Paricalcitol, injection, 5 micrograms in 1 mL and 10 micrograms in 2ml; capsules, 1 microgram, 2 micrograms and 4 micrograms, Zemplar, July 2007
Public summary document for Paricalcitol, injection, 5 micrograms in 1 mL and 10 micrograms in 2ml; capsules, 1 microgram, 2 micrograms and 4 micrograms, Zemplar, July 2007
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Public Summary Documents
Product: Paricalcitol, injection, 5 micrograms in 1 mL and 10 micrograms in 2ml; capsules,
1 microgram, 2 micrograms and 4 micrograms, Zemplar
Sponsor: Abbott Australasia Pty Ltd
Date of PBAC Consideration: July 2007
1. Purpose of Application
The submission sought 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.
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
This drug had not previously been considered by the PBAC.
3. Registration Status
Paricalcitol, 5 micrograms in 1ml and 10 micrograms in 2 mL injections were registered
by the TGA on 1 March 2007 for the treatment for the biochemical manifestations of
secondary hyperparathyroidism associated with chronic kidney disease, stage 5.
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
Section 100 (Highly Specialised Drug) Private hospital authority required
Treatment by a nephrologist of patients with end stage renal disease receiving dialysis
who have secondary hyperparathyroidism (iPTH value > 300 pg/mL).
NOTE: 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
Chronic kidney disease (CKD) 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. Stage five CKD, also known
as end stage renal disease (ESRD) is characterised by kidney failure and patients
require dialysis.
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.
Renal bone disease includes high turnover bone disease, osteoporosis, osteomalacia
and low turnover bone disease.
Paricalcitol is an analogue of calcitriol, the metabolically active form of vitamin
D, which regulates PTH levels and improves calcium and phosphate balance.
6. Comparator
The submission nominated oral calcitriol as the main comparator. Calcitriol is neither
TGA nor PBS listed for secondary hyperparathyroidism associated with end-stage renal
disease (ESRD), but it is commonly used in patients with chronic kidney failure.
The PBAC agreed that oral calcitriol is the appropriate comparator.
7. Clinical Trials
The submission presented three non-randomised retrospective cohort studies as pivotal
evidence comparing intravenous paricalcitol with intravenous calcitriol in haemodialysis
patients and two randomised controlled trials as supportive evidence comparing intravenous
paricalcitol with intravenous calcitriol in haemodialysis patients over 24-32 weeks.
These trials had been published at the time of submission, as follows:
|
Trial ID |
Protocol title/ Publication title |
Publication citation |
|---|---|---|
|
Non-randomised trials – pivotal evidence |
||
|
Dobrez D et al 2004 |
Paricalcitol-treated patients experience improved hospitalization outcomes compared with calcitriol-treated patients in real-world clinical settings. |
Nephrol Dial Transplant 2004, 19(5): 1174-81. |
|
Teng M et al 2003 |
Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy. |
N Engl J Med 2003, 349(5): 446-56. |
|
Tentori F et al 2006 |
Risk of Hospitalisation is decreased among hemodialysis (HD) patients receiving vitamin D (IVVD) therapy. |
American Society of Nephrology (ASN), San Diego. 2006, 14-19 November |
|
Tentori F et al 2006b |
Mortality risk among hemodialysis patients receiving different vitamin D analogs. |
Kidney Int advance online publication 2006 |
|
Randomised trials – supportive evidence |
||
|
95028 |
Suppression of parathyroid hormone secretion in haemodialysis patients: Comparison of paricalcitol with calcitriol. |
Am J Kid Dis 2001, 38 (5 SUPPL. 5): S51-S56. (subgroup of 38 patients) |
|
95028 |
Paricalcitol versus calcitriol in the treatment of secondary hyperparathyroidism. |
Kid Int 2003, 63(4): 1483-90 |
8. Results of Trials
The results of the key studies are summarised in the tables below:
Hazard ratios for all-cause mortality for patients receiving paricalcitol compared
to calcitriol treated patients in Teng (2003) & Tentori (2006b)
|
Model |
Covariates |
Paricalcitol vs. 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 |
In Teng et al (2003), the Kaplan-Meier plot showed that a survival difference between
paricalcitol (n = 29,021) and calcitriol patients (n = 38,378) was evident at the
end of the 36 month follow-up period (p < 0.001). The mortality rate was significantly
lower in the paricalcitol group (18.0 per 100 patient years) than in the calcitriol
group (22.3 per 100 patient years). In both unadjusted and adjusted models, the mortality
difference between paricalcitol and calcitriol remained significant.
In Tentori et al (2006b), survival was significantly better in the paricalcitol treatment
group compared to the calcitriol treatment group. The mortality rate in the paricalcitol
group was 15.3 per 100 patient years compared to 19.6 per 100 patient years in the
calcitriol group. However, after adjustment for baseline variables, the differences
in survival were not statistically significant and may be smaller than previously
reported by Teng et al (2003).
Hospitalisation effect of paricalcitol relative to calcitriol in Dobrez 2004
|
Paricalcitol compared with 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 multivariate analysis indicated that patients who started on paricalcitol had
6.84 fewer hospital days per year and 0.642 fewer hospitalisations per year than calcitriol
patients
(p < 0.0001). In addition, patients who started on paricalcitol were 14% less likely
to be hospitalised (HR = 0.863; p < 0.0001). The results of additional models that
explored the effect of vitamin D treatment indicated paricalcitol patients had lower
hyperparathyroidism-related hospitalisation outcomes than calcitriol patients. However,
as stated in Dobrez et al (2004), 5.6% of paricalcitol patients switched to other
therapy while 41.3% switched therapy in the calcitriol arm during the observation
period.
Two supportive trials 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, these
two trials were relatively short (24-32 weeks) to capture long-term toxicity of paricalcitol
therapy in ESRD patients.
The incidence of hypercalcaemia and/or elevated Ca? in the randomised supportive trials
is reported below:
Proportion of patients who became hypercalcaemic for at least 2 consecutive laboratory
draws and/or had a Ca?>75 at least one period of 4 consecutive laboratory draws
|
Paricalcitol |
Calcitriol |
Relative risk |
Risk difference |
|||
|---|---|---|---|---|---|---|
|
95028 |
24/130 (18.5) |
44/133 (33.1) |
0.56 |
-14.6 |
||
|
95034 |
31/98 (31.6) |
32/99 (32.3) |
0.98 |
-0.7 |
||
|
Pooled |
Fixed |
Random |
Fixed |
Random |
||
|
p value of test for heterogeneity |
0.06 |
0.10 |
||||
|
I2 statistic |
70.9% |
62.9% |
||||
For PBAC’s view, see Recommendation and Reasons.
9. Clinical Claim
The submission described paricalcitol as having significant advantages in effectiveness
over calcitriol.
The PBAC considered that the evidence from the non-randomised retrospective cohort
studies presented does not adequately support the submission’s claim of superiority
over calcitriol in terms of the outcomes of reduced hospitalisations and survival,
and may be more suggestive of non-inferiority between paricalcitol and calcitriol.
10. Economic Analysis
The submission presented a modelled economic evaluation. A cost utility approach was
used.
The resources included in the base case were drug costs and hospitalisation costs.
For the base case modelled incremental discounted cost/extra discounted life year
gained or quality adjusted life year (QALY) over a simulated 5-year horizon, the submission
concluded that paricalcitol is dominant (ie more effective and less costly) versus
calcitriol.
The PBAC noted that dominance of paricalcitol can only be accepted if the methodology
used to determine the paricalcitol hospitalisation rate is accepted, as it appears
that the resultant hospitalisation costs are the key drivers of the model. Given that
the methodology used to determine the paricalcitol hospitalisation rate is not likely
to be valid, the results of the model may not reflect the true cost-effectiveness
of paricalcitol.
11. Estimated PBS Usage and Financial Implications
The submission estimated that in Year 5 of listing the financial cost/year to the PBS (excluding co-payments) would fall in the range $10 – $30 million.
12. Recommendation and Reasons
The PBAC agreed that oral calcitriol is the appropriate comparator. However the clinical
evidence presented compares intravenous paricalcitol against intravenous calcitriol,
and the comparative effectiveness of intravenous versus oral calcitriol is unknown.
Additionally the only two randomised controlled trials presented (studies 95028 and
95034) only examined the effects of treatment on biochemical endpoints and did not
include any relevant clinical endpoints, so it is not known if paricalcitol treatment
will improve bone histology and bone mineral density, reduce fracture rates and/or
ameliorate other clinical symptoms related to secondary hyperparathyroidism or to
a reduced rate of parathyroidectomy. Data relating to quality of life and survival
are also not available from these trials.
The PBAC agreed that there was a trend in the results from the randomised controlled
trials favouring intravenous paricalcitol over intravenous calcitriol in the proportion
of patients who experienced a sustained hypercalcaemic and/or elevated Caא event.
The PBAC did not accept the submission’s claim that this result was statistically
significant based on a fixed effect analysis. The Committee agreed with the evaluation
that a random effects analysis is more appropriate and that based on the random effects
model, the numerical difference in hypercalcaemic and/or elevated Caא events between
paricalcitol and calcitriol is not significant at P<0.05.
The Committee noted that in the absence of clinical endpoint data from direct randomised
controlled studies, the submission’s therapeutic claim relied upon the results of
three non-randomised retrospective cohort studies. The PBAC agreed that selection
bias is inherent in such observational studies, and that without supportive evidence
from randomised controlled trials (even using surrogate endpoints) the submission’s
claim of superiority is highly uncertain. The adjusted analysis in one of the retrospective
cohort studies was not statistically significant and the supportive evidence from
the short randomised controlled trials on biochemical outcomes, such as Caא, did not
show a benefit for paricalcitol over calcitriol.
Overall the PBAC considered that the evidence from the non-randomised retrospective
cohort studies presented does not adequately support the submission’s claim of superiority
over calcitriol in terms of the outcomes of reduced hospitalisations and survival,
and may be more suggestive of non-inferiority between paricalcitol and calcitriol.
The PBAC agreed that there were issues of economic uncertainty. In particular, the
dominance of paricalcitol in the model rests on the acceptance of submission’s claim
of improved survival and reduced hospitalisations, which the PBAC found not to be
adequately supported.
The PBAC therefore rejected the submission on the grounds of insufficient evidence
of superiority over the comparator to support a cost-effectiveness claim.
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 is disappointed with the decision of the PBAC particularly because calcitriol
is neither TGA nor PBS approved for the intended listing. The sponsor believes that
paricalcitol has significant advantages over the comparator and it will continue to
work collaboratively with the PBAC in order to demonstrate this advantage in future
submissions.
