Solifenacin succinate, tablet, 5 mg & 10 mg, Vesicare, July 2007
Public summary document for Solifenacin succinate, tablet, 5 mg & 10 mg, Vesicare, July 2007
Page last updated: 09 November 2007
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Public Summary Document
Product: Solifenacin succinate, tablet, 5 mg & 10 mg, Vesicare
Sponsor: Arrow Pharmaceuticals Pty Ltd
Date of PBAC Consideration: July 2007
1. Purpose of Application
The submission sought a restricted benefit PBS listing for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency or increased urinary frequency in patients where treatment with oxybutynin has failed or is not tolerated.
2. Background
This drug had not previously been considered by the PBAC.
3. Registration Status
Solifenacin was TGA registered on 28 August 2006 for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency or increased urinary frequency.
4. Listing Requested and PBAC’s View
Restricted benefit
Treatment of overactive bladder with symptoms of urge urinary incontinence, urgency
or increased frequency in patients where treatment with oxybutynin has failed or is
not tolerated.
For PBAC’s view, see Recommendation and Reasons.
5. Clinical Place for the Proposed Therapy
People who suffer from Overactive Bladder Syndrome (OAB) experience an unpredictable
urgent need to empty the bladder, that may involve urinary leakage some or all of
the time. The syndrome can impact on a person’s ability to complete their daily activities,
and reduce their quality of life.
Solifenacin is a treatment option for this condition.
6. Comparator
The submission nominated placebo for standard medical management as the main comparator.
The PBAC accepted that placebo for standard medical management would be an appropriate
comparator if solifenacin is used only in the population for whom listing is sought.
However, as there is a substantial risk of utilisation beyond the restriction, oxybutynin
may also be an appropriate comparator. Tolterodine, although currently not listed
on the PBS, may also be an appropriate comparator.
7. Clinical Trials
The submission presented a series of meta-analyses based on the results of eight head-to-head
randomised comparative trials comparing solifenacin (5 mg & 10 mg daily) and placebo
in patients with overactive bladder.
The submission also presented three randomised head-to-head trials comparing solifenacin
(5 mg & 10 mg daily) and tolterodine (4 mg daily) in patients with overactive bladder.
No trial evidence was presented specifically for patients who have failed or are intolerant
to oxybutynin.
The studies published at the time of submission are as follows:
|
Trial/First author |
Protocol title/Publication title |
Publication citation |
|---|---|---|
|
Key trials (solifenacin versus placebo) |
||
|
905-CL-005 |
Solifenacin appears effective and well tolerated in patients with symptomatic idiopathic detrusor overactivity in a placebo- and tolterodine-controlled phase 2 dose-finding study. |
BJU International, (93) 71-77. |
|
905-CL-015 |
Randomized, double-blind placebo-and tolterodine-controlled trial of the once-daily antimuscarinic agent solifenacin in patients with symptomatic overactive bladder. |
BJU International, (93) 303-310. |
|
905-CL-018 |
Randomized, double-blind placebo controlled trial of the once daily antimuscarinic agent solifenacin succinate in patients with overactive bladder. |
J Urol, (172) 1919-1924. |
|
Supportive evidence (uncontrolled clinical trials or other comparators than placebo) |
||
|
905-CL-019 |
Long-term open-label solifenacin treatment associated with persistence with therapy in patients with overactive bladder syndrome. |
Eur Urol (47) 376-384. |
|
905-EC-001 (STAR) |
A comparison of the efficacy and tolerability of solifenacin succinate and extended release tolterodine at treating overactive bladder syndrome: results of the STAR trial. |
Eur Urol, (48) 464-470. |
|
Citations reporting pooled or subgroup analyses |
||
|
905-CL-015 |
Solifenacin is effective for the treatment of OAB dry patients: A pooled analysis. |
Eur Urology (48) 483-487. |
|
905-CL-015 |
Recent developments in the management of overactive bladder: focus on the efficacy and tolerability of once daily solifenacin succinate 5mg. (Pooled analysis) |
Curr Med Res Opin 21 (1) 71-80. |
|
905-CL-015 |
Improved quality of life in patients with overactive bladder symptoms treated with solifenacin. (Pooled analysis for QoL) |
BJU International (95) 81-85. |
|
905-CL-015 |
Redefining response in overactive bladder syndrome. (Pooled analysis for QoL) |
BJU Int (99) 101-106. |
|
905-CL-013 |
Reductions in overactive bladder-related incontinence from pooled analysis of phase III trials evaluating treatment with solifenacin. (Subgroup analysis) |
Int Urogynecol J (17) 512-519. |
|
905-CL-013 |
Solifenacin succinate once daily is superior to placebo in all major overactive bladder symptoms in four trials: results in women. (Subgroup analysis) |
Obstetr Gynecol 103 (S4) 129S. |
|
905-CL-013 |
Efficacy of solifenacin in patients with severe symptoms of overactive bladder: A pooled analysis. (Subgroup analysis) |
Curr Med Res Opin 22 (1) 41-48. |
|
905-CL-013 |
Solifenacin: as effective in mixed urinary incontinence as in urge urinary incontinence. (Subgroup analysis) |
Int Urogynecol J (17) 382-388. |
|
905-CL-013 |
Solifenacin significantly improves all symptoms of overactive bladder syndrome. (Pooled analysis) |
Int J Clin Pract 60 (8) 959-966. |
|
905-CL-013 |
Two randomized, double-blind, placebo-controlled, parallel-group, fixed-dose, multi-center studies assess the efficacy and safety of daily oral administration of 10mg YM905 versus placebo in male and female subjects with overactive bladder. (Pooled analysis) |
J Urol 169 (S4) 349 |
|
905-CL-013 |
Short- and long-term efficacy of solifenacin treatment in patients with symptoms of mixed urinary incontinence. (Sub-group analysis) |
BJU Int (97) 1256-1261 |
|
905-CL-015 |
Efficacy and tolerability of solifenacin in elderly subjects with overactive bladder syndrome: A pooled analysis. |
Am J Geriatr Pharmacol (4) 14-24. |
8. Results of Trials
The submission claimed the data indicate for the primary outcome, the mean number
of micturitions per 24 hours, that treatment with solifenacin (5 and 10 mg combined
or 10 mg alone) results in a statistically significant decrease in the number of micturitions
per 24 hours at 4 weeks: -0.96 (95% CI: -1.13, -0.79) and 12 weeks -1.17 (95%
CI: -1.35, -1.00) compared with placebo.
For the secondary outcome, the proportion of patients achieving less than 8 micturitions
per 24 hours, the data indicate that treatment with solifenacin (5 and 10 mg combined
or 10 mg alone) results in a statistically greater proportion of patients with a mean
of less than 8 micturitions per 24 hours at 4 weeks: RD=0.11 (95% CI: 0.08, 0.14);
8 weeks: RD=0.15 (95% CI: 0.12, 0.18) and 12 weeks: RD=0.14 (95% CI 0.11, 0.17) compared
with placebo.
For the secondary outcome, the proportion of patients becoming continent, the data
indicate that treatment with solifenacin (5 and 10 mg combined or 10 mg alone) results
in a statistically greater proportion of patients becoming continent at 4 weeks: RD=0.17
(95% CI: 0.13, 0.21); 8 weeks: RD=0.16 (95% CI: 0.12, 0.21) and 12 weeks: RD=0.17
(95% CI 0.13, 0.22) compared with placebo.
For the secondary outcome, the proportion of patients with no urgency episodes, the
data indicate that treatment with solifenacin (5 and 10 mg combined) results in a
statistically greater proportion of patients with no urgency episodes at 4 weeks:
RD=0.07 (95% CI: 0.04, 0.11); 8 weeks: RD=0.08 (95% CI: 0.04, 0.12) and 12 weeks:
RD=0.07 (95% CI 0.03, 0.12) compared with placebo.
For the secondary outcome, proportion of patients with no episodes of nocturia, the
data indicate that treatment with solifenacin (5 and 10 mg combined and 10 mg alone)
results in a statistically greater proportion of patients with no episodes of nocturia
at 12 weeks: RD=0.04 (95% CI 0.04, 0.07) compared with placebo. No differences in
the proportion of patients with no episodes of nocturia were observed at 4 and 8 weeks
between the treatment groups.
Solifenacin versus tolterodine
The results of the meta-analyses comparing the effectiveness of solifenacin and tolterodine
are provided below.
Change in mean number (SD) of micturitions per 24 hours at 4 and 12 weeks: solifenacin
versus tolterodine
|
Trial |
4 weeks |
12 weeks |
||||||
|---|---|---|---|---|---|---|---|---|
|
|
Solifenacin |
Tolterodine |
Solifenacin |
Tolterodine |
||||
|
|
N |
Mean (SD) |
N |
Mean (SD) |
N |
Mean (SD) |
N |
Mean (SD) |
|
905-CL-005 |
70 |
-2.33 (2.61) |
37 |
-1.79 (2.04) |
||||
|
905-CL-015 |
530 |
-1.77 (2.69) |
249 |
-1.40 (2.59) |
530 |
-2.40 (3.06) |
250 |
-1.88 (3.00) |
|
905-EC-001 |
556 |
-2.12 (2.43) |
571 |
-1.53 (2.38) |
556 |
-2.42 (2.63) |
571 |
-2.18 (2.88) |
|
Meta-analysis |
-0.52 (-0.74, -0.30)a |
-0.05 (-0.94, 0.84)b |
||||||
Bold typography indicate statistically significant differences between groups
WMD=weighted mean difference
a fixed effects model
b random effects model as I2>50%
Responder analysis
|
Trial |
4 weeks |
8 weeks |
12 weeks |
||||||
|---|---|---|---|---|---|---|---|---|---|
|
Sol |
Tol |
RD |
Sol |
Tol |
RD |
Sol |
Tol |
RD |
|
|
<8 micturitions per 24 hours |
|||||||||
|
905-CL-015 |
104/548 |
51/266 |
0.02 |
129/548 |
54/266 |
0.01 |
161/548 |
65/266 |
0.03 |
|
905-EC-001 |
142/556 |
130/571 |
|
187/556 |
193/572 |
|
208/556 |
202/571 |
|
|
Becoming continent |
|||||||||
|
905-CL-015 |
123/299 |
61/157 |
0.04 |
140/299 |
67/157 |
0.06 |
152/299 |
76/157 |
0.07 |
|
905-EC-001 |
144/364 |
133/378 |
|
190/364 |
170/377 |
|
218/364 |
191/378 |
|
|
No urgency episodes |
|||||||||
|
905-CL-015 |
103/525 |
41/250 |
0.04 |
134/525 |
51/250 |
0.04 |
164/525 |
62/250 |
0.05 |
|
905-EC-001 |
101/556 |
81/566 |
|
150/556 |
171/566 |
|
187/556 |
171/566 |
|
|
No nocturia episodes |
|||||||||
|
905-CL-015 |
50/475 |
29/232 |
-0.01 |
60/475 |
31/232 |
-0.01 |
79/475 |
35/232 |
0.00 |
|
905-EC-001 |
66/479 |
69/496 |
|
85/479 |
96/496 |
|
100/479 |
111/496 |
|
Bold typography indicate statistically significant differences between groups
Sol=solifenacin, Tol=tolterodine, RD=risk difference
a results of a meta-analysis conducted during the evaluation using RevMan, all results
from fixed effects model, unless otherwise indicated
For PBAC’s view of the results, see Recommendation and Reasons.
9. Clinical Claim
The submission claimed that solifenacin has significant advantages in effectiveness
over placebo but is associated with more toxicity.
The PBAC agreed that although the evidence presented supports this claim, this does
not reflect the patient population in whom listing is sought.
10. Economic Analysis
The submission presented a preliminary (trial-based) economic evaluation. The choice
of a cost-effectiveness approach versus placebo was considered appropriate. The resources
included were drug costs and GP consultations to manage dry mouth.
The trial-based incremental cost/extra patient with a mean of < 8 micturitions per
24 hours over 12 weeks was estimated to be <$15,000.
The trial-based incremental cost/ extra patient becoming continent over 12 weeks was
estimated to be <$15,000.
The trial-based incremental cost/ extra patient without urgency episodes over 12 weeks
was estimated to be <$15,000.
The trial-based incremental cost/ extra patient without nocturia episodes over 12
weeks was estimated to be <$15,000.
The submission presented four modelled economic evaluations, each based on a different
definition of response. The choice of the cost-utility approach versus placebo was
considered appropriate. The resources included were drug costs, GP consultations for
dry mouth, and costs associated with invasive treatment of OAB.
The base case modelled incremental discounted cost/extra QALY gained over two years
was estimated to fall:
- in the range $45,000 – 75,000, in the model where definition of response is less than 8 micturitions per 24 hours;
- in the range $15,000 – $45,000, in the model where definition of response is no episodes of urinary incontinence;
- in the range $75,000 – $105,000, in the model where definition of response is no episodes of urgency;
- in the range $75,000 – $105,000, in the model where definition of response is no episodes of nocturia.
For PBAC’s view, see Recommendation and Reasons.
11. Estimated PBS Usage and Financial Implications
The financial cost/year to the PBS (excluding co-payments) was estimated by the submission to be up to <$10 million in Year 3. This was considered a likely under-estimate.
12. Recommendation and Reasons
The PBAC agreed that the acceptability of a placebo comparator depended upon the restriction
being able to confine the use of this product to the proposed population, i.e. where
treatment with oxybutynin has failed or is not tolerated. This is unlikely to be the
case because the definition of failure and intolerance in the requested restriction
were not described and any definitions are unlikely to be effective because of the
large placebo effect observed in the clinical trials. As a consequence the pool of
patients who would be eligible for the requested restriction would be broader than
the intended population. There would be a substantial risk that, in practice, as a
restricted benefit listing, solifenacin would become second line, or most likely,
first line treatment, because it is known that propantheline is rarely used, instead
of oxybutynin. Strengthening the restriction to an Authority required listing, would
be problematic as it would be difficult for the prescriber to provide evidence that
the patient met the authority requirements and compliance activities by Medicare Australia
would not be possible.
Even if the above issues relating to the ability to enforce the restriction were to
be resolved, the inclusion criteria of the trials forming the primary source of evidence
for the submission, did not require patients to have failed or not tolerated oxybutynin
treatment. A subgroup of patients from the trials may have been representative of
the population for whom listing is sought because a proportion of patients enrolled
in four of the eight trials had undergone previous treatment with anti-cholinergics
(including oxybutynin) for OAB. The submission did not present any analyses examining
whether previous failure or intolerance to oxybutynin varies treatment effect from
solifenacin. Thus, although the evidence presented supported the claim of superior
clinical effectiveness over placebo, there were insufficient clinical data to inform
the cost effectiveness of solifenacin in the patient population for which PBS listing
is requested i.e. where treatment with oxybutynin has failed or is not tolerated.
The PBAC also questioned which outcome should be used as a basis for the economic
evaluation. The submission presented results for an extensive range of secondary outcomes.
The PBAC considered that with a condition such as overactive bladder one outcome is
likely to be more clinically meaningful than another. The four economic models presented
in the submission, each based on a different definition of response raised the question
of which cost per QALY should apply. The PBAC considered the definition of cost/QALY
for specific responses to be uninformative because applying the same utility values
to different definitions of response was not appropriate. The results in the four
models were thus driven by the differences in the results for each endpoint, rather
than by the different utilities for each response, and, as noted above, there was
uncertainty about the applicability of the patients to the requested restriction from
whom these results were measured. It was also noted that the models were particularly
sensitive to small differences in the utility weights with the two health states (responder
and non-responder). There was thus considerable uncertainty in the results of the
economic models.
Overall, the PBAC considered that the data presented in the submission did not match
the patient population for whom PBS subsidy was sought, resulting in clinical and
economic uncertainties. The submission was therefore rejected on the basis of uncertain
clinical benefit and uncertain cost effectiveness.
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
Arrow Pharmaceuticals is disappointed with this outcome, however acknowledges the
PBAC comments and concerns. Arrow Pharmaceuticals wishes to address these issues and
will continue to work with the PBAC towards finding a mutually acceptable outcome
to provide an efficacious and tolerable solution for the many patients who suffer
from Overactive
Bladder.
