1 humatrope® (somatropin [rdna origin] for injection) treatment of pediatric patients with...
TRANSCRIPT
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
5
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
6
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
7
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
8
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
9
Raymond L. Hintz, MDProfessor of Pediatrics
Stanford University Medical Center
The Rationale for GH Treatment of Patients with
Non-GHD Short Stature
7509.01
10
• 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
11
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
12
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
14
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
15
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
7512.01
16
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
17
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
20
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”
8368.01
21
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
7514.01
22
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
29
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
31
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
32
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
33
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
36
Overview of sNDA Submission
• Pivotal study - GDCH
• Supportive study - E001
• Supportive data - Meta-analysis (Finkelstein et al., 2002)
7531.01
37
~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
38
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
39
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
41
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
50
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
52
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
54
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
57
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
7555.01
58
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
59
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