1

Humatrope® (somatropin [rDNA origin] for injection)

Treatment of Pediatric Patients with Non-Growth Hormone-

Deficient Short Stature

FDA Advisory Committee MeetingJune 10, 2003

Bethesda, Maryland

Eli Lilly and Company7501.01

2

HumatropeTreatment of Pediatric Patients

with Non-Growth Hormone-Deficient Short Stature

Gregory Enas, PhD

Director, US Regulatory Affairs

Eli Lilly and Company

7502.01

3

FDA-approved Humatrope Doses for Pediatric Indications

Pediatric GH Deficiency

March 1987 0.18 mg/kg/wk (3 days per week)

April 1994 0.30 mg/kg/wk (3 or 6 days per week)

October 1997 0.30 mg/kg/wk (3, 6, or 7 days per week)

Turner Syndrome

March 1997 0.375 mg/kg/wk (3 or 7 days per week)

7503.01

(Other approved pediatric GH doses: 0.16 to 0.70 mg/kg/wk)

4

Introduction

“…there is an urgent need for therapeutic trials

to determine the effect of growth hormone in

short children who do not have a growth

hormone deficiency”

(NICHD International Conference on Uses and

Abuses of GH, 1983)

7504.01

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Guidance Received from Endocrinologic & Metabolic Drugs Advisory Committee

“. . the control group should be a placebo-

treated, randomized group of patients. . .”

and

“. . the subjects should be followed until their

ultimate height is reached” (Sept 1987)

7505.01

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Issues and Questions Regarding GH Treatment for Non-GHD Short Stature1. How will potential risks be managed and safety be

monitored?

2. Will this new indication obviate the need for diagnostic evaluation in children with growth disorders?

3. Will this new indication “open the floodgates” to inappropriate use?

4. Are there ethical issues regarding GH treatment of non-GHD short stature?

5. Is it appropriate to treat patients whose short stature is not clearly associated with a defined “disease”?

6. Should psychological or quality of life benefits be required outcomes of GH treatment?

7. What is the clinical relevance of the efficacy?7610.01

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External ConsultantsRaymond L. Hintz, MDProfessor of PediatricsStanford University Medical CenterSecretaryLawson Wilkins Pediatric EndocrineSociety

Margaret MacGillivray, MDProfessor of Pediatrics, EmeritusUniversity of BuffaloPediatric Endocrine SpecialistSchool of Medicine & BiomedicalSciencesChildren’s Hospital Buffalo

Judith L. Ross, MDProfessor of PediatricsChief, Pediatric EndocrinologyJefferson Medical CollegeThomas Jefferson University

Melvin M. Grumbach, MDEdward B. Shaw Professor ofPediatrics, EmeritusUniversity of California at SanFrancisco School of Medicine

Gary Koch, PhD Professor of BiostatisticsUniversity of North Carolina at ChapelHill

Ron G. Rosenfeld, MDSr Vice-President for Medical AffairsLucile Packard Foundation forChildren’s HealthProfessor of Pediatrics, Professor ofCell and Development BiologyOregon Health & Science Universityand Stanford University

7507.01

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Lilly Advisory Committee Presentation: Humatrope Treatment of Pediatric Patients with Non-GHD Short Stature

Introduction

Rationale for Treatment

Efficacy

Safety

Risk Management Program

Benefit – Risk Assessment

Concluding Statements

Gregory Enas, PhD

Raymond L. Hintz, MD

Gordon Cutler, MD

Charmian Quigley, MBBS

Charmian Quigley, MBBS

Charmian Quigley, MBBS

Margaret MacGillivray, MD

7508.01

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Raymond L. Hintz, MDProfessor of Pediatrics

Stanford University Medical Center

The Rationale for GH Treatment of Patients with

Non-GHD Short Stature

7509.01

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• Growth failure: decline in rate of linear growth

• Short stature: height more than 2.0 standard deviations (SD) below mean for age and sex (American Academy of Pediatrics and American Association of Clinical Endocrinologists)

• There are many endocrine and non-endocrine causes of growth failure and short stature

• Growth Hormone Research Society recommends investigation of children with short stature whose height falls below -2.0 SD scores (SDS)

Growth Failure and Short Stature

7510.01

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Males

Age (y)

30

34

38

42

46

50

54

58

62

66

70

74

78

Hei

ght (

in)

Hei

ght (

cm)

2 4 6 8 10 12 14 16 18 2070

80

90

100

110

120

130

140

150

160

170

180

190

200

0

+2

+1

-1

-2

What is Short Stature?

+2.0 SD (97.7 percentile)

-2.0 SD (2.3 percentile)

Generally accepted definition of normal range

US adult height of -2.0 SDSis equivalent to:

Male 5’ 3.6”Female 4’ 11.1”

7511.01

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Why Treat Short Stature?

8363.01

• Children and adults with short stature, irrespective of cause, may have disadvantages compared to their peers

13

Potential Disadvantages of Short Stature

• Childhood– Juvenilization (Sandberg, 1999)

– Teasing (Voss and Mulligan, 2000)

– Bullying (Voss and Mulligan, 2000)

– Exclusion (Zimet et al 1997)

– Loss of independence/overprotection (Zimet et al 1997)

• Adulthood– Social isolation/reduced marriage rate (Sartorio et al, 1990)

– Perception of lower competence (Melamed, 1992)

– Height limits for certain jobs

– Impact on daily living

• Car safety (Cunningham, 2000)

• Physical challenges in home/workplace

7517.02

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Why Treat Short Stature?

• Children and adults with short stature, irrespective of cause, may have disadvantages compared to their peers

• GH treatment in many conditions improves growth and effectively corrects short stature

8364.02

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Date Indication

1985 Pediatric GH Deficiency

1993 Chronic Renal Insufficiency

1996 Turner Syndrome

2000 Prader – Willi Syndrome

2001 Small for Gestational Age

2003 Non-GHD Short Stature (proposed)

Treatment of growth failure or short stature associated with…

Approved GH Use in Pediatric Growth Disorders

All pediatric indications

approved after 1985 are

non-GHD conditions

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Pediatric Growth Disorders are Heterogeneous in Etiology• GH deficiency

– Hypothalamic disorders (e.g. GHRH deficiency)– Pituitary disorders (e.g. pituitary hypoplasia, genetic mutations)– Trauma– Tumor– Irradiation

• Turner syndrome– 45,X – 45,X/46,XX

– Numerous variants

• Small for gestational age– Russell-Silver syndrome– Maternal hypertension– Maternal smoking– Small maternal pelvis– Various genetic syndromes

8365.02

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Pediatric Growth Disorders are Heterogeneous in Phenotype

8366.01

• GH deficiency– Variable timing and severity of growth failure– Variable clinical features (e.g. cherubic face, adiposity)– Variable GH responses to testing

• Turner syndrome– Variable timing and severity of growth failure– Variable clinical features (e.g. webbed neck, low hairline)

• Small for gestational age– Variable degree of short stature– Presence or absence of additional phenotypic features (e.g.

asymmetry, dysmorphic features)

18

The Patient with Non-GHD Short Stature

• Short stature equivalent to GH deficiency and other causes of growth failure

• Normal GH tests

• Etiology undefined

• Diagnosis by exclusion

• Not eligible for treatment

Courtesy J. Ross, MD, Jefferson Medical College, PA

“James”-2.8 SDS

“Julian”+0.1 SDS

7513.01

Fraternal twins, 7.7 yrs

19

Features of Non-GHD Short Stature

• Growth failure during childhood

• Height < -2.0 SDS

• No distinguishing phenotypic features

• Likely heterogeneous etiology– Familial/genetic

– Abnormal GH/IGF axis

– Abnormal growth plate

• Unimodal distribution of height deficit

8367.01

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Height Distribution of Patients with Non-GHD Short Stature

- 8 - 6 - 4 - 2 0 2 4

0.0

0.2

0.4

0.6

0.8

1.0

Height SDS

Non-GHD Short Stature (n=310)General Population

*M: 5' 1”*F: 4' 9”

*M: 5' 9”*F: 5' 4”

*Adult height equivalent (US)

7 – 8”

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Growth Disorders: Eligibility for GH Therapy

ELIGIBLE

• Peak GH response below threshold

– classified as GH deficient

• Four non-GHD growth disorders (TS, CRI, PWS, SGA) irrespective of

– GH secretion status, or– degree of short stature

INELIGIBLE

• Peak GH response above threshold (termed non-GH deficient) despite equivalent short stature to those with

– GH deficiency and

– other non-GHD conditions

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Why Should Children with Non-GHD Short Stature Be Eligible for GH?

7518.02

• Growth failure is equivalent to that in other growth disorders

• Untreated patients do not achieve their adult height prediction

• GH treatment in other conditions treats the short stature or growth failure, NOT the “disease”

• Unknown or heterogeneous etiology does not justify exclusion from treatment

• Non-GHD short stature is responsive to GH

23

Height SDS of Patients with Growth Disorders at Initiation of GH Treatment

IGHD=Idiopathic GH deficiency; CRI=Chronic renal insufficiency; TS=Turner syndrome; SGA=Small for gestational age; NGHDSS=Non-GHD short stature7519.02

PopulationIGHD CRI TS SGA NGHDSS

Hei

gh

t S

DS

-4

-3

-2

-1

0

National Cooperative Growth Study

Kabi International Growth StudyMean ± SD

24

Why Should Children with Non-GHD Short Stature Be Eligible for GH?

7520.02

• Growth failure is equivalent to that in other growth disorders

• Untreated patients do not achieve their adult height prediction

• GH treatment in other conditions treats the short stature or growth failure, NOT the “disease”

• Unknown or heterogeneous etiology does not justify exclusion from treatment

• Non-GHD short stature is responsive to GH

25

Why Should Children with Non-GHD Short Stature Be Eligible for GH?

7522.02

• Growth failure is equivalent to that in other growth disorders

• Untreated patients do not achieve their adult height prediction

• GH treatment in other conditions treats the short stature or growth failure, NOT the “disease”

• Unknown or heterogeneous etiology does not justify exclusion from treatment

• Non-GHD short stature is responsive to GH

26

Males

Age (y)

30

34

38

42

46

50

54

58

62

66

70

74

78

Hei

ght (

in)

Hei

ght (

cm)

2 4 6 8 10 12 14 16 18 2070

80

90

100

110

120

130

140

150

160

170

180

190

200

0

+3

+2

+1

-1

-2

-3

GH Treats the Short Stature or Growth Failure, Not the “Disease”

Turner Syndrome Non-GHD Short StatureFemales

Age (y)

30

34

38

42

46

50

54

58

62

66

70

74

78

Hei

ght (

in)

Hei

ght (

cm)

2 4 6 8 10 12 14 16 18 2070

80

90

100

110

120

130

140

150

160

170

180

190

200

0

+3

+2

+1

-1

-2

-3

8.7 yrsHeight SDS –3.0

11.0 yrsHeight SDS –2.9

7523.01

• Degree of short stature is similar• Response to treatment is similar and clinically meaningful

27

Why Should Children with Non-GHD Short Stature Be Eligible for GH?

7524.02

• Growth failure is equivalent to that in other growth disorders

• Untreated patients do not achieve their adult height prediction

• GH treatment in other conditions treats the short stature or growth failure, NOT the “disease”

• Unknown or heterogeneous etiology does not justify exclusion from treatment

• Non-GHD short stature is responsive to GH

28

Many Conditions of Unknown or Heterogeneous Etiology Deserve and Receive Treatment

Examples:

• Alopecia

• Anxiety disorder

• Enuresis

• Gynecomastia

• Hirsutism

• Hypercholesterolemia

• Hypertension

• Nicotine addiction

7525.01

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Why Should Children with Non-GHD Short Stature Be Eligible for GH?

7526.02

• Growth failure is equivalent to that in other growth disorders

• Untreated patients do not achieve their adult height prediction

• GH treatment in other conditions treats the short stature or growth failure, NOT the “disease”

• Unknown or heterogeneous etiology does not justify exclusion from treatment

• Non-GHD short stature is responsive to GH

30

Research on GH Treatment of Non-GHD Short Stature Has a Long History

1964-1971 Early studies demonstrate increased growth rate in patients with non-GHD short stature

1983 NICHD international conference recommends studies of GH treatment in non-GHD conditions

1987 FDA advisory committee recommends placebo-controlled study to final height

1985-2000 More than 40 studies published on GH treatment in non-GHD short stature

7528.01

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Improved Height SDS in Response to GH Treatment

Hintz et al.; NEJM 1999; 340: 502-7

80 patientsGH 0.3 mg/kg/wk

7527.02

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Research on GH Treatment of Non-GHD Short Stature Has a Long History

1964-1971 Early studies demonstrate increased growth rate in patients with non-GHD short stature

1983 NICHD international conference recommends studies of GH treatment in non-GHD conditions

1987 FDA advisory committee recommends placebo-controlled study to final height

1985-2000 More than 40 studies published on GH treatment in non-GHD short stature

1988-2001 Lilly clinical trials in non-GHD short stature

8286.01

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Key Reasons Why Children with Non-GHD Short Stature Should Be Eligible for GH

• Growth failure in patients with non-GHD short stature is equivalent to that in other growth disorders

• GH treatment in other conditions treats the short stature or growth failure, NOT the “disease”

• Unknown or heterogeneous etiology does not justify exclusion from treatment

8369.01

34

Efficacy

Gordon Cutler, MD

Director – Growth and Recovery Research and Clinical Investigation

Eli Lilly and Company

7529.01

35

Efficacy Questions

• Is GH treatment effective?

• Is there a dose-response?– 0.37 vs. 0.24 mg/kg/wk

• Are there supportive published data?

• Is the efficacy similar to Turner syndrome?

7530.01

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Overview of sNDA Submission

• Pivotal study - GDCH

• Supportive study - E001

• Supportive data - Meta-analysis (Finkelstein et al., 2002)

7531.01

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~80 subjects

40 Humatrope, 0.22 mg/kg/wkdivided doses 3 days per week

40 Placebo

Protocol Completion(height velocity < 1.5 cm/yr)

Stratified at entry by predicted adult height

and sex

Post-Study Follow-up

Final Height

GDCH Study Design: Randomized, Double-Blind, Placebo-Controlled

1 year

7533.02

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GDCH Efficacy Analysis Populations

• Randomized (n=71): randomized to treatment

• Efficacy Evaluable (EE, n=64): had an on-study height measurement at or beyond 6 months

• Final Height (FH, n=33): in EE population and had height measurement after height velocity < 1.5 cm/yr (including 8 patients who discontinued early)

• Protocol Complete (PC, n=25): remained on-study until final height measurement

7534.01

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GDCH Efficacy Analyses

Population

AnalysisFinal Height (n=33)

Efficacy Evaluable (n=64)

Protocol Complete (n=25)

Primary Final Height SDS (ANCOVA [BPH SDS])

Sensitivity

Protocol

Specified

FH – BPH (cm)

(t-test)

Last Obs. Ht SDS

(ANCOVA)

Final Height SDS

(ANCOVA)

Non-protocol

Specified

Height SDS at 18 Yr

(Repeated Measures)

FH=Final height; BPH=Baseline predicted height; Obs. Ht=Observed height

7535.01

40

Mean ± SD

No significant differences between groups

GDCH Baseline Characteristics (All Randomized Population)

Placebo HumatropeNumber 33 (m 26, f 7) 38 (m 29, f 9)Age (yr) 12.3 1.4 12.5 1.6Bone Age (yr) 10.4 1.7 10.4 1.9Pubertal Stage (n [%])

Stage 1

Stage 2

Stage 3

14 (42%)

15 (46%)

4 (12%)

18 (47%)

18 (47%)

2 (5%)Height SDS -2.8 0.5 -2.7 0.5Predicted Height SDS -2.3 0.8 -2.0 0.8Target Height SDS -1.2 0.7 -1.0 1.0Pre-treatment HV (cm/yr) 4.8 2.1 4.8 1.8Peak GH (g/L) 17.4 9.7 16.2 7.5IGF-I SDS -1.5 1.5 -2.0 1.1

7536.01

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GDCH Primary Efficacy Analysis (FH Population):

Significantly Greater Final Height SDS

-2

-1

0Placebo Humatrope

n = 10 n = 22

Fin

al H

eig

ht

SD

S*

-2.3 ± 0.2

-1.8 ± 0.1

*ANCOVA (BPH SDS)Least squares mean ± SE ( ) = 95% confidence interval

Duration = 4.4 yrEffect = 0.51 SDS (0.10 - 0.92 SDS)

= 3.7 cmp* = 0.017

7537.02

42

GDCH Secondary Efficacy Analyses (EE Population): Significantly Greater Height SDS

*ANCOVA (BPH SDS)Least squares means ± SE; ( ) = 95% confidence interval

‡ Repeated Measures Analysis

Treatment Effect = 0.52 SDS (0.22 – 0.82 SDS)

= 3.8 cmp* = 0.001

-2

-1

0Placebo Humatrope

n = 27 n = 35

Las

t O

bse

rved

Hei

gh

t S

DS

*

-2.4 ± 0.1

-1.9 ± 0.1-2

-1

0Placebo Humatrope

n = 27 n = 35

Hei

gh

t S

DS

at

18 Y

ears

‡

-2.2 ± 0.1

-1.5 ± 0.1

Treatment Effect = 0.69 SDS (0.43 – 0.94 SDS)

= 5.0 cmp‡ < 0.0001

7538.02

43

GDCH Intent-to-treat Analyses (All Randomized Population, n=71): Significantly Greater Last Observed Height SDS

• Nonparametric analyses– Humatrope superior to placebo

• Rank analysis of covariance: p = 0.0024• Generalized Wilcoxon-Mann-Whitney test: p = 0.0015

• Parametric analyses– Humatrope treatment effect

• ANCOVA (BPH SDS): 0.40 ± 0.15p = 0.011

• ANOVA 0.52 ± 0.17p = 0.003

Least Squares Mean ± SE

7539.01

44

GDCH: Bone Age vs. Year on Study

10

12

14

16

18

0 1 2 3 4 5

Bo

ne

Ag

e (y

r)

FH Population

n 21 21 21 20 17 10n 9 10 10 10 7 4

0 1 2 3 4 5

Non-FH Subgroup

13 13 10 5 1 117 15 15 13 5 2

0 1 2 3 4 5

EE Population

Year On Study

34 34 31 25 18 1126 25 25 23 12 6

Mean ± SEHumatropePlacebo7540.02

45

GDCH: Increase in Height SDS vs. Year Before Last Observed Height

0.0

0.5

1.0

-6 -4 -2 0

Incr

ease

in

Hei

gh

t S

DS

Mean Age18.8 ± 0.3 yr

FH Population

0.4 0.5

n 6 14 19 21 21 19 18 22n 4 6 8 9 9 9 8 11

-6 -4 -2 0

Mean Age15.1 ± 0.4 yr

Non-FH Subgroup

0.6

3 7 10 13 138 15 16 17 18

-6 -4 -2 0

Mean Age17.0 ± 0.3 yr

EE Population

Year Relative to Last Observed Height (Year = 0)

0.4

0.5

0.6

6 14 20 24 28 29 31 354 6 10 17 24 25 25 29

0.4 0.5

0.2

0.3 0.5

0.5

Mean ± SEHumatropePlacebo7541.02

46

GDCH (EE Population):Height SDS vs. Year on Study

0 1 2 3 4 5Year on Study

He

igh

t S

DS

-3.0

-2.5

-2.0

-1.5

-1.0

3529

3426

3126

2623

1813

116

nn

Humatrope

Placebo

Mean SE

7542.02

47

GDCH Efficacy Summary

GH Treatment Effect• Primary analysis:• Sensitivity Analyses

– EE Population:• Last observed height SDS:• Height SDS at 18 years:

– All Randomized Population• Last Observed Height SDS:

GH treatment regimen

• Dose = 0.22 mg/kg/wk

• Divided doses 3 days per week

0.51 SDS = 3.7 cm (1.5 in)

0.52 SDS = 3.8 cm0.69 SDS = 5.0 cm

0.40 SDS = 2.9 cm

7544.01

48

0.37 mg/kg/wk

0.24 mg/kg/wk

0.24 mg/kg/wk

Height Velocity Phase

Randomization

24 Month

0.37 mg/kg/wk

Extension to Final Height

End of 2-year core study

• European open-label multicenter study (10 countries)• Divided doses 6 days per week

E001 Study Design: Randomized, Open-Label, Dose-Response

0 12

Final Height

7545.03

(height velocity < 2.0 cm/yr)

49

E001 Analysis Populations

• Randomized (n=239 [161]): randomized to treatment

• Two-year height velocity (n=209 [142]): completed 2 years Humatrope treatment

• Final height (n=50 [34]): height measurement after height velocity < 2.0 cm/yr

[ ] = n with middle dose excluded

7546.01

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E001 Efficacy Analyses

Population

Analysis

Two-year Height Velocity

n=209 [142]

Final Height

n=50 [34]

Primary Increase in Ht Velocity (0-2 yr)

(t-test)

Secondary Last Obs. Ht SDS

(ANCOVA)

Final Height SDS

(ANCOVA)

Height SDS at 18 Years (Repeated Measures)

FH – BPH (cm)

(Paired t-test)

FH=Final height; BPH=Baseline predicted height; Obs. Ht=Observed height;[ ] = n with middle dose excluded

7547.01

51Mean SD

Humatrope Dose (mg/kg/wk)

E001 Baseline Characteristics(All Randomized Population)

0.24 0.37

Number 78 (m 49, f 29) 83 (m 59, f 24)

Age (yr) 9.4 2.4 10.0 2.2

Bone Age (yr) 7.4 2.6 8.0 2.1

Height SDS -3.4 0.8 -3.0 0.5

Predicted Height SDS -2.7 1.0 -2.4 1.1

Target Height SDS -1.3 0.9 -1.2 0.9

Pre-treatment HV (cm/yr) 4.3 1.1 4.3 1.1

Peak GH (g/L) 16.8 7.5 17.0 6.2

7548.01

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0 2Year on Study

Hei

gh

t V

elo

city

(cm

/yr)

p = 0.5

p < 0.001

4

5

6

7

8

9

Dose Effect = 0.8 cm/yr (0.3 – 1.3 cm/yr)p* = 0.003

Mean SE * t-test ( ) = 95% confidence interval7549.01

0.24 mg/kg/wk (n=70)0.37 mg/kg/wk (n=72)

E001 Primary Efficacy Analysis (2-yr HV Population): Significant Dose Effect on Height Velocity

53

E001 Secondary Efficacy Analyses (2-yr HV Population): Significant Dose Effect on Height SDS

*ANCOVA (BPH SDS)Least squares means ± SE; ( ) = 95% confidence interval

‡ Repeated Measures Analysis

Dose Effect = 0.51 SDS (0.15 – 0.87 SDS)

= 3.3 cmp* = 0.006

Dose Effect = 0.44 SDS (0.10 – 0.78 SDS)

= 2.8 cmp‡ = 0.012

-2

-1

0n = 39 n = 48

Las

t O

bse

rved

Hei

gh

t S

DS

*

-2.0 ± 0.1

-1.4 ± 0.1

0.24Humatrope Dose (mg/kg/wk)

0.37

-2

-1

0n = 39 n = 47

Hei

gh

t S

DS

at

18 Y

ears

‡

-1.3 ± 0.2

-0.8 ± 0.1

0.24 0.37

7550.01

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E001 Dose-response Study: Bone Age vs. Year on Study

6

8

10

12

14

16

0 1 2 3 4 5 6 7

Bo

ne

Ag

e (y

r)

FH Populationn 16 15 16 16 14 11 4 5n 16 17 16 17 15 15 8 4

0 1 2 3 4 5 6 7

Non-FH Subgroup54 51 49 40 26 11 4 555 50 49 39 26 9 4 3

0 1 2 3 4 5 6 7

Two Yr HV Population69 66 65 56 40 22 8 1071 67 65 56 41 24 12 7

Year On StudyMean ± SE0.24 mg/kg/wk 0.37 mg/kg/wk7552.01

55

E001 (FH Population): Significant Treatment Effect on FH – BPH (cm)

0

2

4

6

8

10

0.24 0.37

n = 13 n = 13

Fin

al H

eig

ht

Min

us

Ba

sel

ine

Pre

dic

ted

Hei

gh

t (c

m)

5.4 ± 0.9 p* < 0.001

7.2 ± 1.7 p* = 0.001

* Paired t-test (within-group) Mean ± SE

Humatrope Dose (mg/kg/wk)

7553.01

Mean treatment duration = 6.5 yr

56

GDCH & E001: Final Height – Baseline Predicted Height (cm)

Placebo 0.22 Humatrope (mg/kg/wk)3 days per week

0.24 0.37

Mean ± SE

-2

0

2

4

6

8

10

Fin

al H

eig

ht

Min

us

Ba

sel

ine

Pre

dic

ted

Hei

gh

t (c

m)

-0.7 ± 1.3

-2

0

2

4

6

8

10

2.2 ± 0.8

5.4 ± 0.9

7.2 ± 1.7

n=10n=22 n=13 n=13

Humatrope (mg/kg/wk) 6 days per week

GDCH E001

7554.02

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E001 Efficacy Summary

Dose Effect (0.37 vs. 0.24 mg/kg/wk)• Primary analysis

– Increase in 0-2 yr height velocity: 0.8 cm/yr

• Secondary analyses– Last observed height SDS: 0.51 SDS = 3.3 cm– Height SDS at 18 years: 0.44 SDS = 2.8 cm

Treatment Effect• Final Height – Baseline Predicted Height

– 5.4 cm (2.1 in) at 0.24 mg/kg/wk– 7.2 cm (2.8 in) at 0.37 mg/kg/wk

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GDCH & E001 (FH Population): Final Height SDS

Placebo Humatrope (mg/kg/wk) 0.22

GDCH

0.24 0.37

E001

Humatrope (mg/kg/wk)

-2

-1

0

Fin

al H

eig

ht

SD

S*

-2.3 ± 0.2

-1.8 ± 0.1

n = 10 n = 22

-1.6 ± 0.2

-1.2 ± 0.2

n = 13 n = 13

*ANCOVA (BPH SDS) Least squares mean ± SE

3 days per week 6 days per week

3.7 cm

2.9 cm

7556.01

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GDCH & E001: Final Height SDS for Individual Patients

Mean ± SE

-3

-2

-1

0

-2.3

-1.8

Fin

al H

eig

ht

SD

S

-1.7

-1.0

Placebo Humatrope (mg/kg/wk) 0.22

GDCH

0.24 0.37

E001

Humatrope (mg/kg/wk)3 days per week 6 days per week

7557.01

36 %* 55 %*

* Percent of final heights within normal height SDS range

71 %* 94 %*

1016

50

52.3

0.13

Per

cen

tile

60

GDCH & E001 (FH Population):Final Height vs. Baseline Predicted Height (in)

55 60 65 70

55

60

65

70

Fin

al H

eig

ht

(in

)

GDCH

HumatropePlacebo

55 60 65 70

Baseline Predicted Height (in)

E001

0.24 mg/kg/wk0.37 mg/kg/wk

8410.02

61

Meta-analysis of Controlled Studies: GH Treatment Effect (Finkelstein et al., 2002)

• 12 studies with Final Height data (1985-2000)– 4 controlled studies

• Zadik et al., 1992

• Hindmarsh and Brook, 1996

• Buchlis et al., 1998

• McCaughey et al., 1998

• Mean GH effect on adult height: 4 to 6 cm

Mean GH Dose0.31 mg/kg/wk6 times per week

Mean Treatment Duration 5.3 yr

From Finkelstein et al.; Arch Pediatr Adolesc Med 2002

8474.01

62

GDCT: Significant GH-Treatment Effect on Final Height in Turner Syndrome

• Study Design– Randomized, open label, untreated control

– GH Regimen: 0.30 mg/kg/wk, divided doses 6 days per week

• GH Treatment Effect– Primary Analysis

• t-test (p = 0.001): 3.9 cm

– Sensitivity Analysis

• ANCOVA* (p = 0.001): 5.4 cm

* Incorporating effect for mid-parental height SDS Least squares mean

7560.01

63

0

0

E001 and GDCH Height SDS Gain Distribution: Similar to Turner Syndrome

7561.01

-2 0 2 4

Non-GHD Short Stature (Study GDCH)n = 22Mean start age = 12.5 yearsDose = 0.22 mg/kg/wk

-2

0

2

4

Turner Syndrome (Study GDCI)

Change Height SDS (Final - Baseline)

n = 99Mean start age = 10.9 yearsDose = Pooled 0.27 and 0.36mg/kg/wk

-2 0 2 4

Non-GHD Short Stature (Study E001)n = 50Mean start age = 10.3 yearsDose = Pooled 0.24, 0.24/0.37 and 0.37 mg/kg/wk

0204060

204060

Pe

rce

nt

of

Pa

tie

nts

2040

Pe

rce

nt

of

Pa

tie

nts

Pe

rce

nt

of

Pa

tie

nts

60

64

Efficacy Conclusion: GH Increases Final Height in Non-GHD Short Stature

• Consistent efficacy– pivotal placebo-controlled study:– supportive dose-response study:– supportive data from literature:

• Dose-response (0.37 vs. 0.24) – greater height velocity increase: – greater overall height gain:

• Similar efficacy– non-GHD short stature: – Turner syndrome:

3.7 cm

5.4 to 7.2 cm

4 to 6 cm

0.8 cm/yr

2.8 to 3.3 cm

3.7 to 7.2 cm (1.5 to 2.8 in)

3.9 to 5.4 cm (1.5 to 2.1 in)

7562.01

65

What Is the Clinical Relevance of the Efficacy?

• Most patients reached normal height range during childhood

• Similar final height benefit to Turner syndrome

• 62% of final height patients in higher dose group gained more than 2 inches, 31% gained more than 4 inches, and 1 patient gained more than 6 inches, over baseline predicted height

• 94% of final heights in higher dose group were in the normal range

8407.01

66

Safety

Charmian Quigley, MBBS

Senior Clinical Research Physician

Endocrinology

Eli Lilly and Company

7563.01

67

Safety Questions

• Is somatropin safe in pediatric patients?

• Are there any new significant adverse events or safety concerns in this patient population?

• Is there an increased frequency of the adverse events currently described in the product label in this population?  

7564.01

68

Somatropin Safety

• Somatropin has 16-year safety history

• Estimated 200,000 patients exposed world-wide,> 500,000 patient-years

• Well accepted safety profile– 5 currently approved pediatric conditions– Doses up to 0.7 mg/kg/wk

• A number of uncommon, well-characterized events are associated with GH exposure

• Key areas of focus– Carbohydrate metabolism– Neoplasia

• Comprehensive literature addresses safety

• GH Research Society consensus statement*

7565.01 *J Clin Endocrinol Metab 2001; 86: 1868

69

Equivalent Exposure in Registration Studies Included in Safety Comparison

Condition Study N Dose (mg/kg/wk) Patient-years

GHD GDAB 333 0.18 0.24 1232

TS GDCT (136) 74 0.30

1219TS GDCI 229 0.270.36

NGHDSS GDCH (68) 37 0.22

1212NGHDSS E001 239 0.240.37

GHD=Growth hormone deficiency; TS=Turner syndrome; NGHDSS=Non-GHD short stature; N=Number of patients in safety analysis (n = number of patients including control)

7567.01

70

Safety Analyses

• Deaths

• Discontinuations due to adverse events (AEs)

• Serious adverse events (SAEs)– Neoplasia

• Treatment emergent adverse events (TEAEs)

• Adverse events referenced in Humatrope label

• Laboratory data– Carbohydrate metabolism– Insulin-like growth factor I (IGF-I)

7568.01

71

During Study After Study

Condition Study N Humatrope Control Humatrope Control

GHD GDAB 333 1 NA 2 NA

TS GDCT 136 0 1 0 0

TS GDCI 230 0 0 0 0

NGHDSS GDCH 68 0 0 0 0

NGHDSS E001 239 0 NA 1 NA

Patient Deaths During and After Study

7570.01

72

Condition Study N

n (%) patients

discontinuing

GHD GDAB 333 7 (2)

TS GDCT 74 2 (3)

TS GDCI 230 4 (2)

NGHDSS GDCH 37 1 (3)

NGHDSS E001 239 3 (1)

Similar Rates of Discontinuations Due to Adverse Events

N = Patients receiving Humatrope

7571.01

73

Condition Study Nn (%) patients

with SAE

GHD GDAB 333 90 (27)

TS GDCT 74 20 (27)

TS GDCI 230 41 (18)

NGHDSS GDCH 37 5 (14)

NGHDSS E001 239 31 (13)

Serious Adverse Events

N= Patients receiving Humatrope

7572.01

74

Neoplasia

GH Deficiency (333 Humatrope-treated patients)

6 patients– 1 craniopharyngioma (new diagnosis)– 1 papillary thyroid carcinoma (new diagnosis)– 4 intracranial tumors (recurrence/progression)

Turner Syndrome (304 Humatrope-treated patients)

0 patients

Non-GHD Short Stature (276 Humatrope-treated patients)

2 patients– Hodgkin disease (GDCH)– Desmoplastic small round cell tumor (E001)

7573.01

75

Hodgkin DiseaseHodgkin disease stage 3B diagnosed in 11-year old boy whohad received Humatrope for 19 weeks (GDCH)• 2 months pre-study:

– widened mediastinum on chest X-ray (“thymus remnant”)

• Study entry: – high normal erythrocyte sedimentation rate (ESR) 32 mm/hr (N: 1 – 39)– elevated lactic dehydrogenase (LDH) 248 u/L (N: 113 – 226)

• 12 weeks:– abnormal ESR (58 mm/hr)– elevated LDH (257 u/L)

External oncologist (Dr Terry Vik, Riley Hospital for Children): Patient had subclinical disease at study entry

7574.01

76

Desmoplastic Small Round Cell Tumor

• 12-year old boy in 0.24 mg/kg/wk dose group in E001– Diagnosed after 6.4 years on study; died approx. 4 years later– Tumor karyotype: 46,XY,t(11;22)(p13;q12) - hallmark of this tumor– Translocation produces an oncogenic fusion gene: 5’ portion of Ewing

sarcoma gene and 3’ portion of Wilms tumor suppressor gene

• Translocations are not associated with GH treatment

• No other case of this tumor in a GH-treated patient (Lilly pharmacovigilance, literature)

• External expert in the biology of desmoplastic small round cell tumors believes this tumor was unrelated to GH exposure

7575.02

77

Treatment Emergent Adverse Events (TEAEs)

• Majority of TEAEs = common childhood illnesses

• Some differences in pattern of TEAEs between conditions

• No significant differences in rates of TEAEs for– Humatrope vs. Placebo (GDCH)

– 0.24 mg/kg/wk vs. 0.37 mg/kg/wk (E001)

• No new adverse events in non-GHD short stature population

7576.01

78

Comparison of Adverse Events in Current Humatrope Label in Three Patient Populations

GHD TS NGHDSS

Number of Humatrope treated n (%) with event

333 304 276

Otitis media 95 (29) 133 (44) 22 (8)

Scoliosis 5 (2) 1 (0.3) 8 (3)

Hypothyroidism 78 (23) 50 (16) 2 (0.7)

Carbohydrate metabolism

1 (0.3) 1 (0.3) 2 (0.7)

Hypertension 1 (0.3) 15 (5) 1 (0.4)

Slipped capital femoral epiphysis

1 (0.3) 0 (0.0) 1 (0.4)

7578.01

79

E001: No Humatrope Dose Effect on Adverse Events

• Serious adverse events:– 0.24 mg/kg/wk = 11/78 (14%)

– 0.24 0.37 mg/kg/wk = 4/78 (5%)

– 0.37 mg/kg/wk = 16/83 (19%)

• 41 treatment emergent adverse events (TEAEs) occurred in more than a single patient– 9 events most frequent in 0.24 mg/kg/wk group

– 18 events most frequent in 0.24 0.37 mg/kg/wk group

– 11 events most frequent in 0.37 mg/kg/wk group

7579.02

80

Literature on Somatropin Safety

7580.01

Kabi International Growth Study (Wilton P. 1999)

• 25,977 patients

• Approximately 62,400 patient-years exposure

• Events reported as AE/1000 treatment-years

• All conditions 130– Idiopathic GH deficiency 115

– Chronic renal insufficiency 277

– Turner syndrome 148

– Small for gestational age 126

– Idiopathic short stature 89

81

Literature on Somatropin Safety in Non-GHD Conditions: KIGS

Turner Syndrome

Chronic Renal Ins.

Small for Gestation

Idiopathic Short Stature

Patient Number 3019 694 590 3493

Arthralgia 129 102 63 101

Convulsions 155 102 316 152

Diabetes type 2 26 102 0 13

Headache/migraine 349 306 316 317

Intracranial hypertension

78 204 0 0

Scoliosis 272 102 253 25

Slipped capital femoral epiphysis

39 102 0 25

*Event rates are reported as AE/100,000 treatment-years (Wilton P. 1999) 7581.01

82

Literature on Somatropin Safety: NCGSIdiopathic

GHDChronic

Renal Ins.Turner

SyndromeIdiopathic

Short Stature

Patient Number

% of total enrollment

13861

41.8

663

2.0

3416

10.3

5671

17.1

All AEs 28.5 4.8 13.0 10.1

All SAEs 18.8 7.3 7.5 4.6

Deaths 12.8 12.2 4.1 3.4

Leukemia 16.0 4.0 0.0 4.0

Extracranial malignancy 11.1 2.2 15.6 2.2

Intracranial hypertension 30.8 10.3 15.4 2.6

Diabetes 25.4 8.5 15.3 13.6

Slipped femoral epiphysis 31.6 2.6 13.2 0.0

Scoliosis 27.0 0.0 17.2 9.0

* Event rates are reported as % of total events (Maneatis et al. 2000)7582.01

83

GDCH

• Fasting glucose

• Fasting insulin

• QUICKI

• Hemoglobin A1c

• Insulin-like growth factor-I

E001

• Fasting glucose

• Glycosylated

hemoglobin

Laboratory Analyses: Non-GHD Short Stature

7583.01

84

GDCH: Fasting Glucose

7586.02

3.9

5.0

6.1

70

90

110

Baseline Last On Study Baseline Last On Study

Fas

tin

g G

luco

se (

mg

/dL

)

Fas

tin

g G

luco

se (

mm

ol/

L)

85.5

89.7 88.4 89.6

Placebo n = 29 Humatrope n = 36

Mean ± SE

85

E001: Fasting Glucose

No reference range shown as this varied among laboratories7587.01

30

60

90

120

150

2

3

5

7

8

Baseline Endpoint Baseline Endpoint

Fas

tin

g G

luco

se (

mg

/dL

)

Fas

tin

g G

luco

se (

mm

ol/

L)

81.9 81.8 81.2 82.9

0.24 mg/kg/wk n = 59

0.37 mg/kg/wk n = 58

Mean ± SE

86

GDCH: Fasting Insulin

0

20

40

0

144

287

Baseline Last On Study Baseline Last On Study

Fas

tin

g I

nsu

lin

(m

U/m

L)

Fas

tin

g I

nsu

lin

(p

mo

l/L

)

12.68 12.40 11.82 13.20

Placebo n = 28 Humatrope n = 33

Mean ± SE

8222.02

87

GDCH: Quantitative Insulin Sensitivity Check Index (QUICKI)

0.25

0.30

0.35

0.40

0.34 0.34

QU

ICK

I

Baseline Last on Study

Placebo n = 28

0.350.33

Baseline Last on Study

Humatrope n = 33

QUICKI = 1/(log[Fasting Insulin (µU/ml) + log(Fasting Glucose (mg/dl)])

Mean ± SE Mean ± SE

7591.02

88

GDCH: IGF-I Across Study Duration

0 1 2 3 4 5

Year on Study

Mea

n I

GF

-I S

DS

-2

-1

0

1

2p 0.17 0.21 0.01 0.17 0.06 0.04

8408.02

Mean SE

Humatrope (H)Placebo (P)

P3529

3425

3025

2619

1611

116

H

89

Summary: Safety of Humatrope in Non-GHD Short Stature• Single post-study death due to an abdominal tumor, believed

unrelated to Humatrope exposure

• No difference from GH deficiency or Turner syndrome for – Serious adverse events – Discontinuations due to adverse events– Treatment emergent adverse events

• No significant differences in adverse event rates between– Humatrope and placebo (GDCH)– 0.24 and 0.37 mg/kg/wk (E001)

• Laboratory analyses – No Humatrope effect and no dose effect on fasting glucose or

HbA1c– No significant Humatrope effect on insulin sensitivity – IGF-I remained in normal range

7596.01

90

Conclusions: Safety Profile Similar to Approved Indications

• Somatropin is safe in pediatric patients: well characterized safety profile with over 16 years of accumulated experience

 • No new significant adverse events or safety

concerns in this patient population

• No increase in frequency of the adverse events currently described in the product label

7597.01

91

Risk Management Program

7609.01

92

Issues and Questions Regarding GH Treatment for Non-GHD Short Stature1. How will potential risks be managed and safety be

monitored?

2. Will this new indication obviate the need for diagnostic evaluation in children with growth disorders?

3. Will this new indication “open the floodgates” to inappropriate use?

4. Are there ethical issues regarding GH treatment of non-GHD short stature?

5. Is it appropriate to treat patients whose short stature is not clearly associated with a defined “disease”?

6. Should psychological or quality of life benefits be required outcomes of GH treatment?

7. What is the clinical relevance of the efficacy?8376.02

93

Risk Management Program

7611.01

• Appropriate labeling and pharmacovigilance

• Restrictive labeling

• Physician education

• Limited marketing

• Controlled distribution process

• Post-marketing research program

94

Risk Management Program: Restrictive Labeling

“Humatrope is indicated for the long-term

treatment of non-growth hormone-deficient short

stature, defined by height SDS -2.25, in pediatric

patients whose epiphyses are not closed and in

whom diagnostic evaluation excludes causes of

short stature that should be treated by other means”

7612.01

95

Why Was the Height Cut-Off of –2.25 SDS Chosen for the Label Indication?

• Follows FDA recommendation to provide appropriate guidelines to avoid over-prescribing

• Reflects pivotal trial inclusion criterion

• To limit access– Excludes patients with height in normal range

– Excludes almost half of patients with short stature

– Strikes balance between treatment restriction and access

7617.01

96

No Additional Label Restrictions Required

• Only GH label that contains a height restriction

• Excludes 46% of children with non-GHD short stature

• Factors not appropriate as label restrictions– Height velocity– Chronological age– Bone age– IGF-I– Target height (genetic height potential)

• Pediatric endocrinologists integrate these factors in making treatment decisions

8370.02

97

Risk Management Program:Physician Education

Scope• Label restrictions

• Accurate diagnosis

• Benefit-risk

Methods• Physician to physician educational programs

• Continuing medical education7613.01

98

Risk Management Program:Limited Marketing

• Comprehensive training of sales specialists– Patient characteristics

– Diagnostic process

– Benefit-risk

• Sales specialists will call only on pediatric endocrinologists for this indication

• No direct-to-consumer advertising

7614.01

99

Risk Management Program:Controlled Distribution Process

• Statement of Medical Necessity required for new patient diagnoses

• Humatrope shipped only through Lilly-approved closed specialty pharmacies

• Lilly monitors prescribing behavior– Investigation of potential problems – Corrective action includes denial of access to

Humatrope

• Complete details have been provided to FDA7104.01

100

Risk Management Program:Safety Monitoring

• Pharmacovigilance– Screen for adverse events that may be associated with

GH treatment– Evaluation for potential safety concerns– Communication with world-wide regulatory agencies

• Observational post-marketing research program– Genetics and Neuroendocrinology of Short Stature

International Study (GeNeSIS)

7616.01

101

How Will Safety be Monitored?

• Careful monitoring or follow-up is recommended for:– Pre-existing scoliosis– Pre-existing skin lesion– Pre-existing tumor– Hypothyroidism – Insulin resistance and decreased glucose tolerance– Intracranial hypertension– Otitis media and other ear disorder– Slipped capital femoral epiphysis

• These conditions will continue to be monitored in post-marketing research

• No further precautions are necessary

7607.01

102

Risk Management Program:Observational Post-Marketing Research

• Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS)– 30 countries (> 400 study sites)

– Currently 140 US study sites

– Additional sites enrolled on progressive basis

• All Humatrope-treated pediatric patients are eligible to enroll

• Voluntarily untreated controls in 2 sub-studies7105.01

103

Risk Management Program: GeNeSIS Details• Detailed history, diagnostic and efficacy information

– Growth measurements, pubertal status, bone age, etc– Family history– Response to Humatrope

• Comprehensive safety data– Spontaneous adverse events– Protocol identified adverse events– Neoplasia sub-study

• Laboratory information– IGF-I and IGFBP-3 performed as a service for all patients– Other laboratory tests as collected by investigators

• Carbohydrate metabolism• Thyroid function• Other

8288.01

104

Risk Management Program: Reporting of Data• GeNeSIS efficacy and safety data analyzed

and reported annually to investigators

• Safety data– Annual and ad hoc reports to regulatory agencies– Annual reports from all GH manufacturers to

LWPES Drug and Therapeutics Committee

• Monitoring for safety concerns– GeNeSIS data– Spontaneous case reports– Literature reports

8289.01

105

Will New Indication Obviate the Need for Diagnostic Evaluation in Children with Growth Disorders?

• Pediatric endocrinologists are trained to evaluate the causes of growth failure

• Peer professional societies (e.g. LWPES, AAP) provide guidance

• Insurance companies will require work-up and statement of medical necessity

• Label will emphasize need for thorough work-up

• Lilly educational programs will reinforce this need 7618.01

106

Will Approval “Open the Floodgates” for Inappropriate Treatment?• Height threshold of –2.25 SDS will exclude

– All children in the normal range for height – 46% of children with height < –2.0 SDS

• Pediatric endocrinologists are gatekeepers– Observational studies show conservative GH prescribing

• Peer organizations (LWPES/AAP) will update guidelines

• Insurance companies – Will impose controls for financial reasons– Require a statement of medical necessity

• Lilly has a controlled distribution process

• Lilly will promote only to pediatric endocrinologists– No direct-to-consumer marketing

7620.01

107

Will Approval “Open the Floodgates” for Inappropriate Treatment (cont’d)?

Many required decisions will limit GH use

– Decision to consult primary physician

– Decision to refer to pediatric endocrinologist

– Decision to perform diagnostic workup

– Decision to recommend GH therapy to family

– Decision of family to accept therapy

– Decision of insurance company to reimburse for therapy

7619.01

108

How Many Patients with Non-GHD Short Stature Will be Treated?

• Prevalence of non-GHD short stature ≤ -2.25 SDS is approximately 400,000 children between 7 and 15 years of age

• At 5 years after approval, a US total of 30,000-40,000 patients will be on GH treatment due to*– Selective referral by primary care physician– Conservative treatment recommendation by pediatric

endocrinologist– Limited insurer reimbursement

* Model based on Finkelstein et al., 19988426.02

109

Risk Management Conclusions

• Lilly is committed to appropriate use of

Humatrope

• A multi-level program will manage potential

risks

7621.01

110

Benefit – Risk Assessment

7599.01

111

Issues and Questions Regarding GH Treatment for Non-GHD Short Stature1. Will this new indication obviate the need for diagnostic

evaluation in children with growth disorders?

2. Will this new indication “open the floodgates” to inappropriate use?

3. How will safety be monitored and potential risks be managed?

4. Are there ethical issues regarding GH treatment of non-GHD short stature?

5. Is it appropriate to treat patients whose short stature is not clearly associated with a defined “disease”?

6. Should psychological or quality of life benefits be required outcomes of GH treatment?

7. What is the clinical relevance of the efficacy?8377.02

112

Are There Ethical Issues Regarding GH Treatment of Non-GHD Short Stature?

• Social justice related to access to therapy?– Not unique to this indication or GH

– Approved indication would provide more equitable access

• Resource allocation?– GH accounts for a very small proportion of overall health

care budget (< 0.05%)

• Treatment effect vs. cost/discomfort?– Accepted for 4 other non-GHD growth disorders

– Similar for non-GHD short stature

8374.01

113

Are There Ethical Issues Regarding GH Treatment of Non-GHD Short Stature (cont’d)?

• Difficulty in differentiating between “normality” and “abnormality”– Not unique to this indication or GH– Objective criterion proposed for this indication– Pediatric endocrinologists weigh many factors in selecting

appropriate patients for treatment

• Potential for GH to be used as “augmentation” therapy– This potential has existed since GH was first marketed– Pediatric endocrinologists do not support “augmentation”

of height in individuals with normal stature– Label restriction targets children with height SDS ≤ -2.25,

thereby excluding those within normal height range– Risk management program addresses this issue

8375.03

114

Who Should Address Potential Ethical Issues Regarding GH Treatment of Non-GHD Short Stature?

Assuming that the sponsor:– Establishes efficacy, safety, and positive benefit-risk – Provides an effective risk management program– Satisfies FDA requirements sufficient for approval

• Pediatric endocrinologists and families are the most appropriate groups to assess ethical issues

• It is not ethical to exclude from GH treatment children just as short as those currently approved for treatment, when established benefit-risk is similar

8475.01

115

Is It Appropriate to Treat Patients Whose Short Stature Is Not Clearly Associated with a Defined “Disease”?

• Many conditions that deserve and receive treatment may not be accepted as “diseases”:– Enuresis, alopecia, hirsutism, insomnia, social phobia,

obesity

• GH treatment (and label indications) for other growth disorders treats the growth failure or short stature, not the underlying condition or “disease”– e.g. GH has no impact on any feature of chronic renal

insufficiency or Turner syndrome, other than growth

• Growth failure in patients with non-GHD short stature is equivalent to that in other growth disorders

7601.01

116

Should Psychological or Quality of Life Benefits Be Required Outcomes of GH Treatment?

• Not demonstrated for GHD or other growth disorders

• Not required for GH approval for any other growth disorders

• 1987 Endocrinologic and Metabolic Drugs Advisory Committee did not specify other benefits as required outcomes

7605.02

117

What Is the Clinical Relevance of the Efficacy?• Most patients reached normal height range during childhood

• Similar growth improvement to other indications; similar final height benefit to Turner syndrome

• 82% of final height patients in higher dose group gained at least 1 SDS in height

• 62% of final height patients in higher dose group gained more than 2 inches, 31% gained more than 4 inches, and 1 patient gained more than 6 inches, over baseline predicted height

• 94% of final heights in higher dose group were in the normal range

7604.01

118

Height Distribution of Patients with Non-GHD Short Stature

- 8 - 6 - 4 - 2 0 2 4

0.0

0.2

0.4

0.6

0.8

1.0

Height SDS

Non-GHD Short Stature (n=310)General Population

*M: 5' 1”*F: 4' 9”

*M: 5' 9”*F: 5' 4”

*Adult height equivalent (US)

7 – 8”

8287.01

119

Potential Disadvantages of Short Stature

• Childhood– Juvenilization

– Teasing

– Bullying

– Exclusion

– Loss of independence/overprotection

• Adulthood– Social isolation/reduced marriage rate

– Perception of lower competence

– Height limits for certain jobs

– Impact on daily living

• Car safety

• Physical challenges in home/workplace

* Insurance Institute for Highway Safety

10”

8476.02

**

120

Benefit – Risk Assessment

• Humatrope is effective and safe for the

treatment of non-GHD short stature

• Dosage of 0.37 mg/kg/wk confers greater benefit

without evidence of greater risk

• Benefit-risk profile of Humatrope in non-GHD

short stature is favorable and similar to other

indications.

7608.01

121

Reasons to Recommend Approval of Humatrope for Non-GHD Short Stature1. Patients are as short and deserving of treatment as

those with current indications

2. 1987 Endocrinologic and Metabolic Drugs Advisory Committee recommended placebo-controlled study to final height

3. Pivotal study used recommended design

4. Pivotal study demonstrates unequivocal efficacy

5. Supportive study: greater benefit at higher dose

6. Consistent efficacy in published and Lilly studies

7. Efficacy is clinically relevant and similar to other conditions

8. Safety is similar to current indications

Benefit-risk balance justifies approval8292.02

122

Concluding Statements

Margaret MacGillivray, MDProfessor of Pediatrics, Emeritus

University of BuffaloPediatric Endocrine Specialist

School of Medicine & Biomedical SciencesChildren’s Hospital Buffalo

7622.01

123

Growth Hormone – The Past

1985– FDA approved recombinant GH for the treatment of

growth failure in children with GHD• without placebo-controlled study

• in absence of long-term height data

– FDA mandated post-marketing surveillance• few other drugs have received such close scrutiny

1996– FDA approved recombinant GH for the treatment of

short stature associated with Turner syndrome• a non-GHD condition

• the first condition for which final height data were provided

7623.01

124

Growth Hormone – The Present

• GH is approved treatment for the growth failure or short stature associated with 3 additional non-GHD conditions:– Chronic renal insufficiency

– Prader-Willi syndrome

– Children born small for gestational age

• In granting these approvals– GH secretion status was not considered

– No long-term outcome data were required

– Placebo-controlled data were not required

7624.01

125

Challenges to Use of Growth Hormone for Non-GHD Short Stature

No psychological decompensation– Psychological problems not required for GH treatment in

GHD or other non-GHD conditions

They are healthy children with “normal” GH secretion– GH stimulation tests are not gold standard and don’t

predict an individual child’s response to therapy

– Patients don’t spontaneously correct their height

• Lilly’s placebo data and other observational data show that most end up as short adults

7625.02

126

Conclusions

• Unequivocal efficacy and safety data in non-GHD children with significant growth failure have been presented– Double-blind trial– Dose-response study– Meta-analysis

• Evidence from NIH study is particularly meaningful– Positive results despite sub-optimal treatment regimen

• Families have sought treatment for their children’s growth failure for decades

• GH treatment could provide patients with opportunity to achieve height within the normal range

7626.02

127

Recommendation

Humatrope should be approved for

treatment of non-GHD short stature

7627.01

129

Self-image and Behavior Results-GDCH

Judith Ross, M.D.Professor, Department of PediatricsThomas Jefferson University

8453.01

130

Questionnaires

• Self Perception Profile (SPP, 36 item) CHILD REPORT–Assesses domain-specific judgment of competence

and perception of worth

• Child Behavior Checklist (CBCL,118 items) PARENTAL REPORT

– Assesses behavior problems and social competencies

8454.01

131

Protocol

• Questionnaires distributed to child and parent at baseline and yearly

Statistics:• T-tests, year by year across treatment groups

8455.01

132

Results

SPP• Normal at baseline

CBCL• Normal at baseline

8456.01

133

Placebo Humatrope

Patients Number 29 22

Behavior Total 51 ± 11 52 ± 11

Externalize 49 ± 9 49 ± 11

Internalize 52 ± 12 51 ± 11

Baseline Results (CBCL T score, X ± SD): Summary Scores

8457.01

134

Treatment Results

SPP (Child)• No difference between the Humatrope- and placebo-

treated groups during the 4-year treatment interval

CBCL (Parent)• The Humatrope group had improved scores on

Problem Behavior summary score (p < 0.03), Externalizing score (p < 0.02), and Internalizing score (p < 0.05) at the 4-year treatment interval, compared to placebo group.

8458.01

135

Results

CBCL Behavior Total subscale• Summary score of problem behaviors including

social problems, anxiety, depression, somatic complaints etc.

• T score, mean is 50, 1 SD = 10• Higher score indicates more problem behaviors

8459.01

136

Problem Behavioral Total

0 1 2 4

Year on Study

Ch

ang

e in

Sco

re

-10

0

10

20

HP

179

2319

129

93

p 0.71 0.31 0.07 0.03

Mean SE

Humatrope (H)Placebo (P)

8460.03

3

137

ResultsCBCL Behavior Total subscale• Summary score of problem behaviors including

social problems, anxiety, depression, somatic complaints etc.

CBCL Externalizing subscale:• Summary score of problem behaviors

(Delinquent, Aggressive subscales)-includes “acting out” and aggressive behaviors

8461.01

138

External Behavior Total

0 1 2 3 4Year on Study

Ch

ang

e in

Sco

re

-10

-5

0

5

10

15p 0.72 0.61 0.04 0.02

HP

179

2319

129

93

Mean SE

Humatrope (H)Placebo (P)

8462.02

139

ResultsCBCL Behavior Total subscale• Summary score of problem behaviors including social

problems, anxiety, depression, somatic complaints etc.

CBCL Externalizing subscale• Summary score of problem behaviors (Delinquent,

Aggressive subscales)-includes “acting out” and aggressive behaviors.

CBCL Internalizing subscale• Summary score of problem behaviors (Withdrawn,

Somatic, and Anxiety/Depression subscales)-includes excessive worrying and depression.

8463.01

140

Internal Behavior Total

0 1 2 3 4Year on Study

Ch

ang

e in

Sco

re

-10

0

10

20 p 0.4 0.73 0.09 0.05

HP

179

2319

129

93

Mean SE

Humatrope (H)Placebo (P)

8464.02

141

Why Results Are Inconclusive• Small sample size

• Missing or incomplete data

• Drop out bias

• No correction for multiple comparisons (14 subscales)

• No correlation with change in growth rates or height SDS

8465.01

142

Summary• Results controlled for placebo effect

• GH does not have deleterious effects on self-image or behavior

• Trend towards positive GH effect on Problem Behaviors, Externalizing, and Internalizing Behaviors

8466.01

143

Previous ISS Self-image Results

Reference ISS No. Age Height SDS Self-image findings

Sandberg et al.,Ped 1994; 94: 832

258 11 -2.3 More Problem Behavior, Internal, External (CBCL)

Downie, Voss et al.,Arch Dis Childh 1996; 75: 32

28 7-8 -2.4 No difference in self-esteem, < satisfied with height

Stabler et al.,J Ped 1998; 133: 366

86 10.9 -2.8 More Problem Behavior, Internal, External (CBCL)

Steinhausen,

J Endocrinol Invest 2002; 25: 351

16 8.8 -4.0 More Problem Behavior, Internal, External (CBCL)

Theunissen et al.,

J Ped 2002; 140: 507

36 4-10 < 2 Lower social function

8467.01

144

Previous GH Self-Image Results

Reference ISS No. Age Years Self-image findings

Boulton et al.,Acta Paed Scand 1991; 377: 20

66 10.2 2 Improved emotional adjustment

Downie, Voss et al.,Arch Dis Childh 1996; 75: 32

15 7-8 5 No difference inself-esteem

Stabler et al.,J Ped 1998; 133: 366

86 10.9 3 Improved Problem Behavior, Internal, External

Steinhausen,J Endocrinol Invest 2002; 25: 351

93 8.8 2 Improved Problem Behavior, Internal, External

*Theunissen et al.,J Ped 2002; 140: 507

36 4-10 2 No difference inself-esteem

* Randomized control group8468.01

145

ISS and GH for 2 years

Steinhausen et al, J. Endocrinol Invest. 2002; 25:351

Internalizing

Externalizing

Problem Behaviors

8469.01

146

ISS and GH for 3 years

Stabler et al.,J. Pediatr. 1998;133:366

8470.01

147

Results

CBCL Externalizing subscale (Delinquent, Aggressive subscales)-includes “acting out” and aggressive behaviors

• CBCL Delinquent subscale– Bad friends, lie, cheat, run away, steal, swear,

truant• CBCL Aggressive subscale

– Argues, brags, fights, jealous, stubborn, show-off.

8471.01

148

Turner Syndrome: No Dose Effect on Fasting Insulin

0

10

20

30

40

Placebo GH 0.27 GH 0.36

Fas

tin

g I

nsu

lin

(m

cU/m

L) Baseline

0

10

20

30

40

Placebo GH 0.27 GH 0.36

18 months

8252.02A few extreme high values are not displayed

149

GDCH (EE Population): No Humatrope Treatment Effect on Pubertal Progression in Boys

Leschek E. et al.: J. Pediatr 2001; 138: 406 – 410 8156.01

150

GDCH (EE Population): No Humatrope Treatment Effect on Pubertal Onset in Boys

Age at Pubertal Onset (yr)

Criterion for Pubertal OnsetPlacebo (n=12)

Humatrope (n=11)

Testis Volume > 4 mL 13.5 ± 0.5 13.3 ± 0.5

Testosterone > 30 ng/dL 13.5 ± 0.6 14.1 ± 0.4

Leschek E. et al.: J. Pediatr 2001; 138: 406 – 410 8153.01

151

GDCH: Final Height (cm)Males and Females SeparatelyHumatrope vs. Placebo

Males Females

N Mean ± SD N Mean ± SD

Humatrope 18 163.1 ± 6.3 4 152.3 ± 5.6

Placebo 9 159.3 ± 4.4 2 149.0 ± 4.0