# Presentation: 037382

## Slides presented

**by the FDA **
**at the**
**Endocrinologic & Metabolic Drugs**
**Advisory Committee meeting**
**on**
**June 10, 2003**

## Use of GH in idiopathic short stature

**Efficacy for final height**
- 	Guyda Survey 1999 (N= 413)
- 	Lilly GDCH 	(N=25)
- 	Lilly E001	(N= 50)
-   Finkelstein meta-analysis (84 GH –104 C)
**Cost benefit analysis**
- Bailey 1992
- Bryant 2002
**Ethics**
**	**** **Psychosocial enhancement** **
-    Fairness, social policy, resource allocation

## Definition of Idiopathic Short Stature

**Normal size at birth (> - 2 SDS)**
**Significant short stature (< -2 SDS)**
**The tempo of growth may be slow or normal **
**No evidence of:**
**Systemic disease**
**Malnutrition**
**Hypothyroidism**
**GHD**
***	******From: Ranke MB, Towards a consensus on the definition of idiopathic short stature. Horm Res 45:64-66, 1996 ***

## CDC 2000 Normal Statistics

| Z score | Ht 20 y Male
(cm) | Ht 20 y Female
(cm) | Percentile |
| --- | --- | --- | --- |
| - 2.50 | 158 (62”) | 147 (58”) | 0.6 |
| - 2.25 | 160 (63”) | 148.5 (58.5”) | 1.2 |
| - 2.00 | 162.5 | 150.3 | 2.3 |
| - 1.88 | 163.1 | 151.0 | 3rd |
| - 1.65 | 165.0 (65”) | 153.0 (60.5”) | 5th |
| - 1.28 | 167.5 | 155.0 | 10th |
| - 1.00 | 170.0 | 156.9 | 16th |
| 0 | 177.0 | 163.3 | 50th |

**CDC 2000 Normal Statistics**

## Slide 5

## Spontaneous Adult Height in Patients with Idiopathic Short Stature.  Price: Horm Res 45:59, 1996 

_**Study**__**	**__**(N**_**)****	****       ****	**** ****	**_**Males**__**	**_**	****   **_**Females**_
**	****	****	****      ****	****      **_**HT/FAH  SDS**_**	****  **_** **__**HT/FAH SDS**_
**Ranke (25)  1982****	****	****-2.1/-1.1****	****       -2.7/-2.4**
**Volta (41)    1988****	****	****-1.7/-0.9****	****       -1.7/-0.8**
**Brams. (69) 1990****	****	****-2.2/-0.7****	****       -2.1/-0.7**
**Crowne (58) 1991****	****	****-3.4/-1.6****	****       -3.4/-1.5**
**LaFran. (42) 1991****	****	****-2.0/-1.2  ****	****       -2.0/-1.3**
_**Ranke (236) 1995**_**	****	**_**-2.0/-0.8**_**	****       **_**-2.0/-0.8**_
_**Mean (471)**_**	****     ****	****	**_**-2.2/-1.0**_**	****       **_**-2.3/-1.1**_
**Adult height gain****	****	****+ 1.2****	****	****	****+ 1.2**

## Comments on GDCH Study

**Enrollment errors: baseline height velocity was calculated for only six months prior to randomization, subjects included SGA children, older age group with BA of 13 in boys 11 in girls, with Tanner 2 puberty in some, and patients with hypothyroidism treated for only 3m. **
**Therapeutic regimen was inadequate as the dose was low for children with normal GH secretion, and given only 3x weekly. This issue was noted at the FDA meeting in 1987 .**
**High drop out rate: only 16 GH (42%) and 9 placebo (27%) completed the study. Possible bias of positive benefit. **
**The overall treatment effect was very modest: Mean final height gain of + 0.51 SDS or + 3.7 cm. This would move a boy from –2.25 SDS (1.2 % ile) to –1.88 SDS (3****rd**** % ile).**
**He would still be 12 cm below the mean.**
**GDCH psychological data was not provided to FDA.**

## Slide 8

## Females

**N= 4  **

**N= 2  **

**48**

**52**

**56**

**60**

**64**

**68**

**72**

**Last Height (inches)**

**N= 13  **

**N= 5  **

**HUM**

**PLA**

**48**

**52**

**56**

**60**

**64**

**68**

**72**

**Last Height (inches)**

**N= 5  **

**N= 3  **

**HUM**

**PLA**

**<=66**

**>66**

**Females**

**Males**

## Comments on Study E001

**Dose effect from + 0.33 SDS to + 1.29 SDS and +2.3 to + 7.3 cm.**
**Significant numbers overlap GDCH placebo group (Figure 18, Page 32).**
**High drop out rate: 30/239 (12.6%) in first two Years,  and only 50 left in final height cohort (21% of randomized subjects), with almost half being at one Dutch center. **
**The highest drop out for patient request  (38 or 46%) was in the high GH dose group – why if clinical “benefit” was most positive in this group?**

## Finkelstein et al.  Effect of GH therapy in children with ISS: A Meta Analysis.

**Dr. F. Ducharme, Pediatric Editor of Cochrane reviews rated this meta analysis as Level 2 – a mixture of controlled and uncontrolled or non randomized studies, with small numbers, hence a likely bias to positivity. (Level 1 best).**
**Only 4 controlled studies (CCT) to adult height:  84 GH and 104 C. Multiple dropouts reported.**
**Gain observed was + 0.54 SDS (3.6 – 4.6 cm) over predicted, and + 0.84 SDS (5-6 cm) over control group. True estimates by RCT are likely to be smaller than by CCT. **
**NB: < 10****th**** percentile used, and SGA included**.

##   ECONOMIC PERSPECTIVES IN USA:   Bailey A: Growth, Genetics, Hormones 1992

**Defense****	****	****	****$303.6  billion**
**Alcohol****	****	****	****$  25.6  billion**
**Tobacco****	****	****	****$  23.6  billion**
**Medicaid (6-20 yr.)  $   6.2  billion**
**N.I.H.****	****	****	****$   6.8  billion**
**Lowest 1% height   $   3.0  billion **

## Cost effectiveness of adult height gain with GH treatment 

***	******Constructed from data by Bryant et al., Health Technol Assess 2002:Vol 6, No 18, 1-168***

***Cost effectiveness of adult height gain with GH treatment ***

## When is being short a medical problem?

**“****Short stature” is not a medical diagnosis. It is a *****descriptive term***** for a person whose height is considered significantly below the normal range of measurements for that age, gender, racial group or family.**
**Short stature is also a *****statistical term*****, generally referring to people who are shorter than 97% of their age and sex matched peers. Thus, in any population, nearly 3 out of each 100 persons will meet this statistical definition, most with no discernable medical abnormality. **
**Height perception is influenced by a wide variety of factors: culture, gender, family background, and psychological state.**

## Is short stature a psychological burden requiring GH therapy?

**Sandburg 1994: Short stature does not appear to be associated with clinically significant psychosocial morbidity.**
**Gilmore & Skuse 1996, 1997: Little evidence was found to suggest clinic referred untreated prepubertal short children are psychologically maladjusted.**
**Downie et al 1996: To date, no psychological benefits of GH treatment have been demonstrated.**
**Zimet et al 1997: Adults evaluated for SS but not treated with GH as children do not show psychosocial distress or impairment and does not provide a basis for GH treatment of ISS.**

## Equipoise & Benefit Assignment

**	****Equipoise demands that the following three psychological effects are considered before assigning benefit in short children treated with Growth Hormone: **
_***Beneficial***_** - with improved self-esteem due to increased height velocity or increased final adult height (FAH).**
_***Harmful***_*** *****- due to disappointment with FAH or poorer self-esteem due to increased medicalization, daily GH injections, etc. **
_***Neutral***_** – no psychological benefit.**

## The Use of Growth Hormone in ISS Summary and Conclusions I:

**The number of subjects in randomized controlled studies of GH therapy to FH is very limited, including  GDCH.**
**FH gain in GDCH was + 0.51 SDS or + 3.7 cm. Treated data points show considerable overlap with placebo group – is this clinically significant?**
**The majority of studies are uncontrolled, and final adult height attainment over predicted adult height has averaged < 1.0 SDS. **
**This is identical to the spontaneous height gain in children with idiopathic short stature.**

## Summary and Conclusions II:

**In one study of 236 normal short children (Ranke 1995),  67% spontaneously achieved normal adult height, 23% did not, and only 10% did not reach familial target height.**
**Few studies address the downside or negative outcome; in Australia (Cowell 1996), 464 children out of 1362 (34%) who commenced GH therapy for short stature did not complete 3 years of therapy. **
**In GDCH only 28% placebo and 42% GH therapy subjects completed the study.**
**Few studies have addressed the psychological benefit of GH treatment to final height for idiopathic short stature. This remains unproven.**

## Bryant J. Cave C. Mihaylova B. Chase D. McIntyre L. Gerard K. Milne R. Clinical effectiveness and cost-effectiveness of growth hormone in children: a systematic review and economic evaluation. [Review] [105 refs] [Journal Article. Review. Review, Academic] Health Technology Assessment (Winchester, England). 6(18):1-168, 2002.