Zoledronic acid, solution for I.V infusion, 5 mg in 100 mL, Aclasta®, November 2008
Public summary document for Zoledronic acid, solution for I.V infusion, 5 mg in 100 mL, Aclasta® , November 2008
Page last updated: 12 March 2009
Public Summary Document
Product: Zoledronic acid, solution for I.V
infusion, 5 mg in 100 mL, Aclasta®
Sponsor: Novartis Pharmaceuticals Australia Pty
Ltd
Date of PBAC Consideration: November 2008
1. Purpose of Application
The submission requested an Authority required (streamlined) PBS
listing for zoledronic acid for both the primary prevention of
fractures in high risk women (aged over 70 years with a BMD T-score
< -3.0), and the secondary prevention of fractures in
post-menopausal women.
2. Background
At the July 2008 meeting the PBAC recommended an Authority required
listing of zolendronic acid on the PBS for the treatment of
established osteoporosis in patients with a hip fracture due to
minimal trauma and in post-menopausal women with other minimal
trauma fractures on a cost-minimisation basis with alendronate. The
PBAC reaffirmed its view, according to its Guidelines, that
alendronate was the appropriate main comparator as it is the
treatment most likely to be replaced in clinical practice. The
Committee did not accept the results of the cost-effectiveness
analysis presented in the submission because the time-trade-off
study commissioned by the sponsor to explore the utilities
associated with zoledronic acid and alendronate had a number of
biases that favoured zoledronic acid (See also Public Summary
Document of July 2008).
3. Registration Status
Zoledronic acid 5 mg in 100 mL was TGA registered on 23 June 2008 for the following indications:
- Treatment of osteoporosis in patients aged over 50 years of age with a history of at least one low trauma hip fracture, to reduce the incidence of further fractures. Treatment should be restricted to 3 annual doses.
- Treatment of osteoporosis in post-menopausal women, to reduce the incidence of hip, vertebral and non-vertebral fractures. Treatment should be restricted to 3 annual doses.
4. Listing Requested and PBAC’s View
Authority required (STREAMLINED)
Treatment as the sole PBS-subsidised anti-resorptive agent for
osteoporosis in women aged 70 years of age or older with a Bone
Mineral Density (BMD) T-score of -3.0 or less.
The date, site (femoral neck or lumbar spine) and score of the
qualifying BMD measurement must be documented in the patient's
medical records when treatment is initiated.
Authority required (STREAMLINED)
Treatment as the sole PBS-subsidised anti-resorptive agent for
established
post-menopausal osteoporosis in women with fracture due to minimal
trauma. The fracture must have been demonstrated radiologically and
the year of plain x-ray or CT-scan or MRI scan must be documented
in the patient’s medical records when treatment is
initiated.
A vertebral fracture is defined as a 20% or greater reduction in
height of the anterior or mid portion of a vertebral body relative
to the posterior height of that body, or, a 20% or greater
reduction in any of these heights compared to the vertebral body
above or below the affected vertebral body.
For PBAC’s view see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
Zoledronic acid 5 mg would provide an alternative anti-resorptive
treatment option with once yearly dosing and an intravenous route
of administration for the treatment of women with post-menopausal
osteoporosis.
6. Comparator
The submission nominated alendronate sodium as the main comparator
and risedronate sodium as an alternative main comparator. The PBAC
considered that this was appropriate as alendronate was the
treatment most likely to be replaced in clinical practice.
7. Clinical Trials
No changes were made to the trial data for secondary prevention of
postmenopausal osteoporosis (PMO) presented in the July 2008
submission. The basis of the requested indication for primary
prevention was an indirect analysis of one randomised trial of
zoledronic acid (Trial 2301), one randomised trial of alendronate
(FIT-CFA), one randomised trial of risedronate (HIP), one
meta-analysis of risedronate (Heaney et al, 2002) and a PBAC Public
Summary Document from March 2007 for risedronate (R-PSD
2007).
The trials published at the time of the submission are presented in
the table below.
| Trial ID | Protocol title/ Publication title | Publication citation |
| Zoledronic acid vs. placebo | ||
| 2301 (Clinical trial report Study ZOL446H2301) | A multicenter, double-blind, randomized, placebo-controlled study to evaluate the safety and efficacy of zoledronic acid in the treatment of osteoporosis in postmenopausal women taking calcium and vitamin D. | |
| Black DM et al | Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. | N Eng J Med. 2007; 356 (18): 1809-1822 |
| Alendronate trials vs. placebo | ||
| FIT-CFA Cummings SR et al, | Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures. (Clinical fracture arm of FIT trial) | JAMA.1998 Dec 23-30;280(24):2077-82 |
| Risedronate vs. placebo | ||
| HIP McClung MR, Geusens P, Miller PD et al | Hip Intervention Program Study Group. 2001 Effect of risedronate on the risk of hip fracture in elderly women. | N Engl J Med.2001 Feb 1;344(5):333-40 |
| Meta-analysis risedronate | ||
| Heaney et al Meta-analysis | Risedronate reduces the risk of first vertebral fracture in osteoporotic women. Meta-analysis of: VERT-NA (primary prevention data not published separately) HIP (McClung 2001) BMD-MN (Fogelman 2000) BMD-NA (McClung 1997) | Heaney, 2002 Osteoporosis International 2002; 13(6):501-505 |
| Other (risedronate) | ||
| R-PSD | PBAC 2007 Risedronate sodium Public Summary Document, July 2007 | |
PMO = postmenopausal
8. Results of Trials
The data for secondary prevention were the same as that presented
in July 2008. In the primary prevention subpopulation of Trial
2301, zoledronic acid treatment compared with placebo showed a
statistically significant difference only for the outcome of
morphometric vertebral fractures. The indirect analyses between
zoledronic acid and alendronate did not show any statistically
significant differences, though this may reflect a lack of power
and differences between the trial populations.
The PBAC considered that there was an absence of clinical trial
evidence to suggest a clinical advantage of zoledronic acid
relative to alendronate, and that it was uncertain whether
zoledronic acid was non-inferior with alendronate in terms of
comparative effectiveness and toxicity in a primary prevention
post-menopausal osteoporosis population. The PBAC noted that in the
subanalysis of Trial 2301, zoledronic acid treatment compared with
placebo showed a statistically significant difference only for the
outcome of morphometric vertebral fractures. The indirect analyses
between zoledronic acid and alendronate did not show any
statistically significant differences, but this may reflect a lack
of power and differences between the trial populations. However, a
statistically significant treatment effect was observed with
alendronate for morphometric vertebral, non-vertebral and hip
fractures.
No new toxicity data were presented in the submission. The most
common adverse events were the acute phase reaction lasting up to 3
days with zoledronic acid, compared with gastrointestinal problems
with alendronate. No data were reported for adverse events
involving the injection site. As there is less than 12 months
experience internationally with zoledronic acid in a postmenopausal
population there is little relevant data concerning extended
assessment of comparative harms.
The PBAC noted that there was a lack of long-term safety data and
risk for serious unwanted events for zoledronic acid and considered
that the balance of benefits to harms of an intravenous compared to
an oral bisphosphonate preparation for primary prevention is not as
favourable in primary prevention due to injection site reactions
and acute phase reactions.
9. Clinical Claim
In July 2008 the PBAC recommended zoledronic acid on a
cost-minimisation basis in comparison with alendronate for the
secondary prevention indication. The current submission did not
present any new clinical data for this indication. In terms of
primary prevention, the submission described zoledronic acid as
equivalent in terms of comparative effectiveness in a primary
prevention population and equivalent in terms of comparative safety
over alendronate.
10. Economic Analysis
The submission presented a modelled economic evaluation based on an
indirect comparison of randomised trials for the comparison of
zoledronic acid and alendronate in primary prevention. The type of
economic evaluation presented was a cost-utility analysis. The
submission also presented a cost-minimisation analysis of
zoledronic acid versus risedronate in primary prevention.
In general, the model had the same basic structure as that
presented in July 2008, with differing placebo event rates and with
the relative risk of fracture with zoledronic acid and alendronate
equal.
The incremental cost per QALY gained was < $15,000. There was
considerable uncertainly concerning the results of the economic
evaluation, with concerns regarding the structure of the model (not
Markov), the assumption of no differences between utilities of
different fracture states, and the utilities assigned to zoledronic
acid and alendronate treatment.
The model for primary prevention (as with secondary prevention) was
most sensitive to the utilities assigned to zoledronic acid and
alendronate treatment.
For PBAC’s view see Recommendation and Reasons
11. Estimated PBS Usage and Financial Implications
The likely number of patients/year were estimated in the submission
to be between 10,000 and 50,000 in Year 5 for each of primary and
secondary prevention, while the financial cost/year to the PBS for
substitution of alendronate and risedronate for primary prevention
and for secondary prevention were each estimated to be < $10
million in Year 5.
12. Recommendation and Reasons
The PBAC recommended extending the listing of zoledronic acid to
include the treatment of osteoporosis in women aged 70 years of age
or older with a Bone Mineral Density (BMD)
T-score of -3.0 or less on a cost-minimisation basis compared with
alendronate and recommended the equi-effective doses are
alendronate 70 mg weekly for 52 weeks versus zoledronic acid 5 mg
once per year, less the cost of infusing zoledronic acid.
The PBAC noted that the sponsor had recently accepted the listing
for zoledronic acid recommended at the July 2008 PBAC meeting on a
cost-minimisation basis compared with alendronate for the treatment
of established osteoporosis in women with facture due to minimal
trauma and in men with hip fracture due to minimal trauma.
The submission nominated alendronate as the comparator and
risedronate as a secondary comparator and the PBAC considered that
this was appropriate as alendronate was the treatment most likely
to be replaced in clinical practice.
The PBAC considered that there was an absence of clinical trial
evidence to suggest a clinical advantage of zoledronic acid
relative to alendronate, and that it was uncertain whether
zoledronic acid was non-inferior with alendronate in terms of
comparative effectiveness and toxicity in a primary prevention
post-menopausal osteoporosis population. The PBAC noted that in the
subanalysis of Trial 2301, zoledronic acid treatment compared with
placebo showed a statistically significant difference only for the
outcome of morphometric vertebral fractures. The indirect analyses
between zoledronic acid and alendronate did not show any
statistically significant differences, but this may reflect a lack
of power and differences between the trial populations. However, a
statistically significant treatment effect was observed with
alendronate for morphometric vertebral, non-vertebral and hip
fractures.
The PBAC also noted that there was a lack of long-term safety data
and risk for serious unwanted events for zoledronic acid and
considered that the balance of benefits to harms of an intravenous
compared to an oral bisphosphonate preparation for primary
prevention was not as favourable in primary prevention due to
injection site reactions and acute phase reactions.
The PBAC noted that in terms of primary prevention, neither the
guidelines cited in the submission nor any other guidelines
accessed during the evaluation recommended zoledronic acid as a
first-line therapy in primary prevention.
The PBAC agreed that the appropriate approach to modelling
osteoporosis was to use a Markov model, noting that all recently
published economic analyses, including those considered by NICE,
were Markov models. However, the model presented in the submission
was a non-Markov model and included the same time-trade-off (TTO)
study used in the previous submission which was commissioned by the
sponsor to explore the utility Australian patients assign to
treatment with either annual IV or weekly oral bisphosphonate with
different adverse event profiles. The PBAC had previously
considered that this study had a number of biases that favoured
zoledronic acid, and that the low baseline utilities for no
treatment were themselves implausible. The PBAC noted that the
utilities derived from the TTO study was the major driver in the
derivation of cost per QALY and considered that there was
considerable uncertainty about these utilities and that the use of
a non-Markov model also led to economic uncertainty. Therefore, the
PBAC could not recommend an extension to the listing of zoledronic
acid in the primary prevention of osteoporosis on a
cost-effectiveness basis due to uncertainty in the economic
model.
The PBAC, however, recommended that the listing for zoledronic acid
be extended to include the primary prevention of osteoporosis on a
cost-minimisation basis compared with alendronate.
The PBAC noted that there was a potential Quality Use of Medicines
issue regarding the administration of zoledronic acid in hospital
and the subsequent use of oral bisphosphonates on discharge as it
may not be known to the patient or local doctor that the yearly
dose of zoledronic acid has been administered. The PBAC requested
that NPS raise awareness of this issue to prescribers. The PBAC
also requested that the DUSC monitor the first 12 months of
usage.
Recommendation
ZOLEDRONIC ACID, solution for infusion, 5 mg in 100 mL,
Aclasta®, Novartis Pharmaceuticals.
Restriction:
Authority required
Treatment as the sole PBS-subsidised anti-resorptive agent for
osteoporosis in women aged 70 years of age or older with a Bone
Mineral Density (BMD) T-score of -3.0 or less.
The date, site (femoral neck or lumbar spine) and score of the
qualifying BMD measurement must be documented in the patient's
medical records when treatment is initiated.
Treatment as the sole PBS-subsidised anti-resorptive agent for
established osteoporosis in women with fracture due to minimal
trauma. A vertebral fracture is defined as a 20% or greater
reduction in height of the anterior or mid portion of a vertebral
body relative to the posterior height of that body, or, a 20% or
greater reduction in any of these heights compared to the vertebral
body above or below the affected vertebral body. Treatment as the
sole PBS-subsidised anti-resorptive agent for established
osteoporosis in men with hip fracture due to minimal trauma.
In all cases, the fracture must have been demonstrated
radiologically and the year of plain x-ray or CT-scan or MRI scan
must be documented in the patient's medical records when treatment
is initiated.Only one treatment each year for three years per
patient in a lifetime will be PBS-subsidised.NOTE:
Anti-resorptive agents in established osteoporosis include
alendronate sodium, risedronate sodium, disodium etidronate,
raloxifene hydrochloride, strontium ranelate and zoledronic
acid.
Maximum quantity: 1
Number of repeats: 0
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
The sponsor chose not to comment
