Dutasteride, capsule, 500 micrograms, Avodart®, November 2009
Public Summary Document for Dutasteride, capsule, 500 micrograms, Avodart®, November 2009
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Public Summary Document
Product: Dutasteride, capsule, 500 micrograms,
Avodart®
Sponsor: GlaxoSmithKline Australia Pty Ltd
Date of PBAC Consideration: November 2009
1. Purpose of Application
The submission sought an Authority Required (STREAMLINED) listing
for the treatment, in combination with an alpha-antagonist, of
lower urinary tract symptoms due to benign prostatic hyperplasia
(BPH) where treatment has been initiated by a urologist.
2. Background
At the July 2009 meeting, the PBAC rejected a submission seeking an
Authority Required (STREAMLINED) listing for the treatment of
benign prostatic hyperplasia in men over 50 years who meet certain
criteria on the basis of uncertain clinical benefit and highly
uncertain cost effectiveness stemming from the clinical uncertainty
and uncertainty in the utilities applied to the health states in
the economic model.
For further details see the relevant Public Summary Document for
the meeting.
3. Registration Status
Dutasteride was TGA registered on 14 November 2002 for the
treatment of patients with symptomatic benign prostatic hyperplasia
with an enlarged prostate.
4. Listing Requested and PBAC’s View
Authority Required (STREAMLINED)
Treatment, in combination with an alpha-antagonist, of lower
urinary tract symptoms (LUTS) due to benign prostatic hyperplasia
(BPH) where treatment has been initiated by an urologist.
For PBAC’s view see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
Benign prostatic hyperplasia (BPH) is a typically progressive
condition associated with worsening lower urinary tract symptoms
such as hesitant and interrupted weak stream, urgency, leaking or
dribbling and a sense of incomplete voiding leading to more
frequent urination, especially at night. The condition may
eventually require surgery.
When mild symptoms of BPH can no longer be managed by
‘watchful waiting’, current treatment options for
patients with moderate to severe symptoms include treatment with an
alpha antagonist (eg. prazosin, tamsulosin, terazosin) and/or a 5
alpha reductase inhibitor (eg. finasteride, dutasteride) or
surgery.
Dutasteride would provide an alternative treatment for BPH.
6. Comparator
As previously, the submission nominated monotherapy with prazosin
hydrochloride as the main comparator. This was considered
appropriate by the PBAC at the July 2009 meeting.
7. Clinical Trials
The re-submission addressed the following issues, which were raised at the July 2009 PBAC meeting:
- The requirement for International Prostate Symptom Score (IPPS) and Prostate Specific Antigen (PSA) in the restriction
- The relative efficacy and safety of tamsulosin and prazosin
- Sensitivity of the economic evaluation to the utilities of the individual health states
- Likely underestimation of the utilities
The submission identified the following references in support of
its request for listing.
Trial ID/ First Author | Protocol title/Publication title | Citation |
Baladi JF, et al (1996) | An economic evaluation of finasteride for treatment of benign prostatic hyperplasia. | Pharmacoeconomics; 9(5): 443-454 |
Bar-Yosef Y, et al (2008) | Alpha blockers in use for symptomatic benign prostatic hyperplasia--are all drugs born equal? | Harefuah; 147(6): 514-519 |
Berges R, et al (2003) | Impact of therapy used in clinical practice on lower urinary tract symptoms/benign prostatic hyperplasia (LUTS/BPH) disease progression. | European Urology Supplements; 2: 19-24. |
Cowles RS et al (1995) | A prospective randomized comparison of transurethral resection to visual laser ablation of the prostate for the treatment of benign prostatic hyperplasia. | Urology; 46(2): 155-60. |
DiSantostefano RL, et al (2006). | The long-term cost effectiveness of treatments for benign prostatic hyperplasia. | Pharmacoeconomics; 24(2): 171-191. |
Djavan B, et al (2004). | State of the art on the efficacy and tolerability of alpha1-adrenoceptor antagonists in patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia. | Urology; 64: 1081-1088. |
Djavan B, et al (1999). | A meta-analysis on the efficacy and tolerability of á1-adrenoceptor antagonists in patients with lower urinary tract symptoms suggestive of benign prostatic obstruction. | European Urology; 36: 1-13. |
Donovan JL, et al (2000). | A randomized trial comparing transurethral resection of the prostate, laser therapy and conservative treatment of men with symptoms associated with benign prostatic enlargement: the CLasP study. | The Journal of Urology; 164: 65-70. |
Hill B, et al (2004). | Transurethral needle ablation versus transurethral resection of the prostate for the treatment of symptomatic benign prostatic hyperplasia: 5-year results of a prospective, randomized, multicenter clinical trial. | The Journal of Urology; 171: 2336-40. |
Kortmann BB, et al (2002). | Urodynamic effects of alpha-adrenoceptor blockers: a review of clinical trials. | Urology; 62: 1-9. |
MacDonagh RP, et al (1997). | The use of generic measures of health-related quality of life in the assessment of outcome from transurethral resection of the prostate. | British Journal of Urology; 79: 401-408. |
Noble SM, et al (2002). | Transurethral prostate resection, noncontact laser therapy or conservative management in men with symptoms of benign prostatic enlargement? An economic evaluation. | The Journal of Urology; 168: 2476-2482. |
Roehrborn CG, et al (1999). | The effects of transurethral needle ablation and resection of the prostate on pressure flow urodynamics parameters: analysis of the United States randomized study. | The Journal of Urology; 162: 92-7. |
Trueman P, et al (1999). | Prevalence of lower urinary tract symptoms and self-reported diagnosed 'benign prostatic hyperplasia', and their effect on quality of life in a community-based survey of men in the UK. | BJU International; 83: 410-415. |
8. Results of Trials
The following table shows the 48 month data from the ARI40005
(Roehrborn 2008) trial together with the 24 month data which was
used in the previous submission.
Baseline, endpoint, change from baseline and adjusted mean
difference in International Prostate Symptom Score (IPSS) scores at
24 and 48 months (ITT population)
Timepoint | Endpoint | Dutasteride + Tamsulosin | Tamsulosin | Mean difference |
Baseline | Mean IPSS (SD) | 16.6 (6.35) | 16.4 (6.10) | |
24 months | Mean IPSS [SE] | 10.1 [0.16] | 11.9 [0.17] | |
Adjusted Mean Change from baseline [SE] | -6.2 [0.15] | -4.3 [0.15] | -1.8 p<0.001 | |
48 months | Adjusted Mean Change from baseline | -6.3 | -3.8 | -2.5 p<0.001 |
The data showed a greater change in the adjusted mean difference in
IPSS from baseline at 48 months than at 24 months.
The table below summarises the acute urinary retention (AUR) and
BPH surgery rates from ARI40005.
AUR and BPH surgery rates from ARI40005
Dutasteride + Tamsulosin | Tamsulosin | |||
No. Events | No. persons at risk | No. Events | No. persons at risk | |
BPH-surgery | 38 | 1610 | 126 | 1611 |
Risk reduction | 70.6% (57.7%, 79.5%) | |||
AUR | 36 | 1610 | 109 | 1611 |
Risk reduction | 67.6% (52.7%, 77.8%) |
Regarding the comparison between tamsulosin and prazosin, the PBAC
previously considered that the assumption that tamsulosin is of
equal efficacy and safety to prazosin was uncertain. The Pre-PBAC
Response acknowledged that there may be some uncertainty in the
relative efficacy of tamsulosin and prazosin. However, the
incremental difference in BPH symptoms between combination
treatment and alpha-antagonist monotherapy was unlikely to be
significantly affected based on the alpha-blocker used.
The withdrawal rates from treatment were updated and at 48 months
69% of the dutasteride plus tamsulosin group remained on treatment
compared to 61% of the tamsulosin only group. summarised in the
table below.
For PBAC’s view see Recommendation and
Reasons.
9. Clinical Claim
As previously, the submission claimed dutasteride/alpha-blocker
combination treatment to be superior in terms of comparative
effectiveness and inferior in terms of comparative safety over
alpha blocker alone.
For PBAC’s view see Recommendation and
Reasons.
10. Economic Analysis
The submission presented a Markov model running for 10 years with a
cycle length of 3 months. The structure of the model was unchanged
from the previous submission. A new base cost-effectiveness ratio
was calculated.
The effect of all the changes to the inputs of the model lowered
the cost per QALY compared to the previous submission though it
remained between $15,000 to $45,000.
The submission conducted a number of sensitivity analyses varying
the utility values of the health states. The majority of the
results from the sensitivity analyses were between $15,000 -
$45,000.
For PBAC’s view see Recommendation and
Reasons.
11. Estimated PBS Usage and Financial Implications
The estimates were recalculated in this submission and include men
aged 40 years and older. This submission assumed the same
proportion of men aged between 40 and 50 years will have moderate
or severe BPH as the 18 – 50 year old age group. The
submission estimated between 100,000 – 200,000 men are likely
to be on combination therapy by year 5 of listing.
The incremental cost to the Government was estimated to be less
than $10 million by year 5 of listing.
12. Recommendation and Reasons
The PBAC recommended the listing of dutasteride on the PBS as an
authority required (streamlined) benefit for the treatment, in
combination with an alpha-antagonist, of lower urinary tract
symptoms due to benign prostatic hyperplasia (BPH), where treatment
is initiated by a urologist, on the basis of acceptable cost
effectiveness compared with alfa-antagonist alone.
The PBAC considered the removal from the revised restriction of
IPSS, prostate specific antigen level and limitation to men aged 50
years and over appropriate. The PBAC also considered restriction to
initiation by a urologist appropriate, noting that mild BPH
patients were removed from the baseline in the economic model on
the basis that it is unlikely that urologists would be treating
mild BPH with the combination of dutasteride and an
alpha-antagonist.
The PBAC noted that the re-submission included four year data from
trial ARI40005, and that the economic model was updated with the
four year data. The key data provided by the updated trial analysis
are the reduction in AUR and BPH surgery needed by patients treated
with dutasteride in comparison with the alpha-antagonist alone. At
48 months the mean difference in International Prostate Symptom
Score (IPSS) was 2.5 points from baseline for dutasteride in
combination with tamsulosin compared to tamsulosin alone. The acute
urinary retention (AUR) rate at 48 months with combination therapy
compared to tamsulosin alone showed a risk reduction of 67.6 % (CI:
52.7 %, 77.8 %), and the risk reduction for BPH surgery was 70.6 %
(CI: 57.7%, 79.5%).
Updates to the economic model included the removal of mild BPH
patients at baseline and changed proportions of patients with mild,
moderate and severe BPH health states, updated year three and four
BPH transition probabilities, inclusion of four year AUR and
BPH-surgery rate data from ARI40005, updated withdrawal rates from
ARI40005 four year data, updated adverse event rates from ARI40005
four year data, inclusion of an assumption that patients will
continue medical treatment of BPH post BPH-surgery, and amendment
of the cost of BPH-surgery. This resulted in a new base case
incremental cost effectiveness ratio of between $15,000 –
$45,000 per QALY gained. The PBAC noted that of the four year data
on AUR and BPH-surgery rates replaced the estimates used in the
previous submission derived from McConnell et al 2003 and
considered the application of the trial rates to the economic model
reduced the uncertainty in the economic modelling.
The PBAC considered that uncertainty in relation to the variable
sources of utilities remained, despite the further sensitivity
analysis conducted in the re-submission. The sensitivity analysis
in the re-submission was extended to allow for a wider range of
differences between mild, moderate and severe BHP. Nevertheless,
the sensitivity analyses indicated that the incremental cost
effectiveness ratios remained in an acceptable range.
The PBAC noted that the re-submission utilisation estimates were
increased to include men aged 40 years and older. The PBAC
considered uncertainty remained with the utilisation
estimates.
On balance the PBAC concluded that the four year data from trial
ARI40005 provided in the re-submission and incorporated in the
economic model reduced the clinical and economic uncertainty and
the ICER of between $15,000 – $45,000 was acceptable.
Recommendation:
DUTASTERIDE, capsule, 0.5 mg
Restriction:
Authority Required (STREAMLINED)
Treatment, in combination with an alpha-antagonist, of lower
urinary tract symptoms due to benign prostatic hyperplasia where
treatment is initiated by a urologist.
Maximum quantity: 30
Repeats: 5
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
GlaxoSmithKline Australia welcomes the positive recommendation of the PBAC and looks forward to finalising the listing of dutasteride on the PBS for the treatment of benign prostatic hyperplasia.