Paricalcitol, capsule, 1 microgram and 2 micrograms, Zemplar® - March 2011
Page last updated: 01 July 2011
PDF printable version to Paricalcitol, capsule, 1 microgram and 2 micrograms, Zemplar®
(PDF 89 KB)
Public Summary Document
Product: Paricalcitol, capsule, 1 microgram and 2
micrograms, Zemplar®
Sponsor: Abbott Australasia Pty Ltd
Date of PBAC Consideration: March 2011
1. Purpose of Application
The submission sought an Authority Required listing for treatment
of secondary hyperparathyroidism in patients with chronic kidney
disease where treatment with calcitriol is not appropriate.
2. Background
This was the fourth major submission to the PBAC for
paricalcitol.
At the July 2007 meeting, the PBAC considered two submissions, one
for the injection and a minor submission for the capsules, seeking
a section 100 (Highly Specialised Drug) PBS listing for
paricalcitol injection for the treatment by a nephrologist of
patients with end stage renal disease receiving dialysis who have
secondary hyperparathyroidism. The PBAC rejected both submissions
on the grounds of insufficient evidence of superiority over the
comparator to support a cost-effectiveness claim.
At the March 2008 meeting, the PBAC rejected a submission seeking a
Section 85 Authority Required listing for the treatment of patients
with end stage chronic renal disease receiving dialysis who have
secondary hyperparathyroidism because of continued concerns about
the validity of the clinical claim of superiority for paricalcitol
over calcitriol and because of the resulting uncertain
cost-effectiveness.
At the March 2009 meeting, the PBAC rejected a submission seeking a
Section 100 Private Hospital Authority Required listing for the
oral and IV formulation and Section 85 Authority required listing
for the oral formulation for the treatment of patients with end
stage renal disease (Stage 5) receiving dialysis who have secondary
hyperparathyroidism because of the primary use of non-randomised
data to establish the clinical case of superiority of paricalcitol
over calcitriol and uncertain cost effectiveness.
3. Registration Status
Paricalcitol 1 microgram, 2 micrograms and 4 micrograms capsules
were registered by the TGA on 1 March 2007 for the treatment for
the biochemical manifestations of secondary hyperparathyroidism
associated with chronic kidney disease, stages 3, 4 and 5.
4. Listing Requested and PBAC’s View
Authority Required
Treatment of secondary hyperparathyroidism in patients with chronic
kidney disease where treatment with calcitriol is not
appropriate.
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
Chronic kidney disease can affect all the organs and systems of the
body. The disturbances to the body’s chemical balance and
build-up of waste substances in the blood can have extensive
functional consequences, leading to the development of
complications and contributes to the high morbidity and mortality
of CKD.
One of the endocrine complications of CKD is vitamin D deficiency
which leads to the development of secondary hyperparathyroidism, as
vitamin D deficiency promotes parathyroid gland growth and
increased parathyroid hormone (PTH) synthesis. The end result is
elevated serum PTH and abnormal calcium and phosphorus
balance.
The complications associated with chronic secondary
hyperparathyroidism include renal bone disease, cardiovascular
complications and less frequently neurotoxicity and endocrinopathy
(hormone imbalance). Renal bone disease includes high turnover bone
disease, osteoporosis, osteomalacia and low turnover bone
disease.
Paricalcitol, an analogue of calcitriol, the metabolically active
form of vitamin D (antiparathyroid agent), regulates PTH levels,
improves calcium and phosphate balance, and may prevent or treat
metabolic bone disease associated with CKD. Other drugs which are
used to treat secondary hyperparathyroidism include calcitriol and
cinacalcet.
The submission proposed that the place in therapy of paricalcitol
would be in pre-dialysis patients who have been treated with
calcitriol and have developed hypercalcaemia, have increasing iPTH
levels or have developed an intolerance to calcitriol, and who are
not sick enough to commence dialysis and hence qualify for
PBS-subsidised treatment with cinacalcet.
6. Comparator
The submission nominated placebo as the main comparator, which the
PBAC accepted as appropriate.
For PBAC’s view, see Recommendation and
Reasons
7. Clinical Trials
The basis of the re-submission was three identical design, direct
randomised comparative trials (combined and reported as one) for
pre-dialysis CKD comparing paricalcitol and placebo and four
randomised comparative trials for end stage renal disease (ESRD)
(combined and reported as one) comparing paricalcitol and placebo.
The primary outcome was two consecutive decreases from baseline
iPTH levels of 30% or greater. The primary and secondary outcomes
were surrogate outcomes. The trials did not report final outcomes
such as fractures and overall survival. Trials were of short
duration with 12 to 24weeks follow up.
For PBAC’s view, see Recommendation and
Reasons.
The table below details the published trials presented in the
submission:
| Trial/First author | Protocol title / Publication title | Publication citation |
| Direct randomised trials | ||
| Predialysis trials | ||
| Coyne D et al | Paricalcitol capsule for the treatment of secondary hyperparathyroidism in stages 3 and 4 CKD. | Am J Kidney Dis; (2006) 47:263-276. |
| Abboud H et al | A comparison of dosing regimens of paricalcitol capsule for the treatment of secondary hyperparathyroidism in CKD stages 3 and 4. | Am J Nephrol,(2006); 26:105-114. |
| Agarwal R et al | Antiproteinuric effect of oral paricalcitol in chronic kidney disease | Kidney Int; (2005) 68:2823-2828. |
| ESRD trials | ||
| Ross EA et al | Oral paricalcitol for the treatment of secondary hyperparathyroidism in patients on haemodialysis or peritoneal dialysis. | Am J Nephrol; (2007) 28:97-106. |
| Meta-analyses of direct randomised trials | ||
| Palmer SC et al | Meta-analysis: Vitamin D compounds in chronic kidney disease. | Ann Intern Med, 2007; 147:840-853. |
| Palmer SC et al | Vitamin D compounds for people with chronic kidney disease requiring dialysis. | Cochrane Database Syst Rev, 2009, no. 4, article number: CD005633. |
| Palmer SC 2009b | Vitamin D compounds for people with chronic kidney disease not requiring dialysis. | Cochrane Database Syst Rev, 2009, no. 4, article number: CD008175. |
| Geary DF et al | Interventions for bone disease in children with chronic kidney disease. | Database of Syst Rev, 2010, no. 1, article number: CD008327. |
8. Results of Trials
The re-submission presented the results of the trials as a pooled
analysis rather than a meta-analysis.
The pooled results of the primary outcome of two consecutive ≥
30% decreases from baseline in iPTH for the predialysis and ESRD
trials indicated paricalcitol is highly effective at reducing
levels of iPTH compared with placebo treatment.
The PBAC noted that there were similar proportions of patients
experiencing adverse events in the paricalcitol and placebo arms of
the trials presented by the re-submission. There were statistically
significant differences in rates of fevers, urinary tract
infections (higher for paricalcitol) and peripheral vascular
disease (higher for placebo) between groups however these were
infrequent events and unlikely to represent true systematic
differences between the groups.
9. Clinical Claim
The re-submission claimed paricalcitol as superior in terms of
comparative effectiveness and equivalent in terms of comparative
safety over placebo, which based on the supporting data using
levels of iPTH as the primary outcome, the PBAC considered this
description was reasonable.
For PBAC’s view, see Recommendation and
Reasons.
10. Economic Analysis
The economic evaluation used a Markov cohort model limited to CKD
patients with secondary hyperparathyroidism (SHPT) and Stage 3 or
higher disease. The model compared paricalcitol treatment with
standard care in the cohort and contained ten health states.
The model cycle length was one year and patients could either
remain in their current health state each year or transition to a
new health state. Fracture rate was included in the model and
varied between treatment groups in ESRD dialysis patients. The time
horizon of the model was 10 years.
Along with the progression through the stages of CKD eventually to
dialysis, the outcomes used in the economic model included:
- Fracture,
- Non-fatal cardiovascular event,
- Fatal cardiovascular event, and
- Non-cardiovascular related death.
For each of these outcomes and for each stage of CKD the model
assigned a weighted relative risk to both the paricalcitol group
and the placebo group. Utilities were attached to the CKD stages
and a disutility was attached to patients modelled to experience a
fracture. Costs were applied according to treatment and whether a
non-fatal or fatal cardiovascular event or fracture was
experienced.
The incremental cost effectiveness ratio cost per QALY gained was
calculated to be less than $15,000.
Overall survival curves were generated by the economic evaluation
in the re-submission for both treatment groups, and the difference
in survival was underpinned by the assumption that lowering and
controlling iPTH levels in patients would reduce the risk of death,
which had not been demonstrated in the re-submission.
In a sensitivity analysis, conducted during the evaluation, the
relative risk for all-cause mortality in the paricalcitol arm had
been set equal to the risk in the placebo arm for Stages 3 and 4
CKD. Also, the treatment cost reductions had been removed. This
resulted in an ICER of between $15,000-$45,000 per QALY and had a
significant impact on the incremental health gain reducing it from
0.99 to 0.25.
Setting both the all-cause and cardiovascular mortality risks in
CKD Stages 3 and 4 equal to the placebo risks and removing the cost
reductions resulted in an ICER of greater than $200,000 per QALY.
Other potential areas of health gain were not modelled such as a
decrease in utility as CKD progresses or a decrease due to
non-fatal cardiovascular events.
For PBAC’s view, see Recommendation and
Reasons.
11. Estimated PBS Usage and Financial Implications
The likely number of patients per year was estimated by the
re-submission to be less than 10,000 in Year 5 of listing.
The financial cost per year to the PBS was estimated by the
re-submission to be less than $10 million in Year 4 of
listing.
12. Recommendation and Reasons
The PBAC noted that the requested restriction is not manageable as
Medicare Australia has no basis for determining when it is not
appropriate to treat a patient with calcitriol.
The PBAC accepted the nominated main comparator of placebo as
appropriate in patients with chronic kidney disease (CKD) who are
not receiving dialysis for the proposed restriction
–‘…where treatment with calcitriol is not
appropriate’. However, a comparison with calcitriol could
still be useful given this is the therapy that could be substituted
in practice and the need to support the implicit claims of improved
efficacy/reduced hypercalcaemia with paricalcitol, based on the
proposed PBS restriction.
The PBAC noted that the primary outcome of the trials was two
consecutive decreases from baseline iPTH levels of 30% or greater.
The primary and secondary outcomes are surrogate outcomes. The
trials did not report demonstrate improvements in clinical outcomes
such as fractures, cardiovascular events and overall survival. The
trials were of short duration with 12 to 24 weeks follow up.
The PBAC noted that patients with a history of “significant
sensitivity” to drugs similar to the study drug were excluded
from the trials and that patients with vitamin D deficiency were
not excluded from the predialysis trial. In the trials there were
trends towards greater increases in calcium and phosphate
concentrations in the paricalcitol treated groups, the clinical
significance of this is uncertain.
The submission claims paricalcitol is superior in terms of
comparative effectiveness and equivalent in terms of comparative
safety over placebo. Based on the supporting data using levels of
iPTH as the primary outcome, this description was considered
reasonable. However, although paricalcitol is highly effective at
reducing levels of iPTH, it is unclear how this translates to final
outcomes such as reduction in fractures, cardiovascular events or
improved survival.
The key concern arising from the premodelling studies undertaken by
the re-submission is the use of the distribution of patients within
iPTH bands for each stage of CKD from the pivotal trials (not an
outcome of the clinical trials) in combination with a collection of
cohort studies showing an association between increasing iPTH and
increasing risk of event. The result of the pre-modelling study
includes the strong assumption that controlling iPTH levels will
result in reductions of clinically relevant outcomes such as
survival. One of the retrospective cohort studies used (Smith et
al., 2009a), concludes that increasing levels of iPTH were
associated with a significantly elevated risk of mortality and
renal replacement therapy but notes that the study provides no
evidence that treating patients for higher levels of iPTH will
ameliorate poor outcomes. Smith et al, 2009a further states that it
is possible that elevated iPTH may simply be a marker for worsening
CKD coincident with changes in iPTH.
The PBAC considered that it is unacceptable to use relative risks
taken from selected observational studies (that do not demonstrate
that controlling iPTH levels leads to reductions in risk of
assessed events) and then apply these relative risks to changes in
iPTH levels in the pivotal trial population. It is highly unlikely
that the total relative risk reduction associated with differing
iPTH levels is 100% attributable to changes in iPTH alone.
The PBAC recalled that the evidence presented for the cinacalcet
submission also reported change in iPTH as the primary outcome;
however secondary outcomes of CV events, fractures,
parathyroidectomy and mortality were also reported in these 26 week
trials. The recommendation for cinacalcet also included a request
that the sponsor provide ongoing data from the EVOLVE trial when
available as this would provide evidence of efficacy in outcomes
relevant to patients.
Minimal trial evidence is presented to substantiate the clinical
place in therapy or efficacy in the proposed PBS population i.e.
that paricalcitol is effective in controlling iPTH and serum
Ca×P product when calcitriol has failed. Further, although
the submission correctly identifies hypercalcaemia as a reason for
ceasing calcitriol, no evidence is provided to demonstrate that
paricalcitol vs placebo does not cause hypercalcaemia in this
context or evidence that paricalcitol causes fewer episodes of
hypercalcaemia than calcitriol (calcitriol, however was not the
comparator in this submission). The PBAC considered that if
patients have persisting hypercalcaemia after dose reduction of
calcitriol the effects of a vitamin D analogue are highly
uncertain.
The PBAC considered that there were a number of issues of
uncertainty associated with modelled economic evaluation. In
particular, it was considered inappropriate to model a difference
in overall survival, non-fatal cardiovascular events and fractures
between paricalcitol and standard care, derived from the
combination of the pivotal trial iPTH level data and the observed
association between iPTH and risk of event in certain cohort
studies. The Committee was of the view that the re-submission had
not demonstrated a causal relationship between controlling iPTH and
reducing the risk of mortality yet this factor is the key driver of
the model and produces almost all of the health gain. In addition,
the modelled gains in survival from paricalcitol treatment were
considered to be implausibly large.
The PBAC therefore rejected the submission because 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
The sponsor has no comment.
