1. Joint NDAC/DODAC Advisory Committee Meeting March 24, 2005 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 Markham C. Luke, M.D., Ph.D. Lead Medical Officer, FDA Division of Dermatologic and Dental Drug Products

2. Joint NDAC/DODAC Advisory Committee Meeting March 24, 2005 2 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? 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? Outline of Talk

3. Joint NDAC/DODAC Advisory Committee Meeting March 24, 2005 Rx Corticosteroids: Systemic Effects

4. Joint NDAC/DODAC Advisory Committee Meeting March 24, 2005 4 Sodium Retention (mineralocorticoid effect) Glucose Tolerance Growth Suppression –Long term studies are difficult Change in Dose and Potency Osteoporosis HPA Axis Suppression Sodium Retention (mineralocorticoid effect) Glucose Tolerance Growth Suppression –Long term studies are difficult Change in Dose and Potency Osteoporosis HPA Axis Suppression Systemic Effects

5. Joint NDAC/DODAC Advisory Committee Meeting March 24, 2005 5 Relative Potency GlucocorticoidMineralocorticoid Cortisol1.0 Cortisone0.8 Prednisone4<0.1 Triamcinolone5<0.1 Betamethasone250 Dexamethasone250 Aldosterone0.25500

6. Joint NDAC/DODAC Advisory Committee Meeting March 24, 2005 6 What is the Hypothalamic, Pituitary, Adrenal (HPA) axis? CRH = Corticotropin Releasing AVP = Arginine Vasopressin ACTH = Adrenocorticotropin F = Cortisol

7. Joint NDAC/DODAC Advisory Committee Meeting March 24, 2005 HPA Axis Testing

8. Joint NDAC/DODAC Advisory Committee Meeting March 24, 2005 8 Basal testing –Basal plasma and 24 hour urine cortisol Dynamic testing –Adrenal response to stress Basal testing –Basal plasma and 24 hour urine cortisol Dynamic testing –Adrenal response to stress Basal vs. Dynamic Testing

9. Joint NDAC/DODAC Advisory Committee Meeting March 24, 2005 9 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 (ACTH 1-24 ) Test Higher (as labeled) Dose Lower Dose Corticotropin Releasing Hormone Test (CRH)  Experimental Insulin Tolerance Test  Causes hypoglycemia - a potent stress stimulus for the adrenal glands.  Need very close subject monitoring  Undue risk to the subject Cosyntropin (ACTH 1-24 ) Test Higher (as labeled) Dose Lower Dose Corticotropin Releasing Hormone Test (CRH)  Experimental

10. Joint NDAC/DODAC Advisory Committee Meeting March 24, 2005 10 Higher Dose Cosyntropin Test Most commonly used test to evaluate for adrenal suppressionMost commonly used test to evaluate for adrenal suppression Procedure: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 Most commonly used test to evaluate for adrenal suppressionMost commonly used test to evaluate for adrenal suppression Procedure: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

11. Joint NDAC/DODAC Advisory Committee Meeting March 24, 2005 11 Higher Dose Cosyntropin Test Advantages - simple, fast and relatively inexpensiveAdvantages - simple, fast and relatively inexpensive –Outpatient –Approximately 30 minutes Limitations: –Not the most sensitive test A physiologic “hammer” Advantages - simple, fast and relatively inexpensiveAdvantages - simple, fast and relatively inexpensive –Outpatient –Approximately 30 minutes Limitations: –Not the most sensitive test A physiologic “hammer”

12. Joint NDAC/DODAC Advisory Committee Meeting March 24, 2005 12 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 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

13. Joint NDAC/DODAC Advisory Committee Meeting March 24, 2005 Current Testing Recommendations

14. Joint NDAC/DODAC Advisory Committee Meeting March 24, 2005 14 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 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

15. Joint NDAC/DODAC Advisory Committee Meeting March 24, 2005 15 Sequential vs. Concurrent Pediatric Testing Sequential testing – older patients first Concurrent testing – if safety can be assured Sequential testing – older patients first Concurrent testing – if safety can be assured Pediatric Cohorts: < 18 to 12 years old < 12 to 6 years old < 6 to 2 years old < 2 years to 3 months old Pediatric Cohorts: < 18 to 12 years old < 12 to 6 years old < 6 to 2 years old < 2 years to 3 months old

16. Joint NDAC/DODAC Advisory Committee Meeting March 24, 2005 16 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 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 More Current Recommendations

17. Joint NDAC/DODAC Advisory Committee Meeting March 24, 2005 17 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 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 Cosyntropin Test Study Entry Criteria

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

19. Joint NDAC/DODAC Advisory Committee Meeting March 24, 2005 19 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? 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? OTC Topical Corticosteroid Products

20. Joint NDAC/DODAC Advisory Committee Meeting March 24, 2005 20 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? 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? A Risk Exercise

21. Joint NDAC/DODAC Advisory Committee Meeting March 24, 2005 21 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. 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. Answer to Risk Exercise

22. Joint NDAC/DODAC Advisory Committee Meeting March 24, 2005 22 Sample Size Effect on Upper CI Observed Events/Sample Size Upper Adverse Event Rate 95% CI99% CI 0/1026%37% 0/1518%26% 0/2014%21% 0/3010%14% 0/506%9% 0/1003%4.5% 0/3001%1.5% 0/10000.3%0.5%

23. Joint NDAC/DODAC Advisory Committee Meeting March 24, 2005 23 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)? 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)? QuestionQuestion

24. Joint NDAC/DODAC Advisory Committee Meeting March 24, 2005 Back Up Slides

25. Joint NDAC/DODAC Advisory Committee Meeting March 24, 2005 25 Lower Dose Cosyntropin Test Newer testNewer test Method not standardized regarding dose or timing of samplesMethod not standardized regarding dose or timing of samples : –Measure cortisol before and serially post-cosyntropin Other issues: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) Newer testNewer test Method not standardized regarding dose or timing of samplesMethod not standardized regarding dose or timing of samples : –Measure cortisol before and serially post-cosyntropin Other issues: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)

26. Joint NDAC/DODAC Advisory Committee Meeting March 24, 2005 26 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. 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. Cosyntropin Test Results (1)

27. Joint NDAC/DODAC Advisory Committee Meeting March 24, 2005 27 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. 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. Cosyntropin Test Results (2)