Mannitol, capsule containing powder for oral inhalation, 40 mg (for use in inhaler device), Bronchitol® - March 2011
Page last updated: 15 July 2011
Public Summary Document
Product: Mannitol, capsule containing powder for
oral inhalation, 40 mg (for use in inhaler device),
Bronchitol®
Sponsor: Pharmaxis Ltd
Date of PBAC Consideration: March 2011
1. Purpose of Application
The submission sought a Section 100 (Highly Specialised Drug) PBS
listing for the treatment of cystic fibrosis (CF) in both
paediatric (six years and above) and adult populations as either
add on therapy to dornase alfa or in patients intolerant to, or
inadequately responsive to dornase alfa.
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
Mannitol powder for inhalation (Bronchitol®) was TGA
registered on 11 March 2011 for the treatment of cystic fibrosis
(CF) in both paediatric and adult populations six years and above
as either an add-on therapy to dornase alfa or in patients
intolerant to, or inadequately responsive to dornase alfa.
4. Listing Requested and PBAC’s View
The submission proposed two listings, option A and B.
Option A
Section 100 (Highly Specialised Drugs)
Bronchitol is indicated for the treatment of cystic fibrosis (CF)
in both paediatric and adult populations six years and above as
either add-on therapy to dornase alpha or in patients intolerant of
or inadequately responsive to dornase alfa.
Private Hospital Authority Required
Use by cystic fibrosis patients who satisfy all of the following
criteria:
(1) are 6 years of age or older;
(2) have a FEV1 greater than 30% predicted for age, gender and
height
(3) are on dornase alfa or are intolerant or inadequately
responsive to dornase alfa
(4) have evidence of chronic suppurative lung disease (cough and
sputum most days of the week, or greater than 3 respiratory tract
infections of more than 2 weeks' duration in any 12 months, or
objective evidence of obstructive airways disease);
Private hospital authority required
PATIENTS WHO ARE NOT CURRENTLY ON DORNASE ALPHA
Treatment of cystic fibrosis patients who;
- have previously trialled and not met subsidisation criteria for dornase alfa
- Are intolerant to dornase alfa
- Do not continue dornase alfa after clinical assessment
In order for patients to be eligible for participation in the HSD
program, the following conditions must be met:
(1) Patients must be assessed at cystic fibrosis clinics/centres
which are under the control of specialist respiratory physicians
with experience and expertise in the management of cystic fibrosis
and the prescribing of mannitol powder for inhalation therapy under
the HSD program is limited to such physicians. If attendance at
such units is not possible because of geographical isolation,
management (including prescribing) may be by specialist physician
or paediatrician in consultation with such a unit;
(2) The measurement of lung function is to be conducted by
independent (other than the treating doctor) experienced personnel
at established lung function testing laboratories, unless this is
not possible because of geographical isolation;
(3) Prior to mannitol powder for inhalation therapy, a baseline
measurement of FEV1 must be undertaken during a stable
period of the disease;
(4) Patients must be assessed for bronchial hyperresponsiveness as
per TGA approved PI Mannitol Tolerance Test. If the patient has a
positive hyperresponsiveness test they must not be prescribed
Mannitol powder for inhalation. Patients with negative tests may
commence mannitol powder for inhalation therapy.
(5) Initial therapy is limited to 4 weeks' treatment with
Bronchitol at 400 mg BD;
(6) At or towards the end of the initial 4 weeks' trial, patients
must be reassessed and a further FEV1 measurement be
undertaken (single test under conditions as above). Patients who
achieve a 10% or greater improvement in FEV1 (compared
to baseline established prior to mannitol for inhalation treatment)
are eligible for continued subsidy under the HSD program at a dose
of 400mg BD;
(7) Patients who fail to meet a 10% or greater improvement in
FEV1 after the initial 4 weeks' treatment at a dose of
400mg BD, may have 1 further trial in the next 12 months but not
before 3 months after the initial trial;
(8) Following an initial 6 months' therapy, a global assessment
must be undertaken involving the patient, the patient's family (in
the case of paediatric patients) and the treating physician(s) to
establish that all agree that mannitol powder for inhalation
treatment is continuing to produce worthwhile benefits. (Mannitol
powder for inhalation therapy should cease if there is not general
agreement of benefit as there is always the possibility of harm
from unnecessary use.) Further reassessments are to be undertaken
at six-monthly intervals;
(9) Other aspects of treatment, such as physiotherapy, must be
continued;
(10) Where there is documented evidence that a patient already
receiving mannitol powder for inhalation therapy would have met the
criteria for subsidy (i.e. satisfied the criteria for the 4 week
trial and achieved a 10% or greater improvement in FEV1)
then the patient is eligible to continue treatment under the HSD
program. Where such evidence is not available, patients will need
to satisfy the initiation and continuation criteria as for new
patients. (Four weeks is considered a suitable wash-out
period).
Note:
It is highly desirable that all patients be included in the
national cystic fibrosis patient data-base.
Private hospital authority required
TREATMENT OF CYSTIC FIBROSIS PATIENRS CURRENTLY TAKING DORNASE
ALFA
In order for patients to be eligible for participation in the HSD
program, the following conditions must be met:
(1) Patients must have been taking dornase alfa for at least 6
months;
(2) Following an initial 6 months' therapy of dornase alfa, a
global assessment must be undertaken involving the patient, the
patient's family (in the case of paediatric patients) and the
treating physician(s) to establish that all agree that greater
improvement in FEV1 could be achieved with the addition
of mannitol powder for inhalation. (Mannitol powder for inhalation
therapy should not be commenced if there is not general agreement
that greater FEV1 improvement could be attained or if
there is a possibility of harm from unnecessary use.) Further
reassessments are to be undertaken at six-monthly intervals;
(3) The measurement of lung function is to be conducted by
independent (other than the treating doctor) experienced personnel
at established lung function testing laboratories, unless this is
not possible because of geographical isolation;
(4) Prior to mannitol for inhalation therapy, a baseline
measurement of FEV1 must be undertaken during a stable period of
the disease;
(5) Patients must be assessed for bronchial hyperresponsiveness as
per TGA approved PI Mannitol Tolerance Test. If the patient is
hyperresponsive to mannitol they must not be prescribed Mannitol
powder for inhalation. Patients with negative tests may commence
mannitol powder for inhalation therapy.
(6) Initial therapy is limited to 4 weeks' treatment with
Bronchitol at 400mg BD;
(7) At or towards the end of the initial 4 weeks' trial, patients
must be reassessed and a further FEV1 measurement be
undertaken (single test under conditions as above). Patients who
achieve a 10% or greater improvement in FEV1 (compared to first
line dornase alfa therapy [established prior to mannitol for
inhalation treatment]) are eligible for continued subsidy under the
HSD program at a dose of 400mg BD;
(8) Patients who fail to meet a 10% or greater improvement in
FEV1 (compared to first line dornase alpha therapy
baseline after the initial 4 weeks' treatment at a dose of 400mg
BD, may have 1 further add on trial in the next 12 months but not
before 3 months after the initial trial;
(9) Other aspects of treatment, such as physiotherapy, must be
continued;
Note: It is highly desirable that all patients be included in the
national cystic fibrosis patient data-base.
Option B
Section 100 (Highly Specialised Drugs)
Bronchitol is indicated for the treatment of cystic fibrosis (CF)
in both paediatric and adult populations six years and above s
either add-on therapy to dornase alpha or in patients intolerant of
or inadequately responsive to dornase alfa.
Private Hospital Authority Required
Use by cystic fibrosis patients who satisfy all of the following
criteria:
(1) are 6 years of age or older;
(2) are on dornase alfa or are intolerant or inadequately
responsive to rhDNase
Private hospital authority required
PATIENTS WHO ARE NOT CURRENTLY ON DORNASE ALPHA
Treatment of cystic fibrosis patients who;
- have previously trialled and not met subsidisation criteria for Dornase alpha
- are intolerant to dornase alfa
- do not continue dornase alfa after clinical assessment
In order for patients to be eligible for participation in the HSD
program, the following conditions must be met:
(1) Patients must be assessed at cystic fibrosis clinics/centres
which are under the control of specialist respiratory physicians
with experience and expertise in the management of cystic fibrosis
and the prescribing of mannitol powder for inhalation therapy under
the HSD program is limited to such physicians. If attendance at
such units is not possible because of geographical isolation,
management (including prescribing) may be by specialist physician
or paediatrician in consultation with such a unit;
(2) The measurement of lung function is to be conducted by
independent (other than the treating doctor) experienced personnel
at established lung function testing laboratories, unless this is
not possible because of geographical isolation;
(3) Patients must be assessed for bronchial hyperresponsiveness as
per TGA approved PI Mannitol Tolerance Test. If the patient has a
positive hyperresponsiveness test they must not be prescribed
Mannitol powder for inhalation. Patients with negative tests may
commence mannitol powder for inhalation therapy.
(4) Following an initial 6 months' therapy, a global assessment
must be undertaken involving the patient, the patient's family (in
the case of paediatric patients) and the treating physician(s) to
establish that all agree that mannitol powder for inhalation
treatment is continuing to produce worthwhile benefits. (Mannitol
powder for inhalation therapy should cease if there is not general
agreement of benefit as there is always the possibility of harm
from unnecessary use.) Further reassessments are to be undertaken
at six-monthly intervals;
(5) Other aspects of treatment, such as physiotherapy, must be
continued.
Note:
It is highly desirable that all patients be included in the
national cystic fibrosis patient data-base.
Private hospital authority required
TREATMENT OF CYSTIC FIBROSIS PATIENTS CURRENTLY TAKING DORNASE
ALFA
In order for patients to be eligible for participation in the HSD
program, the following conditions must be met:
(1) Patients must have been taking dornase alfa for at least 6
months;
(2) Following an initial 6 months' therapy of dornase alfa , a
global assessment must be undertaken involving the patient, the
patient's family (in the case of paediatric patients) and the
treating physician(s) to establish that all agree that greater
improvement in FEV1 could be achieved with the addition
of mannitol powder for inhalation. (Mannitol powder for inhalation
therapy should not be commenced if there is not general agreement
that greater FEV1 improvement could be attained or if
there is a possibility of harm from unnecessary use.) Further
reassessments are to be undertaken at six-monthly intervals;
(3) The measurement of lung function is to be conducted by
independent (other than the treating doctor) experienced personnel
at established lung function testing laboratories, unless this is
not possible because of geographical isolation;
(4) Patients must be assessed for bronchial hyperresponsiveness as
per TGA approved PI Mannitol Tolerance Test. If the patient is
hyperresponsive to mannitol they must not be prescribed Mannitol
powder for inhalation. Patients with negative tests may commence
mannitol powder for inhalation therapy.
(5) Other aspects of treatment, such as physiotherapy, must be
continued.
Note: It is highly desirable that all patients be included in the
national cystic fibrosis patient data-base.
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
Cystic fibrosis (CF) is a common hereditary disease which affects
the entire body, causing progressive disability and often early
death. CF is caused by a mutation in the gene for the protein
cystic fibrosis transmembrane conductance regulator (CFTR). This
gene is required to regulate the components of sweat, digestive
juices, and mucus.
The aim of treatment of CF is to alleviate symptoms, improve
quality of life and to slow the decline in lung function. This is
achieved by improving airway clearance, by eradicating or
suppressing the growth of bacterial pathogens and attenuating
airway inflammation.
By mid childhood, most patients have increased airway secretions,
and enhancing mucus clearance is a major goal of therapy. Several
strategies have been proven to be effective, including
physiotherapy, local hydration with inhaled moisture, enzymes to
break down the inflammatory cell products, anti-inflammatory agents
and aggressive treatment of bacterial infections. In a proportion
of patients, mucolytic agents are prescribed. Currently dornase
alfa is the only mucolytic agent subsidised on the PBS for use in
CF.
The submission proposed that the place in therapy of mannitol
powder for inhalation is either as add on therapy to dornase alfa
or as an alternative therapy for patients 6 years of age or older
intolerant or inadequately responsive to dornase alfa.
6. Comparator
The submission presented two comparators for dry powder for inhalation (DPI) mannitol based on whether DPI mannitol is used as a monotherapy or add-on therapy:
- For patients who are intolerant or unresponsive to dornase alfa the submission nominated a comparison between DPI mannitol monotherapy vs. re-trial with dornase alfa.
This was not accepted by the PBAC.
- For patients who have an inadequate response to dornase alfa the submission nominated a comparison between dornase alfa plus DPI mannitol add-on therapy vs. dornase alfa alone.
For PBAC’s view, see Recommendation and
Reasons.
7. Clinical Trials
The submission presented one head-to-head cross-over trial of DPI
mannitol vs. dornase alfa vs. DPI mannitol and dornase alfa
combination in children with cystic fibrosis (CF-203, n=26)).
The submission also presented two trials of DPI mannitol vs. a
sub-therapeutic dose of mannitol as control (CF-301, n=295; CF-302,
n=305) and one trial of dornase alfa vs placebo (Fuchs et al
1994) in children and adults with cystic fibrosis.
For the comparison of DPI mannitol as add-on to dornase alfa vs
dornase alfa alone, trials CF-301/CF-302 included predefined
subgroup analyses of patients on concomitant use of dornase alfa;
ie those patients on dornase alfa at baseline continue to use
dornase alfa during the trial.
The table below details the published trials presented in the
submission:
Trial ID/ First author | Protocol title/ Publication title | Publication citation |
DPI mannitol vs. dornase alfa vs. DPI mannitol/dornase alfa combination | ||
CF-203, Minasian et al. | Comparison of inhaled mannitol, daily rhDNase and a combination of both in children with cystic fibrosis: A randomised trial. | Thorax, 2010, 65(1): 51-56 |
Dornase alfa vs. placebo | ||
Fuchs | Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. The Pulmozyme Study Group. | The New England Journal of Medicine, 1994, 331(10): 637-42 |
Shak | Aerosolized recombinant human DNase I for the treatment of cystic fibrosis. | Chest 107(2 Suppl), 1995: 65s-70s |
Oster et al . | Effects of recombinant human DNase therapy on healthcare use and costs in patients with cystic fibrosis. | The Annals of Pharmacotherapy, 1995, 29(5): 459-64 |
8. Results of Trials
Direct comparison (CF-203, n=26)
Based on the key
outcomes (FEV1, protocol defined pulmonary exacerbation
(PDPE) events and quality of life(QOL)) reported in the
head-to-head cross-over trial of DPI mannitol vs. dornase alfa vs.
DPI mannitol/dornase alfa combination (CF-203) the PBAC noted that
there were no statistically significant differences in lung
function (as measured by FEV1 and FVC,
FEV1/FVC, FEF25-75, PEF), PDPE events or
respiratory quality of life scores between treatment groups.
The PBAC acknowledged that trial CF-203 was underpowered and the
larger trials of CF-301/CF-302, which had subgroups of patients on
either both treatments or mannitol monotherapy, did not show a
consistent trend of patients performing worse when the using
mannitol in combination with dornase alfa, the benefit of mannitol
as an add-on therapy remains uncertain.
DPI mannitol vs. control (sub-therapeutic mannitol) (CF-301/CF-302)
The main FEV1 results from the CF-301/CF-302 trials were
reported as either the mean change from baseline to Week 26 or as
the overall change from baseline averaged over the Week 6, 14 and
26 time points. The submission presented both sets of results and a
meta-analysis using the mean change in FEV1 from
baseline to Week 26. For consistency, the meta-analysis was
conducted during the evaluation using the overall change (Week
6-26) in FEV1 from baseline.
The PBAC noted that DPI mannitol was associated with statistically
significant short-term (26 week) improvements in lung function
(FEV1) compared to control in the total CF-301/CF-302
populations (approximately 2-4% absolute FEV1
improvement depending on measure).
The key spirometry outcomes reported in the dornase alfa
users/non-users subgroups of the DPI mannitol vs. control trials
(CF-301, CF-302) showed that DPI mannitol treatment was associated
with a statistically significant improvement in lung function
compared to control both in patients receiving concomitant dornase
alfa (overall FEV1 change 3.20%, p = 0.014) and in
patients not receiving concomitant dornase alfa (overall
FEV1 change 4.65%, p = 0.007).
The key clinical outcomes reported in the total populations of the
DPI mannitol vs. control trials (CF-301, CF-302) were mean
annualised rate of PDPE and PE events per patient.
The PBAC noted that there were no statistically significant
differences in exacerbation rates, use of rescue antibiotics or
hospitalisations between DPI mannitol and control in the
CF-301/CF-302 populations. There was also no statistically
significant difference in exacerbation rates between DPI mannitol
and control in patients using concomitant dornase alfa.
DPI mannitol treatment was associated with a statistically
significant decrease in protocol defined pulmonary exacerbation
(PDPE) rates compared to control in patients that were not using
concomitant dornase alfa (rate ratio 0.48; 95% CI 0.23, 0.99),
although the wide confidence intervals raise uncertainty on the
magnitude of effect. There was no statistically significant
difference in PE rates between treatment groups.
The sponsor provided in its Pre-PBAC response an analysis of the
proportion of patients with PDPE events for the pooled data of
CF-301 and CF-302 (to allow comparison to other studies).
Indirect comparison (CF-301/CF-302 vs. Fuchs 1994)
The outcomes of the indirect comparison are change in
FEV1 (%) from baseline and risk of PDPE events.
Based on the indirect analyses, the submission claimed DPI mannitol
and dornase alfa were comparable in terms of improving lung
function and reducing the risk of exacerbations.
The PBAC noted that the outcome of change in FEV1 from
baseline differed between trials. Results from the CF-301 and
CF-302 trials were based on the mean change in FEV1 from
baseline to Week 26 (end of the study) while the results from the
Fuchs et al (1994) trial were based on the overall change in
FEV1 from baseline averaged across multiple time points
throughout the study (4, 8, 12, 16, 20 and 24 weeks).
The outcome of risk of PDPE events differed between trials. Results from the CF-301 and CF-302 are based on the annualised rate of PDPE events while the results from the Fuchs et al (1994) trial are based on the proportion of patients with PDPE events adjusted for baseline differences in age between treatment arms.
The PBAC also noted the common comparator arms were not the
same; the DPI mannitol trials (CF-301/CF-302) had sub-therapeutic
dose of mannitol in the control arm and potential concomitant use
of dornase alfa, whereas the dornase alfa trial (Fuchs) had a
placebo control.
For PBAC’s view, see Recommendation and
Reasons.
The PBAC noted that similar proportions of patients in the DPI
mannitol and control (sub-therapeutic mannitol) treatment arms
experienced adverse events during the CF-301/CF-302 trials.
Patients were more likely to experience treatment-related events in
the DPI mannitol arm (mainly cough and haemoptysis) compared to
control. In the CF-301 trial, DPI mannitol was associated with a
higher incidence of withdrawals due to adverse events compared to
placebo (16% vs. 8%). There were no published long-term safety data
on DPI mannitol beyond the 6 month timeframe of the clinical
trials.
Adverse events associated with dornase alfa include: voice
alteration, rash, haemoptysis, dyspnoea, pharyngitis and
laryngitis. There were insufficient data to assess whether DPI
mannitol and dornase alfa have comparable safety profiles.
9. Clinical Claim
Monotherapy for patients who are intolerant or unresponsive to dornase alfa (comparator retrial of dornase alfa):
The submission claimed DPI mannitol as being similarly effective to
dornase alfa with a similar safety profile to dornase alfa.
Add-on therapy to dornase alfa for patients who have an inadequate response to dornase alfa (comparator is placebo as add-on to dornase alfa):
The submission claimed that DPI mannitol is more effective than
placebo/control at improving FEV1 outcomes in subjects with cystic
fibrosis either as monotherapy or when used in combination with
dornase alfa. DPI mannitol had higher rates of adverse
events related to treatment and higher rates of withdrawal due to
adverse events than placebo/control.
For the PBAC’s view, see Recommendation and
Reasons.
10. Economic Analysis
The submission presented two economic evaluations:
Monotherapy:
- A cost-minimisation analysis of DPI mannitol monotherapy compared to dornase alfa.
Add-on:
- A modelled cost utility analysis of dornase alfa with DPI mannitol add-on therapy compared with dornase alfa alone.
Cost minimisation (DPI mannitol monotherapy vs. dornase alfa monotherapy)
The submission claimed that DPI mannitol (400 mg twice a day) is
equivalent to dornase alfa (2.5 mg once a day) based on the daily
dose used in the included trials.
The comparative cost of DPI mannitol was less than dornase
alfa.
Cost effectiveness (dornase alfa with DPI mannitol add-on therapy vs. dornase alfa)
The submission presented an economic model that compared the costs
and health outcomes associated with usual care, DPI mannitol alone,
dornase alfa alone, and the combination of DPI mannitol with
dornase alfa in patients with cystic fibrosis.
The submission assumed that the combined results of the control
arms of studies CF-301/CF-302 (which compared DPI mannitol to
sub-therapeutic mannitol) could represent the efficacy of dornase
alfa alone in the economic model.
The economic model assumed that the short-term (26 week)
improvement in lung function (FEV1) associated with DPI
mannitol treatment compared to control would be maintained beyond
the clinical trial duration.
The model assumed that DPI mannitol treatment would reduce
exacerbations compared to control. The risk of exacerbations was a
key driver of the economic model. An incremental cost per quality
adjusted life year gained was calculated to be between
$45,000-$75,000.
The results of the sensitivity analyses indicated that the model
was most sensitive to continuation rules, price of DPI mannitol and
the risk of exacerbations. The sensitivity analyses presented in
the submission suggested that removing the continuation rule or
increasing the requirement to a 10% FEV1 improvement
will lead to higher ICERs compared to the base case (5%
FEV1 improvement).
The PBAC noted that the clinical trial data presented in the
submission did not show a statistically significant reduction in
exacerbations with DPI mannitol add-on therapy. Assuming that
patients treated with DPI mannitol have the same risk of
exacerbation as control patients this increased the ICER from to
between $75,000-$105,000 per QALY.
For PBAC’s view, see Recommendation and
Reasons.
11. Estimated PBS Usage and Financial Implications
The financial cost per year to the PBS was estimated by the
submission to be less than $10 million in the fifth year of
listing. The PBAC considered this an overestimate as the submission
did not include the proposed continuation rules in its estimates
and did not include any cost-offsets due to drug
substitution.
12. Recommendation and Reasons
The PBAC considered the clinical place of mannitol was uncertain.
The PBAC noted a clinician’s comments at the hearing
regarding the place of mannitol in CF therapy. The
clinician’s comments did not support the pre-PBAC response
which suggested that the place of mannitol would be as a
‘last resort’ when other treatment options had failed.
The clinician suggested that a PBS listing for mannitol was
appealing as it provides a unique option for treatment of CF which
does not require nebulisation. Whilst sympathetic with the notion
of CF patients looking for alternatives to nebulised forms of
treatment, the PBAC considered the twice daily regimen for mannitol
of 10 capsules via inhaler, with 5-15minutes of bronchodilator
prior to use, was complex and intensive, particularly for children,
and could possibly result in reduced compliance.
The ACPM recommendation for use of mannitol in second-line reflects
the sponsor’s proposed listing, however, trial data show
there may be broader use for mannitol in CF.
The proposed comparator of a re-trial of dornase alfa, in patients
intolerant or unresponsive to dornase alfa, was not accepted.
Patients not responding to dornase alfa would not be likely to try
it again, nor would they qualify under the continuation criteria
for dornase alfa. Placebo, or hypertonic saline should have been
considered relevant comparators. The clinician considered mannitol
to be sufficiently different to hypertonic saline due to the
different forms of administration. However, the PBAC did not accept
the unique delivery mechanism of mannitol as a sufficient reason to
exclude hypertonic saline as a relevant comparator.
The PBAC questioned the applicability of the trial populations to
the proposed PBS listings and overall, considered the evidence to
support the proposed listings was uncertain. Dornase alfa and
mannitol have separate mechanisms of action. The PBAC was not
convinced that combination use of these drugs would not lead to
worse outcomes. Although acknowledging that trial CF-203 was
underpowered and the larger trials of CF-301/CF-302, which had
subgroups of patients on either both treatments or mannitol
monotherapy, did not show a consistent trend of patients performing
worse when the using mannitol in combination with dornase alfa, the
benefit of mannitol as an add-on therapy remains uncertain. Trial
data also did not support the monotherapy listing for patients who
had failed to achieve an adequate response to dornase alfa. The
indirect comparison with Fuchs (1994) is highly uncertain because
of a lack of exchangeability and differences in the outcome
measures between the trials.
There were no statistically significant differences in exacerbation
rates, use of rescue antibiotics, or hospitalisations between
mannitol and control in CF-301/CF-302 populations. There was also
no statistically significant difference in exacerbation rates
between mannitol and control in patients using concomitant dornase
alfa.
The economic model to support the proposed add-on restriction
resulted in a high and uncertain ICER. The model was dependent on a
number of assumptions (e.g. reduction in exacerbation events,
maintenance of treatment effect) that were not well justified in
the submission. The key source of uncertainty was the use of
different exacerbation rates between mannitol and control in the
model when this was not demonstrated to be statistically
significant in the trials. Given the use of dornase alfa in some,
but not all patients in the two key trials, the data used in the
model was not appropriate.
The cost-minimisation in the monotherapy setting remained highly
uncertain, even with the offer a lower price than dornase
alfa.
The PBAC therefore rejected the submission because the comparator
when dornase alfa has failed was inappropriate and because of
uncertain effectiveness and resulting uncertain cost effectiveness,
when used in combination with dornase alfa.
The PBAC also acknowledged and noted the consumer comments on this
item.
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
Pharmaxis believes that a lack of available prescribing data has
lead to misunderstandings and incorrect conclusions on how existing
therapies are used in cystic fibrosis. Pharmaxis is now working
with the CF community to provide evidence on current use of CF
treatments to allow a better assessment of the true place of
Bronchitol in therapy, and an appropriate comparator for patients
who are not responding to currently available treatments.