than 3 years
      • 250 μg if 3 years or older

   – Measure serum or plasma cortisol
     concentrations before and 30 minutes after
     cosyntropin administration
    Joint NDAC/DODAC Advisory Committee Meeting
    March 24, 2005                                  10
         Higher Dose Cosyntropin Test

• Advantages - simple, fast and relatively
  inexpensive
  – Outpatient
  – Approximately 30 minutes

• Limitations:
  – Not the most sensitive test
       • A physiologic “hammer”




    Joint NDAC/DODAC Advisory Committee Meeting
    March 24, 2005                                11
  Higher Dose Cosyntropin Test Criteria
• Criteria for normal response in Cortrosyn
  (cosyntropin) label (30 minute test):
   – Control basal cortisol level > 5 μg/dL
   – 30 minute level at least 7 μg/dL above basal
     (incremental cortisol rise)
   – 30 minute level should exceed 18 μg/dL

• Basal cortisol levels vary through the day
• Higher basal level  Lower incremental cortisol
  rise
• Normal response is peak cortisol level >18 μg/dL
  at 30 minutes
    Joint NDAC/DODAC Advisory Committee Meeting
    March 24, 2005                                   12
               Current Testing
              Recommendations




Joint NDAC/DODAC Advisory Committee Meeting
March 24, 2005
      Current Recommendations
• October 29, 2003 Advisory Committee
   Higher dose cosyntropin test is a

    sufficient determination of HPA axis
    function with regard to Rx topical
    corticosteroids.
   >18 μg/dL (500 nanomoles/L) post-

    stimulation cortisol level at 30 minutes =
    Not suppressed
   Follow-up for reversibility

    Joint NDAC/DODAC Advisory Committee Meeting
    March 24, 2005                                14
     Sequential vs. Concurrent
         Pediatric Testing
Pediatric Cohorts:
< 18 to 12 years old
< 12 to 6 years old
< 6 to 2 years old
< 2 years to 3 months old

• Sequential testing – older patients first
• Concurrent testing – if safety can be
  assured
 Joint NDAC/DODAC Advisory Committee Meeting
 March 24, 2005                                15
  More Current Recommendations
• Sixty minute cortisol not recommended

• Testing less than 4 weeks apart not recommended

• Monitor local cutaneous adverse events

• Percent of patients suppressed (not mean cortisol
  levels)
   – Mean levels may mask the individual patients

    Joint NDAC/DODAC Advisory Committee Meeting
    March 24, 2005                                    16
         Cosyntropin Test Study Entry
                   Criteria
•   For study entry:
    –        No adrenal suppression

    –       Maximally involved diseased skin
           • Atopic dermatitis – At least 30% body
             surface area
           • Psoriasis – At least 25% body surface area
             involvement


        Joint NDAC/DODAC Advisory Committee Meeting
        March 24, 2005                                    17
Precision of Testing Needed for
             OTC?




 Joint NDAC/DODAC Advisory Committee Meeting
 March 24, 2005
        OTC Topical Corticosteroid
                Products

• For topical corticosteroid drugs to be used
  in an OTC setting, how acceptable is HPA
  axis suppression?

• How many subjects need to be evaluated to
  rule out corticosteroid induced adrenal
  suppression for an OTC product?

    Joint NDAC/DODAC Advisory Committee Meeting
    March 24, 2005                                19
                         A Risk Exercise
• Of 30 subjects treated with topical
  corticosteroids for 4 weeks, zero had a
  cosyntropin stimulation test indicative of
  adrenal suppression (i.e., the rate was 0/30).

• With what risk, if any, of adrenal
  suppression induced by topical
  corticosteroids might these results be
  compatible?
    Joint NDAC/DODAC Advisory Committee Meeting
    March 24, 2005                                20
            Answer to Risk Exercise
• Zero (0) out of 30 subjects rules out, with
  95% confidence, a greater than 10% chance
  for adrenal suppression to occur in the
  global population.

• The sample size determines the extent we
  can rule out adrenal suppression in the
  global population with zero subjects
  suppressed.

    Joint NDAC/DODAC Advisory Committee Meeting
    March 24, 2005                                21
       Sample Size Effect on Upper CI
                                                  Upper Adverse Event Rate
Observed Events/Sample Size
                                                    95% CI       99% CI

                 0/10                                26%          37%
                 0/15                                18%          26%
                 0/20                                14%          21%
                 0/30                                10%          14%
                 0/50                                6%            9%
                0/100                                3%           4.5%
                0/300                                1%           1.5%
               0/1000                               0.3%          0.5%
    Joint NDAC/DODAC Advisory Committee Meeting
    March 24, 2005                                                           22
                                  Question
• Cosyntropin stimulation studies are used to
  inform labeling for Rx products with regard
  to potential for adrenal suppression.

• If cosyntropin stimulation studies are to be
  used for OTC products, how many subjects
  are needed for those studies (i.e., what is the
  level of tolerance for adrenal suppression
  for an OTC product)?
    Joint NDAC/DODAC Advisory Committee Meeting
    March 24, 2005                                23
                 Back Up Slides




Joint NDAC/DODAC Advisory Committee Meeting
March 24, 2005
           Lower Dose Cosyntropin Test
• Newer test
• Method not standardized regarding dose or timing of
  samples:
   – Measure cortisol before and serially post-cosyntropin
• Other issues:
   – Physiologic cosyntropin dosing may be more sensitive
     than supraphysiologic dosing for mild or recent-onset
     secondary adrenal suppression
   – Not commercially available (dilutional errors,
     variability in dose administered among tests, binding to
     plastic tubing)

     Joint NDAC/DODAC Advisory Committee Meeting
     March 24, 2005                                         25
       Cosyntropin Test Results (1)
•   Information to be collected and submitted to the
    FDA for each subject:
    1) Identifier number, age, height, and weight
    2) Dose of cosyntropin used
    3) Pretreatment cosyntropin test results (predose
       and 30 minute postdose plasma or serum
       cortisol concentrations).
    4) End of treatment cosyntropin testing results.
    5) Demonstration of recovery (reversibility) in
       suppressed subjects.


     Joint NDAC/DODAC Advisory Committee Meeting
     March 24, 2005                                 26
       Cosyntropin Test Results (2)
•    Information to be collected and submitted:
    6) Precise time intervals between cosyntropin
        stimulation and blood draw for cortisol
        measurements.
    7) Name and address of laboratory and
        laboratory reference values.
    8) Percentage of body surface area to which the
        topical corticosteroid drug product has been
        applied.
    9) The frequency of application.
    10) The total gram amount of corticosteroid
        product used.
     Joint NDAC/DODAC Advisory Committee Meeting
     March 24, 2005                                27

								
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