C2H
Evaluation Report

C2H1902

Tisagenlecleucel / B-ALL（ KymriahR）

March 2021
Center for Outcomes Researchand Economic Evaluation for HealthNational Institute of Public HealthJAPANCost-effectiveness evaluation oftisagenlecleucel (Kymria) by the academic
group [Version 1.1]

Relapsed or refractory CD19-positive B-cell acute lymphoblastic
leukemia (B-ALL)[November 11, 2020]

[Table of contents]

list of abbreviations .................................................................................4
0. Framework of analysis ..........................................................................6
1. Results by foreign health technology assessment agencys .........................8[Results of review on documents submitted by the manufacturer in Chapter 1].......................................................................................................... 24
2. Systematic review (SR) ...................................................................... 25
2.1 Clinical questions set by academic analysis ....................................... 25
2.2 Study design of SR ........................................................................ 26
2.2.1 Inclusion and exclusion criteria for clinical study ........................... 26
2.2.2. Database used ....................................................................... 27
2.2.3 Search formula used ................................................................ 27
2.2.4 Other ..................................................................................... 31
2.3 Search results............................................................................... 32[Results of review on documents submitted by the manufacturer in Chapter 2].......................................................................................................... 33
2.4 Evaluation of the presence or absence of additional benefit ................. 36
3. Analysis by the academic group of cost-effectiveness .............................. 40
3.1 Presence or absence of the site requiring analysis by the academic groupbased on review results ....................................................................... 40
3.2 Summary of analysis by the academic group required ........................ 41
3.2.1 Analytical methods, parameters, etc. that need to be reconsidered (formajor [significant impact on results]) ................................................. 41
3.2.2 Analytical methods, parameters, etc. that need to be reconsidered(other than 3.2.1) ............................................................................ 41
3.3 Analysis by the academic group policy for major points (points having alarge impact on results) ....................................................................... 42
3.3.1 Parameters used in analysis (estimation of EFS and OS) ................ 42[Details of specific analysis by the academic group] .............................. 42
3.3.2

Details of QOL scores (QOL scores for EFS and PD) .................... 51[Details of specific analysis by the academic group] .............................. 51
3.4 Analysis by the academic group policies for the points that need to be
examined other than 3.3 ..................................................................... 53

2

3.4.1 Details of cost parameters (medical fee point table/National Health
Insurance Drug Price Standard) ......................................................... 53[Details of specific analysis by the academic group] .............................. 53
3.4.2 Details of QOL scores (for Age-related utility) .............................. 55[Details of specific analysis by the academic group] .............................. 55
3.4.3 Estimation of EFS in the blinatumomab group .............................. 57[Details of specific analysis by the academic group] .............................. 57
3.4.4 Details of QOL scores (for Treatment disutility) ............................ 58[Details of specific analysis by the academic group] .............................. 58
3.4.5 Details of QOL scores (for Subsequent HSCT disutility) .................. 59[Details of specific analysis by the academic group] .............................. 59
4. Analytical results ............................................................................... 61
4.1 Results of analysis by the academic group ........................................ 61
4.1.1 Base case incremental costs, incremental effects, and ICER in analysis
by the academic group ........................................................................ 61
4.1.2 Factors that are not reflected in the analysis by the academic group but
can qualitatively influence the ICER ....................................................... 63
4.2 Sensitivity analysis ........................................................................ 65
4.3 Interpretation of analytical results ................................................... 73
4.4 Price adjustment rate..................................................................... 77
4.4.1 Proportion of patients with ALL and DLBCL ..................................... 77
5. References........................................................................................ 78

3

list of abbreviations
Abbreviations

Formal description

ALL

Acute Lymphoblastic Leukemia

alloHSCT

Allogeneic Hematopoietic Stem Cell Transplantation

ASMR

Amelioration du Service Médical Rendu

B-ALL

B-cell Acute Lymphoblastic Leukemia

CAD

Canadian dollar

CADTH

Canadian Agency for Drugs and Technologies in Health

CAR

Chimeric Antigen Receptor

CHRIs

Child Health Ratings Inventory

CI

Confidence interval

CRComplete Remission

EFS

Event-Free Survival

DLBCL

Diffuse Large B-Cell Lymphoma

EQ-5D

EuroQol 5 Dimension

EQ-5D-3L

EuroQol 5 Dimension 3 Level

EQ-5D-5L

EuroQol 5 Dimension 5 Level

HAS

Haute Autorité de SantéHR

Hazard Ratio

HRQL

Health-Related Quality of Life

HUI2Health Utilities Index Mark II

HSCT

Hematopoietic Stem Cell Transplantation

ICER

Incremental Cost-Effectiveness Ratio

IQWiG

Instituts für Qualität und Wirtschaftlichkeit im Gesundheitswesen

MAIC

Matched Adjusted Indirect Comparison

MRD

Minimal Residual Disease

MSAC

Medical Services Advisory Committee

NA

Not Applicable

NICE

National Institute for Health and Care ExcellenceOS

Overall survival

PAS

Patient Access Schemes

4

PD

Progressive Disease

PROMIS

Patient-Reported Outcomes Measurement Information System

QALY

Quality-Adjusted Life Year

QOL

Quality of Life

RCT

Randomized Controlled Trial

SCT

Stem Cell Transplant

SF-36

36-Item Short Form Survey

SMC

Scottish Medicines Agency

SMR

Service Médical Rendu

TTO

Time Trade-Off50. Framework of analysis
Table 0-1 The framework of analysis
Relapsed or refractory CD19-positive B-cell acutelymphoblastic leukemia.
Patients aged 25 years or younger (at the time of treatment)
who meet any of the following criteria (a) and (b) shall be
included.
 Patients with primary disease who have not achieved
remission after the standard chemotherapy was performed
Population

at least twice Patients with relapsed disease who have not achieved
remission after the chemotherapy was performed at leastonce Patients who are not indicated for allogeneic hematopoietic
stem cell transplantation or who have relapsed after
allogeneic hematopoietic stem cell transplantation(a) Population aged <15 years(b) Population aged 15 to 25 years(a) Blinatumomab ± allogeneic hematopoietic stem cellcomparator

transplantation (alloHSCT)(b) Blinatumomab ± alloHSCT and inotuzumab ozogamicin ±alloHSCT
For both populations, (post-relapse) secondary
chemotherapy is standardly administered (± alloHSCT)
according to the clinical practice in Japan or the NCCN
(National Comprehensive Cancer Network) guidelines.

Reason for
selection of"Guideline for Analysis of Cost-Effectiveness Evaluation bycomparator

the Central Social Insurance Medical Council, 2nd Version"indicates that it is appropriate to use "blinatumomab (±alloHSCT)" as a comparator in the population aged <15years, because blinatumomab have a high remission rate.
For the population aged 15 to 25 years, both "blinatumomab6

(± alloHSCT)" and “inotuzumab ozogamicin (± alloHSCT)”
can be selected as comparators, because both have a similar
response rate. Use of inotuzumab ozogamicin is limited topeople aged ≥15 years in Japan.
Other perspectivein addition to
public healthcarepayer

Yes (Details: Analysis including productivity loss
(manufacturer analysis only))No

Outcome unit andthe reason if QALY

Not applicable

is not used.

71. Results by health technology assessment agency
Table 1-1 List of assessments (Including additional benefit)
CountryUK

Organizati
on

Manufacturer

Academic analysis

NICE

・Recommended/Not recommended/Conditionally・Recommended/Not recommended/Conditionally

recommended (Specify: Cancer Drugs

recommended (Specify: Cancer Drugs

Fund)/Other (Fund)/Other (SMCFranceGermany

CanadaResults

HAS

IQWiG

CADTH

)

)

・Status: Final Guidance/Draft/Other

・Status: Final Guidance/Draft/Other

(

(

)

)

・Recommended/Not recommended/Conditionally・Recommended/Not recommended/Conditionally

recommended (Specify: Patient Accessrecommended (Specify: Patient Access

Schemes)/Other (Schemes)/Other ())

･ SMR: Important･ SMR: Important･ ASMR: I/II/III/IV/V･ ASMR: I/II/III/IV/V・ Efficiency assessment: Yes (major ICER

・ Efficiency assessment: Yes (major ICER

value:

value:)/Under assessment/Not performed)/Under assessment/Not performed･ Major/Considerable/Minor/Unquantifiable/No･ Major/Considerable/Minor/Unquantifiable/No

additional benefit

additional benefit

・Recommended/Not recommended/Conditionally・Recommended/Not recommended/Conditionally

recommended (Specify:

recommended (Specify: reduction in price)/ /Other)/Other ()

(Australia

MSAC)

・Recommended/Not recommended/Conditionally・Recommended/Not recommended/Conditionally

recommended (Specify:

recommended (Specify: risk share arrangement)/)/Other ()

Other ()

9

Table 1-2 Implementation of cost-effectiveness analysis in each country
Country

Organization

Implementation
Manufacturer

UK

NICE

Academic analysis

Yes/ No/ Under assessment (with/without

Yes/ No/ Under assessment (with/without

draft)/ Unknown

draft)/ Unknown

SMC

Yes/ No/ Under assessment/ Unknown

Yes/ No/ Under assessment/ Unknown

FranceHAS

Yes/ No/ Under assessment/ Unknown

Yes/ No/ Under assessment/ Unknown

CanadaCADTH

Yes/ No/ Under assessment/ Unknown

Yes/ No/ Under assessment/ Unknown

Australia

MSAC

Yes/ No/ Under assessment/ Unknown

Yes/ No/ Under assessment/ Unknown

10

Table 1-3 Details of cost-effectiveness analysis in each country
Table 1-3-1 Details of cost-effectiveness analysis in UK (NICE)CountryUK
Manufacturer

Organization
URLs

Academic analysis

NICE
https://www.nice.org.uk/guidance/ta554/chapter/1-

Same as in the left

Recommendations
Target technology
Results
If conditionally recommended,

Tisagenlecleucel

Same as in the left

Conditional recommendation

Same as in the left

Cancer Drugs FundSame as in the left

Pediatric and young adult patients up to 25 years of age

Same as in the left

details of the condition
Diseasewith B‑cell acute lymphoblastic leukemia (ALL) that isrefractory, in relapse post-transplant or in second or later
relapseDosageTreatment with tisagenlecleucel comprises a single-dose

Same as in the left

intravenous infusion of tisagenlecleucel.
It is intended for autologous use only and at the following
dosage:

For patients ≤50 kg: 0.2 to 5.0×106 CAR-positive11

viable T cells per kg body weightFor patients >50 kg: 0.1 to 2.5×108 CAR-positive
viable T cells (non-weight based)

Comparator

Blinatumomab and salvage chemotherapy are both

Same as in the left

appropriate comparators and blinatumomab is the main
comparator.
Incremental cost-effectivenessCompany's probabilistic base-case ICER was £20,046 perratio (ICER)QALY gained. The committee concluded the most plausible

Same as in the left

ICERs for tisagenlecleucel compared with blinatumomab
when taking into account all the patient access scheme
discounts were over £30,000 per QALY gained.

12

Table 1-3-2 Details of cost-effectiveness analysis in UK (SMC)
CountryUK
Manufacturer

Organization
URLs

Academic analysis

SMC
https://www.scottishmedicines.org.uk/medicines-

Same as in the left

advice/tisagenlecleucel-kymriah-fullsubmission-smc2129
Target technology
Results
If conditionally recommended,

Tisagenlecleucel

Same as in the left

Conditional recommendation

Same as in the leftPatient Access Scheme

Same as in the left

pediatric and young adult patients up to 25 years of age

Same as in the left

details of the condition
Diseasewith B‑cell acute lymphoblastic leukemia (ALL) that isrefractory, in relapse post-transplant or in second or later
relapseDosageTisagenlecleucel is intended for autologous use only.

Same as in the left

Tisagenlecleucel is to be administered via intravenous
infusion.
A single dose of tisagenlecleucel contains:for patients 50kg and below: 0.2 to 5 x 106 CAR[chimeric antigen receptor] positive viable T cells/kg
body weight13

for patients above 50kg: 0.1 to 2.5 x 108 CARpositive viable T cells (non-weight based)

Comparator

Salvage chemotherapy, blinatumomab or palliative

Same as in the lefttherapies
Incremental cost-effectivenessratio (ICER)ICER versus salvage chemotherapy (with PAS for

Results using PAS prices and list

tisagenlecleucel)

prices for both tisagenlecleucel

Base case: £25,238

and blinatumomab are notdisclosed

14

Table 1-3-3 Details of cost-effectiveness analysis in France (HAS)Country

FranceManufacturer

Organization
URLs

Academic analysis

HAS
https://www.has-sante.fr/jcms/c_2891689/en/kymriah-

Same as in the left

tisagenlecleucel-anti-cd19-car-t
Target technology
Results
If conditionally

Tisagenlecleucel

Same as in the left

Results SMR: Important / ASMR: III

Same as in the left

NA

Same as in the left

pediatric and young adult patients up to 25 years of age

Same as in the leftrecommended, details of thecondition
Diseasewith B-cell acute lymphoblastic leukaemia (ALL) that isrefractory, in relapse post-transplant or in second or later
relapseDosageTisagenlecleucel is intended for autologous use only.

Same as in the left

Tisagenlecleucel is to be administered via intravenous
infusion.
A single dose of tisagenlecleucel contains:for patients 50kg and below: 0.2 to 5 x 106 CAR[chimeric antigen receptor] positive viable T cells/kg

15

body weight.
for patients above 50kg: 0.1 to 2.5 x 108 CAR positive
viable T cells (non-weight based).

Comparator

Incremental costeffectiveness ratio (ICER)

salvage chemotherapy, blinatumomab, inotuzumab, andSalvage chemotherapy,

palliative care

Clofarabine, blinatumomabNA€189,822/QALY for clofarabine
as comparator when time
horizon is limited to 10 years

16Table 1-3-4 Details of cost-effectiveness analysis in Germany (IQWIG)Country

Germany
Manufacturer

Organization
URLs

Academic analysis

IQWIG
https://www.iqwig.de/en/projects28results/projects/health-Same as in the left

economic/g18-11-tisagenlecleucel-b-cell-acutelymphoblasticleukaemia-assessment-according-to-35apara-1-sentence-11-social-code-book-v.10617.html
Target technology

Tisagenlecleucel

Same as in the left

Results

Unquantifiable

Same as in the left

NA

Same as in the left

pediatric and young adult patients up to 25 years of age

Same as in the left

If conditionally recommended,details of the condition
Diseasewith B-cell acute lymphoblastic leukaemia (ALL) that isrefractory, in relapse post-transplant or in second or later
relapseDosageTisagenlecleucel is intended for autologous use only.

Same as in the left

Tisagenlecleucel is to be administered via intravenous
infusion.
A single dose of tisagenlecleucel contains:for patients 50kg and below: 0.2 to 5 x 106 CAR

17

[chimeric antigen receptor] positive viable T cells/kg
body weight.
for patients above 50kg: 0.1 to 2.5 x 108 CAR positive
viable T cells (non-weight based)

Comparator
Incremental cost-effectiveness

None (reason：orphan designation)

Same as in the left

NA

Same as in the left

ratio (ICER)

18

Table 1-3-5 Details of cost-effectiveness analysis in Canada (CADTH)Country

CanadaManufacturer

Organization
URLs

Academic analysis

CADTH
https://www.cadth.ca/tisagenlecleucel-kymriah-pediatric-

Same as in the left

acute-lymphoblastic-leukemia-and-diffuse-large-b-celllymphoma
https://cadth.ca/sites/default/files/pdf/car-t/ct0001op0538-in-brief-e.pdf
Target technology
Results
If conditionally recommended,

Tisagenlecleucel

Same as in the left

Conditional recommendation

Same as in the left

On the condition that there is a reduction in priceSame as in the left

Pediatric and young adult patients three to 25 years oldSame as in the left

details of the condition
Diseasewith B-cell acute lymphoblastic leukemia who are
refractory, have relapsed after allogeneic stem celltransplant (SCT), or are otherwise ineligible for allogeneic
SCT, or have experienced a second or later relapse
DosageThe recommended dose is 0.2-5.0 x 106 CAR-positive

Same as in the left

viable T cells/kg body weight for patients 50 kg and below
and 0.1-2.5 x 108 CAR-positive viable T cells for patients

19

above 50 kg as a single one-timetreatment.
Comparator
Incremental cost-effectivenessratio (ICER)

salvage chemotherapy

Same as in the left

For r/r ALL, tisagenlecleucel, compared with end-of-life

Same as in the left

chemotherapy, was associated with an incremental cost per
quality-adjusted life-year (QALY — a measure of thequantity and quality of life for a patient, as well as value
for money for medical interventions) of CAD$53,269.

20

Table 1-3-6 Details of cost-effectiveness analysis in Australia (MSAC)Country

Australia
Manufacturer

Organization
URLs

Academic analysis

MSAC
http://www.msac.gov.au/internet/msac/pSame as in the left

ublishing.nsf/Content/1519-public
Target technology

Tisagenlecleucel

Same as in the left

Results

Recommendation

Conditional recommendation

NA

Risk share arrangement

If conditionally recommended,details of the condition



A pay only on successful infusion*arrangement;Treatment to be limited to a single dose oftisagenlecleucel, as there is no evidence
currently available informing theeffectiveness or safety of multiple doses;and

A full review of clinical effectiveness, costeffectiveness and budget impact will be
conducted by the MSAC no later than 2 years
post the commencement of public subsidy(note: Novartis will provide a submission to21

initiate this review).
* Successful infusion: patient is infused with
Kymriah with a clinically acceptable cell dose
which is consistent with the expected cell dose
specified prior to apheresis
Diseasepediatric and young adult patients up toSame as in the left

25 years of age with B-cell precursor
acute lymphoblastic leukaemia (ALL) thatis refractory, in relapse posttransplant, orin second or later relapse
Dosage

For patients 50 kg and below: 0.2 toSame as in the left

5.0 x 106 CAR-positive viable T
cells/kg body weight.
For patients above 50 kg: 0.1 to 2.5 x
108 CAR-positive viable T cells (nonweight based).

Comparator

comparator: blinatumomab with theSame as in the left

intention to proceed to allo-SCT (Main),salvage hemotherapy
with the intention to proceed to allo-SCT(Supportive)
Incremental cost-effectivenessNA

Not disclosed

22

ratio (ICER)

23

[Review on the submission by the manufacturer in Chapter 1]
Although generally appropriate, the following matters were inconsistent withthe description in the reports by the health technology assessment agency.
 An ICER was reported for France (HAS). The comparator was clofarabine
combination therapy, with an ICER of €189,822/QALY over a 10-year time
horizon.
 For Australia (MSAC), conditionally recommended by multiple conditions forprice reduction and reimbursement.
 There are no comparison data such as randomized controlled trials (RCTs) that
evaluated the efficacy and safety of tisagenlecleucel. There are no efficacy orsafety data based on direct comparison with the comparator. This has asignificant impact on the uncertainty of results.
 In addition, because there is no strong evidence that the no recurrence isexperienced after 3 or 5 years from the administration of tisagenlecleucel. The
limitation about long-term prognosis is pointed by health technology
assessment agency. For this reason, NICE recommends the use under theCancer Drugs Fund (data collection arrangement), and the period of datacollection is set to be until June 2023 when the follow-up of Study ELIANA iscompleted.

2. Systematic review (SR)
2.1 Clinical questions by the academic group
Table 2-1-1 Clinical question of SR
Item

Establishment of academic analysis
B-cell acute lymphoblastic leukemia

Population

However, limited to patients aged ≤25 years after recurrence
after hematopoietic stem cell transplantation or 2nd or
subsequent chemotherapy
The following therapies for the indication in the population:

Intervention

 Tisagenlecleucel Blinatumomab Inotuzumab ozogamicin

Comparator

All comparators
Any of the following outcomes:
 Survival (duration)
Overall survival rate
・Morbidity
Event-free survival

Outcome

Disease-free survival
Progression-free survival
Recurrence rate
Duration of remission
Frequency and timing of hematopoietic stem cell transplantation
Adverse events
 Health-related quality of life (HRQL)
・RCT

Study design・Controlled study
・Single arm study
・Observational study

Literaturesearch period

From January 2019 to September 202025

2.2 Study design of SR
2.2.1 Inclusion and exclusion criteria for clinical study
Table 2-2-1 Eligibility criteria
Item

Inclusion criteria

Exclusion criteria

Population

 B-cell acute lymphoblastic

 At least 20% patients with T-

leukemiacell acute lymphoblastic

However, limited to patientsleukemia

aged ≤25 years after Patients in complete remission

recurrence after hematopoietic(CR)

stem cell transplantation or 2nd

 Untreated patientsor subsequent chemotherapy

 At least 10 patients in clinicalstudies and at least 20 patientsin observational studies

Intervention

Tisagenlecleucel

Therapies not clinically used

Blinatumomab
Inotuzumab ozogamicin
Comparator

No restrictions

Outcome

At least one of the following
outcomes:・ Survival (duration)
Overall survival rate

・ Morbidity
Event-free survival
Disease-free survival
Progression-free survival
Recurrence rate
Duration of remission
Frequency and timing ofhematopoietic stem celltransplantation

26

Adverse events・ Health-related quality of life
(HRQL)
Study

・ RCT

design・ Controlled study
・ Single arm study
・ Observational study

Type of・ Research report

・ Abstract
・ Noteliterature

・ Editorial
・ Letter
Language

English or Japanese

2.2.2. Database・PubMed・Ichushi

2.2.3 Search formula
Table 2-2-3-1 Search formula for PubMed
Item

Serialnumber

Search formula

Numberof results

Population#1"Precursor Cell Lymphoblastic Leukemia-

53,392Lymphoma"[MeSH] OR "acute lymphocytic
leukemia" OR "acute lymphocytic leukaemia"
OR "acute lymphoblastic leukemia" OR"acute lymphoblastic leukaemia" OR((lymphocyt*[TIAB] OR lymphoblast*[TIAB]
OR lymphat*[TIAB] OR lymphoid*[TIAB])
AND (leukemi*[TIAB] OR leukaemi*[TIAB])
AND acute[TIAB])

27

#2

relapsed OR relapses OR relapsing OR

1,914,491

refractory OR chemorefractory OR
drugresistant OR "drug resistant" OR failed
OR failure OR "transplant ineligible" OR"stem cell transplant ineligible" OR “SCTineligible"
Study

#3

#1 AND #2

14,171#4"Clinical Trials as Topic"[MeSH] OR "Clinical

12,157,85

Trial" [PT] OR "Randomized Controlled Trials

2

designas Topic"[MeSH] OR "Randomized Controlled
Trial" [PT] OR "Cross-Over Studies"[MeSH]
OR "Prospective Studies"[MeSH] OR
random* OR “random allocation” OR
randomized OR randomised OR “doubleblind” OR “singleblind” OR “single blind” OR“double blind” OR “clinical trial” “phase 1” OR“phase 2” OR “phase 1/2” OR "phase1/phase 2" OR “phase 3” OR “phase 4” OR“Clinical Study”[PT] OR “Clinical Trial, PhaseI”[PT] OR “Clinical Trial, Phase II”[PT] OR“Clinical Trial, Phase III”[PT] OR “Clinical
Trial, Phase IV” [PT] OR “Controlled Clinical
Trial”[PT] OR “Multicenter Study”[PT] OR
placebo* OR “prospective study” ORsinglearm OR “single arm” OR open-label OR“open label” OR trial OR “nonblinded” OR
non-blinded OR non-randomized OR
nonrandomized OR non-randomised OR
nonrandomised OR parallel-group OR"parallel study" OR superiority OR noninferiority OR change OR evaluat* OR
prospectiv* OR retrospective* OR baseline
OR cohort or consecutive* OR compare* OR
compara* OR "case series" OR "comparative
studies" OR "follow-up studies" OR registry
OR observational OR nonrandomized OR
nonrandomized
Limitation#5#3 AND #4

8,523

of

#6

#5 AND 2019:2020[DP]877

integration

28

and search
period29

Table 2-2-3-2 Search formula for Ichushi
Item

Serialnumber

Search formula

Numberof results

Population#1

白血病-リンパ腫-前駆細胞リンパ芽球性/TH or 急性18,611リンパ性白血病/AL or 前駆細胞リンパ芽球性白血病/AL or 急性リンパ芽球性白血病/AL or "Acutelymphoblastic leukemia"/AL or ((リンパ/AL or
Lymphoma/AL) and (白血病/TH or 白血病/ALor Leukemia) and (急性/AL or acute/AL))#2(再発/TH or 再発/AL or relapse/AL) or (難治性396,841/AL or refractory/AL) or 化学抵抗性/AL or 薬物
抵抗性/TH or 薬剤耐性/AL or 失敗/AL or 移植不適格/AL or ((幹細胞移植/TH or 幹細胞移植/ALor "stem cell transplantation"/AL) and (不適格
/AL or 不適応/AL or ineligible/AL))Study
design#3#1 AND #2

2,872

#4

ランダム化比較試験/TH or "randomized

523,560

controlled trial"/AL or "randomized controlled
trials"/AL or ランダム割付け/TH or ランダム化/AL or 無作為/AL or クロスオーバー研究/TH or
クロスオーバー試験/AL "Cross-Over Studies"/ALor 二重盲検法/TH or 二重盲検/AL or 一重盲検法/TH or 単盲検/AL or 非盲検/AL or プラセボ/THor プラセボ/AL or 臨床試験/TH or 臨床試験/AL
or "Clinical trials"/AL or "Clinical trial"/AL or比較試験/AL or 比較検討/AL or 対照試験/AL or
比較研究/AL or 対照研究/AL or "臨床研究・疫学研
究"/TH or "Clinical study"/AL or "Clinicalstudies"/AL or "Comparative study"/AL or"Comparative studies"/AL or "Comparative
research"/AL or "comparison study"/AL or"comparison research"/AL or 観察研究/TH or
観察研究/AL or "Observational study"/AL or"Observational studies"/AL or 非ランダム化/AL30

or コホート/AL or 追跡研究/TH or フォローアップ
研究/AL or 並行研究/AL
Limitation#5#3 AND #４

351

of

#6

#5 AND (DT=2019:2020)30

integrationand search
period

2.2.4 OtherNo special notes312.3 Search results
Figure 2-3-1 Flow chart of SR

Identification

Number of literatures identified bydatabase search from 1/1/2019 to
9/26/2020
PubMed: 877
Ichushi-web: 30↓
Number of literatures after excluding
duplicates

Number of literatures excluded→907

from titles and abstracts
870↓
Screening

Number of literatures excluded
with the following reasons:
Number of literatures assessed for full
qualification
37

33

→

Study design (1)Population (18)
Not target technology (13)Not target outcomes (1)↓IncludedNumber of literatures adopted
4(Of them, 3 overlapped with the clinicalstudies selected by the manufacturer)

32

[Review on submission by the manufacturer in Chapter 2]
The results of the SR are:□ Completely consistent with submission by the manufacturer☑ Overall consistent and contains all important literature to evaluate

additional benefit□ There is a discrepancy in the results, and there is a lack of important
literature to evaluate additional benefit.
□ Other ()● Differences from the SR performed by the manufacturer (method).
The results of the SR conducted by the manufacturer are generally
acceptable. On the other hand, since the existing literature search period is
until

2019, an additional search limited to Japanese literatures was

performed until

2019.

Since the additional search should not be confined to the Japanese
population, the academic analysis also conducted both English and Japanese
literature search from 2019 to the latest time point (September 26, 2020).
● Differences from the SR performed by the manufacturer (result).
One additional literature was selected as a result of a SR performed by theacademic group [1]. The literature is shown in Table 2-3-1.

33

Table 2-3-1 List of literatures
Title of article

Blinatumomab in pediatric patients with relapsed/refractory
acute lymphoblastic leukemia: results of the RIALTO trial, an
expanded access study

Author nameLocatelli F et al.

Bibliographic

Blood Cancer J. 2020;10(7):77

information
Test location

19 sites (7 countries)

Study

2014-July 19, 2019enrollment
periodPopulation

Enrolled patients were aged >28 days to <18 years, with
CD19-positive BCP-ALL in second or later relapse, any relapse
after allogeneic hematopoietic stem cell transplantation(alloHSCT), or refractory to other treatments

Key exclusion

Patients with active acute (grade 2–4) or chronic graft-versus-

criteria

host disease (GvHD) requiring systemictreatment, or active central nervous system or testicular
involvement

Details of

Blinatumomab (5–15 µg/m2 per day) was administered as a 6-

intervention

week induction cycle, comprising continuous infusion for 4

methodweeks, followed by a 2-week treatment-free period.

Details ofNAcomparator
Study design

Single-arm study

Blinding method

Open-labelPrimary

Incidence of treatment-emergent and treatment-related

endpoint

adverse events

Key secondary

Morphologic CR (<5% blasts) and MRD response (<10−4

endpoints

leukemic blasts by flow cytometry) in the first two cycles,
relapse-free survival, OS, alloHSCT rate after blinatumomab
treatment, and 100-day mortality after alloHSCT

Statistical

Statistical reporting of this study is descriptive.

methods34

● Validity of the SR performed by the manufacturer.
The clinical study (RIALTO trial) of blinatumomab was detected. The article
was published in July 2020 after submission of the manufacture’s report. The
results of the SR the manufacturer are therefore valid.

35

2.4 Evaluation of additional benefit
Table 2-4-1 Evaluation of additional benefit

Manufacturer

Academic analysis

Population

B-ALL patients aged <15 years

Same as in the left

Intervention

Tisagenlecleucel

Same as in the left

Comparator

Blinatumomab +/- alloHSCTSame as in the left

OutcomeOS

Same as in the left

Additional benefit■ Additional benefit is not shown.

Same as in the left

(Yes/No) "No additional benefit" or "Cannot be judged " Meta-analysis of RCTs  Single RCT

Additional benefit(Study design)Same as in the left

 Prospective comparative observational studies
 Indirect comparison of RCT
 Comparison of single-arm studies
 No clinical study data
In the indirect comparison (OS) between the

The point estimate of conditional HR showed the

Additional benefit

population aged <15 years in the pooled trial data

OS event is approximately(Reason)(B2101J, ELIANA/B2202, ENSIGN/B2205) and theconsiderably smaller than 1. The upper limit of the

population aged <15 years in Gore 2018, the

95% confidence interval of the HR does not cross%, which isconditional HR was(95% CI: []).

1. It is indicated that this product has the number

Based on these results, it was judged that thisof events decreased to approximately

product has additional benefit for the comparator.

the upper limit of confidence interval. Therefore the% even at

judgment of manufacturer on additional benefit isvalid.

37

Table 2-4-2 Evaluation of additional benefit

Manufacturer

Academic analysis

Population

B-ALL patients aged 15 to <25 years

Same as in the left

Intervention

Tisagenlecleucel

Same as in the left

Blinatumomab +/- alloHSCTSame as in the left

Comparator

Inotuzumab +/- alloHSCT

OutcomeOS

Same as in the left

Additional benefit■ Additional benefit is not shown.

Same as in the left

(Yes/No) "No additional benefit" or "Cannot be judged " Meta-analysis of RCTs  Single RCT

Additional benefit(Study design)Same as in the left

 Prospective comparative observational studies
 Indirect comparison of RCT
 Comparison of single-arm studies
 No clinical study data
In the MAIC analysis (OS) between the population

Additional benefit

aged ≥15 years in the pooled trial data (B2101J,(Reason)

ELIANA/B2202, ENSIGN/B220) and the overall
population in Gore 2018 when blinatumomab wasCompared with inotuzumab or blinatumomab, theupper limit of the 95% confidence interval of theconditional HR does not exceed 1 in either case.
Point estimate of HR suggested that this productmay decrease the OS events to approximately

38

used as a comparator, the conditional HR was(95%CI: [to. It is indicated that this product has the]).

number of events decreased by approximately

In the MAIC analysis (OS) between the populationeven at the upper limit of confidence interval.

aged ≥15 years in the pooled trial data (B2101J,

Therefore the judgment of manufacturer on

ELIANA/B2202, ENSIGN/B2205) and the overall

additional benefit is valid.

%

population in Bhojwani 2019 when inotuzumab wasused as a comparator, the conditional HR was(95%CI: []). Based on these results,

it was judged that this product has additional
benefit for the comparator.

393. Cost-effectiveness analysis by the academic group
3.1 Should the cost-effectiveness analysis submitted by the
manufacturer be reconsidered?
□ Nothing special →Terminated in this section☑ YesContinued below→

3.2 Summary of analysis (revise) by the academic group
3.2.1 Major points that need to be reconsidered (significant impact on
results)a) Parameters (estimation of EFS and OS)b) QOL scores (QOL scores for EFS and PD)
3.2.2 Minor points that need to be reconsidered (other than 3.2.1)
a) Cost parameters (drug prices)b) QOL scores (for Age-related utility)c) Estimation of EFS in the blinatumomab groupd) QOL scores (Treatment disutility)e) QOL scores (Subsequent HSCT disutility)41

3.3 Analysis (revision) by the academic group for major points
3.3.1 Parameters (estimation of EFS and OS)
Table 3-3-1-1 Corresponding part of report by manufacturer
In the reports, submitted by the manufacturer
SectionNumber of pages

4.2.1.1

96

Start line number(or figure/table number)
3[Description of report]
The assumption of 5 years as a cure point is considered more conservative.
The long-term ALL survival was modelled using the 2018 Japan life table,with a mortality adjustment using the SMR of 5-year ALL survivors publishedin the literature (Table 13).[30],[38] The same mortality risk was applied to
all treatments. This assumption reduced some of the long-term uncertainties
arising from the extrapolation of data beyond the maximum reported followup. The estimated SMR-adjusted survival rate was applied to all patients who
remain alive from year 5 onwards in the model. A targeted literature review
was conducted to identify publications to inform long-term survival for the
study population (registry or SMR studies). MacArthur et al., 2007 was
identified as the most relevant input source and used to inform the mortalityof 5-year ALL survivors.

[Details of academic analysis (revision)]
According to the manufacture’s analysis, the OS function was extrapolatedusing mortality rate which was estimated by multiplying SMR (standardizedmortality ratio) of the long survivor by mortality rate of general people.
However, this extrapolation can not consider excess mortality in PD patients,
and the OS was overestimated. Therefore, this cannot be regarded as an
appropriate OS extrapolation. For example, in the population aged 15 to 25
years, the life expectancy of patients who had relapsed after the treatment with
Kymriah at 3 years was approximately 10 years or longer.
In addition, the EFS function was extrapolated by a horizontal line (y=C; C is42

a constant) assuming that no event occurs. However, even the patients with
EFS should experience events such as death due to other causes. Death events
that are reflected in OS should be handled as events in EFS. Such extrapolationof EFS function is not appropriate.
Therefore, the OS function was extrapolated using the parametric function
estimated by the manufacturer after the 5th year when the Kaplan-Meier curve
was interrupted. The EFS function was extrapolated after the 5th year using thestandardized mortality ratio used by the manufacturer to account for the deaths
other than other disease. However, if the OS and EFS functions crossed, the OS
function was also extrapolated using the EFS function estimation method.
In the manufacturer’s response to our inquiry (dated2019), it was

described "After 5 years of treatment with Kymriah, long-term survival (cure)
was assumed, and the subsequent OS was extrapolated using the SMR of
MacArthur et al.". The fact that long-term survival (cure) can be achieved bytisagenlecleucel is acceptable. This can be achieved by the "absence ofrecurrence (after the 5th year)". It does not justify the extrapolation of the EFS
curve after the 5th year (cure point) by the horizontal line. It is not also
appropriate that the OS curve extrapolation method is changed when the 5thyear started.
In the population aged <15 years, OS and EFS were reversed within 5 years
in the tisagenlecleucel group. In that case, it is not appropriate to estimate the
OS in the blinatumomab group using the OS of tisagenlecleucel group. Thus,
the estimation of OS in the blinatumomab group was performed using theparametric function in the tisagenlecleucel group and the adjusted hazard ratiosfrom time 0.
As the academic analysis, the estimated life years in the tisagenlecleucelgroup and blinatumomab group in the population aged <15 years were as
described in Table 3-3-1-2. Additionally, the results of academic analysis ofestimated survival curves were shown in Figures 3-3-1-1 to 3-3-1-4.
Similarly, the academic analysis in the population aged 15 to 25 years wereshown in Table 3-3-1-3 and Figures 3-3-1-5 to 3-3-1-10.

43

Table 3-3-1-2 Life years by academic analysis (population aged <15years)
Manufacturer’s submission

Academic analysis

Tisagenlecleucel

Blinatumomab

Tisagenlecleucel

Blinatumomab

group

group

group

group

Life years
(LYs)
EFS
PD

Figure 3-3-1-1 Estimated survival time curve by manufacturer for thetisagenlecleucel group (population aged <15 years)

44

Figure 3-3-1-2 Estimatioed survival time curve by academic analysis forthe tisagenlecleucel group (population aged <15 years)

Figure 3-3-1-3 Estimated survival time curve by manufacturer for the
blinatumomab group (population aged <15 years)

Figure 3-3-1-4 Estimated of survival time curve by academic analysis

45

for the blinatumomab group (population aged <15 years)

46

Table 3-3-1-3 Life years by the academic analysis (population aged 15 to 25 years)
Academic analysis

Manufacturer’s submission
Tisagenlecleucel

Blinatumomab

Inotuzumab

Tisagenlecleucel

Blinatumomab

Inotuzumab

group

group

ozogamicin

group

group

ozogamicingroup
Life years (LYs)
EFS
PD

group

Figure 3-3-1-5 Estimated survival time curve by manufacturer for thetisagenlecleucel group (population aged 15 to 25 years)

Figure 3-3-1-6 Estimated survival time curve by academic analysis forthe tisagenlecleucel group (population aged 15 to 25 years)

Figure 3-3-1-7 Estimated survival time curve by manufacturer for the
blinatumomab group (population aged 15 to 25 years)

Figure 3-3-1-8 Estimated survival time curve by academic analysis forthe blinatumomab group (population aged 15 to 25 years)
Figure 3-3-1-9 Estimated survival time curve by manufacturer for the49inotuzumab ozogamicin group (population aged 15 to 25 years)

Figure 3-3-1-10 Estimated of survival time curve by academic analysis
for the inotuzumab ozogamicin group (population aged 15 to 25 years)50

3.3.2 QOL scores (QOL scores for EFS and PD)
Table 3-3-2-1 Corresponding part of report by manufacturer
In the reports. submitted by the manufacturer
SectionNumber of pages

Start line number (orfigure/table number)

4.2.2.1

80, 83, 105-[Description of report]
Because a trial-based utility score was only available forpatients aged 15

years and above in the ELIANA alone, the base-case utility inputs were basedon published studies and trial-based utility inputs were used in the sensitivity
analysis. Kelly et al., 2015 used a decision analysis to evaluate cranialradiation therapy for pediatric T-cell ALL patients and performed a systematic
literature review (SLR) of utility studies as part of the analysis.[30] While thestudy focused on T-cell ALL, the SLR of utilities included all forms of ALL. The
study used existing mapping functions to convert generic quality-of-life
measure (i.e. SF36 and CHRIs) to preference-based utility estimates (i.e.
HUI2 and EQ-5D). The utility inputs for health states in the state of relapse
and cured after relapse were considered relevant for the CEA model and wasused to inform the utility value for the PD and EFS states respectively in thebase-case model.

[Details of academic analysis (revision)]
The analysis by manufacturer used the QOL scores of 0.91 for EFS and 0.75
for PD. The EFS value of 0.91 was determined by assigning the value of SF-36
obtained from Essig et al. [2] to the formula by Nichol et al. [3], which could
convert SF-36 to HUI2. Essig et al. used SF-36 for data collection of survivors in
Switzerland, who were diagnosed as <16 years of age between 1976 and 2003.
They survived for at least 5 years and ≥16 years of age at the survey. Based on
the analysis of from 457 survivors, it reported they have a higher QOL than thegeneral population.
For the PD value of 0.75, the global HRQOL measured using Child HealthRatings Inventories (CHRIs) in patients undergoing HSCT were measured by
Rodday et al.[4]. They were converted using mapping PROMIS to EQ-5D by
Revicki et al.[5]. Aristides M et al.[6] performed in the UK, reported a PD QOL
score of 0.30 using TTO. Thus, the analysis submitted by the manufacturer
used the conversion of generic quality-of-life measure (SF36 or CHRIs) topreference-based measure (HUI2 or EQ-5D), which had problems such as a
mixture of scales.
On the other hand, ELIANA measured QOL scores using EQ-5D-3L atbaseline, at 1 month, at 3 months and thereafter every 3 months for 2 years.
The results have been reported by Laetsch et al.[7]. In the academic analysis,
QOL scores reported by Laetsch et al. (Table 3-3-2-2) was used as the basecase analysis.
Table 3-3-2-2 QOL score
Manufacturer’s

Academic

submission

analysis

Progressive disease

0.75

0.69

Event-free survival

0.91

0.81

52

3.4 Analysis (revision) by the academic group other than 3.3
3.4.1 Cost parameters (drug prices)
Table 3-4-1-1 Corresponding part of report by manufacturer
In the reports, submitted by the manufacturer
SectionNumber of pages

Start line number (orfigure/table number)

4.2.3

108

22

[Description of report]
For both B-ALL and DLBCL diseases, the costs for the target technology to beanalyzed and the comparator technology were estimated by theaccumulation method based on the medical feeschedule and the National

Health Insurance Drug Price Standard as of October 2019 in principle.

[Details of academic analysis (revision)]
The prices of some medicines used by the manufacturer for analysis was notconsistent with the latest drug price.
In the "Guideline for Analysis of Cost-Effectiveness Evaluation by the Central
Social Insurance Medical Council 2nd Version", it is stated that " Unit costs
should be derived from the latest medical fee schedule,

the National Health

Insurance Drug Price Standard, or similar resources. It is particularly essential
to use the latest unit costs for the selected technology or comparator(s).”.
Academic analysis was performed using the latest drug price (as of April 2020)
for the tisagenlecleucel and the comparators (blinatumomab, inotuzumab
ozogamicin).
Table 3-4-1-2 Drug prices of comparators
Manufacturer’s

Academic analysis

submission

53

Blincyto (blinatumomab)

JPY 281,345

JPY 286,336

Besponsa (inotuzumab ozogamicin)

JPY 1,307,092

JPY 1,331,297

54

3.4.2 QOL scores (for Age-related utility)
Table 3-4-2-1 Corresponding part of report by manufacturer
In the reports, submitted by the manufacturer
SectionNumber of pages

Start line number (orfigure/table number)

4.2.2

107

8

[Description of report]
Age-related utility
Because the utility inputs for the model were estimated based on a pediatricand adolescent population, the model considered additional age-related
decrements as the modelled population became older over the modelled
time horizon. The decrements were calculated based on Janssen 2014,
which described the health utilities of healthy populations by different age
groups using the EQ-5D index population norms based on the Japan timetrade-off value sets.[32] Age-related utility decrements were estimatedbased on the absolute utility values reported for each age group (e.g.
adjustment for age 25-34 was calculated as 0.96/0.97) and were applied to
all alive patients over the modelled time horizon.

[Details of academic analysis (revision)]In the manufacture’s analysis, population norms measured by EQ-5D-3L
based on Tsuchiya et al. was used as the QOL score after cure. However, themost recent population norms in Japan was measured by Shiroiwa et al.[8]using EQ-5D-5L. The academic analysis was performed using the most recent
data in Japan. The population norms by Shiroiwa et al. were shown in Table 34-2-2.

55

Table 3-4-2-2 Population norms of EQ-5D-5L
Manufacturer’s

Academic

submission

analysis

Age <250.97

0.9475

Age 25-34

0.96

0.9475

Age 35-44

0.97

0.9435

Age 45-54

0.94

0.9275

Age 55-64

0.91

0.932

Age 65-74

0.88

0.905

Age 75+

0.77

0.847

56

3.4.3 Estimation of EFS in the blinatumomab group
Table 3-4-3-1 Corresponding part of report by manufacturer
In the reports, submitted by the manufacturer
SectionNumber of pages

Start line number (orfigure/table number)

4.2.1.1

99

10[Description of report]
As such, up to year 5, EFS for blinatumomab was estimated based on its OSdata assuming a constant cumulative HR between OS and EFS over time.
The ratios were estimated based on inotuzumab per Bhojwani 2019.[16] To
estimate an overall cumulative HR between OS and EFS, the ratio was firstestimated as the natural log of OS probability divided by the natural log of
EFS probability at monthly intervals until the end of the observed period. The
overall cumulative HR between OS and EFS was then calculated as theaverage of cumulative HRs at all monthly intervals. This assumption isjustifiable on the basis that EFS is highly correlated with OS.[40][Details of academic analysis (revision)]
The manufacturer’s submission used the assumption that OS and EFS are also
highly correlated in the blinatumomab group, but this assumption is not always
clinically validated. Therefore, in the analysis by the academic group, therobustness of the analytical was investigated by conducting a sensitivity
analysis assuming that the ratio of EFS to OS is 1.00 as the most extreme
assumption.
Table 3-4-3-2 Ratio of EFS to OS
Manufacturer’s

Academic analysis

submission
EFS vs OS ratio

1.00

57

3.4.4 QOL scores (Treatment disutility)
Table 3-4-4-1 Corresponding part of report by manufacturer
In the reports, submitted by the manufacturer
SectionNumber of pages

Start line number (orfigure/table number)

4.2.2

106

16

[Description of report]
Treatment disutility
Inputs for treatment disutility in the treatment phase were based on theestimates from Sung et al., 2003.[31] A decrement of 0.42 was used for allcomparators (i.e., blinatumomab and inotuzumab) and tisagenlecleucel. The
treatment disutility estimates are assumed to capture the utility decrements
for all short-term AEs associated with the treatment, with the exception forthe cytokine release syndrome (CRS).

[Details of academic analysis (revision)]
The manufacture’s analysis used the assumption that the decrease in QOL
score (disutility) was the same between the tisagenlecleucel and thecomparator group. On the other hand, the committee paper of NICE in the UK
pointed out that the disutility (-0.42) during treatment did not apply to theblinatumomab group. Therefore, in the academic analysis, the robustness wasinvestigated by a sensitivity analysis assuming that the decrease in QOL for
blinatumomab is 0 as the most extreme assumption.

58

3.4.5 QOL scores (Subsequent HSCT disutility)
Table 3-4-5-1 Corresponding part of report by manufacturer
In the reports, submitted by the manufacturer
SectionNumber of pages

Start line number (orfigure/table number)

4.2.2

106

34

[Description of report]
Subsequent HSCT disutility
The model assumed patients could receive subsequent HSCT after initial
treatment. Patients receiving subsequent HSCT were assumed to haveadditional HSCT disutility (a decrement of 0.57), derived from Sung et al.,2003.[31] The disutility associated with HSCT was assumed to last for 1. The
rates of subsequent HSCT were obtained from the same clinical trial study
used for the efficacy estimation. Similar to the efficacy inputs, age-groupspecific data was used for the rate of subsequent HSCT where feasible. The
subsequent HSCT disutility considered in the model are summarized in Section
4.2.

[Details of academic analysis (revision)]In the manufacturer’s analysis, this decrease in QOL score (0.57) was applied
for 1 year using Sun et al.. However, in Roddy et al.[4], which was used as a
QOL score of PD in the manufacturer’s analysis, changes in QOL scores after
HSCT were shown. The decrease was smaller than 0.57. In addition, FelderPuig et al.[9] reported QOL scores after HSCT in children. The decrease was in
QOL score was 0.13 per year on average measured by HUI. According toKurosawa et al.[10] surveyed in Japan, the QOL score within 1 year after HSCT
was 0.59. That is, the manufacturer’s analysis may have overestimateddecreases in QOL scores after HSCT.
Therefore, in the academic analysis, robustness was investigated by asensitivity analysis in which 0.13, a decrease in QOL score (disutility), wasapplied for 1 year after HSCT, and the period when 0.57 is used, was limited to59

3 months.

60

4. Results of cost-effectiveness analysis
4.1 Results of academic analysis
 The following analysis should be performed☑ Cost-effectiveness analysis (calculate the ICER)□ Cost-minimization analysis (compare costs with each other)

4.1.1 Results of base case analysis by the academic group(a) Population aged <15 years
The base case analysis by the manufacturer and the academic group areshown in Tables 4-1-1-1 and 4-1-1-2, respectively. The academic group
estimated the ICER to be JPY 2,184,285/QALY compared with blinatumomab,
which was less than JPY 7.5 million/QALY.
Table 4-1-1-1 Base case analysis by the analysis by manufacturer

Effectiveness(QALY)
Tisagenlecleucel

11.11

Comparator

2.07

Incremental
effectiveness

Cost (JPY)(QALY)
9.05

40,448,386

Incremental

ICER

cost (JPY)(JPY/QALY)

18,882,649

2,087,581

21,565,737

61

Table 4-1-1-2 Base case analysis by the academic group

Effectiveness(QALY)
Tisagenlecleucel

9.86

Comparator

1.29

Incremental
effectiveness

Cost (JPY)(QALY)
8.57

40,475,633

Incremental

ICER

cost (JPY)(JPY/QALY)

18,722,085

2,184,285

21,753,548(b) Population aged 15 to 25 years
Compared with blinatumomab, the base case analysis by the manufacturer
and the academic group are shown in Tables 4-1-1-3 and 4-1-1-4, respectively.
The base case results compared with inotuzumab ozogamicin are shown in
Tables 4-1-1-5 and 4-1-1-6. The academic group estimated the ICER to be JPY
2,571,736 /QALY compared with blinatumomab, and JPY 2,747,550/QALY
compared with inotuzumab ozogamicin, which were less than 7.5 million
yen/QALY as with the results by the manufacturer.
Table 4-1-1-3 Base case analysis by the manufacturer (comparator:
blinatumomab)

Effectiveness(QALY)
Tisagenlecleucel

11.58

Comparator

3.01

Incremental
effectiveness

Cost (yen)(QALY)
8.56

40,245,192

Incremental

ICER

cost (yen)(yen/QALY)

17,256,268

2,015,349

22,988,924

62

Table 4-1-1-4 Base case analysis by the academic group (comparator:
blinatumomab)

Effectiveness(QALY)
Tisagenlecleucel

8.55

Comparator

1.91

Incremental
effectiveness

Cost (JPY)(QALY)
6.64

40,258,162

Incremental

ICER

cost (JPY)(JPY/QALY)

17,084,078

2,571,736

23,174,084

Table 4-1-1-5 Base case results by the analysis by manufacturer(comparator: inotuzumab ozogamicin)

Effectiveness(QALY)
Tisagenlecleucel

11.58

Comparator

2.03

Incremental
effectiveness

Cost (JPY)(QALY)
9.55

40,245,192

Incremental

ICER

cost (JPY)(JPY/QALY)

19,049,180

1,994,592

21,196,012

Table 4-1-1-6 Base case analysis by the academic group (comparator:
inotuzumab ozogamicin)

Effectiveness(QALY)
Tisagenlecleucel

8.55

Comparator

1.67

Incremental
effectiveness

Cost (JPY)(QALY)
6.88

40,258,162

Incremental

ICER

cost (JPY)(JPY/QALY)

18,906,157

2,747,550

21,352,005

4.1.2 Factors that are not reflected in the academic analysis but can
influence the ICER
[Factors increasing ICER]

63a) Duration of effect of tisagenlecleucel: This analysis assumes the effect oftisagenlecleucel continues for life time. However, the empirical data do notsupport the duration. The ICER is assumed to be worse than the current
value if the effect of tisagenlecleucel does not continue for life time.
b) Retreatment with tisagenlecleucel: Retreatment with tisagenlecleucel is notconsidered in the current analysis. The ICER is assumed to be worse if theretreatment by tisagenlecleucel is needed for some patients.

644.2 Sensitivity analysis(a) Population aged <15 years
The one-way sensitivity analysis was performed mainly for the parameters
having a large impact on ICER in the manufacturer’s submission. In addition,
the academic group performed scenario analysis by changing the setting
described in 3.4. The results are shown in Tables 4-2-1 to 4-2-6.
Even in the scenario analysis with the most extreme assumption, the ICER oftisagenlecleucel was less than JPY 7.5 million/QALY as compared withblinatumomab.

65

Table 4-2-1 Results of one-way sensitivity analysis
Parameter

Range of parameters
Lower limit

Rationale for setting

Upper limit

ICER range (JPY/QALY)
Lower limit

Upper limit

1,361,145

3,167,566

The influence on ICER is large among the
Discount rate

0%

4%

parameters of the one-way sensitivity
analysis performed by the manufacturer

Table 4-2-2 Scenario analysis: the ratio of EFS to OS in theblinatumomab group is 1.00 (most extreme assumption)

Effectiveness(QALY)
Tisagenlecleucel

9.96

Comparator

1.98

Incremental
effectiveness

Cost (JPY)(QALY)
7.98

40,473,327

Incremental

ICER

cost (JPY)(JPY/QALY)

18,739,516

2,349,241

21,733,811

Table 4-2-3 Scenario analysis: the disutility of treatment withblinatumomab is 0 (most extreme assumption)

Effectiveness(QALY)
Tisagenlecleucel

9.88

Comparator

1.36

Incremental
effectiveness

Cost (JPY)(QALY)
8.52

40,475,633

Incremental

ICER

cost (JPY)(JPY/QALY)

18,722,085

2,197,215

21,753,548

Table 4-2-4 Scenario analysis: the disutility by HSCT is 0.13

Effectiveness(QALY)
Tisagenlecleucel

9.94

Comparator

1.42

Incremental
effectiveness

Cost (JPY)(QALY)
8.52

40,475,633
21,753,548

Incremental

ICER

cost (JPY)(JPY/QALY)

18,722,085

2,197,066

Table 4-2-5 Scenario analysis: the period of disutility by HSCT is limited
to 90 days

Effectiveness(QALY)
Tisagenlecleucel

9.96

Comparator

1.45

Incremental
effectiveness

Cost (JPY)(QALY)
8.51

40,475,633

Incremental

ICER

cost (JPY)(JPY/QALY)

18,722,085

2,199,842

21,753,548

Table 4-2-6 Scenario analysis: the HSCT implementation rate in thetisagenlecleucel treatment group is the same with the comparatorgroup (30.65%) (most extreme assumption)

Effectiveness(QALY)
Tisagenlecleucel

9.79

Comparator

1.29

Incremental
effectiveness

Cost (JPY)(QALY)
8.51

43,651,272

Incremental

ICER

cost (JPY)(JPY/QALY)

21,897,724

2,574,183

21,753,548(b) Population aged 15 to 25 years
The one-way sensitivity analysis was performed mainly for the parameters
having a large impact on ICER in the manufacture’s submission. In addition,
scenario analysis was performed by changing the setting described in 3.4. The
results compared with blinatumomab are shown in Tables 4-2-7 to 4-2-12, andthe results compared with inotuzumab ozogamicin are shown in Tables 4-2-13
to 4-2-16.
Even in the scenario analysis with the most extreme assumption, the ICER oftisagenlecleucel was less than JPY 7.5 million/QALY as compared with bothblinatumomab and inotuzumab ozogamicin.

68

Table 4-2-7 Results of one-way sensitivity analysis (comparator: blinatumomab)
Parameter

Range of parameters
Lower limit

Rationale for setting

Upper limit

ICER range (JPY/QALY)
Lower limit

Upper limit

1,747,541

3,496,074

The influence on ICER is large among the
Discount rate

0%

4%

parameters of the one-way sensitivity
analysis performed by the manufacturer

Table 4-2-8 Scenario analysis: the ratio of EFS to OS in theblinatumomab group is 1.00 (most extreme assumption)

Effectiveness(QALY)
Tisagenlecleucel

8.73

Comparator

2.85

Incremental
effectiveness

Cost (JPY)(QALY)
5.88

40,253,838

Incremental

ICER

cost (JPY)(JPY/QALY)

17,106,019

2,907,616

23,147,819

Table 4-2-9 Scenario analysis: the disutility of treatment withblinatumomab is 0 (most extreme assumption)

Effectiveness(QALY)
Tisagenlecleucel

8.58

Comparator

1.98

Incremental
effectiveness

Cost (JPY)(QALY)
6.60

40,258,162

Incremental

ICER

cost (JPY)(JPY/QALY)

17,084,078

2,588,772

23,174,084

Table 4-2-10 Scenario analysis: the disutility by HSCT is 0.13

Effectiveness(QALY)
Tisagenlecleucel

8.65

Comparator

2.07

Incremental
effectiveness

Cost (JPY)(QALY)
6.58

40,258,162

Incremental

ICER

cost (JPY)(JPY/QALY)

17,084,078

2,596,894

23,174,084

Table 4-2-11 Scenario analysis: the period of disutility by HSCT islimited to 90 days

Effectiveness(QALY)
Tisagenlecleucel

8.67

Incremental
effectiveness

Cost (JPY)(QALY)
6.56

40,258,162

Incremental

ICER

cost (JPY)(JPY/QALY)

17,084,078

2,602,382

Comparator

2.10

23,174,084

Table 4-2-12 Scenario analysis: Assuming that the HSCT
implementation rate in the tisagenlecleucel treatment group is thesame as the comparator group (35.71%) (most extreme assumption)

Effectiveness(QALY)
Tisagenlecleucel

8.47

Comparator

1.91

Incremental
effectiveness

Cost (JPY)(QALY)
6.56

44,355,564

Incremental

ICER

cost (JPY)(JPY/QALY)

21,181,480

3,229,059

23,174,08471

Table 4-2-13 Results of one-way sensitivity analysis (comparator: inotuzumab ozogamicin)
Parameter

Range of parameters
Lower limit

Rationale for setting

Upper limit

ICER range (yen/QALY)
Lower limit

Upper limit

1,882,060

3,703,46

Because the influence on ICER is large
Discount rate

0%4%among the factors of the one-way
sensitivity analysis performed by the
manufacturer

Table 4-2-14 Scenario analysis: the disutility by HSCT is -0.13

Effectiveness(QALY)
Tisagenlecleucel

8.65

Comparator

1.85

Incremental
effectiveness

Cost (JPY)(QALY)
6.79

40,258,162

Incremental

ICER

cost (JPY)(JPY/QALY)

18,906,157

2,783,302

21,352,005

Table 4-2-15 Scenario analysis: the period of disutility by HSCT is set as
90 days

Effectiveness(QALY)
Tisagenlecleucel

8.67

Comparator

1.89

Incremental
effectiveness

Cost (JPY)(QALY)
6.77

40,258,162

Incremental

ICER

cost (JPY)(JPY/QALY)

18,906,157

2,791,132

21,352,005

Table 4-2-16 Scenario analysis: the HSCT implementation rate in thetisagenlecleucel treatment group is same with the comparator group(41.18%) (most extreme assumption)

Effectiveness(QALY)
Tisagenlecleucel

8.45

Comparator

1.67

Incremental
effectiveness

Cost (JPY)(QALY)
6.77

45,594,314

Incremental

ICER

cost (JPY)(JPY/QALY)

24,242,308

3,579,509

21,352,005

4.3 Interpretation of cost-effectiveness analysis(a) Population aged <15 years

Population

Relapsed or refractory CD19-positive B-cell acutelymphoblastic leukemia.

Patients aged 25 years or younger (at the time of treatment)
who meet any of the following criteria (a) and (b) shall be
included.
・ Patients with primary disease who have not achieved
remission after the standard chemotherapy was performedat least twice
・ Patients with relapsed disease who have not achieved
remission after the chemotherapy was performed at least
once
・ Patients who are not indicated for allogeneic hematopoietic
stem cell transplantation or who have relapsed after
allogeneic hematopoietic stem cell transplantation
Comparator

Blinatumomab ± alloHSCTType of the□ Regular product ☑ Product requiring special

thresholdconsideration□ Cost reduction or dominant☑ JPY 5 million or less (JPY 7.5 million or less)□ More than JPY 5 million (more than JPY 7.5 million) andIntervals where
ICER is most likely
to belong

not more than JPY 7.5 million (not more than JPY 11.25
million)□ More than JPY 7.5 million (more than JPY 11.25 million)
and not more than JPY 10 million (not more than JPY 15
million)□ More than JPY 10 million (more than JPY 15 million)□ Equivalent (or inferior) in effectiveness and expensive
The base case analysis showed the ICER of JPY
2,184,285/QALY. In addition, sensitivity analyses of theReason for such
judgment

parameters resulted in the ICER of less than JPY 7.5
million/QALY in all cases.
Based on the above, the ICER in the this population ismost likely to belong to the interval of “JPY 7.5 million orless”.

74

(b) Population aged 15 to 25 years
Relapsed or refractory CD19-positive B-cell acutelymphoblastic leukemia.
Patients aged 25 years or younger (at the time of treatment)
who meet any of the following criteria (a) and (b) shall be
included.
・ Patients with primary disease who have not achieved
Population

remission after the standard chemotherapy was performedat least twice
・ Patients with relapsed disease who have not achieved
remission after the chemotherapy was performed at least
once
・ Patients who are not indicated for allogeneic hematopoietic
stem cell transplantation or who have relapsed after
allogeneic hematopoietic stem cell transplantation

Comparator

Blinatumomab ± alloHSCT and inotuzumab ozogamicin ±alloHSCT

Type of thethreshold□ Regular product ☑ Product requiring special
consideration□ Cost reduction or dominant☑ JPY 5 million or less (JPY 7.5 million or less)□ More than JPY 5 million (more than JPY 7.5 million) andIntervals where
ICER is most likely
to belong

not more than JPY 7.5 million (not more than JPY 11.25
million)□ More than JPY 7.5 million (more than JPY 11.25 million)
and not more than JPY 10 million (not more than JPY 15
million)□ More than JPY 10 million (more than JPY 15 million)□ Equivalent (or inferior) in effectiveness and expensive
The base case analysis showed that the ICER compared

Reason for suchwith blinatumomab is JPY 2,571.73/QALY. The ICER

judgment

compared with inotuzumab ozogamicin is JPY 2,745,550/QALY. In addition, sensitivity analyses of the parameters

75resulted in the ICER of less than 7.5 million yen/QALY in allcases.
Based on the above, the ICER in the this population ismost likely to belong to the interval of “7.5 million yen orless”.

76

4.4 Price adjustment rate
4.4.1 Proportion of patients with ALL and DLBCLFor the proportions of patients with ALL and DLBCL, the manufacturer has
estimatedpatients (%) with ALL andpatients (%) with DLBCL

based on a peak predicted exposure of 216 patients. The manufacturer
explained that estimates were made based onrather than actual clinical data because of not enough time since therecent launch of tisagenlecleucel. This estimate by the manufacturer is
acceptable to the academic group. Therefore% is used as the proportion ofpatients with ALL.

77

5. References[1] Locatelli F, Zugmaier G, Mergen N, Bader P, Jeha S, Schlegel PG, et al.
Blinatumomab in pediatric patients with relapsed/refractory acutelymphoblastic leukemia: results of the RIALTO trial, an expanded accessstudy. Blood Cancer J. 2020 Jul 24;10(7):77.
[2] Essig S, von der Weid NX, Strippoli MP, Rebholz CE, Michel G, Rueegg CS, etal. Health-related quality of life in long-term survivors of relapsed childhood
acute lymphoblastic leukemia. PLoS One. 2012;7(5):e38015.
[3] Nichol MB, Sengupta N, Globe DR. Evaluating quality-adjusted life years:
estimation of the health utility index (HUI2) from the SF-36. Med Decis
Making. 2001 Mar-Apr;21(2):105-12.
[4] Rodday AM, Terrin N, Parsons SK; Journeys to Recovery Study; HSCTCHESS™ Study. Measuring global health-related quality of life in children
undergoing hematopoietic stem cell transplant: a longitudinal study. Health
Qual Life Outcomes. 2013 Feb 26;11:26.
[5] Revicki DA, Kawata AK, Harnam N, Chen WH, Hays RD, Cella D. Predicting
EuroQol (EQ-5D) scores from the patient-reported outcomes measurement
information system (PROMIS) global items and domain item banks in a
United States sample. Qual Life Res. 2009 Aug;18(6):783-91.
[6] Aristides M, Barlev A, Barber B, Gijsen M, Quinn C. Population preference
values for health states in relapsed or refractory B-precursor acutelymphoblastic leukemia in the United Kingdom. Health Qual Life Outcomes.
2015 Nov 16;13:181.
[7] Laetsch TW, Myers GD, Baruchel A, Dietz AC, Pulsipher MA, Bittencourt H, etal. Patient-reported quality of life after tisagenlecleucel infusion in children
and young adults with relapsed or refractory B-cell acute lymphoblastic
leukaemia: a global, single-arm, phase 2 trial. Lancet Oncol. 2019
Dec;20(12):1710-8.
[8] Shiroiwa T, Fukuda T, Ikeda S, Igarashi A, Noto S, Saito S, Shimozuma K.
Japanese population norms for preference-based measures: EQ-5D-3L, EQ5D-5L, and SF-6D. Qual Life Res. 2016 Mar;25(3):707-19.
[9] Felder-Puig R, di Gallo A, Waldenmair M, Norden P, Winter A, Gadner H, Topf
R. Health-related quality of life of pediatric patients receiving allogeneic
stem cell or bone marrow transplantation: results of a longitudinal, multicenter study. Bone Marrow Transplant. 2006 Jul;38(2):119-26.

78

[10] Kurosawa S, Yamaguchi H, Yamaguchi T, Fukunaga K, Yui S, Wakita S, etal. Decision Analysis of Postremission Therapy in CytogeneticallyIntermediate-Risk Acute Myeloid Leukemia: The Impact of FLT3 Internal
Tandem Duplication, Nucleophosmin, and CCAAT/Enhancer Binding Protein
Alpha. Biol Blood Marrow Transplant. 2016 Jun;22(6):1125-32.

79