Azacitidine, powder for injection, 100 mg, Vidaza®
Public summary document for Azacitidine, powder for injection, 100 mg, Vidaza®
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Public Summary Document
Product: Azacitidine, powder for injection, 100
mg, Vidaza®
Sponsor: Celgene Pty Ltd
Date of PBAC Consideration: July 2009
1. Purpose of Application
The submission sought a Section 100 (Highly Specialised Drug)
listing for the treatment of myelodysplastic syndrome (MDS),
chronic myelomonocytic leukaemia (CMML) and acute myeloid leukaemia
(AML) in patients who meet certain criteria.
2. Background
This drug had not previously been considered by the PBAC.
3. Registration Status
At the time of writing, azacitidine was not TGA registered.
4. Listing Requested and PBAC’s View
Section 100 – Highly Specialised Drugs
Private hospital authority required
Treatment of a patient with:
1. MDS classified as Intermediate-2 or high risk according to the International Prognostic Scoring System (IPSS); OR
2. Chronic Myelomonocytic Leukaemia (CMML (10 % - 29 % marrow blasts without Myeloproliferative Disorder); OR
3. Acute Myeloid Leukaemia (AML) with 20-30 % blasts and multi-lineage dysplasia, according to World Health Organisation (WHO) Classification.
Classification of a patient as Intermediate-2 requires a score of
1.5-2.0 on the IPSS, achieved with the possible combinations:
1. 11%-30% marrow blasts with good karyotypic status (normal, -Y alone, del(5q) alone, del(20q) alone), and 0/1 cytopenias; OR
2. 11%-20% marrow blasts with intermediate karyotypic status (other abnormalities), and 0/1 cytopenias; OR
3. 11%-20% marrow blasts with good karyotypic status (normal, -Y alone, del(5q) alone, del(20q) alone), and 2/3 cytopenias; OR
4. 5%-10% marrow blasts with poor karyotypic status (≥ 3 abnormalities or chromosome 7 anomalies), regardless of cytopenias; OR
5. 5%-10% marrow blasts with intermediate karyotypic status (other abnormalities), and 2/3 cytopenias; OR
6. <5% marrow blasts with poor karyotypic status (≥ 3 abnormalities or chromosome anomalies), and 2/3 cytopenias.
Classification of a patient as high risk requires a score of ≥
2.5 on the IPSS, achieved with the possible combinations:
1. 21%-30% marrow blasts with good karyotypic status (normal, -Y alone, del(5q) alone, del(20q) alone), and 2/3 cytopenias; OR
2. 21%-30% marrow blasts with intermediate (other abnormalities) or poor karyotypic status (≥ 3 abnormalities or chromosome 7 anomalies), regardless of cytopenias; OR
3. 11%-20% marrow blasts with poor karyotypic status (≥ 3 abnormalities or chromosome 7 anomalies), regardless of cytopenias; OR
4. 11-20% marrow blasts with intermediate karyotypic status (other abnormalities), and 2/3 cytopenias.
The PBAC considered that azacitidine was more suitable for listing
under Section 85, which was consistent with the listings for all
other chemotherapy agents, however, noted that this would lead to
increased costs for the Government. The PBAC considered that there
may be a substantial risk of leakage outside the requested
restriction into elderly patients with AML (with greater than 30 %
blasts) for which no effective therapy existed. However, a written
Authority would minimise the risk of leakage as would the provision
of the bone marrow biopsy report to Medicare Australia. The PBAC
also considered that continuation criteria would not be
appropriate.
5. Clinical Place for the Proposed Therapy
Azacitidine will be an alternative to best supportive care (BSC)
alone or to BSC plus conventional therapy for patients with
MDS.
6. Comparator
The submission nominated a combination of BSC (which included use
of erythropoietin, deferasirox, desferrioxamine and granulocyte
colony stimulating factor) low dose cytarabine (LDAC) and standard
chemotherapy (AML type protocols consisting of LDAC and an
anthracycline) as the main comparators.
For PBAC's views, see the Recommendations and
Reasons.
7. Clinical Trials
The submission presented one pivotal randomised trial comparing azacitidine 75mg/m2/day with conventional care in patients with IPSS classification INT2/high risk MDS
and one supplementary trial comparing azacitidine with BSC in patients with all MDS
categories.
The studies published at the time of the submission are as follows:
Trial ID/First author | Protocol title/ Publication title | Publication citation |
---|---|---|
Pivotal randomised trial | ||
AZA-001/ Fenaux, P | Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. | The Lancet Oncology (2009). (Published Online February 18). |
Supplementary randomised trial | ||
Silverman, L, 2002 Silverman, L, 2006 Kornblith, A. 2002 | Randomised controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukaemia group B. Further analysis of trials with azacitidine in patients with myelodysplastic syndrome: studies 8421, 8921, and 9221 by the Cancer and Leukaemia Group B." Impact of azacitidine on the quality of life of patients with myelodysplastic syndrome treated in a randomised phase III trial: a Cancer and Leukaemia Group B study. | Journal of Clinical Oncology 2002; 20(10): 2429-2440. Journal of Clinical Oncology 2006; 24(24): 3895-3903. Journal of Clinical Oncology 2002; 20(10): 2441-52. |
8. Results of Trials
Overall survival was increased by a median of 9.4 months in the pivotal trial (p=0.0001)
and by a median of 6.0 months in the supplementary trial (p=0.10.) The figure below
provided a plot of overall survival using a Kaplan-Meier survival analysis. The results
indicated azacitidine to be superior in efficacy to conventional care regimes.
AZA-001 Kaplan-Meier plot of overall survival
For the secondary outcomes, in both trials, the median time to transformation to AML
or death was significantly longer in the azacitidine group compared with the conventional
care/BSC group. The rate of RBC transfusions was approximately 1.7 fold higher in
the conventional care group compared with the azacitidine group. The rate of platelet
transfusions was approximately 1.6 fold higher in the conventional care group compared
with the azacitidine group.
Azacitidine was associated with a number of adverse effects. These were comparable
to drugs used in the comparator arm, namely cytarabine, idarubicin and daunorubicin;
however, these medications only comprised a proportion of conventional care. The major
differences between azacitidine and conventional care were in the rates of neutropenia
and thrombocytopenia (see table below).
Grade 3/4 Treatment Emergent Adverse Events (? 10.0% in the azacitidine group)
Azacitidine (n=175) | Conventional care (n=165) | RR (95% CI) | RD (95% CI) | |
---|---|---|---|---|
Patients with at least 1 TEAE with intensity Grade 3 or 4 | 160 (91.4) | 128 (77.6) | 1.18 (1.07,1.29) | 0.14 (0.06,0.21) |
Blood and lymphatic system disorders | 143 (81.7) | 87 (52.7)* | 1.55 (1.32,1.82) | 0.29 (0.2,0.39) |
Neutropenia | 107 (61.1) | 46 (27.9) | 2.19 (1.67,2.88) | 0.33 (0.23,0.43) |
Thrombocytopenia | 102 (58.3) | 62 (37.6) | 1.55 (1.23,1.96) | 0.21 (0.1,0.31) |
Leukopenia | 26 (14.9) | 9 (5.5) | 2.72 (1.32,5.64) | 0.09 (0.03,0.16) |
Anaemia | 24 (13.7) | 20 (12.1) | 1.13 (0.65,1.97) | 0.02 (-0.06,0.09) |
Febrile neutropenia | 22 (12.6) | 15 (9.1) | 1.38 (0.74,2.57) | 0.03 (-0.03,0.1) |
Neoplasms benign, malignant, and unspecified (incl. Cysts and polyps) | 38 (21.7) | 42 (25.5) | 0.85 (0.58,1.25) | -0.04 (-0.13,0.05) |
Acute myeloid leukaemia | 28 (16.0) | 38 (23.0) | 0.69 (0.45,1.08) | -0.07 (-0.15,0.01) |
Infections and infestations | 52 (29.7) | 46 (27.9) | 1.07 (0.76,1.49) | 0.02 (-0.08,0.12) |
Pneumonia | 18 (10.3) | 15 (9.1) | 1.13 (0.59,2.17) | 0.01 (-0.05,0.08) |
TEAE = treatment-emergent adverse event, RR relative risk, RD risk difference,
*corrected from error in the submission table which had the value as 875 (2.7)
9. Clinical Claim
The submission described azacitidine as superior in terms of comparative effectiveness
and inferior in terms of comparative safety.
For PBAC’s views see Recommendation and Reasons.
10. Economic Analysis
A stepped economic evaluation was presented. The type of evaluation presented was
a cost-effectiveness and cost-utility model with a lifetime time horizon. The three
steps were comprised of a within trial evaluation, extrapolated survival to obtain
life years gained (LYG) and finally the application of utility values to calculate
QALYs.
The model was sensitive to the drug costs (per ml or per vial) and to the utility
values.
For PBAC’s views see Recommendation and Reasons.
11. Estimated PBS Usage and Financial Implications
The estimated financial cost/year to the PBS was in the range of $10 – $30 million
per year in Year 5.
12. Recommendation and Reasons
The PBAC considered that azacitidine was more suitable for listing under Section 85,
which was consistent with the listings for all other chemotherapy agents, however,
noted that this would lead to increased costs for the Government. The PBAC noted that
azacitidine would probably not be suitable for inclusion in the Intravenous Chemotherapy
Supply Program (ICSP) due to its very short shelf life when prepared and low number
of patients, making vial sharing difficult.
The PBAC considered that there may be a substantial risk of leakage outside the requested
restriction into elderly patients with AML (with greater than 30 % blasts) for which
no effective therapy existed. However, a written Authority would minimise the risk
of leakage as would the provision of the bone marrow biopsy report to Medicare Australia.
The PBAC also considered that continuation criteria would not be appropriate given
the absence of trial data indicating that benefit was restricted to patients who achieve
a formally-defined response.
The PBAC agreed that BSC (which included low dose cytarabine and standard chemotherapy)
was the appropriate comparator and that the clinical trial data supported the claim
that azacitidine was significantly more effective than conventional care but was associated
with more toxicity when used for the treatment of INT-2/high risk MDS patients. The
PBAC noted that the pivotal trial showed a median survival gain of 9.4 months and
the supplementary trial showed a median survival gain of 6 months. The PBAC considered
that there was a high clinical need for azacitidine.
The main matters of concern to the PBAC were the utility values and the economic model.
The PBAC noted that there were a number of uncertainties in the methods used to generate
utilities for the submission. These included the use of subscales, the use of EORTC
generated utilities from the Silverman study, the use of an internal commissioned
secondary study to generate utility scores, and the use of algorithms from other studies
super-imposed on this study. However, while the cost per QALY gained estimates for
azacitidine were sensitive to the utility estimates, the paucity of available utility
data was also recognised, particularly as the AZA-001 trial did not capture utilities.
The PBAC considered that the utility values used in the model were uncertain, given
that they were calculated using a number of steps, with each step containing the potential
for error, and were higher than utility values available in the literature.
The PBAC noted that the benefits of azacitidine were extrapolated using a life time
model beyond the end of the trial but the costs were ceased at the end of the trial.
The PBAC considered that this favoured the azacitidine arm because costs of transfusion
(red cell and platelets) and other costs would increase over time because patients
who live longer will eventually progress. Therefore, the azacitidine group would start
incurring higher costs.
The PBAC noted that, the base case of the model assumed that vial sharing occurs between
patients, but considered that this was an unreasonable assumption as azacitidine has
a short expiry date (less than 8 hours) once mixed for use and MDS is not a highly
prevalent condition. The PBAC noted that the ICER increased using the ex-manufacturer
price for Section 100, costed on a per vial basis as opposed to cost per mg and also
correcting the daunorubicin costs. This estimate would be higher if azacitidine is
included in section 85.
The PBAC concluded that both the base-case ICER and the revised ICER were highly uncertain
as the ICER was very sensitive to utilities, duration of therapy and wastage related
to vials.
The PBAC agreed with the DUSC that the estimates of usage presented in the submission
were uncertain and likely to be overestimated.
The PBAC therefore deferred this submission to the August 7 Special PBAC meeting and
requested the Pharmaceutical Evaluation Section provide further analyses of the base
case economic model.
Recommendation
Defer
(See also attached addenda)
13. Context for DecisionThe 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.
ADDENDUM 1
Product: Azacitidine, powder for injection, 100
mg, Vidaza®
Sponsor: Celgene Pty Ltd
Date of PBAC Consideration: August 2009
Purpose of Submission:
The submission sought a Section 100 (Highly Specialised Drug)
listing for the treatment of myelodysplastic syndrome (MDS),
chronic myelomonocytic leukaemia (CMML) and acute myeloid leukaemia
(AML) in patients who meet certain criteria and to address the
concerns of the PBAC regarding the application to the July 2009
PBAC meeting
Background:
At its July 2009 meeting, the PBAC deferred a decision regarding
the application to list azacitidine on the PBS for the treatment of
patients with IPSS INT-2/high risk myelodysplastic syndrome (MDS)
pending further information regarding suggested changes to the
proposed PBS listing, the results of specific sensitivity analyses
around the incremental cost-effectiveness ratio (ICER) and the
structure of the proposed risk sharing arrangement (RSA).
Summary of submission
:The submission addressed the following issues raised by the
PBAC:
Changes to the proposed PBS Listing
The sponsor had no objections to the restriction suggested during
evaluation of the July 2009 submission.
Results of sensitivity analyses
The submission presented further analyses of the base case economic
model.
Recommendations and Reasons:
The PBAC noted the submission addressed all the previous issues of
concern to the PBAC and noted a price reduction was proposed.
However, none of the adjustments to the model greatly changed the
ICER and the PBAC considered that the ICER still remained uncertain
and high.
The PBAC considered that the utilities were still uncertain even
though disutilities were included, which were decreased to 0.3 for
the 7 day duration of treatment. However, the PBAC considered there
was no accumulation of disutility and that the decrease over 7 days
would not reflect any substantial change to the estimates of the
July 2009 submission.
The PBAC considered that there was still uncertainty around the
model construction. The model is a standard decisional model and
the model represents 80-85% of the trial period. There is no long
extrapolation period and no long term treatment effect. Therefore,
the model may underestimate costs.
The PBAC noted that the transfusion costs include patients who
progress and those who do not progress. There are no separate data
on the transfusion costs for the patients who progress. There is
uncertainty as to whether this would make significant differences
to the results. The PBAC also noted that the transfusion cost issue
was not addressed in the proposed risk share arrangement and that
the time in AML transformation was also not included in the
model.
The PBAC noted that the greatest change in the cost per QALY gained
from the base case was attained when the costs of azacitidine were
estimated under a section 100 listing or through the Chemotherapy
Pharmaceuticals Access Program (CPAP) and at the reduced price
proposed. However, the PBAC considered that a section 85 listing
was still more appropriate.
The PBAC also considered that a written authority for a section 85
listing would be needed to minimise the risk of leakage. However,
written authorities are unable to be processed through CPAP and
hence azacitidine would not be eligible for inclusion in the
program. Therefore, the PBAC considered that the ICER of between
$45,000 and $75,000 per QALY gained to be a more realistic
estimation of the ICER
The PBAC acknowledged that there is a high clinical need for
azacitidine as there is no other agent that is clinically effective
and a survival gain has been demonstrated with azacitidine.
However, the PBAC considered that at a further price decrease would
be needed for the ICER to become acceptable and hence deferred the
submission pending further negotiation with the sponsor regarding
the price. Another way in which the cost could be improved would be
the production of additional vial size(s) because of the
considerable wastage that occurs with a 100 mg strength, with an
average use of 1.2 vials.
Recommendation
Defer
ADDENDUM 2
Product: Azacitidine, powder for injection, 100
mg, Vidaza®
Sponsor: Celgene Pty Ltd
Date of PBAC Consideration: September 2009
Purpose of Submission:
The submission sought to address the concerns of the PBAC regarding
the application to the July 2009 and August 2009 PBAC
meetings.
Recommendation and Reasons
The PBAC recommended the listing of azacitidine under section 100
of the PBS for the treatment of myelodysplastic syndrome (MDS) or
chronic myelomonocytic leukaemia (CMML) or acute myeloid leukaemia
(AML) in patients who meet certain criteria on the basis of a high,
but acceptable incremental cost effectiveness ratio (ICER). The
PBAC agreed that supply through section 100 was appropriate
following advice from the Highly Specialised Drugs Working
Party.
In making this recommendation, the PBAC noted that the pivotal
trial showed that treatment with azacitidine resulted in a median
survival gain of 9.4 months and the supplementary trial showed a
median survival gain of 6 months. The PBAC considered that in the
absence of other effective treatments for myelodysplastic
syndromes, there is a high clinical need for azacitidine. In this
context, the ICERs which varied between $45,000 and $75,000 per
QALY were deemed acceptable.
The PBAC noted that in arriving at these ICERs, the sponsor had
offered a further price reduction.
The PBAC agreed that uncertainties about disutility for toxicity
and a potential increase in transfusions post-progression following
treatment with azacitidine were adequately addressed in the
sensitivity analysis.
Recommendation
AZACITIDINE, powder for injection, 100 mg
Restriction: Section 100 (Highly Specialised Drugs Program)
Public and private hospital authority required
Complex - to be finalised
Pack size: 1
Sponsor’s Comment
Celgene welcomes the positive recommendation for Azacitidine from the PBAC. The Company also wishes to acknowledge the collaborative approach taken by the Department of Health and the PBAC in achieving this positive outcome