1. Food and Drug Administration Center for Drug Evaluation and Research Lessons Learned from Growth Studies with Orally Inhaled and Intranasal Corticosteroids (CS) Peter Starke, M.D., FAAP Division of Pulmonary and Allergy Drug Products Stephen E. Wilson, Dr.P.H., CAPT USPHS Division of Biometrics II March 24, 2005

2. Food and Drug Administration Center for Drug Evaluation and Research 2 Outline  Background and presumptions  Growth studies  Longitudinal growth studies  Design issues and limitations  Regulatory history and class labeling  Results of longitudinal growth studies with intranasal and orally inhaled drug products  Issues and conclusions

3. Food and Drug Administration Center for Drug Evaluation and Research 3 Growth Studies: Background and Presumptions  ‘Growth’ is an ‘indicator’ of systemic exposure and of the potential to cause systemic toxicity  Growth suppression is well known side effect of systemic CS use  Class effect: All CS given in sufficiently high doses  Thought to be due to direct bone effect  May also act through secondary mediators/hormones  We believe that growth is the most sensitive indicator of systemic effect  We have seen a growth effect even when an HPA axis study by cosyntropin stimulation was “negative”

4. Food and Drug Administration Center for Drug Evaluation and Research 4 Growth Studies: 2 Types  Knemometry:  2 to 4 week studies  Methodological issues  Consistency of results  Primarily a research tool  Longitudinal growth: Long-term  Designed to measure growth velocity over a 1 year treatment period  Patient population -- need for chronic treatment  Cannot have need for concurrent therapy with a drug that may influence growth

5. Food and Drug Administration Center for Drug Evaluation and Research 5 Longitudinal Growth Studies: Population  Performed during relatively constant growth rate period between ~3 to 9 -11 years Recumbent length: 0-3y Source: http://www.cdc.gov/growthcharts Standing height: 2-20y

6. Food and Drug Administration Center for Drug Evaluation and Research 6 Longitudinal Growth Studies: Measurements  Growth rate measured by serial stadiometry  Recommended periods  Baseline ~3 months  On-treatment ~1 year  Follow-up ~3 months  Growth Guidance*  Draft: Nov, 2001  Now being finalized * http://www.fda.gov/cder/guidance/index.htm

7. Food and Drug Administration Center for Drug Evaluation and Research 7 Longitudinal Growth Studies: Design Issues and Limitations  Technically difficult to perform  Require large numbers of children  Long baseline and treatment periods  Measurement and compliance issues  Statistical issues / recommendations  Not superiority, equivalence, or non-inferiority trials  Presumption of growth effect -- designed to best characterize that effect (i.e., the difference in treatment effect between active and placebo)  “N” affects the 95% CI around the growth effect  The size of the growth effect that is clinically relevant is unknown or not fully known

8. Food and Drug Administration Center for Drug Evaluation and Research 8 Regulatory History  1996-97:  Two longitudinal growth studies were performed to better characterize the systemic risks prior to consideration of taking beclomethasone dipropionate (BDP) nasal spray over-the-counter  Results of other growth studies submitted for orally inhaled products: BDP, TAA, budesonide, and FP  1998: Joint Pulmonary-Allergy and Metabolic-Endocrine Advisory Committee recommended ‘class labeling’ for all orally inhaled and intranasal corticosteroids  AC recommendations implemented

9. Food and Drug Administration Center for Drug Evaluation and Research 9 Recommended Class Labeling: Precautions section  General and Pediatric Use subsections  Orally inhaled / Intranasal corticosteroids may cause a reduction in growth velocity in pediatric patients  Pediatric Use subsection  Growth effect may occur in the absence of laboratory evidence of hypothalamic-pituitary-adrenal axis suppression  Potential for post-treatment "catch-up" growth has not been addressed  Titrate to lowest effective dose for each patient and monitor growth routinely  If reported, cases of growth suppression should be noted in the ADVERSE REACTIONS section

10. Food and Drug Administration Center for Drug Evaluation and Research 10 Intranasal Beclomethasone Dipropionate (BDP) Growth Study (CP93-048) : Design*  Design:  Randomized, double blind, placebo controlled, parallel group, prospective, one year  Inclusions:  Prepubertal children with allergic rhinitis  Age 6-9.5 yrs  Arms:  Intranasal BDP 168 mcg BID n=49  Placebo (vehicle) BID n=49 * Information from Joint Pulmonary-Allergy and Metabolic-Endocrine Advisory Committee presentation of Dr. Saul Malozowski, 1998

11. Food and Drug Administration Center for Drug Evaluation and Research 11 Intranasal BDP Growth Study (CP93-048) : Results  Results: BDP: 5.1 ± 1.5 cm/yr Placebo: 5.8 ± 1.3 cm/yr Delta: -0.7 cm/yr  Statistically significant difference between treatment groups in mean annual growth rates  In the same study, no significant differences were observed between treatment groups for mean basal cortisol or ACTH-stimulated plasma cortisol levels

12. Food and Drug Administration Center for Drug Evaluation and Research 12 Intranasal BDP Growth Study (CP93-048) : Results Growth Rate Percentiles PlaceboBeclomethasone ≤3 4%22% ≤1013%31% ≤2523%43% ≤5035%57%

13. Food and Drug Administration Center for Drug Evaluation and Research 13 Intranasal Drugs (Growth rate in cm/year) Moiety Dose mcg/d N Growth Estimate Delta cm/year 95% CI BDP (CP93-048) 336 2 495.1 ± 1.5 -0.7 NA 0485.8 ± 1.5 Budesonide 1 64 3 1305.91 ± 0.11 -0.27 0.07, -0.62 0616.19 ± 0.16 Fluticasone 1 200 2 566.16 ± 0.23 -0.14 0.27, -0.54 0526.30 ± 0.23 Mometasone 1 100 4 426.95 +0.61 1.10, 0.11 0406.35 1 Data from studies in product labels: budesonide, fluticasone propionate, and mometasone furoate monohydrate 2 Highest approved dose 3 Lowest approved dose 4 Only approved dose for 2-11 year age range (Approved dose  12 y = 200 mcg )

14. Food and Drug Administration Center for Drug Evaluation and Research 14 Orally Inhaled Drugs (Growth rate in cm/year) MoietyDoseNGrowth Est 1 Delta 1 BDP 2 200 mcg BID544.2 ± 2.2 -2.0 0466.2 ± 2.5 Budesonide (respules) 2 4-8y 2 0.5 mg QD1015.9 ± 1.6 -0.3 Non -CS406.2 ± 1.6 9m-3y 2 0.5 mg QD487.8 ± 2.0 -1.7 Non -CS179.5 ± 2.1 Fluticasone 2 100 mcg BID885.7 ± 1.2 -0.6 -0.2 50 mcg BID986.1 ± 1.5 0766.3 ± 1.5 1 Cm/year 2 Data from Dr Malozowski, Advisory Committee meeting, 1998

15. Food and Drug Administration Center for Drug Evaluation and Research 15 Issues  Difficult to perform and to review  Growth studies are not designed to evaluate  Reversibility of growth or HPA axis effects  Changes >1 year or effects on final adult height  We have not identified a clinically relevant effect size

16. Food and Drug Administration Center for Drug Evaluation and Research 16 Conclusions  We use growth as a stand-alone measure  Sensitive indicator of systemic effects HPA-axis and growth study results may be discordant  Surrogate for systemic exposure and potential to cause systemic toxicity  We believe the results are applicable to all age groups  ‘Class effect’ labeling  All orally inhaled & intranasal corticosteroids  Results of submitted studies are added to labels, but the class labeling is not removed

17. Food and Drug Administration Center for Drug Evaluation and Research 17 Division of Pulmonary and Allergy Drug Products Parklawn Building, Room 10B-45 5600 Fishers Lane, HFD-570 Rockville, MD 20857 Phone: 301-827-1050 Fax: 301-827-1271