Briefing Document

Endocrinologic and Metabolic Drugs
Advisory Committee
June 10, 2003

Humatrope®
(somatropin [rDNA origin] for injection)
for Non-Growth Hormone Deficient Short Stature

Volume 1

Lilly Research Laboratories
Eli Lilly and Company
Lilly Corporate Center
Indianapolis, Indiana  46285

AVAILABLE FOR PUBLIC DISCLOSURE WITHOUT REDACTION

Table of Contents

Section                                                                                                     Page

List of Abbreviations....................................................................................... 10

List of Clinical Studies..................................................................................... 15

Executive Summary......................................................................................... 16

1.      Introduction............................................................................................ 22

1.1.     Regulatory History for the Study of Non-Growth Hormone-Deficient Short Stature  22

1.2.     The Rationale for GH Treatment of Non-GHD Short Stature.............. 24

2.      Overview of Clinical Studies................................................................... 31

2.1.     Pivotal Study:  B9R-MC-GDCH....................................................... 31

2.2.     Supportive Study:  B9R-EW-E001.................................................... 31

2.3.     Supportive Peer-Reviewed Literature Studies..................................... 32

3.      Effectiveness of Humatrope..................................................................... 33

3.1.     Pivotal Clinical Study:  GDCH........................................................... 33

3.1.1.       Primary Objective..................................................................... 33

3.1.2.       Study Design............................................................................. 33

3.1.3.       Inclusion/Exclusion Criteria........................................................ 34

3.1.4.       Summary of Key Protocol Changes........................................... 35

3.1.4.1.       Entry Height Criterion.......................................................... 35

3.1.4.2.       Final Height Criterion........................................................... 36

3.1.4.3.       Poststudy Summary Visit..................................................... 36

3.1.4.4.       Termination of Blinded Treatment Period.............................. 36

3.1.5.       Population Definitions................................................................ 36

3.1.6.       Patient Disposition..................................................................... 38

3.1.7.       Baseline Patient Characteristics.................................................. 40

3.1.8.       Efficacy Data............................................................................. 43

3.1.8.1.       Primary Efficacy Analysis (Final Height SDS)....................... 43

3.1.8.2.       Sensitivity Analyses.............................................................. 44

3.1.8.3.       Additional Analyses of Interest............................................. 51

3.1.9.       Efficacy Summary...................................................................... 55

3.2.     Supportive Study:  B9R-EW-E001.................................................... 55

3.2.1.       Objectives................................................................................. 55

3.2.2.       Study Design............................................................................. 56

3.2.3.       Inclusion/Exclusion Criteria........................................................ 56

3.2.4.       Population Definitions................................................................ 57

3.2.5.       Patient Disposition..................................................................... 57

3.2.6.       Baseline Patient Characteristics.................................................. 59

3.2.7.       Efficacy Data............................................................................. 61

3.2.7.1.       Dose-Response Effect on Height Velocity............................ 61

3.2.7.2.       Dose-Response Effect on Height SDS................................. 62

3.2.7.3.       Significant Treatment Effect on Final Height.......................... 65

3.2.8.       E001 Efficacy Summary............................................................ 67

3.2.9.       Comparative Efficacy Summary................................................. 68

3.3.     Supportive Data:  Meta-Analysis of Effect of Growth Hormone Therapy on Height in Children with Idiopathic Short Stature................................................ 71

3.3.1.       Growth Hormone Effect on Final Height..................................... 71

3.3.1.1.       Controlled Studies............................................................... 71

3.3.1.2.       Uncontrolled Studies............................................................ 73

3.3.1.3.       Summary............................................................................. 75

3.4.     Height SDS Gain Similar to Height SDS Gain in Turner Syndrome...... 75

3.5.     Humatrope Dosage and Frequency of Administration......................... 77

3.5.1.       Humatrope Dosage................................................................... 78

3.5.2.       Frequency of Administration...................................................... 78

3.5.3.       Clinical Relevance of Height Gain in Non-GHD Short Stature..... 79

3.6.     Overall Efficacy Conclusions.............................................................. 80

4.      Safety..................................................................................................... 81

4.1.     Introduction....................................................................................... 81

4.2.     Overview of Clinical Studies Included in Safety Comparison............... 81

4.2.1.       Study GDAB............................................................................ 82

4.2.2.       Study GDCT............................................................................. 83

4.2.3.       Study GDCI.............................................................................. 83

4.2.4.       Study GDCH............................................................................ 84

4.2.5.       Study E001............................................................................... 84

4.3.     Exposure........................................................................................... 84

4.4.     Deaths............................................................................................... 87

4.4.1.       Summary Comparison............................................................... 87

4.4.2.       Growth Hormone Deficiency..................................................... 87

4.4.3.       Turner Syndrome...................................................................... 88

4.4.4.       Non‑Growth Hormone-Deficient Short Stature.......................... 88

4.5.     Discontinuations Due to Adverse Events............................................. 88

4.5.1.       Summary Comparison............................................................... 90

4.5.2.       Growth Hormone Deficiency..................................................... 90

4.5.3.       Turner Syndrome...................................................................... 90

4.5.4.       Non-Growth Hormone-Deficient Short Stature.......................... 90

4.6.     Serious Adverse Events..................................................................... 91

4.6.1.       Summary Comparison............................................................... 93

4.6.2.       Growth Hormone Deficiency..................................................... 93

4.6.3.       Turner Syndrome...................................................................... 94

4.6.4.       Non-Growth Hormone-Deficient Short Stature.......................... 95

4.7.     Treatment-Emergent Adverse Events................................................. 99

4.7.1.       Summary Comparison............................................................. 103

4.7.2.       Growth Hormone Deficiency................................................... 103

4.7.3.       Turner Syndrome.................................................................... 103

4.7.4.       Non-Growth Hormone-Deficient Short Stature........................ 103

4.8.     Adverse Events Referenced in the Current Humatrope Label............ 106

4.8.1.       Summary Comparison............................................................. 107

4.8.2.       Otitis Media............................................................................ 108

4.8.3.       Scoliosis.................................................................................. 108

4.8.4.       Hypothyroidism....................................................................... 109

4.8.5.       Alterations in Carbohydrate Metabolism.................................. 109

4.8.6.       Hypertension........................................................................... 109

4.8.7.       Slipped Capital Femoral Epiphysis........................................... 109

4.9.     Safety Information from the Literature on GH Treatment in Non-GHD Short Stature 110

4.10.   Clinical Laboratory Evaluation.......................................................... 111

4.10.1.     Carbohydrate Metabolism....................................................... 112

4.10.1.1.     Summary Comparison....................................................... 115

4.10.1.2.     Growth Hormone Deficiency.............................................. 115

4.10.1.3.     Turner Syndrome............................................................... 115

4.10.1.4.     Non-Growth Hormone Deficient Short Stature................... 115

4.10.2.     Insulin-Like Growth Factor-I................................................... 120

4.10.2.1.     Turner Syndrome............................................................... 122

4.10.2.2.     Non‑Growth Hormone Deficient Short Stature................... 122

4.10.3.     Thyroid Function..................................................................... 123

4.10.3.1.     Growth Hormone Deficiency.............................................. 126

4.10.3.2.     Turner Syndrome............................................................... 126

4.10.3.3.     Non‑Growth Hormone Deficient Short Stature................... 126

4.11.   Overall Safety Conclusions.............................................................. 127

5.      Benefit/Risk Assessment....................................................................... 128

6.      Risk Management................................................................................. 133

6.1.     Introduction..................................................................................... 133

6.2.     Specific Concerns............................................................................ 133

6.2.1.       Inappropriate Prescribing......................................................... 133

6.2.2.       Lack of Adequate Diagnostic Evaluation.................................. 134

6.2.3.       Emergence of New Adverse Events......................................... 134

6.3.     Elements of the Lilly Risk Management Process................................ 134

6.3.1.       Restrictive Humatrope Labeling for Non-GHD Short Stature.... 134

6.3.2.       Physician Education................................................................. 136

6.3.2.1.       Physician-to-Physician Programs (Lilly-Sponsored)............ 137

6.3.2.2.       Continuing Medical Education............................................ 137

6.3.3.       Limited Marketing................................................................... 137

6.3.3.1.       Limited Sales Force........................................................... 137

6.3.3.2.       Sales Force Training on the Humatrope Benefit/Risk Profile and Appropriate Use                                                                                          138

6.3.3.3.       No Direct-to-Consumer Advertising.................................. 138

6.3.4.       Controlled Distribution Process................................................ 138

6.3.5.       Safety Monitoring and Analysis................................................ 139

6.3.5.1.       Pharmacovigilance............................................................. 139

6.3.5.2.       Postmarketing Surveillance Research.................................. 139

6.4.     External Factors.............................................................................. 141

6.4.1.       The Pediatric Endocrine Community........................................ 141

6.4.2.       Professional Physician Societies............................................... 141

6.4.3.       Insurance Companies.............................................................. 142

6.5.     Conclusions..................................................................................... 142

7.      Summary and Conclusions.................................................................... 145

7.1.     Height Gain..................................................................................... 145

7.2.     Dosage............................................................................................ 145

7.3.     Dose Frequency.............................................................................. 145

7.4.     Safety.............................................................................................. 146

7.5.     Conclusion...................................................................................... 146

8.      References........................................................................................... 147

Table of Contents

Table                                                                                                         Page

Table 1.         Mean Height SDS of Patients with Growth Disorders at Initiation of Growth Hormone Treatment 28

Table 2.         Demographics and Other Baseline Characteristics ^a Study GDCH.. 41

Table 3.         Final Height Standard Deviation Score Analysis of Covariance Final Height Population Study GDCH.. 43

Table 4.         Modified Intent-to-Treat Analysis Efficacy Evaluable Population Study GDCH   45

Table 5.         Intent-to-Treat Analyses of Last Observed Height SDS All Randomized Population Study GDCH.. 46

Table 6.         Analyses of Adult Height Protocol Complete and Final Height Populations Study GDCH   47

Table 7.         Additional Endpoint Height Analyses Efficacy Evaluable Population Study GDCH   52

Table 8.         Additional Final Height Analyses Final Height Population Study GDCH   53

Table 9.         Additional Final Height Analyses Protocol Complete Population Study GDCH   54

Table 10.       Demographics and Other Baseline Characteristics Study E001. 60

Table 11.       Height Velocity Changes from Pretreatment to 2-Year Endpoint Two-Year Height Velocity Population Study E001. 62

Table 12.       Secondary Efficacy Analyses Two‑Year Height Velocity Population Study E001  63

Table 13.       Final Height Standard Deviation Score Analysis of Covariance Final Height Population Study E001. 64

Table 14.       Final Height Characteristics Final Height Population Study E001. 66

Table 15.       Final Height Results:  Meta-Analysis of Controlled Trials ^a. 72

Table 16.       Results of Meta‑Analysis of Uncontrolled Studies from Peer‑Reviewed Literature ^a 74

Table 17.       Clinical Studies Included in Safety Comparison. 82

Table 18.       Time on Study. 86

Table 19.       Patient Deaths During and After Study. 87

Table 20.       Discontinuations Due to Adverse Events. 89

Table 21.       Serious Adverse Events. 92

Table 22.       Patient Diagnosed with Hodgkin Disease:  Timecourse of Events. 97

Table 23.       Treatment-Emergent Adverse Events. 100

Table 24.       Summary of Treatment-Emergent Adverse Events by Clinically Relevant Categories Safety Population Study GDCH..... 105

Table 25.       Adverse Events Referenced in Humatrope Label 107

Table 26.       Somatropin Safety in Non-GHD Conditions Kabi International Growth Study (KIGS) 110

Table 27.       Somatropin Safety in the National Cooperative Growth Study (NCGS) 111

Table 28.       Carbohydrate Metabolism Changes from Baseline to Endpoint 113

Table 29.       Insulin-Like Growth Factor-I Changes from Baseline to Endpoint 121

Table 30.       Thyroid Function Changes from Baseline to Endpoint 124

Table 31.       Risk Management Elements and External Factors Related to Approval of Non-GHD Short Stature. 144

 

 

Table of Contents

Figure                                                                                                       Page

Figure 1.        A diagnostic algorithm for investigation of short stature.. 26

Figure 2.        Design of Study GDCH. 34

Figure 3.        Patient disposition for Study GDCH. 39

Figure 4.        Bone age versus year on study for Study GDCH. 48

Figure 5.        Increase in height SDS over baseline versus year on study relative to last observed height (year=0) in Study GDCH.. 49

Figure 6.        Height standard deviation score by year on study for the Efficacy Evaluable Population (Study GDCH). 51

Figure 7.        Design of Study E001. 56

Figure 8.        Patient disposition for Study E001. 58

Figure 9.        Bone age versus year on study in Study E001. 65

Figure 10.      Final height minus baseline predicted height (cm) in the Final Height Populations of Studies GDCH and E001. 67

Figure 11.      Comparative summary of Studies GDCH and E001:  Final height SDS. 69

Figure 12.      Significant number of GH treated patients achieved normal height in Studies GDCH and E001. 70

Figure 13.      Mean difference in height standard deviation scores between treatment and control groups for predicted adult height (at baseline) and achieved adult height for controlled studies.  73

Figure 14.      Mean adult height standard deviation scores predicted at baseline and achieved for uncontrolled studies. 75

Figure 15.      Distribution of height standard deviation score change (baseline to final height) in patients treated with Humatrope (Study GDCH and Study GDCI). 77

Figure 16.      Mean fasting glucose by year on study for Study GDCH.. 116

Figure 17.      Mean fasting insulin by year on study for Study GDCH..