Public Summary Document – July 2018 PBAC Meeting

5.08 LUMACAFTOR with IVACAFTOR,

Tablet containing lumacaftor 100 mg with ivacaftor
125 mg,
Orkambi®,
Vertex Pharmaceuticals (Australia) Pty Ltd
1 Purpose of Application
1.1 The submission presented an application for Section 100 (Highly Specialised Drugs
Program) listing for lumacaftor 100 mg with ivacaftor 125 mg in a fixed dose
combination (lumacaftor/ivacaftor) for the treatment of patients with cystic fibrosis
(CF) aged 6–11 years who are homozygous for the F508del mutation in the CF
transmembrane conductance regulator (CFTR) gene. The key components of the
submission are presented in Table 1.
1.2 This is the first submission for lumacaftor/ivacaftor for this indication in this age
group. Lumacaftor 200 mg/ivacaftor 125 mg for the treatment of CF in patients aged
12 years and older who are homozygous for the F508del mutation in the CFTR gene
was first considered by the PBAC in March 2016. A minor resubmission was
considered in November 2016, and a major resubmission was considered and
rejected in July 2017. A subsequent resubmission was lodged in April 2018.
1.3 The submission presented one pivotal trial comparing lumacaftor/ivacaftor with
placebo in children 6-11 years, and a cost-utility analysis (CUA) of
lumacaftor/ivacaftor + Best Supportive Care (BSC) versus BSC alone for its use in all
children 2 and over with an F508del mutation in the CFTR gene. In accordance with
the TGA registration status of the product and TGA-PBAC parallel process
arrangements, consideration of the evidence for this submission was restricted to
children 6 and over.
Table 1: Key components of the clinical issue addressed by the submission
Component Description
Population CF patients aged 6–11 years who are homozygous for the F508del mutation in the CFTR gene.
Intervention Two tablets (containing lumacaftor 100 mg/ivacaftor 125 mg) taken orally every 12 hours with total
daily dose of 400 mg for lumacaftor and 500 mg for ivacaftor.
Comparator Best Supportive Care
Outcomes Primary outcome: LCI2.5.
Secondary outcomes: ppFEV1, sweat chloride, nutritional status (BMI, BMI-for-age z-score, weight,
weight-for-age z-score, height, height-for-age z-score, stature, stature-for-height), LCI5.0, pulmonary
exacerbation and quality of life (CFQ-R Respiratory Domain Score)
Clinical claim In CF patients aged 6-11 years who are homozygous for the F508del mutation, lumacaftor/ivacaftor
plus BSC is superior in terms of effectiveness compared with BSC alone and non-inferior in terms of
safety compared to BSC alone.
Abbreviations: BMI = body mass index; BSC=best supportive care CF=cystic fibrosis; CFQ-R=Cystic Fibrosis Questionnaire-Revised;
CFTR=cystic fibrosis transmembrane conductance regulator; FE-1=faecal elastase 1; FEV=forced expiratory volume;
IRT=immunoreactive trypsinogen; LCI2.5=lung clearance index at 2.5% of starting concentration; ppFEV1= percent predicted forced
expiratory volume in one second; TSQM=Treatment Satisfaction Questionnaire for Medication.
Source: Table 1.1.1, p.30 of the submission.

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2 Requested listing
2.1 This submission requested PBS listing for lumacaftor/ivacaftor (Orkambi TM) in CF
patients aged 6–11 years who are homozygous for the F508del mutation in the CFTR
gene (see Table 2).
Table 2: Summary of proposed listing
Name, Restriction, Max. №.of Dispensed Price Proprietary Name and
Manner of administration and form Qty Rpts for Max. Qty Manufacturer
Pack Vertex
lumacaftor 100 mg/ ivacaftor 125 mg Orkambi
containing 5 $''''''''''''''''' Pharmaceuticals
tablets ™
112 tablets (Australia) Pty Ltd
Category/ Section 100 Highly Specialized Drug Program
Program:
PBS indication: Treatment of cystic fibrosis in patients aged ≥2 years who are homozygous for the F508del mutation in
the CFTR gene.
Treatment phase: Initial
Restriction: Authority Required
Treatment criteria: Patients must be assessed through a cystic fibrosis clinic/centre which is under the control of specialist
respiratory physicians with experience and expertise in the management of cystic fibrosis. If
attendance at such a unit is not possible because of geographical isolation, management (including
prescribing) may be in consultation with such a unit,
AND
Patient must be homozygous for the F508del mutation in the CFTR gene
AND
The treatment must be given concomitantly with standard therapy for this condition.
Clinical criteria: Treatment of cystic fibrosis in patients who are homozygous for the F508del mutation in the CFTR
gene.
Population criteria: Patients must be aged ≥2 years.
Prescriber criteria: The authority application must be in writing and must include:
(1) a completed authority prescription form; and
(2) a completed Cystic Fibrosis Lumacaftor with Ivacaftor Authority Application Supporting Information
Form; and
(3) a signed patient acknowledgement; or an acknowledgement signed by a parent or authorized
guardian; if applicable; and
(4) a copy of the pathology report detailing the molecular testing for the patient being homozygous for
the F508del mutation on the CFTR gene
Abbreviations: CFTR=Cystic Fibrosis transmembrane conductance regulator; PBS= Pharmaceutical Benefits Scheme
Source: Table 1.4.2, p.58 of the submission.

For more detail on PBAC’s view, see section 7 PBAC outcome.

3 Background
Registration status
3.1 TGA status: The submission was made under TGA-PBAC Parallel Process. At the time
of PBAC consideration, the TGA delegate had indicated an intention to approve for
registration, subject to the sponsor committing to ‘facilitating the provision of long
term efficacy and safety date from use in the Australian Health Care setting’.
3.2 At the time of submission to the PBAC, a TGA application had not been lodged for
lumacaftor/ivacaftor in patients aged 2-5 years.

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Previous PBAC consideration

3.3 This is the first time the PBAC has considered a submission for lumacaftor/ivacaftor
for this age group.
3.4 The PBAC has considered submissions for lumacaftor/ivacaftor for use in patients
aged 12 years and older on three separate occasions. The PBAC considered a fourth
submission for lumacaftor/ivacaftor for the 12+ age group concurrently with this
submission. See public summary document (PSD) for item 7.10 from July 2018.

4 Population and disease

4.1 CF is a rare, genetic, systemic disease caused by a mutation in the CFTR gene that
encodes an epithelial chloride channel, the CFTR protein. The failure to regulate
chloride transport in the lungs, pancreas, intestinal tract, biliary tract, sweat glands,
and reproductive tract results in the multi-system pathology typically exhibited by
children with CF early in life. Patients with CF are pancreatic insufficient from an
early age. The most common mutation in Australia is F508del (which results in
deletion of phenylalanine in the CFTR protein), which is present in at least one allele
in approximately 90% of CF patients. Approximately 50% of CF patients are
homozygous for the F508del mutation in Australia.

5 Comparator
5.1 The PBAC accepted best supportive care (BSC) as nominated by the submission, as
the comparator. The PBAC previously accepted that BSC is the appropriate
comparator for the 12+ population.

6 Consideration of the evidence

Sponsor hearing
6.1 The sponsor requested a combined hearing for both lumacaftor with ivacaftor
submissions (patients aged 6 – 11 years [item 5.08] and patients aged 12 years and
older – [item 7.10]). The presentation focussed predominantly on treatment
outcomes in younger patients (aged 6 - 11 years); however, the clinician noted the
benefits of treatment with lumacaftor/ivacaftor in both age groups. The clinician
stressed the importance of early treatment in CF to prevent or delay lung damage
and reduce the rate of decline in lung function; noting that lung function declines
over time, particularly beyond the age of 10, and that changes that occur to the
lungs between the ages of 5 – 12 can be reversible. The clinician considered that the
Lung Clearance Index (LCI) was a useful outcome measure that allows changes to be
observed in early lung disease and in response to a question from the PBAC,
indicated that a 15% change in LCI was thought to be clinically meaningful. The PBAC
noted that the absolute change in LCI observed in Study 109 (10%) was less than
15%.

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6.2 In response to a question from the PBAC in relation to the availability of data on the
use of lumacaftor/ivacaftor for periods of longer than 24 weeks, the clinician
indicated that such data were now available.
6.3 The PBAC noted that a 96 week open label extension study (Study VX15-809-110,
also referred to as Study 110) in 6 – 11 year olds is underway, and that preliminary
data from that study was presented at the 31st Annual North American Cystic
Fibrosis Conference, Indianapolis, Indiana, November 2-4, 2017 (Chilvers M 2017 1,
PBAC July 2018 Submission, Section 2, Attachments). According to the information
including in the poster, at the time of its preparation, all but one of 239 subjects had
completed 72 weeks of study treatment.
6.4 The PBAC noted its ESC had requested further information on the expected
completion date of Study 110, but the sponsor did not provide this information in its
pre-PBAC response. However, the PBAC noted that the US clinical trials website
reports August 2018 as the expected study completion date
(https://clinicaltrials.gov/ct2/show/NCT02544451?term=VX15-809-110&rank=1). An
August 2018 study completion date is also consistent with the last patient study visit
for the studies that preceded Study 110 (and from which patients in Study 110 were
drawn) having taken place on 20 September 2016 (CSR Protocol VX14-809-109, 18
January 2017).
6.5 The PBAC further noted that the US clinical trials website reports that the following
outcome measures have been included in Study 110.

Primary Outcome Measures:

1. Treatment Cohort: Assess safety and tolerability of long term treatment of

lumacaftor in combination with ivacaftor, based on treatment emergent
adverse events and changes in clinical laboratory values, vital signs, and
spirometry.

Secondary Outcome Measures:

1. Treatment Cohort: Absolute change in Lung Clearance Index 2.5 (LCI2.5)

(subjects from Study 109 and the Study 011B LCI Substudy only)
2. Treatment Cohort: Absolute change in sweat chloride
3. Treatment Cohort: Absolute change in body mass index (BMI)
4. Treatment Cohort: Absolute change in Cystic Fibrosis Questionnaire Revised
(CFQ-R) respiratory domain score
5. Observational Cohort: Safety, as determined by serious adverse events (SAEs)
6. Treatment Cohort: Absolute change in Lung Clearance Index 5.0 (LCI5.0)
(subjects from Study 109 and the Study 011B LCI Substudy only)

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Chilvers M-809_110_IA2_NACFC_2017_Poster278_Presented.pdf

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7. Treatment Cohort: Absolute change in percent predicted forced expiratory

volume in 1 second (ppFEV1)
8. Treatment Cohort: Relative change in ppFEV1
9. Treatment Cohort: Absolute change in body mass index (BMI)-for-age-z-score
10. Treatment Cohort: Absolute change in weight
11. Treatment Cohort: Absolute change in weight-for-age-z-score
12. Treatment Cohort: Absolute change in height
13. Treatment Cohort: Absolute change in height-for-age-z-score
14. Treatment Cohort: Absolute change in Treatment Satisfaction Questionnaire
for Medication (TSQM) domains
15. Treatment Cohort: Time-to-first pulmonary exacerbation (subjects from Study
109 only)
16. Treatment Cohort: Event of having at least 1 pulmonary exacerbation (subjects
from Study 109 only)
17. Treatment Cohort: Number of pulmonary exacerbations (subjects from Study
109 only)
18. Treatment Cohort: Rate of change in LCI2.5 (subjects from Study 109 and the
Study 011B LCI Substudy only)
19. Treatment Cohort: Rate of change in LCI5.0 (subjects from Study 109 and the
Study 011B LCI Substudy only).
20. Treatment Cohort: Rate of change in ppFEV1.

6.6 The PBAC noted the sponsor’s commitment in the pre-PBAC response to providing
the data from Study 110 when finalised.
6.7 The PBAC considered it appropriate for the sponsor to provide further outcome data
for ivacaftor/lumacaftor in the 6 – 11 age group for the PBAC’s consideration,
particularly in the context of a long term treatment for young children which has the
potential to cause adverse events. In this context, the PBAC noted that a full report
of the planned interim analysis of Study 110 (as referred to in Chilvers, M 2017)
should now be available and that data for the full study period should be available in
the near future.

Consumer comments
6.8 The PBAC noted and welcomed the input from individuals (3980), health care
professionals (45) and organisations (5) via the Consumer Comments facility on the
PBS website for both lumacaftor with ivacaftor submissions combined (patients aged
6 – 11 years [item 5.08] and patients aged 12 years and older – [item 7.10]). The
comments described a range of benefits of treatment with lumacaftor/ivacaftor,
including improvement in lung function, reduction in chest infections and
exacerbations, weight gain, fewer hospital visits, fewer medications to be consumed
on a daily basis, slowing disease progression, and improvement in quality of life. The
comments noted that the very high cost of the drug on the private market puts it out
of the financial reach of Australian patients and a number of comments expressed

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frustration that lumacaftor/ivacaftor has not yet been recommended for listing,
despite a number of submissions being made to the PBAC.
6.9 The PBAC noted the advice received from the Cystic Fibrosis Centre Directors
(representing interests from the Cystic Fibrosis Specialist Interest Group of the
Thoracic Society of Australia and New Zealand, and Cystic Fibrosis Australia), Cystic
Fibrosis Australia and Cystic Fibrosis SA. The PBAC specifically noted the advice that
the use of lumacaftor/ivacaftor may halt or slow decline in lung function; reduce
hospital stays, IV treatments and hospitalisation costs; and improve nutritional
status and quality of life. The advice received from the Cystic Fibrosis Centre
Directors also noted that in the experience of Australian CF physicians who have
used this drug in trials and on the compassionate Special Access Scheme, patients
have experienced a reduction in acute respiratory exacerbations. The advice states
that “acute respiratory exacerbations in CF result in worsening of lung function,
permanent loss of lung function and decreased survival” and that “any therapy that
reduces the rate of acute exacerbations is likely therefore to have a very beneficial
effect on the clinical course of patients with CF.” The PBAC noted that although this
advice was supportive of the evidence provided in the submission, the authors were
not able to provide data from Australian patients to substantiate these observations
ahead of PBAC consideration.

Clinical trials
6.10 The submission was based on one randomised clinical trial comparing
lumacaftor/ivacaftor to placebo, Study 109 (VX15-809-109). In addition, one
supplementary supportive open-label, two part study (Study 011) was included.
6.11 The submission excluded one potentially relevant study, Study 110, on the basis that
it was currently ongoing and complete data were not yet available. At noted above,
the PBAC considered that data from this study would provide important information
on the efficacy and safety of lumacaftor/ivacaftor in patients 6 – 11 years.
6.12 Details of the trials presented in the submission are provided in Table 3.

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Table 3: Trials and associated reports presented in the submission

Trial ID Protocol title/ Publication title Publication citation
A Randomized, Double-blind, Placebo-controlled Multicenter, Parallel
group, Phase 3 Study of lumacaftor in combination with ivacaftor in
January 2017
Patients 6 through 11 Years with Treatment-naive Cystic Fibrosis,
Homozygous for the F508del-CFTR Mutation
Ratjen F, Hug C, Marigowda M, et al. Efficacy and safety of lumacaftor The Lancet Respiratory
Study 109 and ivacaftor in subjects aged 6–11 years with cystic fibrosis homozygous Medicine. 2017; 5(7): 557–
for F508del-CFTR: a randomized, placebo-controlled phase 3 trial. 567
Brody AS, Nagle SK, Owen CA, et al. Effect of lumacaftor/ivacaftor on
North American Cystic
total, bronchiectasis, and air trapping computed tomography scores in
Fibrosis Conference,
children with Cystic Fibrosis Homozygous for F508del: Exploratory
Indianapolis, USA, 2017.
imaging substudy
North American Cystic
Nagle SK, Brody AS, Woods J, et al. Feasibility of ultrashort echo time
Fibrosis Conference,
magnetic resonance imaging to evaluate the effect of lumacaftor/ivacaftor
Indianapolis, USA, 2017
therapy in children with cystic fibrosis homozygous for F508del
An Open-label, Phase 3 Study to Evaluate the Pharmacokinetics, Safety
and Tolerability of Lumacaftor in Combination with Ivacaftor in Patients 6
Study 011 March 2016.
Through 11 Years of Age With Cystic Fibrosis, Homozygous for the
F508del-CFTR Mutation
British Thoracic Society
Chilvers M, Tian S, Marigowda G, et al. An open-label extension (EXT)
Winter Meeting, United
study of lumacaftor/ivacaftor (LUM/IVA) therapy in subjects aged 6 to 11
Kingdom, 2017. Thorax.
years with cystic fibrosis (CF) homozygous for F508del-CFTR.
2017; 72(Suppl 3): A58
Source: Table 2.1.3, p.63-64 of the submission.

6.13 The key features of the direct randomised trial(s) are summarised in Table 4.
Table 4: Key features of the included evidence
Design/ Use in modelled
Trial N Risk of bias Patient population Outcomes
duration evaluation
Lumacaftor/ivacaftor vs. placebo
Primary: LCI2.5
CF patients aged
Secondary:; ppFEV1; nutritional
6–11 years who
status;
R, DB are homozygous
Study 109 204 Low LCI5.0; sweat chloride,; ppFEV1
24 weeks for the F508del
CFQ-R Respiratory Domain
mutation in the
Score; Pulmonary exacerbation
CFTR gene
TSQM domain score; FEV1; IRT
High due to CF patients aged Secondary endpoints: sweat
lack of 6–11 years who chloride ; BMI and BMI for age z
OL blinding are homozygous score; weight and weight for age
Study 011 68 Not used
26 weeks Low for for the F508del z score; height and height for age
other types mutation in the z score; CFQ-R respiratory
of bias CFTR gene domain score; TSQM; ppFEV1
Abbreviations: DB=double blind; OL=open label; R=randomised.
Source: Compiled during the evaluation. CSR 109 and CSR 011.

6.14 The LCI is a surrogate outcome that measures the number of lung turnovers needed
to reduce the marker gas concentration to the pre-defined fraction of the starting
concentration. The primary outcome in Study 109 used LCI 2.5 to demonstrate the
number of turnovers to reach the concentration of 2.5% of the marker gas.
6.15 The submission nominated a minimum clinically important difference (MCID) for the

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primary outcome of LCI2.5, and for the secondary outcome of CFQ-R for Study 109.
The proposed MCID for LCI2.5 was a change in response of 0.5-1.0 units. The MCID for
LCI2.5 was based on feedback from the Vertex Advisory Board (4 board members).
There is no established, externally validated, MCID for LCI. It is uncertain how the
improvement in LCI2.5 affects survival. The LCI2.5 was not used as a primary outcome in
previous submissions and was not used in the economic model in the current
submission.
6.16 In the Pre-Sub-Committee Response (PSCR) the sponsor stated that it selected LCI as
the primary outcome based on clinical and scientific advice; and noted advice
received from the European Medicines Agency Committee for Medicinal Products for
Human Use (EMA CHMP) that “The CHMP agrees that LCI can provide a more
sensitive outcome measure than FEV1 in early lung disease such as that present in
the majority of patients who are 6 to 11 years of age, thereafter agree with the use
of LCI as a measurement of lung function to evaluate the efficacy of LUM/IVA
combination therapy in this target population”.
6.17 The PBAC agreed with its ESC that the use of the LCI as the primary endpoint in the
clinical studies may be reasonable, but noted that there was uncertainty in: the
clinical implications of changes observed; the longer-term benefits of these changes;
and the relationship of these changes to patient relevant outcomes. The PBAC did
not accept the sponsor’s apparent assertion that by making these observations it
would “effectively penalise the younger children for the very presence of an
additional lung function outcome in their pivotal trial”.
6.18 The PBAC noted that the outcome of ppFEV 1, typically used as a key outcome in the
management and research of CF, was a secondary outcome in Study 109, and is the
only outcome from Study 109 used to estimate the treatment effect in the economic
model.

Comparative effectiveness
6.19 The results for the primary efficacy outcome in Study 109 are presented in Table 5.
The results of Study 109 showed a statistically significant difference of -1.09 units in
LCI2.5 in those treated with lumacaftor/ivacaftor compared with placebo. Part B of
the supportive study, Study 011, included an LCI sub-study which reported an
absolute change in LCI2.5 from baseline of -0.97 units in those treated with
lumacaftor/ivacaftor compared with placebo.

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Table 5: Absolute change from baseline in LCI2.5 at week 24 by MMRM based on FAS in Study 109
Study 109
LCI2.5 (units) Lumacaftor 200 mg q12h/ ivacaftor 250
Placebo (N=101)
mg q12h (N=103)
Baselinea
Mean (SD) 10.30 (2.36) 10.26 (2.24)
Absolute change through Week 24
LS Mean (SE) -1.01 (0.13) 0.08 (0.13)
LS mean difference (95% CI) -1.09 (-1.43, -0.75)
P value <0.0001
Abbreviations: CI=confidence interval; FAS=full analysis set; LS=least squares; MMRM=mixed model repeated measures; LCI2.5=lung
clearance index 2.5; q12h=every 12 hours; q12h=every 12 hours SD=standard deviation; SE=standard error.
Note: a includes all patients without any post-baseline assessments.
Source: Table 2.1.15 p.86 of the submission

6.20 The PBAC noted the sponsor’s comments in the pre-PBAC response
“Furthermore, regarding the MCID construct, it may be informative for the PBAC
members to contrast the magnitude of the LCI improvement seen with LUM/IVA®
treatment in just 24 weeks of the pivotal trial (1.09 unit improvement in 24 weeks)
with that reported as CF natural history by Stanojevic, Davis et al, 2017. They report
the annual decline in LCI in 2.5 to 6-year old patients to be 0.4 units/year — equating
approximately 0.18 unit worsening in 24 weeks. We trust the PBAC can reasonably
interpret the clinical meaningfulness of a directional difference in the context of
expected natural history”
6.21 The PBAC further noted that in contrast to the results reported by Stanojevic, the
mean worsening in LCI in the placebo treated group on study 109 was 0.08 units.
6.22 The PBAC agreed that the directional change in LCI observed over 24 weeks in
lumacaftor/ivacaftor in Study 109 was positive but remained uncertain what this
change would mean in terms of the overall health of this patient cohort over the
longer term.
6.23 The absolute and relative changes in ppFEV 1 at week 24 were statistically significant
and showed 3% and 3.8% improvements in favour of lumacaftor/ivacaftor
respectively (see Table 6).

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Table 6: Absolute change from baseline in secondary lung function outcomes (ppFEV1) in Study 109
Lumacaftor 200 mg q12h/ ivacaftor 250
ppFEV1 mg q12h Placebo (N=101)
N=103
MMRM analysis of absolute change in ppFEV1 from baseline through Week 24 (FAS)
Baselinea
Mean (SD) 88.8 (13.7) 90.7 (10.8)
Absolute change through Week 24
LS Mean (SE) 2.5 (0.9) -0.5 (0.9)
LS mean difference (95% CI) 3.0 (0.5, 5.5)
P value 0.0195
MMRM analysis of relative change in ppFEV1 from baseline through Week 24 (FAS)
Baselinea
Mean (SD) 1.5 (11.1) -1.7 (7.8)
Relative change through week 24
LS Mean (SE) 3.8 (1.2) 0.0 (1.2)
LS mean difference (95% CI) 3.8 (0.7, 7.0)
P value 0.0174
Abbreviations: CI=confidence interval; FAS=full analysis set; LS=least squares; MMRM=mixed model repeated measures;
ppFEV1=percent predicted forced expiratory volume in one second; LCI 2.5=lung clearance index 2.5; q12h=every 12 hours SD=standard
deviation; SE=standard error
Note: a includes all patients without any post-baseline assessments
Source: Table 2.1.17, p. 91 of the submission

6.24 The results from Study 109 showed no statistically significant difference between
lumacaftor/ivacaftor or placebo in either the number of pulmonary exacerbations
(PEx) or the proportion of patients having at least one PEx over 24 weeks. The
evaluation noted that these results should be interpreted with caution due to the
small number of patients with events. Previously (July 2017), the PBAC had been
informed by the sponsor that avoidance of PEx was a major clinical benefit of the use
of lumacaftor/ivacaftor in patients aged 12 and over with the F508del mutation in
the CFTR gene. It is feasible that the absence of such an effect in Study 109 is due to
a lower baseline risk of PEx in this population due to better baseline lung health,
relative to older populations, but this has not been substantiated.
6.25 The absolute change in the CFQ-R domain at week 24 showed no statistically
significant difference between lumacaftor/ivacaftor and placebo. The submission
noted that there was a within group improvement in CFQ-R domain scores for both
treatment groups, but this did not achieve statistical significance (p=0.063). This
apparent lack in difference in CFQ-R scores is reflected in a lack of difference in
patient reported acceptability of effectiveness, safety, convenience, or overall
satisfaction associated with lumacaftor/ivacaftor
6.26 There was a statistically significant reduction in LCI5.0 for lumacaftor/ivacaftor
compared with placebo of -0.44 week 24.
6.27 The results showed a statistically significant reduction in absolute sweat chloride for
lumacaftor/ivacaftor compared with placebo of 20.8 mmol/L at day 15 and
24.9 mmol/L at week 24.
6.28 The impact of lumacaftor/ivacaftor on BMI and BMI for age z scores at week 24 was

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not statistically significantly different from placebo. Similarly, the impact of

treatment on weight, weight for age Z-scores, height and height for age Z-scores at
week 24 was not statistically significantly different from placebo.
6.29 The PSCR and pre-PBAC responses argued that although there is currently no longer-
term data available for 6-11 year old patients, the magnitude of the ppFEV1
improvement at week 24 (3.0%) is similar to that observed in the ≥12-year old
patients (2.8%); and therefore it is anticipated that efficacy would follow a similar
pattern to that observed in the ≥12-year old patients who are homozygous for the
F508del mutation. The PSCR further stated that that “the main objective of CF
treatment is to minimise the rate of deterioration over time” and that although not
directly applicable to patients aged 6-11 years, the reduction in the rate of decline of
ppFEV1 observed in patients aged 12+ (42%), 12 – 17 years (45%) and ≥18-year
(41%), suggests that “the longer-term impact of Orkambi of slowing the trajectory of
FEV1 over time is consistent across age groups”.
6.30 The PBAC considered that overall, the data available for lumacaftor/ivacaftor in the
6-11 age group are supportive of a benefit from treatment, particularly in terms of
LCI and ppFEV1, but considered that the impact of lumacaftor/ivacaftor on
improvements in long-term lung function and survival was uncertain.

Comparative harms
6.31 A summary of the adverse events for lumacaftor/ivacaftor versus placebo is
presented in Table 7. Based on the relative risks estimated during the evaluation (see
Table 8), there were no categories of AEs that occurred statistically significantly more
frequently with lumacaftor/ivacaftor compared with placebo. With respect to
specific events, there was a higher risk of productive cough (RR=2.94 (95%CI 1.22,
7.11)) among patients treated with lumacaftor/ivacaftor compared with placebo, but
no difference in the risk of infections and infestations. There was very limited long-
term evidence supporting safety of lumacaftor/ivacaftor for treatment of CF in
patients aged 6-11 years beyond the 24 weeks reported in Study 109 (Chilvers M
2017, poster).

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Table 7: Summary of key adverse events in the trials

Study 109 Lumacaftor 200 mg q12h/ Placebo RR (95% CI)*
ivacaftor 250 mg q12h N=101
N=103
Total number of AEs 573 562 N/A
Patients with any AEs n (%) 98 (95.1) 98 (97.0) 0.98 (0.927, 1.036)
Patients with AEs by maximum severity N/A
Mild 46 (44.7) 41 (40.6) 0.87 (0.635, 1.202)
Moderate 49 (47.6) 49 (48.5) 0.98 (0.737, 1.304)
Severe 3 (2.9) 8 (7.9) 0.65 (0.111, 3.830)
Life-threatening 0 0 N/A
Missing 0 0 N/A
Patients with AEs leading to treatment discontinuation n 3 (2.9) 2 (2.0) 0.65 (0.111, 3.830)
(%)
Patients with AEs leading to treatment interruption n (%) 9 (8.7) 3 (3.0) 0.33 (0.091, 1.172)
Patients with SAEs n (%) 13 (12.6) 11 (10.9) 0.83 (0.390, 1.764)
Patients with related SAEs n (%) 2 (1.9) 3 (3.0) 1.47 (0.251, 8.618)
Patients with AEs leading to death n (%) 0 0 N/A
Abbreviations: AEs=adverse events; MedDRA=Medical Dictionary for Regulatory Activities; N=total sample size; n=number of patients;
PT=preferred term; SAEs=serious adverse events; SOC=system organ class.
Notes: *Calculated values. RR not provided by the submission.
Source: Table 2.1.24 p 105 of the submission

6.32 On the basis of the direct evidence from Study 109 presented by the submission the
frequency of adverse events being reported was comparable between
lumacaftor/ivacaftor and placebo groups. The most common AE in patients who
received lumacaftor/ivacaftor were cough (44.7% compared to 46.5%), infective
pulmonary exacerbation (19.4%), productive cough (17.5% compared to 5.9%), nasal
congestion (16.5% compared to 7.9), oropharyngeal pain (14.6% compared to 9.9%),
pyrexia (14.6% compared to 19.8%), upper respiratory tract infection (12.6%
compared to 9.9%) and headache (12.6 compared to 8.9). A total of 5 (2.5%) patients
had SAEs considered related (related or possibly related, as determined by the
investigator) to the study drug (3 (3.0%) in placebo and 2 (1.9%) in
lumacaftor/ivacaftor group).

Benefits/harms
6.33 A summary of the comparative benefits and harms for lumacaftor/ivacaftor versus
placebo in children 6-11 years of age is presented in Table 8.

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Table 8: Summary of comparative benefits and harms for lumacaftor/ivacaftor and placebo
Benefits
Absolute change from baseline in LCI2.5 at 24 weeks
Lumacaftor/ivacaftor Placebo Mean difference*:
Mean ∆ Mean ∆ Lumacaftor/ivacaftor vs.
Study 109
N baseline SD N baseline SD placebo
LCI2.5 LCI2.5 (95% CI)
103 10.30 2.36 101 10.26 2.24 -1.09 (-1.43, -0.75)
Absolute change from baseline in ppFEV1 at 24 weeks
Lumacaftor/ivacaftor Placebo Mean difference*:
Mean ∆ Mean ∆ Lumacaftor/ivacaftor vs.
Study 109
N baseline SD N baseline SD placebo
ppFEV1 ppFEV1 (95% CI)
103 88.8 13.7 101 90.7 10.8 3.0 (0.5, 5.5)
Harms
Lumacaftor/ Event rate/100 patients*
Placebo RR RDa
ivacaftor Lumacaftor/
n/N (95% CI) Placebo (95% CI)
n/N ivacaftor
Total number of patients with AEs
Study 109 98 /103 98/101 0.98 (0.927, 1.036) 95.1 97.0 -1.88 (-7.19, 3.42)
Total number of SAEs
1.73 (-7.01,
Study 109 13/103 11/101 0.83 (0.390, 1.764) 12.6 10.9
10.56)
AEs leading to treatment discontinuation n (%)
Study 109 3/103 2/101 1.47 (0.251, 8.618) 2.91 1.98 0.93 (-3.30, 5.17)
AEs related to study drug
Study 109 2/103 3/101 0.65 (0.111, 3.830) 1.94 2.97 -1.03 (-5.28, 3.22)
*Maximum duration of follow-up: Study 109 = 4 weeks
Abbreviations: AE = adverse event; CI = confidence interval; FEV 1 = predicted expiratory volume in one second; HR = hazard ratio; LCI =
lung clearance index; PBO = placebo pp = percent predicted; RD = risk difference; RR = risk ratio; SAE = serious adverse event; SD =
standard deviation;
Note: a calculated by the Commentary
Source: Table 2.1.15 p.86, Table 2.1.17, p. 91, Table 2.1.24 p 105 of the submission

6.34 On the basis of direct evidence from Study 109 presented by the submission, the
comparison of lumacaftor/ivacaftor and placebo resulted in:
 An improvement of 1.09 units in lung clearance index after 24 weeks of
treatment.
 An increase in the lung capacity (as measured by the percent predicted
forced expiratory volume) of 3% after 24 weeks of treatment.
 No difference in the likelihood of harm over 24 weeks of treatment.

Clinical claim
6.35 The submission described lumacaftor/ivacaftor as superior in terms of effectiveness
compared with BSC and non-inferior in terms of safety compared to BSC. The
submission stated that lumacaftor/ivacaftor improved key CF treatment outcomes
that are associated with prolongation of life expectancy; LCI 2.5 and ppFEV1. The
submission stated that the safety and efficacy profile of lumacaftor/ivacaftor in CF
aged 6-11 years is comparable to that observed in other age groups (i.e. CF patients

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aged ≥12 years).

6.36 The PBAC considered that the therapeutic conclusion presented in the submission
was not adequately supported over the longer term for the following reasons:
 While the data showed statistically significant differences in the LCI 2.5 and
ppFEV1 based on 24 weeks of data, the long-term implications of those
differences are unknown. This is particularly relevant in light of the data from
the PROGRESS study that demonstrated that the modest ppFEV1 increase in
lumacaftor/ivacaftor treated patients was not maintained in the longer term,
with the improvement from baseline not being statistically significant at 120
weeks (PROGRESS).
 There is no established minimum clinically important change in LCI and it is
uncertain how improvements in LCI 2.5 may contribute to patient relevant
outcomes that lead to improvements in survival or quality of life.
 The claim lumacaftor/ivacaftor is non-inferior to BSC in terms of comparative
safety is not adequately supported, particularly in the absence of long-term
data.
6.37 Thus, while there is evidence of a difference in efficacy in favour of
lumacaftor/ivacaftor compared with placebo in the short-term, the data presented
by the submission does not inform that comparison over the long-term, which is
particularly relevant in the context of a life-long condition and treatment.

Economic analysis
6.38 The submission presented a cost utility analysis economic evaluation, based on
direct randomised trials and implementing a modelled evaluation, comparing
lumacaftor/ivacaftor with BSC. The economic evaluation presented included all
patients aged 2 years and older with the F508del mutation (2 – 5, 6-11 and 12+).
6.39 While the submission presented a model which incorporated patients 2 years and
over, the clinical data presented were for those aged 6-11 only. The economic model
was evaluated for patients aged 6-11 years, and for those 6 and older, or 12 and
older by using the ‘patient filter’ functionality provided in the Excel workbook.
Aspects of the model specification or outputs which were specific to the 2-5 age
group were not evaluated.
6.40 As in previous lumacaftor/ivacaftor submissions (March 2016, November 2016 and
July 2017) and lumacaftor monotherapy submissions (July 2013 submission and
March 2014 resubmission) the model was based on the Cox-proportional hazard
(CPH) survival model described in Liou et al (2001). The model structure is the same
as that previously evaluated by the PBAC. There are some changes to the model
inputs (costs, treatment effects) to capture the paediatric population aged ≥ 6 years
and the application of the submissions’ initially proposed annual financial cap of
$'''''''''''''' per patient.

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6.41 Given that the submission presented the same model structure and inputs (for
children aged 12 and over) as considered previously by the PBAC, the key model
inputs varied by the PBAC in its respecification of the base case at its July 2017
meeting (para 6.57, July 2017 PSD), and how they have been addressed in the
current submission, are summarised in Table 9.
Table 9: Summary of variations made by PBAC to previous model and how they have been considered in this submission
Component Previous PBAC Preferred Scenarios Current Approach
Price reductions were reinstated.
Ivacaftor/ Removal of the 5% statutory price reduction A utilisation cap resulting in a price of $'''''''''''''''' per
Lumacaftor cap and and ''''''% generic price reduction. patient per year is utilised.
price adjustments Removal of the proposed cap. Removal of price reductions and the cap is tested in
sensitivity analyses (Table 13).
The post 24 week decline in ppFEV1 for
Assumed that the decline in ppFEV1 for
Sustained clinical lumacaftor/ivacaftor was set at ''''''% of that of BSC.
lumacaftor/ivacaftor post 24 weeks was 100%
effect Varied to ''''''%, '''''''% and '''''''''% in sensitivity analyses
of that seen in BSC.
(Table 13).
Assumed that all CF hospitalisations are due to PEx,
and that there was a reduction of 61% of
Assumed that only 75% of CF hospitalisations
Cost reductions due hospitalisations. Varied to 0% reduction in sensitivity
are due to PEx and therefore eligible for cost-
to hospitalisations analyses (Table 13).
reductions.
The submission also assumed no reduction in PEx
among children 6-11.
Abbreviations: BSC=best supportive care; CF=cystic fibrosis; PEx=pulmonary exacerbations; ppFEV 1 =percent predicted forced expiratory
volume in one second.
Source: Compiled during the evaluation from the July 2017 PBAC Public Summary Document, Lumacaftor/Ivacaftor.

6.42 The model initially provided with the July 2018 submission adjusted the rate of
decline in the lumacaftor/ivacaftor treatment group to '''''% of that in the BSC group;
reinstates the 5% and ''''''% price reductions; and assumes that all CF hospitalisations
are due to PEx, and that there was a reduction of 61% of hospitalisations.
6.43 The key components of the economic evaluation are presented in Table 10.
Table 10: Summary of model structure and rationale
Component Summary
Lifetime in the modelled base case.
Time horizon Patients aged ≥ 12 years: 24 weeks in TRAFFIC/TRANSPORT and PROGRESS
(extension to 96 weeks). Patients aged 6-11 years: 24 weeks in Study 109.
Outcomes Quality-adjusted life years.
Individual patient microsimulation. Liou CPH model used to apply the effect of nine risk
Methods used to generate results
factors on the baseline hazard of mortality.
As a microsimulation, changes are recorded in the underlying risk factors (as above) for
Health states each patient. Utility values are applied to health states based on ppFEV1 status of
normal (>90%), mild (70-90%), moderate (40-70%) and severe (<40%).
Cycle length Four weekly cycle for the initial two years, annual thereafter.
Modelled survival using Liou CPH model. Treatment effects were based on Study 109
(ppFEV1 for patients aged 6-11 years) and TRAFFIC/TRANSPORT (weight-for-age z-
score).
Transition probabilities
Changes in treatment effect and patient characteristics over time from PROGRESS
(decline in ppFEV1 post 24 weeks) and change in weight-for-age z-score.
Baseline hazard function from Cystic Fibrosis Registry of Ireland 2013.
Abbreviations: CPH = Cox Proportional Hazards; FEV1 =forced expiratory volume in one second; pp = percent predicted;
Source: Table 3.1.1, p.151 of the submission

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6.44 The key drivers of the model are in Table 11.

Table 11: Key drivers of the model
Description Method/Value Impact
Annual Cap of $''''''''''''''''' applied for lumacaftor/ivacaftor High, favours
Proposed Financial Cap
drug cost lumacaftor/ivacaftor
Treatment effect continued beyond 24 week trial period for
Modelled change in ppFEV1 in High, favours
life time. Updated data from extension trial PROGRESS
lumacaftor/ivacaftor patients. lumacaftor/ivacaftor
were not included in the model.
Modelled change in ppFEV1 in High, favours
Annual decline in ppFEV1 after the first 24 weeks
BSC patients. lumacaftor/ivacaftor
Assumption of price reduction at High, favours
''''''% price reduction at end of patent life
patent expiry. lumacaftor/ivacaftor
Assumption of reduction in PE- 61% reduction in PE-related hospitalisation costs;
Moderate, favours
related hospitalisation costs for estimated by multiplying hospitalisation costs associated
lumacaftor/ivacaftor
lumacaftor/ivacaftor. with BSC by 0.61.
Liou et al (2001), extrapolation of effect of intermediate High, favours
Extrapolation of survival
outcomes on survival. lumacaftor/ivacaftor
Abbreviations: BSC = best supportive care; PE = pulmonary exacerbation; ppFEV 1= per cent predicted forced expiratory volume in one
second.
Source: compiled during the evaluation.

6.45 Results from the economic evaluation with a respecified base case (to reflect use
only in those 6 and over) are presented in Table 12. These results show that the cost
per QALY gained for patients 6 and over was estimated to be $105,000 - $200,000.
Restricting the analysis to those aged 6-11 years reduced the ICER to $105,000 -
$200,000 per QALY, while it increased to $105,000 - $200,000 per QALY when
restricting the analysis to those 12 and over. These ICERs include the future price
reductions (described in 6.49 below).

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Table 12: Results of the economic evaluation

Step and component Lumacaftor/ivacaftor Best supportive care Increment
Patients aged 6 years and older, revised base case with cap
Costs $''''''''''''''''''''' $469,441 $''''''''''''''''''
QALYs 8.30 6.08 2.21
Incremental cost/extra QALY gained $''''''''''''''''''
Patients aged 6-11 years, scenario with cap
Costs $'''''''''''''''''' $611,930 $''''''''''''''''''''
QALYs 13.89 10.70 3.19
Incremental cost/extra QALY gained $''''''''''''''''''
Patients aged 6-11 years, scenario without cap
Costs $''''''''''''''''''''' $611,930 $'''''''''''''''''''''''
QALY 13.89 10.70 3.19
Incremental cost/extra QALY gained $'''''''''''''''''''''
Patients aged 12 years and older, scenario with cap
Costs $''''''''''''''''''''' $437,044 $'''''''''''''''''''''
QALYs 6.91 4.94 1.97
Incremental cost/extra QALY gained $'''''''''''''''''
Patients aged 12 years and older, scenario without cap
Costs $'''''''''''''''''''''''''' $437,044 $'''''''''''''''''''''''''
QALY 6.91 4.94 1.97
Incremental cost/extra QALY gained $''''''''''''''''''
Abbreviations: QALY=quality adjusted life year.
Note: Base case ICER from the submission of patients aged 2 years and older is $''''''''''''''''' per QALY gained with incremental cost of
$''''''''''''''''' and incremental QALY of 2.29.
Source: Compiled during the evaluation setting the patient filter to patients aged 6 years and older. Excel spreadsheet “Orkambi 2+ cost
effectiveness model March 2018 FINAL’, sheet ‘Results’.

The redacted table shows ICERs in the range of $105,000/QALY – more than
$200,000/QALY.

6.46 The model initially provided with the July 2018 submission incorporated a decline in
ppFEV1 in lumacaftor/ivacaftor patients beyond the 24 weeks trial period to life time
at a rate of ''''''% of BSC decline (declines of '''''% and '''''% were tested in the
sensitivity analysis; Table 13). This decline was informed by the longer term ppFEV 1
data from the extension trial PROGRESS, which showed that patients on
lumacaftor/ivacaftor had a decline in FEV that was 58% that of matched control
group in follow up to 96 weeks. This differs from the July 2017 resubmission of
lumacaftor/ivacaftor in patients aged 12 years and older as previously it was
assumed that there was no decline in ppFEV 1 post 24 weeks in the
lumacaftor/ivacaftor treated patients. Sensitivity analysis setting the decline to 100%
of BSC (see Table 14) resulted in an ICER of more than $200,000.
6.47 Of the three treatment effect characteristics captured by the Liou CPH model, the
only input value specific to patients aged 6 to 11 taken from Study 109 was for
ppFEV1. The model assumed that patients aged 6 to 11 years would have the same
changes in weight-for-age z-score (which was available from Study 109, where there
was no significant difference) as the patients aged 12 years and older from
PROGRESS. Using the weight-for-age z-score from Study 109 (same for
lumacaftor/ivacaftor and BSC) had minimal impact on the ICER.

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6.48 The submission assumed that there would be no difference in PEx for patients aged 6
to 11 years between those treated with BSC and lumacaftor/ivacaftor. This was
appropriate given that Study 109 did not find any statistically significant differences
in the number of PEx. However, the PBAC noted that the submission applied a 61.5%
reduction to hospitalisation-specific disease management costs for the
lumacaftor/ivacaftor arm of the model for all age groups controlling for ppFEV 1,
which was not justified by the evidence presented in the submission.
6.49 The submission applied a 5% statutory price reduction after 5 years and a '''''%
reduction in cost following generic entry after loss of exclusivity date (7.94 years) to
this cap. The PBAC has previously considered that the application of such price
reductions is inappropriate (paragraph 6.42, July 2017 PSD). The ESC noted that
removing these price reductions in the model resulted in an increase to the base
case ICER (for patients aged 6 years and over) from $105,000/QALY - $200,000/QALY
to more than $200,000/QALY. Further, the ESC noted that with tezacaftor/ivacaftor
on the horizon (recently approved overseas for patients aged 12 years and older and
currently under consideration by the TGA) use of lumacaftor with ivacaftor post-loss
of exclusivity may be displaced by this other combination.
6.50 The sensitivity analyses conducted during the evaluation for patients aged 6 years
and older which resulted in a variation in the ICER of more than '''''% are presented
in Table 13 (and in the tornado diagram at Figure 1). These show that the largest
single impact on the ICER was due to the application of the proposed financial cap
and associated price reductions (removal of the cap resulting in an ICER of more than
$200,000 per QALY).
Table 13: Results of sensitivity analyses, patients aged ≥ 6 years (change of 10% or more).
Incremental ICER (cost per
Incremental
Analysis description effect additional QALY
cost ($)
(QALYs) gained)
Base case for 6 years and older $''''''''''''''''''''' 2.21 $'''''''''''''''''''''
Costs/prices
No financial cap, use effective price $'''''''''''''''''''''''' 2.21 $'''''''''''''''''''''
No reduction in price due to LOE and no F1 statutory price reduction $''''''''''''''''''''' 2.21 $'''''''''''''''''
No financial cap or price reduction due to LOE or F1 statutory price reduction $''''''''''''''''''''''' 2.21 $''''''''''''''''''''''
Cost of cystic fibrosis disease management in lumacaftor/ivacaftor arm same $''''''''''''''''''' 2.21 $''''''''''''''''''''
as BSC (set 61.5% to 0% reduction)
Effects
Set annual decline in ppFEV1 in lumacaftor/ivacaftor treated patients to ''''% $''''''''''''''''''''' 4.69 $'''''''''''''''''
of BSC
Set annual decline in ppFEV1 in lumacaftor/ivacaftor treated patients to '''''% $''''''''''''''''' 3.35 $'''''''''''''''''''''
of BSC
Set annual decline in ppFEV1 in lumacaftor/ivacaftor treated patients to '''''''% $''''''''''''''''' 1.37 $'''''''''''''''''''
of BSC
Set annual decline in ppFEV1 in lumacaftor/ivacaftor treated patients to $''''''''''''''''''' 0.73 $'''''''''''''''''''''
'''''''''% of BSC
Abbreviation: BSC=best supportive care; FEV1=forced expiratory volume in one second; LOE=loss of exclusivity
Source: Compiled during the evaluation setting the patient filter to patients aged 6 years and older Excel spreadsheet “Orkambi 2+ cost
effectiveness model March 2018 FINAL’, sheet ‘Results’.

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The redacted table shows ICERs in the range of $75,000/QALY – more than $200,000/QALY.
Figure 1: Tornado diagram for sensitivity analysis – patients aged 6 years and older (change of 10% or more)

Abbreviations: BSC= best supportive care; CPH=Cox proportional hazard; DM=disease management; LOE=loss of exclusivity;
PE=pulmonary exacerbation; ppFEV1= percent predicted forced expiratory volume in one second;
Note: Only scenarios with a greater than 10% change in the base ICER were reported.
Source: Compiled during the evaluation setting the patient filter to patients aged 6 years and older Excel spreadsheet “Orkambi 2+ cost
effectiveness model March 2018 FINAL’, sheet ‘Results’.

6.51 An additional multivariate sensitivity analysis was conducted for patients aged 6
years and older to remove the reduction in hospitalisations due to PE, remove the
future price reductions (LOE and F1), and assume parallel FEV 1 decline (100% of BSC)
in the both arms. This resulted in an ICER of more than $200,000 (see Table 14).

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Table 14: Results of updated sensitivity analyses, patients aged ≥ 6 years

Analysis description (patients aged 6 years and older) Incremental cost Incremental ICER (cost per
($) effect (QALYs) additional QALY
gained)
Base case for 6 years and older $''''''''''''''''' 2.21 $''''''''''''''''''''
Univariate sensitivity analysis
Remove the future price reductions (LOE and no F1 statutory $''''''''''''''''''' 2.21 $''''''''''''''''''''
price reduction)
Remove the reduction in hospitalisations due to PE so cost of $''''''''''''''''' 2.21 $'''''''''''''''''''''
cystic fibrosis disease management same as BSC (set 61.5%
to 0% reduction)
Set annual decline in FEV1 in lumacaftor/ivacaftor treated $''''''''''''''''' 0.73 $''''''''''''''''''''
patients to 100% of BSC
Multivariate sensitivity analysis
Remove the reduction in hospitalisations due to PE, remove $''''''''''''''''''''' 0.73 $''''''''''''''''''
the future price reductions (LOE and F1), and assume parallel
FEV1 decline (100% of BSC) in the 2 arms.
Abbreviation: BSC=best supportive care; FEV1=forced expiratory volume in one second; LOE=loss of exclusivity

6.52 The pre-PBAC response revised the overall Financial Cap offer (covering the 2 – 5, 6 -
11 and 12+ age groups) to more than $100 million (circa 61.3% rebate) from the
more than $100 million offered in the July 2018 submission, to achieve an effective
price per treated patient of $'''''''''''' per year.
6.53 The pre-PBAC response also revised the rate of decline for the on-treatment group in
the economic model to 42%. These changes resulted in revised ICERs of
$105,000/QALY - $200,000/QALY (see Table 15) for the 2+ population,
$105,000/QALY - $200,000/QALY for the 6+ population, and $105,000/QALY -
$200,000/QALY for the 12+ population.
Table 15: Estimated ICER at effective price of $''''''''''''' per patient per year and with rate of decline 42% of BSC
Patient cohort (years) ICER
≥2 $''''''''''''''''''
≥6 $''''''''''''''''''
≥ 12 $''''''''''''''''''''''
Source: pre-PBAC response – lumacaftor with ivacaftor patients 12 years and older (p.3) and compiled during the evaluation

Drug cost/patient/year: $''''''''''''

6.54 The pre-PBAC response offers a total expenditure cap which it states will deliver a
cost per patient of $'''''''''''''' per year vis-à-vis a list price of $18,750 per 28 days
treatment (approx $244,000 per year).

Estimated PBS usage & financial implications

6.55 The sponsors pre-PBAC revised estimates for patients 2+ and older are presented in
Table 16.

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Table 16: Submission’s pre-PBAC estimated use and financial implications, patients aged 2 years and older
Source Year 1 Year 2 Year 3 Year 4 Average/ Total
Treated Section 4 ''''''''''' '''''''''''' '''''''''''' ''''''''''''' Average: '''''''''''
patients spreadsheet,
Cost to Govt
PBS, row 5
Proposed Suggested $'''''''''''''''''''''''' $'''''''''''''''''''''''''''' $''''''''''''''''''''''''''''' $''''''''''''''''''''''''''''''' Total:
Financial distribution $''''''''''''''''''''''''''''''''
Cap
Source: Table 3 of pre-PBAC response, item 7.10 July 2018

The redacted table shows that the total estimated number of patients over 4 years was less
than 10,000 and the net cost to the PBS would be more than $100 million.

6.56 The PBAC considered the submission’s estimates for the 6-11 age group to be too
high for the following reasons as documented in the ESC advice:
o The estimate of the prevalent pool of 6 – 11 year olds is higher than would be
expected based on the estimate of 40 incident patients homozygous for the
F508 del mutation each year. On the basis of this incidence figure, it would be
expected that the prevalent pool of 6 – 11 year olds would be closer to 240
(ie 6 x 40).
o The submission assumed that patients could only discontinue therapy in the
first year. This is based on the pooled discontinuation rates from TRAFFIC and
TRANSPORT (6.8% applied to patients aged 6 years and older). The final
PROGRESS study report indicates that 14.9% of the Final Analysis Set for this
study discontinued study treatment because of an “adverse event” or
“subject refused further dosing” (PROGRESS study report Version 1.0, 25
October 2016, pp 78).
In addition, a reasonable assumption is that discontinuing patients will
discontinue treatment throughout the year, so that on average each patient
receives the equivalent of half of a year’s supply in the year in which they
discontinue treatment.
Note: The final PROGRESS study report indicates “Other” was the most
frequent reason for treatment discontinuation (36.1% of overall subjects),
and the vast majority of these discontinuations were because subjects
transitioned from study drug to the commercially available supply of drug
(PROGRESS study report Version 1.0, 25 October 2016, pp 77). The PBAC does
not propose that the discontinuations reported as resulting from patients
moving to commercially available drug be taken account for in adjusting the
submission’s estimates.
o The submission assumed that patients who become eligible for treatment
each year receive a full year of treatment. A more reasonable assumption is
that initiating patients will commence treatment throughout the year, so that

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on average each patient receives the equivalent of half of a year’s supply in

the year in which they commence treatment.
6.57 The PBAC noted the revised financial impact of listing lumacaftor/ivacaftor in the 6+
population (ie 6-11 and 12+) taking into account these issues as reported in Table 17.
Table 17: Estimated use and financial implications, patients aged 6 years and older
Year 1 Year 2 Year 3 Year 4 Year 5
Number of patients treated* ''''''''''' ''''''''''''' ''''''''''''' ''''''''''''' '''''''''''''
Number of scripts
dispensed '''''''''''''''' '''''''''''''''' '''''''''''''''' '''''''''''''''' ''''''''''''''
Gross cost to PBS/RPBS $''''''''''''''''''''''''''''' $''''''''''''''''''''''''''''' $'''''''''''''''''''''''''''''' $'''''''''''''''''''''''''''''''' $'''''''''''''''''''''''''''''''
With rebate applied
With ''''''' '''''% rebate
($'''''''''''''''''' per patient per
year) $'''''''''''''''''''''''''' $ '''''''''''''''''''''''''''' $ ''''''''''''''''''''''''''''' $ '''''''''''''''''''''''''' $ '''''''''''''''''''''''''''
* This number includes and adjustment to all for patients initiating and discontinuing treatment throughout the year (i.e. the patient number
is expressed as the number treated for a full year equivalents)
Source: Compiled by the secretariat based on submission section 4 spreadsheet with adjustments to remove patients <12 years, to allow
discontinuations in year 2 in line with outcomes of PROGRESS study, and with initiating patients in year 3 onwards receiving the
equivalent of half of a year’s supply in the year in which they commence treatment

The redacted table shows that the total estimated number of patients over 5 years was less
than 10,000 and the net cost to the PBS would be more than $100 million.

6.58 The PBAC noted that the sponsor '''''''''''''''''' '''''' '''''''''''''''' ''''''''' ''''''' ''''''''''''' '''''
''''''''''''''''''' ''''''''''''''' ''' ''''''''''''''''' '''''''' '''''''''''' '''''''''''''' ''''''''''''' ''''''''' ''''''''''''''''' '''
'''''''''''''''''''' '''''''''''' ''''''''''''''' '''''''''''' ''''''''''''''''''''''. In its pre-PBAC Response, the
sponsor reiterated its willingness to be ''''''''''''''' ''''''''''''''''''' '''''' ''''''''''''''''''''''' '''' ''''''
'''''''''''''' ''''''''' '''''''' ''''''''''''''''''' ''' '''''' ''''''''''''' ''''''''''''''''' (see Table 16).
6.59 The PBAC considered this approach to be associated with a significant risk '''''''' ''''''
''''''''''''''''''''''' '''''''''''' '''''''' ''' ''''''''''''' ''''''''''''''' ''''''''' '''''''''''''' ''''''' ''''''''''''' ''''''' '''''''' ''''' ''''''
'''''''''''''''''' '''' '''''''' ''''''''' ''' '''''''''''''''''''''' ''''' ''''''' '''''''''''''' '''''''''''''''' ''''''''' '''''''''''' ''''''''''''''''
'''''''' '''''''''' ''''''''''''''''''''''' ''''''' '''''''''' ''''''''''' ''''''''''''''''''' ''''' '''''''''''''''''' ''' ''''''''''''''''' '''''''''''''
''''''''''''''' '''''''''''''''''''''''''' ''''' '''''''''''''' '''''' '''''''''''''''''''''''''''' '''''' ''''''''''''''' '''''''''' ''''''' '''''
''''''''''' ''''''''''''''''' ''''''' '''' '''''''''''''' '''''' '''''''''' '''''' ''''' '''''''''''''''''''''''''' ''''''''''' '''''''''''
''''''''''''''''''''''''''' ''''''''''''''''' ''''''' ''''''''

Managed Access Program

6.60 The PBAC considered that, in the event it decides to recommend the listing of
ivacaftor/lumacaftor be extended to include the 6 – 11 age group, it would likely also
recommend a Managed Access Program (MAP) of the type described in the PSD for
item 7.10 from July 2018.
For more detail on PBAC’s view, see section 7 PBAC outcome.

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 Public Summary Document – July 2018 PBAC Meeting

7 PBAC Outcome
7.1 The PBAC deferred making a recommendation to list ivacaftor/lumacaftor on the PBS
for patients aged 6–11 years who are homozygous for the F508del mutation in the
CFTR gene to enable the TGA to finalise its negotiations with the sponsor with
respect to the provision of long term efficacy and safety data from use in the
Australian Health Care setting.
7.2 The PBAC was reassured by the data from the 24 week randomised, placebo
controlled study, Study 109, which showed a similar improvement in ppFEV1 in the 6
– 11 year age cohort as that observed in the 12+ year cohort, despite the group
having less potential to improve ppFEV1 than older patient cohorts.
7.3 The PBAC agreed with the rationale for commencing treatments that slow the
progression of damage early in the course of a disease. However the PBAC
considered the evidence that ivacaftor/lumacaftor is a disease modifying treatment
that prevents declines in lung function in patients with Cystic Fibrosis in the long
term and improves survival is not yet available.
7.4 The PBAC considered it appropriate for the sponsor to provide further outcome data
for ivacaftor/lumacaftor in the 6 – 11 age group for the PBAC’s consideration,
particularly in the context of a long term treatment for young children which has the
potential to cause adverse events. The PBAC noted that a full report of the planned
interim analysis of Study 110 (as referred to in Chilvers M, 2017) should now be
available and that data for the full study period should be available in the near
future.

Outcome:
Deferred

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 Public Summary Document – July 2018 PBAC Meeting

Addendum to the July 2018 PBAC Minutes:

5.08 LUMACAFTOR with IVACAFTOR,

Tablet containing lumacaftor 100 mg with ivacaftor
125 mg,
Orkambi®,
Vertex Pharmaceuticals (Australia) Pty Ltd
8 Background
8.1 At its July 2018 meeting, the PBAC deferred making a recommendation to list
lumcaftor/ivacaftor on the PBS for patients with Cystic Fibrosis (CF) aged 6–11 years
who are homozygous for the F508del mutation in the CF transmembrane
conductance regulator (CFTR) gene to enable the Therapeutic Goods Administration
(TGA) to finalise its negotiations with the sponsor with respect to the provision of
long term efficacy and safety data from use in the Australian Health Care setting.
TGA Status
8.2 Subsequent to the July 2018 meeting, on 10 August 2018, the TGA delegate
approved lumacaftor/ivacaftor for registration for use in children aged 6 – 11 years
with the following conditions:
 For the purpose of collecting post-market data, [Vertex] should encourage
(where feasible) prescribers to notify the Australian CF registry when patients
commence treatment with ORKAMBI so that this is entered as a descriptive
factor.
 [Vertex is] required to provide the TGA with evidence of the long term efficacy
and safety of ORKAMBI when initiated in patients aged 6-11 years in the form of
an ongoing post market observational study. The data should include data from
both Australian and International CF registries. It should include the impact of
ORKAMBI on FEV1, rate of decline in FEV 1, exacerbations, BMI, diabetes, time to
lung transplant, mortality and if possible time off work/school, as well as safety.
It should include a comparison of patients not treated with ORKAMBI, preferably
controlled for age. It should also include data about safety. Reports should be
provided every 5 years for the next 20 years.
 [Vertex] should include details of this post-market study in an updated
Australian Specific Annex (ASA) to the EU Risk Management Plan (RMP) and
submit it to the TGA for review within three months of the date of this approval
letter.
8.3 Following the resolution of the TGA registration, the PBAC was requested by the
Minister’s delegate to reconsider the listing of lumacaftor/ivacaftor for the
treatment of patients with cystic fibrosis (CF) aged 6–11 years.

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 Public Summary Document – July 2018 PBAC Meeting

Estimated PBS usage and financial implications

8.4 The estimated financial impact of extending the listing to include the 6 – 11 year age
group was estimated in July 2018 as follows:
Table 18: Estimated use and financial implications, patients aged 6 years and older at $'''''''''''''' per patient per year

Year 1 Year 2 Year 3 Year 4 Year 5

Number of patients treated* '''''''''' ''''''''''' '''''''''''' ''''''''''''' ''''''''''
Number of scripts
dispensed '''''''''''''''' '''''''''''''' ''''''''''''''' '''''''''''''''' ''''''''''''''''
Gross cost to PBS/RPBS $'''''''''''''''''''''''''''''''' $''''''''''''''''''''''''''' $''''''''''''''''''''''''''''' $''''''''''''''''''''''''''' $'''''''''''''''''''''''''''''
With rebate applied
With ''''''''''''''% rebate
($'''''''''''''''' per patient per
year) $'''''''''''''''''''''''''''' $ ''''''''''''''''''''''''''''' $ ''''''''''''''''''''''''' $ '''''''''''''''''''''''''' $ ''''''''''''''''''''''''''''
Cost for 12+ group with
''''''''''''''% rebate applied $'''''''''''''''''''''''''''' $''''''''''''''''''''''''''''' $'''''''''''''''''''''''' $'''''''''''''''''''''''''''' $'''''''''''''''''''''''''''
Additional cost for 6 – 11
year group $'''''''''''''''''''''''''' $''''''''''''''''''''''''' $'''''''''''''''''''''''' $''''''''''''''''''''''''' $'''''''''''''''''''''''''''''
Source: Table 17, PBAC PSD item 5.08 July 2018 & Table 17, PBAC PSD item 7.10 July 2018

The redacted table shows that the total estimated number of patients over 5 years was less
than 10,000 and the net cost to the PBS would be more than $100 million.

Managed Access Program and risk share arrangements

8.5 In July 2018, the PBAC considered that, in the event it decides to recommend the
listing of ivacaftor/lumacaftor be extended to include the 6 – 11 age group, it would
likely also recommend a Managed Access Program (MAP) of the type described in
the PSD for item 7.10 (paragraph 6.60 above)
8.6 In July 2018, the PBAC considered that a MAP for lumacaftor/ivacaftor would allow
patients in the 12 years and older age group to access treatment through the PBS
whilst providing the sponsor with an extended period to provide further data to
satisfy the PBAC that the benefits of treatment are sustained over a longer period
(paragraphs 6.73 – 6.79 of the July 2018 PBAC PSD, item 7.10).
8.7 Under such an MAP, subsidy could be paid at the sponsor’s asking price of $''''''''''''''
per patient per year for a period of two and a half years to allow the sponsor to
provide further data to satisfy the PBAC that the differences in the rates of decline in
lung function (ppFEV1) and pulmonary exacerbations observed in the PROGRESS
study are sustained over a longer time period of at least 4 years in real clinical
practice.
8.8 If, by the end of the two and a half year initial period of the MAP, the sponsor’s
assumptions on rate of decline have not been substantiated or have only been
partially substantiated, through a submission to the PBAC and the PBAC affirming the
cost-effectiveness of the medicine, the PBAC considered that the price paid for
lumacaftor/ivacaftor should reduce to a level consistent with the evidence provided.

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 Public Summary Document – July 2018 PBAC Meeting

If that were the case, the minimum price paid in the second half of the MAP would
be $''''''''''''' per patient per year consistent with the assumption that patients
treated with lumacaftor/ivacaftor maintain an advantage over untreated patients
after 96 weeks, but that treated patients decline at a similar rate to untreated
patients. Indicative costs of including patients aged 6 – 11 years in a MAP consistent
with that recommended for patients aged 12 years and older are presented in Table
19.
Table 19: Indicative cost to Commonwealth of listing lumacaftor/ivacaftor for patients aged 6 years and over

Year 1 Year 2 Year 3 Year 4 Year 5 Total

MAP
conditions
met
$''''''''''''''''''''''''''' $ '''''''''''''''''''''''''' $ '''''''''''''''''''''''''' $ '''''''''''''''''''''''''' $ ''''''''''''''''''''''''''''' $'''''''''''''''''''''''''''
MAP
conditions
not met
$''''''''''''''''''''''''''''' $ '''''''''''''''''''''''''' $''''''''''''''''''''''''' $'''''''''''''''''''''''' $'''''''''''''''''''''''''' $'''''''''''''''''''''''''''''

8.9 In July 2018, the PBAC also noted that the sponsor plans to bring forward new
treatments for patients who are homozygous for the f508del mutation in the CFTR
gene, with tezacaftor with ivacaftor currently undergoing regulatory review and a
triple therapy combination treatment in clinical trials. The PBAC recognised that this
might limit the availability of longer term data for lumacaftor with ivacaftor but
considered that the MAP could allow the PBAC to be provided with longer term data
for patients treated continuously with lumacaftor with ivacaftor, as well as treatment
with tezacaftor with ivacaftor or triple therapy, or through consecutive periods of
treatment with more than one of these regimens.
8.10 At that time the PBAC also considered that it would be appropriate for the Minister
to enter into a deed with the sponsor to specify the annual patient cost, overall
financial caps and terms of the MAP.

9 PBAC Outcome
9.1 The PBAC recommended, out of session, the listing of lumacaftor with ivacaftor for
patients with CF aged 6–11 years who are homozygous for the F508del mutation in
the CFTR gene on the basis that it should be available only under special
arrangements under section 100 (Highly Specialised Drugs Program) and only in the
circumstances: for the treatment of patients with CF aged 6 - 11 years who are
homozygous for the F508del mutation in the CFTR gene. The PBAC recommended
the special arrangements and circumstances described Section 10 below.
9.2 The PBAC is satisfied that lumacaftor with ivacaftor provides, for some patients, a
significant improvement in efficacy over best supportive care.
9.3 Consistent with its recommendation for lumacaftor/ivacaftor in patients with CF
aged 12 years and older, the PBAC recommendation for listing in patients aged 6 - 11

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 Public Summary Document – July 2018 PBAC Meeting

years was based on, among other matters, its assessment that the cost-effectiveness
of lumacaftor/ivacaftor would be acceptable if the following measures were
implemented to contain risks associated with the cost-effectiveness and overall cost
of the drug to the PBS.
 A Managed Access Program as described in paragraphs 8.5 – 8.10 above;
 A Special Pricing Arrangement to give effect to the offered price of $'''''''''''''
per patient per year; and
 Caps on ''''''''' ''''''''''''''''''''''' in line with the estimates in Table 19 above.

9.4 In addition, the PBAC recalled that at its July meeting it considered it appropriate for
the sponsor to provide further outcome data for ivacaftor/lumacaftor in the 6 – 11
age group for the PBAC’s consideration, particularly in the context of a long term
treatment for young children which has the potential to cause adverse events. On
that basis, the PBAC also recommended that:
 Vertex provide PBAC with an interim report of the post-market study it is
undertaking for the TGA, at the same time as it submits to data to the PBAC
to satisfy the MAP (on or before the first quarter of the third year of listing);
and
 the interim and final results from study 110 (96 weeks open use in 6 - 11 year
olds) be submitted to the PBAC within 1 month of the reports being finalised
unless one or both reports has already been finalised, in which case the
relevant report must be provided to the PBAC within one month of the
commencement of subsidy.

9.5 The PBAC recognised the potential clinical value of lumacaftor/ivacaftor in the
treatment of cystic fibrosis in patients aged 6 – 11 years who are homozygous for the
F508del mutation and recognised the strong support for subsidised access to this
medicine and acknowledged the many consumer comments and the correspondence
from the Cystic Fibrosis Centre Directors, Cystic Fibrosis Australia and Cystic Fibrosis
SA relating to this submission.
9.6 The PBAC did not consider that lumacaftor/ivacaftor should be treated as
interchangeable with any other drugs.
9.7 The PBAC advised that lumacaftor/ivacaftor is not suitable for prescribing by nurse
practitioners.
9.8 The PBAC recommended that the Early Supply Rule should not apply.

Outcome:
Recommended

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 Public Summary Document – July 2018 PBAC Meeting

10 Recommended listing
Add new item:

Name, Restriction, Max. №.of Proprietary Name and

Manner of administration and form Qty Rpts Manufacturer
Pack Vertex
lumacaftor 100 mg/ ivacaftor 125 mg containin Orkambi Pharmaceutical
5
tablets g 112 ™ s (Australia) Pty
tablets Ltd
Category / Section 100 – Highly Specialised Drugs Program
Program
Prescriber type: Dental Medical Practitioners Nurse practitioners Optometrists
Midwives
PBS Indication: Cystic Fibrosis
Treatment phase: Initial
Restriction: Authority Required - In Writing

Treatment Must be treated by a specialist respiratory physician with expertise in cystic fibrosis, OR
criteria: Must be treated in consultation with a specialist respiratory physician with expertise in cystic fibrosis if
attendance is not possible due to geographic isolation;
AND
Must be treated in a centre with expertise in cystic fibrosis, OR
Must be treated in consultation with a centre with expertise in cystic fibrosis if attendance is not possible
due to geographic isolation.
Clinical criteria: Patient must be homozygous for the F508del mutation in the cystic fibrosis transmembrane conductance
regulator (CFTR) gene;
AND
The treatment must be given concomitantly with standard therapy for this condition.
Population Patient must be aged between 6 and 11 years inclusive.
criteria:
Prescriber The patient must be registered in the Australian Cystic Fibrosis Database Registry. Treatment must not
Instructions: be given to a patient who has an acute upper or lower respiratory infection, pulmonary exacerbation, or
changes in therapy (including antibiotics) for pulmonary disease in the last 4 weeks prior to commencing
this drug.

The authority application must be in writing and must include:

(1) a completed authority prescription form; and
(2) a completed Cystic Fibrosis Lumacaftor with Ivacaftor Authority Application Supporting Information
Form; and
and
(3) a copy of the pathology report detailing the molecular testing for the patient being homozygous for the
F508del mutation on the CFTR gene; and
(4) the result of a FEV1 measurement performed within a month prior to the date of application. Note:
FEV1, must be measured in an accredited pulmonary function laboratory, with documented no acute
infective exacerbation at the time FEV1 is measured; and
(5) evidence that the patient has either chronic sinopulmonary disease or gastrointestinal and nutritional
abnormalities; and
(6) a copy of a current medication history; and
(7) height and weight measurements at the time of application; and
(8) a baseline measurement of the number of days of CF-related hospitalisation (including hospital-in-the
home) in the previous 12 months.

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 Public Summary Document – July 2018 PBAC Meeting

Administrative Special pricing arrangements apply

Advice:
No increase in the maximum number of repeats may be authorised.

No increase in the maximum quantity or number of units may be authorised.

Any queries concerning the arrangements to prescribe may be directed to the Department of Human
Services on 1800 700 270 (hours of operation 8 a.m. to 5 p.m. EST Monday to Friday).

Prescribing information (including Authority Application forms and other relevant documentation as
applicable) is available on the Department of Human Services website at www.humanservices.gov.au

Applications for authority to prescribe should be forwarded to:

Department of Human Services
Complex Drugs
Reply Paid 9826
HOBART TAS 7001

Category / Section 100 – Highly Specialised Drugs Program

Program
Prescriber type: Dental Medical Practitioners Nurse practitioners Optometrists
Midwives
PBS Indication: Cystic Fibrosis
Treatment phase: Continuing
Restriction: Authority Required - In Writing

Treatment criteria: Must be treated by a specialist respiratory physician with expertise in cystic fibrosis, OR
Must be treated in consultation with a specialist respiratory physician with expertise in cystic
fibrosis if attendance is not possible due to geographic isolation;
AND
Must be treated in a centre with expertise in cystic fibrosis, OR
Must be treated in consultation with a centre with expertise in cystic fibrosis if attendance is
not possible due to geographic isolation.
Clinical criteria: Patient must have previously received PBS-subsidised treatment with this drug for this
condition
AND
The treatment must be given concomitantly with standard therapy for this condition.
Population criteria Patient must be aged between 6 and 11 years inclusive.
Prescriber Instructions Treatment must not be given to a patient who has an acute upper or lower respiratory
infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for
pulmonary disease in the last 4 weeks prior to commencing this drug.

Patients who have an acute infective exacerbation at the time of assessment for continuing
therapy may receive an additional one month's supply in order to enable the assessment to
be repeated following resolution of the exacerbation.

The authority application must be in writing and must include:

(1) a completed authority prescription form; and
(2) a completed Cystic Fibrosis Lumacaftor with Ivacaftor Authority Continuing Application
Supporting Information Form; and
(3) the result of a FEV1 measurement performed within a month prior to the date of
application. Note: FEV1, must be measured in an accredited pulmonary function laboratory,
with documented no acute infective exacerbation at the time FEV1 is measured; and
(4) a copy of a current medication history; and
(5) height and weight measurements at the time of application; and

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 Public Summary Document – July 2018 PBAC Meeting

(6) the number of days of CF-related hospitalisation (including hospital-in-the home) in the
previous 6 months.
Administrative Advice: Special pricing arrangements apply

No increase in the maximum number of repeats may be authorised.

No increase in the maximum quantity or number of units may be authorised.

Any queries concerning the arrangements to prescribe may be directed to the Department
of Human Services on 1800 700 270 (hours of operation 8 a.m. to 5 p.m. EST Monday to
Friday).

Prescribing information (including Authority Application forms and other relevant

documentation as applicable) is available on the Department of Human Services website at
www.humanservices.gov.au

Applications for authority to prescribe should be forwarded to:

Department of Human Services
Complex Drugs
Reply Paid 9826
HOBART TAS 7001

11 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.

12 Sponsor’s Comment
The sponsor had no comment.

30