Food and Drug AdministrationCenter for Drug Evaluation and Research

Lessons Learned from Growth Studies with

Orally Inhaled and Intranasal Corticosteroids (CS)

Peter Starke, M.D., FAAPPeter Starke, M.D., FAAPDivision of Pulmonary and Allergy Drug ProductsDivision of Pulmonary and Allergy Drug Products

Stephen E. Wilson, Dr.P.H., CAPT USPHSStephen E. Wilson, Dr.P.H., CAPT USPHS Division of Biometrics II

March 24, 2005March 24, 2005

Food and Drug AdministrationCenter 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

Food and Drug AdministrationCenter 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”

Food and Drug AdministrationCenter 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

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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

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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

Food and Drug AdministrationCenter 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

Food and Drug AdministrationCenter 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

Food and Drug AdministrationCenter 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

Food and Drug AdministrationCenter 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

Food and Drug AdministrationCenter 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

Food and Drug AdministrationCenter for Drug Evaluation and Research 12

Intranasal BDP Growth Study (CP93-048): Results

Growth Rate Percentiles

Placebo Beclomethasone

≤3 4% 22%

≤10 13% 31%

≤25 23% 43%

≤50 35% 57%

Food and Drug AdministrationCenter for Drug Evaluation and Research 13

Intranasal Drugs (Growth rate in cm/year)

Moiety Dosemcg/d

NGrowth

EstimateDelta

cm/year95% CI

BDP(CP93-048)

336 2 49 5.1 ± 1.5-0.7 NA

0 48 5.8 ± 1.5

Budesonide 1 64 3 130 5.91 ± 0.11 -0.27 0.07, -0.62

0 61 6.19 ± 0.16

Fluticasone 1 200 2 56 6.16 ± 0.23-0.14 0.27, -0.54

0 52 6.30 ± 0.23

Mometasone 1 100 4 42 6.95+0.61 1.10, 0.11

0 40 6.35

1 Data from studies in product labels: budesonide, fluticasone propionate, and mometasone furoate monohydrate2 Highest approved dose3 Lowest approved dose4 Only approved dose for 2-11 year age range (Approved dose 12 y = 200 mcg )

Food and Drug AdministrationCenter for Drug Evaluation and Research 14

Orally Inhaled Drugs (Growth rate in cm/year)

Moiety Dose N Growth Est 1 Delta 1

BDP 2200 mcg BID 54 4.2 ± 2.2

-2.00 46 6.2 ± 2.5

Budesonide (respules) 2

4-8y 20.5 mg QD 101 5.9 ± 1.6

-0.3Non -CS 40 6.2 ± 1.6

9m-3y 20.5 mg QD 48 7.8 ± 2.0

-1.7Non -CS 17 9.5 ± 2.1

Fluticasone 2

100 mcg BID 88 5.7 ± 1.2 -0.6

-0.250 mcg BID 98 6.1 ± 1.5

0 76 6.3 ± 1.5

1 Cm/year2 Data from Dr Malozowski, Advisory Committee meeting, 1998

Food and Drug AdministrationCenter 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

Food and Drug AdministrationCenter 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

Food and Drug AdministrationCenter for Drug Evaluation and Research 17

Division of Pulmonary and Allergy Drug Products

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