Imatinib mesylate, tablets, 100 mg and 400 mg (base), Glivec, March 2008
Public summary document for Imatinib mesylate, tablets, 100 mg and 400 mg (base), Glivec, March 2008
Page last updated: 04 July 2008
Public Summary Documents
Product: Imatinib mesylate, tablets, 100 mg and 400 mg (base), Glivec
Sponsor: Novartis Pharmaceuticals Australia Pty Ltd
Date of PBAC Consideration: March 2008
1. Purpose of Application
The submission sought to extend the current listing for imatinib to include the treatment of four rare diseases: dermatofibrosarcoma protuberans (DFSP), hypereosinophilic syndrome/chronic eosinophilic leukaemia (HES/CEL), myelodysplastic/myeloproliferative diseases (MDS/MPD) and aggressive systemic mastocytosis (ASM).
2. Background
At the July 2007 meeting, the PBAC rejected a submission for imatinib for these rare diseases based on uncertain clinical benefit and uncertain cost-effectiveness. The PBAC expressed its sympathy for patients with these conditions, acknowledging that effective treatments are limited. The Committee further accepted that because of the rarity of these conditions, any data to support a PBS listing would have limitations. However, the PBAC considered that there was only very weak evidence of greater efficacy of imatinib over standard care, particularly with regards durable benefit. The data were limited to response rates in case series, with and without imatinib, and with no controlled data, and minimal long term follow up. The data were very sparse with considerable residual statistical uncertainty and the PBAC considered that the effects of imatinib appeared moderate, at best. The clinical benefits of observed responses were also uncertain because of a lack of follow up data.
3. Registration Status
Imatinib is TGA registered for the following indications:
- Patients with chronic myeloid leukaemia (CML).
- Adult patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph+ ALL) integrated with chemotherapy.
- Adult patients with relapsed or refractory Ph+ ALL as monotherapy.
- Adult patients with myelodysplastic/ myeloproliferative diseases (MDS/MPD) associated with platelet derived growth factor receptor (PDGFR) gene re-arrangements, where conventional therapies have failed. (10 May 2007)
- Adult patients with aggressive systemic mastocytosis (ASM), where conventional therapies have failed. (10 May 2007)
- Adult patients with hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukaemia (CEL). (10 May 2007)
- Patients with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumours (GIST). (10 May 2007)
- Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans (DFSP). (10 May 2007)
4. Listing Requested and PBAC’s View
Dermatofibrosarcoma protuberans:
Section 85 Authority Required
Initial PBS-subsidised treatment, for up to 6 months, of an adult patient with unresectable,
recurrent and/or metastatic dermatofibrosarcoma protuberans.
1) Where the application for authority to prescribe is being sought on the basis of
unresectable tumour, written evidence in support of that claim must be provided
2) Where the application for authority to prescribe is being sought on the basis of
metastatic disease, the most recent CT scan, MRI or ultrasound assessment of the tumour
must be provided
Continuing PBS-subsidised treatment of an adult patient with unresectable, recurrent
and/or metastatic dermatofibrosarcoma protuberans who has previously been issued with
an authority prescription for imatinib and who has demonstrated a response.
Hypereosin
ophilic syndrome/ Chronic eosinophilic leukaemia:
Section 85 Authority Required
Initial PBS-subsidised treatment, for up to 6 months, of an adult patient with hypereosinophilic
syndrome and/or chronic eosinophilic leukaemia which has been confirmed by the detection
of the FIP1L1-PDGFRA fusion gene.
NOTE: Any queries concerning the detection of the FIP1L1- PDGFRA fusion gene may be
directed to Medicare Australia.
Continuing PBS-subsidised treatment of an adult patient with hypereosinophilic syndrome
and/or chronic eosinophilic leukaemia who has previously been issued with an authority
prescription for imatinib and who has demonstrated a response.
Myelodysplastic / myeloproliferative disorders:
Section 85 Authority Required
Initial PBS-subsidised treatment, for up to 6 months, of an adult patient with myelodysplastic
syndromes or myeloproliferative disorders
1) which has been confirmed by the detection of platelet-derived growth factor receptor
(PDGFR) gene re-arrangements by standard karyotyping, or where the karyotyping is
not informative for technical reasons, a demonstration of 5q33 abnormalities on FISH,
and
2) that the patient has previously failed an adequate trial of one or more of the
following conventional therapy:
- cytarabine
- etoposide
- hydroxyurea
- interferon
NOTE: Any queries concerning the FISH detection of 5q33 abnormalities may be directed
to Medicare Australia.
Continuing PBS-subsidised treatment of an adult patient with myelodysplastic syndromes
or myeloproliferative disorders who has previously been issued with an authority prescription
for imatinib and who has demonstrated a response.
Aggressive Systemic Mastocytosis
Section 85 Authority Required
Initial PBS-subsidised treatment, for up to 6 months, of an adult patient with aggressive
systemic mastocytosis
1) which has been confirmed by the detection of the FIP1L1-PDGFRA fusion gene and
demonstration of the absence of the D816V c-kit mutation; and
2) where the patient has previously failed an adequate trial of one or more of the
following conventional therapy:
- corticosteroids
- hydroxyurea
- interferon
NOTE: Any queries concerning the detection of the FIP1L1- PDGFRA fusion gene and the
demonstration of the absence of the D816V c-kit mutation may be directed to Medicare
Australia.
Continuing PBS-subsidised treatment of an adult patient with aggressive systemic mastocytosis
who has previously been issued with an authority prescription for imatinib and who
has demonstrated a response.
See Recommendations and Reasons for PBAC’s view.
5. Clinical Place for the Proposed Therapy
Imatinib is used in the treatment of a variety of malignancies, such as the four rare diseases above, as the pathogenesis of the disease may involve one or more of the tyrosine kinase enzymes, which is known to be inhibited by the drug.
6. Comparator
The re-submission nominated standard medical management (as detailed below) as the
comparator. This was accepted as appropriate by the PBAC.
Dermatofibrosarcoma protuberans:
The submission nominated radiotherapy as the main comparator for patients with unresectable,
recurrent and/or metastatic DFSP. In patients who may not be receiving radiotherapy
(50%) standard medical management (placebo) may be the comparator.
Hypereosinophilic syndrome / Chronic eosinophilic
leukaemia:
The submission nominated standard chemotherapy (alkylating agents, corticosteroids,
hydroxyurea and interferon) as the main comparator.
Myelodysplastic / myeloproliferative disorders:
The submission nominated standard medical management/best supportive care as the main
comparator. However, an alternative comparator may also be chemotherapy (cytarabine,
etoposide, hydroxyurea and interferon).
Aggressive Systemic Mastocytosis:
The submission nominated standard medical management/best supportive care as the main
comparator. However, an alternative comparator may also be chemotherapy (corticosteroids,
hydroxyurea and interferon).
7. Clinical Trials
No randomised trials were found in an updated literature search, although approximately
15 new case series were found and reported. The re-submission pooled results from
case series (from imatinib and non-imatinib case series). The re-submission stated
that these case series provided more information on whether patients were carrying
particular sensitive molecular targets. The re-submission presented a non-randomised
trial, Study B2225, (a case series study of imatinib following failure of standard
therapeutic options in patients with DFSP, HES/CEL, MDS/MDP and ASM), which was also
included in the previous submission, but this was not used in the economic evaluation.
8. Results of Trials
The key results are summarised in the table below.
Aggregated response rates of the case series
|
Disease |
Imatinib |
Comparator |
|---|---|---|
|
DFSP |
11/12 (92%) |
85/106 * 20% (16%)a |
|
HES/CEL |
11/11 (100%) |
52/79 (66%) |
|
MDS/MPD (BSC) |
15/16 (94%) |
0/14 (0%) |
|
MDS/MPD (Chemotherapy) |
15/16 (94%) |
97/206 * 206/510 (19%) b |
|
MDS/MPD (Duration of response for chemotherapy - months) |
49.0 (n=10) |
10.3 (n=27) |
|
ASM |
16/17 (94%) |
30/64 (47%) |
Notes: aThis assumption is adopted in calculating the cost-effectiveness of radiotherapy
in the economic evaluation.
b Response rate for all patients weighted by proportion of patients with 5q33 abnormalities,
i.e. 47%*206/510=19%
For DFSP the re-submission combined all the response rates (partial, transient, complete
and stable disease) for the imatinib case series and the non-imatinib case series.
The re-submission stated that the response rate for imatinib is 92%, while the response
rate for non-imatinib is 80%. The re-submission argued that only approximately 20%
of all the patients represented in this case series would be most representative of
patients eligible under the proposed PBS listing.
For the response rates in MDS/MPD the resubmission calculated an overall response
by weighting the response rates for chemotherapy (47%) by the proportion of patients
who have chromosome 5 or 7 abnormalities (40%).
The PBAC noted the response rates were not defined consistently across studies and
could include partial or complete haematological or molecular response. Various case
series did not even define a response.
The re-submission stated that, in most cases, there was inadequate reporting in the
case series and that any statistical approaches to address potential bias, confounding
and pooling of results would not have made up for the lack of robustness in the case
series data.
The PBAC noted the submission proposed several diagnostic tests as part of the restriction.
The submission obtained preliminary information obtained from the various testing
facilities indicate that the costs for each of the tests are approximately
- $200 (for FISH or RT-PCR testing of FIP1L1-PDGFRA)
- $250 (for FISH testing of 5q33 abnormalities)
- $2000 (for PCR testing of D816V c-kit mutation analysis)
These costs were used in the economic evaluation.
The re-submission did not present new toxicity data. Toxicity information from Study
B2225 was provided in the previous submission. Gastrointestinal disorders, general
disorders, skin complaints and oedema at various sites were the most frequently reported
adverse events.
9. Clinical Claim
The re-submission suggested that imatinib produced good response rates in all four
diseases.
The PBAC accepted the clinical claims of effectiveness in these rare disease subsets
with respect to high response rates. The PBAC noted that the quality of reported responses
with imatinib is substantially superior to those with standard care and considered
that the case report data clearly reflect a clinically important benefit to patients
who respond to imatinib.
10. Economic Analysis
An economic evaluation was presented. The cost-effectiveness analysis was based on
non-randomised case series and no modelling was further conducted. The resources included
were drug costs and the costs of testing patients with PDGFR gene-rearrangements (in
patients with MDS/MPD) and patients without D816V c-kit mutation (in patients with
ASM). The incremental costs per extra responder are summarised in the table below.
Incremental cost per responder for all diseases
|
ICER |
|
|
Incremental cost/extra responder for DFSP |
$15,000 - $45,000 |
|
Incremental cost/extra responder for HES/CEL |
$45,000 - $75,000 |
|
Incremental cost/extra responder for MDS/MPD (BSC) |
$45,000 - $75,000 |
|
Incremental cost/extra responder for MDS/MPD (Chemotherapy) |
$45,000 - $75,000 |
|
Incremental cost/extra month for MDS/MPD (Chemotherapy) |
<$15,000 |
|
Incremental cost/extra responder for ASM |
$45,000 - $75,000 |
The PBAC noted that the results of the cost-effectiveness analysis were subject to significant uncertainty.
11. Estimated PBS Usage and Financial Implications
The estimated likely number of patients per year who would be eligible for imatinib
under the PBS for each disease was considerably less than 10,000 in Year 5.
The financial cost per year to the PBS was estimated to be less than $10 million in
Year 5.
The re-submission requested a rule of rescue for MDS/MPD and ASM. The requested restriction
positions imatinib after the failure of conventional therapy for these diseases. Left
untreated, the prognosis of these patients is often poor. Imatinib is designated an
orphan drug for the treatment of MDS/MPD and ASM.
See Recommendations and Reasons for PBAC's view.
12. Recommendation and Reasons
The PBAC recommended the listing of imatinib on the PBS for dermatofibrosarcoma protuberans
(DFSP), hypereosinophilic syndrome/chronic eosinophilic leukaemia (HES/CEL), myelodysplastic/myeloproliferative
diseases (MDS/MPD) and aggressive systemic mastocytosis (ASM) based on acceptable
clinical benefit and acceptable but high cost-effectiveness compared with standard
medical management.
The PBAC accepted the clinical claims of effectiveness in these rare disease subsets
with respect to high response rates despite the small numbers of patients and the
absence of high quality trial data. The PBAC noted that the quality of reported responses
with imatinib is substantially superior to those with standard care and considered
that the case report data clearly reflect a clinically important benefit to patients
who respond to imatinib.
The PBAC agreed that the results of the cost-effectiveness analysis are subject to
significant uncertainty, and without more information, it is more appropriate to assume
that the non-imatinib therapy would be of a similar efficacy to imatinib in sub-groups
of the population. The PBAC noted there is the risk of ongoing use in patients who
are not benefiting or in whom benefit is only equivalent to cheaper therapies (i.e.
incomplete responses).
The PBAC recommended that the restrictions be administered through the Tasmanian Specialised
Drugs Program similar to the other listings for imatinib, to enable data collection,
that applications for initial authorisations be in writing and that, to be eligible
for continuing therapy, patients HES/CEL, MDS/MPD and ASM must achieve a complete
response confirmed by a blood test, or, in the case of DFSP, a demonstrated response
but the disease remains unresectable.
The PBAC did not consider that the rule of rescue requested for MDS/MPD and ASM was
appropriate as other therapies with some efficacy, although inadequate, are available
and the clinical data proving a rescue are insufficient.
Recommendation
IMATINIB MESYLATE, tablets, 100 mg (base) and 400 mg (base)
Restriction: NOTE:
Any queries concerning the arrangements to prescribe imatinib may be directed to Medicare
Australia on 1800 700 270 (hours of operation 8 a.m. to 5 p.m. EST Monday to Friday).
Prescribing information (including Authority Application forms) is available on the
Medicare Australia website at www.medicareaustralia.gov.au.
Applications for authority to prescribe imatinib should be forwarded to:
Medicare Australia
Prior Written Approval of Specialised Drugs
Reply Paid 9826
GPO Box 9826
HOBART TAS 7001
For each disease, written authority is required at initiation and for continuation.
Dermatofibrosarcoma protuberans:
Authority Required
Initial PBS-subsidised treatment of a patient with unresectable, locally recurrent
or metastatic dermatofibrosarcoma protuberans.
Maximum dose: 800mg/day
(1) Where the application for authority to prescribe is being sought on the basis
of unresectable tumour, written evidence in support of that claim must be provided;
and
(2) Where the application for authority to prescribe is being sought on the basis
of locally recurrent disease, the site of the local recurrence must be specified;
and
(3) Where the application for authority to prescribe is being sought on the basis
of metastatic disease, the site(s) of metastatic disease must be provided .
Applications for authorisation for initial treatment must be made in writing and must
include:
(a) a completed authority prescription form; and
(b) a completed Rare Diseases Imatinib PBS Authority Application – Supporting Information
Form; and
(c) a signed patient acknowledgement.
Authority Required
Continuing PBS-subsidised treatment of a patient with unresectable, locally recurrent
or metastatic dermatofibrosarcoma protuberans who has previously been issued with
an authority prescription for imatinib and who has demonstrated a response, but whose
disease remains unresectable.
Maximum dose: 800 mg/day
Applications for authorisation must be made in writing and must include:
(a) a completed authority prescription form; and
(b) a completed Rare Diseases Imatinib PBS Authority Application – Supporting Information
Form; and
(c) a statement that the disease has not progressed on imatinib therapy
Quantity: 60 (100 mg), 30 (400 mg)
Repeats: 2
No increase in maximum repeats will be authorised
Hypereosinophilic syndrome or Chronic eosinophilic leukaemia:
Authority Required
Initial PBS-subsidised treatment of a patient with hypereosinophilic syndrome or chronic
eosinophilic leukaemia requiring treatment and confirmed to carry the FIP1L1-PDGFRA
fusion gene
Maximum dose: 400 mg/day
Applications for authorisation for initial treatment must be made in writing and must
include:
(a) a completed authority prescription form; and
(b) a completed Rare Diseases Imatinib PBS Authority Application – Supporting Information
Form; and
(c) a copy of the pathology report confirming the presence of the FIP1L1-PDGFRA fusion
gene; and
(d) a copy of the full blood examination report confirming the presence of hypereosinophilic
syndrome or chronic eosinophilic leukaemia; and
(e) details of organ involvement requiring treatment, including a copy of the radiology,
nuclear medicine, respiratory function or anatomical pathology reports as appropriate;
and
(f) a signed patient acknowledgement.
Authority Required
Continuing PBS-subsidised treatment of a patient with hypereosinophilic syndrome or
chronic eosinophilic leukaemia who has previously been issued with an authority prescription
for imatinib and who has achieved and maintained a complete haematological response.
Applications for authorisation must be made in writing and must include:
(a) a completed authority prescription form; and
(b) a completed Rare Diseases Imatinib PBS Authority Application – Supporting Information
Form; and
(c) a copy of the full blood examination report which demonstrates a complete haematological
response, with a normal eosinophil count; and
(d) a statement that the disease has not progressed on imatinib therapy.
Maximum dose: 400 mg/day
Quantity: 60 (100mg), 30 (400 mg)
Repeats: 2
NOTE:
No increase in maximum repeats will be authorised.
PDGFRB fusion gene-positive Myelodysplastic or myeloproliferative disorder:
Authority Required
Initial PBS-subsidised treatment of a patient with a myelodysplastic or myeloproliferative
disorder where
3) there is confirmed evidence of a platelet-derived growth factor receptor (PDGFR)
gene re-arrangement either by standard karyotyping, or FISH, or PDGFRB fusion gene
transcript; and
4) the patient has previously failed an adequate trial of one or more of the following
conventional therapy:
- cytarabine
- etoposide
- hydroxyurea
Maximum dose: 400 mg/day
Applications for authorisation for initial treatment must be made in writing and must
include:
(a) a completed authority prescription form; and
(b) a completed Rare Diseases Imatinib PBS Authority Application – Supporting Information
Form; and
(c) a copy of the pathology report confirming the platelet-derived growth factor receptor
(PDGFR) gene re-arrangement; and
(c) a copy of the bone marrow biopsy report which demonstrates the presence of a myelodysplastic
or myeloproliferative disorder; and
(d) details of the prior therapy trialled and the response; and
(e) a signed patient acknowledgement.
Authority Required
Continuing PBS-subsidised treatment of a patient with a PDGFRB fusion gene-positive
myelodysplastic or myeloproliferative disorder who has previously been issued with
an authority prescription for imatinib and who has demonstrated a clinically significant
response.
Maximum dose: 400 mg/day
Applications for authorisation must be made in writing and must include:
(a) a completed authority prescription form; and
(b) a completed Rare Diseases Imatinib PBS Authority Application – Supporting Information
Form; and
(c) a statement that the disease has not progressed on imatinib therapy
Quantity: 60 (100mg), 30 (400 mg)
Repeats: 2
NOTE:
No increase in maximum repeats will be authorised.
Aggressive Systemic Mastocytosis with Eosinophilia
Authority Required
Initial PBS-subsidised treatment of a patient with aggressive systemic mastocytosis
with eosinophilia where
3) there is confirmed evidence of the FIP1L1-PDGFRA fusion gene; and
4) the patient has previously failed an adequate trial of one or more of the following
conventional therapy:
- corticosteroids
- hydroxyurea
Maximum dose: 400 mg/day
Applications for authorisation for initial treatment must be made in writing and must
include:
(a) a completed authority prescription form; and
(b) a completed Rare Diseases Imatinib PBS Authority Application – Supporting Information
Form; and
(c) a copy of the pathology report confirming the presence of the FIP1L1-PDGFRA fusion
gene; and
(d) a copy of the bone marrow biopsy report and/or other tissue biopsy report confirming
the diagnosis of aggressive systemic mastocytosis and a copy of the full blood examination
report demonstrating eosinophilia; and
(e) details of symptomatic organ involvement requiring treatment, including a copy
of the radiology, nuclear medicine, respiratory function or anatomical pathology reports
as appropriate; and
(f) details of prior treatment trialled and the response; and
(g) a signed patient acknowledgement.
Authority Required
Continuing PBS-subsidised treatment of a patient with aggressive systemic mastocytosis
confirmed to carry the FIP1L1-PDGFRA fusion gene, who has previously been issued with
an authority prescription for imatinib and who has demonstrated a clinically significant
response.
Maximum dose: 400 mg/day
Applications for authorisation must be made in writing and must include:
(a) a completed authority prescription form; and
(b) a completed Rare Diseases Imatinib PBS Authority Application – Supporting Information
Form; and
(c) a statement that the disease has not progressed on imatinib therapy.
Quantity: 60 (100mg), 30 (400 mg)
Repeats: 2
NOTE:
No increase in maximum repeats will be authorised.
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.
