C2H
Evaluation Report

C2H1902

Tisagenlecleucel / DLBCL（ 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 diffuse large B-cell lymphoma(DLBCL)[November 11, 2020]

[Table of contents]

list of abbreviations .................................................................................4
0. Framework of analysis ..........................................................................6
1. Results by foreign health technology assessment agencys .........................7[Results of review on documents submitted by the manufacturer in Chapter 1].......................................................................................................... 23
2. Systematic review (SR) ...................................................................... 24
2.1 Clinical questions set by academic analysis ....................................... 24
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 ................................................................ 28
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 ................. 34
3. Analysis by the academic group of cost-effectiveness .............................. 38
3.1 Presence or absence of the site requiring analysis by the academic groupbased on review results ....................................................................... 38
3.2 Summary of analysis by the academic group required ........................ 39
3.2.1 Analytical methods, parameters, etc. that need to be reconsidered (formajor [significant impact on results]) ................................................. 39
3.2.2 Analytical methods, parameters, etc. that need to be reconsidered(other than 3.2.1) ...............................................................................
3.3 Analysis by the academic group policy for major points (points having alarge impact on results) ....................................................................... 40
3.3.1 Mean age in the target patient population [only in the population aged
<70 years]...................................................................................... 40[Details of academic analysis (revision)] ............................................. 41
3.3.2 How to extrapolate survival time curves (PFS and OS) [only in the
population aged <70 years] .............................................................. 43[Details of academic analysis (revision)] ............................................. 442

3.3.3 Data source of efficacy parameters and method of extrapolation ofsurvival time curves (PFS and OS) for tisagenlecleucel [only in the population
aged ≥70 years] .............................................................................. 50[Details of academic analysis (revision)] ............................................. 51
3.3.4 QOL scores for PFS .................................................................. 56[Details of academic analysis (revision)] ............................................. 56
3.4 Analysis by the academic group policies for the points that need to be
examined other than 3.3 ..................................................................... 58
3.4.1 Details of cost parameters (National Health Insurance Drug Price
Standard of salvage chemotherapy) .................................................... 58[Details of academic analysis (revision)] ............................................. 58
3.4.2 Details of cost parameters (salvage chemotherapy price reference). 61[Details of academic analysis (revision)] ............................................. 61
3.4.3 About the state cost of PFS (Excel) ............................................. 64[Details of academic analysis (revision)] ............................................. 64
4. Analytical results ............................................................................... 65
4.1 Results of analysis by the academic group ........................................ 65
4.1.1 Base case incremental costs, incremental effects, and ICER in analysis
by the academic group ........................................................................ 65
4.1.2 Factors that are not reflected in the analysis by the academic group but
can qualitatively influence the ICER ....................................................... 67
4.2 Sensitivity analysis ........................................................................ 68
4.3 Interpretation of analytical results ................................................... 75
4.4 Price adjustment rate..................................................................... 77
4.4.1 Proportion of patients with ALL and DLBCL ..................................... 77
4.4.2 Proportion of patients with DLBCL ................................................. 77
5. References........................................................................................ 78

3

list of abbreviations
Abbreviations Formal description
AIC

Akaike’s Information Criterion

ALL

Acute Lymphoblastic Leukemia

ASCT

Autologous hematopoietic Stem Cell Transplant

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

C2H

Center for Outcomes Research and Economic Evaluation for HealthCI

Confidence Interval

DLBCL

Diffuse Large B-Cell Lymphoma

EQ-5D

EuroQol 5 Dimension

EQ-5D-5L

EuroQol 5 Dimension 5 Level

HAS

Haute Autorité de SantéHR

Hazard Ratio

HRQL

Health-Related Quality of Life

HSCT

Hematopoietic Stem Cell Transplantation

ICER

Incremental Cost-Effectiveness Ratio

IQWiG

Instituts für Qualität und Wirtschaftlichkeit im Gesundheitswesen

MAIC

Matched Adjusted Indirect Comparison

MSAC

Medical Services Advisory Committee

NA

Not Applicable

NICE

National Institute for Health and Care ExcellenceOS

Overall survival

PAS

Patient Access Schemes

PD

Progressive Disease

PFS

Progression Free Survival

QALY

Quality-Adjusted Life Year

QOL

Quality of Life

4

R-CHOP

Rituximab with Cyclophosphamide, Doxorubicin, Vincristine, andPrednisone

R-DHAP

Rituximab with Dexamethasone, Cisplatin, and Cytarabine

R-GEMOX

Rituximab with Gemcitabine and Oxaliplatin

R-ICE

Rituximab with Ifosfamide, Carboplatin, and Etoposide

RCT

Randomized Controlled Trial

RL

RelapseSCT

Stem Cell Transplant

SMC

Scottish Medicines Agency

SMR

Service Médical Rendu

50. Framework of analysis
Table 0-1 The framework of analysis
Patients with relapsed or refractory CD19-positive diffuse
large B-cell lymphoma (DLBCL) who are divided into the
Population

following age groups:(a) <70 years(b) ≥70 years
Population (a): Salvage chemotherapy +/- allogeneic

comparator

hematopoietic stem cell transplantation (HSCT)
Population (b): Salvage chemotherapy

Reason for
selection ofcomparator
Other perspectivein addition to
public healthcare
payer

Salvage chemotherapy +/- allogeneic HSCT is the standard
and effective for these DLBCL patients. For the population(b), allogeneic HSCT is generally not performed considering
their age. Therefore comparators are determined as above.
Yes(Details: Analysis including productivity loss
(manufacturer analysis only))No

Outcome unit andthe reason if QALY

Not applicable

is not used.

6

1

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

Organizati

Results

on
UK

NICE

SMC

FranceHAS

Manufacturer

Academic analysis

・Recommended/Not

・Recommended/Not recommended/Conditionally

recommended/Conditionally recommended

recommended (Specify: Cancer Drugs(Specify: Cancer Drugs Fund)/Other (Fund)/Other ())

・Status: Final Guidance/Draft/Other

・Status: Final Guidance/Draft/Other

(

(

)

)

・Recommended/Not

・Recommended/Not recommended/Conditionally

recommended/Conditionally recommended

recommended (Specify: Patient Access(Specify:

Schemes)/Other ()/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:

294,381 €/QALY over 10 years)/Under)/Under assessment/Not performed

assessment/Not performed
Germany

IQWiG･ Major/Considerable/Minor/Unquantifiable/No･ Major/Considerable/Minor/Unquantifiable/No

additional benefit

additional benefit

CanadaCADTH・Recommended/Not

・Recommended/Not recommended/Conditionally

recommended/Conditionally recommended

recommended (Specify: reduction in price)/(Specify: On the condition that there is a

/Other (substantial reduction in price)/Other (Australia

MSAC

)

)

・Recommended/Not

・Recommended/Not recommended/Conditionally

recommended/Conditionally recommended

recommended (Specify: risk sharing(Specify:

arrangement)/ Other ()/Other ())

8

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

9

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
Target technology
Results
If conditionally recommended,

Academic analysis

NICE
https://www.nice.org.uk/guidance/ta567

Same as in the left

Tisagenlecleucel

Same as in the left

Conditional recommendation

Same as in the left

Cancer Drugs FundSame as in the left

Adult patients with relapsed or refractory diffuse large B-

Same as in the left

details of the condition
Diseasecell lymphoma (DLBCL) after two or more lines ofsystemic therapy
DosageTreatment with tisagenlecleucel comprises a single-dose

Same as in the left

intravenous infusion. It is intended for autologous use
only and the dosage for adults with diffuse large B-cell
lymphoma is 0.6 to 6.0x108 CAR-positive viable T cells.
Comparator
Incremental cost-effectivenessratio (ICER)Salvage chemotherapy excluding pixantrone

Same as in the left

Company’s base case: (ICER): £46,325

Same as in the left

The committee: ranged between £42,991 and £55,403

10

per QALY gained11

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-resubmission-smc2200/
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

Adult patients with relapsed or refractory diffuse large B-

Same as in the left

details of the condition
Diseasecell lymphoma (DLBCL) after two or more lines ofsystemic therapy
DosageTisagenlecleucel is intended for autologous use only.

Same as in the left

Tisagenlecleucel is to be administered via intravenous
infusion.
The recommended single dose of tisagenlecleucel for
DLBCL patients is 0.6 to 6.0 x 108 chimeric antigen
receptor (CAR)-positive viable T cells (non-weight based).
Comparator
Incremental cost-effectivenessSalvage chemotherapy

Same as in the left

Base-case results – with PAS

Same as in the left

12

ratio (ICER)

Vs [R-]Gem-Ox ICER: £44,330
Vs [R-]GDP ICER: £44,151

13

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

FranceManufacturer

Organization
URLs
Target technology
Results
If conditionally recommended,

Academic analysis

HAS
https://www.has-sante.fr/jcms/pprd_2982962/en/kymriah

Same as in the left

Tisagenlecleucel

Same as in the left

SMR: Important / ASMR: IV

Same as in the left

NA

Same as in the left

Adult patients with relapsed or refractory diffuse large B-

Same as in the left

details of the condition
Diseasecell lymphoma (DLBCL) after two or more lines of systemic
therapy
DosageTreatment with tisagenlecleucel comprises a single-dose

Same as in the left

intravenous infusion of tisagenlecleucel. It is intended forautologous use only and the dosage for adults with diffuse
large B-cell lymphoma is 0.6 to 6.0x108 CAR-positive viable
T cells.
Comparator

Salvage chemotherapy, Yescarta, palliative care, andSalvage chemotherapies

alloSCT if patient eligible



R-DHAP



R-ICE



R-GEMOX

14

Incremental cost-effectivenessNA

294 381 €/QALY over 10 years

ratio (ICER)

15

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/projects-results/projects/health-Same as in the left

economic/g18-10-tisagenlecleucel-diffuse-large-b-celllymphoma-assessment-according-to-35a-para-1-sentence11-social-code-book-v.10620.html
Target technology

Tisagenlecleucel

Same as in the left

Results

Unquantifiable

Same as in the left

NA

Same as in the left

Adult patients with relapsed or refractory diffuse large B-

Same as in the left

If conditionally recommended,details of the condition
Diseasecell lymphoma (DLBCL) after two or more lines of systemic
therapy
DosageTreatment with tisagenlecleucel comprises a single-dose

Same as in the left

intravenous infusion of tisagenlecleucel. It is intended forautologous use only and the dosage for adults with diffuse
large B-cell lymphoma is 0.6 to 6.0x108 CAR-positive viable
T cells.
Comparator

None (reason：orphan designation)

Same as in the left

16

Incremental cost-effectiveness

NA

Same as in the left

ratio (ICER)

17

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

CanadaManufacturer

Organization
URLs

Manufacturer

CADTH
https://cadth.ca/sites/default/files/pdf/car-t/ct0001-

https://cadth.ca/sites/default/fil

op0538-in-brief-e.pdf

es/pdf/car-t/op0538tisagenlecleucel-economicreport-DLBCL-jan2019.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

Adult patients with relapsed or refractory large B-cell

Same as in the left

details of the condition
Diseaselymphoma after two or more lines of systemic therapy
including diffuse large B-cell lymphoma 33 (DLBCL) nototherwise specified, high grade B-cell lymphoma and
DLBCL arising from follicular lymphoma
DosageTisagenlecleucel is recommended as a single, onetime

Same as in the lefttreatment (0.6 to 6.0 x 10 CAR-positive viable T cells).
8Comparator
Incremental cost-effectivenesssalvage chemotherapy

Same as in the left

For r/r DLBCL, tisagenlecleucel, compared with palliative

Same as in the left18

ratio (ICER)

chemotherapy, was associated with an incremental cost per
QALY of CAD$211,870.

19

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/pub

Same as in the left

lishing.nsf/
Content/1519.1-public
Target technology

Tisagenlecleucel

Same as in the left

SupportConditional recommendation

If conditionally recommended,

An initial progress review at Year 1 to

Risk-sharing arrangement

details of the conditionassess appropriateneness of patient

Results

Treatment must be delivered by aeligibility criteria and patient numbers, withhaematologist working in a multi-a full review of clinical effectiveness,disciplinary team specialising in thecosteffectiveness and budget impact to beprovision of CAR-T cell therapy;

conducted by the MSAC no later than 2public hospital with appropriate credentials;

years post the commencement of public
subsidy

Treatment must be delivered in a tertiaryGovernance and prescribing rules to ensure
treatment is directed to patients most likely
to benefit;No payment for tisagenlecleucel for an
unsuccessful infusion;20



No payment for tisagenlecleucel if a patientis apheresed but does not receive theinfusion of engineered lymphocytes;

A limit to one successful CAR-T infusion per
lifetime;

Data on the use of tisagenlecleucel for B
cell lymphoma’s in Australia should berecorded by the Australian Bone Marrow
Transplant Recipient Registry, with the costof data collection met by the applicant



An initial progress review at Year 1 toassess appropriateneness of patienteligibility criteria and patient numbers, witha full review of clinical effectiveness,
costeffectiveness and budget impact to be
conducted by the MSAC no later than 2
years post the commencement of public
subsidy (note: Novartis will provide a
submission to initiate this review)

DiseaseAdult patients with relapsed or refractory

Same as in the left

diffuse large B-cell lymphoma (DLBCL) after
two or more lines of systemic therapy

21

Dosage

0.6 to 6.0 x 108 CAR-positive viable T cells

Same as in the left

(non-weight based)
Comparator

Salvage chemotherapy with the intention to

Salvage chemotherapy regimen

proceed to allo- or auto-SCT
Incremental cost-effectivenessNA

Not disclosed

ratio (ICER)

22

[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.
 For the UK (SMC), there is a discrepancy between Table 1-1 and Table 1-3-2 inthe manufacturer's report. Table 1-3-2 referred to conditional recommendation.
 An ICER was reported for France (HAS). The comparator at this time wassalvage chemotherapy with an ICER of 294,381 €/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.

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
Adult patients with relapsed or refractory DLBCL
However, limited to patients who meet any of the following criteria
and are not indicated for autologous hematopoietic stem cell

Populationtransplantation (ASCT) or relapsed after ASCT:・ Failure to achieve a complete response with chemotherapy orrecurrence with chemotherapy after at least two chemotherapies
in patients with initial disease and at least one chemotherapy
after recurrence in patients with relapsed disease

Intervention
Comparator

The following therapies for the indication in the population:
・ Tisagenlecleucel
Clinically used salvage chemotherapy
Any of the following outcomes:
・ Survival (duration)
Overall survival rate

・ Efficacy
Event-free survival
Disease-free survival
Progression-free survival (PFS)

OutcomeResponse rate
Remission rate
Recurrence rate

・ Safety
Adverse events・

Health-related quality of life (HRQL)

24

・ RCT
Study design

・ Controlled study
・ Single arm study
・ Observational studies in some cohorts of RCTs

LiteraturesearchFrom January 1, 2019 to September 24, 2020

period25

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

Population

Inclusion criteria

Exclusion criteria

・ Adult patients with relapsed

・ Patients with low-grade non-or refractory DLBCL treated

Hodgkin's lymphomawith ≥2 lines of・ Population in which <80%

chemotherapy who have

patients underwent R-CHOP

failed, are ineligible for, or dotherapy

not consent to ASCT・ Patients who meet the・ Non-specified DLBCL,

following criteria

primary mediastinal large B-

Patients with active hepatitis B

cell lymphoma, high-grade B-

infection

cell lymphoma, or DLBCL

Patients with active hepatitis C

arising from follicular

infection

lymphoma

Patients with active human・ ≥80% patients with DLBCL

immunodeficiency virus

arising from DLBCL or

infection

follicular lymphoma if other

Patients with central nervous

histology is included andsystem lesion caused byresults for the DLBCL

malignant tumor

subgroup are not reported
Available therapies
Intervention

Therapies not clinically used
CAR-T therapy other thantisagenlecleucel

Comparator

No restrictions
At least one of the following
outcomes:

Outcome・ Survival (duration)OS

26

・ Efficacy
Event-free survival
Disease-free survival
PFS
Response rate
Remission rate
Recurrence rate・ Frequency and timing ofstem cell transplantation

・ Safety
Adverse events・ Health-related quality of life
(HRQL)・ RCT・ Sample size less than 5・ Controlled study
Study design

・ Single arm study
・ Observational studies insome cohorts of RCTs
・ Research report

・ Abstract

Type of・ Noteliterature

・ Editorial
・ Letter

Language

English or Japanese

2.2.2 Database・ PubMed・ Ichushi

27

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

Serialnumber

Search formula

Population#1"lymphoma, large b-cell, diffuse"[MeSH] OR "lymphoma,
primary cutaneous anaplastic large cell"[MeSH] ORDLBCL OR “Diffuse large B-cell lymphoma” OR((Lymphoma*[TIAB]) AND (diffuse[TIAB] OR "BCell"[TIAB] OR "Large Cell"[TIAB] OR Anaplastic[tiab] OR
Primary[TIAB] OR "Aggressive NHL"[TIAB] OR "nonHodgkin*"[TIAB]))#2

Recurrence[TIAB] OR recurrent[TIAB] OR
recurring[TIAB] OR refractory[TIAB] OR relaps*[TIAB]
OR "R/R"[TIAB] OR fail*[TIAB]

Study
design#3#1 AND #2#4"Clinical Trials as Topic"[Mesh] OR "Clinical Trial" [PT] OR"Randomized Controlled Trials as Topic"[Mesh] OR"Randomized Controlled Trial" [PT] OR "Cross-OverStudies"[Mesh] OR "Prospective Studies"[Mesh] OR
random* OR “random allocation” OR randomized OR
randomised OR “double-blind” OR “singleblind” OR“single blind” OR “double blind” OR “clinical trial” “phase1” OR “phase 2” OR “phase 1/2” OR "phase 1/phase 2"
OR “phase 3” OR “phase 4” OR “Clinical Study”[PT] OR“Clinical Trial, Phase I”[PT] OR “Clinical Trial, PhaseII”[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” OR singlearm 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 non-inferiority OR change OR evaluat*28

OR prospectiv* OR retrospective* OR baseline OR cohort
or consecutive* OR compare* OR compara* OR "caseseries" OR "comparative studies" OR "follow-up studies"
OR registry OR observational
Limitation of#5#3 AND #4

integration#6#5 AND 2019:2020[DP]and search
period29

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

Serialnumber

Search formula

Population#1リンパ腫-びまん性大細胞型 B 細胞性/TH or びまん性大細胞型 B
細胞性リンパ腫/AL or "Diffuse large B-cell lymphoma"/ALor ((リンパ/AL or Lymphoma/AL) and (原発性/AL or
primary/AL or 未分化/AL or anaplastic/AL or 攻撃性/TH or
攻撃性/AL or aggressive/AL or びまん性/AL or diffuse/AL
or B 細胞/TH or B 細胞/AL or B-Cell/AL or "B cell"/AL or
大細胞/AL or "Large Cell"/AL or リンパ腫-非 Hodgkin/TH or
非ホジキン/AL or non-Hodgkin/AL or "non Hodgkin"/AL)#2(再発/TH or 再発/AL or relapse/AL) or (難治性/AL or
refractory/AL) or 失敗/AL

Study design#3#1 AND #2#4

ランダム化比較試験/TH or "randomized controlled trial"/ALor "randomized controlled trials"/AL or ランダム割付け/THor 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"/AL or 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/TH or 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 "Clinicalstudy"/AL or "Clinical studies"/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
非ランダム化/AL 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 of#5#3 AND #4

integration#6#5 AND (DT=2019:2020)and search
period30

2.2.4 OtherNo special notes312.3 Search results
As a result of a SR, JULIET study, a clinical trial of tisagenlecleucel, wasobtained. This literature was also considered in the evaluation of the additional
benefit of manufacturers, and no new qualified literature was obtained toevaluate the additional benefit.
Figure 2-3-1 Flow chart of SR

Identification

Number of literatures identified bydatabase search from 1/1/2019 to
9/24/2020
PubMed: 1,371
Ichushi-web: 5↓
Number of literatures after excluding
duplicates

Number of literatures excluded

→

1,376

from titles and abstracts
1,347

Screening↓
Number of literatures excluded
with the following reasons:

Number of literatures assessed for full
qualification
29

→

28
Study design (7)Population (13)Results not available (8)↓IncludedNumber of literatures adopted
132

[Review on submission by the manufacturer in Chapter 2]
The results of the SR are:□ Completely consistent with those 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 fromto,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 24, 2020).


Differences from the SR performed by the manufacturer (result).
The number of literatures included in the screening differed because thesearch period was different. However there was no difference in the literatures
critical to the evaluation of additional benefit.
Validity of the SR performed by the manufacturer.
It is not appropriate to limit the scope of SR to the Japanese population.

However, the review included all the literatures critical to the evaluation of
additional benefit.

33

2.4 Evaluation of additional benefit
The manufacturer’s explanation about the presence or absence of additional benefit is reasonable for population aged
<70 years and that aged ≥70 years, with additional benefit for the comparator.
Table 2-4-1 Evaluation of additional benefit [Population aged <70 years]
Manufacturer

Academic analysis

Population

DLBCL patients aged <70 years

Same as in the left

Intervention

Tisagenlecleucel

Same as in the left

Comparator

Rescue chemotherapy +/- allogeneic HSCT

Same as in the left

OutcomeOS

Same as in the left

Additional benefit■ additional benefit is shownSame as in the left

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

Additional benefit(Study design) Prospective comparative observational studies
 Indirect comparison of RCT
 Comparison of single-arm studies
 No clinical study data

Same as in the left

The point estimate of conditional HR assumes
The conditional HR (OS) was]) in the MAIC analysis(95% CI: [of the population aged

the OS event is to approximately, which isconsiderably smaller than 1. It is indicated that

Additional benefit<70 years in JULIET Study versus CORAL extension

this product has the number of events(Reason)studies (all patients were aged ≤70 years). Based on

decreased by approximately

these results, it was judged that this product has

upper limit of confidence interval. Therefore theadditional benefit for the comparator.

judgment of manufacturer on additional benefit% even at theis valid.

Table 2-4-2 Evaluation of additional benefit [Population aged ≥70 years]
Manufacturer

Academic analysis

Population

DLBCL patients aged ≥70 years

Same as in the left

Intervention

Tisagenlecleucel

Same as in the left

Comparator

Rescue chemotherapy

Same 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 "Additional benefit

 Meta-analysis of RCTs  Single RCT(Study design) Prospective comparative observational studies

Same as in the left

35 Indirect comparison of RCT
 Comparison of single-arm studies

 No clinical study data
As for the efficacy data in the intervention group

Since the number of patients aged ≥70 years is(tisagenlecleucel), the number of patients aged ≥70

very limited and the number of events is, the academic analysis also

years who correspond to this population is limited toamong patients who received this product in the
JULIET study. In addition, the amount of information

population to evaluate additional benefit in thefor analysis of OS and progression-free survival

population aged ≥70 years.

(number of events by the survival time analysis
method) is
Additional benefit(Reason)supports the use of data from the entire

patients. Originally, the JULIET study was

The point estimate of conditional HR assumes
the OS event is approximately, which isdesigned without assuming analysis by age, resulting

considerably smaller than 1. It is indicated thatin a very small sample size and reduced statisticalthis product has the number of events

power when stratified by age. Therefore, it is difficult

decreased by approximately

to examine the comparability in indirect comparison

upper limit of confidence interval. Therefore theand to adjust the data using statistical methods. Basedjudgment of manufacturer on additional benefit

on the above, it is extremely difficult to judge only theis valid.

% even at theadditional benefit based on the results of extraction ofpatients aged ≥70 years in the JULIET Study. In C2Hof the 3rd meeting of the Expert Committee of CostEffectiveness Evaluation held on

2019, acomment was obtained that if it becomes difficult to36

show the additional benefit by constructing a
subpopulation that was not originally assumed, it isacceptable to refer to the results of the entire
population before segmentation, and in this case, theentire population without age division. The conditional
HR was

(95% CI: []) in the MAIC

analysis (OS) between the entire population in the
JULIET Study and the CORAL extension studies (allpatients were aged ≤70 years). Since the additional
benefit was confirmed by indirect comparison of theentire population, it was judged that this product has
additional benefit for the comparator also for thispatient population.

37

3. Cost-effectiveness analysis by the academic group
3.1 Should the cost-effectiveness analysis submitted by the
manufacturer be reconsidered?
□

Nothing special

☑ Yes

→

Terminated in this section→

Continued 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) Mean age in the target patient population [only in the population aged<70]b) Extrapolation of survival curves (PFS and OS) [only in the population aged
<70 years]c)Data source of survival curves (PFS and OS) for tisagenlecleucel [only inthe population aged ≥70 years]d) QOL scores for PFS

3.2.2 Minor points that need to be reconsidered (other than 3.2.1)
a) Cost parameters (drug prices)b) Cost parameters (salvage chemotherapy)c)

Cost of PFS (Excel model)

393.3 Analysis by the academic group for major points
3.3.1 Mean age in the patient population [only in the population aged
<70 years]
Table 3-3-1-1 Corresponding part of report by manufacturer
In the reports, submitted by the manufacturer
SectionNumber of pages

5.1.4

176

Start line number(or figure/table number)
5[Description of report]
Change in starting age (DLBCL only)
The starting age for the bace case analysis was set at
population to be analyzed aged <70 years andyears for theyears at that aged ≥70

years (Section 5.2). These are the mean age of patients included in thetisagenlecleucel efficacy data by population to be analyzed. In general, theage representative of the patients included in the efficacy data will be used as
the starting age for the analysis in the cost-effectiveness analysis. For the
population to be analyzed aged ≥70 years, we received a comment from C2H
that the starting age for analysis was 70 years in the discussion with C2H
held on2019, and it can be said that the age ofyears is amore conservative setting.
In addition, according to an Internet survey conducted on clinicians by us (fordetails, see 5.1.5), the intention to prescribe CAR-T therapy including
tisagenlecleucel varies greatly by age group, and it is therefore consideredinappropriate to use age composition such as cancer registration data andepidemiological data as the starting age for analysis. As a scenario analysis,
ICER was analyzed when the starting age for analysis was changed (Section
5.1.2).
The mean age of DLBCL patients aged <70 years was calculated from thedata ofwhich was consideredin the scenario analysis. When the starting age was set atyears, there

was no major difference in the results from the base-case. For patients aged40

≥70 years, no scenario analysis has been set because the intention ofprescription is markedly limited, and since the basic analysis was aconservative analysis compared with the patients aged 70 years for which
comments were given by C2H, scenario analysis regarding the starting age
has not been performed.
[Details of academic analysis (revision)]
The mean age of the population in the base-case analysis was changed to 57
years instead ofyears. It was higher than that used by the manufacturer(early 50s).
The manufacturer used the mean age of the population enrolled in the clinicalstudies. However the characteristics of patients enrolled in the clinical studies
are not consistent with those of patients treated with tisagenlecleucel in theactual clinical practice. Therefore, the mean age of the patient with DLBCL aged
<70 who underwent autologous transplantation was estimated by the following
procedures, usingNDB；National Database of Health Insurance Claims andSpecific Health Checkups of Japan. In principle, the patients treated withtisagenlecleucel have undergone autologous transplantation. Therefore, the ageof patients estimated from the claim database is more appropriate. This value isalso consistent with the mean age based on data from
submitted by the manufacturer.
Table 3-3-1-2 Changes of the starting age

Starting age

Manufacturer’s

Academic

submission

analysis
57[Estimation method and results based on the claims database]
Patients aged <70 years with DLBCL-related disease name (International
Classification of Diseases-10 code: C833) between October 2018 and
September 2019 were included. The month when the autologous transplantrelated claim code (hematopoietic stem cell transplantation [bone marrowtransplantation] [autologous transplantation]: 150266410, hematopoietic stem
cell transplantation [peripheral blood stem cell transplantation] [autologous
41

transplantation]: 150266310) is included in the patients was defined as themonth when the stem cell transplantation was performed in the DLBCL patient.
The age was estimated from the age class recorded in this month (5-yearincrements). The mean age was calculated by multiplying the frequency foreach class by the class value and dividing by the number of patients. The
median was also calculated.
As a result, 380 patients were included (the table below). Mean and medianage were 56.8 and 57.0 years, respectively.
Table 3-3-1-3 Number of patients by age classAge classn%

0 to 39 years old*

24

6.3%

40-44

15

3.9%

45-49

28

7.4%

50-54

56

14.7%

55-59

67

17.6%

60-64

114

30.0%

65-69

76

20.0%

Total

380

100.0%*For the age of 0 to 39 years, a total value is shown because there are cells inwhich the number of patients is less than 10.

42

3.3.2 Extrapolation of survival curves (PFS and OS) [only in the
population aged <70 years]
Table 3-3-2-1 Corresponding part of report by manufacturer
In the reports, etc. submitted by the manufacturer
SectionNumber of pages

4.2.1.2

101-103

Start line number(or figure/table number)
Figure 27, 28[Description of report]
Estimation of survival curve (OS)The OS associated with tisagenlecleucel infusion was based on the data fromthe JULIET trial among patients <70 years (data cut-off:). It wasdefined as starting from the time of infusion per JULIET trial protocol. The OS
for patients in the tisagenlecleucel arm but not infused was the same as thatof the salvage chemotherapy. The OS associated with salvage chemotherapy
was derived from the published Kaplan-Meier (KM) curves in the CORAL
extension studies, and was defined from the time of last relapse.[11], [12]CORAL is considered to be more appropriate for this age-specific populationgroup since all patients are less than 70 years old. Pseudo-patient level data
were then derived based on the KM data using the algorithm outlined in
Guyot et al. 2012.[35] The number of event information was incorporated
into the reconstruction of individual patient data (IPD).
For both tisagenlecleucel infused patients and salvage chemotherapy, theobserved OS were used during the trial period until year 3. Afterwards, those
who remained alive were assumed long-term survivors of DLBCL. Maurer etal., 2014 identified “patients with DLBCL who achieve event-free status at 24
months (EFS24) have a subsequent overall survival equivalent to that of theage- and sex-matched general population”, based on prospective patientdata. The assumption of 3 years as a cure point is considered moreconservative.[42] The long-term DLBCL survival was modelled using the 2018
Japan life table, with a mortality adjustment using the standardized mortality
ratio (SMR) of DLBCL longterm survivors published in literature.[38], [42]43The same mortality risk was applied to all patients who remained alive fromyear 3 onwards in the model. This assumption reduced some of the long-term
uncertainties arising from data extrapolation beyond the maximum reported
follow-up. A targeted literature review was conducted to identify publications
to inform long-term survival for the study population (registry or SMR
studies). Maurer et al., 2014 was identified as the most relevant input source
and used to inform the mortality of long-term DLBCL survivors.[42]The predicted OS curves for tisagenlecleucel and salvage chemotherapy in thebase-case analysis are reported in Figure 27.
Estimation of survival curve (PFS)The PFS of tisagenlecleucel infused patients was based on the data from the
JULIET trial (data cut-off:) among patients <70 years. To beconsistent with the approach used for the OS estimation, observed data wereused during the trial period until year 3. After year 3, the cumulative survival
probabilities of PFS were assumed to flatten up until they reached OS. PFS
was assumed to be less than or equal to OS at all time points. The PFS for
patients in the tisagenlecleucel arm but not infused was the same as that of
the salvage chemotherapy.
PFS data for salvage chemotherapy were not available in the literature. In theabsence of data, the PFS curve was derived from the OS curve assuming a
constant cumulative HR over time, i.e., the cumulative hazard function for
PFS would be proportional to cumulative hazard function for OS. The ratio
was based on the (R)-ICE and (R)-DHAP arms from Gisselbrecht et al.
2010.[43] To estimate an overall cumulative HR between OS and PFS, theratio was first estimated as the natural log of OS probability divided by thenatural log of PFS probability at yearly intervals until the end of the observed
period. The overall cumulative HR between OS and PFS was then calculated
as the average of cumulative HRs at all yearly intervals. This assumption isjustifiable on the basis that PFS is highly correlated with OS.[44] The
predicted PFS curves for tisagenlecleucel and salvage chemotherapy in thebase-case analysis are reported in Figure 28.
[Details of academic analysis (revision)]
According to the manufacture’s analysis, after three years (cure point) the OS
44

function was extrapolated using mortality rate which was estimated bymultiplying SMR (standardized mortality ratio) of the long survivor by mortality
rate of general people. However, this extrapolation cannot consider excess
mortality in PD/RL patients, and the OS was overestimated. Therefore, thiscannot be regarded as an appropriate OS extrapolation. For example, the life
expectancy of the PD/RL patient after 3 years was approximately 10 years ormore in the population aged <70 years.
In addition, the PFS function was extrapolated by a horizontal line (y=C; C isa constant) assuming that no event occurs. However, even the patients withPFS should experience events such as death due to other causes. Death events
that are reflected in OS should be handled as events in PFS. Such extrapolationof EFS function is not appropriate.
In the manufacturer’s response to our inquiry (dated2020), it was

described "After 3 years of treatment with Kymriah, long-term survival (cure)
was assumed, and the subsequent OS was extrapolated using the SMR ofMaurer et al. in 2014.". The fact that long-term survival (cure) can be achievedby tisagenlecleucel was acceptable. This could be achieved by the "absence ofrecurrence (after the 3rd year)". It did not justify the extrapolation of the EFS
curve after the 3rd year (cure point) by the horizontal line. It is not also
appropriate that the OS curve extrapolation method is changed when the 5thyear started.
The OS function was extrapolated using the parametric function estimated by
the manufacturer when the Kaplan-Meier curve is interrupted (the Cycle 37
after the 3rd year (Cycle 36)). The manufacturer did not use a parametricfunction to estimate survival time curves for DLBCL population. Therefore, byextrapolating the integrated function by weighting each parametric function
based on the weighted AIC, we estimate OS curve.
It does not actually occur that the mortality rate estimated by the parametric
OS function is smaller than the SMR-based mortality rate by the manufacturer.
If such case occurs, the OS function was extrapolated by switching the curve tothe mortality rate based on the SMR at the time point.
The PFS function was extrapolated after the Cycle 37 year using thestandardized mortality ratio used by the manufacturer to account for the deaths
other than other disease. However, if the OS and PFS functions crossed, the OS
function was also extrapolated using the PFS function estimation method.

45

46

Table 3-3-2-2 Estimated life years
Manufacturer’s submission(starting age:

Academic analysis (starting age:years)

57 years)

Tisagenlecleucel

SalvageTisagenlecleucel

Salvagegroup

chemotherapy

groupchemotherapy+/- allogeneic+/- allogeneic

HSCT group

HSCT group

Life years
PFS
PD/RL

47

Figure 3-3-2-1 Estimated survival curve by manufacturer for thetisagenlecleucel group

Figure 3-3-2-2 Estimated survival curve by academic analysis for thetisagenlecleucel group48

Figure 3-3-2-3 Estimated survival curve by manufacturer for salvage
chemotherapy +/- allogeneic HSCT group

Figure 3-3-2-4 Estimated survival curve by academic analysis forsalvage chemotherapy +/- allogeneic HSCT group49

3.3.3 Data source of survival curves (PFS and OS) for tisagenlecleucel[only in the population aged ≥70 years]
Table 3-3-3-1 Corresponding part of report by manufacturer
In the reports, etc. submitted by the manufacturer
SectionNumber of pages

4.2.1.3

103-105

Start line number(or figure/table number)
Figure 29, 30[Description of report]
Estimation of survival curve (OS)The OS associated with tisagenlecleucel infusion was based on the data fromthe JULIET trial among patients ≥70 years (data cut-off:).[29] It

was defined as starting from the time of infusion per JULIET trial protocol.
The OS for patients in the tisagenlecleucel arm but not infused was the sameas that of the salvage chemotherapy. The OS associated with salvage
chemotherapy was derived from the published Kaplan-Meier (KM) curves forpatients without subsequent SCT in the CORAL extension studies, and was
defined from the time of last relapse.[11], [12] Pseudo-patient level data
were then derived based on the KM data using the algorithm outlined in
Guyot et al. 2012.[35] The number of event information was incorporated
into the reconstruction of individual patient data (IPD). For bothtisagenlecleucel infused patients and salvage chemotherapy, theobserved OS were used during the trial period until year 3. Afterwards, those
who remained alive were assumed long-term survivors of DLBCL. Maurer etal., 2014 identified “patients with DLBCL who achieve event-free status at 24
months (EFS24) have a subsequent overall survival equivalent to that of theage- and sex-matched general population”, based on prospective patientdata. The assumption of 3 years as a cure point is considered moreconservative. The longterm DLBCL survival was modelled using the 2018
Japan life table, with a mortality adjustment using the standardized mortality
ratio (SMR) of DLBCL longterm survivors published in literature.[38], [42]The same mortality risk was applied to all patients who remained alive from50

year 3 onwards in the model. This assumption reduced some of the long-term
uncertainties arising from data extrapolation beyond the maximum reported
follow-up. A targeted literature review was conducted to identify publications
to inform long-term survival for the study population (registry or SMR
studies). Maurer et al., 2014 was identified as the most relevant input source
and used to inform the mortality of long-term DLBCL survivors.[42] The
predicted OS curves for tisagenlecleucel and salvage chemotherapy in thebase-case analysis are reported in Figure 29.
Estimation of survival curve (PFS)The PFS of tisagenlecleucel infused patients was based on the data from the
JULIET trial (data cut-off: July 1, 2019) among patients ≥70 years.[29] To beconsistent with the approach used for the OS estimation, observed data wereused during the trial period until year 3. After year 3, the cumulative survival
probabilities of PFS were assumed to flatten up until they reached OS. PFS
wasassumed to be less than or equal to OS at all time points. The PFS

for patients in the tisagenlecleucel arm but not infused was the same as thatof the salvage chemotherapy. PFS data for salvage chemotherapy were notavailable in the literature.[11], [12] In the absence of data, the PFS curve
was derived from the OS curve assuming a constant cumulative HR overtime, i.e., the cumulative hazard function for PFS would be proportional tocumulative hazard function for OS. The ratio was based on the (R)-ICE and(R)-DHAP arms from Gisselbrecht et al. 2010.[43] To estimate an overall
cumulative HR between OS and PFS, the ratio was first estimated as thenatural log of OS probability divided by the natural log of PFS probability atyearly intervals until the end of the observed period. The overall cumulative
HR between OS and PFS was then calculated as the average of cumulative
HRs at all yearly intervals. This assumption is justifiable on the basis that PFS
is highly correlated with OS.[44] The predicted PFS curves fortisagenlecleucel and salvage chemotherapy in the base-case analysis arereported in Figure 30.
[Details of academic analysis (revision)]
In analyzing the population aged ≥70 years, the manufacturer estimated OS
and PFS functions using the data of patients aged ≥70 years in the JULIET51

Study. However, the proportion of the population aged ≥70 years in the JULIET
Study was only%(), which was% of the entire

population.
As a result, the OS in the population aged ≥70 years waswhich is more than(% at 3 years,% higher than the OS in the population aged <70 years%) and the OS in the entire population (the population aged ≥70 years was%). In addition, the PFS in% at 3 years, which is more thandifferent from the PFS in the population aged <70 years (in the entire population (%%) and the PFS%).

However, it is not appropriate to use the data of small population that issensitive to random error, unless there is evidence to support that older patientis associated with a greater effect of tisagenlecleucel. Therefore, it is more
appropriate to analyze the population aged ≥70 years using the data of theentire population by assuming that there is no heterogeneity with the treatment
effect in the entire population. The manufacturer uses the entire population toshow additional benefit of population aged ≥70 years as follows;"Among patients who received this product in the JULIET Study, only
patients aged ≥70 years correspond to this population. In addition, the amountof information for analysis of OS and progression-free survival (number of
events by the survival time analysis method) is

patients. (...) For the above

reasons, it is extremely difficult to judge only the additional benefit based on
the results of extracting only the patients aged ≥70 years in the JULIET study."
Only in the estimation of cost-effectiveness, it is inconsistent that limited dataof patients aged ≥70 years is used..
For the OS and PFS functions through the 3rd year (Cycle 36), theparameters used by the manufacturer in each population shall be weighted by
the sample size for each population (aged <70 years,); aged ≥70 years,

and pooled, as we don’t have the data of entire population.
Thereafter, the OS and PFS functions were extrapolated in the same manneras Section 3.3.2. However, in and after Cycle 37, the parametric function of OS
based on the entire population results in the JULIET Study is not included in the
documents/data submitted by the manufacturer. Therefore, the OS function to
be used for extrapolation shall be estimated by weighting the function52

estimated from the population aged <70 years (weighted AIC) and the function
estimated from the population aged ≥70 years (weighted AIC), respectively.
This shall be extrapolated in and after Cycle 37 of the OS function.
Table 3-3-3-2 Estimated life years
Manufacturer’s submission

Academic analysis

Tisagenlecleucel

SalvageTisagenlecleucel

Salvagegroup

chemotherapy

groupchemotherapy

group

group

Life years
PFS
PD/RL

53

Figure 3-3-3-1 Estimation of survival time curve by manufacturer forthe tisagenlecleucel group

Figure 3-3-3-2 Estimation of survival time curve by academic analysis
for the tisagenlecleucel group

54

Figure 3-3-3-3 Estimation of survival time curve by manufacturer forsalvage chemotherapy group

Figure 3-3-3-4 Estimation of survival time curve by academic analysis
for salvage chemotherapy group55

3.3.4 QOL scores for PFS
Table 3-3-4-1 Corresponding part of report by manufacturer
In the reports, etc. submitted by the manufacturer
SectionNumber of pages

4.2.2.2

107

Start line number(or figure/table number)Table 4.2.2.2[Description of report]
Health states utility
Because JULIET data did not collect EQ-5D data directly, a targeted literature
review was conducted to identify publications that report quality-of-life
measures for the population. The utility inputs used in the base-case wereobtained from Chen et al. 2017, where micro-simulation models weredeveloped to study the cost-effectiveness of precision treatment strategies for
DLBCL patients.[33]These inputs were also used in the most recent CEA model of CAR-T therapies
for the adult lymphoma population developed by the Institute for Clinical andEconomic Review. In the DSA, an alternative set of utility values wereconsidered based on SF-36 data collected from the JULIET data. A mapping
algorithm was used to convert the SF-36 data to derive the utility measures.
[Details of academic analysis (revision)]
The manufacturer used 0.83 as a QOL score for PFS. However, this PFS value
is almost the same as the population norms of EQ-5D-5L in patients aged ≥70
years (male: 0.866, female: 0.828) shown by Shiroiwa et al.[1]. It is possiblethat QOL scores after the age of 70 may be overestimated.
For this reason, the academic analysis used 0.70, which reflects the actual
status more based on Lin JK et al.[2] for the patients with PFS and age of 70
years or older. Therefore, for the population aged <70 years, the QOL score of
PFS was set as 0.70 when they reach to 70 years old (if the starting age wasset at 57 years, Cycle 156). For the population aged ≥70 years, the QOL scoreof PFS was set as 0.70 from Cycle 0 because the starting age wasyears.
56

Table 3-3-4-2 QOL scores in PFS
Manufacturer’s

Academic analysis

submission
Population aged <70
years

0.83 (total time

0.83 (time horizon up to age ofhorizon)<70 years)
0.70 (time horizon after age of
70 years)Population aged ≥70
years

0.83 (total time

0.70 (total time horizon)

horizon)57

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, etc. submitted by the manufacturer
SectionNumber of pages

4.2.3

108

Start line number(or figure/table number)
22[Description of report]
For both B-ALL and DLBCL diseases, the costs for the target technology to beanalyzed and the comparator were estimated by the accumulation 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’s analysis,
particularly the price of medicines for the salvage chemotherapy, is notconsistent with the latest drug prices.
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, 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).”Analysis by the academic group shall be performed using the latest drug price(as of April 2020) [3]. For dexamethasone (oral) and prednisone (oral), thecited product is also inappropriate (originally, injection shall be used), so therevision was shown in Section 3.4.2.

58

Table 3-4-1-2 Drug prices that need to be changed

Drug nameName of product considered

Drug price

Drug priceto be quoted by the(before(aftermanufacturerchange)change)4,172.0

3,680.0yenyen

2,997.0

2,865.0

yen

yen

Etoposide

VePesid Injection 100 mg 5 mL

Ifosfamide

Ifomide for Injection 1 g

Carboplatin

Rituximab

Gemcitabine

Paraplatin Injection 450 mg 45

24,464.0

mL

yen

Rituxan Intravenous Infusion

157,855.0

148,996

500 mg 50 mL

yen

yen

Gemcitabine for I.V. Infusion 1

8,495.0g/25 mL "Sandoz" etc.

yen

Dexamethasone

Decadron Injection 6.6 mg 2

(oral)

mL

CisplatinNA

Cisplatin Intravenous Drip

7,099.0

3,874.0

Infusion 50 mg “Pfizer” 100 mL

yen

yen

1,769.0

1,732.0yen

yen

Cytarabine for I.V. Infusion 1 g

5,156.0

4,715.0"TEVA"

yen

yen

314.0 yen299.0 yen

1,254.0

1,277.0yen

yen

4,351.0

3,957.0

yenyen

2,638.0

2,521.0

yenyen

167.0 yenNA

Succinate for Injection 100 mg
AFP 1 gCytarabine

Dexamethasone

Cyclophosphamide

Decadron Injection 6.6 mg 2
mL
Endoxan for Injection 500 mg
Doxorubicin Hydrochloride

Doxorubicin

7,180 yen314.0 yen

Methylprednisolone Sodium
Methylprednisolone

21,155 yen

Injection 50 mg "Sandoz" 25
mL etc.

Vincristine

Oncovin for Injection 1 mg

Prednisone (oral)

Prednisolone Sodium Succinate

59

for Injection 20 mg “F” etc.

60

3.4.2 Cost parameters (salvage chemotherapy)
Table 3-4-2-1 Corresponding part of report by manufacturer
In the reports, etc. submitted by the manufacturer
SectionNumber of pages

4.2.3.2

127-132

Start line number(or figure/table number)Table 28

[Description of report]
Salvage chemotherapy cost
Because there is no consensus on a standard regimen for salvage
chemotherapy in r/r DLBCL and CORAL extension studies did not reportspecific regimens, the treatment cost of salvage chemotherapy was estimatedas the average of five different chemotherapy regimens suggested by key
opinion leaders in Japan, including (R)-ICE, (R)-GDP, (R)-ESHAP, (R)-DHAP,and (R)-EPOCH. In the basecase, it was assumed that all patients received
the treatments in combination with rituximab. Drug acquisition costs were
calculated as a function of unit drug costs, dosing, administration cost, andtreatment duration. The treatment cost and administration cost of salvage
chemotherapy were obtained from the official gazette released by MHLW. For(R)-ICE dosing schedules and cycles were from Kewalramani 2004.[55] For(R)-GDP dosing schedules and cycles were from Crump 2004.[56] For (R)ESHAP dosing schedule was from Martin 2008, and dosing cycles were from
National Guideline Alliance 2016.[22], [57] For (R)-DHAP dosing schedules
and cycles were from Oki 2008.[58] For (R)-EPOCH dosing schedule andcycles were from Jermann 2004.[59][Details of academic analysis (revision)]
Although dexamethasone used in (R)-GDP therapy and prednisone used in(R)-EPOCH therapy are both oral drugs, the prices of injections were referred toin the manufacturer’s submission. It is necessary to re-calculate with the pricesof oral drugs using the latest one (April 2020) [3]. The daily dose wascalculated based on body surface area offor the population aged <70

61years andfor the population aged ≥70 years, and the corresponding

number of tablets required per day was calculated.
Table 3-4-2-2 Drug prices need to be changed
Brand name in the
Drug namemanufacturer’s

Replacing

Drug pricebrand namesubmission
Dexamethasone(oral)

Decadron
Phosphate Injection

JPY 314.0

6.6 mg 2 mL

Drug price

LenaDex

JPY 172.1

Tablets 4mg/tabletRrednisolone

JPY 9.8

Tablets 5 mg

/tabletPrednisolone
Prednisone

Sodium Succinate(Oral)

for Injection

JPY 167.0

20 mg “F”, etc.

Table 3-4-2-3 Number of tablets in the population aged <70 years
Daily dose
Drug name

Replacing

Dose per(calculated based

brand nametableton body surface
area of

Dexamethasone

LenaDex(oral)

Tablets 4mg

Prednisone

Rrednisolone(Oral)

Tablets 5 mg

4 mg/tablet

5 mg/tablet)

Number oftablets per
day

40 mg

40/4 = 10=

120/5 =

60×

≒ 120 mg

24

Table 3-4-2-4 Number of tablets in the population aged ≥70 years
Daily dose
Drug name

Replacing

Dose per(calculated based

brand nametableton body surface
area of

Dexamethasone

LenaDex

4 mg/tablet

40 mg

)

Number oftablets perday
40/4 = 1062

(oral)Tablets 4mg

Prednisone

Rrednisolone(Oral)

Tablets 5 mg

5 mg/tablet

60×=≒ 110 mg110/5 =
2263

3.4.3 Cost of PFS (Excel model)
Table 3-4-3-1 Corresponding part of report by manufacturer
In the reports, etc. submitted by the manufacturer
SectionNumber of pages

Excel modelTrace sheet

Start line number(or figure/table number)
NA[Description of report]
NA[Details of academic analysis (revision)]As the monthly cost for PFS, different values have to be used for (a) the firstyear, (b) the second year, (c) the third to fifth years, and (d) the sixth year andthereafter. However, in the Excel file submitted by the manufacturer, themonthly cost for the third year was referred to as the costs for the second year.
Accordingly, the monthly cost to be used for the second year was JPY 1,036 forthe tisagenlecleucel group and JPY 383 for the comparator group .

64

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 <70 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 8,084,464/QALY compared with salvage
chemotherapy +/- allogeneic HSCT, 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

5.70

Comparator

2.46

Incremental
effectiveness

Cost (JPY)(QALY)
3.23

37,362,788

Incremental

ICER

cost (JPY)(JPY/QALY)

17,649,143

5,459,234

19,713,646

65

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

Effectiveness(QALY)
Tisagenlecleucel

4.16

Comparator

1.56

Incremental
effectiveness

Cost (JPY)(QALY)
2.60

33,423,970

Incremental

ICER

cost (JPY)(JPY/QALY)

20,991,305

8,084,464

12,432,665(b) Population aged ≥70 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 12,538,653/QALY compared with salvage
chemotherapy.
Table 4-1-1-3 Base case analysis by the analysis by manufacturer

Effectiveness(QALY)
Tisagenlecleucel

3.64

Comparator

1.16

Incremental
effectiveness

Cost (JPY)(QALY)
2.47

21,450,349

Incremental

ICER

cost (JPY)(JPY/QALY)

12,934,205

5,231,584

8,516,144

66

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

Effectiveness(QALY)
Tisagenlecleucel

2.16

Comparator

0.92

Incremental
effectiveness

Cost (JPY)(QALY)
1.24

24,112,176

Incremental

ICER

cost (JPY)(JPY/QALY)

15,548,531

12,538,653

8,563,645

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

674.2 Sensitivity analysis(a) Population aged <70 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 QOL of PFS,
assuming the value 0.70 continued from the starting age (57 years). Next, thebest-case and worst-case fitting to OS curve was applied. As a result, ICER was
lower than JPY 7.5 million JPY/QALY when QOL score of PFS was increased by
10%. This parameter was associated with large uncertainty.

68

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

Range of parameters

Rationale for setting

Lower limit

Upper limit<70 years:<70 years:

0.747

0.913

≥70 years:≥70 years:

0.63

0.77

(-10%)(+10%)

0.351

0.429

The life years of PD/RL varied in(-10%)(+10%)

analysis by the academic group.

Salvage chemotherapy

897,490

1,495,816

price(-25%)(+25%)QOL scores in PFS

QOL scores in PD/RL

ICER range (JPY/QALY)
Lower limit

Upper limit

7,336,913

9,001,632

8,052,054

8,117,135

8,024,502

8,144,426

6,021,582

10,344,761

The influence on ICER is large among
the parameters of the one-way
sensitivity analysis performed by the
manufacturer

The value of salvage chemotherapy
varied in analysis by the academic
group.
The influence on ICER is large among

Discount rate

0%

4%

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

Table 4-2-2 Scenario analysis: 0.70 continues as QOL score of PFS fromthe starting age (57 years)

Effectiveness(QALY)
Tisagenlecleucel

3.79

Comparator

1.42

Incremental
effectiveness

Cost (JPY)(QALY)
2.36

33,423,970

Incremental

ICER

cost (JPY)(JPY/QALY)

20,991,305

8,880,499

12,432,665

Table 4-2-3 Scenario analysis: Exponential curve was fitted OS function
in both groups (the prognosis of PD/RL was assumed to be the mostpessimistic)

Effectiveness(QALY)
Tisagenlecleucel

4.08

Comparator

1.32

Incremental
effectiveness

Cost (JPY)(QALY)
2.76

32,140,264

Incremental

ICER

cost (JPY)(JPY/QALY)

23,598,799

8,555,809

8,541,465

Table 4-2-4 Scenario analysis: Exponential curve was fitted to OS
function only in the tisagenlecleucel group (when the prognosis of
PD/RL was assumed to be the most pessimistic)
EffectIncremental(QALY)

effect (QALY)

Tisagenlecleucel

4.15

2.59

Comparator

1.56

Cost (JPY)
33,252,035

Incremental

ICER

cost (JPY)(JPY/QALY)

20,819,370

8,051,277

12,432,665

Table 4-2-5 Scenario analysis: Gompertz curve was fitted to in bothgroups (when the prognosis of PD/RL was assumed to be the mostpessimistic)Effectiveness(QALY)
Tisagenlecleucel

4.42

Comparator

1.75

Incremental
effectiveness

Cost (JPY)(QALY)
2.66

37,594,880

Incremental

ICER

cost (JPY)(JPY/QALY)

22,077,347

8,287,742

15,517,533

Table 4-2-6 Scenario analysis: Gompertz curve was fitted to OS
function only in the tisagenlecleucel group (when the prognosis of
PD/RL was assumed to be the most optimistic)

Effectiveness(QALY)
Tisagenlecleucel

4.36

Comparator

1.56

Incremental
effectiveness

Cost (JPY)(QALY)
2.80

36,713,489

Incremental

ICER

cost (JPY)(JPY/QALY)

24,280,824

8,670,069

12,432,665(b) Population aged ≥70 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 best-case and worst-case fitting to OS curve was applied. As a result, there
was no parameters which ICER was decreased to less than JPY 11.25 million.
.

71

Table 4-2-7 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

11,336,812

14,025,531

12,456,644

12,621,749

12,450,980

12,626,326

10,321,473

14,858,393

The influence on ICER is large
QOL scores in PFS

0.63

0.77

among the parameters of the one-(-10%)(+10%)

way sensitivity analysis performedby the manufacturer

0.351

0.429

The life years of PD/RL varied in(-10%)(+10%)

analysis by the academic group.

Salvage chemotherapy

895,309

1,492,181

price(-25%)(+25%)QOL scores in PD/RL

The value of salvage chemotherapy
varied in analysis by the academic
group.
The influence on ICER is large

Discount rate

0%4%among the parameters of the oneway sensitivity analysis performedby the manufacturer

Table 4-2-8 Scenario analysis: Exponential curve was fitted OS function
in both groups (the prognosis of PD/RL was assumed to be the mostpessimistic)

Effectiveness(QALY)
Tisagenlecleucel

2.02

Comparator

0.66

Incremental
effectiveness

Cost (JPY)(QALY)
1.36

21,875,005

Incremental

ICER

cost (JPY)(JPY/QALY)

17,561,781

12,866,493

4,313,224

Table 4-2-9 Scenario analysis: Exponential curve was fitted to OS
function only in the tisagenlecleucel group (when the prognosis of
PD/RL was assumed to be the most pessimistic)
EffectIncremental(QALY)

effect (QALY)

Tisagenlecleucel

2.16

1.23

Comparator

0.92

Cost (JPY)24,000,216
8,563,645

Incremental

ICER

cost (JPY)(JPY/QALY)

15,436,571

12,518,404

Table 4-2-10 Scenario analysis: Gompertz curve was fitted to in bothgroups (when the prognosis of PD/RL was assumed to be the mostpessimistic)
Effectiveness(QALY)
Tisagenlecleucel

2.28

Comparator

0.98

Incremental
effectiveness

Cost (JPY)(QALY)
1.30

26,079,232

Incremental

ICER

cost (JPY)(JPY/QALY)

16,528,684

12,706,111

9,550,548

Table 4-2-11 Scenario analysis: Gompertz curve was fitted to OS function
only in the tisagenlecleucel group (when the prognosis of PD/RL wasassumed to be the most optimistic)

Effectiveness(QALY)
Tisagenlecleucel

2.25

Comparator

0.92

Incremental
effectiveness

Cost (JPY)(QALY)
1.33

25,585,780

Incremental

ICER

cost (JPY)(JPY/QALY)

17,022,135

12,784,609

8,563,645

74

4.3 Interpretation of analytical results(a) Population aged <70 years
Among the patients with relapsed or refractory CD19Population

positive diffuse large B-cell lymphoma, the population aged
<70 years

Comparator

Salvage chemotherapy +/- allogeneic HSCT

Type 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 results of base csae analysis showed the ICER of JPY

Reason for such
judgment

8,084,464 /QALY. Since the results of the one-way
sensitivity analysis showed similar tendency, it is most likelythat the ICER belongs to the interval of “more than JPY 7.5
million and not more than JPY 11.25 million”.

75

(b) Population aged ≥70 years

Population to beanalyzed

Among the patients with relapsed or refractory CD19positive diffuse large B-cell lymphoma, the population aged
≥70 years

Comparator

Salvage chemotherapy

Reference value□ Regular product ☑ Product requiring special

for ICER

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 results of base case analysis showed the ICER of

Reason for such
judgment

12,538,653 JPY/QALY. Since the results of the one-way
sensitivity analysis showed similar tendency, it is most likelythat the ICER belongs to the interval of “more than 11.25
million JPY and not more than 15 million JPY”.

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 not enough time since the recent
launch of tisagenlecleucel. This estimate by the manufacturer is acceptable tothe academic group. Therefore% is used as the proportion of patients withALL.
4.4.2 Proportion of patients with DLBCLThe populations include two patient groups with <70 years of age and ≥ 70
years of age. It is necessary to calculate the weight for each price adjustmentrate. The manufacturer has submitted survey data fromfor the proportion of age groups (every 5 years of age)considering administration of CAR-T therapy. This estimation shows that the
proportion of patients decreased as age increased, and the proportion ofpatients aged <70 years versus ≥70 years is% and%, respectively. Thisestimate by the manufacturer is acceptable to the academic group. Therefore it
is appropriate to use% and% as the proportion of patients with DLBCL ineach population.

77

5. References[1] 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.
[2] Lin JK, Muffly LS, Spinner MA, Barnes JI, Owens DK, Goldhaber-Fiebert JD.
Cost Effectiveness of Chimeric Antigen Receptor T-Cell Therapy in Multiply
Relapsed or Refractory Adult Large B-Cell Lymphoma. J Clin Oncol. 2019
Aug 20;37(24):2105-19.
[3] Ministry of Health, Labour and Welfare, "List of Products Included in the NHIPrice List and Information on Generic Drugs (applied on August 26,
2020)"[Online] Available:
https://www.mhlw.go.jp/topics/2020/04/tp20200401-01.html. [Accessed:
2020 Sep 30].

78