Paricalcitol, injection, 2 micrograms in 1 mL and 5 micrograms in 1 mL; capsules, 1 microgram, 2 micrograms, Zemplar® , March 2009
Public summary document for Paricalcitol, injection, 2 micrograms in 1 mL and 5 micrograms in 1 mL; capsules, 1 microgram, 2 micrograms, Zemplar® , March 2009
Page last updated: 03 July 2009
Public Summary Document
Product: Paricalcitol, injection, 2 micrograms in
1 mL and 5 micrograms in 1 mL; capsules, 1 microgram, 2 micrograms,
Zemplar®
Sponsor: Abbott Australasia Pty Ltd
Date of PBAC Consideration: March 2009
1. Purpose of Application
The submission sought a Section 100 (Highly Specialised Drug)
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.
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 was the third submission for paricalcitol.
At the July 2007 meeting, the PBAC rejected two submissions for
paricalcitol, one for the injection and a minor submission for the
capsules, for the treatment by a nephrologist of patients with end
stage renal disease receiving dialysis who have secondary
hyperparathyroidism on the grounds of insufficient evidence of
superiority over the comparator, oral calcitriol, to support a
cost-effectiveness claim.
At the March 2008 meeting, the PBAC rejected the application for
paricalcitol capsules 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.
3. Registration Status
Paricalcitol, 1 microgram and 2 micrograms capsules were TGA
registered on 21 March 2007 for the treatment of the biochemical
manifestations of secondary hyperparathyroidism associated with
chronic kidney disease, stages 3, 4 and 5.
Paricalcitol, 5 micrograms in 1ml injection was registered by the
TGA on 21 March 2007 for the treatment of the biochemical
manifestations of secondary hyperparathyroidism associated with
chronic kidney disease, stage 5.
Paricalcitol, 2 micrograms in 1 mL injection was registered by the
TGA on 29 October 2008 for the treatment of the biochemical
manifestations of secondary hyperparathyroidism associated with
chronic kidney disease.
4. Listing Requested and PBAC’s View
Section 85 Authority Required(Oral
formulation only)
Treatment by a nephrologist of patients with chronic kidney disease
(Stage 5) receiving dialysis who have secondary hyperparathyroidism
(iPTH value > 300 pg/mL or 31.8 pmol/L)
Section 100 Highly Specialised Drugs(Oral and
IV formulations)
Private Hospital Authority Required
Treatment by a nephrologist of patients with chronic kidney disease
(Stage 5) receiving dialysis who have secondary hyperparathyroidism
(iPTH value > 300 pg/mL or 31.8 pmol/L)
For PBAC’s view, see Recommendation and
Reasons.
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.
The PBAC considered this was appropriate, as previously, if the
calcium level was between 2.4mmol/L and 2.8mmol/L.
7. Clinical Trials
The basis of the submission was:
1. For evidence on mortality and hospitalisation: Two pivotal
non-randomised cohort studies (Teng 2003 and Dobrez 2004) and four
supplementary non-randomised cohort studies.
2. For evidence of (i) a lower rate for paricalcitol of
hypercalcaemia and/or elevated calcium-phosphate product, and (ii)
similar biochemistry effects generally to support the
submission’s claim of a
mortality and hospitalisation benefit: Four direct randomised
comparative trials comparing paricalcitol and calcitriol used for
seven meta-analyses and two ‘lumped’ analyses.
3. For supportive evidence of similar PTH control of paricalcitol
and cinacalcet in order to be able to apply the paricalcitol
mortality and hospitalisation effects to cinacalcet patients in the
model: Twelve
randomised comparative trials (seven comparing paricalcitol and
placebo, five comparing cinacalcet and placebo) for an indirect
analysis of paricalcitol and cinacalcet on control of PTH.
4. For supplementary evidence supporting dosing recommendations and
translating intravenous to oral doses because many of the trials
were done using the intravenous formulation yet the listing
also
includes the oral formulation: Two dose strategy trials and four
bioequivalence studies.
The trials published at the time of submission are listed below:
| Trial ID/First Author | Protocol title/Publication title | Publication citation |
| Randomised trials of biochemistry outcomes comparing IV paricalcitol vs IV ** calcitriol | ||
| 95028 Sprague et al | Suppression of parathyroid hormone section in hemodialysis patients | Am J Kidney Dis 2001;38 (Suppl 5):S51-S56 |
| Cohort studies of survival and hospitalisations | ||
| Primary cohort studies | ||
| Teng (2003) | Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy | NEJM 2003;349:446-456 |
| Dobrez (2004) | Paricalcitol-treated patients experience improved hospitalization outcomes compared with calcitriol-treated patients | Nephrol Dialysis Transplant 2004;19:1174-1181 |
| Supportive cohort studies | ||
| Tentori (2006) | Mortality risk among hemodialysis patients receiving different vitamin D analogs | Kidney International 2006; 1858-1865. |
| Kalantar-Zadeh (2005) | Survival predictability of time-varying indicators of bone disease in maintenance hemodialysis | Kidney International 2005; 70,771-780. |
| Young (2006) | Vit D therapy and mortality in the dialysis outcomes and practice patterns study (DOPPS) | J Am Soc Nephrol 16: 2005 (abstract) |
| Shinaberger (2008) * | Ratio of paricalcitol dosage to PTH level and survival in maintenance hemodialysis | Clin J Am Soc Nephrol 2008, doi:10.2215/CJN.01760408 |
| Supportive randomised trials of paricalcitol vs placebo | ||
| M03635 (oral) * | Ross: Oral paricalcitol for secondary hyperparathyroidism | Am J Nephrol 2008;28:97-106 |
| Supportive randomised trials of cinacalcet vs placebo | ||
| Trial 173 * | Block: Cinacalcet for secondary hyperparathyroidism | NEJM 2004;350:1516-1525 |
| Trial 182 * | ||
| Trial 188 * | Lindberg: Cinacalcet for secondary hyperparathyroidism – a randomised trial | J Am Soc Nephrol 2005;16:800-807 |
| Trial 141 * | Malluche: An assessment of cinacalcet on bone histology in dialysis patients | Clin Nephrol 2008;69:269-277 |
| Japanese trial * | Fukagama: Cinacalcet decreases PTH in Japanese dialysis patients | Nephrol Dialysis Transplant 2008;23:328-335 |
| Supportive bioequivalence studies | ||
| Mazess(2003) * | A review of intravenous and oral vitamin D hormone therapy in hemodialysis patients. | Clin Nephrol 2003;59:319-325 |
| Levine (1996) * | Pharmacokinetics and efficacy of pulse oral vs intravenous calcitriol in hemodialysis patients | J Am Soc Nephrol 1996;7:488-496 |
* signifies trials new to this submission
8. Results of Trials
The submission presented the same two pivotal non-randomised cohort
studies (Teng 2003 and Dobrez 2004) as in the March 2008
application and four supplementary non-randomised cohort studies as
evidence for the claim of improved survival and decreased
hospitalisations with paricalcitol over calcitriol.
The results of the survival analysis are unchanged from the
previous submission, see March 2008 PSD.
However, the results of hospitalisation rates by multivariate
analysis have changed by using the full ITT population instead of
the subset used in the previous submission and are shown
below:
Hospitalisation by multivariate analysis from the Dobrez
(2004) non-randomised study
| Hospitalisation outcome measure | Paricalcitol N = 4,611 | Calcitriol N = 6,832 |
| No. hospitalisations per patient per year, mean | 1.97 | 2.61 |
| 0.64/yr fewer hospitalisations for paricalcitol | ||
| No. hospital days per patient per year, mean | 13.0 | 19.8 |
| 6.2 fewer hospital days for paricalcitol | ||
The value of 0.64 fewer hospitalisations per year used in the
economic model was in contrast to the value of 0.85 fewer
hospitalisations used in the previous two submissions.
The results on the rates of hypercalcaemia and/or elevated calcium
phosphate product used for supportive biochemistry evidence are
shown below:
Rate of hypercalcaemia and/or elevated calcium-phosphate
product in the randomised paricalcitol (P) vs calcitriol (C)
trials
| Description | Trial included in analysis (+ = yes, - = no) | Result (95% CI) p value | I 2 value* (95% CI) | |||
| 95027 IV P v oral C | 95028 IV P v IV C | 95034 IV P v IV C | M02516 IV P v IV C | |||
| A. Meta-analysis of proportion with hypercalcaemia +/or elevated CP product | - | + | + | + | Paricalcitol 22.6% (=77/340) Calcitriol 30.6% (=106/346**) RR=0.75(0.53,1.04)** P=0.09** | 42% (0%, 82%) |
| B. ‘Lumped’ analysis of proportion with hypercalcaemia +/or elevated CP product | - | + | + | - | Paricalcitol 24.1% (=55/228) Calcitriol 32.8% (=76/232) RR=0.74(0.57,0.95) NR | Not a meta-analysis |
| Random effects meta-analysis of analysis B | - | + | + | - | RR=0.74 (0.43, 1.29) | 71% (0%, 93%) |
| Random effects meta-analysis as in A but using initial definition*** of hypercalcaemia and/or elevated calcium-product | - | + | + | + | Paricalcitol 53.5% (=182/340) Calcitriol 53.2% (=184/346) RR=1.01 (0.79, 1.29) | 68.1% (0%, 91%) |
* Calculated during the evaluation from the data provided in the
submission
** The data appear to have been incorrectly transcribed in the
submission, so the meta-analysis was conducted during the
evaluation
*** The original definition in the trial reports used the first
occurrence of hypercalcemia or of the calcium-phosphate product,
compared to the definition used in the submission which was two
consecutive elevations of calcium and four consecutive evaluations
of the calcium-phosphate product. The full protocols, amendments,
and statistical analysis plans were not provided in the
submission.
Abbreviations: CP=calcium-phosphate, NR=not reported, RR=relative
risk
The submission presented new toxicity data from the two trials
(Trial 95027 and M02516) new to this submission, but the results
did not differ from those in the previous submission.
For PBAC’s view, see Recommendation and
Reasons.
9. Clinical Claim
The submission described paricalcitol as superior in terms of
comparative effectiveness (survival and hospitalisations) and
equivalent in terms of comparative safety over calcitriol. It added
that these findings were supported by the biochemistry comparisons
of paricalcitol versus calcitriol.
The PBAC did not consider that paricalcitol is superior in terms of
comparative effectiveness (survival and hospitalisations) and
equivalent in terms of comparative safety over calcitriol as the
survival and hospitalisation results, although supportive of the
submission’s claim, are not conclusive because there are no
randomised trial data on survival and hospitalisations.
10. Economic Analysis
An updated modelled economic evaluation was presented which
consisted of a cost-utility, single cohort Markov model of two
states, dialysis and death, beginning at age 60 and extending over
a 10-year horizon in quarterly cycles. Cinacalcet was captured in
the current modelling as a sensitivity analysis by switching those
patients having hypercalcaemia or elevated calcium-phosphate levels
from their initiated therapy (paricalcitol or calcitrol) to
cinacalcet.
The sensitivity analyses showed that the mortality treatment effect
and its duration and the hospitalisation treatment effect were the
most prominent drivers of the model.
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 10,000 in Year 5 and the financial cost per year to the PBS
was estimated to be in the range of $10 – $30 million in Year
5.
12. Recommendation and Reasons
The PBAC agreed that patients receiving paricalcitol should not
have elevated serum calcium and phosphate levels as high serum
calcium levels are considered a reason to cease vitamin D
supplements (CARI Guidelines, Vitamin D in Dialysis 2006) and
considered the restriction as requested on iPTH levels alone to be
sufficient.
The submission nominated oral calcitriol as the comparator which
was considered appropriate, as previously, if the calcium was
between 2.4mmol/L and 2.8mmol/L
As pivotal evidence for the claim of improved survival and
decreased hospitalisations with paricalcitol over calcitriol the
submission presented the same two non-randomised cohort studies
(Teng 2003 and Dobrez 2004) as in the application considered in
March 2008 and four supplementary non-randomised cohort studies.
The PBAC again considered that the key issue in the submission was
the inability to establish whether there was a mortality benefit
for paricalcitol over calcitriol in dialysis patients given the use
of the large non-randomised study (Teng et al) as evidence. The
Committee agreed with the ESC that both observational cohorts had a
number of limitations, being susceptible to bias (e.g. lack of
control over risk assignment, differential loss to follow-up,
differences in the stage of disease) and so did not provide the
level of empirical evidence equivalent to that provided by a
randomised controlled clinical trial. The PBAC also agreed with the
ESC that the reported 16% improvement in overall survival gain was
implausibly large in dialysis patients and considered that the Teng
Study was hypothesis generating and that a prospective randomised
study was needed to confirm the findings of the Teng Study.
The PBAC therefore did not accept the claim in the submission of a
16 % improvement in the survival with paricalcitol over calcitriol,
based on the results of Teng et al (2003).
Similarly, the PBAC was unable to ascertain if hospitalisation
rates are affected by treatment with paricalcitol compared to
calcitriol given the use of a non-randomised study (Dobrez et al,
2004) presented in support of the claim of reduced hospitalisation
rates with paricalcitol.
Therefore, the PBAC did not consider that paricalcitol is superior
in terms of comparative effectiveness (survival and
hospitalisations) and equivalent in terms of comparative safety
over calcitriol as the survival and hospitalisation results,
although supportive of the submission’s claim, are not
conclusive because there are no randomised trial data to support
these claims on survival and hospitalisations.
For evidence that paricalcitol treatment results in a lower rate of
hypercalcaemia and/or elevated calcium-phosphate product and
similar biochemistry effects generally, and to support the
submission’s claim of a mortality and hospitalisation
benefit, the submission presents four direct randomised comparative
trials comparing paricalcitol and calcitriol, which were used for
seven meta-analyses and two ‘lumped’ analyses.
The PBAC considered that the major use of the results of the
randomised trial to determine the rate of switching to cinacalcet
triggered by hypercalcaemia and/or calcium-phosphate product (the
22.6% and 30.6% rates for paricalcitol and calcitriol) was
uncertain as it relies on analyses that are not statistically
significant and entail heterogeneity.
The PBAC also considered the economic evaluation to be uncertain as
it relies on the evidence from non-randomised clinical trials. The
Committee noted that the mortality treatment effect, its duration
and the hospitalisation treatment effect were the most prominent
drivers of the model.
The PBAC noted advice from the Highly Specialised Drugs Working
Party that paricalcitol did not meet all the criteria for listing
under the Highly Specialised Drugs Program.
The PBAC rejected the submission for paricalcitol due to the
primary use of non-randomised data to establish the clinical case
of superiority of paricalcitol over calcitriol 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
The Sponsor is working with the PBAC to achieve PBS listing for
paricalcitol.
