Lanthanum Carbonate Hydrate, chewable tablet, 500 mg (base), 750 mg (base), 1 g (base), Fosrenol®, March 2007
Public summary document for Lanthanum Carbonate Hydrate, chewable tablet, 500 mg (base), 750 mg (base), 1 g (base), Fosrenol®, March 2007
Page last updated: 13 July 2007
Public Summary Document
Product: Lanthanum Carbonate Hydrate, chewable
tablet, 500 mg (base),
750 mg (base), 1 g (base), Fosrenol®
Sponsor: Orphan Australia Pty Ltd
Date of PBAC Consideration: March 2007
1. Purpose of Application:
To seek an Authority required listing for the treatment of
hyperphosphataemia in adult patients with chronic renal failure on
dialysis whose serum calcium levels are at least 2.60 mmol/L.
2. Background:
This drug has not previously been considered by the PBAC.
3. Registration Status:
Lanthanum carbonate is TGA-registered for the treatment of
hyperphosphataemia in adults with chronic renal failure on
haemodialysis or continuous ambulatory peritoneal dialysis
(CAPD).
4. Listing Requested and PBAC’s View:
Authority required
Initial treatment of hyperphosphataemia, for up to 8 weeks, in
adult patients with chronic renal failure on dialysis whose serum
calcium levels are at least 2.60 mmol/L.
Continuing treatment of hyperphosphataemia, in adult patients with
chronic renal failure on dialysis who have demonstrated a response,
defined as serum calcium levels less than 2.60 mmol/L, following
the completion of an 8-week trial with lanthanum carbonate.
The PBAC did not comment on the requested
restriction.
5. Clinical place for the proposed therapy:
Lanthanum carbonate would provide an alternative therapeutic to
calcium-based phosphate binders for the treatment of
hyperphosphataemia in adult patients with chronic renal failure who
need haemodialysis or continuous ambulatory peritoneal
dialysis.
6. Comparator:
The submission nominated calcium carbonate as the main comparator,
which was considered appropriate by the PBAC.
7. Clinical Trials
The scientific basis of the comparison was a pivotal randomised trial (LAM-IV-301)
comparing lanthanum with calcium carbonate on phosphate level control in adult patients
with chronic renal failure on dialysis over 6-month period; 2 supportive trials: LAM-IV-303
which is a 1-year trial comparing lanthanum to calcium on bone histomorphometry and
LAM-IV-307, which is a 2-year comparative safety study. The following table lists
the trials as published at the time of submission.
| Trial ID | Title |
| Pivotal trial | |
| LAM-IV-301 |
A Phase III Open Label, Comparator Controlled Parallel Group Study to Assess the Efficacy and Safety of Lanthanum Carbonate for reduction of Gastrointestinal Phosphate Absorption and Maintenance of Control of Serum Phosphate in Chronic Renal Failure Patients Receiving Hemodialysis Publications Hutchison AJ, Maes B, Vanwalleghem J, Asmus G, Mohamed E, Schmieder R, Backs W, Jamar R, Vosskuhler A. Efficacy, tolerability, and safety of lanthanum carbonate in hyperphosphatemia: a 6-month, randomized, comparative trial versus calcium carbonate. Nephron Clin Pract. 2005;100(1):c8-19. Hutchison AJ, on Behalf of the Lanthanum Study G. The novel, non-aluminium, non-calcium phosphate binder, Fosrenol, is an effective treatment for hyperphosphataemia and has a good safety profile [abstract]. Journal of the American Society of Nephrology: JASN. 2002;13(September, Program and Abstracts):385a-6a. |
| Supportive trials | |
| LAM-IV-303 |
A Phase III, Multi-Centre, Open Label, Study to Investigate the Effect of Lanthanum Carbonate compared with Calcium Carbonate on Renal Bone disease in Chronic Renal Failure Patients Receiving Dialysis Publications Freemont AJ, Hoyland JA, Denton J; Lanthanum Carbonate SPD405-303 Study Group. The effects of lanthanum carbonate and calcium carbonate on bone abnormalities in patients with end-stage renal disease. Clin Nephrol. 2005 Dec; 64(6):428-37. D'Haese PC, Spasovski GB, Sikole A, Hutchison A, Freemont TJ, Sulkova S, Swanepoel C, Pejanovic S, Djukanovic L, Balducci A, Coen G, Sulowicz W, Ferreira A, Torres A, Curic S, Popovic M, Dimkovic N, De Broe ME. A multicenter study on the effects of lanthanum carbonate (Fosrenol) and calcium carbonate on renal bone disease in dialysis patients. Kidney Int Suppl. 2003 Jun; (85):S73-8. Spasovski GB.Sikole A.Gelev S.Masin-Spasovska J.Freemont T.Webster I.Gill M.Jones C.De Broe ME.D'Haese PC. Evolution of bone and plasma concentration of lanthanum in dialysis patients before, during 1 year of treatment with lanthanum carbonate and after 2 years of follow-up. Nephrology Dialysis Transplantation. 21(8):2217-24, 2006 Aug. Freemont T. Malluche HH. Utilization of bone histomorphometry in renal osteodystrophy: demonstration of a new approach using data from a prospective study of lanthanum carbonate. Clinical Nephrology.63(2):138-45, 2005 Feb. De Broe ME, D'Haese PC, Freemont TJ, Webster i> Gill M, Spasovski GB. Comparative effects of lanthanum carbonate (fosrenol) and calcium carbonate on renal bone disease in dialysis patients: results from a large, long-term clinical trial [abstract]. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association European Renal Association. 2003; 18(Suppl 4):682. Freemont A, Jones C. The effects of the phosphate binders lanthanum carbonate and calcium carbonate on bone: a comparative study in patients with chronic kidney disease [abstract]. 41st Congress European Renal Association European Dialysis and Transplantation Association Lisbon, Portugal, May 15 18, 2004. 2004:106. |
| LAM-IV-307 |
An Open Label, Randomized, Multicenter, Phase III, Comparator Controlled Parallel Group Study to Assess the Long-Term Safety and Efficacy of Lanthanum Carbonate in Chronic Renal Failure Patients Receiving Hemodialysis. Publications Finn WF; SPD 405-307 Lanthanum Study Group. Lanthanum carbonate versus standard therapy for the treatment of hyperphosphatemia: safety and efficacy in chronic maintenance hemodialysis patients. Clin Nephrol. 2006 Mar;65(3):191-202. Finn WF, Joy MS, Webster I, Gill M, for the Lanthanum Study G. A long-term (2-year) assessment of the safety and efficacy of lanthanum carbonate (forenol), a non-calcium, non-aluminium phosphate binder for the treatment of hyperphosphataemia [abstract]. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association European Renal Association. 2003;18 (Suppl 4):686. |
8. Results of trials
The primary outcome in the key trial LAM-IV-301 showed that
lanthanum is inferior to calcium carbonate in controlling serum
phosphate at the end of the 5-week titration phase (p=0.002). The
slower response in lanthanum patients was attributed to a more
cautious approach to dosing lanthanum. At the end of the
maintenance phase, proportions of phosphate controlled patients
were similar in both arms (p=0.73). However, it should be noted
that the analysis from week 5 to week 25 involved only responders,
so the similarity in results in the two treatment groups was
expected (see comments below). The submission claimed that
lanthanum offers similar effectiveness to calcium carbonate as a
phosphate binding agent. The Last Observation Carried Forward (LOCF
analysis) at the end of the maintenance phase indicated that
lanthanum is less effective than calcium carbonate in reducing
phosphate levels (p=0.043). This LOCF analysis is likely to be
biased in favour of the calcium arm due to patients treated with
calcium being withdrawn due to hypercalcaemia rather than
hyperphosphataemia.
Primary and Secondary outcomes of the comparative randomised trials (ITT)
| Trial | Primary outcome | Lanthanum | Calcium/ Standard | p value | |
| LAM-IV-301 (key trial) | PO4 controlled patients (PO4 ≤ 1.80mmol/L) at titration (Wk 5) n/N(%) | 262/453 (57.8%) | 147/209 (70.3%) | 0.002 | |
| LAM-IV-307 (supportive trial) | PO4 controlled patients (PO4 ≤1.90mmol/L) at maintenance (%) | Wk 52 | 47.0% | 49.2% | NS |
| Wk 78 | 48.1% | 51.5% | |||
| Yr 2 | 45.9% | 48.9% | |||
| LAM-IV-303 (supportive trial) | Bone histomorphometry | ||||
| Secondary outcomes | |||||
| LAM-IV-301 (key trial) | PO4 controlled patients (PO4 ≤ 1.80mmol/L) at maintenance (Wk 25) n/N(%)* | 146/222 (65.8%) | 78/122 (63.9%) | 0.73 | |
| PO4 controlled patients (PO4 ≤ 1.80mmol/L) at maintenance (Wk 25) (LOCF analysis)* | 182/510 (35.7%) | 111/257 (43.2%) | 0.043 | ||
| Hypercalcaemic episode (any occurrence above the ULN range) (%)* | 5.7% | 37.9% | <0.001 | ||
| LAM-IV-303 (supportive trial) | Hypercalcaemic episode (serum calcium above ULN, >2.65mmol/L) (%) | 6% | 48% | NR | |
PO4 = phosphate, ULN = upper limit of the normal, LOCF = last
observation carried forward, NS = not significant, NR = not
reported
* These comparisons are confounded by the differential withdrawal
of non-responding patients prior to the maintenance phase from week
5 to week 25. These data cannot be viewed as a true comparison
between the treatments.
The PBAC noted that in the pivotal trial LAM-IV-301, the primary
efficacy analysis of the PO4 control at the end of the 5-week
titration period, indicated an inferiority of lanthanum in
phosphate control compared with calcium carbonate. The PBAC was
advised that considering the multiple disorders of mineral
metabolism (hyperphosphataemia, hypercalcemia and secondary
hyperparathyroidism) in end stage renal disease (ESRD) and the
complexity of their interrelationship, the sole biochemical
measurement of PO4 level as a surrogate endpoint was
questionable.
A post hoc survival analysis on the 2-year safety trial of
LAM-IV-307 showed no significant difference in overall survival
benefits in lanthanum compared to sevelamer or standard therapies
but claimed a benefit in subjects over 65 years. The PBAC was
advised this mortality analysis is possibly subject to a range of
biases due to the high and differential drop-out rates and the
unbalanced co-interventions in the study.
The calcium targets and subgroups considered by the model have been
defined to be in line with the boundaries of the calcium bands
established by Block et al (2004) (Mineral metabolism, mortality,
and morbidity in maintenance hemodialysis.” J Am Soc Nephrol
15(8): 2208-18) to describe the relative risks of mortality
associated with elevated calcium levels. However, as stated in the
paper by Block et al (2004), no definitive mortality benefit could
be concluded due to the absence of an interventional trial. The
study sample was restricted to hemodialysis patients which meant
that the extrapolation to peritoneal dialysis patients was
inappropriate.
The main thrust of the application was that lanthanum is
equi-effective to calcium carbonate in controlling serum phosphate
levels and superior to calcium carbonate in avoiding an adverse
effect – hypercalcemia. However, the PBAC was advised the
pivotal efficacy trial, LAM-IV-301, had some unusual and
sub-optimal features that made it difficult to assess the validity
of these claims. Study 301 involved a washout, where participants
stopped their prior phosphate binder, were assessed for
eligibility, randomised and then entered a titration phase of 5
weeks duration. This was followed by a 20 week maintenance phase.
The trial was open, unblinded and used envelopes to determine the
randomisation sequence. There were several potential sources of
bias. In addition, the titration phase (5 weeks) appeared to have
been too short to enable true steady state effects to be achieved
with lanthanum. Participants only entered the maintenance phase if
they achieved the target reduction in phosphate levels, that is,
the maintenance phase involved responders only.
The incidences of treatment emergent adverse events were similar
for patients treated with lanthanum and calcium carbonate or other
standard phosphate binders. There was an increased incidence of
nausea and vomiting, and fewer hypercalcaemic episodes in lanthanum
treated patients. However, only short term safety data were
provided, and lanthanum will be taken longer term. The CARI (Caring
for Australasians with Renal Impairment) guidelines have called for
bone biopsy studies of long-term lanthanum treatment to satisfy
safety concerns. The episodes of hypercalcemia were based on
biochemical measurements only and their true clinical significance
is not established in the trial results.
9. Clinical Claim
The submission claimed that lanthanum offers similar effectiveness
to calcium salts as a phosphate binding agent and has an improved
safety profile.
The PBAC rejected the claim as it was not convinced the trial
presented adequately supported a conclusion of equivalent efficacy
of lanthanum and calcium in reducing PO4 levels. Further, there was
a lack of data to conclusively link detected treatment effects with
subsequent patient relevant outcomes such as a reduction in
mortality.
Full details in the Recommendation and Reasons
10. Economic Evaluation
A preliminary economic evaluation was presented. The choice of the
cost-effectiveness approach was based on an assumption of similar
efficacy in terms of lowered phosphate levels and a lower rate of
hypercalcemia and PBAC considered the first was not demonstrated in
the pivotal clinical trial based on the results after the 5-week
titration period. The resources included were drug costs. The
overall comparative costs and outcomes for each alternative and the
incremental costs and outcomes are summarised below.
The trial-based incremental cost/extra hypercalcaemic episode
avoided over 25 weeks was <$10,000.
A modelled economic evaluation was presented adopting a
cost-utility approach (based on a lower rate of hypercalcemia with
associated improvement in survival).
The model was based on the assumption that phosphate control is
equivalent in patients regardless of whether they receive calcium
or lanthanum and regardless of their initial phosphate level.
(However, as stated above, the PBAC considered the equi-efficacy of
lanthanum and calcium carbonate has not been established.)
The base case modelled incremental discounted cost/extra discounted
QALY gained life-time was $45,000-75,000. The incremental cost per
QALY was highly sensitive to time horizon, The model was most
sensitive to the model duration, the utility value for End Stage
Renal Failure, the annual cost of lanthanum, the targeted calcium
level, and the discounting rates.
11. Estimated PBS Usage and Financial Implications:
The submission estimated the net cost to the PBS would be <$10
million. PBAC considered this was a likely underestimate.
12. Recommendation and Reasons
The PBAC acknowledges there is a high clinical need for phosphate
binders other than calcium for use in the treatment of
hyperphosphataemia in patients with chronic renal failure on
dialysis. However, the Committee had concerns about the clinical
evidence presented in terms of whether it demonstrates that
lanthanum has similar effectiveness to calcium salts in controlling
serum phosphate.
The estimate of the extent of mortality benefit with lanthanum in
the economic model was based solely on the surrogate measure of
serum calcium and used ‘hypercalcemic events’ from the
pivotal clinical trial, LAM-IV-301. These events were classified as
the occurrence of calcium levels above the upper limit of normal;
individuals suffering these events were not necessarily identified
as ill or admitted to hospital and it is not clear whether they
suffered any short or long term harm. This raised concerns, not
whether hypercalcemia has adverse effects, but rather that the
trial outcome has not been shown to be clinically significant in
individual patients. In the hearing, it was acknowledged that there
is currently no controlled prospective evidence that reducing
calcium levels in patients with previously elevated levels leads to
changes in mortality rates. The epidemiological data from Block
(2004), while it established an association between higher serum
calcium and an increased risk of death, did not address this
fundamental issue. Thus it was not possible to establish with
confidence a quantitative link between the extent of a projected
reduction in mortality following any reduction in elevated calcium
levels.
Furthermore, the mean serum calcium levels and their respective
confidence intervals in the calcium treated group (ie. the high
risk group) in trial 301 fell in the range 2.2 – 2.6 mmol/L
(approximately 9.0 to < 10.5 mg/dl). Block et al (2004) found
these levels (or levels of 2.4 to 2.5 mmol/L) to fall within the
non-attributable mortality group. Patients with serum calcium
levels greater than 2.65 mmol/L, ie those targeted by the proposed
PBS listing, were excluded from the trial, so that the trial
population was not representative of the population to be treated
under the PBS.
The post hoc survival analysis on the 2-year safety trial of
LAM-IV-307 showed no significant difference in overall survival
benefits in lanthanum compared to standard therapies but claimed a
benefit in subjects over 65 years. However, this mortality analysis
was possibly subject to a range of biases due to the high and
differential drop-out rates and the unbalanced co-interventions in
the study. These concerns also hampered interpretation of the
indirect comparison of these data with the results of the DCOR
trial of sevelamer.
Another issue that which cast doubt on both the results of the
economic modelling and the submission’s clinical claim of
equi-effectiveness with calcium carbonate in controlling serum
phosphate was that the design of trial 301 was flawed. The
Committee considered that the only valid efficacy analysis from
this trial was PO4 control at the end of the 5-week titration
period. The standard pre-defined Last Observation Carried Forward
(LOCF) analysis, indicated lanthanum is significantly inferior to
calcium carbonate. The “missing=failure” analysis
presented in the pre-PBAC response was a post-hoc analysis and
therefore subject to significant limitations. Overall the Committee
was not convinced that the trial presented adequately supports a
conclusion of equivalent efficacy of lanthanum and calcium
carbonate in reducing PO4.
The PBAC also questioned the appropriateness of the time horizon
for the model in end stage renal failure. The incremental cost per
Quality Adjusted Life Year (QALY) is highly sensitive to the
model’s time horizon. The PBAC considered this ICER to be
unacceptably high and subject to significant uncertainties.
The Committee therefore rejected the submission because of a high
and uncertain cost-effectiveness ratio that primarily resulted from
a lack of data to conclusively link detected treatment effects with
subsequent patient relevant outcomes such as a reduction in
mortality.
The PBAC requested the Secretariat arrange a stakeholder meeting
between the Committee and representatives of the sponsors of all
the new phosphate binder products for use in end stage renal
disease and the relevant peak clinician and consumer
associations.
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 by the PBAC rejection and will continue
to work with the PBAC and clinicians to make PBS-subsidised
Fosrenol available to patients with chronic renal failure on
dialysis.
