Cinacalcet hydrochloride, tablets, 30 mg, 60 mg and 90mg, Sensipar, November 2007
Public summary document for Cinacalcet hydrochloride, tablets, 30 mg, 60 mg and 90mg, Sensipar, November 2007
Page last updated: 29 February 2008
Public Summary Document
Product: Cinacalcet hydrochloride, tablets, 30 mg, 60 mg and 90mg, Sensipar
Sponsor: Amgen Australia Pty Ltd
Date of PBAC Consideration: November 2007
1. Purpose of Application
The submission sought listing as a Section 100 (Highly Specialised Drugs) Private
hospital authority required item for use in patients with end stage renal disease
receiving dialysis who have uncontrolled secondary hyperparathyroidism (SHPT).
Highly Specialised Drugs are medicines for the treatment of chronic conditions, which,
because of their clinical use or other special features, are restricted to supply
to public and private hospitals having access to appropriate specialist facilities.
2. Background
Submissions seeking a PBS listing of cinacalcet for the treatment of secondary hyperparathyroidism in patients with end stage renal disease receiving dialysis were rejected at the November 2005 PBAC meeting and again at the July 2006 PBAC meeting because of uncertain extent of clinical benefit and the resultant uncertain, thus inadequately demonstrated, cost-effectiveness. (See also Public Summary Documents for November 2005 and July 2006).
3. Registration Status
Cinacalcet was TGA registered on 25 January 2005 for the following indications:
- Cinacalcet may be used to treat the biochemical manifestations of secondary hyperparathyroidism in patients with end stage renal disease, receiving dialysis. Cinacalcet should be used as adjunctive therapy.
- Cinacalcet is indicated for the treatment of hypercalcemia in patients with parathyroid carcinoma.
- Cinacalcet may be used to treat the biochemical manifestations of primary hyperparathryoidism in patients for whom parathryoidectomy is not a treatment option.
4. Listing Requested and PBAC’s View
Section 100
Private Hospital Authority Required
1. Initial treatment for up to 6 months, by a nephrologist for patients with CKD-5D
who have sustained secondary hyperparathyroidism with iPTH ≥50 pmol/L, not responding
to conventional therapy.
Continuation criteria: a decrease of ≥30% in iPTH concentrations after 6 months treatment.
2. Initial treatment for up to 6 months, by a nephrologist for patients with CKD-5D
who have sustained secondary hyperparathyroidism with iPTH >15 pmol/L and <50 pmol/L
AND an (adjusted) serum calcium concentration ≥2.6 mmol/L, not responding to conventional
treatment.
Continuation criteria: an iPTH level >15 pmol/L and an (adjusted) serum calcium concentration
<2.6 mmol/L after six months treatment.
Note: Intact PTH should be monitored four weekly (measured ≥12 hours post dose) and
dose titrated until an appropriate iPTH concentration is achieved. During the titration
phase, approval will be limited to sufficient supply for four weeks treatment at a
time, with doses between 30 and 180 mg/day according to the patient’s response and
tolerability.
Note: Approval will be limited to provide sufficient quantity for 4 weeks treatment
and up to 5 repeats for doses between 30 and 180 mg/day according to the patient’s
response and tolerability. Intact PTH should be monitored quarterly (measured ≥12
hours post dose) and dose adjusted as necessary to maintain an appropriate iPTH concentration.
Sustained = at least 2 blood samples collected over a period of 2-4 months.
Grandfathering:
Continuing treatment by a nephrologist for patients with CKD-5D, with a prior diagnosis
of secondary hyperparathyroidism who were receiving treatment with cinacalcet prior
to [insert effective PBS listing date], who met the initial treatment criteria defined
as an iPTH concentration ≥50 pmol/L OR an iPTH concentration >15 pmol/L and <50 pmol/L
AND an (adjusted) serum calcium concentration ≥2.6 mmol/L AND who meet the continuation
criteria.
For PBAC’s view, see Recommendation and Reasons.
5. Clinical Place for the Proposed Therapy
Cinacalcet would assist with the management of uncontrolled secondary hyperparathyroidism
by reducing parathyroid levels while simultaneously lowering serum calcium and phosphorus
levels in chronic kidney disease in patients receiving dialysis.
6. Comparator
The submission nominated placebo plus standard medical management as the main comparator.
This was previously accepted by the PBAC.
Standard medical management includes dietary modification, vitamin D products in association
with calcium based phosphate binders and dialysate-based interventions.
7. Clinical Trials
The pivotal trials included in the submission were Study 172, 188, 183, 240, (blinded
extension of studies 172 and 183) and 141. The supportive evidence included were Study
187 and Study 130, which had not previously been submitted. Study 130 was an open-label,
single-arm, multi-centre trial that investigated long term safety and efficacy of
cinacalcet.
The object of the trials was to assess the effects of cinacalcet on biochemical parameters
(i.e. intact Parathyroid hormone, calcium and phosphate levels).
The direct randomised trials published at the time of submission were as follows:
|
Trial ID/First author |
Protocol title/ Publication title |
Publication citation |
|---|---|---|
|
Direct randomised trials |
||
|
172 |
A phase 3 study to assess the efficacy and safety of an oral calcimimetic agent (AMG 073) in secondary hyperparathyroidism of end stage renal disease treated with hemodialysis, 08 August 2003 |
Kidney International 2005, 68(4):1793-1800 |
|
183 |
A phase 3 study to assess the efficacy and safety of an oral calcimimetic agent (AMG 073) in secondary hyperparathyroidism of end stage renal disease treated with hemodialysis, 15 August 2003 |
Kidney International 2005, 68(4):1793-1800 |
|
188 |
A placebo-controlled, double-blind, multicenter study to assess the efficacy and safety
of an oral calcimimetic agent (AMG 073) in secondary hyperparathyroidism of chronic
kidney disease (hemodialysis and peritoneal dialysis), 12 August 2003 |
Kidney International 2005, 68(4):1793-1800 |
|
141 |
Cinacalcet HCL reduced bone turnover and bone marrow fibrosis in hemodialysis patients with secondary hyperparathyroidism (HPT) [abstract] |
41st Congress. European Renal Association. European Dialysis and Transplantation Association. Lisbon, Portugal, May 15-18, 2004. |
|
Supplementary randomised trial |
||
|
OPTIMA |
OPTIMA: An open-label, randomised study using cinacalcet to improve achievement of K/DOQI targets in patients with ESRD |
East and North Hertfordshire NHS Trust |
|
Meta-analyses of direct randomised trials |
||
|
Cunningham trials (Trials 172, 183, 188, 240, &141) |
Danese, Olson, et al: Effects of the calcimimetic cinacalcet HCl on cardiovascular disease, fracture, and health-related quality of life in secondary hyperparathyroidism. |
Kidney International 2005, 68(4):1793-1800 |
8. Results of Trials
The results of the primary outcome analyses are reproduced in the table below.
Comparative summary of results of direct randomised trials: Proportion of patients
attaining PTH level of ≤26.5pmol/L
|
Trial |
Duration |
Cinacalcet |
Placebo |
p-value* |
ARD (95% CI) |
NNT (95% CI) |
|---|---|---|---|---|---|---|
|
Trial 172 |
26 wks |
84/205 (41%) |
8/205 |
<0.001 |
0.37 (0.30, 0.44) |
3 (2.3, 3.3) |
|
Trial 183 |
26 wks |
76/166 (46%) |
11/165 (7%) |
<0.001 |
0.39 (0.31, 0.48) |
3 (2.1, 3.2) |
|
Trial 188 |
26 wks |
104/292 (35%) |
6/101 |
<0.001 |
0.29 (0.22, 0.37) |
3 (2.7, 4.5) |
|
Lumped analysis |
264/663 (40%) |
25/471 (5%) |
<0.001 |
0.35 (0.30, 0.39) |
3 (2.6, 3.3) |
|
|
Pooled analysis |
<0.001 |
0.36 (0.31, 0.40) |
3 (2.5, 3.2) |
|||
* Cochran-Mantel-Haenszel test
The events used in the July 2006 submission and the current submission are the safety
data on deaths, cardiovascular hospitalisations, fractures, and parathyroidectomy
surgery from Trials 172, 183, and 188 plus the extension trial (Trial 240) and a small
bone study (Trial 141).
Results of patient-relevant events, 95% confidence intervals, and heterogeneity tests
(I2) in meta-analyses of direct randomised trials are as follows:
|
Event |
Risk difference (95% CI) |
Hazard ratio* (95% CI) |
Hazard ratio (95% CI) |
|---|---|---|---|
|
Death |
-0.01 (-0.03, 0.01) |
0.76 (0.43, 1.34) |
0.81 (0.45, 1.45) |
|
Cardiovascular hospitalization |
-0.03 (-0.07, 0.00) |
0.58 (0.37, 0.93) |
0.61 (0.43, 0.86) |
|
Fractures |
-0.02 (-0.04, 0.00) |
0.45 (0.21, 0.96) |
0.46 (0.22, 0.95) |
|
Parathyroidect-omy surgery |
-0.02 (-0.04, -0.01) |
0.15 (0.03, 0.62) |
0.07 (0.01, 0.55) |
* Although the submission calls these hazard ratios, technically they are relative risks.
For PBAC’s view of these results, see Recommendation and Reasons.
9. Clinical Claim
The re-submission claimed that cinacalcet had advantages in effectiveness over placebo
add-on to standard care and the toxicity data showed more nausea and vomiting compared
to placebo.
For PBAC’s view of this claim, see Recommendation and Reasons.
10. Economic Analysis
The submission presented an updated preliminary trial-based economic evaluation. The
trial-based incremental cost per extra life year gained was estimated to be greater
than $200,000.
The submission presented an updated modelled economic evaluation. The PBAC noted that
the cost offsets in the modelled evaluation had been significantly reduced compared
to the prior submission and that a price reduction attempted to address the uncertainty
in the clinically relevant outcomes.
The base case modelled incremental discounted cost per extra discounted quality adjusted
life year was estimated by the submission to be in the range $15,000 to $45,000 for
the clinical practice based dose (ADD=62mg).
For PBAC’s view, see Recommendation and Reasons.
11. Estimated PBS Usage and Financial Implications
The likely number of patients per year was estimated to be less than 5,000 in Year
5.
The financial cost per year to the PBS was estimated to be in the range $10 million
to
$30 million in Year 5.
12. Recommendation and Reasons
The PBAC recommended the listing of cinacalcet on the PBS for the treatment for up
to 6 months, by a nephrologist, for a patient with chronic kidney disease on dialysis
(CKD-5D) who have sustained secondary hyperparathyroidism with iPTH ≥50 pmol/L, not
responding to conventional therapy on the basis of acceptable cost-effectiveness compared
with placebo.
The PBAC agreed that cinacalcet should also be listed in section 85 for maintenance
treatment as suggested by the Australian and New Zealand Society of Nephrology, to
enable patients in rural areas easier access to continuing treatment. The PBAC considered
that the requested restriction was tight and clinically manageable.
The PBAC noted new toxicity data on case reports of hypotension and worsening heart
failure including two cases with a positive re-challenge. The PBAC considered that
the risk/benefit profile of cinacalcet may develop further as its exposure increases.
The PBAC expressed some concern regarding the extrapolation of significant changes
in surrogate endpoints to patient relevant outcomes, but considered that the data
supported changes in iPTH (with subsequent reduction in parathyroidectomies) and reductions
in cardiovascular related hospitalisations and fractures. The PBAC noted that the
cost offsets in the modelled evaluation had been significantly reduced compared to
the prior submission and that a price reduction attempted to address the uncertainty
in the clinically relevant outcomes.
The PBAC considered that there was uncertainty in all three dosing assumptions used
in the modelled economic analysis but noted that this was addressed through the proposed
risk sharing arrangement.
The PBAC requested the sponsor provide ongoing data from the EVOLVE trial when available
as this would provide evidence of efficacy in outcomes relevant to patients. The commitment
to provide the PBAC with ongoing data on the efficacy and cost-effectiveness of cinacalcet,
taking into account any changes in the treatment algorithm occurring over time, should
also be incorporated into the risk sharing agreement.
Recommendation
Restriction: Authority required
Maintenance therapy, following initiation and stabilisation of treatment with cinacalcet,
of a patient with chronic kidney disease on dialysis who has after 6 months treatment:
(i) a decrease of at least 30% in iPTH concentrations; or
(ii) iPTH greater than 15 pmol/L and an (adjusted) serum calcium concentration of
less than 2.6 mmol/L.
Note: During the titration phase, intact PTH should be monitored four weekly (measured
at least 12 hours post dose) and dose titrated until an appropriate iPTH concentration
is achieved. During the titration phase, approval will be limited to sufficient supply
for four weeks treatment at a time, with doses between 30 and 180 mg per day according
to the patient’s response and tolerability.
Note: During the maintenance phase, approval will be limited to provide sufficient
quantity for 4 weeks treatment up to a maximum of 6 months supply for doses between
30 and 180 mg per day according to the patient’s response and tolerability. Intact
PTH should be monitored quarterly (measured at least 12 hours post dose) and dose
adjusted as necessary to maintain an appropriate iPTH concentration.
Maximum quantity: 28 (30mg, 60 mg and 90mg)
No of repeats: 5
Restriction: Section 100 (Highly Specialised Drug)
Private Hospital Authority Required
Management, including initiation and stabilisation, by a nephrologist, of a patient
with chronic kidney disease on dialysis who has sustained secondary hyperparathyroidism
with iPTH of at least 50 pmol/L, not responding to conventional therapy.
Note: During the titration phase, intact PTH should be monitored four weekly (measured
at least 12 hours post dose) and dose titrated until an appropriate iPTH concentration
is achieved. During the titration phase, approval will be limited to sufficient supply
for four weeks treatment at a time, with doses between 30 and 180 mg per day according
to the patient’s response and tolerability.
Note: During the maintenance phase, approval will be limited to provide sufficient
quantity for 4 weeks treatment up to a maximum of 6 months supply for doses between
30 and 180 mg per day according to the patient’s response and tolerability. Intact
PTH should be monitored quarterly (measured at least 12 hours post dose) and dose
adjusted as necessary to maintain an appropriate iPTH concentration.
“Sustained” means the abnormality was detected on at least 2 blood samples collected
over a period of 2 to 4 months.
Pack size: 28 (30mg, 60 mg and 90mg)
Private Hospital Authority Required
Management, including initiation and stabilisation, by a nephrologist, of a patient
with chronic kidney disease on dialysis who has sustained secondary hyperparathyroidism
with iPTH of at least 15 pmol/L and less than 50 pmol/L AND an (adjusted) serum calcium
concentration at least 2.6 mmol/L, not responding to conventional treatment.
Note: During the titration phase, intact PTH should be monitored four weekly (measured
at least 12 hours post dose) and dose titrated until an appropriate iPTH concentration
is achieved. During the titration phase, approval will be limited to sufficient supply
for four weeks treatment at a time, with doses between 30 and 180 mg per day according
to the patient’s response and tolerability.
Note: During the maintenance phase, approval will be limited to provide sufficient
quantity for 4 weeks treatment up to a maximum of 6 months supply for doses between
30 and 180 mg per day according to the patient’s response and tolerability. Intact
PTH should be monitored quarterly (measured at least 12 hours post dose) and dose
adjusted as necessary to maintain an appropriate iPTH concentration.
“Sustained” means the abnormality was detected on at least 2 blood samples collected
over a period of 2to 4 months.
Pack size: 28 (30mg, 60 mg and 90mg)
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
Amgen is pleased that cinacalcet will be made available through the PBS to Australian dialysis patients with secondary hyperparathyroidism.
