Strontium Ranelate, sachet containing granules for oral suspension, 2 g, Protos November 2006
Public Summary Document for Strontium Ranelate, sachet containing granules for oral suspension, 2 g, Protos, November 2006
Page last updated: 16 March 2007
Public Summary Document
Product: Strontium Ranelate, sachet containing granules for oral suspension, 2 g,
Protos
Sponsor: Servier Laboratories (Australia) Pty Ltd
Date of PBAC Consideration: November 2006
1. Purpose of Application
The submission sought a new Authority Required PBS listing for initial and continuing treatment for the primary prevention of fractures due to osteoporosis in postmenopausal women.
2. Background
The PBAC had not previously considered a submission for strontium for the primary
prevention of osteoporosis.
At the July 2005 meeting, the PBAC recommended an Authority Required listing for strontium
for initial and continuing treatment for established postmenopausal osteoporosis in
patients with fracture due to minimal trauma on a cost-minimisation basis compared
to alendronate for the outcome of morphometric vertebral fracture. The equi-effective
doses were strontium 2 g daily and alendronate 70 mg weekly.
To date, the company had not accepted the prices offered and listing had not eventuated.
3. Registration Status
4. Listing Requested and PBAC’s View
Authority required
Initial treatment for the primary prevention of fractures due to osteoporosis in postmenopausal
patients of age 75 or greater with Bone Mineral Density (BMD) T-score of
-3.0 or less.
Continuing treatment for osteoporosis where the patient has previously been issued
with an authority prescription for this drug.
The PBAC noted that in its Pre-Sub-Committee Response the sponsor had redefined its
requested listing to second-line, to restrict use to women 70 years of age or older
with a BMD T-score -3.0 or less, who have a contraindication or intolerance to alendronate
70 mg.
5. Clinical Place for the Proposed Therapy
30% to 50% of women and 15-30% of men will suffer a fracture related to osteoporosis
in their lifetime. Fractures increase morbidity and mortality and impose a financial
burden on the community. The overall mortality is about 20% in the first 12 months
after hip fracture.
Strontium ranelate has a dual effect on bone metabolism, both increasing bone formation
and decreasing bone resorption. It may be used in the primary prevention of fractures
due to osteoporosis as well as in patients who have established osteoporosis that
is defined as a fracture due to minimal trauma.
6. Comparator
The submission originally nominated placebo as the comparator. The PBAC noted that the proposal for the amended restriction wording supported placebo as the appropriate comparator. However, the PBAC considered that there was a considerable risk of usage outside the intended population. In view of this concern, a comparison with alendronate was important because it provided an informative frame of reference.
7. Clinical Trials
The submission presented the Treatment of Peripheral Osteoporosis (TROPOS) trial,
a multicentre, multinational, randomised, double-blind, placebo-controlled study as
the pivotal trial, which was designed to assess the efficacy of a 2 g daily dose of
strontium in reducing the incidence of osteoporosis-related peripheral fracture as
compared to placebo in osteoporotic postmenopausal women at risk (femoral neck BMD
≤ 0.600 g/cm2 i.e. T-score < -2.5). The sample size for this study was 4932 women
in the intention-to-treat (ITT) population with a mean follow-up of 2.5 years.
This trial had been published at the time of submission, as follows:
|
Trial/First author |
Protocol title |
Publication citation |
|---|---|---|
|
TROPOS |
Strontium ranelate reduces the risk of nonvertebral fractures in postmenopausal women with osteoporosis: Treatment of Peripheral Osteoporosis (TROPOS) study. |
Journal of Clinical Endocrinology and Metabolism 2005; 90 (5):2816-22. |
Two post hoc sub-group analyses were undertaken.
Primary prevention subgroup
This subgroup was defined as patients having no prevalent osteoporosis-related peripheral
or prevalent vertebral fracture at inclusion in the Fracture International Run-in
for Strontium Trials (FIRST) study, which was a calcium and vitamin D normalisation
protocol, being a run-in study to TROPOS. This group was considered the main subgroup
of interest for the submission as it represented the target population: the “primary
prevention” of fractures due to osteoporosis in postmenopausal women. There were two
subsets in this subgroup:
a) peripheral fractures - patients having at least one post-baseline measurement for
occurrence of peripheral fractures (2,687 women, comprising 54% of ITT population)
b) vertebral fractures - patients with one assessable vertebral x-ray at baseline
and at least one assessable post-baseline vertebral x-ray between Month 0 and Month
36 (1,960 women, comprising 40% of ITT).
High risk subgroup
This subgroup was defined according to the age range (≥ 74 years) with low femoral
neck BMD (T-score ≤ -3.0) at inclusion. This subgroup represented 40% of the intention-to-treat
(ITT) analysis. At inclusion, approximately one third of patients had at least one
prevalent vertebral fracture and about 40% had a peripheral fracture. The efficacy
from this subgroup was supportive.
8. Results of Trials
The results from the TROPOS trial showed that the incidence over time of patients
with at least one osteoporosis-related peripheral fracture was not statistically significant
different to the incidence of peripheral fractures between strontium and placebo.
In the post hoc high risk subgroup there was a statistically significant difference
in peripheral fractures, favouring strontium in the key trial’s primary analysis.
In the overall trial analysis there was a statistically significant difference in
osteoporosis-related peripheral fractures, favouring strontium in the key trial’s
primary analysis, but there was no statistically significant difference in proximal
femur fractures between strontium and placebo. In the overall trial analysis there
was a statistically significant difference in any peripheral or clinical vertebral
fracture, favouring strontium.
In the post hoc primary prevention subgroup and the high risk subgroup there was a
statistically significant difference in osteoporosis-related peripheral fractures,
favouring strontium. In the post hoc primary prevention subgroup there was no statistically
significant difference in hip/proximal femur fractures between strontium and placebo.
In the post hoc high risk subgroup there was a statistically significant difference
in hip fractures between treatments.
As was seen with the overall trial population, there were more adverse events associated
with the gastrointestinal and nervous systems in the strontium group compared with
the placebo group for the high risk population.
For PBAC’s comments on these results, see Recommendation and Reasons.
9. Clinical Claim
10. Economic Analysis
The submission presented a preliminary economic evaluation using a cost-effectiveness
approach. The PBAC accepted this as valid. The resources included were drug costs
and costs for fractures (hospital, nursing home, rehabilitation, GP visits).
The submission estimated that the trial-based incremental cost per extra fracture
avoided would be in the range of $15,000 - $45,000. During the evaluation, the incremental
cost per hip fracture avoided was calculated to be in the range $45,000 – $75,000.
The submission presented a modelled economic evaluation using a cost-utility approach.
The PBAC accepted this as valid. The population in the model were women aged 75-110
with no prior fractures and a BMD T-score of ≤-3.0 at age 75. The resources included
were drug costs and costs for fractures (hospital, nursing home, rehabilitation, GP
visits).
The submission estimated that the base case modelled incremental discounted cost per
extra quality adjusted life year (QALY) would be in the range $15,000 - $45,000.
11. Estimated PBS Usage and Financial Implications
The submission estimated that in Year 4 of listing the number of eligible patients would be > 200,000 and the financial cost to the PBS (excluding co-payments) would be in the range $10 – $30 million.
12. Recommendation and Reasons
The PBAC noted that in its Pre-Sub-Committee Response the sponsor had redefined its
requested listing to second-line, to restrict use to women 70 years of age or older
with a BMD T-score -3.0 or less, who have a contraindication or intolerance to alendronate
70 mg. Such a proposal supported placebo as the appropriate comparator. However, the
PBAC considered there was a considerable risk of the risk of usage outside the intended
population. In view of this concern, a comparison with alendronate was important because
it provided an informative frame of reference.
There was no statistically significant difference in the incidence of peripheral fractures
in the ITT population between strontium and placebo. Although there was a statistically
significant difference in the post hoc high risk sub-group in the incidence of peripheral
fractures, the PBAC was concerned that it may not be of clinical significance. In
the type of fracture that the PBAC considered to be of most clinical importance, hip
fracture, the statistically significant difference in the high risk subgroup result
for hip fracture between strontium and placebo was considered marginal. The PBAC noted
that there was no statistical difference between strontium and placebo for hip fracture
in the ITT population. The PBAC thus considered that the evidentiary basis establishing
strontium ranelate as superior to placebo in the requested high risk sub-group was
weak.
The PBAC also noted the evidentiary basis presented in the Pre-Sub-Committee Response
and during the hearing for establishing the equivalence of strontium and alendronate
was incomplete and weak. Gastro-intestinal adverse effects, particularly diarrhoea
are common in patients taking strontium ranelate. However, comparative toxicity of
alendronate and strontium was not presented and thus it is unclear how many alendronate
intolerant patients will tolerate strontium. Based on the comparison presented, the
PBAC concluded there was no basis for a price advantage for strontium over alendronate.
The PBAC considered that there were a number of uncertainties that arose from the
economic model. Because the model made some assumptions leading to an overestimate
of the ICER, and other assumptions leading to an underestimate, it was very uncertain
what the net effect of these biases would be.
Therefore, the PBAC rejected the submission because of uncertain clinical benefit
and uncertain and unacceptable cost effectiveness.
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
Servier will continue to work with the PBAC to identify options to achieve PBS-listing for strontium.
