Thalidomide, capsule, 50 mg Thalidomide Pharmion®, March 2009
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Public Summary Document
Product:Thalidomide, capsule, 50 mg Thalidomide
Pharmion®
Sponsor:Celgene Pty Ltd
Date of PBAC Consideration:March 2009
1. Purpose of Application
The submission sought an extension to the current Section 100
Highly Specialised Drug listing to include treatment of patients
newly diagnosed with multiple myeloma.
2. Background
At the March 2005 meeting, the PBAC recommended a Section 100
(Highly Specialised Drug) listing for thalidomide for the treatment
of patients with relapsed/refractory multiple myeloma on the basis
of a high, but acceptable cost-effectiveness ratio compared with a
weighted average of a mixture of salvage treatments. Listing was
effective from 1 February 2006.
3. Registration Status
Thalidomide was TGA registered on 13 March 2008 for:
Multiple Myeloma
- in combination with melphalan and prednisone for the treatment of patients with untreated multiple myeloma equal to or greater than 65 years or ineligible for high dose chemotherapy.
- in combination with dexamethasone for induction therapy prior
to high dose chemotherapy with autologous stem cell rescue, for the
treatment of patients with untreated myeloma.
Thalidomide is also TGA registered for the following indications:
- as monotherapy, for the treatment of multiple myeloma after failure of standard therapies;
- Erythema Nodosum Leprosum (ENL)
- for the acute treatment of
cutaneous manifestations of moderate to severe erythema nodosum
leprosum (ENL).
- not indicated as monotherapy for such ENL treatment in the presence of moderate to severe neuritis.
- maintenance therapy for prevention and suppression of the cutaneous manifestations of ENL recurrence.
Thalidomide Pharmion is prescribed and dispensed through the
Thalidomide Risk Management Program.
4. Listing Requested and PBAC’s View
The sponsor proposed two (2) options for listing, with option 1
being the sponsors preferred listing.
Option 1
Private Hospital Authority Required
Treatment of a patient newly diagnosed with multiple myeloma.
Note: Patients receiving thalidomide under the PBS listing must be
registered in the Thalidomide Risk Management Program.
Option 2
Private Hospital Authority Required
Treatment of a patient newly diagnosed with multiple myeloma who is
ineligible for treatment with high dose chemotherapy or a stem cell
transplant.
Note: Patients receiving thalidomide under the PBS listing must be
registered in the Thalidomide Risk Management Program.
For PBAC’s view see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
Multiple myeloma is a disorder in which malignant plasma cells
accumulate in the bone marrow and produce immunoglobulin, usually
monoclonal IgG or IgA (M-protein or paraprotein). It can be a
rapidly progressing condition for which there is no cure. Current
treatment for younger newly diagnosed patients includes high dose
chemotherapy (HDC) followed by a stem cell transplantation
(SCT).
Thalidomide would provide an alternative induction therapy regimen
in patients undergoing HDC/SCT and would be an additional therapy
in patients ineligible for HDC/SCT.
6. Comparator
For the patient population eligible for HDC/SCT, vincristine in
combination with adriamycin was the nominated comparator. For the
patient population ineligible to receive HDC/SCT, placebo was the
nominated comparator. The PBAC considered the comparators were
appropriate.
7. Clinical Trials
For the patient population ineligible for HDC/SCT, the submission
presented five randomised trials comparing thalidomide (as part of
a melphalan-prednisone-thalidomide (MPT) regimen, thalidomide dose
range 100-400 mg/day) with placebo (as a melphalan and prednisone
(MP) regimen) in patients with newly diagnosed multiple myeloma.
For the patient population eligible for induction treatment prior
to HDC/SCT, the submission presented four randomised trials
comparing thalidomide (in different chemotherapy regimens,
thalidomide dose range 200-400 mg/day) with various comparators in
patients with newly diagnosed multiple myeloma.
All of the studies relating to patients ineligible for HDC/SCT had
been published at the time of the submission, as follows:
| Trial/First author | Protocol title | Publication Citation |
| Direct randomised trials | ||
| Facon et al | Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomised trial. Author's Reply (The Lancet 2008). | The Lancet, 370 (9594): 1209-1218, 2007. The Lancet, 371: 984 – 985, 2008. |
| Hulin et al | Melphalan-prednisone-thalidomide (MP-T) demonstrates a significant survival advantage in elderly patients >= 75 years with multiple myeloma compared with melphalan-prednisone (MP) in a randomized, double-blind, placebo-controlled trial, IFM 01/01. Comparison of melphalan-prednisone-thalidomide (MP-T) to melphalan-prednisone (MP) in patients 75 years of age or older with untreated multiple myeloma (MM). Preliminary results of the randomized, double-blind, placebo controlled IFM 01-01 trial. | ASH, Blood. 110: Abstract 75, 2007. Journal of Clinical Oncology ASCO Annual Meeting Proceedings, 25(18S): 8001, 2007. |
| Palumbo et al Palumbo et al Rus and Palumbo et al | Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisolone alone in elderly patients with multiple myeloma: randomised controlled trial. Oral melphalan, prednisone, and thalidomide in elderly patients with multiple myeloma: updated results of a randomized, controlled trial. Thalidomide in front line treatment in multiple myeloma: serious risk of venous thromboembolism and evidence for thromboprophylaxis. | The Lancet, 367: 825-831, 2006. Blood Epublished Online: 1-25, 2008. Journal of Thrombosis and Haemostasis, 2:2063-5, 2004. |
| Wijermans et al | Melphalan prednisone versus melphalan prednisone thalidomide in induction therapy for multiple myeloma in elderly patients: first interim results of the Dutch Cooperative Group HOVON. | European Hematology Association (EHA) 13th Congress, Copenhagen, 2008. |
| Waage et al Gulbrandsen et al | Melphalan-prednisone-thalidomide to newly diagnosed patients with multiple myeloma: a placebo controlled randomised phase 3 trial. A randomised placebo controlled study with melphalan prednisone versus melphalan prednisone thalidomide: quality of life and toxicity. | Blood 110(Abstract 78), 2007. European Hematology Association (EHA), Copenhagen, Denmark, 2008. |
| Meta-analyses of direct randomised trials | ||
| Hicks et al | A meta-analysis and systematic review of thalidomide for patients with previously untreated multiple myeloma. | Cancer Treatment Reviews, 34 (5): 442-452, 20, 2008. |
All of the studies relating to patients eligible for HDC/SCT had been published at the time of the submission, as follows:
| Trial/First author | Protocol title | Publication Citation |
| Direct randomised trial(s) | ||
| Rajkumar et al Kumar et al | Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: A clinical trial coordinated by the eastern cooperative oncology group. Eastern Cooperative Oncology Group E1A00: phase III randomized study of dexamethasone with or without thalidomide in patients with newly diagnosed multiple myeloma. A randomised phase III trial of thalidomide plus dexamethasone versus dexamethasone in newly diagnosed multiple myeloma (E1A00): A trial coordinated by the Eastern Cooperative Oncology Group (abstract). Thalidomide Plus Dexamethasone Versus Dexamethasone Alone in Newly Diagnosed Multiple Myeloma (E1A00): Results of a Phase III Trial Coordinated by the Eastern Cooperative Oncology Group (abstract). Effect of Thrombotic Events on Overall Survival in Patients with Newly Diagnosed Myeloma: Analysis from a Randomized Phase III Trial of Thalidomide Plus Dexamethasone Versus Dexamethasone in Newly Diagnosed Multiple Myeloma (E1A00) (abstract). | Journal of Clinical Oncology, 24(3): 431-436, 2006. Clinical advances in hematology & oncology, H&O 1(3): 188-189, 2003. Journal of Clinical Oncology: ASCO annual meeting proceedings, 22(14s): 558, 2004. Blood, 104(11 Part 1): 63, 2004. Blood, 110(11): 803a, 2007. |
| Barlogie et al Zangari et al Talamo et al Zangari et al, | Thalidomide and hematopoietic-cell transplantation for multiple myeloma. Total therapy 2 without thalidomide in comparison with total therapy 1: role of intensified induction and post-transplantation consolidation therapies. Duration of survival in patients with myeloma treated with thalidomide. Eight-year median survival in multiple myeloma after total therapy 2: Roles of thalidomide and consolidation chemotherapy in the context of total therapy 1. Avascular necrosis of femoral and/or humeral heads in multiple myeloma: results of a prospective study of patients treated with dexamethasone-based regimens and high-dose chemotherapy. Increased risk of deep-vein thrombosis in patients with multiple myeloma receiving thalidomide and chemotherapy. | New England Journal of Medicine, 354(10): 1021-1030, 2006. Blood, 107(7): 2633-8, 2006. New England Journal of Medicine, 359(2): 210-212, 2008. British Journal of Haematology, 141(4): 433-444, 2008. Journal of clinical oncology: official journal of the American Society of Clinical Oncology, 23(22): 5217-23, 2005. Blood, 98(5): 1614-1615, 2001. |
| Macro et al | Dexamethasone+Thalidomide (Dex/Thal) Compared with VAD as a Pre-Transplant Treatment in Newly Diagnosed Multiple Myeloma (MM): A Randomized Trial (abstract). | Blood, 108 (11 Part 1): 22, 2006. |
| Lokhorst et al (2008) (HOVON-50/ GMMG-HD3) Lokhorst, H Breitkreutz, et al Goldschmidt et al | Thalidomide in induction treatment increases the very good partial response rate before and after high-dose therapy in previously untreated multiple myeloma. Phase III Randomized Study of Doxorubicin, Dexamethasone, and High-Dose Melphalan With or Without Thalidomide in Patients With Multiple Myeloma. Thalidomide in newly diagnosed multiple myeloma: Influence of thalidomide treatment on peripheral blood stem cell collection yield. Joint HOVON-50/GMMG-HD3 randomized trial on the effect of thalidomide as part of a high-dose therapy regimen and as maintenance treatment for newly diagnosed myeloma patients. | Haematologica, 93(1): 124-7, 2008. National Institutes of Health, Clinical Trials Gov ( http://www.clinicaltrials.gov ), 2003. Leukemia, 21(6): 1294-1299, 2007. Annals of Hematology, 82(10): 654-659, 2003. |
| Meta-analyses of direct randomised trials | ||
| Hicks et al | A meta-analysis and systematic review of thalidomide for patients with previously untreated multiple myeloma. | Cancer Treatment Reviews, 34(5): 442-452, 2008. |
8. Results of Trials
The results of the trials for the ineligible HDC/SCT patient population are presented below:
| Facon 2007 | Hulin 2007 | Palumbo 06/08 | Wijermans 2008 | Waage 2007 | ||||||
| MPT n=125 | MP n=196 | MPT n=113 | MP n=116 | MPT n=167 | MP n=164 | MPT n=152 | MP N=149 | MPT n=182 | MP n=175 | |
| Overall survival | ||||||||||
| Median months (s.e.) | 51.6 (4.5) | 33.2 (3.2) | 45.3 (1.6) | 27.7 (2.1) | 45.0 | 47.6 | NR | NR | 29 | 33 |
| HR (95%CI) | 0.59 (0.46,0.81) | 0.66 (0.44,1.00) | 1.04 (0.76, 1.44) | NR | NR | |||||
| p-value | 0.0006 | 0.03 | 0.79 | 0.28 | NS | |||||
| PFS | ||||||||||
| Median months (s.e.) | 27.5 (2.1) | 17.8 (1.4) | 24.1 (2.0) | 19.0 (1.4) | 21.8 | 14.5 | NR | NR | 16 | 14 |
| HR (95%CI) | 0.51 (0.39, 0.66) | NR | 0.63 (0.48, 0.81) | NR | NR | |||||
| p-value | <0.0001 | 0.001 | <0.001 | 0.08 | NS | |||||
| Response rate (CR+VGPR+PR) | ||||||||||
| n (%) | 91 (85) | 78 (51) | 103 (91) | 45 (39) | 115 (68.9) | 78 (47.6) | 96 (63) | 70 (47) | 76 (42) | 49 (28) |
| p-value | <0.001 | <0.001 | <0.001 | <0.001 | 0.006 | |||||
| RR (95%CI) | 1.67 (1.40, 1.99) | 2.35 (1.86, 2.97) | 1.45 (1.20, 1.75) | 1.34 (1.09, 1.66) | 1.49 (1.11, 1.99) | |||||
| RD (95%CI) | 0.34 (0.24, 0.45) | 0.52 (0.42, 0.63) | 0.21 (0.11, 0.32) | 0.16 (0.05, 0.27) | 0.14 (0.04, 0.24) | |||||
| NNT (95% CI) | 3 (2, 4) | 2 (2, 2) | 5 (3, 9) | 6 (4, 20) | 7 (4, 25) | |||||
Abbreviations: s.e.: standard error, PFS: progression-free
survival, RR: relative risk, RD: risk difference, NNT: number
needed to treat, NS: not significant, NR: not reported, CR:
complete response, VGPR: very good partial response, PR: partial
response, HR: hazard ratio.
Bolded typography indicates statistically significant
differences
The addition of thalidomide to the MP regimen resulted in increased
overall survival in two (Facon (2007), Hulin (2007)) of the three
trials in which this was the primary outcome (Facon (2007), Hulin
(2007) and Waage (2007)). Information regarding the Waage (2007)
trial was lacking, although the authors suggested that the lack of
efficacy might be due to a number of early deaths among elderly
patients with Stage I disease treated in the MPT arm.
The addition of thalidomide to the MP regimen resulted in
statistically significant progression-free survival differences
between treatment groups in favour of thalidomide for Facon (2007),
Hulin (2007) and Palumbo (06/08) at the 1% level of significance
and at the 10% level of significance for Wijermans (2008). A
non-statistically significant difference was observed for
progression-free survival in Waage (2007). The PBAC noted as
progression free survival (PFS) was a secondary outcome of the
Waage (2007) trial, the trial might not have been powered to detect
a difference in this outcome.
Response rates were statistically significantly greater for
patients in whom thalidomide was added to the MP regimen compared
with those who received MP alone in all trials.
The results of the trials for the eligible HDC/SCT patient
population are presented below:
| Rajkumar 2006 | Lokhorst 2008 | Barlogie 2006 | Macro 2006 | |||||
| TD n=99 | D n=100 | TAD n=201 | VAD n=201 | TD comb. n=314 | D comb. n=337 | TD n=100 | VAD n=104 | |
| ≥PR, n (%) | 62 (62.6) | 41 (41) | 145 (72) | 109 (54) | 187 (60) | 136 (40) | NR | NR |
| RD % (95% CI) | 22 (8, 35) | 18 (9, 27) | 19 (12, 27) | - | ||||
| p-value | 0.0017 | <0.001 | <0.001 | - | ||||
| ≥VGPR, n (%) | NR | NR | 66 (33) | 30 (15) | NR | NR | 35 b (34.7) | 13 b (12.6) |
| RD % (95% CI) | - | 18 (10, 26) | - | 23 (11, 34) | ||||
| p-value | - | <0.001 | - | 0.002 | ||||
| CR + VGPR + PR, n (%) | 62 (62.6) | 41 (41) | 145 (72.0) | 109 (54.0) | 187 (60.0) | 136 (40.0) | NR | NR |
| p-value | 0.0017 | <0.001 | <0.001 | NA | ||||
| RR (95%CI) | 1.53 (1.15,2.02) | 1.33 (1.14, 1.55) | 1.48 (1.26, 1.73) | NA | ||||
| RD (95%CI) | 0.22 (0.08, 0.35) | 0.18 (0.09, 0.27) | 0.19 (0.12, 0.27) | NA | ||||
| NNT (95% CI) | 5 (3, 13) | 6 (4, 11) | 5 (4, 8) | NA | ||||
Abbreviations: TD: thalidomide and dexamethasone, D: dexamethasone,
VAD: vincristine, Adriamycin and dexamethasone, PR: partial
response, CR: complete response, VGPR: very good partial response,
RR: relative risk, RD: risk difference, NNT: number needed to
treat, CI: confidence interval, NR: not reported, NA: not
applicable.
The primary outcome for the induction setting presented by the
submission was limited to response rates prior to HDC/SCT. Best
response to treatment was the primary outcome in Rajkumar (2006),
with Lokhorst (2008) and Macro (2006) also having primary outcomes
based on response rates. Statistically significant differences
between treatment groups in favour of thalidomide were observed in
all four trials for patients achieving at least a partial response
(PR). Additionally, Rajkumar (2006) and Barlogie (2006) showed a
statistically significantly higher rate of CR following thalidomide
treatment.
Overall response rate was the primary outcome in Lokhorst (2008),
with Rajkumar (2006) and Macro (2006) also having response rate
primary outcomes. Statistically significant differences between
treatment groups in favour of thalidomide were observed in the
three trials. Additionally, Rajkumar (2006) and Barlogie (2006)
showed a statistically significantly higher rate of complete
response (CR) following thalidomide treatment.
Five-year event-free survival (defined as time to disease
progression, relapse or death from any cause from enrolment) was
the primary outcome measure for the Barlogie (2006) trial. The
thalidomide group had higher five year event free survival compared
with the control group (56% versus 44%, respectively;
p<0.01).
Overall survival was reported for both Barlogie (2006) and Rajkumar
(2006). Mean survival was 70.1 weeks (standard error=27.7) for the
thalidomide and dexamethasone (TD) group and 68.1 weeks (standard
error = 28.7) for the dexamethasone (D) group in the Rajkumar
(2006) trial. This was not statistically significant
different.
A post-hoc analysis of eight year survival data was conducted as
part of the Barlogie trial (Barlogie et al (2008)). The overall
eight year survival estimates were 56% for the thalidomide group
compared with 45% in the control group (p=0.09). It was reported
that the lack of difference in overall survival may be due in part
to significantly shorter survival after relapse in the thalidomide
group than in the control group (median 1.1 years versus 2.7 years;
p = 0.001).
For patients ineligible for HDC/SCT, adverse events were reported
more frequently in patients treated with MPT compared with those
receiving MP. Adverse Events (AEs) of note were those which have
been previously associated with the use of thalidomide –
notably peripheral neuropathy, neutropenia, rash, somnolence, deep
vein thrombosis (DVT) and constipation. This increased occurrence
of AEs was generally associated with a higher rate of treatment
discontinuation among MPT treated patients compared with MP.
Despite this, there was no difference in AE related deaths among
the thalidomide treated patients, compared with those who received
MP alone.
For patients eligible for HDC/SCT, AEs were reported more
frequently in patients treated with TD, compared with those
receiving dexamethasone alone or in combination. As expected, skin,
neurological, cardiac and thromboembolic events have been
identified previously as potential adverse reactions to thalidomide
and events of this type were generally more frequently experienced
in the thalidomide groups. This increased toxicity did not lead to
more deaths in thalidomide-treated patients.
9. Clinical Claim
The submission claimed that for patients ineligible for HDC/SCT,
thalidomide in combination with melphalan and prednisone was
superior in terms of comparative effectiveness and inferior in
terms of comparative safety over melphalan and prednisone
alone.
The PBAC considered that this was reasonable but considered that
there is some uncertainty about the size of the survival
benefit.
For patients eligible for induction treatment prior to HDC/SCT, the
submission claimed that thalidomide in combination with
dexamethasone was superior in terms of comparative effectiveness
and inferior in terms of comparative safety over the group of
therapies currently used in the induction setting.
For PBAC’s view, see Recommendation and
Reasons.
10. Economic Analysis
A three-step economic evaluation was presented for the ineligible
HDC/SCT patient population (referred to as the MPT model) and a
cost-per-responder model was presented for the HDC/SCT eligible
patient population.
The MPT stepped model was a decision analytic model and involved
the within trial truncated overall survival from the Facon (2007)
trial presented as cost per life year gained. Step two extrapolated
the survival based on a Weibull function to a lifetime horizon of
fifteen years.
Step three incorporated quality of life using published utility
values obtained from van Agthoven (2006) [van Agthoven et al (2004)
- a cost-utility analysis comparing intensive chemotherapy alone to
intensive chemotherapy followed by myeloablative chemotherapy with
autologous stem-cell rescue in newly diagnosed patients with stage
II/III multiple myeloma: a prospective randomised phase III study,
European Journal of Cancer 40: 1159-1169, 2004.] The key driver of
the MPT model was the cost of thalidomide and the extrapolated
survival estimate using the Weibull method. Sensitivity analyses
using the straight line extrapolation method returned a cost per
QALY in the range of $15,000 – $45,000 compared with a lower
estimate for the Weibull extrapolation (which was in the same range
of $15,000 - $45,000).
In patients eligible for transplant, for the cost per responder
analysis, the submission used direct trial-based data from Macro
(2006) as the input to the evaluation. The outcome was the
proportion of patients achieving at least a very good partial
response (VGPR) to induction treatment therapy over 3 cycles (3
months’ treatment duration). The difference in treatment
response across the two treatment groups (TD versus VAD) was used
as the incremental response. No discounting was applied as the
duration of the model is less than one year. Utilising corrected
values for the refill cost of drug delivery into a venous catheter
port, the estimated incremental cost per responder was in the range
of $15,000 – $45,000.
11. Estimated PBS Usage and Financial Implications
The submission estimated in Year 5 the financial cost/year to the
PBS to be between $10 – $20 million in Year 5.
12. Recommendation and Reasons
The PBAC recommended an extension to the Section 100 listing for
thalidomide to include the treatment of a patient newly diagnosed
with multiple myeloma (first-line setting) on the basis of
acceptable cost-effectiveness at the current rather than the
requested price.
Of the two options nominated by the sponsor for PBAC consideration,
the PBAC considered that Option 1 (which includes patients eligible
and ineligible for high dose chemotherapy followed by stem cell
transplantation (HDC/SCT)) to be the most clinically appropriate.
The PBAC considered that it is not possible to accurately forecast
for all patients at diagnosis whether a SCT will be performed.
Given this, it is not appropriate or equitable to categorise
patients as eligible or ineligible for SCT at diagnosis for the
purpose of a PBS indication.
Based on the clinical trial data from patients nominated as
ineligible for HDC/SCT, the PBAC considered that the
submission’s therapeutic claims were reasonable, i.e., that
compared with melphalan and prednisone alone (MP), thalidomide in
combination with melphalan and prednisone (MPT) is superior in
terms of comparative effectiveness and inferior in terms of
comparative safety. However, the PBAC also considered that there is
some uncertainty about the size of the survival benefit.
The PBAC noted that a three-step economic evaluation (referred to
as the MPT model) was presented for the ineligible HDC/SCT patient
population in terms of incremental cost per extra life-year gained.
The PBAC further noted that the trial data upon which this economic
evaluation is based are from the most favourable of the five
randomised trials, the Facon (2007) trial and hence may
overestimate the true survival benefit. The key drivers of the MPT
model are the cost of thalidomide and the extrapolated survival
using the Weibull method, and that the latter may also have
overestimated the overall survival of patients. Sensitivity
analyses undertaken using a more conservative straight line
extrapolation method returned an incremental cost effectiveness
ratio (ICER) per QALY in the $15,000 – $45,000 range compared
with a lower estimate for the Weibull extrapolation (which was also
in the $15,000 - $45,000 range). The PBAC considered that the true
estimate of the ICER in terms of incremental life-years gained was
probably between the two point estimates and towards the higher
estimate if the Facon-based trial results were also an overestimate
of survival.
The PBAC noted that only the disutility of peripheral neuropathy as
an adverse effect of thalidomide treatment is included in the
model. Disutilities associated with other adverse events such as
constipation and somnolence were not considered. The
pre-sub-Committee response argued that the study from which the
utilities are derived (van Agthoven et al. 2004) permitted
treatment with vincristine, adriamycin and dexamethasone (VAD),
cyclophosphamide and melphalan, and as such, the utility values
reflect the disutility of adverse events associated with the
treatment of multiple myeloma. The PBAC considered that the
disutilities due to thalidomide toxicity had not been fully
considered in the model, requiring adjustment in sensitivity
analyses.
The PBAC noted that the costs of concomitant bisphosphonate therapy
were excluded in both arms of the model. The Pre-Sub-Committee
Response assumed that there is no long-term difference in
bisphosphonate use between the two groups because the average
survival for the MPT (54.5 months) and MP (36.7 months) are well
beyond two years. The PBAC considered that this statement is
incorrect and that failure to include true bisphosphonate costs
underestimates the ICER.
The PBAC agreed that each of these concerns increased the
uncertainty of the ICER, and suggested that the base case presented
was more favourable than the true estimate. Although the
sponsor’s Pre-PBAC Response argues that the sensitivity
analyses indicate that even allowing for some of this uncertainty,
the ICER per QALY is no more than $45,000, the PBAC noted that
these were not comprehensive because not all relevant disutilities
and costs were considered in economic model, and the most
favourable base-case trial data were used.
Regarding trial-based data from patients receiving induction
treatment prior to a planned HDC/SCT, the PBAC noted that no
statistically significant differences in overall survival were
reported. The PBAC accepted that any benefit of thalidomide over
its comparators for the most relevant outcome (survival) in
patients who had HDC/SCT is uncertain. For the most mature study
(Barlogie et al (2008)), a published post-hoc analysis of the
survival data was included, but these results could have been
confounded. Nevertheless, the PBAC noted that the post-hoc analysis
of eight-year survival data conducted as part of the Barlogie trial
reported that the lack of difference in overall survival (56%
thalidomide group compared with 45% control group) may be due in
part to significantly shorter survival after relapse in the
thalidomide group than in the control group (median 1.1 years
versus 2.7 years; p=0.001). However, the PBAC did also note that
the design of the available studies mitigated against drawing
conclusions concerning overall survival benefits.
Thus, despite a significant advantage for thalidomide and
dexamethasone over dexamethasone alone in terms of response rates,
the PBAC did not accept that this had convincingly been shown to
predict an overall survival benefit. The PBAC did note that
thalidomide does improve response rates in SCT-eligible trial
participants to as great a degree or extent as observed for
SCT-ineligible patients where a survival advantage was
demonstrated.
The PBAC noted that an analysis reporting incremental cost per
extra responder was presented for the HDC/SCT eligible patient
population. For this analysis, the submission used direct
trial-based data from Macro (2006) as the input to the economic
evaluation. The PBAC considered that this economic evaluation did
not form an adequate basis to assess overall cost-effectiveness in
terms of the key patient relevant outcome (improved survival). The
PBAC noted that the cost per responder was highly sensitive to the
type of comparator and number of cycles of thalidomide and also
very likely sensitive to the time-point chosen to measure response.
Therefore, this did not allow a fair comparison between different
therapies.
Overall, across both subgroups in the first-line setting for
multiple myeloma, the PBAC considered that there was an acceptable
clinical basis to recommend the listing of thalidomide, but the
Committee did not accept that acceptable cost-effectiveness had
been demonstrated at the price requested. The PBAC therefore
recommended approval at the current price of thalidomide.
The PBAC acknowledged that thalidomide was effective in all stages
of multiple myeloma and that its use is limited by cumulative
toxicity. The PBAC noted that if thalidomide is PBS-subsidised in
first-line therapy, then there will be less use of thalidomide in
second and subsequent lines, as each patient will have a ceiling
with respect to total lifetime exposure due to cumulative toxicity
or to the expiry of clinical benefit.
Recommendation
THALIDOMIDE, capsule, 50 mg.
Replace the current restriction with the following:
Restriction:
Caution: Thalidomide is a category X drug and must
not be given to
pregnant women. Pregnancy in female patients or in the partners
of
male patients must be avoided during treatment and for 1 month
after cessation of treatment.
Section 100 (Highly Specialised Drug)
Private Hospital Authority Required
Multiple myeloma.
Note: Patients receiving thalidomide under the PBS listing must be
registered in the Thalidomide Risk Management Program.
Pack size: 28
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
Celgene accepts the recommendation made by the PBAC and welcomes
this expanded access to thalidomide for all patients with multiple
myeloma.
