1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with...
-
Upload
allison-reynolds -
Category
Documents
-
view
226 -
download
5
Transcript of 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with...
![Page 1: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/1.jpg)
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
![Page 2: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/2.jpg)
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
![Page 3: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/3.jpg)
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)
![Page 4: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/4.jpg)
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
![Page 5: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/5.jpg)
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
![Page 6: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/6.jpg)
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
![Page 7: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/7.jpg)
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
![Page 8: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/8.jpg)
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
![Page 9: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/9.jpg)
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
![Page 10: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/10.jpg)
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
![Page 11: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/11.jpg)
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
![Page 12: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/12.jpg)
12
Why Treat Short Stature?
8363.01
• Children and adults with short stature, irrespective of cause, may have disadvantages compared to their peers
![Page 13: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/13.jpg)
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
![Page 14: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/14.jpg)
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
![Page 15: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/15.jpg)
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
![Page 16: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/16.jpg)
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
![Page 17: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/17.jpg)
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)
![Page 18: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/18.jpg)
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
![Page 19: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/19.jpg)
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
![Page 20: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/20.jpg)
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
![Page 21: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/21.jpg)
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
![Page 22: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/22.jpg)
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
![Page 23: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/23.jpg)
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
![Page 24: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/24.jpg)
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
![Page 25: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/25.jpg)
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
![Page 26: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/26.jpg)
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
![Page 27: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/27.jpg)
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
![Page 28: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/28.jpg)
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
![Page 29: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/29.jpg)
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
![Page 30: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/30.jpg)
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
![Page 31: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/31.jpg)
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
![Page 32: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/32.jpg)
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
![Page 33: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/33.jpg)
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
![Page 34: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/34.jpg)
34
Efficacy
Gordon Cutler, MD
Director – Growth and Recovery Research and Clinical Investigation
Eli Lilly and Company
7529.01
![Page 35: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/35.jpg)
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
![Page 36: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/36.jpg)
36
Overview of sNDA Submission
• Pivotal study - GDCH
• Supportive study - E001
• Supportive data - Meta-analysis (Finkelstein et al., 2002)
7531.01
![Page 37: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/37.jpg)
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
![Page 38: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/38.jpg)
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
![Page 39: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/39.jpg)
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
![Page 40: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/40.jpg)
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
![Page 41: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/41.jpg)
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
![Page 42: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/42.jpg)
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
![Page 43: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/43.jpg)
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
![Page 44: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/44.jpg)
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
![Page 45: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/45.jpg)
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
![Page 46: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/46.jpg)
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
![Page 47: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/47.jpg)
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
![Page 48: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/48.jpg)
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)
![Page 49: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/49.jpg)
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
![Page 50: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/50.jpg)
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
![Page 51: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/51.jpg)
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
![Page 52: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/52.jpg)
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
![Page 53: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/53.jpg)
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
![Page 54: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/54.jpg)
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
![Page 55: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/55.jpg)
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
![Page 56: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/56.jpg)
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
![Page 57: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/57.jpg)
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
![Page 58: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/58.jpg)
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
![Page 59: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/59.jpg)
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
![Page 60: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/60.jpg)
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
![Page 61: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/61.jpg)
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
![Page 62: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/62.jpg)
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
![Page 63: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/63.jpg)
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
![Page 64: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/64.jpg)
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
![Page 65: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/65.jpg)
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
![Page 66: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/66.jpg)
66
Safety
Charmian Quigley, MBBS
Senior Clinical Research Physician
Endocrinology
Eli Lilly and Company
7563.01
![Page 67: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/67.jpg)
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
![Page 68: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/68.jpg)
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
![Page 69: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/69.jpg)
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
![Page 70: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/70.jpg)
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
![Page 71: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/71.jpg)
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
![Page 72: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/72.jpg)
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
![Page 73: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/73.jpg)
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
![Page 74: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/74.jpg)
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
![Page 75: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/75.jpg)
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
![Page 76: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/76.jpg)
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
![Page 77: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/77.jpg)
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
![Page 78: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/78.jpg)
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
![Page 79: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/79.jpg)
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
![Page 80: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/80.jpg)
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
![Page 81: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/81.jpg)
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
![Page 82: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/82.jpg)
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
![Page 83: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/83.jpg)
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
![Page 84: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/84.jpg)
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
![Page 85: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/85.jpg)
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
![Page 86: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/86.jpg)
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
![Page 87: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/87.jpg)
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
![Page 88: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/88.jpg)
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
![Page 89: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/89.jpg)
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
![Page 90: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/90.jpg)
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
![Page 91: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/91.jpg)
91
Risk Management Program
7609.01
![Page 92: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/92.jpg)
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
![Page 93: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/93.jpg)
93
Risk Management Program
7611.01
• Appropriate labeling and pharmacovigilance
• Restrictive labeling
• Physician education
• Limited marketing
• Controlled distribution process
• Post-marketing research program
![Page 94: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/94.jpg)
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
![Page 95: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/95.jpg)
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
![Page 96: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/96.jpg)
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
![Page 97: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/97.jpg)
97
Risk Management Program:Physician Education
Scope• Label restrictions
• Accurate diagnosis
• Benefit-risk
Methods• Physician to physician educational programs
• Continuing medical education7613.01
![Page 98: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/98.jpg)
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
![Page 99: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/99.jpg)
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
![Page 100: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/100.jpg)
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
![Page 101: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/101.jpg)
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
![Page 102: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/102.jpg)
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
![Page 103: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/103.jpg)
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
![Page 104: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/104.jpg)
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
![Page 105: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/105.jpg)
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
![Page 106: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/106.jpg)
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
![Page 107: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/107.jpg)
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
![Page 108: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/108.jpg)
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
![Page 109: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/109.jpg)
109
Risk Management Conclusions
• Lilly is committed to appropriate use of
Humatrope
• A multi-level program will manage potential
risks
7621.01
![Page 110: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/110.jpg)
110
Benefit – Risk Assessment
7599.01
![Page 111: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/111.jpg)
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
![Page 112: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/112.jpg)
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
![Page 113: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/113.jpg)
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
![Page 114: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/114.jpg)
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
![Page 115: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/115.jpg)
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
![Page 116: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/116.jpg)
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
![Page 117: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/117.jpg)
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
![Page 118: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/118.jpg)
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
![Page 119: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/119.jpg)
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
**
![Page 120: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/120.jpg)
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
![Page 121: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/121.jpg)
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
![Page 122: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/122.jpg)
122
Concluding Statements
Margaret MacGillivray, MDProfessor of Pediatrics, Emeritus
University of BuffaloPediatric Endocrine Specialist
School of Medicine & Biomedical SciencesChildren’s Hospital Buffalo
7622.01
![Page 123: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/123.jpg)
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
![Page 124: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/124.jpg)
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
![Page 125: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/125.jpg)
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
![Page 126: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/126.jpg)
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
![Page 127: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/127.jpg)
127
Recommendation
Humatrope should be approved for
treatment of non-GHD short stature
7627.01
![Page 128: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/128.jpg)
![Page 129: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/129.jpg)
129
Self-image and Behavior Results-GDCH
Judith Ross, M.D.Professor, Department of PediatricsThomas Jefferson University
8453.01
![Page 130: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/130.jpg)
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
![Page 131: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/131.jpg)
131
Protocol
• Questionnaires distributed to child and parent at baseline and yearly
Statistics:• T-tests, year by year across treatment groups
8455.01
![Page 132: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/132.jpg)
132
Results
SPP• Normal at baseline
CBCL• Normal at baseline
8456.01
![Page 133: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/133.jpg)
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
![Page 134: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/134.jpg)
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
![Page 135: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/135.jpg)
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
![Page 136: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/136.jpg)
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
![Page 137: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/137.jpg)
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
![Page 138: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/138.jpg)
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
![Page 139: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/139.jpg)
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
![Page 140: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/140.jpg)
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
![Page 141: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/141.jpg)
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
![Page 142: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/142.jpg)
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
![Page 143: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/143.jpg)
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
![Page 144: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/144.jpg)
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
![Page 145: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/145.jpg)
145
ISS and GH for 2 years
Steinhausen et al, J. Endocrinol Invest. 2002; 25:351
Internalizing
Externalizing
Problem Behaviors
8469.01
![Page 146: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/146.jpg)
146
ISS and GH for 3 years
Stabler et al.,J. Pediatr. 1998;133:366
8470.01
![Page 147: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/147.jpg)
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
![Page 148: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/148.jpg)
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
![Page 149: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/149.jpg)
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
![Page 150: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/150.jpg)
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
![Page 151: 1 Humatrope® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone- Deficient Short Stature FDA Advisory Committee.](https://reader036.fdocuments.us/reader036/viewer/2022070407/56649e245503460f94b12bd8/html5/thumbnails/151.jpg)
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