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® (Mania)
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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 ‘adjunctive therapy to mood stabilisers, for up to 6
months, of an episode of acute mania associated with bipolar I
disorder’.
2. Background
For background information on previous PBAC considerations of quetiapine, refer to
the July 2010 Public Summary Document (PSD) for quetiapine.
3. Registration Status
On 17 October 2008 quetiapine was registered by the TGA for the
treatment of acute mania associated with bipolar I disorder in
combination with lithium or sodium valproate.
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.
Treatment of depressive episodes associated with bipolar
disorder
4. Listing Requested and PBAC’s View
Authority Required (STREAMLINED)
Adjunctive therapy to mood stabilisers for up to 6 months, of an
episode of acute mania associated with bipolar I disorder.
The PBAC did not comment on the requested restriction.
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
requested would provide an additional atypical antipsychotic
treatment option for adjunctive therapy of mania associated with
bipolar disorder.
6. Comparator
The submission nominated risperidone as the comparator as it was
the only atypical antipsychotic drug subsidised on the PBS for use
as adjunct therapy for acute mania in bipolar I disorder. This was
previously considered appropriate by the PBAC.
7. Clinical Trials
The basis of the submission was two direct randomised
placebo-controlled trials (RCTs) of quetiapine as adjunct therapy
to a mood stabiliser (lithium or sodium valproate) (CSR99 and
CSR100), and two of risperidone as adjunct therapy to a mood
stabiliser (lithium, sodium valproate or carbamazepine) (Yatham
2003 & Sachs 2002). The submission undertook an indirect
comparison of quetiapine and risperidone as adjunct treatment to
mood stabilisers, using placebo as the common comparator.
The studies published at the time of the submission are as
follows:
| Trial ID / First author | Protocol title / Publication title | Publication citation |
| Quetiapine + mood stabiliser vs placebo+ mood stabiliser | ||
| CSR 99/ Sachs G et al | Quetiapine with lithium or valproate for the treatment of bipolar mania: a randomised, double-blind, placebo-controlled study. | Bipolar Disorders 2004; 6: 213-223 |
| CSR 100/ Yatham L et al | A double blind, randomized, placebo-controlled trial of quetiapine as an add-on therapy to lithium or valproate for the treatment of bipolar mania. | International Clinical Psychopharmacology 2007: 212-220 |
| Risperidone + mood stabiliser vs mood stabiliser + placebo | ||
| Yatham L et al | Mood stabilisers plus risperidone or placebo in the treatment of acute mania: International, double-blind, randomised controlled trial. | British J Psych 2003 (182) 141-147 |
| Sachs G et al | Combination of a mood stabilizer with risperidone or haloperidol for treatment of acute mania: a double blind placebo-controlled comparison of efficacy and safety. | Am J Psychiatry 2002 (159): 1146-1154 |
8. Results of Trials
The following tables summarise the results of the indirect comparison of quetiapine
and risperidone for the primary and secondary outcomes of the trials.
Summary of results of the indirect comparison for the primary outcome – change in
YMRS from baseline to day 21 (mITT, LOCF)
| Trial ID | Trials of quetiapine | Trials of risperidone | ||||
| Tmt effect WMD (95%CI) | QET + mood stabiliser Mean | PBO + mood stabiliser Mean | PBO + mood stabiliser Mean | RISP + mood stabiliser Mean | Tmt effect WMD (95% CI) | |
| Quetiapine BID vs risperidone QD (including CBZ) | ||||||
| CSR 99 | -3.83 (-8.19, 0.53) | -13.76 | -9.93 | - | - | - |
| CSR 100 | -2.0 (-6.81,2.81) | -15.2 | -13.2 | - | - | - |
| Yatham 2003 | -10.3 | -14.5 | -4.20 (-8.22, -0.18) | |||
| Sachs 2002 | - | - | - | -8.2 | -14.3 | -6.10 (-10.08, -2.12) |
| Pooled a | -3.01 (-6.23, 0.22) | - | - | - | -5.16 (-7.99, -2.32) | |
| Indirect estimate of effect b (95% CI) | 2.15 (-2.14, 6.44) | |||||
| Quetiapine BID vs risperidone QD (excluding CBZ) | ||||||
| CSR 99 | -3.83 (-8.19, 0.53) | -13.76 | -9.93 | |||
| CSR 100 | -2.0 (-6.81, 2.81) | -15.2 | -13.2 | |||
| Yatham 2003 | -9.80 | -15.20 | -5.40 (-9.84,-0.96) | |||
| Sachs 2002 | - | - | - | -8.20 | -14.30 | -6.10 (-10.09,-2.11) |
| Pooled a | -3.01 (-6.23, 0.22) | -5.79 (-8.76, -2.82) | ||||
| Indirect estimate of effect b (95% CI) | 2.78 (-1.60, 7.16 ) | |||||
Bold =statistical significance.Italics= updated during the evaluation.
Abbreviations: mITT= modified intention to treat population (treated and analysed
patients); LOCF= last observation carried forward; WMD= weighted mean difference;
QET= quetiapine; PBO= placebo; RISP= risperidone; CSR= Clinical Study Report; CI =
confidence interval; n = number with event; N = number in group; RR = relative risk
a pooled using the random effects model
b inferred as proposed drug over main comparator
Summary of results of the indirect comparison for ‘YMRS response’ (≥50% change in
YMRS)
| Trial ID | Trials of quetiapine | Trials of risperidone | ||||
| Tmt effect RR (95% CI) | QET + mood stabiliser Resp. (%) | PBO + mood stabiliser Resp. (%) | PBO + mood stabiliser Resp. (%) | RISP + mood stabiliser Resp. (%) | Tmt effect RR (95% CI) | |
| mITT analysis (treated and analysed population) | ||||||
| CSR 99 | 2.60 (1.70, 4.09) | 45/81 (56%) | 19/89 (21%) | -- | -- | -- |
| CSR 100 | 1.13 (0.88, 1.48) | 59/104 (57%) | 48/96 (50%) | -- | -- | -- |
| Yatham 2003 | -- | -- | -- | 30/73 (41%) | 40/69 (59%) | 1.41 (1.01, 2.00) |
| Sachs 2002 | -- | -- | -- | NR | NR | -- |
| Pooled a | 1.69 (0.73, 3.88) | 104/185 (56%) | 67/185 (36%) | 30/73 (41%) | 40/69 (59%) | 1. 41 (1.01, 2.00) |
| Indirect estimate of effect b (95% CI) | 1.19 (0.49, 2.96) | |||||
| ITT analysis (randomised population) | ||||||
| CSR 99 | 2.60 (1.67, 4.13) | 45/91 (49%) | 1 9/100 (19%) | -- | -- | -- |
| CSR 100 | 1.22 (0.93, 1.60) | 59/106 (56%) | 48/105 (46%) | -- | -- | -- |
| Yatham 2003 | -- | -- | -- | 30/76 (39%) | 40/75 (53%) | 1.35 (0.95, 1.92) |
| Sachs 2002 | -- | -- | -- | NR | NR | -- |
| Pooled a | 1.74 (0.81, 3.73) | 104/197 (53%) | 67/205 (33%) | 30/76 (39%) | 40/75 (53%) | 1.35 (0.95, 1.92) |
| Indirect estimate of effect b (95% CI) | 1.29 (0.56, 2.99) | |||||
Bold =statistical significance. Italics= updated during the evaluation.
Abbreviations: QET=quetiapine; RISP= risperidone; CI = confidence interval; n = number
with event; N = number in group; RR = relative risk; Resp= response; REM= random effects
model.
a pooled using the random effects model
b inferred as proposed drug over main comparator
For PBAC’s view of these results, see Recommendation and Reasons
The submission reported that the pooled analysis of the two quetiapine trials (Yatham
L, et al. Quetiapine versus placebo in combination with lithium or valproate for the treatment
of bipolar mania. J Clin Psychopharmacology 2004(24); 6: 599-606) showed quetiapine was associated
with a significantly higher proportion of patients achieving YMRS response (RR 1.34,
95% CI 1.08, 1.66). Using the random-effects model used in the evaluation, there was
no significant improvement in the pooled analysis of the CSR 99 and CSR 100 for the
modified intention to treat population (treated and analysed patients) (RR 1.69 95%
CI 0.73, 3.88) or the intention to treat (ITT) population (RR 1.74 95% CI 0.81, 3.73).
Risperidone (Yatham 2003) was associated with significantly more patients achieving
YMRS response than placebo, however the lower boundary of the confidence interval
was close to the boundary for no-effect (RR 1.41 95% CI 1.01, 2.00). The data for
the population excluding the patients treated with carbamazepine was not reported
for the YMRS response outcome, so it was not possible to determine if risperidone
was associated with a significant improvement in the patients treated with other mood
stabilisers (lithium and sodium valproate).
One of the main issues was whether it is appropriate to conduct an indirect comparison
of quetiapine and risperidone using these data, given the differences between the
trial populations. Key issues of difference were that the baseline YMRS scores for
risperidone were lower than the quetiapine trials and that most patients in the quetiapine
trials were already receiving a mood stabiliser at baseline; whereas, the risperidone
trials enrolled patients who initiated risperidone concurrently with a mood stabiliser.
The submission claimed the results of the indirect comparisons indicated there was
no significant difference between quetiapine and risperidone in terms of YMRS response.
Given the issues identified above, and that the indirect comparison was based on secondary
outcomes from the trials, this conclusion should be interpreted with caution.
In the clinical trials, quetiapine was associated with significantly more somnolence,
dry mouth, asthenia and postural hypotension than placebo. Risperidone was associated
with a higher rate of extrapyramidal-related adverse effects in Yatham 2003. All trials
reported a statistically significant weight gain in patients who received active atypical
antipsychotic treatment. Overall, the submission did not provide convincing evidence
that quetiapine and risperidone had comparable safety and tolerability profiles. However,
given the limited data available from the trials further information to inform this
comparison was unlikely to be forthcoming.
9. Clinical Claim
The submission described quetiapine as non-inferior to risperidone
in terms of comparative effectiveness and equivalent in terms of
comparative safety. The PBAC considered that the evidence presented
did not support this claim given the identified issues with the
trials included in the indirect comparisons.
10. Economic Analysis
The submission presented a cost-minimisation analysis. Quetiapine
474.80 mg was assumed to be equivalent to risperidone 3.92 mg,
corresponding to a dose relativity of 121.18 mg: 1 mg for
quetiapine and risperidone.
11. Estimated PBS Usage and Financial Implications
No estimate of the likely number of patients per year prescribed
quetiapine for this indication was provided in the submission. The
submission considered a quetiapine listing for adjunct therapy to
mood stabilisers for acute mania with bipolar I disorder would be
cost-neutral, because of the cost-minimisation approach used in
economic evaluation.
12. Recommendation and Reasons
The submission claimed that quetiapine demonstrated a statistically
significant improvement over placebo with respect to the primary
outcome, change in total YMRS score from baseline to day 21, in CSR
99 but not CSR 100. When the appropriate random-effects model was
used, neither CSR 100 nor CSR 99 showed a statistically significant
benefit over placebo for change in YMRS. The random effects
meta-analysis of the quetiapine data also demonstrated that the
change in YMRS is no longer statistically significant, with a
weighted mean difference (WMD) -3.01 (-6.23, 0.22). When the
random-effects model was used to meta-analyse the risperidone data,
the change in YMRS was statistically significant for both the
overall analysis, WMD -5.16 (-7.99, -2.32), and the analysis
excluding patients who were treated with carbamazepine, WMD -5.79
(-8.76, -2.82).
The indirect comparisons demonstrated no significant difference
between risperidone and quetiapine at the 5% level, but the
associated 95% confidence intervals were wide and included the
minimum clinically important difference (MCID) (4-6 points on the
YMRS scale). Therefore, a clinically important difference between
quetiapine and risperidone cannot be ruled out. The placebo
response in trial CSR 100 (international, multi-centre trial) was
more than double that in CSR 99 (US trial), also suggesting there
are considerable differences in the populations included in these
trials. Cochran’s Q statistic was significant (8.33,
p=0.0039), corresponding to an I2 statistic of 88%,
indicating high heterogeneity. This was likely to invalidate the
results of the meta-analysis of quetiapine trials and the inclusion
of the pooled effect in the indirect comparison.
Overall, the PBAC was of the opinion that differences in mood
stabiliser use and YMRS score at baseline demonstrated that there
were important differences in the trial populations, which may
invalidate the indirect comparison between risperidone and
quetiapine.
The PBAC rejected listing on the basis that quetiapine as add-on
therapy to lithium or valproate had not demonstrated
non-inferiority to the comparator and as such was not acceptable
for consideration in a cost minimisation analysis.
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.
