Sevelamer Hydrochloride, tablet, 800 mg, Renagel November 2006
Public summary document for Sevelamer Hydrochloride, tablet, 800 mg, Renagel
Page last updated: 02 March 2007
Public Summary Document
Product: Sevelamer Hydrochloride, tablet, 800 mg, Renagel
Sponsor: Genzyme Australasia Pty Ltd
Date of PBAC Consideration: November 2006
1. Purpose of Application
The resubmission requested an authority required listing for the treatment of high phosphate levels (hyperphosphataemia), in adult patients with chronic kidney disease on dialysis.
2. Background
At the March 2006 meeting, the PBAC rejected a submission for a restricted benefit
listing for the treatment of hyperphosphatemia, in adult patients with chronic kidney
disease on dialysis whose serum phosphate is not controlled on other products because
of a lack of convincing evidence of increased efficacy or safety overall, and a high
and uncertain cost-effectiveness.
The PBAC agreed that, should listing proceed, an authority required listing is appropriate.
3. Registration Status
Sevelamer was registered on 28 June 2005 for the management of hyperphosphatemia in adult patients with stage 4 and 5 chronic kidney disease.
4. Listing Requested and PBAC’s View
The re-submission proposed three PBS listings, with option 1 being the preferred wording.
Option 1
Authority required
Treatment of hyperphosphataemia, in adult patients with chronic kidney disease on
dialysis.
Option 2- Alternative PBS indication.
Authority required
Treatment of hyperphosphataemia, in adult patients with chronic kidney disease on
dialysis whose serum phosphate is not controlled on other products and where:
(a) serum phosphate is greater than 1.6 mmol/L, or
(b) serum calcium x phosphate product is greater than 4.0 mmol2/L2.
Option 3 – Limited PBS indication.
Authority required
Treatment of hyperphosphataemia, in adult patients with chronic kidney disease on
dialysis whose serum phosphate is not controlled on other products and where:
(a) serum phosphate is greater than 1.6 mmol/L, or
(b) serum calcium x phosphate product is greater than 4.0 mmol2/L2,
and the patient is:
(a) aged ≥ 65 years, or
(b) new to dialysis, or
(c) an Aboriginal or Torres Strait Islander person.
The PBAC considered that the most restrictive of the proposed restrictions would be
most likely to identify the population in whom treatment with sevelamer could be cost-effective
ie option 3.
5. Clinical Place for the Proposed Therapy
6. Comparator
The resubmission nominated calcium carbonate (Caltrate) as the main comparator. This is as previously agreed by the PBAC.
7. Clinical Trials
The resubmission presented new trial data including the Statistical Analysis Plan
and more detailed results for the Dialysis Clinical Outcomes Revisited (DCOR) trial,
and a new trial, the RENAGEL In New Dialysis (RIND) study. The RIND study was a randomised,
open-label, parallel group study of 114 adult patients new to haemodialysis.
The RIND trial had been published at the time of re-submission, as follows:
|
Trial/First author |
Protocol title/Publication title |
Publication citation |
|---|---|---|
|
RIND |
||
|
Spiegel DM, 2006. |
Calcium containing phosphate binders are associated with increased mortality risk in hemodialysis patients compared to sevelamer. |
XLIII Congress of the European Renal Association (ERA)/European Dialysis and Transplant Association (EDTA). July 15-18 2006 Glasgow, United Kingdom. |
|
Block GA, 2005. |
Effects of sevelamer and calcium on coronary artery calcification in patients new to hemodialysis. |
Kidney International. 68(4): 1815-1824. |
The DCOR study had not been published at the time of re-submission.
The resubmission also included seven supportive trials included in the previous submission,
reporting biochemical outcomes and vascular calcification.
8. Results of Trials
Mortality was the primary outcome for the DCOR study. In the RIND study, all-cause
mortality was a secondary endpoint of a randomised trial previously reported whose
primary endpoint was change at 18 months in coronary artery calcification. For all
evaluable patients in the RIND study the result for mortality was statistically significant.
The results and epidemiological data showing vascular calcification was a risk factor
for cardiovascular morbidity and mortality assumed that changes in vascular calcification
with sevelamer would translate into changes in mortality and cardiovascular morbidity
outcomes.
The RIND and Treat to Goal studies provided data on coronary artery calcium (CAC)
scores. The change from baseline in CAC score was the primary end-point for the RIND
study and a secondary end-point in the Treat to Goal study. The analysis showing all
cause mortality is higher where CAC score is higher, provided no link between the
surrogate and mortality.
The resubmission presented new toxicity meta-analyses demonstrating fewer hypercalcaemic
episodes and more dyspepsia episodes in sevelamer treated patients, but overall no
differences in all adverse gastrointestinal events.
For PBAC’s comments on these results, see Recommendation and Reasons.
9. Clinical Claim
The resubmission described sevelamer as having significant advantages in effectiveness over calcium and having similar or less toxicity.
10. Economic Analysis
The resubmission presented updated preliminary economic evaluations, which included
costs of hospitalisations and dyspepsia.
The re-submission estimated that the incremental cost effective ratios (ICERs) for
the base case would be > $200,000 for the all population and in the range $45,000
– $75,000 for the > 65 year old subgroup in DCOR.
The resubmission presented an updated modelled economic evaluation for two settings:
The DCOR > 65 year old population and the RIND population (patients new to dialysis)
which included costs of hospitalisations and dyspepsia.
The resubmission estimated that the base case modelled incremental discounted cost
per extra life year saved would be in the range $15,000 – $45,000 for the DCOR > 65
year old population and in the range $15,000 – $45,000 for the RIND population.
11. Estimated PBS Usage and Financial Implications
12. Recommendation and Reasons
The PBAC considered that the most restrictive of the proposed restrictions would be
most likely to identify the population in whom treatment with sevelamer could be cost-effective,
ie treatment of hyperphosphataemia, in adult patients with chronic kidney disease
on dialysis whose serum phosphate is not controlled on other products and where: (a)
serum phosphate is greater than 1.6 mmol/L, or (b) serum calcium x phosphate is greater
than 4.0 mmol2/L2 and the patient is: (a) aged >65 years, or (b) new to dialysis,
or (c) an Aboriginal or Torres Strait Islander person.
The PBAC considered that there are some doubts about the validity of the DCOR and
RIND mortality results. The DCOR results relied on acceptance of a pre-specified subgroup
analysis where the primary analysis was not statistically significant and acceptance
that heterogeneity of a subgroup result implies effect modification by age. In the
RIND study mortality was a pre-specified secondary endpoint and there were differential
drop-out rates. The coronary artery calcification results involve substantial missing
data, and no empirical data have been presented to support the assumption that vascular
calcification changes with observed with sevelamer translate into cardiovascular benefits.
The PBAC noted that the submission used the RIND study to validate the mortality difference
in the less than 65 and over 65 sub-groups ie the mortality in RIND was being considered
compatible with the over 65 sub-group in DCOR. The submission used the surrogate outcome
of vascular calcification, which has been accepted in heart disease, for kidney disease.
The PBAC considered that the pivotal uncertainties were whether the reduction in calcification
reported in the supportive trials, the RIND Study and the Treat to Goal Study was
an appropriate surrogate measure to predict mortality, and the extent of mortality
benefit with sevelamer.
The sponsor’s Pre-PBAC Response reported statements from the CARI Guidelines (April
2006) purporting to support these claims, but the PBAC noted other statements in these
Guidelines that cast doubt on such claims. For example the Shaheen et al study (2004)
stated that “Mortality studies are needed to clarify the overall impact of sevelamer
use”. Comment on the Treat to Goal Study was that “Changes in vascular calcification
may not be due to calcium use but related to other properties of sevelamer, such as
lowered LDL-cholesterol”. Further, the quote in the Pre-PBAC Response stating “reduced
vascular and cardiac calcification (a surrogate measure for cardiac disease) with
sevelamer holds promise for better patient management” was qualified with the words
“however, at the time of the literature search no survival benefit had been established.”
The PBAC concluded that although it was biologically plausible that reduction in calcification
leads to a reduction in mortality, insufficient evidence had been provided in the
submission to support the claim. Further, any reduction in mortality may be due to
the ability of sevelamer to lower LDL-cholesterol.
Given the uncertainty about the extent of mortality benefit, there was uncertainty
about the results of the modelled economic analysis, which were sensitive to the estimates
of incremental survival.
Therefore, the PBAC rejected the submission because of uncertain clinical benefit
and uncertain cost-effectiveness.
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
Genzyme Australasia thanks the PBAC for its consideration in listing sevelamer hydrochloride. The company is disappointed in the rejection of its application. However, Genzyme remain committed to working with the PBAC to ensure its product is made available to those patients with end stage renal disease who may benefit from sevelamer.
