Trastuzumab, powder for I.V. infusion, 60 mg and 150 mg, Herceptin® - July 2011
Page last updated: 11 November 2011
Public Summary Document
Product: Trastuzumab, powder for I.V. infusion,
60 mg and 150 mg, Herceptin®
Sponsor: Roche Products Pty Ltd
Date of PBAC Consideration: July 2011
1. Purpose of Application
The submission sought to extend the current Section 100 Authority
required listing to include treatment of human epidermal growth
factor receptor 2 (HER2) positive advanced (equivalent to stage III
or IV) adenocarcinoma of the stomach or gastro-oesophageal junction
(referred to as advanced gastric cancer), in patients who have not
received prior anti-cancer treatment for advanced disease, in
combination with cisplatin and either capecitabine or
5-fluorouracil (5-FU), with a WHO performance status of 2 or
less.
The submission also requested listing on the Intravenous
Chemotherapy Supply Program.
2. Background
This drug had not previously been considered by the PBAC for this
indication.
Trastuzumab for the treatment of HER2 positive early breast cancer
commencing concurrently with adjuvant chemotherapy following
surgery has been available on the PBS since 1 December 2006.
3. Registration Status
The TGA registration of trastuzumab 150 mg was extended on 17
September 2010 to include the new indication:
“For use in combination with cisplatin and either capecitabine or 5-FU for the treatment of patients with HER2 positive advanced adenocarcinoma of the stomach or gastro-oesophageal junction who have not received prior anti-cancer treatment for their metastatic disease.”
Trastuzumab is also TGA indicated for:
- Treatment of patients with HER2 positive localised breast cancer following surgery and in association with chemotherapy and, if applicable, radiotherapy.
- Treatment of patients with metastatic breast cancer who have tumours that over express HER2:
- as monotherapy for the treatment of those patients who have received one or more chemotherapy regimens for their metastatic disease;
- in combination with taxanes for the treatment of those patients who have not received chemotherapy for their metastatic disease; or
- in combination with an aromatase inhibitor for the treatment of post-menopausal patients with hormone-receptor positive metastatic breast cancer.
Trastuzumab powder for injection 60 mg was TGA registered for the
above indications on 3 December 2010.
4. Listing Requested and PBAC’s View
Section 100 Authority Required
Initial treatment for HER2 positive advanced (equivalent to stage
III or IV) adenocarcinoma of the stomach or gastro-oesophageal
junction, in patients who have not received prior treatment for
advanced disease, in combination with cisplatin and either
capecitabine or 5-fluorouracil, with a WHO performance status of 2
or less.
Continuing treatment for HER2 positive advanced (equivalent to
stage III or IV) adenocarcinoma of the stomach or
gastro-oesophageal junction in combination with cisplatin and
either capecitabine or 5-fluorouracil, where the patient has
previously received treatment with PBS-subsidised
trastuzumab.
Trastuzumab must not be used in patients with a left ventricular
ejection fraction (LVEF) of less than 45% and/or with symptomatic
heart failure. Cardiac function must be tested by a suitable method
including, for example ECHO or MUGA, prior to seeking the initial
authority approval and then a 3 monthly intervals during
treatment.
The submission proposed the following three options for testing
HER2 positivity for inclusion in the restriction to determine
eligibility for PBS-subsidised treatment with trastuzumab:
Scenario 1
Immunohistochemical (IHC) evidence of HER2 over expression as
described by a 3+ IHC score. For cases with a score of less than 3+
by IHC, confirmation of HER2 positive status by ISH is
mandatory.
Scenario 2:
Immunohistochemical (IHC) evidence of HER2 over expression as
described by a 2+ IHC score, subsequently confirmed as exhibiting
HER2 gene amplification by in situ hybridisation (ISH).
Immunohistochemical (IHC) evidence of HER2 over expression at the
3+ level.
Scenario 3:
Immunohistochemical (IHC) evidence of HER2 over expression as
described by a 3+ IHC score.
The PBAC considered that the interpretation of the entire
submission relied heavily on how HER2 positivity/over expression is
defined, in terms of both test methodologies used and test
algorithm applied.
For PBAC’s view, see Recommendations and
Reasons.
5. Clinical Place for the Proposed Therapy
Gastric cancer is the fourth most commonly diagnosed cancer and the
second most common cause of cancer-related deaths worldwide. Most
patients present with inoperable advanced or metastatic disease
requiring palliative treatment. Five-year survival for advanced or
metastatic gastric cancer is around 5-10%, with median overall
survival (OS) being less than 1 year.
Currently, approved chemotherapy regimens for advanced gastric
cancer include triplet regimens epirubicin + cisplatin +
capecitabine (ECX) or 5-FU (ECF), and doublet regimens cisplatin +
capecitabine (CX) or cisplatin + 5-FU (CF).
Trastuzumab, in combination with chemotherapy, was proposed as an
alternative first-line treatment option for HER2 positive advanced
gastric cancer.
6. Comparator
The submission nominated cisplatin plus a fluoropyrimidine (CF),
where the fluoropyrimidine is 5-fluorouaracil or capecitabine, as
the comparator for trastuzumab + cisplatin + a fluoropyrimidine
(HCF). This was the comparator treatment arm in the key trastuzumab
trial (ToGA) presented in the submission. This is not the current
standard of care in clinical practice, which is triplet therapy
consisting of epirubicin, cisplatin and fluoropyrimidine (ECF) and
was the comparator presented in the submission’s estimates of
financial implications, rather than the CF doublet chemotherapy.
The PBAC considered the appropriate comparator is triplet therapy
(ECF or ECX).
Comparator for HER2 testing
No evidence was presented comparing HCF versus ECF in the situation
where there is no testing for the biomarker. Thus a comparative
assessment of the impact of testing versus no testing and the
comparative treatment effect of adding trastuzumab to CF in the no
testing setting was not possible. It was therefore unclear whether
trastuzumab resulted in an overall survival (OS) benefit
irrespective of targeting according to biomarker status.
No evidence was presented of ECF (or CF) use in a HER2 negative
population. Therefore determining whether HER2 status is an
independent prognostic modifier, from a comparison between the
biomarker positive and biomarker negative control treatment arms,
was not possible from the evidence presented.
7. Clinical Trials
The submission presented one randomised open-label trial (ToGA), comparing trastuzumab
(8 mg/kg IV loading dose on day one followed by 6 mg/kg IV infusion once every three
weeks) in combination with cisplatin (80 mg/m2 IV infusion on day 1) and a fluoropyrimidine (either capecitabine (1,000 mg/m2 orally twice daily for 14 days) or 5-FU (800 mg/m2/day IV infusion over five days)) versus the same regimen of doublet chemotherapy
alone (CF), as first-line therapy in patients with HER2-positive advanced gastric
cancer. The primary outcome was overall survival (OS).
The published trial presented in the submission is shown in the table below.
| Trial ID / First author | Protocol title/ Publication title | Publication citation |
|
ToGA BO18255
Bang et al. |
Clinical Study Report – BO18255: An open label randomised multicentre Phase III study of trastuzumab in combination with a fluoropyrimidine and cisplatin versus chemotherapy alone as first-line therapy in patients with HER2 positive advanced gastric cancer. Report No. 1032349, August 2009 Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. |
August 2009
The Lancet 2010; 376 (9742): 687-697 |
HER2=Human epidermal growth factor receptor 2.
8. Results of Trials
The OS results are summarised below.
Scenario 1 = IHC3+, or ISH+ irrespective of IHC status
(Intention-to-treat (ITT) population of ToGA trial):
Summary of OS (Scenario 1, ToGA ITT population)
| Overall survival | HCF (N=294) | CF (N=290) |
| Patients with event (Death from any cause) | 167 (56.8%) | 182 (62.8%) |
| Patients without events* | 127 (43.2%) | 108 (37.2%) |
| Time to event (months) | ||
| Median (95% CI) # | 13.8 (12, 16) | 11.1 (10, 13) |
| p-value (log-rank test) | 0.0046 | |
| Hazard ratio (95% CI) | 0.74 (0.60, 0.91) | |
* Censored; # Kaplan-Meier estimate; CI=confidence interval;
CF=cisplatin/fluoropyrimidine;
HCF=trastuzumab/cisplatin/fluoropyrimidine;
ITT=intent-to-treat
The observed hazard ratio (non-stratified analysis) indicated a 26%
reduction in the risk of death over the trial duration which was
statistically significant (HR: 0.74; 95% CI: 0.60, 0.91; p=0.0046)
for patients in the HCF arm, compared with patients in the CF
arm.
The statistically significant increase in the primary outcome of OS
in the intention-to-treat analysis of the ToGA trial (a gain of 2.7
months from a median of 11.1 months without trastuzumab to a median
of 13.8 months with trastuzumab) was accepted as convincing
evidence of trastuzumab’s clinical effectiveness in HER2
positive patients as defined for this trial. However the PBAC also
noted that the median OS in the doublet control arm (CF alone) is
numerically greater than the results of four epirubicin studies
with similar sample sizes, which does not support the initial
biological arguments that HER2 positive status would identify a
group of patients with a worse prognosis. The PBAC also questioned
the clinical importance of the extent of OS gain, particularly as
the comparison was not against triplet chemotherapy.
The results for the pre-specified HER2 subgroups are summarised
below.
OS by pre-specified HER2 subgroups
| HER2 Result (ToGA) § | HCF | CF | HR (95%CI) | ||||
| N | Events (death) | Median time to death (months) | N | Events (death) | Median time to death (months) | ||
| IHC0/FISH+ | 23 | 15 | 10.6 | 38 | 24 | 7.2 | 0.92 (0.48, 1.76) |
| IHC1+/FISH+ | 38 | 28 | 8.7 | 32 | 21 | 10.2 | 1.24 (0.70, 2.20) |
| IHC2+/FISH+ | 80 | 51 | 12.3 | 79 | 53 | 10.8 | 0.75 (0.51, 1.11) |
| IHC3+/FISH+ | 131 | 61 | 17.9 | 125 | 76 | 12.3 | 0.58 (0.41, 0.81) |
| IHC3+/FISH- | 9 | 5 | 17.5 | 6 | 4 | 17.7 | 0.83 (0.20, 3.38) |
Bolded=statistically significant
§Results not presented for IHC no result/FISH+ and
IHC3+/FISH no result
CF=cisplatin/fluoropyrimidine; CI=confidence interval;
FISH=fluorescence in situ hybridisation;
HCF=trastuzumab/cisplatin/fluoropyrimidine; HER2=human epidermal
growth factor receptor 2; IHC=immunohistochemistry.
The results of testing for interaction as a likelihood ratio test
between treatment and “HER2 Result” as a covariate
(amongst a total of 15 separate covariate tests in each case) were
not statistically significant. The PBAC noted that this negative
overall test for interaction between treatment effect of adding
trastuzumab to CF with varying HER2 expression in FISH+ patients
cast doubt on the interpretability of the post hoc subgroup
analyses presented in the submission.
Scenario 2 = IHC2+ and ISH+, or IHC3+ irrespective of
ISH status (base case, ‘high’ HER2, post hoc
subgroup):
The submission claimed that there was little contribution to the
overall increase in efficacy from the subgroups with low expression
of HER2 protein (IHC0/FISH+: HR=0.92; 95% CI: 0.48, 1.76;
IHC1+/FISH+: HR=1.24; 95% CI: 0.70, 2.20) and that the main effect
was derived in the subgroups of patients expressing high levels of
HER2 protein (IHC2+/FISH+: HR=0.75; 95% CI: 0.51, 1.11;
IHC3+/FISH+: HR=0.58; 95% CI: 0.41, 0.81). This led to a post hoc
categorisation and analysis of two subgroups in the study report:
“high HER2” and “low HER2” expressing
subgroups. The addition of trastuzumab to chemotherapy in the
‘high’ HER2 expressing group (Scenario 2) resulted in a
median overall survival of 16.0 months for HCF versus 11.8 months
for CF: non-stratified HR=0.65 (95% CI: 0.51, 0.83) with a
statistically significant interaction test (p=0.036) of the
treatment effect and the HER2 category for OS between the
groups.
The choice of the ‘high’ HER2 expressing population as
the base case was determined from post hoc subgroup analyses. The
OS between treatment arms, in the IHC3+/FISH- subgroup (HR=0.83;
95% CI: 0.20, 3.38) and the IHC2+/FISH+ subgroup (HR: 0.75; 95% CI:
0.51, 1.11) was not statistically significant.
Scenario 3 = IHC3+ irrespective of ISH status (post
hoc subgroup):
The submission stated that the OS benefit in this group is greater
than in the ‘high’ HER2 expressing subgroup (Scenario
2). The result for this latter group was mostly driven by the
IHC3+/FISH+ population which made up the majority of the
“IHC3+ regardless of FISH status” population. There
were no baseline data provided in the submission or Clinical Study
Report to assess the comparability between treatment groups for
this subgroup of patients.
Overall, the OS results of the post hoc analyses presented as
Scenarios 2 and 3 were interpreted cautiously by the PBAC as they
were not pre-specified.
Results for progression free survival (PFS) for all scenarios were
consistent with the results for OS.
The PBAC noted that no incremental effect was detected on quality
of life, but patients in the trastuzumab arm of the trial
experienced 22% more adverse events than patients in the control
arm of the trial.
The safety profile of trastuzumab was similar to that for other
indications, for example breast cancer. The ToGA trial population
was a low-risk population for toxicity, obtained by stringent
exclusion criteria particularly for cardiovascular risks associated
with trastuzumab (others include cancer-related, haematological,
biochemical, physiological, and general exclusion criteria). These
trastuzumab-related exclusion criteria resulted in a trend towards
the null in terms of the drug’s comparative safety. In
clinical practice, such stringent exclusion criteria are unlikely
to be applied to a similar extent. Thus the observed
trastuzumab-related adverse events from the ToGA trial would have
likely been an underestimate of adverse events in clinical
practice.
Cardiac events from the ToGA trial: 9 (3.1%) patients in the CF arm
experienced ≥1 cardiac Grade ≥3 AE compared with 4 (1.4%)
patients in the HCF arm. The number of events was too small in
either treatment arm for any meaningful comparison.
The Periodic Safety Update Report did not indicate any additional
new safety signals to those already recognised to be associated
with trastuzumab.
9. Clinical Claim
The submission described trastuzumab, when used in combination with
CF as superior in terms of comparative effectiveness and no worse
in terms of comparative safety over CF alone.
Based on the supporting data for comparative effectiveness, this
description was reasonable for the ITT population (Scenario 1) and
the pre-specified subgroup IHC3+/FISH+. Post hoc analyses for the
‘high’ HER2 expressing subgroup (Scenario 2 base case)
and the IHC3+ regardless of FISH status subgroup (Scenario 3), also
supported this contention. However, the comparative effectiveness
of HCF versus the currently accepted comparator in clinical
practice (ECF), in HER2 tested or non-tested advanced gastric
cancer patients, remained unclear.
Based on the supporting data for comparative safety, the claim in
the submission with respect to comparative safety was not
reasonable. Overall, there are some additional adverse events in
the HCF arm compared to the CF arm (patients in the HCF arm
experienced about 22% more adverse events than patients in the CF
arm) from the ToGA trial safety population. It was acknowledged
that current practice is aimed at avoiding cardiovascular events by
the application of cardiovascular eligibility criteria and
prospective cardiac monitoring for trastuzumab. This would be
important as the ToGA trial population was a low-risk population
for toxicity, obtained by stringent exclusion criteria. A higher
trastuzumab-related toxicity profile, compared to the ToGA trial,
would be anticipated in clinical practice.
10. Economic Analysis
A stepped economic evaluation was presented. The economic model
sought to compare the proposed scenario in which both HER2 testing
and trastuzumab are subsidised against the current scenario where
neither HER2 testing nor trastuzumab are subsidised.
Based on modelled evaluation costs and quality adjusted life years
(QALYs) gained over a 5-year time horizon, the incremental cost per
extra QALY gained for Scenario 1 was in the range of $75,000 -
$105,000.
Based on modelled evaluation costs and QALYs gained over a 5-year
time horizon, the incremental cost per extra QALY gained for
Scenarios 2 and 3 was in the range of $45,000 - $75,000.
11. Estimated PBS Usage and Financial Implications
The submission estimated total net costs to the PBS (including
patient co-payment) to be less than $10 million in each of
Scenarios 1, 2 and 3 in year 5.
12. Recommendation and Reasons
The PBAC decided not to recommend trastuzumab for gastric cancer as
proposed on the basis of unacceptably high and uncertain
incremental cost-effectiveness ratios. In reaching this conclusion,
all three scenarios proposed in the submission were considered and
rejected.
The PBAC accepted ESC advice that the interpretation of the entire
submission relies heavily on how HER2 positivity/over expression is
defined, in terms of both test methodologies used and test
algorithm applied.
The PBAC considered that the determination of HER2 positive status
using various in situ hybridisation (ISH) tests and/or
immunohistochemistry (IHC) tests is less certain in gastric cancer
than in breast cancer. HER2 status in the key randomised trial
(ToGA) was assessed under optimal circumstances, with a single
laboratory assessing all samples using a battery of tests which
were combined to influence the overall conclusion. For example, IHC
testing helped locate those parts of a specimen which would be most
suitable for further investigation by fluorescence ISH (FISH).
Alternative testing strategies (such as IHC alone or FISH alone)
and examination across multiple laboratories (especially if the
assessment of IHC is in a different laboratory than the assessment
of FISH) are both likely to produce greater discordance about which
samples are FISH positive or IHC3+. Further, evidence from the
Australian GaTHER study demonstrates the well-described variability
in HER2 status determinations across laboratories and across the
three current ISH test options and particularly across the current
IHC test options. Scoring systems to determine test results also
vary across breast cancer and gastric cancer and across
laboratories; for example the ToGA trial relied on a HER2:CEP17
ratio >2.0 in concluding FISH positivity, whereas in breast
cancer it is now widely accepted that >2.2 is FISH positive and
ratios between 1.8 and 2.2 are equivocal. Similarly, use of
absolute HER2 copy number, use of single and/or dual probes and
assessment of surface and invasive components of the cancer may
also vary between laboratories. Greater variability of HER2
positivity is also expected with specimens from endoscopy biopsies
rather than resections (and more ToGA participants with biopsy
specimens were diagnosed HER2 positive than were participants with
resection specimens) and with specimens from metastases rather than
the original tumour. In the event that trastuzumab is to be
reconsidered, the PBAC accepted advice to have the Medical Services
Advisory Committee’s (MSAC) input on the comparative
analytical performance in normal Australian laboratory conditions.
Against this evidentiary standard, examining the various HER2
positive definitions, HER2 tests and testing strategies would be
informative.
The PBAC further considered that the prognostic impact of HER2
positive status on prognosis and on predicting variation in the
treatment effect of trastuzumab is also less certain in gastric
cancer than in breast cancer. There is emerging evidence, including
from the ToGA trial, that being HER2 positive may confer a more
favourable prognosis in gastric cancer than being HER2 negative. If
so, the biological basis for trastuzumab’s pharmacological
effect in inhibiting HER2 signalling is not as compelling as it is
in breast cancer. The ToGA trial assessed the treatment effect of
trastuzumab in patients who were HER2 positive defined as being
FISH positive and/or IHC3 positive; the comparative treatment
effect of trastuzumab in patients who are FISH negative and IHC0,
IHC1 or IHC2 has not been investigated.
In addition, the PBAC considered that there is less biological
plausibility in the claimed linkage between HER2 positive status
and the incremental effect of trastuzumab arising from the greater
amount of discordance across IHC and FISH results in gastric
cancer, where 131 (24%) of FISH positive patients in the ToGA trial
were IHC0 or IHC1+ and a further 159 (29%) of FISH positive
patients were IHC2+. FISH assesses gene amplification in the cell
nucleus and IHC assesses protein expression on the cell surface,
and closer concordance between these results would have given
greater support to the underlying biological rationale and greater
confidence in the post hoc subgroup analyses relied on in the
submission.
The PBAC noted that, with only 3% of the ToGA population having
locally advanced (Stage III) disease, any reconsideration of
trastuzumab in gastric cancer should be limited to those with
metastatic (Stage IV) disease. For similar reasons with reference
to the ToGA trial, trastuzumab should not be continued after
disease progression. Any PBS restriction would also need to specify
a suitable definition of HER2 positive status consistent with PBAC
acceptance of a sufficient incremental treatment effect of adding
trastuzumab and MSAC advice on the adequacy of HER2 testing
strategies to accurately identify patients according to this
definition.
The PBAC considered that the appropriate comparator is triplet
chemotherapy, such as epirubicin with cisplatin and either
5-fluorouracil or capecitabine (ECF or ECX) rather than doublet
therapy such as cisplatin and either 5-fluorouracil or capecitabine
(CF), and that triplet chemotherapy has been established to be more
effective than doublet chemotherapy, albeit on comparatively weak
evidence. As the evidence from the ToGA trial compared the addition
of trastuzumab to CF against CF alone, this was a source of
uncertainty in the submission.
The statistically significant increase in the primary outcome of
overall survival in the intention-to-treat analysis of the ToGA
trial (a gain of 2.7 months from a median of 11.1 months without
trastuzumab to a median of 13.8 months with trastuzumab) was
accepted as convincing evidence of trastuzumab’s clinical
effectiveness in HER2 positive patients as defined for this trial.
However the PBAC also noted that the median overall survival in the
doublet control arm (CF alone) is numerically greater than the
results of four epirubicin studies with similar sample sizes, which
does not support the initial biological arguments that HER2
positive status would identify a group of patients with a worse
prognosis. The PBAC also questioned the clinical importance of the
extent of overall survival gain, particularly as the comparison was
not against triplet chemotherapy. The PBAC noted that no
incremental effect was detected on quality of life, but patients in
the trastuzumab arm of the trial experienced 22% more adverse
events than patients in the control arm of the trial.
The economic model sought to compare the proposed scenario in which
both HER2 testing and trastuzumab are subsidised against the
current scenario where neither HER2 testing nor trastuzumab are
subsidised.
The economic model for the intention-to-treat population (Scenario
1) estimated a base case discounted incremental cost in the range
of $75,000 - $105,000 per extra discounted quality-adjusted
life-year gained, which the PBAC considered to be unacceptably high
and uncertain. Uncertainties highlighted in the sensitivity
analyses included the effectiveness of current therapy in the
comparator scenario and the HER2 negative patients in the proposed
scenario. In both these cases, the approach taken in the submission
was favourable to trastuzumab. This is of particular concern given
doubts about whether being HER2 positive confers a poorer prognosis
in gastric cancer. Other important uncertainties include the
comparison against less effective doublet chemotherapy and the lack
of adjustment for less optimal HER2 testing in Australia. In both
these cases, the approach taken in the submission was also
favourable to trastuzumab.
The PBAC also considered two alternative scenarios based on post
hoc subgroups proposed in the submission. The reliability of these
scenarios was considered to be insufficiently justified given the
negative result of the pre-specified test for interaction between
the treatment effect of trastuzumab and five pre-specified HER2
subgroups: four being defined by patients being FISH positive and
in one of the four different IHC states, and the other being
defined by patients being FISH negative and IHC3+. The post hoc
subgroups were defined differently: IHC3+ irrespective of FISH
status OR IHC2+ and FISH positive (Scenario 2) or IHC3+
irrespective of FISH status (Scenario 3). The PBAC noted that the
median overall survival in the control arm tended to increase
numerically as the definition of HER2 positivity for each subgroup
was increased with reference to their IHC state, which again does
not support the initial biological arguments that HER2 positive
status would identify a group of patients with a worse prognosis.
Both post hoc subgroup scenarios were associated with numerically
larger gains in overall survival and numerically more favourable
incremental cost-effectiveness ratios, with Scenario 3 numerically
more favourable than Scenario 2. The PBAC considered these ratios
to still be unacceptably high and even more uncertain than the base
case from the overall analysis.
The PBAC considered that MSAC input would be informative on: (a)
the analytical performance and effective analytical performance of
IHC and ISH and various strategies of combining these tests; (b)
the HER2 copy number data from the ToGA trial; (c) clarifying the
prognostic significance of HER2 status in gastric cancer; (d) an
implementation strategy for HER2 testing of gastric cancer in
Australia which marries what is practical with the data available
from ToGA; (e) a more detailed assessment of the GaTHER study, with
particular reference to IHC variability which is not included in
the submission and with reference to concordance in terms of who
would and would not be eligible for trastuzumab according to
different definitions of HER2 positive rather than reference to
Kappa statistics.
Recommendation:
Reject
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 had no further comment.
