Teriparatide, solution for injection, in a 3mL cartridge contained in a pre-filled disposable delivery device (pen), 250 micrograms/mL, Forteo, July 2005
Public Summary Document for Teriparatide, solution for injection, in a 3mL cartridge contained in a pre-filled disposable delivery device (pen), 250 micrograms/mL, Forteo, July 2005.
Page last updated: 24 October 2005
Public Summary Document
Product: Teriparatide, solution for injection, in a 3mL cartridge contained in a pre-filled disposable delivery device (pen), 250 micrograms/mL, Forteo
Sponsor: Eli Lilly Australia Pty Ltd
Date of PBAC Consideration: July 2005
1. Purpose of Application
This application sought listing on the Pharmaceutical Benefits Scheme (PBS) as an authority required benefit for the treatment of severe vertebral osteoporosis.
This was the third application seeking listing of Teriparatide on the PBS. Two previous
applications (June 2003 and March 2004) were rejected by the Pharmaceutical Benefits
Advisory Committee (PBAC) because of doubts about the claims of superior effectiveness
over alendronate as the accepted comparator, and the resulting uncertain cost-effectiveness.
The PBAC also had concerns about the estimated use of Teriparatide including the risk of inappropriate use, and the resulting overall cost to the PBS, as presented in the previous submissions.
3. Registration Status
Teriparatide was registered by the TGA on 22 May 2003 for the treatment of osteoporosis
in postmenopausal women and the treatment of primary osteoporosis in men when other
agents are considered unsuitable and when there is a high risk of fractures.
Under the terms of registration the following limitations apply:
1. The maximal lifetime exposure to Teriparatide for an individual patient is 18 months.
2. Patients will need to read the Consumer Medicine Information leaflet and pen User Manual before starting therapy with Teriparatide and re-read them each time the prescription is renewed.
3. Patients should be made aware that Teriparatide caused osteosarcoma in rats and that the clinical relevance of these findings is unknown.
Informed consent needs to be obtained from each patient before starting therapy to ensure that the 18-month lifetime limit is understood.
4. Listing Requested and PBAC’s View
The sponsor requested the following listing:
Initial treatment for severe established osteoporosis in men and postmenopausal women with evidence of one severe painful osteoporotic vertebral fracture. Evidence of the fracture/deformity must be demonstrated radiologically and the year of plain x-ray or CT-scan or MRI scan must be included in the authority application.
A severe vertebral fracture is defined as 40% reduction in height of the anterior or mid portion of a vertebral body relative to the posterior height of that body, or, greater than 40% reduction in any of these heights compared to the vertebral body above or below the affected vertebral body.
Continuing treatment where the patient has previously been issued with an authority prescription for this drug.
Teriparatide is available with a lifetime maximum of 18 months Teriparatide therapy (18 pens), a maximum of 18 pens will be reimbursed through the PBS. Teriparatide must be initiated only by a specialist/consulting physician treating osteoporosis
The PBAC noted that the requested listing was broader than the current TGA approved indication as it does not limit use to those patients in whom other agents are considered unsuitable.
The sponsor had no objections to a change in its requested restriction to reflect this, and PBAC agreed that any restriction wording would need to reflect the requirement that Teriparatide be limited to where other agents are considered unsuitable as well as stipulating that patients have sustained a severe painful osteoporotic (SQ3) fracture.
5. Clinical Place for the Proposed Therapy
Osteoporosis affects the skeleton and is characterised by low bone mass and micro-architectural
deterioration of bone tissue with a subsequent increase in bone fragility and susceptibility
to fracture. Osteoporosis is defined by the measurement of bone mineral density. Established
osteoporosis denotes the presence of one of more fragility fractures.
Teriparatide is indicated for the treatment of osteoporosis in postmenopausal women and the treatment of primary osteoporosis in men when other agents are considered unsuitable and when there is a high risk of fractures.
The submission nominated placebo for no therapy as the comparator.
Although accepting that patients with one or more SQ3 fractures represented a sub-group of patients with minimal trauma fracture at greater clinical need, the PBAC did not agree that placebo is an appropriate comparator for these patients. The PBAC considered that alendronate was the appropriate comparator on the basis that despite apparent “failure” of an anti-resorptive, the evidence available does not support an argument that these agents are ineffective in treating this patient sub-group and that treatment would continue to be offered given the greater clinical need. Anti-resorptive therapy is also likely to be re-commenced after completion of a course of Teriparatide.
Thus, an anti-resorptive, specifically alendronate as the most frequently prescribed drug in the group, was considered to be the appropriate comparator.
See also sponsor’s comments.
7. Clinical Trials
The submission presented data from one key randomised placebo controlled study (GHAC) and one supportive observational trial (GHBJ, a follow-up study on a subset of patients from GHAC). Both studies were published at the time of submission, as follows:
|GHAC/Neer RM GHAC/Gallagher JC||Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. Teriparatide reduces the fracture risk associated with increasing number and severity of osteoporotic fractures.||New England Journal of Medicine 2001;344:1434-1441. Journal of Clinical Endocrinology
|GHBJ/Lindsay R||Sustained vertebral fracture reduction after withdrawal of Teriparatide in postmenopausal women with osteoporosis.||Archives of Internal Medicine 2004;164:2024-30.|
The submission presented a new analysis using a sub-group of 204 patients from the GHAC study treated with either Teriparatide 20 micrograms per day or placebo with severe prevalent vertebral fractures (SQ3) at baseline rather than the entire cohort of 1085 patients.
This analysis had been published as Gallagher (2005).
A severe fracture (SQ3) is defined as one in which there is a more than approximately 40% reduction in anterior, mid and/or posterior vertebral height.
8. Results of Trials
The key results of the full GHAC trial population and the sub-group were severe vertebral
factures are summarised in the table below.
Results for outcome, all vertebral fractures, in the full Trial GHAC and for the 181-patient sub-group of Trial GHAC used in the preliminary economic evaluation
RD (95% CI)
RR (95% CI)
|Patients: all (n=892)
Outcome: all vertebral fractures
|Patients: baseline severe fracture (n=181)
Outcome: all vertebral fractures
Given the conclusion that placebo is not the main comparator, the clinical data did not give an informative basis for the PBAC to consider the listing of Teriparatide in this patient group.
The PBAC noted that no new primary toxicity data were presented in the re-submission. However data from the uncontrolled follow-up study was presented. The re-submission analysed the data on back pain and showed it is related to vertebral fracture number and severity, but did not take this analysis further.
9. Clinical Claim
The submission claimed that Teriparatide is significantly more effective but has more toxicity than the comparator, no therapy.
10. Economic Analysis
An updated preliminary trial-based economic evaluation was presented using the treatment
effects seen in the GHAC sub-group with severe vertebral fractures. The trial-based
incremental cost per extra new vertebral fracture avoided was in the range of
$45,000 – $75,000.
An updated modelled economic evaluation was also presented. This was a cost-utility analysis. The base case modelled incremental discounted cost per extra discounted quality adjusted life year (QALY) gained was < $15,000. Varying some of the key assumptions in the model increased the base case modelled incremental discounted cost per extra discounted life-year to between the range of $45,000 - $75,000.
Given the conclusion that placebo is not the appropriate comparator, the economic model also did not give an informative basis for the PBAC to consider the listing of Teriparatide in this patient group.
For the PBAC’s view on the economic analysis see Reasons and Recommendations.
11. Estimated PBS Usage and Financial Implications
The submission estimated that less than 10,000 patients would commence treatment with Teriparatide in year 4 of listing. The net financial cost to the PBS was estimated to be between $10 million- $30 million in year 4 of listing.
The PBAC considered that the estimates presented in the submission to be low with the main areas of uncertainty to be the expected use in elderly patients (especially those over 85 years of age), the rate of uptake and the potential for poor compliance and failure to continue therapy for a full course of treatment.
12. Recommendation and Reasons
Although not a reason for rejection, the PBAC agreed that any restriction would need to be in accordance with the TGA-approved indication, but noted that the sponsor had no objections to any change in its requested restriction to reflect this. Thus any wording would need to reflect the requirement that Teriparatide be limited to where other agents are considered unsuitable as well as stipulating that patients have sustained a severe painful osteoporotic (SQ3) fracture.
Although accepting that patients with one or more SQ3 fractures represented a sub-group of patients with minimal trauma fracture at greater clinical need, the PBAC did not agree that placebo is an appropriate comparator for these patients. Despite apparent “failure” of an anti-resorptive in this situation, the evidence available does not support an argument that these agents are ineffective in treating this patient sub-group and that treatment would continue to be offered given the greater clinical need. Further, as confirmed by the sponsor in its hearing, in relation to raloxifene, the post hoc analysis of the severe vertebral fracture sub-group of the MORE II trial by Delmas et al showed a relative risk of 0.74 (95% CI: 0.54, 0.99), which is not different from the relative risk of 0.70 (95% CI: 0.6, 0.9) for the MORE II trial overall. Thus patients would be continued on anti-resorptives in the absence of Teriparatide. Further, clinicians are very unlikely to use Teriparatide in combination with an anti-resorptive and the sponsor, in its Pre-Sub-Committee Response, accepted that any restriction should limit the use of Teriparatide accordingly. Thus, an anti-resorptive, specifically alendronate as the most frequently prescribed drug in the group, was considered to be the appropriate comparator. Anti-resorptive therapy is also likely to be re-commenced after completion of a course of Teriparatide. Thus the relevant comparison for the intended target population would be continuing alendronate versus interrupting alendronate to administer up to an 18-month course of Teriparatide, followed by a resumption of alendronate.
Given the conclusion that placebo is not the appropriate comparator, the comparative clinical data and the economic model did not give an informative basis for the PBAC to consider the listing of Teriparatide in this patient group. The PBAC recalled that previous submissions had not been able to make a case that Teriparatide is superior to alendronate in patients who have sustained a fracture whilst on treatment with alendronate in a wider patient population, but which would have included patients in the severe vertebral fracture group.
The PBAC also considered that there was uncertainty due to many of the clinical assumptions and many of the data inputs into the model, particularly the derivation of the utility estimates based on expert opinion scored using the AQoL multi-attribute utility instrument. The PBAC also agreed that there is insufficient basis to substitute the results for the post hoc sub-group analysis from the GHAC trial of Teriparatide in place of the overall ITT analysis as the basis to be relied upon when considering the therapeutic and economic performance of Teriparatide in patients eligible according to the requested restriction. The test for treatment effect modification for the relative risk conducted as part of the evaluation of the submission using summary data from the trial was not statistically significant across the two baseline fracture sub-groups of “severe” and “non-severe”, leading the PBAC to the conclusion that the overall trial results should form the basis of any clinical or economic evaluation.
The PBAC acknowledged there is a clinical need for an effective treatment in this patient group, but rejected the submission because of the inappropriate comparator and the resulting uncertain clinical benefit and uncertain cost effectiveness of Teriparatide.
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
Eli Lilly disagrees with a number of comments made during the evaluation of this submission. This re-submission was developed in consultation with clinical experts in Australia and overseas, using prospective clinical data from well-designed clinical trials. The analysis conducted by evaluator based on summary data is refuted. It is methodologically inferior to the analyses conducted by sponsor using patient-level data. Many of the main points raised in the evaluation and advice received were included in the PBAC submission, these include a sensitivity analysis comparing Teriparatide to an anti-resorptive and statements related to the safety/toxicology of Teriparatide.
Eli Lilly does acknowledge the need to address some of the uncertainties raised in the submission and is currently planning to resubmit an application for PBS listing for Teriparatide.