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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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
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
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
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
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
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
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.
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.