Etanercept, injection set containing 4 vials powder for injection 25 mg and 4 pre-filled syringes solvent 1 mL, Enbrel ®, July 2005
Public Summary Document for Etanercept, injection set containing 4 vials powder for injection 25 mg and 4 pre-filled syringes solvent 1 mL, Enbrel ®, July 2005
Page last updated: 11 November 2005
Product: ETANERCEPT, injection set containing 4 vials powder for injection 25 mg and 4 pre-filled
syringes solvent 1 mL, Enbrel ®
Sponsor: Wyeth Australia Pty Ltd
Date of PBAC Consideration: July 2005
1. Purpose of Application
This application sought an authority required listing on the Pharmaceutical Benefits Scheme (PBS) for certain adults with severe chronic plaque psoriasis.
2. Background
This is a request for subsidy of a new use of a drug currently listed on the PBS. Etanercept is currently listed for the treatment of rheumatoid arthritis, ankylosing spondylitis and polyarticular juvenile chronic arthritis.
3. Registration Status
Etanercept is registered for the treatment of adult patients with moderate to severe chronic plaque psoriasis, who are candidates for phototherapy or systemic therapy.
4. Listing Requested and PBAC’s View
The sponsor requested an Authority Required listing for a subset of patients within the registered indication. Under the requested listing, initial treatment would have been limited to patients with severe chronic plaque psoriasis who met certain criteria including a failure to achieve an adequate response to specified psoriasis therapies and a PASI score > 15 or in certain other severe cases with a PASI < 15. Eligibility for continuing PBS-subsidised treatment would have been dependent of the patient relapsing after achieving at least a 50% reduction in PASI score from baseline in the initial treatment period.
The PBAC considered that there were several problems with the requested restriction in its intended aim in terms of rigorously identifying both eligible patients and then adequate responders. The PBAC also noted that the National Institute for Clinical Excellence (NICE) in the UK has released a preliminary consultation report which considered an alternative PASI threshold for severe psoriasis, and PASI improvement for determining whether patients can continue therapy. The PBAC did not consider these issues with the restriction wording to constitute a reason for rejection.
5. Clinical Place for the Proposed Therapy
Psoriasis is a chronic, incurable inflammatory disorder that, although not life-threatening, can severely impact on a patient’s quality of life. Current psoriasis therapies reduce the symptoms but do not provide a permanent cure for this chronic disease. Etanercept is proposed as a last line therapy for patients with severe psoriasis that are unresponsive to, contraindicated to, or intolerant to conventional psoriasis therapies.
6. Comparator
The sponsor nominated placebo as the main comparator, as etanercept was positioned as a last line treatment for severe chronic plaque psoriasis in patients unresponsive to conventional systematic therapies
The PBAC accepted this as appropriate.
7. Clinical Trials
The key clinical evidence was from three randomised, double-blind, placebo-controlled, parallel-design, multi-centre trials (Leonardi et al, 2003; Gottlieb et al 2003 and Papp et al, 2005). Across the three trials, 415 patients were treated with etanercept 25mg twice weekly, 358 patients with 50mg twice weekly, and 414 patients with placebo.
(Note: the patient numbers in this Public Summary Document are taken from the cited publications. They may vary slightly from the numbers considered by PBAC which were taken from the sponsor’s internal reports. These differences do not affect the overall conclusions).
The primary outcome measure in all three trials was the PASI 75 (proportion of patients with ?75% reduction from baseline PASI (Psoriasis Area and Severity Index (PASI)).
Two of the studies had been published at the time of submission and one trial has been published subsequently, as follows:
|
Trial/first author |
Protocol/Publication title |
Publication citation |
|---|---|---|
| Gottlieb AB | A randomized trial of etanercept as monotherapy for psoriasis | Arch Dermatol 2003; 139:1627-1632. |
| Leonardi CL | Etanercept as monotherapy in patients with psoriasis | N Engl J Med 2003; 349:2014-2022. |
| Papp KA | A global phase III randomized controlled trial of etanercept in psoriasis: safety, efficacy, and effect of dose reduction | Brit J Derm 2005; 152:1304-1312 |
8. Results of Trials
The Intent To Treat (ITT) results of the key trials are summarised in the following table for the outcome PASI 75 at 12 and 24 weeks of treatment.
(Note: the results reported in this Public Summary Document are taken from the cited publications. They may vary slightly from the numbers considered by PBAC which were taken from the sponsor’s internal reports. These differences do not affect the overall conclusions).
|
Trial |
Week 12 |
ARD (95% CI) |
RR (95% CI) |
NNT (95% CI) |
|
|---|---|---|---|---|---|
|
|
Etanercept (25mg BIW) |
Placebo |
|
|
|
| Gottlieb et al |
17/57 (30%) |
1/55 (2%) |
0.25 (0.14, 0.37) |
16.0 (2.2, 116.8) |
4 (3, 5) |
| Leonardi et al |
55/162 (34%) |
6/166 (4%) |
0.28 (0.21, 0.36) |
8.9 (3.9, 20.1) |
3 (3, 4) |
| Papp et al |
67/196 (34%) |
6/193 (3%) |
0.31 (0.24, 0.38) |
11.0 (4.9, 24.8) |
3 (3,4) |
| Pooled |
139/415 (33%) |
13/414 (3%) |
0.30 (0.26, 0.35) |
10.7 (6.0, 18.5) |
3 (3,4) |
|
Week 24 |
|||||
| Gottlieb et al |
32/57 (56%) |
3/55 (5%) |
0.46 (0.32, 0.60) |
10.0 (3.2, 31.0) |
2 (2, 3) |
|
Week 12 |
|||||
|
Etanercept (50mg BIW) |
Placebo |
||||
| Papp et al |
96/194 (49%) |
6/193 (3%) |
0.46 (0.39, 0.54) |
15.9 (7.2, 35.4) |
2 (2, 3) |
| Leonardi et al |
81/164 (49%) |
6/166 (4%) |
0.43 (0.35, 0.52) |
13.2 (5.9, 29.4) |
2 (2, 3) |
|
Pooled |
177/358 (49.4%) |
12/359 (3.3%) |
0.46 (0.41, 0.52) |
14.8 (8.4, 26.1) |
2 (2, 2.4) |
|
|
Etanercept (50mg BIW) |
Etanercept (25mg BIW) |
|
|
|
| Papp et al |
96/194 (49%) |
67/196 (34%) |
0.15 (0.06, 0.25) |
1.45 (1.14, 1.84) |
7 (4, 17) |
| Leonardi et al |
81/164 (49%) |
55/162 (34%) |
0.15 (0.05, 0.25) |
1.45 (1.13, 1.88) |
7 (4,17) |
|
Pooled |
177/358 (49%) |
122/358 (34%) |
0.15 (0.08,0.23) |
1.45 (1.21,1.73) |
7 ( 4, 13) |
All three trials, showed that significantly more patients treated with etanercept at 25mg twice weekly or 50mg twice weekly exhibited a 75% improvement in PASI scores from baseline (the primary outcome) at 12 weeks and 24 weeks compared with patients treated under placebo conditions. Further, patients treated with etanercept at 25mg twice weekly or 50mg twice weekly exhibited significant improvements for all the secondary outcomes across the trials including 50% and 90% improvement in PASI scores.
With few exceptions, there was no statistically significant difference in any trial between the numbers of subjects reporting adverse events (either infectious or non-infectious) in groups treated with either 25mg twice weekly or 50mg twice weekly of etanercept compared with placebo over a 12 week period. However, significantly more subjects treated with 50mg or 25mg twice weekly of etanercept reported injection-site reactions compared with placebo. Monitoring of adverse events was not reported beyond 24 weeks after initiation of treatment.
9. Clinical Claim
The submission claimed etanercept was significantly more effective than placebo but had more toxicity.
The PBAC accepted that etanercept has significant advantages in effectiveness over placebo up to 24 weeks after initiation of treatment, but displays more toxicity over the same time period. The PBAC noted that etanercept is an effective drug in terms of both a PASI 50 and a PASI 75 improvement.
10. Economic Analysis
The submission presented a preliminary trial based economic evaluation. The PBAC considered that the choice of the cost-effectiveness approach was valid. The resources included were drug costs only.
A modelled economic evaluation was also presented. The resources included were drug costs only as the drug is self administered. The PBAC considered that the choice of the cost-effectiveness approach was valid.
The base case modelled incremental discounted cost per extra discounted quality adjusted life year (QALY) was in the range of $45,000 - $75,000 for treatment with both the 25 and 50mg twice weekly regimens.
The PBAC considered that the model was subject to considerable uncertainty and results varied by an unacceptable amount per extra QALY gained. (Refer to Recommendations and Reasons)
11. Estimated PBS Usage and Financial Implications
The submission estimated the financial cost per year to the PBS to be up to $30 – $60 million per year by the fourth year of listing with the 50mg twice weekly regimen and the 25mg twice weekly regimen. Specialist visits and monitoring of the condition for evidence of relapse were not included in the expenditure.
12. Recommendation and Reasons
The PBAC accepted the submission’s claim that etanercept has significant advantages in effectiveness over placebo up to 24 weeks after initiation of treatment, but displays more toxicity over the same time period. The PBAC noted that etanercept is an effective drug in terms of both a PASI 50 and a PASI 75 improvement.
The PBAC considered that the base case incremental costs per extra QALY gained were high. The PBAC noted that the Pre-PBAC Response acknowledged that the omission in the model of a subsequent trial of re-treatment in initial treatment failures tends to bias the model in favour of etanercept and applying a longer duration before the subsequent trial of re-treatment would reduce but not eliminate this bias.
The PBAC also noted a number of other issues of uncertainty about the model, including doubts about whether the fixed proportional relationship between PASI and BSA scores is adequately demonstrated given that the BSA represents only one dimension of the PASI. It is also unclear whether the claimed relationship is maintained longitudinally rather than cross-sectionally because only cross-sectional evidence of the relationship is provided.
The PBAC did not accept the assumption that the response to etanercept for all subsequent treatment cycles after a demonstrated response to the initial cycle of treatment is 100%. The PBAC agreed with the ESC that this assumption maximises the extent of benefit whilst halving costs in subsequent cycles.
Further, the 10-year duration of the model averages the higher initial costs of identifying non-responders (and the higher costs of the initial 50mg dose of etanercept in the primary model) across a larger number of subsequent cycles. Any shorter duration of the model would yield less favourable incremental cost-effectiveness ratios. Furthermore, the model relies on follow-up after the first to second course of therapy in a single study to estimate the duration of the treatment-free period between treatment courses.
The PBAC noted that the consistent effect of all these uncertainties is to overestimate the QALY gain and thus bias the estimate of incremental cost per extra QALY gained in favour of etanercept. The combined effect is likely to be substantial.
The PBAC also noted from the sensitivity analyses that the incremental cost per extra QALY gained for patients achieving a PASI 75 response was greater than the base-case for patients with a PASI 50 response. This was because analysis substituted the lower response rates (for etanercept, placebo and thus also the increment), without increasing the extent of the utility gain in the model for a PASI 75, which would be expected to be greater than that for a PASI 50.
Despite good evidence of clinical effectiveness and a demonstrated clinical need for a drug to treat this group of patients, the PBAC rejected the submission because of uncertain and unacceptable cost-effectiveness.
Recommendation
Reject
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 will be making a re-submission and looks forward to continuing to work with the PBAC.
