Somatropin (Recombinant human growth hormone), injection, 5 mg (15 i.u.) and 12 mg (36 i.u.) in 1 mL cartridge (with preservative), Genotropin® - July 2011
Page last updated: 11 November 2011
Public Summary Document
Product: Somatropin (Recombinant human growth
hormone), injection, 5 mg (15 i.u.) and 12 mg (36 i.u.) in 1 mL
cartridge (with preservative), Genotropin®; powder
for injection, 5 mg (15 i.u.) and 12 mg (36 i.u.) with diluent in
pre-filled pen (with preservative), Genotropin
GoQuick®; injection, 0.6 mg (1.8 i.u.), 0.8 mg (2.4
i.u.), 1 mg (3 i.u.), 1.2 mg (3.6 i.u.), 1.4 mg (4.2 i.u.), 1.6 mg
(4.8 i.u.), 1.8 mg (5.4 i.u.), and 2 mg (6 i.u.) with diluent in
single use syringe (without preservative), Genotropin
MiniQuick®
Sponsor: Pfizer Australia Pty Ltd
Date of PBAC Consideration: July 2011
1. Purpose of Application
The submission requested an extension of the current Section 100
(Human Growth Hormone Program) listing to include treatment of
severe adult growth hormone deficiency (AGHD).
2. Background
Somatropin has been subsidised through PBS under the Section 100
Human Growth Hormone Program, in accordance with the
‘Guidelines for the Availability of Human Growth Hormone
(hGH) as a Pharmaceutical Benefit’ since August 1993.
At the March 2008 meeting, the PBAC recommended amending the
listing of Genotropin branded somatropin products 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. Listing was effective 1 July 2009.
In September 2010, new “Guidelines for the Pharmaceutical
Benefits Scheme Growth Hormone Program” took effect which are
an amalgamation of the ‘Guidelines for the Availability of
Human Growth Hormone (hGH) as a Pharmaceutical Benefit (July
2008)’ and the ‘Guidelines for the Availability of
Human Growth Hormone (hGH) as a Pharmaceutical Benefit for the
treatment of Prader-Willi Syndrome (February 2009)’.
3. Registration Status
Genotropin brand of somatropin is TGA registered for the following indications:
- 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;
- For 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
The submission proposed to extend the current Section 100 (Human Growth Hormone Program)
criteria for availability to read as follows, with the requested listing shown in
bold:
“Genotropin branded products are also available for the treatment of Prader-Willi
Syndrome and for the treatment of adults with severe growth hormone deficiency in accordance with the ‘Guidelines for the Pharmaceutical Benefits Scheme Growth
Hormone Program”.
The submission proposed that further details of the proposed criteria for availability
would be contained in the “Guidelines for the Pharmaceutical Benefits Scheme Growth
Hormone Program”. The submission proposed the following eligibility criteria for inclusion
in the Guidelines:
Proposed restriction for initiation of treatment with Genotropin for adult growth
hormone deficiency (AGHD)
| Aetiology of disease | Proposed eligibility criteria |
| Adults with severe growth hormone deficiency with onset in childhood (of organic or idiopathic origin) |
X.X.1 Eligibility criteria Adults with a history of severe growth hormone deficiency in childhood who have:
|
| Adults with severe growth hormone deficiency with onset in adulthood |
X.X.1 Eligibility criteria Adults who have:
|
Abbreviations: IGF-I, insulin-like growth factor 1; ng, nanogram; mL, millilitres;
QoL-AGHDA, Quality of Life Assessment of Growth Hormone Deficiency in Adults
For PBAC’s view, see Recommendation and Reasons.
5. Clinical Place for the Proposed Therapy
Growth hormone is released into the circulation from the anterior
pituitary gland to elicit various known biological actions in many
cell types and tissues. Adults with growth hormone deficiency have
impaired health, including abnormal body composition, reduced
physical fitness, increased cardiovascular risk factors,
osteopaenia and impaired psychological function.
The submission proposed that the listing of Genotropin branded
somatropin would provide a subsidised treatment option for severe
AGHD patients with impaired quality of life.
6. Comparator
The submission nominated standard care (SC), which consists of
regular monitoring by an endocrinologist, medical management of
signs and symptoms and management of risk factors arising from AGHD
as appropriate, as the main comparator.
The PBAC considered this appropriate.
7. Clinical Trials
The submission presented 39 randomised controlled trials comparing
somatropin with placebo in patients with AGHD. The PBAC noted that
an impaired QoL at baseline was not an entry criterion for the
trials, which limited the applicability of these trials to the
requested listing for patients with impaired QoL as measured by the
quality of life assessment for growth hormone deficiency in adults
(QoL-AGDHA) instrument. The PBAC additionally noted that the trials
presented in the submission used various QoL instruments and that
only two of the trials used the instrument of QoL-AGHDA used in the
proposed restriction.
The submission used body composition outcomes (lean body mass - LBM
and fat mass - FM) as supportive outcomes. The submission presented
meta-analyses for Nottingham Health Profile (NHP) (6 trials for
total score, 15 trials for part-scores), Psychological General
Well-Being Index (PGWB) (8 trials), LBM (17 trials for change, 5
trials for percentage change) and FM (20 trials).
It was noted that the trials presented had high risk of bias,
including uncertain blinding, post-randomisation selection bias and
high risk of outcomes reporting bias. In general, randomisation was
either not clearly reported or by third-party randomisation. All
trials were reported to be double-blind, however not all
publications described whether outcome assessors were blinded. The
submission described that the patient populations in which the
analyses were undertaken included intention to treat, per protocol
or other analyses. In general there was limited information on how
the trials dealt with missing data. As many publications and study
reports were more than 10 years old, limited information was
available on the trial methodology, and therefore it was uncertain
whether bias may have been introduced in the trials.
The published trials presented in the submission are shown in the
table below.
| Trial ID / First author | Protocol title / Publication title | Publication citation |
| Cuneo et al. | The Australian multicenter trial of growth hormone (GH) treatment in GH- deficient adults. | J Clin Endocrinol Metab 1998; 83(1):107-116 |
| Chihara et al. (2004) | Adult GH deficiency in Japanese patients: Effects of GH treatment in a randomised, placebo-controlled trial. | Eur J Endocrinol 2004; 151(3):343-350 |
| Urushihara et al. | Heterogeneity in responsiveness of perceived quality of life to body composition changes between adult- and childhood-onset Japanese hypopituitary adults with GH deficiency during GH replacement. | Eur J Endocrinol 2007; 156(6):637-645 |
| Shimatsu A et al. | Growth hormone deficiency and replacement therapy in Japan: Results of placebo-controlled double-blind study and open-label extension study. A Decade of HypoCCS: The Changing Face of Pituitary Disease. | BioScientifica Ltd, Bristol; 2008; 171-81 |
| Chihara et al. (2006a) | Efficacy and safety of growth hormone (GH) in the treatment of adult Japanese patients with GH deficiency: A randomised, placebo-controlled study. | Growth Horm IGF Res 2006a;16(2):132-142 |
| Chihara et al. (2006b) | Effect of growth hormone treatment on trunk fat accumulation in adult GH-deficient Japanese patients: A randomised, placebo-controlled trial. | Curr Med Res Opin 2006b; 22(10):1973-1979 |
| Chihara et al. (2006c) | Growth hormone (GH) effects on central fat accumulation in adult Japanese GH deficient patients: 6-month fixed-dose effects persist during second 6-month individualized-dose phase. | Endocr J 2006c; 53(6):853-858 |
| Chihara et al. (2008) | Efficacy and safety of individualized growth hormone treatment in adult Japanese patients with growth hormone deficiency. | Growth Horm IGF Res 2008; 18(5):394-403 |
| Chihara et al. (2010) | Dose-dependent changes in body composition during growth hormone (GH) treatment in Japanese patients with adult GH deficiency: A randomized, placebo-controlled trial. | Growth Horm IGF Res 2010; 20(3):205-211 |
| Christ et al. (2004) | Effects of growth hormone (GH) replacement therapy on low-density lipoprotein apolipoprotein B100 kinetics in adult patients with GH deficiency: A stable isotope study. | J Clin Endocrinol Metab 2004; 89(4):1801-1807 |
| Christ et al. (1999) | Effects of Growth Hormone (GH) Replacement Therapy on Very Low Density Lipoprotein Apoliproprotein B100 Kinetics in Patients with Adult GH Deficiency: A stable isotope study. | J Clin Endocrinol Metab 1999; 84:307-316 |
| Engstrom et al. | Effects of Growth Hormone (GH) on Ghrelin, Leptin, and Adiponectin in GH-Deficient Patients. | J Clin Endocrinol Metab 2003; 88(11):5193-5198. |
| Burman et al. (1997) | Growth hormone (GH)-deficient men are more responsive to GH replacement therapy than women. | J Clin Endocrinol Metab 1997; 82(2):550-555. |
| Burman et al. (1995) | Quality of life in adults with growth hormone (GH) deficiency: Response to treatment with recombinant human GH in a placebo-controlled 21-month trial. | J Clin Endocrinol Metab 1995; 80(12):3585-3590. |
| Ezzat et al. | Gender-specific responses of lean body composition and non-gender-specific cardiac function improvement after GH replacement in GH-deficient adults. | J Clin Endocrinol Metab 2002; 87(6):2725-2733. |
| Florkowski et al. (1996) | Low-dose growth hormone replacement lowers plasma leptin and fat stores without affecting body mass index in adults with growth hormone deficiency. | Clin Endocrinol 1996; 45(6):769-773 |
| Florkowski et al. (1998) | Growth hormone replacement does not improve psychological well-being in adult hypopituitarism: A randomized crossover trial. | Psychoneuroendocrinology 1998; 23(1):57-63 |
| Hoffman et al. | Growth Hormone (GH) Replacement Therapy in Adult-Onset GH Deficiency: Effects on Body Composition in Men and Women in a Double-Blind, Randomized, Placebo-Controlled Trial. | J Clin Endocrinol Metab 2004; 89(5):2048-2056 |
| Hwu et al. | Growth hormone (GH) replacement reduces total body fat and normalizes insulin sensitivity in GH-deficient adults: A report of one-year clinical experience. | J Clin Endocrinol Metab 1997; 82(10):3285-3292 |
| Johannsson et al. | The individual responsiveness to growth hormone (GH) treatment in GH- deficient adults is dependent on the level of GH-binding protein, body mass index, age, and gender. | J Clin Endocrinol Metab 1996; 81(4):1575-1581 |
| Jorgensen et al. | Growth hormone versus placebo treatment for one year in growth hormone deficient adults: Increase in exercise capacity and normalization of body composition. | Clin Endocrinol 1996; 45(6):681-688 |
| Mahajan et al. | Atypical depression in growth hormone deficient adults, and the beneficial effects of growth hormone treatment on depression and quality of life. | Eur J Endocrinol 2004; 151(3):325-332 |
| Mesa et al. | Growth hormone deficiency in adults: Effects of replacement therapy on body composition and health-related quality of life. | Med Clin 2003; 120(2):41-46 |
| Oertel et al. | The effect of growth hormone substitution on cognitive performance in adult patients with hypopituitarism. | Psychoneuroendocrinology 2004; 29(7):839-850 |
| Rodriguez-Arnao et al. | Effects of growth hormone replacement on physical performance and body composition in GH deficient adults. | Clin Endocrinol 1999; 51(1):53-60 |
| Sneppen et al. | Bone mineral content and bone metabolism during physiological GH treatment in GH-deficient adults - An 18-month randomised, placebo-controlled, double blinded trial. | Eur J Endocrinol 2002; 146(2):187-195 |
| Snyder et al. | Effect of growth hormone replacement on BMD in adult-onset growth hormone deficiency. | J Bone Miner Res 2007; 22(5):762-770 |
| Soares et al. | Impact of recombinant human growth hormone (RH-GH) treatment on psychiatric, neuropsychological and clinical profiles of GH deficient adults: A placebo-controlled trial. | Arq Neuro-Psiquiatr 1999; 57(2 A):182-189 |
| Underwood et al. | Growth Hormone (GH) Dose-Response in Young Adults with Childhood-Onset GH Deficiency: A Two-Year, Multicenter, Multiple-Dose, Placebo-Controlled Study. | J Clin Endocrinol Metab 2003; 88(11):5273-5280 |
| Verhelst et al. | Two years of replacement therapy in adults with growth hormone deficiency. | Clin Endocrinol 1997; 47(4):485-494 |
| Wallymahmed et al. | Quality of life, body composition and muscle strength in adult growth hormone deficiency: The influence of growth hormone replacement therapy for up to 3 years. | Clin Endocrinol 1997; 47(4):439-446 |
| Weaver et al. | The effect of low dose recombinant human growth hormone replacement on regional fat distribution, insulin sensitivity, and cardiovascular risk factors in hypopituitary adults. | J Clin Endocrinol Metab 1995; 80(1):153-159 |
| Woodhouse et al. | Measures of submaximal aerobic performance evaluate and predict functional response to growth hormone (GH) treatment in GH-deficient adults. | J Clin Endocrinol Metab 1999; 84(12):4570-4577 |
| Meta-analyses of direct randomised trials | ||
| Arwert et al. | The influence of growth hormone (GH) substitution on patient-reported outcomes and cognitive functions in GH-deficient patients: A meta-analysis. | Growth Horm IGF Res 2005; 15(1):47-54 |
| Bryant et al. | Clinical effectiveness and cost-effectiveness of growth hormone in adults in relation to impact on quality of life: A systematic review and economic evaluation. | Health Technol Assess 2002; 6(19) |
| Deijen et al. | Differential effect sizes of growth hormone replacement on quality of life, well-being and health status in growth hormone deficient patients: A meta-analysis. | Health Qual Life Outcomes 2005; 3 |
| Fassbender et al. | Treatment of proven growth hormone deficiency in adults with recombinant human growth hormone according to evidence-based criteria. | Dtsch Med Wochenschr 2005; 130(45):2589-2595 |
| Maison et al. | Impact of Growth Hormone (GH) Treatment on Cardiovascular Risk Factors in GH-Deficient Adults: A Metaanalysis of Blinded, Randomized, Placebo-Controlled Trials. | J Clin Endocrinol Metab 2004; 89(5):2192-2199 |
| Mardh et al. | Growth Hormone Replacement Therapy in Adult Hypopituitary Patients with Growth Hormone Deficiency: Combined Data from 12 European Placebo Controlled Clinical Trials. | Endocrinol Metab Suppl 1994; 1:43-49 |
8. Results of Trials
Quality of life outcomes
The PBAC noted the meta-analysis presented in the submission of
trials reporting the Nottingham Health Profile (NHP) score did not
result in a statistically significant improvement in the total NHP
score nor any of the sub scores (unweighted and weighted) for
somatropin. The PBAC also noted the meta-analysis of trials using
PGWB reported a statistically significant increase in the total
score and the components of positive well-being and vitality
compared to placebo treatment. However the clinical significance of
an improvement of one to four points on the 110 point PGWB scale
was unclear. Additionally the PBAC noted that two trials (Hoffman
2004 and Underwood 2003), which were excluded from the PGWB
meta-analysis because detailed data were not available in the
publications, reported that treatment with somatropin resulted in
no significant change in QoL using a number of assessment tools
including the PGWB, and that inclusion of these trials in the PGWB
meta-analysis may have resulted in the difference in PGWB scores no
longer reaching statistical significance. The PBAC also noted that
the two trials that assessed QoL using the QoL-AGHDA did not
present details about baseline values and improvement, but both
reported no significant effect of treatment with somatropin.
The table below presents the results of disease specific QoL
instruments used in the clinical trials.
Results for disease specific quality of life
instruments
| Trial ID | Somatropin | Placebo | Mean difference (SOM–PBO) | |||
| N | endpoint - baseline | N | endpoint - baseline | |||
| QoL-AGHDA | ||||||
| Chihara 2006a | 37 | NR | 36 | NR | No significant treatment effects reported (p=0.5588) | |
| Mesa 2003 | 85 | NR | 80 | NR | No significant treatment effects reported | |
| DSQ | ||||||
| Florkowski 1998 | 10 | NR | 10 | NR | No significant treatment effects reported | |
NR = not reported; SOM = somatropin; PBO = placebo; QoL-AGHDA =
Quality of Life Assessment of Growth Hormone Deficiency in Adults;
DSQ = Disease Specific Questionnaire Florkowski 1998 reported that
somatropin treatment did not result in statistically significantly
better treatment effects using the disease specific questionnaire
(DSQ) compared to placebo treatment. Another unpublished study did
not demonstrate statistically significant improvement in the growth
hormone deficiency questionnaire (GHDQ) score for
somatropin. The submission noted that none of the trials
were restricted to patients with impaired QoL at baseline.
Body composition outcomes
Somatropin resulted in a statistically significant increase in LBM
and a statistically significant decrease in FM compared to placebo.
The mean difference in LBM was 2.3 kg (95% CI: 1.7, 2.9) and the
mean difference in FM was -2.6 kg (95% CI: -3.0, -2.1). There were
differences in methodology of measuring LBM and FM between the
trials, including duration of the trial and patient
characteristics, which may have explained the heterogeneity
observed in the meta-analyses. The submission did not discuss
whether the changes in LBM and FM were clinically relevant, and did
not provide a minimum clinical important difference. As most trials
were six months in duration the sustainability of the differences
in body composition was uncertain. Two trials were of 2 years in
duration, Snyder 2007 and Underwood 2003. Both trials reported no
statistically significant difference in FM, while for LBM, Snyder
2007 reported no statistically significant difference, and
Underwood 2003 reported a statistically significant
difference.
The submission did not provide meta-analyses of the safety outcomes
of the 39 included trials, as safety outcomes were not consistently
reported across the trials. The submission presented adverse events
from the clinical trial reports combined, for an unpublished study
separately and a summary of adverse events reported in
publications.Somatropin appeared to be associated with more adverse
events than placebo treatment. The most common adverse events were
oedema, musculoskeletal pain/stiffness and athralgias
(non-inflammatory joint pain). The submission stated that the
adverse events were in general mild and these patients recovered
either spontaneously or after dose reductions, stating that of
those trials that reported somatropin dose reductions due to oedema
and joint pain, approximately 36% to 60% of the patients had
complete recovery.
The submission provided additional data on potential safety
concerns beyond those identified in the clinical trials from the
Australian Product Information (PI), the open-label period of the
clinical trials, the Periodic Safety Update Report (PSUR) up to
March 2009, and two observational studies KIMS (Pfizer
International Metabolic Database) and HypoCSS (Hypopituitary
Control and Complications Study).
The submission stated that the frequency of adverse events reported
in the open-label extension phase appeared to be similar to the
double-blind period, with the exception of upper respiratory tract
infection which appeared to be increased in most clinical trial
reports (7.8% in double blind period; 38.1% in open-label extension
period).
The most common adverse events reported in the observational study
KIMS were arthralgia, influenza-like symptoms, upper respiratory
tract infection and headache.
The submission did not present an extended assessment of adverse
events in other patients groups, such as children, treated with
somatropin.
9. Clinical Claim
The submission described somatropin as superior in terms of
comparative effectiveness (improvement in QoL and body composition)
and inferior in terms of comparative safety over placebo.
The PBAC considered the clinical benefit of somatropin was
uncertain. The PBAC accepted the submission’s claim that
somatropin is inferior in terms of short-term safety to placebo.
The PBAC considered that the long-term safety of somatropin is
uncertain.
10. Economic Analysis
The submission presented a stepped economic evaluation based on
data from a subgroup analysis of the KIMS observational study in
AGHD patients.
The economic model was a semi-Markov cohort model with three health
states: 1) on treatment, 2) discontinue treatment, and 3) death. In
the somatropin arm of the model patients started in the
on-treatment health state and could remain in this health state,
discontinue treatment or die. For the patients who discontinue
treatment, the QoL-AGHDA scores returned immediately to baseline
values. Once a somatropin patient discontinued treatment, there was
no possibility to restart treatment. This assumption may not have
been valid, as the requested listing included a reference that
patients can restart somatropin treatment for AGHD. For placebo
treatment, patients started in the discontinue treatment state and
could stay in this state or transition to the death state. The
cycle length in the model was one month, and a half cycle
correction was included. The duration of the model was five years.
This may not be not appropriate as AGHD is a life-long disease and
the submission did not propose any discontinuation criteria, so it
was assumed that treatment would be chronic. The model did not
assume any waning of efficacy for somatropin over time.
The submission estimated that the ICER for somatropin was in the
range of $45,000 - $75,000/QALY. The PBAC considered that the ICER
for somatropin compared to placebo treatment was likely to be
higher than the specific figure arrived at in the submission
because the submission may have:
- underestimated the incremental cost:
- the daily dose of somatropin may have been underestimated;
- costs for the treatment of adverse events have been excluded; and
- costs of increased monitoring (thyroid function and glucose tolerance) were excluded;
- overestimated the QALY gain for somatropin:
- the QoL-AGHDA results were derived from an observational database (KIMS) which
- included very few untreated patients to act as a control arm;
- may have had selection bias of included patients;
- may have had reporting bias, as follow-up beyond baseline was limited, due to underreporting and/or discontinuation due to lack of efficacy (e.g. at 1 year only 48% of patients had an QoL-AGHDA assessment decreasing to 4% of patients at year 5;
- the model assumed that 75% of the efficacy of that estimated at one year is already achieved after only two weeks of treatment; and
- the transformation equation from QoL-AGHDA to utility value, including age and sex as variables, had a R2=0.36, indicating uncertainty surrounding the transformation step, and was based on mapping from a general population survey.
Varying the QoL-AGHDA initiation criteria changed the ICER, with
higher inclusion criteria resulting in lower ICERs. The submission
did not present an analysis including all patients with severe AGHD
(i.e. without the requirement for impaired QoL). This may not be
appropriate as somatropin improved body composition at six months
in clinical trials which may result in leakage to patients with
normal QoL.
As there was uncertainty surrounding the efficacy of somatropin in
improving QoL, a sensitivity analysis was performed during the
evaluation, reducing the efficacy by 50% at each time point. This
may have reflected the bias in the observational database, with
underreporting of QoL-AGHDA for patients who do not achieve a
reduction.
The results of the sensitivity analyses indicated that the model
was most sensitive to treatment efficacy and the somatropin dose.
The model was to a lesser extent sensitive to the uncertainty
surrounding the transformation of QoL-AGHDA to utilities.
For PBAC’s views, see Recommendations and
Reasons.
11. Estimated PBS Usage and Financial Implications
The submission estimated the total net cost to the PBS to be less
than $10 million year 5.
12. Recommendation and Reasons
The PBAC considered the comparator of standard care, consisting of
regular monitoring by an endocrinologist, medical management of
signs and symptoms, and management of risk factors arising from
adult growth hormone deficiency (AGHD), appropriate.
The submission presented 39 randomised controlled trials comparing
somatropin with placebo in patients with AGHD with a normal quality
of life (QoL). The PBAC noted that an impaired QoL at baseline was
not an entry criterion for the trials, which limited the
applicability of these trials to the requested listing for patients
with impaired QOL as measured by the QoL-AGDHA instrument. The PBAC
additionally noted that the trials presented in the submission used
various QoL instruments and that only two of the trials used the
instrument of QoL-AGHDA used in the proposed restriction.
The PBAC noted the meta-analysis presented in the submission of
trials reporting the Nottingham Health Profile (NHP) score did not
result in a statistically significant improvement in the total NHP
score nor any of the sub scores (unweighted and weighted) for
somatropin. The PBAC also noted the meta-analysis of trials using
Psychological General Well-Being Index (PGWB) reported a
statistically significant increase in the total score and the
components of positive well-being and vitality compared to placebo
treatment. However the clinical significance of an improvement of
one to four points on the 110 point PGWB scale was unclear.
Additionally the PBAC noted that two trials (Hoffman 2004 and
Underwood 2003), which were excluded from the PGWB meta-analysis,
reported that treatment with somatropin resulted in no significant
change in QoL using a number of assessment tools including the
PGWB, and that inclusion of these trials in the PGWB meta-analysis
may have resulted in the difference in PGWB scores no longer
reaching statistical significance. Importantly, the PBAC also noted
that the two trials that assessed QoL using the QoL-AGHDA reported
no significant effect of treatment with somatropin.
The PBAC noted the heterogeneity and small size of the trials. The
PBAC further noted that the trials had limited follow up, and hence
that long term effects of treatment with somatropin were
uncertain.
The PBAC accepted the submission’s claim that somatropin is
inferior in terms of short-term safety to placebo. The PBAC
considered that the long-term safety of somatropin is
uncertain.
The PBAC noted that the clinical trial evidence presented in the
submission was not translated to form the basis of the economic
evaluation as the submission considered the patient populations in
the trials were not applicable to the requested PBS patient
population as: the entry criteria did not include patients impaired
QoL at baseline; the trials generally used generic QoL instruments
(not AGHD specific); and the trials typically had small patient
populations. The submission analysed a subgroup of patients with
impaired baseline QoL from the Pfizer International Metabolic
Database (KIMS) for the economic evaluation. The PBAC noted that
the KIMS database is an observational database which contains few
untreated patients and hence considered that the KIMS data were
non-comparative and likely to be highly selective of patients
successfully treated with somatropin.
The PBAC considered there were significant uncertainties and
potential sources of selection bias associated with the subgroup of
patients from the KIMS database used in the economic evaluation.
The PBAC noted that the subset of patients with a QoL-AGHDA of 15
or greater at baseline was chosen to match the requested PBS
population, but it was unclear what the clinical reasons for the
selection of this baseline score were. The PBAC also noted that
patients who did not have follow-up at each time point were
excluded from the analysis, with 390 patients with a QoL-AGHDA of
15 or greater at baseline reducing to 17 patients at year 5. The
PBAC considered that the exclusion of patients without follow-up
was a source of bias in favour of somatropin in that patients who
continued treatment were the most likely to be responding to
treatment as those with lack of efficacy or adverse effects were
more likely to discontinue treatment. Further, patients who did not
complete QoL questionnaires were likely to have poorer QOL than
those who did.
The submission transformed QoL-AGHDA total scores from the KIMS
sample of patients to EQ-5D index scores based on a published
transformation algorithm (Koltowska-Haggstrom 2007), which was
based on mapping of QoL-AGHDA to EQ-5D of a large general
population sample and assumed 100 % correlation between these
instruments. The PBAC considered this increased the uncertainty,
noting that this approach may not capture important aspects of QoL
associated with the requested PBS patient population, particularly
as the requested PBS population were patients with a reasonably low
quality of life on the QoL-AGHDA at baseline, and there were very
few patients in the Koltowska-Haggstrom sample with QoL in this
range.
The PBAC hence considered that the ICERs generated from the
economic evaluation were highly uncertain.
The PBAC hence rejected the submission on the basis of uncertain
clinical benefit and highly uncertain cost effectiveness.
The PBAC acknowledged and noted the consumer comments received in
its consideration of somatropin.
The PBAC recommended amending the wording of the listing of
somatropin to correctly reflect the current version of the
Guidelines for the PBS Growth Hormone Program, noting that there
are no longer separate guidelines for the availability of growth
hormone for the treatment of Prader-Willi Syndrome.
The PBAC further recommended amending the wording of the listing of
somatropin to remove the description of Genotropin branded
products.
Recommendation:
Reject
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 is disappointed with the PBAC’s decision as there is a
significant unmet clinical need for patients with severe adult
growth hormone deficiency.
