Alendronate sodium, tablet, 70 mg Fosamax® Once Weekly, Alendronate sodium with Colecalciferol, tablet, 70 mg – 70 micrograms, Fosamax Plus®, July 2006
Page last updated: 27 October 2006
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Public Summary Document
Product: Alendronate sodium, tablet, 70 mg Fosamax® Once Weekly,
Alendronate sodium with Colecalciferol, tablet, 70 mg – 70 micrograms, Fosamax Plus®
Sponsor: Merck Sharp and Dohme (Australia) Pty Ltd
Date of PBAC Consideration: July 2006
1. Purpose of Application
The submission sought an extension to the PBS-listing of alendronate tablet 70 mg
(Fosamax Once Weekly) and alendronate tablet 70 mg with colecalciferol 70 mcg (Fosamax
Plus) to include patients with low bone mineral density (BMD) and without prevalent
fracture.
2. Background
Alendronate 10 mg tablet was recommended for listing at the February 1997 PBAC meeting,
the 70 mg tablet was listed on 1 May 2001 and the 70 mg tablet with colecalciferol
70 mcg was listed on 1 August 2006.
The PBAC has considered and rejected a number of applications to extend the listing
of alendronate (and risedronate and raloxifene) to include patients without prevalent
fracture for alendronate (and risedronate and raloxifene).
The most recent consideration was a joint submission to the March 2005 meeting.
The PBAC rejected the application because of uncertain but over-estimated extent of
long-term clinical benefit and resulting uncertain cost-effectiveness which does not
provide a sufficiently confident basis to conclude that the cost-effectiveness is
acceptable.
3. Registration Status
Alendronate 70 mg tablets were first approved by TGA on 7 February 2001 for the treatment
of osteoporosis in postmenopausal women.
With amendment, the current TGA registered indication for Fosamax for the treatment
of osteoporosis is:
Osteoporosis must be confirmed by: the finding of low bone mass of at least 2 standard deviations below the gender specific mean for young adults or by the presence of osteoporotic fracture.
4. Requested Listing and PBAC’s view:
An authority required listing was sought for:
Initial treatment of osteoporosis for patients at high risk of fracture.
A high risk of fracture is defined as:
- The presence of an existing 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 included in the authority application. 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; OR
- A bone mineral density (BMD) T-score of -3.0 or less in a patient aged 70 years or older. The initial authority application must state the date, site (femoral neck OR lumbar spine) and score of the qualifying BMD measurement.
The radiological and/or laboratory reports supporting eligibility under (b) must be available for audit by the HIC.
Continuing treatment for osteoporosis in patients with either a fracture due to minimal
trauma and/or a bone mineral density T score of -3.0 or less, where the patient has
previously been issued with an authority prescription for this drug.
The revised eligibility criteria as detailed above were proposed by the sponsor in
its pre-sub-Committee response.
The PBAC’s view was that BMD scanning of the patients who will potentially become
eligible for PBS-subsidised treatment under the expanded listing is not currently
funded through Medicare and that the logistics and funding of this BMD scanning would
require resolution prior to any PBS listing. See also the Recommendations and Reasons.
5. Clinical Place for the Proposed Therapy
If alendronate were listed on the PBS for prevention of fracture, it would provide
a treatment for the prevention of fracture in osteoporotic patients considered to
have a similar risk of fracture as patients who have had a prior fracture due to minimal
trauma.
6. Comparator
The comparator was placebo or ‘watchful waiting’ (patient monitoring and standard
management with calcium and vitamin D).
7. Clinical Trials
The key trial in the current re-submission was the same as that presented in previous alendronate submissions, the Fracture Intervention Trial (FIT). The re-submission was based on an a priori defined subgroup analysis of patients with a BMD T-score ≤-2.5 in the Clinical Fracture Arm of FIT. This trial was published as:
| 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. |
8. Results of Trials
The submission provided the key results of the Fracture Intervention Trial (FIT) Clinical Fracture Arm (CFA) for the entire population (CFA) and the subgroup of patients with a baseline BMD T-score ≤-2.5 (CFA T≤-2.5) to show comparative effectiveness (table below).
| Fracture/ population |
Alendronate | Placebo | RD (95% CI) | RR (95% CI) |
|---|---|---|---|---|
| Any clinical | ||||
| - CFA |
272/2214 (12.3%) |
312/2218 (14.1%) |
-1.8% (-3.8, 0.2) |
0.87 (0.75, 1.02) |
| - CFA T≤-2.5 |
107/819 (13.1%) |
159/812 (19.6%) |
-6.5% (-10.1, -2.9) |
0.67 (0.53, 0.83) |
| Morphometric Vertebral | ||||
| - CFA |
43/2057 (2.1%) |
78/2077 (3.8%) |
-1.7% (-2.7, -0.6) |
0.56 (0.39, 0.80) |
| - CFA T≤-2.5 |
22/757 (2.9%) |
44/763 (5.8%) |
-2.9% (-5.0, -0.8) |
0.50 (0.31, 0.83) |
| Clinical vertebral | ||||
| - CFA |
18/2214 (0.8%) |
27/2218 (1.2%) |
-0.4% (-1.0, 0.2) |
0.67 (0.37, 1.20) |
| - CFA T≤-2.5 |
12/819 (1.5%) |
14/812 (1.7%) |
-0.3% (-1.6, 1.0) |
0.85 (0.40, 1.79) |
| Non-vertebral | ||||
| - CFA |
261/2214 (11.8%) |
294/2218 (13.3%) |
-1.5% (-3.4, 0.5) |
0.89 (0.76, 1.04) |
| - CFA T≤-2.5 |
101/819 (12.3%) |
150/812 (18.5%) |
-6.1% (-9.7, -2.7) |
0.67 (0.53, 0.84) |
| Hip | ||||
| - CFA |
19/2214 (0.9%) |
24/2218 (1.1%) |
-0.2% (-0.8, 0.4) |
0.79 (0.44, 1.43) |
| - CFA T≤-2.5 |
8/819 (1.0%) |
18/812 (2.2%) |
-1.2% (-2.6, 0.0) |
0.44 (0.20, 0.98) |
| Wrist | ||||
| - CFA |
83/2214 (3.7%) |
70/2218 (3.2%) |
0.6% (-0.5, 1.7) |
1.19 (0.87, 1.62) |
| - CFA T≤-2.5 |
34/819 (4.2%) |
38/812 (4.7%) |
-0.5% (-2.6, 1.5) |
0.89 (0.57, 1.39) |
| Other* | ||||
| - CFA |
182/2214 (8.2%) |
227/2218 (10.2%) |
-2.0% (-3.7, -0.3) |
0.80 (0.67, 0.97) |
| - CFA T≤-2.5 |
71/819 (8.7%) |
111/812 (13.7%) |
-5.0% (-8.1, -2.0) |
0.63 (0.48, 0.84) |
CFA: Clinical Fracture Arm of the FIT; CFA T≤-2.5: subgroup analysis of patients with a BMD T-score ≤-2.5 in the Clinical Fracture Arm of the FIT; *Non-hip, -spine, -wrist
The results of the FIT trial for any clinical fractures show that overall in the CFA
arm, that is, patients who had no prevalent vertebral fracture at the time of enrolment
in the trial, the overall risk of a clinical fracture was no different between alendronate
and placebo. There was a relative risk of 0.87 with confidence intervals that overlap
1, during an average follow-up period of 4 years. With respect to the sub-group, the
fracture risk is higher, as shown by the placebo event rate of 14% in the overall
population as opposed to 19.6% in the sub-group. In addition, the relative risk reduction
is statistically significant for any clinical fracture, morphometric vertebral, non-vertebral
fractures, hip and other vertebral fractures. The test for effect modification conducted
during the evaluation also confirmed that that this subgroup is an effect modifier
for these outcomes. Therefore, although the overall results are not significant there
is a qualitative interaction in one subgroup that is significantly different than
the overall group.
No new toxicity data were presented in the re-submission. The toxicity data from the
previous re-submission indicated similar rates of adverse events, including upper
gastrointestinal adverse events in alendronate- and placebo-treated patients.
9. Clinical Claim
The submission claimed that alendronate has significant advantages in effectiveness
over placebo and has similar or less toxicity.
For the PBAC’s views see the Recommendation and Reasons
10. Economic Analysis
A preliminary economic evaluation was presented. The trial-based incremental discounted
cost per extra discounted patient avoiding clinical fracture or vertebral fracture
over four years compared to placebo was estimated to be between $15,000 and $45,000.
An updated modelled economic evaluation was presented. The structure of the model
was the same as that presented in the March 2005 re-submission. There were, however,
concerns regarding the appropriateness of the baseline fracture risks and fracture
multipliers used in the model, which may significantly overestimate the effectiveness
and cost-effectiveness of alendronate.
The ESC requested that additional calibration exercises be undertaken in order to
establish the most reliable estimate for baseline fracture rates for the Australian
population and take into account all fracture types not only hip fractures.
The final set of baseline fracture rates is presented below.
| Population based case | Hip fracture | Clinical vertebral fracture | All vertebral | |||
|---|---|---|---|---|---|---|
| MODEL | Hip fracture | Clinical vertebral fracture | All vertebral | |||
|
T -score< -3.0 |
T -score< -3.0 |
T -score< -3.0 |
||||
| Male | Female | Male | Female | Male | Female | |
| 70-74 | 1.9% | 1.2% | 1.4% | 0.6% | 4.7% | 2.1% |
| 75-79 | 0.5% | 1.7% | 1.3% | 0.3% | 4.4% | 1.0% |
| 80+ | 2.2% | 3.0% | 1.6% | 2.7% | 5.3% | 9.1% |
| T-score< -3.0 | T-score < -3.0 | T-score < -3.0 | ||||
| Male | Female | Male | Female | Male | Female | |
| 70-74 | 3.9% | 2.0% | 5.2% | 3.0% | 17.5% | 10.0% |
| 75-79 | 4.2% | 2.5% | 6.7% | 3.1% | 22.4% | 10.3% |
| 80+ | 4.4% | 3.0% | 8.2% | 3.2% | 27.4% | 10.6% |
The incremental costs per QALY gained decreased as age increased. The incremental
cost-effectiveness ratios based on the re-calibration of baseline fracture rates ranged
from less than $15,000 to between $30,000 and $68,000 in females in the 80-84 and
70-74 years age brackets respectively, and from $16,000 to $32,000 in males in 80-84
and 70-79 years age brackets respectively.
11. Estimated PBS Usage and Financial Implications
The likely number of patients on therapy in the fourth year of listing was estimated
to be between 50,000 to 100,000, while the financial cost to the PBS was estimated
to be between $15-$30 million in the fourth year of listing.
12. Recommendation and Reasons
The PBAC recommended the listing of 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 revised eligibility criteria were proposed by the sponsor in its pre-sub-Committee
response.
The PBAC agreed that the data presented from the clinical fracture arm (CFA) of the
Fracture Intervention Trial (FIT) supported the conclusion that alendronate reduces
morphometric vertebral, hip, non-vertebral and other fractures, but not clinical vertebral
fractures, in the patients with a T score ≤ -2.5. A T score <-2.5 was a treatment
effect modifier. There remained some residual areas of uncertainty namely that the
primary outcome (analysis of all clinical fractures in the entire population in the
CFA arm) of CFA-FIT was negative, whether the subgroup from the CFA-FIT was representative
of the proposed PBS population, and the likely post-hoc specification of the sub-group
in CFA-FIT. However the Committee agreed that overall, there was reasonably good,
but not conclusive evidence that alendronate is effective in the high risk group of
the CFA arm which approximates the proposed patient population in the Australian context.
There was trial evidence in both absolute terms as well as relative terms, supporting
the hypothesis that the benefit of alendronate depends on the baseline risk of the
patients and that there will be a higher benefit in the subgroup.
The PBAC did not accept the submission’s claim that the toxicity of alendronate is
equivalent to placebo. The Committee considered this claim to be untrue for gastro-intestinal
events and for osteonecrosis of the jaw, which although rare, is very difficult to
treat.
The Committee noted that the same economic model was presented as in the March 2005
submission but with updated unit costs, re-analysed baseline fracture risks, revised
health state utilities and BMD screening costs included. Although the economic model
in the submission was initially for the 60+ age group with a T score ≤ -2.5 which
resulted in cost effectiveness ratios that were uncertain and high, the data from
the narrower indication (age ≥70, T-score < -3.0) resulted in acceptable cost effectiveness,
with the cost per QALY ranging from less than $15,000 to between $45,000 and $75,000
in females in the 80 – 84 and 70 – 74 age brackets respectively, and from $15,000
to $45,000 in males in the 80 – 84 and 70 – 74 age brackets respectively.
An area of major concern to the PBAC was that of case finding through BMD scanning.
The Committee noted that BMD scanning of the patients who will potentially become
eligible for PBS-subsidised treatment under the expanded listing is not currently
funded through Medicare. This issue was not addressed at the time of the PBAC consideration.
The PBAC considered that the logistics and funding of BMD scanning requires resolution
prior to any PBS listing.
The PBAC recommended the current restriction for use in secondary prevention not be
changed at the present time.
Recommendation
Alendronate, tablet, 70 mg; Alendronate sodium with colecalciferol (vitamin D3), tablet,
70 mg-70 micrograms (2800 i.u.)
Amend restriction to read:
Authority required
Initial treatment as the sole PBS-subsidised anti-resorptive agent for osteoporosis
in patients aged 70 years of age or older and with a BMD T-score of -3.0 or less.
The initial authority application must state the date, site (femoral neck or lumbar
spine) and score of the qualifying BMD measurement. Continuing treatment as the sole
anti-resorptive agent for osteoporosis in patients aged 70 years of age or older and
with a BMD T-score of -3.0 or less where the patient has previously been issued with
an authority prescription for this drug.
Initial treatment as the sole PBS-subsidised anti-resorptive agent for established
osteoporosis in patients 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 included in the authority application.
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; Continuing treatment as the sole PBS-subsidised
anti-resorptive agent for osteoporosis in patients with fracture due to minimal trauma,
where the patient has previously been issued with an authority prescription for this
drug
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
Merck Sharp & Dohme welcomes the PBAC’s decision to make alendronate available on the PBS for use in primary prevention of osteoporosis. The sponsor notes the PBAC’s concerns with respect to the reimbursement of BMD testing and is working with the Department of Health to put a solution in place.
