Eltrombopag olamine, tablets, 25 mg and 50 mg, Revolade®
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Product: Eltrombopag olamine, tablets, 25 mg and
50 mg, Revolade®
Sponsor: GlaxoSmithKline Australia Pty Ltd
Date of PBAC Consideration: November 2010
1. Purpose of Application
The submission sought a Section 100 (Highly Specialised Drugs
Program) Authority Required listing for adult patients with chronic
immune (idiopathic) thrombocytopenia purpura (ITP).
Highly Specialised Drugs are medicines for the treatment of chronic
conditions, which, because of their clinical use or other special
features, are restricted to supply to public and private hospitals
having access to appropriate specialist facilities
2. Background
This drug had not previously been considered by the PBAC.
3. Registration Status
Eltrombopag olamine was TGA registered on 2 July 2010 for the
treatment of adult patients with chronic ITP who have an inadequate
response or are intolerant to corticosteroids and
immunoglobulins.
4. Listing Requested and PBAC’s View
Section 100 (program not specified)
Authority required
Initiation
For initial treatment, as the sole PBS-subsidised thrombopoietin
receptor agonist (TRA), of an adult patient with chronic ITP who
is:
- Splenectomised and:
- who has an inadequate response to splenectomy, OR
- who requires additional chronic intervention to maintain a response post splenectomy where the intervention is associated with unacceptable toxicity; OR
NOTE:
Inadequate response is defined as a persistent platelet count of:
- less than or equal to 20,000/microlitre or
- 20,000 – 30,000/microlitre where the patient is experiencing bleeding or has a history of bleeding in this platelet range.
Continuation
For continuing treatment of an adult patient with chronic ITP who
has displayed a sustained platelet response or a significant
reduction in bleeding events during the first six (6) months of
treatment.
NOTE:
A sustained platelet response is defined as a platelet count
greater than or equal to 50,000/microlitre on at least four
occasions; or a platelet count greater than 30,000/microlitre AND a
doubling of baseline platelet count, on at least four
occasions.
The PBAC noted that the sponsor, in its Pre-Sub-Committee response,
agreed that the restriction for eltrombopag should be consistent
with that recommended for romiplostim and considered this to be
appropriate.
5. Clinical Place for the Proposed Therapy
Chronic ITP is a long-term autoimmune disorder characterised by
persistently low platelet counts (thrombocytopenia) and cutaneous
and mucosal bleeding. Bleeding can range from mild (bruising and
purpura) to severe (intracranial or gastrointestinal haemorrhage)
and can sometimes result in death. The major therapeutic goal for
ITP is to increase platelet count to a safe level while minimising
treatment-related toxicity. First-line treatment typically involves
corticosteroids for asymptomatic patients with low platelet counts
or with mild bleeding symptoms, and high-dose corticosteroids,
intravenous immunoglobulin (IVIg) and/or platelet transfusions for
patients with clinically significant bleeding. Splenectomy is
recommended as second-line therapy.
The submission proposed eltrombopag as an alternative to
romiplostim for patients where splenectomy has failed or is
contraindicated and where patients are unresponsive/intolerant to
corticosteroids and IVIg therapy.
6. Comparator
The submission nominated romiplostim as the comparator. This was
accepted by the PBAC.
7. Clinical Trials
The submission presented one randomised trial comparing eltrombopag
25-75 mg, administered orally once a day, with placebo (both given
in addition to standard care) in both splenectomised and
non-splenectomised adult patients with chronic ITP (RAISE); and two
randomised trials comparing romiplostim (weekly injection titrated
to effect) with placebo (both given in addition to standard care),
the first in splenectomised patients with chronic ITP (Kuter
2008S), and the second in non-splenectomised patients with chronic
ITP (Kuter 2008NS).
Details of the published trials are presented in the following
table.
Trials and associated reports presented in the
submission
| Trial ID/First Author | Protocol title/Publication title | Publication citation |
| RAISE Cheng G, et al (2010) | Eltrombopag for management of chronic immune thrombocytopenia (RAISE): a 6-month, randomised, phase 3 study. | Lancet 2010; Early Online Publication, 24 August 2010 doi:10.1016/S0140-6736(10)60959-2 |
| George JN, et al. | Improved quality of life for romiplostim-treated patients with chronic immune thrombocytopenic purpura: results from two randomized, placebo-controlled trials. | British Journal of Haematology 2008; 144:409-415 |
| George JN, et al . | Abstract 1314 | Blood 2007; 110 |
| Gernsheimer TB, et al. | Abstract 2 | Blood 2007; 110 |
| Jamali F, et al. | Romiplostim for the treatment of chronic immune (idiopathic) thrombocytopenic purpura. | Oncology 2009; 23:704-9. |
| Kuter DJ, et al. (2008) | Effect of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial. | Lancet 2008; 371:395-403 |
| Kuter DJ, et al. (2007) | Abstract 565 | Blood 2007; 110 |
| Lyons R, et al. | Abstract 1300 | Blood 2007; 110 |
| Pullarkat V, et al. (2007) | Abstract 1304 | Blood 2007; 110 |
| Pullarkat VA, et al. (2009) | Quantifying the reduction in immunoglobulin use over time in patients with immune mediated thrombocytopenic purpura receiving romiplostim (AMG531). | American Journal of Hematology 2009; 84:538-40. |
No trials directly comparing eltrombopag with romiplostim were
identified.
There was concern regarding the exchangeability of the trials,
arising from differences in the patient populations and the conduct
of the trials. Some of the key differences between the RAISE and
Kuter studies are presented in the table below.
Differences between RAISE and Kuter trials
| RAISE Eltrombopag | Kuter 2008 Romiplostim | |
| % Placebo group achieving platelet response | 6.5% | 2.4% |
| Median duration of ITP (yr) | 1.6 (E)/2.3 (P) | 2.5 (R)/2.5 (P) |
| % With ≥ 3 prior treatments | 56%(E)/52%(P) | 65%(R)/60%(P) |
| Proportion receiving rescue treatment | 38%(E)/63%(P) | 22%(R)/60%(P) |
E = Eltrombopag; R = Romiplostim; P = Placebo
For PBAC’s view of the trials, see Recommendation and
Reasons.
8. Results of Trials
The submission presented the results of an indirect comparison of
eltrombopag and romiplostim, with placebo as the common comparator.
As none of the predefined outcomes of the trials were comparable, a
post hoc analysis of durable platelet response and overall platelet
response (the primary and main secondary outcomes of the
romiplostim trials) was performed in the intention-to-treat (ITT)
population of the RAISE trial. As randomisation in the RAISE trial
was stratified by splenectomy status, the submission also presented
separate post hoc analyses for the splenectomised and
non-splenectomised subgroups.
The submission did not define the non-inferiority margin for the
comparison.
The surrogate outcomes used in the indirect comparison defined a
treatment response in terms of the proportion of patients with
platelet counts above an arbitrary platelet count threshold of 50 x
109/L. The submission acknowledged that platelet count
was an imperfect measure of bleeding risk because the relationship
between the two is not linear. Therefore, changes in these
‘surrogate’ outcomes were not necessarily predictive of
the magnitude of the comparative treatment effect in terms of
clinically relevant outcomes, such as clinically important bleeding
and mortality. The submission acknowledged that the relationship
between the surrogates and patient relevant outcomes is difficult,
but argued that “romiplostim was approved for listing based
largely on these surrogate outcomes.” Further, the submission
noted that outcomes ‘any’ and ‘clinically
meaningful bleeding’ were significantly reduced in
eltrombopag patients in the RAISE study, but that these outcomes
could not be used in the indirect comparison as the romiplostim
studies included bleeding outcomes only as adverse events.
The submission claimed that, based on the results of the indirect
comparison, it can be concluded that eltrombopag and romiplostim
provide similar rates of durable platelet response in the target
PBS population of adults with chronic refractory ITP. The PBAC
considered that this conclusion was not adequately supported by the
evidence. See Recommendations and Reasons.
The most common adverse events in the RAISE trial and the
romiplostim trials included headache, diarrhoea, nausea,
nasopharyngitis, fatigue and upper respiratory tract infection. The
submission stated that, while differences in reporting methods made
it difficult to draw any meaningful conclusions about the relative
safety of eltrombopag and romiplostim, their safety profiles are at
least comparable, and eltrombopag may result in fewer adverse
events than romiplostim.
The PBAC considered that differences in the base-line risks of the
trial populations and in the reporting of adverse events between
the trials made it difficult to reliably assess the comparative
safety of eltrombopag and romiplostim. See Recommendation and
Reasons.
9. Clinical Claim
The submission claimed eltrombopag to be non-inferior to
romiplostim in terms of both comparative effectiveness and
comparative safety. The PBAC did not accept this claim. See
Recommendation and Reasons.
10. Economic Analysis
The submission presented a cost minimisation analysis. On the basis
of the trial data, the submission estimated that eltrombopag 55.2
mg/day and romiplostim 276.2 mcg/week are equi-effective.
11. Estimated PBS Usage and Financial Implications
The financial savings per year to the PBS estimated by the
submission were less than $10 million in Year 5. The
submission’s estimate was uncertain, and relied on estimated
cost savings from substitution for romiplostim.
12. Recommendation and Reasons
The PBAC noted that the sponsor, in its Pre-Sub-Committee response,
agreed that the restriction for eltrombopag should be consistent
with that recommended for romiplostim and agreed that this is
appropriate.
The submission’s nomination of romiplostim as the appropriate
comparator was accepted.
The Committee noted that the submission presented one randomised
trial comparing eltrombopag 25-75 mg, administered orally once a
day, with placebo (both given in addition to standard care) in both
splenectomised and non-splenectomised adult patients with chronic
ITP (RAISE); and two randomised trials comparing romiplostim
(weekly injection titrated to effect) with placebo (both given in
addition to standard care), the first in splenectomised patients
with chronic ITP (Kuter 2008S), and the second in
non-splenectomised patients with chronic ITP (Kuter 2008NS). The
PBAC considered that the patient populations of these trials were
not representative of the more restricted high-risk subgroup of
chronic ITP patients for whom PBS listing was sought. In addition,
the indirect comparison was based on post-hoc analyses of the RAISE
study. However, the PBAC acknowledged that, currently, these are
the only available data and that the recommendation to list
romiplostim had been made on the basis of the Kuter trials.
Further, as none of the predefined outcomes of the trials were
comparable, a post hoc analysis of durable platelet response and
overall platelet response (the primary and main secondary outcomes
of the romiplostim trials) was performed in the intention-to-treat
(ITT) population of the RAISE trial. As randomisation in the RAISE
trial was stratified by splenectomy status, the submission also
presented separate post hoc analyses for the splenectomised and
non-splenectomised subgroups. The PBAC considered that there were
considerable concerns regarding the exchangeability of the trials,
arising from differences in the patient populations and the conduct
of the trials. On this basis, the appropriateness of an indirect
determination of the comparative treatment effect for eltrombopag
and romiplostim, using these trials, was uncertain.
There was a higher placebo response, lower medium duration of ITP,
lower proportion of patients with greater than or equal to 3 prior
treatments and a higher proportion of patients receiving rescue
medication in the eltrombopag trial. Overall the PBAC considered it
likely that the patients in the RAISE trial had milder ITP than the
patients in the Kuter trials.
The submission claimed that, based on the results of the indirect
comparison, it could be concluded that eltrombopag and romiplostim
provide similar rates of durable platelet response in the target
PBS population of adults with chronic refractory ITP. This
conclusion was not adequately supported by the evidence. The point
estimates of the comparative treatment effect all favoured
romiplostim. Additionally, non-inferiority margins were not defined
for the comparison. Further, in particular, due to the low event
rates in the placebo arms of the trials, and also the substantial
potential for confounding, the results of the indirect comparison
of eltrombopag and romiplostim were subject to considerable
uncertainty. In addition, the width of the confidence intervals
indicated that the indirect comparison was not adequately powered
for statistical testing of non-inferiority, especially in the
patient subgroups in which patient numbers were small
(splenectomised/non-splenectomised). These factors resulted in
considerable uncertainty around any conclusions drawn from this
comparison regarding the relative efficacy of eltrombopag and
romiplostim.
The PBAC also considered that differences in the base-line risks of
the trial populations and in the reporting of adverse events
between the trials made it difficult to reliably assess the
comparative safety of eltrombopag and romiplostim. This was clearly
illustrated by the differences in reporting in both active and
placebo arms in reporting of epistaxis (5% vs. 10%, and 32% vs.
24%, respectively) and petechiae (2% vs. 2% and 17% vs. 22%,
respectively). These results also suggested that romiplostim may be
more effective than eltrombopag in reducing bleeding events.
The PBAC considered that there was insufficient evidence to draw
any reliable conclusions regarding the comparative safety of
eltrombopag and romiplostim in patients with chronic ITP. In
particular, there were no comparative safety data on the long-term
use of these treatments. However, it was considered possible that
eltrombopag is less effective than romiplostim, and that the case
for non-inferiority had not been made.
The submission presented a cost minimisation analysis. The PBAC
noted that the equi-effective doses proposed by the submission were
based on the ITT populations of the trials and not the high risk
sub-groups
The PBAC noted that the submission’s estimate of the
equi-effective doses remained highly uncertain on the following
grounds:
- There are four distinct patient groups in the requested listing: splenectomised initiating patients, non-splenectomised initiating patients, splenectomised continuing patients, and non-splenectomised continuing patients. Doses, and therefore equi-effective doses, varied between these patient subgroups.
- Using the mean dose to determine the total cost of romiplostim was not accurate, as it was the distribution of doses in the splenectomised and non-splenectomised populations that determine the number and size of vials used and, therefore, the extent of wastage as a result of partially used vials.
- The cost-minimisation analysis was incomplete as it only considered the drug costs of eltrombopag and its comparator, ignoring possible differences in the utilisation of other relevant resources. The March 2010 Public Summary Document for romiplostim noted the uncertainty relating to the rate of IVIg use, as reduction in IVIg use represented the major cost offset in the model, without which cost-effectiveness could not be demonstrated.
The PBAC noted that the Pre-PBAC response reported that use of
rescue medication was similar between the two drugs. However, given
that it is likely that in the eltrombopag trial, patients were less
severely affected than those in the romiplostim trials, this
comparison was not considered useful.
The PBAC therefore rejected that submission on the basis of
uncertain clinical effectiveness in comparison with
romiplostim.
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 recognises the difficulties involved in the clinical
comparison considered and is working with the PBAC to find a
solution which will enable eltrombopag to be made more accessible
to patients with chronic refractory ITP as soon as possible.
