# Presentation: 248186

## 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

## 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

## 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”

## 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

## Longitudinal Growth Studies: Population

- Performed during relatively constant growth rate period between ~3 to 9 -11 years

- Source: http://www.cdc.gov/growthcharts

## 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

## 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

## 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

## 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

## 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

## 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

## Intranasal BDP Growth Study (CP93-048): Results

| Growth Rate Percentiles | Placebo | Beclomethasone |
| --- | --- | --- |
|   ≤3 |   4% | 22% |
| ≤10
 | 13% | 31% |
| ≤25
 | 23% | 43% |
| ≤50
 | 35% | 57% |

## Intranasal Drugs (Growth rate in cm/year)

| Moiety | Dosemcg/d | N | Growth Estimate | Delta
cm/year | 95% 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 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 )

## Orally Inhaled Drugs (Growth rate in cm/year) 

| Moiety | Dose | N | Growth Est 1 | Delta 1 |
| --- | --- | --- | --- | --- |
| BDP 2 | 200 mcg BID | 54 | 4.2 ± 2.2 | -2.0 |
|  | 0 | 46 | 6.2 ± 2.5 |  |
| Budesonide (respules) 2 |  |  |  |  |
| 4-8y 2 | 0.5 mg QD | 101 | 5.9 ± 1.6 | -0.3 |
|  | Non -CS | 40 | 6.2 ± 1.6 |  |
| 9m-3y 2 | 0.5 mg QD | 48 | 7.8 ± 2.0 | -1.7 |
|  | Non -CS | 17 | 9.5 ± 2.1 |  |
| Fluticasone 2 | 100 mcg BID | 88 | 5.7 ± 1.2 | -0.6
-0.2 |
|  | 50 mcg BID | 98 | 6.1 ± 1.5 |  |
|  | 0 | 76 | 6.3 ± 1.5 |  |
| 1 Cm/year
2 Data from Dr Malozowski, Advisory Committee meeting, 1998 |  |  |  |  |

## 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

## 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

## 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