Mannitol, capsule containing powder for oral inhalation, 40 mg (for use in inhaler device), Bronchitol® - November 2011
Page last updated: 02 March 2012
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: November 2011
1. Purpose of Application
The submission requested an Authority Required listing for the treatment of cystic fibrosis (CF):
- as an alternative to dornase alfa in a patient who has previously failed PBS-subsidised initiation criteria for dornase alfa; OR
- as a monotherapy alternative to dornase alfa in a patient who has discontinued dornase alfa despite a previous successful trial and is considering recommencing therapy; OR
- as a monotherapy alternative to dornase alfa in a patient currently on dornase alfa or where a change of therapy might improve outcome based on clinical global assessment.
2. Background
At the March 2011 meeting, the PBAC 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 considered the clinical place of mannitol was uncertain
and questioned the applicability of the trial populations to the
proposed PBS listings and overall, considered the evidence to
support the proposed listings was uncertain. 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.
The PBAC noted that the cost-minimisation in the monotherapy
setting remained highly uncertain, even with the offer of a lower
price than dornase alfa.
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.
Mannitol powder for inhalation was designated an orphan drug by the
TGA on
16 April 2009 for use in the treatment of patients with cystic
fibrosis to improve lung function and reduce pulmonary
exacerbations.
4. Listing Requested and PBAC’s View
The submission proposed two listings, Option A and B.
Option A
Bronchitol is indicated for the treatment of cystic fibrosis (CF) in both paediatric
and adult populations six years and above 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 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 ALFA
Treatment of cystic fibrosis patients who;
i. have previously trialled and not met subsidisation criteria for Dornase alfa
ii. Are intolerant to dornase alfa
iii. 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 Bronchitol Initiation Dose Assessment. 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 400mg 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 Section 85 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 Section 85. 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 PATIENTS CURRENTLY TAKING DORNASE ALFA
In order for patients to be eligible for participation in Section 85, 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 by switching to mannitolpowder 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 Bronchitol 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 Section 85 at a dose of 400mg BD;
(8) Patients who fail to meet a 10% or greater improvement in FEV1 (compared to first line dornase alfa 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
Bronchitol is indicated for the treatment of cystic fibrosis (CF) in both paediatric
and adult populations six years and above 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) or are intolerant or inadequately responsive to dornase alfa
Private Hospital Authority Required
PATIENTS WHO ARE NOT CURRENTLY ON DORNASE ALFA
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 Section 85, 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 Section 85 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 Bronchitol 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 Section 85, 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 Bronchitol 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 mucous.
The aim of treatment of CF is to alleviate symptoms, improve quality of life and to
slow the decline in lung function by improving airway clearance, 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 for patients 6 years of age or older who are intolerant or inadequately responsive
to dornase alfa.
The PBAC agreed there is a clinical need for additional treatment options for patients
with CF, however further consultation with clinicians is required to ascertain the
appropriate clinical place in therapy of mannitol.
6. Comparator
The submission nominated dornase alfa as the comparator. This was not accepted by the PBAC in March 2011. The submission presented new sources of evidence to support its choice of comparator as follows:
- Further background on the burden of treatment in CF and the need for an alternative to dornase alfa.
- Evidence from the BIOGRID dataset that patients taking dornase alfa do have ‘on’ and ‘off’ treatment episodes.
- Hypertonic saline manufacturing data for Australia.
- Physician Survey data of dornase and hypertonic saline use in 8 out of 19 Australian CF clinics (treating more than 50% of Australian CF patients aged over 6 years).
The PBAC noted that dornase alfa, the comparator in the
re-submission, was unchanged from the previous submission. The PBAC
considered this to be inappropriate and that hypertonic saline or
usual care (placebo) are appropriate comparators. The PBAC
considered that there could be some substitution of dornase alfa by
mannitol, and hence dornase alfa as part of a mixed comparison may
be reasonable.
7. Clinical Trials
The re-submission presented four studies that were included in the March 2011 submission:
- one head-to-head trial comparing three treatment arms (dry powder inhaler (DPI) mannitol vs. dornase alfa vs. DPI mannitol plus dornase alfa combination) in children with cystic fibrosis (CF-203);
- two trials of DPI mannitol vs. control (sub-therapeutic mannitol) (CF-301, CF-302);
- one trial of dornase alfa vs placebo (Fuchs et al 1994) in children and adults with cystic fibrosis.
The re-submission also presented new results from unpublished
open-label extensions of the CF-301 (up to 78 weeks follow-up) and
CF-302 (up to 52 weeks follow-up) trials.
Details of the studies published at the time of submission are
shown in the table below:
| Trial ID / First author | Protocol title / Publication title | Publication citation |
|---|---|---|
| Mannitol vs. Dornase alfa | ||
| DPM-CF-203 2008 | ||
| Minasian et al. 2010 | Comparison of inhaled mannitol, daily rhDNase and a combination of both in children with cystic fibrosis: a randomised trial | Thorax 65(1): 51-6 |
| Mannitol vs placebo | ||
| DPM-CF-301 2009 | ||
| Bilton D et al Investigators 2011 | Inhaled dry powder mannitol in cystic fibrosis: an efficacy and safety study | ERJ 2011(published ahead of print on April 8 2011). |
| Bilton et al 2009 | Randomized, double blind, placebo-controlled phase III study of inhaled dry powder mannitol (bronchitol) in CF [abstract] | Pediatric Pulmonology 44 Suppl 32: 286, Abstract no: 216. |
| Bilton et al 2009 | Randomised, double-blind, placebo-controlled phase III study of inhaled dry powder mannitol in cystic fibrosis [Abstract]. | European Respiratory Society Annual Congress, Vienna, Austria, September 12 16: [1619] |
| Bilton et al 2009. | Randomised, double blind, placebo-controlled phase III study of bronchitol (inhaled powder mannitol) in Cystic Fibrosis CF [abstract]. | Journal of Cystic Fibrosis 8 Suppl 2: S25, Abstract no: 95. |
| DPM-CF-302 2008 | ||
| Aitken ML et al 2010 | Six-month administration of inhaled mannitol in cystic fibrosis - A safety and efficacy study | Pediatric Pulmonology 2010; 45:SUPPL. 33 (299). |
| Dornase alfa versus placebo | ||
| Fuchs et al. 1994 | 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 331(10): 637-42 |
| Also published as: | ||
| Shak 1995 | Aerosolized recombinant human DNase I for the treatment of cystic fibrosis | Chest 107(2 Suppl): 65s-70s |
| Oster et al 1995 | Economic analysis: Effects of recombinant human DNase therapy on healthcare use and costs in patients with cystic fibrosis | The Annals of pharmacotherapy 29(5): 459-64. |
8. Results of Trials
The re-submission primarily focused on forced expiratory volume in first second of
expiration (FEV1) and exacerbation (PDPE, protocol-defined pulmonary exacerbation) outcomes in the
non-dornase user subgroups of the CF-301/CF-302 trials as these measures are used
in an indirect comparison of DPI mannitol and dornase alfa.
The key FEV1 outcomes reported in the DPI mannitol vs. control trials (CF-301, CF-302) are shown
in the following table:
Key FEV1 outcomes reported in the DPI mannitol vs. control trials (CF-301, CF-302)
| Trial ID | DPI mannitol | Control (sub mannitol) | Treatment effect |
|---|---|---|---|
| Overall change ( Week 6-26) i n FEV 1 (mL) from baseline (95% CI) | |||
| CF-301 non-dornase user (N = 132) | 152.80 (106.87, 198.73) | 48.46 (-4.35, 101.27) | 104.34 (36.08, 172.61) |
| CF-302 non-dornase user (N = 76) | 142.31 (69.62, 215.00) | 55.81 (-32.86, 144.48) | 86.50 (-23.78, 196.79) |
| Pooled analysis of dornase alfa non-users | 96.50 (34.92, 158.07) | ||
| Overall change (Week 6-26) in FEV 1 (%) from baseline (95% CI) | |||
| CF-301 non-dornase user (N = 132) | 8.02 (5.46, 10.58) | 3.51 (0.54, 6.48) | 4.52 (0.65, 8.38) |
| CF-302 non-dornase user (N = 76) | 10.43 (6.04, 14.82) | 5.27 (-0.10, 10.63) | 5.16 (-1.51, 11.84) |
| Pooled analysis of dornase alfa non-users | 4.88 (1.24, 8.51) | ||
| Overall change (Week 6-26) in FEV 1 (% predicted) from baseline (95% CI) | |||
| CF-301 non-dornase user (N = 132) | 3.75 (2.35, 5.14) | 1.16 (-0.44, 2.76) | 2.59 (0.50, 4.67) |
| CF-302 non-dornase user (N = 76) | 4.51 (2.07, 6.95) | 1.73 (-1.26, 4.73) | 2.78 (-0.94, 6.50) |
| Pooled analysis of dornase alfa non-users | 2.63 (0.61, 4.64) | ||
Abbreviations: CI, confidence interval; FEV1, forced expiratory volume in first second
of expiration
DPI mannitol was generally associated with modest improvements in lung function (FEV1) compared to control (difference of 4.88%; 95% CI 1.24%, 8.51%) in non-dornase users
that was sustained over the 26 weeks of the studies. This improvement was statistically
significant in the CF-301 trial and the pooled analysis but did not reach statistical
significance in the CF-302 trial. The clinical importance of these changes in FEV1 is unclear as the subjects had mean baseline FEV1 around 65% of predicted values. The European Medicines Agency (EMA) recently raised
concerns that the improvement in FEV1 seen with DPI mannitol treatment may not be sufficient to improve the patients’ condition.
The EMA also raised concerns that the improvement in FEV1 was not consistent across all age groups (Bronchitol fact sheet, EMA/CHMP/474477/2011;
EMEA/H/C/0012, 23rd June 2011)
Data from the open-label extensions suggested that FEV1 improvements seen during the double-blind phase of the trials (26 weeks) may be maintained
for at least 52 weeks. Patients previously treated with the control in the double-blind
phase achieved similar FEV1 results to the active treatment group when switched to DPI mannitol.
The re-submission acknowledged that both the CF-301 and CF-302 trials reported differential
discontinuations between the DPI mannitol and control arms (CF-301: 34% vs. 25%; CF-302:
16% vs. 11%, respectively). Adverse events and withdrawal of consent appeared to be
the main reasons for the difference in discontinuations. To address the potential
impact of patient dropouts on the estimated treatment effect the re-submission presented
multiple post-hoc analyses of FEV1 outcome data from the CF-301 and CF-302 trials using various imputation methods.
The re-submission claimed that the consistency of treatment effects across imputation
methods demonstrated the validity of the methods used in the primary FEV1 analyses.
The key exacerbation outcomes reported in the DPI mannitol vs. control trials (CF-301,
CF-302) are shown in the following table:
Key exacerbation outcomes reported in the DPI mannitol vs. control trials (CF-301,
CF-302)
| Outcome | DPI mannitol | Control (sub mannitol) | Rate Ratio (95% CI) | Hazard ratio (95% CI) |
|---|---|---|---|---|
| Proportion of patients with PDPE events [n/N (%)] | ||||
| CF-301 non-dornase users | 10/81 (12.3) | 12/51 (23.5) | 0.59 (0.24, 1.47) | 0.59 (0.25, 1.38) |
| CF-302 non-dornase users | 4/47 (8.5) | 7/29 (24.1) | 0.34 (0.10, 1.09) | NR |
| Pooled analysis of dornase alfa non-users | 0.58 (0.31, 1.07) | 0.44 (0.21, 0.94) | ||
Abbreviations: NR, not reported; PDPE, protocol-defined pulmonary exacerbations
Individually, neither of the key trials demonstrated a statistically significant reduction
in exacerbations with DPI mannitol therapy compared to control. A pooled analysis
of non-dornase users suggested that DPI mannitol may reduce the risk of pulmonary
exacerbations (HR 0.44, 95% CI 0.21, 0.94) however the pooled rate ratio did not reach
statistical significance (RR 0.58, 95% CI 0.31, 1.07). These estimates were based
on limited patient numbers with a small number of events and there are wide confidence
intervals around each estimate. The re-submission did not address the potential impact
of differential discontinuations on exacerbation outcomes which may limit the validity
of the results.
The main analysis in the re-submission was an indirect comparison of the pooled DPI
mannitol results (CF-301, CF-302) against dornase alfa (Fuchs et al 1994) using the
control/placebo arms as a common comparator.
It should be noted that the DPI mannitol trials used a sub-therapeutic dose of mannitol
in the control arm, whereas the dornase alfa trial were placebo-controlled.
A summary of the pooled DPI mannitol results (CF-301, CF-302) against dornase alfa
(Fuchs et al 1994) using the control/placebo arms as a common comparator is shown
in the following table:
Summary of results from the indirect comparison
| Trial | DPI mannitol | Control/ Placebo | Dornase alfa | Treatment effect (95% CI) |
|---|---|---|---|---|
| Overall change in FEV 1 (%) from baseline | ||||
| CF-301/CF-302 (non-dornase users) | 9.4 (13.9) | 4.6 (13.1) | - | 4.9 (1.1, 8.7) |
| Fuchs (1994) | - | 0 (10.8) | 5.8 (12.6) | 5.8 (4.0, 7.6) |
| Indirect estimate of effect [mean difference (95% CI)] | -0.9 (-5.1, 3.3) | |||
| Proportion of patients with PDPE events [n/N, (%)] | ||||
| CF-301/CF-302 (non-dornase users) | 14/128 (10.9%) | 19/80 (23.8%) | - | RR: 0.39 (0.21, 0.73) |
| OR: 0.31 (0.14, 0.67) | ||||
| HR: 0.44 (0.21, 0.94) | ||||
| Fuchs (1994) | - | 89/325 (27.4%) | 71/322 (22.0%) | RR: 0.81 (0.61, 1.06) |
| OR: 0.75 (0.52, 1.07) | ||||
| HR: 0.78 (0.57, 1.06) a | ||||
| Indirect estimate of effect (95% CI) | RR: 0.49 (0.25, 0.96) | |||
| OR: 0.41 (0.18, 0.97) | ||||
| HR: 0.56 (0.25, 1.27) | ||||
Abbreviations: CI, confidence interval; FEV1, forced expiratory volume in one second;
HR, hazard ratio; OR, odds ratio; PDPE, protocol defined pulmonary exacerbation; RR,
relative risk Note: Difference in FEV1 treatment effect > 0 favours DPI mannitol
The indirect analysis did not demonstrate any statistically significant difference
in FEV1 outcomes between DPI mannitol and dornase alfa. DPI mannitol treatment was associated
with a statistically significant reduction in exacerbations compared to dornase alfa
in terms of relative risk and odds ratio but not hazard ratio. Based on the indirect
analyses, the re-submission claimed that both DPI mannitol and dornase alfa are comparable
in terms of improving lung function and reducing the risk of exacerbations. However,
the PBAC considered it is unclear whether the study populations are sufficiently similar
to justify an indirect analysis.
Patients in the non-dornase user subgroups of the CF-301 and CF-302 trials were generally
older (23-24 years) with better lung function (FEV1 approximately 65% of predicted) compared to patients enrolled in the Fuchs et al
(1994) trial (age approximately 18-19 years, FEV1 approximately 60% of predicted). Additionally, it is likely that the clinical management
of cystic fibrosis patients has changed over time given that the dornase alfa trial
was conducted approximately 10-15 years before the DPI mannitol trials. Improvements
in lung function and a reduction in exacerbations shown with DPI mannitol were achieved
on top of these changes in treatment practices, including high levels of inhaled antibiotics.
Finally, the DPI mannitol trials reported relatively high discontinuation rates (approximately
30% in CF-301 and 15% in CF-302) compared to the dornase alfa trial (approximately
3%) which could suggest some underlying differences between trials that may limit
any indirect comparison between treatments.
For PBAC’s view of these results, see Recommendation and Reasons.
The re-submission did not update the comparative safety data.
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. DPI mannitol was also associated with
a higher incidence of withdrawals due to adverse events compared to control. Adverse
events associated with dornase alfa include: voice alteration, rash, haemoptysis,
dyspnoea, pharyngitis and laryngitis.
The EMA recently raised concerns about the safety of DPI mannitol treatment, particularly
with respect to narrowing of the airways in the lungs and haemoptysis.
During the evaluation, the sponsor provided additional adverse event data from the
open-label extensions of CF-301 and CF-302. The most common treatment-related adverse
events (possibly, probably or definitely related to DPI mannitol treatment) during
the open-label extensions were cough, haemoptysis, wheezing, productive cough, asthma,
dyspnoea, throat irritation, condition aggravated, bacteria sputum identified and
headache.
For PBAC’s view, see Recommendation and Reasons.
9. Clinical Claim
The re-submission described DPI mannitol monotherapy as
non-inferior to dornase alfa in terms of comparative effectiveness
(FEV1 outcomes) and similar in terms of comparative
safety.
The re-submission also described DPI mannitol monotherapy as
superior to placebo/control in terms of comparative effectiveness
(FEV1 outcomes) and inferior in terms of comparative
safety. Although the submission presented a clinical claim against
placebo/control, no economic analysis based on this claim was
presented.
The PBAC considered that the indirect comparison of DPI mannitol
(non-dornase users) and dornase alfa presented in the submission
suggested that both therapies have similar treatment effects in
terms of FEV1 and exacerbations compared to control.
However, it was unclear whether the study populations were
sufficiently similar to justify an indirect analysis. Additionally,
there were insufficient data to assess whether DPI mannitol and
dornase alfa have comparable safety profiles.
10. Economic Analysis
The re-submission presented a cost minimisation analysis of DPI
mannitol monotherapy vs. dornase alfa, and calculated a weighted
price to account for some substitution of DPI mannitol for
hypertonic saline (based on expected usage patterns).
Based on the indirect analysis, the equi-effective dose of DPI
mannitol is 400 mg twice daily compared to dornase alfa 2.5 mg once
daily.
For PBAC’s view, see Recommendation and
Reasons.
11. Estimated PBS Usage and Financial Implications
The likely number of patients/year was estimated by the submission
to be less than 10,000 in Year 5, similar to the previous
submission.
A net financial saving/year to the PBS was estimated by the
submission over the first 5 years compared to a financial cost/year
in the previous submission. The financial implications are to be
further verified.
For PBAC’s view, see Recommendation and
Reasons.
12. Recommendation and Reasons
The PBAC considered that the clinical place of mannitol in the
treatment of cystic fibrosis (CF) remains uncertain. The PBAC
considered the extent to which mannitol, dornase alfa and
hypertonic saline are used cyclically or in combination, which
combinations are used and when treatments are added-on in clinical
practice remains unclear. The PBAC considered the survey results
referred to in the re-submission provided insufficient evidence to
adequately inform the clinical place in therapy of mannitol. The
PBAC agreed there is a clinical need for additional treatment
options for patients with CF, however further consultation with
clinicians is required to ascertain the appropriate clinical place
in therapy of mannitol.
The PBAC noted that dornase alfa, the comparator in the
re-submission, was unchanged from the previous submission. The PBAC
considered this to be inappropriate and that hypertonic saline or
usual care (placebo) are appropriate comparators. However a
clinical comparison to hypertonic saline was not presented. The
PBAC considered that there could be some substitution of dornase
alfa by mannitol, and hence dornase alfa as part of a mixed
comparison may be reasonable. The PBAC, however noted that the
extent that mannitol would substitute for dornase alfa is
uncertain.
The PBAC noted that the trials presented as clinical evidence were
the same as in the previous submission with the addition of results
from unpublished open-label extensions of the CF-301 and CF-302
trials. The PBAC noted that the re-submission presented limited
data on hypertonic saline (the Cochrane review). No data addressing
the comparative efficacy and safety of mannitol versus hypertonic
saline or for switching from dornase alfa to mannitol was
presented. The PBAC also noted that the results of the indirect
comparison suggested that mannitol and dornase alfa have similar
treatment effects in terms of FEV1 and exacerbations
when compared to control. However, patients enrolled in CF-301 and
CF-302 and Fuchs 1994 were different populations, discontinuation
rates were substantially different between the trials and the
management of cystic fibrosis between when Fuchs study (1994) and
CF-301 and CF-302 trials were conducted has probably changed.
The PBAC considered insufficient data was presented to assess
whether mannitol and dornase alfa have comparable safety profiles.
The PBAC noted that mannitol was associated with an increased risk
of cough (25.4% vs 20.3%) and haemoptysis (11.9% vs 8.5%) compared
to control.
The PBAC noted the submission presented a cost minimisation
analysis of mannitol monotherapy versus dornase alfa. The PBAC
considered the issues regarding the place in therapy of mannitol,
the comparator and the clinical efficacy flowed into the economic
evaluation. The PBAC noted that the weighted price proposed for
mannitol was based on the assumption of substitution of dornase
alfa and hypertonic saline, based on estimated usage patterns. The
PBAC considered this was highly uncertain as the submission did not
present any data on the comparative efficacy and safety to
hypertonic saline. The sponsor provided survey results in its
Pre-Sub Committee Response. However the PBAC noted that these
results were not evaluated and the PBAC considered that they
provided insufficient evidence to adequately support the
substitution estimates.
The PBAC further noted that there was potential for use of mannitol
outside the requested monotherapy PBS listing as add-on therapy,
because the place in therapy of mannitol is uncertain and
mannitol’s TGA registration includes add-on therapy.
The PBAC therefore rejected the submission because the comparator
was inappropriate, and on the basis of uncertain clinical
effectiveness and uncertain cost effectiveness.
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 look forward to working with the PBAC to further reduce
uncertainty, and to make a new treatment option available for
Australian CF patients.
