Paricalcitol, capsules, 1 microgram, 2 micrograms and 4 micrograms, Zemplar, March 2008
Public summary document for Paricalcitol, capsules, 1 microgram, 2 micrograms and 4 micrograms, Zemplar, March 2008
Page last updated: 04 July 2008
Public Summary Documents
Product:Paricalcitol, capsules, 1 microgram, 2 micrograms and 4 micrograms, Zemplar
Sponsor: Abbott Australasia Pty Ltd
Date of PBAC Consideration: March 2008
1. Purpose of Application
The submission sought a Section 85 Authority Required listing for the treatment of patients with end stage chronic renal disease receiving dialysis who have secondary hyperparathyroidism.
2. Background
This was the second submission for paricalcitol. At its July 2007 meeting, the PBAC
considered that the evidence from the non-randomised retrospective cohort studies
presented did not adequately support the submission’s claim of superiority over calcitriol
in terms of the outcomes of reduced hospitalisations and survival, and was more suggestive
of non-inferiority between paricalcitol and calcitriol.
The PBAC rejected the submission on the grounds of insufficient evidence of superiority
over the comparator to support a cost-effectiveness claim.
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 by a nephrologist of patients with end stage renal disease receiving dialysis
who have secondary hyperparathyroidism (iPTH value > 300 pg/mL (30pmol/L) AND
(i) Phosphate >1.6mmol/L OR
(ii) Ca > 2.4 mmol/L
NB: Intact PTH should be monitored quarterly (measured at least 12 hours post dose)
and the dose adjusted as necessary to maintain an appropriate iPTH level.
See Recommendation and Reasons for PBAC’s view.
5. Clinical Place for the Proposed Therapy
Paricalcitol, an analogue of calcitriol, the metabolically active form of vitamin D, regulates parathyroid hormone (PTH) levels, improves calcium and phosphate balance, and may prevent or treat metabolic bone disease associated with chronic kidney disease (CKD).
6. Comparator
The submission nominated oral calcitriol as the main comparator. This was previously agreed by the PBAC.
7. Clinical Trials
The re-submission presented new trial data. Two new non-randomised observational studies
reported by Kalantar-Zadeh (2006), Lee (2007) (based on the same study) and Young
(2006) along with three non-randomised retrospective cohort studies which were presented
in the prior submission, are provided in this submission as pivotal evidence. The
newly presented publications by Kalantar-Zadeh (2006) and Lee (2007) examined the
association between the administration of paricalcitol and mortality in stratified
paricalcitol dose groups or subgroups defined by baseline characteristics, respectively.
The poster presentation by Young (2006) was new to this submission, which demonstrated
survival benefits associated with paricalcitol and/or calcitriol compared to no vitamin
D therapy. Neither of the newly included non-randomised studies compared paricalcitol
and calcitriol directly. Three previously considered non-randomised observational
studies (Dobrez 2004; Teng 2003; Tentori 2006a and 2006b) compared survival and hospitalisation
benefits between IV paricalcitol and IV calcitriol.
Seven randomised, placebo-controlled paricalcitol trials and one meta-analysis on
calcitriol vs. placebo were new to this submission and served as supportive evidence.
Paricalcitol and calcitriol were indirectly compared on controlling iPTH levels in
haemodialysis patients.
8. Results of Trials
The key results were unchanged from the previous submission and are summarised in
the tables below.
Hazard ratios for all-cause mortality for patients receiving IV paricalcitol compared
to IV calcitriol treated patients in Teng (2003) and Tentori (2006b)
|
Model |
Covariates |
IV paricalcitol vs. IV calcitriol |
||
|---|---|---|---|---|
|
n |
HR (95%CI) |
p value |
||
|
Teng (2003) |
||||
|
1 |
Unadjusted |
67,399 |
0.81 (0.78, 0.85) |
< 0.001 |
|
2 |
Age, gender, race, diabetes status, duration of dialysis |
66,950 |
0.86 (0.82, 0.89) |
< 0.001 |
|
3 |
Model 2 + study-entry period |
66,950 |
0.90 (0.86, 0.95) |
< 0.001 |
|
4 |
Model 3 + SMR |
66,950 |
0.89 (0.85, 0.94) |
< 0.001 |
|
5 |
Model 4 + dialysis access |
66,950 |
0.89 (0.85, 0.93) |
< 0.001 |
|
6 |
Model 5 + albumin, calcium, phosphorus, PTH, ALP, haemoglobin, ferritin, bicarbonate, dialysate calcium and creatinine |
30,012 |
0.84 (0.79, 0.90) |
< 0.001 |
|
Tentori (2006b) |
||||
|
1 |
Unadjusted |
7,731 |
0.78 (0.69, 0.89) |
< 0.05 |
|
2 |
Age, gender, race, cause of ESRD, year started HD, time on HD before first vitamin D administration |
7,731 |
0.79 (0.68, 0.92) |
< 0.05 |
|
3 |
Model 2 + baseline serum calcium, phosphorus, PTH, albumin,, Kt/V, creatinine, and Hct labs |
6,107 |
0.93 (0.78, 1.11) |
NS |
|
4 |
Model 3 + clinic SMR |
6,107 |
0.94 (0.79, 1.13) |
NS |
|
5 |
Model 4 + time-varying labs |
6,107 |
0.95 (0.79, 1.13) |
NS |
Hospitalisation effect of IV paricalcitol relative to IV calcitriol in Dobrez 2004
|
IV paricalcitol compared to IV calcitriol |
p value |
||
|---|---|---|---|
|
ITT (N=11,443) |
Efficacy subset analysis* |
||
|
No. of hospital admissions per year |
-0.642 |
-0.846 |
<0.0001 |
|
No. of hospital days per year |
-6.84 |
-9.17 |
<0.0001 |
|
Risk of first all-cause hospitalization |
HR: 0.863 |
- |
<0.0001 |
|
No. of hyperparathyroidism-related hospital admissions per year |
-0.297 |
- |
<0.0001 |
|
No. of hyperparathyroidism-related hospital days per year |
-4.03 |
- |
<0.01 |
|
Risk of first hyperparathyroidism-related hospitalization |
HR: 0.878 |
- |
<0.0001 |
*the subset of patients who remained on their initial vitamin D therapy without switching
treatment
The study by Young (2006) demonstrated an informal indirect comparison of mortality
associated with paricalcitol and calcitriol, with no vitamin D therapy being the common
reference.
Kalantar-Zadeh (2006) and Lee (2007) demonstrated the administration of paricalcitol
reduced all-cause mortality compared to patients who did not receive paricalcitol.
Young (2006) reported an indirect comparison on survival benefit between IV paricalcitol
and oral vitamin D. The adjusted model showed that IV paricalcitol was associated
with a significant reduction in all-cause mortality (RR: 0.85 (95% CI: 0.74, 0.97))
whereas no significant reduction is provided by oral vitamin D (RR: 0.95 (95% CI:
0.87, 1.03)). However, the oral vitamin D arm was a mix of oral vitamin D analogues,
but largely made up of calcitriol.
In addition, the difference between the two RR estimates was non-significant (p=0.162).
Results from Young (2006) indicated that both IV paricalcitol and IV calcitriol significantly
reduced all-cause mortality when compared to no vitamin D therapy [RR= 0.85 (95% CI:
0.74, 0.97), RR= 0.91 (95% CI: 0.83, 0.99), respectively].
The above results on the direct and/or indirect comparisons between paricalcitol and
calcitriol were all derived from non-randomised observational studies. The PBAC noted
non-randomised observational studies are prone to selection bias and other confounders
which cannot be fully adjusted for in statistical analyses. The PBAC had previously
expressed concerns about the use of non-randomised observational studies as pivotal
studies to claim the superiority of paricalcitol over calcitriol.
The Committee agreed that the Teng (2003) study, despite concerns regarding non-randomisation,
is supportive of a significant mortality advantage for intravenous paricalcitrol over
intravenous calcitriol. As the study is large, the differences in the study populations
at baseline are not great, the mortality difference is large and the finding of reduced
mortality is supported by other, albeit non-randomised, studies. However, the data
provided to support a reduction in hospitalization rates with paricalcitol (Dobrez
(2004) was more difficult to interpret and this remained a significant area of uncertainty
for the PBAC.
The PBAC also remained concerned that most studies presented examined intravenous
(IV) paricalcitol, while the submission requests listing for oral paricalcitol. An
indirect comparison based on two meta-analyses showed that oral/intravenous paricalcitol
significantly reduced iPTH compared to placebo (-333.37 pg/ml (95%CI: -385.00, -183.22)),
in contrast, calcitriol failed to show a significant reduction in iPTH (-156.00 pg/ml
(95% CI: -330.89, 18.89)).
No results on the comparison of oral paricalcitol (the proposed drug) and oral calcitriol
(the nominated main comparator) were presented in this re-submission. Although the
bioequivalence of IV and oral paricalcitol has been established, the bioequivalence
of IV and oral calcitriol remains uncertain. Therefore, the relative effectiveness
of oral paricalcitol vs. oral calcitriol was not clear.
No new toxicity data were presented in the re-submission.
Two head-to-head trials on paricalcitol vs. calcitriol showed that paricalcitol had
a similar safety profile to calcitriol except for significantly higher nervous system
adverse events in paricalcitol patients (p=0.028). No advantage of hypercalcaemia
in paricalcitol was evident. However, the PBAC noted, these two trials were relatively
short (24-32 weeks) to capture long-term toxicity of paricalcitol therapy in ESRD
patients.
9. Clinical Claim
Paricalcitol was described as having significant advantages in effectiveness over
calcitriol. No interpretation was made on the comparative safety.
For PBAC’s views see Recommendation and Reasons.
10. Economic Analysis
An updated modelled economic evaluation was presented. The changes to the previous
model were to adjust the intravenous paricalcitol dose to oral paricalcitol using
a multiplication factor of 1.28 derived from the PI, and update drug costs. The approach
to determination of hospitalisation rate had not been updated (the PBAC has previously
expressed concerns about the approach).
Over a simulated 5-year horizon, paricalcitol was dominant versus calcitriol. The
PBAC noted that the dominance of paricalcitol could only be accepted if the methodology
used to determine the paricalcitol hospitalisation rate was accepted.
The model was most sensitive to the hospitalisation rate, hospitalisation costs, the
hazard ratio for mortality, and the inclusion of dialysis cost. The result of the
sensitivity analysis on the variation of hazard ratio of mortality is counterintuitive.
With the increase of the hazard ratio, which means an increase in the paricalcitol
mortality rate, paricalcitol becomes even stronger in dominating over calcitriol.
11. Estimated PBS Usage and Financial Implications
The submission estimated likely number of patients was less than 10,000 in
Year 5 at a financial cost/year to the PBS of between $10-30 million in Year 5.
12. Recommendation and Reasons
The PBAC noted that this new submission proposed to list oral paricalcitol only. It
also provided new clinical evidence in the form of two additional non-randomised cohort
studies together with seven randomised placebo-controlled paricalcitol (IV or oral
) trials and a meta-analysis of calcitriol (IV or oral) for an indirect comparison
of paricalcitol versus calcitriol on iPTH reduction.
The hearing clarified the clinical place of paricalcitol as a treatment for hyperparathyroidism
in a patient with end stage renal disease whose serum calcium is higher than 2.4 mmol
per litre but less than 2.8 mmol per litre, at which later point it is appropriate
to discontinue treatment with paricalcitol and commence treatment with cinacalcet
(noting however that the cinacalcet clinical studies used Vitamin D as an adjunct).
The PBAC agreed that this clarification meant it was inappropriate to align the paricalcitol
restriction with the cinacalcet one as suggested by the Restrictions Working Group.
However, the PBAC noted that there was a lack of concordance between the submission
and the treatment algorithm presented at the hearing with most of the subjects in
the large cohort studies presented being not representative of the proposed PBS population,
particularly in regards to serum calcium and iPTH levels at baseline, which were lower
than those required by the proposed listing restriction.
The Committee agreed that the Teng (2003) study, despite concerns regarding non-randomisation,
is supportive of a significant mortality advantage for intravenous paricalcitrol over
intravenous calcitriol, as the study is large, the differences in the study populations
at baseline are not great, the mortality difference is large and the finding of reduced
mortality is supported by other, albeit non-randomised, studies. However, the data
provided to support a reduction in hospitalisation rates with paricalcitol (Dobrez
(2004)) was more difficult to interpret and this remained a significant area of uncertainty
for the PBAC.
The PBAC also remained concerned that most studies presented examined IV paricalcitol,
while the submission requests listing for oral paricalcitol. Additionally, although
the indirect comparison based on two meta-analyses shows that oral/intravenous paricalcitol
significantly reduces iPTH compared to placebo (-333.37 pg/ml (95%CI: -385.00, -183.22)),
and in contrast, calcitriol fails to show a significant reduction in iPTH (-156.00
pg/ml (95% CI: -330.89, 18.89)); the results of the indirect comparison are of borderline
significance (p=0.057), and the inclusion of the meta-analysis on calcitriol may not
be appropriate. Furthermore, no conclusion about comparative safety can be drawn because
the presented safety data are based on two short-term trials only.
Many of the issues of economic uncertainty for the PBAC arose from the issues of clinical
uncertainty identified above. The Committee noted that the revised submission had
not updated the methodological approach used in determining hospitalisation rates
about which the PBAC previously expressed concern, and that the model is highly sensitive
to the hospitalisation rate. For example, at the hospitalisation rate of 85% used
in the base case, paricalcitol is dominant, a reduction in hospitalisation rate to
64% increases the estimated incremental cost effectiveness ratio (ICER) to between
$15,000 and $45,000 per extra quality adjusted life year (QALY) gained and decreasing
the hospital rate further to 21% increases the ICER to between $105,000 and $200,000
per extra QALY gained.
The PBAC welcomed the sponsor’s coverage with evidence development (CED) proposal
in principle, but noted that the two randomised trials upon which this proposal was
based excluded patients with baseline calcium levels higher that 2.5 or 2.6 mmol per
litre, which means that they will largely exclude patients representative of the PBS
population and have very limited usefulness for the proposed CED.
Thus overall, members rejected the application 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.
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.
