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