Quetiapine, tablets, 25 mg, 100 mg, 200 mg and 300 mg (as fumarate), Seroquel®, and tablets (modified release), 50 mg, 200 mg, 300 mg and 400 mg (as fumarate), Seroquel XR® (depressive episodes)
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400 mg (as fumarate), Seroquel XR ® (PDF 36 KB)
Product: Quetiapine, tablets, 25 mg, 100 mg, 200
mg and 300 mg (as fumarate), Seroquel®, and tablets
(modified release), 50 mg, 200 mg, 300 mg and 400 mg (as fumarate),
Seroquel XR®
Sponsor: AstraZeneca Australia Pty Ltd
Date of PBAC Consideration: November 2010
1. Purpose of Application
The submission sought an Authority Required (Streamlined) listing
for ‘depressive episodes associated with bipolar
disorder’.
2. Background
For background information on previous PBAC considerations of quetiapine, refer to
the July 2010 Public Summary Document for quetiapine.
3. Registration Status
On 3 June 2009 quetiapine was registered by the TGA for the
treatment of depressive episodes associated with bipolar
disorder.
Other registered bipolar disorder indications for the immediate and
modified release formulations include:
Maintenance treatment of bipolar 1 disorder, as monotherapy or in
combination with lithium or sodium valproate, for the prevention of
relapse/recurrence of manic, depressive or mixed episodes.
Treatment of acute mania associated with bipolar I disorder as
monotherapy or in combination with lithium or sodium
valproate.
4. Listing Requested and PBAC’s View Authority Required
(STREAMLINED)
Depressive episodes associated with bipolar disorder.
The submission proposed amending and simplifying the restriction
wording to: “Treatment of bipolar disorder” should the
PBAC recommend the two quetiapine submissions considered at this
meeting (adjunctive therapy to mood stabilisers of an episode of
acute mania associated with bipolar I disorder and depressive
episodes associated with bipolar disorder). The submission stated
that the addition of the above indications will mean that all
phases of bipolar disorder will be subsidised on the PBS as
monotherapy of an episode of acute mania associated with bipolar I
disorder and maintenance treatment of bipolar I disorder as either
monotherapy or in combination with lithium or sodium valproate are
already either listed or recommended.
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
Bipolar disorder is a psychiatric illness that is characterised by
one or more manic, depressed or mixed episodes. The listing of
quetiapine would provide a subsidised atypical antipsychotic drug
for treatment of depressive episodes associated with bipolar
disorder.
6. Comparator
The re-submission nominated olanzapine as the comparator for the
assessment of clinical efficacy, but given olanzapine is neither
TGA approved nor PBS listed for this indication, a
cost-effectiveness analysis versus placebo was also presented. The
PBAC did not consider olanzapine to be an appropriate main
comparator.
For PBAC’s view, see Recommendation and Reasons.
7. Clinical Trials
The basis of the submission was an indirect comparison of quetiapine and olanzapine
using placebo as the common comparator. A meta-analysis of 5 randomised placebo controlled
quetiapine trials (BOLDER I & II, EMBOLDEN I & II, and study 002) was presented and
compared with one randomised placebo controlled olanzapine trial (Tohen et al 2003).
Citations for BOLDER I & II, EMBOLDEN I & II, and Tohen 2003 have been previously
reported in the quetiapine PSD from March 2009 PBAC meeting.
Additional studies published at the time of the submission are as follows:
| Trial ID / First author | Protocol title / Publication title | Publication citation |
| Placebo-controlled randomised trials of quetiapine | ||
| Trial D144CC00002 (Study 002) Suppes T et al | Effectiveness of the extended release formulation of quetiapine as monotherapy for the treatment of acute bipolar depression. | Journal of Affective Disorders 2010; 121:106-115. |
8. Results of Trials
The re-submission undertook an indirect comparison between
quetiapine 300 mg once daily versus olanzapine once daily in
patients with bipolar I depression, using placebo as the common
reference.
Quetiapine vs. olanzapine (primary outcome of the trials)
The primary outcome of the trials was change in the
Montgomery-Asberg Depression Rating Scale (MADRS) score from
baseline to week 8. The mean difference in the change from baseline
MADRS score between quetiapine 300 mg and olanzapine 9.7 mg was
-2.0 (95% CI: -4.9, 1.0) which was within the non-inferiority
threshold nominated by the re-submission (minimum clinically
important difference (MCID) 1.6 – 1.9). The mean difference
for the indirect comparison of quetiapine 600 mg and olanzapine was
-2.2 (95% CI: -5.8, 1.4)
The re-submission demonstrated that quetiapine (300 mg and 600 mg
per day) was non-inferior to olanzapine 9.7 mg per day in bipolar-I
patients. However, this information did not support the listing of
quetiapine under the proposed restriction because: (1) The
presented evidence only demonstrated non-inferiority in bipolar I
patients, when the requested restriction would allow treatment of
patients with both bipolar I and bipolar II;
(2) The evidence presented supported the use of quetiapine as
monotherapy, and the requested restriction would also allow for use
as adjunct treatment; and (3) As stated previously by the PBAC,
olanzapine was not an appropriate comparator because it was not TGA
registered or PBS approved for use in this indication, nor was it
identified by the clinical expert survey as the treatment most
likely to be replaced.
Quetiapine vs. placebo (secondary outcomes of the trials)
For the secondary outcome of MADRS response and remission, the
results showed that quetiapine was more effective than placebo for
treating bipolar depression in patients with both bipolar I and
bipolar II. Patients treated with quetiapine were statistically
significantly more likely to achieve response or remission on the
MADRS at eight weeks, compared with placebo.
An investigation of the effectiveness of quetiapine vs. lithium and
paroxetine was undertaken during the evaluation using results from
the EMBOLDEN trials. Compared with lithium, a significant
improvement in MADRS score from baseline was demonstrated for 600
mg quetiapine. Compared with paroxetine, a statistically
significant improvement in MADRS score from baseline was
demonstrated fro both 300 mg and 600 mg quetiapine.
Lithium did not demonstrate a significant improvement compared with
placebo for MADRS response or remission, however there was no
significant difference between lithium and either dose of
quetiapine for these outcomes.
For PBAC’s view of the results, see Recommendation and
Reasons.
The addition of Study 002 did not appreciably affect the analysis
of safety. As previously, the incidence of discontinuations due to
adverse events associated with olanzapine and quetiapine treatment
appeared to be similar and there was no evidence to suggest that
quetiapine had a worse safety profile than olanzapine in short-term
treatment (up to 8 weeks) of episodes of bipolar depression. From
the post-hoc analysis of the five placebo-controlled trials,
quetiapine was associated with significantly more somnolence,
sedation, dizziness, headache, constipation, weight gain, increased
appetite, anxiety, headache, dry mouth, insomnia, dyspepsia and
nausea compared with placebo treatment.
9. Clinical Claim
As previously accepted by the PBAC, the submission claimed
quetiapine to be non-inferior to olanzapine in terms of comparative
efficacy and comparative safety.
10. Economic Analysis
The re-submission presented a cost-utility analysis of quetiapine
compared with placebo, based on five placebo-controlled trials of
quetiapine. The model assumed patients would use the mean medial
quetiapine dose from the clinical trials, 269.4 mg daily. The model
included the costs and health outcomes for health states
representing successfully treated bipolar depression
(‘response’ and ‘remission’) and persisting
symptoms (‘no response’ and ‘drop
out’).
The time horizon for the model was eight weeks, the duration of the
trials, with a cycle length of one week. A half-cycle correction
was applied. Patients moved from bipolar depression into the other
health states (‘drop out’, ‘response not
remission’ and ‘remission’) according to the
transition probabilities calculated using a linear response to
treatment. Costs included in the model were those directly relating
to quetiapine treatment and costs associated with bipolar
depression.
The estimated incremental cost-effectiveness ratio (ICER) of
quetiapine compared with placebo was in the range of $15,000 -
$45,000 per extra quality adjusted life year (QALY) gained.
The model was most sensitive to changes in the dose (cost) of
quetiapine used; at the 300 mg dose, the incremental
cost-effectiveness ratio (ICER) increased but still in the range
$15,000 - $45,000 and was in the range $75,000 - $105,000 for the
600 mg dose.
11. Estimated PBS Usage and Financial Implications
The likely number of patients per year was estimated in the
resubmission to be less than 10,000 per year in Year 1, while the
financial cost per year to the PBS was estimated to be less than
$10 million in Year 5.
12. Recommendation and Reasons
The PBAC did not consider the submission’s proposal to list
quetiapine with the simplified restriction “Treatment of
bipolar disorder” to be appropriate as the evidence presented
was limited to bipolar I disorder. Listing with this more liberal
restriction would likely lead to a significant increase in costs to
the PBS in a population in whom there was a lack of evidence of
comparative effectiveness and cost effectiveness.
The PBAC considered that what the sponsor had presented, in having
an active comparator (olanzapine) for efficacy but providing a
comparison against placebo to allow a cost-effectiveness judgement
to be made, was not unreasonable as PBAC had not seen any
cost-effectiveness evidence for olanzapine in this indication.
However, the main issue of concern to the PBAC again remained the
choice of comparator. Although olanzapine was neither TGA
registered nor PBS listed for the acute treatment of depressive
episodes in bipolar disorder, the more fundamental question was
what quetiapine would replace in practice for this indication and
the PBAC considered that this was lithium in combination with an
antidepressant rather than olanzapine, as this was the most
commonly prescribed treatment at present. This conclusion was
supported by the Expert Opinion Report provided by the sponsor, in
which olanzapine was not identified as the treatment most likely to
be replaced if quetiapine were to be listed.
The re-submission undertook an indirect comparison between
quetiapine 300 mg once daily versus olanzapine once daily in
patients with bipolar I depression, using placebo as the common
reference. However, the patients in the olanzapine trial were
likely to have had more complex disease than the quetiapine
patients. The PBAC has previously accepted non-inferiority with
olanzapine, although clinical equivalence has only been
demonstrated in bipolar I patients. Quetiapine was more effective
than placebo for treating bipolar depression in patients with both
bipolar I and bipolar II. The results of the EMBOLDEN trial showed
no significant improvement in MADRS total score from baseline with
quetiapine 300 mg compared with lithium, however the comparison of
quetiapine 600 mg and lithium did reach significance. Compared with
paroxetine, both quetiapine 300 mg and 600 mg demonstrated a
statistically significant improvement. The PBAC noted that these
analyses relied on the last observation carried forward (LOCF) data
from the clinical trials, and therefore may overestimate treatment
effect. The re-submission claimed that the 300 mg dose of
quetiapine would be used in clinical practice for this indication.
At this dose, quetiapine demonstrated a significant improvement
compared with paroxetine but not lithium.
When the current price for quetiapine is used, the PBAC
acknowledged that the incremental cost-effectiveness ratio (ICER)
of quetiapine compared with placebo decreased to be in the range of
$15,000 - $45,000. However, in clinical practice patients with
depressive episodes associated with bipolar would otherwise be
receiving an active treatment and the data do not allow a
cost-effectiveness evaluation against the most common drugs
currently used to treat this condition. As noted above, the PBAC
did not consider olanzapine to be an appropriate main
comparator.
The PBAC therefore rejected the submission on the basis the main
comparator was inappropriate and insufficient data were available
to the PBAC to form a view about a comparison of quetiapine with
lithium or paroxetine.
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 is disappointed at this outcome.
