Cost-effectiveness evaluation offluticasone furoate/umeclidinium
bromide/vilanterol trifenatate (Trelegy Ellipta)
by the academic group[Version 1.3]
[November 12, 2020]1【Table of contents】
Table of abbreviations ..............................................................................4
0. Analytical framework ............................................................................6
1. Summary of other HTA agency reviews ...................................................9
1.1 Summary .......................................................................................9
1.2 Review results .............................................................................. 19
1.3 Issues raised in HTA agencies ......................................................... 19
2. Evaluation of additional benefit ............................................................ 21
2.1 Summary of additional benefit assessment by the manufacturer andreview results .................................................................................... 21
2.2 Systematic review by the academic group ......................................... 24
2.2.1 Clinical questions ..................................................................... 24
2.2.2 Implementation flow ................................................................ 26
2.2.3 Inclusion and exclusion criteria .................................................. 26
2.2.4 Database ................................................................................ 27
2.2.5 Search formula ........................................................................ 27
2.2.6 Search results ......................................................................... 36
2.2.7 Summary of clinical trials .......................................................... 39
2.2.8 Availability for additional benefit assessment ............................... 42
2.3 Results of additional benefit assessment ........................................... 44
3. Evaluation of cost-effectiveness ........................................................... 64
3.1 Summary of manufacturer’s results and review by academic group ...... 64
3.2 Summary of revisions by academic group ......................................... 68
3.3 Methods of the revised base case analysis ........................................ 69
3.3.1 Cost-effectiveness in population C and D ..................................... 69
3.3.2 Cost-minimization analysis in population E, F, and I ...................... 70
3.3.3 Cost-effectiveness analysis in population G, H, J, K, and L (Settings ofbackground factors) ......................................................................... 72
3.3.4 Cost-effectiveness analysis in population G, H, J, K, and L (Settings ofsurvival probability).......................................................................... 74
3.4 Methods of the revised scenario analysis .......................................... 80
3.4.1 Cost-effectiveness analysis in population G, H, J, K, and L (Settings in
Utilities) ......................................................................................... 80
4. Results of cost-effectiveness assessment............................................... 82
4.1 Summary ..................................................................................... 82
4.2 Revised base case analysis ............................................................. 85
4.2.1 Cost-effectiveness in population C and D ..................................... 85
4.2.2 Cost-minimization analysis in population E, F, and I ...................... 85
4.2.3 Cost-effectiveness analysis in population G, H, J, K, and L (Settings ofbackground factors) ......................................................................... 85
4.2.4 Cost-effectiveness analysis in population G, H, J, K, and L (Settings of2

survival rate)................................................................................... 87
4.3 Revised sensitivity analysis ............................................................. 89
4.4 Revised scenario analysis ............................................................... 95
4.4.1 Cost-effectiveness analysis in population G, H, J, K, and L (Settings ofutility) ............................................................................................ 95
4.5 Interpretation of results ................................................................. 97
4.6 Proportion of patients in the analyzed population ............................. 109
4.6.1 Methods and results of estimating the proportion of patients ........ 109
5. References...................................................................................... 116
6. Supplementary material ................................................................... 118
Table A-1 Summary of subgroup analysis studies .................................. 118
Table A-2 Bayesian interpretation of rate ratios of exacerbation ............... 122
Table A-3 Revisions of the model (Settings of background factors) ........... 123
Table A-4 Revisions of the model (Settings of survival probability) ........... 127
Table A-5 Revisions of the model (Settings of utility) .............................. 128
Table A-6 Results of the cost-effectiveness evaluation using a cutoff of
150/μL for eosinophil count ................................................................ 130

3

Table of abbreviations
Abbreviations Formal expression
ACT
ASMR
AUD
CAD
CADTH
CAT
CDEC
CEA
CFB
CI
CMA
COPD
CUA
EOS
EQ-5D
ESC
FEV1
FF
FVC
G-BA
GOLD
HAS
HTA
HRQL
ICER
ICS
IQWiG
LABA
LAMA
MCID
MITT
mMRC
MMRM
NHS
NICE
PBAC
PRISMA

Appropriate Comparator Therapy
Amelioration du Service Médical Rendu
Australian dollar
Canadian dollar
Canadian Agency for Drugs and Technologies in Health
COPD Assessment Test
Canadian Drug Expert Committee
Cost-Effectiveness Analysis
Change from Baseline
Confidence Interval
Cost-Minimization Analysis
Chronic Obstructive Pulmonary Disease
Cost-Utility Analysis
Eosinophil granulocyte
EuroQol 5 Dimension
Economics Subcommittee
Forced Expiratory Volume in one second
Fluticasone Furoate
Forced Vital Capacity
Gemeinsame Bundesausschuss
Global Initiative for Chronic Obstructive Lung Disease
Haute Autorité de SantéHealth Technology Assessment
Health-Related Quality of Life
Incremental Cost-Effectiveness Ratio
Inhaled corticosteroid
Instituts für Qualität und Wirtschaftlichkeit im
Gesundheitswesen
Long-Acting Beta2-Agonist
Long-Acting Muscarinic Antagonist
Minimum Clinically Important Difference
Multiple Inhaler Triple Therapy
modified Medical Research Council
Mixed effect Models for Repeated Measures
National Health Service
National Institute for Health and Care Excellence
Pharmaceutical Benefits Advisory Committee
Preferred Reporting Items for Systematic Reviews and MetaAnalyses
4

QALY
QOL
RCT
RR
SE
SGRQ
SMC
SMR
SR
UMEC
VI

Quality-Adjusted Life Year
Quality of Life
Randomized Controlled Trial
Relative Risk
Standard Error
St George's Respiratory Questionnaire
Scottish Medicines Agency
Service Médical Rendu
Systematic Review
Umeclidinium
Vilanterol50. Analytical framework
The evaluated product is fluticasone furoate/umeclidinium bromide/vilanterol
trifenatate (Trelegy 100 Ellipta 14 doses, Trelegy 100 Ellipta 30 doses)(FF/UMEC/VI) and the manufacturer is GlaxoSmithKline K.K. FF/UMEC/VI is atherapeutic agent for chronic obstructive pulmonary disease (chronic
bronchitis/emphysema) (COPD) and was selected as a target product of thecost-effectiveness evaluation at Central Social Insurance Medical Council on
May 15, 2019. The market size of FF/UMEC/VI is 23.6 billion yen and thecategory of the cost-effectiveness evaluation is H1 (The market size is 10 billion
yen or more). The analytical framework of FF/UMEC/V was established asshown in Table 0-1 after the Expert Committee of Cost-Effectiveness evaluation
on September 12, 2019 and October 4, 2019.

6

Table 0-1 Analytical framework
The target disease is chronic obstructive pulmonary disease (chronic bronchitis/emphysema) (COPD).
In this evaluation, the following subpopulations of A-L will be analyzed in principle, but the presence
and extent of additional benefit will first be assessed based on the results of subgroup analyses of the
IMPACT trial (or other literature, if available).
Prior therapy

Population

Triple therapy

Dual therapy

Details of the priortherapy

MITT (triple therapy
with inhalation of 2
drug products)

ICS/LABA

Prior therapy: Dual therapy (LAMA/LABA)
or monotherapy (LAMA)
monotherapy
Other

LAMA

Eosinophil count< 100/μL≥ 100/μL

Comparator

A

B

MITT
(triple therapy withinhalation of 2 drug
products)C

D

ICS/LABAE

F

LAMA/LABAGH

ICS/LABAI

J

LAMA/LABAK

L

ICS/LABA

Non analyzed

Eosinophil count 100/μL will be the main analysis with a cutoff of 100/μL, and a sensitivity analysis of
150/μL will also be performed.

Comparator

For the price of comparator, the least expensive inhalant that contains the relevant two components
should be used in accordance with the description in 4.1.3 of Guideline for Analysis of CostEffectiveness Evaluation by the Central Social Insurance Medical Council, 2nd Version, “If single
comparator cannot be determined based on item “4.1”, the comparator(s) should be selectedconsidering the comparators in randomized controlled trials (RCTs), referred technology when7

determining the official price, cost-effectiveness, and other factors, based on agreement in
consultation.".
Reason for selectionof comparator
Other perspectivein addition to publichealthcare payer

It is appropriate to select ICS/LABA and LAMA/LABA, which are usually used for a dual therapy, as acomparator. However, when comparing triple therapy, MITT (triple therapy with inhalation of 2 drug
products) should be used.
Yes (Details:

Outcome and thereason if QALY is not
used.

Not applicable

Other

Not applicable

)

No

8

1. Summary of other HTA agency reviews
1.1 Summary
The manufacturer reported the results of the evaluation of FF/UMEC/VI byhealth technology assessment (HTA) organizations in the UK, France, Germany,
Canada, and Australia. In response to this, the academic group conducted asurvey on the evaluation results of FF/UMEC/VI at these agencies andcompared the results with those reported by the manufacturer. The evaluation
status was summarized in Tables 1-1 and 1-2.
Next, the academic group reviewed the details of economic evaluation of
FF/UMEC/VI in these countries. The economic evaluation of FF/UMEC/VI was
conducted only by CADTH in Canada and PBAC in Australia. Details of the costeffectiveness evaluation were summarized and compared with details of thereport by the manufacturer (Table1-3 and 1-4).

9

Table 1-1 Evaluation Status
Country Organization
UK

Evaluation results
Manufacturer

Academic group

NICE▪ No assessment or recommendation
NICE has not completed a formal assessment of
FF/UMEC/VI in COPD but has reviewed the evidence
for local decision-making purposes. Guidance todecision makers: The acquisition cost of FF/UMEC/VI
is less than that of other combinations of ICS/LABA
plus LAMA in 2 inhalers. A 30-day supply oftreatment with FF, UMEC, and VI costs £44.50(excluding VAT) when the triple-therapy inhaler(FF/UMEC/VI) is prescribed. This compares with£49.50 (excluding VAT) when FF and VI areprescribed in a dual therapy inhaler (FF/VI 92/22
μgs) together with UMEC in a single-therapy inhaler(UMEC 55 μg).

<No guidance on technology assessment,
only summary of clinical evidence>
Indication: Adult patients with moderate tosevere COPD who are not adequately treatedwith ICS/LABA.
The drug cost of telergy is smaller than that of
MITT (₤44.5 and ₤49.5 per month for Telergy
and MITT, respectively).

SMC▪ Recommendation (Abbreviated submission)
FF/UMEC/VI was accepted for restricted use within
NHS Scotland Indication under review: maintenancetreatment in adult patients with moderate to severe
COPD who are not adequately treated by a
combination of an ICS and a LABA
SMC restriction: in patients with severe COPD (FEV1<50% predicted normal) A similar restriction is inplace for other ICS/LABA containing treatments
including Relvar, Symbicort, Fortair (not launched inJapan), and Trimbow (not launched in Japan).

<Conditional recommendation>
 SMC restriction: Patients with severe COPD(%FEV1 < 50%)
 Indication: Maintenance therapy in adultpatients with moderate to severe COPD whohave not been adequately treated with
ICS/LABA.
 The drug cost of Trelegy is less than that of
MITT.

10

FF/UMEC/VI costs less than inhalers containing FF/VI
92/22 μg and UMEC 55 μg administered separately.
FranceHAS▪ Outcome of review
FF/UMEC/VI is a fixed combination which represents
a therapeutic alternative in patients with severe
COPD treated unsatisfactorily by the combination of
an ICS and a LABA or by the combination of a LABA
and a LAMA. FF/UMEC/VI has no place in the
management of moderate COPD.
▪ SMR
Moderate: in treatment of severe COPD in adults
treated unsatisfactorily by the combination of
ICS/LABA or LABA/LAMA (reimbursable indication)
Insufficient: in moderate COPD adults patientstreated unsatisfactorily by the combination of
ICS/LABA or LABA/LAMA (non reimbursable
indication)▪ ASMR
V: in the management of severe COPD patients<SMR: Moderate (Severe COPD),
Insufficient (Moderate COPD), ASMR: V(Lack of clinical improvement), efficiency
assessment: Not performed>
 Clinical benefit for management of adultpatients with severe COPD, who are notsufficiently treated with ICS/LABA, is low andthe benefit for the treatment strategy has notbeen demonstrated.
 Clinical benefit is insufficient to justify
reimbursement in the management ofmoderate COPD.
 Although Trelegy was statistically superior to
ICS/LABA and ICS/LABA in FEV1, thedifference was minimal.

Germany

IQWiG▪ No additional benefit
FF/UMEC/VI has been the subject of two benefit
assessments; in ICS+LABA pretreated patients(launch label) in March 2018, and in LAMA+LABA
pretreated patients (label extension) in November
2018. In both assessments, the Federal Joint
Committee (G-BA) defined the Appropriate
Comparator Therapy (ACT) as patient-individualized
optimization of the existing therapy (either
ICS+LABA or LAMA+LABA). For the benefit<No additional benefit>
 An appropriate comparator technology is
MITT and there is no additional benefit incomparison to it.

11assessment in LAMA+LABA pretreated patients the
G-BA also subsequently changed the ACT definition
to ICS+LAMA+LABA triple therapy before publishing
the assessment determination, as a result ofchanges in COPD guidelines.
As a consequence, the comparators in FF/UMEC/VI
trials (IMPACT study and FULFIL study) did notmatch the ACT definitions for the benefit
assessments, therefore the decision of the G-BA wasadded benefit not proven.

<Conditional recommendation>
 A triple-drug therapy should not be used as
an initial treatment for COPD.
 It should be used when COPD is notcontrolled by optimal two-drug combination
therapy.
 The cost of Trelegy should not exceed thereimbursement price of MITT.

CanadaCADTH▪ Recommendation
The CADTH Canadian Drug Expert Committee(CDEC) recommended that FF/UMEC/VI was
reimbursed for the long-term, once daily,
maintenance treatment of COPD, including chronic
bronchitis and/or emphysema, if the following
criteria and condition were met:
Criteria: 1) Patients should not be started on triple
inhaled therapy as initial therapy for COPD. 2) For
use in patients who are not controlled on optimaldual-inhaled therapy for COPD Condition: Drug plan
cost of FF/UMEC/VI should not exceed the drug plan
cost of treatment with any triple therapies
reimbursed for COPD (LAMA/ LABA/ICS).

Australia

PBAC▪ Recommendation<Conditional recommendation>
The PBAC recommended the Authority Required  Limited to the treatment of patients with(STREAMLINED) listing of FF/UMEC/VI in December
COPD who have a predicted FEV1 of less than2017 for treatment of COPD in patients with FEV1
50% and who experience repeated worsening<50%
predicted
andhistoryofrepeated

12

exacerbations with significant symptoms despite
maintenance with dual therapy LAMA and LABA, or
ICS.
The PBAC recommended an extension to the existing
listing of FF/UMEC/VI in March 2019 for COPD,
specifically the removal of the FEV1 threshold fromthe clinical criteria in the restriction.

of symptoms despite two-drug therapy(March 2017).
Expansion of Trelegy to an existing list andremoval of the threshold of FEV1 wererecommended (March 2019).

13

Table 1-2 Status of economic evaluation
Country
Organization
Manufacturer
UK
NICE
None
SMC
None
FranceHAS
NA (clinical effectiveness
only)
Germany
IQWiG
NA (clinical effectiveness
only)
CanadaCADTH
Present
Australia
PBAC
Present

Academic analysis
None
None
None
None
Present
Present

14

Table 1-3 Details of cost-effectiveness analysis in Canada (CADTH)Country
CanadaManufacturer
Organization
URL

Academic analysis

CADTH
https://www.cadth.ca/sites/default/files/cdr/compl
ete/SR0562_cdr_complete_Trelegy_Ellipta_Aug_27_18.pdf
https://www.cadth.ca/sites/default/files/cdr/pharmacoeconomic/SR0562_TrelegyEllipta_PE_Report.pdf

https://www.cadth.ca/fluticasonefuroateumeclidiniumvilanterol

Targettechnology

FF/UMEC/VI

FF/UMEC/VI

Evaluation
results

Recommendation

Conditional recommendation

The CADTH CDEC recommended that FF/UMEC/VI
was reimbursed for the long-term, once daily,
maintenance treatment of COPD, including chronic
bronchitis and/or emphysema, if the following
criteria and condition were met:
Criteria: 1) Patients should not be started on triple
inhaled therapy as initial therapy for COPD. 2) For
use in patients who are not controlled on optimaldual-inhaled therapy for COPD.
Condition: Drug plan cost of FF/UMEC/VI should
not exceed the drug plan cost of treatment withany triple therapies reimbursed for COPD (LAMA/
LABA/ ICS).



COPD

COPD

Once-daily single-dose inhalationOnce-daily single-dose inhalation

Details of thecondition

Target disease
Usage and

A triple-drug therapy should not be used as an
initial treatment for COPD.
It should be used when COPD is not controlled by
optimal two-drug combination therapy.
The cost of Trelegy should not exceed thereimbursement price of MITT.

15

Dosage
Comparator

ICER

1) FF/VI
2) UMEC/VI
3) FP 250μg/ SAL 50μg + TIO 18μg
4) FP 500μg/ SAL 50μg + TIO 18μg(1) FF/VI(2) UMEC/VI(3) FP 250μg/ SAL 50μg + TIO 18μg(4) FP 500μg/ SAL 50μg + TIO 18μg

<GSK>1) CAD19,649/QALY (CAD2,598/0.1322QALYs)
2) CAD14,864/QALY (CAD1,801/0.1211QALYs)
3) Dominant (-CAD482/0.0050QALYs)
4) Dominant (-CAD1,670/0.028QALYs)<Manufacturer>(1) CAD19,649/QALY(2) CAD14,864/QALY(3) Dominant(4) Dominant<CADTH>
1) CAD21,189/QALY (CAD2,793/0.132QALYs)
2) CAD17,002/QALY (CAD2,065/0.121QALYs)
3) CAD137,990/QALY (CAD674/0.005QALYs)
4) Dominant (-CAD34/0.022QALYs)<CADTH>(1) CAD21,189/QALY(2) CAD17,022/QALY(3) CAD137,990/QALY(4) Dominant

16

Table 1-4 Details of cost-effectiveness analysis in Australia (PBAC)Country
Australia
Manufacturer
Organization
URL

Academic analysis

PBAC
http://www.pbs.gov.au/industry/listing/elements/p
bacmeetings/psd/2019-03/files/fluticasone-psdarch-2019.pdf

http://www.pbs.gov.au/pbs/industry/listing/elements/pb
ac-meetings/psd/2017-12/fluticasone-psd-december2017https://www.pbs.gov.au/info/industry/listing/elements/p
bac-meetings/psd/2019-03/fluticasone-fuorate-psdmarch-2019

Targettechnology

FF/UMEC/VI

FF/UMEC/VI

Evaluation
results

Recommendation

Conditional recommendation

The PBAC recommended the Authority Required(STREAMLINED) listing of FF/UMEC/VI in
December 2017 for treatment of COPD in patientswith FEV1 <50% predicted and history of repeatedexacerbations with significant symptoms despite
maintenance with dual therapy LAMA and LABA, or
ICS.
The PBAC recommended an extension to theexisting listing of FF/UMEC/VI in March 2019 for
COPD, specifically the removal of the FEV1
threshold from the clinical criteria in the
restriction.



COPD

COPD

Details of thecondition

Target disease

Limited to the treatment of patients with COPD whohave a predicted FEV1 of less than 50% and who
experience repeated worsening of symptoms despite
two-drug therapy (March 2017).
Expansion of Trelegy to an existing list and removalof the threshold of FEV1 were recommended (March2019).

17

Usage andDosageOnce-daily single-dose inhalationOnce-daily single-dose inhalation

Comparator

UMEC/VI

UMEC/VI

AUD15,000/QALY<Manufacturer>
AUD15,000/QALY<ESC>
AUD15,000~AUD45,000/QALY

ICER

18

1.2 Review results
As a result of the review on the assessment of Trelegy by HTA organizations,details of the report by the manufacturer were generally appropriate except
following points.
(1) The interpretation of evaluations by SMC, CADTH, and PBAC differed interms of whether the results were "recommended" or "conditionally
recommended.
(2) Some of the reported ICERs of FF/UMEC/VI by CADTH were different (theICER for FF/UMEC/VI compared to UMEC/VI is CAD17,002/QALY in the
manufacturer’s report, but the correct value is CAD17,022/QALY).
(3) The reported ICERs of FF/UMEC/VI by PBAC were different (themanufacturer’s report does not mention the revised results by ESC, but
PBAC reports the revised ICER by ESC as AUD15,000~AUD45,000/QALY. ).
1.3 Issues raised in HTA agencies
Considering the issues raised in the assessment process by HTA organizations,the issues that may be helpful for this evaluation was summarized as follows.
<NICE>(1) It is not clear that the abrupt discontinuation of ICS in the LAMA/LABA
arm of the IMPACT trial may have affected the outcome of exacerbations.
That is, in the ICS/LABA arm, 38% of patients had been treated with
ICS/LABA/LAMA prior to randomization, and treatment was stepped down.
(2) The IMPACT study showed a statistically significant difference in the SGRQ
between the ICS/LABA/LAMA group and the dual therapy group. However,the difference was -1.8 points, which was less than the " minimal clinicallyimportant difference (MCID)" of -4 points in the total SGRQ score.
However, a higher percentage of patients in the ICS/LABA/LAMA group
had improved scores above the MCID (42% v.s. 34%) compared to dual
therapy groups.
<IQWiG>(1) In the LAMA/LABA arm of the IMPACT trial, ICS was abruptly stopped at
the start of the trial, despite previous exacerbations. Treatment without
ICS in the control group is different from the usual step-down in realpractice and is not appropriate. It is doubtful that patients randomized to
LAMA/LABA in the IMPACT trial received adequate treatment. Therefore,
the IMPACT trial cannot be used to evaluate the efficacy of FF/UMEC/VI
compared with LAMA/LABA.
<CADTH>19

(1) Step-down from combination therapy including ICS may be considered inview of the patient's condition and avoidance of risks such as pneumonia
due to ICS.
(2) There is uncertainty in the prediction of exacerbation occurrence andhealth-related quality of life based on the model submitted by the
manufacturer.
(3) In the manufacturer's model, utilities are estimated based on an imprecise
mapping algorithm, and superior results for FF/UMEC/VI compared withcomparators have not been observed in the IMPACT trial.
<PBAC>(1) The manufacturer requested that the drug price of FF/UMEC/VI be thesame as that of MITT, but this was deemed unreasonable because thecost-effectiveness of triple therapy had not been evaluated in the past.
(2) The ESC believed that CEA could be implemented based on the IMPACT
study.

20

2. Evaluation of additional benefit
2.1 Summary of additional benefit assessment by the manufacturer andreview results
The manufacturer did not perform a systematic review (SR) on evaluation of
additional benefit of FF/UMEC/VI and identified 5 manufacturer sponsoredclinical studies of FF/UMEC/VI (Study 207608, Study 207609, Study 200812,
IMPACT study, FULFIL study). 207608 and 207609 were used to examine
additional benefit in populations A and B, and IMPACT was used in populations
C-L. In addition to exacerbation specified in the analysis framework, themanufacturer used FEV1 and SGRQ as outcome measures for the additional
benefit assessment. In addition to populations A-L, the manufacturer also
submitted additional benefit assessments for subpopulations by pretreatment(PT-1 to PT-5), subpopulations by blood eosinophil counts level (EOS-1 to EOS4), and ITT populations (ITT-1 and ITT-2). As a result of the manufacturer's
analysis, FF/UMEC/VI was found to have additional benefit in all populations
except for populations A and B. For these, the following issues are raised.
<SR was not performed>
In accordance with the "Guideline for Analysis of Cost-Effectiveness Evaluationby the Central Social Insurance Medical Council, 2nd Version", a SR should be
conducted to evaluate the presence of additional benefit[1]. On the other hand,
the manufacturer did not conduct a SR and identified five studies, as there were
no comparative studies other than the manufacturer sponsored RCTs thatexamined the clinical question in this evaluation. This made it difficult to assess
the validity of the methodology and results of the systematic review.
<Setting of the target population>
The ITT population in IMPACT study may include various populations withdifferent treatment effects in the target population due to study design issues.
To consider the heterogeneity, it is reasonable to analyze the groups separately
according to the clinical status of the previous treatment and eosinophil count,as per the analysis framework determined by the Expert Committee (Table 01). Therefore, academic group thought it is appropriate to assess the additional
benefit based on the target populations A to L and to handle results of othertarget populations (PT-1 to PT-5, EOS-1 to EOS-4, ITT-1, ITT-2) presented by
the manufacturer as reference information.
<Selection of clinical study>【Population A, B】
21The manufacturer employed 207608 and 207609 for additional benefit
assessment in the populations A and B, while IMPACT study in the populations
C to L. In contrast, the systematic review conducted by the academic group
identified 200812 study as available for benefit assessment in populations A
and B, and the FULFIL study in populations C-D, G-H, and K-L (see 2.2.8).
However, the results based on these studies were not included in the
manufacturer's report.
【Population C-F】
The manufacturer used the results of the subgroup analysis in IMPACT study forbenefit assessment in the populations C-F. The clinical question in the
population C-F is whether continuing triple therapy with FF/UMEC/VI has
additional clinical benefit compared to stepping down to dual therapy for COPD
patients receiving triple therapy as prior therapy (populations C and D:
withdrawal of LAMA and switch to ICS/LABA, population E and F: withdrawal of
LAMA and switch to ICS/LABA).
A response to a query on the manufacturer’s report (August 17, 2020) indicates“The GOLD 2020 guidelines recommend that the response to treatment step-up
should be periodically reviewed and that treatment step-down should beconsidered if no clinical benefit is observed and/or adverse effects occur. The
guideline also suggests that patients should be kept under close medical
surveillance when treatment changes, especially step-down, are considered.
(p.2)”. Therefore, benefit assessment in this population should include
consideration of step-down in real practice, i.e., a step-down made only when
considered clinically appropriate after a close examination of the patient's
clinical condition. In the IMPACT study, due to the problems of the trial design,
there was the possibility that patients receiving triple therapy as prior therapy
might have been randomly assigned to the dual therapy regardless of theclinical indication for step-down. If some patients were randomized to the dual
therapy despite the inappropriateness of step-down, the risk of exacerbation in
the dual therapy group might be increased due to interruption of clinicallyinappropriate drugs, and the treatment effect of FF/UMEC/VI might beoverestimated.
In addition, according to the response to the inquiry (August 17, 2020),"Patients in subgroup C-F were receiving triple therapy at the time of screening,but there was no information on what treatment they were receiving
throughout the year prior to randomization. (p.2)". Therefore, it is notnecessarily appropriate to use the IMPACT study to evaluate the additional
benefit of FF/UMEC/VI compared to step-down to two-drug combination therapy
in the C-F population.
【Population G-L】
22

As per the manufacturer's assessment, it is appropriate to conduct theassessment using the IMPACT study.
<Selection of outcome measures>
The manufacturer used a rate ratio of exacerbation, a difference between achange from baseline (CFB) in FEV1, and a difference between CFB in SGRQ as
outcome measures in the additional benefit assessment, stating that “Because
COPD is a disease with diverse pathophysiological mechanisms and clinicalfeatures, outcomes of COPD drugs need to be assessed comprehensively withrespect to exacerbation frequency, lung function, and SGRQ total score.”.
On the other hand, the decision of the Expert Committee on Cost-EffectivenessEvaluation stated that "Exacerbations should be used as the outcome measures
for the additional benefit assessment.”. Therefore, in the additional benefit
assessment by academic group, the treatment effect in avoiding exacerbations
was used, in accordance with the decision of the Expert Committee, and theresults of other endpoints were treated as reference information.

23

2.2 Systematic review by the academic group
2.2.1 Clinical questions
To assess the additional benefit of FF/UMEC/VI, a systematic review (SR) basedon the clinical questions shown in Table 2-1 was conducted. The target
population for the analysis was set up by dividing the population into 12 groupsof A~L as shown in Table 2-1, but instead of constructing individual search
formulas, a single search formula was constructed in accordance with Table 2-1.
In the process of screening the literature identified by the search, the relevant
literature was identified from the viewpoint of the possibility of examining theadditional benefit of FF/UMEC/VI in A~L. Since the information on the clinical
trials of FF/UMEC/VI were provided by the manufacturer, this systematic review
was limited to the published literature.
The outcome measure was set as exacerbation, in accordance with thestatement in the decision of the Expert Committee on Cost-EffectivenessEvaluation that "Exacerbation should be used as the outcome measure toassess additional benefit.”. Therefore, the results of other endpoints (FEV1 and
SGRQ) were treated as reference information.

24

Table 2-1 Clinical questions of SR
Item
Setting in the assessment by academic group
Population
COPD
Intervention FF/UMEC/VI
Comparator
Prior therapy< 100/μL ≥ 100/μL

B

C

D

ICS/LABAE

F

LAMA/LABAGH

ICS/LABA

Prior therapy: Dual-drugtherapy (LAMA/LABA)
or prior therapy with a single
drug (LAMA)

IJ

LAMA/LABA

Single drug

K

L

ICS/LABA

Other

LiteraturesearchperiodComparator

A

Dual-drug
therapyStudy
designEosinophil count

MITT (tripledrug therapy
with inhalationof 2 drug
products)

Triple-drugtherapy

Outcome

Details of theprior therapy
MITT (tripledrug therapy
with inhalationof 2 drug
products)

ICS/LABALAMA

Not included inanalysis

Exacerbation
A two-step SR was conducted.
(1) A systematic review to identify previously published systematic
reviews that include clinical trials evaluating FF/UMEC/VI.
(2) A systematic review that identifies RCTs of FF/UMEC/VI that havebeen published since the most recent RCT in the previously
reported systematic review in (1).
(1) Before the start of the Phase I study of FF/UMEC/VI (January2013) ~ October/November 2019(2) Approximate time since publication of the most recent RCT in thepreviously reported systematic review identified in (1) (January2018) ~ November 201925

2.2.2 Implementation flow
To evaluate additional benefit of FF/UMEC/VI, a two-step SR was conductedwith reference to the Minds Clinical Guidelines Development Manual [2]. In thefirst phase, a systematic review was conducted to identify previously publishedsystematic reviews that included clinical trials that evaluated FF/UMEC/VI. In
the second stage, a systematic review was conducted to identify RCTs of
FF/UMEC/VI that were published after the most recent RCT in the previously
reported systematic review identified in the first stage (Figure 2-1).
(1) A SR to identify a previously reported SRs(2) A systematic review to identify RCTs
published since the most recent RCT in
the previously reported SR

Identification of RCTs included in theprevious SRs

Identification of RCTs after previously
published SRs

Identification of RCTs for additional
benefit assessment

Figure 2-1 Flow of a systematic review
In the literature search process for the systematic review, a search formula wasconstructed by a medical information service/literature search expert by
combining the criteria of disease and drug names, study design, and search
period. Screening of the literature based on abstracts and subsequentidentification of RCTs for additional benefit assessment was conducted by two
independent reviewers in a blinded fashion. Literature was accepted or rejectedaccording to predetermined inclusion and exclusion criteria, and any
disagreements that arose during this process were resolved throughconsultation between the reviewers. The summary of the RCTs finally identified
was summarized, and the duration of treatment, sample size, age, gender, rate
ratio of exacerbations, hazard ratio of exacerbations, and the possibility ofconsidering the analyzed populations A~L were summarized for each study.
2.2.3 Inclusion and exclusion criteria
The main inclusion and exclusion criteria for systematic reviews are listed
below.
26

<Inclusion criteria>
 The target disease is COPD.
 Intervention includes a triple-drug therapy composed of ICS, LAMA, and
LABA.
 Prespecified study design (The first step is a SR; the second step is an
RCT).
 Published between the given starting point and October/November 2019.
<Exclusion criteria>
 A triple-drug therapy does not include FF/UMEC/VI.
 No comparative technology set in the analysis population A~L.
 Exacerbation is not included in the outcome.
 Not written in English or Japanese.
2.2.4 Database
PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL),
Cochrane Database of Systematic Reviews, and Ichushi-Web were used forcollection of the target studies.
2.2.5 Search formula
The search formula of the SR to identify previously reported SRs is shown
below.
Search formula used for PubMed
Date of search: October 31, 2019(“Pulmonary Disease, Chronic Obstructive”[MH] OR “chronic obstructive
pulmonary disease”[TIAB] OR “chronic obstructive pulmonary diseases”[TIAB] OR“chronic airflow obstruction”[TIAB] OR “chronic airflow obstructions”[TIAB] OR“chronic obstructive airway disease”[TIAB] OR “chronic obstructive airway
diseases”[TIAB] OR “chronic obstructive lung disease”[TIAB] OR “chronic
obstructive lung diseases”[TIAB]) AND (“Drug Combinations”[MH] OR “Drug
Therapy, Combination”[MH] OR (triple[TIAB] AND (therapy[TIAB] OR
combination[TIAB])) OR ((“Adrenergic beta-2 Receptor Agonists”[MH] OR“LABA”[TIAB]) AND (“Long acting muscarinic antagonists”[TIAB] OR“LAMA”[TIAB] OR “Muscarinic Antagonists”[MH]) AND (“Adrenal Cortex
Hormones”[MH] OR corticosteroid[TIAB] OR corticosteroids[TIAB])) OR((“fluticasone furoate”[NM] OR “fluticasone furoate”[TIAB] OR“GW685698”[TIAB]) AND (“vilanterol”[NM] OR vilanterol[TIAB] OR“GW642444M”[TIAB]) AND (“GSK573719”[NM] OR GSK573719[TIAB] OR
Umeclidinium[TIAB])) OR “trelegy ellipta”[ALL]) AND systematic[SB] AND

27

(“2013/01/01”[PDAT] : “2019/12/31”[PDAT])
Number of literatures: 46

28

Search formula used for Embase
Date of search: November 7, 2019((EMB.EXACT.EXPLODE("chronic obstructive lung disease")) OR ("chronic
obstructive pulmonary disease") OR ("chronic airflow obstruction") OR ("chronic
obstructive airway disease") OR "copd") AND ((EMB.EXACT.EXPLODE("fluticasone
furoate plus umeclidinium plus vilanterol")) OR ("trelegy ellipta") OR(EMB.EXACT.EXPLODE("beta 2 adrenergic receptor stimulating agent")) OR("adrenergic beta-2 receptor agonists") OR "laba" OR ("long acting muscarinic
antagonist") OR "lama" OR EMB.EXACT.EXPLODE("corticosteroid") OR ("adrenal
cortex hormones" OR "fluticasone") OR EMB.EXACT.EXPLODE("fluticasone")) AND((EMB.EXACT.EXPLODE("drug combination") OR
EMB.EXACT.EXPLODE("combination drug therapy")) OR ("drug combination
therapy") OR "triple") AND (EMB.EXACT.EXPLODE("systematic review") OR"systematic") AND PD(2013-2019)
Number of literatures: 88

29

Search formula used for Cochrane
Date of search: November 1, 2019
#1 (COPD):ti,ab,kw OR ("chronic obstructive pulmonary disease"):ti,ab,kw OR("chronic obstructive airway disease"):ti,ab,kw OR ("chronic obstructive lungdisease"):ti,ab,kw (Word variations have been searched)#2 MeSH descriptor: [Pulmonary Disease, Chronic Obstructive] explode all trees#3 ("LABA"):ti,ab,kw OR ("long acting beta agonists"):ti,ab,kw AND ("long acting
beta agonist"):ti,ab,kw (Word variations have been searched)#4 MeSH descriptor: [Adrenergic beta-Agonists] explode all trees#5 ("LAMA"):ti,ab,kw OR ("Long acting muscarinic antagonists"):ti,ab,kw AND("Long acting muscarinic antagonist"):ti,ab,kw (Word variations have been
searched)#6 MeSH descriptor: [Muscarinic Antagonists] explode all trees#7 ("corticosteroid"):ti,ab,kw OR ("corticosteroids"):ti,ab,kw OR("steroids"):ti,ab,kw (Word variations have been searched)#8 MeSH descriptor: [Adrenal Cortex Hormones] explode all trees#9 (fluticasone furoate):ti,ab,kw (Word variations have been searched)#10 (vilanterol):ti,ab,kw (Word variations have been searched)#11 (umeclidinium):ti,ab,kw (Word variations have been searched)#12 (triple):ti,ab,kw OR (combination):ti,ab,kw (Word variations have been
searched)#13 (#1 or #2) and (((#3 or #4) and (#5 or #6) and (#7 or #8)) or (#9 and#10 and #11)) and #12 with Publication Year from 2013 to 2019, in Reviews
Number of literatures: 930

Search formula used for Ichushi
Date of search: November 1, 2019("肺疾患-慢性閉塞性"/TH or 慢性閉塞性肺疾患/TA or "慢性閉塞性気道疾患"/TA or "慢性気流閉塞"/TA or "COPD"/TA or "Chronic Obstructive Pulmonary Diseases"/TA or"Chronic Obstructive Pulmonary Disease"/TA or "Chronic Airflow Obstruction"/TA
or "Chronic Obstructive Lung Diseases"/TA or "Chronic Obstructive Lung
Disease"/TA) and (多剤併用/TA or 多数薬剤投与/TH or "多剤併用療法"/TH) and("Adrenergic Beta-2 Receptor Agonists"/TH or "LABA"/TA or "Long-Acting Beta2
Agonist"/TA or β2/TA or "Muscarinic Antagonists"/TH or "LAMA"/TA or "LongActing Muscarinic Antagonists"/TA or ムスカリン/TA or 副腎皮質ホルモン/TH or
corticosteroid/TA or (("Fluticasone Furoate"/TH or "fluticasone furoate"/TA or フル
チカゾンフロアート/TA or フランカルボン酸フルチカゾン/TA or GW685698/TA) and("Vilanterol"/TH or vilanterol/TA or GW642444M/TA or ビランテロール/TA) and(Umeclidinium/TH or umeclidinium/TA or GSK573719/TA or ウメクリジニウム/TA)) or"trelegy ellipta"/TA) and (PT=原著論文 and (メタアナリシス/TH or システマティックレビュー/TH)) and DT=2013:2019
Number of literatures: 1

31

The search formula of SR to identify RCTs published after the recent RCT in thepreviously reported SRs is shown below.
Search formula used for PubMed
Date of search: November 20, 2019("Pulmonary Disease, Chronic Obstructive"[MH] OR "chronic obstructive
pulmonary disease"[TIAB] OR "chronic obstructive pulmonary diseases"[TIAB] OR"chronic airflow obstruction"[TIAB] OR "chronic airflow obstructions"[TIAB] OR"chronic obstructive airway disease"[TIAB] OR "chronic obstructive airway
diseases"[TIAB] OR "chronic obstructive lung disease"[TIAB] OR "chronic
obstructive lung diseases"[TIAB]) AND ("Drug Combinations"[MH] OR "Drug
Therapy, Combination"[MH] OR (triple[TIAB] AND (therapy[TIAB] OR
chemotherapy[TIAB] OR combination[TIAB])) OR (("Adrenergic beta-2 Receptor
Agonists"[MH] OR "LABA"[TIAB]) AND ("Long acting muscarinic
antagonists"[TIAB] OR "LAMA"[TIAB] OR "Muscarinic Antagonists"[MH]) AND("Adrenal Cortex Hormones"[MH] OR corticosteroid[TIAB] OR
corticosteroids[TIAB])) OR (("fluticasone furoate"[NM] OR "fluticasone
furoate"[TIAB] OR "GW685698"[TIAB]) AND ("vilanterol"[NM] ORvilanterol[TIAB] OR "GW642444M"[TIAB]) AND ("GSK573719"[NM] OR
GSK573719[TIAB] OR Umeclidinium[TIAB])) OR "trelegy ellipta"[ALL]) AND(("Randomized Controlled Trial"[PT] OR "randomized controlled trial"[TI] OR"randomized controlled trials"[TI] OR "double blind"[TIAB] OR "Randomized
Controlled Trials as Topic"[MH]) NOT systematic[SB]) AND("2018/01/01"[PDAT] : "2019/12/31"[PDAT])
Number of literatures: 95

32

Search formula used for Embase
Date of search: November 1, 2019(((EMB.EXACT.EXPLODE("chronic obstructive lung disease")) OR ("chronic
obstructive pulmonary disease") OR ("chronic airflow obstruction") OR ("chronic
obstructive airway disease") OR "copd") AND ((EMB.EXACT.EXPLODE("fluticasone
furoate plus umeclidinium plus vilanterol")) OR ("trelegy ellipta") OR(EMB.EXACT.EXPLODE("beta 2 adrenergic receptor stimulating agent")) OR("adrenergic beta-2 receptor agonists") OR "laba" OR ("long acting muscarinic
antagonist") OR "lama" OR EMB.EXACT.EXPLODE("corticosteroid") OR ("adrenal
cortex hormones" OR "fluticasone") OR EMB.EXACT.EXPLODE("fluticasone")) AND((EMB.EXACT.EXPLODE("drug combination") OR
EMB.EXACT.EXPLODE("combination drug therapy")) OR ("drug combination
therapy") OR "triple")) AND (EMB.EXACT.EXPLODE("randomized controlled trial"))AND PD(2018-2019)
Number of literatures: 109

33

Search formula used for Cochrane
Date of search: November 1, 2019
#1 (COPD):ti,ab,kw OR ("chronic obstructive pulmonary disease"):ti,ab,kw OR("chronic obstructive airway disease"):ti,ab,kw OR ("chronic obstructive lungdisease"):ti,ab,kw (Word variations have been searched)#2 MeSH descriptor: [Pulmonary Disease, Chronic Obstructive] explode all trees#3 ("LABA"):ti,ab,kw OR ("long acting beta agonists"):ti,ab,kw AND ("long acting
beta agonist"):ti,ab,kw (Word variations have been searched)#4 MeSH descriptor: [Adrenergic beta-Agonists] explode all trees#5 ("LAMA"):ti,ab,kw OR ("Long acting muscarinic antagonists"):ti,ab,kw AND("Long acting muscarinic antagonist"):ti,ab,kw (Word variations have been
searched)#6 MeSH descriptor: [Muscarinic Antagonists] explode all trees#7 ("corticosteroid"):ti,ab,kw OR ("corticosteroids"):ti,ab,kw OR("steroids"):ti,ab,kw (Word variations have been searched)#8 MeSH descriptor: [Adrenal Cortex Hormones] explode all trees#9 (fluticasone furoate):ti,ab,kw (Word variations have been searched)#10 (vilanterol):ti,ab,kw (Word variations have been searched)#11 (umeclidinium):ti,ab,kw (Word variations have been searched)#12 (triple):ti,ab,kw OR (combination):ti,ab,kw (Word variations have been
searched)#13 (#1 or #2) and (((#3 or #4) and (#5 or #6) and (#7 or #8)) or (#9 and#10 and #11)) and #12 with Publication Year from 2018 to 2019, in Randomized
Controlled Trial
Number of literatures: 174

34

Search formula used for Ichushi
Date of search: November 1, 2019("肺疾患-慢性閉塞性"/TH or 慢性閉塞性肺疾患/TA or "慢性閉塞性気道疾患"/TA or "慢性気流閉塞"/TA or "COPD"/TA or "Chronic Obstructive Pulmonary Diseases"/TA or"Chronic Obstructive Pulmonary Disease"/TA or "Chronic Airflow Obstruction"/TA
or "Chronic Obstructive Lung Diseases"/TA or "Chronic Obstructive Lung
Disease"/TA) and (多剤併用/TA or 多数薬剤投与/TH or "多剤併用療法"/TH) and("Adrenergic Beta-2 Receptor Agonists"/TH or "LABA"/TA or "Long-Acting Beta2
Agonist"/TA or β2/TA or "Muscarinic Antagonists"/TH or "LAMA"/TA or "LongActing Muscarinic Antagonists"/TA or ムスカリン/TA or 副腎皮質ホルモン/TH or
corticosteroid/TA or (("Fluticasone Furoate"/TH or "fluticasone furoate"/TA or フル
チカゾンフロアート/TA or フランカルボン酸フルチカゾン/TA or GW685698/TA) and("Vilanterol"/TH or vilanterol/TA or GW642444M/TA or ビランテロール/TA) and(Umeclidinium/TH or umeclidinium/TA or GSK573719/TA or ウメクリジニウム/TA)) or"trelegy ellipta"/TA) and PT=原著論文 and DT=2018:2019
Number of literatures: 635

2.2.6 Search results
The results of the SR were summarized in Figure 2-2, referring to the flowchart
recommended by the PRISMA statement.
(1) The SR to identify previously reported SRs(2) The SR to identify RCTs published since

the most recent RCT in the previously
reported SRs

Identificat
ion

Number of literatures identified bydatabase search (n=144[PubMed (n=46), Embase (n=88),
Cochrane (n=9), Ichushi (n=1)]

Number ofliteratures after
excluding
duplicates (n=141)
Screening

Eligibility

Number of literatures
identified by databasesearch (n=384 [PubMed(n=95), Embase(n=109), Cochrane(n=174), Ichushi (n=6)]

Number of
added
literatures
which wereidentified fromother data
sources (n=2)

Number of literatures
after excluding
duplicates (n=285)

Number ofscreenedliteratures(n=141)

Numberof
excluded
literatures(n=127)

Number of screened
literatures(n=285)

Number of
excluded
literatures(n=255)

Number of target
literatures on
evaluation ofeligibility (n=14)

Numberof
excluded
literatures(n=8)

Number of target
literatures on evaluationof eligibility(n=30)

Number of
excluded
literatures(n=26)

Number ofpreviously reported
SRs (n=6)

IncludedNumber of RCTs on
FF/UMEC/VI (n=4)

Number of RCTs on
FF/UMEC/VI (n=4)

Number of identified literatures on an RCT of FF/UMEC/VI (n=8)- IMPACT study: Major paper (n=1), related paper (n=2)
・FULFIL study：Major paper (n=1)、repated paper (n=3)
・200812 study：Major paper (n=1)

Figure 2-2 Flow chart of SR by the academic group36

As a result of the SR to identify previously reported SRs, following 6 SRs wereidentified.
<A list of previously reported SRs>
1.
2.

3.

4.
5.

6.

Calzetta L, Cazzola M, Matera MG, Rogliani P. Adding a LAMA to ICS/LABA Therapy: A
Meta-analysis of Triple Combination Therapy in COPD. Chest. 2019;155(4):758-770.
Cazzola M, Rogliani P, Calzetta L, Matera MG. Triple therapy versus single and dual longacting bronchodilator therapy in COPD: a systematic review and meta-analysis. Eur
Respir J. 2018;52(6).
Lai CC, Chen CH, Lin CYH, Wang CY, Wang YH. The effects of single inhaler triple therapy
vs single inhaler dual therapy or separate triple therapy for the management of chronic
obstructive pulmonary disease: a systematic review and meta-analysis of randomized
controlled trials. Int J Chron Obstruct Pulmon Dis. 2019;14:1539-1548.
Langham S, Lewis J, Pooley N, et al. Single-inhaler triple therapy in patients with chronic
obstructive pulmonary disease: a systematic review. Respir Res. 2019;20(1):242.
Zayed Y, Barbarawi M, Kheiri B, et al. Triple versus dual inhaler therapy in moderate-tosevere COPD: A systematic review and meta-analysis of randomized controlled trials.
Clin Respir J. 2019;13(7):413-428.
Zheng Y, Zhu J, Liu Y, et al. Triple therapy in the management of chronic obstructive
pulmonary disease: systematic review and meta-analysis. BMJ. 2018;363:k4388.

37

As a result of the review of these systematic reviews, the following four RCTs
were identified as being consistent with this clinical question. A total of three
RCTs on FF/UMEC/VI were identified: 1 and 4 are from the IMPACT trial, 2 fromthe FULFIL trial, and 3 from the 200812 trial.
<A list of RCTs in the previously reported SRs>
1.
2.

3.

4.

Lipson DA, Barnhart F, Brealey N, et al. Once-Daily Single-Inhaler Triple versus Dual
Therapy in Patients with COPD. N Engl J Med. 2018;378(18):1671-1680.
Lipson DA, Barnacle H, Birk R, et al. FULFIL Trial: Once-Daily Triple Therapy for Patientswith Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med.
2017;196(4):438-446.
Bremner PR, Birk R, Brealey N, Ismaila AS, Zhu CQ, Lipson DA. Single-inhaler
fluticasone furoate/umeclidinium/vilanterol versus fluticasone furoate/vilanterol plus
umeclidinium using two inhalers for chronic obstructive pulmonary disease: arandomized non-inferiority study. Respir Res. 2018;19(1):19.
ClinicalTrials.gov. Registration information of IMPACT study(https://clinicaltrials.gov/ct2/show/NCT02164513)

38

A systematic review aimed at identifying RCTs published since the most recent
RCT in the previously reported systematic review identified four randomized
controlled trials. Of these, 1, 2, and 3 were post-hoc analyses of the FULFIL
trial, and 4 were post-hoc analyses of the IMPACT trial.
<A list of RCTs that were published after the recent study in thepreviously reported SRs>
1.
2.
3.

4.

Naya I, Compton C, Ismaila AS, et al. Preventing clinically important deterioration withsingle-inhaler triple therapy in COPD. ERJ Open Res. 2018;4(4).
Halpin DMG, Birk R, Brealey N, et al. Single-inhaler triple therapy in symptomatic COPD
patients: FULFIL subgroup analyses. ERJ Open Res. 2018;4(2).
Zheng J, Zhong N, Wang C, et al. The Efficacy and Safety of Once-daily Fluticasone
Furoate/Umeclidinium/Vilanterol Versus Twice-daily Budesonide/Formoterol in a
Subgroup of Patients from China with Symptomatic COPD at Risk of Exacerbations(FULFIL Trial). COPD. 2018;15(4):334-340.
Kato M, Tomii K, Hashimoto K, et al. The IMPACT Study - Single Inhaler Triple Therapy(FF/UMEC/VI) Versus FF/VI And UMEC/VI In Patients With COPD: Efficacy And Safety In
A Japanese Population. Int J Chron Obstruct Pulmon Dis. 2019;14:2849-2861.

As a result of a series of systematic reviews, the three RCTs of FF/UMEC/VI
identified were the IMPACT study, the FULFIL study, and the 200812 study. The
studies 207608 and 207609 reported by the manufacturer were not identified inthis systematic review because they had not been published as original papers.
2.2.7 Summary of clinical trials
Outline of the 3 RCTs (IMPACT study, FULFIL study, Study 200812) which wereidentified as a clinical study including FF/UMEC/VI were shown in Table 2-2.
Outline of 4 papers of the post hoc analysis of IMPACT study and FULFIL study
is shown in Table A-1 in Attachment.

39

Table 2-2 List of literatures
Study name IMPACTFULFIL200812

Title ofarticleOnce Daily SingleInhaler Triple versus
Dual Therapy inPatients with COPD

FULFIL trial: OnceDaily Triple Therapy
for Patients with
Chronic Obstructive
Pulmonary Disease

Single-inhaler
fluticasone
furoate/umeclidinium/vilanterol versus
fluticasone
furoate/vilanterol plus
umeclidinium using
two inhalers forchronic obstructive
pulmonary disease: arandomized noninferiority study

Authorname

Lipson DA, et al.

Lipson DA, et al.

Bremner PR, et al.

Bibliographic N Engl J Med.
information 2018;378(18):16711680.

Am J Respir Crit CareMed.
2017;196(4):438446.

Respir Res.
2018;19(1):19.

Test location Multicenter (37countries)

Multicenter (16countries)

Multicenter (12countries)

Study
enrollment
periodFrom June 2014 to
July 2017

From January 2015 to From June 2016 toApril 2016
March 2017

Targetpopulation≥ 40 years old,
diagnosed as COPD,
has a history ofsmoking, CAT ≥ 10,
FEV1/FVC < 0.7,
receiving amaintenance therapy,
has a history of
exacerbation withinprevious 12 months
etc.

≥ 40 years old,
diagnosed as COPD,
CAT ≥ 10, receiving amaintenance therapy,
has a history of
exacerbation withinprevious 12 months
etc.

Key
exclusion
criteria

A patient who has
asthma at present, apatient who has otherrespiratory diseases,a person who has
experienced
exacerbation before a

A patient who has
A patient who has
asthma at present, a asthma at present, apatient who haspatient who has otherunabsorbed
respiratory diseases
pneumonia/exacerbati etc.
on etc.

≥ 40 years old,
diagnosed as COPD,
has a history ofsmoking, CAT ≥ 10,
FEV1/FVC < 0.7,
receiving amaintenance therapy,
has a history of
exacerbation withinprevious 12 months
etc.

40

study or during a runin period etc.
Details ofintervention
methodFF/UMEC/VI group(n=4151)：

Details ofcomparator

ICS/LABA group(n=4134)：FF/VI 100

FF/UMEC/VI group(n=911 24 weeks,
n=210 52 weeks)：

FF/UMEC/VI group(n=527)：FF/UMEC/VI

ICS/LABA group(n=899 24 weeks,
n=220 52 weeks)：

MITT group (n=528)：

FF/UMEC/VI 100
100 mcg/62.5mcg/25
mcg/62.5mcg/25 mcg FF/UMEC/VI 100
mcg
mcg/62.5mcg/25 mcg

mcg/25 mcg
LAMA/LABA group(n=2070)：UMEC/VI

BUD/FOR 400mcg/12
mcg

FF/UMEC/VI 100
mcg/62.5 mcg/25
mcg

62.5 mcg/25 mcg
StudydesignPhase III, RCT

Phase III, RCT

Phase III, RCT

Blinding
methodDouble-blind

Double-blind

Double-blind

Primary
endpoint

Incidence ofmoderate/severe
exacerbation event(52 weeks)- Change in FEV1
- Change in FEV1trough (24 weeks)trough (24 weeks)- Change in FEV1trough (52 weeks)- Change in SGRQ (24weeks)- Change in SGRQ (52weeks)

Key
secondary
endpoints- Change in FEV1trough- Change in SGRQ
- Time to first
Incidence ofmoderate/severe
exacerbation event- Incidence ofmoderate/severe
exacerbation event(population witheosinophil count ≥150)- Time to firstincidence ofmoderate/severe
exacerbation event(population with

- Incidence ofmoderate/severe
exacerbation event(24 weeks)- Incidence ofmoderate/severe
exacerbation event(52 weeks) etc.

- Change in SGRQ (24weeks)- Time to first
Incidence ofmoderate/severe
exacerbation event(24 weeks) etc.

41

eosinophil count ≥150)- Incidence of severe
exacerbation event
etc.
Statisticalmethods- Incidence of
exacerbation was
analyzed with thegeneralized linear
model assuming anegative binomial
distribution- Amount of change
was analyzed with
MMRM
- Time to event was
analyzed with Cox
proportional-hazards
model- Amount of change
was analyzed with
MMRM
- Incidence of
exacerbation was
analyzed with thegeneralized linear
model assuming anegative binomial
distribution- Amount of change
was analyzed with
MMRM
- Time to event was
analyzed with Cox
proportional-hazards
model

2.2.8 Availability for additional benefit assessment
The statistics of the three RCTs identified as clinical trials including FF/UMEC/VI(IMPACT, FULFIL, and 200812 trials) and the possibility of considering analytic
population A~L in the assessment by academic group were summarized (Table
2-3). As a result, the data from the IMPACT study can be used for additional
benefit assessment of the target population C~L. The data from the FULFIL
study can potentially be used for additional benefit assessment of populations
C, D, G, H, K, and L, and the data from the 200812 study can potentially be
used for assessment of populations A and B.
However, because the results of these trials were not subjected to subgroup
analyses consistent with the research questions of this analysis, it was notpossible to examine the treatment effects of each analytic population from thepublished literature alone. Therefore, the additional usefulness in this analysis
was based on the subgroup analysis of the IMPACT study submitted by the
manufacturer. The data from both the FULFIL and 200812 studies showed thatthe results for the overall population were similar to those of the IMPACT study
and other studies used in the evaluation.

42

Table 2-3 Statistics of clinical trials and the possibility of considering the population for analysis

Study

Treatment
group

Treatment
period(week) Sample
size

IMPACTFULFIL

Data
Incidence
Mean
of
age
exacerbation

Age
SD

Rate ratio of exacerbation
Hazard ratio of(FF/UMEC/VI vsexacerbation (FF/UMEC/VI Possibility ofconsidering
comparator)
vs comparator)
the95%CI 95%CI
95%CI 95%CI
Proporti
population
Point
Point
upper
lower
lower
upper
on of
for analysis
estimate
estimate
limit
limit
limit
limit
male

FF/UMEC/VI

52

4151

0.91

65.3

8.2

0.666

-

-

-

-

-

-

ICS/LABA

52

4134

1.07

65.3

8.3

0.665

0.85

0.8

0.9

0.85

0.8

0.91

LAMA/LABA

52

2070

1.21

65.2

8.3

0.655

0.75

0.7

0.81

0.84

0.78

0.91

FF/UMEC/VI

24

911

0.22

64.2

8.6

0.744

-

-

-

-

-

-

ICS/LABA

24

899

0.34

63.7

8.7

0.737

0.65

0.49

0.86

-

-

-

ICS/LABA

52

220

0.36

63.7

8.7

0.737

0.56

0.37

0.85

-

-

-

FF/UMEC/VI

24

527

-

66.7

8.5

0.742

-

-

-

-

-

-

200812

C-L

C,D,G,H,K,L

A,B
MITT

24

528

-

65.9

8.8

0.746

-

-

-

0.87

0.68

1.12

43

2.3 Results of additional benefit assessment
The target population in this analysis was established by dividing the population
into 12 populations of A~L as shown in Table 0-1. The additional benefit of
FF/UMEC/VI in the A~L population was assessed based on the manufacturer's
report, the systematic review by the academic group, and additional literature
review conducted as necessary. The results are shown in Tables 2-4 to 2-14.
Table 2-4 Evaluation of additional benefit (Population A and B)
Population A and B(Patients receiving triple therapy with two inhaled drugs,
Target population
eosinophil count less than 100/μL for A and more than
100/μL for B)
Intervention

FF/UMEC/VI

Comparator

MITT

OutcomeExacerbation

Presence orabsence ofadditional benefit

With additional benefit ■ "No additional benefit" or"Cannot be judged"■ Meta-analysis of RCTs (Pooled analysis of several RCTs)

Data serving as
the rationale forjudgment□ Single RCT
Prospective comparative observational studies
Indirect comparison of RCT
Comparison of single-arm studies
No clinical study dataReason for judging
the presence orabsence ofadditional benefitThe manufacturer conducted an additional benefit
assessment on the combined population of A-B.
Treatment efficacy was assessed using the results of the
combined analysis of the two non-inferiority trials(207608 and 207609). As an outcome measure, theincidence of moderate or severe exacerbations in eachgroup was reported: 11% (80/729) in the FF/UMEC/VI
group and 11% (77/731) in the MITT group. The
manufacturer reported that FF/UMEC/VI had "noadditional benefit" or " Cannot be judged" in thispopulation.
There was no statistically significant difference inexacerbation risk between treatment groups, and thesimilarity of point estimates of exacerbation rates does
not indicate any additional benefit of FF/UMEC/VI
compared with MITT.

44

Table 2-5 Evaluation of additional benefit (Population C)
Population C(Patients receiving triple therapy with two inhaled drugs,
Target population
appropriate for step-down withdrawal from LAMA, andeosinophil count less than 100/μL)
Intervention

FF/UMEC/VI

Comparator

ICS/LABA

OutcomeExacerbation

Presence orabsence ofadditional benefit□ With additional benefit"No additional benefit" or"Cannot be judged"
It was judged as unable to be analyzed.
□ Meta-analysis of RCTs ・ Single RCTData serving as
the rationale forjudgment

Prospective comparative observational studies
Indirect comparison of RCT
Comparison of single-arm studies
 No clinical study data
Reason for judging
the presence orabsence ofadditional benefitBased on the subgroup analysis of the IMPACT study,
the manufacturer reported the incidence rate ofmoderate or severe COPD exacerbations (case/personyear) in the FF/UMEC/VI group and the comparisongroup as 1.13 [0.99~1.28] and 1.37 [1.19~1.57],
respectively. They also reported the rate ratio ofmoderate or severe COPD exacerbations as 0.83
[0.69~0.99] (p=0.044), and determined that
FF/UMEC/VI had additional benefit.
In the IMPACT study, there was the possibility thatpatients receiving triple therapy as pretreatment may
have been randomly assigned to the dual therapy
regardless of the clinical indication for step-down due tostudy design issues. If patients were randomized to thedual therapy despite the inappropriateness of stepdown, the risk of exacerbation in the dual therapy group
might be increased by interruption of clinicallyinappropriate drugs, and the treatment effect of
FF/UMEC/VI might be overestimated. For this reason, it
is not appropriate to use the IMPACT trial to assess
additional benefit in this population.
On the other hand, there are no clinical trials comparing
the continued use of triple therapy with the withdrawalof LAMA and the use of ICS/LABA in patients on triple
therapy for whom the clinical relevance of excluding
LAMA has been confirmed. In the first place, clinicians

45

are of the opinion that it is not common to exclude LAMA
alone in a step-down in actual clinical practice.
Therefore, since there are no data on LAMA withdrawal
in these populations, the additional benefit of
FF/UMEC/VI in these populations could not be
considered and the study was classified as"unanalyzable”.

46

Table 2-6 Evaluation of additional benefit (Population D)
Population D(Patients receiving triple therapy in inhaled formulations, forTarget population
whom a step-down procedure to wean off LAMA isappropriate, and have an eosinophil count of 100/μL or
higher)Intervention

FF/UMEC/VI

Comparator

ICS/LABA

OutcomeExacerbation

Presence orabsence ofadditional benefit□ With additional benefit ・ "No additional benefit" or"Cannot be judged"
It was judged as unable to be analyzed.
□ Meta-analysis of RCTs ・ Single RCTData serving as
the rationale forjudgment

Prospective comparative observational studies
Indirect comparison of RCT
Comparison of single-arm studies
 No clinical study data
Reason for judging
the presence orabsence ofadditional benefitBased on the subgroup analysis of the IMPACT study,
the manufacturer reported the incidence rate ofmoderate or severe COPD exacerbations (case/personyear) in the FF/UMEC/VI group and the comparisongroup as 1.25 [1.16~1.34] and 1.46 [1.35~1.57],
respectively. They also reported the rate ratio ofmoderate or severe COPD exacerbations as 0.86
[0.77~0.95] (p=0.003), and determined that
FF/UMEC/VI had additional benefit.
In the IMPACT study, there was the possibility thatpatients receiving triple therapy as pretreatment may
have been randomly assigned to the dual therapy
regardless of the clinical indication for step-down due tostudy design issues. If patients were randomized to thedual therapy despite the inappropriateness of stepdown, the risk of exacerbation in the dual therapy group
might be increased by interruption of clinicallyinappropriate drugs, and the treatment effect of
FF/UMEC/VI might be overestimated. For this reason, it
is not appropriate to use the IMPACT trial to assess
additional benefit in this population.
On the other hand, there are no clinical trials comparing
the continued use of triple therapy with the withdrawalof LAMA and the use of ICS/LABA in patients on triple
therapy for whom the clinical relevance of excluding

47

LAMA has been confirmed. In the first place, clinicians
are of the opinion that it is not common to exclude LAMA
alone in a step-down in actual clinical practice.
Therefore, since there are no data on LAMA withdrawal
in these populations, the additional benefit of
FF/UMEC/VI in these populations could not be
considered and the study was classified as"unanalyzable”.

48

Table 2-7 Evaluation of additional benefit (Population E)
Population E(Patients receiving triple therapy with two inhalation
Target population
formulations, for whom a step-down from ICS is appropriate,
and whose eosinophil count is less than 100/μL)
Intervention

FF/UMEC/VI

Comparator

LAMA/LABA

OutcomeExacerbation

Presence orabsence ofadditional benefit□ With additional benefit ■ "No additional benefit" or"Cannot be judged"■ Meta-analysis of RCTs  Single RCTData serving as
the rationale forjudgment Prospective comparative observational studies
 Indirect comparison of RCT
 Comparison of single-arm studies
 No clinical study data
Reason for judging
the presence orabsence ofadditional benefitBased on the subgroup analysis of the IMPACT study,
the manufacturer reported the incidence rate ofmoderate or severe COPD exacerbations (case/personyear) in the FF/UMEC/VI group and the comparisongroup as 1.13 [0.99 to 1.28] and 1.45 [1.22 to 1.73],
respectively. They also reported the rate ratio ofmoderate or severe COPD exacerbations as 0.78 [0.63
to 0.97] (p = 0.023), and determined that FF/UMEC/VI
had additional benefit.
In the IMPACT study, there was the possibility thatpatients receiving triple therapy as pretreatment may
have been randomly assigned to the dual therapy
regardless of the clinical indication for step-down due tostudy design issues. If patients were randomized to thedual therapy despite the inappropriateness of stepdown, the risk of exacerbation in the dual therapy group
might be increased by interruption of clinicallyinappropriate drugs, and the treatment effect of
FF/UMEC/VI might be overestimated. For this reason, it
is not appropriate to use the IMPACT trial to assess
additional benefit in this population.
According to the European Respiratory Society position
on ICS discontinuation in COPD patients (May 2020),
discontinuation of ICS is recommended for COPD
patients without a history of frequent exacerbations[3].

49







The results of a meta-analysis of trials that evaluatedthe impact of stepping down from ICS (COSMIC,WISDOM, INSTEAD, and SUNSET trials) suggest thatwithdrawal from ICS is not necessarily associated withan increased risk of exacerbations[3]. It reported thatthe rate ratio of moderate or severe COPD exacerbationsin the ICS withdrawal group compared with the ICS
continuation group was 1.05 [0.97~1.13][3]. In
addition, when the time to the first moderate or severe
COPD exacerbation was analyzed, the hazard ratio of the
ICS withdrawal group compared with the ICS
continuation group was reported to be 1.04
[0.94~1.16][3]. Furthermore, an analysis of the
proportion of patients who experienced at least one
moderate or severe COPD exacerbation reported an
odds ratio of 0.84 [0.63~1.14] in the ICS withdrawal
group compared with the ICS continuation group[3].
The results of the SUNSET study, which evaluated theeffect of withdrawal from ICS from triple therapy,
suggested that withdrawal from ICS was not necessarily
associated with an increased risk of exacerbation[4]. It
was reported that the rate ratio of moderate or severe
COPD exacerbations in the ICS withdrawal groupcompared to the ICS continuation group was 1.08
[0.83~1.40][4].
Based on the above, it cannot be said that the additional
benefit of continuing FF/UMEC/VI therapy has been
demonstrated in this population, i.e., those for whom
step-down implementation is deemed appropriate basedon clinically appropriate evaluation.

50

Table 2-8 Evaluation of additional benefit (Population F)
Population F(Patients receiving triple therapy with two inhalers,Target population
appropriate for step-down withdrawal from ICS, andeosinophil count ≥100/μL)
Intervention

FF/UMEC/VI

Comparator

LAMA/LABA

OutcomeExacerbation

Presence orabsence ofadditional benefit

With additional benefit ■ "No additional benefit" or"Cannot be judged"■ Meta-analysis of RCTs

Data serving as
the rationale forjudgmentSingle RCT

Prospective comparative observational studies
Indirect comparison of RCT
Comparison of single-arm studies
No clinical study data
Reason for judging
the presence orabsence ofadditional benefitBased on the subgroup analysis of the IMPACT study,
the manufacturer reported the incidence rate ofmoderate or severe COPD exacerbations (case/personyear) in the FF/UMEC/VI group and the comparisongroup as 1.25 [1.16 to 1.34] and 1.86 [1.69 to 2.05],
respectively. They also reported the rate ratio ofmoderate or severe COPD exacerbations as 0.67 [0.59
to 0.76] (p < 0.001), and determined that FF/UMEC/VI
had additional benefit.
In the IMPACT study, there was the possibility thatpatients receiving triple therapy as pretreatment may
have been randomly assigned to the dual therapy
regardless of the clinical indication for step-down due tostudy design issues. If patients were randomized to thedual therapy despite the inappropriateness of stepdown, the risk of exacerbation in the dual therapy group
might be increased by interruption of clinicallyinappropriate drugs, and the treatment effect of
FF/UMEC/VI might be overestimated. For this reason, it
is not appropriate to use the IMPACT trial to assess
additional benefit in this population.
According to the European Respiratory Society position
on ICS discontinuation in COPD patients (May 2020),
discontinuation of ICS is recommended for COPD
patients without a history of frequent exacerbations[3].

51







The results of a meta-analysis of trials that evaluatedthe impact of stepping down from ICS (COSMIC,WISDOM, INSTEAD, and SUNSET trials) suggest thatwithdrawal from ICS is not necessarily associated withan increased risk of exacerbations[3]. It reported thatthe rate ratio of moderate or severe COPD exacerbationsin the ICS withdrawal group compared with the ICS
continuation group was 1.05 [0.97~1.13][3]. In
addition, when the time to the first moderate or severe
COPD exacerbation was analyzed, the hazard ratio of the
ICS withdrawal group compared with the ICS
continuation group was reported to be 1.04
[0.94~1.16][3]. Furthermore, an analysis of the
proportion of patients who experienced at least one
moderate or severe COPD exacerbation reported an
odds ratio of 0.84 [0.63~1.14] in the ICS withdrawal
group compared with the ICS continuation group[3].
The results of the SUNSET study, which evaluated theeffect of withdrawal from ICS from triple therapy,
suggested that withdrawal from ICS was not necessarily
associated with an increased risk of exacerbation[4]. It
was reported that the rate ratio of moderate or severe
COPD exacerbations in the ICS withdrawal groupcompared to the ICS continuation group was 1.08
[0.83~1.40][4].
Based on the above, it cannot be said that the additional
benefit of continuing FF/UMEC/VI therapy has been
demonstrated in this population, i.e., those for whom
step-down implementation is deemed appropriate basedon clinically appropriate evaluation.

52

Table 2-9 Evaluation of additional benefit (Population G)
Population G
Target population(Patients receiving ICS/LABA combination therapy andeosinophil count less than 100/μL)
Intervention

FF/UMEC/VI

Comparator

ICS/LABA

OutcomeExacerbation

Presence orabsence ofadditional benefit
Data serving as
the rationale forjudgment■ With additional benefit  "No additional benefit" or"Cannot be judged"
 Meta-analysis of RCTs  Single RCT Prospective comparative observational studies
 Indirect comparison of RCT
 Comparison of single-arm studies
 No clinical study dataReason for judging
the presence orabsence ofadditional benefitBased on the subgroup analysis of the IMPACT study,
the manufacturer reported the incidence rate ofmoderate or severe COPD exacerbations (case/personyear) in the FF/UMEC/VI group and the comparisongroup as 0.65 [0.54 to 0.78] and 0.83 [0.70 to 0.98],
respectively. They also reported the rate ratio ofmoderate or severe COPD exacerbations as 0.78 [0.61
to 1.00] (p = 0.050), and determined that FF/UMEC/VI
had additional benefit.
These results show a trend toward improvement in the
FF/UMEC/VI group, although the p-value slightly
exceeds 0.05. Considering the possible lack of power
associated with the subgroup analysis, the additional
benefit of FF/UMEC/VI in this population is indicated.

53

Table 2-10 Evaluation of additional benefit (Population H)
Population H
Target population(Patients receiving ICS/LABA combination therapy andeosinophil count ≥100/μL)
Intervention

FF/UMEC/VI

Comparator

ICS/LABA

OutcomeExacerbation

Presence orabsence ofadditional benefit
Data serving as
the rationale forjudgment■ With additional benefit  "No additional benefit" or"Cannot be judged"
 Meta-analysis of RCTs  Single RCT Prospective comparative observational studies
 Indirect comparison of RCT
 Comparison of single-arm studies
 No clinical study dataReason for judging
the presence orabsence ofadditional benefitBased on the subgroup analysis of the IMPACT study,
the manufacturer reported the incidence rate ofmoderate or severe COPD exacerbations (case/personyear) in the FF/UMEC/VI group and the comparisongroup as 0.73 [0.65 to 0.81] and 0.89 [0.80 to 0.98],
respectively. They also reported the rate ratio ofmoderate or severe COPD exacerbations as 0.82 [0.71
to 0.95] (p = 0.008), and determined that FF/UMEC/VI
had additional benefit.
The improvement in exacerbations with statisticalsignificance demonstrates the additional benefit of
FF/UMEC/VI in this population.

54

Table 2-11 Evaluation of additional benefit (Population I)
Population I(Patients who are receiving only LAMA or a combination
Target population
therapy with LAMA/LABA in addition to their eosinophil countof < 100/μL)
Intervention

FF/UMEC/VI

Comparator

LAMA/LABA

OutcomeExacerbation

Presence orabsence ofadditional benefit
Data serving as
the rationale forjudgment

 With additional benefit ■ "No additional benefit" or"Cannot be judged"
 Meta-analysis of RCTs  Single RCT Prospective comparative observational studies
 Indirect comparison of RCT
 Comparison of single-arm studies
 No clinical study data
Reason for judging
the presence orabsence ofadditional benefit

Based on the subgroup analysis of the IMPACT study,
the manufacturer reported the incidence rate ofmoderate or severe COPD exacerbations (case/personyear) in the FF/UMEC/VI group and the comparisongroup as 0.68 [0.53 to 0.87] and 0.50 [0.32 to 0.77],
respectively. They also reported the rate ratio ofmoderate or severe COPD exacerbations as 1.37 [0.83
to 2.24] (p = 0.217), and determined that FF/UMEC/VI
had additional benefit.
Although not statistically significant, among the C-L
subpopulations evaluated using the IMPACT study, thepoint estimate of the rate ratio of exacerbations
exceeded 1 only in this population I, indicating a trend
toward a higher incidence of exacerbations in the
FF/UMEC/VI group.
The benefit of adding steroids is not always clear
clinically in this population, where steroid-free LAMA or
LAMA/LABA is prescribed based on clinical judgment andeosinophil counts are low. From this perspective, theclinician's opinion that the higher rate of exacerbationsin this population alone raises questions about thebenefit of additional steroids is consistent with clinicalpractice.
A post-hoc analysis of the IMPACT trial showed that
there was no difference in the frequency of
exacerbations between treatments in a patient

55





population with low eosinophil counts[5].
Assuming that the exacerbation rate ratio data reported
in the IMPACT trial is a posterior distribution oftreatment effect (assuming a lognormal distribution) andinterpreted in a Bayesian manner, the probability thatthe exacerbation rate ratio is less than 1 (FF/UMEC/VI issuperior) is 81.06 The probability that the rate ratio ofexacerbations is less than 1 (FF/UMEC/VI is superior) is
81.06%~100.0% in the other populations, while it is
only 10.69% in the population I, which is relatively low(Table A-2). In addition, the probability that the rate
ratio of exacerbations is less than 0.95 (i.e., the risk is
reduced by 5% or more by FF/UMEC/VI) is only 7.42%
in population I, compared to 71.09%~100.0% in theother populations (Table A-2).
From the above, the additional benefit of FF/UMEC/VI inthis population has been demonstrated.

56

Table 2-12 Evaluation of additional benefit (Population J)
Population J
Target population(Patients receiving LAMA monotherapy or LAMA/LABA
combination therapy with eosinophil count ≥100/μL)
Intervention

FF/UMEC/VI

Comparator

LAMA/LABA

OutcomeExacerbation

Presence orabsence ofadditional benefit
Data serving as
the rationale forjudgment■ With additional benefit  "No additional benefit" or"Cannot be judged"
 Meta-analysis of RCTs  Single RCT Prospective comparative observational studies
 Indirect comparison of RCT
 Comparison of single-arm studies□ No clinical study dataReason for judging
the presence orabsence ofadditional benefitBased on the subgroup analysis of the IMPACT study,
the manufacturer reported the incidence rate ofmoderate or severe COPD exacerbations (case/personyear) in the FF/UMEC/VI group and the comparisongroup as 0.79 [0.69 to 0.91] and 0.98 [0.82 to 1.17],
respectively. They also reported the rate ratio ofmoderate or severe COPD exacerbations as 0.81 [0.65
to 1.01] (p = 0.065), and determined that FF/UMEC/VI
had additional benefit.
These results show a trend toward improvement in the
FF/UMEC/VI group, although the p-value slightly
exceeds 0.05. Considering the possible lack of power
associated with the subgroup analysis, the additional
benefit of FF/UMEC/VI in this population is indicated.

57

Table 2-13 Evaluation of additional benefit (Population K)
Population K
Target population(Patients receiving LAMA monotherapy and eosinophil countless than 100/μL)
Intervention

FF/UMEC/VI

Comparator

ICS/LABA

OutcomeExacerbation

Presence orabsence ofadditional benefit
Data serving as
the rationale forjudgment■ With additional benefit  "No additional benefit" or"Cannot be judged"
 Meta-analysis of RCTs  Single RCT Prospective comparative observational studies
 Indirect comparison of RCT
 Comparison of single-arm studies
 No clinical study dataReason for judging
the presence orabsence ofadditional benefitBased on the subgroup analysis of the IMPACT study,
the manufacturer reported the incidence rate ofmoderate or severe COPD exacerbations (case/personyear) in the FF/UMEC/VI group and the comparisongroup as 0.58 [0.40 to 0.83] and 0.86 [0.62 to 1.19],
respectively. They also reported the rate ratio ofmoderate or severe COPD exacerbations as 0.67 [0.41
to 1.09] (p = 0.104), and determined that FF/UMEC/VI
had additional benefit.
These results show a trend toward improvement in the
FF/UMEC/VI group, although the p-value slightly
exceeds 0.05. Considering the possible lack of power
associated with the subgroup analysis, the additional
benefit of FF/UMEC/VI in this population is indicated.

58

Table 2-14 Evaluation of additional benefit (Population L)
Population L
Target population(Patients receiving LAMA monotherapy and eosinophil count≥100/μ)Intervention

FF/UMEC/VI

Comparator

ICS/LABA

OutcomeExacerbation

Presence orabsence ofadditional benefit
Data serving as
the rationale forjudgment■ With additional benefit  "No additional benefit" or"Cannot be judged"
 Meta-analysis of RCTs  Single RCT Prospective comparative observational studies
 Indirect comparison of RCT
 Comparison of single-arm studies
 No clinical study dataReason for judging
the presence orabsence ofadditional benefitBased on the subgroup analysis of the IMPACT study,
the manufacturer reported the incidence rate ofmoderate or severe COPD exacerbations (case/personyear) in the FF/UMEC/VI group and the comparisongroup as 0.63 [0.50, 0.79] and 0.72 [0.59, 0.88],
respectively. They also reported the rate ratio ofmoderate or severe COPD exacerbations as 0.87 [0.64
to 1.19] (p = 0.392), and determined that FF/UMEC/VI
had additional benefit.
These results show a trend toward improvement in the
FF/UMEC/VI group, although the p-value slightly
exceeds 0.05. Considering the possible lack of power
associated with the subgroup analysis, the additional
benefit of FF/UMEC/VI in this population is indicated.

59Based on the results of the additional benefit assessment described above, it isappropriate to conduct a cost-effectiveness evaluation of FF/UMEC/VI as shownin Table 2-15.
Table 2-15 The results of additional benefit assessment
Prior
therapy

Details of
the priortherapy

Eosinophil countComparator< 100/μL≥ 100/μLA
No additional
benefit.
CMA

B
No additional
benefit.
CMA

MITT(triple-drugtherapy withinhalation of 2
drug products)

C
Additional benefit
is unknown.
Unable to beanalyzed

D
Additional benefit
is unknown.
Unable to beanalyzed

ICS/LABAE
It cannot to besaid that
additional benefit
is indicated.
CMA

F
It cannot to besaid that additional
benefit isindicated.
CMA

LAMA/LABAICS/LABAG
With additional
benefit.
CEA

H
With additional
benefit.
CEA

ICS/LABA

Prior therapy:
Dual-drug therapy(LAMA/LABA)
or prior therapy with asingle drug (LAMA)I
It cannot to besaid that
additional benefit
is indicated.
CMA

J
With additional
benefit.
CEA

LAMA/LABA

Singledrug

KWith additional
benefit.
CEA

L
With additional
benefit.
CEA

ICS/LABA

Tripledrugtherapy

Dualdrugtherapy

Other

MITT
(triple-drugtherapywithinhalationof 2 drug
products)

LAMA

Not included in analysis

The additional benefit of FF/UMEC/VI when the eosinophil count cutoff was set
at 150/μL was not reported by the manufacturer. On the other hand, therelative risk (RR) of moderate and severe exacerbations was reported as a60

parameter of treatment effect for conducting a cost-effectiveness evaluation
when the cutoff for eosinophil count was set at 150/μL (Table 2-16). When
compared with the data on the rate ratio of exacerbations when the cutoff foreosinophil count was set at 100/μL (Table 2-17), the trends in the estimates oftreatment effect were generally consistent. Therefore, the evaluation of
additional benefit when the cutoff for eosinophil count was set at 150/μL wastreated in the same way as when the cutoff for eosinophil count was set at
100/μL.

61

Table 2-16 Relative risk of exacerbation with eosinophil count of
150/uL as cutoff
Priortherapy

Details of
the priortherapy

Eosinophil countComparator< 150/μL≥ 150/μL
MITT(Triple-drugtherapywithinhalationof 2 drug
products)

A

B

C
Moderate:RR=0.78,
SE=0.06, p=0.001
Severe:RR=0.92,
SE=0.15, p=0.591

D
Moderate:RR=0.92,
SE=0.06, p=0.224 ICS/LABA
Severe:RR=0.71,
SE=0.10, p=0.017

E
Moderate:RR=0.78,
SE=0.07, p=0.006
Severe:RR=1.01,
SE=0.21, p=0.961

F
Moderate:RR=0.66,
SE=0.05, p<0.001 LAMA/LABA
Severe:RR=0.50,
SE=0.08, p<0.001

ICS/LABAG
Moderate:RR=0.74,
SE=0.08, p=0.003
Severe:RR=1.17,
SE=0.26, p=0.462

H
Moderate:RR=0.81,
SE=0.07, p=0.022 ICS/LABA
Severe:RR=0.77,
SE=0.15, p=0.173

Prior therapy:
Dual-drug therapy(LAMA/LABA)
or prior therapy with asingle drug (LAMA)

I
Moderate:RR=1.08,
SE=0.20, p=0.687
Severe:RR=1.05,
SE=0.48, p=0.909

J
Moderate:RR=0.84,
SE=0.12, p=0.229 LAMA/LABA
Severe:RR=0.54,
SE=0.16, p=0.032

Singledrug

KModerate:RR=0.73,
SE=0.16, p=0.145
Severe:RR=0.66,
SE=0.36, p=0.387

L
Moderate:RR=0.81,
SE=0.16, p=0.276 ICS/LABA
Severe*:RR=0.81,
SE=0.16, p=0.276

Triple-drugtherapyDual-drug
therapy

Other

MITT
(Tripledrugtherapywithinhalationof 2 drug
products)

LAMA

Non target for the analysis# Prepared from values reported by the manufacturer# RR: Relative risk
*The RR of severe exacerbation of L was difficult to estimate, so the
manufacturer substituted a moderate RR.
62

Table 2-17 Rate ratio of exacerbations with eosinophil count of 100/uL
as cutoff
Prior
therapy

Details of
the priortherapy

Eosinophil count< 100/μL

Comparator≥ 100/μL

A

B

MITT
(Triple-drugtherapywithinhalationof 2 drug
products)

C0.83 [0.69, 0.99]
p=0.044D
0.86 [0.77, 0.95]
p=0.003

ICS/LABA

E
0.78 [0.63, 0.97]
p=0.023

F
0.67 [0.59, 0.76]
p<0.001

LAMA/LABAICS/LABA

G
0.78 [0.61, 1.00]
p=0.050H
0.82 [0.71, 0.95]
p=0.008

ICS/LABA

Prior therapy:
Dual-drug therapy(LAMA/LABA)
or prior therapy with asingle drug (LAMA)

I
1.37 [0.83, 2.24]
p=0.217J
0.81 [0.65, 1.01]
p=0.065

LAMA/LABA

Single drug

K
0.67 [0.41, 1.09]
p=0.104L
0.87 [0.64, 1.19]
p=0.392

ICS/LABA

Triple-drugtherapyDual-drug
therapy

Other

MITT
(Triple-drugtherapy withinhalation of
2 drugproducts)

LAMA

Non target for the analysis# Prepared from values reported by the manufacturer# Rate ratio

63

3. Evaluation of cost-effectiveness3.1 Summary of manufacturer’s results and review by academic group<Summary of CMA for populations A and B>
The manufacturer conducted a cost-minimization analysis assuming equivalenceof effects between treatments for populations A and B. In the cost-minimization
analysis, the consumption of medical resources other than the cost of drug
therapy was assumed to be equal, and the cost of drug therapy for one year in
the combined population of A and B was compared. As a result, the total annual
cost of FF/UMEC/VI and the comparator [MITT] (lowest cost ICS/LABA + lowest
cost LAMA) were estimated to be JPY107,721 and JPY125,910, respectively,
indicating that the cost of FF/UMEC/VI was JPY18,189 lower than that of MITT.
<Summary of CEA for populations C to L>
A cost-effectiveness analysis was conducted in the target population C-L,
assuming that FF/UMEC/VI had an additional benefit over the comparator. The
Galaxy COPD model was used to estimate the ICERs of FF/UMEC/VI by
extrapolating the difference in the CFB of FEV1 between FF/UMEC/VI and thecomparator. The model incorporated a risk estimation equation based onprospective studies from overseas, which predicted COPD symptoms (FEV1,
percentage of dyspnea symptoms, percentage of cough and sputum
symptoms), occurrence of exacerbations, and exercise capacity (6-minute walkdistance) for the next cycle based on the difference in FEV1 CFB and baseline
background factors. From these predicted values of COPD pathology, medical
costs, quality of life (SGRQ, utilities), and survival rates in the same cycle were
estimated. Using these predicted COPD pathophysiological values andbackground factors, the predicted pathophysiological values for the next cycle
were further calculated, and by repeating the same process thereafter, thelong-term costs and QALYs for each treatment group and the ICERs for
FF/UMEC/VI were estimated (Table 3-1).

64

Table 3-1 Results of the base case analysis by the manufacturer
Population

A＋B

Description

Treatment

Effectiveness(QALY)

Incremental
effectiveness(QALY)

Prior therapy: MITT

FF/UMEC/VI--(CMA#)
C
(CEA)
D
(CEA)

MITT
Prior therapy: MITT

Incremental
cost (JPY)-18,189

Cost saving

-

-

-

-

125,910

4.902

0.133

4,139,444-5,460

FF/VI

4.769

-

4,144,904-

Prior therapy: MITT

FF/UMEC/VI

4.910

0.140

4,112,646-32,258

EOS ≥ 100/μL

FF/VI

4.769

-

4,144,904-

Prior therapy: MITT

FF/UMEC/VI

4.845

0.075

4,297,127

58,632

EOS < 100/μL

UMEC/VI

4.769-

4,238,495-

Prior therapy: MITT

FF/UMEC/VI

4.905

0.136

3,874,014

EOS ≥ 100/μL

UMEC/VI

4.769-

4,238,495-

Prior therapy: ICS+LABA

FF/UMEC/VI

4.879

0.110

4,297,829

152,925

EOS < 100/μL

FF/VI

4.769

-

4,144,904-

Prior therapy: ICS+LABA

FF/UMEC/VI

4.920

0.151

4,222,901

77,997

EOS ≥ 100/μL

FF/VI

4.769

-

4,144,904-

FF/UMEC/VI

4.880

0.111

4,651,551

413,056

F
(CEA)
G
(CEA)
H
(CEA)
I
(CEA)

Prior therapy: LAMA/LABA
or LAMAICER (JPY/QALY)

107,721

EOS < 100/μL

E
(CEA)

J
(CEA)

FF/UMEC/VI

Cost (JPY)EOS < 100/μL

UMEC/VI

4.769-

4,238,495

Prior therapy: LAMA/LABA
or LAMA

FF/UMEC/VI

4.920

0.150

3,843,478

EOS ≥ 100/μL

UMEC/VI

4.769-

4,238,495

Dominant
Dominant
779,044--364,480-

Dominant
1,396,294
517,736
3,726,572--395,017
-

K
(CEA)

Prior therapy: LAMA

FF/UMEC/VI

5.023

0.254

3,948,004

EOS < 100/μL

FF/VI

4.769

-

4,144,904

-

L
(CEA)

Prior therapy: LAMA

FF/UMEC/VI

4.981

0.212

4,286,733

141,829

EOS ≥ 100/μL

FF/VI

4.769

-

4,144,904-

Dominant--196,900

Dominant
669,299-# Annual drug costs was compared in CMA
65

<Critique on the setting of drug costs in CMA>
The manufacturer used the cheapest drug price in the cost-minimization
analysis for population A and B, assuming that the dosage form of MITT is
ICS/LABA + LAMA. Since there is no single ICS drug that is covered byinsurance for COPD in Japan, the manufacturer's setting is reasonable.
<Critique on the model used in CEA>The Galaxy COPD model used in the cost-effectiveness analysis is elaborate andcomplex, and has recently been published as original articles but the following
points need to be kept in mind when using it for decision making in this system.
 Improvement in FEV1, rather than avoidance of exacerbations as
determined in the analytical framework, is used as an input parameter tothe model to estimate various treatment effects, which is not necessarily
consistent with the discussion in the assessment of additional benefit, andshould be interpreted with caution.
 The model is designed to predict various events and estimate outcomesusing the difference in CFB of FEV1. However, when the predicted values ofexacerbation RR and SGRQ by the model deviate from the observed values
in clinical trials, these values have to be calibrated manipulatively, which
limits the predictive performance of the model relying only on FEV1.
 There is a tendency for the model to overestimate the incidence of
exacerbations and underestimate the mortality rate compared to theobserved values of the prospective studies on which the risk estimation
equation is based[6].
On the other hand, it is possible to consider a re-analysis by academic groupbased on the structure of the Galaxy COPD model for the following reasons.
 Based on the results of the manufacturer’s report and additional literature
review, the Galaxy COPD model has some validity in representing thepathogenesis and prognosis of COPD.
 Even if the extrapolation method using FEV1 is used, if (1) the treatment
effect of avoiding exacerbations is recognized in the additional benefit
assessment and (2) the treatment effect of avoiding exacerbations (rateratio of exacerbations) confirmed in clinical trials is appropriately reflectedin the model, a certain degree of validity is ensured, and therefore, it ispossible to discuss cost-effectiveness in accordance with the analyticalframework.
 There is not necessarily sufficient consensus on the optimal model structure
to be used for health economic evaluation in the field of COPD, and it isdifficult to determine the superiority or inferiority among multiple models[6].
<Critique on the parameter settings in the CEA model>
66







The manufacturer used the data from ITT population of the IMPACT trial toset parameters for background factors that are assumed to affect theoutcome in the Galaxy COPD model. On the other hand, according to thepost-hoc analysis of the IMPACT study, the distribution of patient
background factors such as age and gender differed between the ITT
population and the Japanese population[7]. Therefore, in order to estimate
the ICER of FF/UMEC/VI to be evaluated that better matches the real world
settings in Japan, it is necessary to change the settings of the backgroundfactors of the patient population entered into the model to match theJapanese population.
The manufacturer uses the risk estimation equation in the Galaxy COPD
model (which predicts survival based on the predicted values of COPD
pathology, including FEV1) to estimate ICERs with different survival rates
between treatment groups based on the difference in CFB of FEV1, but sucha setting is not necessarily valid. In other words, if there is a difference in
FEV1, there will be a difference in mortality in the model, but the results ofthe post-hoc analysis of the IMPACT trial, for example, suggest that there isno difference in life expectancy between treatments in some of theanalyzed populations [8]. Therefore, in order to more accurately estimate
the ICERs of FF/UMEC/VI, it is necessary to consider a setting in which
there is no difference in survival between treatments in the relevant
analytic population.
The manufacturer estimates the ICER of FF/UMEC/VI using the risk
estimation equation in the Galaxy COPD model (which predicts the SGRQ
based on the predicted values of COPD pathology including FEV1) and themapping algorithm (which predicts the utilities based on the SGRQ).
However, there are some challenges in doing so. That is, the IMPACT study
showed a statistically significant difference between FF/UMEC/VI andcomparator in the CFB of SGRQ, and the percentage of patients whoachieved the minimum clinically significant difference (MCID) of 4 units wasreported to be 42% in the FF/UMEC/VI group and 34% in the control group.
Therefore, FF/UMEC/VI has a certain improvement effect on health-related
quality of life[9, 10]. On the other hand, there is no empirical reportshowing that FF/UMEC/VI is superior to the comparator in utility weights
such as EQ-5D. Therefore, from the perspective of providing reference
information that contributes to decision-making, it is necessary to consider
a setting in which utility weights do not differ between treatments as a
scenario analysis.

673.2 Summary of revisions by academic group
Following the results of a review on the cost-effectiveness evaluation by the
manufacturer and the additional benefit assessment by academic group, arevised analysis of the cost-effectiveness evaluation is necessary to be
conducted as follows.
<Revised base case analysis>(1) For populations A and B, no revised analysis was conducted because theanalytical methods submitted by the manufacturer were appropriate.
(2) For populations C and D, no revised analysis of the cost-effectivenessassessment was conducted because of the difficulty in assessing additional
benefit.
(3) For populations E, F, and I, a cost-minimization analysis assuming
equivalence of efficacy among treatments were conducted because theadditional benefit of FF/UMEC/VI over the comparator was notdemonstrated.
(4) For populations G, H, J, K, and L, a revised cost-effectiveness analysis was
performed changing the parameter settings of the background factors of
the Galaxy COPD model to the statistics of the Japanese population,
because it is suggested that the background factors of patients differ
between the ITT population of the IMPACT study and the Japanese
population.
(5) For populations G, H, J, K, and L, a revised cost-effectiveness analysis was
performed assuming that the survival rates of FF/UMEC/VI and comparator
in the Galaxy COPD model were the same value (the mean of both),because the post-hoc analysis of the IMPACT trial suggest that there is nodifference in prognosis between the treatments in these populations.
<Revised scenario analysis>(1) For populations G, H, J, K, and L, scenario analysis was performed
assuming that the utility weights of FF/UMEC/VI and comparator in the
Galaxy COPD model were the same value (the mean of both), because
superiority of FF/UMEC/VI to comparator has not been indicated in utility
weights.

683.3 Methods of the revised base case analysis
3.3.1 Cost-effectiveness in population C and D
Table 3-2 Corresponding part of report by manufacturer
In the reports, submitted by the manufacturer
SectionNumber of pages

5.1.1

P94

Start line number(or figure/table number)Table 5-2 Summary of theresult of CUA 1<Description of report>
A report by the manufacturer, excerpted/summarized from Table 5-2
Population Description Treatment Effectiv Incremental Cost (JPY) Incremental
eness effectivenes
cost (JPY)(QALY)s (QALY)
C

D

ICER
(JPY
/QALY)

Prior
therapy:
MITT
EOS <100/μL

FF/UMEC/
VI

4.902

0.133

4,139,444-5,460 Dominant

FF/VI

4.769

-

4,144,904-

Priortherapy:
MITT
EOS ≥100/μL

FF/UMEC/
VI

4.910

0.140

4,112,646-32,258 Dominant

FF/VI

4.769

-

4,144,904---< Details of academic analysis (revision)> The cost-effectiveness assessment for populations C and D were treated as
unanalyzable based on the results of the additional benefit assessment.

69

3.3.2 Cost-minimization analysis in population E, F, and I
Table 3-3 Corresponding part of report by manufacturer
In the reports, etc. submitted by the manufacturer
SectionNumber of pages

5.1.1

P94

Start line number(or figure/table number)Table 5-2 Summary of theresult of CUA 1<Description of report>
A report by the manufacturer, excerpted/summarized from Table 5-2
Population Description Treatment Effectiv Incremental Cost (JPY) Incremental
eness effectivenes
cost (JPY)(QALY)s (QALY)
E

F

I

ICER
(JPY
/QALY)

Prior
therapy:
MITT
EOS <100/μL

FF/UMEC/
VI

4.845

0.075

4,297,127

58,632779,044

UMEC/VI

4.769-

4,238,495-

Priortherapy:
MITT
EOS ≥100/μL

FF/UMEC/
VI

4.905

0.136

3,874,014

UMEC/VI

4.769-

4,238,495-

Priortherapy:
LAMA/LABA
or LAMA
EOS <100/μL

FF/UMEC/
VI

4.880

0.111

4,651,551

413,056 ¥3,726,572

UMEC/VI

4.769-

4,238,495---364,480 Dominant--< Details of academic analysis (revision)> For populations E, F, and I, a cost-minimization analysis was performed
assuming that the effects of FF/UMEC/VI were equivalent to those of thecomparator, as no additional benefit of FF/UMEC/VI over the comparator
was shown.
 Assuming that the consumption of medical resources other than the drug
costs was equivalent, annual drug costs in the FF/UMEC/VI group and thecomparator (LAMA/LABA) group were estimated and compared.
 Similar to the manufacturer's method, the annual drug costs (= [unit drug
price] × [number of inhalations per day] / [number of inhalations per kit] ×365) for the FF/UMEC/VI and LAMA/LABA groups were estimated andcompared.
 The drug price of FF/UMEC/VI was set to be JPY 8,853.80 (JPY 295.13 perday).
 The least expensive LAMA/LABA should be Ultibro inhalation capsules (JPY70245.5 per day [drug price standard as of October 2019]).

71

3.3.3 Cost-effectiveness analysis in population G, H, J, K, and L(Settings of background factors)
Table 3-4 Corresponding part of report by manufacturer
In the reports, etc. submitted by the manufacturer
SectionNumber of pages

Response to an inquiry
on the report submitted
by the manufacturer(August 17, 2020)

P8

Start line number(or figure/table number)Table 2 Comparison of
integrated ITT population
and Japanese specificbaseline characteristics<Description of report>
Table 2 Comparison of ITT population and Japanese specific baselinecharacteristics
Parameter

ITT(1) Female (%)(2) Age (years old), mean
(3) BMI: Low (<21, %)(3) BMI: Middle (21 to 30, %)(3) BMI: High (>30, %)(4) Every comorbidity of CVD(%)(5) Ever other comorbidity (%)(6) Previous history of
exacerbation ≥1 (%)(7) mMRC score ≥2 (%)(8) Current smoker (%)(9) Height (cm), mean(10) Number of exacerbations in
the year before (moderate orsevere), mean per person(11) Moderate exacerbation(12) Severe exacerbation(13) Total score of SGRQ at thetime of start(14) %FEV1 at the time of start
FEV1 of results (based onentered predictive values [%]and baseline characteristics)*(15) 6-minute walk distance(m)*

34.00%
65.3
17.0%
58.0%
25.0%
44.0%

Japanese
specific
SE=0.08

7.14%
70.54
38.62%
59.53%
1.85%
33.60%

SE=0.37

57.0%
99.9%

55.03%
100.00%

37.0%
35.0%
167.5
1.71

SE=0.09
SE=0.01

22.28%
24.07%
163.991.72

SE=0.36
SE=0.06

SE=0.2

1.36
0.37
40.34

SE=0.79

1.41
0.30
50.70
45.5%
1215.3

SE=0.1%50.19%
1248.3

SE=0.81%365.8

SE=2.74

387.91SE=2.74* The value is calculated with the model.

< Details of academic analysis (revision)> In the manufacturer’s submission, the parameters of background factors
72that were assumed to affect the outcome were commonly used for the ITT
population settings. Based on the results of the post-hoc analysis of the
IMPACT trial, it was assumed that the Japanese population tended to have(1) older age, (2) lower BMI, (3) current smoker/low, (4) higher %FEV1, (5)lower SGRQ, and (6) lower eosinophil count, and relatively lower COPD
symptoms and risk compared to the ITT population[7]. Therefore, it wasnecessary to change the background factors of patients to those of theJapanese population in order to more accurately estimate the ICERs of
FF/UMEC/VI.
The revised analysis was performed based on the information on the
background factors of the Japanese population provided by the
manufacturer in the response to the inquiry on the report submitted by the
manufacturer (August 17, 2020) (Table A-3). In addition, a comparison wasmade with the results using the background factors of the Japanese
population presented by the manufacturer in the response to the inquiry.

73

3.3.4 Cost-effectiveness analysis in population G, H, J, K, and L(Settings of survival probability)
Table 3-5 Corresponding part of report by manufacturer
In the reports, etc. submitted by the manufacturer
SectionNumber of pages

Attachment data C. Risk
equation parameters

P237~P240

Start line number(or figure/table number)Table C-9 Final outcome
equation 2, coefficient for
Weibull survival model<Description of report># There is no detailed description on making a distinction in a survival rate
between treatment groups< Details of academic analysis (revision)> In the manufacturer’s submission, the CEA was performed assuming a
difference in survival between treatment groups based on an indirect
estimate using a risk estimation formula, which is not necessarily
appropriate.
 Post-hoc analysis of the IMPACT trial suggested that (1) there was nodifference in all-cause mortality between FF/UMEC/VI and ICS/LABA in
populations with pretreatment other than MITT (ICS/LABA, LAMA/LABA or
LAMA), and (2) there was no difference in all-cause mortality between
FF/UMEC/VI and ICS/LABA in populations with pretreatment including ICS(MITT or ICS/LABA), and (3) there was no difference in all-cause mortality
between FF/UMEC/VI, ICS/LABA, and LAMA/LABA in populations without
ICS as pretreatment (LAMA/LABA or LAMA) (Figure 3-1)[8].
 Therefore, in the revised CEA for populations G, H, J, K, and L, it wasnecessary to consider settings that do not differ in survival rates between
treatment groups.
 The manufacturer's model uses different survival rates estimated from FEV1
under different conditions for the FF/UMEC/VI and comparator arms.
However, after discontinuation of treatment in both groups, the survival
rates estimated for the comparator group were used.
 In the revised analysis, the survival rates estimated under each condition
for the FF/UMEC/VI and comparator were averaged and used as the survival
rates during and after treatment for each group (Table A-4).

74

Figure 3-1 A relationship between the result of the post hoc analysis on
prognosis of IMPACT study and the analytical framework [8](a)A correspondence between subgroups of the post hoc analysis and theanalytical framework

Prior therapy

Details of
the priortherapy

Eosinophil count< 100/μL≥ 100/μL

Comparator

A

B

MITT (Tripledrug therapy
with inhalationof 2 drug
products)C

D

ICS/LABAE

F

LAMA/LABAICS/LABAGH

ICS/LABA

Prior therapy: Dual-drugtherapy (LAMA/LABA)
or prior therapy with asingle drug (LAMA)

IJ

LAMA/LABA

Single drug

K

L

ICS/LABA

Triple-drugtherapyDual-drug
therapy

Other

MITT
(Triple-drugtherapy withinhalation of
2 drugproducts)

LAMA

Not included in analysis

75

(b)

Group 1 (blue, populations A to F)

76

(c)

Group 2 (green, populations A to H)

77

(d)

Group 3 (yellow, populations G to L)

78

(e)

Group 4 (red, populations I to L)79

3.4 Methods of the revised scenario analysis
3.4.1 Cost-effectiveness analysis in population G, H, J, K, and L(Settings in Utilities)
Table 3-6 Corresponding part of report by manufacturer
In the reports, etc. submitted by the manufacturer
Section
4.2.2 Details of QOL
valuesNumber of pages

Start line number(or figure/table number)

P84~85

Line 32<Description of report>
Utilities were estimated from predicted SGRQ in each model cycle, based on thefollowing process:1. The model predicted SGRQ-C in each model cycle (see equation in Appendix
C)
2. SGRQ-C was converted to SGRQ using equation 1: (29)
Equation 1: SGRQ = SGRQ-C*0.9 + 3.1
3. SGRQ was then transformed to an EuroQOL-5 Dimension (EQ-5D) utility
estimate using the algorithm developed by Starkie et al., presented in equation
2: (30)Equation 2: EQ-5D = 0.9617 - 0.0013*SGRQ total - 0.0001*SGRQ total2+
0.0231*%male
Utilities in subsequent cycles were calculated from the model-predicted SGRQ
scores using the same approach. With a baseline SGRQ of 50.7, the resulting
starting utility is 0.676. The model applies half-cycle correction to the QALY
estimates for each cycle.
< Details of academic analysis (revision)> The manufacturer’s model used a multi-step estimation method using a risk
estimation equation and a mapping algorithm to differentiate utility weights
between treatment groups, but the appropriateness of this method wascontroversial.
 Although the IMPACT trial showed a statistically significant improvement in
SGRQ in the FF/UMEC/VI group, there was no report showing thesuperiority of FF/UMEC/VI for utilities directly measured by EQ-5D.
80






Therefore, it was necessary to examine the setting in which there was nodifference in utility weights between treatments.
In the manufacturer's model, different utility weights estimated under
different conditions were used for the FF/UMEC/VI and the comparatorgroups. However, after discontinuation of treatment in both groups, theutilities estimated for the comparator were used.
In the revised analysis, the utilities estimated under each condition in the
FF/UMEC/VI and comparator groups were averaged and used as the utilities
during and after treatment for each group (Table A-5).

81

4. Results of cost-effectiveness assessment
4.1 Summary
The results of the revised base case analysis were summarized in Table 4-1. In
the revised analysis, populations C and D were deemed unanalyzable based on
the results of additional benefit assessment. For populations E, F, and I, a cost
minimization analysis was performed. For groups G, H, J, K, and L, a revised
cost-effectiveness analysis was conducted in which the background factors werechanged to those of the Japanese population and the parameter for survival
rate was changed to the same value (mean value of both) between thetreatment groups. The results of the cost-effectiveness evaluation by the
manufacturer were shown in the rightmost column of Table 4-1. There was nochange in the base case analysis for groups A and B, and FF/UMEC/VI became“cost saving” compared to MITT, as did the results of the manufacturer. For
populations C and D, according to the manufacturer's results, FF/UMEC/VI was
Dominant compared to ICS/LABA, but the revised analysis judged thispopulation to be unanalyzable, and ICERs were not estimated. According to the
manufacturer's submission, the results of the ICER in the populations E, F, and I
were JPY 779,044/QALY, Dominant, and JPY 3,726,572/QALY, respectively.
However, the revised analysis showed that FF/UMEC/VI became “costincreasing” compared to LAMA/LABA in this population. The results of therevised analysis for populations G, H, and L showed that the ICER of
FF/UMEC/VI was less than JPY 5 million/QALY, similar to the results for the
manufacturer. The results of the revised analysis of the populations J and K
showed that FF/UMEC/VI was dominant compared to the comparator, as did theresults of the manufacturer. The results of additional CEA were summarized inTable A-6, assuming that the additional benefit assessment was the same whenthe eosinophil count cutoff was set at 150/μL as when it was set at 100/μL.

82

Table 4-1 Results of the revised basic analysis
Population

Description

Treatment

Effective Incremental Cost (JPY) Incrementalness(QAL effectivenes
cost (JPY)Y)
s (QALY)

ICER by theacademicgroup

ICER by the
manufacturer(JPY/QALY)(JPY/QALY)
FF/UMEC/VI--

107,721-18,189

Cost saving

Cost saving

MITT

-

-

125,910---

Prior therapy:
MITT

FF/UMEC/VI

-

-

-

-

Unable to beanalyzed

Dominant(Dominant)

EOS < 100/μL

FF/VI

-

-

-

-

-

-

Prior therapy:
MITT

FF/UMEC/VI

-

-

-

-

Unable to beanalyzed

Dominant

EOS ≥ 100/μL

FF/VI

-

-

-

-

-

-

Prior therapy:
MITT

FF/UMEC/VI--

107,721

18,114

EOS < 100/μL

UMEC/VI--

89,608

-

A,B
(CMA)

Prior therapy:
MITT

C(Unable tobeanalyzed)
D(Unable tobeanalyzed)
E
(CMA)
F
(CMA)
G
(CEA)
H
(CEA)
I

Prior therapy:
MITT

FF/UMEC/VI--

107,721

18,114

EOS ≥ 100/μL

UMEC/VI--

89,608-

Prior therapy:
ICS+LABA

FF/UMEC/VI

5.498

0.055

3,242,120

100,408

EOS < 100/μL

FF/VI

5.443

-

3,141,711-

Prior therapy:
ICS+LABA

FF/UMEC/VI

5.564

0.070

3,209,063

22,941

EOS ≥ 100/μL

FF/VI

5.494

-

3,186,122-

Prior therapy:

FF/UMEC/VI--

107,721

Cost
increasing

779,044--

Cost
increasing

Dominant--

1,833,684

1,396,294--

328,585

517,736--

18,114 Cost increase

3,726,572

83

(CMA)

J
(CEA)

K
(CEA)
L
(CEA)

LAMA/LABA orLAMA
EOS < 100/μL

UMEC/VI--

89,608-

Prior therapy:
LAMA/LABA or
LAMA

FF/UMEC/VI

5.568

0.066

2,940,676-345,791

EOS ≥ 100/μL

UMEC/VI

Prior therapy:
LAMA

5.503

-

3,286,467-

FF/UMEC/VI

5.652

0.139

3,016,838-185,338

EOS < 100/μL

FF/VI

5.513

-

3,202,176-

Prior therapy:
LAMA

FF/UMEC/VI

5.662

0.093

3,293,670

44,982

EOS ≥ 100/μL

FF/VI

5.569

-

3,248,688---

Dominant

Dominant--

Dominant

Dominant--

483,056

669,299--84

4.2 Revised base case analysis
For the populations A and B, the analyses submitted by the manufacturer werereasonable and therefore accepted. For the other populations, the results wereas follows.
4.2.1 Cost-effectiveness in population C and D
Since these populations were judged as “unable to analyze”, ICERs were notestimated (Table 4-1).
4.2.2 Cost-minimization analysis in population E, F, and I
Results of the CMA of FF/UMEC/VI compared to LAMA/LABA were as follows.
 Annual drug cost of FF/UMEC/VI = [a unit price of the drug] x [number ofdaily inhalation]/[number of inhalations per kit] × 365=8,853.80 × 1/30 ×
365=JPY 107,721.2
 Annual drug cost of LAMA/LABA = [a unit price of the drug] x [number ofdaily inhalation]/[number of inhalations per kit] ×365) =245.5 × 1/1 × 365= JPY 89,607.5
 Incremental cost of FF/UMEC/VI compared to LAMA/LABA = JPY 107,721.2– JPY 89,607.5 yen = JPY 18,113.7 (cost increasing)
4.2.3 Cost-effectiveness analysis in population G, H, J, K, and L(Settings of background factors)
Table 4-2 shows the results of the revised CEA in which the background factor
was changed to the Japanese population setting for populations G, H, J, K, and
L (Table 4-1 shows the results when the changes in 4.2.3 and 4.2.4 were madesimultaneously.). When the results of this analysis were compared with theresults by the manufacturer at the time of the response to the inquiry (August17, 2020), it was confirmed that there was no deviation.

85

Table 4-2 The results of revised analysis in populations G, H, J, K, and L (Settings of background factors)
Population

G

H

J

K
L

Description

Treatment

Effectiven Increment
essal(QALY)
effectivene
ss (QALY)
5.474
0.104

Prior therapy:
ICS+LABA

FF/UMEC/VI

EOS < 100/μL

FF/VI

5.370

Prior therapy:
ICS+LABA

FF/UMEC/VI

5.520

EOS ≥ 100/μL

FF/VI

5.370

Prior therapy:
FF/UMEC/VI
LAMA/LABA or LAMA

5.519

EOS ≥ 100/μL

UMEC/VI

5.370

Prior therapy: LAMA

FF/UMEC/VI

5.601

EOS < 100/μL

FF/VI

5.370

Prior therapy: LAMA

FF/UMEC/VI

5.590

EOS ≥ 100/μL

FF/VI

5.370

Cost (JPY)3,217,944

Incremental
cost (JPY)ICER byacademic group(JPY /QALY)

134,692

1,289,873

77,719516,577

3,083,252
0.150

3,160,970
3,083,252

0.149

2,882,462-292,130

Dominant-126,361

Dominant

3,174,592
0.231

2,956,890
3,083,252

0.220

3,214,998

131,746597,743

3,083,25286

4.2.4 Cost-effectiveness analysis in population G, H, J, K, and L(Settings of survival rate)
Table 4-3 shows the results of revised analysis in which the survival rate waschanged to the same value across treatment groups in populations G, H, J, K,
and L (Table 4-1 describes the results when the changes in 4.2.3 and 4.2.4
were made simultaneously.).

87

Table 4-3 The results of revised analysis in populations G, H, J, K, and L (Settings of survival rate)
Population

G

H

J

K
L

Description

Treatment

Effectiven
ess(QALY)

Incremental
effectiveness (QALY)

Prior therapy:
ICS+LABA

FF/UMEC/VI

4.902

0.069

EOS < 100/μL

FF/VI

4.833

Prior therapy:
ICS+LABA

FF/UMEC/VI

4.958

EOS ≥ 100/μL

FF/VI

4.870

Prior therapy:
LAMA/LABA or LAMA

FF/UMEC/VI

4.965

EOS ≥ 100/μL

UMEC/VI

4.882

Prior therapy: LAMA

FF/UMEC/VI

5.070

EOS < 100/μL

FF/VI

4.893

Prior therapy: LAMA

FF/UMEC/VI

5.040

EOS ≥ 100/μL

FF/VI

4.923

Cost (JPY)

4,341,524

Incremental
cost (JPY)ICER byacademic group(JPY /QALY)

109,054

1,580,733

11,167127,044

4,232,470
0.088

4,295,572
4,284,405

0.084

3,935,451-462,679

Dominant-273,509

Dominant

4,398,130
0.177

4,044,813
4,318,322

0.117

4,398,684

40,224344,499

4,358,460

88

4.3 Revised sensitivity analysis
One-way sensitivity analyses were conducted for the populations G, H, J, K, andL, excluding populations A, B, E, F, and I, which were subject to cost
minimization analysis, and population C and D, which were unable to analyze(Table 4-4 to Table 4-8). The range of variation of the parameters were inaccordance with the manufacturer's submission. In the population G, the rate
ratio of severe exacerbations and the setting of SGRQ-C suggested that theconclusion of cost-effectiveness evaluation of FF/UMEC/VI might change (Table
4-4). The results also showed that the ICER of FF/UMEC/VI was significantly
affected by the setting of the rate ratio of severe exacerbations in the
population L (Table 4-8).

89

Table 4-4 The results of the sensitivity analysis in population G (Prior
therapy: ICS+LABA +EOS < 100/μL)
Results of the basic analysis: ICER=JPY1,833,684/QALY
Scenario
Lower Upper Results of the lower Results of the upper
limit
limit
limit
limit
(JPY/QALY)(JPY/QALY)
Rate ratio of severe
0.61
1.67
Dominant
11,525,432
exacerbation
Change in SGRQ-C
-4.89
0.67
813,993
Dominated(Nondominant)Rate ratio of
0.56
0.95
1,523,232
2,235,982
moderate
exacerbation
Health care cost of
50%
200%
2,062,810
1,375,431
moderate
exacerbation
Change in FEV1 (mL)-4802,095,005
1,709,860
Annual disease50%
200%
1,936,225
1,628,601
management cost
Time frame of the
5
10
2,113,222
1,884,209
analysis (year)
Health care cost of
50%
200%
1,801,644
1,897,763
severe exacerbation
Discount rate
0%4%
1,794,340
1,870,705

90

Table 4-5 Results of the sensitivity analysis in population H (Prior
therapy: ICS+LABA + EOS ≥ 100/μL)
Results of the basic analysis：ICER=JPY328,585/QALY
Scenario

Lower
limit

Upper
limit

Results of the lower
limit(JPY/QALY)

Rate ratio of severe
exacerbation

0.65

1.27

Dominant

Health care cost of
severeexacerbation

50%

200%

859,207

Change in SGRQ-C

-4.33

-1.00

206,408

845,106

Health care cost ofmoderate
exacerbation

50%

200%

463,29059,175Rate ratio ofmoderate
exacerbation

0.69

0.94

171,083

568,085

Annual disease
management cost

50%

200%

455,555

74,644

Time frame of theanalysis (year)510592,792

386,232

Change in FEV1
(mL)

58

110

442,817

277,488

Discount rate

0%4%

291,156

363,312Results of the upper
limit(JPY/QALY)
4,324,593
Dominant

91

Table 4-6 Results of the sensitivity analysis in population J (Prior
therapy: LAMA/LABA or LAMA + EOS ≥ 100/μL)
Results of the basic analysis: Dominant
Results of theResults of the upper
Scenario
Lower
Upper
lower limit
limit
limit
limit
(JPY/QALY)(JPY/QALY)
Change in SGRQ-4.78-0.22
Dominant
Dominant
C
Health care cost
50%
200%
Dominant
Dominantof severe
exacerbation
Rate ratio of
0.31
0.88
Dominant
Dominant
severeexacerbation
Rate ratio of
0.69
1.12
Dominant
Dominant
moderate
exacerbation
Annual disease
50%
200%
Dominant
Dominant
management
cost
Health care cost
50%
200%
Dominant
Dominantof moderate
exacerbation
Time frame of
5
10
Dominant
Dominant
the analysis(year)
Change in FEV1
37
123
Dominant
Dominant(mL)
Discount rate
0%4%
Dominant
Dominant

92

Table 4-7 Results of the sensitivity analysis in population K (Prior
therapy: LAMA + EOS < 100/μL)
Results of the basic analysis: Dominant
Results of theResults of the upper
Scenario
Lower
Upper
lower limit
limit
limit
limit
(JPY/QALY)(JPY/QALY)
Change in SGRQ-C -10.33-0.56
Dominant
Dominant
Rate ratio of
0.4
1.08
Dominant
1,020,839
severeexacerbation
Health care cost of
50%
200%
Dominant
Dominant
severeexacerbation
Rate ratio of
0.4
1.08
Dominant
Dominant
moderate
exacerbation
Health care cost of
50%
200%
Dominant
Dominant
moderate
exacerbation
Change in FEV1
-26
169
Dominant
Dominant(mL)
Annual disease
50%
200%
Dominant
Dominant
management cost
Time frame of the
5
10
Dominant
Dominant
analysis (year)
Discount rate
0%4%
Dominant
Dominant

93

Table 4-8 Results of the sensitivity analysis in population L (Prior
therapy: LAMA + EOS ≥ 100/μL)
Results of the basic analysis: ICER=JPY483,056/QALY
Results of theResults of the upper
Scenario
Lower
Upper
lower limit
limit
limit
limit
(JPY/QALY)(JPY/QALY)
Rate ratio of
0.46
1.94
Dominant
9,048,398
severeexacerbation
Change in SGRQ-C
-6.44
-0.67
275,779
2,359,729
Health care cost of
50%
200%
778,956
Dominant
severeexacerbation
Rate ratio of
0.63
1.21
213,249
839,825
moderate
exacerbation
Annual disease50%
200%
603,027
243,116
management cost
Time frame of the
5
10
719,698
529,790
analysis (year)
Health care cost of
50%
200%
545,692
357,786
moderate
exacerbation
Change in FEV1
104
215
569,991
430,622(mL)
Discount rate
0%4%450,206
513,72094

4.4 Revised scenario analysis
4.4.1 Cost-effectiveness analysis in population G, H, J, K, and L(Settings of utility)
Table 4-9 shows the results of the scenario analysis in which the utility waschanged to the same value among the treatment groups in the costeffectiveness analysis for the populations G, H, J, K, and L.

95

Table 4-9 The scenario analysis assuming that the utility was equivalent
Population

G

H

J

K

L

Description

Treatment

Effectiveness (QALY)

Incremental
effectiveness (QALY)

Cost (JPY)

Incremental
cost (JPY)Prior therapy:
ICS+LABA

FF/UMEC/V
I

4.897

0.042

4,297,829

152,925

EOS < 100/μL

FF/VI

4.855

-

4,144,904-

Prior therapy:
ICS+LABA

FF/UMEC/V
I

4.944

0.064

4,222,901

77,997

EOS ≥ 100/μL

FF/VI

4.879

-

4,144,904-

Prior therapy:
LAMA/LABA or
LAMA

FF/UMEC/V
I

4.945

0.068

3,843,478

EOS ≥ 100/μL

UMEC/VI

4.876-

4,238,495

Prior therapy: LAMA

FF/UMEC/V
I

5.071

0.079

3,948,004

EOS < 100/μL

FF/VI

4.992

-

4,144,904-

Prior therapy: LAMA

FF/UMEC/V
I

5.012

0.097

4,286,733

141,829

EOS ≥ 100/μL

FF/VI

4.914

-

4,144,904--395,017-196,900

ICER byacademic
group(JPY/QALY)
3,676,921
1,214,796
Dominant

Dominant
1,456,611-

96

4.5 Interpretation of results
Table 4-10 to Table 4-21 show the interpretation of the results by academic
group for population A~L.
Table 4-10 Interpretation of the results in population A
Population A
Population(Patients receiving triple therapy with two inhaled drugs,
eosinophil count less than 100/μL)
Comparator
MITT (Triple-drug therapy with inhalation of 2 drug products)
technology
Reference■ Regular product ☐ Product requiring special consideration
value forICER
■ Cost reduction or dominant□ 5 million yen or less (7.5 million yen or less)Intervals□ More than 5 million yen (more than 7.5 million yen) and not
where ICER
more than 7.5 million yen (not more than 11.25 million yen)
is most likely □ More than 7.5 million yen (more than 11.25 million yen) andto belong
not more than 10 million yen (not more than 15 million yen)
□ More than 10 million yen (more than 15 million yen)
□ Efficacy equivalent (or inferior) and expensive
Reason for
The results of base case analysis showed that it was cost saving
such
compared to the comparator.
judgment

97

Table 4-11 Interpretation of the results in population B
Population B
Population(Patients receiving triple therapy with two inhaled drugs,
eosinophil count more than 100/μL)
Comparator
MITT (Triple-drug therapy with inhalation of 2 drug products)
technology
Reference■ Regular product ☐ Product requiring special consideration
value forICER
■ Cost reduction or dominant□ 5 million yen or less (7.5 million yen or less)Intervals□ More than 5 million yen (more than 7.5 million yen) and not
where ICER
more than 7.5 million yen (not more than 11.25 million yen)
is most likely □ More than 7.5 million yen (more than 11.25 million yen) andto belong
not more than 10 million yen (not more than 15 million yen)
□ More than 10 million yen (more than 15 million yen)
□ Efficacy equivalent (or inferior) and expensive
Reason for
The results of base case analysis showed that it was cost saving
such
compared to the comparator.
judgment98

Table 4-12 Interpretation of the results in population C
Population C(Patients receiving triple therapy with two inhaled drugs,
Population
appropriate for step-down withdrawal from LAMA, and eosinophil
count less than 100/μL)
Comparator
ICS/LABA
technology
Reference■ Regular product ☐ Product requiring special consideration
value forICER
□ Cost reduction or dominant□ 5 million yen or less (7.5 million yen or less)□ More than 5 million yen (more than 7.5 million yen) and not
Intervals
where ICER
more than 7.5 million yen (not more than 11.25 million yen)
is most likely □ More than 7.5 million yen (more than 11.25 million yen) andto belong
not more than 10 million yen (not more than 15 million yen)
□ More than 10 million yen (more than 15 million yen)
□ Efficacy equivalent (or inferior) and expensive
Reason for
It was judged as “unable to analyze” because there was no clinical
such
data.
judgment99

Table 4-13 Interpretation of the results in population D
Population D(Patients receiving triple therapy in inhaled formulations, forPopulation
whom a step-down procedure to wean off LAMA is appropriate,and have an eosinophil count of 100/μL or higher)
Comparator
ICS/LABA
technology
Reference■ Regular product ☐ Product requiring special consideration
value forICER
□ Cost reduction or dominant□ 5 million yen or less (7.5 million yen or less)□ More than 5 million yen (more than 7.5 million yen) and not
Intervals
where ICER
more than 7.5 million yen (not more than 11.25 million yen)
is most likely □ More than 7.5 million yen (more than 11.25 million yen) andto belong
not more than 10 million yen (not more than 15 million yen)
□ More than 10 million yen (more than 15 million yen)
□ Efficacy equivalent (or inferior) and expensive
Reason for
It was judged as “unable to analyze” because there was no clinical
such
data.
judgment100

Table 4-14 Interpretation of the results in population E
Population E(Patients receiving triple therapy with two inhalation formulations,
Population
for whom a step-down from ICS is appropriate, and whose
eosinophil count is less than 100/μL)
Comparator
LAMA/LABA
technology
Reference■ Regular product ☐ Product requiring special consideration
value forICER
□ Cost reduction or dominant□ 5 million yen or less (7.5 million yen or less)□ More than 5 million yen (more than 7.5 million yen) and not
Intervals
more than 7.5 million yen (not more than 11.25 million yen)where ICER
is most likely □ More than 7.5 million yen (more than 11.25 million yen) andnot more than 10 million yen (not more than 15 million yen)
to belong□ More than 10 million yen (more than 15 million yen)
■ Efficacy equivalent (or inferior) and expensive
Reason for
It has not been shown to have additional benefit for populations
suchwhere a step-down from ICS is clinically appropriate. “Costjudgment
increasing”

101Table 4-15 Interpretation of the results in population F
Population F(Patients receiving triple therapy with two inhalers, appropriate
Population
for step-down withdrawal from ICS, and eosinophil count≥100/μL)
Comparator
LAMA/LABA
technology
Reference■ Regular product ☐Product requiring special consideration
value forICER
□ Cost reduction or dominant□ 5 million yen or less (7.5 million yen or less)□ More than 5 million yen (more than 7.5 million yen) and not
Intervals
where ICER
more than 7.5 million yen (not more than 11.25 million yen)
is most likely □ More than 7.5 million yen (more than 11.25 million yen) andto belong
not more than 10 million yen (not more than 15 million yen)
□ More than 10 million yen (more than 15 million yen)
■ Efficacy equivalent (or inferior) and expensive
Reason for
It has not been shown to have additional benefit for populations
suchwhere a step-down from ICS is clinically appropriate. “Costjudgment
increasing”

102Table 4-16 Interpretation of the results in population G
Population G
Population(Patients receiving ICS/LABA combination therapy and eosinophil
count less than 100/μL)
Comparator
ICS/LABA
technology
Reference■ Regular product ☐ Product requiring special consideration
value forICER
□ Cost reduction or dominant■ 5 million yen or less (7.5 million yen or less)Intervals□ More than 5 million yen (more than 7.5 million yen) and not
where ICER
more than 7.5 million yen (not more than 11.25 million yen)
is most likely □ More than 7.5 million yen (more than 11.25 million yen) andto belong
not more than 10 million yen (not more than 15 million yen)
□ More than 10 million yen (more than 15 million yen)
□ Efficacy equivalent (or inferior) and expensive
The results of base case analysis showed the ICER of JPY
1,833,684 /QALY. Although the one-way sensitivity analysis
Reason forindicated that the ICER was below JPY 5 million/QALY in the mainsuchanalysis, although the results suggested that the judgment on the
judgment
cost-effectiveness of FF/UMEC/VI varied in some settings.
Based on the above, the ICERs in this analysis population are
most likely to belong to the interval below JPY 5 million/QALY.

103

Table 4-17 Interpretation of the results in population H
Population H
Population(Patients receiving ICS/LABA combination therapy and eosinophil
count ≥100/μL)
Comparator
ICS/LABA
technology
Reference■ Regular product ☐ Product requiring special consideration
value forICER
□ Cost reduction or dominant■ 5 million yen or less (7.5 million yen or less)Intervals□ More than 5 million yen (more than 7.5 million yen) and not
where ICER
more than 7.5 million yen (not more than 11.25 million yen)
is most likely □ More than 7.5 million yen (more than 11.25 million yen) andto belong
not more than 10 million yen (not more than 15 million yen)
□ More than 10 million yen (more than 15 million yen)
□ Efficacy equivalent (or inferior) and expensive
The results of base case analysis showed the ICER of JPY 328,585
Reason for/QALY. Also, the one-way sensitivity analysis and the scenario
suchanalysis both showed that it was under JPY 5 million/QALY.
Based on the above, the ICERs in this analysis population are
judgment
most likely to belong to the interval below JPY 5 million/QALY.

104

Table 4-18 Interpretation of the results in population I
Population I
Population(Patients who are receiving only LAMA or a combination therapy
with LAMA/LABA in addition to their eosinophil count of < 100/μL)
Comparator
LAMA/LABA
technology
Reference■ Regular product ☐ Product requiring special consideration
value forICER
□ Cost reduction or dominant□ 5 million yen or less (7.5 million yen or less)□ More than 5 million yen (more than 7.5 million yen) and not
Intervals
more than 7.5 million yen (not more than 11.25 million yen)where ICER
is most likely □ More than 7.5 million yen (more than 11.25 million yen) andnot more than 10 million yen (not more than 15 million yen)
to belong□ More than 10 million yen (more than 15 million yen)
■ Efficacy equivalent (or inferior) and expensive
Reason forsuch
No additional benefit has been shown. “Cost increasing”
judgment

105

Table 4-19 Interpretation of the results in population J
Population
Population J(Patients receiving LAMA monotherapy or LAMA/LABA combination
therapy with eosinophil count ≥100/μL)
Comparator
LAMA/LABA
technology
Reference■ Regular product ☐ Product requiring special consideration
value forICER
■ Cost reduction or dominant□ 5 million yen or less (7.5 million yen or less)Intervals□ More than 5 million yen (more than 7.5 million yen) and not
where ICER
more than 7.5 million yen (not more than 11.25 million yen)
is most likely □ More than 7.5 million yen (more than 11.25 million yen) andto belong
not more than 10 million yen (not more than 15 million yen)
□ More than 10 million yen (more than 15 million yen)
□ Efficacy equivalent (or inferior) and expensive
The results of base case analysis showed that FF/UMEC/VI
became dominant. Also, the one-way sensitivity analysis and the
Reason for
scenario analysis both showed that it would be cost saving or
suchdominant.
judgment
Based on the above, the ICER in the target population is most
likely to be cost-saving or dominant.

106

Table 4-20 Interpretation of the results in population K
Population K
Population(Patients receiving LAMA monotherapy and eosinophil count lessthan 100/μL)
Comparator
ICS/LABA
technology
Reference■ Regular product ☐ Product requiring special consideration
value forICER
■ Cost reduction or dominant□ 5 million yen or less (7.5 million yen or less)Intervals□ More than 5 million yen (more than 7.5 million yen) and not
where ICER
more than 7.5 million yen (not more than 11.25 million yen)
is most likely □ More than 7.5 million yen (more than 11.25 million yen) andto belong
not more than 10 million yen (not more than 15 million yen)
□ More than 10 million yen (more than 15 million yen)
□ Efficacy equivalent (or inferior) and expensive
The results of base case analysis showed that FF/UMEC/VI
became dominant. Also, the one-way sensitivity analysis and the
Reason for
scenario analysis both showed that it would be cost saving or
suchdominant.
judgment
Based on the above, the ICER in the target population is most
likely to be cost-saving or dominant.

107

Table 4-21 Interpretation of the results in population L
Population L
Population(Patients receiving LAMA monotherapy and eosinophil count≥100/μ)Comparator
ICS/LABA
technology
Reference■ Regular product ☐ Product requiring special consideration
value forICER
□ Cost reduction or dominant■ 5 million yen or less (7.5 million yen or less)Intervals□ More than 5 million yen (more than 7.5 million yen) and not
where ICER
more than 7.5 million yen (not more than 11.25 million yen)
is most likely □ More than 7.5 million yen (more than 11.25 million yen) andto belong
not more than 10 million yen (not more than 15 million yen)
□ More than 10 million yen (more than 15 million yen)
□ Efficacy equivalent (or inferior) and expensive
The results of base case analysis showed the ICER of JPY
483,056/QALY. Although the one-way sensitivity analysis
Reason forindicated that the ICER was below JPY 5 million/QALY in the mainsuchanalysis, although the results suggested that the judgment on the
judgment
cost-effectiveness of FF/UMEC/VI varied in some settings.
Based on the above, the ICERs in this analysis population are
most likely to belong to the interval below JPY 5 million/QALY.

108

4.6 Proportion of patients in the analyzed population
4.6.1 Methods and results of estimating the proportion of patients
The manufacturer sets the proportion of the patients based on the target
population in IMPACT study. Since the IMPACT study is an RCT, it may notreflect the actual proportion of patients in clinical practice in Japan. The
proportion of patients in the analyzed population was estimated using theanonymous receipt information and anonymous specific health checkup
information database.
In December 2019, the target population was patients with COPD and a
combination of three components (ICS/LABA/LAMA) or two components(ICS/LABA or LABA/LAMA) of the target drugs shown in Table 4-22 wererecorded as the same prescription in medical outpatient or dispensing receipts.
The target population was those with three components (ICS/LABA/LAMA) or
two components (ICS/LABA or LABA/LAMA) recorded as the same prescription.
However, if there were multiple prescriptions in December 2019, the mostrecent prescription was included. The combinations of 1 to 3 components of thetarget drug that occurred in the prescriptions prior to the prescriptions
identified above and were consistent with the previous treatment of the target
population were counted. If the previous prescription did not occur before
January 2019, the patient was excluded. To divide the target population byeosinophil count, we used the proportion of patients based on the IMPACT study
as described in the manufacturer report (Table 4-23), because this database
does not contain eosinophil count data. As a result, the total number of eligible
patients was 456,635, of which 424,339 met the pretreatment criteria for the
analysis population. The percentage of patients is shown in Table 4-24.
The proportion of patients in the analysis group C and D is 0%, becauseclinicians believe that patients receiving triple therapy are unlikely to be
stepped down to LAMA only.

109

Table 4-22 Target medicines
Claims computerized
Product nameprocessing system code
621929601

Asmanex Twisthaler 100 μg 60 doses, 6 mg 100 μg

622014501

Asmanex Twisthaler 200 μg 60 doses, 12mg

620004885

Adoair 100 Diskus, 28 blisters

620007565

Adoair 100 Diskus, 60 blisters

621781401

Adoair 100 Diskus 28 puffs, 28 blisters

621829501

Adoair 100 Diskus 60 puffs, 60 blisters

621981201

Adoair 125 Aerosol 120 puffs, 12.0 g

621981301

Adoair 250 Aerosol 120 puffs, 12.0 g

620004886

Adoair 250 Diskus 28 blisters

620007566

Adoair 250 Diskus 60 blisters

621781501

Adoair 250 Diskus 28 puffs, 28 blisters

621829601

Adoair 250 Diskus 60 puffs, 60 blisters

620004887

Adoair 500 Diskus 28 blisters

620007567

Adoair 500 Diskus 60 blisters

621781601

Adoair 500 Diskus 28 puffs, 28 blisters

621829701

Adoair 500 Diskus 60 puffs, 60 blisters

620009104

Adoair 50 Air 120 puffs, 12.0 g

621895501

Adoair 50 Aerosol 120 puffs, 12.0 g

622552201

Arnuity 100 μg Ellipta 30 doses

622552301

Arnuity 200 μg Ellipta 30 doses

622426401

Anoro Ellipta 30 doses

622363901

Anoro Ellipta 7 doses

622287701

Ultibro inhalation capsules622414701

Eklira 400 μg Genuair 30 doses

622414801

Eklira 400 μg Genuair 60 doses

622415901

Encruse 62.5 μg Ellipta 30 puffs

622415801

Encruse 62.5 μg Ellipta 7 puffs

622180901

Oxis 9 μg Turbuhaler 28 doses, 252 μg (9 μg)

622277401

Oxis 9 μg Turbuhaler 60 doses, 540 μg (9 μg)

620004889

Alvesco 100 μg Inhaler 112 puffs, 11.2 mg 6.6 g

622057501

Alvesco 100 μg Inhaler 56 puffs, 5.6 mg 3.3 g

620004890

Alvesco 200 μg Inhaler 56 puffs, 11.2 mg 3.3 g

620004888

Alvesco 50 μg Inhaler 112 puffs, 5.6 mg 6.6 g

622096401

Onbrez inhalation capsules 150 μg

110660462002

Qvar 100 Aerosol 15 mg 8.7 g

660462001

Qvar 50 Aerosol 7 mg 8.7 g

622210401

Seebri inhalation capsules 50 μg

621950701

Symbicort Turbuhaler 30 doses

621950801

Symbicort Turbuhaler 60 doses

622450101

Spiolto Respimat 28 puffs

622450201

Spiolto Respimat 60 puffs

622507801

Spiriva 1.25 μg Respimat 60 puffs, 75 μg

621984201

Spiriva 2.5 μg Respimat 60 puffs, 150 μg

620002421

Spiriva inhalation capsules 18 μg

660462003

Serevent 25 Rotadisk 25 μg

620001944

Serevent 50 Diskus, 50 μg 60 blisters

660462004

Serevent 50 Rotadisk, 50 μg

622678801

Trelegy 100 Ellipta 14 doses

622678901

Trelegy 100 Ellipta 30 doses

620005290

Pulmicort 100 μg Turbuhaler 112 doses, 11.2 mg

620005292

Pulmicort 200 μg Turbuhaler 112 doses, 22.4 mg

620005291

Pulmicort 200 μg Turbuhaler 56 doses, 11.2 mg

620004366

Pulmicort Respules 0.25 mg, 2 mL

620004367

Pulmicort Respules 0.5 mg, 2 mL

622687001

Breztri Aerosphere 56 inhalations

622700201

BudeForu Drypowder inhaler 30 doses “JG”

622702601

BudeForu Drypowder inhaler 30 doses “MYL”

622816601

BudeForu Drypowder inhaler 30 doses “Nipro”

622700301

BudeForu Drypowder inhaler 60 doses “JG”

622702701

BudeForu Drypowder inhaler 60 doses “MYL”

622816701

BudeForu Drypowder inhaler 60 doses “Nipro”

621572201

Flutide 100 μg Aerosol 60 puffs, 11.67 mg 7.0 g

620000453

Flutide 100 Air 12.25 mg 7.0 g

660451013

Flutide 100 Diskus 100 μg 60 blisters

660421113

Flutide 100 Rotadisk 100 μg

660451016

Flutide 200 Diskus 200 μg 60 blisters

660421114

Flutide 200 Rotadisk 200 μg

621512601

Flutide 50 μg Aerosol 120 puffs, 8.83 mg 10.6 g

660462011

Flutide 50 Air 9.72 mg 10.6 g

660451012

Flutide 50 Diskus 50 μg 60 blisters

660421112

Flutide 50 Rotadisk 50 μg

111

622278201

Flutiform 125 Aerosol 120 puffs

622278001

Flutiform 125 Aerosol 56 puffs

622278101

Flutiform 50 Aerosol 120 puffs

622277901

Flutiform 50 Aerosol 56 puffs

622279201

Relvar 100 Ellipta 14 doses

622375501

Relvar 100 Ellipta 30 doses

622279301

Relvar 200 Ellipta 14 doses

622375601

Relvar 200 Ellipta 30 doses

112

Table 4-23 Proportion of patients by eosinophil count based on IMPACT
study
Eosinophil count < 100
Eosinophil count ≥ 100
Populationn%Population
n
%
A,C,E
961
24% B,D,F
3,004
76%
G
768
26% H
2,202
74%
I,K
411
25% J,L
1,243
75%# Prepared from values reported by the manufacturer

113

Triple-drugtherapy

Table 4-24 Proportion of patients
A: A combination of
A prescription before A
prescriptions in
December 2019

Population

Proportion of patients

n

%

n

%

n

%

ICS/LABA/LAMA

A+B

78,13818.4%

A

18,938

4.5%

B59,20014.0%

LAMA/LABA

E+F

1,244

0.3%

E

302

0.1%

F

942

0.2%

G+H

230,09954.2%

G59,500 14.0%

H

170,599

40.2%

I+J

111,025

26.2%

I

27,588

6.5%

J83,437

19.7%

K+L

3,833

0.9%

K

952

0.2%

L

2,881

0.7%

317,058

74.7%

ICS/LABA/LAMA

Dual-drug
therapy

ICS/LABA/LAMA
ICS/LABAICS/LABAICS/LABA/LAMA
LAMA/LABA

Single drug

LAMA/LABA
LAMA/LABALAMA

ICS/LABA/LAMA
ICS/LABA
Total

424,339 100.0%

107,281 25.3%# As to the populations C and D, the proportion of the patient number is treated as 0%.

114

Table 4-25 Summary of the results
Population

Proportion ofpatients

Additional benefit

ICER

A

4.5%

Not shown

Cost saving

B

14.0%

Not shown

Cost saving

C

0%“Unable to analyze”

D0%“Unable to analyze”

E

0.1%

Not shown

Cost increasing

F

0.2%

Not shown

Cost increasing

G

14.0%

Yes

< JPY 5 million/QALY

H

40.2%

Yes

< JPY 5 million/QALY

I

6.5%

Not shown

Cost increasing

J

19.7%

Yes

Dominant

K

0.2%

Yes

Dominant

L

0.7%

Yes

< JPY 5 million/QALY

115

5. References
1.
National Institute of Public Health, Center for Outcomes Research andEconomic Evaluation for Health (C2H). Guideline for Preparing CostEffectiveness Evaluation to the Central Social Insurance Medical Council,
Version 2.0 approved by CSIMC on 20th February, 2019.
2.
Noriko Kojimahara, Takeo Nakayama, Toshio Morizane, Naohito
Yamaguchi and Masahiro Yoshida eds. Minds Manual for Guideline Development
2017. Tokyo: Japan Council for Quality Health Care, 2017.
3.
Chalmers JD, Laska IF, Franssen FME, Janssens W, Pavord I, Rigau D, etal. Withdrawal of inhaled corticosteroids in COPD: a European Respiratory
Society guideline. Eur Respir J. 2020;55(6). Epub 2020/05/06. doi:
10.1183/13993003.00351-2020. PubMed PMID: 32366483.
4.
Chapman KR, Hurst JR, Frent SM, Larbig M, Fogel R, Guerin T, et al.
Long-Term Triple Therapy De-escalation to Indacaterol/Glycopyrronium inPatients with Chronic Obstructive Pulmonary Disease (SUNSET): A Randomized,
Double-Blind, Triple-Dummy Clinical Trial. Am J Respir Crit Care Med.
2018;198(3):329-39. Epub 2018/05/22. doi: 10.1164/rccm.201803-0405OC.
PubMed PMID: 29779416.
5.
Pascoe S, Barnes N, Brusselle G, Compton C, Criner GJ, Dransfield MT,
et al. Blood eosinophils and treatment response with triple and dual
combination therapy in chronic obstructive pulmonary disease: analysis of the
IMPACT trial. Lancet Respir Med. 2019;7(9):745-56. Epub 2019/07/10. doi:
10.1016/S2213-2600(19)30190-0. PubMed PMID: 31281061.
6.
Hoogendoorn M, Feenstra TL, Asukai Y, Briggs AH, Hansen RN, Leidl R,
et al. External Validation of Health Economic Decision Models for Chronic
Obstructive Pulmonary Disease (COPD): Report of the Third COPD Modeling
Meeting. Value Health. 2017;20(3):397-403. Epub 2017/03/16. doi:
10.1016/j.jval.2016.10.016. PubMed PMID: 28292484.
7.
Kato M, Tomii K, Hashimoto K, Nezu Y, Ishii T, Jones CE, et al. The
IMPACT Study - Single Inhaler Triple Therapy (FF/UMEC/VI) Versus FF/VI And
UMEC/VI In Patients With COPD: Efficacy And Safety In A Japanese Population.
Int J Chron Obstruct Pulmon Dis. 2019;14:2849-61. Epub 2019/12/17. doi:
10.2147/COPD.S226601. PubMed PMID: 31839705; PubMed Central PMCID:PMCPMC6904247.
8.
Lipson DA, Crim C, Criner GJ, Day NC, Dransfield MT, Halpin DMG, et al.
Reduction in All-Cause Mortality with Fluticasone
Furoate/Umeclidinium/Vilanterol in Patients with Chronic Obstructive Pulmonary
Disease. Am J Respir Crit Care Med. 2020;201(12):1508-16. Epub 2020/03/13.
doi: 10.1164/rccm.201911-2207OC. PubMed PMID: 32162970; PubMed Central
PMCID: PMCPMC7301738.
9.
Jones PW. Interpreting thresholds for a clinically significant change in116

health status in asthma and COPD. Eur Respir J. 2002;19(3):398-404. Epub
2002/04/09. doi: 10.1183/09031936.02.00063702. PubMed PMID: 11936514.
10.
The National Institute for Health and Care Excellence. Chronic
obstructive pulmonary disease: fluticasone furoate, umeclidinium and vilanterol(Trelegy) Evidence summary [ES18]. 2018.

117

6. Supplementary material
Table A-1 Summary of subgroup analysis studies
Study name FULFIL Subgroup analysis

FULFIL Subgroup analysis

FULFIL Subgroup analysis

IMPACT Subgroup analysis

Title ofarticlePreventing clinicallyimportant deterioration
with single-inhaler triple
therapy in COPD

Single-inhaler triple therapy The Efficacy and Safety of
The IMPACT Study – Single
in symptomatic COPD
Once-daily Fluticasone
Inhaler Triple Therapy
patients: FULFIL subgroup Furoate/Umeclidinium/Vilan (FF/UMEC/VI) Versus FF/VI
analyses
terol Versus Twice-daily
And UMEC/VI In Patients
Budesonide/Formoterol in a With COPD: Efficacy And
Subgroup of Patients from Safety In A Japanese
China with Symptomatic
Population
COPD at Risk of
Exacerbations (FULFIL Trial)

Authorname

Naya I, et al.

Halpin DMG, et al.

Zheng J, et al.

M Kato et al.

Bibliographic ERJ Open Res. 2018;4:
information 00047-2018.

COPD. 2018;15(4):334340.

ERJ Open Res. 2018;4(2).
pii: 00119-2017.

Int J Chron Obstruct
Pulmon Dis.
2019;14:2849–2861.

Test location Multicenter (16 countries)

Multicenter (16 countries)

Multicenter (16 countries)

Multicenter (37 countries)

Study
enrollment
periodFrom January 2015 to April From January 2015 to April From January 2015 to April From June 2014 to July
2016
2016
2016
2017

Targetpopulation≥ 40 years old, diagnosed
as COPD, CAT ≥ 10,
receiving a maintenancetherapy, has a history of
exacerbation within≥ 40 years old, diagnosed
as COPD, CAT ≥ 10,
receiving a maintenancetherapy, has a history of
exacerbation within≥ 40 years old, diagnosed
as COPD, CAT ≥ 10,
receiving a maintenancetherapy, has a history of
exacerbation within≥ 40 years old, diagnosed
as COPD, has a history ofsmoking, CAT ≥ 10,
FEV1/FVC < 0.7, receiving amaintenance therapy, has a118

previous 12 months etc. (Apaper for evaluation ofclinical importantdifference: CID)

previous 12 months etc. (A previous 12 months etc. (Asubgroup analysis by prior subgroup analysis in China)
therapy, severity, and ahistory of exacerbation)

history of exacerbation
within previous 12 months
etc. (subgroup analysis inJapan)

Key
exclusion
criteria

A patient who has asthma
at present, a patient who
has unresolved
pneumonia/exacerbationetc.

A patient who has asthma
at present, a patient who
has unresolved
pneumonia/exacerbationetc.

A patient who has asthma
at present, a patient who
has unresolved
pneumonia/exacerbationetc.

A patient who has asthma
at present, a patient who
has other respiratory
diseases, a person who has
experienced exacerbation
before a study or during a
run-in period etc.

Details ofintervention
methodTrelegy group (n = 911 24
weeks, n = 210 24 weeks):
FF/UMEC/VI 100 mcg/62.5
mcg/25 mcg

Trelegy group (n=911 24
weeks, n=210 24 weeks)：

Trelegy group (n=911 24
weeks, n=210 24 weeks)：

Trelegy group (n=4151)：

FF/UMEC/VI 100 mcg/62.5
mcg/25 mcg

FF/UMEC/VI 100 mcg/62.5
mcg/25 mcg

Details ofcomparator

ICS/LABA group (n=899 24 ICS/LABA group (n=899 24 ICS/LABA group (n=899 24 ICS/LABA groups
weeks, n=220 52 weeks)： weeks, n=220 52 weeks)： weeks, n=220 52 weeks)： (n=4134)：FF/VI 100
BUD/FOR 400mcg/12 mcg

BUD/FOR 400mcg/12 mcg

BUD/FOR 400mcg/12 mcg

FF/UMEC/VI 100 mcg/62.5
mcg/25 mcg

mcg/25 mcg
LAMA/LABA groups(n=2070)：UMEC/VI 62.5
mcg/25 mcg

StudydesignPhase III, RCT

Phase III, RCT

Phase III, RCT

Phase III, RCT

Blinding
methodDouble-blind

Double-blind

Double-blind

Double-blind119Primary
endpoint- Change in FEV1 (24weeks)- Change in FEV1 (52weeks)- Change in SGRQ (24weeks)- Change in SGRQ (52weeks)- Change in FEV1 (24weeks)- Change in FEV1 (52weeks)- Change in SGRQ (24weeks)- Change in SGRQ (52weeks)- Change in FEV1 (24weeks)- Change in FEV1 (52weeks)- Change in SGRQ (24weeks)- Change in SGRQ (52weeks)

Incidence ofmoderate/severe
exacerbation event (52weeks)

Key
secondary
endpoints- Incidence ofmoderate/severe
exacerbation event (24weeks)- Incidence ofmoderate/severe
exacerbation event (52weeks) etc.

- Incidence ofmoderate/severe
exacerbation event (24weeks)- Incidence ofmoderate/severe
exacerbation event (52weeks) etc.

- Incidence ofmoderate/severe
exacerbation event (24weeks)- Incidence ofmoderate/severe
exacerbation event (52weeks) etc.

- Change in FEV1
- Change in SGRQ
- Time to first incidence ofmoderate/severe
exacerbation event- Incidence ofmoderate/severe
exacerbation event(Population with ≥eosinophil count 150)、- Time to first incidence ofmoderate/severe
exacerbation event(Population with ≥eosinophil count 150)
・Incidence of severe
exacerbation event

Statisticalmethods- Amount of change is- Amount of change is- Amount of change is- Incidence of exacerbation
analyzed with MMRM
analyzed with MMRM
analyzed with MMRM
is analyzed with the- Incidence of exacerbation - Incidence of exacerbation - Incidence of exacerbation generalized linear model120

is analyzed with thegeneralized linear model
assuming a negative
binomial distribution

is analyzed with thegeneralized linear model
assuming a negative
binomial distribution

is analyzed with thegeneralized linear model
assuming a negative
binomial distribution

assuming a negative
binomial distribution- Amount of change isanalyzed with MMRM
- Time to event is analyzed
with Cox proportionalhazards model

121

Table A-2 Bayesian interpretation of rate ratios of exacerbation
Targetpopulation[1] Point[2] Lower
estimate of limit ofa rate ratio 95% CI of
a rate ratio[3] Upper
limit of
95% CI of
a rate ratio[4] Point
estimate ofa rate ratio(logarithm)[5] Lower
limit of
95% CI of
a rate ratio(logarithm)[7] SE of a[6] Upper
rate ratio
limit of
95% CI of (logarithm)
a rate ratio(logarithm)[8]
Probabilityof a rate
ratio to be
1 or less[9]
Probabilityof a rate
ratio to be
1 or more[10]
Probabilityof a rate
ratio to be
0.95 orless[11]
Probabilityof a rate
ratio to be
0.95 or
more

C

0.83

0.69

0.99

-0.19

-0.37

-0.01

0.09

97.85%

2.15%

92.87%

7.13%

D

0.86

0.77

0.95

-0.15

-0.26

-0.05

0.05

99.76%

0.24%

96.84%

3.16%

E

0.78

0.63

0.97

-0.25

-0.46

-0.03

0.11

98.80%

1.20%

96.33%

3.67%

F

0.67

0.59

0.76

-0.40

-0.53

-0.27

0.06

100.00%0.00%

100.00%

0.00%

G

0.78

0.61

1.00

-0.25

-0.49

0.00

0.13

97.56%

2.44%

94.10%

5.90%

H

0.82

0.71

0.95

-0.20

-0.34

-0.05

0.07

99.62%

0.38%

97.62%

2.38%

I

1.37

0.83

2.24

0.31

-0.19

0.81

0.25

10.69%

89.31%

7.42%

92.58%

J

0.81

0.65

1.01

-0.21

-0.43

0.01

0.11

96.95%

3.05%

92.19%

7.81%

K

0.67

0.41

1.09

-0.40

-0.89

0.09

0.25

94.58%

5.42%

91.92%

8.08%

L

0.87

0.64

1.19

-0.14

-0.45

0.17

0.16

81.06%

18.94%

71.09%

28.91%# Assuming that the distributions of rate ratio from the clinical trial were posterior distributions for treatment effect(lognormal distribution was assumed), the probability that the rate ratio of exacerbations would be less than 1(FF/UMEC/VI is superior) and the probability that the rate ratio of exacerbations would be less than 0.95 (FF/UMEC/VI isassociated with a risk reduction of 5% or more) was calculated, respectively.
# Excel computational expression[4]=LN([1]), [5]=LN([2]), [6]=LN([3]), [7]=([6]-[5])/(1.96*2), [8]=NORM.DIST(LN(1), [4], [7], TRUE), [9]=1-[8],[10]=NORM.DIST(LN(0.95), [4], [7], TRUE), [11]=1-[10]122Table A-3 Revisions of the model (Settings of background factors)
Sheet "Baseline Demographics"
Before change

Parameters
Gender

FF/VI

FF/UMEC/VI%%

Female

34%

34%

Male

66%

66%

Age
BMI

mean

SE

mean

SE

65.3

0.08

65.3

0.08

%

%

Low (<21, %)

17%

17%

Med (21-30, %)

58%

58%

High (>30, %)

25%

25%

Any CVD Comorbidity (%)

44%

44%

Without Comorbidity

56%

56%

Any Other Comorbidity (%)

57%

57%

Without comorbidity

43%

43%

0 Prior Exacerbations at baseline (%)

0%0%History of exacerbation, 1 or more (%)

100%

100%

mMRC score >= 2 (%)

37%

37%

63%

63%

35%

35%

Score of 0 or 1 (%)
Current Smokers (%)
Former Smokers (%)

65%

65%

Mean

SE

Mean

SE

Height (cm)167.500.09

167.500.09

Fibrinogen (ug/dl)

477.462.37

477.462.37

123Number of Moderate and Severe Exacerbations in Prior Year (Average
per person)

1.71

0.01

1.71

Moderate Exacerbations

82%

1.41

82%

1.41

Severe Exacerbations

18%

0.30

18%

0.30

SGRQ

50.70

Starting SGRQ-C or SGRQ

SGRQ

50.70

Resulting HRQL

0.676

Starting FEV1% Predicted

45.50%

Resulting FEV1

1215.36 Minute Walk Distance (meters)

365.79

0.25

0.01

0.25

0.676
0.15%

45.50
%

0.15%

1215.32.74

365.792.74

124

After change

Parameters
Gender

FF/VI

FF/UMEC/VI%%

Female

7.14%

7.14%

Male

92.86%

92.86%

mean

SE

mean

SE

Age

70.54

0.37

70.54

0.37

BMI

%

%

Low (<21, %)38.62%

38.62%Med (21-30, %)59.53%

59.53%High (>30, %)

1.85%

1.85%

Any CVD Comorbidity (%)

33.60%

33.60%

Without Comorbidity

66.40%

66.40%

Any Other Comorbidity (%)

55.03%

55.03%

Without comorbidity

44.97%

44.97%

0 Prior Exacerbations at baseline (%)

0.00%

0.00%

History of exacerbation, 1 or more (%)

100.00%100.00%mMRC score >= 2 (%)

22.28%

22.28%

77.72%

77.72%

24.07%

24.07%

Score of 0 or 1 (%)
Current Smokers (%)
Former Smokers (%)

75.93%

75.93%

Mean

SE

Mean

SE

Height (cm)163.990.36

163.990.36

Fibrinogen (ug/dl)

468.762.37

468.762.37

125

Number of Moderate and Severe Exacerbations in Prior Year
(Average per person)

1.72

0.06

1.72

Moderate Exacerbations

79%

1.36

79%

1.36

Severe Exacerbations

21%

0.37

21%

0.37

SGR
Q

40.34

Starting SGRQ-C or SGRQ
Resulting HRQL

SGRQ

40.34
0.777

Starting FEV1% Predicted

50.19%

Resulting FEV1

1248.36 Minute Walk Distance (meters)

0.79

387.91

0.06

0.79

0.777
0.81
%

50.19%

0.81%

1248.32.74

387.91

2.74

126

Table A-4 Revisions of the model (Settings of survival probability)
Before change

After change

Sheet”RefDrug”(R44-R75)=IF(R43<0.01,0,(EXP(-((_t*365.25*EXP((_I+MMULT($G44:$H44,R$6:R$7)+R$29*$J44+M
MULT($L44:$O44,R$30:R$33)+_fWScale)))^(1/$R$34)))))=AVERAGE(IF(R43<0.01,0,(EXP(-((_t*365.25*EXP((_I+MMULT($G44:$H44,R$6:R$7)+R$29*$J44+MMUL
T($L44:$O44,R$30:R$33)+_fWScale)))^(1/$R$34))))),IF(drug!R43<0.01,0,(EXP(-((_t*365.25*EXP((_I+MMULT(drug!$G44:drug!$H44,drug!R$6:drug!R$7)+drug!R$29*drug!$J44+MMULT(drug!$L44:drug!$O4
4,drug!R$30:drug!R$33)+_fWScale)))^(1/drug!$R$34))))))

Sheet”RefDrug”(R123-R154)=IF(R122<0.01,0,(EXP(-(($E123*365.25*EXP((_I+MMULT($G123:$H123,R$6:R$7)+R$29*$J123+MMULT($L123:$O123,R$30:R$33)+_fWScale)))^(1/$R$34)))))

＝R44

Sheet
”drug”(R44-R75)=IF(R43<0.01,0,(EXP(-((_t*365.25*EXP((_I+MMULT($G44:$H44,R$6:R$7)+R$29*$J44+M
MULT($L44:$O44,R$30:R$33)+_fWScale)))^(1/$R$34)))))=AVERAGE(IF(R43<0.01,0,(EXP(-((_t*365.25*EXP((_I+MMULT($G44:$H44,R$6:R$7)+R$29*$J44+MMUL
T($L44:$O44,R$30:R$33)+_fWScale)))^(1/$R$34))))),IF(RefDrug!R43<0.01,0,(EXP(-((_t*365.25*EXP((_I+MMULT(RefDrug!$G44:RefDrug!$H44,RefDrug!R$
6:RefDrug!R$7)+RefDrug!R$29*RefDrug!$J44+MMULT(RefDrug!$L44:RefDrug!$O44,RefDrug!R$30:RefDrug!
R$33)+_fWScale)))^(1/RefDrug!$R$34))))))

Sheet”drug”(R123-R154)=IF(R122<0.01,0,(EXP(-(($E123*365.25*EXP((_I+MMULT($G123:$H123,R$6:R$7)+R$29*$J123+MMULT($L123:$O123,R$30:R$33)+_fWScale)))^(1/$R$34)))))

＝R44

127

Table A-5 Revisions of the model (Settings of utility)
Before change

After change

Sheet”RefDrug”(Q43-Q75)=IF(R43=0,0,(IF(0.9617 0.0013*(P43*0.9+3.1) 0.0001*(P43*0.9+3.1)^2 + 0.0231*(1$Z$14)<0,0,0.9617 - 0.0013*(P43*0.9+3.1) 0.0001*(P43*0.9+3.1)^2 + 0.0231*(1$Z$14))))*Utility_SA=IF(R43=0,0,AVERAGE(IF(R43=0,0,(IF(0.9617 0.0013*(P43*0.9+3.1) - 0.0001*(P43*0.9+3.1)^2 +0.0231*(1-$Z$14)<0,0,0.9617 - 0.0013*(P43*0.9+3.1)- 0.0001*(P43*0.9+3.1)^2 + 0.0231*(1$Z$14)))),IF(drug!R43=0,0,(IF(0.9617 0.0013*(drug!P43*0.9+3.1) 0.0001*(drug!P43*0.9+3.1)^2 + 0.0231*(1drug!$Z$14)<0,0,0.9617 - 0.0013*(drug!P43*0.9+3.1)- 0.0001*(drug!P43*0.9+3.1)^2 + 0.0231*(1drug!$Z$14))))))*Utility_SA

Sheet”RefDrug”(Q122-Q154)=IF(R122=0,0,(IF(0.9617 0.0013*(P122*0.9+3.1) 0.0001*(P122*0.9+3.1)^2 + 0.0231*(1$Z$14)<0,0,0.9617 - 0.0013*(P122*0.9+3.1) 0.0001*(P122*0.9+3.1)^2 + 0.0231*(1$Z$14))))*Utility_SA

=Q43

128

Sheet”drug”(Q43-Q75)=IF(R43=0,0,(IF(0.9617 0.0013*(P43*0.9+3.1) 0.0001*(P43*0.9+3.1)^2 + 0.0231*(1$Z$14)<0,0,0.9617 - 0.0013*(P43*0.9+3.1) 0.0001*(P43*0.9+3.1)^2 + 0.0231*(1$Z$14))))*Utility_SA=IF(RefDrug!R43=0,IF(R43=0,0,(IF(0.9617 0.0013*(P43*0.9+3.1) - 0.0001*(P43*0.9+3.1)^2 +0.0231*(1-$Z$14)<0,0,0.9617 - 0.0013*(P43*0.9+3.1)- 0.0001*(P43*0.9+3.1)^2 + 0.0231*(1$Z$14)))),AVERAGE(IF(R43=0,0,(IF(0.9617 0.0013*(P43*0.9+3.1) - 0.0001*(P43*0.9+3.1)^2 +0.0231*(1-$Z$14)<0,0,0.9617 - 0.0013*(P43*0.9+3.1)- 0.0001*(P43*0.9+3.1)^2 + 0.0231*(1$Z$14)))),IF(RefDrug!R43=0,0,(IF(0.9617 0.0013*(RefDrug!P43*0.9+3.1) 0.0001*(RefDrug!P43*0.9+3.1)^2 + 0.0231*(1RefDrug!$Z$14)<0,0,0.9617 0.0013*(RefDrug!P43*0.9+3.1) 0.0001*(RefDrug!P43*0.9+3.1)^2 + 0.0231*(1RefDrug!$Z$14))))))*Utility_SA

Sheet”drug”(Q122-Q154)=IF(R122=0,0,(IF(0.9617 0.0013*(P122*0.9+3.1) 0.0001*(P122*0.9+3.1)^2 + 0.0231*(1$Z$14)<0,0,0.9617 - 0.0013*(P122*0.9+3.1) 0.0001*(P122*0.9+3.1)^2 + 0.0231*(1$Z$14))))*Utility_SA

=Q43

129

Table A-6 Results of the cost-effectiveness evaluation using a cutoff of 150/μL for eosinophil count
ICER by the
Description
Treatment Effectiv Incrementa Cost (JPY) Incrementa
Populationeness(Qll cost (JPY) academic group(JPY/QALY)
ALY)
effectivene
A＋B
(CMA)
C
(Unable tobeanalyzed)
D(Unable tobeanalyzed)
E
(CMA)
F
(CMA)
G
(CEA)
H
(CEA)
I

Prior therapy:
MITT

FF/UMEC/VI

-

MITT

-

ss (QALY)-

107,721-18,189

125,910ICER by the
manufacturer(JPY/QALY)

Cost saving

Cost saving

-

-

-

Prior therapy:
MITT

FF/UMEC/VI

-

-

-

-

Unable to beanalyzed

EOS < 100/μL

FF/VI

-

-

-

-

-

-

Prior therapy:
MITT

FF/UMEC/VI

-

-

-

-

Unable to beanalyzed

Dominant

EOS ≥ 100/μL

FF/VI

-

-

-

-

-

-

Prior therapy:
MITT

FF/UMEC/VI--

107,721

18,114 Cost increasing

580,531

EOS < 100/μL

UMEC/VI--

89,608--

Prior therapy:
MITT

FF/UMEC/VI--

107,721

18,114 Cost increasing

EOS ≥ 100/μL

UMEC/VI--

89,608-

Prior therapy:
ICS+LABA

FF/UMEC/VI

5.537

0.066

3,381,419

EOS < 100/μL

FF/VI

5.471

-

3,164,643-

Prior therapy:
ICS+LABA

FF/UMEC/VI

5.560

0.070

3,104,397-78,643

EOS ≥ 100/μL

FF/VI

5.490

-

3,183,040-

Prior therapy:

FF/UMEC/VI--

107,721

216,775

18,114-

3,297,647

691,075

Dominant
2,435,085--

Dominant

Dominant--

Cost increase

1,163,973

130

(CMA)

J
(CEA)

K
(CEA)
L
(CEA)

LAMA/LABA orLAMA
EOS < 100/μL

UMEC/VI--

89,608-

Prior therapy:
LAMA/LABA or
LAMA

FF/UMEC/VI

5.556

0.066

2,935,405

EOS ≥ 100/μL

UMEC/VI

5.491-

3,276,588

Prior therapy:
LAMA

FF/UMEC/VI

5.718

0.184

3,046,167

EOS < 100/μL

FF/VI

5.534

-

3,220,465-

Prior therapy:
LAMA

FF/UMEC/VI

5.629

0.049

3,198,358-60,494

EOS ≥ 100/μL

FF/VI

5.580

-

3,258,852--341,183-174,297--

Dominant

Dominant--

Dominant

Dominant--

Dominant-

29,275-# The result of additional benefit assessment was assumed to be the same as in a case setting 100/μL as a cut-off value of
eosinophil count.

131