Rituximab, solution for I.V infusion, 100 mg in 10 mL, 500 mg in 50 mL, Mabthera®
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Product: Rituximab, solution for I.V infusion, 100
mg in 10 mL, 500 mg in 50 mL, Mabthera®
Sponsor: Roche Products Pty Ltd
Date of PBAC Consideration: November 2010
1. Purpose of Application
The submission sought to address concerns of the PBAC from the
March 2010 meeting, regarding the cost-effectiveness of rituximab
in the treatment of patients with CD20 positive chronic lymphocytic
leukaemia (CLL) in combination with chemotherapy.
2. Background
At the March 2010 meeting, the PBAC deferred a submission requesting an extension
to the current listing for rituximab to include a Section 85 Authority Required listing
and inclusion in the Chemotherapy Pharmaceutical Access Program (CPAP) for the treatment
of CD20 positive, chronic lymphocytic leukaemia, in combination with chemotherapy,
to request the sponsor recalculate the incremental cost-effectiveness in the modelled
economic evaluation to include consideration of the uncertainties identified by the
PBAC. These included the time horizon, ages of patients entering the model, the impact
of reducing treatment effect over time and the effect of varying patients’ baseline
risk.
Full details are available in the March 2010 Public Summary Document available.
3. Registration Status
Rituximab was registered for first-line treatment of patients with
CD20 positive CLL in combination with chemotherapy by the TGA on 26
August 2009.
On 8 January 2010, the TGA extended the registration of rituximab
to include treatment of patients with CD20 positive CLL in
combination with chemotherapy, other than as first line.
Rituximab is also TGA registered for the treatment of certain types
of B-cell non-Hodgkin lymphoma and rheumatoid arthritis under
certain conditions.
4. Listing Requested and PBAC’s View
Authority Required
CD20 positive, chronic lymphocytic leukaemia, in combination with
chemotherapy.
NOTE:
Not for use as monotherapy.
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
CLL is the most common chronic leukaemia and comprises 30% of all
adult leukaemias. The majority of patients with CLL are
asymptomatic at diagnosis. Symptoms appear with disease progression
and are generally related to cytopenias due to bone marrow
infiltration of malignant cells. Treatment is usually initiated
when patients become symptomatic, when there is a high tumour
burden or evidence of rapidly progressive disease.
Rituximab in combination with chemotherapy would provide an
additional treatment option for CLL. The submission proposed that
in the first line setting, rituximab would be added to fludarabine
and cyclophosphamide (FC), chlorambucil, or cyclophosphamide,
vincristine and prednisone (CVP) chemotherapy protocols, and in the
relapsed/refractory setting to cyclophosphamide, doxorubicin,
vincristine and prednisone (CHOP), CVP or FC chemotherapy
protocols.
6. Comparator
The re-submission nominated chemotherapy alone (fludarabine plus
cyclophosphamide) as the comparator. This was previously accepted
by the PBAC.
The re-submission also presented the results of a sensitivity
analysis to assess the incremental cost-effectiveness of the
addition of rituximab to chlorambucil compared with chlorambucil
alone.
7. Clinical Trials
The submission presented two randomised trials (CLL-8 and REACH)
comparing the combination of rituximab with fludarabine and
cyclophosphamide (R-FC) with fludarabine plus cyclophosphamide (FC)
in patients with CLL. This was unchanged from the previous
submission.
Citations for CLL-8 and REACH have been previously reported in the
March 2010 Public Summary Document.
8. Results of Trials
Results from the trials have been previously reported in the March
2010 Public Summary Document.
The PBAC accepted that the combination of fludarabine with
cyclophosphamide is the most effective chemotherapy for the
treatment of CLL and that chlorambucil is less effective compared
with FC by a factor of two (based on data from Catovsky et al.
Assessment of fludarabine plus cyclophosphamide for patients
with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a
randomised controlled trial, Lancet 2007; 370:
230–39.
The PBAC considered that rituximab has benefits when used in
combination with other chemotherapy but the magnitude and
durability of such benefits were uncertain.
No new toxicity data were presented in the submission, with the
exception of the additional note about the increased risk of
progressive multifocal leukoencephalopathy (PML) with rituximab use
reported in the latest Product Information.
At the March 2010 meeting, the PBAC agreed that rituximab was more
toxic than chemotherapy alone and this was supported by the
clinical evidence which demonstrated that there was increased
neutropenia and febrile neutropenia. Significantly more Grade 3 and
4 adverse events occurred with the addition of rituximab in both
key trials. Neutropenia, febrile neutropenia, and leucopenia were
key drivers of safety concerns with rituximab and might affect
patient quality of life.
For PBAC’s view, see Recommendation and
Reasons.
9. Clinical Claim
The re-submission claimed that rituximab is more effective and more
toxic than the comparator of chemotherapy alone.
For PBAC’s view, see Recommendation and
Reasons.
10. Economic Analysis
The modelled economic evaluation presented at the March 2010
meeting, was a five-step process and remained unchanged in the
re-submission.
The incremental cost per QALY gained in the base case was between
$15,000 and $45,000 for the R-FC combination.
A sensitivity analysis assessed the incremental cost-effectiveness
for combination R-FC of a patient entry age of 60 versus 70 years,
assuming a continuing benefit of rituximab over the 10-year period.
The incremental cost effectiveness ratio (ICER) for combination
R-FC using a starting age of 60 years and a 15-year time horizon
was in the range of between $15,000 and $45,000 per QALY (effect of
rituximab maintained) to between $45,000 and $75,000 per QALY
(progression curves converge rapidly).
A sensitivity analysis was conducted to assess the incremental
cost-effectiveness of the addition of rituximab to chlorambucil
compared to chlorambucil alone. The re-submission doubled the rate
of progression (Catovsky et al) and with an increased patient age
of 70, a time horizon of 15 years and continued benefit with
rituximab, the cost-effectiveness in this setting was estimated to
be in the range of $45,000 to $75,000 per QALY (base case
analysis).
For the scenario of rituximab used in combination with chlorambucil
and a starting age of 70 years, a 10 year time horizon and
durability of benefit which tapered to control group over five
years after year five, a rapid convergence of time unprogressed
curves beyond 5 years and a doubled baseline rate of progression,
the base case ICER was estimated to be in the range of $45,000 to
$75,000 per QALY. With convergence of the time unprogressed and
overall survival beyond 5 years, the base case ICER was estimated
to be in the range of $75,000 to $105,000 per QALY.
For PBAC’s view, see Recommendation and
Reasons.
11. Estimated PBS Usage and Financial Implications
The likely number of patients per year was estimated in the
re-submission to be less than 10,000 (including first-line and
relapsed patients) in year 5 after listing. This is unchanged from
the previous submission.
The re-submission estimated the net financial cost per year to the
PBS as a result of the listing to be in the range of $10 to $30
million in Year 5.
12. Recommendation and Reasons
The PBAC recommended the listing of rituximab in combination with
fludarabine and cyclophosphamide (R-FC) on the PBS as an Authority
Required listing and in the Section 100 Chemotherapy
Pharmaceuticals Access Program (CPAP) for CD20 positive, chronic
lymphocytic leukaemia on the basis of a high but acceptable
cost-effectiveness ratio compared with FC.
The PBAC agreed that the NOTE stating that rituximab is not
PBS-subsidised for monotherapy was appropriate and should be
included.
The PBAC noted that no new clinical trial data were presented.
However, the PBAC previously agreed in March 2010 that the outcome
of progression-free survival (PFS) measured in the CLL-8 and REACH
trials concurred with the clinical claim of superiority. Further,
as for the PFS data, combining the overall survival (OS) data from
trials CLL-8 and REACH was reasonable as there was no significant
heterogeneity in this analysis and that it was reasonable to assume
that treatment with rituximab would improve survival.
The PBAC agreed that for combination R-FC, a starting age of 60
years and a 15-year time horizon was appropriate in the economic
model and that the ICER was most likely in the range of between
$15,000 and $45,000 per QALY (effect of rituximab maintained) to
between $45,000 and $75,000 per QALY (progression curves converged
rapidly, which was considered by the PBAC to be high, but
acceptably cost-effective.
The PBAC accepted that the combination of fludarabine with
cyclophosphamide is the most effective chemotherapy for the
treatment of CLL and that chlorambucil is less effective compared
with FC by a factor of two (based on the data from Catovsky et al).
The PBAC considered that if the PBS listing of rituximab was
restricted to use with FC alone, there may be toxicity issues with
use of this combination in the elderly and that there may be
potential for leakage to use in combination with other chemotherapy
despite being restricted to use with FC alone.
The PBAC considered that rituximab has benefits when used in
combination with other chemotherapy but the magnitude and
durability of such benefits were uncertain. The PBAC noted that a
sensitivity analysis was conducted in the re-submission to assess
the incremental cost-effectiveness of the addition of rituximab to
chlorambucil compared chlorambucil alone. The re-submission doubled
the rate of progression (Catovsky et al) and with an increased
patient age of 70, a time horizon of 15 years and continued benefit
with rituximab, the cost-effectiveness in this setting was
estimated to be in the range of $45,000 to $75,000 per QALY (base
case analysis).
However, the PBAC considered that the most plausible scenario
analysis when rituximab is used in combination with chlorambucil
was age 70 years, a 10 year time horizon and durability of benefit
which tapered to control group over five years after year five.
With those inputs, a rapid convergence of time unprogressed curves
beyond 5 years and a doubled baseline rate of progression, the base
case ICER was estimated to be in the range of $45,000 to $75,000
per QALY. With convergence of the time unprogressed and overall
survival beyond 5 years, the base case ICER was estimated to be in
the range of $75,000 to $105,000 per QALY. The PBAC concluded that
the combination of rituximab with chlorambucil/other chemotherapy
was not cost-effective unless the ICER for the combination with
non-FC chemotherapy was in the same range as the ICER for R-FC. The
PBAC noted that it may be prepared to consider the matter out of
session should the ICER for combination with non-FC chemotherapy be
reduced to within this range and would consider recommending the
restriction be changed to allow use of rituximab “in
combination with chemotherapy”.
The PBAC did not recommend rituximab for inclusion in the list of
PBS medicines for prescribing by nurse practitioners as
chemotherapy agents are excluded.
Further out-of-session PBAC consideration:
Further to the November 2010 PBAC recommendation for PBS listing of
rituximab in combination with fludarabine and cyclophosphamide
(R-FC), the PBAC recommended out-of-session the listing of
rituximab in combination with non-FC chemotherapy on the PBS on the
basis of a high but acceptable cost-effectiveness ratio. The PBAC
recommended an Authority Required listing and listing in the
Section 100 Chemotherapy Pharmaceuticals Access Program (CPAP) for
CD20 positive, chronic lymphocytic leukaemia in combination with
chemotherapy.
The PBAC noted the alternative proposal provided by the sponsor
out-of-session for the use of rituximab in combination with non-FC
chemotherapy, which resulted in ICERs in the same range as the
ICERs for R-FC.
Recommendation:
RITUXIMAB, solution for I.V. infusion, 100 mg in 10mL and 500 mg in
50mL, Mabthera®
Extend the current restriction to include:
Restriction: Authority Required
CD20 positive, chronic lymphocytic leukaemia, in combination with chemotherapy.
NOTE:
Rituximab is not PBS-subsidised for use as monotherapy.
Maximum quantity: 2
Repeats: 5
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 has no further comment.
