Somatropin, powder for injection and diluent (cartridge), 5 mg per mL, 12 mg per mL (with preservative), powder for injection and diluent (single dose syringes) in strengths from 0.6 mg – 2 mg per 0.25 mL, Genotropin and Genotropin MiniQuick, March 2008
Public summary document for Somatropin, powder for injection and diluent (cartridge), 5 mg per mL, 12 mg per mL (with preservative), powder for injection and diluent (single dose syringes) in strengths from 0.6 mg – 2 mg per 0.25 mL, Genotropin and Genotropin MiniQuick, March 2008
Page last updated: 04 July 2008
Public Summary Documents
Product: Somatropin, powder for injection and diluent (cartridge), 5 mg per mL, 12
mg per mL (with preservative), powder for injection and diluent (single dose syringes)
in strengths from 0.6 mg – 2 mg per 0.25 mL, Genotropin and Genotropin MiniQuick
Sponsor: Pfizer Australia Pty Ltd
Date of PBAC Consideration: March 2008
1. Purpose of Application
The application sought an extension to the Section 100 human Growth Hormone (hGH) program and the “Guidelines for the Availability of human Growth Hormone (hGH) as a Pharmaceutical Benefit” to allow treatment for the improvement of body composition and short stature associated with Prader-Willi Syndrome (PWS) in paediatric patients.
2. Background
The PBAC had previously considered several submissions seeking PBS availability of
hGH in patients with PWS. Overall, the submissions were rejected due to the limitations
around the evidence to support the extent of benefit and the resulting uncertain cost-effectiveness
of the treatment. The PBAC also noted that a proportion of children with PWS could
access hGH if meeting the growth related criteria of the Guidelines.
3. Registration Status
Genotropin 5 mg per mL, 12 mg per mL and Genotropin MiniQuick (all strengths) are registered with TGA and indicated for:
- treatment of short stature due to decreased or failed secretion of pituitary growth hormone;
- treatment of adults with severe growth hormone deficiency as diagnosed in the insulin tolerance test for growth hormone deficiency and defined by peak growth hormone concentrations of less than 2.5 nanogram/mL;
- growth disturbances associated with gonadal dysgenesis (Turner's syndrome);
- improvement of body composition and treatment of short stature associated with Prader-Willi syndrome (PWS) in paediatric patients;
- treatment of growth disturbance in children with chronic renal insufficiency whose height is on or less than twenty-fifth percentile and whose growth velocity is on or less than twenty-fifth percentile for bone age. Chronic renal insufficiency is defined as glomerular filtration rate of less than 50 mL/min/1.73m2.
4. Listing Requested and PBAC’s View
Section 100: Human Growth Hormone Program
Improvement of body composition and treatment of short stature associated with Prader-Willi
Syndrome in paediatric patients.
The sponsor also requested a revision of the current Growth Hormone Guidelines to
include use of Genotropin for children with Prader-Willi Syndrome.
For PBAC’s view, see Recommendation and Reasons.
5. Clinical Place for the Proposed Therapy
Prader-Willi Syndrome (PWS) is a complex, multi-system, genetic disorder characterised by neonatal hypotonia, developmental delay, short stature, behavioural abnormalities, childhood-onset obesity, hypothalamic hypogonadism, and characteristic appearance. The greatest morbidity and mortality in the syndrome is attributed to complications resulting from being overweight or obese, related to the central distribution of fat in the abdomen, chest and neck areas. In paediatric patients who have growth hormone deficiency due to PWS, treatment with Genotropin stimulates linear growth and normalises concentrations of IGF-1 (insulin-like growth factor-1) and produces improvements in body composition and lipid metabolism.
6. Comparator
The re-submission nominated placebo as the main comparator. This was accepted by the PBAC as appropriate.
7. Clinical Trials
The re-submission presented seven randomised comparative trials comparing somatropin
and placebo, and one supportive randomised long-term case-control study comparing
somatropin and placebo.
The studies as published at the time of the re-submission are presented in the table
below.
|
Trial/First author |
Protocol title |
Publication citation |
|---|---|---|
|
Randomised comparative trials |
||
|
Carrel 1999 |
Growth hormone improves body composition, fat utilization, physical strength and agility, and growth in Prader-Willi syndrome: A controlled study. |
The Journal of pediatrics, 1999. 134(2): p. 215-21. |
|
Festen 2007a |
Adiponectin levels in prepubertal children with Prader-Willi syndrome before and during growth hormone therapy. |
J-Clin-Endocrinol-Metab. 92(4): p. 1549-54. |
|
Festen 2007b |
Thyroid hormone levels in children with Prader-Willi syndrome before and during growth hormone treatment. |
Clin Endocrinol. Oxford. 67(3):449-56. |
|
Haqq 2003 |
Effects of growth hormone on pulmonary function, sleep quality, behavior, cognition, growth velocity, body composition, and resting energy expenditure in Prader-Willi syndrome. |
The Journal of clinical endocrinology and metabolism, 2003. 88(5): p. 2206-12. |
|
Hauffa 1997 |
One-year results of growth hormone treatment of short stature in Prader-Willi syndrome. |
Acta paediatrica (Oslo Norway: 1992). Supplement, 1997. 423: p. 63-5. |
|
Lindgren 1997 |
Effects of growth hormone treatment on growth and body composition in Prader-Willi syndrome: a preliminary report The Swedish National Growth Hormone Advisory Group. |
Acta paediatrica (Oslo Norway : 1992). Supplement, 1997. 423: p. 60-2. |
|
Whitman 2004* |
Growth hormone improves body composition and motor development in infants with Prader-Willi syndrome after six months. |
Journal of pediatric endocrinology & metabolism : JPEM, 2004. 17(4): p. 591-600. |
|
Supportive study |
||
|
Angulo 2007 |
Final adult height in children with Prader-Willi syndrome with and without human growth hormone treatment. |
American journal of medical genetics. Part A, 2007. 143(13): p. 1456-61. |
8. Results of Trials
A meta-analysis was undertaken to combine the results of the studies, where appropriate,
to give an overall view of the effect of hGH on patients regardless of their stature
or age at entry. The key results from the meta-analysis are summarised in the table
below.
Summary of results from the meta-analysis
|
Outcome |
Population |
WMD Somatropin vs. No Treatment |
|---|---|---|
|
Height velocity |
All trials |
5.94 cm/year (95% CI: 5.05, 6.82). |
|
Excluding infants |
5.93 cm/year (95% CI: 4.77, 7.09) |
|
|
Height SDS |
All trials |
1.04 (95% CI: 0.58, 1.51) |
|
% body fat |
All trials |
-9.58% (95% CI: –12.70%, –6.46%) |
|
LBM |
All trials |
3.01 kg (95% CI: 1.24, 4.78) |
|
Excluding infants |
4.0 kg (95% CI: 2.54, 5.46) |
|
|
BMI |
All trials |
-2.21 (95% CI –3.14, -1.27) |
Abbreviations: WMD= weighted mean difference; SDS= standard deviation score; LBM=lean
body mass; BMI= body mass index.
Children treated with somatropin experienced significant improvements in height standard
deviation score (SDS), percentage body fat, lean body mass and body mass index compared
with untreated children.
All studies reported either a significant difference or trend towards significant
difference favouring somatropin treatment over placebo.
The results for the outcome of respiratory function are summarised in the following
tables.
Inspiratory muscle strength (cm/H2O) at baseline and 1 year
|
Trial ID |
hGH treatment |
Untreated control |
||||
|---|---|---|---|---|---|---|
|
n/N |
Baseline Mean (SD) |
Endpoint Mean (SD) |
n/N |
Baseline Mean (SD) |
Endpoint Mean (SD) |
|
|
Carrel (1999) |
35/35 |
45.8 |
55.7 |
19/19 |
44.8 |
40.4 |
1Paired t-test before and after GH therapy, compared with either baseline values of
treated patients or 12 month values of untreated patients
Expiratory muscle strength (cm/H2O) at baseline and 1 year
|
Trial ID |
hGH treatment |
Untreated control |
||||
|---|---|---|---|---|---|---|
|
n/N |
Baseline Mean (SD) |
Endpoint Mean (SD) |
n/N |
Baseline Mean (SD) |
Endpoint Mean (SD) |
|
|
Carrel (1999) |
35/35 |
54.6 |
69.3 (20.8) |
19/19 |
58.8 |
46.0 |
1Paired t-test before and after GH therapy, compared with either baseline values of
treated patients or 12 month values of untreated patients
The results indicate that after 12 months therapy children receiving somatropin show
significant improvements in both inspiratory and expiratory muscle strength compared
with baseline values of treated patients, or end point values of untreated patients.
The PBAC noted that the prevalence of diabetes among PWS patients who have not received
hGH intervention is significantly higher than among those who have been treated with
hGH.
The re-submission presented a summary of the most recent Periodic Safety Update Report
(PSUR) for somatropin. The key results are summarised below.
A total of 671 cases containing 1,120 events were included in the PSUR, with the most
commonly reported adverse events being headache, scoliosis, neoplasm recurrence and
incorrect dose administered. Events reported in >2% of cases are shown the table below.
Events reported in >2% of all cases (11 Aug 2004 – 10 Aug 2006)
|
Preferred term |
Number of cases (%) |
|---|---|
|
Headache |
33 (4.9) |
|
Condition aggravated |
31 (4.6) |
|
Scoliosis |
31 (4.6) |
|
Neoplasm recurrence |
26 (3.9) |
|
Incorrect dose administered |
31 (3.1) |
|
Pyrexia |
19 (2.8) |
|
Fatigue |
18 (2.7) |
|
Drug exposure during pregnancy |
18 (2.7) |
|
Drug administration error |
16 (2.4) |
The key finding of the PSUR was that “there were no major findings bearing on the established overall safety of somatropin”.
9. Clinical Claim
The submission claimed that somatropin was therapeutically superior to the comparator, with higher toxicity. Based on the supporting data, the PBAC considered this description was reasonable.
10. Economic Analysis
A stepped modelled economic evaluation was presented. The model was in two parts.
Part A modelled subjects from the age of six months to 17 years, and were treated
with somatropin. All survivors at age 18 years were channelled into Part B of the
model. Part B simulated the follow-up of subjects from age 18 years to a maximum of
50 years. Part B of the model did not directly apply any effects or costs of treatment
with somatropin. The effects of treatment (from Part A) are mediated by the difference
between the placebo and somatropin groups in the proportions of subject with and without
diabetes at baseline in Part B. In other words, for patients aged ≥ 18 years, Part
B of the model assumed that no additional mortality benefit was associated with somatropin
beyond that already achieved in earlier life.
The economic evaluation produced an incremental cost per extra Quality-Adjusted Life-Year
(QALY) gained between $45,000 and $75,000.
11. Estimated PBS Usage and Financial Implications
The submission estimated that the likely number of patients per year to be less than 10,000 in Year 5 with an estimated financial cost per year to the PBS of less than $10 million in Year 5.
12. Recommendation and Reasons
The PBAC recommended amending the listing of somatropin on the PBS under the Section
100 Human Growth Hormone Program to include improvement of body composition and short
stature associated with Prader-Willi Syndrome (PWS) in patients up to 18 years of
age on the basis of high but acceptable cost-effectiveness compared with placebo.
The PBAC accepted that the administration of somatropin to PWS patients less than
18 years results in significant improvements in body composition and respiratory muscle
strength and there appears to be a reduction in mortality, and in some patients there
may also be a reduced prevalence of diabetes, both of which are clinically important
benefits. The PBAC considered that use of somatropin in PWS be limited to patients
up to 18 years of age as there is no data outside this age group.
The PBAC did not consider the rule of rescue applicable although acknowledging that
patient numbers are small and as a result, the database is limited.
The PBAC considered that the incremental cost /extra QALY gained of between $45,000
and $75,000, although associated with some uncertainty, represents acceptable cost-effectiveness.
The PBAC requested the Growth Hormone Advisory Committee provide advice to the PBAC
on the amendments required to the ‘Guidelines for the Availability of Human Growth
Hormone (hGH) as a Pharmaceutical Benefit’ for the provision of growth hormone to
patients up to the age of 18 years for the management of PWS.
13. Context for Decision
The PBAC helps decide whether and, if so, how medicines should be subsidised in Australia. It considers submissions in this context. A PBAC decision not to recommend listing or not to recommend changing a listing does not represent a final PBAC view about the merits of the medicine. A company can resubmit to the PBAC or seek independent review of the PBAC decision.
14. Sponsor’s Comment
Pfizer Australia (the Sponsor) is delighted with the PBAC’s decision to recommend
the inclusion of Genotropin on the PBS for children with PWS. The sponsor believes
the availability of this medicine provides a significant advance in the treatment
paradigm for these children with PWS. The Sponsor appreciates the opportunity to work
with the stakeholders to achieve this positive outcome for children with PWS and their
families in Australia.
