Joint NDAC/DODAC Advisory Committee Meeting March 24, 2005 Rx Topical Corticosteroids and Testing for Adrenal Suppression Markham C. Luke, M.D., Ph.D

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

Rx Topical Corticosteroids and Rx Topical Corticosteroids and Testing for Adrenal Testing for Adrenal

SuppressionSuppression

Rx Topical Corticosteroids and Rx Topical Corticosteroids and Testing for Adrenal Testing for Adrenal

SuppressionSuppression

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

2Joint NDAC/DODAC Advisory Committee Meeting Joint NDAC/DODAC Advisory Committee Meeting March 24, 2005March 24, 2005

1) Rx Topical Corticosteroids: Systemic Effects

2) HPA axis testinga) Tests availableb) Cosyntropin stimulation testing

3) Current testing recommendations4) How precise an estimate of adrenal

suppression potential is needed for OTC?

1) Rx Topical Corticosteroids: Systemic Effects

2) HPA axis testinga) Tests availableb) Cosyntropin stimulation testing

3) Current testing recommendations4) How precise an estimate of adrenal

suppression potential is needed for OTC?

Outline of TalkOutline of TalkOutline of TalkOutline of Talk


Rx Corticosteroids: Systemic Rx Corticosteroids: Systemic EffectsEffects

Rx Corticosteroids: Systemic Rx Corticosteroids: Systemic EffectsEffects


• 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 EffectsSystemic EffectsSystemic EffectsSystemic Effects


Relative PotencyRelative PotencyRelative PotencyRelative 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


What is the Hypothalamic, What is the Hypothalamic, Pituitary, Adrenal (HPA) axis?Pituitary, Adrenal (HPA) axis?

What is the Hypothalamic, What is the Hypothalamic, Pituitary, Adrenal (HPA) axis?Pituitary, Adrenal (HPA) axis?

CRH = Corticotropin Releasing

AVP = Arginine Vasopressin

ACTH = Adrenocorticotropin

F = Cortisol


HPA Axis TestingHPA Axis TestingHPA Axis TestingHPA Axis Testing


• 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 TestingBasal vs. Dynamic TestingBasal vs. Dynamic TestingBasal vs. Dynamic Testing


Dynamic Tests of HPA Axis Dynamic Tests of HPA Axis FunctionFunction

Dynamic Tests of HPA Axis Dynamic Tests of HPA Axis FunctionFunction

• Insulin Tolerance TestCauses hypoglycemia - a potent stress stimulus for

the adrenal glands.Need very close subject monitoringUndue risk to the subject

• Cosyntropin (ACTH1-24) Test• Higher (as labeled) Dose• Lower Dose

• Corticotropin Releasing Hormone Test (CRH)Experimental

• Insulin Tolerance TestCauses hypoglycemia - a potent stress stimulus for

the adrenal glands.Need very close subject monitoringUndue risk to the subject

• Cosyntropin (ACTH1-24) Test• Higher (as labeled) Dose• Lower Dose

• Corticotropin Releasing Hormone Test (CRH)Experimental


Higher Dose Cosyntropin TestHigher Dose Cosyntropin TestHigher Dose Cosyntropin TestHigher Dose Cosyntropin Test

• Most commonly used test to evaluate for adrenal Most commonly used test to evaluate for adrenal suppressionsuppression

• 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 Most commonly used test to evaluate for adrenal suppressionsuppression

• 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


Higher Dose Cosyntropin TestHigher Dose Cosyntropin TestHigher Dose Cosyntropin TestHigher Dose Cosyntropin Test

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

• Limitations:– Not the most sensitive test

• A physiologic “hammer”

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

• Limitations:– Not the most sensitive test

• A physiologic “hammer”


Higher Dose Cosyntropin Test CriteriaHigher Dose Cosyntropin Test CriteriaHigher Dose Cosyntropin Test CriteriaHigher 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


Current Testing Current Testing RecommendationsRecommendations

Current Testing Current Testing RecommendationsRecommendations


Current RecommendationsCurrent RecommendationsCurrent RecommendationsCurrent 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


Sequential vs. Concurrent Sequential vs. Concurrent Pediatric TestingPediatric Testing

Sequential vs. Concurrent Sequential vs. Concurrent Pediatric TestingPediatric 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


• 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 RecommendationsMore Current RecommendationsMore Current RecommendationsMore Current Recommendations


• 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 Cosyntropin Test Study Entry CriteriaCriteria

Cosyntropin Test Study Entry Cosyntropin Test Study Entry CriteriaCriteria


Precision of Testing Needed for Precision of Testing Needed for OTC?OTC?

Precision of Testing Needed for Precision of Testing Needed for OTC?OTC?


• 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 OTC Topical Corticosteroid ProductsProducts

OTC Topical Corticosteroid OTC Topical Corticosteroid ProductsProducts


• 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 ExerciseA Risk ExerciseA Risk ExerciseA 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.

• 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 ExerciseAnswer to Risk ExerciseAnswer to Risk ExerciseAnswer to Risk Exercise


Sample Size Effect on Upper CISample Size Effect on Upper CISample Size Effect on Upper CISample Size Effect on Upper CI

Observed Events/Sample SizeUpper Adverse Event Rate

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%


• 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)?

QuestionQuestionQuestionQuestion


Back Up SlidesBack Up SlidesBack Up SlidesBack Up Slides


Lower Dose Cosyntropin TestLower Dose Cosyntropin TestLower Dose Cosyntropin TestLower Dose Cosyntropin Test

• Newer testNewer test • Method not standardized regarding dose or timing of Method not standardized regarding dose or timing of

samplessamples:

– 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 Method not standardized regarding dose or timing of

samplessamples:

– 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)


• Information to be collected and submitted to the FDA for each subject:1) Identifier number, age, height, and weight2) Dose of cosyntropin used3) 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 weight2) Dose of cosyntropin used3) 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)Cosyntropin Test Results (1)Cosyntropin Test Results (1)Cosyntropin Test Results (1)


• 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)Cosyntropin Test Results (2)Cosyntropin Test Results (2)Cosyntropin Test Results (2)

Documents

Joint NDAC/DODAC Advisory Committee Meeting March 24, 2005 Rx Topical Corticosteroids and Testing for Adrenal Suppression Markham C. Luke, M.D., Ph.D