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-abbreviations)

List of Clinical Studies [15](#list-of-clinical-studies)

Executive Summary [16](#executive-summary)

1\. Introduction [22](#introduction)

1.1. Regulatory History for the Study of Non-Growth Hormone-Deficient
Short Stature
[22](#regulatory-history-for-the-study-of-non-growth-hormone-deficient-short-stature)

1.2. The Rationale for GH Treatment of Non-GHD Short Stature
[24](#the-rationale-for-gh-treatment-of-non-ghd-short-stature)

2\. Overview of Clinical Studies [31](#overview-of-clinical-studies)

2.1. Pivotal Study: B9R-MC-GDCH [31](#pivotal-study-b9r-mc-gdch)

2.2. Supportive Study: B9R-EW-E001 [31](#supportive-study-b9r-ew-e001)

2.3. Supportive Peer-Reviewed Literature Studies
[32](#supportive-peer-reviewed-literature-studies)

3\. Effectiveness of Humatrope [33](#effectiveness-of-humatrope)

3.1. Pivotal Clinical Study: GDCH [33](#pivotal-clinical-study-gdch)

3.1.1. Primary Objective [33](#primary-objective)

3.1.2. Study Design [33](#study-design)

3.1.3. Inclusion/Exclusion Criteria [34](#inclusionexclusion-criteria)

3.1.4. Summary of Key Protocol Changes
[35](#summary-of-key-protocol-changes)

3.1.4.1. Entry Height Criterion [35](#entry-height-criterion)

3.1.4.2. Final Height Criterion [36](#final-height-criterion)

3.1.4.3. Poststudy Summary Visit [36](#poststudy-summary-visit)

3.1.4.4. Termination of Blinded Treatment Period
[36](#termination-of-blinded-treatment-period)

3.1.5. Population Definitions [36](#population-definitions)

3.1.6. Patient Disposition [38](#patient-disposition)

3.1.7. Baseline Patient Characteristics
[40](#baseline-patient-characteristics)

3.1.8. Efficacy Data [43](#efficacy-data)

3.1.8.1. Primary Efficacy Analysis (Final Height SDS)
[43](#primary-efficacy-analysis-final-height-sds)

3.1.8.2. Sensitivity Analyses [44](#sensitivity-analyses)

3.1.8.3. Additional Analyses of Interest
[51](#additional-analyses-of-interest)

3.1.9. Efficacy Summary [55](#efficacy-summary)

3.2. Supportive Study: B9R-EW-E001 [55](#supportive-study-b9r-ew-e001-1)

3.2.1. Objectives [55](#objectives)

3.2.2. Study Design [56](#study-design-1)

3.2.3. Inclusion/Exclusion Criteria [56](#inclusionexclusion-criteria-1)

3.2.4. Population Definitions [57](#population-definitions-1)

3.2.5. Patient Disposition [57](#patient-disposition-1)

3.2.6. Baseline Patient Characteristics
[59](#baseline-patient-characteristics-1)

3.2.7. Efficacy Data [61](#efficacy-data-1)

3.2.7.1. Dose-Response Effect on Height Velocity
[61](#dose-response-effect-on-height-velocity)

3.2.7.2. Dose-Response Effect on Height SDS
[62](#dose-response-effect-on-height-sds)

3.2.7.3. Significant Treatment Effect on Final Height
[65](#significant-treatment-effect-on-final-height)

3.2.8. E001 Efficacy Summary [67](#e001-efficacy-summary)

3.2.9. Comparative Efficacy Summary [68](#comparative-efficacy-summary)

3.3. Supportive Data: Meta-Analysis of Effect of Growth Hormone Therapy
on Height in Children with Idiopathic Short Stature
[71](#supportive-data-meta-analysis-of-effect-of-growth-hormone-therapy-on-height-in-children-with-idiopathic-short-stature)

3.3.1. Growth Hormone Effect on Final Height
[71](#growth-hormone-effect-on-final-height)

3.3.1.1. Controlled Studies [71](#controlled-studies)

3.3.1.2. Uncontrolled Studies [73](#uncontrolled-studies)

3.3.1.3. Summary [75](#summary)

3.4. Height SDS Gain Similar to Height SDS Gain in Turner Syndrome
[75](#height-sds-gain-similar-to-height-sds-gain-in-turner-syndrome)

3.5. Humatrope Dosage and Frequency of Administration
[77](#humatrope-dosage-and-frequency-of-administration)

3.5.1. Humatrope Dosage [78](#humatrope-dosage)

3.5.2. Frequency of Administration [78](#frequency-of-administration)

3.5.3. Clinical Relevance of Height Gain in Non-GHD Short Stature
[79](#clinical-relevance-of-height-gain-in-non-ghd-short-stature)

3.6. Overall Efficacy Conclusions [80](#overall-efficacy-conclusions)

4\. Safety [81](#safety)

4.1. Introduction [81](#introduction-1)

4.2. Overview of Clinical Studies Included in Safety Comparison
[81](#overview-of-clinical-studies-included-in-safety-comparison)

4.2.1. Study GDAB [82](#study-gdab)

4.2.2. Study GDCT [83](#study-gdct)

4.2.3. Study GDCI [83](#study-gdci)

4.2.4. Study GDCH [84](#study-gdch)

4.2.5. Study E001 [84](#study-e001)

4.3. Exposure [84](#exposure)

4.4. Deaths [87](#deaths)

4.4.1. Summary Comparison [87](#summary-comparison)

4.4.2. Growth Hormone Deficiency [87](#growth-hormone-deficiency)

4.4.3. Turner Syndrome [88](#turner-syndrome)

4.4.4. Non‑Growth Hormone-Deficient Short Stature
[88](#nongrowth-hormone-deficient-short-stature)

4.5. Discontinuations Due to Adverse Events
[88](#discontinuations-due-to-adverse-events)

4.5.1. Summary Comparison [90](#summary-comparison-1)

4.5.2. Growth Hormone Deficiency [90](#growth-hormone-deficiency-1)

4.5.3. Turner Syndrome [90](#turner-syndrome-1)

4.5.4. Non-Growth Hormone-Deficient Short Stature
[90](#non-growth-hormone-deficient-short-stature)

4.6. Serious Adverse Events [91](#serious-adverse-events)

4.6.1. Summary Comparison [93](#summary-comparison-2)

4.6.2. Growth Hormone Deficiency [93](#growth-hormone-deficiency-2)

4.6.3. Turner Syndrome [94](#turner-syndrome-2)

4.6.4. Non-Growth Hormone-Deficient Short Stature
[95](#non-growth-hormone-deficient-short-stature-1)

4.7. Treatment-Emergent Adverse Events
[99](#treatment-emergent-adverse-events)

4.7.1. Summary Comparison [103](#summary-comparison-3)

4.7.2. Growth Hormone Deficiency [103](#growth-hormone-deficiency-3)

4.7.3. Turner Syndrome [103](#turner-syndrome-3)

4.7.4. Non-Growth Hormone-Deficient Short Stature
[103](#non-growth-hormone-deficient-short-stature-2)

4.8. Adverse Events Referenced in the Current Humatrope Label
[106](#adverse-events-referenced-in-the-current-humatrope-label)

4.8.1. Summary Comparison [107](#summary-comparison-4)

4.8.2. Otitis Media [108](#otitis-media)

4.8.3. Scoliosis [108](#scoliosis)

4.8.4. Hypothyroidism [109](#hypothyroidism)

4.8.5. Alterations in Carbohydrate Metabolism
[109](#alterations-in-carbohydrate-metabolism)

4.8.6. Hypertension [109](#hypertension)

4.8.7. Slipped Capital Femoral Epiphysis
[109](#slipped-capital-femoral-epiphysis)

4.9. Safety Information from the Literature on GH Treatment in Non-GHD
Short Stature
[110](#safety-information-from-the-literature-on-gh-treatment-in-non-ghd-short-stature)

4.10. Clinical Laboratory Evaluation
[111](#clinical-laboratory-evaluation)

4.10.1. Carbohydrate Metabolism [112](#carbohydrate-metabolism)

4.10.1.1. Summary Comparison [115](#summary-comparison-5)

4.10.1.2. Growth Hormone Deficiency [115](#growth-hormone-deficiency-4)

4.10.1.3. Turner Syndrome [115](#turner-syndrome-4)

4.10.1.4. Non-Growth Hormone Deficient Short Stature
[115](#non-growth-hormone-deficient-short-stature-3)

4.10.2. Insulin-Like Growth Factor-I
[120](#insulin-like-growth-factor-i)

4.10.2.1. Turner Syndrome [122](#turner-syndrome-5)

4.10.2.2. Non‑Growth Hormone Deficient Short Stature
[122](#nongrowth-hormone-deficient-short-stature-1)

4.10.3. Thyroid Function [123](#thyroid-function)

4.10.3.1. Growth Hormone Deficiency [126](#growth-hormone-deficiency-5)

4.10.3.2. Turner Syndrome [126](#turner-syndrome-6)

4.10.3.3. Non‑Growth Hormone Deficient Short Stature
[126](#nongrowth-hormone-deficient-short-stature-2)

4.11. Overall Safety Conclusions [127](#overall-safety-conclusions)

5\. Benefit/Risk Assessment [128](#benefitrisk-assessment)

6\. Risk Management [133](#risk-management)

6.1. Introduction [133](#introduction-2)

6.2. Specific Concerns [133](#specific-concerns)

6.2.1. Inappropriate Prescribing [133](#inappropriate-prescribing)

6.2.2. Lack of Adequate Diagnostic Evaluation
[134](#lack-of-adequate-diagnostic-evaluation)

6.2.3. Emergence of New Adverse Events
[134](#emergence-of-new-adverse-events)

6.3. Elements of the Lilly Risk Management Process
[134](#elements-of-the-lilly-risk-management-process)

6.3.1. Restrictive Humatrope Labeling for Non-GHD Short Stature
[134](#restrictive-humatrope-labeling-for-non-ghd-short-stature)

6.3.2. Physician Education [136](#physician-education)

6.3.2.1. Physician-to-Physician Programs (Lilly-Sponsored)
[137](#physician-to-physician-programs-lilly-sponsored)

6.3.2.2. Continuing Medical Education
[137](#continuing-medical-education)

6.3.3. Limited Marketing [137](#limited-marketing)

6.3.3.1. Limited Sales Force [137](#limited-sales-force)

6.3.3.2. Sales Force Training on the Humatrope Benefit/Risk Profile and
Appropriate Use
[138](#sales-force-training-on-the-humatrope-benefitrisk-profile-and-appropriate-use)

6.3.3.3. No Direct-to-Consumer Advertising
[138](#no-direct-to-consumer-advertising)

6.3.4. Controlled Distribution Process
[138](#controlled-distribution-process)

6.3.5. Safety Monitoring and Analysis
[139](#safety-monitoring-and-analysis)

6.3.5.1. Pharmacovigilance [139](#pharmacovigilance)

6.3.5.2. Postmarketing Surveillance Research
[139](#postmarketing-surveillance-research)

6.4. External Factors [141](#external-factors)

6.4.1. The Pediatric Endocrine Community
[141](#the-pediatric-endocrine-community)

6.4.2. Professional Physician Societies
[141](#professional-physician-societies)

6.4.3. Insurance Companies [142](#insurance-companies)

6.5. Conclusions [142](#conclusions)

7\. Summary and Conclusions [145](#summary-and-conclusions)

7.1. Height Gain [145](#height-gain)

7.2. Dosage [145](#dosage)

7.3. Dose Frequency [145](#dose-frequency)

7.4. Safety [146](#safety-1)

7.5. Conclusion [146](#conclusion)

8\. References [147](#references)

**Table of Contents**

Table Page

[Table 1. Mean Height SDS of Patients with Growth Disorders at
Initiation of Growth Hormone Treatment 28](#__RefHeading___Toc39468338)

[Table 2. Demographics and Other Baseline Characteristics a Study GDCH
41](#__RefHeading___Toc39468339)

[Table 3. Final Height Standard Deviation Score Analysis of Covariance
Final Height Population Study GDCH 43](#__RefHeading___Toc39468340)

[Table 4. Modified Intent-to-Treat Analysis Efficacy Evaluable
Population Study GDCH 45](#__RefHeading___Toc39468341)

[Table 5. Intent-to-Treat Analyses of Last Observed Height SDS All
Randomized Population Study GDCH 46](#__RefHeading___Toc39468342)

[Table 6. Analyses of Adult Height Protocol Complete and Final Height
Populations Study GDCH 47](#__RefHeading___Toc39468343)

[Table 7. Additional Endpoint Height Analyses Efficacy Evaluable
Population Study GDCH 52](#__RefHeading___Toc39468344)

[Table 8. Additional Final Height Analyses Final Height Population Study
GDCH 53](#__RefHeading___Toc39468345)

[Table 9. Additional Final Height Analyses Protocol Complete Population
Study GDCH 54](#__RefHeading___Toc39468346)

[Table 10. Demographics and Other Baseline Characteristics Study E001
60](#__RefHeading___Toc39468347)

[Table 11. Height Velocity Changes from Pretreatment to 2-Year Endpoint
Two-Year Height Velocity Population Study E001
62](#__RefHeading___Toc39468348)

[Table 12. Secondary Efficacy Analyses Two‑Year Height Velocity
Population Study E001 63](#__RefHeading___Toc39468349)

[Table 13. Final Height Standard Deviation Score Analysis of Covariance
Final Height Population Study E001 64](#__RefHeading___Toc39468350)

[Table 14. Final Height Characteristics Final Height Population
Study E001 66](#__RefHeading___Toc39468351)

[Table 15. Final Height Results: Meta-Analysis of Controlled Trials a
72](#__RefHeading___Toc39468352)

[Table 16. Results of Meta‑Analysis of Uncontrolled Studies from
Peer‑Reviewed Literature a 74](#__RefHeading___Toc39468353)

[Table 17. Clinical Studies Included in Safety Comparison
82](#__RefHeading___Toc39468354)

[Table 18. Time on Study 86](#__RefHeading___Toc39468355)

[Table 19. Patient Deaths During and After Study
87](#__RefHeading___Toc39468356)

[Table 20. Discontinuations Due to Adverse Events
89](#__RefHeading___Toc39468357)

[Table 21. Serious Adverse Events 92](#__RefHeading___Toc39468358)

[Table 22. Patient Diagnosed with Hodgkin Disease: Timecourse of Events
97](#__RefHeading___Toc39468359)

[Table 23. Treatment-Emergent Adverse Events
100](#__RefHeading___Toc39468360)

[Table 24. Summary of Treatment-Emergent Adverse Events by Clinically
Relevant Categories Safety Population Study GDCH
105](#__RefHeading___Toc39468361)

[Table 25. Adverse Events Referenced in Humatrope Label
107](#__RefHeading___Toc39468362)

[Table 26. Somatropin Safety in Non-GHD Conditions Kabi International
Growth Study (KIGS) 110](#__RefHeading___Toc39468363)

[Table 27. Somatropin Safety in the National Cooperative Growth Study
(NCGS) 111](#__RefHeading___Toc39468364)

[Table 28. Carbohydrate Metabolism Changes from Baseline to Endpoint
113](#__RefHeading___Toc39468365)

[Table 29. Insulin-Like Growth Factor-I Changes from Baseline to
Endpoint 121](#__RefHeading___Toc39468366)

[Table 30. Thyroid Function Changes from Baseline to Endpoint
124](#__RefHeading___Toc39468367)

[Table 31. Risk Management Elements and External Factors Related to
Approval of Non-GHD Short Stature 144](#__RefHeading___Toc39468368)

Table of Contents

Figure Page

[Figure 1. A diagnostic algorithm for investigation of short stature.
26](#__RefHeading___Toc39468369)

[Figure 2. Design of Study GDCH. 34](#__RefHeading___Toc39468370)

[Figure 3. Patient disposition for Study GDCH.
39](#__RefHeading___Toc39468371)

[Figure 4. Bone age versus year on study for Study GDCH.
48](#__RefHeading___Toc39468372)

[Figure 5. Increase in height SDS over baseline versus year on study
relative to last observed height (year=0) in Study GDCH.
49](#__RefHeading___Toc39468373)

[Figure 6. Height standard deviation score by year on study for the
Efficacy Evaluable Population (Study GDCH).
51](#__RefHeading___Toc39468374)

[Figure 7. Design of Study E001. 56](#__RefHeading___Toc39468375)

[Figure 8. Patient disposition for Study E001.
58](#__RefHeading___Toc39468376)

[Figure 9. Bone age versus year on study in Study E001.
65](#__RefHeading___Toc39468377)

[Figure 10. Final height minus baseline predicted height (cm) in the
Final Height Populations of Studies GDCH and E001.
67](#__RefHeading___Toc39468378)

[Figure 11. Comparative summary of Studies GDCH and E001: Final height
SDS. 69](#__RefHeading___Toc39468379)

[Figure 12. Significant number of GH treated patients achieved normal
height in Studies GDCH and E001. 70](#__RefHeading___Toc39468380)

[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](#__RefHeading___Toc39468381)

[Figure 14. Mean adult height standard deviation scores predicted at
baseline and achieved for uncontrolled studies.
75](#__RefHeading___Toc39468382)

[Figure 15. Distribution of height standard deviation score change
(baseline to final height) in patients treated with Humatrope
(Study GDCH and Study GDCI). 77](#__RefHeading___Toc39468383)

[Figure 16. Mean fasting glucose by year on study for Study GDCH.
116](#__RefHeading___Toc39468384)

[Figure 17. Mean fasting insulin by year on study for Study GDCH.
117](#__RefHeading___Toc39468385)

[Figure 18. Qualitative Insulin Sensitivity Check Index (QUICKI)
baseline to endpoint in Study GDCH. 118](#__RefHeading___Toc39468386)

[Figure 19. Analysis of covariance of last on study QUICKI using
baseline QUICKI as the covariate. 119](#__RefHeading___Toc39468387)

[Figure 20. No Humatrope dose effect on fasting glucose.
120](#__RefHeading___Toc39468388)

[Figure 21. IGF-I increased modestly in Humatrope-treated patients in
Study GDCH. 122](#__RefHeading___Toc39468389)

[Figure 22. No significant GH-related change in free thyroxine in Study
GDCH. 126](#__RefHeading___Toc39468390)

# List of Abbreviations

  ------------ ----------------------------------------------------------
  **Symbol**   **Definition**

  AACE         American Association of Clinical Endocrinologists

  AAP          American Academy of Pediatrics

  AE           adverse event

  ANCOVA       analysis of covariance

  ANOVA        analysis of variance

  BA           bone age

  BPH          baseline predicted final height

  BSA          body surface area

  CA           chronological age

  CFR          Code of Federal Regulation

  CIB          clinical investigator's brochure

  CME          continuing medical education

  CRF          clinical report form or case report form

  CRI          chronic renal insufficiency

  CSR          clinical study report

  CT           clinical trial

  DHEAS        dehydroepiandrosterone sulfate

  DSMB         Data and Safety Monitoring Board

  ERB          Ethical Review Board

  FDA          Food and Drug Administration

  ELECT        Eli Lilly Event Classification Terms

  FSH          follicle-stimulating hormone

  GCP          good clinical practice

  GeNeSIS      Genetics and Neuroendocrinology of Short Stature
               International Study

  GH           growth hormone

  GHD          growth hormone deficiency, or growth hormone deficient

  GMP          good manufacturing practice

  GRS          Growth Hormone Research Society

  HbA1c        hemoglobin A1c (glycosylated hemoglobin)

  HGHPRC       Human Growth Hormone Protocol Review Committee

  HHS          Department of Health and Human Services

  ICD          informed consent document

  ICH          International Conference on Harmonisation

  IGF-I        insulin-like growth factor-I, also known as somatomedin-C

  IND          investigational new drug

  IRB          Institutional Review Board

  ISS          idiopathic short stature

  IU           International Units

  IUGR         intrauterine growth retardation

  KIGS         Kabi International Growth Study

  LH           luteinizing hormone

  LOCF         last observation carried forward

  LSM          least squares mean

  MQA          Medical Quality Assurance
  ------------ ----------------------------------------------------------

Continued

  ------------ ----------------------------------------------------------
  **Symbol**   **Definition**

  NCGS         National Cooperative Growth Study

  NCHS         National Center for Health Statistics

  NGHDSS       non-growth hormone deficient short stature

  NIH          National Institutes of Health

  NICHD        National Institute of Child Health and Human Development

  NOS          not otherwise specified

  NVSS         normal variant short stature

  OGTT         oral glucose tolerance test

  pre-sNDA     pre-supplemental New Drug Application

  SAE          serious adverse event

  SAP          statistical analysis plan

  SCFE         slipped capital femoral epiphysis

  SD           standard deviation

  SDS          standard deviation score

  SE           standard error of mean

  SGA          small for gestational age

  SHOX         short stature homeobox-containing gene on the X-chromosome

  TEAE         treatment-emergent adverse event

  TIW          three times per week

  TSH          thyroid-stimulating hormone

  WWPE         World-Wide Pharmacovigilance and Epidemiology
  ------------ ----------------------------------------------------------

Definitions of Terms

+--------------+-------------------------------------------------------+
| Adult height | See final height.                                     |
+--------------+-------------------------------------------------------+
| Adverse      |                                                       |
| event        |                                                       |
+--------------+-------------------------------------------------------+
| Clinical     | Any undesirable experience, unanticipated benefit, or |
| trial        | pregnancy that occurs after informed consent for the  |
| adverse      | study has been obtained, without regard to the        |
| event        | possibility of a causal relationship and without      |
|              | regard to treatment group assignment, even if no      |
| AE           | study drug has been taken.                            |
+--------------+-------------------------------------------------------+
| Clinical     | Any adverse event in a clinical study patient that    |
| trial        | results in one of the following criteria:             |
| serious      |                                                       |
| adverse      | -   Death;                                            |
| event        |                                                       |
|              | -   Initial or prolonged inpatient hospitalization;   |
| SAE          |                                                       |
|              | -   Life-threatening consequences;                    |
|              |                                                       |
|              | -   Severe or permanent disability;                   |
|              |                                                       |
|              | -   Cancer\* (other than cancers diagnosed prior to   |
|              |     enrollment in studies involving patients with     |
|              |     cancer);                                          |
|              |                                                       |
|              | -   Congenital anomaly in the offspring of the        |
|              |     patient;                                          |
|              |                                                       |
|              | -   Other significant consequence.                    |
|              |                                                       |
|              |     \*As of 10 January 2001, cancer was removed from  |
|              |     the SAE list based on International Conference on |
|              |     Harmonisation (ICH) guidelines.                   |
+--------------+-------------------------------------------------------+
| Bone age     | Apparent developmental age of skeleton based on hand  |
|              | and wrist radiograph compared to normal standards     |
| BA           | (for example, normal bone age for a 12-year old child |
|              | would be approximately 11-13 years).                  |
+--------------+-------------------------------------------------------+
| Declaration  | A document that defines an international standard for |
| of Helsinki  | the conduct of clinical trials and has been adopted   |
|              | as legally enforceable by many countries and          |
|              | jurisdictions.                                        |
+--------------+-------------------------------------------------------+
| Eli Lilly    | A dictionary developed by Eli Lilly and Company that  |
| Event        | was used to describe, catalog, analyze, and report    |
| Cl           | all adverse events (AEs).                             |
| assification |                                                       |
| Terms        |                                                       |
|              |                                                       |
| ELECT        |                                                       |
+--------------+-------------------------------------------------------+
| Enrollment   |                                                       |
| Process      |                                                       |
+--------------+-------------------------------------------------------+
| **Screen**   | The act of determining if an individual meets minimum |
|              | requirements to become part of a pool of potential    |
|              | candidates for participation in a clinical study.     |
+--------------+-------------------------------------------------------+
| **Enter**    | The act of obtaining informed consent for             |
|              | participation in a clinical study from individuals    |
|              | deemed potentially eligible to participate in the     |
|              | clinical study. Individuals *entered* into a study    |
|              | are those for whom informed consent documents (ICDs)  |
|              | for the study have been signed by the potential study |
|              | participants or their legal representatives.          |
+--------------+-------------------------------------------------------+
| **Ran        | In clinical trials, the assignment of a study         |
| domization** | participant to a treatment group in such a way that   |
|              | all possible treatment group assignments are equally  |
|              | probable, serving to avoid the introduction of known  |
|              | or unknown bias.                                      |
+--------------+-------------------------------------------------------+
| **Enroll**   | For this study, enrollment was the act of assigning   |
|              | an individual to a treatment group.                   |
|              |                                                       |
|              | A person who was *entered* into the study was         |
|              | potentially eligible to be *enrolled* in the study,   |
|              | but was required to meet all inclusion/exclusion      |
|              | specified in the protocol before being *enrolled*     |
|              | (assigned to a treatment group). Individuals who      |
|              | *entered* into the study, but failed to meet          |
|              | inclusion/exclusion criteria were not eligible to     |
|              | participate in the study, and did not initiate        |
|              | therapy.                                              |
+--------------+-------------------------------------------------------+
| Final height | Generally a term used in clinical trials that refers  |
|              | to near-adult height, that is, the height at          |
|              | near-completion of growth. The definition may vary    |
|              | between trials and is often defined as advanced bone  |
|              | age (\>16 years in boys and \>14 years in girls)      |
|              | and/or slowing of growth rate (0.5 --2.0 cm/y).       |
+--------------+-------------------------------------------------------+
| Final Height | Patients on whom a final height measurement was       |
| Population   | obtained.                                             |
+--------------+-------------------------------------------------------+
| Height       | The number of standard deviations from the mean for   |
| standard     | age and gender (normal range is --2 to +2 SDS).       |
| deviation    |                                                       |
| score (SDS)  |                                                       |
+--------------+-------------------------------------------------------+
| Height       | Gain in height per time (normal: 5-7 cm/y before      |
| velocity     | puberty, and 6-12 cm/y during puberty).               |
| (cm/y)       |                                                       |
+--------------+-------------------------------------------------------+
| Two-Year     | Patients who had a height measurement at Visit 10 in  |
| Height       | Study E001.                                           |
| Velocity\    |                                                       |
| Population   |                                                       |
+--------------+-------------------------------------------------------+
| Incidence    | The incidence of adverse events is defined as the     |
|              | percent of patients reporting at least one adverse    |
|              | event at any time after baseline.                     |
+--------------+-------------------------------------------------------+
| Int          | An analysis of study participants by the groups to    |
| ent-to-treat | which they were assigned by random allocation, even   |
| analysis     | if the study participant did not take the assigned    |
|              | treatment, did not receive the correct treatment, or  |
|              | otherwise did not follow the protocol. Such an        |
|              | analysis is sometimes referred to as "analyze as      |
|              | randomized" or "intention‑to‑treat."                  |
+--------------+-------------------------------------------------------+
| P            | The sum of the days of exposure for all treated       |
| atient-years | patients divided by 365.25.                           |
+--------------+-------------------------------------------------------+
| Predicted    | The predicted adult height is calculated on the basis |
| Height       | of gender, current height, age, and bone age.         |
+--------------+-------------------------------------------------------+
| Pretreatment | The value obtained by computing the rate of growth    |
| growth rate  | between the height measurement taken approximately 12 |
|              | months prior to Visit 2, and the height measurement   |
|              | taken at Visit 2.                                     |
+--------------+-------------------------------------------------------+
| Standard     | The standard deviation score corresponding to a       |
| deviation    | particular observation is a number that indicates how |
| score        | many standard deviations (SD) the observation is from |
|              | the reference population mean. It is positive or      |
| SDS          | negative according to whether the observation lies    |
|              | above or below the mean.                              |
+--------------+-------------------------------------------------------+
| Study drug   | Refers to Humatrope or placebo.                       |
+--------------+-------------------------------------------------------+
| Target       | The sex-adjusted average of parent's heights (this is |
| height       | the patient's genetic target).                        |
+--------------+-------------------------------------------------------+
| Treatm       | Any adverse event that was not present at baseline or |
| ent-emergent | any pre-existing condition or event present at        |
| adverse      | baseline that increased in severity during the study. |
| event\       |                                                       |
| \            |                                                       |
| *TEAE*       |                                                       |
+--------------+-------------------------------------------------------+

# List of Clinical Studies

  ------------------ ----------------------------------------------------
  **STUDY**          **TITLE**

  Pivotal:           

  B9R-MC-GDCH\       Humatrope in Non-Growth Hormone Deficient Children
  Clinical Phase 3   with Short Stature.

  Supportive:        

  B9R-EW-E001\       The Efficacy and Safety of Biosynthetic Authentic
  Clinical Phase 3   Human Growth Hormone in Short Prepubertal Children
                     with Normal Growth Hormone Response to Standard
                     Provocation Tests.

  Meta-analysis\     Finkelstein BS, Imperiale TF, Speroff T, Marrero U,
  Peer-Reviewed      Radcliffe DJ, Cuttler L. 2002. Effect of growth
  Literature         hormone therapy on height in children with
                     idiopathic short stature. A meta-analysis. Arch
                     Pediatr Adolesc Med 156:230-240.
  ------------------ ----------------------------------------------------

# Executive Summary

This briefing document has been developed to aid the FDA Advisory
Committee in evaluating Humatrope® (somatropin \[rDNA origin\] for
injection) as a treatment for pediatric patients with non-growth
hormone-deficient short stature (non-GHD short stature); meeting
scheduled for 10 June 2003. Throughout this document, the term
somatropin refers to all brands of recombinant growth hormone (GH).
Humatrope refers specifically to the Lilly brand of somatropin.
Humatrope is a recombinant DNA-derived human growth hormone, identical
in amino acid sequence to the 22-kd native human growth hormone. It was
approved on 08 March 1987 as replacement therapy "for the long-term
treatment of children who have growth failure due to an inadequate
secretion of normal endogenous growth hormone." On 11 March 1997,
Humatrope was also approved for the treatment of short stature
associated with Turner syndrome. Currently these are the only two
pediatric indications for which Humatrope is approved. Humatrope has
been approved at dosages up to 0.375 mg/kg/wk. This document summarizes
the clinical efficacy and safety data for Humatrope in pediatric
patients with non-GHD short stature and the benefits and risks of such
treatment.

**[INTRODUCTION]{.underline}**

The 1983 International Conference on Uses and Abuses of Growth Hormone
recognized a need for studies in "short children who do not have growth
hormone deficiency" (Underwood 1984). In 1987, the FDA Endocrinologic
and Metabolic Drugs Advisory Committee further defined this need by
recommending that a study to evaluate GH treatment in this population be
a randomized, placebo-controlled trial to final height.

A pivotal trial, Study B9R-MC-GDCH, was designed and conducted in the US
by Lilly and the National Institutes of Health between 1988 and 2001.
Study GDCH (n=71) was, as recommended by the FDA Advisory Committee, a
double-blind, randomized, placebo-controlled study to final height.

Somatropin treatment is currently approved for 5 pediatric indications
(growth hormone deficiency \[GHD\], chronic renal insufficiency, Turner
syndrome, Prader-Willi syndrome, and children born small for gestational
age), the latter 4 being non-GHD conditions. The average height of
patients with non-GHD short stature is very similar to that of other
pediatric growth disorders. Patients who do not pass the growth hormone
treatment eligibility test (growth hormone response to stimulation falls
above a defined threshold) and do not have one of the approved non-GHD
indications have no approved treatment, despite an equivalent degree of
short stature.

Over the past four decades the inequity of treatment availability for
patients with non-GHD short stature led to a large volume of research
(Finkelstein et al. 2002) on somatropin treatment in this patient
population, culminating in Lilly's pivotal and supporting studies, which
were conducted between 1988 and 2001.

**[EFFICACY]{.underline}**

Evidence for the efficacy of Humatrope treatment in pediatric patients
with non-GHD short stature is presented. Data sources include: one
pivotal trial - US, double-blind, randomized placebo-controlled study to
final height; one supportive trial - European multicenter, 2‑year,
three-arm, open-label, dose-response study with extension to final
height; and a published meta-analysis on the effect of growth hormone
treatment on height velocity and final height in patients with non-GHD
short stature (Finkelstein et al. 2002).

Humatrope was effective in increasing final height as shown by the
results of the pivotal study and the supportive dose-response study.
Study GDCH (0.22 mg/kg/wk, given in divided doses 3 times per week)
involved patients with a baseline mean height well below the normal
range (-2.8 standard deviation score \[SDS\]). After a mean treatment
duration of 4.4 years, and at a mean age of 18.8 years, the mean final
height of the Humatrope-treated group was within the normal range, at
-1.8 SDS, and was significantly greater than that of the placebo-treated
group, which remained below the normal range, at -2.3 SDS. The primary
analysis, prespecified in the protocol, was an analysis of covariance
(ANCOVA) of final height SDS, with baseline predicted height SDS as the
covariate. The mean treatment effect by this analysis was 0.51 SDS (95%
CI: 0.10 to 0.92 SDS), corresponding to 3.7 cm (p=0.017). Sensitivity
analyses indicated a mean treatment effect of 2.8 to 5.0 cm. These
included intent-to-treat analyses, by both non-parametric and parametric
methods that confirmed the significantly greater height SDS of the
Humatrope-treated patients. These gains in height SDS were achieved
without any untoward effect on skeletal maturation or pubertal
development.

Study B9R-EW-E001 (n=239) was a multicenter, 2-year, three-arm,
open-label, dose-response study with extension to final height. Patients
were randomized to one of three treatment regimens: 0.24 mg/kg/wk; 0.24
mg/kg/wk the first year and 0.37 mg/kg/wk thereafter or 0.37 mg/kg/wk;
all dosages were given in divided doses 6 times per week. A
dose-response effect for Humatrope was demonstrated by a greater
increment in height velocity over the first 2 years of treatment for the
patient group that received 0.37 mg/kg/wk compared with the group that
received 0.24 mg/kg/wk (between-dose effect: 0.8 cm/y, 95% CI: 0.3 to
1.3 cm/y, p = 0.003). Furthermore, a greater overall height gain, by
approximately 3 cm, was observed at the higher dosages (incremental
effect of 0.37 mg/kg/wk versus 0.24 mg/kg/wk).

In addition to the above evidence for dose-response, within-group
analyses of final height minus baseline predicted height provided an
estimate of treatment effect. This is a conservative estimate of
treatment effect because untreated patients with non-GHD short stature
have been shown, on average, to reach an adult height below their
baseline predicted height (Bramswig et al. 1990; Ranke et al. 1995;
Buchlis et al. 1998; Rekers-Mombarg et al. 1999), as did the
placebo-treated patients in Study GDCH. The mean treatment effect sizes
for this efficacy measure were 5.4 cm, 6.7 cm, and 7.2 cm for the
dosages of 0.24 mg/kg/wk, 0.24→0.37 mg/kg/wk, and 0.37 mg/kg/wk,
respectively. Thus, the mean gain in adult height attributable to GH
treatment with the 0.37 mg/kg/wk dosage was approximately 7 cm compared
to the height that patients were predicted to achieve in the absence of
treatment.

The supportive literature meta-analysis addressed the effect of GH
therapy on height in children with non‑GHD short stature (referred to as
idiopathic short stature in the paper). The meta-analysis includes 38
studies, of which 4 studies that included a concurrent control group
provide final height data. For these 4 studies, the mean weighted GH
dosage was 0.31 mg/kg/wk given in divided doses 6 times per week. The
mean duration of treatment was 5.3 years. The between-group differences
in achieved adult height for these 4 studies suggested a mean GH
treatment effect of 5 to 6 cm (Finkelstein et al. 2002). Thus, published
studies support the efficacy of GH in non-GHD short stature, with the
magnitude of benefit being similar to that observed in the Lilly pivotal
and supportive dose-response studies.

The efficacy of Humatrope in increasing final height of patients with
non-GHD short stature is similar to that seen in the approved indication
for Turner syndrome. Study B9R-CA-GDCT was a randomized, open-label
study in patients with Turner syndrome, with an untreated control group
as the comparator. The Humatrope dosage was 0.30 mg/kg/wk, given in
divided doses 6 times per week. A planned interim analysis indicated a
between-group difference in final height (t-test) of 3.9 cm (p=0.001). A
sensitivity analysis, an ANCOVA, with mid-parental height SDS as the
covariate, indicated a treatment effect of 5.4 cm (p=0.001). Thus, in
the only other study to date with a long-term randomized control group
to final height, the GH treatment effect was similar to that observed in
the pivotal study of patients with non-GHD short stature.

Following the recommendation of the 1987 Endocrinologic and Metabolic
Drugs Advisory Committee, Lilly conducted studies of patients with
non-GHD short stature and focused on the treatment of their short
stature. Neither Study GDCH nor Study E001 provided evidence of
potential benefits in quality of life or psychological well-being.
However, several lines of evidence suggest that the magnitude of
GH-induced height gain in patients with non-GHD short stature was large
enough to be clinically meaningful. First, the GH-induced height gain in
patients with non-GHD short stature was similar to that achieved in
Turner syndrome. Second, the mean heights of Humatrope-treated patients
in Study GDCH, and of the 0.37 mg/kg/wk dosage group in Study E001,
moved into the normal range during the course of treatment. Third,
whereas most final height SDS values of placebo-treated patients in
Study GDCH were below normal, and all were below the 5th percentile, 94%
of final height SDS values among the 0.37 mg/kg/wk dosage group of Study
E001 were within the normal range.

**[SAFETY]{.underline}**

Somatropin has a 16-year safety history and is currently approved for
five pediatric indications and dosages up to 0.7 mg/kg/wk. Worldwide it
can be estimated that as many as 200,000 patients have been exposed to
somatropin, representing over 500,000 patient-years of treatment.

In this document, the safety of Humatrope in patients with non-GHD short
stature is evaluated by comparing the data collected in the non-GHD
short stature clinical trials (Studies GDCH \[n=68; Humatrope=37\] and
E001 \[n=239\]) with the safety data obtained in the clinical trials of
Humatrope in patients with GHD (Study B9R-MC-GDAB \[n=333\]) and those
with Turner syndrome (Study GDCT \[n=136; Humatrope=74\] and Study
B9R-MC-GDCI \[n=230\]), the two pediatric populations for which
Humatrope is currently approved.

Regarding deaths, discontinuations due to adverse events (AEs), or
serious adverse events (SAEs) there were no meaningful differences
identified between treatment groups or across studies or conditions.

Rates of SAEs were somewhat greater in the GHD and Turner syndrome
studies than in the non-GHD short stature studies. This probably relates
to the higher baseline rates of serious illnesses in patients with GHD
and Turner syndrome, particularly neurological disorders associated with
GHD and ear and cardiac disorders associated with Turner syndrome,
predisposing these patients to adverse events. The rates of serious
adverse events reported for the Humatrope-treated groups are as follows:
Study GDAB (GHD), n=90 (27%); Study GDCT (Turner syndrome), n=20 (27%);
Study GDCI (Turner syndrome), n=41 (18%); Study GDCH (non-GHD short
stature), n=5 (14%); Study E001 (non-GHD short stature), n=31 (13%).

In both the GHD and the non-GHD short stature studies, there were two
cases of newly diagnosed neoplasia, described in detail in the Safety
section (Section 4) of this document. Neither case of neoplasia in the
non-GHD short stature studies (Hodgkin lymphoma and desmoplastic small
round cell tumor) was considered causally related to Humatrope exposure.

Patterns of treatment-emergent adverse events (TEAEs) differed somewhat
between patient populations, mainly due to the presence of underlying
disease in the GHD and Turner syndrome populations. There were no
statistically significant differences in TEAE rates between Humatrope
and placebo groups in the pivotal study. Except for scoliosis, all AEs
currently referenced in the Humatrope label occurred at similar or lower
rates in patients with non-GHD short stature. Scoliosis was evaluated
with added vigilance at the NIH and AE rates were found to be similar
between the Humatrope and placebo treatment groups. There was no
evidence of a Humatrope effect on parameters of carbohydrate metabolism
in either of the two non-GHD short stature studies, and IGF-I
concentrations, measured only in Study GDCH, remained physiologic.

Overall, the safety profile of Humatrope treatment in this new patient
population does not differ in a clinically meaningful way from that seen
in the currently approved pediatric indications and no new safety
language is required in the label.

**[BENEFIT-RISK ASSESSMENT]{.underline}**

Benefits of Humatrope treatment in patients with non-GHD short stature
are improved linear growth in childhood (allowing a degree of catch-up
to peers) and increased height at completion of linear growth. The
magnitude of the benefit is similar to that seen in patients with Turner
syndrome. The risks to pediatric patients identified in the current
Humatrope label are quite low, relatively mild, readily manageable, and
in some cases, transient. No new risks have been identified for patients
with non-GHD short stature. The benefit-risk profile of Humatrope
treatment in patients with non-GHD short stature is similar to that seen
in Turner syndrome. Humatrope is safe and effective for the treatment of
non-GHD short stature at a dosage of up to 0.37 mg/kg/wk.

In light of evidence for a positive benefit-risk profile, the following
label indication is proposed:

*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.*

**[RISK MANAGEMENT PROGRAM]{.underline}**

Lilly has identified areas of potential concern regarding approval of
this new indication: inappropriate prescribing, lack of adequate
diagnostic evaluation prior to initiation of treatment, and emergence of
new adverse events.

Potential concerns will be addressed by the following elements of the
Lilly Risk Management Program:

\[1\] Lilly is proposing a restrictive label to help establish
appropriate use of Humatrope for this indication; the proposed
indication excludes other causes of short stature and, unlike all
previous pediatric indications, defines a maximum height threshold
(height SDS ≤‑2.25) for initiating treatment. This is a more
conservative threshold than the definition of short stature of height
SDS ≤‑2.0 (AAP 1997; AACE 2003).

\[2\] Physicians will be trained (according to FDA guidelines) regarding
the changes to the label and the restrictions for this patient
population.

\[3\] Marketing will be limited to endocrinologists only, with no
direct-to-consumer advertising.

\[4\] A proprietary controlled distribution process contributes to
assuring appropriate prescribing and distribution of Humatrope to all
patients including those with non-GHD short stature.

\[5\] Pharmacovigilance and a post-marketing research program (Genetics
and Neuroendocrinology of Short Stature International Study \[GeNeSIS\])
will continue to collect and analyze prospectively defined adverse
events as well as spontaneously reported adverse events. These data are
analyzed annually and reported to investigators.

\[6\] Additionally, there are a number of external factors that also
mitigate these concerns independent of Lilly, including: 1) professional
judgment of pediatric endocrinologists; 2) guidelines for growth hormone
usage developed by professional endocrine societies; and 3) the
requirement by insurance companies for demonstration of medical need.

**[CONCLUSION]{.underline}**

Humatrope is safe and effective in pediatric patients with non-GHD short
stature. The approval of Humatrope for pediatric patients with non-GHD
short stature will correct the current inequity in treatment
availability for this population.

# 1. Introduction

Humatrope® (somatropin \[rDNA origin\] for injection) is a recombinant
DNA-derived human growth hormone, identical in amino acid sequence to
the 22-kd native human growth hormone. Humatrope was approved on 08
March 1987 (NDA 19‑640) as replacement therapy "for the long-term
treatment of children who have growth failure due to an inadequate
secretion of normal endogenous growth hormone." On 11 March 1997,
Humatrope was also approved for the treatment of short stature due to
Turner syndrome. Currently, these are the only two pediatric indications
for which Humatrope is approved.

Eli Lilly and Company submits this briefing document to the
Endocrinologic and Metabolic Drugs Advisory Committee of the Food and
Drug Administration in support of the application for approval of
Humatrope as treatment for non-growth hormone-deficient short stature
(non-GHD short stature). Lilly realizes that a number of issues and
concerns exist regarding the implications of an approval for this
indication. Therefore, to support this application, this briefing
document, in addition to presenting detailed analysis of safety and
efficacy, will address the following questions:

-   Is it appropriate to treat patients whose short stature is not
    clearly associated with a defined "disease"?

-   Is GH effective in these patients, and is the magnitude of benefit
    clinically relevant?

-   Should psychological benefits be a required outcome of GH treatment?

-   Is this treatment safe in this patient population?

-   Why was the height cut-off of --2.25 SDS chosen for the label
    indication?

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

-   Will this new indication "open the floodgates" to inappropriate use?

These issues will be addressed within the appropriate sections of this
document, and will be summarized in the Benefit-Risk (Section 5) and
Risk-Management (Section 6) sections.

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

This section summarizes key milestones, or interactions and agreements
reached between the US Food and Drug Administration (FDA) Division of
Metabolic and Endocrine Drug Products and Eli Lilly and Company (Lilly)
regarding Lilly studies of efficacy and safety of Humatrope in pediatric
patients with non‑GHD short stature. Throughout this document, once each
specific protocol has been identified by its full study code, all
subsequent referrals will be by the final four letters alone (for
example, Study B9R‑MC‑GDCH will be referred to as Study GDCH).

**18 June 1986:** Lilly submitted an investigational new drug
application (IND 28,574) to support studies of Humatrope for
non-hypopituitary indications.

**07 July 1987:** Lilly submitted to IND 28,574 the protocol for
Study GDCH. Study GDCH was a double‑blind, randomized, parallel,
placebo‑controlled clinical study of Humatrope to final height in
pediatric patients with non[-GHD]{.smallcaps} short stature.

**28 September 1987:** The Endocrinologic and Metabolic Drugs Advisory
Committee of the FDA met to provide guidance for GH manufacturers
regarding studies of GH treatment in pediatric patients with non-GHD
forms of short stature. The committee unanimously agreed that the
critical endpoint was final height and that such studies should include
a control group. Although there were concerns about the type and
feasibility of the control, the committee recommended, "...the control
group should be a placebo‑treated, parallel, randomized group of
patients..." and "...the subjects should be followed until their
ultimate height is reached..." (FDA 1987, Dr Philip Troen).

**22 January 1988:** Study GDCH was initiated by Lilly and the National
Institute of Child Health and Human Development (NICHD) of the National
Institutes of Health (NIH).

**1992:** There was a challenge to the study by a third party who
asserted that the study was being conducted contrary to the principles
that should be followed when using children in medical research. In
response to this challenge, the NIH convened an external advisory panel,
the Human Growth Hormone Protocol Review Committee (HGHPRC). The HGHPRC
concluded that the protocol addressed an important public health need
and did not violate any of the applicable Department of Health and Human
Services (HHS) regulations cited in the challenge (45 Code of Federal
Regulations \[CFR\] Part 46). It was recommended that a Data and Safety
Monitoring Board (DSMB) be convened to conduct an independent review of
the study on a regular basis. The role of the DSMB was to provide an
independent review of the accumulating data in the study, and to
evaluate the appropriateness of continuing the study in the context of
these data and any other relevant published data. No formal statistical
stopping rules were instituted. The external DSMB was subsequently
convened and reviewed interim data, unblinded at the treatment group
level, at each of its meetings.

**28 October 1993:** The external DSMB met for the first time to conduct
an independent review of the study. After a detailed examination of
data, the DSMB recommended continuation of Study GDCH. The DSMB convened
again on 14 October 1994, 18 April 1996, 03 June 1997, 08 June 1998, and
24 June 1999, each meeting returning a recommendation for continuation
of the study.

**05 June 2000:** The DSMB met and recommended that the
placebo‑controlled study be terminated, that active patients be offered
the option to receive open‑label treatment, and that the results be
disseminated as soon as possible. At that time, patients were reaching
final height at a rate of 2 patients per year and it would have required
approximately 5 additional years before the remaining patients reached
final height. Therefore, the DSMB unanimously concluded, "...the study
is not maturing sufficiently to justify the maintenance of a placebo
injection control group." (written communication, Data Monitoring
Committee Report, 05 June 2000).

**31 July 2001:** A pre‑supplemental New Drug Application (pre‑sNDA)
meeting between Lilly and the FDA was held to discuss a plan by Lilly to
submit a data package in support of an indication for non-GHD short
stature. The FDA indicated that the planned submission appeared to be
acceptable for review.

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

Over the past 40 years there have been significant advances in the
understanding and management of childhood growth disorders. When human
growth hormone (GH) was first introduced as a therapeutic agent in 1958,
its use was restricted to children with the most severe forms of growth
hormone deficiency (GHD) due to hypopituitarism. Availability was
limited by the supply of GH, due to both its human source and to the
complex and time‑consuming extraction and purification procedures
required. Following the withdrawal of pituitary-derived human GH and the
introduction of recombinant DNA-derived GH in the mid 1980s, treatment
became available for children with less severe forms of GHD. In
addition, the potential value of GH treatment for impaired growth due to
other conditions began to be investigated. In 1985 recombinant methionyl
GH (somatrem) was approved for treatment of pediatric patients with
growth failure due to inadequate secretion of endogenous GH. Natural
sequence recombinant DNA-derived GH (somatropin) was first approved for
the same indication in 1987 (initial dosage approved was 0.18 mg/kg/wk;
current approved dosage range is 0.18 to 0.30 mg/kg/wk). In the 16 years
following its introduction, the safety and efficacy of somatropin has
been established and treatment approved for four additional pediatric
disorders in patients who are not GHD. These approvals allowed
physicians to provide safe and effective treatment for impaired growth
in children with chronic renal insufficiency, Turner syndrome,
Prader-Willi syndrome, and children born small for gestational age (SGA)
who fail to catch up in height. The goal of treatment in these patients
is to treat the growth impairment and not the underlying condition.
Currently, the approved dosage range across these pediatric indications
(all brands of somatropin combined) is 0.18 to 0.70 mg/kg/wk.

Growth failure and short stature are among the most common reasons for
which children are evaluated by pediatric endocrinologists. The term
"growth failure" refers to the decline in the rate of linear growth
(height velocity) that, if persistent, results in short stature. Various
definitions of short stature can be found in the literature; however,
the most commonly used and generally accepted definition is provided by
the American Association of Clinical Endocrinologists (AACE) and the
American Academy of Pediatrics (AAP), and defines short stature as
height more than 2.0 standard deviations below the population mean (AAP
1997; AACE 2003). By US standards, this is equivalent to 5'3.6" for an
adult male, and 4'11.1" for an adult female. Because there are numerous
endocrine and non-endocrine causes of growth failure and short stature,
careful and comprehensive investigation is required to determine the
cause. The Growth Hormone Research Society (GRS) recommends
investigation of children with short stature whose height falls below
-2.0 standard deviation scores (SDS) (GRS 2000).

Investigation of growth failure or short stature includes detailed
history, assessment of the patient's and family's patterns of growth
over time, physical examination with specific attention to body
proportions and phenotypic markers of certain syndromes, and a number of
biochemical, radiological and sometimes genetic evaluations as outlined
in the diagnostic algorithm presented in Figure 1.

![](media/image1.wmf){width="5.909027777777778in" height="6.175in"}

> \* Patients with Turner syndrome have variable shortness of the
> forelimbs, which becomes more apparent with age. These patients may
> also have other skeletal anomalies such as short fourth metacarpal,
> increased carrying angle, high-arched palate, and Madelung deformity.\
> Note: This figure was compiled from the following references: Parkin
> 1989; Schwartz and Bercu 1992; Van den Brande and Rappaport 1993;
> Blizzard and Johanson 1994; Reiter and Rosenfeld 1998; Hintz and
> Ritzen 1999.
>
> Abbreviations: GH = growth hormone; GHD = growth hormone deficiency;
> IGF‑I = insulin‑like growth factor‑I; IGFBP-3 = insulin‑like growth
> factor binding protein‑3; NGHDSS = non‑growth hormone deficient short
> stature.

[]{#__RefHeading___Toc39468369 .anchor}Figure 1. A diagnostic algorithm
for investigation of short stature.

The final step in the diagnostic process is a growth hormone stimulation
test, in which pharmacological agents are administered to provoke
release of pituitary GH stores. Patients whose peak responses to
stimulation fall below a defined threshold are classified as GHD and are
eligible for GH treatment. In contrast, patients whose GH responses
exceed the specified threshold are deemed non-GHD and are ineligible for
GH treatment, despite phenotypes and degrees of short stature
essentially indistinguishable from those with GHD. Patients, their
families, and physicians find this inequity frustrating. The inequity of
this situation is further exacerbated by the fact that patients with
chronic renal insufficiency, Turner syndrome, Prader-Willi syndrome, and
those born small for gestational age are eligible for GH treatment
irrespective of their GH secretion status or degree of short stature.

The lack of approved therapy for patients who have neither GHD, nor one
of the 4 non-GHD conditions listed above, led to much discussion in the
pediatric endocrine community over many years, regarding why such
children should or should not be eligible for GH treatment. In assessing
this question, the following points should be considered:

1.  Children and adults with short stature may have disadvantages with
    respect to their peers, irrespective of the cause of the short
    stature.

2.  The growth failure in patients with non-GHD short stature is
    equivalent to that seen in other growth disorders.

3.  The majority of untreated patients with non-GHD short stature fail
    to achieve their adult height prediction.

4.  GH treatment in other pediatric conditions treats the growth failure
    or short stature, not the underlying condition or "disease".

5.  Absence of a known etiology for the growth failure does not justify
    exclusion from treatment.

6.  The growth failure in patients with non-GHD short stature is
    responsive to GH treatment.

Each of the first five points above are discussed further in the
following paragraphs, while the sixth point is discussed in the Efficacy
Section (Section 3) of this document.

First, children and adults with short stature, irrespective of cause,
may have a number of disadvantages in life relative to their
normal-stature peers. Short children may be subject to juvenilization,
teasing, bullying, exclusion from activities and peer groups and
impairment of the normal progression toward independence (Sandberg 1999;
Voss and Mulligan 2000). In adulthood there may be problems of social
isolation, reduced marriage rates, perceptions of lower competence, and
ineligibility for certain occupations that have specific minimum height
requirements. There are a number of potential employers, such as
construction companies, the aviation and aerospace industries, and the
military, that have minimum height standards for employees. Furthermore,
aspects of daily living such as driving a car, accessing cupboards,
using kitchen or bathroom benches or sinks, and using standard height
furniture in workplaces may provide additional challenges.

Second, there is marked concordance in the severity of growth failure
and short stature among the various growth disorders for which
somatropin treatment is typically prescribed (Table 1). In two large
postmarketing research programs (the National Cooperative Growth Study
\[NCGS\] and the Kabi International Growth Study \[KIGS\]), height SDS
at initiation of GH treatment was well below normal across the various
conditions. Table 1 shows a remarkable similarity between patients with
non‑GHD short stature (referred to in these reports as idiopathic short
stature) and patients with conditions for which somatropin is currently
approved. The values in the table represent mean height SDS ± standard
deviation at the initiation of GH treatment.

[]{#__RefHeading___Toc39468338 .anchor}Table 1. Mean Height SDS of
Patients with Growth Disorders at Initiation of Growth Hormone Treatment

  ----------------------- ----------------- ----------------- -----------------
  **Condition**           **Mean Height     **Corresponding   **Corresponding
                          SDS**             adult male        adult female
                                            height\           height\
                                            (feet, inches)**  (feet, inches)**

  Idiopathic GHD          -2.8 ± 1.1 a      5 ft, 1.3 in      4 ft, 9.1 in

  Idiopathic Short        -2.9 ± 0.9 a      5 ft, 1.0 in      4 ft, 8.8 in
  Stature                                                     

  Chronic Renal           -2.6 ± 0.8 b      5 ft, 1.9 in      4 ft, 9.6 in
  Insufficiency                                               

  Turner Syndrome         -2.8 ± 1.0 c      NA                4 ft, 9.1 in

  Small for Gestational   -2.8 ± 0.9 d      5 ft, 1.3 in      4 ft, 9.1 in
  Age                                                         
  ----------------------- ----------------- ----------------- -----------------

Note: Values represent mean ± SD. Conversion of height SDS to feet and
inches was based on Kuczmarski et al. 2000.

Abbreviations: GHD = growth hormone deficiency; SDS = standard deviation
score.

a Root et al. 1998.

b Fine et al. 1996.

c Ranke et al. 2000.

d Ranke et al. 2003.

These observational study data also demonstrate the relative severity of
short stature in patients entering GH treatment compared to accepted
definitions of short stature (AAP 1997; AACE 2003) and with the
recommended height threshold for further investigation (GRS 2000), of
--2.0 SDS. This finding reflects the fact that pediatric
endocrinologists carefully evaluate children with short stature and take
a conservative approach, providing GH treatment to those with the
greatest need.

Third, in addition to the equivalence of their short stature at
baseline, as demonstrated in a number of studies, untreated patients
with non-GHD short stature achieve adult heights that fall below the
adult heights predicted for them during childhood (Bramswig et al. 1990;
Ranke et al. 1995; Buchlis et al. 1998; Rekers-Mombarg et al. 1999).

Fourth, GH treatment in pediatric patients with growth disorders is
intended to treat the growth failure or short stature, not the
underlying condition or "disease". This is evidenced by the language of
the label indication for each of the conditions for which somatropin is
currently approved. Somatropin is indicated for: "the long‑term
treatment of pediatric patients who have **growth failure** due to an
inadequate secretion of normal endogenous growth hormone"; "the
treatment of **short stature** associated with Turner syndrome in
patients whose epiphyses are not closed"; "treatment of **growth
failure** associated with chronic renal insufficiency up to the time of
renal transplantation"; "long-term treatment of **growth failure** due
to Prader-Willi syndrome"; "long-term treatment of **short stature** in
children born small for gestational age who fail to manifest catch-up
growth by age 2". Indeed, in each of the above conditions, while the
etiology of the disorder itself may be known (for example, complete or
partial loss of one X-chromosome in Turner syndrome), the cause of the
growth disturbance is only partially understood, if at all. The key
distinction between patients with non-GHD short stature and those with
conditions for which somatropin is currently approved is that most of
the latter have additional problems beyond their growth disturbance
(such as ovarian failure in Turner syndrome) that are not addressed by
somatropin. The exception is the child born small for gestational age,
whose short stature is typically the only clinical abnormality.

Fifth, the fact that children with non-GHD short stature are regarded by
some as having no "disease", does not justify excluding them from
effective treatment. There are many such conditions in both pediatric
and adult patients that deserve and receive treatment. Examples include
enuresis, hypertension, hypercholesterolemia, erectile dysfunction,
alopecia, hirsutism, gynecomastia, anxiety disorder, and nicotine
addiction. Whether or not any of these conditions is formally considered
a "disease" appears to have no bearing on the appropriateness of
treating the condition. Prevention of pregnancy is also an accepted
therapeutic aim for a condition that is not considered a disease.

Recognizing the unmet medical need of patients with non-GHD short
stature the 1983 International Conference on Uses and Abuses of Growth
Hormone, was convened by the National Institute of Child Health and
Human Development (NICHD) and issued this consensus statement:
"....there is an urgent need for therapeutic trials to determine the
effect of growth hormone in short children who do not have growth
hormone deficiency" (Underwood 1984). Subsequently, the Endocrinologic
and Metabolic Drugs Advisory Committee of the FDA provided guidance for
GH manufacturers regarding studies of GH treatment in pediatric patients
with non-GHD forms of short stature. The committee unanimously agreed
that the critical endpoint was final height and that such studies should
include a control group. Although there were concerns about the type and
feasibility of the control, the committee recommended, "...the control
group should be a placebo‑treated, parallel, randomized group of
patients..." and "...the subjects should be followed until their
ultimate height is reached..." (FDA 1987, Dr Philip Troen). In the 16
years following the introduction of recombinant GH, more than 40 studies
have been undertaken in the non-GHD short stature patient population.
Efficacy has been demonstrated by improvements in height velocity,
although few of these studies have followed patients to adult height and
none have been placebo controlled (Finkelstein et al. 2002).

"Lessening the disability of severe short stature has been the goal of
GH therapy for three decades" (Allen et al. 1994). However, for patients
whose growth failure is not associated with one of the five conditions
for which GH is currently approved, this goal is currently unattainable.
To address this deficit, Lilly undertook two long-term studies of the
safety and efficacy of GH treatment in patients with non‑GHD short
stature. The pivotal study, Study GDCH, specifically followed the FDA
Advisory Committee's 1987 recommendation and is the only randomized,
double-blind, placebo-controlled study to final height in this patient
population. Study GDCH unequivocally demonstrates that GH treatment is
effective in patients with non-GHD short stature. The efficacy of GH in
this condition is also supported by Study E001, a second large,
long-term, randomized, dose-response study, and by data from a
comprehensive meta-analysis of the peer-reviewed literature (Finkelstein
et al. 2002).

The establishment of clear efficacy of GH treatment in patients with
non-GHD short stature, in the absence of any new safety concerns,
provides the scientific, medical, regulatory, and ethical justification
for approval of Humatrope treatment for these patients.

# 2. Overview of Clinical Studies

The efficacy of Humatrope for the treatment of non-GHD short stature is
addressed by: one randomized, placebo-controlled, pivotal clinical
trial; one randomized, dose-response study; and a recent meta-analysis
of the peer-reviewed literature. Brief summaries of these studies are
provided below, while detailed information regarding study design,
patient demographics, and efficacy data are provided in the following
section (Section 3). The safety of Humatrope treatment in patients with
non-GHD short stature is addressed (Section 4) by comparison of Lilly
studies in this patient population with studies undertaken in patients
with GHD and with Turner syndrome.

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

Study GDCH was a double‑blind, randomized, parallel, placebo‑controlled
study to final height in pediatric patients with non-GHD short stature
(n=71). The primary objective of the study was to determine whether
final height of patients with non-GHD short stature treated with
Humatrope (0.22 mg/kg/wk, administered in divided doses 3 times per week
\[TIW\]) would be greater than that of a placebo-treated group. The
primary efficacy variable was final height, expressed as a standard
deviation score (SDS) relative to the general population of the same age
and gender (final height SDS).

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

Study E001 was an open-label, three-arm, randomized, parallel,
dose-response study. Pediatric patients with non-GHD short stature
(n=239) were randomly assigned to receive one of the following three
Humatrope regimens (administered in divided doses 6 times per week):

-   Dose 1: 0.24 mg/kg/wk;

-   Dose 2: 0.24 mg/kg/wk for 1 year, followed by 0.37 mg/kg/wk; or

-   Dose 3: 0.37 mg/kg/wk.

The primary objective of this study was to determine the efficacy of two
different Humatrope dosages (0.24 versus 0.37 mg/kg/wk) in stimulating
an increase in height velocity in pediatric patients with non-GHD short
stature. The increase in height velocity during the initial 2 years of
treatment was the primary variable used to evaluate dose-response effect
among the Humatrope dosage regimens. Final height SDS was a secondary
outcome measure, as were the following variables: final height minus
baseline height (cm and SDS); final height minus baseline predicted
height (cm and SDS); and final height minus target height (cm and SDS).

## 2.3. Supportive Peer-Reviewed Literature Studies

A recent meta‑analysis (Finkelstein et al. 2002) provides supportive
evidence from the literature for the effectiveness of GH treatment in
pediatric patients with non-GHD short stature. The data reported in this
meta‑analysis are derived from 10 controlled studies and 28 uncontrolled
studies that used recombinant GH (somatropin) from several
manufacturers. Of these studies, 12 (4 controlled and 8 uncontrolled;
total number of patients = 454) provide data on adult height, and will
be used to support the use of Humatrope in pediatric patients with
non-GHD short stature.

# 3. Effectiveness of Humatrope

## 3.1. Pivotal Clinical Study: GDCH

Study GDCH was a double‑blind, randomized, parallel, placebo‑controlled
study to final height in pediatric patients with non-GHD short stature.

### 3.1.1. Primary Objective

The primary objective of the study was to determine whether final
height, defined as the last height obtained after height velocity had
fallen below 1.5 cm/y, would be greater in patients treated with
Humatrope than in those who received placebo injections.

### 3.1.2. Study Design

Study GDCH consisted of a screening period and a blinded treatment
period. Patients in the Humatrope group received 0.074 mg/kg Humatrope
by subcutaneous injection, 3 times per week (total dose 0.22 mg/kg/wk:
standard of care at the time for GHD was 0.18 mg/kg/wk); patients in the
placebo group received placebo injections 3 times per week.
Participation in the primary (blinded) treatment period ended either
when the patient reached final height (protocol completion) or at the
time of closure of the blinded study, by Lilly, at which time eligible
patients were offered the opportunity to enter an optional, open‑label
extension phase. Figure 2 presents the study design. The open‑label
extension phase is omitted for clarity, since no efficacy data are being
collected from the open-label, single arm (Humatrope only) extension.

![](media/image2.wmf){width="5.763194444444444in"
height="3.265277777777778in"}

\+ Only the subset of patients on whom lower leg measurements were
obtained attended study Visits 2 to 4 and 6.\
\* Poststudy summary visit (Visit 99): 1 year after protocol completion
for patients completing the protocol; at final height for patients who
discontinued the study before protocol completion.

[]{#__RefHeading___Toc39468370 .anchor}Figure 2. Design of Study GDCH.

Patients who completed the study were asked to return for a final height
measurement 1 year after protocol completion. This poststudy follow‑up
visit was referred to as Visit 99. In addition, patients who
discontinued the study prior to protocol completion were asked to return
for a final height measurement after height velocity, measured locally,
had fallen below 1.5 cm/y. This poststudy follow‑up visit was also
referred to as Visit 99.

Patient enrollment began in January 1988 and continued through
July 1999, when it was ended at the request of the DSMB in view of the
length of the treatment required. The blinded treatment period ended in
February 2001.

### 3.1.3. Inclusion/Exclusion Criteria

Inclusion criteria were: age 10-16 (boys) or 9-15 years (girls); bone
age ≤13 (boys) or ≤11 years (girls); Tanner stage breast or genital
development ≤2; proportionate short stature; and peak stimulated GH \>7
μg/L. Patients were included if their height standard deviation score
(SDS) or predicted adult height SDS within 1 year prior to study entry
was ≤‑2.5. During the period from May 1988 to February 1993 a cutoff of
-2.25 SDS was used. Section 3.1.4.1 provides a detailed explanation of
these changes. Children with stimulated GH concentration \>7 μg/L were
considered GH-sufficient based on normative data generated with the same
GH assay (Marin et al. 1994). Thus, the term, "non-GHD short stature"
refers to children who have normal stimulated GH concentrations as
defined above. It is not meant to imply that GH has no role in the
etiology of the short stature. Patients were excluded if they had a
chronic illness, a known genetic syndrome, had ever received GH,
estrogen, or androgen treatment or were currently receiving other drugs
likely to affect growth, including methylphenidate and similar
stimulants. Patients with hypothyroidism were eligible to enroll after
thyroid function tests had been normal for at least 3 months on
replacement therapy.

When this study was designed in the 1980s, patients who were born
small-for-gestational age (SGA) were not excluded by the protocol, and 6
of the 71 patients enrolled met criteria for SGA (birth weight SDS ≤‑2.0
according to Table III of Usher and McLean \[1969\]). Because these
patients met the inclusion criteria for the study, they are included in
the study statistical analyses. At the pre-supplemental New Drug
Application meeting between Lilly and the FDA, on 31 July 2001, the FDA
indicated that a formal statistical analysis of SGA and non-SGA groups
would not be necessary. Nonetheless, analyses showed no differential
treatment effect between the effect in SGA patients and the effect in
non-SGA patients.

### 3.1.4. Summary of Key Protocol Changes

#### 3.1.4.1. Entry Height Criterion

In response to a suggestion by the FDA to improve the balance of the two
treatment groups, a stratified randomization was added in May 1988 (a
total of 3 patients had been enrolled in the study at that time), with
patients grouped by gender and predicted adult height. In addition, to
increase the rate of patient enrollment, the entry height criterion was
changed from height standard deviation score (SDS) or predicted height
SDS ≤-2.5 to height SDS or predicted height SDS ≤-2.25 (based on stature
data from the National Center for Health Statistics \[NCHS\] Growth
Charts \[1976\] and measured within the 12 months prior to Visit 1).
Based upon current US height standards (Kuczmarski et al. 2000), a
height SDS of -2.5 corresponds to an adult height of 5 feet, 2.2 inches
(157.9 cm) in males and 4 feet, 9.8 inches (146.9 cm) in females. A
height SDS of -2.25 corresponds to 5 feet, 2.9 inches (159.8 cm) in
males and 4 feet, 10.5 inches (148.5 cm) in females. Patients with
height SDS \<-2.25 represent the shorter 54% of patients who meet the
American Academy of Pediatrics definition of short stature (height SDS
\<-2.0 \[AAP 1997\]).

The entry criteria for upper height limit and predicted adult height
were changed in February 1993. At the recommendation of the Human Growth
Hormone Protocol Review Committee, an independent panel appointed by the
NIH Director, the inclusion criterion of height SDS or predicted height
SDS ≤-2.25 was changed back to that of the original protocol, stating
that patients must have height SDS or predicted height SDS ≤‑2.5.
Thirty-seven patients of the final 68 who received study drug (Humatrope
or placebo) were enrolled on the basis of height SDS or predicted height
SDS ≤‑2.25, during the period from May 1988 to February 1993. Of these
37 patients, six (2 Humatrope, 4 placebo) had a height SDS or predicted
height SDS at eligibility assessment between ‑2.5 and -2.25.

#### 3.1.4.2. Final Height Criterion

The original protocol defined the criterion for protocol completion as
the achievement of height velocity \<0.5 cm/y, based on measurements
made at 12‑month intervals. Two patients (1 Humatrope, 1 placebo)
completed the protocol with this criterion. In January 1994 (a total of
45 patients had been enrolled in the study at that time), the criterion
for protocol completion was changed from height velocity \<0.5 cm/y to
height velocity \<1.5 cm/y. This criterion was changed to address the
issue of drop-outs that occur as the height velocity slows down upon the
approach of final height. As the slow‑down progresses, the patient is
less likely to want to continue injections and more likely to drop out
of the study.

#### 3.1.4.3. Poststudy Summary Visit

To gather height and safety data for an intent‑to‑treat analysis, a
poststudy summary visit (Visit 99) was added in January 1994 (a total of
45 patients had been enrolled in the study at that time) for those
patients who had completed the study or who had discontinued the study
prior to protocol completion.

#### 3.1.4.4. Termination of Blinded Treatment Period

In response to the recommendation made by the DSMB on 05 June 2000, the
blinded treatment period of the study was terminated in January 2001 (a
total of 71 patients had been enrolled in the study at that time). An
open‑label extension phase was implemented to provide Humatrope‑treated
patients the opportunity to continue on Humatrope treatment and to allow
placebo‑treated patients the option to receive Humatrope treatment.

### 3.1.5. Population Definitions

The following populations were defined in the protocol:

**Randomized Patients (n=71):** Seventy‑one patients enrolled in the
study and were randomized into treatment groups (38 Humatrope,
33 placebo). Analysis of this population serves as an intent-to-treat
analysis for this study.

**Safety Population (n=68):** Of the 71 randomized patients, 3 patients
discontinued the study prior to receiving any study drug (1 Humatrope
\[physician decision\]; 2 placebo \[protocol entry criteria not met\]).
The remaining 68 patients were included in the *Safety Population*
(37 Humatrope, 31 placebo).

**Efficacy Evaluable Population (n=64):** Assessment of efficacy
required at least 6 months study drug treatment. Of the 68 patients in
the *Safety Population,* 3 patients discontinued without a height
measurement at 6 months (Visit 5: 2 Humatrope \[adverse event (1),
patient decision (1)\]; 1 placebo \[patient decision\]). One additional
placebo patient (Patient 008-1201), described below, who received growth
hormone (GH) outside the study, was excluded from the *Efficacy
Evaluable Population*. The remaining 64 patients were included in the
*Efficacy Evaluable Population* (35 Humatrope, 29 placebo). Analysis of
this population serves as a modified intent‑to‑treat analysis for this
study.

Patient 008-1201 was randomized to the placebo treatment group but was
excluded from the *Efficacy Evaluable* and *Final Height Populations*.
This patient discontinued the study at Visit 5, 6 months after
randomization, but returned for a final height visit, as requested.
Because the patient had a height measurement at Visit 5 and a final
height measurement, she would have qualified for the *Efficacy
Evaluable* and *Final Height Populations*. However, it was learned that
this patient had received growth hormone (GH) treatment for
approximately 4 years (personal communication, Ellen Leschek, MD) after
discontinuing the study. Because of the documented receipt of GH
treatment, this patient was excluded from the *Efficacy Evaluable* and
*Final Height Populations* but was included in the *Safety Population*
for the placebo group. Patient 008-1201 did not have any adverse events
after discontinuing the study.

**Protocol Complete Population (n=25):** Of the 64 patients from the
*Efficacy Evaluable* *Population*, 39 patients (19 Humatrope,
20 placebo) discontinued the study prior to reaching final height
(height velocity \<1.5 cm/y). Twenty-five patients completed the
protocol (16 Humatrope, 9 placebo) and were included in the *Protocol
Complete Population.*

**Final Height Population (n=33):** The 25 patients in the *Protocol
Complete Population* form the core of the *Final Height Population*. In
addition, 8 patients in the *Efficacy Evaluable Population*, who
discontinued the study prior to protocol completion (after a treatment
duration averaging 2.7 years) but returned for a final height
measurement, while still blinded to treatment assignment (6 Humatrope,
2 placebo), were included in the *Final Height Population*. Therefore,
there were 33 patients in the *Final Height Population* (22 Humatrope,
11 placebo). In addition, 4 patients returned for a final height
measurement but were excluded from the *Final Height Population* because
they were not included in the *Efficacy Evaluable Population* for the
following reasons: did not receive study drug (1 Humatrope, 1 placebo),
discontinued at Visit 1 (1 placebo), received GH after discontinuing
from the study (1 placebo).

At the conclusion of the blinded phase of the study, there were 39
patients in the *Efficacy Evaluable Population* who had discontinued the
protocol prior to protocol completion (19 Humatrope, 20 placebo).
Additional information was obtained regarding these patients from the
NIH investigators regarding the efforts to obtain final height data for
these 39 patients. Of the 39 patients, 21 patients were still growing
and were not eligible to be recalled for a final height measurement (11
Humatrope, 10 placebo). Eighteen patients were known or considered
likely to have a height velocity \<1.5 cm/y and to be eligible to return
for final height measurement (8 Humatrope, 10 placebo). Six of the
18 patients (1 Humatrope, 5 placebo) were lost to follow-up and could
not be contacted despite multiple attempts (phone calls, certified
letters, and assistance of referring physicians). Of the remaining 12
patients, 4 (1 Humatrope, 3 placebo) declined to return, and 8 patients
(6 Humatrope, 2 placebo) returned and were included in the *Final Height
Population* as described above.

The role of the *Final Height Population* and the *Protocol Complete
Population* is to obtain a clinically interpretable assessment and
estimate of treatment effect for patients with reasonably complete data.
The role of the modified intent-to-treat and intent-to-treat analyses
are to demonstrate statistical existence of treatment effect and to
verify that the estimates of treatment effect are comparable to
estimates from the *Final Height* and the *Protocol Complete*
*Populations*. This is the paradigm by which *Final Height, Protocol
Complete, Efficacy Evaluable Populations* and modified intent-to-treat
and intent-to-treat analyses are complementary in confirming efficacy.

### 3.1.6. Patient Disposition

Figure 3 illustrates patient disposition.

![](media/image3.wmf){width="5.985416666666667in"
height="8.165277777777778in"}

[]{#__RefHeading___Toc39468371 .anchor}Figure 3. Patient disposition for
Study GDCH.

The most common primary reason for early discontinuation in both
treatment groups was patient decision. Discontinuation due to Sponsor
Decision (n=8) refers to the termination of the blinded treatment period
in response to the DSMB recommendation of 05 June 2000.

### 3.1.7. Baseline Patient Characteristics

Table 2 provides patient demographics at baseline. The Humatrope and
placebo treatment groups were well balanced and comparable at baseline
in the five populations. There were no significant differences between
the Humatrope and placebo treatment groups for any of the variables in
any of the patient populations.

[]{#__RefHeading___Toc39468339 .anchor}Table 2. Demographics and Other
Baseline Characteristics a\
Study GDCH

+-----------------------+----------+----------+---+-----------+---------+
|                       | **All    |          |   | **Safety\ |         |
|                       | Rand     |          |   | Pop       |         |
|                       | omized** |          |   | ulation** |         |
|                       |          |          |   |           |         |
|                       | **Pa     |          |   |           |         |
|                       | tients** |          |   |           |         |
+-----------------------+----------+----------+---+-----------+---------+
| **Variable**          | **Hum    | **P      |   | **Hu      | **Pl    |
|                       | atrope** | lacebo** |   | matrope** | acebo** |
+-----------------------+----------+----------+---+-----------+---------+
| Number of patients    | 38       | 33       |   | 37        | 31      |
+-----------------------+----------+----------+---+-----------+---------+
| Male                  | 29       | 26       |   | 29        | 24      |
+-----------------------+----------+----------+---+-----------+---------+
| Female                | 9        | 7        |   | 8         | 7       |
+-----------------------+----------+----------+---+-----------+---------+
| Ethnic origin         |          |          |   |           |         |
+-----------------------+----------+----------+---+-----------+---------+
| African descent       | 0        | 1        |   | 0         | 1       |
+-----------------------+----------+----------+---+-----------+---------+
| Asian                 | 0        | 1        |   | 0         | 1       |
+-----------------------+----------+----------+---+-----------+---------+
| Caucasian             | 30       | 25       |   | 30        | 23      |
+-----------------------+----------+----------+---+-----------+---------+
| Hispanic              | 7        | 4        |   | 7         | 4       |
+-----------------------+----------+----------+---+-----------+---------+
| Other                 | 1        | 2        |   | 0         | 2       |
+-----------------------+----------+----------+---+-----------+---------+
| Peak growth hormone   | 16.2 ±   | 17.4 ±   |   | 16.3 ±    | 17.2 ±  |
| concentration (μg/L)  | 7.5      | 9.7      |   | 7.6       | 9.8     |
+-----------------------+----------+----------+---+-----------+---------+
| IGF-I concentration   | -2.0 ±   | -1.5 ±   |   | -1.9 ±    | -1.4 ±  |
| SDS                   | 1.1      | 1.5      |   | 1.1       | 1.5     |
+-----------------------+----------+----------+---+-----------+---------+
| Chronological age (y) | 12.5 ±   | 12.3 ±   |   | 12.5 ±    | 12.2 ±  |
|                       | 1.6      | 1.4      |   | 1.6       | 1.4     |
+-----------------------+----------+----------+---+-----------+---------+
| Bone age (y)          | 10.4 ±   | 10.4 ±   |   | 10.4 ±    | 10.3 ±  |
|                       | 1.9      | 1.7      |   | 1.9       | 1.7     |
+-----------------------+----------+----------+---+-----------+---------+
| Height SDS            | -2.7 ±   | -2.8 ±   |   | -2.8 ±    | -2.8 ±  |
|                       | 0.5      | 0.5      |   | 0.5       | 0.5     |
+-----------------------+----------+----------+---+-----------+---------+
| Pre-treatment height  | 4.8 ±    | 4.8 ±    |   | 4.8 ± 1.8 | 4.8 ±   |
| velocity (cm/y)       | 1.8      | 2.1      |   |           | 2.1     |
+-----------------------+----------+----------+---+-----------+---------+
| Predicted height SDS  | -2.0 ±   | -2.3 ±   |   | -2.0 ±    | -2.3 ±  |
|                       | 0.8      | 0.8      |   | 0.8       | 0.8     |
+-----------------------+----------+----------+---+-----------+---------+
| Target height SDS b   | -1.0 ±   | -1.2 ±   |   | -1.0 ±    | -1.2 ±  |
|                       | 1.0      | 0.7      |   | 1.0       | 0.8     |
+-----------------------+----------+----------+---+-----------+---------+

(continued)

Note: Values represent mean ± standard deviation (SD).

Abbreviation: IGF-I = insulin-like growth factor-I; SDS = standard
deviation score.

a There were no significant differences between the Humatrope and
placebo treatment groups for any of the patient populations for any of
the variables.

b Target height represents the gender‑adjusted midparental height.

Table 2. Demographics and Other Baseline Characteristics a\
Study GDCH (concluded)

  -------------------- --------------- ------------- -- --------------- ------------- -- --------------- -------------
                       **Efficacy                       **Final Height\                  **Protocol      
                       Evaluable\                       Population**                     Complete\       
                       Population**                                                      Population**    

  **Variable**         **Humatrope**   **Placebo**      **Humatrope**   **Placebo**      **Humatrope**   **Placebo**

  Number of patients   35              29               22              11               16              9

  Male                 27              23               18              9                13              7

  Female               8               6                4               2                3               2

  Ethnic origin                                                                                          

  African descent      0               1                0               1                0               1

  Asian                0               0                0               0                0               0

  Caucasian            29              22               18              7                14              5

  Hispanic             6               4                4               1                2               1

  Other                0               2                0               2                0               2

  Peak growth hormone  16.5 ± 7.7      17.3 ± 10.0      17.0 ± 7.7      17.6 ± 13.8      17.7 ± 7.6      18.6 ± 15.2
  concentration (μg/L)                                                                                   

  IGF-I concentration  -1.9 ± 1.1      -1.5 ± 1.5       -1.8 ± 1.2      -1.7 ± 1.1       -1.9 ± 1.1      -1.8 ± 1.1
  SDS                                                                                                    

  Chronological age    12.5 ± 1.6      12.3 ± 1.3       12.5 ± 1.6      12.9 ± 1.1       12.4 ± 1.5      12.9 ± 1.2
  (y)                                                                                                    

  Bone age (y)         10.4 ± 1.9      10.4 ± 1.6       10.4 ± 1.9      10.7 ± 1.1       10.2 ± 1.6      10.8 ± 1.2

  Height SDS           -2.7 ± 0.5      -2.8 ± 0.5       -2.7 ± 0.6      -2.8 ± 0.6       -2.7 ± 0.6      -2.9 ± 0.6

  Pre-treatment height 4.9 ± 1.8       4.9 ± 2.1        5.2 ± 1.8       5.6 ± 2.4        5.2 ± 2.0       5.3 ± 2.2
  velocity (cm/y)                                                                                        

  Predicted height SDS -2.0 ± 0.8      -2.3 ± 0.8       -2.1 ± 0.7      -2.3 ± 0.8       -2.2 ± 0.7      -2.4 ± 0.8

  Target height SDS b  -0.9 ± 0.9      -1.2 ± 0.8       -1.1 ± 1.0      -1.3 ± 0.7       -1.1 ± 1.1      -1.4 ± 0.7
  -------------------- --------------- ------------- -- --------------- ------------- -- --------------- -------------

Note: Values represent mean ± standard deviation (SD).

Abbreviation: IGF-I = insulin-like growth factor-I; SDS = standard
deviation score.

a There were no significant differences between the Humatrope and
placebo treatment groups for any of the patient populations for any of
the variables.

b Target height represents the gender‑adjusted midparental height.

### 3.1.8. Efficacy Data

The protocol stated that the primary efficacy analysis would be an
analysis of covariance (ANCOVA) of final height SDS, with baseline
predicted height as the covariate, in the *Final Height Population*
(n=33).

Protocol-specified sensitivity analyses included analysis of last
observed height SDS by ANCOVA in the *Efficacy Evaluable Population*
(n=64), which serves as a modified intent-to-treat analysis for the
study, final height SDS by ANCOVA in the *Protocol Complete Population*
(n=25); and final height minus baseline predicted height (cm) by t‑test
in the *Final Height Population*. In addition, a non-protocol specified,
repeated measures analysis of height SDS at 18 years was included as an
additional modified intent‑to‑treat analysis. The repeated measures
analysis uses repeated height SDS measurements over time, rather than
just the last observed height SDS. Lastly, intent-to-treat analyses, by
both nonparametric and parametric methods, were performed in the
*Randomized Population* (n=71).

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

The primary efficacy variable was final height, expressed as a SDS
relative to the general population of the same age and gender (final
height SDS). The primary efficacy analysis was of final height SDS for
the *Final Height Population*. Between‑group comparisons were performed
using analysis of covariance (ANCOVA), with baseline predicted height
SDS as the covariate (Table 3). The two‑sided significance level for
this analysis was set at α=0.05.

[]{#__RefHeading___Toc39468340 .anchor}Table 3. Final Height Standard
Deviation Score\
Analysis of Covariance\
Final Height Population\
Study GDCH

+-------------------+-----------+----------+--------------+-----------+
| **Variable**      | **H       | **Pl     | *            | **        |
|                   | umatrope\ | acebo**\ | *Treatment** | p-value** |
|                   | (n=22)**  | **       |              |           |
|                   |           | (n=10)** | **Effect b\  |           |
|                   |           | **a**    | (95% CI)**   |           |
+-------------------+-----------+----------+--------------+-----------+
|                   |           |          |              |           |
+-------------------+-----------+----------+--------------+-----------+
| Final height SDS  | -1.81 ±   | -2.32 ±  | 0.51 ± 0.20  | 0.017     |
|                   | 0.11      | 0.17     |              |           |
| (ANCOVA using BPH |           |          | (0.10-0.92)  |           |
| SDS as a          |           |          |              |           |
| covariate)        |           |          |              |           |
+-------------------+-----------+----------+--------------+-----------+

Note: Values represent least squares mean (LSM) ± standard error (SE).

Abbreviations: ANCOVA = analysis of covariance; BPH = baseline predicted
height; CI = confidence interval; n = number of patients; SDS = standard
deviation score.

a Only 10 patients were included in this analysis, as baseline predicted
height was missing for 1 patient due to a missing baseline bone age
x-ray.

b Value represents the difference in the final height SDS between the
Humatrope‑treated group and the placebo‑treated group.

The mean age at assessment of final height for the *Final Height
Population* was 18.6 years for Humatrope‑treated patients and 19.1 years
for placebo‑treated patients.

By ANCOVA, the patients who received Humatrope for 4.6 ± 1.6 (mean ± SD)
years achieved a final height SDS of ‑1.81 ± 0.11 (least squares mean
\[LSM\] ± standard error \[SE\]), while those who received placebo
injections for 4.1 ± 1.7 years achieved a final height SDS of
‑2.32 ± 0.17, resulting in a mean Humatrope effect on final height SDS
of 0.51 ± 0.20, 95% confidence interval (CI): 0.10 -- 0.92 SDS
(p=0.017). The Humatrope effect of 0.51 SDS corresponds to a mean
difference between groups of 3.7 cm.

Because one placebo patient in the *Final Height Population* was not
included in the primary efficacy analysis due to missing data for the
covariate (baseline predicted height SDS), the analysis was re-run for
the full *Final Height Population* (n=33) by using a linear regression
estimate for the missing baseline predicted height SDS value. This
analysis gave a similar mean Humatrope effect on final height SDS of
0.48 ± 0.19 SDS, 95% CI: 0.09 -- 0.88 SDS (p=0.017).

The primary efficacy analysis was completed for all patients for whom
final height data were available, including patients who discontinued
the study before protocol completion (*Final Height Population*). A
number of patients in the *Efficacy Evaluable Population* either
discontinued early and did not return for a final height measurement
(n = 23) or remained in the study and were still growing at termination
of the blinded treatment period (n = 8). These patients are referred to
as the Non‑Final Height subgroup of the *Efficacy Evaluable Population*
(n = 31). The *Final Height Population* (n = 33) and Non‑Final Height
subgroup (n = 31) comprise the total *Efficacy Evaluable Population*
(n = 64). Since 31 of 64 patients from the *Efficacy Evaluable
Population* were not available for final height measurement, the issue
of potential dropout bias must be considered.

#### 3.1.8.2. Sensitivity Analyses

To address the potential dropout bias described above, two modified
intent-to-treat analyses (*Efficacy Evaluable Population*) and four
intent-to-treat analyses (*Randomized Population*) were performed to
assess the robustness of the results of the primary analysis.

The first modified intent-to-treat analysis was an ANCOVA of last
observed height SDS (using baseline predicted height SDS as the
covariate) for the *Efficacy Evaluable Population* (Table 4). The
Humatrope effect for this analysis (0.52 ± 0.15 SDS, 95% CI: 0.22 --
0.82 SDS, p=0.001) was similar to that observed in the primary analysis
(0.51 ± 0.20 SDS, p=0.017).

[]{#__RefHeading___Toc39468341 .anchor}Table 4. Modified Intent-to-Treat
Analysis\
Efficacy Evaluable Population\
Study GDCH

+--------------------------+-----------+----------+----------+--------+
| **Analysis**             | **Hu      | **P      | **Tre    | **p-v  |
|                          | matrope** | lacebo** | atment** | alue** |
|                          |           |          |          |        |
|                          | **n=35**  | **n=27   | **       |        |
|                          |           | a**      | Effect** |        |
+--------------------------+-----------+----------+----------+--------+
|                          |           |          |          |        |
+--------------------------+-----------+----------+----------+--------+
| > Last observed height   | -1.89 ±   | -2.40 ±  | 0.52 ±   | 0.001  |
| > SDS (ANCOVA using BPH  | 0.10      | 0.11     | 0.15 b   |        |
| > SDS as a covariate)    |           |          |          |        |
+--------------------------+-----------+----------+----------+--------+
|                          |           |          |          |        |
+--------------------------+-----------+----------+----------+--------+
| > Height SDS at age 18\  | -1.52 ±   | -2.20 ±  | 0.69 ±   | \<     |
| > (Repeated measures     | 0.11      | 0.12     | 0.13 c   | 0.0001 |
| > linear model)          |           |          |          |        |
+--------------------------+-----------+----------+----------+--------+

Note: Values represent least squares mean (LSM) ± standard error (SE).

Abbreviations: ANCOVA = analysis of covariance; BPH = baseline predicted
height; n = number of patients; SDS = standard deviation score.

a Two of the 29 patients in the placebo group did not have a baseline
predicted height due to missing bone age x-rays and were not included in
this analysis.

b Value represents the difference in the last observed height SDS
between the Humatrope-treated group and the placebo-treated group.

c Value represents the difference in the height SDS at age 18 years
between the Humatrope‑treated group and the placebo‑treated group.

To further address the issue of potential bias due to missing final
height data, a repeated measures analysis of efficacy for the combined
*Final Height Population* and Non‑Final Height subgroup of the *Efficacy
Evaluable Population* was performed. Repeated measures models are useful
when repeated measurements are taken on the same patient and these
measurements are correlated with each other. This methodology is robust
to the biases resulting from missing data (Verbeke and
Molenberghs 2000). Data were incorporated from 62 patients for whom
baseline predicted height and all other necessary data for the
statistical model were available. A standard linear model would have
used the endpoint height SDS values for each patient as the response
variable, whereas this model used height SDS values throughout the
course of the study (at ages 10-18). Using these measured heights, the
model estimated least squares mean height SDS at each age. The
comparison of interest was height SDS for Humatrope‑treated patients
versus placebo‑treated patients at age 18 years.

Table 4 summarizes the results of the repeated measures analysis. The
mean effect of Humatrope on height SDS at age 18 years was 0.69 ± 0.13
SDS, 95% CI: 0.43 -- 0.94 SDS (p\<0.0001), corresponding to a mean
between‑group height difference of 5.0 cm. Thus, the two modified
intent-to-treat analyses gave similar Humatrope treatment effects as the
primary efficacy analysis.

To provide further evidence against dropout bias two nonparametric and
two parametric intent-to-treat analyses of last observed height SDS for
the entire *Randomized Population* (n=71) were performed. The two
non-parametric analyses were a rank analysis of covariance (ANCOVA) and
a generalized Wilcoxon-Mann-Whitney test of last observed height SDS
(Stokes et al. 2000). The results of these analyses demonstrated that
Humatrope was superior to placebo with p=0.0024 (rank ANCOVA) and
p=0.0015 (generalized Wilcoxon-Mann-Whitney test).

As a second intent-to-treat approach, an ANCOVA, with baseline predicted
height SDS as covariate, of last observed height SDS was performed. This
analysis yielded a Humatrope treatment effect of 0.40 ± 0.15 SDS
(p=0.011) (Table 5). For this analysis, the 5 missing baseline predicted
height SDS values for the covariance analysis were imputed by linear
regression using baseline height SDS and age as independent variables.
For patients missing postbaseline height data (n=2), their baseline
height SDS was used as endpoint. Without incorporating the effect of the
covariate, ANOVA indicated a Humatrope treatment effect of 0.52 ± 0.17
SDS (p=0.003). These modified intent-to-treat analyses (*Efficacy
Evaluable Population*) and intent-to-treat analyses (*Randomized
Population*), by their similarity to the primary efficacy analysis,
provide strong evidence against dropout bias in the primary efficacy
analysis.

[]{#__RefHeading___Toc39468342 .anchor}Table 5. Intent-to-Treat Analyses
of Last Observed Height SDS\
All Randomized Population\
Study GDCH

+--------------------------+-----------+----------+----------+--------+
| **Analysis**             | **Hu      | **P      | **Tre    | **p-v  |
|                          | matrope** | lacebo** | atment** | alue** |
|                          |           |          |          |        |
|                          | **n=38**  | **n=33** | **       |        |
|                          |           |          | Effect** |        |
+--------------------------+-----------+----------+----------+--------+
| > ANCOVA (using BPH SDS  | -1.96 ±   | -2.36 ±  | 0.40 ±   | 0.011  |
| > as a covariate)        | 0.10      | 0.11     | 0.15     |        |
+--------------------------+-----------+----------+----------+--------+
| > ANOVA                  | -1.90 ±   | -2.42 ±  | 0.52 ±   | 0.003  |
|                          | 0.11      | 0.12     | 0.17     |        |
+--------------------------+-----------+----------+----------+--------+

Abbreviations: ANCOVA = analysis of covariance; ANOVA = analysis of
variance; BPH = baseline predicted height; n = number of patients in
treatment group; SDS = standard deviation score.

The close similarity of the treatment effect results in the *Final
Height Population* (n=33), *Efficacy Evaluable Population* (n=64), and
*Randomized Population* (n=71) indicates that similar conclusions about
efficacy are supported by the analyses in all 3 populations.

Two additional protocol-specified sensitivity analyses were performed
(Table 6).

[]{#__RefHeading___Toc39468343 .anchor}Table 6. Analyses of Adult
Height\
Protocol Complete and Final Height Populations\
Study GDCH

+--------------------------+-----------+----------+----------+--------+
| **Analysis**             | **Hu      | **P      | **Tre    | **p-v  |
|                          | matrope** | lacebo** | atment** | alue** |
|                          |           |          |          |        |
|                          |           |          | **       |        |
|                          |           |          | Effect** |        |
+--------------------------+-----------+----------+----------+--------+
| Final Height Analysis\   | n=16      | n=9      |          |        |
| (PC Population)          |           |          |          |        |
+--------------------------+-----------+----------+----------+--------+
| > Final height SDS a\    | -1.86 ±   | -2.32 ±  | 0.46 ±   | 0.061  |
| > (ANCOVA using BPH SDS  | 0.14      | 0.18     | 0.23     |        |
| > as a covariate)        |           |          |          |        |
+--------------------------+-----------+----------+----------+--------+
|                          |           |          |          |        |
+--------------------------+-----------+----------+----------+--------+
| Final Height Analysis    | n=22      | n=10     |          |        |
|                          |           |          |          |        |
| (FH Population)          |           |          |          |        |
+--------------------------+-----------+----------+----------+--------+
| > Final height minus BPH | 2.15 ±    | -0.67 ±  | 2.83 ±   | 0.075  |
| > (cm) b\                | 0.84      | 1.31     | 1.53     |        |
| > (t-test)               |           |          |          |        |
+--------------------------+-----------+----------+----------+--------+

Abbreviations: ANCOVA = analysis of covariance; BPH = baseline predicted
height; FH = Final Height; n = number of patients; PC = Protocol
Complete; SDS = standard deviation score.

a Values represent least squares mean (LSM) ± standard error (SE).

b Values represent mean ± standard error (SE).

First, an ANCOVA of final height SDS in the *Protocol Complete
Population*, with baseline predicted height SDS as the covariate,
indicated a mean ± SE treatment effect of 0.46 ± 0.23 SDS, corresponding
to 3.3 cm, p=0.061. Second, a between-group t-test of final height minus
baseline predicted height yielded a mean ± SE treatment effect of
2.83 ± 1.53 cm, p=0.075. Both of these sensitivity analyses yielded
treatment effects that were similar to those of the protocol-specified
primary and modified intent-to-treat analyses. Although both treatment
effects failed to reach statistical significance, this was not
surprising because of the reduction in statistical power due to reduced
sample size for these subgroup analyses.

Given that intent-to-treat analyses are preferred in clinical trials,
the question arises 'Why the primary analysis was restricted to the
final height data, which were available from only a subset of randomized
patients?' The answer relates to uncertainty about how the between-group
difference in height SDS (GH-treated versus control) would change over
time. Specifically, there was concern that GH might accelerate not just
height velocity, but also epiphyseal fusion, perhaps producing an
earlier attainment of the same final height rather than an increase in
adult height. Such a result would be manifest as a transient increase in
height, relative to the control group, that would not be sustained
because of the earlier cessation of growth in the GH-treated patients.
Thus, the maximum GH treatment effect on height SDS would occur during
treatment, and the inclusion of non-final height SDS data in an
intent-to-treat analysis could lead to an overestimate of what the GH
treatment effect would be if measured only at final height. Concern
about the possibility of overestimating the GH treatment effect led to
the decision to limit the primary analysis to patients with final height
measurements.

To evaluate the possibility of an earlier epiphyseal fusion during GH
treatment, we examined whether or not bone maturation was accelerated by
Humatrope treatment. Figure 4 illustrates bone age versus year on study
for the Humatrope and placebo arms of the *Final Height Population*, the
non-final height subgroup of the *Efficacy Evaluable Population*, and
the entire *Efficacy Evaluable Population*. In each of these groups,
there were no significant differences in bone age between the Humatrope
and placebo arms. Thus, there is no evidence that this GH treatment
regimen advanced the tempo of skeletal maturation. Consistent with these
observations, there was no between-group difference in the mean age at
which final height was attained (Humatrope, 18.6 ± 0.4 years; placebo,
19.1 ± 0.4 years, p=0.43).

![](media/image4.wmf){width="5.433333333333334in"
height="4.201388888888889in"}

Abbreviations: EE = Efficacy Evaluable; FH = Final Height; H =
Humatrope; n = number of patients; P = placebo; SE = standard error.

[]{#__RefHeading___Toc39468372 .anchor}Figure 4. Bone age versus year on
study for Study GDCH.

From these data, one would not predict that the GH-induced gains in
height SDS would transiently increase and then decline, since bone age
was not accelerated. To examine the actual time-course of height SDS
gains, Figure 5 shows the increase in height SDS for patients in the two
treatment arms, plotted against the year before the last observed height
SDS for each patient. The time at which final height or last observed
height was measured for each patient was set equal to zero to
synchronize the observations in relation to the last height observation.
This allows one to focus on the between-group differences in height SDS
gain during the several years before measurement of final height or last
observed height.

![](media/image5.wmf){width="5.583333333333333in"
height="4.322916666666667in"}

Abbreviations: EE = Efficacy Evaluable; FH = Final Height; n= number of
patients; SE = standard error.

[]{#__RefHeading___Toc39468373 .anchor}Figure 5. Increase in height SDS
over baseline versus year on study relative to last observed height
(year=0) in Study GDCH.

The temporal pattern of between-group differences in height SDS gain (a
measure of GH treatment effect) was an increase during the early years
of treatment, followed by stabilization of the GH treatment effect
during the 3 years before measurement of final height or last observed
height (Figure 5). For the *Final Height Population* (Figure 5, left
panel), the mean GH treatment effect on height SDS gain was 0.42 SDS, 3
years before final height measurement (at a mean age of 15.5 years), and
0.51 SDS at final height measurement (mean age 18.8 years). For the
non-final height subgroup of the *Efficacy Evaluable Population*
(Figure 5, middle panel), the mean GH treatment effect at last observed
height was 0.55 SDS (at a mean age of 15.1 years and mean treatment
duration of 3.0 years). Thus, the mean GH treatment effect for the
non-final height subgroup at last observed height was similar to that
for the *Final Height Population* at final height measurement. After
combining these two groups, which comprise the *Efficacy Evaluable
Population* (Figure 5, right panel), the mean GH treatment effect on
height SDS gain was 0.5495 SDS, 3 years before last observed height (at
a mean age of 14.4 years), and 0.55 SDS at last observed height (mean
age 17.0 years). Thus, once the between-group difference in height SDS
gain had stabilized, after approximately 3 years of treatment, the GH
treatment effect remained stable during the several years until
attainment of final height.

The evidence in Figure 5 against a transient GH treatment effect removes
the principal objection to inclusion of non-final height data in the
analysis of GH treatment effect. Indeed, based on the data of Figures 4
and 5, the earlier concern that inclusion of such data would produce an
overestimation of the GH treatment effect is not justified for the
treatment regimen used in this study. Moreover, the efficacy analyses
described previously showed similar treatment effects for the primary
efficacy analysis in the *Final Height Population*, for the modified
intent-to-treat analyses in the *Efficacy Evaluable Population*, and for
the intent-to-treat analyses in the *Randomized Population*. From these
observations we conclude that the Humatrope treatment effect is robust
across the different study populations and that the primary efficacy
analysis shows no indication of having been affected by dropout bias.

One potential misinterpretation of Figure 5 deserves comment. The fact
that the GH treatment effect, during continued GH administration,
stabilizes in the 3 years before attaining final height does not imply
that the treatment effect would remain stable if GH treatment were to be
discontinued 3 years before attaining final height. Studies have shown
that such discontinuation is followed by a "catch-down" deceleration of
height velocity to levels below those of the general population (Zadik
et al. 1996; Lampit et al. 1998). Up to 18 months may be required before
height velocity returns to baseline levels. For this reason GH
administration is generally continued until a satisfactory adult height
has been achieved or until the decline in height velocity indicates that
near-final height has been attained.

To illustrate the mean height SDS for the two treatment arms in the
initial years of treatment, Figure 6 displays height SDS by year on
study for the *Efficacy Evaluable Population.*

![](media/image6.wmf){width="5.127083333333333in"
height="3.9590277777777776in"}

Note: This population includes all patients who received ≥6 months study
drug, whether or not they achieved final height. Data are
cross‑sectional. The dashed line at --2 SDS represents the lower limit
of the normal range for the general population (AAP 1997).

Abbreviation: H = Humatrope; n = number of patients; P = placebo;
SDS = standard deviation score.

[]{#__RefHeading___Toc39468374 .anchor}Figure 6. Height standard
deviation score by year on study for the Efficacy Evaluable Population
(Study GDCH).

By 2 years of treatment, the mean height SDS for the Humatrope-treated
patients was close to the lower limit of the normal range.
Discontinuation rates were similar during the early years of the study.
For example, at 3 years of treatment, the continuation rate was 70% (23
out of 33 patients) for the placebo group compared to 68% (26 out of
38 patients) for the Humatrope group.

#### 3.1.8.3. Additional Analyses of Interest

Tables 7-9 provide additional supportive evidence for efficacy of
Humatrope in the *Efficacy Evaluable, Final Height,* and *Protocol
Complete Populations*. Statistically significant differences or trends
in final height characteristics were observed between the treatment
groups. All of these analyses support the conclusion that Humatrope
increases final height in pediatric patients with non-GHD short stature.

[]{#__RefHeading___Toc39468344 .anchor}Table 7. Additional Endpoint
Height Analyses\
Efficacy Evaluable Population\
Study GDCH

+----------------------------------+--------+--------+-----------+-----+
| **Analysis**                     | **Huma | **Pl   | **Tr      | **  |
|                                  | trope\ | acebo\ | eatment** | p-v |
|                                  | (n     | (n     |           | alu |
|                                  | =35)** | =29)** | **Effect  | e** |
|                                  |        |        | a (95%    |     |
|                                  |        |        | CI)**     |     |
+----------------------------------+--------+--------+-----------+-----+
| Endpoint Height (cm) - Baseline  | -2.20  | -6.02  | 3.82      | 0.  |
| Predicted Height (cm) b          | ± 1.94 | ± 1.77 | (-1.59 -- | 163 |
|                                  |        |        | 9.23)     |     |
+----------------------------------+--------+--------+-----------+-----+
| Endpoint Height SDS - Baseline   | 0.13 ± | -0.21  | 0.34      | 0.  |
| Predicted Height SDS b           | 0.13   | ± 0.13 | (-0.04 -- | 079 |
|                                  |        |        | 0.72)     |     |
+----------------------------------+--------+--------+-----------+-----+
| Endpoint Height (cm)             | 157.14 | 150.86 | 6.27      | 0.  |
|                                  | ± 1.93 | ± 1.90 | (0.80 --  | 025 |
|                                  |        |        | 11.75)    |     |
+----------------------------------+--------+--------+-----------+-----+
| Height Gain (cm) (Endpoint       | 24.27  | 19.55  | 4.72      | 0.  |
| Height - Baseline Height) c      | ± 1.56 | ± 1.36 | (0.49 --  | 029 |
|                                  |        |        | 8.95)     |     |
+----------------------------------+--------+--------+-----------+-----+
| Endpoint Height SDS              | -1.83  | -2.45  | 0.62      | 0.  |
|                                  | ± 0.12 | ± 0.10 | (0.29 --  | 000 |
|                                  |        |        | 0.95)     |     |
+----------------------------------+--------+--------+-----------+-----+
| Height SDS Gain (Endpoint Height | 0.91 ± | 0.36 ± | 0.55      | 0.  |
| SDS - Baseline Height SDS) c     | 0.11   | 0.07   | (0.27 --  | 000 |
|                                  |        |        | 0.83)     |     |
+----------------------------------+--------+--------+-----------+-----+
| Target Height (cm) - Endpoint    | 9.32 ± | 13.04  | -3.73     | 0.  |
| Height (cm)                      | 1.89   | ± 2.23 | (-9.59 -- | 209 |
|                                  |        | d      | 2.14)     |     |
+----------------------------------+--------+--------+-----------+-----+
| Target Height SDS - Endpoint     | 0.88 ± | 1.22 ± | -0.34     | 0.  |
| Height SDS                       | 0.16   | 0.17 d | (-0.81 -- | 156 |
|                                  |        |        | 0.13)     |     |
+----------------------------------+--------+--------+-----------+-----+

Note: Values represent mean ± standard error. P-values are from t-tests.

Abbreviation: CI = confidence interval; n = number of patients; SDS =
standard deviation score.

a Value represents the mean difference between the Humatrope-treated
group and the placebo-treated group.

b Two of the 29 patients in the placebo group did not have a baseline
predicted height, due to missing bone age x-rays, and therefore could
not\
be included in this analysis.

c Height gain is from start of treatment to endpoint height.

d Four of the 29 patients in the placebo-treated group did not have a
target height.

[]{#__RefHeading___Toc39468345 .anchor}Table 8. Additional Final Height
Analyses\
Final Height Population\
Study GDCH

+--------------------------------+--------+----------+----------+-----+
| **Analysis**                   | **Huma | **       | **Tre    | **  |
|                                | trope\ | Placebo\ | atment** | p-v |
|                                | (n     | (n=11)** |          | alu |
|                                | =22)** |          | **Effect | e** |
|                                |        |          | a (95%   |     |
|                                |        |          | CI)**    |     |
+--------------------------------+--------+----------+----------+-----+
| Final Height SDS -- Baseline   | 0.32 ± | -0.14 ±  | 0.46     | 0.  |
| Predicted Height SDS           | 0.12   | 0.19 b   | (0.02 -- | 043 |
|                                |        |          | 0.89)    |     |
+--------------------------------+--------+----------+----------+-----+
| Final Height (cm)              | 161.12 | 157.46 ± | 3.66     | 0.  |
|                                | ± 1.58 | 1.77     | (-1.58   | 165 |
|                                |        |          | -- 8.90) |     |
+--------------------------------+--------+----------+----------+-----+
| Height Gain (cm) (Final Height | 28.30  | 22.58 ±  | 5.71     | 0.  |
| -- Baseline Height) c          | ± 1.57 | 2.08     | (0.27 -- | 040 |
|                                |        |          | 11.15)   |     |
+--------------------------------+--------+----------+----------+-----+
| Final Height SDS               | -1.77  | -2.34 ±  | 0.57     | 0.  |
|                                | ± 0.17 | 0.17     | (0.03 -- | 039 |
|                                |        |          | 1.10)    |     |
+--------------------------------+--------+----------+----------+-----+
| Height SDS Gain (Final Height  | 0.93 ± | 0.42 ±   | 0.51     | 0.  |
| SDS-Baseline Height SDS) c     | 0.16   | 0.07     | (0.04 -- | 034 |
|                                |        |          | 0.97)    |     |
+--------------------------------+--------+----------+----------+-----+
| Target Height (cm) -- Final    | 4.71 ± | 7.10 ±   | -2.39    | 0.  |
| Height (cm)                    | 1.37   | 1.81 d   | (-7.23   | 321 |
|                                |        |          | -- 2.45) |     |
+--------------------------------+--------+----------+----------+-----+
| Target Height SDS -- Final     | 0.66 ± | 1.02 ±   | -0.36    | 0.  |
| Height SDS                     | 0.19   | 0.25 d   | (-1.04   | 280 |
|                                |        |          | -- 0.31) |     |
+--------------------------------+--------+----------+----------+-----+

Note: Values represent mean ± standard errors. P-values are from
t-tests.

Abbreviation: CI = confidence interval; n = number of patients; SDS =
standard deviation score.

a Value represents the mean difference between the Humatrope-treated
group and the placebo-treated group.

b n=10 for placebo, as one patient did not have a baseline predicted
height due to missing bone age x-ray.

c Height gain is from start of treatment to final height.

d n=10 for placebo, as one patient did not have a target height value
reported.

[]{#__RefHeading___Toc39468346 .anchor}Table 9. Additional Final Height
Analyses\
Protocol Complete Population\
Study GDCH

+---------------------------------+--------+---------+-----------+-----+
| **Analysis**                    | *      | **P     | **Tr      | **  |
|                                 | *Humat | lacebo\ | eatment** | p-v |
|                                 | rope** | (n=9)** |           | alu |
|                                 |        |         | **Effect  | e** |
|                                 | **(n   |         | a (95%    |     |
|                                 | =16)** |         | CI)**     |     |
+---------------------------------+--------+---------+-----------+-----+
| Final Height (cm) -- Baseline   | 2.40 ± | -0.04 ± | 2.44      | 0.  |
| Predicted Height (cm)           | 1.05   | 1.29    | (-1.08 -- | 165 |
|                                 |        |         | 5.96)     |     |
+---------------------------------+--------+---------+-----------+-----+
| Final Height SDS -- Baseline    | 0.35 ± | -0.04 ± | 0.40      | 0.  |
| Predicted Height SDS            | 0.15   | 0.18    | (-0.10 -- | 111 |
|                                 |        |         | 0.89)     |     |
+---------------------------------+--------+---------+-----------+-----+
| Final Height (cm)               | 160.69 | 156.38  | 4.31      | 0.  |
|                                 | ± 1.73 | ± 1.96  | (-1.37 -- | 130 |
|                                 |        |         | 9.98)     |     |
+---------------------------------+--------+---------+-----------+-----+
| Height Gain (cm) (Final Height  | 28.81  | 22.15 ± | 6.66      | 0.  |
| -- Baseline Height) b           | ± 1.69 | 2.45    | (0.65 --  | 031 |
|                                 |        |         | 12.68)    |     |
+---------------------------------+--------+---------+-----------+-----+
| Final Height SDS                | -1.81  | -2.41 ± | 0.59      | 0.  |
|                                 | ± 0.20 | 0.19    | (-0.03 -- | 062 |
|                                 |        |         | 1.22)     |     |
+---------------------------------+--------+---------+-----------+-----+
| Height SDS Gain (Final Height   | 0.91 ± | 0.45 ±  | 0.46      | 0.  |
| SDS -- Baseline Height SDS) b   | 0.16   | 0.07    | (-0.01 -- | 055 |
|                                 |        |         | 0.93)     |     |
+---------------------------------+--------+---------+-----------+-----+
| Target Height (cm) -- Final     | 5.44 ± | 7.25 ±  | -1.81     | 0.  |
| Height (cm)                     | 1.67   | 2.02    | (-7.39 -- | 509 |
|                                 |        |         | 3.77)     |     |
+---------------------------------+--------+---------+-----------+-----+
| Target Height SDS -- Final      | 0.75 ± | 1.03 ±  | -0.28     | 0.  |
| Height SDS                      | 0.23   | 0.28    | (-1.06 -- | 459 |
|                                 |        |         | 0.50)     |     |
+---------------------------------+--------+---------+-----------+-----+

Note: Values represent mean ± standard error. P-values are from t-tests.

Abbreviation: n = number of patients; SDS = standard deviation score.

a Value represents the mean difference between the Humatrope-treated
group and the placebo-treated group.

b Height gain is from start of treatment to final height.

### 3.1.9. Efficacy Summary

The hypothesis of Study GDCH was that treatment with Humatrope would
increase the adult height of patients with non-GHD short stature. The
primary analysis supports this hypothesis. By ANCOVA, patients in the
*Final Height Populatio*n who received Humatrope had a significantly
greater mean final height SDS than those who received placebo,
indicating a Humatrope effect on final height SDS of 0.51 SDS, which
corresponds to 3.7 cm. Four additional analyses (3 protocol-specified
and 1 nonprotocol‑specified; Section 3.1.8), which were performed to
investigate the robustness of the results from the primary analysis,
also support the efficacy of Humatrope in patients with non-GHD short
stature. These included two modified intent-to-treat analyses in the
*Efficacy Evaluable Population*, which indicated a mean Humatrope effect
of 3.8 to 5.0 cm, and two sensitivity analyses, in subpopulations of the
*Efficacy Evaluable Population*, which indicated a mean treatment effect
of 2.8 to 3.3 cm. Lastly, intent-to-treat analyses, by both
nonparametric and parametric methods, confirmed the significantly
greater height SDS of the Humatrope treated patients. These gains in
height SDS were achieved without any untoward effect on skeletal
maturation or pubertal development. In conclusion, Humatrope increases
the adult height of patients with non-GHD short stature.

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

Study E001 was a multicenter, randomized, dose-response study conducted
in 10 European countries.

### 3.2.1. Objectives

The primary objective of this study was to determine the ability of two
different Humatrope dosages (0.24 mg/kg/wk versus 0.37 mg/kg/wk) to
increase height velocity during the first 2 years of treatment in
patients with non-GHD short stature.

A secondary objective of this study was to determine whether increasing
the dosage of Humatrope from 0.24 mg/kg/wk to 0.37 mg/kg/wk for the
second year of treatment would sustain the first-year increase in height
velocity during the second year of treatment. Ordinarily, the
improvement in height velocity over baseline is smaller in the second
year of treatment than in the first year. An additional secondary
objective was to assess the long-term effect of different Humatrope
dosages in patients who were followed to final height (defined as height
measured after height velocity had fallen below 2 cm/y). The less
stringent final height criterion for Study E001 compared to Study GDCH
(height velocity \<2 cm/y versus \<1.5 cm/y) reflected the independent
design of the two studies and the lack of a generally accepted criterion
for final height.

As was common in clinical studies in the 1980s, the original analytical
plans were described at a high level rather than as detailed statistical
analysis plans. Furthermore, because the clinical study report for
Study E001 was prepared after the investigators had published a
substantial amount of data from this unblinded study, a prospective
statistical analysis plan was not possible. For consistency with the
pivotal study, the analyses performed for Study E001 conform as closely
as possible, given differences in study design, to those performed for
Study GDCH.

### 3.2.2. Study Design

The core study consisted of a screening phase of up to 12 months, during
which patients were assessed for study eligibility, followed by a
2-year, three‑arm, randomized, open‑label, dose‑response phase (Figure
7). Patients were randomized to one of three Humatrope treatment arms:
Dose 1 = 0.24 mg/kg/wk; Dose 2 = 0.24 mg/kg/wk for the first year, then
0.37 mg/kg/wk (abbreviated as 0.24→0.37); Dose 3 = 0.37 mg/kg/wk.
Humatrope was given in divided doses 6 times per week. Participation in
the core dose‑response phase of Study E001, for which the primary
endpoint was the increase in height velocity measured from 0 to 2 years,
ended when the patient completed 2 years on treatment (Visit 10).

![](media/image7.wmf){width="5.999305555555556in"
height="2.4902777777777776in"}

Note: Visit 11 occurred 12 months after Visit 10. Visit 11 procedures
were repeated every 12 months until final height was attained.

[]{#__RefHeading___Toc39468375 .anchor}Figure 7. Design of Study E001.

### 3.2.3. Inclusion/Exclusion Criteria 

Patients were included who were prepubertal and had chronological age
≥5 years, height SDS ≤‑2.0, plasma GH peak above 20 mU/L (10 μg/L) in
response to a standard stimulation test, bone age \<10 years (females)
or \<12 years (males), height velocity below the 25th percentile for age
before age 10 years for girls and age 12 years for boys (or, if above
these age limits, below the 25th percentile for bone age), and normal
thyroid function. The different cutoffs used to determine sufficient GH
secretion in Study E001 versus Study GDCH (\>10 μg/L versus \>7 μg/L,
respectively) reflect the lack of a generally accepted criterion due to
differences in assay characteristics and in the particular stimulation
protocol employed (DTCLWPES 1995; Sizonenko et al. 2001). Patients were
excluded if they had a chronic illness, a known genetic syndrome, had
ever received GH, or were currently receiving other drugs likely to
affect growth.

### 3.2.4. Population Definitions

**All Randomized Patients (n=239):** Of 261 patients who entered the
study, 22 were ineligible or discontinued prior to randomization. The
remaining 239 patients comprise the *All Randomized Patients*
population: Dose 1, n=78; Dose 2, n=78; Dose 3, n=83.

**Two-Year Height Velocity Population (n=209):** Of the 239 randomized
patients, 30 (13%) discontinued prior to reaching the primary 2-year
endpoint. The remaining 209 patients (87% of randomized patients)
comprise the *Two-Year Height Velocity Population*: Dose 1, n=70; Dose
2, n=67; Dose 3, n=72.

**Final Height Population (n=50):** Of the 209 patients who completed
the core 2‑year height velocity phase of the study 173 entered the final
height extension phase. Fifty of these patients attained final height on
study, or returned for final height measurement at a post-study
follow-up: Dose 1, n=17; Dose 2, n=16; Dose 3, n=17. This includes one
patient (Dose 1) who discontinued the study at Visit 3 (prior to 1 year
of treatment) who was followed to final height post-treatment and was
included in the *Final Height Population*.

### 3.2.5. Patient Disposition

Figure 8 illustrates patient disposition.

![](media/image8.wmf){width="5.125in" height="7.360416666666667in"}

a One patient who discontinued at Visit 3 was followed to final height
post-treatment and was therefore also included in the Final Height
Population.

[]{#__RefHeading___Toc39468376 .anchor}Figure 8. Patient disposition for
Study E001.

### 3.2.6. Baseline Patient Characteristics

Table 10 provides baseline demographics for *All Randomized Patients*,
*Two‑Year Height Velocity Population*, and *Final Height Population.*

[]{#__RefHeading___Toc39468347 .anchor}Table 10. Demographics and Other
Baseline Characteristics\
Study E001

  ---------------- ------------ ------------- -------- ------------ ------------- -------- ---------- ------------- --------
  **Population**   **All                               **Two-Year                          **Final                  
                   Randomized                          Height                              Height**                 
                   Patients**                          Velocity**                                                   

  **Humatrope      **Dose 1\    **Dose 2\     **Dose   **Dose 1\    **Dose 2\     **Dose   **Dose 1\  **Dose 2\     **Dose
  Dosage\          0.24**       0.24→0.37**   3\       0.24**       0.24→0.37**   3\       0.24**     0.24→0.37**   3\
  (mg/kg/wk)**                                0.37**                              0.37**                            0.37**

  Number of        78           78            83       70           67            72       17         16            17
  patients                                                                                                          

  Male             49           50            59       45           43            51       11         9             11

  Female           29           28            24       25           24            21       6          7             6

  Ethnic origin                                                                                                     

  Asian            0            2             0        0            2             0        0          0             0

  Caucasian        78           76            83       70           65            72       17         16            17

  Peak GH          16.8 ± 7.5   17.6 ± 9.9    17.0 ±   16.6 ± 6.8   17.5 ± 10.5   16.9 ±   14.2 ± 4.7 16.8 ± 11.8   14.3 ±
  concentration                               6.2                                 6.1                               3.4
  (μg/L)                                                                                                            

  IGF-I            89.0 ± 44.4  100.2 ± 65.5  99.4 ±   88.9 ± 45.4  103.8 ± 67.4  102.6 ±  80.4 ±     113.2 ± 54.6  109.1 ±
  concentration                               48.6                                49.1     32.7                     61.3
  (μg/L)                                                                                                            

  Chronological    9.4 ± 2.4    9.9 ± 2.2     10.0 ±   9.4 ± 2.5    9.8 ± 2.1     10.0 ±   10.4 ± 2.3 10.4 ± 2.1    10.2 ±
  age (y)                                     2.2                                 2.2                               2.1

  Bone age (y)     7.4 ± 2.6    8.1 ± 2.3     8.0 ±    7.4 ± 2.6    8.0 ± 2.3     8.0 ±    8.5 ± 2.1  8.5 ± 2.1     8.9 ±
                                              2.1                                 2.0                               1.9

  Height SDS a     -3.4 ± 0.8   -3.2 ± 0.7    -3.0 ±   -3.4 ± 0.8   -3.2 ± 0.7    -3.0 ±   -3.3 ± 0.8 -3.1 ± 0.8    -2.9 ±
                                              0.5                                 0.5                               0.6

  Predicted height -2.7 ± 1.0   -2.8 ± 1.1    -2.4 ±   -2.8 ± 1.0   -2.9 ± 1.0    -2.3 ±   -2.5 ± 1.1 -2.6 ± 0.9    -2.3 ±
  SDS a                                       1.1                                 1.1                               0.9

  Target height    -1.3 ± 0.9   -1.2 ± 1.0    -1.2 ±   -1.3 ± 0.9   -1.1 ± 0.9    -1.2 ±   -1.2 ± 1.1 -0.8 ± 1.1    -0.9 ±
  SDS b                                       0.9                                 0.9                               0.9

  Pretreatment     4.3 ± 1.1    4.4 ± 1.3     4.3 ±    4.2 ± 1.1    4.5 ± 1.3     4.4 ±    4.7 ± 1.4  5.1 ± 2.0     4.4 ±
  height velocity                             1.1                                 1.1                               1.5
  (cm/y)                                                                                                            
  ---------------- ------------ ------------- -------- ------------ ------------- -------- ---------- ------------- --------

Note: Values represent mean ± standard deviation (SD).

Abbreviation: GH = growth hormone; IGF-I = insulin-like growth factor-I;
SDS = standard deviation score.

a There were statistically significant differences (p\<0.05) among the
three dose groups for the *All Randomized* and the *Two-Year Height
Velocity* populations.

b Target height represents the gender‑adjusted midparental height.

There were significant differences (p\<0.05) among the Humatrope dosage
groups for height SDS and predicted height SDS for *All Randomized
Patients* and *Two‑Year Height Velocity Population*. To account for
this, analyses were performed using baseline predicted height SDS as a
covariate. There were no other statistically significant differences
among the dosage groups for baseline characteristics.

### 3.2.7. Efficacy Data

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

The primary efficacy variable was increase in height velocity (cm/y)
from baseline to 2‑year endpoint. The protocol-specified primary
efficacy analysis was of the difference in height velocity increase
between the group that received the Humatrope dosage of 0.24 mg/kg/wk
and the group that received 0.37 mg/kg/wk. Between‑group comparisons
were performed using analysis of variance (ANOVA) with a two‑sided
significance level of 0.05.

Table 11 presents the effect of Humatrope dosage on height velocity from
pretreatment to 2‑year endpoint.

[]{#__RefHeading___Toc39468348 .anchor}Table 11. Height Velocity Changes
from Pretreatment to 2-Year Endpoint\
Two-Year Height Velocity Population\
Study E001

+------------------------+-------------+--------------+----------------+
| **Humatrope Dosage\    | **Dose 1**  | **Dose 2**   | **Dose 3**     |
| (mg/kg/wk)**           |             |              |                |
|                        | **0.24**    | *            | **0.37**       |
|                        |             | *0.24→0.37** |                |
+------------------------+-------------+--------------+----------------+
|                        |             |              |                |
+------------------------+-------------+--------------+----------------+
| Number of Patients     | 68          | 66           | 71             |
+------------------------+-------------+--------------+----------------+
|                        |             |              |                |
+------------------------+-------------+--------------+----------------+
| **Baseline**           |             |              |                |
+------------------------+-------------+--------------+----------------+
| > Height Velocity      | 4.23 ± 0.14 | 4.45 ± 0.14  | 4.35 ± 0.14    |
| > (cm/y)               |             |              |                |
+------------------------+-------------+--------------+----------------+
| Difference (cm/y)      | Dose 2 --   | Dose 3 --    | Dose 3 -- Dose |
|                        | Dose 1      | Dose 2       | 1              |
+------------------------+-------------+--------------+----------------+
|                        | 0.23 ± 0.20 | -0.10 ± 0.20 | 0.12 ± 0.20    |
+------------------------+-------------+--------------+----------------+
| p-value                | 0.264       | 0.608        | 0.534          |
+------------------------+-------------+--------------+----------------+
|                        |             |              |                |
+------------------------+-------------+--------------+----------------+
| **Endpoint**           |             |              |                |
+------------------------+-------------+--------------+----------------+
| > Height Velocity      | 7.49 ± 0.16 | 7.61 ± 0.16  | 8.39 ± 0.16    |
| > (cm/y)               |             |              |                |
+------------------------+-------------+--------------+----------------+
| Effect (cm/y)          | Dose 2 --   | Dose 3 --    | Dose 3 -- Dose |
|                        | Dose 1      | Dose 2       | 1              |
+------------------------+-------------+--------------+----------------+
|                        | 0.11 ± 0.23 | 0.78 ± 0.23  | 0.90 ± 0.23    |
+------------------------+-------------+--------------+----------------+
| p-value                | 0.619       | 0.001        | \<0.001        |
+------------------------+-------------+--------------+----------------+
|                        |             |              |                |
+------------------------+-------------+--------------+----------------+
| **Change**             |             |              |                |
+------------------------+-------------+--------------+----------------+
| > Height Velocity      | 3.27 ± 0.18 | 3.16 ± 0.19  | 4.04 ± 0.18    |
| > (cm/y)               |             |              |                |
+------------------------+-------------+--------------+----------------+
| Effect (cm/y)          | Dose 2 --   | Dose 3 --    | Dose 3 -- Dose |
|                        | Dose 1      | Dose 2       | 1              |
+------------------------+-------------+--------------+----------------+
|                        | -0.11 ±     | 0.89 ± 0.26  | 0.78 ± 0.26    |
|                        | 0.26        |              |                |
+------------------------+-------------+--------------+----------------+
| p-value                | 0.672       | 0.001        | 0.003          |
+------------------------+-------------+--------------+----------------+
|                        |             |              |                |
+------------------------+-------------+--------------+----------------+

Note: Values represent least squares mean ± standard error (SE).

By ANOVA, patients who received 0.37 mg/kg/wk Humatrope achieved a
significantly greater pretreatment to 2‑year endpoint increase in height
velocity than patients who received 0.24 mg/kg/wk (dose effect = 0.8
cm/y, 95% CI: 0.3 -- 1.3 cm/y, p=0.003) or those who received
0.24 mg/kg/wk for the first year and then 0.37 mg/kg/wk thereafter (mean
± SE dose effect = 0.9 ± 0.3 cm/y, p=0.001). There was no statistically
significant difference in height velocity change between the 0.24
mg/kg/wk and the 0.24→0.37 mg/kg/wk groups (p=0.672).

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

To evaluate long-term outcome in the broader population of study
patients, ANCOVA and repeated measures analyses of height SDS were
performed for the *Two‑Year Height Velocity Population* (Table 12).
These analyses are analogous to those performed in the *Efficacy
Evaluable Population* of Study GDCH (Table 4). The number of patients
available for these analyses are less than for the primary height
velocity endpoint because both the ANCOVA and repeated measures analysis
used baseline predicted height SDS as a covariate. Some children were
too young to perform a height prediction because the Bayley-Pinneau
method requires a minimum bone age of 6 to 7 years (depending on gender
and relation of chronologic age to bone age).

[]{#__RefHeading___Toc39468349 .anchor}Table 12. Secondary Efficacy
Analyses\
Two‑Year Height Velocity Population\
Study E001

+--------------+---------+---------+---------+----------+--------------+
| **Humatrope  | **Dose  | **Dose  | **Dose  | **Dose** | **p-value\   |
| Dosage\      | 1**     | 2**     | 3**     |          | (Dose 1 vs   |
| (mg/kg/wk)** |         |         |         | **       | Dose 3)**    |
|              | *       | **0.24  | *       | Effect** |              |
|              | *0.24** | →0.37** | *0.37** |          |              |
+--------------+---------+---------+---------+----------+--------------+
|              |         |         |         |          |              |
+--------------+---------+---------+---------+----------+--------------+
| **Variable** |         |         |         |          |              |
+--------------+---------+---------+---------+----------+--------------+
| ANCOVA       |         |         |         |          |              |
+--------------+---------+---------+---------+----------+--------------+
| n            | 39      | 52      | 48      |          |              |
+--------------+---------+---------+---------+----------+--------------+
| > Last       | -1.95   | -1.87   | -1.45   | 0.5      | 0.006        |
| > observed\  |  ± 0.13 |  ± 0.12 |  ± 0.12 | 1 ± 0.18 |              |
| > height SDS |         |         |         | b        |              |
| > a          |         |         |         |          |              |
+--------------+---------+---------+---------+----------+--------------+
|              |         |         |         |          |              |
+--------------+---------+---------+---------+----------+--------------+
| Repeated     |         |         |         |          |              |
| measures     |         |         |         |          |              |
+--------------+---------+---------+---------+----------+--------------+
| n            | 39      | 52      | 47      |          |              |
+--------------+---------+---------+---------+----------+--------------+
| > Height SDS | -1.26   | -1.56   | -0.82   | 0.4      | 0.012        |
| > at age     |  ± 0.16 |  ± 0.15 |  ± 0.14 | 4 ± 0.17 |              |
| > 18 years c |         |         |         | d        |              |
+--------------+---------+---------+---------+----------+--------------+

Abbreviations: ANCOVA = analysis of covariance; n = number of patients
who had a baseline predicted height measurement, required for the
ANCOVA; SDS = standard deviation score; vs = versus.

a Data are expressed as least squares mean (LSM) ± standard error (SE)
from ANCOVA, with baseline predicted height (BPH) SDS as the covariate.

b Value represents the difference in the endpoint height SDS between the
Dose 1 group and the Dose 3 group.

c Data are expressed as least squares mean (LSM) ± standard error (SE)
from repeated measures linear model for measured or estimated height SDS
at age 18 years.

d Value represents the difference in the height SDS at age 18 years
between the Dose 1 group and the Dose 3 group.

Patients in the *Two-Year Height Velocity Population* had a mean age of
15 years at last observed height SDS after a mean treatment period of
5.1 years. By ANCOVA, patients in the *Two-Year Height Velocity
Population* who received 0.37 mg/kg/wk Humatrope had a greater last
observed height SDS than those who received 0.24 mg/kg/wk (p=0.006). The
mean between-dose effect size, that is, the incremental increase in last
observed height SDS for the 0.37 mg/kg/wk dose group versus the
0.24 mg/kg/wk group, was 0.51 SDS (corresponding to 3.3 cm), 95% CI:
0.15 -- 0.87 SDS (p=0.006).

By repeated measures analysis of height SDS at age 18 years, for the
same patients, the mean between-dose effect size was 0.44 SDS
(corresponding to 2.8 cm), 95% CI: 0.10 -- 0.78 SDS (p=0.012). These
data indicate that the higher dose resulted in last observed height SDS
and height SDS at age 18 years that were 2.8 to 3.3 cm greater for the
0.37 mg/kg/wk than for the 0.24 mg/kg/wk dose group.

The analyses of the between-dose effect size do provide insight into the
overall height SDS gain in the 0.37 mg/kg/wk dosage group. The overall
treatment effect of the 0.37 mg/kg/wk dosage can be conceptualized as
the between-dose effect of the 0.37 mg/kg/wk dosage versus the
0.24 mg/kg/wk dosage (2.8 to 3.3 cm in the above analyses) plus the
treatment effect of the lower 0.24 mg/kg/wk dosage. The treatment effect
of the lower dose could be estimated roughly, based upon the results of
the slightly lower (0.22 mg/kg/wk) dosage utilized in Study GDCH. The
treatment effect in Study GDCH was 3.7 cm, suggesting that the overall
treatment effect of the 0.37 mg/kg/wk dosage would be approximately 6 to
7 cm, or 1 SDS.

Table 13 provides the between-group dose effect analysis for final
height SDS in the *Final Height Population*.

[]{#__RefHeading___Toc39468350 .anchor}Table 13. Final Height Standard
Deviation Score\
Analysis of Covariance\
Final Height Population\
Study E001

+-----------------+---------+---------+---------+----------+--------+
| **Humatrope     | **Dose  | **Dose  | **Dose  | **Dose** | **p-   |
| Dosage          | 1\      | 2\      | 3**     |          | value\ |
| (mg/kg/wk)**    | (       | (0.24→  |         | **Effect | (Dose  |
|                 | 0.24)** | 0.37)** | **(     | a**      | 1 vs   |
|                 |         |         | 0.37)** |          | Dose   |
|                 |         |         |         |          | 3)**   |
+-----------------+---------+---------+---------+----------+--------+
| Final Height    | n=13    | n=13    | n=13    |          |        |
| Analysis        |         |         |         |          |        |
+-----------------+---------+---------+---------+----------+--------+
| > Final height  | -1.65 ± | -1.38 ± | -1.19 ± | 0.45 ±   | 0.086  |
| > SDS (ANCOVA   | 0.18    | 0.18    | 0.18    | 0.26     |        |
| > using BPH SDS |         |         |         |          |        |
| > as a          |         |         |         |          |        |
| > covariate)    |         |         |         |          |        |
+-----------------+---------+---------+---------+----------+--------+

Note: Values represent least squares mean ± standard error (SE).

Abbreviations: ANCOVA = analysis of covariance; BPH = baseline predicted
height; n = number of patients; SDS = standard deviation score.

a Value represents the difference in final height SDS between Dose 3 and
Dose 1.

After a mean treatment period of 6.5 years for the *Final Height
Population*, and at a mean age of 18 years, the mean between-dose effect
(0.37 mg/kg/wk versus 0.24 mg/kg/wk) on final height SDS, by ANCOVA with
baseline predicted height SDS as the covariate, was 0.45 SDS,
corresponding to 2.9 cm (p=0.09). This between-dose effect size was
similar to the dose effect on last observed height SDS and on height SDS
at age 18 years for the patients who completed 2 years of treatment
(0.51 and 0.44 SDS, respectively). Although the effect did not reach
statistical significance, this was not surprising because of the
reduction of statistical power due to small sample size in this subgroup
analysis.

As mentioned in relation to Study GDCH, the major rationale for
continuing GH treatment studies to adult height has been the concern
that GH might accelerate bone maturation, epiphyseal fusion, and
cessation of linear growth, producing an earlier attainment of the same
final height rather than an increase in adult height. To address this
concern, we examined whether the higher GH dosage of 0.37 mg/kg/wk
accelerated bone maturation compared to the 0.24 mg/kg/wk dosage (Figure
9).

![](media/image9.wmf){width="5.997222222222222in"
height="4.636805555555555in"}

Abbreviations: Dose 1 = 0.24 mg/kg/wk; Dose 2 = 0.24 →0.37 mg/kg/wk;
Dose 3 = 0.37 mg/kg/wk; FH = final height; HV = height velocity; n =
number of patients; SE = standard error; Yr = year.

[]{#__RefHeading___Toc39468377 .anchor}Figure 9. Bone age versus year on
study in Study E001.

Figure 9 shows bone age versus year on study for the 0.24 mg/kg/wk,
0.24→0.37 mg/kg/wk, and 0.37 mg/kg/wk dosage groups of the *Final Height
Population* (left panel), for patients who completed 2 years of
treatment but did not have a final height measurement (middle panel),
and for the entire *Two-Year Height Velocity Population* (right panel).
In each population or subgroup, there were no apparent between-dose
effects on the rate of bone age progression. Thus, the higher dosage of
0.37 mg/kg/wk had no discernible effect on bone age progression compared
to the 0.24 mg/kg/wk dosage.

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

The previous section focused on the between-dose effect size on height
velocity and on height SDS. This section will assess the overall
treatment effect on final height for each of the three dosage groups.
Because there was no untreated control group in this study, this was
done by comparing the final height of patients in each dose group with
the height that they were predicted to achieve without treatment.

Table 14 provides a summary of final height characteristics for the
*Final Height Population.* Mean duration of treatment was 6.1 ± 2.3, 6.3
± 2.2, and 7.0 ± 2.0 years for the 0.24 mg/kg/wk, 0.24→0.37 mg/kg/wk,
and 0.37 mg/kg/wk groups, respectively.

[]{#__RefHeading___Toc39468351 .anchor}Table 14. Final Height
Characteristics\
Final Height Population\
Study E001

+---------------------+---------------+---------------+----------------+
| **Humatrope Dosage\ | **Dose 1**    | **Dose 2**    | **Dose 3**     |
| (mg/kg/wk)**        |               |               |                |
|                     | **0.24**      | **0.24→0.37** | **0.37**       |
+---------------------+---------------+---------------+----------------+
|                     |               |               |                |
+---------------------+---------------+---------------+----------------+
| Number of patients  | 13            | 13            | 13             |
+---------------------+---------------+---------------+----------------+
| FH - BPH (cm) a     | 5.36 ± 0.89   | 6.66 ± 1.14   | 7.21 ± 1.66    |
+---------------------+---------------+---------------+----------------+
| p-value b           | \<0.001       | \<0.001       | 0.001          |
+---------------------+---------------+---------------+----------------+
|                     |               |               |                |
+---------------------+---------------+---------------+----------------+
| Number of patients  | 17            | 16            | 17             |
+---------------------+---------------+---------------+----------------+
| FH SDS - BH SDS a   | 1.55 ± 0.14   | 1.52 ± 0.27   | 1.85 ± 0.20    |
+---------------------+---------------+---------------+----------------+
| p-value b           | \<0.001       | \<0.001       | \<0.001        |
+---------------------+---------------+---------------+----------------+
|                     |               |               |                |
+---------------------+---------------+---------------+----------------+
| Number of patients  | 17            | 16            | 17             |
+---------------------+---------------+---------------+----------------+
| TH - FH (cm) a      | 3.78 ± 1.78   | 5.31 ± 2.42   | 1.33 ± 1.21    |
+---------------------+---------------+---------------+----------------+
| p-value b           | 0.050         | 0.045         | 0.288          |
+---------------------+---------------+---------------+----------------+

Abbreviations: BH = baseline height; BPH = baseline predicted height;
FH = final height; SDS = standard deviation score; TH = target height.

a Data are expressed as mean ± standard error (SE).

b p‑values refer to a within‑group *t* test of the null hypothesis that
mean value equals zero.

All three treatment groups showed a significant treatment effect, as
evidenced by mean final height minus baseline predicted height that
ranged from 5.4 to 7.2 cm (lower dose to higher dose) and mean final
height SDS minus baseline height SDS that ranged from 1.6 to 1.9 SDS
(lower dose to higher dose). Furthermore, patients who received the
Humatrope dosage of 0.37 mg/kg/wk reached a final height that was not
significantly below target height (gender‑adjusted midparental height),
indicating that they came close to achieving their genetic potential for
height.

The validity of final height minus baseline predicted height as an
efficacy measure depends on the accuracy of the Bayley-Pinneau method in
predicting the adult height that patients with non-GHD short stature
would have achieved in the absence of treatment. Since published studies
in approximately 400 untreated patients show that the actual adult
height of untreated patients falls short of the Bayley-Pinneau predicted
height by up to 5 cm in males \[Bramswig et al. 1990; Ranke et al. 1995;
Buchlis et al. 1998; Rekers-Mombarg et al. 1999\]), final height minus
baseline predicted height should provide a conservative estimate of
treatment effect. In Study GDCH, placebo-treated patients failed to
achieve their baseline predicted height, consistent with the published
studies cited above, whereas patients treated with 0.37 mg/kg/wk,
administered in divided doses 6 times per week, exceeded their baseline
predicted height by 7.2 cm (Figure 10).

![](media/image10.wmf){width="5.540972222222222in"
height="4.272916666666666in"}

Note: Values represent mean ± SE

Abbreviations: n = number of patients; SE = standard error.

[]{#__RefHeading___Toc39468378 .anchor}Figure 10. Final height minus
baseline predicted height (cm) in the Final Height Populations of
Studies GDCH and E001.

The above data support the validity of final height minus baseline
predicted height as a conservative measure of GH treatment effect in
patients with non-GHD short stature. From these data we conclude that
the mean gain in adult height attributable to GH treatment with the 0.37
mg/kg/wk dosage is at least 7.2 cm.

### 3.2.8. E001 Efficacy Summary

The primary objective of this study was to determine the efficacy of two
different Humatrope dosages (0.24 mg/kg/wk versus 0.37 mg/kg/wk) in
stimulating an increase in height velocity during the first 2 years of
treatment in patients with non-GHD short stature. By ANOVA, patients who
received 0.37 mg/kg/wk Humatrope had a greater increase in height
velocity after 2 years of treatment than patients who received
0.24 mg/kg/wk (between-dose effect: 0.8 cm/y, 95% CI: 0.3 -- 1.3 cm/y,
p=0.003). Furthermore, patients who received 0.37 mg/kg/wk from the
start of treatment had a significantly greater increase in height
velocity than those who received 0.24 mg/kg/wk for the first year,
followed by 0.37 mg/kg/wk for the second year (between-dose effect: 0.9
± 0.3 (SE) cm/y, p=0.001). Thus, the primary efficacy analysis supported
the hypothesis that the dosage of 0.37 mg/kg/wk is more effective in
increasing two-year height velocity than either of the lower dosage
regimens.

Secondary analyses indicated a mean between-dose effect (incremental
effect of 0.37 mg/kg/wk versus 0.24 mg/kg/wk) on last observed height
SDS, height SDS at 18 years, and final height SDS corresponding to 3.3
cm, 2.8 cm, and 2.9 cm, respectively. Each of these analyses was
statistically significant except for the last analysis (p=0.09), which
had reduced statistical power because of the smaller size of the *Final
Height Population*. From the above dose-response analyses, we conclude
that the dosage of 0.37 mg/kg/wk is more effective than the dosage of
0.24 mg/kg/wk, producing a significantly greater height velocity, by 0.8
cm/y, and a significantly greater last observed height SDS and height
SDS at age 18 years, by 2.8 to 3.3 cm.

In addition to evidence for dose-response, within-group analyses of
final height minus baseline predicted height, which provide a
conservative estimate of treatment effect for this population (since
untreated patients on average fail to achieve their baseline predicted
height \[Bramswig et al. 1990; Ranke et al. 1995; Buchlis et al. 1998;
Rekers-Mombarg et al. 1999\]), showed that GH treatment significantly
increased final height above baseline predicted height for each of the
three dosage groups. The mean treatment effect size for this efficacy
measure ranged from 5.4 cm at the 0.24 mg/kg/wk dosage to 7.2 cm at the
0.37 mg/kg/wk. Thus, the mean gain in adult height attributable to GH
treatment with the 0.37 mg/kg/wk dosage was approximately 7 cm compared
to the height that the patients were predicted to achieve in the absence
of treatment.

### 3.2.9. Comparative Efficacy Summary

Figure 11 presents a comparative summary of final height SDS from the
two studies, Study GDCH (0.22 mg/kg/wk, administered 3 times per week)
and Study E001 (0.24 or 0.37 mg/kg/wk, administered 6 times per week).

![](media/image11.wmf){width="5.504861111111111in"
height="4.250694444444444in"}

\*Analysis of covariance (ANCOVA) model incorporating effect for
baseline predicted height standard deviation score (SDS); values are
least squares mean ± standard error (SE).

Note: The dashed line represents the lower limit of the normal range for
the general population (AAP 1997).

Abbreviations: n = number of patients.

[]{#__RefHeading___Toc39468379 .anchor}Figure 11. Comparative summary of
Studies GDCH and E001: Final height SDS.

In Study GDCH the mean increase in height SDS between the
Humatrope‑treated and placebo-treated groups was 0.51 SDS (corresponding
to 3.7 cm). In Study E001, the mean between-dose effect between the
higher (0.37 mg/kg/wk) and lower (0.24 mg/kg/wk) dosage was 0.45 SDS
(corresponding to 2.9 cm). Although the latter effect did not achieve
statistical significance (p=0.086), analyses of last observed height SDS
and height SDS at age 18 years both gave statistically significant
between-dose effects of a similar magnitude (0.51 SDS \[p=0.006\] and
0.44 SDS \[p=0.012\], respectively). Thus, the overall GH treatment
effect of the 0.37 mg/kg/wk dosage can be conceptualized as being
comprised of 2 components: the incremental effect of the dosage of
0.37 mg/kg/wk compared to 0.24 mg/kg/wk, and the effect of the 0.24
mg/kg/wk dosage compared to the height that an untreated group would
have achieved. From Figure 10, this overall treatment effect was 7.2 cm,
or approximately 1 SD, obtained by comparing the final height of these
patients to the height that was predicted to have occurred in the
absence of treatment. Figure 12 shows the individual final height data
of these patients.

![](media/image12.wmf){width="5.75in" height="4.44375in"}

Note: Values represent mean ± standard error (SE). The dashed line at
‑2.0 SDS represents the normal range for the general population (AAP
1997).

Abbreviations: SDS = standard deviation score; SE = standard error.

[]{#__RefHeading___Toc39468380 .anchor}Figure 12. Significant number of
GH treated patients achieved normal height in Studies GDCH and E001.

For the placebo patients, final height SDS for most patients remained
below the normal range. At the 0.22 mg/kg/wk dosage, given in divided
doses 3 times per week, 55% of final height SDS values were within the
normal range. At the 0.24 mg/kg/wk dosage, given in divided doses 6
times per week, 71% of final height SDS values were within the normal
range. For the 0.37 mg/kg/wk dosage, all but one final height SDS, or
94%, were within the normal range. The one patient with final height SDS
below normal had a gain in height SDS of approximately 1 during
treatment. Thus, the 0.37 mg/kg/wk dosage resulted in nearly all adult
height measurements falling within the normal range.

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

The unmet medical need of patients with non-GHD short stature has been
recognized since modern GH testing enabled the differential diagnosis of
GHD and non-GHD short stature in the 1960s. To address this need, a
large number of studies have been undertaken. A recent meta‑analysis of
38 studies, which fulfilled specific inclusion criteria, provides a
careful and comprehensive analysis of recombinant GH treatment in
patients with non-GHD short stature (Finkelstein et al. 2002) and is
summarized here as supportive evidence of efficacy. The objective of
this meta‑analysis was to evaluate short‑term and long‑term effects of
treatment with recombinant GH in patients with non‑GHD short stature
(referred to as idiopathic short stature \[ISS\] in this paper) by a
review of the literature from 1985 to 2000. Thirty-eight studies
(10 controlled, 28 uncontrolled) met the following principal inclusion
criteria: patients' initial height below the 10th percentile (most of
the long-term studies, however, had entry criterion of height SDS≤-2.0
\[2.3 percentile\]); no previous treatment with GH, sex steroids or
anabolic agents; normal stimulated GH concentrations (≥10 μg/L); absence
of comorbid conditions; on-study treatment with recombinant GH; and
inclusion of major outcome measures of height velocity or height SDS.
Two types of analyses were performed: aggregate and paired. Aggregate
analyses provided pooled estimates across all studies reporting each
growth variable. Paired analyses provided pooled estimates across those
studies reporting the given variable both at baseline and as an outcome.

Controlled studies were defined as those having a concurrent control
group, either randomized or nonrandomized. For brevity, only the data
reported for the controlled studies that included adult or final height
as an outcome will be discussed. Similar GH treatment effects, however,
were reported in the uncontrolled final height studies.

### 3.3.1. Growth Hormone Effect on Final Height

#### 3.3.1.1. Controlled Studies

Among the 10 controlled studies included in the meta-analysis, adult
height was measured only in the following four controlled studies,
representing data from 188 children: Zadik et al. 1992, Hindmarsh and
Brook 1996, Buchlis et al. 1998, and McCaughey et al. 1998. Across these
four studies, the weighted mean age at study start was 10.8 years and
mean duration of treatment was 5.3 years. The weighted average GH dosage
for the children in these studies was 0.31 mg/kg/wk, and in each study
the dosage was given in divided doses 6 times per week. Table 15
presents the final height results for the meta‑analysis of the
controlled studies.

[]{#__RefHeading___Toc39468352 .anchor}Table 15. Final Height Results:
Meta-Analysis of Controlled Trials a

  -------------------- ------------ ---------------------------------------
  **Growth Variable**  **Patients   ***Difference* Between Treatment and
                       (N)\         Control Groups:\
                       (Studies     Pooled Estimate,\
                       \[n\])**     Mean ± SD (95% CI)**

  Childhood height SDS              

  Baseline                          

  Aggregate            408 (9)      0.02 ± 0.05 (-0.08 to 0.12)

  Paired b             36 (2)       0.12 ± 0.11 (-0.09 to 0.33)

  1 year               36 (2)       0.60 ± 0.18 (0.26 to 0.95)

                                    

  Adult height SDS                  

  Predicted                         

  Aggregate            118 (4)      0.30 ± 0.12 (0.07 to 0.53)

  Paired b             106 (3)      0.13 ± 0.16 (-0.18 to 0.44)

  Achieved                          

  Aggregate            125 (4)      0.84 ± 0.19 (0.46 to 1.22)

  Paired b             112 (3)      0.78 ± 0.22 (0.35 to 1.21)
  -------------------- ------------ ---------------------------------------

Abbreviations: CI = confidence interval; SD = standard deviation; SDS =
standard deviation score.

a Table modified from Finkelstein et al. (2002) Table 2.

b "Paired" indicates analysis of only those studies reporting this
variable at baseline and follow-up.

While no significant differences between treatment and control groups
were noted at baseline, the mean difference in adult height SDS between
the treatment group and the control group ranged from 0.78 (paired
analysis) to 0.84 (aggregate analysis), which corresponds to 5 to 6 cm.

The between‑group difference (GH versus control) for achieved adult
height SDS was also compared with the between‑group difference for
baseline predicted height SDS. In this analysis, the adult height SDS
achieved by the GH‑treated patients exceeded baseline predicted height
SDS by 0.54 (aggregate analysis) to 0.65 (paired analysis), which
corresponds to 3.6 to 4.6 cm. Figure 13 presents this comparison of the
mean difference in height SDS between treatment and control groups for
baseline predicted adult height and achieved adult height.

![](media/image13.wmf){width="5.997222222222222in"
height="4.636805555555555in"}

Note: Recreated from Finkelstein et al. (2002). For Government Use
Only - No Further Reproduction Permitted.

\* No measure of variation was provided for predicted adult height in
this study; therefore, it was not included in the analysis of
differences between treatment and control groups.

[]{#__RefHeading___Toc39468381 .anchor}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.

The GH effect on final height is reflected by the significantly greater
difference between treatment and control groups for achieved adult
height SDS and by the difference between groups for the gain in height
SDS over baseline predicted height SDS.

#### 3.3.1.2. Uncontrolled Studies

Adult height was measured in the following 8 uncontrolled studies: Loche
et al. 1994, Lopez‑Siguero et al. 1996, Zadik et al. 1996, Bernasconi et
al. 1997, Schmitt et al. 1997, Zadik and Zung 1997, Hintz et al. 1999,
and Pasquino et al. 2000. Across these 8 studies, the mean duration of
treatment was 4.7 years, and the weighted average GH dosage was
0.27 mg/kg/wk, given in divided doses 6 times per week. Table 16
presents the results of the meta‑analysis of the uncontrolled studies.

[]{#__RefHeading___Toc39468353 .anchor}Table 16. Results of
Meta‑Analysis of Uncontrolled Studies from Peer‑Reviewed Literature a

  -------------------- ------------ ---------------------------------------
  **Growth Variable**  **Patients   ***Outcome*:\
                       (N)\         Pooled Estimate,\
                       (Studies     Mean ± SE (95% CI)**
                       \[n\])**     

  Childhood height SDS              

  Baseline                          

  Aggregate            550 (25)     -2.72 ± 0.05 (-2.82 to -2.63)

  Paired b             209 (10)     -2.62 ± 0.09 (-2.79 to -2.44)

  1 year               209 (10)     -2.19 ± 0.10 (-2.39 to -1.99)

                                    

  Adult height SDS                  

  Predicted                         

  Aggregate            311 (9)      -2.18 ± 0.17 (-2.52 to -1.85)

  Paired b             212 (6)      -2.25 ± 0.23 (-2.74 to -1.77)

  Achieved                          

  Aggregate            246 (8)      -1.62 ± 0.07 (-1.77 to -1.47)

  Paired b             208 (6)      -1.62 ± 0.09 (-1.80 to -1.45)
  -------------------- ------------ ---------------------------------------

Abbreviations: CI = confidence interval; SE = standard error; SDS =
standard deviation score.

a Table modified from Finkelstein et al. (2002) Table 4.

b "Paired" indicates analysis of only those studies reporting this
variable at baseline and follow-up.

Analysis of the data derived from the uncontrolled studies demonstrates
similar efficacy to that seen in the controlled studies. The difference
between achieved adult height SDS and baseline predicted height SDS
ranged from 0.56 (aggregate analysis) to 0.63 (paired analysis), which
corresponds to 3.8 to 4.5 cm. Figure 14 presents the paired analysis
comparison of baseline predicted height SDS versus achieved adult height
SDS for the uncontrolled studies.

![](media/image14.wmf){width="5.66875in" height="4.377777777777778in"}

Note: Recreated from Finkelstein et al. (2002). For Government Use
Only - No Further Reproduction Permitted.

Abbreviation: SD = standard deviation.

[]{#__RefHeading___Toc39468382 .anchor}Figure 14. Mean adult height
standard deviation scores predicted at baseline and achieved for
uncontrolled studies.

In all but one study (Bernasconi et al. 1997), the GH‑treated patients
achieved a significantly greater adult height SDS than was predicted at
baseline. The study in which adult height SDS did not exceed the
baseline prediction was found to have the greatest baseline predicted
height. The authors acknowledge that lack of apparent GH effect may have
reflected a bias due to overestimation of baseline predicted height.

#### 3.3.1.3. Summary

In summary, the studies in this meta‑analysis of GH treatment in
patients with non‑GHD short stature demonstrate an average GH-induced
gain in adult height of approximately 4 to 6 cm.

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

To compare the response to GH in patients with non-GHD short stature
with that of a non-GHD patient population for whom Humatrope treatment
is already approved, the magnitude of the Humatrope effect in patients
with non-GHD short stature in Study GDCH was compared to that in
patients with Turner syndrome. In a randomized, controlled study of
Humatrope treatment to final height in patients with Turner syndrome
(Study GDCT, the only study to date with a long-term randomized
untreated control group), patients treated with Humatrope
(0.30 mg/kg/wk, administered in divided doses 6 times per week \[versus
0.22 mg/kg/wk, given 3 times per week, in Study GDCH\]) were taller than
untreated patients by an average of 3.9 cm (p=0.001). When final height
was adjusted for midparental height (target height), Humatrope‑treated
patients achieved a mean final height 5.4 cm greater than that of
untreated patients (ANCOVA, p=0.001). Both of these analyses are from
the planned interim analysis of Study GDCT that was used to support the
US approval of Humatrope treatment in patients with Turner syndrome.
Thus, the Humatrope treatment effect from the primary efficacy analysis
was similar to that for Study GDCH patients with non-GHD short stature
(3.9 versus 3.7 cm, respectively).

As shown in Figure 15, the effect of Humatrope treatment on the
distribution of height SDS change from baseline to final height was also
similar in patients with non-GHD short stature (Study GDCH) and those
with Turner syndrome (Study GDCI \[Section 4.2.3 provides additional
details of this study\]). For the analysis of Study GDCI, final height
was defined as the last height measured after attaining bone age
≥14 years, when more than 98% of adult height has been achieved
(Greulich and Pyle 1959).

![](media/image15.wmf){width="4.252777777777778in"
height="5.511111111111111in"}

Abbreviations: n = number of patients; GHD = growth hormone deficiency;
SDS = standard deviation score.

[]{#__RefHeading___Toc39468383 .anchor}Figure 15. Distribution of height
standard deviation score change (baseline to final height) in patients
treated with Humatrope (Study GDCH and Study GDCI).

For both of these non‑GHD patient populations, the distributions of
height SDS change are unimodal with similar magnitude and variability.

## 3.5. Humatrope Dosage and Frequency of Administration

This section summarizes the rationale for the recommendation that in
treatment of patients with non-GHD short stature, Humatrope should be
administered at a dosage of up to 0.37 mg/kg/wk in divided doses 3 to 7
times per week.

### 3.5.1. Humatrope Dosage

Study E001 provides evidence for the dose‑response effect of Humatrope
in pediatric patients with non-GHD short stature. Compared with patients
who received 0.24 mg/kg/wk Humatrope, the group that received the higher
dosage of 0.37 mg/kg/wk achieved a significantly greater gain in height
velocity at 2 years (4.0 versus 3.3 cm/y, p=0.003), greater gain in
endpoint height SDS (effect: 0.51 SDS; p=0.006, ANCOVA), and a greater
gain in height SDS at age 18 years (effect: 0.44 SDS; p=0.012, repeated
measures analysis).

For the limited number of patients in the *Final Height Population*,
other secondary endpoints (such as final height SDS \[ANCOVA,
Table 13\], final height minus baseline predicted height \[cm\], final
height SDS minus baseline height SDS, and target height minus final
height \[cm\]) showed similar dose‑dependent trends that did not reach
statistical significance (Table 14). Taken together, these data support
the greater efficacy of the Humatrope dosage of 0.37 mg/kg/wk compared
to 0.24 mg/kg/wk for the treatment of pediatric patients with non-GHD
short stature.

Dose‑response studies in patients with Turner syndrome and in those with
GHD provide evidence for the greater efficacy of GH at increasing
dosages over the range of 0.18 to 0.70 mg/kg/wk. For example, in
Study GDCI, patients who received 0.36 mg/kg/wk of Humatrope achieved a
significantly greater increase in height SDS than those who received
0.27 mg/kg/wk (1.0 versus 0.6 SDS) (Quigley et al. 2002). Additionally,
de Muinck Keizer‑Schrama et al. (1999) reported a significantly greater
gain in height SDS in patients with Turner syndrome who received higher
dosages of GH (0.63 mg/kg/wk and 0.47 mg/kg/wk) compared with those who
received a lower dosage (0.32 mg/kg/wk). A similar dose‑response
relationship has been observed in pediatric patients with GHD. In a
2‑year, randomized, dose‑response study, the dosages of 0.35 mg/kg/wk
and 0.70 mg/kg/wk resulted in a significantly greater cumulative
increase in height SDS than the dosage of 0.18 mg/kg/wk (Cohen et
al. 2002). A second study of high‑dosage (0.70 mg/kg/wk) versus
conventional dosage (0.30 mg/kg/wk) treatment in pubertal GHD patients
yielded a mean incremental final height gain for the high‑dosage group
compared to the conventional‑dosage group of 4.6 cm (p=0.001) (Mauras et
al. 2000). Thus, recent dose‑response studies in patients without GHD
and those with GHD support the greater effectiveness of dosages in the
range of 0.35 to 0.70 mg/kg/wk compared to lower dosages.

### 3.5.2. Frequency of Administration

Humatrope was administered in divided doses TIW in Study GDCH, a regimen
typical in the 1980s, when this study was begun. Since then, a 3‑year,
randomized study in patients with non-GHD short stature has shown that
daily administration yields a greater cumulative height gain, by about
20%, compared to thrice‑weekly administration of the same total dose
(Hopwood et al. 1993). Based upon these data and similar observations in
GHD patients (Smith et al. 1988; Rosenbloom et al. 1990; Blethen et
al. 1993; MacGillivray et al. 1996), daily administration has become
standard of care, because it is more effective, is considered more
physiologic, and may improve compliance. Thus, while the TIW Humatrope
regimen in Study GDCH demonstrated efficacy, better outcomes are
anticipated with daily dosing. Consequently, Lilly recommends that
Humatrope should be administered in divided doses 3 to 7 times per week.

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

Following the recommendation of the 1987 Endocrinologic and Metabolic
Drugs Advisory Committee, Lilly studies of patients with non-GHD short
stature focused on the treatment of their short stature. Neither Study
GDCH nor Study E001 provided evidence of potential benefits in quality
of life or psychological well-being. Similarly, evidence for such
benefits was not required as a basis for approval for any of the current
pediatric indications. However, several lines of evidence suggest that
the magnitude of GH-induced height gain in patients with non-GHD short
stature was clinically meaningful. First, GH-induced height gain in
patients with non-GHD short stature was similar to that achieved in
Turner syndrome. Short stature in patients with Turner syndrome has been
an approved indication for GH treatment since 1996, and GH is widely
used to treat short stature in these patients (DTCLWPES 1995; Wilton
1999; Maneatis et al. 2000; AACE 2003). Second, the mean heights of
Humatrope-treated patients in Study GDCH, and of the 0.37 mg/kg/wk
dosage group in Study E001, moved into the normal range during the
course of treatment. During the course of treatment, the majority of
these children no longer had short stature, thereby diminishing the
disadvantages of short stature during childhood, which may include being
treated as younger than one's actual age (juvenilization) (Sandberg
1999), increased risk of teasing and bullying (Voss and Mulligan 2000),
and reduced opportunity to participate in age-appropriate activities.
Third, whereas the final heights for placebo-treated patients (Study
GDCH) were all below the 5th percentile of the normal population, and
most were below the lower limit of normal, 94% of final heights for
patients who received the higher dosage (0.37 mg/kg/wk) in Study E001
were within the normal range. Thus, as adults, these patients no longer
had short stature, thereby diminishing or eliminating potential
disadvantages of adult short stature, which may include failure to meet
minimum height requirements for certain occupations, difficulty or
inability to safely operate a motor vehicle or overcome structural
challenges in the home or workplace, and the prejudice of being
perceived as having lower competence than individuals of normal stature.

In summary, during the course of GH treatment, most patients with
non-GHD short stature had a height that moved into the normal range.
Additionally, GH treatment in the 0.37 mg/kg/wk dosage group of
Study E001 resulted in 94% of final height measurements falling within
the normal range, thus conferring on these patients the lifelong benefit
of normal adult stature.

## 3.6. Overall Efficacy Conclusions

The efficacy of Humatrope treatment in increasing the final height of
pediatric patients with non-GHD short stature has been demonstrated for
the first time, through a randomized, double‑blind, placebo‑controlled
study (Study GDCH). Study E001 and the recent meta-analysis by
Finkelstein et al. (2002), which summarizes several peer-reviewed,
controlled studies to final height, support the efficacy of GH treatment
in this patient population. The magnitude of the treatment effect was
3.7 cm for the primary endpoint of the pivotal study, and 7.2 cm for the
gain in height over baseline predicted height for the 0.37 mg/kg/wk
dosage group of the dose-response study. A GH dose-response effect was
demonstrated in Study E001: patients who received Humatrope at a dosage
of 0.37 mg/kg/wk had significantly greater improvement in 2-year height
velocity, by 0.8 cm/y, and significantly greater height SDS at age 18
years, by 2.8 cm, than those who received 0.24 mg/kg/wk. These findings
are consistent with the dose‑response relationship observed in patients
with Turner syndrome and in patients with GHD. In conclusion, Humatrope
at dosages up to 0.37 mg/kg/wk is effective in increasing the final
height of pediatric patients with non-GHD short stature.

# 4. Safety

## 4.1. Introduction

During the 16 years that somatropin has been commercially available, an
estimated 200,000 patients (equivalent to over 500,000 patient-years of
exposure) worldwide have been exposed to somatropin. There are currently
five approved pediatric indications for the use of somatropin and
dosages have been approved up to 0.70 mg/kg/wk. Two large postmarketing
research programs have published safety data collected over
approximately 10 to 15 years. The National Cooperative Growth Study
(Maneatis et al. 2000) reported safety data collected from 1985‑1999 on
33,161 patients (approximately 113,000 patient-years). Adverse events
(AEs) were reported for 2387 patients (7.2%) with a total of 2632 AEs,
representing 23 events per 1000 patient-years. There were 156 deaths
(0.5%) and serious adverse events (SAEs) were reported for 799 patients
(2.4%). The Kabi International Growth Study (Wilton 1999) reported
safety data collected from 1988-1998 on 25,977 patients, representing
approximately 62,400 patient‑years. There were 8321 AEs reported
representing 133 events per 1000 patient‑years. Although there are a
number of uncommon, well‑characterized events that have been associated
with somatropin exposure, the overall safety profile is well
established.

In correspondence between Lilly and the FDA, prior to submission of the
sNDA, it was agreed that the safety of Humatrope in pediatric patients
with non-GHD short stature would be evaluated by a comparison between
the safety findings in the non-GHD short stature population and the
safety in pediatric populations for which Humatrope is currently
approved. Therefore, this section will compare the safety of Humatrope
among pediatric patients with GHD (Study B9R-MC-GDAB) and Turner
syndrome (Studies B9R-CA-GDCT and B9R‑MC‑GDCI) and those with non‑GHD
short stature (Studies GDCH and E001). These three regulatory
submissions involved similar numbers of patients and similar total
patient-years of exposure. Two primary safety questions are
addressed: 1) What are the rates of adverse events in the non-GHD short
stature population compared to the rates in patients with GHD or Turner
syndrome? The key comparison will be between the Humatrope-treated
patient groups across these patient populations. 2) Are there any new
adverse events specific to the non-GHD short stature population? Within
this safety discussion, a general summary across the three patient
populations will be presented at the beginning of each section, followed
by detailed review of relevant cases within each population.

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

Table 17 provides a summary of the clinical studies included in the
safety comparison.

[]{#__RefHeading___Toc39468354 .anchor}Table 17. Clinical Studies
Included in Safety Comparison

+--------+-----+-----+---+---------------+-------------+--------------+---+
| *      | **S | **  |   | **Age and     | **Humatrope | **Design**   |   |
| *Condi | tud | N** |   | Gender\       | dose**      |              |   |
| tion** | y** |     |   | Entry         |             |              |   |
|        |     |     |   | Criteria**    | **(         |              |   |
|        |     |     |   |               | mg/kg/wk)** |              |   |
+--------+-----+-----+---+---------------+-------------+--------------+---+
|        |     |     |   |               |             |              |   |
+--------+-----+-----+---+---------------+-------------+--------------+---+
| GHD    | G   | 333 |   | Males and     | 0.18-0.24   | Open‑label,  |   |
|        | DAB |     |   | females,      |             | single-arm   |   |
|        |     |     |   |               |             |              |   |
|        |     |     |   | age ≥2 y      |             |              |   |
+--------+-----+-----+---+---------------+-------------+--------------+---+
| TS     | G   | 136 |   | Females,      | 0.30        | Open-label,  |   |
|        | DCT | (H: |   |               |             | randomized,  |   |
|        |     | 74) |   | age ≥7 y      |             | untreated    |   |
|        |     |     |   |               |             | control, to  |   |
|        |     |     |   |               |             | final height |   |
+--------+-----+-----+---+---------------+-------------+--------------+---+
| TS     | G   | 230 |   | Females,      | 0.27        | D            |   |
|        | DCI |     |   |               |             | ouble‑blind, |   |
|        |     |     |   | age ≥5 y      | 0.36        | randomized,  |   |
|        |     |     |   |               |             | parallel,    |   |
|        |     |     |   |               |             | placebo      |   |
|        |     |     |   |               |             | control      |   |
|        |     |     |   |               |             | (first       |   |
|        |     |     |   |               |             | 1.5 years),  |   |
|        |     |     |   |               |             | extension to |   |
|        |     |     |   |               |             | final height |   |
+--------+-----+-----+---+---------------+-------------+--------------+---+
| N      | G   | 68  |   | Males,        | 0.22        | D            |   |
| on-GHD | DCH | (H: |   |               |             | ouble-blind, |   |
| short  |     | 37) |   | ages 10 to    |             | randomized,  |   |
| s      |     |     |   | 16 y          |             | parallel,    |   |
| tature |     |     |   |               |             | placebo      |   |
|        |     |     |   | Females,      |             | control, to  |   |
|        |     |     |   |               |             | final height |   |
|        |     |     |   | ages 9 to     |             |              |   |
|        |     |     |   | 15 y          |             |              |   |
+--------+-----+-----+---+---------------+-------------+--------------+---+
| N      | E   | 239 |   | Males and     | 0.24        | Open‑label,  |   |
| on-GHD | 001 |     |   | females, age  |             | three‑arm,   |   |
| short  |     |     |   | ≥5 y          | 0.240.37   | randomized,  |   |
| s      |     |     |   |               |             | parallel,    |   |
| tature |     |     |   |               | 0.37        | 2‑year       |   |
|        |     |     |   |               |             | do           |   |
|        |     |     |   |               |             | se‑response, |   |
|        |     |     |   |               |             | with         |   |
|        |     |     |   |               |             | extension    |   |
|        |     |     |   |               |             | phase to     |   |
|        |     |     |   |               |             | final height |   |
+--------+-----+-----+---+---------------+-------------+--------------+---+

Abbreviations: GHD = growth hormone deficiency; H = Humatrope;
N = number of patients in safety analysis; TS = Turner syndrome.

### 4.2.1. Study GDAB

Study GDAB was an open‑label, single‑arm study of Humatrope treatment in
patients with growth hormone deficiency (GHD). The intent of the study
was to evaluate efficacy of Humatrope treatment to increase height
velocity in patients with GHD. Initially, Humatrope was administered
intramuscularly or subcutaneously 3 times per week (TIW) in a dosage of
0.18 mg/kg/wk. The protocol was subsequently amended to allow an
increase in frequency of administration up to 6 times per week, and
dosage up to 0.24 mg/kg/wk based upon the patient's height velocity.
Three hundred thirty-three patients were enrolled in the study. A
*Safety Population* was not defined in the protocol; therefore, the data
provided in this safety comparison are for all enrolled patients.

### 4.2.2. Study GDCT

Study GDCT is an open‑label, randomized, untreated control study to
final height in patients with Turner syndrome. Patients were randomized
to one of two treatment groups: Humatrope (0.30 mg/kg/wk) or Untreated
Control. Humatrope was administered subcutaneously in divided doses 6
times per week. Ethinyl estradiol replacement therapy was given to
patients in both treatment groups who were at least 13 years of age and
had been in the study for at least 12 months. After 1 year of treatment
with ethinyl estradiol, patients at least 15 years of age received
cyclic treatment with ethinyl estradiol and medroxyprogesterone acetate.
Of 140 randomized patients, 136 were included in the *Safety
Population*. The *Safety Population* is defined as those patients who
were randomized and either received any study drug (Humatrope, n=74) or
had postbaseline safety data (Control, n=62). The data provided in this
safety comparison are for the *Safety Population*.

### 4.2.3. Study GDCI

Study GDCI was a double‑blind, randomized, placebo‑controlled (first 1.5
years), parallel study of the effect of Humatrope at two different
doses, with or without low‑dose ethinyl estradiol, on height velocity in
patients with Turner syndrome. After the 1.5-year placebo‑controlled
phase, patients entered an extension to final height. Patients were
randomized to one of the following five treatment groups:

\[1\] Humatrope (0.27 mg/kg/wk) with oral placebo,

\[2\] Humatrope (0.27 mg/kg/wk) with low‑dose ethinyl estradiol,

\[3\] Humatrope (0.36 mg/kg/wk) with oral placebo,

\[4\] Humatrope (0.36 mg/kg/wk) with low‑dose ethinyl estradiol, or

\[5\] Placebo injections with oral placebo for the first 1.5 years:
following a blinded interim analysis, the placebo/placebo treatment
group was reassigned to Humatrope (0.36 mg/kg/wk) with oral placebo,
without unblinding the patients or investigators.

For comparative purposes, treatment groups have been pooled for this
Safety Summary. The group designated as "Dose 1" includes patients
treated with 0.27 mg/kg/wk Humatrope and with either oral placebo or
with low‑dose ethinyl estradiol. The group designated as "Dose 2"
includes all patients who received 0.36 mg/kg/wk Humatrope at any time
during the study, including those who were originally assigned to the
placebo/placebo group and were reassigned to the 0.36 mg/kg/wk group
after 1.5 years on study. Study drug injections were administered
subcutaneously in divided doses TIW for the first 6 years and 6 times
per week thereafter, without a change in the weekly dosage. Ethinyl
estradiol or its placebo equivalent was given orally on a daily basis,
beginning at 8 years of age in patients weighing at least 20 kg. Of
232 randomized patients 230 were included in the *Safety Population*,
defined as those patients who received any study drug. The data provided
in this safety comparison are for the *Safety Population*.

### 4.2.4. Study GDCH

Section 3.1.9 provides a summary of the pivotal trial (Study GDCH) for
this sNDA. Seventy‑one patients with non‑GHD short stature were
randomized to receive either Humatrope (0.22 mg/kg/wk, administered in
divided doses by subcutaneous injection TIW) or placebo injections.
Sixty‑eight of these patients received study drug and were included in
the *Safety Population*. The data provided in this safety comparison are
for the *Safety Population*.

### 4.2.5. Study E001

Section 3.2.8 provides a summary of the supportive study (Study E001)
for this sNDA. Two hundred thirty‑nine patients with non-GHD short
stature were randomized to receive one of three Humatrope regimens,
given in divided doses by subcutaneous injection 6 times per week
(Dose 1: 0.24 mg/kg/wk; Dose 2: 0.24 mg/kg/wk for the first year, then
0.37 mg/kg/wk thereafter, subsequently abbreviated as 0.24→0.37; Dose 3:
0.37 mg/kg/wk). A S*afety Population* was not defined in the protocol;
therefore, the data provided in this safety comparison are for *All
Randomized Patients*.

## 4.3. Exposure

Exposure was defined as the number of years that a patient was in the
study and was calculated by using dates of on‑study visits. This
represents the time from the first treatment visit to the last on-study
visit. Patient compliance was defined as the total number of injections
recorded divided by the total number of expected injections, based on
the number of years the patient was in the study. Table 18 provides a
summary of study drug exposure.

Study GDCI was placebo‑controlled for the first 1.5 years. Thereafter,
patients in the placebo injection/oral placebo treatment group were
transitioned to the 0.36 mg/kg/wk Humatrope/oral placebo group without
unblinding either the patients or the investigators. For this study,
exposure in Table 18 represents exposure to any study drug, including
both the time during which these patients received placebo treatment and
the time during which they received Humatrope treatment. Thus, for
Study GDCI, mean exposure to any study drug was 4.3 years, and exposure
to Humatrope was approximately 4.0 years.

The number of patients and the duration of Humatrope exposure were
similar in each of the three conditions. Patient numbers and total
patient‑years of exposure to Humatrope were: GHD -- 333 patients,
1232 patient-years; Turner syndrome -- 304 patients, 1219 patient-years;
non-GHD short stature -- 276 patients, 1212 patient-years.

[]{#__RefHeading___Toc39468355 .anchor}Table 18. Time on Study

  ----------- --------------- -- --------------- ------------- -- --------------- -- --------------- ------------- -- -- ------ ---------------
              **GH\              **Turner\                                           **Non-Growth                               
              Deficiency**       Syndrome**                                          Hormone                                    
                                                                                     Deficient\                                 
                                                                                     Short Stature**                            

              **GDAB**           **GDCT**                         **GDCI**           **GDCH**                                   **E001**

              **N=333**          **N=136**                        **N=230**          **N=68**                                   **N=239**

              **Humatrope** a    **Humatrope** b **Control**      **Humatrope** c    **Humatrope** d **Control**                **Humatrope** e

                                                                                                                                

  Time on                                                                                                                       
  study (y)                                                                                                                     

  n           333                74              62               229 f              37              31                  239    

  Mean        3.7                4.1             3.7              4.3                3.7             3.3                 4.5    

  Median      NR                 4.3             4.0              4.2                3.6             3.5                 4.2    

  SD          2.7                1.5             1.6              2.2                1.9             1.6                 2.4    

  Minimum     0.0                0.3             0.2              0.3                0.0             0.0                 0.0    

  Maximum     8.3                6.8             6.6              8.1                9.1             6.1                 11.8   
  ----------- --------------- -- --------------- ------------- -- --------------- -- --------------- ------------- -- -- ------ ---------------

Note: The Control group for Study GDCT was a randomized, untreated
control, whereas for Study GDCI and Study GDCH the group was a\
randomized, placebo control.

Abbreviations: GH = growth hormone; N = number of patients in safety
analysis; n = number of patients in group; NR = not reported in the
original analysis submitted to the FDA; SD = standard deviation.

a Dose = 0.18 mg/kg/wk to 0.24 mg/kg/wk.

b Dose = 0.30 mg/kg/wk.

c Dosage groups have been pooled: Dose 1 = 0.27 mg/kg/wk;
Dose 2 = 0.36 mg/kg/wk. The Dose 2 group includes those patients who
received\
placebo for the first 1.5 years and then transitioned to 0.36 mg/kg/wk
Humatrope treatment. Values in the table are derived from total time on\
study drug and not just on Humatrope treatment. Mean exposure for study
drug (Humatrope and placebo) was 4.3 years, and mean exposure\
for Humatrope was approximately 4.0 years. Thus, mean Humatrope exposure
(4.0 years) was approximately 2.7 times the exposure for the placebo
treatment (1.5 years).

d Dose = 0.22 mg/kg/wk.

e Dosage groups have been pooled: Dose 1 = 0.24 mg/kg/wk;
Dose 2 = 0.24 mg/kg/wk for the first year, and then 0.37 mg/kg/wk
thereafter; Dose 3 = 0.37 mg/kg/wk.

f One patient was lost to follow‑up at an unspecified date after
Visit 12. It was not possible to precisely calculate this patient's
number of years\
in the study; therefore, this patient was not included in this analysis.

## 4.4. Deaths

Table 19 provides a summary of patient deaths that occurred both during
and after the clinical trials.

[]{#__RefHeading___Toc39468356 .anchor}Table 19. Patient Deaths During
and After Study

  --------------- ----------- ------- --------------- ------------- --------------- -------------
                                      **During**                    **After**       

  **Condition**   **Study**   **N**   **Humatrope**   **Control**   **Humatrope**   **Control**

                                                                                    

  GHD a           GDAB        333     1               NA            2               NA

  TS              GDCT        136     0               1 b           0               0

  TS              GDCI        230     0               0             0               0

  Non-GHD short   GDCH        68      0               0             0               0
  stature                                                                           

  Non-GHD short   E001        239     0               NA            1 c             NA
  stature                                                                           
  --------------- ----------- ------- --------------- ------------- --------------- -------------

Note: The Control group for Study GDCT was a randomized, untreated
control, whereas\
for Study GDCI and Study GDCH it was a randomized, placebo control.

Abbreviations: GHD = growth hormone deficiency; N = number of patients
in safety\
analysis; NA = not applicable; TS = Turner syndrome.

a One patient death (due to aspiration) occurred during the study, and
two additional deaths (one each due to apnea and due to surgical
complications) were reported after patients discontinued from the study.
Section 4.4.2 provides additional detail.

b Death due to ruptured aortic aneurysm.

c This patient, who had been diagnosed with a desmoplastic small round
cell tumor \[tumor karyotype: 46,XY,t(11;22)(p13;q12)\], died
approximately 4 years after discontinuation from the study.
Section 4.4.4 provides additional detail.

### 4.4.1. Summary Comparison

Two patient deaths were reported during these clinical studies involving
1006 patients, 913 of whom received Humatrope: 1 patient with GHD
receiving Humatrope in Study GDAB and 1 patient with Turner syndrome in
the Untreated Control group of Study GDCT. Three additional deaths
occurred after Humatrope-treated patients discontinued from the studies:
2 patients with GHD and 1 patient with non-GHD short stature. None of
the deaths were considered by the investigators or the Sponsor to be
causally related to Humatrope treatment. Details of the individual cases
in each patient population are provided in the following sections.

### 4.4.2. Growth Hormone Deficiency

In Study GDAB, a 6‑year‑old male, with GHD and cerebral palsy, who had
received Humatrope for approximately 6 months died due to aspiration
during an afternoon nap. The investigator and the Sponsor consider this
event to be causally unrelated to study drug.

Two additional deaths were reported after patients discontinued the
study; neither was considered by the Sponsor to be causally related to
study drug. The first patient, a 5‑year‑old male, was hospitalized for
flu symptoms, hypoglycemia, and severe dehydration approximately
4.5 months after discontinuation from Study GDAB. After a respiratory
arrest the patient was resuscitated and placed on ventilator support but
died shortly thereafter. A second patient, a 20‑year‑old male with a
history of craniopharyngioma, which had been treated 3 years prior to
study entry, died approximately 3 weeks after discontinuation from the
study. Following vascular complications during surgery to remove a
suprasellar cyst, the patient became comatose with a flat
electroencephalogram (EEG) and died after discontinuation of life
support.

### 4.4.3. Turner Syndrome

In Study GDCT, a 13‑year‑old patient in the Untreated Control group, who
was receiving oral ethinyl estradiol only, died due to a ruptured aortic
aneurysm during hospitalization for chest pain. Neither the investigator
nor the Sponsor could exclude a possible causal relationship between
treatment with ethinyl estradiol and this patient's death.

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

In Study E001, a 12‑year‑old male with non-GHD short stature, who had
received 0.24 mg/kg/wk Humatrope for approximately 6.4 years, died due
to desmoplastic small round cell tumor approximately 4 years after
discontinuing the study. As described in detail in Section 4.6.4, the
Sponsor believes that the occurrence of this tumor is unrelated to
Humatrope treatment.

## 4.5. Discontinuations Due to Adverse Events

Table 20 provides a summary of patient discontinuations due to adverse
events (AEs).

[]{#__RefHeading___Toc39468357 .anchor}Table 20. Discontinuations Due to
Adverse Events

![](media/image16.png){width="8.872916666666667in"
height="2.747916666666667in"}

Note: The Control group for Study GDCT was a randomized, untreated
control, whereas for Study GDCI and Study GDCH the group was a
randomized, placebo control.

Abbreviations: AE = adverse event; GH = growth hormone; N = number of
patients in safety analysis; n = number of patients.

a Dose = 0.18 mg/kg/wk to 0.24 mg/kg/wk.

b Dose = 0.30 mg/kg/wk.

c Dosage groups have been pooled: Dose 1 = 0.27 mg/kg/wk;
Dose 2 = 0.36 mg/kg/wk. To facilitate comparison between
Humatrope‑treated patients and control patients, data are presented for
the first 1.5 years, the period during which the study was placebo
controlled. During the total period of Humatrope treatment (mean
exposure to Humatrope was approximately 4.0 years), 4 patients
(1.7%) discontinued due to an AE.

d Dose = 0.22 mg/kg/wk.

e Dosage groups have been pooled: Dose 1 = 0.24 mg/kg/wk;
Dose 2 = 0.24 mg/kg/wk for the first year, and then 0.37 mg/kg/wk
thereafter; Dose 3 = 0.37 mg/kg/wk.

f Although this patient was reported as discontinued due to AE, the AE,
in fact, occurred after the patient had discontinued from the study. Due
to site error, however, the reason for discontinuation was checked as an
AE on the clinical report form (CRF).

### 4.5.1. Summary Comparison

There were fewer than 3% discontinuations due to AEs in any of the
Humatrope‑treated groups across all conditions. Rates of discontinuation
due to AEs are consistent across the three patient populations and the
five studies. There was no pattern suggestive of an increased frequency
of discontinuation in patients with non-GHD short stature. Details of
the individual cases are provided in the following sections, if not
discussed in detail elsewhere (for example, under Serious Adverse
Events).

### 4.5.2. Growth Hormone Deficiency

In Study GDAB, 7 of 333 (2.1%) patients discontinued due to AEs. Of
these, 4 discontinued due to diagnosis, recurrence or progression of
intracranial tumors. As these were considered serious adverse events
they are discussed in further detail (Section 4.6.2). The remaining 3 of
these 7 patients discontinued due to accidental injury, anxiety
regarding injections, and personality disorder.

### 4.5.3. Turner Syndrome

In Study GDCT, 2 of 74 (2.7%) Humatrope-treated patients discontinued
due to AEs. One patient who experienced intracranial hypertension due to
a malfunctioning ventriculo‑peritoneal shunt is discussed in further
detail (Section 4.6.3). The second patient discontinued due to increased
serum glutamic oxaloacetic transaminase (SGOT). The investigator and the
Sponsor considered a possible causal relationship to Humatrope treatment
as occasional, transient, self-limiting elevations in liver
transaminases have been reported in patients with Turner syndrome
receiving GH treatment (Salerno 2000).

In Study GDCI, 4 of 230 (1.7%) patients discontinued due to AEs that
occurred while patients were receiving Humatrope. One patient, discussed
in further detail in Section 4.8.3 discontinued due to progression of
scoliosis. The other three discontinuations were due to a
gastrointestinal disorder, migraine, and a vascular disorder. The
Sponsor considered the gastrointestinal disorder to be causally
unrelated to Humatrope treatment. The vascular disorder was originally
deemed by the Sponsor to possibly be causally related to Humatrope
treatment; however, the Sponsor now considers this event to be
unrelated, as aortic aneurysm is a known complication of Turner
syndrome. The Sponsor cannot exclude a possible causal relationship
between Humatrope treatment and the reported migraine.

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

In Study GDCH, 1 of 37 (2.7%) Humatrope-treated patients discontinued
upon diagnosis of Stage 3B Hodgkin disease (discussed in Section 4.6.4).
One of 31 (3.2%) placebo-treated patients discontinued the study after
an accidental injury.

In Study E001, 3 patients discontinued due to AEs. One patient
discontinued after diagnosis of a desmoplastic small round cell tumor
\[tumor karyotype: 46,XY,t(11;22)(p13;q12)\]. The second patient, a
16-year-old male patient who was receiving Humatrope 0.37 mg/kg/wk,
discontinued the study after diagnosis of a slipped capital femoral
epiphysis following trauma. Both of these events were classified as
serious they are discussed in greater detail (Section 4.6.4). The third
patient, a 14-year-old female who was receiving 0.24 mg/kg/wk Humatrope,
was withdrawn from the study due to decreased glucose tolerance. This
event is discussed in detail in Section 4.8.5, under Alterations in
Carbohydrate Metabolism.

## 4.6. Serious Adverse Events

Table 21 provides a summary of serious adverse events (SAEs).

[]{#__RefHeading___Toc39468358 .anchor}Table 21. Serious Adverse Events

![](media/image17.png){width="8.83125in" height="3.032638888888889in"}

Note: The Control group for Study GDCT was a randomized, untreated
control, whereas for Study GDCI and Study GDCH the group was a
randomized, placebo control.

Abbreviations: GH = growth hormone; N = number of patients in safety
analysis; n = number of patients; SAE = serious adverse event.

a Dose = 0.18 mg/kg/wk to 0.24 mg/kg/wk.

b Dose = 0.30 mg/kg/wk.

c Dosage groups have been pooled: Dose 1 = 0.27 mg/kg/wk;
Dose 2 = 0.36 mg/kg/wk. To facilitate comparison between
Humatrope‑treated patients and controlled patients, data are presented
for the first 1.5 years, the period during which the study was placebo
controlled. During the total period of Humatrope treatment (mean
exposure for Humatrope was approximately 4.0 years), 51 SAEs were
reported for 41 (17.8%) patients (for 1 patient an SAE was reported
during placebo treatment and during Humatrope treatment).

d Dose = 0.22 mg/kg/wk.

e Dosage groups have been pooled: Dose 1 = 0.24 mg/kg/wk;
Dose 2 = 0.24 mg/kg/wk for the first year, and then 0.37 mg/kg/wk
thereafter; Dose 3 = 0.37 mg/kg/wk.

### 4.6.1. Summary Comparison

The overall SAE rate was somewhat lower in the non-GHD short stature
population than in the GHD and Turner syndrome populations, likely due
to higher rates of baseline disease in the latter populations. In
addition, the SAE profile varied somewhat between the populations. The
majority of SAEs for the GHD and Turner syndrome populations were
hospitalizations for illness or surgeries related to the underlying
disease, while the majority of the SAEs reported for the non-GHD short
stature patient population were hospitalizations for accidental injuries
or acute illnesses. As expected, SAEs associated with neurological
disorders or ear disorders were reported less frequently in the non-GHD
short stature patient population than in patients with GHD or Turner
syndrome. Details of the individual cases in each patient population are
provided in the following sections.

### 4.6.2. Growth Hormone Deficiency

In Study GDAB, 157 serious adverse events were reported for 90 of
333 (27%) patients. The majority of these events were hospitalizations,
with surgical procedure being the most common reason for
hospitalization. Six SAEs were reported in relation to intracranial
tumors: one newly diagnosed, four recurrent or progressive and one
stable. A 14‑year‑old male patient was diagnosed with a
craniopharyngioma after approximately 2.8 years of Humatrope treatment
and discontinued the study because of this event. No information
regarding prestudy central nervous system imaging is available for this
patient and the Sponsor cannot exclude a possible causal relationship
between Humatrope treatment and the diagnosis of craniopharyngioma. The
four cases of intracranial tumor recurrence or progression included
three cases of craniopharyngioma and one of germinoma. Two patients with
history of craniopharyngioma discontinued due to recurrence of the
condition after approximately 1 year and 2 years respectively, on study.
One patient with recurrence/progression of craniopharyngioma remained on
study. One patient discontinued after approximately 5 months of
Humatrope treatment due to enlargement of a suprasellar germinoma. One
additional patient was hospitalized for treatment (implantation of
radioisotope) of a preexisting craniopharyngioma. However, this
procedure was not performed for progression of the tumor, but rather,
this was a scheduled surgical procedure to prevent future growth of the
craniopharyngioma. Current studies (Moshang et al. 1996; Swerdlow et
al. 2000) indicate no increase in the recurrence rate of intracranial
tumors in GH‑treated patients with a history of intracranial tumor.

Additional SAEs associated with neurological disorders included
hospitalizations for concussion (acute brain syndrome \[n=1\]), cerebral
vascular accident (n=1), convulsions or seizures (n=5; seven events: 2
patients \[3 events\] had a history of seizure disorder, 2 patients had
a seizure associated with either an infection and high fever or
influenza, and 1 patient with a history of craniopharyngioma was
diagnosed with probable temporal lobe seizure), and dysfunction or
replacement of ventriculo‑peritoneal shunts (n=3; six events).
One patient was monitored in hospital for intracranial hypertension
after complaints of headaches and vomiting; however, no increased
intracranial pressure was observed.

One patient with history of nasopharyngeal lymphoma was hospitalized
because of an enlarged thymus, which was found to be non-malignant on
biopsy. The Sponsor could not exclude a possible causal relationship
between the thymus hypertrophy and Humatrope treatment.

Papillary carcinoma of the thyroid was reported in a patient who had a
history of acute lymphoblastic leukemia treated with chemotherapy, total
body irradiation, and bone marrow transplantation. After surgical
removal of the tumor, the patient continued on Humatrope treatment and
had no evidence of tumor at study discontinuation more than 6 years
later.

SAEs related to ear disorders were reported for 3 patients
(hospitalization for myringotomy \[n=2\] and surgery for replacement of
pressure equalization tubes \[n=1\]).

One patient, an 18‑year‑old male with a bone age of approximately
13 years, was hospitalized for hip surgery following a slipped capital
femoral epiphysis. After clinical deterioration, he was hospitalized
approximately 1 year later for prophylactic hip pinning. Humatrope
treatment was continued during the events. At the time (1986 and 1987),
the events were not deemed related to study drug. In 1989, however, the
Humatrope label was changed to reflect new information indicating an
association between endocrine disorders, such as GHD, and slipped
capital femoral epiphyses. Rapid linear growth has been proposed as a
major risk factor for the development of slipped capital femoral
epiphysis (Alexander 1976). Thus, the Sponsor believes that a
relationship between a Humatrope‑stimulated growth spurt and the slipped
capital femoral epiphysis in this patient cannot be excluded.

### 4.6.3. Turner Syndrome

In Study GDCT, 31 SAEs were reported for 20 of 74 (27%) patients who
received Humatrope treatment. The majority of these events were
hospitalizations, most often for surgical procedures. There were
numerous surgical procedures for ear disorders, including surgery for
chronic mastoiditis, removal of a cholesteatoma, a combined
mastoidectomy/nasoplasty/tympanoplasty, a tympanoplasty and ear surgery
not otherwise specified (NOS). The greater occurrence of SAEs in
Humatrope‑treated patients (27%) compared with control patients (13%)
was largely attributable to a higher rate of hospitalization in the
Humatrope-treated group.

There were two events related to neurological disorders reported for
1 patient. This patient had intracranial hypertension due to
ventriculo‑peritoneal shunt malfunction. The patient was hospitalized
for repair of the shunt, and Humatrope was discontinued. The Sponsor
considered a possible causal relationship between the intracranial
hypertension and Humatrope treatment. Subsequent shunt valve replacement
surgery was also performed.

Study GDCI was placebo controlled for the first 1.5 years of its
duration, so the SAE data are reviewed in two ways: first, by
between-group comparison (Humatrope versus placebo) for the controlled
phase and second, across the whole study for all Humatrope-treated
patients. During the 1.5‑year, placebo‑controlled phase of the study the
frequency of SAEs for the Humatrope‑treated patients and placebo‑treated
patients was similar (5.4% and 8.7%, respectively). During the entire
course of the study (approximately 4.0 years mean Humatrope exposure),
51 SAEs were reported for 41 of 230 (18%) patients who received
Humatrope treatment. The most frequent SAE was hospitalization for
surgical procedure. As in Study GDCT, there were numerous events related
to ear disorders. These included surgery for chronic mastoiditis,
mastoidectomy, eardrum repair and ear surgery NOS. Patients with Turner
syndrome are known to have a higher rate of otitis media, deafness, and
other ear disorders than patients of similar age who do not have Turner
syndrome; however, these surgical procedures occurred more frequently in
patients treated with Humatrope than in patients in the control groups
of both studies. The relationship to Humatrope treatment is unknown;
however, these data are reported in the current Humatrope label. There
were no neoplasms or neurological disorders reported during this study.

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

In Study GDCH two SAEs were reported in patients (6.5%) receiving
placebo injections (injuries sustained an a motor vehicle accident \[1
patient\], black widow spider bite \[1 patient\]) and five SAEs were
reported for 5 of 37 (13.5%) patients who received Humatrope treatment.
Four patients were hospitalized for acute injury or illness (alcohol
ingestion \[1 patient\], injuries sustained in a fall \[1 patient\], and
fractured leg \[2 patients\]).

The fifth patient, an 11‑year‑old male who had received Humatrope for
approximately 19 weeks, was diagnosed with Stage 3B Hodgkin disease. At
the time of the initial report, a relationship between Hodgkin disease
and Humatrope treatment could not be excluded. However, a number of
important pieces of clinical information obtained retrospectively
provide strong evidence against such a relationship (Table 22):

-   First, a chest x-ray performed prior to study entry, but obtained
    only retrospectively, was reported by the radiologist as follows:
    "the mediastinum is widened somewhat I suspect probably because of
    thymus remnant".

-   Second, at study entry this patient had a relatively high
    sedimentation rate (sedimentation rate: 32 mm/h; reference range:
    l to 39 mm/h) and mild elevation of lactic dehydrogenase (LDH: 248
    U/L; reference range: 113 to 226 U/L), a nonspecific marker of
    systemic disease.

-   Third, 12 weeks after the start of Humatrope treatment, the
    patient's sedimentation rate was elevated (58 mm/h) and LDH remained
    elevated (257 U/L). Lymphadenopathy was noted after 4 months of
    treatment, and Stage 3B Hodgkin disease was diagnosed shortly
    thereafter.

Stage 3 Hodgkin disease indicates an advanced stage of the disease,
involving lymph node sites on both sides of the diaphragm but without
evidence of extra‑nodal involvement (Norris et al. 1975). The
presentation with "B" symptoms (systemic symptoms such as fever, night
sweats, and significant weight loss) and the advanced stage of disease
(Stage 3B) suggests that the disease had been present subclinically for
quite some time prior to presentation. An external pediatric oncologist
reviewed the clinical, radiographic and laboratory findings for this
patient, and indicated that the high normal baseline ESR and the
elevated LDH were consistent with the presence of subclinical Hodgkin
disease (Terry Vik, MD, Riley Hospital for Children, Indianapolis, IN).
Dr. Vik also indicated that progression to Stage 3B Hodgkin disease can
be expected to take approximately 6 months to 1 year when untreated and,
that there are no data to support a concern that growth hormone may have
increased the rate of tumor progression. Dr. Vik concluded that the
clinical and laboratory evidence suggested the patient had subclinical
Hodgkin disease at study entry. In light of the additional clinical
information discovered retrospectively and the clinical judgment of an
experienced pediatric oncologist, the Sponsor considers a causal
relationship between Humatrope treatment and the patient's Hodgkin
disease unlikely. This determination is supported by the baseline
findings (report of widened mediastinum on chest x‑ray, elevated LDH,
and borderline high ESR), the short treatment interval (19 weeks), and
the advanced stage of disease (3B) at diagnosis; each factor suggests
the patient had preexisting subclinical disease at study entry.

[]{#__RefHeading___Toc39468359 .anchor}Table 22. Patient Diagnosed with
Hodgkin Disease: Timecourse of Events

+-----------+-------------------------------+-------------------------+
| **Date**  | **Events**                    | **Status of Humatrope   |
|           |                               | Therapy**               |
+-----------+-------------------------------+-------------------------+
|           |                               |                         |
+-----------+-------------------------------+-------------------------+
| 19 Jul    | LDH 207 U/L (RR: 113-226)     | 5 months prior to       |
| 1989      |                               | enrollment              |
+-----------+-------------------------------+-------------------------+
| Oct 1989  | Chest x-ray with widened      | 2 months prior to       |
|           | mediastinum noted             | enrollment              |
+-----------+-------------------------------+-------------------------+
| 11 Dec    | ESR 32 mm/h (RR: 1-39)        | Humatrope started       |
| 1989      |                               | (Visit 1)               |
|           | LDH 248 U/L                   |                         |
+-----------+-------------------------------+-------------------------+
| 12 Mar    | ESR 58 mm/h                   | On Humatrope for 3      |
| 1990      |                               | months (Visit 4)        |
|           | LDH 257 U/L                   |                         |
+-----------+-------------------------------+-------------------------+
| Apr 1990  | Lymphadenopathy reported      | On Humatrope for 4      |
|           |                               | months                  |
+-----------+-------------------------------+-------------------------+
| 23 Apr    |                               | Humatrope stopped\      |
| 1990      |                               | (total = 19 weeks)      |
+-----------+-------------------------------+-------------------------+
| 25 Apr    | Hospitalized and Stage 3B     |                         |
| 1990      | Hodgkin disease diagnosed     |                         |
+-----------+-------------------------------+-------------------------+
| 11 May    | Chemotherapy started          |                         |
| 1990      |                               |                         |
+-----------+-------------------------------+-------------------------+
|           |                               |                         |
+-----------+-------------------------------+-------------------------+

Abbreviations: ESR = erythrocyte sedimentation rate; GH = growth
hormone; LDH = lactic dehydrogenase; RR = reference range.

Hodgkin disease is the third most common malignancy in patients under
20 years of age, representing 7.8% of all cancers, with an annual
incidence of 1.3 per 100,000 population (Edwards et al. 2002). Between
March 1987 and February 2002, an estimated 60,000 patients had received
Humatrope. Based on an estimated average duration of exposure of 5
years, this represents approximately 300,000 patient years of exposure.
This is one of only two reports of Hodgkin disease in the Lilly
Pharmacovigilance database for Humatrope. Thus, for the overall
Humatrope‑treated patient population, there does not appear to be an
excess of Hodgkin disease over that expected for the general population.

In Study E001, 38 SAEs were reported for 31 of 239 (13%) patients. The
majority of the serious events were hospitalizations, predominantly for
surgical procedures. There were no significant dose-related differences
in the rates of SAEs reported in this study: SAEs were reported for 11
of 78 (14%) patients in the 0.24 mg/kg/wk Humatrope dosage group, 4 of
78 (5%) patients in the 0.240.37 mg/kg/wk dosage group, and 16 of
83 (19%) patients in the 0.37 mg/kg/wk dosage group.

There was one report of neoplasm; a desmoplastic small round cell tumor,
in a 12‑year‑old male patient who had received 0.24 mg/kg/wk Humatrope
treatment for approximately 6.4 years. This patient discontinued the
study due to this event and died approximately 4 years after study
discontinuation. Karyotype analysis of the tumor revealed a chromosomal
translocation \[tumor karyotype: 46,XY,t(11;22)(p13;q12)\] and a
duplication of the short arm of chromosome 1. The translocation
breakpoints represent the chromosomal loci of two important
tumor-related genes: 11p13 is the locus of the Wilms tumor suppressor
gene (WT1) and 22q12 is the locus of the Ewing Sarcoma gene (EWS). This
chromosomal translocation is a hallmark of this rare tumor type,
producing a fusion gene that comprises the 5' portion of the EWS gene
and the 3' portion of the WT1 gene (Gerald et al. 1998). This abnormal
fusion gene encodes an oncogenic chimeric transcription factor that
places the oncogenic transactivating power of the EWS transcription
factor upstream of the gene-targeting zinc finger region of WT1. This
highly oncogenic transcription factor is believed to be responsible for
the development of this tumor (Gerald et al. 1998). Incidence rates for
this rare tumor are not available, as only a limited number of cases
have been reported in the medical literature (Gerald et al. 1998);
however, this tumor has been reported to occur predominantly in
adolescent males (Kushner et al. 1996; Gerald et al. 1998). At the time
of the event, the tumor karyotype information was not known and
causality was unassessed by the investigator; however, the Sponsor
believes that the occurrence of this neoplasm is not causally related to
Humatrope treatment, since previous reports suggest that the genetic
event leading to the EWS‑WT1 gene fusion is of primary importance in the
development of desmoplastic small round cell tumor (Gerald et al. 1998).
The Lilly Pharmacovigilance database contains no other report of
desmoplastic small round cell tumor and furthermore, there is no case of
desmoplastic small round cell tumor reported in the 16-years of
literature on safety of somatropin.

There was one event of slipped capital femoral epiphysis in a
16-year-old patient who had received 0.37mg/kg/wk Humatrope for more
than 5 years. During an epileptic seizure the patient, who had known
epilepsy for which he was receiving valproate sodium, fell and broke the
head of his right femur. A hospital examination detected slipped capital
femoral epiphysis. Slipped capital femoral epiphysis occurs primarily
during childhood growth spurts, with male gender, rapid growth, and
puberty being postulated as risk factors for this disorder in the
general population (Alexander 1976; Loder et al. 1995). Consequently,
although the slipped capital femoral epiphysis in this patient occurred
in the setting of a traumatic femoral fracture, the possibility that the
development of slipped capital femoral epiphysis was related to a
Humatrope‑stimulated growth spurt cannot be excluded. A greater
frequency of slipped capital femoral epiphysis has been observed in
GH‑treated patients with GHD than in the general population (Rappaport
and Fife 1985). The occurrence of slipped capital femoral epiphysis in
GH‑treated patients with non-GHD short stature is similar to that of the
general population (Blethen et al. 1996). The current Humatrope label
includes information indicating an association between endocrine
disorders and slipped capital femoral epiphysis.

With regard to neurological disorders, there were six reports of
convulsions or epilepsy among 3 patients in Study E001. Five of these
six events were reported for 2 patients with preexisting epilepsy (one
event reported for 1 patient and four events reported for the second
patient). The remaining convulsion was associated with otitis
media/maxillary sinusitis. There was one SAE related to an ear disorder
(hospitalization for insertion of a transtympanic drain).

## 4.7. Treatment-Emergent Adverse Events

Table 23 summarizes data for treatment-emergent adverse events (TEAEs),
defined as any event that developed or worsened during the study. The
events are presented in order of decreasing frequency for all events
reported in ≥10% of Humatrope‑treated patients in the pivotal study,
Study GDCH. Thus, for the other studies, the events may not be in order
of decreasing frequency for a particular study.

[]{#__RefHeading___Toc39468360 .anchor}Table 23. Treatment-Emergent
Adverse Events

![](media/image18.wmf){width="8.913194444444445in"
height="5.082638888888889in"}

Table 23. Treatment-Emergent Adverse Events (continued)

![](media/image19.png){width="8.872916666666667in"
height="4.976388888888889in"}

Table 23. Treatment-Emergent Adverse Events (concluded)

![](media/image20.png){width="8.8375in" height="1.4986111111111111in"}

Note: Events listed in this table are ranked according to decreasing
frequency in the Humatrope treatment arm of Study GDCH. The Control
group for Study GDCT was a randomized, untreated control, whereas for
Study GDCI and Study GDCH it was randomized, placebo controlled (Study
GDCI was placebo-controlled for the first 1.5 years of study).

Abbreviations: GH = growth hormone; N = number of patients; n = number
of patients with the TEAE; NR = not reported.

a Dose = 0.18 mg/kg/wk to 0.24 mg/kg/wk.

b Dose = 0.30 mg/kg/wk.

c Data include only those events reported during the placebo‑controlled
phase of the study (first 1.5 years).

d Dosage groups have been pooled: Dose 1 = 0.27 mg/kg/wk;
Dose 2 = 0.36 mg/kg/wk.

e Dose = 0.22 mg/kg/wk.

f Dosage groups have been pooled: Dose 1 = 0.24 mg/kg/wk;
Dose 2 = 0.24 mg/kg/wk for the first year, and then 0.37 mg/kg/wk
thereafter; Dose 3 = 0.37 mg/kg/wk.

### 4.7.1. Summary Comparison

As expected in pediatric studies, TEAEs were reported for the majority
of patients in each of the three patient populations. The majority of
events for each patient population represented common childhood
illnesses such as rhinitis, pharyngitis and flu syndrome. The overall
frequency of events was similar across conditions; however,
between-study comparisons of these events are difficult due to
differences in study design and data collection methods. For example,
Study GDCH was unique among these studies in utilizing a patient diary
to collect adverse event data. Consequently, treatment emergent adverse
event data collection for this study was possibly more complete than for
any of the other studies. This likely explains the greater frequency of
reporting of a number of events in the non-GHD short stature patient
population of Study GDCH than in the GHD or Turner syndrome patient
populations. There were, however, no statistically significant
differences between the Humatrope and placebo treatment groups in the
rate of occurrence of any of these TEAEs and no statistically
significant differences in overall rates of total TEAEs between the
dosage groups in Study E001.

### 4.7.2. Growth Hormone Deficiency

The five most frequently reported events were rhinitis, pharyngitis,
fever, headache, and infection. The high frequency of these events in a
pediatric clinical trial is not surprising, given the high frequency of
such events in the general pediatric population.

### 4.7.3. Turner Syndrome

The most frequently reported events were rhinitis, pharyngitis,
headache, infection, flu syndrome, and fever. In both Study GDCT and
Study GDCI, otitis media was reported significantly more frequently for
patients receiving Humatrope than for patients in the control group.
Patients with Turner syndrome are known to have a higher rate of otitis
media, hearing deficits and other ear disorders than patients of similar
age who do not have Turner syndrome. The relationship to Humatrope
treatment is unknown; however, this information is included in the
current Humatrope label.

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

Study GDCH was unique among these studies in utilizing a patient diary
to collect adverse event data. The patient's parent(s) completed this
diary at home and study site personnel transferred data to the clinical
report forms (CRFs) at each study visit. The most frequently reported
events in the Humatrope-treated group of Study GDCH were rhinitis,
pharyngitis, cough increased, flu syndrome, accidental injury, and
headache. There were no statistically significant differences between
the Humatrope and placebo treatment groups in the rate of occurrence of
reported TEAEs in Study GDCH. However, while the differences in
reporting rate were not statistically significant, there were a number
of events reported more often in Humatrope-treated than placebo-treated
patients that have potential clinical relevance and warrant further
discussion.

Back pain was reported in 10 Humatrope-treated patients (27%) compared
with 3 placebo-treated patients (10%). Individual case review of the
Humatrope-treated patients revealed: 4 associated with injury or strain;
1 associated with viral illness; 1 in a patient diagnosed with Hodgkin
disease (discussion Section 4.6.4); 3 reported as mild and at a single
visit; and 1 case reported as mild and at multiple visits. Thus, the
Sponsor does not believe that the higher occurrence rate of back pain in
Humatrope-treated patients in Study GDCH reflects a clinically
meaningful effect of Humatrope.

Acne, bone disorder, lymphadenopathy and myalgia were each reported in 9
Humatrope treated patients (24%) compared with 4 placebo-treated
patients (13%). Acne was reported at multiple visits for most of the
affected patients, and was of mild severity for all Humatrope-treated
patients. The event term of "Bone Disorder" includes 7 reports of
scoliosis in Humatrope-treated patients and 4 in placebo-treated
patients. All events were reported as "trace" or "mild". Scoliosis is
discussed in further detail (Section 4.8.3). Of the 9 Humatrope-treated
patients for whom lymphadenopathy was reported, this finding was
associated with intercurrent infections such as pharyngitis, upper
respiratory infection or infectious mononucleosis in 8 patients and was
noted at only a single visit in 6 patients. One of the patients for whom
lymphadenopathy was reported was the patient subsequently diagnosed with
Hodgkin disease (Section 4.6.4). Of the 9 reports of myalgia in
Humatrope-treated patients 4 were associated with injuries or
intercurrent illness. In 4 of the remaining 5 patients the event was
reported well into study (18 months or later) and was transient. In the
fifth patient the event was reported only at the last visit on study.

The AEs for Study GDCH (Table 23) were further evaluated to determine if
the differences in the reporting rates between the treatment groups
could represent possible safety signals. Using actual terms and comments
reported by the investigators, all adverse events were assessed and
grouped into clinically relevant categories. For example, events
contained in the "Ear" category, include reports of ear pain, otitis
media, ear disorder, ear infection, etc. This evaluation and analysis
was undertaken to ensure that no relevant events would be missed, and
that events would not be double-counted. For example,
investigator-reported otitis media, with ear pain and ear stuffiness,
would not be counted as 3 events. Rather, it would be one event in the
Ear category.

Table 24 summarizes data for treatment emergent adverse events, grouped
into clinically relevant categories.

[]{#__RefHeading___Toc39468361 .anchor}Table 24. Summary of
Treatment-Emergent Adverse Events by Clinically Relevant Categories\
Safety Population\
Study GDCH

  ----------------------- --------------- --------- ------------- --------- ------------ --------- -----------
                          **Humatrope**             **Placebo**             **Total**              

                          **(N=37)**                **(N=31)**              **(N=68)**             

  **Event                 **n**           **(%)**   **n**         **(%)**   **n**        **(%)**   **p-value
  Classification**                                                                                 a**

  PATIENTS WITH \>= 1     36              (97.3)    30            (96.8)    66           (97.1)    1.00
  TEAE                                                                                             

  PATIENTS WITH NO TEAE   1               (2.7)     1             (3.2)     2            (2.9)     1.00

  Infection, viral        31              (83.8)    26            (83.9)    57           (83.8)    1.00

  Gastrointestinal        19              (51.4)    22            (71.0)    41           (60.3)    0.137

  Accidental injury       19              (51.4)    19            (61.3)    38           (55.9)    0.468

  Headache/Migraine       20              (54.1)    15            (48.4)    35           (51.5)    0.808

  Skin/Hair               16              (43.2)    18            (58.1)    34           (50.0)    0.330

  Muscular/skeletal       19              (51.4)    14            (45.2)    33           (48.5)    0.635

  Systemic conditions     16              (43.2)    16            (51.6)    32           (47.1)    0.626

  Infection, bacterial    17              (45.9)    13            (41.9)    30           (44.1)    0.809

  Joint disorders/pain    17              (45.9)    11            (35.5)    28           (41.2)    0.462

  Hemopoetic system       15              (40.5)    12            (38.7)    27           (39.7)    1.00

  Ear                     15              (40.5)    11            (35.5)    26           (38.2)    0.803

  Injection site          13              (35.1)    10            (32.3)    23           (33.8)    1.00

  Central nervous system  11              (29.7)    9             (29.0)    20           (29.4)    1.00

  Laboratory abnormality  10              (27.0)    10            (32.3)    20           (29.4)    0.790

  Renal/Urinary tract     9               (24.3)    9             (29.0)    18           (26.5)    0.784

  Eye                     9               (24.3)    7             (22.6)    16           (23.5)    1.00

  Dental                  8               (21.6)    4             (12.9)    12           (17.6)    0.525

  Head and neck           6               (16.2)    5             (16.1)    11           (16.2)    1.00

  Scoliosis               7               (18.9)    4             (12.9)    11           (16.2)    0.742

  Cardiovascular          6               (16.2)    4             (12.9)    10           (14.7)    0.745

  Reproductive            7               (18.9)    3             (9.7)     10           (14.7)    0.326

  Respiratory             5               (13.5)    5             (16.1)    10           (14.7)    1.00

  Allergy                 5               (13.5)    4             (12.9)    9            (13.2)    1.00

  Surgical procedure      7               (18.9)    2             (6.5)     9            (13.2)    0.166

  Infection, fungal and   6               (16.2)    2             (6.5)     8            (11.8)    0.275
  parasitic                                                                                        

  Bone disorder, other    4               (10.8)    2             (6.5)     6            (8.8)     0.681

  Chest Pain              2               (5.4)     2             (6.5)     4            (5.9)     1.00

  Endocrine               0                         3             (9.7)     3            (4.4)     0.090

  Benign                  0                         1             (3.2)     1            (1.5)     0.456
  neoplasms/growths                                                                                

  Hypoglycemia            0                         1             (3.2)     1            (1.5)     0.456
  ----------------------- --------------- --------- ------------- --------- ------------ --------- -----------

Abbreviations: N = number of patients in treatment group; n = number of
patients with event.

a Frequencies are analyzed using a Fisher's Exact test.

There were no statistically significant differences in the frequency of
treatment-emergent events, grouped into clinically relevant categories,
between the Humatrope-treated and placebo-treated patients. However,
Humatrope-treated patients did have a greater frequency of treatment
emergent events in the categories of Reproductive, Fungal and Parasitic
Infection, and Surgical Procedures.

Events in the Reproductive category occurred in 7 (18.9%)
Humatrope-treated patients and 3 (9.7%) placebo-treated patients. The
events in the Humatrope-treated patients included conditions that
commonly occur during adolescence such as breast tenderness or soreness,
painful menses, and pubertal gynecomastia. All events were rated as
mild, did not result in discontinuation from study, and for the majority
of patients, resolved prior to study completion.

Parasitic or fungal infections occurred in 6 (16.2%) Humatrope-treated
patients and 2 (6.5%) placebo-treated patients. The events in the
Humatrope-treated patients were: athlete's foot, pinworms, tinea cruris,
ringworms, fungal mouth sore, and yeast infection. All events were rated
as mild, did not result in discontinuation from study, and for the
majority of patients, resolved prior to study completion.

Surgical procedures were performed on 7 (18.9%) patients in the
Humatrope-treated group and 2 (6.5%) patients in the placebo-treated
group. The surgical procedures in the Humatrope-treated patients were:
mole removal, surgery on bursa, unilateral orchidectomy, sutures, wart
removal, posttraumatic surgery, lymph node removal. The diverse nature
of these surgical procedures does not suggest an association with
Humatrope treatment.

In Study E001 there were slight, but not significant, dose-related
differences in overall rates of total TEAEs. TEAEs were reported for 47
of 78 (60%) patients in the 0.24 mg/kg/wk Humatrope dosage group, 57 of
78 (73%) patients in the 0.240.37 mg/kg/wk group and 58 of 83 (70%)
patients in the 0.37 mg/kg/wk dosage group. Between-group comparisons of
occurrence rates for individual events are of limited clinical
significance since the majority of events were reported in just a single
patient. Of the 41 TEAEs that were reported in more than a single
patient in any treatment group, 9 events were reported with greatest
frequency in the 0.24 mg/kg/wk Humatrope dosage group, 18 were reported
with greatest frequency in the 0.240.37 mg/kg/wk group and 11 events
were reported with greatest frequency in the 0.37 mg/kg/wk Humatrope
dosage group; three events were reported with equal frequency in the
0.24 and 0.240.37 mg/kg/wk dosage groups. There were statistically
significant differences among treatment groups for bronchitis, diarrhea,
and anemia, but none of these differences was dose related.

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

This section discusses a number of treatment emergent adverse events
that are currently referenced in the Humatrope label, as they have been
reported in patients receiving somatropin. These events include otitis
media, scoliosis, hypothyroidism, hypertension, alterations of
carbohydrate metabolism and slipped capital femoral epiphysis. Table 25
summarizes these data. Edema, benign intracranial hypertension, and
gynecomastia are also referenced in the Humatrope label. Edema and
intracranial hypertension are not included or discussed here, as there
were no cases reported in the non-GHD short stature population.
Gynecomastia is not discussed because the 3 patients (2 Humatrope,
1 placebo) for whom gynecomastia were reported were all pubertal at the
time and transient gynecomastia occurs as a physiologic event during
normal male puberty. The structure of this section differs from that of
the preceding sections in that each condition is discussed in summary
format, rather than on a by-population basis.

Unless otherwise noted, the following discussions are restricted to
patients who received Humatrope treatment.

### 4.8.1. Summary Comparison

Overall, patients with non-GHD short stature had a similar or reduced
rate of TEAEs that are currently referenced in the Humatrope label.
Compared with GHD patients, those with non-GHD short stature had similar
rates of slipped capital femoral epiphysis and alterations in
carbohydrate metabolism. Hypothyroidism, hypertension, and otitis media
occurred less often in patients with non‑GHD short stature than in those
with GHD or Turner syndrome. Scoliosis was reported more frequently in
the non-GHD short stature patient population of Study GDCH than in the
GHD and Turner syndrome patient populations (Section 4.8.3).

[]{#__RefHeading___Toc39468362 .anchor}Table 25. Adverse Events
Referenced in Humatrope Label

  ------------------- ------------- -------------------- -----------------
                      GHD           Turner syndrome      Non-GHD short
                                                         stature

  Number of           333           304                  276
  Humatrope-Treated                                      
  Patients                                               

  Number (%) of                                          
  patients with event                                    

  Otitis Media        95 (28.5)     133 (43.8)           22 (8.0)

  Scoliosis           5 (2.0)       1 (0.3)              8 (2.9)

  Hypothyroidism      78 (23.4)     50 (16.4)            2 (0.7)

  Alterations in      1 (0.3)       1 (0.3)              2 (0.7)
  carbohydrate                                           
  metabolism                                             

  Hypertension        1 (0.3)       15 (4.9)             1 (0.4)

  Slipped Capital     1 (0.3)       0                    1 (0.4)
  Femoral Epiphysis                                      
  ------------------- ------------- -------------------- -----------------

Presented in order of decreasing frequency for the non-GHD short stature
population.

Abbreviation: GHD = growth hormone deficiency.

In both Study GDCH and Study E001, there were no statistically
significant differences between treatment groups (GDCH: Humatrope versus
placebo; E001: Dose 1 versus Dose 2 or Dose 3) for any of the events
examined.

### 4.8.2. Otitis Media

Otitis media was reported in 29% of patients with GHD and in more than
40% of patients with Turner syndrome receiving Humatrope. Ear disorders
were reported more frequently in Humatrope-treated patients than in
control patients for both of the Turner syndrome studies. The
relationship between Humatrope treatment and otitis media in patients
with Turner syndrome is not clear; however, this information is provided
in the current Humatrope label. In the non-GHD short stature patient
population, otitis media was reported in 7% of patients in Study E001,
16% of the Humatrope‑treated patients in Study GDCH and 7% of the
placebo‑treated patients. When all forms of ear disorder (ear infection,
otitis media, otitis externa, ear pain and ear disorder) are evaluated
together, excluding patients who were counted twice for the same
condition at the same visit (for example, "ear pain" and "otitis
media"), there were similar numbers of affected patients in the
Humatrope and placebo groups (Humatrope: 15 of 37 patients \[41%\],
placebo: 11 of 31 patients \[36%\]).

### 4.8.3. Scoliosis

The occurrence or worsening of scoliosis during GH treatment is an
uncommon event, and the relationship to GH treatment is uncertain. In
the study of patients with GHD, scoliosis was reported for 5 of 333 (2%)
patients. All cases were of mild degree. In the Turner syndrome studies,
a 16‑year‑old patient who had received placebo injections for 1.5 years
followed by Humatrope treatment for 1.7 years, discontinued after
3.2 years on study due to diagnosis and subsequent worsening of thoracic
scoliosis. It could not be determined whether the scoliosis was present
at study entry. Therefore the Sponsor deemed that a causal relationship
to study drug could not be excluded. In the non-GHD short stature
patient population, scoliosis was reported for 16% of all patients in
Study GDCH (Humatrope-treated and placebo‑treated combined) and for
0.4% of patients in Study E001. Because scoliosis has been reported as a
possible adverse effect of somatropin therapy (Dymling and Willner
1978), the NIH investigators paid particularly close attention to this
and performed a screening examination for scoliosis at each study visit.
This examination consisted of the standard forward bending test used in
school screening examinations, which has been reported to have a
positive predictive value of 43% (Morais et al. 1985). Morais et al.
reported that the screening test was positive in 11.4% of children
examined and upon more rigorous investigation, idiopathic scoliosis was
confirmed in 43% of those examined. Consequently, the prevalence of true
scoliosis in Study GDCH was likely lower than the 19% and 13% of
Humatrope-treated and placebo-treated patients, respectively, and was
likely closer to that reported in the general population. Furthermore,
all reported cases of scoliosis were rated as mild, often reported as
"trace scoliosis", no x-rays were performed, and no progression or
treatment was reported for any patient.

### 4.8.4. Hypothyroidism

On-study development or worsening of hypothyroidism was reported in 23%
of patients with GHD and 16% of patients with Turner syndrome. On-study
development of hypothyroidism was reported in only 2 of 276 (0.7%)
Humatrope-treated patients with non-GHD short stature (Study GDCH, n=0
\[0%\]; Study E001, n=2 \[1%\]). Hypothyroidism was also reported in 2
patients in the placebo group of Study GDCH.

### 4.8.5. Alterations in Carbohydrate Metabolism

There were few AEs related to carbohydrate metabolism reported in any of
the 3 patient populations. The following terms were included in the
search for conditions related to changes in carbohydrate metabolism:
hyperglycemia, impaired glucose tolerance, decreased glucose tolerance,
glucose intolerance, insulin resistance, and diabetes mellitus.
Hyperglycemia was reported in 3 patients, one in each of the GHD, Turner
syndrome and non-GHD short stature patient populations. In the Turner
syndrome studies, type 1 diabetes mellitus was reported for a single
patient. There were no reports of diabetes mellitus in the non-GHD short
stature studies. However, there was one report of decreased glucose
tolerance in a patient in Study E001. A 13-year, 11-month-old female
patient who had received Humatrope 0.24 mg/kg/wk for over 8 years had a
borderline high HbA1c of 6.1% (upper limit of normal on the assay was
6.0%). The patient had no clinical symptoms of glucose intolerance,
however an oral glucose tolerance test was performed as specified in the
protocol for any patient with above-normal HbA1c. Because serum glucose
was above the cut-point of 11.0 mmol/L at the 2‑hour timepoint
(11.1 mmol/L \[200 mg/dL\]) the patient's Humatrope was discontinued and
the patient was withdrawn from the study. The HbA1c was normal (5.3%)
when repeated 1 year after discontinuation of Humatrope. A second
patient in Study E001 had a single reported event of fasting
hyperglycemia at 6 years on study. However, fasting glucose was normal
when repeated locally and it was likely that the elevated value
reflected either inadequate fasting or a laboratory error.

### 4.8.6. Hypertension

Hypertension was reported in a single GHD patient in Study GDAB and in
15 of 304 (4.9%) patients with Turner syndrome, a patient group known to
be at risk for hypertension. Two events in patients with Turner syndrome
were classified as serious because the patients were hospitalized for
evaluation. In patients with non‑GHD short stature, Study GDCH, mild
hypertension was reported in a single patient 1 week after initiation of
Humatrope treatment. The hypertension resolved after approximately
5.5 months without treatment and without discontinuation of Humatrope.

### 4.8.7. Slipped Capital Femoral Epiphysis

One case of slipped capital femoral epiphysis was reported in each of
the GHD and non‑GHD short stature patient populations. Since these
events were associated with hospitalization they are discussed in the
Serious Adverse Events sections of this document, Sections 4.6.2, and
4.6.4 above.

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

The most recent safety update from the Kabi International Growth Study
(KIGS) sponsored by Pharmacia (Wilton 1999) reports adverse event data
for almost 26,000 patients entered into the global database between 1988
and 1998. This represents approximately 62,400 years of somatropin
exposure. Adverse events were reported for the overall database at a
rate of 130 events per 1000 treatment years. When the event rates were
evaluated by condition the following rates per 1000 treatment years were
found: GH deficiency 95-245 (depending on the cause of the GHD); Turner
syndrome 148; chronic renal insufficiency 277; idiopathic short stature
(equivalent to non-GHD short stature) 89. Table 26 presents a summary of
data for patients with various non-GHD growth disorders obtained from
the KIGS database (Wilton 1999) for events of special interest. For most
of these events there is a trend toward greater frequency in patients
with Turner syndrome or chronic renal insufficiency, likely due to the
presence of underlying disease in these patient groups. Although the
data should be interpreted with caution due to variation in patient
numbers among the conditions, overall, there was no evidence in this
database of any greater risk of adverse events in patients with non-GHD
short stature than in other somatropin-treated non-GHD patients.

[]{#__RefHeading___Toc39468363 .anchor}Table 26. Somatropin Safety in
Non-GHD Conditions\
Kabi International Growth Study (KIGS)

+-----------------------+---------+----------+-----------+-----------+
| **Event a**           | *       | *        | **Small   | **I       |
|                       | *Turner | *Chronic | for       | diopathic |
|                       | Syn     | Renal    | Ge        | Short     |
|                       | drome** | F        | stational | Stature   |
|                       |         | ailure** | Age**     | b**       |
|                       | **(N=   |          |           |           |
|                       | 3019)** | **(      | **        | **(       |
|                       |         | N=694)** | (N=590)** | N=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          | 78      | 204      | 0         | 0         |
| hypertension          |         |          |           |           |
+-----------------------+---------+----------+-----------+-----------+
| Scoliosis             | 272     | 102      | 253       | 25        |
+-----------------------+---------+----------+-----------+-----------+
| Slipped capital       | 39      | 102      | 0         | 25        |
| femoral epiphysis     |         |          |           |           |
+-----------------------+---------+----------+-----------+-----------+

Abbreviation: N = number of patients.

a Event rates are reported as adverse event/100,000 treatment years
(from Wilton 1999)

b Equivalent to non-GHD short stature.

Additional safety data are provided from the large US
Genentech-sponsored National Cooperative Growth Study (NCGS) database.
Table 27 presents a summary of data for patients with various growth
disorders, obtained from the most recent NCGS safety update (Maneatis et
al. 2000). As noted in the KIGS data, the occurrence rate for all
adverse events and those of special interest is lower in the patients
with non-GHD (idiopathic) short stature than in those with other growth
disorders, when the proportion of events that occurred in this
population is compared with the proportion of patients with idiopathic
short stature in the total database.

[]{#__RefHeading___Toc39468364 .anchor}Table 27. Somatropin Safety in
the National Cooperative Growth Study (NCGS)

+-------------------------+---------+---------+-----------+-----------+
|                         | **Idi   | **      | **Turner  | **I       |
|                         | opathic | Chronic | S         | diopathic |
|                         | Growth  | Renal   | yndrome** | Short     |
|                         | Hormone | I       |           | Stature   |
|                         | Defic   | nsuffic |           | b**       |
|                         | iency** | iency** |           |           |
+-------------------------+---------+---------+-----------+-----------+
| Number of patients (N)  | N=13861 | N=663   | N=3416    | N=5671    |
|                         |         |         |           |           |
| (% of total enrollment) | (41.8%) | (2.0%)  | (10.3%)   | (17.1%)   |
+-------------------------+---------+---------+-----------+-----------+
| **Event a**             |         |         |           |           |
+-------------------------+---------+---------+-----------+-----------+
| > All adverse events    | 28.5    | 4.8     | 13.0      | 10.1      |
+-------------------------+---------+---------+-----------+-----------+
| > All serious adverse   | 18.8    | 7.3     | 7.5       | 4.6       |
| > events                |         |         |           |           |
+-------------------------+---------+---------+-----------+-----------+
| > Deaths                | 12.8    | 12.2    | 4.1       | 3.4       |
+-------------------------+---------+---------+-----------+-----------+
| > Leukemia              | 16.0    | 4.0     | 0.0       | 4.0       |
+-------------------------+---------+---------+-----------+-----------+
| > Extracranial          | 11.1    | 2.2     | 15.6      | 2.2       |
| > malignancy            |         |         |           |           |
+-------------------------+---------+---------+-----------+-----------+
| > Intracranial          | 30.8    | 10.3    | 15.4      | 2.6       |
| > hypertension          |         |         |           |           |
+-------------------------+---------+---------+-----------+-----------+
| > Diabetes c            | 25.4    | 8.5     | 15.3      | 13.6      |
+-------------------------+---------+---------+-----------+-----------+
| > Slipped capital       | 31.6    | 2.6     | 13.2      | 0.0       |
| > femoral epiphysis     |         |         |           |           |
+-------------------------+---------+---------+-----------+-----------+
| > Scoliosis             | 27.0    | 0.0     | 17.2      | 9.0       |
+-------------------------+---------+---------+-----------+-----------+

a Event rates are reported as percent of total events (from Maneatis et
al. 2000).

b Equivalent to non-GHD short stature.

c All patients with diabetes mellitus and glucose intolerance.

The low rates of adverse events in these two databases, which contain
data for over 9000 patients with non-GHD short stature, representing
over 27,000 patient-years of somatropin exposure, provide added
reassurance of the safety of somatropin in this patient population.

## 4.10. Clinical Laboratory Evaluation

This section discusses three areas of clinical relevance with respect to
the possible impact of GH treatment: 1) carbohydrate metabolism, 2)
insulin-like growth factor I, and 3) thyroid function. Although other
laboratory analyses were performed in many of the studies, these are not
discussed, as the results were unremarkable. A detailed comparison
between studies was not possible because the studies used different
laboratory methodologies, with different reference ranges, and, in some
cases, measured different analytes (for example, glycosylated hemoglobin
versus HbA1c). In addition, the exact timing of sample collection
relative to the prior Humatrope dose was not specified in the protocols
and is therefore not available. In Study GDCH the laboratory results
were assessed centrally, whereas in the multi-center study, Study E001,
individual investigators were responsible for interpretation and
follow-up of patients' laboratory results.

### 4.10.1. Carbohydrate Metabolism

Growth hormone is a physiologic insulin antagonist that causes reduction
in peripheral glucose disposal. Therefore, mild reduction in insulin
sensitivity is an expected consequence of somatropin treatment. Table 28
provides baseline values and changes from baseline to endpoint for
fasting glucose, fasting insulin and glycosylated hemoglobin or HbA1c.

[]{#__RefHeading___Toc39468365 .anchor}Table 28. Carbohydrate Metabolism
Changes from Baseline to Endpoint

![](media/image21.png){width="8.709722222222222in"
height="4.013888888888889in"}

Note: Values represent mean ± standard deviation (SD), except in Study
GDAB, where values represent the median. Study GDCI was placebo
controlled for the first 1.5 years; however, placebo control data for
laboratory values were not summarized separately in the clinical study
report and, thus, placebo control data for Study GDCI are not presented
in this table. For each of the studies, endpoint refers to the last
visit on treatment.

Abbreviations: GH = growth hormone; Hgb = hemoglobin; N = number of
patients in safety analysis; n = number of patients with baseline or
endpoint value; ND = not determined.

a Dose = 0.18 mg/kg/wk to 0.24 mg/kg/wk.

b Dose = 0.30 mg/kg/wk.

c Dose = 0.27 mg/kg/wk.

d Dose = 0.36 mg/kg/wk. This column includes placebo‑treated patients
who were transitioned to Humatrope treatment after 1.5 years.

e Dose = 0.22 mg/kg/wk.

f Dosage groups have been pooled: Dose 1 = 0.24 mg/kg/wk;
Dose 2 = 0.24 mg/kg/wk for the first year, and then 0.37 mg/kg/wk
thereafter; Dose 3 = 0.37 mg/kg/wk.

g Values below the quantifiable limit of the assay were imputed to be
zero.

h For Study GDCH, values represent adjusted hemoglobin A1c (HbA1c), with
normal values between 0 and 1.0.

#### 4.10.1.1. Summary Comparison

Fasting blood glucose values were similar among the three patient
populations and remained essentially unchanged with Humatrope treatment.
Glycosylated hemoglobin or HbA1c, available only for patients with
Turner syndrome and those with non‑GHD short stature, also showed
essentially no change from baseline to endpoint.

Mean fasting insulin concentrations were within the reference range in
both the Turner syndrome (Study GDCI) and the non-GHD short stature
(Study GDCH) patient populations at study baseline; however, the values
were higher in both treatment groups in Study GDCH than in Study GDCI.
As the patients in Study GDCH were older at baseline than those in Study
GDCI, this finding likely reflects the physiologic insulin resistance of
puberty in the non-GHD short stature population. In patients with Turner
syndrome, mean fasting insulin approximately doubled between baseline
and endpoint, although final values remained within the reference range.
In contrast, in patients with non‑GHD short stature, there was a smaller
increase, approximately 10% in mean fasting insulin concentration from
baseline to endpoint, in the Humatrope group and again, the mean
endpoint value was within the reference range. To further address any
potential impact of Humatrope on insulin sensitivity in patients with
non-GHD short stature a number of additional analyses were performed
that specifically assess insulin sensitivity by evaluating fasting
insulin in the context of blood glucose. As detailed in
Section 4.10.1.4, these analyses demonstrate no statistically
significant or clinically relevant difference between the placebo and
Humatrope treatment groups for change in insulin sensitivity from
baseline to endpoint. In Study E001, no difference was detected between
Humatrope dosage groups for change from baseline to endpoint for mean
fasting glucose or glycosylated hemoglobin.

#### 4.10.1.2. Growth Hormone Deficiency

In the GHD patient population, fasting glucose values did not change
appreciably during the study. Neither insulin nor HbA1c was measured in
this study.

#### 4.10.1.3. Turner Syndrome

In Studies GDCT and GDCI, there were no statistically significant
between‑group differences for mean fasting glucose or glycosylated
hemoglobin at study endpoint (Study GDCT: Humatrope versus Untreated
Control; Study GDCI: Humatrope 0.27 mg/kg/wk versus Humatrope
0.36 mg/kg/wk). Serum insulin was measured only in Study GDCI, in which
mean fasting insulin values approximately doubled between baseline and
endpoint. However, endpoint insulin concentrations remained within the
normal range.

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

Figure 16 and Figure 17 display mean fasting glucose and insulin by year
on study, respectively, for Study GDCH. No statistically significant or
clinically meaningful differences between treatment groups were detected
for either of these parameters across the duration of the study.

![](media/image22.wmf){width="5.326388888888889in"
height="4.113194444444445in"}

Abbreviations: H = Humatrope; n= number of patients; P = placebo;
SE = standard error.

[]{#__RefHeading___Toc39468384 .anchor}Figure 16. Mean fasting glucose
by year on study for Study GDCH.

![](media/image23.wmf){width="5.497916666666667in"
height="4.245833333333334in"}

Abbreviations: H = Humatrope; n= number of patients; P = placebo;
SE = standard error.

[]{#__RefHeading___Toc39468385 .anchor}Figure 17. Mean fasting insulin
by year on study for Study GDCH.

Furthermore, there were no statistically significant differences between
treatment groups for change‑to‑endpoint values for fasting glucose,
fasting insulin, or adjusted HbA1c (Table 28). However, there was a mild
increase of 10% in mean fasting insulin from baseline to endpoint in the
Humatrope group. To further evaluate this finding the fasting glucose
and insulin values were analyzed by methods that specifically assess
insulin sensitivity. While not as rigorous as clamp studies, the
Quantitative Insulin Sensitivity Check Index (QUICKI) is a
well-validated method of assessing insulin sensitivity either in a
between-group fashion or longitudinally (Katz et al. 2000) in a given
study. However, because results may be significantly affected by assay
differences it is not useful for comparison across studies. This
analysis showed a 6% reduction in apparent insulin sensitivity from
baseline to endpoint in the Humatrope-treated group (Figure 18).
However, when individual patient values are assessed there is no
evidence of a clinically relevant difference in the pattern of change
from baseline to endpoint across the Humatrope-treated versus the
placebo-treated patient groups.

![](media/image24.wmf){width="5.997222222222222in" height="4.63125in"}

Note: QUICKI = 1/(log\[Fasting Insulin (μU/mL)\] + log\[Fasting Glucose
(mg/dL)\]). If a patient has multiple results of fasting glucose or
fasting insulin at a timepoint, the mean value was used.

Abbreviations: QUICKI = Quantitative Insulin Sensitivity Check Index;
SE = standard error.

[]{#__RefHeading___Toc39468386 .anchor}Figure 18. Qualitative Insulin
Sensitivity Check Index (QUICKI) baseline to endpoint in Study GDCH.

Since there was a slight imbalance between the groups for QUICKI at
baseline, an analysis of covariance (ANCOVA) was performed incorporating
the baseline value in the model. As shown in Figure 19, this analysis
demonstrated no Humatrope treatment effect on insulin sensitivity after
baseline values were accounted for (p=0.67). Similar findings were
obtained when the insulin and glucose data were evaluated using the
homeostasis model of insulin sensitivity (HOMA-S; Bonora et al. 2000).
Taken together the results provide no evidence for a clinically
meaningful Humatrope effect on insulin sensitivity in this patient
population.

![](media/image25.wmf){width="5.997222222222222in"
height="4.636805555555555in"}

Note: p-value is between group p-value from the analysis of covariance
(ANCOVA) model. QUICKI = 1/log\[Fasting Insulin (μU/mL)\] + log\[Fasting
Glucose (mg/dL)\]). Line represents regression line from ANCOVA analysis
(Model: Last on-study QUICKI = Therapy baseline QUICKI). Values are
means at a visit, if patient had more than one result assayed.

[]{#__RefHeading___Toc39468387 .anchor}Figure 19. Analysis of covariance
of last on study QUICKI using baseline QUICKI as the covariate.

In Study E001, there were no statistically significant or clinically
relevant differences between dosage groups for change from baseline to
endpoint values for fasting glucose (Figure 20) or glycosylated
hemoglobin. The overall patterns of fasting glucose and glycosylated
hemoglobin values were similar for the three dosage groups throughout
the study, indicating no evidence of dose‑related Humatrope effect.

![](media/image26.wmf){width="5.586111111111111in"
height="4.311805555555556in"}

Note: No reference range shown as this varied among laboratories.

Abbreviations: n= Number of patients; SD = standard deviation.

[]{#__RefHeading___Toc39468388 .anchor}Figure 20. No Humatrope dose
effect on fasting glucose.

In summary, although GH is a physiologic insulin antagonist there was no
evidence of significant somatropin-induced insulin resistance in Study
GDCH and no evidence of any dose effect on fasting glucose in Study
E001.

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

Insulin-like growth factor I (IGF‑I) values were available only for
patients with Turner syndrome in Study GDCI and those with non‑GHD short
stature in Study GDCH. Table 29 provides a summary of the baseline and
changes from baseline to endpoint values. In the Turner syndrome study,
GDCI, the expected dose-dependent rise in IGF-I from baseline to
endpoint was seen. In the non-GHD short stature study, Study GDCH, the
Humatrope group showed an improvement in IGF-I of 0.7 SDS, while the
placebo group showed a smaller increase of 0.2 SDS.

[]{#__RefHeading___Toc39468366 .anchor}Table 29. Insulin-Like Growth
Factor-I Changes from Baseline to Endpoint

  ------------------ --------------- --------------- -- --------------- ------------- -------------
                     **Turner                           **Non-GHD Short               
                     Syndrome                           Stature                       
                     (GDCI)**                           (GDCH)**                      

                     **N=230**                          **N=68**                      

                     **Humatrope** a **Humatrope** b    **Humatrope** c **Control**   **p-value** d

                                                                                      

  Number of patients                                                                  

  in treatment group 93              137                37              31            

                                                                                      

  IGF-I (ng/mL)                                                                       

  n                  81              124                33              27            

  Baseline           136 ± 76        142 ± 89           190 ± 74        226 ± 100     

  Change to endpoint 188 ± 165       241 ± 239          187 ± 123       103 ± 105     0.007

                                                                                      

  IGF-I SDS e                                                                         

  n                  NA              NA                 33              27            

  Baseline           NA              NA                 -1.9 ± 1.1      -1.4 ± 1.6    

  Change to endpoint NA              NA                 0.7 ± 2.3       0.2 ± 1.3     0.273
  ------------------ --------------- --------------- -- --------------- ------------- -------------

Note: Values represent mean ± standard deviation (SD). Study GDCI was
placebo-controlled for the first 1.5 years; however, placebo-control
data for laboratory values were not summarized separately in the
clinical study report. Therefore, placebo control data are not presented
in this table for Study GDCI. For both studies, endpoint refers to the
last visit on treatment.

Abbreviations: IGF‑I = insulin-like growth factor‑I; IGF‑I
SDS = insulin-like growth factor‑I standard deviation score; N = number
of patients in safety analysis; n = number of patients with baseline or
endpoint value; NA = not applicable.

a Dose = 0.27 mg/kg/wk.

b Dose = 0.36 mg/kg/wk. This column includes placebo‑treated patients
who were transitioned to Humatrope\
treatment after 1.5 years.

c Dose = 0.22 mg/kg/wk.

d p-values pertain to a test of between‑group differences for
Study GDCH.

e Insulin‑like growth factor‑I standard deviation score (IGF‑I
SDS) = (patient value -- mean value) / SD. Values for mean and SD are
based\
on the appropriate reference range for the patient's age and gender.

#### 4.10.2.1. Turner Syndrome

In patients with Turner syndrome in Study GDCI, change in mean IGF‑I
concentration from baseline to endpoint was greater for the
0.36 mg/kg/wk dosage group than for the 0.27 mg/kg/wk dosage group, as
expected, demonstrating the dose‑dependent IGF‑I response to GH.

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

In patients with non-GHD short stature in Study GDCH, mean serum IGF‑I
at baseline was below the 10th percentile for the age and gender matched
general population and remained well below the mean value for the
general population at endpoint (mean IGF‑I SDS \<‑1.0) in both treatment
groups. Thus, in this patient population, Humatrope treatment promoted
partial restoration of subnormal IGF‑I concentrations and did not raise
mean IGF‑I levels above those of the age- and gender-matched general
population. Figure 21 displays the mean and individual patient IGF-I
concentrations at baseline and endpoint for both treatment groups.

![](media/image27.wmf){width="5.120138888888889in"
height="3.953472222222222in"}

Note: Two extreme low values have been omitted from Humatrope endpoint.
The area between the two dashed lines represents the normal range for
the general population (AAP 1997).

Abbreviations: IGF-I = insulin-like growth factor-I; n = number of
patients; SE = standard error; SDS = standard deviation score.

[]{#__RefHeading___Toc39468389 .anchor}Figure 21. IGF-I increased
modestly in Humatrope-treated patients in Study GDCH.

There was no significant difference between the Humatrope and placebo
treatment groups for the proportion of patients who had serum IGF-I
concentrations more than 2.0 SD above the age- and gender-appropriate
mean for chronological age at any post-baseline measurement (Humatrope:
9 of 35 patients \[26%\]; placebo: 7 of 28 patients \[25%\]).

### 4.10.3. Thyroid Function

Table 30 provides baseline values and changes from baseline to endpoint
for thyroid function tests, which were similar among the three patient
populations.

[]{#__RefHeading___Toc39468367 .anchor}Table 30. Thyroid Function
Changes from Baseline to Endpoint

![](media/image28.png){width="8.913194444444445in"
height="4.093055555555556in"}

Note: The Control group for Study GDCT was a randomized, untreated
control, whereas for Study GDCI and Study GDCH it was a randomized,\
placebo control. Values represent mean ± standard deviation (SD), except
in Study GDAB, where values represent the median. Study GDCI was placebo
controlled for the first 1.5 years; however, placebo control data for
laboratory values were not summarized separately in the clinical study
report and, thus, placebo control data for Study GDCI are not presented
in this table. For each of the studies, endpoint refers to the last
visit on treatment.

Abbreviations: GH = growth hormone; N = number of patients in safety
analysis; n = number of patients with baseline or endpoint value;
ND = not determined; T4 = thyroxine; TSH = thyroid‑stimulating hormone.

a Dose = 0.18 mg/kg/wk to 0.24 mg/kg/wk.

b Dose = 0.30 mg/kg/wk.

c Dose = 0.27 mg/kg/wk.

d Dose = 0.36 mg/kg/wk. This column includes placebo‑treated patients
who were transitioned to Humatrope treatment after 1.5 years.

e Dose = 0.22 mg/kg/wk.

f Dosage groups have been pooled: Dose 1 = 0.24 mg/kg/wk;
Dose 2 = 0.24 mg/kg/wk for the first year, and then 0.37 mg/kg/wk
thereafter; Dose 3 = 0.37 mg/kg/wk.

g Free thyroxine index. Reference range = 1.6 to 4.3.

h Free T4 (pmol/L). Reference range = 10 to 26 pmol/L.

#### 4.10.3.1. Growth Hormone Deficiency

Median values for total T4, free thyroxine index, and TSH declined
slightly from baseline to endpoint. However this finding was felt to be
of minimal clinical significance.

#### 4.10.3.2. Turner Syndrome

Mean total T4 values increased across the duration of the study by
approximately 20% in both treatment groups in Study GDCT but were
essentially unchanged in Study GDCI. Mean TSH doubled in the higher
Humatrope dosage group of Study GDCI. However, this was predominately
due to a single patient's elevated TSH value at the final study visit
and was not considered clinically relevant.

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

Centrally-measured thyroid function tests were available only for
patients in Study GDCH. There were no statistically significant or
clinically relevant differences between treatment groups for baseline or
change‑to‑endpoint values for T4, free T4, or TSH. There was no evidence
of an effect of Humatrope treatment on thyroid function in these
patients. Figure 22 displays the mean and individual patient free-T4
concentrations at baseline and endpoint for both treatment groups.

![](media/image29.wmf){width="5.0055555555555555in"
height="3.859722222222222in"}

Note: The area between the two dashed lines represents the reference
range\
for the assay.

Abbreviation: SE = standard error.

[]{#__RefHeading___Toc39468390 .anchor}Figure 22. No significant
GH-related change in free thyroxine in Study GDCH.

## 4.11. Overall Safety Conclusions

The safety of Humatrope treatment in patients with non-GHD short stature
is demonstrated by the similarities in rates of serious adverse events,
discontinuations due to adverse events, and laboratory data, including
measures of insulin sensitivity, between the Humatrope and
placebo-treated groups in Study GDCH. In addition, the lack of
significant difference between dosage groups in Study E001 indicates
absence of a dose effect on safety in these patients. The adverse event
profile for serious adverse events and discontinuations due to adverse
events, in patients with non‑GHD short stature, was similar to that of
patients for whom Humatrope is currently approved and no new safety
signals were seen. While some differences in the pattern of TEAEs were
seen between patients with non‑GHD short stature and those with GHD or
Turner syndrome, the differences primarily reflect the underlying
disease state differences between these patient groups and do not
suggest any clinically meaningful change in the adverse event profile
for pediatric patients being treated with Humatrope. Importantly, these
conclusions are based on similar numbers of patients and similar total
patient-years of exposure among these three regulatory submissions.

Data from two large postmarketing studies support the safety of
somatropin in the non-GHD short stature patient population. Finally,
laboratory data, including analysis of insulin sensitivity, failed to
demonstrate any new findings in this patient population. In summary,
patients with non-GHD short stature treated with Humatrope at dosages
ranging from 0.22 to 0.37 mg/kg/week are at no greater risk from this
treatment than patients with GHD treated at 0.18 to 0.24 mg/kg/wk or
patients with Turner syndrome receiving 0.27 to 0.36 mg/kg/wk. The
Sponsor therefore believes that the safety of Humatrope treatment in
patients with non-GHD short stature has been demonstrated and the
precautions listed in the current Humatrope label address the key risks
of Humatrope exposure. There are no new safety concerns specific to this
patient population and no new precautions should be added to the label.

# 5. Benefit/Risk Assessment

Since the 1960s the pediatric endocrine community has sought to
understand the potential value of GH treatment in pediatric patients
with non-GHD growth disorders, with respect both to short term and to
long term growth. In 1987 an FDA advisory committee recommended that the
efficacy of GH in patients with non-GHD short stature be assessed by a
randomized, placebo-controlled trial to final height. To address the
unanswered questions regarding efficacy and safety of somatropin in this
patient group Lilly conducted two randomized, controlled, clinical
trials between 1988 and 2001. The data obtained from these studies
clearly demonstrate the efficacy and safety of Humatrope treatment in
patients with non-GHD short stature. However, the potential approval of
this new indication raises a number of questions that must be addressed
to enable clear assessment of the benefit-to-risk relationship:

-   Is it appropriate to treat patients whose short stature is not
    clearly associated with a defined "disease"?

-   Is GH effective in these patients, and is the magnitude of the
    benefit clinically relevant?

-   Should psychological benefits be a required outcome of GH treatment?

-   Is this treatment safe in this patient population?

-   Why was the height cut-off of --2.25 SDS chosen for the label
    indication?

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

-   Will this new indication "open the floodgates" to inappropriate use?

The first four points will be discussed in this Benefit-Risk section and
the latter three points will be discussed in the Risk Management section
that follows.

**Is it appropriate to treat patients whose short stature is not clearly
associated with a defined "disease"?** Some authors have posited that
patients with non-GHD short stature should not receive the benefit of GH
treatment because they do not have a "disease". However, this cannot be
regarded as a rational or ethical reason for withholding an effective
therapy. There are a number of conditions, both childhood and adulthood,
for which treatment is deserved and received, despite the fact that many
would not accept these patients as having a "disease". Examples include
enuresis, hypertension, hypercholesterolemia, erectile dysfunction,
alopecia, hirsutism, gynecomastia, anxiety disorder, and nicotine
addiction. While it appears to be a moot point as to whether or not
these conditions represent diseases, few would argue against the
appropriateness of effective treatment for these conditions.

Furthermore, with respect to pediatric growth disorders, somatropin
treatment aims to treat growth failure or short stature, not the
underlying condition. Clearly, somatropin has no impact on the
deficiency of X‑chromosomal material and associated phenotypic and
functional problems of Turner syndrome. Somatropin simply provides an
increase in linear growth and adult height for these patients, with the
potential for mitigating the disadvantages associated with the lifelong
short stature that these patients would otherwise face. The fact that
children with non-GHD short stature have an as-yet undefined etiology
for their growth failure (likely a heterogeneous collection of
etiologies), and are therefore regarded by some as having no "disease"
does not justify excluding them from effective treatment. The key
distinction between patients with non-GHD short stature and those with
conditions for which somatropin is currently approved is not whether a
disease is present, but rather, that most of the latter conditions have
additional problems beyond their growth disturbance (such as ovarian
failure in Turner syndrome) that are not addressed by somatropin. The
absence of additional health problems in patients with non-GHD short
stature should not penalize them with respect to their eligibility for
treatment of the key problem that they share with patients with other
growth disorders - short stature.

**Is GH effective in these patients, and is the magnitude of the benefit
clinically relevant?** The second key point to be addressed in assessing
the benefit-risk relationship is the efficacy of somatropin treatment in
patients with non-GHD short stature, and the clinical relevance of that
efficacy. The efficacy of treatment in this patient population must be
assessed by evaluating the data from three key sources. First, the
pivotal, placebo-controlled trial of Humatrope treatment in patients
with non-GHD short stature demonstrated statistically significantly
greater final height in Humatrope treated patients compared with those
who received placebo injections. Second, the supportive dose-response
study in this patient population demonstrated a marked and significant
increase in height velocity, which almost doubled during the first 2
years of Humatrope treatment, allowing many patients to reach normal
height range during childhood. Third, the supportive data from the
literature meta-analysis indicate a similar improvement in final height
to that seen in the Lilly clinical trials. These findings translate into
two key benefits for these patients: an increase in height during
childhood, allowing patients with non-GHD short stature to catch up to
their normal-stature peers during childhood, and increased final height
after completion of linear growth.

The magnitude of the final height benefit -- a key factor in evaluation
of the benefit-risk profile -- should be assessed with reference to the
complete package of clinical data provided. The key study for evaluation
of the final height improvement is the pivotal, placebo-controlled
clinical trial, Study GDCH. The most robust estimate of the average
benefit is obtained from the primary efficacy analysis, which
demonstrated a mean 0.51 SDS greater final height in Humatrope-treated
than placebo-treated patients, equivalent to 3.7 cm. A number of
sensitivity analyses and secondary analyses provide strong support,
indicating a range of the mean final height effect of 2.8 to 5.0 cm.

In assessing the benefit of Humatrope in the pivotal trial, the
relatively low Humatrope dosage (0.22 mg/kg/wk), injection frequency (3
times per week), and the relatively late age at initiation of therapy,
should be considered. Final height data from the supportive
dose-response trial allow assessment of benefit obtained from a higher
Humatrope dosage (0.37 mg/kg/wk), administered in divided doses 6 times
per week, starting at a younger age. Because of the difference in study
design between the pivotal trial and the supportive study, the final
height benefit in the latter study is evaluated in a different manner.
Since there was no untreated control group in this study,
treatment-related gains in final height were assessed with reference to
the adult height predicted at baseline, prior to treatment. This is the
standard method by which final height gain is assessed in the majority
of studies in the literature, essentially using patients as their own
controls. For the lower dosage Humatrope treatment group (0.24 mg/kg/wk)
the gain in final height over baseline predicted height was 5.4 cm; for
the higher dosage group (0.37 mg/kg/wk) the gain was 7.2 cm. These data
should be evaluated in the context of previously reported data
indicating that height predictions tend to overestimate the true
achieved adult height in untreated patients with non-GHD short stature,
potentially reducing the apparent treatment effect. The benefit of
somatropin treatment, demonstrated in Lilly clinical trials in patients
with non-GHD short stature, is supported by controlled studies to final
height in the peer‑reviewed literature summarized in a recent
meta-analysis (Finkelstein et al. 2002), demonstrating an average
GH-induced gain in adult height of approximately 4 to 6 cm.

Several lines of evidence indicate that the magnitude of GH-induced
height gain in patients with non-GHD short stature was large enough to
be clinically meaningful. First, the GH-induced height gains in patients
with non-GHD short stature were similar to the final height benefit
demonstrated for patients with Turner syndrome obtained in the pivotal
clinical trial for Turner syndrome that formed the basis of the 1996
supplemental NDA for approval of Humatrope in treatment of short stature
associated with Turner syndrome (3.9 to 5.4 cm). Second, the mean
heights of Humatrope-treated patients in the pivotal trial for non-GHD
short stature (Study GDCH), and of the 0.37 mg/kg/wk dosage group in the
supportive study (Study E001), moved into the normal range during the
course of treatment, indicating that many patients had caught up to
their peers during childhood. Third, whereas the final heights for
placebo-treated patients in Study GDCH were all below the 5th percentile
for the general population, and most were below the lower limit of
normal, 94% of final heights for patients who received the higher dosage
(0.37 mg/kg/wk) in Study E001 were within the normal range.

In addition to evaluating the benefit of Humatrope treatment itself, the
impact of Humatrope dose on this benefit should also be considered. The
incremental final height benefit of a higher dose of Humatrope is
assessed by a number of secondary analyses of dose-response data in
Study E001. Patients who received the higher Humatrope dosage (0.37
mg/kg/wk) achieved an additional 2.8 to 3.3 cm of height benefit (by
analysis of last observed height SDS, final height SDS and height SDS at
age 18 years) above and beyond the gains achieved by the patients who
received the lower Humatrope dose. These findings are consistent with
the dose‑response effect of somatropin treatment observed in patients
with Turner syndrome (Quigley et al. 2002) and in those with GHD (Mauras
et al. 2000; Cohen et al. 2002).

While adult height has been identified as the primary measure upon which
benefit of somatropin treatment should be assessed, the importance of
shorter term changes in growth, evidenced by increased height velocity,
should not be underestimated. Improvements in height velocity provide
affected children with the opportunity to catch up to their
normal-stature peers during childhood, thereby reducing height
discrepancies during an important period of development. Marked catch-up
growth was noted in all treatment groups of Study E001, with almost a
doubling of height velocity over the first 2 years of treatment.
Furthermore, there was a significantly greater effect of the higher
Humatrope dosage of 0.37 mg/kg/wk compared with the lower dosage of
0.24 mg/kg/wk.

To summarize the clinical relevance of the efficacy data, more than half
of the patients treated at a relatively low GH dosage and frequency,
started at a relatively late age, and almost all patients treated at a
higher dosage and frequency, starting at a younger age, achieved normal
final height, conferring on these patients the lifelong benefit of
normal adult stature. Thus, as adults, these patients no longer had
short stature, therefore diminishing the disadvantages of adult short
stature, which may include failure to meet minimum height requirements
for certain occupations, difficulty or inability to safely operate a
motor vehicle or overcome structural challenges in the home or
workplace, and being perceived as having lower competence than
individuals of normal stature. A substantial degree of catch-up growth
occurred during the course of treatment, returning many affected
patients to within the normal height range during childhood. Thus,
during treatment, many of these children no longer had short stature,
potentially diminishing the disadvantages they may suffer during
childhood. Both the long-term and the shorter-term growth effects
represent clinically relevant benefits for affected patients. These two
key benefits of Humatrope treatment in patients with non-GHD short
stature provide affected patients the opportunity for improved growth
during childhood and a similar degree of improved final height to that
currently available to patients with other growth disorders.
Furthermore, the magnitude of final height benefit is similar to the
magnitude seen in another non-GHD growth disorder for which somatropin
treatment has been approved, Turner syndrome.

**Should psychological benefits be a required outcome of GH treatment?**
While the evidence for stature-related benefit of somatropin treatment
in patients with non-GHD short stature is now clear, the question of the
psychological impact of this benefit remains. Following the
recommendation of the 1987 Endocrinologic and Metabolic Drugs Advisory
Committee, Lilly studies in this patient population focused on treatment
of their growth disorder. None of the studies that led to approval of GH
for the treatment of growth failure or short stature in each of the
current indications provided evidence for potential benefits in quality
of life or psychological well-being. Moreover, neither Study GDCH nor
Study E001 provided evidence for such potential benefits. Some authors
have proposed that GH treatment of patients with non-GHD short stature
is unjustified unless such benefit can be demonstrated. However, this
position is ethically untenable, since it subjects children with an
equal severity of impairment (short stature) to a higher burden of proof
than those patients for which somatropin has been previously approved.
In fact, this patient group has already been held to a higher standard
than most others, by having been required to demonstrate a benefit of
treatment on final height, rather than simply on short-term growth.
Approvals for somatropin treatment were granted on the basis of improved
height velocity alone for patients with GHD, chronic renal
insufficiency, Prader-Willi syndrome, and those born small for
gestational age. Only in patients with Turner syndrome were final height
improvements also demonstrated and included in the application for
approval.

**Is this treatment safe in this patient population?** In assessing the
benefit-to-risk relationship, the safety of GH treatment in this patient
population must be carefully evaluated. The risks associated with
Humatrope treatment in patients with non-GHD short stature are similar
to those encountered by other pediatric populations presently treated
with Humatrope and are described in the current Humatrope label. While
some differences in the pattern of TEAEs were seen between patients with
non-GHD short stature and those with GHD or Turner syndrome, the
differences primarily reflect the underlying disease state differences
between these patient groups and do not suggest any clinically
meaningful change in the adverse event profile for Humatrope treatment
in pediatric patients.

Given clear evidence of benefit, similar to that for Turner syndrome, a
non‑GHD condition for which Humatrope is currently approved, and no
evidence of greater risk of therapy in patients with non‑GHD short
stature, Lilly believes that the benefit-risk assessment supports the
approval of Humatrope for this indication and proposes the following
label indication: *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.*

Such patients should be treated with a weekly dosage of up to
0.37 mg/kg, administered in divided doses 3 to 7 times per week. This
dosage recommendation is supported by the greater efficacy of the dosage
of 0.37 mg/kg/wk, which was obtained without any apparent increase in
risk over the dosage of 0.24 mg/kg/wk.

# 6. Risk Management

## 6.1. Introduction

Since the 1987 approval of Humatrope for treatment of pediatric patients
with growth failure due to GH deficiency, Lilly has actively addressed
the potential for inappropriate use of the medication with a
multi-faceted risk management approach. As the anabolic properties of
growth hormone have become more widely known, somatropin has been
targeted as a drug of potential abuse for non-medicinal purposes. Lilly
has been and continues to be committed to assuring that prescribing and
distribution of Humatrope for such non-medicinal purposes does not
occur.

Lilly recognizes that an approval for treatment of children with non-GHD
short stature raises several potential new concerns. The first concern
is that Humatrope will be prescribed inappropriately for patients whose
stature exceeds that given in accepted guidelines for short stature
evaluation and treatment -- that this new indication will "open the
floodgates" for inappropriate prescribing. The second concern is the
potential that patients with short stature will not receive an adequate
diagnostic evaluation to detect illnesses that require interventions
different from, or in addition to, Humatrope. Finally, there is concern
about the possibility that new adverse events, unobserved in clinical
trials, may emerge with the approved treatment of larger numbers of
children with non-GHD short stature. In addition to these concerns, this
section of the document will address the rationale for the choice of a
height threshold of --2.25 SDS as the eligibility criterion for
treatment in this patient population.

Since the initial approval of Humatrope for treatment of growth failure
associated with GH deficiency, Lilly has had measures in place to
address concerns similar to those listed above. Lilly believes that
these measures, combined with a number of important external factors,
will assure that Humatrope treatment is available only to appropriate
patients. These measures include restrictive labeling, thorough
education for potential prescribing physicians, limited marketing to a
select physician group, a proprietary controlled distribution process,
and post-marketing safety surveillance and monitoring.

This section begins by summarizing each of these specific concerns and
concludes with details regarding the internal measures and external
factors in place that address each of the concerns. These concerns and
the risk management measures that address them are also detailed in
Table 31 (Section 6.5).

## 6.2. Specific Concerns

### 6.2.1. Inappropriate Prescribing 

The concern has been raised that a new indication for treatment of
patients without a defined etiology for their growth failure will "open
the floodgates" to broad prescribing of Humatrope for large numbers of
children who are shorter than average but within the normal range. There
is concern that parents will seek therapy for such children in the hope
of offering them some perceived physical or social benefit and that
physicians will be placed under pressure to prescribe somatropin
inappropriately. The potential health economic impact of such
inappropriate prescribing is significant.

### 6.2.2. Lack of Adequate Diagnostic Evaluation

The concern exists that if eligibility for somatropin treatment no
longer requires a given level of GH secretion or a named disease entity
then physicians will forego the appropriate diagnostic work-up in the
interest of their time, the patient's time and expense, and obtaining
therapy in an expedient manner. Clearly this would place a number of
patients at potential risk for failure to detect serious medical
conditions that require treatments in addition to, or other than,
Humatrope. Of particular concern are: 1) failure to perform screening
tests for other conditions such as hypothyroidism or gastrointestinal
malabsorption that require specific medical therapies; 2) the potential
abandonment of laboratory investigation of GH secretion status, which
could lead to failure to diagnose significant forms of severe GH
deficiency due to underlying organic conditions such as intracranial
tumors.

### 6.2.3. Emergence of New Adverse Events

The potential exists that new adverse events, unobserved in the pivotal
and supportive clinical trials and in prior practice, may emerge in the
new patient population. Furthermore, the occurrence rates of adverse
events currently referenced in the Humatrope label may differ in the new
population when larger numbers of patients are exposed to the
medication.

To address these important concerns the following sections summarize the
system of checks and balances currently in place, both sponsored by and
external to Lilly, that will manage the risks associated with an
approved indication for treatment of children with non-GHD short
stature. While no single factor will entirely mitigate these potential
risks, the combined effect of all of these measures will assure that
Humatrope treatment is reserved for patients with the appropriate
medical need.

## 6.3. Elements of the Lilly Risk Management Process

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

The label language for this indication contains a clearly-stated height
threshold above which a patient is ineligible for therapy. This
restriction is unique among somatropin indications, placing a
substantially greater degree of control on treatment eligibility for
patients with this condition than on patients with any other condition
for which somatropin is approved.

Lilly proposes the following:

*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.*

The proposed label indication for patients with non-GHD short stature
will be the most restrictive label of any in place for pediatric growth
disorders in the US. None of the currently approved pediatric
indications for somatropin (growth failure or short stature caused by
GHD, chronic renal insufficiency, Turner syndrome, Prader-Willi
syndrome, and patients born small for gestational age) include a
threshold for the definition of short stature in the labeling. However,
in the first four of these disorders, potential patients are identified
by the existence of a generally-recognized disease or condition
underlying the growth impairment; the patient whose short stature is a
consequence of having been born small for gestational age is readily
identified on the basis of birth weight. The number affected and
therefore treatment-eligible patients with GHD, chronic renal
insufficiency, Turner syndrome and Prader-Willi syndrome is limited by
the prevalence of each condition. However, patients with any of these
conditions are eligible for therapy irrespective of their actual
attained height, height velocity (growth rate) or adult height
potential. For example, a child of tall parents with an organic form of
GHD diagnosed before growth failure has caused a substantial decline
across the percentile channels is eligible for treatment even if current
height is at the 90th percentile. Similarly, no specific slow rate of
growth is defined for treatment of "growth failure associated with
chronic renal insufficiency". In the case of non-GHD short stature, the
underlying cause of the growth impairment is not known, and the
diagnosis is made after excluding other causes of short stature
(Figure 1, Section 2.1). The key clinical feature of the condition is
simply the presence of significant short stature in the absence of
associated pathology; therefore, Lilly believes a quantitative
definition is needed in the label to target treatment to the appropriate
patient.

Although short stature has been defined as height SDS ≤‑2.0 by the
American Academy of Pediatrics (AAP 1997) and the American Association
of Clinical Endocrinologists (AACE 2003), and this definition has been
used in most published studies of non-GHD short stature (including the
supportive study in this application \[E001\]), Lilly has selected a
more restrictive definition for the label. This more restrictive
definition:

-   is consistent with the population studied in the pivotal study
    (GDCH);

The majority of patients in Study GDCH were enrolled under the entry
criterion of height SDS ≤‑2.25.

-   discourages inappropriate use;

Lilly is aware of the concern that Humatrope may be prescribed
inappropriately for children of normal stature (height SDS between -2.0
and +2.0) and believes that the targeted label indication will help
focus prescribing on a more limited set of patients. Using height SDS
≤‑2.25 to identify the intended population for treatment excludes from
treatment all patients of normal stature and 46% of patients with
non-GHD short stature who would otherwise be eligible with height SDS
≤‑2.0 as the criterion (assuming a Gaussian distribution of height).
This restricted definition of short stature sets a limit that
discourages selection of low-normal stature patients for treatment. It
achieves this goal, however, by excluding from treatment some patients
with non-GHD short stature for whom pediatric endocrinologists may wish
to prescribe Humatrope.

-   follows FDA recommendation;

Lilly believes that the proposed non-GHD short stature label indication
is responsive to an FDA request made in pre-sNDA communications that
Lilly provide specific guidelines in the label regarding the target
population.

-   strikes the best balance;

Lilly believes that the definition "height SDS ≤‑2.25"strikes the best
balance between the goals of discouraging inappropriate GH use in
normal-stature children and providing equitable access to safe and
effective treatment for patients with non-GHD short stature. The
definition also provides a limit to the number of potential patients in
a way similar to the limits in place for the currently-approved
indications.

-   reinforces the need for appropriate diagnostic evaluation;

Lilly believes that including the language "and in whom diagnostic
evaluation excludes causes of short stature that should be treated by
other means" helps to ensure that a proper diagnostic evaluation is
performed. Since there are other causes of short stature such as chronic
illness, hypothyroidism and gastrointestinal malabsorption, to name a
few, that require specific therapies that may or may not include
Humatrope, this language is necessary to ensure proper diagnosis and
treatment.

-   establishes guidance for non-GHD short stature prescribing.

Prescribing of various brands of somatropin for patients with non-GHD
short stature has occurred in the past without an approved indication
(Table 1). This has resulted in a lack of consistency in diagnosis,
prescribing, reimbursement, and consequently, inequitable access to
treatment. Approval of Humatrope for this indication establishes
restrictions for appropriate prescribing that will reduce this
inconsistency.

### 6.3.2. Physician Education

Several informational programs will be implemented to maximize physician
awareness of the appropriate criteria for diagnosis and treatment of
non‑GHD short stature, the importance of undertaking a thorough
diagnostic work-up in patients with growth disorders, and the risks and
benefits of Humatrope treatment in these patients. This information will
be conveyed primarily through physician-to-physician and continuing
medical education programs.

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

The objective of these physician-led programs is to ensure that
potential prescribing physicians understand the restrictive label,
specifically the appropriate patient for treatment of non‑GHD short
stature and the importance of a proper diagnostic evaluation. These
programs will address the diagnosis and management of non-GHD short
stature and the benefits and risks of Humatrope treatment. Lilly sales
specialists will organize and conduct these programs in accordance with
FDA guidelines. Diagnostic criteria and safety information will be
presented to physicians in a controlled and responsible manner. The
materials used in the physician-to-physician programs will be derived
from the pivotal and supportive study data, as well as data available
from previously published studies. The potential risks to patients of
omitting standard diagnostic evaluations for children with growth
disorders will be emphasized.

#### 6.3.2.2. Continuing Medical Education

Continuing medical education (CME) programs will also be available to
provide qualified physicians complete, correct information on diagnosis
and treatment of pediatric patients with non‑GHD short stature and to
ensure that they understand the benefits and risks of using Humatrope in
these patients and the importance of pursuing a comprehensive diagnostic
work-up in children with growth disorders. Since CME programs are
well-attended and valued by physicians, these initiatives will encourage
widespread understanding of the important limitations around this new
indication. The programs, funded by Lilly, will be developed and
controlled by independent third parties.

### 6.3.3. Limited Marketing 

Lilly is committed to a limited marketing program for the non-GHD short
stature indication. Marketing for Humatrope focuses specifically on
endocrinologists. The diagnosis and treatment of pediatric growth
disorders are complex, and patients require a thorough, comprehensive
diagnostic evaluation. Endocrinologists are the primary medical
specialists specifically trained in the evaluation and treatment of
growth disorders. Promotion to these physicians is primarily provided by
a limited sales force, which will be trained to educate physicians about
the restrictive label for and appropriate use in patients with non-GHD
short stature.

#### 6.3.3.1. Limited Sales Force

A limited (\<100), experienced group of sales specialists will call only
on pediatric endocrinologists to discuss Humatrope for the treatment of
non‑GHD short stature. These sales specialists will focus on discussion
of the FDA-approved label for the indication. Lilly Humatrope sales
specialists do not call on family practitioners or general
pediatricians.

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

Lilly endocrine sales specialists already have extensive relationships
with pediatric endocrinologists through discussions of other indications
for which Humatrope is approved. These sales specialists have been
extensively trained about growth disorders and their diagnosis and
management. Upon approval of Humatrope for non-GHD short stature, sales
specialists will receive additional training about the label
restrictions for the new indication, including the appropriate patient
population for this indication, the importance of a thorough diagnostic
evaluation, and the benefits and risks of Humatrope treatment for
non-GHD short stature.

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

No direct-to-consumer advertisements (for example, television, magazine,
newspaper, health fairs, billboards, sporting events) for Humatrope will
be undertaken. Lilly does, however, maintain a Humatrope internet site,
which will be updated to provide information about non‑GHD short stature
for patients and physicians when this indication is approved.
Specifically, the web site will:

-   provide informational materials to physicians and/or patients
    regarding the importance of a thorough diagnostic work-up for all
    patients with growth disorders;

-   explain the concept of height standard deviation scores (SDS);

-   explain the label-defined height SDS limit for treatment of patients
    with non-GHD short stature;

-   provide educational materials about non-GHD short stature and the
    restrictions for approved use in this patient group.

The consumer portion of the internet site will focus on patients already
diagnosed with non‑GHD short stature and/or prescribed Humatrope and
will not include content intended to bring patients into their doctors'
offices to inquire about the product.

### 6.3.4. Controlled Distribution Process

Lilly has had a controlled distribution process in place since Humatrope
was initially approved in 1987. This process is currently being revised
(independent of this application) to provide even greater control of the
process. Some of the key distribution controls and evaluation steps are
listed below:

-   Lilly only promotes the use of Humatrope for short stature to
    pediatric endocrinologists.

-   Lilly requires that physicians prescribing Humatrope for short
    stature be approved by Lilly based on a pediatric endocrine
    specialty.

-   Insurers and Lilly require a Statement of Medical Necessity
    including documentation of diagnosis prior to approval of
    reimbursement and Humatrope shipment.

-   Once medical necessity has been established and shipment is
    authorized, product is shipped through Lilly-approved closed
    specialty pharmacies.

-   Data provided to Lilly will be audited regularly to identify
    potential problems with inappropriate prescribing and distribution.

-   Lilly will investigate potential problems and take appropriate
    corrective action, including elimination of access to Humatrope.

Lilly has provided the FDA complete details of the Humatrope controlled
distribution process. The FDA has agreed that Lilly may retain some
levels of detail in confidence to maintain the integrity of the process.

Appropriate use has and will always be an important concern for Lilly.
Thus, the company will continue to perform regular audits of our current
system and make appropriate changes and improvements in the system over
time to promote the responsible, appropriate use of Humatrope.

### 6.3.5. Safety Monitoring and Analysis

#### 6.3.5.1. Pharmacovigilance

Lilly is committed to the worldwide safety monitoring of its drug
products before and after marketing approval. The Lilly World-Wide
Pharmacovigilance and Epidemiology (WWPE) department collects, monitors,
evaluates, and communicates information about adverse events in patients
treated with Lilly products. As part of this process, the WWPE safety
surveillance team uses various methods to identify, assess, and evaluate
potential safety signals. Adverse events associated with the use of
Humatrope will be screened for specific terms of interest, driven by
non-GHD short stature clinical trial findings. Included in this
screening will be terms that occurred more frequently in
Humatrope-treated patients than in controls, as well as terms such as
neoplasm and diabetes mellitus, that have received close attention for
many years. By these methods, Lilly will monitor the risks of Humatrope
in patients with non‑GHD short stature in order to ensure its safe and
effective use, identify infrequent adverse events through post-marketing
surveillance and monitor the accuracy, relevance, and usefulness of the
label.

#### 6.3.5.2. Postmarketing Surveillance Research

The Genetics and Neuroendocrinology of Short Stature International Study
(GeNeSIS; Protocol GDFC) collects comprehensive efficacy and safety data
on pediatric patients treated with Humatrope, and serves as a global
postmarketing observational research program for Lilly. This program
gathers information on adverse event frequencies by documenting, at each
visit, spontaneous adverse events, and the presence or absence of
protocol-identified adverse events that are either referenced in the
Humatrope label or have been reported in association with somatropin
use. The program also collects laboratory information regarding
carbohydrate metabolism, thyroid function, IGF-I, and IGF binding
protein-3 (IGFBP-3), whenever these tests are obtained by the patient's
physician. This information is reported to regulatory agencies on a
regular basis.

GeNeSIS is being conducted currently in over 400 study sites in 30
countries and has enrolled more than 4000 patients. At the present time,
Lilly has enlisted approximately 140 study sites in the US. Additional
study sites are being enrolled on a progressive basis. All
Humatrope-treated pediatric patients, including those with non-GHD short
stature, are eligible to enroll in this program at active study sites.
This program is ongoing and patients can enter the study at any time. At
study entry detailed historical and diagnostic information is collected
pertaining to the basis of the growth disorder. Since this is an
observational study, patients are reviewed on the schedule under which
they are usually seen by their physicians, typically once every 6
months. A variety of efficacy and safety data are collected at each
study visit, including patient age, height and other growth measurements
(for example, weight, sitting height, arm span), pubertal status, bone
age, Humatrope dosage, concomitant medications, and occurrence of any
adverse events. In addition, the presence or absence of a number of
specific medical conditions are prospectively solicited: arthralgia,
edema, gynecomastia, hypoglycemia, increase in skin nevi, scoliosis,
slipped capital femoral epiphysis, visual field defect, otitis media,
pseudotumor cerebri (intracranial hypertension), hypothyroidism, and
diabetes mellitus. Laboratory data collected at each visit (where
available), include: IGF-I, IGFBP-3, other IGF-I related analyses,
fasting glucose, TSH, thyroxine, free thyroxine, other thyroid function
tests, luteinizing hormone (LH), follicle-stimulating hormone (FSH),
estradiol, testosterone DHEAS (dehydroepiandrosterone), prolactin and
any other relevant analyses.

In addition to the core protocol, GeNeSIS includes four sub-studies that
address specific scientific questions:

\[1\] DNA analysis sub-study: Characterization of gene defects
associated with hypopituitarism, growth failure, or short stature.

\[2\] Growth-prediction sub-study: Development of accurate growth
prediction models using clinical data (auxologic parameters, bone age)
and biochemical data (IGF-I and IGFBP-3, urinary bone markers).

\[3\] SHOX deficiency sub-study: Characterization of the clinical,
endocrine and other features associated with SHOX (short stature
homeobox-containing gene on the X-chromosome) deficiency and related
disorders including Turner syndrome.

\[4\] Neoplasia sub-study: Characterization of the natural history of
neoplastic disease in children evaluated or treated for endocrine
disorder or growth disorder.

Patients are followed throughout the duration of their treatment and
physicians are encouraged to continue to follow these patients in the
study after discontinuing Humatrope. The study data are analyzed
annually and reported to the study investigators. Furthermore, this
information is reported to regulatory agencies on a regular basis.
GeNeSIS provides the mechanism by which patients with non-GHD short
stature will be followed long-term in a thorough and comprehensive
fashion, to provide clearer understanding of the efficacy and safety of
Humatrope in the observational setting.

## 6.4. External Factors

In addition to the measures established by Lilly to manage the risks
identified above for the new indication, a number of external factors
exist that act naturally to further assure the appropriate use of
somatropin in children with growth disorders. These factors include the
pediatric endocrine community, professional physician societies, and
insurance companies.

### 6.4.1. The Pediatric Endocrine Community 

Pediatric endocrinologists are highly trained specialists who are
professionally committed to the appropriate prescribing of somatropin.
To some extent these physicians perceive themselves to be "gatekeepers"
of access to this therapy and will act as a natural barrier to treatment
of inappropriate patients. In addition, there has been extensive
discussion within the pediatric endocrine community for many years
regarding the appropriateness of treatment of various patient groups,
including those with non-GHD short stature, and it can be expected that
this intrinsic set of peer-related checks and balances will remain in
place.

Pediatric endocrinologists recognize that the cause of a child's growth
failure must be rigorously determined and uniquely understand the
sophisticated processes necessary to diagnose the basis of various
growth disorders. Lilly believes that pediatric endocrinologists will
continue to perform an appropriate diagnostic evaluation to seek first
to understand the cause of the growth disorder before determining the
appropriate therapy.

### 6.4.2. Professional Physician Societies

Professional organizations such as the Lawson Wilkins Pediatric
Endocrine Society, the American Academy of Pediatrics, the American
Association of Clinical Endocrinologists, and the Endocrine Society
regularly create and publish guidelines for appropriate diagnosis and
management of conditions treated with somatropin.

### 6.4.3. Insurance Companies

Insurance companies that provide reimbursement for the costs of
medications are highly motivated to restrict the use of expensive
treatments, and therefore require documentation of medical need prior to
authorizing the dispensing of such medications. The vast majority of
pediatric patients treated with Humatrope receive the medication with
some form of third-party reimbursement. These insurers require proof of
medical necessity, which includes the patient's medical history, results
of physical examination, diagnosis, and results of supporting diagnostic
procedures. The insurers' review processes (and possible appeals)
average 2 months and may take longer than a year, illustrating the depth
and intensity of their review.

## 6.5. Conclusions

Key issues raised in the introduction of this document relating to risk
management for a new indication for Humatrope treatment in patients with
non-GHD short stature have been addressed, specifically:

-   Why was the height cut-off of --2.25 SDS chosen for the label
    indication?

This threshold provides a level of restriction on prescribing not
previously seen in pediatric growth disorders, excluding from treatment
all normal-stature children and almost half of the children that would
be considered pathologically short by conventional criteria. Further,
this threshold represents the height criterion under which the majority
of patients in the pivotal trial were enrolled.

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

Lilly believes that pediatric endocrinologists, as careful clinicians
focused on making an accurate diagnosis of a child's growth disorder,
will continue to follow a rigorous diagnostic process, seeking first to
understand the cause of the condition before determining the appropriate
therapy. In fact, because the proposed label indication contains the
statement "*and in whom diagnostic evaluation excludes causes of short
stature that should be treated by other means"* physicians will be
instructed to undertake a standard, thorough diagnostic evaluation in
order to confidently make the diagnosis of non-GHD short stature. Peer
professional societies such as the Lawson Wilkins Pediatric Endocrine
Society and others will likely publish revised guidelines that will
continue to reinforce the necessity for a thorough diagnostic
evaluation. In addition, through seminars, physician-to-physician
education, continuing medical education programs and interaction with
professional societies Lilly will ensure that the appropriateness of a
thorough diagnostic workup is reinforced. Furthermore, insurance
companies require proof of medical need before authorizing reimbursement
for somatropin treatment.

-   Will this new indication "open the floodgates" to inappropriate use?

Many factors will guard against this. First, the label language for this
indication contains a clear height threshold above which a patient is
ineligible for therapy. This is unique among somatropin indications,
placing a substantially greater degree of control on patients with this
condition than on those with other indications, and excluding from
treatment all children within the normal height range and almost half of
children with pathologically short stature. Second, pediatric
endocrinologists are careful, highly trained specialists who,
themselves, are concerned about potential for over-use of GH and
perceive themselves to be "gatekeepers" of access to this therapy and
will act as a natural barrier to treatment of inappropriate patients.
Third, Lilly has in place a proprietary, controlled distribution process
that limits and will continue to limit, access to Humatrope. Fourth,
peer professional organizations such as the Lawson Wilkins Pediatric
Endocrine Society, the American Academy of Pediatrics, The American
Association of Clinical Endocrinologists will likely update their
guidelines for prescribing of somatropin to include recommendations for
appropriate prescribing for this condition. Fifth, insurance companies
have a financial disincentive for reimbursement of the cost of
somatropin for inappropriate patients and require a statement of medical
necessity to be completed before a prescription may be filled. Sixth,
Lilly promotes Humatrope only to endocrinologists and does not engage in
direct to consumer marketing for Humatrope.

In conclusion, Lilly has been and remains committed to the correct uses
of Humatrope for appropriate patients. To assure continued appropriate
use after approval of treatment for patients with non-GHD short stature
Lilly has in place a multi-level program (Table 31) to manage the
potential risks associated with Humatrope treatment of this patient
population. These steps include a restricted label indication, a
comprehensive physician education program, continued controlled
distribution, limited marketing, and safety surveillance through a
worldwide pharmacovigilance system and the GeNeSIS observational
research program.

[]{#__RefHeading___Toc39468368 .anchor}Table 31. Risk Management
Elements and External Factors Related to Approval of Non-GHD Short
Stature

+-----------------------+-----------------------+----------------------+
| **Potential Risks**   | **Risk Management     | **External           |
|                       | Element(s)**          | Factor(s)**          |
+-----------------------+-----------------------+----------------------+
| Inappropriate         | Restrictive labeling: | Pediatric            |
| prescribing           | specific description  | Endocrinologists     |
|                       | of appropriate        |                      |
|                       | patient               | Professional         |
|                       |                       | Societies            |
|                       | Physician education   |                      |
|                       |                       | Insurance companies  |
|                       | Limited marketing     |                      |
|                       |                       |                      |
|                       | -   Marketing only to |                      |
|                       |     endocrinologists  |                      |
|                       |                       |                      |
|                       | -   No                |                      |
|                       |                       |                      |
|                       |    direct-to-consumer |                      |
|                       |     marketing         |                      |
|                       |                       |                      |
|                       | Controlled            |                      |
|                       | distribution process  |                      |
+-----------------------+-----------------------+----------------------+
| Lack of thorough      | Restrictive labeling  | Pediatric            |
| diagnostic evaluation |                       | Endocrinologists     |
| prior to initiation   | Physician education   |                      |
| of treatment          |                       | Professional         |
|                       | Marketing to          | Societies            |
|                       | endocrinologists      |                      |
|                       |                       | Insurance companies  |
+-----------------------+-----------------------+----------------------+
| Emergence of New      | Postmarketing studies | Pediatric            |
| Adverse Events        |                       | Endocrinologists     |
|                       | Pharmacovigilance     |                      |
+-----------------------+-----------------------+----------------------+

# 7. Summary and Conclusions

## 7.1. Height Gain

Evidence from one placebo‑controlled pivotal study (Study GDCH) and one
dose‑response supportive study (Study E001) demonstrates that Humatrope
treatment increases final height in pediatric patients with non-GHD
short stature. The mean gain in final height relative to placebo was
3.7 cm for Study GDCH, and the mean gain in final height relative to
baseline predicted height ranged from 5.4 to 7.2 cm for the three dosage
groups in Study E001. These gains in final height are similar to the
average gain in adult height of 4 to 6 cm reported in a meta‑analysis of
the literature on controlled studies of GH treatment of patients with
non‑GHD short stature (Finkelstein et al. 2002). These findings
translate into two key benefits for these patients: an increase in
height during childhood, allowing patients with non-GHD short stature to
catch up to their normal-stature peers during childhood, and increased
final height after completion of linear growth. Whereas the final
heights for placebo-treated patients (Study GDCH) were all below the 5th
percentile of the normal population, and most were below the lower limit
of normal, 94% of final heights for patients who received the higher
dosage (0.37 mg/kg/wk) in Study E001 were within the normal range. The
average height gains attained in patients with non-GHD short stature
were similar to that observed in the pivotal study for Humatrope
treatment in Turner syndrome.

## 7.2. Dosage

Study E001 demonstrates greater efficacy of Humatrope at a dosage of
0.37 mg/kg/wk compared to a dosage of 0.24 mg/kg/wk (a dosage similar to
the 0.22 mg/kg/wk administered in the pivotal study, Study GDCH) for the
treatment of pediatric patients with non‑GHD short stature. Recent
dose‑response studies in patients with Turner syndrome (de Muinck
Keizer‑Schrama et al. 1999; Quigley et al. 2002) and in patients with
GHD (Mauras et al. 2000; Cohen et al. 2002) support a greater
effectiveness of Humatrope in the range of 0.35 to 0.70 mg/kg/wk
compared to lower dosages.

## 7.3. Dose Frequency

The greater gain in height SDS observed in the lower dosage group of
Study E001 (0.24 mg/kg/wk), in which patients received 6 times per week
dosing of Humatrope compared to the TIW dosing in Study GDCH
(0.22 mg/kg/wk), supports the efficacy of 6 times per week
administration of Humatrope. Daily administration has become standard of
care because it is more effective, is considered to be more
physiological, and may improve compliance. Daily or 6 times per week
dosing is recommended for the recently approved indications of
Prader‑Willi syndrome and of patients born small for gestational age. In
the peer‑reviewed literature, one study has reported greater efficacy of
daily versus TIW GH dosing in patients with non-GHD short stature
(Hopwood et al. 1993), and similar observations have been reported for
patients with GHD (Smith et al. 1988; Rosenbloom et al. 1990; Blethen et
al. 1993; MacGillivray et al. 1996). Thus, Lilly recommends a dose
frequency of 3 to 7 times per week for pediatric patients with non‑GHD
short stature.

## 7.4. Safety

Based on the review of comparative safety data from the clinical studies
in the GHD, Turner syndrome, and non-GHD short stature patient
populations, the overall safety profile of Humatrope for pediatric
patients with non-GHD short stature is comparable to that for the
approved indications, and all appropriate warnings, precautions, and
contraindications are already included in the Humatrope label.
Additionally, two large GH postmarketing research programs conducted by
other pharmaceutical companies, with a combined total of more than
9000 GH-treated patients with non‑GHD short stature, have observed lower
rates of AEs associated with GH treatment in patients with non-GHD short
stature than in patients with GHD or Turner syndrome (Wilton 1999;
Maneatis et al. 2000).

## 7.5. Conclusion

Patients with non-GHD short stature are just as short, and just as
deserving of treatment, as children with GHD, chronic renal
insufficiency, Turner syndrome, Prader-Willi syndrome, or children born
small for gestational age, and the lack of approved treatment for these
children represents a major inequity and unmet need.

The results presented in this briefing document support the safety and
efficacy of: *Humatrope, at a dosage of up to 0.37 mg/kg/wk,
administered in divided doses 3 to 7 times per week, for the treatment
of non-GHD 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.*

Humatrope should be approved for patients with non-GHD short stature so
that these patients, and their physicians, will have equitable access to
safe and effective therapy.

After approval, Lilly will assist pediatric endocrinologists, through an
effective risk-management program, to focus treatment on the appropriate
patients.

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