Carmustine, implant, 7.7 mg, Gliadel®, March 2007
Public summary document for Carmustine, implant, 7.7 mg, Gliadel®, March 2007
Page last updated: 13 July 2007
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Public Summary Document
Product: Carmustine, implant, 7.7 mg,
Gliadel®
Sponsor: Orphan Australia Pty Ltd
Date of PBAC Consideration: March 2007
1. Purpose of Application
To extend the current restricted benefit listing to include the
treatment of recurrent glioblastoma multiforme in patients for whom
surgical resection is indicated.
2. Background
At the November 2005 meeting, the PBAC recommended listing
carmustine implant as a restricted benefit for newly-diagnosed
glioblastoma multiforme (GBM) as an adjunct to surgery and
radiation on a cost-minimisation basis with one pack of eight
carmustine 7.7 mg implants being equivalent to a course of
temozolomide capsules. Based on the indirect comparison across the
two trials provided in the submission, the PBAC concluded that,
overall, carmustine was no worse than temozolomide for glioblastoma
multiforme, the main indication within the requested
restriction.
At its March 2006 the PBAC considered an application to expand the
patient population of the current restriction for carmustine to
include high grade malignant gliomas rather than limiting treatment
to patients with glioblastoma multiforme. The PBAC noted that only
16% patients in the key Trial T-301 were not diagnosed with
glioblastoma multiforme.
The PBAC rejected the submission because of insufficient evidence
of benefit, in terms of survival gain or quality of life
improvements, or in the cost effectiveness of carmustine in the
broader population.
3. Registration Status
Carmustine implant is registered by the TGA for use in
newly-diagnosed high-grade malignant glioma patients as an adjunct
to surgery and radiation. Gliadel is also indicated for use as an
adjunct to surgery to prolong survival in patients with recurrent
glioblastoma multiforme (GBM) for whom surgical resection is
indicated.
4. Listing Requested and PBAC’s View
Restricted benefit
Recurrent glioblastoma multiforme in patients for whom surgical
resection is indicated.
See Recommendation and Reasons for the PBAC’s
view
5. Clinical Place for the Proposed Therapy
Carmustine implants will provide an alternative treatment option to
temozolomide for patients for whom surgery is appropriate for
recurrent glioblastoma multiforme (GBM).
6. Comparator
The submission nominated temozolomide given orally as the
comparator in the setting of recurrent GBM.
The PBAC considered that standard medical management of recurrent
GBM eg surgical resection or focal radiotherapy or other
chemotherapy (eg carboplatin and etoposide) as minor comparators
would also have been appropriate.
7. Clinical Trials
Two sets of randomised controlled trials were provided as a basis for indirect comparison
between carmustine implants and temozolomide (TMZ). The key trial Study 8802, compared
carmustine implants and standard care (tumour resection and radiotherapy) with placebo
implants and standard care (tumour resection and radiotherapy) in patients with recurrent
malignant glioma over a median follow-up of 71 months. The other key trial, Yung et
al, compared TMZ after radiotherapy with procarbazine (PCB) after radiotherapy in
patients with glioblastoma multiforme at first relapse, over a median follow-up of
24 months.
These trials have been published at the time of submission as follows:
| Trial/First author | Protocol title/Publication title | Publication citation |
|---|---|---|
| STUDY 8802/Brem H et al (1995) | Placebo-controlled trial of safety and efficacy of intra-operative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas | Lancet 1995; 345(8956):1008-12 |
| Yung WK et al (2000) | A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse. | British Journal of Cancer 2000; 83(5):588-93. |
The submission assumed that procarbazine has not been shown to have any significant
effect on survival in glioblastoma multiforme patients and can be considered to act
as placebo.
8. Results of Trials
The results of the key trials are summarised in the table below.
Key results of the comparative randomised trials*
| Outcome | Study 8802 100% GBM a (N=145) | Yung W et al, 2000 91% GBM, 9% non-GBM (N=220) | ||
| Placebo plus standard care (N=73) |
Carmustine plus standard care (N=72) |
TMZ plus previous radiotherapy (N=110) | PCB plus previous radiotherapy (N=110) | |
| 6 months survival (95% CI) | 26 (36%) (NR) p=0.020 | 40 (56%) (NR) | 67 (60%) (51%, 70%) p=0.019 | 50 (44%) (35%, 53%) |
| Adjusted b risk ratio (95%CI) | 0.53 (0.33, 0.83) | 0.73 (0.58, 0.96) | ||
| Overall survival Adjusted b hazard ratio for death - Cox multiple regression (95%CI) | 0.67 (0.48, 0.95) | NR | ||
| 65% GBM, 35% non-GBM (N=222) | 91% GBM, 9% non-GBM (N=220) | |||
| Placebo + standard care N=112 | Carmustine + standard care N=110 | TMZ + prior radiotherapy N=110 | PCB + prior radiotherapy N=110 | |
| 6 months survival (95% CI) | 53 (47%) (38%, 57%) p<0.061 | 66 (60%) (51%, 69%) | 67 (60%) (51%, 70%) p<0.019 | 50 (44%) (35%, 53%) |
| Adjusted risk ratio for death (95% CI) | 0.58 (0.39, 0.86) | 0.73 (0.58, 0.96) | ||
| Overall survival, median (months) (95%CI) | 5.42 (4.73, 6.44) | 7.24 (6.05, 8.54) | 7.2 c NR | 5.7 c NR |
| Incremental survival (months) | 1.82 (p=0.297) | 1.50 (p=0.33) | ||
| Unadjusted hazard ratio for death (95%CI) | 0.83 (0.63, 1.10) p=0.19 | 0.69 d (NR) p=0.019 | ||
Italics = calculated during the evaluation;
* the primary efficacy outcome for the trial by Yung et al was progression free survival
at 6 months whereas the primary efficacy outcome in Study 8802 was survival at 6 months:
only the outcomes common to the key trials are considered during the evaluation; a whole trial population in Study 8802 constituted 65% GBM patients and 35% non GBM
patients. Subgroup analysis was pre-planned; b adjusted for drug treatment, KPS, local radiation versus whole brain, active versus
quiescent, previous nitrosourea versus none, >75% resection versus < 75% resection,
age, interval from previous resection, tumour type (GBM, AA); c estimated from the Kaplan Meier curve in Yung et al (2000); d calculated from the inverse of the hazard ratio for survival (1/1.44); PCB = procarbazine;
GBM = glioblastoma multiforme; AA = anaplastic astrocytoma; KPS = Karnofsky Performance
Score; PFS = progression free survival.
Whilst the primary efficacy outcome in the trial Yung et al is progression-free survival
(PFS), in the carmustine trial, Study 8820, it is six month survival. The PBAC agreed
this was justifiable given the unsuitability of PFS as an outcome in a carmustine
treated group where post operative oedema, enhancement of the implants and the subsequent
effects of radiotherapy might bias such measurement. The suitability of the population
for whom listing of carmustine wafers was sought was further complicated by the fact
that in current clinical practice, temozolomide may not be utilised for patients unresponsive
to the drug (likely the majority of patients with recurrent glioblastoma multiforme).
The PBAC noted advice that unequal distributions of prognostic indicators between
the populations in the two key trials, the lack of a common reference and differences
in the measurement of the primary outcome of survival made the indirect comparison
between carmustine implants and TMZ in recurrent glioblastoma multiforme difficult
and ultimately inappropriate. The adjusted benefits observed take into account the
different prognostic factors between groups within the trials rather than between
the relevant trial arm in both studies. A comparison of the absolute risks between
carmustine and standard care with temozolomide after radiotherapy further appeared
to be inappropriate.
The two key trials used different tools to investigate patients ‘quality of life’
at various time points (Karnofsky Performance Score (KPS) and Mini-Mental State Examination
in Study 8802 versus the EORTC (European Organisation for Research and Treatment of
Cancer) Quality of Life Questionnaire (QLQ-C30 (+3) in Yung et al 2000). An assessment
of the comparability of these two measurement tools was not provided. In both trials,
a sustained deterioration in quality of life scores occurred during disease progression.
Quality of life reduction at time of surgery for both carmustine and placebo arms
was most likely related to brain surgery.
9. Clinical Claim
The submission claimed that carmustine implants were at least as
effective as temozolomide with the same or less toxicity. This
claim was based on an indirect comparison.
The PBAC considered that the groups were not strictly comparable
and there remains significant uncertainty around the indirect
comparison and the claim that carmustine is no worse than
temozolomide in the treatment of recurrent GBM.
For further details, see Recommendation and Reasons.
10. Economic Analysis
A preliminary economic evaluation was presented. The PBAC advised
the choice of the cost-minimisation approach was not considered
valid, as the trials did not contain adequate information, such
that many assumptions were required and variables sourced
externally.
The Pre-Sub-Committee Response disagreed with the re-calculation
undertaken during the evaluation which was based on 3 cycles of
temozolomide. A trial-based incremental cost per extra survival was
undefined because there was no survival benefit.
A modelled economic evaluation was not presented. However, the PBAC
advised modelling was required to generate an adequate economic
analysis.
11. Estimated PBS Usage and Financial Implications
The submission predicted that less than 10,000 patients would be
treated in Year 1 at a cost of less than 10 million per year.
12. Recommendation and Reasons
The PBAC noted that the sponsor clarified that the requested
restriction appropriately should exclude combined treatment of
PBS-subsidised carmustine and temozolomide, in line with the
current wording for newly diagnosed patients.
The submission had nominated temozolomide given orally as the
comparator. The PBAC considered that standard medical management of
recurrent glioblastoma multiforme (GBM) eg surgical resection or
focal radiotherapy or other chemotherapy (eg carboplatin and
etoposide) as minor comparators would also have been
appropriate.
The PBAC noted that the submission had based its comparison on the
Yung et al trial which compared temozolomide after radiotherapy
with procarbazine after radiotherapy in patients with glioblastoma
multiforme at first relapse, over a median follow-up of 24 months.
The PBAC considered that the submission’s assumption, that
procarbazine has not been shown to have any significant effect on
survival in GBM patients and can be considered to act as a placebo,
was not supported by the evidence provided.
The PBAC was of the opinion that the unequal distributions of
prognostic indicators between the populations in the two key
trials, the lack of a common reference and differences in the
measurement of the primary outcome of survival hamper the
comparison between carmustine implants and temozolomide in
recurrent glioblastoma multiforme. The Pre-Sub-Committee Response
stated that, despite the lack of a common reference, all the
generally accepted prognostic factors such as age, KPS and previous
nitrosourea chemotherapy in the two trials are similar. The
Pre-PBAC Response also discussed its view that patients enrolled in
the Yung et al did not have a poorer prognosis in comparison with
patients enrolled in the carmustine trial, but noted that the
proportions of patients with GBM, a more severe grade of
astrocytoma and also a generally accepted prognostic factor, did
differ across the trials. The PBAC concurred with ESC advice that
the groups are not strictly comparable and there remains
significant uncertainty around the indirect comparison and the
claim that carmustine is no worse than temozolomide in the
treatment of recurrent GBM.
A further problem about the trial population in the key carmustine
study arose because it was carried out 18 years ago. Since 1989,
pathological diagnosis of brain tumours has changed, in particular
1p/19q codeletion to identify the oligodendroglial phenotype, which
has a better prognosis than GBM and greater chemosensitivity. Thus,
some patients in the key trial may have been misclassified as GBMs.
Further, new imaging techniques are now available to assist in the
diagnosis of recurrent disease, and this causes further uncertainty
when in making cross-trial comparisons. Furthermore, surgical
techniques have changed and patients now will be exposed to
multimodality treatments which are different from those available
in 1989.
The PBAC also indicated that any comparison would need to base the
cost of carmustine on a full pack of 8 wafers, as with use in the
primary setting, because it is not practical to expect unused
wafers from an open packet to be stored adequately for future
use.
Although there was disagreement about the appropriate number of
temozolomide cycles in the comparator arm, this was not considered
by the PBAC to be a pivotal issue in its decision to reject the
submission.
The PBAC therefore rejected the submission because of uncertain
clinical effectiveness resulting from the lack of a common
reference, the unequal distribution of additional therapy received
between the two trial populations, inadequate demographic data for
the subgroup in which listing was requested and other possible
unequal distributions of prognostic factors between the two key
trial populations.
13. Context for Decision
The PBAC helps decide whether and, if so, how medicines should be
subsidised in Australia. It considers submissions in this context.
A PBAC decision not to recommend listing or not to recommend
changing a listing does not represent a final PBAC view about the
merits of the medicine. A company can resubmit to the PBAC or seek
independent review of the PBAC decision.
14. Sponsor’s Comment
The sponsor is disappointed by the PBAC rejection and intends to
work with the PBAC to make PBS-subsidised carmustine implant
available to the small group of patients, with recurrent
glioblastoma multiforme, for whom surgical resection is
indicated.
