Cost-effectiveness evaluation of ravulizumab(Ultomiris) by the academic group[Version 1.2]
[Version 1, December 25, 2020]1

[Table of contents][Table of abbreviations] ................................................................................................... 3
0. Analytical framework ................................................................................................... 5
1. Summary of other HTA agency reviews ...................................................................... 7
1.1 Summary ............................................................................................................... 7
1.2 Review results ....................................................................................................... 9
1.3 Issues raised in HTA agencies ............................................................................ 10
2. Evaluation of additional benefit ................................................................................. 14
2.1 Systematic review by the academic group .......................................................... 14
2.1.1 Clinical questions.......................................................................................... 14
2.1.2 Implementation flow...................................................................................... 14
2.1.3 Inclusion and exclusion criteria..................................................................... 15
2.1.4 Database ...................................................................................................... 15
2.1.5 Search formula ............................................................................................. 15
2.1.6 Search results............................................................................................... 18
2.1.7 Summary of clinical trials .............................................................................. 20
2.2 Summary of additional benefit assessment by the manufacturer and review
results.................................................................................................................. 28
2.3 Results of additional benefit assessment ............................................................ 31
3. Evaluation of cost-effectiveness ............................................................................... 40
3.1 Summary of manufacturer’s results and review by academic group................... 40
3.1.1 Summary of CEA compared to eculizumab .................................................. 40
3.1.2 Summary of CEA compared to BSC............................................................. 42
3.1.3 Issues on CEA compared to eculizumab ...................................................... 44
3.1.4 Issues on CEA compared to BSC................................................................. 47
3.2 Summary of revisions by academic group .......................................................... 49
3.3 Methods of revised analysis ................................................................................ 50
4. Results of cost-effectiveness assessment ................................................................ 54
4.1 Revised base case analysis ................................................................................ 54
4.2 Revised scenario analysis................................................................................... 58
4.3 Interpretation of results ....................................................................................... 60
5. References ............................................................................................................... 612

[Table of abbreviations]
Abbreviation

Formal description

ACT

Appropriate Comparator Therapy

AE

Adverse Event

AUD

Australian Dollar

BSCBest Supportive Care

BTH

Breakthrough Hemolysis

C5Complement component 5

CAC

Complement Amplifying Condition

CADTH

Canadian Agency for Drugs and Technologies in Health

CEA

Cost-Effectiveness Analysis

CI

Confidence Interval

DCE

Discrete Choice Experiment

DPC

Diagnosis Procedure Combination

EBM

Evidence-Based Medicine

EORTC

European Organization for Research and Treatment of Cancer

QLQ-C30

Quality-of-Life-Questionnaire-Core-30

EQ-5D

EuroQol 5 Dimension

FACIT

Functional Assessment of Chronic Illness Therapy

HAS

Haute Autorité de SantéHIV

Human Immunodeficiency Virus

HTA

Health Technology Assessment

ICER

Incremental Cost-Effectiveness Ratio

IQWiG

Instituts für Qualität und Wirtschaftlichkeit im Gesundheitswesen

LDH

Lactate Dehydrogenase

MAVE

Major Adverse Vascular Events

NICE

National Institute for Health and Care Excellence

PBAC

Pharmaceutical Benefits Advisory Committee

PNH

Paroxysmal Nocturnal Hemoglobinuria

pRBC

packed Red Blood Cell

PRISMA

Preferred Reporting Items for Systematic Reviews andMeta-Analyses

QALY

Quality-Adjusted Life Year

QOL

Quality of Life
3

RCT

Randomized Controlled Trial

RQ

Research Question

SMC

Scottish Medicines Agency

SR

Systematic Review

ULN

Upper Limit of Normal

4

0. Analytical framework
The evaluated product is ravulizumab (Ultomiris) and the manufacturer is Alexion
Pharma G.K. Ravulizumab is a therapeutic agent for paroxysmal nocturnal
hemoglobinuria (PNH) and was selected as a target product of the cost-effectivenessevaluation at Central Social Insurance Medical Council (CSIMC) on August 28, 2019.
The market size of ravulizumab is JPY 33.1 billion and the category of thecost-effectiveness evaluation is H1 (The market size is 10 billion yen or more). The
analytical framework of ravulizumab was established as shown in Table 0-1 after the
Expert Committee of Cost-Effectiveness evaluation on December 12, 2019.
Table 0-1 Analytical framework
Population

Paroxysmal nocturnal hemoglobinuria

Comparator

Eculizumab (Soliris)
In Japan, eculizumab is the only drug indicated for paroxysmal
nocturnal hemoglobinuria, the indication of ravulizumab. Therefore,

Reason for selectionof comparator

eculizumab is considered appropriate, being “a technology likely to bea substitute for the technology analyzed as of the time when thetechnology analyzed is introduced to treat the target population ofanalysis, which has a higher therapeutic effect and is used widely in
medical practice.”

Other perspectivein addition to public

Yes (Details:)No

healthcare payer
Outcome and thereason if QALY is not

Not applicable (QALY is used CEA)

used.
The following sensitivity analysis (scenario analysis) is performed.
Analysis compared to best supportive care (BSC)
A conventional therapy (BSC) except for eculizumab can be theOther

comparator technology for “patients who have an indication foreculizumab therapy but remain untreated.” However, because thenumber of relevant patients was expected to be limited and there
might be uncertainty in the analysis, it was considered to perform theanalysis not by base case analysis but by sensitivity analysis

5

(scenario analysis).

6

1. Summary of other HTA agency reviews
1.1 Summary
The manufacturer reported results of the evaluations of ravulizumab by HTA agencies inother countries. Accordingly, the evaluation results by these agencies were investigatedand compared with manufacturer’s submission. A summary of the evaluations in thesecountries is provided in Table 1-1. In the next step, the cost-effectiveness evaluations ofravulizumab by HTA agencies in these countries were reviewed in detail. A
cost-effectiveness evaluation of ravulizumab was performed only in Australia (Table
1-2).
Table 1-1 Evaluation Status
Country

Organization

Evaluation results
Manufacturer

Academic group
Evaluation ongoing

UK

France

NICE

Evaluation ongoing[Final scope was published inJuly 2020.][1]

SMC

None

None

HAS

None

None
RQ1: Adult patients withparoxysmal nocturnal
hemoglobinuria (PNH) withhemolysis with clinicalsymptoms indicative of highdisease activity

Germany

IQWiG

No description in

ACT: eculizumab

manufacturer’s submission<No additional benefit>
RQ2: Adult patients with PNH
who are clinically stable after
having been treated witheculizumab for at least the past
6 months
ACT: eculizumab

7

<No additional benefit>[November 2019, February2020][2, 3]
Canada

CADTH

None

None
Not recommended

Australia

PBAC

None

(rejected)[4][November 2020]*The submission date of the report of the manufacturer was May 2020.
Table 1-2 Details of cost-effectiveness analysis in Australia (PBAC)Country

Australia

Organization

PBAC[4]URL

https://www.pbs.gov.au/info/industry/listing/elements/pbac-meetings/psd/2020-07/batch_2/ravulizumab-solution-concentrate-fo
r-iv-infusion-300-mg

Target technology

Ravulizumab

Evaluation results

Not recommended

Details of the condition

Not applicableTarget disease

PNH

Comparator(1) Eculizumab (primary comparator)(2) BSC (secondary comparator)

ICER(1) Not disclosed(2) ≥AUD200,000/QALY

8

1.2 Review results
As a results of review by the academic group, the manufacturer's report did not include
the evaluation status in Germany [5]. This was investigated, and it was found that
evaluation results of ravulizumab had been published in November 2019 and February2020 and ravulizumab had been reported to show “no additional benefit”[2, 3]. In
addition, although the evaluation result in Australia was stated as “none” in the report ofthe manufacturer, it was found that evaluation results had been published in November
2020 later than the submission of the report of the manufacturer (May 2020), showingthat ravulizumab was “not recommended”[4].

91.3 Issues raised in HTA agencies
Considering the issues raised in the assessment process by HTA organizations, theissues that may be helpful for this evaluation was summarized as follows.
<NICE>[1]

While the evaluation of ravulizumab has been ongoing at NICE, the final scopeincludes the following outcome measures that should be considered to be includedin evaluation: overall survival, hemolysis (measured by LDH level), breakthroughhemolysis, transfusion avoidance, stabilized hemoglobin, thrombotic events,
adverse reactions to treatment, and health-related QOL (HRQOL) (patients andcarers).

<IQWiG>[2, 3]
Additional benefit of ravulizumab versus eculizumab was examined by IQWiG for
the following two target populations.


RQ1: Adult patients with paroxysmal nocturnal hemoglobinuria (PNH) withhemolysis with clinical symptom(s) indicative of high disease activity



RQ2: Adult patients with PNH who are clinically stable after having beentreated with eculizumab for at least the past 6 months



RQ1 and RQ2 were evaluated on the basis of 301 study and 302 study, respectively,
using the following outcome measures: all-cause mortality, MAVEs, fatigue(FACIT-Fatigue), transfusion avoidance, HRQOL, serious AEs, discontinuation due
to AEs, and meningococcal infection.



From the evaluation, it was concluded that neither RQ1 nor RQ2 indicated any
additional benefit of ravulizumab versus eculizumab.



Subsequently, in February 2020, a report of supplementary evaluation using BTH
as an outcome measure was published. In this evaluation, BTH is defined as "atleast one new or worsening symptom or sign of intravascular hemolysis (fatigue,hemoglobinuria, abdominal pain, dyspnea, anemia [hemoglobin <10 g/dL], major
adverse vascular event [MAVE], dysphagia, erectile dysfunction)" and, at the sametime, "patients must have Lactate dehydrogenase (LDH) must be elevated to atleast twice the ULN after LDH has fallen below 1.5 x upper limit of normal (ULN) at

10

the time of treatment". After review, BTH was not used to evaluate ravulizumab for
the following reasons.
The symptoms used to define BTH (fatigue, abdominal pain, dyspnea,
dysphagia, and erectile dysfunction) include subjective factors in patients.



Clinical studies did not assure the complete recording of the aforementioned
symptoms.



301 and 302 are open-label studies with high risk of bias.

<PBAC>[4]The manufacturer evaluated additional benefit and cost-effectiveness ofravulizumab versus eculizumab (primary comparator) and BSC (secondary
comparator) in adult patients with PNH.



The following outcome measures were used for the evaluation of additional benefit:
for comparison with eculizumab, transfusion avoidance, the presence or absence ofhemolysis, occurrence of BTH, QOL, and stabilization of hemoglobin; forcomparison with BSC, transfusion avoidance, QOL, and the presence or absenceof hemolysis.

The manufacturer reported the noninferiority of ravulizumab to eculizumab in termsof efficacy and safety. The manufacturer asserted that ravulizumab was superior toeculizumab in terms of occurrence of BTH based on the results of meta-analysis of
301 and 302.



However, PBAC determined that no additional benefit of ravulizumab on BTH had
been demonstrated because of the following reasons.


301 study was a noninferiority study with the primary endpoints of transfusion
avoidance and normalization of LDH levels, and 302 study was a noninferiority
study with the primary endpoint of percent change in LDH; in the individual
studies alone, the power to detect statistically significant differences in BTH
might have been insufficient. Meanwhile, whereas 301 involved patients naive
to complement inhibitor therapy, 302 involved patients previously treated withcomplement inhibitor therapy; considering the difference in target population,
pooled analysis by meta-analysis might be inappropriate.

In 301 and 302, eculizumab therapy was performed every 14 days, and theadjustment of dosing schedule within the 2-day timeframe (or adjustment by adose increase), which is considered as needed, was not performed for the
management of BTH. For this reason, there is uncertainty about bringing the11results of these clinical studies into general use in patient populations in actual
clinical settings.


BTH, which is characterized by increased LDH levels, cannot be said to beclinically significant unless associated with other clinical characteristics such as
fatigue and the need of transfusion.

The manufacturer reported that ravulizumab is superior to BSC in terms of efficacy
and inferior to BSC in terms of safety.

However, because the comparison of ravulizumab with BSC was based on indirectcomparison using eculizumab as the anchor, PBAC pointed out the problem withthe robustness of indirect comparison, such as the compatibility between theclinical studies of ravulizumab (301 and 302) and the clinical trial of eculizumab(TRIUMPH study).

Conversely, because ravulizumab was pharmacologically similar to eculizumab andboth drugs were determined to be noninferior in terms of efficacy, PBAC considered
it reasonable to assume the superiority of ravulizumab to BSC in terms of efficacy.

However, PBAC considered that there was uncertainty about the appropriatenessor inappropriateness of assuming the superiority of eculizumab in terms ofprognosis, which was shown in the previous evaluation of eculizumab versus BSC,
in the evaluation of ravulizumab versus BSC, as well as about the degree of
improvement in prognosis with ravulizumab versus BSC.



The manufacturer performed CEA of ravulizumab versus eculizumab using thedecision-tree model. For the analysis period of 1 year, ICER of ravulizumab versus
eculizumab was estimated by considering the improvement in QOL resulting fromthe avoidance of transfusion and BTH and reduced costs of hospital visits due toravulizumab.

However, PBAC did not consider these results reliable because of the following
reasons.


There was significant uncertainty about the estimation of disutility oftransfusions because there were problems with the robustness of discrete
choice experiment and the method used for mapping.

The assertion of the manufacturer that the incidence of BTH was lower in the
ravulizumab group than in the eculizumab group was not supported, and theconsideration of BTH in the model was not fully justified.



The manufacturer performed CEA of ravulizumab versus BSC using the
combination of partitioned survival analysis and the Markov model. The 3 states,
12

survival with PNH, survival with remission, and death, were considered for themodel, and long-term outcomes were simulated over 55 years based on the datafrom a retrospective observational study. Consequently, the ICER of ravulizumab
versus BSC was reported to be ≥AUD200,000/QALY.


However, PBAC did not consider that the model of the manufacturer was useful for
supporting decision making because it lacked face validity. In addition, PBAC
pointed out some problems including inappropriate setting of improvement inprognosis associated with ravulizumab versus BSC.



Sensitivity analysis showed that there was significant uncertainty in the ICER of
ravulizumab versus BSC associated with the analysis period, survival curve,
spontaneous remission rate, patient age, and utility weight settings, and the ICER
was ≥AUD200,000/QALY in any of these cases.

13

2. Evaluation of additional benefit
2.1 Systematic review by the academic group
2.1.1 Clinical questions
To examine additional benefit of ravulizumab, a SR of randomized controlled trials by
the academic group was performed based on the research questions as presented inTable 2-1. In the base case analysis, the target population was set as patients with PNH,
intervention as ravulizumab, and the comparator as eculizumab. In the scenario
analysis, the target population was set as patients with PNH, intervention as
ravulizumab, and the comparator as BSC (symptomatic therapy other than complement
inhibitor therapy). For each of the two research questions, a search formula wasdeveloped and a search using the designated databases was performed. The outcomes
were efficacy and safety, and the period of search was from before the start of the phase
III study of ravulizumab to the date of literature search.
Table 2-1 Research questions of SR by the academic analysis
Item

Base case analysis

Scenario analysis

Population

PNH

PNH

Intervention

Ravulizumab

RavulizumabComparator

Eculizumab

Best supportive care
(symptomatic therapy other thancomplement inhibitor therapy)

Outcome

Efficacy and safety

Efficacy and safety

Study design

Randomized controlled trial

Randomized controlled trial

Literature search period

January 2016 through January

January 2016 through January

2020

2020

2.1.2 Implementation flow
In the literature search operation, an expert of medical information service/literaturesearch developed the search formula by combining conditions for disease name, drug
name, study design, and search period. Screening based on publication abstracts andthe following operation to identify relevant RCTs for the evaluation of additional benefit
14were performed with blinding by 2 independent reviewers. Inclusion or exclusion of
publications was determined on the basis of the prespecified inclusion and exclusion
criteria, and inconsistencies between the reviewers occurring in the process of these
operations were resolved through discussion by both reviewers. The RCTs identified
were summarized in a table form with a summary of results.
2.1.3 Inclusion and exclusion criteria
The key inclusion and exclusion criteria for the SR are presented as follows.
<Inclusion criteria>

The target disease is PNH.



The intervention is ravulizumab.

The comparator is eculizumab and BSC for the base case and scenario analyses,
respectively.

The study design is randomized controlled trial.

Published during the designated period.

<Exclusion criteria>

Abstract or meeting minutes

Not written in English or Japanese

2.1.4 Database
PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL),
Cochrane Database of SRs, and Ichushi-Web were used for collection of the target
studies.
2.1.5 Search formula
The search formulas for the SR for base case analysis are presented as follows.
Search formula for PubMed
Date of search: January 16, 2020

15

("Hemoglobinuria, Paroxysmal"[MH] OR "nocturnal hemoglobinuria"[TIAB] OR "paroxysmal
hemoglobinuria"[TIAB] OR "marchiafava micheli"[TIAB]) AND ("ravulizumab"[NM] OR
ravulizumab[TIAB] OR ultomiris[TIAB]) AND ("eculizumab"[NM] OR eculizumab[TIAB] OR
soliris[TIAB] OR h5g1[TIAB]) AND ("Randomized Controlled Trial"[PT] OR ("randomized"[TI]AND (trial[TI] OR trials[TI])) OR "Randomized Controlled Trials as Topic"[MH])AND("2016"[PDAT] : "3000"[PDAT])
Number of publications: 9

Search formula for Embase
Date of search: January 16, 2020
EMB.EXACT.EXPLODE("paroxysmal nocturnal hemoglobinuria") AND
EMB.EXACT.EXPLODE("ravulizumab") AND EMB.EXACT.EXPLODE("eculizumab") AND(EMB.EXACT.EXPLODE("randomized controlled trial") OR ALL(random AND trial)) AND
PD(2016-2020)
Number of publications: 15

Search formula for Cochrane
Date of search: January 16, 2020
#1 ("nocturnal hemoglobinuria"):ti,ab,kw OR (”paroxysmal hemoglobinuria”):ti,ab,kw (Wordvariations have been searched)#2 MeSH descriptor: [Hemoglobinuria, Paroxysmal] explode all trees#3 #1 OR #2#4 (ravulizumab):ti,ab,kw OR (ultomiris):ti,ab,kw (Word variations have been searched)#5 (eculizumab):ti,ab,kw OR (soliris):ti,ab,kw OR (h5g1):ti,ab,kw (Word variations have been
searched)#6 #3 AND #4 AND #5 with Cochrane Library publication date from Jan 2016 to present
Number of publications: 10

Search formula for Ichushi
Date of search: January 16, 2020
(hemoglobinuria-paroxysmal/TH or hemoglobinuria/TI or "paroxysmal hemoglobinuria"/TI or"nocturnal hemoglobinuria"/TI or "marchiafava micheli"/TI or "marchiafava micheli"/TA) and(Ravulizumab/TH or ravulizumab/TA or ultomiris/TA or ravulizumab/TA or ravulizumab/TA) and(Eculizumab/TH or eculizumab/TA or eculizumab/TA or soliris/TA or eculizumab/TA) and16

(DT=2016:2020 and PT=original article and PT=excluding case report and case)Number of publications: 0

The search formulas for the SR for scenario analysis are presented as follows.
Search formula for PubMed
Date of search: January 16, 2020("Hemoglobinuria, Paroxysmal"[MH] OR "nocturnal hemoglobinuria"[TIAB] OR "paroxysmal
hemoglobinuria"[TIAB] OR "marchiafava micheli"[TIAB]) AND (“ravulizumab”[NM] OR
ravulizumab[TIAB] OR ultomiris[TIAB]) AND ("Randomized Controlled Trial"[PT] OR("randomized"[TI] AND (trial[TI] OR trials[TI])) OR "Randomized Controlled Trials as
Topic"[MH]) AND ("2016"[PDAT] : "3000"[PDAT])
Number of publications: 9

Search formula for Embase
Date of search: January 16, 2020
EMB.EXACT.EXPLODE("paroxysmal nocturnal hemoglobinuria") AND
EMB.EXACT.EXPLODE("ravulizumab") AND (EMB.EXACT.EXPLODE("randomized
controlled trial") OR ALL(random AND trial)) AND PD(2016-2020)
Number of publications: 15

Search formula for Cochrane
Date of search: January 16, 2020
#1 ("paroxysmal nocturnal hemoglobinuria"):ti,ab,kw OR ("paroxysmal
hemoglobinuria"):ti,ab,kw OR ("marchiafava micheli"):ti,ab,kw (Word variations have been
searched)#2 MeSH descriptor: [Hemoglobinuria, Paroxysmal] explode all trees#3 #1 OR #2#4 (ravulizumab):ti,ab,kw OR (ultomiris):ti,ab,kw (Word variations have been searched)#5 #3 #4 with Cochrane Library publication date from Jan 2016 to present
Number of publications: 10

Search formula for Ichushi
Date of search: January 16, 202017

(hemoglobinuria-paroxysmal/TH or hemoglobinuria/TI or "paroxysmal hemoglobinuria"/TI or"nocturnal hemoglobinuria"/TI or "marchiafava micheli"/TI or "marchiafava micheli"/TA) and(Ravulizumab/TH or ravulizumab/TA or ultomiris/TA or ravulizumab/TA or ravulizumab/TA) and(DT=2016:2020 and PT=original article and PT=excluding case report and case)Number of publications: 0

2.1.6 Search results
The results of the SR were summarized as shown in Figure 2-1 with reference to theflow chart recommended by PRISMA Statement.
Base case analysis (comparison with

Scenario analysis (comparison with BSC)

eculizumab)
Identification

Screening

Eligibility

Included

No. of publications identified through database

No. of publications identified through databasesearchsearch(n = 34)(n = 34)[PubMed (n = 9), Embase (n = 15),

[PubMed (n = 9), Embase (n = 15),

Cochrane (n = 10), Ichushi (n = 0)]

Cochrane (n = 10), Ichushi (n = 0)]

No. of publications after

No. of publications after

duplicates removed (n = 28)

duplicates removed (n = 28)

No. of publications screened

No. ofNo. of publications screened

No. of(n = 28)

publications(n = 28)

publications

excluded

excluded(n = 22)(n = 22)

No. of publications assessed

No. ofNo. of publications assessed

No. offor eligibility (n = 6)

publications

for eligibility (n = 6)

publications

No. of RCTs (n = 3)*

excluded

excluded(n = 4)(n = 6)

No. of RCTs (n = 0)18

Figure 2-1 Flow chart of SR by the academic group*One of the studies was identified through the process of monitoring new clinical studies,etc., published after completion of the SR.

19

<List of publications for the base case analysis>(1) Lee JW, Sicre de Fontbrune F, Wong Lee Lee L, et al. Ravulizumab (ALXN1210) vseculizumab in adult patients with PNH naive to complement inhibitors: the 301 study. Blood.
2019;133(6):530-539.
(2) Kulasekararaj AG, Hill A, Rottinghaus ST, et al. Ravulizumab (ALXN1210) vs eculizumab in
C5-inhibitor-experienced adult patients with PNH: the 302 study. Blood.
2019;133(6):540-549.
(3) Ishiyama K, Nakao S, Usuki K, et al. Results from multinational phase 3 studies ofravulizumab (ALXN1210) versus eculizumab in adults with paroxysmal nocturnal
hemoglobinuria: subgroup analysis of Japanese patients. Int J Hematol.
2020;112(4):466-476.

The SR showed that the 2 studies, 301 and 302, were the RCTs that were relevant to
the research questions for the base case analysis (comparison with eculizumab) ((1)
and (2) in the list of publications for the base case analysis). In addition, 1 article on
subgroup analysis of the Japanese populations in 301 and 302 was identified throughthe process of monitoring new clinical studies, etc., published after completion of the SR((3) in the list of publications for the base case analysis). No randomized controlled study
that was relevant to the research questions for the scenario analysis (comparison with
BSC) could be found.
2.1.7 Summary of clinical trials
A summary of the 2 RCTs (301 and 302) that were relevant to the research questions forthe base case analysis (comparison with eculizumab) is provided in Table 2-2. The
results of subgroup analysis of the Japanese populations in 301 and 302 are also
summarized in Table 2-2.

20

Table 2-2 List of literatures
Study name

ALXN1210-PNH-301 study[6]Lee JW, Sicre de Fontbrune F, Wong Lee Lee L, et al.

Bibliographic

Ravulizumab (ALXN1210) vs eculizumab in adult patients withinformation

PNH naive to complement inhibitors: the 301 study. Blood.
2019;133(6):530-539.

ALXN1210-PNH-302 study[7]Kulasekararaj AG, Hill A, Rottinghaus ST, et al. Ravulizumab(ALXN1210) vs eculizumab in C5-inhibitor-experienced adultpatients with PNH: the 302 study. Blood. 2019;133(6):540-549.

Clinicaltrials.
gov registry#NCT02946463#NCT03056040

Multicenter

Multicenter

December 2016 through January 2018

June 2017 through March 2018

information
Study sites
Studyenrollment
periodTargetPatients ≥18 years of age with PNH who are naive topopulation

complement inhibitors

Male or female ≥18 years of age at the time of informed

Patients ≥18 years of age with PNH who are clinically stable
after having been treated with eculizumab for at least the past 6monthsconsent

consent
EligibilitycriteriaMale or female ≥18 years of age at the time of informed

PNH diagnosis confirmed using high-sensitivity flowTreated with eculizumab for at least 6 months prior to Day 1

cytometry

Presence of ≥1 PNH-related symptoms within 3 months
before screening

Presence of ≥1 PNH-related symptoms within 3 months
before screening

LDH level ≤1.5 times the upper limit of normal at screening21

LDH level ≥1.5 times the upper limit of normal at screening

Meningococcal vaccination within 3 years prior to, or at thetime of, initiating study treatment



Meningococcal vaccination within 3 years prior to, or at thetime of, initiating study treatment

Female patients of childbearing potential and male patients

Female patients of childbearing potential and male patientswith a female partner of childbearing potential need to follow

with a female partner of childbearing potential need to follow

the protocol-specified guidance to avoid pregnancy during

the protocol-specified guidance to avoid pregnancy during

treatment and for 8 months after the last study treatment.

treatment and for 8 months after the last study treatment.
Previous treatment with a complement inhibitor



Platelet count of <30,000/mm3 or absolute neutrophil countof <500/μL at screening



History of bone marrow transplantation

Body weight of <40 kg at screening



History of meningococcal infection, history of unexplained

An LDH level >2 times the ULN during the 6 months
preceding Day 1

A major adverse vascular event (MAVE) observed during
the 6 months preceding Day 1



Platelet count of <30,000/mm3 or absolute neutrophil countof <500/μL at screening

Key

recurrent infection, or history of active systemic bacterial,History of bone marrow transplantation

exclusion

viral, or fungal infection within 14 days prior to initiatingBody weight of <40 kg at screening

criteria

study treatment



History of meningococcal infection, history of unexplained

A fever with a temperature of ≥38°C within 7 days prior torecurrent infection, or history of active systemic bacterial,

initiating study treatment

viral, or fungal infection within 14 days prior to initiating

HIV infection

study treatment

Participation in another clinical study before initiation of

study treatment, or receipt of an investigational treatment
and being within 30 days or 5 half-lives of the therapeutic

A fever with a temperature of ≥38°C within 7 days prior toinitiating study treatment

Presence of HIV infection

22

drug used (whichever is longer)Participation in another clinical study before initiation of

Females who plan to become pregnant or are pregnant or

study treatment, or receipt of an investigational treatment

breastfeeding

and being within 30 days or 5 half-lives of the therapeutic

Females who have a positive pregnancy test result at

drug used (whichever is longer)

screening or on Day 1



Females who plan to become pregnant or are pregnant orbreastfeeding

Females who have a positive pregnancy test result at
screening or on Day 1



Ravulizumab (n = 125)

Ravulizumab (n = 97)

Weight-based dosing: An initial dose (Day 1) and

Weight-based dosing: A loading dose on Day 1 followed by
Details ofinterventional
methodmaintenance doses (Day 15 and every 8 weeks thereafter)

maintenance doses of ravulizumab (Day 15 and every 8

given

weeks thereafter)

Treatment duration: 26 weeks

Treatment duration: 26 weeks*A loading dose on Day 1 (for patients weighing ≥40 and <60 kg,*After the 4-week screening period, subjects were stratified

2,400 mg; for patients weighing ≥60 and <100 kg, 2,700 mg; andaccording to transfusion history (the presence or absence of afor patients weighing ≥100 kg, 3,000 mg). Maintenance doses

history of pRBC transfusion during the year before initiating(for patients weighing ≥40 and <60 kg, 3,000 mg; for patients

study treatment) and randomly assigned in a 1:1 ratio either toweighing ≥60 and <100 kg, 3,300 mg; and for patients weighing

switch to ravulizumab (ravulizumab group) or continue≥100 kg, 3,600 mg)

eculizumab (eculizumab group).
*Day 1 of ravulizumab therapy is 2 weeks after the last dose of
eculizumab.

23

*A loading dose on Day 1 (for patients weighing ≥40 and <60 kg,
2,400 mg; for patients weighing ≥60 and <100 kg, 2,700 mg; andfor patients weighing ≥100 kg, 3,000 mg). Maintenance doses(for patients weighing ≥40 and <60 kg, 3,000 mg; for patientsweighing ≥60 and <100 kg, 3,300 mg; and for patients weighing≥100 kg, 3,600 mg)

Details ofEculizumab (n = 121)

Eculizumab (n = 98)

An induction dose of 600 mg (Days 1, 8, 15, and 22) and

Maintenance doses of 900 mg (every 2 weeks)maintenance doses of 900 mg (Day 29 and every 2 weeks

Treatment duration: 26 weeks

comparator

thereafter)Treatment duration: 26 weeks

Study design

Phase III, randomized

Phase III, randomized

Blinding

Open-label

Open-label

methodPrimaryProportion of achieving transfusion avoidance

Percent change in LDH

endpointProportion of achieving normalization of LDH levels

KeyPercent change in LDH

Proportion of patients with BTH

secondary

Change in total FACIT-Fatigue score



Change in total FACIT-Fatigue score

endpoints



Proportion of patients with BTH

Proportion of achieving transfusion avoidance

24





Proportion of achieving transfusion avoidance: 73.6% in thefrom baseline was −0.82% in the ravulizumab group andbetween-group difference was 6.8% (95% CI: −4.66% to8.39% in the eculizumab group. The between-group

18.14%) and the lower limit of the 95% CI was above −20%,

difference was −9.21% (95% CI: −18.84% to 0.42%) andthe noninferiority margin, demonstrating the noninferiority of

the upper limit of the 95% CI was below 15%,

ravulizumab.

demonstrating the noninferiority of ravulizumab.

Proportion of achieving normalization of LDH levels: 53.6%

Proportion of patients with BTH: 0% in the ravulizumabin the ravulizumab group and 49.4% in the eculizumab

group and 5.1% (5/98 patients) in the eculizumab group,group. The adjusted odds ratio for the ravulizumab groupwith the between-group difference of −5.1% (95% CI:

versus the eculizumab group was 1.187 (95% CI: 0.796 to−18.99% to 8.89%).
Proportion of achieving transfusion avoidance: 87.6% in thenoninferiority margin, demonstrating the noninferiority ofravulizumab group and 82.7% in the eculizumab group, withravulizumab.

the between-group difference of 5.5% (95% CI: −4.27% toPercent change in LDH: The least square mean percent

15.68%).

change from baseline was −76.84% in the ravulizumabPercent change in LDH: The least square mean change

ravulizumab group and 66.1% in the eculizumab group. The

1.769) and the lower limit of the 95% CI was above 0.39, theEfficacyTotal FACIT-Fatigue score: The least square mean changegroup and −76.02% in the eculizumab group, with thefrom baseline was 2.01 in the ravulizumab group and 0.54

between-group difference of −0.83% (95% CI: −5.21% toin the eculizumab group, with the between-group difference

3.56%).

of 1.47 (95% CI: −0.21 to 3.15).

Proportion of patients with BTH: 4.0% (5/125 patients) in the
ravulizumab group and 10.7% (13/121 patients) in theeculizumab group, with the between-group difference of−6.7% (95% CI: −14.21% to 0.18%).

25



Total FACIT-Fatigue score: The least square mean change
from baseline was 7.07 in the ravulizumab group and 6.40
in the eculizumab group, with the between-group differenceof 0.67 (95% CI: −1.21 to 2.55).

Safety

Incidence rate of adverse reactions: 40.8% (51/125

patients) in the ravulizumab group and 41.3% (50/121

in the ravulizumab group and 14.3% (14/98 patients) in thepatients) in the eculizumab groupeculizumab group

The ravulizumab group, 18 patients; the eculizumab group,Efficacy in
the Japanese
population[8]Proportion of achieving transfusion avoidance: 83.3% in thePercent change in LDH: The percent change from baseline

ravulizumab group and 53.3% in the eculizumab group, withwas 8.34% in the ravulizumab group and 15.77% in thethe between-group difference of 30.0% (95% CI: −4.56% toeculizumab group, with the between-group difference of

59.60%).

−7.42% (95% CI: −21.85% to 7.01%).

Proportion of achieving normalization of LDH levels: 52.1%

group, with the between-group difference of 0.719% (95%

Proportion of patients with BTH: There were no patientswith BTH in both groups.

in the ravulizumab group and 60.2% in the eculizumabThe ravulizumab group, 5 patients; the eculizumab group, 7
patients

15 patients

Incidence rate of adverse reactions: 24.7% (24/97 patients)

Proportion of achieving transfusion avoidance: 80.0% in the

CI: 0.158% to 3.267%).

ravulizumab group and 57.1% in the eculizumab group, with

Proportion of patients with BTH: There were no patientsthe between-group difference of 22.9% (95% CI: −36.23%

with BTH in both groups.

to 71.64%).

26

Safety in theJapanese
population[8]Incidence of adverse reactions: 94.4% (17/18 patients) inIncidence of adverse reactions: 100% (5/5 patients) in thethe ravulizumab group and 93.3% (14/15 patients) in the

ravulizumab group and 85.7% (6/7 patients) in theeculizumab groupeculizumab group27

2.2 Summary of additional benefit assessment by the manufacturer and review
results
The methodology of the SR performed by the manufacturer to examine additional
benefit of ravulizumab was generally appropriate. Through the SR, the manufacturer
identified the following 6 publications related to the RCTs to evaluate the efficacy andsafety of ravulizumab (301 and 302).

(1)

Alexion Pharmaceuticals. Academic in confidence. A phase 3, randomized, open-label,
active-controlled study of ALXN1210 versus eculizumab in complement inhibitor-naïve adultpatients with PNH. Clinical study report. 2018.

(2)

Alexion Pharmaceuticals. Academic in confidence. A phase 3, randomized, open-label,
active-controlled study of ALXN1210 versus eculizumab in adult patients with paroxysmal
nocturnal hemoglobinuria (PNH) currently treated with eculizumab. Clinical study report.
2018.

(3)

Lee JW, Sicre de Fontbrune F, Wong Lee Lee L, et al. Ravulizumab (ALXN1210) vseculizumab in adult patients with PNH naive to complement inhibitors: the 301 study. Blood.
2019;133(6):530-539.

(4)

Brodsky RA, De Latour RP, Rottinghaus ST, et al. A Prospective Analysis of BreakthroughHemolysis in 2 Phase 3 Randomized Studies of Ravulizumab (ALXN1210) Versus
Eculizumab in Adults with Paroxysmal Nocturnal Hemoglobinuria. Paper presented at:
American Society of Hematology2018; San Diego, CA.

(5)

Weitz IC, Kulagin A, Nakao S, et al. A Phase 3 Study of Ravulizumab (ALXN1210) Versus
Eculizumab in Adults with Paroxysmal Nocturnal Hemoglobinuria Naive to Complement
Inhibitors: Results of a Subgroup Analysis with Patients Stratified by Baseline Hemolysis
Level, Transfusion History, and Demographics. Paper presented at: American Society of
Hematology2018; San Diego, CA.

(6)

Kulasekararaj AG, Hill A, Rottinghaus ST, et al. Ravulizumab (ALXN1210) vs eculizumab in
C5-inhibitor-experienced adult patients with PNH: the 302 study. Blood.
2019;133(6):540-549.

Publications (1) and (2) were clinical study reports of the manufacturer that wereavailable from the clinicaltrials.gov registry information. Publications (3) and (6) were
the original article about 301 and 302, respectively, and identical to the publications
identified by the academic analysis. Publications (4) and (5), which were records of28

presentation at a scientific meeting, were determined to be excluded because they met
the exclusion criteria for the SR of the academic analysis (“Abstract or meeting
minutes”). Through the monitoring of new clinical studies, etc., performed after the SRof the academic analysis, 1 original article on subgroup analysis of the Japanese
populations in 301 and 302 was identified in addition to the following 6 publications[8].
The manufacturer used the following three outcome measures for the evaluation of
additional benefit: reduction in the incidence rate of free C5-related BTH, transfusion
avoidance, and improvement in QOL associated with extended dosing intervals.
<Reduction in free C5-related BTH>
In 301 and 302, the occurrence of BTH was defined as “the observation of ≥1 new orworsening symptom or sign of intravascular hemolysis (fatigue, hemoglobinuria,
abdominal pain, shortness of breath [dyspnea], anemia [hemoglobin <10 g/dL], MAVEs[including thrombosis], dysphagia, or erectile dysfunction) in the presence of LDH ≥2times the upper limit of normal after on-treatment reduction of LDH to <1.5 times theupper limit of normal.”However, free C5-related BTH came from the additional analysis of the proportion ofpatients with BTH, an endpoint prespecified for 301 and 302[6, 7] and the use of free C5
testing is rare in actual clinical settings; therefore, its appropriateness as a measure for
additional benefit assessment is unclear[9]. According to HTA agencies in othercountries, it was pointed out that because 301 and 302 were open-label studies, thepossibility of information bias and detection bias could not be ruled out in efficacy andsafety evaluations using such an endpoint.
<Transfusion avoidance>
Transfusion avoidance was set as the primary endpoint for 301 and as a secondary
endpoint for 302[6, 7]. In both studies, transfusion avoidance was defined as “theproportion of subjects who remained transfusion-free and did not require a transfusion
per protocol-specified guidelines during the study period up to Day 183 (Week 26)”.
Whether a subject required a transfusion or not was based on “a hemoglobin level≤9 g/dL with signs or symptoms of sufficient severity to warrant transfusion or ahemoglobin level ≤7 g/dL regardless of the presence of signs or symptoms.”
According to HTA agencies in other countries, it was pointed out that because 301 and302 were open-label studies, the possibility of information bias and detection bias could

29not generally be ruled out in efficacy and safety evaluations using such an endpoint.
<Improvement in QOL associated with extended dosing intervals>
Improvement in QOL associated with extended dosing intervals was not included in theendpoints set for 301 and 302, and no reports have been presented of demonstration of
the improvement in the relevant patient population.

30

2.3 Results of additional benefit assessment
An additional benefit of ravulizumab was evaluated on the basis of the report by the
manufacturer, the SR by the academic group, and other information including theadditional literature review conducted as necessary. The results of the evaluation arepresented in Tables 2-3, 2-6, and 2-7.
Table 2-3 Additional benefit assessment (reduction in free C5-related BTH)
Target population

Paroxysmal nocturnal hemoglobinuria

Intervention

RavulizumabComparator

Eculizumab

OutcomeReduction in free C5-related BTH

Presence or absence□ With additional benefitof additional benefit■ “No additional benefit” or “Cannot be determined”□ Meta-analysis of RCTs ■ Single RCT (2 RCTs)

Data serving as therationale for judgment□ Prospective, controlled, observational study□ Indirect comparison of RCTs
□ Comparison of single-arm studies□ No relevant clinical study data

□ Other
Although ravulizumab was shown to be noninferior in the two RCTs toevaluate the efficacy and safety of ravulizumab (301 and 302), theelevation of free C5 levels to ≥0.5 μg/mL and the occurrence of freeC5-related BTH, which were observed in the eculizumab group, were notobserved in the ravulizumab group. Consequently, the manufacturer
Reason for judging
the presence orasserted that there was additional benefit of ravulizumab on reduction in
the incidence rate of free C5-related BTH[10].

absence of additional
benefit

However, it cannot be concluded that additional benefit of ravulizumab
was shown because of the following.
(1) The results of 301 and 302 did not demonstrate that ravulizumab
was superior to eculizumab in terms of the incidence rate of BTH
including free C5-related BTH with a statistically significant
difference[6, 7].

31

(2) Free C5-related BTH came from the additional analysis of the
proportion of patients with BTH, a prespecified endpoint, and the useof free C5 testing is rare in actual clinical settings; therefore, its
appropriateness as a measure for the evaluation of additional benefit
is unclear[9].
(3) Ravulizumab therapy is given with dose adjustments inconsideration of patient's body weight (a dose is set for each of thefollowing three categories of patient's body weight: 40–60 kg, 60–
100 kg, and ≥100 kg)[11]. By contrast, eculizumab therapy is given
at a fixed dose independent of patient's body weight[12]. Therefore,
the possibility of insufficient doses of eculizumab in patients with ahigher body weight resulting in the higher incidence of freeC5-related BTH in the eculizumab group cannot be ruled out.
Actually, detailed examination of the data of 301 and 302 showedthat the populations <60 kg had no free C5-related BTH, suggestingthat free C5-related BTH occurred in patients with a higher bodyweight (Tables 2-5 and 2-6 and Figures 2-2, 2-3, 2-4, and 2-5)[13].
As a reference, the mean body weight of the Japanese population
was 58.1 kg at the time of the initial dose in the post-marketingsurveillance.

Table 2-4 Relationship of body weight with breakthrough hemolysis in 301 study
Ravulizumab arm

Eculizumab arm

N = 125

N = 1215/125 (0/125)

13/121 (7/121)<60 kg2/41 (0/41)

3/38 (0/38)≥60 kg3/84 (0/84)

10/83 (7/83)

Number of patients with free C5-related

0/125 (0/125)

5/121 (5/121)<60 kg0/41 (0/41)

0/38 (0/38)≥60 kg0/84 (0/84)

5/83 (5/83)

Number of patients with breakthroughhemolysisbreakthrough hemolysis

The number of patients with insufficient blood concentrations of the drug is indicated inparentheses. The table was prepared on the basis of the report on the occurrence

32status of adverse events in the individual cases in 301[13].

120.0
110.0
Body weight (kg)

100.0
90.0
80.0
70.0
60.0
50.0
40.0
0.5

Ravulizumab(N = 5)

1.5

Eculizumab(N = 13)

2.5

Figure 2-2 Body weight distribution in patients with breakthrough hemolysis (301
study)▲ denotes patients with insufficient blood concentrations of the drug.

33

120.0
110.0
Body weight (kg)

100.0
90.0
80.0
70.0
60.0
50.0
40.0
0.5

Ravulizumab(N = 0)1.5

Eculizumab(N = 5)2.5

Figure 2-3 Body weight distribution in patients with free C5-related breakthroughhemolysis (301 study)▲ denotes patients with insufficient blood concentrations of the drug.
Table 2-5 Relationship of body weight with breakthrough hemolysis in 302 study
Ravulizumab arm

Eculizumab arm

N = 97

N = 980/97 (0/97)

5/98 (2/98)<60 kg0/27 (0/27)

0/22 (0/22)≥60 kg0/70 (0/70)

5/76 (2/76)

Number of patients with free C5-related

0/97 (0/97)

2/98 (2/98)<60 kg0/27 (0/27)

0/22 (0/22)≥60 kg0/70 (0/70)

2/76 (2/76)

Number of patients with breakthroughhemolysisbreakthrough hemolysis

The number of patients with insufficient blood concentrations of the drug is indicated inparentheses. The table was prepared on the basis of the report on the occurrence
status of adverse events in the individual cases in Study 302[13].

34120.0
110.0
Body weight (kg)

100.0
90.0
80.0
70.0
60.0
50.0
40.0
0.5

Ravulizumab(N = 0)1.5

Eculizumab(N = 5)2.5

Figure 2-4 Body weight distribution in patients with breakthrough hemolysis (302
study)▲ denotes patients with insufficient blood concentrations of the drug.

120.0
110.0
Body weight (kg)

100.0
90.0
80.0
70.0
60.0
50.0
40.0
0.5

Ravulizumab(N = 0)1.5

Eculizumab(N = 2)2.5

35

Figure 2-5 Body weight distribution in patients with free C5-related breakthroughhemolysis (Study 302)
▲ denotes patients with insufficient blood concentrations of the drug.
Table 2-6 Additional benefit assessment (transfusion avoidance)
Target population

Paroxysmal nocturnal hemoglobinuria

Intervention

RavulizumabComparator

Eculizumab

OutcomeTransfusion avoidance

Presence or absence□ With additional benefitof additional benefit■ “No additional benefit” or “Cannot be determined”□ Meta-analysis of RCTs ■ Single RCT (2 RCTs)

Data serving as therationale for judgment□ Prospective, controlled, observational study□ Indirect comparison of RCTs
□ Comparison of single-arm studies□ No relevant clinical study data

□ Other
Transfusion avoidance was significantly higher in the ravulizumab groupthan in the eculizumab group in the two RCTs to evaluate the efficacy
and safety of ravulizumab (301 and 302). Consequently, themanufacturer asserted that there was additional benefit of ravulizumabon transfusion avoidance[10].
Reason for judging
the presence orabsence of additional
benefit

However, it cannot be concluded that additional benefit of ravulizumab
was shown because of the following.
(1) The results of 301 and 302 did not demonstrate that ravulizumab
was superior to eculizumab in terms of the frequency of transfusion
with a statistically significant difference[6, 7].
(2) HTA agencies in other countries, etc., pointed out that information
bias may be introduced in an open-label study with the use of an
endpoint such as transfusion.

Table 2-7 Additional benefit assessment (improvement in QOL associated withextended dosing intervals)

36

Target population

Paroxysmal nocturnal hemoglobinuria

Intervention

RavulizumabComparator

Eculizumab

Outcome

Improvement in QOL associated with extended dosing intervals

Presence or absence□ With additional benefitof additional benefit■ “No additional benefit” or “Cannot be determined”□ Meta-analysis of RCTs ■ Single RCT (2 RCTs)□ Prospective, controlled, observational study

Data serving as the□ Indirect comparison of RCTs

rationale for judgment □ Comparison of single-arm studies□ No relevant clinical study data

■ Other (investigation using a discrete choice experiment in the general
population)
On the basis of the finding that an investigation using a discrete choice
experiment in overseas general population showed that utility weights
can be expected to improve with a reduction in dosing frequency fromthat at 2-week intervals assumed for eculizumab therapy to that at
8-week intervals assumed for ravulizumab, the manufacturer asserted
that there was additional benefit of ravulizumab on improvement in QOL
associated with extended dosing intervals[10, 14].
However, it cannot be concluded that additional benefit of ravulizumab
Reason for judging
the presence orabsence of additional
benefitwas shown because of the following.
(1) The result of the investigation based on a discrete choice experiment
was not relevant to patients but came from an investigation ofpreferences of the general population. Therefore, it is not anappropriate outcome measure for the evaluation of additional
benefits.
(2) No reports on the demonstration of improvement in utility weights
associated with extended dosing intervals in patients with PNH inclinical studies have been reported to date.
(3) The manufacturer performed statistical analysis using a linear mixed
model by mapping EORTC QLQ-C30 scores in 301 and 302 to
EQ-5D. However, the statistical analysis did not show thatravulizumab was superior to eculizumab in terms of utility weights

37

with a statistically significant difference[10].

On the basis of the results of additional benefit assessment, it is appropriate to perform
cost-effectiveness evaluation of ravulizumab as shown in Table 2-8.

38

Tale 2-8 Results of the evaluation of additional benefit and the methodology ofcost-effectiveness evaluation
Population

Paroxysmal nocturnal hemoglobinuria

Target productRavulizumabComparator

Eculizumab<Reduction in free C5-related BTH>
It cannot be concluded that additional benefit was shown.

Results of additional benefit
assessment<Transfusion avoidance>
It cannot be concluded that additional benefit was shown.
<Improvement in QOL associated with extended dosingintervals>
It cannot be concluded that additional benefit was shown.

Method ofcost-effectivenessCost-minimization analysis

evaluation
A conventional therapy (BSC) except for eculizumab can be thecomparator technology for “patients who have an indication for
Sensitivity analysis(Scenario analysis)

eculizumab therapy but remain untreated.” However, because
the number of relevant patients was expected to be limited andthere might be uncertainty in the analysis, it was considered toperform the cost-effectiveness analysis not by base caseanalysis but by sensitivity analysis (scenario analysis).

393. Evaluation of cost-effectiveness3.1 Summary of manufacturer’s results and review by academic group
3.1.1 Summary of CEA compared to eculizumab
The manufacturer performed the cost-effectiveness analysis assuming that there wasadditional benefit of ravulizumab over eculizumab on reduction in the incidence rate offree C5-related BTH, transfusion avoidance, and improvement in QOL associated withextended dosing intervals. In the cost-effectiveness analysis, a Markov model of 8
health states including death was used (Figure 3-1)[10]. The patient age was 55.6 years
at the start of the analysis, and the upper limit of age for analysis was set at 100 years.
An annual discount rate of 2% was applied to costs and effects[10]. The costs, effects,
and ICER were estimated for each treatment group by cohort simulation. The main
assumptions in the model used for analysis were as follows[10].


No free C5-related BTH occurs during treatment with ravulizumab.



Patients with a history of BTH have an increased incidence rate of BTH
thereafter.



The incidence rate of the first free C5-related BTH decreases after a certain
period of time from the initiation of analysis.

The risk of death in each treatment group is comparable with that in the general
population.

The occurrences of free C5-related BTH and CAC BTH have no effect on the riskof death.

Red blood cell transfusion does not occur twice or more in 1 cycle.

40

A
Transition of PNH conditions
A:：PNHの状態推移
Free C5-related
遊離C5関連BTHあり
BTH present

History of free
遊離C5関連BTH既往
C5-related BTH present
あり、かつ
and freeC5-related
遊離C5関連BTHあり
BTH present

BTH
absent
BTHなし

History of free
遊離C5関連BTH既往
C5-related
BTH present
あり、かつ
and BTHなし
BTH absent

BTH
absentCAC BTHあり

History of free
遊離C5関連BTH既往
C5-related BTH present
あり、かつ
and free
CAC BTHpresent
CAC
BTHあり

Spontaneous
自然寛解
remission

BB:：死亡への推移
Transition to death

General
death
一般死亡
*Any
health state※ BTHの既往・発accordingto
生別の全ての健
history/occurrence
康状態から自然寛
of BTH can
解に移行可能transition tospontaneous
remission.

*Anyhealth state during life can※ 一般死亡へは生存中の全ての健康状
transition
to general death.
態から移行可能

Orange denotes
of PNH with BTH, green denotes
healthof PNH without BTH, and blue denotes the health
オレンジは
PNH health
で BTHstatesが発生している健康状態、緑は
PNH で
BTHstatesが発生していない健康状態、青は自然寛解の健康状態
state of spontaneous remission.
を示す。

Figure 3-1 Model structure of the manufacturer[10]The additional benefit of ravulizumab on reduction in the incidence rate of freeC5-related BTH, transfusion avoidance, and improvement in QOL associated withextended dosing intervals was reflected on the following settings in the model[10].
(1) Set a certain difference in the incidence rate of free C5-related BTH (assume thatthe incidence rate is 0 in the ravulizumab group whereas it occurs at a certain
rate in the eculizumab group).
(2) Set a certain difference in the rate of transfusion and transfusion volume (setvalues based on the data of each treatment group in 301 study).
(3) Set a certain difference in baseline utility weight (assuming improvement in QOL
associated with extended dosing intervals, calculate the utility weight for the
ravulizumab group at a premium of 0.069 over the utility weight for theeculizumab group).
The results of the base case analysis were summarized as shown in Tables 3-1–
3-3[10].
Table 3-1 Results of base case analysis of CEA by the manufacturer
Effectiveness

Incremental(QALY)

effectiveness

Cost (JPY)

Incremental

ICER

cost (JPY)(JPY/QALY)(QALY)Ravulizumab

19.86

1.25

855,544,150

8,892,169

7,109,296

41

Eculizumab

18.61

846,651,981

Table 3-2 Breakdown of estimated QALY by health state (reported by the
manufacturer)
Health state

Ravulizumab

Eculizumab

Spontaneous remission

3.89

3.89

BTH absent

15.97

11.05

Free C5-related BTH present

0.00

0.01

CAC BTH present

0.01

0.00

History of free C5-related BTH present and BTH absent

0.00

3.64

History of free C5-related BTH present and free C5-related BTH

0.00

0.02

History of free C5-related BTH present and free CAC BTH present

0.00

0.00

Total

19.86

18.61

present

Table 3-3 Breakdown of estimated costs by item (reported by the manufacturer)
Item

Ravulizumab (JPY)

Eculizumab (JPY)

Cost difference (JPY)

Acquisition cost

853,396,454

841,774,241

11,622,213

Management cost

1,375,533

3,655,765−2,280,232

Treatment cost for BTH

23,084104,207−81,123

Cost of transfusion

728,885

1,097,575−368,690

Cost of vaccines

20,194

20,194

0855,544,150

846,651,981

8,892,169

Total

3.1.2 Summary of CEA compared to BSC
The manufacturer performed scenario analysis for the case in which the comparator
technology is changed to BSC using the model in Figure 3-1. With the assumption that
“It is considered that patients receiving BSC therapy, who are not receiving ravulizumab
or eculizumab, an anti-complement C5 antibody, have high concentrations of free C5 inblood all the time and thereby suffer frequent free C5-related BTH. Therefore, only thehealth state ‘history of free C5-related BTH present and free C5-related BTH present’
was considered as the PNH condition for the scenario analysis, which could transition to42

either ‘spontaneous remission’ or ‘general death,’ ” the manufacturer performed theanalysis with the following changes in the settings[10].
(1) Patients in the BSC group remain in the state “history of free C5-related BTH
present and free C5-related BTH present.”(2) Transfusion occurs constantly in patients in the BSC group.
(3) The risk of death is higher in patients in the BSC group than in the general
population. (Hazard ratio for general death rate is 4.76.)(4) No drug acquisition or management cost is incurred in the BSC group.
The results of the scenario analysis by comparison with BSC were summarized asshown in Tables 3-4–3-6[10].
Table 3-4 Results of scenario analysis of CEA by the manufacturer
Effectiveness

Incremental(QALY)

effectiveness

Cost (JPY)

Incremental

ICER

cost (JPY)(JPY/QALY)

819,004,596

101,700,385(QALY)Ravulizumab

19.86

BSC

11.81

8.05

855,544,150
36,539,554

Table 3-5 Breakdown of estimated QALY by health state (reported by the
manufacturer)
Health state

Ravulizumab

BSC

Spontaneous remission

3.89

3.09

BTH absent

15.97

0.00

Free C5-related BTH present

0.00

0.00

CAC BTH present

0.01

0.00

History of free C5-related BTH present and BTH absent

0.00

0.00

0.00

8.72

present

0.00

0.00

Total

19.86

11.81

History of free C5-related BTH present and free C5-related BTH
present
History of free C5-related BTH present and free CAC BTH

Table 3-6 Breakdown of estimated costs by item (reported by the manufacturer)

43

Item

Ravulizumab (JPY)

Acquisition cost

853,396,454

0853,396,454

Management cost

1,375,533

01,375,533

Treatment cost for BTH

23,08426,995,823−26,972,740

Cost of transfusion

728,885

9,543,731−8,814,846

Cost of vaccines

20,1940

20,194

855,544,150

36,539,554

819,004,596

Total

BSC (JPY)

Cost difference (JPY)

3.1.3 Issues on CEA compared to eculizumab
The manufacturer performed the cost-effectiveness analysis assuming additional
benefit of ravulizumab over eculizumab on reduction in the incidence rate of freeC5-related BTH, transfusion avoidance, and improvement in QOL associated withextended dosing intervals. However, it cannot be concluded that the results of additional
benefit assessment showed any additional benefit on any of the outcome measures.
Therefore, it is inappropriate to perform a cost-effectiveness analysis, and it isappropriate to perform a cost-minimization analysis assuming that there is no difference
between the treatment effects of ravulizumab and eculizumab.
< Issues on the model used for CEA>
In the cost-effectiveness analysis of ravulizumab, the manufacturer estimated long-term
outcomes in patients with PNH using a Markov model of 8 health states including death(Figure 3-1). Although in recent years there have been original articles published on
cost-effectiveness analyses using a similar model structure, the following issues arefound regarding structural uncertainty in the model[15].
Free C5-related BTH came from the additional analysis of the proportion of patientswith BTH, a prespecified endpoint, and the use of free C5 testing is rare in actual
clinical settings; therefore, its appropriateness as a measure for the evaluation oftherapeutic effect is unclear[9].



The increased risk of subsequent free C5-related BTH in patients with a history of
BTH is not fully justified. The data submitted by the manufacturer show anincreasing tendency in terms of point estimates, but with no statistical difference,
etc., suggesting uncertainty[10].

<Issues on the setting for BTH>
44

The manufacturer estimated the incidence rate of BTH in each treatment group using
the data of the post-marketing surveillance of eculizumab. However, the setting of acertain difference in the incidence rate of BTH between ravulizumab and eculizumab isinappropriate because of the following issue.
It was not demonstrated that ravulizumab was superior to eculizumab in terms of
the incidence rate of BTH with a statistically significant difference.

<Issues on the setting for transfusion>
The manufacturer performed the cost-effectiveness analysis based on the data of therate of transfusion and transfusion volume in 301 study. However, the setting of acertain difference in the rate of transfusion and transfusion volume between
ravulizumab and eculizumab is inappropriate because of the following issues.
It was not demonstrated that ravulizumab was superior to eculizumab in terms of
the proportion of transfusion with a statistically significant difference.



No statistically significant difference in transfusion volume was demonstrated
between the treatment groups.

<Issues on the improvement in utility weight associated with extended dosingintervals>
The manufacturer performed the cost-effectiveness analysis assuming that utility
weights can be expected to improve with a reduction in dosing frequency from that at
2-week intervals assumed for eculizumab therapy to that at 8-week intervals assumed
for ravulizumab. More specifically, improvement in utility weights associated withextended dosing frequency was estimated by applying a mixed logit model using
treatment selection (ravulizumab and eculizumab) as an objective variable and 5
attributes (life expectancy, dosing frequency, meningococcal infection, symptoms, andtransfusion) as explanatory variables to the data of the discrete choice experiment(DCE) in overseas general population (Sweden)[14]. On the basis of these results, thebaseline utility weights for the ravulizumab group was calculated using the setting that a
premium of 0.069 is given over the baseline utility weights for the eculizumab group[14].
However, it is inappropriate to consider improvement in utility weights associated withextended dosing intervals for the ravulizumab group because of the following issues.
No reports on the demonstration of improvement in utility weights associated withextended dosing intervals in patients with PNH in clinical studies have beenreported to date.

45

The manufacturer performed statistical analysis using a linear mixed model by
mapping EORTC QLQ-C30 scores in 301 and 302 to EQ-5D. However, thestatistical analysis did not show that ravulizumab was superior to eculizumab interms of utility weights with a statistically significant difference[10].



The DCE submitted by the manufacturer is for an investigation of preferences ofoverseas general population (Sweden) and does not necessarily reflect thepreferences of the Japanese population. Particularly, the number of hospital/clinic
visits per citizen is 2.7 in Sweden, whereas it is 12.6 in Japan, showing asubstantial difference[16]. Therefore, the possibility that the improvement in utility
weights associated with decreased dosing frequency was overestimated in theJapanese population cannot be ruled out. Even supposing that a difference isobserved in utility weight, there is no basis for saying that the difference ismaintained throughout life.

<Issues on the cost parameters>
To estimate management cost for the ravulizumab and eculizumab groups and the costof thrombosis testing when BTH occurs, the manufacturer calculated the relevant costs
using a commercial claims database. The medical information database (EBM
provider®) provided by Medical Data Vision Co., Ltd. (MDV), including medical data and
DPC data, which had been established with the authorization for secondary use
obtained from DPC hospitals was used as the data source[10]. However, the following
points need to be noted.
The description of the extraction conditions for analysis objects (PNH and BTH
testing) is insufficient, and the appropriateness of the definition of PNH for theclaims is unclear.

Regarding the estimated number of patients affected by PNH (the number ofpatients who had Specific Medical Expenses Recipient Certificate for PNH as of theend of fiscal year 2018, 764), the number of patients with PNH who visited hospitals
from April 2016 to December 2019 extracted from the EBM provider (DPC claims
data relevant to approximately 24% [413 institutions] of the national DPC hospitals
are registered as of June 2020) was 102; however, it lacks data from an existing
epidemiological study, etc., that allow examination of the representativeness of data,
and the representativeness is unclear.



There is uncertainty about the appropriateness of the cost items adopted for the
analysis of claims data. More specifically, no sufficient data that allow examination46

of the comprehensiveness of management cost (outpatient medical treatment)
items that should be considered and the appropriateness of adoption or
non-adoption for the cost items excluded as infrequently used medical treatments
were presented by the manufacturer.
Sensitivity analysis was performed to examine the effect of uncertainty in theaforementioned cost parameters; however, a variation range of ±20% was set
across them and its appropriateness is unclear.
3.1.4 Issues on CEA compared to BSC
The manufacturer performed the scenario analysis by comparison with BSC assumingthat in the BSC group patients in the virtual cohort are alive with constant freeC5-related BTH unless they die or achieve spontaneous remission. However, nosufficient rationale to justify this assumption was presented. Therefore, caution isrequired in the interpretation of the scenario analysis by comparison with BSC
performed by the manufacturer.
In the scenario analysis by comparison with BSC, the manufacturer assumed that thehazard ratio for death in the BSC group versus the general population was 4.76 basedon an epidemiological study[10]. However, the following points need to be noted.
The epidemiological study cited by the manufacturer involved a comparison ofclinical courses of patients with PNH in Japan and the United States; however, it
did not include any description of hazard ratio for death for the patients versus thegeneral population, showing no rationale for the estimation of 4.76[17].

However, it is possible to consider analyses based on the value of hazard ratio as usedby the manufacturer because of the following reasons.
A registry study in patients with PNH in Korea reported that mortality was 4.81
times higher in patients with PNH with hemolysis prior to the launch of
eculizumab (LDH ≥1.5 × ULN) than in the general population (standardizedmortality ratio compared with the general population matched for age and sex:
4.81 [95% CI: 3.03 to 6.59])[18].

A retrospective study in patients with PNH in the U.K. reported that the hazard
ratio for patients treated versus untreated with eculizumab was 0.21 [95% CI:
0.05 to 0.88] (on the basis of the interpretation of the reciprocal of the reported
value as the hazard ratio for patients untreated versus treated with eculizumab, it

47

is calculated as 1/0.21 = 4.762)[19].
In the scenario analysis by comparison with BSC, the manufacturer included only thetreatment cost for BTH and the cost of transfusion in the calculation without considering
the occurrence of drug acquisition and management costs in the BSC group. In aprevious study regarding cost-effectiveness analysis of eculizumab, the occurrence ofadditional costs was considered for the cost items of treatment related to renal
complications, Warfarin therapy, and treatment cost related to thrombotic events in the
BSC group but not in the eculizumab group[20]. Therefore, the costs might have been
underestimated in the BSC group in the submitted model, and caution is required in theinterpretation of the scenario analysis by comparison with BSC performed by the
manufacturer.

48

3.2 Summary of revisions by academic group
On the basis of the results of additional benefit assessment by academic group, thefollowing revised analysis of cost-effectiveness evaluation needs to be performed.
<Base case analysis>

Perform a cost-minimization analysis, assuming that effects are similar between thetherapies, because it cannot be concluded that an additional benefit of ravulizumab
over eculizumab was shown.

For the cost-minimization analysis, compare the total of drug acquisition andmanagement costs between the ravulizumab and eculizumab groups, assumingthat the consumption of medical resources other than the acquisition andmanagement costs is the same between the groups.

<Sensitivity analysis (Scenario analysis)>
Regarding the scenario analysis by comparison with BSC, the analyses submitted
by the manufacturer were accepted in spite of the various limitations in them.

49

3.3 Methods of revised analysis
Table 3-7 Corresponding part of report by manufacturer
In the reports, etc. submitted by the manufacturer
SectionPage

Starting line number(or table/figure number)

4. Details of analytical

P37 to 44-

methods<Description of the report>
Omitted< Details of academic analysis (revision)>
It cannot be concluded that the additional benefit assessment of ravulizumab showed
any additional benefit on any of the outcome measures. Therefore, it is inappropriate toperform a cost-effectiveness analysis, and it is appropriate to perform a
cost-minimization analysis assuming that there is no difference between the treatment
effects of ravulizumab and eculizumab.
In the revised analysis, the estimated drug acquisition and management costs werecompared between the ravulizumab and eculizumab groups, assuming that theconsumption of medical resources other than the acquisition and management costs
was the same between the groups.
The acquisition cost of ravulizumab was estimated in consideration of the body weight
distribution in the Japanese population because the dose of ravulizumab was adjusted
according to the patient's body weight. The body weight distribution in the Japanese
population was set on the basis of the data from the post-marketing surveillance ofeculizumab, which were used for the calculation of ravulizumab price (Table 3-8).

50

Table 3-8 Patient body weight distribution in the post-marketing surveillance ofeculizumab (provided by the manufacturer)
Body weight

No. of

Proportion

Body weight

No. of

Proportiongroup

patients

of patientsgrouppatients

of patients*1*2

In the same way as the drug prices and calculation method in the model of the
manufacturer, the drug acquisition and management costs incurred every 2 weeks wereconsidered. The unit price settings for the costs are presented in Table 3-9.
Table 3-9 Unit costs
Item

Unit price (JPY)

Amount per vial (mg)Price of ravulizumab (JPY/vial)

730,894300

Management cost of ravulizumab (JPY/dose)

11,761-Price of eculizumab (JPY/vial)

604,716

300

7,856

-

Management cost of eculizumab (JPY/dose)

The drug dose settings are presented in Table 3-10. The usual starting dose ofravulizumab is 2,400–3,000 mg, followed by 3,000–3,600 mg/dose (loading dose) after
2 weeks of the initial dose, and 3,000–3,600 mg/dose (maintenance doses) every 8
weeks thereafter, which are administered via intravenous infusion in consideration of
the patient's body weight. The dose of eculizumab is started at 600 mg/dose and51

administered via intravenous infusion for a total of 4 doses including the initial dose(loading doses) at once-weekly intervals, followed after a 1-week interval (4 weeks after
the initial dose) by 900 mg/dose administered via intravenous infusion at subsequentintervals of 2 weeks (maintenance doses).
In the analysis, the relevant analyses were performed with the settings (a)–(d)presented as follows.
(a)

Estimation of costs for the 8 weeks of maintenance doses

For simplification, drug acquisition and management costs were estimated for the 8
weeks of maintenance dose period assuming patients receiving long-term complement
inhibitor therapy.
(b)

Estimation of costs including the loading dose cost for the lifetime

Drug acquisition and management costs were estimated for patients in the virtual cohort
in the analysis model of the manufacturer from the starting age of 55.62 to 100 years.
(c)

Estimation of costs including the loading dose cost for the lifetime inconsideration of discount rate

Drug acquisition and management costs were estimated for patients in the virtual cohort
in the analysis model of the manufacturer from the starting age of 55.62 to 100 years.
An annual discount rate of 2% was applied to the cost calculation.
(d)

Estimation of costs including the loading dose cost for the lifetime inconsideration of discount and survival rates

Drug acquisition and management costs were estimated for patients in the virtual cohort
in the analysis model of the manufacturer from the starting age of 55.62 to 100 years.
An annual discount rate of 2% was applied to the cost calculation, and the survival ratein the analysis model of the manufacturer was considered in the cost calculation.
Table 3-10 Drug dose settings

Body weight

No. of

Proportion

patients

of patients

Ravulizumab
dose [initial
dose] (mg)

Ravulizumab Eculizumab Eculizumab
dose

dose [up to dose [Week[subsequent

Week 2]

4 onwards]

doses] (mg)

(mg)

(mg)

52

≥40 and<60 kg≥60 and<100 kg≥100 kg

352

58.18%

2400

3000

249

41.16%

2700

3300

4

0.66%

3000

3600

600

900

53

4. Results of cost-effectiveness assessment
4.1 Revised base case analysis
The results of the re-analysis of the cost-minimization analysis of ravulizumab versus
eculizumab are presented in Tables 4-1–4-5. Because all of the analysis results for (a)–(d) showed increased cost of ravulizumab compared with that of eculizumab, the resultsfor (a), which was the easiest to interpret, was regarded as the main analysis results.
(a)

Estimation of costs for the 8 weeks of maintenance doses

Comparison of costs (acquisition and management costs) for the 8 weeks ofmaintenance dose period showed that the cost of ravulizumab was increased by
343,163 JPY as compared with that of eculizumab (Tables 4-1 and 4-2).
Table 4-1 Cost-minimization analysis of ravulizumab versus eculizumab(estimation of costs for the 8 weeks of maintenance doses)
Item

Ravulizumab arm

Eculizumab arm

Incremental cost

(JPY)

(JPY)

(JPY)

Acquisition cost

7,619,419

7,256,592

362,827

Management cost

11,761

31,425−19,664

7,631,180

7,288,017

343,163

Total

54

Table 4-2 Calculation process for the cost-minimization analysis (estimation of costs for the 8 weeks of maintenance doses)
Acquisition cost of ravulizumab (JPY)(A) Patient's(B) Patient's(C) Patient's

body weightbody weightbody weight

40–60 kg

60–100 kg≥100 kg[58.18%][41.16%][0.66%]

0

7,308,940

8,039,834

2

04Management

Acquisition cost

Management
cost of(D) Weighted

cost ofaverage of A to

ravulizumab

C [100%](JPY)8,770,728

7,619,419

11,761

1,814,148

7,856

0

0

0

0

1,814,148

7,856

0

0

0

0

0

1,814,148

7,856

6

0

0

0

0

0

1,814,148

7,856

Total

7,308,940

8,039,834

8,770,728

7,619,419

11,761

7,256,592

31,425Weekof eculizumab(JPY)eculizumab
(JPY)

55

(b)

Estimation of costs including the loading dose cost for the lifetime

Comparison of costs (acquisition and management costs) including the loading dose
cost for the lifetime showed that the cost of ravulizumab was increased by JPY
106,283,512 as compared with that of eculizumab (Table 4-3).
Table 4-3 Cost-minimization analysis of ravulizumab versus eculizumab(estimation of costs including the loading dose cost for the lifetime)
Item

Ravulizumab arm

Eculizumab arm

Incremental cost

(JPY)

(JPY)

(JPY)

Acquisition cost

2,215,789,123

2,103,806,964

111,982,159

Management cost

3,422,350

9,120,998−5,698,648

2,219,211,473

2,112,927,962

106,283,512

Total

(c)

Estimation of costs including the loading dose cost for the lifetime inconsideration of discount rate

Comparison of costs (acquisition and management costs) including the loading dose
cost for the lifetime in consideration of discount rate showed that the cost of ravulizumab
was increased by JPY 72,451,369 as compared with that of eculizumab (Table 4-4).
Table 4-4 Cost-minimization analysis of ravulizumab versus eculizumab(estimation of costs including the loading dose cost for the lifetime inconsideration of discount rate)
Item

Ravulizumab arm

Eculizumab arm

Incremental cost

(JPY)

(JPY)

(JPY)

Acquisition cost

1,476,420,040

1,400,175,873

76,244,167

Management cost

2,281,126

6,073,924−3,792,798

1,478,701,166

1,406,249,797

72,451,369

Total

(d)

Estimation of costs including the loading dose cost for the lifetime inconsideration of discount rate and survival rate

Comparison of costs (acquisition and management costs) including the loading dose56

cost for the lifetime in consideration of discount and survival rates showed that the costof ravulizumab was increased by JPY 55,307,436 as compared with that of eculizumab(Table 4-5).
Table 4-5 Cost-minimization analysis of ravulizumab versus eculizumab(estimation of costs including the loading dose cost for the lifetime inconsideration of discount and survival rates)
Item

Ravulizumab arm

Eculizumab arm

Incremental cost

(JPY)

(JPY)

(JPY)

Acquisition cost

1,103,856,648

1,045,716,344

58,140,304

Management cost

1,706,071

4,538,938−2,832,868

1,105,562,719

1,050,255,283

55,307,436

Total

57

4.2 Revised scenario analysis
The results of the re-analysis of the cost-effectiveness analysis of ravulizumab versus
BSC are presented in Tables 4-6–4-8.
Table 4-6 Results of the scenario analysis of the cost-effectiveness analysis
Effectivene

Incrementalss (QALY)

effectiveness

Cost (JPY)

Incremental

ICER

cost (JPY)(JPY/QALY)

819,004,596

101,700,385(QALY)Ravulizumab

19.86

BSC

11.81

8.05

855,544,150
36,539,554

Table 4-7 Breakdown of estimated QALY by health state
Health state

Ravulizumab

BSC

Spontaneous remission

3.89

3.09

BTH absent

15.97

0.00

Free C5-related BTH present

0.00

0.00

CAC BTH present

0.01

0.00

History of free C5-related BTH present and BTH absent

0.00

0.00

0.00

8.72

BTH present

0.00

0.00

Total

19.86

11.81

History of free C5-related BTH present and freeC5-related BTH present
History of free C5-related BTH present and free CAC

Table 4-8 Breakdown of estimated costs by item
Item

Ravulizumab(JPY)

BSC(JPY)

Cost
difference(JPY)

Acquisition cost

853,396,454

0853,396,454

Management cost

1,375,533

01,375,533

Treatment cost for BTH

23,08426,995,823−26,972,740

Cost of transfusion

728,885

9,543,731−8,814,846

Cost of vaccines

20,1940

20,19458

Total

855,544,150

36,539,554

819,004,596

59

4.3 Interpretation of results
The interpretation of the revised analysis by the academic group is summarized asshown in Table 4-9.
Table 4-9 Interpretation of revised analysis results
Population

Paroxysmal nocturnal hemoglobinuria

Comparator

Eculizumab

Referencevalue for ICER

□ Regular product ■ Product requiring special consideration□ Cost reduction or dominant□ 5 million yen or less (7.5 million yen or less)Intervals where
ICER is most
likely to belong□ More than 5 million yen (more than 7.5 million yen) and not more than 7.5
million yen (not more than 11.25 million yen)
□ More than 7.5 million yen (more than 11.25 million yen) and 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
Revised analysis using cost-minimization analysis showed that the cost of
Reason for the

ravulizumab was increased by JPY 343,163 as compared with that ofdecision

eculizumab for the 8 weeks of maintenance dose period. Likewise, costestimations with other conditions also showed increased cost of ravulizumab.
Although there were analytical issues in the scenario analysis by comparison

Referencewith BSC, the ICER of ravulizumab versus BSC was estimated to be
JPY101,700,385/QALY.

60

5. References
1.

NICE: Single Technology Appraisal Ravulizumab for treating paroxysmal
nocturnal haemoglobinuria Final Scope. [Online] Available:
https://www.nice.org.uk/guidance/gid-ta10690/documents/final-scope-2 2020.

2.

IQWiG: Ravulizumab (paroxysmal nocturnal haemoglobinuria)–Benefit
assessment according to §35a Social Code Book V. [Online] Available:
https://www.iqwig.de/en/projects-results/projects/drug-assessment/a19-59-ravali
zumab-benefit-assessment-according-to-35a-social-code-book-v.12495.html
2019.

3.

IQWiG: Ravulizumab (paroxysmal nocturnal haemoglobinuria)–Addendum toCommission A19-59. [Online] Available:
https://www.iqwig.de/en/projects-results/projects/drug-assessment/a19-104-rav
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9-59.12822.html 2020.

4.

PBAC: Ravulizumab: Solution concentrate for I.V. infusion 300 mg in 30 mL;
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7/batch_2/ravulizumab-solution-concentrate-for-iv-infusion-300-mg 2020.

5.

National Instiute of Public Health: A descriptive form and guide for analysis
results related to cost-effective analyses of drugs and medical devices. [Online]
Available: https://c2h.niph.go.jp/tools/system/Reporting_Format_Jap.pdf 2019.

6.

Lee JW, Sicre de Fontbrune F, Wong Lee Lee L, Pessoa V, Gualandro S,
Fureder W, Ptushkin V, Rottinghaus ST, Volles L, Shafner L et al: Ravulizumab(ALXN1210) vs eculizumab in adult patients with PNH naive to complement
inhibitors: the 301 study. Blood 2019, 133(6):530-539.

7.

Kulasekararaj AG, Hill A, Rottinghaus ST, Langemeijer S, Wells R,
Gonzalez-Fernandez FA, Gaya A, Lee JW, Gutierrez EO, Piatek CI et al:
Ravulizumab (ALXN1210) vs eculizumab in C5-inhibitor-experienced adultpatients with PNH: the 302 study. Blood 2019, 133(6):540-549.

8.

Ishiyama K, Nakao S, Usuki K, Yonemura Y, Ikezoe T, Uchiyama M, Mori Y,
Fukuda T, Okada M, Fujiwara SI et al: Results from multinational phase 3
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9.

Peffault de Latour R, Brodsky RA, Ortiz S, Risitano AM, Jang JH, Hillmen P,
Kulagin AD, Kulasekararaj AG, Rottinghaus ST, Aguzzi R et al: Pharmacokinetic
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two phase 3 randomised, multicentre studies. Br J Haematol 2020,
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10.

Alexion Pharma G.K.: Cost-effectiveness evaluation of ravulizumab [version 1.0]
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Package insert for ULTOMIRIS® for Intravenous Infusion 300 mg. [Online]
Available: https://pins.japic.or.jp/pdf/newPINS/00068175.pdf.

12.

Package insert for SOLIRIS® for Intravenous Infusion 300 mg. [Online]
Available: https://pins.japic.or.jp/pdf/newPINS/00058745.pdf.

13.

Alexion Pharma G.K.: A summary of the application dossier of ravulizumab,
ULTOMIRIS for Intravenous Infusion 300 mg. [Online] Available:
https://www.pmda.go.jp/drugs/2019/P20190716002/index.html 2019.

14.

Lloyd A, Gallop K, Ali S, Myren K, Sierra J, Anokhina K, Patriquin C, Hill A,
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2020, Orlando, FL, USA. [Online] Available:
https://www.ispor.org/heor-resources/presentations-database/presentation/intl2
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15.

O'Connell T, Buessing M, Johnson S, Tu L, Thomas SK, Tomazos I: Cost-Utility
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Nishimura J, Kanakura Y, Ware RE, Shichishima T, Nakakuma H, Ninomiya H,
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Jang JH, Kim JS, Yoon SS, Lee JH, Kim YK, Jo DY, Chung J, Sohn SK, Lee JW:
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Coyle D, Cheung MC, Evans GA: Opportunity cost of funding drugs for rarediseases: the cost-effectiveness of eculizumab in paroxysmal nocturnal
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63