Etanercept, injection set containing 4 vials powder for injection 25 mg and 4 pre-filled syringes solvent 1 mL, and injection set containing 4 vials powder for injection 50 mg and 4 pre-filled syringes solvent 1 mL, Enbrel®, March 2007
Public summary document for Etanercept, injection set containing 4 vials powder for injection 25 mg and 4 pre-filled syringes solvent 1 mL, and injection set containing 4 vials powder for injection 50 mg and 4 pre-filled syringes solvent 1 mL, Enbrel®, March 2007
Page last updated: 13 July 2007
Public Summary Document
Product: Etanercept, injection set containing 4
vials powder for injection 25 mg and 4 pre-filled syringes solvent
1 mL, and injection set containing 4 vials powder for injection 50
mg and 4 pre-filled syringes solvent 1 mL, Enbrel®
Sponsor: Wyeth Australia Pty Ltd
Date of PBAC Consideration: March 2007
1. Purpose of Application
To request that the PBAC consider changing the current PBS
restriction for patients with severe chronic plaque psoriasis to
include a mechanism for allowing a proportion of ‘high
needs’ patients to access continuous treatment and also to
allow an initial treatment period of 24 weeks for all patients
instead of the currently approved 12 weeks.
2. Background
At the July 2005 meeting, the PBAC rejected a submission for
etanercept for an Authority Required listing for certain adults
with severe chronic plaque psoriasis because of uncertain and
unacceptable cost-effectiveness.
At the March 2006 meeting, the PBAC recommended listing for
patients with severe chronic plaque psoriasis on a
cost-minimisation basis concluding that, based on an indirect
comparison, etanercept was no worse than efalizumab for the
treatment of severe refractory chronic plaque psoriasis.
3. Registration Status
Etanercept is registered by the TGA (for use in psoriasis) for the
treatment of adult patients with moderate to severe chronic plaque
psoriasis, who are candidates for phototherapy or systemic therapy.
Safety and efficacy beyond 12 months have not been
demonstrated.
4. Listing Requested and PBAC’s View
The submission requested that patients be treated for an initial 24
weeks (instead of 12 weeks) with 50 mg per week (either as 25 mg
twice weekly or 50 mg once weekly) and then undergo a mandatory
period of treatment withdrawal period of 12 weeks, as per the
current PBS listing. Those patients who relapse within this 12 week
withdrawal period will be classified as early relapsers, and have
the option of receiving treatment using a new continuous regimen at
the same dose of 50 mg per week. Those patients who do not relapse
within the 12 week withdrawal period remained eligible for
intermittent therapy as per the current PBS listing. The proposed
definition of relapse was a return to 75% of pre-treatment
Psoriasis Activity and Severity Index (PASI) score. (A detailed
restriction wording was proposed).
The PBAC did not comment on the requested restriction.
5. Clinical Place for the Proposed Therapy
A treatment for severe chronic plaque psoriasis.
6. Comparator
The submission nominated the current treatment algorithm i.e.
etanercept 25mg twice weekly (or etanercept 50mg weekly)
administered for 12 weeks initially and then, in responders,
administered intermittently (at least 12 weeks off-therapy followed
by another 12 weeks on therapy).
See Recommendations and Reasons for PBAC’s
view.
7. Clinical Trials
The submission presented two trials, CSR-51139 and CSR-51727, and a
withdrawal and extension study of CSR-51727 (CSR-51820) which
constituted the primary source of evidence.
These trials have been published at the time of submission as
follows:
Primary Enbrel RCTs
| Clinical Study Report No. | Title | Publication/s |
| CSR-51139 | Double-blind, placebo-controlled, phase 2 study of etanercept (Enbrel) in the treatment of psoriasis: final report. | Gottlieb AB, Matheson RT, Lowe N et al. A randomized trial of etanercept as monotherapy for psoriasis. Arch Dermatol 2003; 139:1627-1632. |
| CSR-51727 | Multicenter, dose-ranging study of the safety and efficacy of etanercept in psoriasis: final 24-week report. | Leonardi CL, Powers JL, Matheson RT et al. Etanercept as monotherapy in patients with psoriasis. N Engl J Med 2003; 349:2014-2022. |
| Feldman SR, Kimball AB, Krueger GG, et al. Etanercept improves the health-related quality of life of patients with psoriasis: Results of a phase III randomized clinical trial. J Am Acad Dermatol 2005; 53(5):887-889. | ||
| CSR-51820 | Multicenter dose-ranging study of the safety and efficacy of etanercept in psoriasis: withdrawal and retreatment final report. | Gordon KB, Gottlieb AB, Leonardi CL, et al. Clinical response in psoriasis patients discontinued from and then reinitiated on etanercept therapy. J Dermatol Treat 2006; 17(1):9-17 |
| Krueger GG, Elewski B, Papp K, et al. Patients with psoriasis respond to continuous open-label etanercept treatment after initial incomplete response in a randomized, placebo-controlled trial. J Am Acad Dermatol 2006; 54(3 SUPPL. 2):S112-S119 | ||
| Krishnan KR, Cella D, Woolley M, et al. Etanercept improves symptoms of depression and fatigue in patients with psoriasis. 158th Annual Meeting of the American Psychiatric Association; 2005 May 21-26; Atlanta., GA |
Other clinical trial data was presented as supportive
evidence.
8. Results of Trials
In addition to the ITT data presented below, additional analyses
were conducted. The submission claimed that the analyses presented
suggested that more patients treated with etanercept 25mg given
twice weekly achieved PASI responses at week 24 than at week 12.
The model presented in the submission applied the response rates
observed for the sub-group of patients with PASI 15 following 12
weeks and 24 weeks of etanercept therapy.
(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).
Achievement of PASI 75 response at Week 12 and Week 24 in patients treated with etanercept 25mg BIW
| 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) |
| Week 24 | |||||
| Gottlieb et al | 32/57 (56%) | 3/5 (5%) | 0.46 (0.32,0.60) | 10.0 (3.2, 31.0) | 2 (2, 3) |
The PBAC noted an issue with the comparison of outcomes at 12 weeks
with those at 24 weeks that was not discussed in the submission was
the potential for confounding of results that occurs in the context
of a disease that generally flares and recedes over time. In such a
condition, the potential for regression to a mean state over time
becomes an important consideration.
Results for the PASI outcomes for the comparison of the placebo
(for 12 weeks followed by etanercept 25mg for 12 weeks) and
etanercept 25mg for 24 weeks arms of CSR-51727 at 24 weeks were
presented in the submission. It was acknowledged that this
comparison was not the ideal comparison (as the arm where
etanercept was delivered for 12 weeks had patients initially
treated with placebo followed by 12 weeks of etanercept) however
the comparison across arms was performed at the same time point
which may be important in the context of a disease that flares and
recedes over time.
The submission presented results of analyses of time to disease
relapse from CSR-51820 and CSR-51139, the former as pivotal
evidence and the latter as supportive evidence.
According to the current (and requested restriction) patients are
eligible for continued treatment with etanercept if they achieve
the equivalent of a PASI 75 response. In the requested restriction,
relapse was defined as a return to 75% of baseline PASI score. In
CSR-51820, patients were eligible for re-treatment if they achieved
a PASI 50 response at week 24 and the definition of relapse was a
50% loss of PASI improvement. The submission presented results of a
post hoc analysis based on patients achieving a PASI 75 at week
24.
The median time to relapse was 12 weeks for PASI 75 responders in
the placebo-crossover ITT group. By comparison, the median time to
relapse for PASI 75 responders in the etanercept ITT group was 16
weeks. The submission claimed that the results appear to suggest
that treatment with etanercept 25mg twice weekly for 24 weeks might
lead to longer time to relapse compared with treatment with the
same dosage for 12 weeks.
The submission presented results from the treatment withdrawal and
follow-up phase of trial CSR-51139. Time to disease relapse was
defined in this trial as “a return to 75% of the baseline
PASI or the start of systemic therapy, whichever came first”.
As noted by the submission, although this definition was more
consistent with the proposed PBS relapse criteria than the
definition of relapse in CSR-51820, the number of subjects who
entered the extended follow-up period was small (three subjects in
the placebo arm and 17 subjects in the etanercept-treated
arm).
The submission presents results of an analysis of response to
re-treatment of PASI 50 responders from trial CSR-51820. Results
comparing outcomes 24 weeks after re-treatment with outcomes after
the initial treatment period were provided in the submission. On
the basis of these results, the submission claimed that the overall
effect of re-treatment was similar to the effect of initial
treatment. On this basis, the model presented in the submission
assumed that patients responding to the initial course of
etanercept will continue to respond to future courses of continuing
etanercept therapy. The applicability of these results to the PBS
setting was uncertain given that the definition of response is PASI
50 rather than PASI 75.
9. Clinical Claim
The submission claimed that the proposed initial treatment period
of 24 weeks has significant advantages over the current initial
treatment period of 12 weeks, being significantly more effective
than the current regimen but associated with increased toxicity due
to the longer time on drug rather than decreased tolerance over
time.
See Recommendations and Reasons for PBAC’s
view.
10. Economic Analysis
A preliminary economic evaluation was presented. The only resource
included was drug costs. The trial-based incremental per extra PASI
75 responder over 24 weeks was between $15,000 and $45,000.
A modelled economic evaluation was presented. Outcomes were
expressed in terms of QALYs, which are derived from affected BSA
(body surface area) scores. The resources included were drug costs
and hospitalisation costs. The base case modelled incremental
discounted cost per extra discounted QALY gained over 10 years was
between $45,000 and $75,000.
The PBAC noted the results of the modelled economic evaluation
represented a best-case scenario. The PBAC also noted issues
concerning the modelled economic evaluation.
11. Estimated PBS Usage and Financial Implications
The submission estimated that the likely number of packs per year
(accounting for market share) was up to 28,857 in Year 5 following
change to restriction (with an associated cost of between $30 to
$60 million). The net financial cost per year to the PBS from
extension of the listing of etanercept was estimated to be $10 to
$30 million per year.
12. Recommendation and Reasons
The PBAC noted that none of the trials presented by the submission
addressed the appropriate clinical question (i.e. the comparative
efficacy and safety of: (i) etanercept 50 mg/week or 25 mg twice
weekly administered for 12 weeks initially (followed by a 12- week
discontinuation period) to patients satisfying the PBS eligibility
criteria and then, in responders, used intermittently (12 weeks
on-treatment, 12 weeks off-treatment) versus (ii) etanercept 50
mg/week or 25 mg twice weekly administered for 24 weeks to patients
satisfying the PBS eligibility criteria and then used
intermittently (12 weeks on-treatment, 12 weeks off-treatment) in
some patients (responders to treatment who do not relapse within a
12-week discontinuation period) and used continuously in other
responders (patients who relapse within the 12 week discontinuation
period).
Although, some evidence was presented to support increasing the
initial treatment period to 24 weeks, this was based on the results
of a post-hoc analysis.
The submission provided insufficient evidence to support a claim
that continuous etanercept (50mg/week) has advantages over
intermittent etanercept (50mg/week for 12 weeks followed by a
12-week treatment-free period) in patients who relapse within 12
weeks of discontinuing etanercept after response to initial
treatment. The Pre-Sub-Committee Response argument that there is a
clinical need for continuous treatment and that it is unreasonable
to require these patients to have to return to their severe
baseline, before being eligible to resume treatment, did not assist
in addressing the lack of evidence.
The PBAC acknowledged that, although efalizumab was also an
appropriate comparator, it had previously accepted that etanercept
given intermittently, with a 12-week initiation course, was of
similar safety and efficacy to continuous efalizumab. However, a
comparison with efaluzimab would have given extra support to
support a claim of superiority.
The PBAC also noted a number of issues raised concerning the
modelled economic evaluation, which meant there was uncertainty
about the resulting incremental cost effectiveness ratio. The ESC
advised that the cost per QALY of between $45,000 and $75,000
represented a ‘best-case’ scenario because, in general,
the assumptions used in the model were likely to maximise the
difference between intermittent and continuous etanercept treatment
regimens, and thus favour the proposed continuous treatment
regimen. Despite arguments in the Pre-PBAC Response contending that
a cost per QALY between $15,000 and $45,000 was the
‘best-case’ scenario, the PBAC agreed that a higher per
QALY represented the more plausible cost-effectiveness ratio that
still favours etanercept.
The PBAC thus rejected the submission because of uncertainty about
the clinical evidence for the proposed model of treatment and
inadequate evidence supporting the role of continuous vs
intermittent treatment, and because of a high and uncertain 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
Wyeth will determine a course of action based on an evaluation of the PBAC's comments. Wyeth continues to believe that there is a small group of psoriasis patients who would benefit significantly from continuous therapy with etanercept. A re-evaluation of the available evidence and available economic modelling methods is required to address the views of the PBAC.
