Duloxetine hydrochloride, capsule, 30 mg and 60 mg, Cymbalta, July 2007
Public summary document for Duloxetine hydrochloride, capsule, 30 mg and 60 mg, Cymbalta, July 2007
Page last updated: 09 November 2007
Public Summary Document
Product: Duloxetine hydrochloride, capsule, 30 mg and 60 mg, Cymbalta
Sponsor: Eli Lilly Australia Pty Ltd
Date of PBAC Consideration: July 2007
1. Purpose of Application
The submission sought a restricted benefit PBS listing for treatment of major depressive
disorder.
2. Background
This drug had not previously been considered by the PBAC.
3. Registration Status
Duloxetine was registered by the TGA on 14 March 2007 for the treatment of major depressive disorder.
4. Listing Requested and PBAC’s View
Restricted benefit
Major depressive disorders
See Recommendation and Reasons for the PBAC’s View.
5. Clinical Place for the Proposed Therapy
Major depressive disorder is a major public health problem and is the most common
mental disorder in Australia. Major depressive disorder is projected to be the second
leading cause of mortality and disability worldwide by 2020.
Major depressive disorder is a common and chronic illness that is characteristically
relapsing and remitting in nature with an estimated 50% of sufferers relapsing following
resolution of a depressive episode. Estimates for lifetime prevalence range from 10-25%
for females and 5-12% for males. On average, one in five people will experience depression
in their lives and about 100,000 adults will live with depression each year in Australia.
Duloxetine is a serotonin and noradrenalin reuptake inhibitor (SNRI) indicated for
the treatment of major depressive disorder.
6. Comparator
Appropriately, the submission nominated venlafaxine as the main comparator.
7. Clinical Trials
The submission presented two randomised controlled trials comparing 60mg to 120mg
duloxetine with 75mg to 225mg venlafaxine as pivotal evidence. The trials were conducted
over 8 weeks and the results were pooled.
A meta-analysis was presented as supportive evidence.
The full list of trials forming the basis of the submission is tabulated below.
Pivotal evidence
|
Trial/First author |
Protocol title |
Publication citation |
|---|---|---|
|
HMBU |
||
|
Perahia D et al 2006 |
Comparing Duloxetine and Venlafaxine in the Treatment of Major Depressive Disorder using a Global Benefit-Risk Approach. |
New Clinical Drug Evaluation Unit (NCDEU) Conference June 6-9, 2005; Boca Raton, FL. |
|
HMCQ |
||
|
Perahia D et al 2005 |
Comparing Duloxetine and Venlafaxine in the Treatment of Major Depressive Disorder using a Global Benefit-Risk Approach. |
New Clinical Drug Evaluation Unit (NCDEU) Conference June 6-9, 2005; Boca Raton, FL. |
|
Perahia D et al |
A randomized, double-blind comparison of duloxetine and venlafaxine in the treatment of patients with major depressive disorder. |
Journal of Psychiatric Research. In Press. |
Supportive evidence
|
Trial/First author |
Protocol title |
Publication citation |
|---|---|---|
|
Vis et al., 2005 |
Duloxetine and Venlafaxine-XR in the Treatment of Major Depressive Disorder: a Meta-Analysis of Randomized Clinical Trials. |
Annals of Pharmacotherapy. 39(11):1798-807, 2005. |
8. Results of Trials
The results of the key trials are summarised in the table below.
Global benefit risk estimates
|
GBR |
Duloxetine 60 mg daily |
Venlafaxine 150 mg daily |
p-value |
|||
|---|---|---|---|---|---|---|
|
Pooled Period II |
Mean |
SE |
Mean |
SE |
||
|
|
Linear score |
–1.418 |
0.195 |
–1.079 |
0.193 |
0.217 |
|
|
Log ratio score |
–0.811 |
0.123 |
–0.616 |
0.117 |
0.252 |
|
GBR |
Duloxetine 60–120 mg daily |
Venlafaxine 150–225 mg daily |
p-value |
|||
|
Pooled Period II/III |
Mean |
SE |
Mean |
SE |
||
|
|
Linear score |
–0.349 |
0.214 |
–0.121 |
0.203 |
0.440 |
|
|
Log ratio score |
–0.186 |
0.114 |
–0.067 |
0.112 |
0.456 |
N is the number of patients with at least one post-baseline HAMD17 score. Abbreviation:
GBR, global benefit-risk.
The PBAC considered that the primary outcome measure of global benefit-risk (GBR)assessment
(Chuang-Stein et al. 1991) which was used in the two presented trials did not provide
an optimal basis to assess the non-inferiority of duloxetine and venlafaxine. The
GBR is a composite outcome measured on a categorical scale and the GBR-based outcome
data are therefore difficult to interpret. The Committee considered that the data
provided for mean change from baseline to endpoint in HAMD17 scores provided the more
appropriate basis upon which to assess the submission’s claim of non-inferiority,
noting that the HAMD17 has been relied on by PBAC in previous assessment of the comparative
efficacy of treatments for major depressive disorder.
HAMD17 total scores: Change from base line to endpoint: study period II and II/III
|
Therapy |
N |
Baseline |
Endpoint change |
|||
|---|---|---|---|---|---|---|
|
Mean |
SD |
LS mean |
SE |
p-value |
||
|
HMBU |
||||||
|
Period II |
159 |
23.1 |
3.85 |
–12.3 |
0.49 |
0.763 |
|
HMCQ |
||||||
|
Period II |
159 |
22.3 |
3.42 |
–11.2 |
0.54 |
0.338 |
Abbreviations: SD, standard deviation; LS least square mean; SE, standard error.
There has been concern for the potential of hepatic toxicity due to duloxetine. Hepatotoxicity
was not addressed in the submission, but was addressed in the statement of facts and
contention for the administrative appeals tribunal. One serious adverse event was
reported in the two head to head randomised controlled trials. The type of event was
not identified. A significantly greater number of patients discontinued duloxetine
treatment (40, 12.1%), compared with venlafaxine (21, 6.2%; p=0.008), due to adverse
events.
For PBAC’s view of these results, see Recommendations and Reasons.
9. Clinical Claim
The submission claimed that duloxetine was no worse than venlafaxine in terms of effectiveness
and toxicity. The PBAC did not accept this claim.
10. Economic Analysis
The submission presented a preliminary economic evaluation. The choice of the cost-minimisation
approach was considered valid. The resources included were drug costs.
The equi-effective doses in the context of cost-minimisation based on the trial data
were estimated by the submission to be duloxetine 60mg to 120mg for duration as necessary
and venlafaxine 150mg to 225mg for duration as necessary.
As the PBAC did not accept the submissions clinical claim, the results of the economic
analysis were not considered valid.
11. Estimated PBS Usage and Financial Implications
The financial savings/year to the PBS minus any savings in use of other drugs was estimated by the submission to be < $10 million in Year 4. This was considered to be a likely over-estimate as the overall market is not expected to grow, or grow more rapidly, as a result of listing duloxetine.
12. Recommendation and Reasons
The PBAC noted that the pooled results of the two randomised controlled studies comparing
duloxetine 60 mg to 120 mg daily with venlafaxine 150 mg to 225 mg daily (following
an initial two weeks treatment with 75 mg daily) had failed to demonstrate that duloxetine
was non-inferior to venlafaxine using the pre-specified non-inferiority margin for
mean change in the HAMD17. The upper bounds of the 1-sided 97.5% confidence intervals
for the treatment group difference in mean change in HAMD17 between the duloxetine
and venlafaxine groups exceeded the non-inferiority margin of 1.15. The PBAC did not
accept the sponsor’s argument in the pre-PBAC response, that the pre-specified non-inferiority
margin may have been overly restrictive resulting in a false negative result.
Although the Committee accepted as plausible the sponsor’s argument that the higher
discontinuation rate in the duloxetine group might be due to the design of the study
in which all duloxetine patients were started on a full therapeutic dose of 60 mg
whereas the venlafaxine patients were titrated from a lower dose of 75 mg, thus favouring
the venlafaxine group, the PBAC remained concerned that, in the presented trials,
discontinuations due to adverse events were approximately double in the duloxetine
treated group compared to the venlafaxine group. Furthermore the adverse event data
were from a short term trial in relatively young patients (mean age circa 40 years),
whereas in clinical practice duloxetine was likely to be used longer term and in older
patients and might therefore be associated with additional or more serious toxicity.
The submission did not provide any additional safety data that might address this
concern.
The PBAC thus rejected the submission because it had failed to demonstrate that duloxetine
is non-inferior to the comparator in terms of effectiveness and because of uncertainty
about its comparative safety.
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 application was rejected by the PBAC at its meeting in July 2007 on the basis
that non-inferiority versus the agreed comparator was not adequately demonstrated.
Eli Lilly acknowledges that further analysis and explanation of the clinical trial
findings would be helpful in any future consideration of CYMBALTA by the PBAC. Expert
opinion indicates that patient response to currently available antidepressants is
variable and additional antidepressant options are still required.
The sponsor refers to its own website (www.lilly.com.au) for more details.
