Tobramycin, solution for inhalation, single dose units, 300 mg in 5 mL, 56, TOBI® - March 2011
Page last updated: 01 July 2011
Public Summary Document
Product: Tobramycin, solution for inhalation,
single dose units, 300 mg in 5 mL, 56, TOBI®
Sponsor: Novartis Pharmaceuticals Australia Pty
Ltd
Date of PBAC Consideration: March 2011
1. Purpose of Application
The submission sought a Section 100 (Highly Specialised Drug) PBS
listing for tobramycin solution for inhalation, 300 mg in 5 mL, for
the treatment of a Pseudomonas aeruginosa respiratory
infection in a patient with Cystic Fibrosis (CF).
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
At the March 2000 and September 2002 meetings, the PBAC rejected
submissions from the previous sponsor for a Section 100 listing for
tobramycin ampoules for nebulisation, 300 mg in 5 mL
(TOBI®), on the basis of unacceptable
cost-effectiveness and doubts over the magnitude and duration of
benefit.
3. Registration Status
Tobramycin 300 mg 5 mL solution for inhalation was TGA registered
on 15 February 2000 for the management of cystic fibrosis patients
with Pseudomonas aeruginosa infections.
4. Listing Requested and PBAC’s View
Section 100 (Highly Specialised Drugs Program)
Public hospital Authority Required (STREAMLINED)
Private hospital Authority Required
PBS – subsidised treatment by a respiratory physician at a
cystic fibrosis clinic/centre. If patient attendance at such a
centre is not possible because of geographical isolation,
management (including prescribing) may be by a specialist physician
or paediatrician in consultation with a cystic fibrosis
clinic/centre.
Patients must satisfy all of the following criteria:
- has a confirmed diagnosis of cystic fibrosis; and
- positive culture for pulmonary Pseudomonas aeruginosa from a sputum, oropharyngeal or bronchoalveolar lavage/bronchoscopy sample, within the last six months
Note
Before treatment with tobramycin solution for inhalation is
commenced, the patient should have his or her lung function
measured by experienced personnel at an established cystic fibrosis
clinic/centre or lung function testing facility. Lung function
should be monitored periodically while the patient is on tobramycin
solution for inhalation.
With long term treatment, periodic testing that the Pseudomonas
aeruginosa infection remains susceptible to tobramycin should
be performed.
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
Cystic fibrosis (CF) is a genetic disorder affecting cells in the
exocrine glands. This results in abnormal ion transport and
hydration at epithelial cell surfaces. In the lung, mucous
clearance is compromised, and this allows bacterial infections to
persist in static mucous. Over time, the resultant sub-optimal
inflammatory response to the infection contributes to lung damage
and progressive impairment of lung function. Patients with cystic
fibrosis therefore have a greater risk of chronic lung infections
and intermittently receive courses of antibiotics by injection or
nebulisation to manage these infections. If chronically colonised
with the organism Pseudomonas aeruginosa they may require
multiple courses of intravenous aminoglycoside antibiotics for the
management of pulmonary exacerbations. The number of patients with
CF in Australia in 2008 as recorded by the Australian Cystic
Fibrosis Data Registry (ACFDR) was 2,843.
The submission proposed the place in therapy of tobramycin solution
for inhalation in cystic fibrosis would be to replace the
“off label” use of preservative free parenteral
formulations of tobramycin via nebuliser, when inhaled tobramycin
is required.
6. Comparator
The submission nominated placebo or standard care without the use
of inhaled tobramycin as the comparator, which the PBAC agreed was
an acceptable comparator in the management of chronic Ps.
aeruginosa infection.
For PBAC’s view, see Recommendation and
Reasons.
7. Clinical Trials
The submission presented the following studies in support of the
comparative effectiveness of tobramycin solution for inhalation
(TSI) to placebo for management of Pseudomonas aeruginosa
infection in patients with cystic fibrosis:
1. Management of chronic P. aeruginosa infection
The submission presented the pooled results (Ramsey 1999; Quittner 2002) from two blinded randomised trials (Trial 002 and Trial 003) comparing TSI with placebo (both in addition to standard care), one open-label, supplementary randomised trial comparing TSI with standard care (Murphy 2004), and one supplementary non-comparative study (Study 004, Moss 2001, Moss 2002), which was the 96 week extension trial of 002/003. For PBAC’s view, see Recommendation and Reasons.
2. Eradication of early P. aeruginosa infection
The submission presented one direct randomised trial comparing TSI
and placebo, in the absence of other anti-pseudomonal antibiotics
(Gibson 2003), and one supplementary trial comparing two durations
of TSI therapy (28 days vs 56 days) (Ratjen 2010).
The submission did not present any trials in support of the use of
TSI for treatment of acute exacerbations of lung disease.
The table below details the published trials presented in the
submission:
| Trial ID | Protocol title/ Publication title | Publication citation |
| Management of chronic infection | ||
| Randomised controlled trials | ||
| Ramsey BW et al | Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. | New England Journal of Medicine 1999; 340:23-30. |
| Quittner A et al | Effects of tobramycin solution for inhalation on global ratings of quality of life in patients with cystic fibrosis and Pseudomonas aeruginosa infection. | Pediatric Pulmonology 2002; 33:269-276 |
| Murphy T et al | Treatment with tobramycin solution for inhalation reduces hospitalisations in young CF subjects with mildling disease. | Pediatric Pulmonology 2004; 38:314-20. |
| Supplementary non-comparative studies | ||
| Moss R et al | Administration of aerosolized antibiotics in cystic fibrosis patients. | Chest 2001; 120 (Suppl 3):107S-113S. |
| Moss RB. et al | Long-term benefits of inhaled tobramycin in adolescent patients with cystic fibrosis. | Chest 2002; 121:55-63. |
| Eradication of early infection | ||
| Randomised trials | ||
| Gibson RL et al | Significant microbiological effect of inhaled tobramycin in young children with cystic fibrosis. | American Journal of Respiratory and Critical Care Medicine 2003; 167:841-49. |
| Ratjen F et al | Treatment of early Pseudomonas aeruginosa infection in patients with cystic fibrosis: the ELITE trial. | Thorax 2010; 65:286-91. |
8. Results of Trials
1. Management of chronic P. aeruginosa infection
TSI was administered twice daily in alternating periods of 28 days
on treatment followed by 28 days off treatment.
The submission reported the results from Ramsey 1999, which
analysed the pooled data from Trials 002 and 003. Whilst Chuchalin
2007 was not included in the submission due to differences in the
formulations of tobramycin (300 mg/4 mL in Chuchalin 2007 vs 300
mg/5 mL in the submission), the PBAC considered the similar design
to trials 002 and 003 and it being more recent than those trials
meant that Chuchalin 2007 was informative and relevant.
The main primary outcome in Trial 002 and Trial 003 and Chuchalin
2007 was mean change in forced expiratory volume in 1 second
(FEV1) % of predicted from baseline to the end of the
third ‘on-treatment’ phase (Week 20).
In the management of chronic Ps. aeruginosa infection,
Ramsey 1999 only reported the change in FEV1 %
predicted, which was the main primary outcome, as a relative
measure. This was not considered appropriate by the PBAC. The only
data on the absolute change in FEV1 % predicted was for
the pooled populations of the two trials, which were sourced during
the evaluation from the Commentary on the March 2000 PBAC
submission. The PBAC noted that, although there was a statistically
significant difference between the treatment groups in both the
pooled Trials 002/003 and Chuchalin 2007, the mean treatment effect
was approximately 6% and the PBAC questioned the clinical important
of this difference.
In Trials 002 and 003 there was a significant decrease in the
density of Ps.aeruginosa in sputum samples from
patients randomised to TSI during the active cycle. The effects of
TSI were not sustained during the ‘off-treatment’
phase. The magnitude of the reduction in the density of Ps.
aeruginosa during the ‘on-treatment’ phase appeared
to decrease with each successive cycle.
Secondary outcomes in Trials 002 and 003 included the number of
patients hospitalised and the time to first hospitalisation.
The submission presented the results of an open-label extension
study (Study 004), which enrolled subjects from Trials 002 and 003.
Patients randomised to placebo in Trials 002 and 003 were switched
to TSI at the beginning of the extension study. There were no
comparative data for the effectiveness of TSI beyond 24 weeks of
treatment.
As cystic fibrosis is a progressive disease, FEV1 will decrease
with the natural progression of the disease. Therefore, in the
absence of a control arm, it is not possible to estimate the extent
of any treatment effect, nor is it possible to determine if this
effect is sustained over time.
For PBAC’s comments on these results, see Recommendation
and Reasons.
2. Eradication of early P. aeruginosa infection
In Gibson 2003, TSI was administered twice daily for 28 days. The
primary outcome was the mean change in P. aeruginosa density
in bronchoalveolar lavage (BAL) fluid from baseline to end of
treatment. This trial was terminated early after an interim
efficacy analysis which was not stipulated in the trial
protocol.
P. aeruginosa eradication therapy results (Gibson 2003)
| TSI N=8 | Placebo N=13 | Risk difference (95% CI) | |
| Change in density Pa (baseline to Day 28), log 10 CFU/mL Mean (SD) | -5.25 (2.34) | 0.30 (2.15) | 5.55 (3.46, 7.64) |
| Adjusted for stopping rule | 5.36 (3.52, 7.54) | ||
| Patients free of Pa at day 28 by BAL sampling, n/N (%) | 8/8 (100%) | 1/13 (7.4%) | 92% (70%, 114%) |
| Patients free of Pa at day 56 by OP sampling, n/N (%) | 6/8 (75.0%) | 3/13 (23.1%) | 52% (14%, 90%) |
BAL=bronchoalveolar lavage; CFU=colony forming units; CI=confidence
interval; Pa=P. aeruginosa; OP=oropharyngeal
While there was a clinically important reduction in P.
aeruginosa density, and a significant difference in the number
of patients free of infection at both end of treatment and 28 days
after discontinuation of treatment, the PBAC noted that this trial
did not establish if “eradication” was maintained over
a clinically important time-frame, nor how this translated into
patient-relevant final outcomes, such as hospitalisation and
survival. The data at 56 days was considered more relevant than at
28 days, but overall remain uncertain based on the quality of the
data.
The PBAC noted that in Trials 002 and 003, the only adverse events
(AEs) reported by considerably more TSI patients than placebo
patients were voice alteration (13% vs 7%, respectively) and
tinnitus (3% vs 0%, respectively). All episodes of tinnitus
resolved with discontinuation of TSI and were not associated with
loss of hearing.
9. Clinical Claim
1. Management of chronic P. aeruginosa infection
The submission described TSI as superior in terms of comparative
effectiveness and non-inferior in terms of comparative safety over
placebo, which was considered reasonable.
2. Eradication of early P. aeruginosa infection
The submission described TSI as superior in terms of comparative effectiveness and non-inferior in terms of comparative safety over placebo. The claim that TSI is superior to placebo in terms of the comparative effectiveness for
short-term
eradication of
early P. aeruginosa infection was considered reasonable,
although it was only supported by one small randomised trial that
was terminated early as a result of an unplanned interim analysis.
The PBAC noted that there were insufficient data to make any
conclusions regarding the comparative safety of TSI in this
indication.
10. Economic Analysis
Management of chronic infection:
A trial-based economic evaluation was presented based on the rate
of hospitalisations in the pooled populations of Trials 002 and
003. An incremental cost per extra hospitalisation avoided over 24
weeks was calculated to be less than $15,000.
Eradication of early infection
The resources considered in the economic evaluation were costs of
tobramycin, outpatient services and pathology services. The outcome
used in the evaluation was the proportion of patients with a P.
aeruginosa-negative BAL culture at the end of treatment (28
days).
An incremental cost per patient free of P.aeruginosa at the
end of treatment was calculated to be less than $15,000.
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 5,000 in Year 5.
The financial cost per year to the PBS was estimated to be less
than $10 million in Year 5.
12. Recommendation and Reasons
The PBAC recommended the listing of tobramycin solution for
inhalation (TSI) on the PBS with an Authority Required
(STREAMLINED) listing for the management of proven Pseudomonas
aeruginosa infection in a patient with cystic fibrosis on the
basis of acceptable cost effectiveness compared with placebo. The
PBAC acknowledged that there is a high clinical need to allow PBS
access to this treatment which is currently the standard of care,
that the price provided acceptable cost-effectiveness, and although
the data are poor, a clinical benefit is demonstrated and likely to
be underestimated.
The PBAC agreed that placebo or standard care without the use of
inhaled tobramycin was an acceptable comparator in the management
of chronic Ps. aeruginosa infection, although it noted that
use (in the trial) without the addition of IV and oral antibiotics
in the eradication of early Ps. aeruginosa infection was not
consistent with current clinical guidelines. Although the clinical
treatment paradigm for inhaled antibiotics was uncertain, the PBAC
acknowledged that this had now become standard practice. Even
taking into account areas of uncertainty around continuous versus
intermittent therapy and duration of benefit, the PBAC recognised
that this was an area of clinical need.
The PBAC noted that the two key randomised trials presented in the
submission (Trials 002 and 003) were more than 10 years old and had
previously been considered by PBAC in 2000 and 2002. Another
randomised trial (Chuchalin 2007) was identified during the
evaluation but not included by the sponsor due to differences in
the formulations of tobramycin (300 mg/4 mL in Chuchalin 2007 vs
300 mg/5 mL in the submission). While PBAC accepted this, it was
nonetheless informative and relevant to consideration as it was of
similar design to Trials 002 and 003 and featured more recent
data.
In the management of chronic Ps. aeruginosa infection,
Trials 002 and 003 only reported the change in FEV1 %
predicted, which was the main primary outcome, as a relative
measure. This was not considered appropriate by the PBAC. The only
data on the absolute change in FEV1 % predicted was for
the pooled populations of the two trials. The PBAC noted that,
although there was a statistically significant difference between
the treatment groups in both the pooled Trials 002/003 and
Chuchalin 2007, the mean treatment effect was approximately 6% and
the PBAC questioned the clinical important of this
difference.
At the Hearing the clinician emphasised that the primary focus was
to decrease the loss of lung function and that better long-term
outcomes resulted from earlier commencement on therapy. It was also
noted that a clinically meaningful change in FEV1 %
predicted depended on patients baseline lung function and that
patients with good lung function have more to lose. Thus, in the
older tobramycin trials where patients had poor lung function at
baseline (approximately 50% FEV1 % predicted), it was
difficult to show large absolute changes in FEV1 %
predicted.
The PBAC noted that in Trials 002 and 003 there was a significant
decrease in the density of Ps. aeruginosa in sputum samples
from patients randomised to TSI during the active cycle but that
the effects of TSI were not sustained during the
‘off-treatment’ phase. The magnitude of the reduction
in the density of Ps. aeruginosa during the
‘on-treatment’ phase appeared to decrease with each
successive cycle. In the Chuchalin 2007 study, the PBAC noted that
the statistically significant difference in hospitalisations
between treatment arms supported the findings reported in Trial
002. The difference in hospitalisation rate was used as the basis
of the economic evaluation.
In the eradication of early Ps. aeruginosa infection, the
primary outcome in the key trial (Gibson 2003) was the mean change
in Ps. aeruginosa density in bronchoalveolar lavage fluid
from baseline to end of treatment. The PBAC noted that the
submission did not establish how this translated into
patient-relevant final outcomes, such as hospitalisation and
survival however considered that eradication is a reasonable
clinical outcome. The data at 56 days was considered more relevant
than at 28 days, but overall remain uncertain based on the quality
of the data.
For the management of chronic Ps. aeruginosa infection, a
trial-based economic evaluation was presented based on the rate of
hospitalisations in the pooled populations of Trials 002 and 003.
The PBAC noted that the current hospitalisation rates of cystic
fibrosis patients in Australia were likely to be lower than the
trial-based estimates based on a US trial conducted fourteen years
ago. Based on a Section 85 listing, the incremental cost per extra
hospitalisation avoided was less than $15,000.
Given there is a possibility for tobramycin to be used
continuously, rather then one month on/one month off, a risk share
arrangement with expenditure thresholds based upon 6.5
prescriptions per patient per year may be necessary to ensure PBS
use reflects the treatment paradigm considered for establishing
cost effectiveness.
The PBAC noted the consumer comments received for this item. The
Committee also noted the advice from the Highly Specialised Drugs
Working Party, that the submission did not meet all the criteria
for a highly specialised drug.
The PBAC recommended that tobramycin solution for inhalation is not
suitable for inclusion in the list of PBS medicines for prescribing
by nurse practitioners or midwives.
Recommendation:
TOBRAMYCIN, solution for inhalation, single dose units, 300 mg in 5
mL, 56
Restriction:
Authority Required (STREAMLINED)
Management of a proven Pseudomonas aeruginosa infection in a patient with cystic fibrosis.
NOTE:
Special Pricing Arrangements apply.
No applications for increased maximum quantities and/or repeats will be authorised.
Max qty: 56
Repeats: 2
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
Novartis welcomes the PBAC’s decision to recommend the
listing of tobramycin solution for inhalation on the PBS for
patients with cystic fibrosis who have a high clinical need for
this treatment.
