Humatrope® (somatropin [rDNA origin] for injection ...

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  • Humatrope® (somatropin [rDNA origin] for injection ...

    1. 1. Humatrope ® (somatropin [rDNA origin] for injection) Treatment of Pediatric Patients with Non-Growth Hormone-Deficient Short Stature FDA Advisory Committee Meeting June 10, 2003 Bethesda, Maryland Eli Lilly and Company 7501.01
    2. 2. Humatrope Treatment of Pediatric Patients with Non-Growth Hormone-Deficient Short Stature Gregory Enas, PhD Director, US Regulatory Affairs Eli Lilly and Company 7502.01
    3. 3. FDA-approved Humatrope Doses for Pediatric Indications 7503.01 (Other approved pediatric GH doses: 0.16 to 0.70 mg/kg/wk) 0.30 mg/kg/wk (3, 6, or 7 days per week) October 1997 0.375 mg/kg/wk (3 or 7 days per week) March 1997 Turner Syndrome 0.30 mg/kg/wk (3 or 6 days per week) April 1994 0.18 mg/kg/wk (3 days per week) March 1987 Pediatric GH Deficiency
    4. 4. Introduction <ul><li>“… 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” </li></ul><ul><li>( NICHD International Conference on Uses and Abuses of GH , 1983) </li></ul>7504.01
    5. 5. Guidance Received from Endocrinologic & Metabolic Drugs Advisory Committee <ul><li>“ . . the control group should be a placebo-treated, randomized group of patients. . .” </li></ul><ul><li>and </li></ul><ul><li>“ . . the subjects should be followed until their ultimate height is reached” ( Sept 1987 ) </li></ul>7505.01
    6. 6. Issues and Questions Regarding GH Treatment for Non-GHD Short Stature <ul><li>How will potential risks be managed and safety be monitored? </li></ul><ul><li>Will this new indication obviate the need for diagnostic evaluation in children with growth disorders? </li></ul><ul><li>Will this new indication “open the floodgates” to inappropriate use? </li></ul><ul><li>Are there ethical issues regarding GH treatment of non-GHD short stature? </li></ul><ul><li>Is it appropriate to treat patients whose short stature is not clearly associated with a defined “disease”? </li></ul><ul><li>Should psychological or quality of life benefits be required outcomes of GH treatment? </li></ul><ul><li>What is the clinical relevance of the efficacy? </li></ul>7610.01
    7. 7. External Consultants <ul><li>Raymond L. Hintz, MD </li></ul><ul><li>Professor of Pediatrics </li></ul><ul><li>Stanford University Medical Center </li></ul><ul><li>Secretary </li></ul><ul><li>Lawson Wilkins Pediatric Endocrine </li></ul><ul><li>Society </li></ul><ul><li>Margaret MacGillivray, MD </li></ul><ul><li>Professor of Pediatrics, Emeritus </li></ul><ul><li>University of Buffalo </li></ul><ul><li>Pediatric Endocrine Specialist </li></ul><ul><li>School of Medicine & Biomedical </li></ul><ul><li>Sciences </li></ul><ul><li>Children’s Hospital Buffalo </li></ul><ul><li>Judith L. Ross, MD </li></ul><ul><li>Professor of Pediatrics </li></ul><ul><li>Chief, Pediatric Endocrinology </li></ul><ul><li>Jefferson Medical College </li></ul><ul><li>Thomas Jefferson University </li></ul><ul><li>Melvin M. Grumbach, MD </li></ul><ul><li>Edward B. Shaw Professor of </li></ul><ul><li>Pediatrics, Emeritus </li></ul><ul><li>University of California at San </li></ul><ul><li>Francisco School of Medicine </li></ul><ul><li>Gary Koch, PhD </li></ul><ul><li>Professor of Biostatistics </li></ul><ul><li>University of North Carolina at Chapel </li></ul><ul><li>Hill </li></ul><ul><li>Ron G. Rosenfeld, MD </li></ul><ul><li>Sr Vice-President for Medical Affairs </li></ul><ul><li>Lucile Packard Foundation for </li></ul><ul><li>Children’s Health </li></ul><ul><li>Professor of Pediatrics, Professor of </li></ul><ul><li>Cell and Development Biology </li></ul><ul><li>Oregon Health & Science University </li></ul><ul><li>and Stanford University </li></ul>7507.01
    8. 8. Lilly Advisory Committee Presentation: Humatrope Treatment of Pediatric Patients with Non-GHD Short Stature <ul><li>Introduction </li></ul><ul><li>Rationale for Treatment </li></ul><ul><li>Efficacy </li></ul><ul><li>Safety </li></ul><ul><li>Risk Management Program </li></ul><ul><li>Benefit – Risk Assessment </li></ul><ul><li>Concluding Statements </li></ul><ul><li>Gregory Enas, PhD </li></ul><ul><li>Raymond L. Hintz, MD </li></ul><ul><li>Gordon Cutler, MD </li></ul><ul><li>Charmian Quigley, MBBS </li></ul><ul><li>Charmian Quigley, MBBS </li></ul><ul><li>Charmian Quigley, MBBS </li></ul><ul><li>Margaret MacGillivray, MD </li></ul>7508.01
    9. 9. Raymond L. Hintz, MD Professor of Pediatrics Stanford University Medical Center The Rationale for GH Treatment of Patients with Non-GHD Short Stature 7509.01
    10. 10. <ul><li>Growth failure: decline in rate of linear growth </li></ul><ul><li>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) </li></ul><ul><li>There are many endocrine and non-endocrine causes of growth failure and short stature </li></ul><ul><li>Growth Hormone Research Society recommends investigation of children with short stature whose height falls below -2.0 SD scores (SDS) </li></ul>Growth Failure and Short Stature 7510.01
    11. 11. What is Short Stature? +2.0 SD ( 97.7 percentile ) -2.0 SD ( 2.3 percentile ) Generally accepted definition of normal range <ul><li>US adult height of -2.0 SDS </li></ul><ul><li>is equivalent to: </li></ul><ul><ul><li>Male 5’ 3.6” </li></ul></ul><ul><ul><li>Female 4’ 11.1” </li></ul></ul>7511.01
    12. 12. Why Treat Short Stature? <ul><li>Children and adults with short stature, irrespective of cause, may have disadvantages compared to their peers </li></ul>8363.01
    13. 13. Potential Disadvantages of Short Stature <ul><li>Childhood </li></ul><ul><ul><li>Juvenilization (Sandberg, 1999) </li></ul></ul><ul><ul><li>Teasing (Voss and Mulligan, 2000) </li></ul></ul><ul><ul><li>Bullying (Voss and Mulligan, 2000) </li></ul></ul><ul><ul><li>Exclusion (Zimet et al 1997) </li></ul></ul><ul><ul><li>Loss of independence/overprotection (Zimet et al 1997) </li></ul></ul><ul><li>Adulthood </li></ul><ul><ul><li>Social isolation/reduced marriage rate (Sartorio et al, 1990) </li></ul></ul><ul><ul><li>Perception of lower competence (Melamed, 1992) </li></ul></ul><ul><ul><li>Height limits for certain jobs </li></ul></ul><ul><ul><li>Impact on daily living </li></ul></ul><ul><ul><ul><li>Car safety (Cunningham, 2000) </li></ul></ul></ul><ul><ul><ul><li>Physical challenges in home/workplace </li></ul></ul></ul>7517.02
    14. 14. Why Treat Short Stature? <ul><li>Children and adults with short stature, irrespective of cause, may have disadvantages compared to their peers </li></ul><ul><li>GH treatment in many conditions improves growth and effectively corrects short stature </li></ul>8364.02
    15. 15. Approved GH Use in Pediatric Growth Disorders Treatment of growth failure or short stature associated with… All pediatric indications approved after 1985 are non-GHD conditions 7512.01 Non-GHD Short Stature (proposed) 2003 Indication Date Small for Gestational Age 2001 Prader – Willi Syndrome 2000 Turner Syndrome 1996 Chronic Renal Insufficiency 1993 Pediatric GH Deficiency 1985
    16. 16. Pediatric Growth Disorders are Heterogeneous in Etiology <ul><li>GH deficiency </li></ul><ul><ul><li>Hypothalamic disorders (e.g. GHRH deficiency) </li></ul></ul><ul><ul><li>Pituitary disorders (e.g. pituitary hypoplasia, genetic mutations) </li></ul></ul><ul><ul><li>Trauma </li></ul></ul><ul><ul><li>Tumor </li></ul></ul><ul><ul><li>Irradiation </li></ul></ul><ul><li>Turner syndrome </li></ul><ul><ul><li>45,X </li></ul></ul><ul><ul><li>45,X/46,XX </li></ul></ul><ul><ul><li>Numerous variants </li></ul></ul><ul><li>Small for gestational age </li></ul><ul><ul><li>Russell-Silver syndrome </li></ul></ul><ul><ul><li>Maternal hypertension </li></ul></ul><ul><ul><li>Maternal smoking </li></ul></ul><ul><ul><li>Small maternal pelvis </li></ul></ul><ul><ul><li>Various genetic syndromes </li></ul></ul>8365.02
    17. 17. Pediatric Growth Disorders are Heterogeneous in Phenotype <ul><li>GH deficiency </li></ul><ul><ul><li>Variable timing and severity of growth failure </li></ul></ul><ul><ul><li>Variable clinical features (e.g. cherubic face, adiposity) </li></ul></ul><ul><ul><li>Variable GH responses to testing </li></ul></ul><ul><li>Turner syndrome </li></ul><ul><ul><li>Variable timing and severity of growth failure </li></ul></ul><ul><ul><li>Variable clinical features (e.g. webbed neck, low hairline) </li></ul></ul><ul><li>Small for gestational age </li></ul><ul><ul><li>Variable degree of short stature </li></ul></ul><ul><ul><li>Presence or absence of additional phenotypic features (e.g. asymmetry, dysmorphic features) </li></ul></ul>8366.01
    18. 18. The Patient with Non-GHD Short Stature <ul><li>Short stature equivalent to GH deficiency and other causes of growth failure </li></ul><ul><li>Normal GH tests </li></ul><ul><li>Etiology undefined </li></ul><ul><li>Diagnosis by exclusion </li></ul><ul><li>Not eligible for treatment </li></ul>Courtesy J. Ross, MD, Jefferson Medical College, PA “ James” -2.8 SDS “ Julian” +0.1 SDS 7513.01 Fraternal twins, 7.7 yrs
    19. 19. Features of Non-GHD Short Stature <ul><li>Growth failure during childhood </li></ul><ul><li>Height < -2.0 SDS </li></ul><ul><li>No distinguishing phenotypic features </li></ul><ul><li>Likely heterogeneous etiology </li></ul><ul><ul><li>Familial/genetic </li></ul></ul><ul><ul><li>Abnormal GH/IGF axis </li></ul></ul><ul><ul><li>Abnormal growth plate </li></ul></ul><ul><li>Unimodal distribution of height deficit </li></ul>8367.01
    20. 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) 8368.01 7 – 8”
    21. 21. Growth Disorders: Eligibility for GH Therapy <ul><li>ELIGIBLE </li></ul><ul><li>Peak GH response below threshold </li></ul><ul><ul><li>classified as GH deficient </li></ul></ul><ul><li>Four non-GHD growth disorders (TS, CRI, PWS, SGA) irrespective of </li></ul><ul><ul><li>GH secretion status, or </li></ul></ul><ul><ul><li>degree of short stature </li></ul></ul><ul><li>INELIGIBLE </li></ul><ul><li>Peak GH response above threshold (termed non-GH deficient) despite equivalent short stature to those with </li></ul><ul><ul><li>GH deficiency and </li></ul></ul><ul><ul><li>other non-GHD conditions </li></ul></ul>7514.01
    22. 22. Why Should Children with Non-GHD Short Stature Be Eligible for GH? <ul><li>Growth failure is equivalent to that in other growth disorders </li></ul><ul><li>Untreated patients do not achieve their adult height prediction </li></ul><ul><li>GH treatment in other conditions treats the short stature or growth failure, NOT the “disease” </li></ul><ul><li>Unknown or heterogeneous etiology does not justify exclusion from treatment </li></ul><ul><li>Non-GHD short stature is responsive to GH </li></ul>7518.02
    23. 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 stature 7519.02 Population IGHD CRI TS SGA NGHDSS Height SDS -4 -3 -2 -1 0 National Cooperative Growth Study Kabi International Growth Study Mean ± SD
    24. 24. Why Should Children with Non-GHD Short Stature Be Eligible for GH? <ul><li>Growth failure is equivalent to that in other growth disorders </li></ul><ul><li>Untreated patients do not achieve their adult height prediction </li></ul><ul><li>GH treatment in other conditions treats the short stature or growth failure, NOT the “disease” </li></ul><ul><li>Unknown or heterogeneous etiology does not justify exclusion from treatment </li></ul><ul><li>Non-GHD short stature is responsive to GH </li></ul>7520.02
    25. 25. Why Should Children with Non-GHD Short Stature Be Eligible for GH? <ul><li>Growth failure is equivalent to that in other growth disorders </li></ul><ul><li>Untreated patients do not achieve their adult height prediction </li></ul><ul><li>GH treatment in other conditions treats the short stature or growth failure, NOT the “disease” </li></ul><ul><li>Unknown or heterogeneous etiology does not justify exclusion from treatment </li></ul><ul><li>Non-GHD short stature is responsive to GH </li></ul>7522.02
    26. 26. GH Treats the Short Stature or Growth Failure, Not the “Disease” Turner Syndrome Non-GHD Short Stature 8.7 yrs Height SDS –3.0 11.0 yrs Height SDS –2.9 7523.01 <ul><li>Degree of short stature is similar </li></ul><ul><li>Response to treatment is similar and clinically meaningful </li></ul>
    27. 27. Why Should Children with Non-GHD Short Stature Be Eligible for GH? <ul><li>Growth failure is equivalent to that in other growth disorders </li></ul><ul><li>Untreated patients do not achieve their adult height prediction </li></ul><ul><li>GH treatment in other conditions treats the short stature or growth failure, NOT the “disease” </li></ul><ul><li>Unknown or heterogeneous etiology does not justify exclusion from treatment </li></ul><ul><li>Non-GHD short stature is responsive to GH </li></ul>7524.02
    28. 28. Many Conditions of Unknown or Heterogeneous Etiology Deserve and Receive Treatment <ul><li>Examples: </li></ul><ul><li>Alopecia </li></ul><ul><li>Anxiety disorder </li></ul><ul><li>Enuresis </li></ul><ul><li>Gynecomastia </li></ul><ul><li>Hirsutism </li></ul><ul><li>Hypercholesterolemia </li></ul><ul><li>Hypertension </li></ul><ul><li>Nicotine addiction </li></ul>7525.01
    29. 29. Why Should Children with Non-GHD Short Stature Be Eligible for GH? <ul><li>Growth failure is equivalent to that in other growth disorders </li></ul><ul><li>Untreated patients do not achieve their adult height prediction </li></ul><ul><li>GH treatment in other conditions treats the short stature or growth failure, NOT the “disease” </li></ul><ul><li>Unknown or heterogeneous etiology does not justify exclusion from treatment </li></ul><ul><li>Non-GHD short stature is responsive to GH </li></ul>7526.02
    30. 30. Research on GH Treatment of Non-GHD Short Stature Has a Long History 7528.01 FDA advisory committee recommends placebo-controlled study to final height 1987 NICHD international conference recommends studies of GH treatment in non-GHD conditions 1983 More than 40 studies published on GH treatment in non-GHD short stature 1985-2000 Early studies demonstrate increased growth rate in patients with non-GHD short stature 1964-1971
    31. 31. Improved Height SDS in Response to GH Treatment Hintz et al.; NEJM 1999; 340: 502-7 80 patients GH 0.3 mg/kg/wk 7527.02
    32. 32. Research on GH Treatment of Non-GHD Short Stature Has a Long History 8286.01 FDA advisory committee recommends placebo-controlled study to final height 1987 NICHD international conference recommends studies of GH treatment in non-GHD conditions 1983 Lilly clinical trials in non-GHD short stature 1988-2001 More than 40 studies published on GH treatment in non-GHD short stature 1985-2000 Early studies demonstrate increased growth rate in patients with non-GHD short stature 1964-1971
    33. 33. Key Reasons Why Children with Non-GHD Short Stature Should Be Eligible for GH <ul><li>Growth failure in patients with non-GHD short stature is equivalent to that in other growth disorders </li></ul><ul><li>GH treatment in other conditions treats the short stature or growth failure, NOT the “disease” </li></ul><ul><li>Unknown or heterogeneous etiology does not justify exclusion from treatment </li></ul>8369.01
    34. 34. Efficacy Gordon Cutler, MD Director – Growth and Recovery Research and Clinical Investigation Eli Lilly and Company 7529.01
    35. 35. Efficacy Questions <ul><li>Is GH treatment effective? </li></ul><ul><li>Is there a dose-response? </li></ul><ul><ul><li>0.37 vs. 0.24 mg/kg/wk </li></ul></ul><ul><li>Are there supportive published data? </li></ul><ul><li>Is the efficacy similar to Turner syndrome? </li></ul>7530.01
    36. 36. Overview of sNDA Submission <ul><li>Pivotal study - GDCH </li></ul><ul><li>Supportive study - E001 </li></ul><ul><li>Supportive data - Meta-analysis ( Finkelstein et al., 2002 ) </li></ul>7531.01
    37. 37. GDCH Study Design: Randomized, Double-Blind, Placebo-Controlled ~80 subjects 40 Humatrope, 0.22 mg/kg/wk divided 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 1 year 7533.02
    38. 38. GDCH Efficacy Analysis Populations <ul><li>Randomized (n=71): randomized to treatment </li></ul><ul><li>Efficacy Evaluable (EE, n=64): had an on-study height measurement at or beyond 6 months </li></ul><ul><li>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) </li></ul><ul><li>Protocol Complete (PC, n=25): remained on-study until final height measurement </li></ul>7534.01
    39. 39. GDCH Efficacy Analyses FH=Final height; BPH=Baseline predicted height; Obs. Ht=Observed height 7535.01 Protocol Complete (n=25) Efficacy Evaluable (n=64) Final Height (n=33) Analysis Height SDS at 18 Yr (Repeated Measures) Non-protocol Specified Final Height SDS (ANCOVA) Last Obs. Ht SDS (ANCOVA) FH – BPH (cm) (t-test) Protocol Specified Sensitivity Final Height SDS (ANCOVA [BPH SDS]) Primary Population
    40. 40. GDCH Baseline Characteristics (All Randomized Population) Mean ± SD No significant differences between groups 7536.01 18 (47%) 18 (47%) 2 (5%) 14 (42%) 15 (46%) 4 (12%) Pubertal Stage (n [%]) Stage 1 Stage 2 Stage 3 4.8  1.8 4.8  2.1 Pre-treatment HV (cm/yr) -2.0  1.1 -1.5  1.5 IGF-I SDS 16.2  7.5 17.4  9.7 Peak GH (  g/L) 38 (m 29, f 9) 33 (m 26, f 7) Number -1.2  0.7 -2.3  0.8 -2.8  0.5 10.4  1.7 12.3  1.4 Placebo 12.5  1.6 Age (yr) -1.0  1.0 Target Height SDS -2.0  0.8 Predicted Height SDS -2.7  0.5 Height SDS 10.4  1.9 Bone Age (yr) Humatrope
    41. 41. GDCH Primary Efficacy Analysis ( FH Population ) : Significantly Greater Final Height SDS -2 -1 0 Placebo Humatrope n = 10 n = 22 Final Height SDS* -2.3 ± 0.2 -1.8 ± 0.1 *ANCOVA (BPH SDS) Least squares mean ± SE ( ) = 95% confidence interval 7537.02 = 4.4 yr = 0.51 SDS (0.10 - 0.92 SDS) Effect = 0.017 p* = 3.7 cm Duration
    42. 42. GDCH Secondary Efficacy Analyses (EE Population): Significantly Greater Height SDS *ANCOVA (BPH SDS) Least squares means ± SE; ( ) = 95% confidence interval ‡ Repeated Measures Analysis -2 -1 0 Placebo Humatrope n = 27 n = 35 Last Observed Height SDS* -2.4 ± 0.1 -1.9 ± 0.1 -2 -1 0 Placebo Humatrope n = 27 n = 35 Height SDS at 18 Years ‡ -2.2 ± 0.1 -1.5 ± 0.1 7538.02 = 0.52 SDS (0.22 – 0.82 SDS) Effect = 0.001 p* = 3.8 cm Treatment = 0.69 SDS (0.43 – 0.94 SDS) Effect < 0.0001 p ‡ = 5.0 cm Treatment
    43. 43. GDCH Intent-to-treat Analyses (All Randomized Population, n=71): Significantly Greater Last Observed Height SDS <ul><li>Nonparametric analyses </li></ul><ul><ul><li>Humatrope superior to placebo </li></ul></ul><ul><ul><ul><li>Rank analysis of covariance: p = 0.0024 </li></ul></ul></ul><ul><ul><ul><li>Generalized Wilcoxon-Mann-Whitney test: p = 0.0015 </li></ul></ul></ul><ul><li>Parametric analyses </li></ul><ul><ul><li>Humatrope treatment effect </li></ul></ul><ul><ul><ul><li>ANCOVA (BPH SDS): 0.40 ± 0.15 </li></ul></ul></ul><ul><ul><ul><li>p = 0.011 </li></ul></ul></ul><ul><ul><ul><li>ANOVA 0.52 ± 0.17 </li></ul></ul></ul><ul><ul><ul><li>p = 0.003 </li></ul></ul></ul><ul><li>Least Squares Mean ± SE </li></ul>7539.01
    44. 44. GDCH: Bone Age vs. Year on Study 10 12 14 16 18 0 1 2 3 4 5 Bone Age (yr) FH Population n 21 21 21 20 17 10 n 9 10 10 10 7 4 0 1 2 3 4 5 Non-FH Subgroup 13 13 10 5 1 1 17 15 15 13 5 2 0 1 2 3 4 5 EE Population Year On Study 34 34 31 25 18 11 26 25 25 23 12 6 Mean ± SE Humatrope Placebo 7540.02
    45. 45. GDCH: Increase in Height SDS vs. Year Before Last Observed Height 0.0 0.5 1.0 -6 -4 -2 0 Increase in Height SDS Mean Age 18.8 ± 0.3 yr FH Population 0.4 0.5 n 6 14 19 21 21 19 18 22 n 4 6 8 9 9 9 8 11 -6 -4 -2 0 Mean Age 15.1 ± 0.4 yr Non-FH Subgroup 0.6 3 7 10 13 13 8 15 16 17 18 -6 -4 -2 0 Mean Age 17.0 ± 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 35 4 6 10 17 24 25 25 29 0.4 0.5 0.2 0.3 0.5 0.5 Mean ± SE Humatrope Placebo 7541.02
    46. 46. GDCH (EE Population): Height SDS vs. Year on Study 0 1 2 3 4 5 Year on Study Height SDS -3.0 -2.5 -2.0 -1.5 -1.0 35 29 34 26 31 26 26 23 18 13 11 6 n n Humatrope Placebo Mean  SE 7542.02
    47. 47. GDCH Efficacy Summary <ul><li>GH Treatment Effect </li></ul><ul><li>Primary analysis: </li></ul><ul><li>Sensitivity Analyses </li></ul><ul><ul><li>EE Population: </li></ul></ul><ul><ul><ul><li>Last observed height SDS: </li></ul></ul></ul><ul><ul><ul><li>Height SDS at 18 years: </li></ul></ul></ul><ul><ul><li>All Randomized Population </li></ul></ul><ul><ul><ul><li>Last Observed Height SDS: </li></ul></ul></ul><ul><li>GH treatment regimen </li></ul><ul><li>Dose = 0.22 mg/kg/wk </li></ul><ul><li>Divided doses 3 days per week </li></ul><ul><li>0.51 SDS = 3.7 cm (1.5 in) </li></ul><ul><li>0.52 SDS = 3.8 cm </li></ul><ul><li>0.69 SDS = 5.0 cm </li></ul><ul><li>0.40 SDS = 2.9 cm </li></ul>7544.01
    48. 48. E001 Study Design: Randomized, Open-Label, Dose-Response 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 <ul><li>European open-label multicenter study (10 countries) </li></ul><ul><li>Divided doses 6 days per week </li></ul>0 12 Final Height 7545.03 (height velocity < 2.0 cm/yr)
    49. 49. E001 Analysis Populations <ul><li>Randomized (n=239 [161]): randomized to treatment </li></ul><ul><li>Two-year height velocity (n=209 [142]): completed 2 years Humatrope treatment </li></ul><ul><li>Final height (n=50 [34]): height measurement after height velocity < 2.0 cm/yr </li></ul>[ ] = n with middle dose excluded 7546.01
    50. 50. E001 Efficacy Analyses FH=Final height; BPH=Baseline predicted height; Obs. Ht=Observed height; [ ] = n with middle dose excluded 7547.01 Final Height n=50 [34] Two-year Height Velocity n=209 [142] FH – BPH (cm) (Paired t-test) Height SDS at 18 Years (Repeated Measures) Final Height SDS (ANCOVA) Last Obs. Ht SDS (ANCOVA) Secondary Increase in Ht Velocity (0-2 yr) (t-test) Primary Analysis Population
    51. 51. E001 Baseline Characteristics (All Randomized Population) Mean  SD Humatrope Dose (mg/kg/wk) 7548.01 17.0  6.2 16.8  7.5 Peak GH (  g/L) 4.3  1.1 4.3  1.1 Pre-treatment HV (cm/yr) -1.2  0.9 -1.3  0.9 Target Height SDS -2.4  1.1 -2.7  1.0 Predicted Height SDS -3.0  0.5 -3.4  0.8 Height SDS 8.0  2.1 7.4  2.6 Bone Age (yr) 10.0  2.2 9.4  2.4 Age (yr) 83 (m 59, f 24) 78 (m 49, f 29) Number 0.37 0.24
    52. 52. E001 Primary Efficacy Analysis (2-yr HV Population): Significant Dose Effect on Height Velocity 0 2 Year on Study Height Velocity (cm/yr) p = 0.5 p < 0.001 4 5 6 7 8 9 Mean  SE * t-test ( ) = 95% confidence interval 7549.01 0.24 mg/kg/wk (n=70) 0.37 mg/kg/wk (n=72) = 0.003 p* = 0.8 cm/yr (0.3 – 1.3 cm/yr) Dose Effect
    53. 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 -2 -1 0 n = 39 n = 48 Last Observed Height SDS* -2.0 ± 0.1 -1.4 ± 0.1 0.24 Humatrope Dose (mg/kg/wk) 0.37 -2 -1 0 n = 39 n = 47 Height SDS at 18 Years ‡ -1.3 ± 0.2 -0.8 ± 0.1 0.24 0.37 7550.01 = 0.51 SDS (0.15 – 0.87 SDS) Effect = 0.006 p* = 3.3 cm Dose = 0.44 SDS (0.10 – 0.78 SDS) Effect = 0.012 p ‡ = 2.8 cm Dose
    54. 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 Bone Age (yr) FH Population n 16 15 16 16 14 11 4 5 n 16 17 16 17 15 15 8 4 0 1 2 3 4 5 6 7 Non-FH Subgroup 54 51 49 40 26 11 4 5 55 50 49 39 26 9 4 3 0 1 2 3 4 5 6 7 Two Yr HV Population 69 66 65 56 40 22 8 10 71 67 65 56 41 24 12 7 Year On Study Mean ± SE 0.24 mg/kg/wk 0.37 mg/kg/wk 7552.01
    55. 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 Final Height Minus Baseline Predicted Height (cm) 5.4 ± 0.9 p* < 0.001 7.2 ± 1.7 p* = 0.001 * Paired t-test (within-group) Mean ± SE Humatrope Dose (mg/kg/wk) 7553.01 Mean treatment duration = 6.5 yr
    56. 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 Final Height Minus Baseline Predicted Height (cm) -0.7 ± 1.3 -2 0 2 4 6 8 10 2.2 ± 0.8 5.4 ± 0.9 7.2 ± 1.7 n=10 n=22 n=13 n=13 Humatrope (mg/kg/wk) 6 days per week GDCH E001 7554.02
    57. 57. E001 Efficacy Summary <ul><li>Dose Effect (0.37 vs. 0.24 mg/kg/wk) </li></ul><ul><li>Primary analysis </li></ul><ul><ul><li>Increase in 0-2 yr height velocity: 0.8 cm/yr </li></ul></ul><ul><li>Secondary analyses </li></ul><ul><ul><li>Last observed height SDS: 0.51 SDS = 3.3 cm </li></ul></ul><ul><ul><li>Height SDS at 18 years: 0.44 SDS = 2.8 cm </li></ul></ul><ul><li>Treatment Effect </li></ul><ul><li>Final Height – Baseline Predicted Height </li></ul><ul><ul><li>5.4 cm (2.1 in) at 0.24 mg/kg/wk </li></ul></ul><ul><ul><li>7.2 cm (2.8 in) at 0.37 mg/kg/wk </li></ul></ul>7555.01
    58. 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 Final Height SDS* -2.3 ± 0.2 -1.8 ± 0.1 n = 10 n = 22 -1.6 ± 0.2 -1.2 ± 0.2 n = 13 n = 13 *ANCOVA (BPH SDS) Least squares mean ± SE 3 days per week 6 days per week 3.7 cm 2.9 cm 7556.01
    59. 59. GDCH & E001: Final Height SDS for Individual Patients Mean ± SE -3 -2 -1 0 -2.3 -1.8 Final Height SDS -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 %* 10 16 50 5 2.3 0.13 Percentile
    60. 60. GDCH & E001 (FH Population): Final Height vs. Baseline Predicted Height (in) 55 60 65 70 55 60 65 70 Final Height (in) GDCH Humatrope Placebo 55 60 65 70 Baseline Predicted Height (in) E001 0.24 mg/kg/wk 0.37 mg/kg/wk 8410.02
    61. 61. Meta-analysis of Controlled Studies: GH Treatment Effect (Finkelstein et al., 2002) <ul><li>12 studies with Final Height data (1985-2000) </li></ul><ul><ul><li>4 controlled studies </li></ul></ul><ul><ul><ul><li>Zadik et al., 1992 </li></ul></ul></ul><ul><ul><ul><li>Hindmarsh and Brook, 1996 </li></ul></ul></ul><ul><ul><ul><li>Buchlis et al., 1998 </li></ul></ul></ul><ul><ul><ul><li>McCaughey et al., 1998 </li></ul></ul></ul><ul><li>Mean GH effect on adult height: 4 to 6 cm </li></ul>Mean GH Dose 0.31 mg/kg/wk 6 times per week Mean Treatment Duration 5.3 yr From Finkelstein et al.; Arch Pediatr Adolesc Med 2002 8474.01
    62. 62. GDCT: Significant GH-Treatment Effect on Final Height in Turner Syndrome <ul><li>Study Design </li></ul><ul><ul><li>Randomized, open label, untreated control </li></ul></ul><ul><ul><li>GH Regimen: 0.30 mg/kg/wk, divided doses 6 days per week </li></ul></ul><ul><li>GH Treatment Effect </li></ul><ul><ul><li>Primary Analysis </li></ul></ul><ul><ul><ul><li>t-test (p = 0.001): 3.9 cm </li></ul></ul></ul><ul><ul><li>Sensitivity Analysis </li></ul></ul><ul><ul><ul><li>ANCOVA* (p = 0.001): 5.4 cm </li></ul></ul></ul>* Incorporating effect for mid-parental height SDS Least squares mean 7560.01
    63. 63. E001 and GDCH Height SDS Gain Distribution: Similar to Turner Syndrome 0 0 7561.01 -2 0 2 4 Non-GHD Short Stature (Study GDCH) n = 22 Mean start age = 12.5 years Dose = 0.22 mg/kg/wk -2 0 2 4 Turner Syndrome (Study GDCI) Change Height SDS (Final - Baseline) n = 99 Mean start age = 10.9 years Dose = Pooled 0.27 and 0.36 mg/kg/wk -2 0 2 4 Non-GHD Short Stature (Study E001) n = 50 Mean start age = 10.3 years Dose = Pooled 0.24, 0.24/0.37 and 0.37 mg/kg/wk 0 20 40 60 20 40 60 Percent of Patients 20 40 Percent of Patients Percent of Patients 60
    64. 64. Efficacy Conclusion: GH Increases Final Height in Non-GHD Short Stature <ul><li>Consistent efficacy </li></ul><ul><ul><li>pivotal placebo-controlled study: </li></ul></ul><ul><ul><li>supportive dose-response study: </li></ul></ul><ul><ul><li>supportive data from literature: </li></ul></ul><ul><li>Dose-response (0.37 vs. 0.24) </li></ul><ul><ul><li>greater height velocity increase: </li></ul></ul><ul><ul><li>greater overall height gain: </li></ul></ul><ul><li>Similar efficacy </li></ul><ul><ul><li>non-GHD short stature: </li></ul></ul><ul><ul><li>Turner syndrome: </li></ul></ul><ul><li> 3.7 cm </li></ul><ul><li>5.4 to 7.2 cm </li></ul><ul><li>4 to 6 cm </li></ul><ul><li>0.8 cm/yr </li></ul><ul><li>2.8 to 3.3 cm </li></ul><ul><li>3.7 to 7.2 cm (1.5 to 2.8 in) </li></ul><ul><li>3.9 to 5.4 cm (1.5 to 2.1 in) </li></ul>7562.01
    65. 65. What Is the Clinical Relevance of the Efficacy? <ul><li>Most patients reached normal height range during childhood </li></ul><ul><li>Similar final height benefit to Turner syndrome </li></ul><ul><li>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 </li></ul><ul><li>94% of final heights in higher dose group were in the normal range </li></ul>8407.01
    66. 66. Safety Charmian Quigley, MBBS Senior Clinical Research Physician Endocrinology Eli Lilly and Company 7563.01
    67. 67. Safety Questions <ul><li>Is somatropin safe in pediatric patients? </li></ul><ul><li>Are there any new significant adverse events or safety concerns in this patient population? </li></ul><ul><li>I s there an increased frequency of the adverse events currently described in the product label in this population?   </li></ul>7564.01
    68. 68. Somatropin Safety <ul><li>Somatropin has 16-year safety history </li></ul><ul><li>Estimated 200,000 patients exposed world-wide, </li></ul><ul><li>> 500,000 patient-years </li></ul><ul><li>Well accepted safety profile </li></ul><ul><ul><li>5 currently approved pediatric conditions </li></ul></ul><ul><ul><li>Doses up to 0.7 mg/kg/wk </li></ul></ul><ul><li>A number of uncommon, well-characterized events are associated with GH exposure </li></ul><ul><li>Key areas of focus </li></ul><ul><ul><li>Carbohydrate metabolism </li></ul></ul><ul><ul><li>Neoplasia </li></ul></ul><ul><li>Comprehensive literature addresses safety </li></ul><ul><li>GH Research Society consensus statement* </li></ul>7565.01 *J Clin Endocrinol Metab 2001; 86: 1868
    69. 69. Equivalent Exposure in Registration Studies Included in Safety Comparison 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 0.24 0.37 0.27 0.36 0.22 0.30 0.18  0.24 Dose (mg/kg/wk) E001 GDCH GDCI GDCT GDAB Study 1232 333 GHD 1219 (136) 74 TS 229 TS 239 NGHDSS 1212 (68) 37 NGHDSS Patient-years N Condition
    70. 70. Safety Analyses <ul><li>Deaths </li></ul><ul><li>Discontinuations due to adverse events (AEs) </li></ul><ul><li>Serious adverse events (SAEs) </li></ul><ul><ul><li>Neoplasia </li></ul></ul><ul><li>Treatment emergent adverse events (TEAEs) </li></ul><ul><li>Adverse events referenced in Humatrope label </li></ul><ul><li>Laboratory data </li></ul><ul><ul><li>Carbohydrate metabolism </li></ul></ul><ul><ul><li>Insulin-like growth factor I (IGF-I) </li></ul></ul>7568.01
    71. 71. Patient Deaths During and After Study 7570.01 NA 1 NA 0 239 E001 NGHDSS 0 0 0 0 68 GDCH NGHDSS 0 0 0 0 230 GDCI TS 0 0 1 0 136 GDCT TS NA 2 NA 1 333 GDAB GHD Control Humatrope Control Humatrope N Study Condition After Study During Study
    72. 72. Similar Rates of Discontinuations Due to Adverse Events N = Patients receiving Humatrope 7571.01 n (%) patients discontinuing 3 (1) 239 E001 NGHDSS 1 (3) 37 GDCH NGHDSS 4 (2) 230 GDCI TS 2 (3) 74 GDCT TS 7 (2) 333 GDAB GHD N Study Condition
    73. 73. Serious Adverse Events N= Patients receiving Humatrope 7572.01 31 (13) 239 E001 NGHDSS 5 (14) 37 GDCH NGHDSS 41 (18) 230 GDCI TS 20 (27) 74 GDCT TS 90 (27) 333 GDAB GHD n (%) patients with SAE N Study Condition
    74. 74. Neoplasia <ul><li>GH Deficiency (333 Humatrope-treated patients) </li></ul><ul><li>6 patients </li></ul><ul><ul><li>1 craniopharyngioma (new diagnosis) </li></ul></ul><ul><ul><li>1 papillary thyroid carcinoma (new diagnosis) </li></ul></ul><ul><ul><li>4 intracranial tumors (recurrence/progression) </li></ul></ul><ul><li>Turner Syndrome (304 Humatrope-treated patients) </li></ul><ul><li>0 patients </li></ul><ul><li>Non-GHD Short Stature (276 Humatrope-treated patients) </li></ul><ul><li>2 patients </li></ul><ul><ul><li>Hodgkin disease (GDCH) </li></ul></ul><ul><ul><li>Desmoplastic small round cell tumor (E001) </li></ul></ul>7573.01
    75. 75. Hodgkin Disease <ul><li>Hodgkin disease stage 3B diagnosed in 11-year old boy who </li></ul><ul><li>had received Humatrope for 19 weeks (GDCH) </li></ul><ul><li>2 months pre-study: </li></ul><ul><ul><li>widened mediastinum on chest X-ray (“thymus remnant”) </li></ul></ul><ul><li>Study entry: </li></ul><ul><ul><li>high normal erythrocyte sedimentation rate (ESR) 32 mm/hr (N: 1 – 39) </li></ul></ul><ul><ul><li>elevated lactic dehydrogenase (LDH) 248 u/L (N: 113 – 226) </li></ul></ul><ul><li>12 weeks: </li></ul><ul><ul><li>abnormal ESR (58 mm/hr) </li></ul></ul><ul><ul><li>elevated LDH (257 u/L) </li></ul></ul><ul><li>External oncologist (Dr Terry Vik, Riley Hospital for Children): Patient had subclinical disease at study entry </li></ul>7574.01
    76. 76. Desmoplastic Small Round Cell Tumor <ul><li>12-year old boy in 0.24 mg/kg/wk dose group in E001 </li></ul><ul><ul><li>Diagnosed after 6.4 years on study; died approx. 4 years later </li></ul></ul><ul><ul><li>Tumor karyotype: 46,XY,t(11;22)(p13;q12) - hallmark of this tumor </li></ul></ul><ul><ul><li>Translocation produces an oncogenic fusion gene: 5’ portion of Ewing sarcoma gene and 3’ portion of Wilms tumor suppressor gene </li></ul></ul><ul><li>Translocations are not associated with GH treatment </li></ul><ul><li>No other case of this tumor in a GH-treated patient (Lilly pharmacovigilance, literature) </li></ul><ul><li>External expert in the biology of desmoplastic small round cell tumors believes this tumor was unrelated to GH exposure </li></ul>7575.02
    77. 77. Treatment Emergent Adverse Events (TEAEs) <ul><li>Majority of TEAEs = common childhood illnesses </li></ul><ul><li>Some differences in pattern of TEAEs between conditions </li></ul><ul><li>No significant differences in rates of TEAEs for </li></ul><ul><ul><li>Humatrope vs. Placebo (GDCH) </li></ul></ul><ul><ul><li>0.24 mg/kg/wk vs. 0.37 mg/kg/wk (E001) </li></ul></ul><ul><li>No new adverse events in non-GHD short stature population </li></ul>7576.01
    78. 78. Comparison of Adverse Events in Current Humatrope Label in Three Patient Populations 7578.01 8 (3) 1 (0.3) 5 (2) Scoliosis 1 (0.4) 15 (5) 1 (0.3) Hypertension 2 (0.7) 1 (0.3) 1 (0.3) Carbohydrate metabolism 2 (0.7) 50 (16) 78 (23) Hypothyroidism 22 (8) 133 (44) 95 (29) Otitis media 0 (0.0) 304 TS 1 (0.4) 276 NGHDSS 1 (0.3) 333 GHD Slipped capital femoral epiphysis Number of Humatrope treated n (%) with event
    79. 79. E001: No Humatrope Dose Effect on Adverse Events <ul><li>Serious adverse events: </li></ul><ul><ul><li>0.24 mg/kg/wk = 11/78 (14%) </li></ul></ul><ul><ul><li>0.24  0.37 mg/kg/wk = 4/78 (5%) </li></ul></ul><ul><ul><li>0.37 mg/kg/wk = 16/83 (19%) </li></ul></ul><ul><li>41 treatment emergent adverse events (TEAEs) occurred in more than a single patient </li></ul><ul><ul><li>9 events most frequent in 0.24 mg/kg/wk group </li></ul></ul><ul><ul><li>18 events most frequent in 0.24  0.37 mg/kg/wk group </li></ul></ul><ul><ul><li>11 events most frequent in 0.37 mg/kg/wk group </li></ul></ul>7579.02
    80. 80. Literature on Somatropin Safety <ul><li>Kabi International Growth Study (Wilton P. 1999) </li></ul><ul><li>25,977 patients </li></ul><ul><li>Approximately 62,400 patient-years exposure </li></ul><ul><li>Events reported as AE/1000 treatment-years </li></ul><ul><li>All conditions 130 </li></ul><ul><ul><li>Idiopathic GH deficiency 115 </li></ul></ul><ul><ul><li>Chronic renal insufficiency 277 </li></ul></ul><ul><ul><li>Turner syndrome 148 </li></ul></ul><ul><ul><li>Small for gestational age 126 </li></ul></ul><ul><ul><li>Idiopathic short stature 89 </li></ul></ul>7580.01
    81. 81. Literature on Somatropin Safety in Non-GHD Conditions: KIGS *Event rates are reported as AE/100,000 treatment-years ( Wilton P. 1999) 7581.01 Idiopathic Short Stature Small for Gestation Chronic Renal Ins. Turner Syndrome 3493 590 694 3019 Patient Number 25 0 102 39 Slipped capital femoral epiphysis 25 253 102 272 Scoliosis 0 0 204 78 Intracranial hypertension 317 316 306 349 Headache/migraine 13 0 102 26 Diabetes type 2 152 316 102 155 Convulsions 101 63 102 129 Arthralgia
    82. 82. Literature on Somatropin Safety: NCGS * Event rates are reported as % of total events ( Maneatis et al. 2000) 7582.01 2.2 15.6 2.2 11.1 Extracranial malignancy 0.0 13.2 2.6 31.6 Slipped femoral epiphysis Idiopathic Short Stature Turner Syndrome Chronic Renal Ins. IdiopathicGHD 5671 17.1 3416 10.3 663 2.0 13861 41.8 Patient Number % of total enrollment 9.0 17.2 0.0 27.0 Scoliosis 13.6 15.3 8.5 25.4 Diabetes 2.6 15.4 10.3 30.8 Intracranial hypertension 4.0 0.0 4.0 16.0 Leukemia 3.4 4.1 12.2 12.8 Deaths 4.6 7.5 7.3 18.8 All SAEs 10.1 13.0 4.8 28.5 All AEs
    83. 83. <ul><li>GDCH </li></ul><ul><li>Fasting glucose </li></ul><ul><li>Fasting insulin </li></ul><ul><li>QUICKI </li></ul><ul><li>Hemoglobin A 1c </li></ul><ul><li>Insulin-like growth factor-I </li></ul>Laboratory Analyses: Non-GHD Short Stature <ul><li>E001 </li></ul><ul><li>Fasting glucose </li></ul><ul><li>Glycosylated hemoglobin </li></ul>7583.01
    84. 84. GDCH: Fasting Glucose 7586.02 3.9 5.0 6.1 70 90 110 Baseline Last On Study Baseline Last On Study Fasting Glucose (mg/dL) Fasting Glucose (mmol/L) 85.5 89.7 88.4 89.6 Placebo n = 29 Humatrope n = 36 Mean ± SE
    85. 85. E001: Fasting Glucose No reference range shown as this varied among laboratories 7587.01 30 60 90 120 150 2 3 5 7 8 Baseline Endpoint Baseline Endpoint Fasting Glucose (mg/dL) Fasting Glucose (mmol/L) 81.9 81.8 81.2 82.9 0.24 mg/kg/wk n = 59 0.37 mg/kg/wk n = 58 Mean ± SE
    86. 86. GDCH: Fasting Insulin 0 20 40 0 144 287 Baseline Last On Study Baseline Last On Study Fasting Insulin (mU/mL) Fasting Insulin (pmol/L) 12.68 12.40 11.82 13.20 Placebo n = 28 Humatrope n = 33 Mean ± SE 8222.02
    87. 87. GDCH: Quantitative Insulin Sensitivity Check Index (QUICKI) 0.25 0.30 0.35 0.40 0.34 0.34 QUICKI Baseline Last on Study Placebo n = 28 0.35 0.33 Baseline Last on Study Humatrope n = 33 QUICKI = 1/(log[Fasting Insulin ( µ U/ml) + log(Fasting Glucose (mg/dl)]) Mean ± SE Mean ± SE 7591.02
    88. 88. GDCH: IGF-I Across Study Duration 0 1 2 3 4 5 Year on Study Mean IGF-I SDS -2 -1 0 1 2 p 0.17 0.21 0.01 0.17 0.06 0.04 8408.02 Mean  SE Humatrope (H) Placebo (P) P 35 29 34 25 30 25 26 19 16 11 11 6 H
    89. 89. Summary: Safety of Humatrope in Non-GHD Short Stature <ul><li>Single post-study death due to an abdominal tumor, believed unrelated to Humatrope exposure </li></ul><ul><li>No difference from GH deficiency or Turner syndrome for </li></ul><ul><ul><li>Serious adverse events </li></ul></ul><ul><ul><li>Discontinuations due to adverse events </li></ul></ul><ul><ul><li>Treatment emergent adverse events </li></ul></ul><ul><li>No significant differences in adverse event rates between </li></ul><ul><ul><li>Humatrope and placebo (GDCH) </li></ul></ul><ul><ul><li>0.24 and 0.37 mg/kg/wk (E001) </li></ul></ul><ul><li>Laboratory analyses </li></ul><ul><ul><li>No Humatrope effect and no dose effect on fasting glucose or HbA1c </li></ul></ul><ul><ul><li>No significant Humatrope effect on insulin sensitivity </li></ul></ul><ul><ul><li>IGF-I remained in normal range </li></ul></ul>7596.01
    90. 90. Conclusions: Safety Profile Similar to Approved Indications <ul><li>Somatropin is safe in pediatric patients: well characterized safety profile with over 16 years of accumulated experience </li></ul><ul><li>  </li></ul><ul><li>No new significant adverse events or safety concerns in this patient population </li></ul><ul><li>No increase in frequency of the adverse events currently described in the product label </li></ul>7597.01
    91. 91. Risk Management Program 7609.01
    92. 92. Issues and Questions Regarding GH Treatment for Non-GHD Short Stature <ul><li>How will potential risks be managed and safety be monitored? </li></ul><ul><li>Will this new indication obviate the need for diagnostic evaluation in children with growth disorders? </li></ul><ul><li>Will this new indication “open the floodgates” to inappropriate use? </li></ul><ul><li>Are there ethical issues regarding GH treatment of non-GHD short stature? </li></ul><ul><li>Is it appropriate to treat patients whose short stature is not clearly associated with a defined “disease”? </li></ul><ul><li>Should psychological or quality of life benefits be required outcomes of GH treatment? </li></ul><ul><li>What is the clinical relevance of the efficacy? </li></ul>8376.02
    93. 93. Risk Management Program <ul><li>Appropriate labeling and pharmacovigilance </li></ul><ul><li>Restrictive labeling </li></ul><ul><li>Physician education </li></ul><ul><li>Limited marketing </li></ul><ul><li>Controlled distribution process </li></ul><ul><li>Post-marketing research program </li></ul>7611.01
    94. 94. Risk Management Program: Restrictive Labeling <ul><li>“Humatrope is indicated for the long-term </li></ul><ul><li>treatment of non-growth hormone-deficient short </li></ul><ul><li>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 ” </li></ul>7612.01
    95. 95. Why Was the Height Cut-Off of –2.25 SDS Chosen for the Label Indication? <ul><li>Follows FDA recommendation to provide appropriate guidelines to avoid over-prescribing </li></ul><ul><li>Reflects pivotal trial inclusion criterion </li></ul><ul><li>To limit access </li></ul><ul><ul><li>Excludes patients with height in normal range </li></ul></ul><ul><ul><li>Excludes almost half of patients with short stature </li></ul></ul><ul><ul><li>Strikes balance between treatment restriction and access </li></ul></ul>7617.01
    96. 96. No Additional Label Restrictions Required <ul><li>Only GH label that contains a height restriction </li></ul><ul><li>Excludes 46% of children with non-GHD short stature </li></ul><ul><li>Factors not appropriate as label restrictions </li></ul><ul><ul><li>Height velocity </li></ul></ul><ul><ul><li>Chronological age </li></ul></ul><ul><ul><li>Bone age </li></ul></ul><ul><ul><li>IGF-I </li></ul></ul><ul><ul><li>Target height (genetic height potential) </li></ul></ul><ul><li>Pediatric endocrinologists integrate these factors in making treatment decisions </li></ul>8370.02
    97. 97. Risk Management Program: Physician Education <ul><li>Scope </li></ul><ul><li>Label restrictions </li></ul><ul><li>Accurate diagnosis </li></ul><ul><li>Benefit-risk </li></ul><ul><li>Methods </li></ul><ul><li>Physician to physician educational programs </li></ul><ul><li>Continuing medical education </li></ul>7613.01
    98. 98. Risk Management Program: Limited Marketing <ul><li>Comprehensive training of sales specialists </li></ul><ul><ul><li>Patient characteristics </li></ul></ul><ul><ul><li>Diagnostic process </li></ul></ul><ul><ul><li>Benefit-risk </li></ul></ul><ul><li>Sales specialists will call only on pediatric endocrinologists for this indication </li></ul><ul><li>No direct-to-consumer advertising </li></ul>7614.01
    99. 99. Risk Management Program: Controlled Distribution Process <ul><li>Statement of Medical Necessity required for new patient diagnoses </li></ul><ul><li>Humatrope shipped only through Lilly-approved closed specialty pharmacies </li></ul><ul><li>Lilly monitors prescribing behavior </li></ul><ul><ul><li>Investigation of potential problems </li></ul></ul><ul><ul><li>Corrective action includes denial of access to Humatrope </li></ul></ul><ul><li>Complete details have been provided to FDA </li></ul>7104.01
    100. 100. Risk Management Program: Safety Monitoring <ul><li>Pharmacovigilance </li></ul><ul><ul><li>Screen for adverse events that may be associated with GH treatment </li></ul></ul><ul><ul><li>Evaluation for potential safety concerns </li></ul></ul><ul><ul><li>Communication with world-wide regulatory agencies </li></ul></ul><ul><li>Observational post-marketing research program </li></ul><ul><ul><li>Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS) </li></ul></ul>7616.01
    101. 101. How Will Safety be Monitored? <ul><li>Careful monitoring or follow-up is recommended for: </li></ul><ul><ul><li>Pre-existing scoliosis </li></ul></ul><ul><ul><li>Pre-existing skin lesion </li></ul></ul><ul><ul><li>Pre-existing tumor </li></ul></ul><ul><ul><li>Hypothyroidism </li></ul></ul><ul><ul><li>Insulin resistance and decreased glucose tolerance </li></ul></ul><ul><ul><li>Intracranial hypertension </li></ul></ul><ul><ul><li>Otitis media and other ear disorder </li></ul></ul><ul><ul><li>Slipped capital femoral epiphysis </li></ul></ul><ul><li>These conditions w ill continue to be monitored in post-marketing research </li></ul><ul><li>No further precautions are necessary </li></ul>7607.01
    102. 102. Risk Management Program : Observational Post-Marketing Research <ul><li>Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS) </li></ul><ul><ul><li>30 countries (> 400 study sites) </li></ul></ul><ul><ul><li>Currently 140 US study sites </li></ul></ul><ul><ul><li>Additional sites enrolled on progressive basis </li></ul></ul><ul><li>All Humatrope-treated pediatric patients are eligible to enroll </li></ul><ul><li>Voluntarily untreated controls in 2 sub-studies </li></ul>7105.01
    103. 103. Risk Management Program: GeNeSIS Details <ul><li>Detailed history, diagnostic and efficacy information </li></ul><ul><ul><li>Growth measurements, pubertal status, bone age, etc </li></ul></ul><ul><ul><li>Family history </li></ul></ul><ul><ul><li>Response to Humatrope </li></ul></ul><ul><li>Comprehensive safety data </li></ul><ul><ul><li>Spontaneous adverse events </li></ul></ul><ul><ul><li>Protocol identified adverse events </li></ul></ul><ul><ul><li>Neoplasia sub-study </li></ul></ul><ul><li>Laboratory information </li></ul><ul><ul><li>IGF-I and IGFBP-3 performed as a service for all patients </li></ul></ul><ul><ul><li>Other laboratory tests as collected by investigators </li></ul></ul><ul><ul><ul><li>Carbohydrate metabolism </li></ul></ul></ul><ul><ul><ul><li>Thyroid function </li></ul></ul></ul><ul><ul><ul><li>Other </li></ul></ul></ul>8288.01
    104. 104. Risk Management Program: Reporting of Data <ul><li>GeNeSIS efficacy and safety data analyzed and reported annually to investigators </li></ul><ul><li>Safety data </li></ul><ul><ul><li>Annual and ad hoc reports to regulatory agencies </li></ul></ul><ul><ul><li>Annual reports from all GH manufacturers to LWPES Drug and Therapeutics Committee </li></ul></ul><ul><li>Monitoring for safety concerns </li></ul><ul><ul><li>GeNeSIS data </li></ul></ul><ul><ul><li>Spontaneous case reports </li></ul></ul><ul><ul><li>Literature reports </li></ul></ul>8289.01
    105. 105. Will New Indication Obviate the Need for Diagnostic Evaluation in Children with Growth Disorders? <ul><li>Pediatric endocrinologists are trained to evaluate the causes of growth failure </li></ul><ul><li>Peer professional societies (e.g. LWPES, AAP) provide guidance </li></ul><ul><li>Insurance companies will require work-up and statement of medical necessity </li></ul><ul><li>Label will emphasize need for thorough work-up </li></ul><ul><li>Lilly educational programs will reinforce this need </li></ul>7618.01
    106. 106. Will Approval “Open the Floodgates” for Inappropriate Treatment? <ul><li>Height threshold of –2.25 SDS will exclude </li></ul><ul><ul><li>All children in the normal range for height </li></ul></ul><ul><ul><li>46% of children with height < –2.0 SDS </li></ul></ul><ul><li>Pediatric endocrinologists are gatekeepers </li></ul><ul><ul><li>Observational studies show conservative GH prescribing </li></ul></ul><ul><li>Peer organizations (LWPES/AAP) will update guidelines </li></ul><ul><li>Insurance companies </li></ul><ul><ul><li>Will impose controls for financial reasons </li></ul></ul><ul><ul><li>Require a statement of medical necessity </li></ul></ul><ul><li>Lilly has a controlled distribution process </li></ul><ul><li>Lilly will promote only to pediatric endocrinologists </li></ul><ul><ul><li>No direct-to-consumer marketing </li></ul></ul>7620.01
    107. 107. Will Approval “Open the Floodgates” for Inappropriate Treatment (cont’d)? <ul><li>Many required decisions will limit GH use </li></ul><ul><ul><li>Decision to consult primary physician </li></ul></ul><ul><ul><li>Decision to refer to pediatric endocrinologist </li></ul></ul><ul><ul><li>Decision to perform diagnostic workup </li></ul></ul><ul><ul><li>Decision to recommend GH therapy to family </li></ul></ul><ul><ul><li>Decision of family to accept therapy </li></ul></ul><ul><ul><li>Decision of insurance company to reimburse for therapy </li></ul></ul>7619.01
    108. 108. How Many Patients with Non-GHD Short Stature Will be Treated? <ul><li>Prevalence of non-GHD short stature ≤ -2.25 SDS is approximately 400,000 children between 7 and 15 years of age </li></ul><ul><li>At 5 years after approval, a US total of 30,000-40,000 patients will be on GH treatment due to* </li></ul><ul><ul><li>Selective referral by primary care physician </li></ul></ul><ul><ul><li>Conservative treatment recommendation by pediatric endocrinologist </li></ul></ul><ul><ul><li>Limited insurer reimbursement </li></ul></ul>* Model based on Finkelstein et al., 1998 8426.02
    109. 109. Risk Management Conclusions <ul><li>Lilly is committed to appropriate use of Humatrope </li></ul><ul><li>A multi-level program will manage potential risks </li></ul>7621.01
    110. 110. Benefit – Risk Assessment 7599.01
    111. 111. Issues and Questions Regarding GH Treatment for Non-GHD Short Stature <ul><li>Will this new indication obviate the need for diagnostic evaluation in children with growth disorders? </li></ul><ul><li>Will this new indication “open the floodgates” to inappropriate use? </li></ul><ul><li>How will safety be monitored and potential risks be managed? </li></ul><ul><li>Are there ethical issues regarding GH treatment of non-GHD short stature? </li></ul><ul><li>Is it appropriate to treat patients whose short stature is not clearly associated with a defined “disease”? </li></ul><ul><li>Should psychological or quality of life benefits be required outcomes of GH treatment? </li></ul><ul><li>What is the clinical relevance of the efficacy? </li></ul>8377.02
    112. 112. Are There Ethical Issues Regarding GH Treatment of Non-GHD Short Stature? <ul><li>Social justice related to access to therapy? </li></ul><ul><ul><li>Not unique to this indication or GH </li></ul></ul><ul><ul><li>Approved indication would provide more equitable access </li></ul></ul><ul><li>Resource allocation? </li></ul><ul><ul><li>GH accounts for a very small proportion of overall health care budget (< 0.05%) </li></ul></ul><ul><li>Treatment effect vs. cost/discomfort? </li></ul><ul><ul><li>Accepted for 4 other non-GHD growth disorders </li></ul></ul><ul><ul><li>Similar for non-GHD short stature </li></ul></ul>8374.01
    113. 113. Are There Ethical Issues Regarding GH Treatment of Non-GHD Short Stature (cont’d)? <ul><li>Difficulty in differentiating between “normality” and “abnormality” </li></ul><ul><ul><li>Not unique to this indication or GH </li></ul></ul><ul><ul><li>Objective criterion proposed for this indication </li></ul></ul><ul><ul><li>Pediatric endocrinologists weigh many factors in selecting appropriate patients for treatment </li></ul></ul><ul><li>Potential for GH to be used as “augmentation” therapy </li></ul><ul><ul><li>This potential has existed since GH was first marketed </li></ul></ul><ul><ul><li>Pediatric endocrinologists do not support “augmentation” of height in individuals with normal stature </li></ul></ul><ul><ul><li>Label restriction targets children with height SDS ≤ -2.25, thereby excluding those within normal height range </li></ul></ul><ul><ul><li>Risk management program addresses this issue </li></ul></ul>8375.03
    114. 114. Who Should Address Potential Ethical Issues Regarding GH Treatment of Non-GHD Short Stature? <ul><li>Assuming that the sponsor: </li></ul><ul><ul><li>Establishes efficacy, safety, and positive benefit-risk </li></ul></ul><ul><ul><li>Provides an effective risk management program </li></ul></ul><ul><ul><li>Satisfies FDA requirements sufficient for approval </li></ul></ul><ul><li>Pediatric endocrinologists and families are the most appropriate groups to assess ethical issues </li></ul><ul><li>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 </li></ul>8475.01
    115. 115. Is It Appropriate to Treat Patients Whose Short Stature Is Not Clearly Associated with a Defined “Disease”? <ul><li>Many conditions that deserve and receive treatment may not be accepted as “diseases”: </li></ul><ul><ul><li>Enuresis, alopecia, hirsutism, insomnia, social phobia, obesity </li></ul></ul><ul><li>GH treatment (and label indications) for other growth disorders treats the growth failure or short stature , not the underlying condition or “disease” </li></ul><ul><ul><li>e.g. GH has no impact on any feature of chronic renal insufficiency or Turner syndrome, other than growth </li></ul></ul><ul><li>Growth failure in patients with non-GHD short stature is equivalent to that in other growth disorders </li></ul>7601.01
    116. 116. Should Psychological or Quality of Life Benefits Be Required Outcomes of GH Treatment? <ul><li>Not demonstrated for GHD or other growth disorders </li></ul><ul><li>Not required for GH approval for any other growth disorders </li></ul><ul><li>1987 Endocrinologic and Metabolic Drugs Advisory Committee did not specify other benefits as required outcomes </li></ul>7605.02
    117. 117. What Is the Clinical Relevance of the Efficacy? <ul><li>Most patients reached normal height range during childhood </li></ul><ul><li>Similar growth improvement to other indications; similar final height benefit to Turner syndrome </li></ul><ul><li>82% of final height patients in higher dose group gained at least 1 SDS in height </li></ul><ul><li>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 </li></ul><ul><li>94% of final heights in higher dose group were in the normal range </li></ul>7604.01
    118. 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) 8287.01 7 – 8”
    119. 119. Potential Disadvantages of Short Stature <ul><li>Childhood </li></ul><ul><ul><li>Juvenilization </li></ul></ul><ul><ul><li>Teasing </li></ul></ul><ul><ul><li>Bullying </li></ul></ul><ul><ul><li>Exclusion </li></ul></ul><ul><ul><li>Loss of independence/overprotection </li></ul></ul><ul><li>Adulthood </li></ul><ul><ul><li>Social isolation/reduced marriage rate </li></ul></ul><ul><ul><li>Perception of lower competence </li></ul></ul><ul><ul><li>Height limits for certain jobs </li></ul></ul><ul><ul><li>Impact on daily living </li></ul></ul><ul><ul><ul><li>Car safety </li></ul></ul></ul><ul><ul><ul><li>Physical challenges in home/workplace </li></ul></ul></ul>* Insurance Institute for Highway Safety 8476.02 * 10”
    120. 120. Benefit – Risk Assessment <ul><li>Humatrope is effective and safe for the treatment of non-GHD short stature </li></ul><ul><li>Dosage of 0.37 mg/kg/wk confers greater benefit without evidence of greater risk </li></ul><ul><li>Benefit-risk profile of Humatrope in non-GHD short stature is favorable and similar to other indications. </li></ul>7608.01
    121. 121. Reasons to Recommend Approval of Humatrope for Non-GHD Short Stature <ul><li>Patients are as short and deserving of treatment as those with current indications </li></ul><ul><li>1987 Endocrinologic and Metabolic Drugs Advisory Committee recommended placebo-controlled study to final height </li></ul><ul><li>Pivotal study used recommended design </li></ul><ul><li>Pivotal study demonstrates unequivocal efficacy </li></ul><ul><li>Supportive study: greater benefit at higher dose </li></ul><ul><li>Consistent efficacy in published and Lilly studies </li></ul><ul><li>Efficacy is clinically relevant and similar to other conditions </li></ul><ul><li>Safety is similar to current indications </li></ul>Benefit-risk balance justifies approval 8292.02
    122. 122. Concluding Statements Margaret MacGillivray, MD Professor of Pediatrics, Emeritus University of Buffalo Pediatric Endocrine Specialist School of Medicine & Biomedical Sciences Children’s Hospital Buffalo 7622.01
    123. 123. Growth Hormone – The Past <ul><li>1985 </li></ul><ul><ul><li>FDA approved recombinant GH for the treatment of growth failure in children with GHD </li></ul></ul><ul><ul><ul><li>without placebo-controlled study </li></ul></ul></ul><ul><ul><ul><li>in absence of long-term height data </li></ul></ul></ul><ul><ul><li>FDA mandated post-marketing surveillance </li></ul></ul><ul><ul><ul><li>few other drugs have received such close scrutiny </li></ul></ul></ul><ul><li>1996 </li></ul><ul><ul><li>FDA approved recombinant GH for the treatment of short stature associated with Turner syndrome </li></ul></ul><ul><ul><ul><li>a non-GHD condition </li></ul></ul></ul><ul><ul><ul><li>the first condition for which final height data were provided </li></ul></ul></ul>7623.01
    124. 124. Growth Hormone – The Present <ul><li>GH is approved treatment for the growth failure or short stature associated with 3 additional non-GHD conditions : </li></ul><ul><ul><li>Chronic renal insufficiency </li></ul></ul><ul><ul><li>Prader-Willi syndrome </li></ul></ul><ul><ul><li>Children born small for gestational age </li></ul></ul><ul><li>In granting these approvals </li></ul><ul><ul><li>GH secretion status was not considered </li></ul></ul><ul><ul><li>No long-term outcome data were required </li></ul></ul><ul><ul><li>Placebo-controlled data were not required </li></ul></ul>7624.01
    125. 125. Challenges to Use of Growth Hormone for Non-GHD Short Stature <ul><li>No psychological decompensation </li></ul><ul><ul><li>Psychological problems not required for GH treatment in GHD or other non-GHD conditions </li></ul></ul><ul><li>They are healthy children with “normal” GH secretion </li></ul><ul><ul><li>GH stimulation tests are not gold standard and don’t predict an individual child’s response to therapy </li></ul></ul><ul><ul><li>Patients don’t spontaneously correct their height </li></ul></ul><ul><ul><ul><li>Lilly’s placebo data and other observational data show that most end up as short adults </li></ul></ul></ul>7625.02
    126. 126. Conclusions <ul><li>Unequivocal efficacy and safety data in non-GHD children with significant growth failure have been presented </li></ul><ul><ul><li>Double-blind trial </li></ul></ul><ul><ul><li>Dose-response study </li></ul></ul><ul><ul><li>Meta-analysis </li></ul></ul><ul><li>Evidence from NIH study is particularly meaningful </li></ul><ul><ul><li>Positive results despite sub-optimal treatment regimen </li></ul></ul><ul><li>Families have sought treatment for their children’s growth failure for decades </li></ul><ul><li>GH treatment could provide patients with opportunity to achieve height within the normal range </li></ul>7626.02
    127. 127. Recommendation <ul><li>Humatrope should be approved for treatment of non-GHD short stature </li></ul>7627.01
    128. 129. Self-image and Behavior Results-GDCH Judith Ross, M.D. Professor, Department of Pediatrics Thomas Jefferson University 8453.01
    129. 130. Questionnaires <ul><li>Self Perception Profile (SPP, 36 item) </li></ul><ul><li>CHILD REPORT </li></ul><ul><ul><li>Assesses domain-specific judgment of competence and perception of worth </li></ul></ul><ul><li>Child Behavior Checklist (CBCL,118 items) </li></ul><ul><li>PARENTAL REPORT </li></ul><ul><ul><li>Assesses behavior problems and social competencies </li></ul></ul>8454.01
    130. 131. Protocol <ul><li>Questionnaires distributed to child and parent at baseline and yearly </li></ul><ul><li>Statistics: </li></ul><ul><li>T-tests, year by year across treatment groups </li></ul>8455.01
    131. 132. Results <ul><li>SPP </li></ul><ul><li>Normal at baseline </li></ul><ul><li>CBCL </li></ul><ul><li>Normal at baseline </li></ul>8456.01
    132. 133. Baseline Results (CBCL T score, X ± SD): Summary Scores 8457.01 51 ± 11 52 ± 12 Internalize 49 ± 11 49 ± 9 Externalize 52 ± 11 51 ± 11 Behavior Total 22 29 Patients Number Humatrope Placebo
    133. 134. Treatment Results <ul><li>SPP (Child) </li></ul><ul><li>No difference between the Humatrope- and placebo-treated groups during the 4-year treatment interval </li></ul><ul><li>CBCL (Parent) </li></ul><ul><li>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. </li></ul>8458.01
    134. 135. Results <ul><li>CBCL Behavior Total subscale </li></ul><ul><li>Summary score of problem behaviors including social problems, anxiety, depression, somatic complaints etc. </li></ul><ul><li>T score, mean is 50, 1 SD = 10 </li></ul><ul><li>Higher score indicates more problem behaviors </li></ul>8459.01
    135. 136. Problem Behavioral Total 0 1 2 4 Year on Study Change in Score -10 0 10 20 H P 17 9 23 19 12 9 9 3 p 0.71 0.31 0.07 0.03 Mean  SE Humatrope (H) Placebo (P) 8460.03 3
    136. 137. Results <ul><li>CBCL Behavior Total subscale </li></ul><ul><li>Summary score of problem behaviors including social problems, anxiety, depression, somatic complaints etc. </li></ul><ul><li>CBCL Externalizing subscale: </li></ul><ul><li>Summary score of problem behaviors (Delinquent, Aggressive subscales)-includes “acting out” and aggressive behaviors </li></ul>8461.01
    137. 138. External Behavior Total 0 1 2 3 4 Year on Study Change in Score -10 -5 0 5 10 15 p 0.72 0.61 0.04 0.02 H P 17 9 23 19 12 9 9 3 Mean  SE Humatrope (H) Placebo (P) 8462.02
    138. 139. Results <ul><li>CBCL Behavior Total subscale </li></ul><ul><li>Summary score of problem behaviors including social problems, anxiety, depression, somatic complaints etc. </li></ul><ul><li>CBCL Externalizing subscale </li></ul><ul><li>Summary score of problem behaviors (Delinquent, Aggressive subscales)-includes “acting out” and aggressive behaviors. </li></ul><ul><li>CBCL Internalizing subscale </li></ul><ul><li>Summary score of problem behaviors (Withdrawn, Somatic, and Anxiety/Depression subscales)-includes excessive worrying and depression. </li></ul>8463.01
    139. 140. Internal Behavior Total 0 1 2 3 4 Year on Study Change in Score -10 0 10 20 p 0.4 0.73 0.09 0.05 H P 17 9 23 19 12 9 9 3 Mean  SE Humatrope (H) Placebo (P) 8464.02
    140. 141. Why Results Are Inconclusive <ul><li>Small sample size </li></ul><ul><li>Missing or incomplete data </li></ul><ul><li>Drop out bias </li></ul><ul><li>No correction for multiple comparisons (14 subscales) </li></ul><ul><li>No correlation with change in growth rates or height SDS </li></ul>8465.01
    141. 142. Summary <ul><li>Results controlled for placebo effect </li></ul><ul><li>GH does not have deleterious effects on self-image or behavior </li></ul><ul><li>Trend towards positive GH effect on Problem Behaviors, Externalizing, and Internalizing Behaviors </li></ul>8466.01
    142. 143. Previous ISS Self-image Results 8467.01 Lower social function < 2 4-10 36 Theunissen et al., J Ped 2002; 140: 507 More Problem Behavior, Internal, External (CBCL) -4.0 8.8 16 Steinhausen, J Endocrinol Invest 2002; 25: 351 More Problem Behavior, Internal, External (CBCL) -2.8 10.9 86 Stabler et al., J Ped 1998; 133: 366 No difference in self-esteem, < satisfied with height -2.4 7-8 28 Downie, Voss et al., Arch Dis Childh 1996; 75: 32 More Problem Behavior, Internal, External (CBCL) -2.3 11 258 Sandberg et al., Ped 1994; 94: 832 Self-image findings Height SDS Age ISS No. Reference
    143. 144. Previous GH Self-Image Results * Randomized control group 8468.01 No difference in self-esteem 2 4-10 36 *Theunissen et al., J Ped 2002; 140: 507 Improved Problem Behavior, Internal, External 2 8.8 93 Steinhausen, J Endocrinol Invest 2002; 25: 351 Improved Problem Behavior, Internal, External 3 10.9 86 Stabler et al., J Ped 1998; 133: 366 No difference in self-esteem 5 7-8 15 Downie, Voss et al., Arch Dis Childh 1996; 75: 32 Improved emotional adjustment 2 10.2 66 Boulton et al., Acta Paed Scand 1991; 377: 20 Self-image findings Years Age ISS No. Reference
    144. 145. ISS and GH for 2 years Steinhausen et al, J. Endocrinol Invest. 2002; 25:351 Internalizing Externalizing Problem Behaviors 8469.01
    145. 146. ISS and GH for 3 years Stabler et al., J. Pediatr. 1998; 133:366 8470.01
    146. 147. Results <ul><li>CBCL Externalizing subscale (Delinquent, </li></ul><ul><li>Aggressive subscales)-includes “acting out” and </li></ul><ul><li>aggressive behaviors </li></ul><ul><li>CBCL Delinquent subscale </li></ul><ul><ul><li>Bad friends, lie, cheat, run away, steal, swear, truant </li></ul></ul><ul><li>CBCL Aggressive subscale </li></ul><ul><ul><li>Argues, brags, fights, jealous, stubborn, show-off. </li></ul></ul>8471.01
    147. 148. Turner Syndrome: No Dose Effect on Fasting Insulin 0 10 20 30 40 Placebo GH 0.27 GH 0.36 Fasting Insulin (mcU/mL) Baseline 0 10 20 30 40 Placebo GH 0.27 GH 0.36 18 months 8252.02 A few extreme high values are not displayed
    148. 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
    149. 150. GDCH (EE Population): No Humatrope Treatment Effect on Pubertal Onset in Boys Leschek E. et al.: J. Pediatr 2001; 138: 406 – 410 8153.01 14.1 ± 0.4 13.5 ± 0.6 Testosterone > 30 ng/dL 13.3 ± 0.5 13.5 ± 0.5 Testis Volume > 4 mL Humatrope (n=11) Placebo (n=12) Criterion for Pubertal Onset Age at Pubertal Onset (yr)
    150. 151. GDCH: Final Height (cm) Males and Females Separately Humatrope vs. Placebo Mean ± SD N Mean ± SD N 9 18 Placebo Humatrope 149.0 ± 4.0 2 159.3 ± 4.4 152.3 ± 5.6 4 163.1 ± 6.3 Females Males

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