Alendronate Sodium, tablet equivalent to 70 mg alendronic acid, Fosamax Once Weekly, Alendronate Sodium with Colecalciferol, tablet equivalent to 70 mg alendronic acid with 70 micrograms colecalciferol, Fosamax Plus, March 2008
Public summary document for Alendronate Sodium, tablet equivalent to 70 mg alendronic acid, Fosamax Once Weekly, Alendronate Sodium with Colecalciferol, tablet equivalent to 70 mg alendronic acid with 70 micrograms colecalciferol, Fosamax Plus,March 2008
Page last updated: 18 July 2008
Public Summary Documents
Product: Alendronate Sodium, tablet equivalent to 70 mg alendronic acid, Fosamax Once
Weekly, Alendronate Sodium with Colecalciferol, tablet equivalent to 70 mg alendronic
acid with 70 micrograms colecalciferol, Fosamax Plus.
Sponsor: Merck Sharp & Dohme (Australia) Pty Limited.
Date of PBAC Consideration: March 2008.
1. Purpose of Application
To seek a change to the listing of these items from patients aged 70 years of age or older with a bone mineral density (BMD) T-score of -3.0 or less to patients aged 70 years of age or older with a BMD T-score of -2.5 or less.
2. Background
At its meeting in July 2006 the PBAC made a recommendation to list alendronate as
the sole PBS-subsidised anti-resorptive agent for the treatment of osteoporosis in
patients aged 70 years of age or older and with a BMD T-score of -3.0 or less on a
cost effectiveness basis over placebo.
The current submission seeks to determine the cost-effectiveness of alendronate at
the new prices in a population of patients aged 70 years of age or older and with
a BMD T-score of -2.5 or less. The submission argues that due to the 12.5% price reduction
(effective September 2007) and the mandated decrease by 2% each year for the next
three years, the cost-effectiveness of alendronate has improved and thus use in a
broader patient population is now warranted.
3. Registration Status
Fosamax Plus Once Weekly was registered by the TGA on 8 March 2006 and is indicated
for the treatment of osteoporosis in select patients where vitamin D supplementation
is recommended.
Fosamax Once Weekly was registered by the TGA on 9 February 2001 and is indicated
for the treatment of osteoporosis. Osteoporosis must be confirmed by the finding of
low bone mass of at least two standard deviations below the gender specific mean for
young adults, or by the presence of osteoporotic fracture.
4. Listing Requested and PBAC’s View
Authority Required (STREAMLINED)
Treatment as the sole PBS-subsidised anti-resorptive agent for osteoporosis in a patient
aged 70 years of age or older with a Bone Mineral Density (BMD) T-score of -2.5 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.
The PBAC considered the wording of the requested restriction appropriate.
5. Clinical Place for the Proposed Therapy
If alendronate PBS-eligibility were expanded to include patients with a BMD T-score of -2.5 or less it would extend treatment for the prevention of fracture to osteoporotic patients whose absolute risk of fracture is less than for those covered under the current listing.
6. Comparator
The submission nominates watchful waiting (patient monitoring and standard management with calcium and vitamin D, i.e. placebo) as the primary comparator. This was considered appropriate by the PBAC.
7. Clinical Trials
The submission made no changes to the trial data presented in the previous submission
of July 2006, i.e. Fraction Intervention Trial (FIT) data. New supplementary data
were presented from the FIT Long-Term Extension trial (FLEX) in women who had completed
three years of alendronate treatment in the treatment groups of the FIT trial, both
with and without vertebral fracture at FIT baseline (i.e. both vertebral fracture
arm (VFA) and clinical fracture arm(CFA)). The FLEX trial was a randomised controlled
trial, which investigated the effect of continuation of alendronate on fracture rates
for a further five years post-FIT trial.
These trials have been published as detailed below.
|
Trial/First author |
Publication title |
Publication citation |
|---|---|---|
|
Cummings et al. (FIT) |
Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures. |
JAMA 1998; 280:2077-82. |
|
Black DM et al. |
Effects of continuing or stopping alendronate after 5 years of treatment, the Fracture Intervention Trial Long-Term Extension (FLEX: a randomized trial. |
JAMA 2006; 296: 2927–2938. |
8. Results of Trials
The key results are summarised in the table below.
Proportion of patients in the FIT CFA T -2.5 subgroup who experienced fractures during
the 4.2 years of follow-up
|
Fracture type |
Alendronate |
Placebo |
RR (95% CI) |
RD (95% CI) |
NNT |
|---|---|---|---|---|---|
|
Primary outcome |
|||||
|
Any clinical |
107 ( 13.1%) |
159 (19.6%) |
0.67 (0.53, 0.83) |
-6.5% (-10.1, -2.9) |
15 |
|
Secondary outcomes |
|||||
|
Clinical vertebral |
1 2 ( 1.5%) |
14 ( 1.7%) |
0.85 (0.40, 1.79) |
-0.3% ( -1.6, 1.0) |
386 |
|
Hip |
8 ( 1.0%) |
18 ( 2.2%) |
0.44 (0.20, 0.98) |
-1.2% ( -2.6, 0.0) |
81 |
|
Wrist |
34 ( 4.2%) |
38 ( 4.7%) |
0.89 (0.57, 1.39) |
-0.5% ( -2.6, 1.5) |
189 |
|
Non-hip, -spine, or -wrist |
71 ( 8.7%) |
111 (13.7%) |
0.63 (0.48, 0.84) |
-5.0% ( -8.1, -2.0) |
20 |
|
Non-vertebral (combined) |
101 |
150 (18.5%) |
0.67 (0.53, 0.84) |
-6.1% ( -9.7, -2.7) |
16 |
|
N=757 |
N=763 |
||||
|
Morphometric Vertebral |
22 ( 2.9%) |
44 ( 5.8%) |
0.50 (0.31, 0.83) |
-2.9% ( -5.0, -0.8) |
35 |
|
Multiple vertebral |
2 ( 0.3%) |
6 ( 0.8%) |
0.34 (0.08, 1.45) |
-0.5% ( -1.2, 0.2) |
192 |
Abbreviations: N= number of patients with an incident fracture, CI = confidence interval,
NNT = number-needed-to-treat, RR = relative risk, RD = risk difference.
The PBAC noted these are the same data presented in the previous submission. All clinical
fractures combined, i.e. all fractures causing symptoms, showed a statistically significant
rate reduction, as did morphometric (non-symptomatic) vertebral fracture, and non-hip,
non-spine, non-wrist fracture. Of the three major clinical fracture types (hip, vertebral,
and wrist), hip fractures are the only type that show a significant fracture rate
reduction with alendronate treatment (though the upper limit of the 95% CI is 0.98).
In the FLEX extension trial a post hoc analysis of women with BMD T scores -2.5 (who
had completed at least three years of alendronate treatment in FIT) did not show any
statistically significant differences in fracture rates between women who continued
alendronate treatment for a further five years compared with women who ceased treatment.
The trial data did not show a marked increase in adverse effects.
The PBAC noted that an extended assessment of harms shows that gastrointestinal problems
remain an issue of concern.
The assessment noted recent reports (2006-2007) which suggest that the suppression
of bone turnover by alendronate and other bisphosphonates may lead to increased risk
of fracture, particularly of the subtrochanteric region of the femur, which has not
been considered in previous submissions.
With respect to osteonecrosis of the jaw (ONJ), the assessment advised of a recent
Australian study that identified cases of ONJ by a postal survey of Australian oral
and maxillofacial surgeons and other dental specialists and Adverse Drug Reactions
Advisory Committee (ADRAC) data, correlated with prescription and dental extraction
data (Mavrokokki et al, 2007). The findings were:
- the frequency of ONJ in osteoporotic patients treated with bisphosphonates was 1
in 8,470 (0.01%)
- the overall frequency of extraction-related ONJ associated with alendronate is 1
in 1,130 (0.09%)
- the mean total dose of oral alendronate at the onset of ONJ was 9,060 ( 7,269) mg,
which corresponds to an average time to onset from initiation of therapy (with 100%
compliance) of 2.5 years
- osteoporosis patients accounted for nearly one third of patients with ONJ associated
with a bisphosphonate (36/114, 31.6%)
The sponsor considered these events, although serious, to be extremely rare, and would
have negligible impact on the risk/benefit ratio when viewed in the context of the
number of fractures which will occur in an untreated population.
9. Clinical Claim
The submission claimed that alendronate is associated with superior efficacy and similar
toxicity compared with placebo.
Based on the information available to the PBAC at the meeting it was unable to accept
that alendronate has superior efficacy and similar toxicity compared with placebo.
10. Economic Analysis
The PBAC noted the current submission failed to identify how to incorporate the adverse
events associated with alendronate treatment into the model. This was considered relevant
to the current request, which sought to extend alendronate’s listing to a broader,
primary prevention population where the benefits-to-harms ratio is particularly important.
This was addressed by the sponsor with the impact shown to be very small.
The type of economic evaluation presented was a cost-utility analysis. The model has
three health states: well (free from fracture), post-fracture, and death, with a time
horizon of 10 years, and uses a Monte Carlo simulation.
The submission presented the base case results of the modelled economic evaluation
using results for the entire population with BMD ≤ -2.5. The PBAC considered that
the more appropriate base case was the population who are currently not eligible for
alendronate treatment, but would be eligible if the proposed restriction was recommended,
i.e. patients with a BMD T-score between -3.0 and -2.5, rather than the entire population
with a BMD T-score ≤ -2.5.
A sensitivity analysis with the population with BMD T-scores of -3.0 to -2.5 was conducted
with a time horizon of 10 years. Incremental costs per Quality-Adjusted Life-Year
(QALY) were calculated to be:
|
Population |
ICER range |
|---|---|
|
Males 70-74 years |
$75,000 to $105,000 |
|
Males 75-79 years |
$15,000 to $45,000 |
|
Males 80-84 years |
$15,000 to $45,000 |
|
Females 70-74 years |
$45,000 to $75,000 |
|
Females 74-79 years |
$15,000 to $45,000 |
|
Females 80-84 years |
$15,000 to $45,000 |
The model was very sensitive to the baseline and relative risk estimates of vertebral
and hip fractures, as well as the time horizon used. The PBAC noted the optimal duration
of alendronate treatment has not been established, but limited data suggest that it
may be appropriate for non-high risk patients to stop treatment after five years.
The data suggest that discontinuing therapy after five years does not reverse the
benefits of prior alendronate treatment.
11. Estimated PBS Usage and Financial Implications
The submission estimated the likely number of packs dispensed per year to be in the
range of 50,000 to 100,000 in Year 5.
The financial cost per year to the PBS was estimated to be less than $10 million in
Year 5. This estimation is only for the increase in usage in patients with no prevalent
fracture and BMD T-scores -2.5 and >-3.0, which is additional to those already funded
under the existing restriction i.e. with a prevalent fracture or BMD T-score -3.0.
12. Recommendation and Reasons
The PBAC considered the wording of the requested restriction and the nominated comparator
were appropriate.
The PBAC noted that of the three major types of osteoporotic clinical fractures, alendronate
only showed a statistically significant reduction in hip fractures in women with a
BMD T score <-2.5 in the FIT CFA trial, compared with placebo. There was no statistically
significant effect in this subgroup on the rate of the other two major fractures types,
clinical (symptomatic) vertebral fracture and wrist fractures. There was a statistically
significant reduction in morphometric (non-symptomatic) vertebral fractures and non-hip,
non-spine, non-wrist fractures.
The comparative toxicity of alendronate was of concern to the PBAC given that the
request for a further extension for use in the primary prevention setting would make
alendronate available to more than twice as many patients as under the current restriction.
The PBAC considered there was a change in risk benefit ratio in making alendronate
available to a population at lower risk of fracture and at the same risk of adverse
events.
The PBAC noted that although the trial data do not show a marked increase in adverse
effects, the extended assessment of harms shows that gastrointestinal problems remain
an issue of concern.
The PBAC also noted recent reports (2006-2007) suggest that suppression of bone turnover
by alendronate and other bisphosphonates may lead to increased risk of fracture, particularly
of the subtrochanteric region of the femur, which has not been considered in previous
submissions. These emerging concerns of increased risk of insufficiency fracture have
not been addressed in the submission, although they were later addressed by the sponsor.
With respect to increasing reports of osteonecrosis of the jaw, which is a serious
adverse effect and difficult to treat, given this is a rare condition, somewhat lesser
weight was placed on the impact of this adverse event compared to those mentioned
above.
The PBAC was therefore unable to accept the clinical claim that alendronate is associated
with superior efficacy and similar toxicity compared to placebo.
The PBAC further considered the most appropriate comparisons in the modelled economic
evaluation were those relating only to the additional group for which listing was
sought. In this group the weighted average incremental cost effectiveness ratio (ICER)
per QALY was between $45,000 and $75,000 for men and between $15,000 and $45,000 for
women, higher than those accepted when alendronate was recommended for listing for
patients with a BMD T-score <-3. The PBAC noted that inclusion of the adverse events
in the modelled evaluation would, to some extent, offset gains in terms of reduction
of fracture rates and further increase the ICERs, and that not only is the ICER higher
for the incremental group than the average cost-effectiveness across the whole population,
but it is more uncertain, because of the altered risk-benefit ratio.
The PBAC rejected the application because of concerns of a less favourable ratio of
harms to benefits in this wider population and an unacceptable cost-effectiveness
ratio.
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 disagrees with the PBAC's decision. The harms to benefits ratio in the
requested population has been accepted by the TGA and has recently been reviewed and
accepted by the TGA in respect of FOSAMAX PLUS. The incidence of the adverse events
particularly noted by the PBAC is very rare and causality of insufficiency fractures
has not been demonstrated. For more information, the sponsor refers you to www.msd-australia.com.au.
