【キムリア点滴静注】に関する費用対効果評価 [第 1.1 版]【提出者名】ノバルティス ファーマ株式会社【提出日】 2020 年 2 月 21 日(第 1.0 版の提出日【2020 年 2 月 14 日】)

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【目次】

0. 要旨 ...................................................................................................5
1. 対象となる医薬品･医療機器の性質 ............................................................. 13
1.1 名称 ............................................................................................. 13
1.2 保険償還価格 ................................................................................. 13
1.3 治療効果のメカニズム ........................................................................ 13
1.4 対象疾患 ....................................................................................... 13
1.5 使用方法等 .................................................................................... 16
1.6 対象疾患の治療における当該医薬品･医療機器の位置づけ ............................. 18
1.7 主な有害事象 .................................................................................. 22
1.8 他国の医療技術評価機関における評価結果 ............................................... 23
2. 費用効果分析における分析条件の設定......................................................... 34
2.1 分析対象とする集団 .......................................................................... 34
2.2 比較対照 ....................................................................................... 35
2.3 分析の立場と費用の範囲 .................................................................... 38
2.4 効果指標 ....................................................................................... 38
2.5 分析期間 ....................................................................................... 38
2.6 割引率.......................................................................................... 38
2.7 分析条件の設定の要約 ...................................................................... 39
3. 追加的有用性 ...................................................................................... 41
3.1 クリニカルクエスチョン ......................................................................... 41
3.1.1 B-ALL ..................................................................................... 41
3.1.2 DLBCL .................................................................................... 42
3.2 システマティックレビュー ....................................................................... 44
3.2.1 B-ALL ..................................................................................... 44
3.2.2 DLBCL .................................................................................... 54
3.3 クリニカルクエスチョン(異なる比較対照あるいは単群試験) [該当する場合のみ] ..... 61
3.4 システマティックレビュー (異なる比較対照あるいは単群試験) [該当する場合のみ] .. 61
3.5 既存データの再解析 .......................................................................... 62
3.6 メタアナリシスの詳細 [該当する場合のみ] ............................................... 62
3.7 間接比較やネットワークメタアナリシスの結果 [該当する場合のみ] ..................... 62
3.7.1 B-ALL: Kymriah(tisagenlecleucel) vs. Blinatumomab ..................... 62
3.7.2 B-ALL: Kymriah (tisagenlecleucel) vs. Inotuzumab........................ 652

3.7.3 DLBCL: Kymriah(tisagenlecleucel) vs. Salvage Chemotherapy +/- HSCT..................................................................................................... 66
3.8 追加的有用性の有無に関する評価 ......................................................... 70
4. 分析方法の詳細 ................................................................................... 73
4.1 分析方法 ....................................................................................... 73
4.1.1 費用対効果の算出方法 ................................................................. 73
4.1.1.1 B-ALL ............................................................................... 73
4.1.1.2 DLBCL .............................................................................. 74
4.1.2 モデルで使用した仮定 .................................................................. 75
4.2 分析で使用したパラメータ ..................................................................... 79
4.2.1 有効性･安全性等のパラメータの詳細 ................................................. 90
4.2.1.1 B-ALL ............................................................................... 90
4.2.1.2 DLBCL: 70 歳未満 .............................................................. 101
4.2.1.3 DLBCL: 70 歳以上 .............................................................. 103
4.2.2 QOL 値の詳細 ......................................................................... 105
4.2.2.1 B-ALL ............................................................................. 105
4.2.2.2 DLBCL ............................................................................ 107
4.2.3 費用のパラメータの詳細 .............................................................. 108
4.2.3.1 B-ALL ............................................................................. 108
4.2.3.2 DLBCL ............................................................................ 123
5. 分析結果 ......................................................................................... 139
5.1 基本分析(費用対効果評価専門組織で決定された分析枠組みによる分析)の結果 .. 139
5.1.1 基本分析の増分費用、増分効果、増分費用効果比 ................................... 139
5.1.2 感度分析 .................................................................................. 142
5.1.2.1 DSA: B-ALL ........................................................................ 142
5.1.2.2 DSA: DLBCL ....................................................................... 149
5.1.2.3 PSA: B-ALL ........................................................................ 156
5.1.2.4 PSA: DLBCL ....................................................................... 163
5.1.3 分析の妥当性の検討 .................................................................... 170
5.1.3.1 B-ALL ................................................................................ 170
5.1.3.2 DLBCL ............................................................................... 171
5.1.4 分析結果の解釈 .......................................................................... 173
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5.1.5 価格調整率の重み [該当する場合のみ] .............................................. 176
5.1.6 価格の引き上げ [該当する場合のみ] ................................................. 178
5.2 公的介護費用や生産性損失を含めた分析 [該当する場合のみ] ...................... 178
5.3 その他の分析 [該当する場合のみ] ...................................................... 179
6. 再分析用のデータ ............................................................................... 186
7. 実施体制 ......................................................................................... 187
8. 参考文献 ......................................................................................... 188
Appendix A. Detailed tables of clinical studies included in SLRs .................. 193
A-1. B-ALL ....................................................................................... 193
A-2. DLBCL ...................................................................................... 200
Appendix B. Search Terms for SLRs ........................................................ 207
B-1. B-ALL (Global) ........................................................................... 207
B-2. B-ALL (Japanese) ....................................................................... 210
B-3. DLBCL (Global) .......................................................................... 212
B-4. DLBCL (Japanese) ...................................................................... 213
Appendix C. Summary of goodness of fit statistics and weights for survival
distributions ....................................................................................... 216
C-1. B-ALL: OS ................................................................................. 216
C-2. B-ALL: EFS ............................................................................... 217

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0. 要旨
資料全体を通じて、公開することが困難な部分については黄色マーカーで示す。

分析対象技術名 [1.1 節]
他国の医療技術評価機関における評価結果 [1.8 節]

キムリア点滴静注(tisagenlecleucel)
NICE, SMC, HAS, IQWiG, CADTH, MSAC
1.再発又は難治性の CD19 陽性の B 細胞性急性リンパ芽球性白血病（B-ALL）対象とする疾患･集団 [2.1 節]（一部割愛）•

15 歳未満の集団•

15 歳以上 25 歳以下の集団

2.再発又は難治性の CD19 陽性のびまん性大細胞型 B 細胞
リンパ腫（DLBCL）•

70 歳未満の患者及び 70 歳以上の患者のサブグ
ループに分けて分析を実施する。

(B-ALL)•

15 歳未満の集団：ブリナツモマブ（同種 HSCT を含む）」、•

15 歳以上 25 歳以下の集団：「ブリナツモマブ（同種 HSCTを含む）」、「イノツズマブ オゾガマイシン（同種 HSCT を含

比較対照技術名 [2.2 節]

む）」(DLBCL)

分析の立場と費用の範囲 [2.3
節]•

70 歳未満の患者：サルベージ化学療法+/-同種 HSCT•

70 歳以上の患者：サルベージ化学療法

基本分析では公的医療費支払者の立場から、公的医療費のみを含めた分析を行う。なお、生産性損失を含めた分析も補助的に実施する。

使用する効果指標 [2.4 節]

B-ALL, DLBCL 共に QALY を用いる

設定した分析期間 [2.5 節]

B-ALL, DLBCL 共に生涯を用いる
B-ALL, DLBCL の両方で、費用･効果ともに年率 2%で割引

割引率 [2.6 節]

く。感度分析では費用･効果を同率で年率 0%から 4%の範囲で変化させる。

システマティックレビューのクリニ
カルクエスチョン [3.1/3.3 節](B-ALL)

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(DLBCL：>=70 歳)■ 追加的有用性あり □ 「追加的有用性なし」あるいは「あるとは判断できない」
B-ALL:
The cost-effectiveness model was developed in
Microsoft Excel®. The analysis used a decision tree
approach to determine the proportion of patients
initially assigned to tisagenlecleucel who continued
to infusion. After the initial decision-tree partition,
patients on tisagenlecleucel enter into the partitioned
survival model. Patients on the comparators directly
enter into the partitioned survival model. The modelcomprised of three mutually exclusive health states:(i) event-free survival (EFS), (ii) progressive disease(PD) and (iii) death. EFS was defined as the timefrom the date of treatment initiation to the earliest
date of death, relapse, or treatment failure. All
patients began in EFS at the model start. The
費用対効果の分析方法の概要

proportion of patients in the EFS health state of the[4.1.1 項、4.2 節等]

model was set to be equal to the EFS curve of eachtreatment. The PD state included alive patients who
progressed or relapsed. The proportion of patients in
the PD health state was set to be equal to thedifference between the proportion of living patients,
which was based on the OS curve, and the proportionof EFS patients. During each cycle, patients wereredistributed among the three health states, withdeath being the absorbing state. A monthly model
cycle was used for estimating the proportion ofpatients in each heath state over time. Subsequent
HSCT was considered in the model since subsequent
HSCT is an important treatment option in the clinicalpathway of r/r pALL patients. Subsequent HSCT was
not modelled as a distinct health state, but theefficacy benefit of subsequent HSCT was captured in8the OS and EFS estimates of each treatment arm,and the cost and disutility of subsequent HSCT wasadded separately for each treatment arm using agegroup specific HSCT rate data if available.
Half-cycle correction was applied, in order to accountfor the real-world in which patients transition to thesubsequent health state continuously throughout agiven cycle. Treatment costs before maintenancetherapy initiation (if applicable) were applied as onetime costs in the model, which were not affected by
the half-cycle correction.
DLBCL:
The cost-effectiveness model was developed in
Microsoft Excel®. The analysis used a decision tree
approach to determine the proportion of patients
initially assigned to tisagenlecleucel who continued
to infusion.
After the initial decision-tree partition, patients on
tisagenlecleucel enter into the partitioned survival
model. Patients on salvage chemotherapy directly
enter into the partitioned survival model. The modelcomprised of three mutually exclusive health states:(i) PFS, (ii) PD/RL and (iii) death. PFS was defined as
the time from the date of tisagenlecleucel infusion ortreatment initiation to the date of first documented
progression or death due to any cause. All patientsbegan in PFS at the model start. The proportion ofpatients in the PFS health state of the model was set
to be equal to the PFS curve of each treatment. The
PD/RL state included alive patients who progressedor relapsed. The proportion of patients in the PD/RL
health state was set to be equal to the difference
between the proportion of living patients, which was
based on the OS curve, and the proportion of PFS
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patients.

Duringeach

cycle,

patients

wereredistributed among the three health states, withdeath being the absorbing state. A monthly model
cycle was used for estimating the proportion ofpatients in each heath state over time. Subsequent
SCT, including both allo SCT and auto SCT, wasconsidered only in the < 70 model. The efficacy
benefit of subsequent SCT was captured in the OS
and PFS estimates of each treatment arm. The costanddisutilityofsubsequent

SCT

were added

separately for the proportion of patients who
received

theSCT

treatment

based

on

trial

observation for tisagenlecleucel and literature for thecomparator.
Half-cycle correction was applied, in order to accountfor the real-world in which patients transition to thesubsequent health state continuously throughout agiven cycle. Treatment costs were applied as onetime costs in the model, which were not affected by
the half-cycle correction.
B-ALL:(B-ALL:<15 歳)
本対象集団における ICER は¥2,087,581 であり、これは価
格調整の閾値である 750 万円を下回り、DSA においても基本分析と大きく結果が異なることはなかった。
結果の概要 [5.1 節]

また、確率論的感度分析（PSA）においては、ICER が 750 万
円以下となる確率は 100%であった。以上より、「750 万円以下」が ICER の所属する区間として妥当と判断する。
(B-ALL：>=15 歳)【比較対照】ブリナツモマブ

10本対象集団における ICER は¥2,015,349 であり、これは価
格調整の閾値である 750 万円を下回り、DSA においても基本分析と大きく結果が異なることはなかった。
また、確率論的感度分析（PSA）においては、ICER が 750 万
円以下となる確率は 100%であった。
【比較対照】イノツズマブ
本対象集団における ICER は¥1,994,592 であり、これは価
格調整の閾値である 750 万円を下回り、DSA においても基本分析と大きく結果が異なることはなかった。
また、確率論的感度分析（PSA）においては、ICER が 750 万
円以下となる確率は 100%であった。
両比較対照群の分析結果から、「750 万円以下」が ICER の所属する区間として妥当と判断する。

DLBCL:(DLBCL：<70 歳)
本対象集団における ICER は¥5,459,234 であり、これは価
格調整の閾値である 750 万円を下回る。DSA においても、ほぼ全ての場合において ICER が 750 万円を下回っており、
750 万円を超えるのは割引率を 4%に変更した場合、及び分析期間を年にした場合に限られる。その場合 ICER はそれ

ぞれ¥7,789,845 と¥9,263,162 であった。分析期間については、『2.5 分析期間』で述べられている通り、「十分に長い分析期間」とすることから生涯、とすることが妥当と考える。他の
DSA の結果を考慮し、 ICER の所属する区間は 750 万円以下が妥当であると考える。
また、確率論的感度分析（PSA）においては、ICER が 750 万
円以下となる確率は 97.6%であることから、「750 万円以下」
が ICER の所属する区間として妥当と判断する。
(DLBCL：>=70 歳)

11本報告においては、参考までに 70 歳以上の集団においても検証を行い、その結果は 5.1.2.2 に記載したとおり、基本分析の結果は¥5,231,584 であった。
「3.8 追加的有用性の有無に関する評価」に記載する通り、本
分析対象集団においては、介入群（tisagenlecleucel）と比較対照群ともに有効性データのリミテーションが大きく、これらのデータに基づく分析結果の解釈には、十分に留意する必要がある。
□ 費用削減あるいはドミナント■ 500 万円以下 (750 万円以下)□ 500 万円超 (750 万円超)かつ 750 万円以下 (1125
ICER の所属する確率が最も高いと考える区間万円以下)□ 750 万円超 (1125 万円超)かつ 1000 万円以下
(1500 万円以下)□ 1000 万円超 (1500 万円超)
□ 効果が同等（あるいは劣り）、かつ費用が高い

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1. 対象となる医薬品･医療機器の性質
1.1 名称
販売名：キムリア点滴静注
一般名：チサゲンレクルユーセル
1.2 保険償還価格
本品は、再生医療等製品であり、医薬品の区分にて保険償還価格が決定された。2019 年 5 月
22 日収載時保険償還価格は下記のとおりである。

算

算定方式

原価計算方式

原製品総原価23,632,062 円

価

営業利益

4,137,694 円

計

流通経費

682,000 円

算

消費税

2,276,140 円
有用性加算(I)(A=35%)、市場性加算(I)(A=10%)

定
補正加算

加算係数=0.2(加算前)
1 患者あたり 30,727,896 円

外国平均価格調整
算定薬価

(加算後)
⇔

33,493,407 円

なし
1 患者あたり 33,493,407 円

消費税の増税により、2019 年 10 月 1 日に保険償還価格が下記に変更となった。
1 患者あたり 34,113,655 円
1.3 治療効果のメカニズム
本品は、患者末梢血由来の T 細胞に、遺伝子組換えレンチウイルスベクターを用いて CD19 を特異的に認識する CAR を導入し、培養・増殖させた T 細胞を構成細胞とし、医薬品と同様に薬理的作用による治療効果を期待して、点滴で静脈内に投与される再生医療等製品である。
本品に遺伝子導入される CAR は、CD19 を特異的に認識するマウス由来 scFv、ヒト CD8α ヒン
ジ及び膜貫通ドメイン、並びにシグナル伝達ドメインである CD3-ζ 及び 4-1BB から構成され、CD19 を発現した細胞を認識すると、導入 T 細胞に対して増殖、活性化、標的細胞に対する攻撃及び細胞の持続・残存に関する信号を伝達する。本品のこれらの作用により、CD19 陽性の B 細胞性の腫瘍に対し、腫瘍細胞を死滅させる効果が長期に持続することが期待される。
1.4 対象疾患
本品の効能、効果又は性能は下記のとおりである（添付文書より抜粋）。

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1. 再発又は難治性の CD19 陽性の B 細胞性急性リンパ芽球性白血病。ただし、以下のいずれかの場合に限る。
•

初発の患者では標準的な化学療法を 2 回以上施行したが寛解が得られない場合•

再発の患者では化学療法を 1 回以上施行したが寛解が得られない場合•

同種造血幹細胞移植の適応とならない又は同種造血幹細胞移植後に再発した場合

2. 再発又は難治性の CD19 陽性のびまん性大細胞型 B 細胞リンパ腫。ただし、以下のいずれかの場合であって、自家造血幹細胞移植の適応とならない又は自家造血幹細胞移植後に再発した患者に限る。
•

初発の患者では化学療法を 2 回以上、再発の患者では再発後に化学療法を 1 回以上施行し、化学療法により完全奏効が得られなかった又は完全奏効が得られたが再発した
場合•

濾胞性リンパ腫が形質転換した患者では通算 2 回以上の化学療法を施行し、形質転換
後には化学療法を 1 回以上施行したが、形質転換後の化学療法により完全奏効が得られなかった又は完全奏効が得られたが再発した場合

なお、本品の指定から分析結果の提出時までの間に、保険適用となる疾患が追加される予定はない。

分析対象とする疾患の疫学的性質（B-ALL）•

ALL は骨髄のリンパ系前駆細胞が腫瘍化により過剰に増殖し，急速に進行する疾患であり，B-ALL が ALL の約 80%を占める。[1]ALL では正常な造血機能が阻害され、白血球減少、貧血、血小板減少に伴う症状（全身倦怠感，出血等）や腫瘍増殖による局所症状（リンパ節腫脹や肝脾腫等）が生じる。ALL は年齢にかかわらず発症するが、好発
年齢は 2～5 歳で、診断時の年齢は全体の 60%が 20 歳未満である。

•

ALL の総患者数は約 5,000 人と報告されている（厚生労働省平成 26 年患者調査）。
小児の ALL 患者では一次治療により 80%以上の患者で治癒が得られるが、約 20%の小児の ALL 患者は再発し、再発した場合ほとんどの患者は最終的にこの疾患により死亡に至る。小児の ALL は小児がんの死因の第 1 位であり、特に再発又は難治性の小児の ALL は生存期間（中央値）が 3～6 ヵ月と予後不良の疾患である。[2]–[5]（DLBCL）•「再発又は難治性の CD19 陽性のびまん性大細胞型 B 細胞リンパ腫」は、Figure 1 に示すとおり、成熟 B 細胞由来の悪性リンパ腫であり、非ホジキンリンパ腫の 30%～
35%を占める。[6]14Figure 1 悪性リンパ腫の分類•

DLBCL は全身に広がるリンパ組織から発生するため病変の部位によって症状は異なるが、リンパ節腫大、節外病変、全身症状（発熱、体重減少、寝汗）等が認められる。また、
DLBCL は女性に比べやや男性で多く発症する。DLBCL はあらゆる年齢層で発症するが、発症率は年齢とともに増加し、半数以上の患者は 60 歳以上で診断される。悪性リンパ腫の総患者数は 2014 年時点で 64,000 人と推計され、約 33%が DLBCL であることから総患者数は約 21,000 人と推計される。[7], [8]

分析対象とする疾患における当該医薬品･医療機器の使用(見込)者数
保険償還時の使用見込み数は、ピーク時市場規模予測で 216 名である。
当該医薬品･医療機器を使用する患者の主な年齢(層)や性別等
本品の 2 つの適応症は共に希少疾病を対象としており、対象患者数は非常に限られている。また、本品は、原材料として用いる非動員末梢血単核球を患者さんから採取後に製品製造を行うことから、投与までに一定の期間を要する。適格性の判断においては、適正使用ガイド等を用いて実施されている。日本の実臨床における症例数が限られることから、臨床試験における年齢区分を下記のとおり示す。

15

＜医療機関での白血球アフェレーシス～製造施設への輸送＞
1. 白血球アフェレーシス
十分量の T リンパ球を含む非動員抹消血単核球を採取する。
2. 白血球アフェレーシス産物の凍結保存
採取後速やかに白血球アフェレーシス産物を調製し、液体窒素気相下で凍結保存する。
3. 白血球アフェレーシス産物の輸送
凍結保存した白血球アフェレーシス産物を、梱包して本品製造施設へ輸送する。
＜医療機関での受入れ～投与＞
4. 本品の受領及び保存
凍結した状態で本品を受領し、使用直前まで液体窒素気相下で凍結保存する。
5. 投与前の前処置
本品の投与予定日前の 1 週間以内の末梢血白血球数が 1,000/μL を超える場合、本品投与の 2 日前までに以下のリンパ球除去化学療法を前処置として行う。前処置の化学療法の特性や患者の状態を考慮の上、前処置から本品投与までに必要な間隔を設定する。
1. 再発又は難治性の CD19 陽性の B 細胞性急性リンパ芽球性白血病に用いる場合のリンパ球除去化学療法
1. シクロホスファミド水和物 500mg/m2 を 1 日 1 回 2 日間点滴静注及びフルダラビンリン酸エステル 30 mg/m2 を 1 日 1 回 4 日間点滴静注する。
なお、患者の状態により適宜減量する。
2. シクロホスファミド水和物による Grade 4 の出血性膀胱炎の既往がある、又はシクロホスファミド水和物に抵抗性を示した患者には、シタラビン 500 mg/m2 を 1 日 1 回 2 日間点滴静注及びエトポシド 150 mg /m2 を 1 日 1
回 3 日間点滴静注する。なお、患者の状態により適宜減量する。
2. 再発又は難治性の CD19 陽性のびまん性大細胞型 B 細胞リンパ腫に用いる場合のリンパ球除去化学療法
1. シクロホスファミド水和物 250 mg /m2 を 1 日 1 回 3 日間点滴静注及びフルダラビンリン酸エステル 25 mg/m2 を 1 日 1 回 3 日間点滴静注する。なお、患者の状態により適宜減量する。
2. シクロホスファミド水和物による Grade 4 注）の出血性膀胱炎の既往がある、又はシクロホスファミド水和物に抵抗性を示した患者には、ベンダムスチン塩
酸塩 90 mg/m2 を 1 日 1 回 2 日間点滴静注する。なお、患者の状態により適宜減量する。
6. 本品の投与投与直前に本品を解凍し、適応症に応じて下記のとおり単回静脈内投与する。
17

1. 再発又は難治性の CD19 陽性の B 細胞性急性リンパ芽球性白血病に用いる場合
通常、25 歳以下（投与時）の患者には、体重に応じて以下の投与量を単回静脈内投与する。
• 体重 50 ㎏以下の場合には、CAR 発現生 T 細胞として 0.2×106～5.0×106 個/㎏• 体重 50 ㎏超の場合には、CAR 発現生 T 細胞として 0.1×108～2.5×108 個（体重問わず）
2. 再発又は難治性の CD19 陽性のびまん性大細胞型 B 細胞リンパ腫に用いる場合
通常、成人には、CAR 発現生 T 細胞として 0.6×108～6.0×108 個（体重問わず）を単回静脈内投与する。

本品の製造に先立ち白血球アフェレーシスを、本品の投与予定日前の1週間以内の末梢血白血
球数が1,000/μLを超える場合には移植細胞の生着促進等を目的としたリンパ球除去化学療法（以下、「LD化学療法」という）を行う必要があり、さらに本品の投与によりサイトカイン放出症候群（以下、「CRS」という）等の重篤な又は死亡に至る可能性がある副作用が認められる可能性がある。したがって、アフェレーシスの実施中、LD化学療法の実施中、本品の投与中及び投与後には、患者の観察を十分に行い、異常が認められた場合には、発現した事象に応じた専門的な知
識と経験を持つ医師により、必要に応じてICU等において集学的な全身管理を含む適切な措置を行う必要がある。使用にあたっては、最適使用推進ガイドラインにあるとおり、下記施設での使用のみとなる。
ア 日本造血細胞移植学会が定める移植施設認定基準の全ての項目を満たす診療科（認定カテゴリー1）を有する施設
イ 認定カテゴリー1 に準ずる診療科（認定基準のうち、移植コーディネーターの配置に係る基準以外を満たす診療科）を有する施設
1.6 対象疾患の治療における当該医薬品･医療機器の位置づけ【本品の革新性】
本品による治療の概略を Figure 2 に示す。白血球アフェレーシスにより患者から採取した T 細胞は採取施設で凍結され，米国の製造施設に送られ［1］，レンチウイルスベクターを用い遺伝子導入が行われる［2］。次に CAR 発現 T 細胞を ex vivo で培養増殖させ［3］，リンパ球除去化
学療法を行った後［4］，CTL019 を患者へ投与する［5］。投与された CAR 発現生 T 細胞が B
細胞性腫瘍に対し抗腫瘍効果を発揮する。
本品は，臨床上有用な新規作用機序を有し，希少疾病用医薬品の指定を受けて開発・承認された薬剤であり，国内で初めて承認される細胞遺伝子改変細胞療法である。

18

Figure 2 本品の治療概略【B-ALL】
B-ALL の既存治療およびアンメットニーズ
現在，再発又は難治性の小児 ALL に対する治療選択肢としては大量化学療法に続く同種
HSCT，救援化学療法，免疫療法，支持療法等があり，このうち唯一治癒が期待できるのは同種
HSCT である。しかしながら同種 HSCT であっても効果は限定的であり，移植に関連した致死的な移植片対宿主病（GVHD），長期の免疫抑制に伴う侵襲性の全身性感染症や晩期障害（成長障害等）といった合併症も問題となる。再発又は難治性の小児 ALL 患者に対する「第三寛解期（CR3）以降の同種 HSCT」，「寛解が得られていない状態での同種 HSCT」，又は「同種 HSCT
施行後の再発に対する 2 回目の同種 HSCT」の 1 年生存率は 25%～55%，5 年生存率は20%～45%と報告されている。
再発・難治性 ALL に対する治療選択肢は，同種造血幹細胞移植，クロファラビン，イノツズマブ
オゾガマイシン，ブリナツモマブなどが国内で承認されているが，治療後に深い寛解を維持できずに再発する患者も多い。同種造血幹細胞移植は，再発・難治性 ALL に対する治癒可能な治療選択肢の一つだが，適応患者が限定的である上，合併症を発現する場合は重症となる場合がある。
ALL に対する超大量化学療法や全身放射線照射治療などによる，晩期障害が発現する場合は入院が長期に及ぶ場合も多く，就学年齢の学童児が通学できない等により小児の成長に影響を及ぼす。
ALL の治療目標は治癒を目指すことであり，特に長期予後と関連があるとされている残存病変（MRD）が陰性となる深い寛解の持続を目指すことである。再発又は難治性の小児 ALL 患者に対して長期に深い寛解をもたらし，同種造血幹細胞移植を実施しなくても良好な治療効果をもたらすことが期待でき，かつ忍容性の高い安全性プロファイルを有する新たな治療が望まれていた。

標準的な治療フローと当該医薬品の位置づけ
B-ALL における治療の概要を下記(Figure 3)に示す。当該医薬品の治療対象患者を緑色で示
す。
19

o

自家造血幹細胞移植併用大量化学療法を施行した患者の約 60%は，移植後に再発する•

自家造血幹細胞移植の適応とならない患者や自家造血幹細胞移植後に再発した

患者は，予後不良であり，新たな治療選択肢が求められている。
o

自家造血幹細胞移植の適応とならない患者では，OS 中央値は 4.4 ヵ月，1 年及び2 年 OS はそれぞれ 23%，16%である[11]o

自家造血幹細胞移植後に再発し，三次治療を受けた患者では，OS 中央値は 10 ヵ
月で，1 年 OS は 39%である[12]o

自家造血幹細胞移植後 1 年以内に再発した患者の OS 中央値は 6.2 ヵ月である[13]•

国内でも上記に示したエビデンスを主な根拠として外国と同様の治療戦略が造血器腫瘍診療ガ
イドラインで推奨されており（日本血液学会 2018），再発又は難治性で自家 HSCT に適応がな
いか，又は自家 HSCT 後に再発した DLBCL 患者では現時点で治癒をもたらす標準的な治療法はないため，持続的な奏効を得て長期予後の改善につなげることができる新規の治療法が早急に求められていた。
診療ガイドラインにおける本品の位置づけは下記のとおりである。
＜診療ガイドライン＞
NCCN ガイドライン（B-Cell Lymphomas，ver.1.2020）[14]：本品は， DLBCL に組織学的形質転換した FL 患者に対する選択肢の一つである（Preferred）。
標準的な治療フローと当該医薬品の位置づけ
当該医薬品の治療対象患者を赤枠でしめす(Figure 4)。

21

Figure 4 DLBCL における治療の概要

1.7 主な有害事象
リスク管理計画書に示された重篤な有害事象は下記のとおりである。
1. サイトカイニン放出症候群
サイトカイン放出症候群があらわれることがあるので、患者の状態を十分に観察し、適宜、血液検査等を実施すること。高熱、悪寒、筋肉痛、関節痛、悪心、嘔吐、下痢、発汗、発疹、食欲不振、疲労、頭痛、低血圧、脳症、呼吸困難、頻呼吸、低酸素症、臓器障害（一過性の心不全及び不整脈、腎不全、AST 増加、ALT 増加、ビリルビン増加を含む）等の異常が認められた場合には、製造販売業者が提供するサイトカイン放出症候群管理アルゴリズム等に従い、適切な処置を行うこと。また、サイトカイン放出症候群を発現した患者で播種性血管内凝固症
候群、毛細血管漏出症候群、血球貪食症候群、マクロファージ活性化症候群が報告されている。
2. 神経系事象
脳症等の神経系事象があらわれることがあるので、頭痛、せん妄、不安、浮動性めまい、振戦等の症状があらわれた場合は、患者の状態を十分に観察し、異常が認められた場合には、適切な処置を行うこと。
3. 感染症
細菌、真菌、あるいはウイルス等による重度の感染症（敗血症、肺炎等）があらわれることがあり、死亡に至った例が報告されている。また、発熱性好中球減少症があらわれることがある。
22

)

他(
オーストラリア

MSAC･ 推奨/非推奨/条件つき推奨(具体的に:
(

)/その他

NA

)

・DLBCL
国名評価結果 (記載例)

機関名

リスト価格
(現地通貨建)

イギリス

NICE

･ 推奨/非推奨/条件つき推奨(具体的に: Cancer
Drug Fund)/その他 (£282,000)･ 評価ステータス: 最終ガイダンス/ドラフト/その他
(
SMC

)

･ 推奨/非推奨/条件つき推奨(具体的に:

)/その他

()
フランス

HAS

･ SMR: important€･ ASMR: I/II/III/IV/V･ 効率性評価: あり(主な ICER の値:)/評価中/

未実施
IQWiG

ドイツ

･Major/Considerable/Minor/Unquantifiable/No€

additional benefit
カナダ

CADTH

･ 推奨/非推奨/条件つき推奨(具体的に: On the

CADcondition that there is a substantial reductionin price)/その他(
オーストラリア

MSAC)･ 推奨/非推奨/条件つき推奨(具体的に:
(

)/その他

NA

)

【各国における費用対効果評価の詳細】
1. 評価の有無の一覧
2020 年月日現在の結果を下記に示す。

B-ALL
国名

機関名

イギリス

NICE

評価結果の有無あり/ なし/ 評価中(ドラフトあり/なし)/不明

24

SMC

あり/ なし/ 評価中/不明

フランス

HAS

あり/ なし/ 評価中/不明

カナダ

CADTH

あり/ なし/ 評価中/不明

オーストラリアPBACあり/ なし/ 評価中/不明

DLBCL
国名

機関名

評価結果の有無

イギリス

NICE

あり/ なし/ 評価中(ドラフトあり/なし)/不明

SMCあり/ なし/ 評価中/不明

フランス

HAS

あり/ なし/ 評価中/不明

カナダ

CADTH

あり/ なし/ 評価中/不明

オーストラリアPBACあり/ なし/ 評価中/不明

2. 評価結果の詳細
2020 年月日現在の結果を下記に示す。

【B-ALL】
国名

イギリス

機関名

NICE

評価結果の URL など

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

評価対象技術評価結果
条件付き推奨の場合は、そのキムリア点滴静注
条件つき推奨
Cancer Drugs Fund

条件の詳細
評価対象疾患

pediatric and young adult patients up to 25 years ofage with B-cell acute lymphoblastic leukemia (ALL)that is refractory, in relapse post-transplant or insecond or later relapse

使用方法 (※)

Treatment with tisagenlecleucel comprises asingle-dose intravenous infusion of tisagenlecleucel.
It is intended for autologous use only and at thefollowing dosage:•

For patients ≤50 kg: 0.2 to 5.0×106
CAR-positive viable T cells per kg body weight.
25•For patients >50 kg: 0.1 to 2.5×108
CAR-positive viable T cells (non-weight based).

比較対照

Blinatumomab and salvage chemotherapy are both
appropriate comparators and blinatumomab is themain comparator

主要な増分費用効果比の値

Company's probabilistic base-case ICER was£20,046 per QALY gained. The committee concluded
the most plausible ICERs for tisagenlecleucelcompared with blinatumomab when taking into
account all the patient access scheme discounts wereover £30,000 per QALY gained.

国名

イギリス

機関名

SMC

評価結果の URL など

https://www.scottishmedicines.org.uk/medicinesadvice/tisagenlecleucel-kymriah-fullsubmissionsmc2129/

評価対象技術評価結果
条件付き推奨の場合は、そのキムリア点滴静注
条件つき推奨
Patient Access Scheme

条件の詳細
評価対象疾患

pediatric and young adult patients up to 25 years ofage with B-cell acute lymphoblastic leukemia (ALL)that is refractory, in relapse post-transplant or insecond or later relapse

使用方法 (※)

Tisagenlecleucel is intended for autologous use only.
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 weight.

•

for patients above 50kg: 0.1 to 2.5 x 108 CAR
positive viable T cells (non-weight based).
26

比較対照

Salvage chemotherapy, blinatumomab or palliative
therapies

主要な増分費用効果比の値

ICER versus salvage chemotherapy (with PAS fortisagenlecleucel)
Base case :

国名

フランス

機関名

HAS

評価結果の URL など£25,238https://www.hassante.fr/jcms/pprd_2982962/en/kymriah

評価対象技術評価結果
条件付き推奨の場合は、そのキムリア点滴静注
SMR: Important / ASMR: III
NA

条件の詳細
評価対象疾患

pediatric and young adult patients up to 25 years ofage with B-cell acute lymphoblastic leukaemia (ALL)that is refractory, in relapse post-transplant or insecond or later relapse

使用方法 (※)

Tisagenlecleucel is intended for autologous use only.
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 weight.

•

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

比較対照

salvage chemotherapy, blinatumomab, inotuzumab,
and palliative care

主要な増分費用効果比の値

NA

国名

ドイツ

機関名

IQWIG

評価結果の URL など

https://www.iqwig.de/en/projects27

results/projects/health-economic/g18-11tisagenlecleucel-b-cell-acute-lymphoblasticleukaemia-assessment-according-to-35a-para-1sentence-11-social-code-book-v.10617.html
評価対象技術

キムリア点滴静注

評価結果

Unquantifiable

条件付き推奨の場合は、その

NA

条件の詳細
評価対象疾患

pediatric and young adult patients up to 25 years ofage with B-cell acute lymphoblastic leukaemia (ALL)that is refractory, in relapse post-transplant or insecond or later relapse

使用方法 (※)

Tisagenlecleucel is intended for autologous use only.
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 weight.

•

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

比較対照なし（理由：orphan designation）

主要な増分費用効果比の値

NA

国名

カナダ

機関名

CADTH

評価結果の URL など

https://cadth.ca/sites/default/files/pdf/car-t/ct0001op0538-in-brief-e.pdf

評価対象技術評価結果
条件付き推奨の場合は、そのキムリア点滴静注
条件つき推奨On the condition that there is a reduction in price

条件の詳細
評価対象疾患

Pediatric and young adult patients three to 25 years
old with B-cell acute lymphoblastic leukemia who are28refractory, have relapsed after allogeneic stem celltransplant (SCT), or are otherwise ineligible forallogeneic SCT, or have experienced a second or later
relapse.
使用方法 (※)

The recommended dose is 0.2-5.0 x 106 CAR-positive
viable T cells/kg body weight for patients 50 kg andbelow and 0.1-2.5 x 108 CAR-positive viable T cells
for patients above 50 kg as a single one-timetreatment.

比較対照
主要な増分費用効果比の値

salvage chemotherapy
For r/r ALL, tisagenlecleucel, compared with end-oflife chemotherapy, was associated with anincremental cost per quality-adjusted life-year (QALY— a measure of the quantity and quality of life for apatient, as well as value for money for medical
interventions) of CAD$53,269

国名オーストラリア

機関名

MSAC

評価結果の URL など

http://www.msac.gov.au/internet/msac/publishing.ns
f/Content/1519-public

評価対象技術

キムリア点滴静注

評価結果

推奨

条件付き推奨の場合は、その

NA

条件の詳細
評価対象疾患

pediatric and young adult patients up to 25 years ofage with B-cell precursor acute lymphoblastic
leukaemia (ALL) that is refractory, in relapse posttransplant, or in second or later relapse

使用方法 (※)• For patients 50 kg and below: 0.2 to 5.0 x 106 CARpositive viable T cells/kg body weight.
• For patients above 50 kg: 0.1 to 2.5 x 108 CARpositive viable T cells (non-weight based).

比較対照

comparator: blinatumomab with the intention to29

proceed to allo-SCT (Main), salvage chemotherapy
with the intention to proceed to allo-SCT (Supportive)
主要な増分費用効果比の値

NA【DLBCL】
国名

イギリス

機関名

NICE

評価結果の URL など
評価対象技術評価結果
条件付き推奨の場合は、そのhttps://www.nice.org.uk/guidance/ta567
キムリア点滴静注
条件つき推奨
Cancer Drugs Fund

条件の詳細
評価対象疾患Adult patients with relapsed or refractory diffuse large
B-cell lymphoma (DLBCL) after two or more lines ofsystemic therapy

使用方法 (※)

Treatment with tisagenlecleucel comprises asingle-dose intravenous infusion of tisagenlecleucel.
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.

比較対照
主要な増分費用効果比の値

Salvage chemotherapy excluding pixantrone
Company’s base case: (ICER): £46,325
The committee: ranged between £42,991 and£55,403 per QALY gained

国名

イギリス

機関名

SMC

評価結果の URL など

https://www.scottishmedicines.org.uk/medicinesadvice/tisagenlecleucel-kymriah-resubmissionsmc2200/

評価対象技術評価結果
条件付き推奨の場合は、そのキムリア点滴静注
条件つき推奨
Patient Access Scheme

条件の詳細
30

評価対象疾患

Adult patients with relapsed or refractory diffuse large
B-cell lymphoma (DLBCL) after two or more lines ofsystemic therapy

使用方法 (※)

Tisagenlecleucel is intended for autologous use only.
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-weightbased).

比較対照
主要な増分費用効果比の値

Salvage chemotherapy
Base-case results – with PAS
Vs [R-]Gem-Ox

ICER: £44,330

Vs [R-]GDP

ICER: £44,151

国名

フランス

機関名

HAS

評価結果の URL など

https://www.hassante.fr/jcms/pprd_2982962/en/kymriah

評価対象技術評価結果
条件付き推奨の場合は、そのキムリア点滴静注
SMR: Important / ASMR: IV
NA

条件の詳細
評価対象疾患Adult patients with relapsed or refractory diffuse large
B-cell lymphoma (DLBCL) after two or more lines ofsystemic therapy

使用方法 (※)

Treatment with tisagenlecleucel comprises asingle-dose intravenous infusion of tisagenlecleucel.
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.

比較対照Salvage chemotherapy, Yescarta, palliative care, andalloSCT if patient eligible

主要な増分費用効果比の値

NA
31

国名

ドイツ

機関名

IQWIG

評価結果の URL など

https://www.iqwig.de/en/projectsresults/projects/health-economic/g18-10tisagenlecleucel-diffuse-large-b-cell-lymphomaassessment-according-to-35a-para-1-sentence-11social-code-book-v.10620.html

評価対象技術

キムリア点滴静注

評価結果

Unquantifiable

条件付き推奨の場合は、その

NA

条件の詳細
評価対象疾患Adult patients with relapsed or refractory diffuse large
B-cell lymphoma (DLBCL) after two or more lines ofsystemic therapy

使用方法 (※)

Treatment with tisagenlecleucel comprises asingle-dose intravenous infusion of tisagenlecleucel.
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.

比較対照なし（理由：orphan designation）

主要な増分費用効果比の値

NA

国名

カナダ

機関名

CADTH

評価結果の URL など

https://cadth.ca/sites/default/files/pdf/car-t/ct0001op0538-in-brief-e.pdf

評価対象技術評価結果
条件付き推奨の場合は、そのキムリア点滴静注
条件つき推奨On the condition that there is a reduction in price

条件の詳細
評価対象疾患Adult patients with relapsed or refractory large B-cell
lymphoma after two or more lines of systemic
therapy including diffuse large B-cell lymphoma
32

(DLBCL) not otherwise specified, high grade B-cell
lymphoma and DLBCL arising from follicularlymphoma
使用方法 (※)

Tisagenlecleucel is recommended as a single, onetime treatment (0.6 to 6.0 x 108 CAR-positive viable
T cells).

比較対照
主要な増分費用効果比の値

salvage chemotherapy
For r/r DLBCL, tisagenlecleucel, compared withpalliative chemotherapy, was associated with anincremental cost per QALY of CAD$211,870.

国名オーストラリア

機関名

MSAC

評価結果の URL など

http://www.msac.gov.au/internet/msac/publishing.ns
f/Content/1519.1-public

評価対象技術評価結果
条件付き推奨の場合は、その条件の詳細

キムリア点滴静注
SupportAn initial progress review at Year 1 to assess
appropriateneness of patient eligibility criteria andpatient numbers, with a full review of clinicaleffectiveness, costeffectiveness and budget impact tobe conducted by the MSAC no later than 2 years post
the commencement of public subsidy

評価対象疾患Adult patients with relapsed or refractory diffuse large
B-cell lymphoma (DLBCL) after two or more lines ofsystemic therapy

使用方法 (※)

0.6 to 6.0 x 108 CAR-positive viable T cells (nonweight based)

比較対照

Salvage chemotherapy with the intention to proceed
to allo- or auto-SCT

主要な増分費用効果比の値

NA33

2. 費用効果分析における分析条件の設定
2019 年月日に実施された費用対効果評価専門組織において、決定された分析対象集団

およびは比較対照は、Section 2.1 および 2.2.に示したとおりである。分析枠組の決定にあたっては、当初より弊社意見は、全体集団を 1 つの集団としてみなして分析をするものであった。参考
までに、2019 年

月日第一回分析前協議において提出した弊社意見における分析案は下記のとおりであった。
•

B-ALL：サブグループの設定は行わず、対照技術は•

DLBCL ： サ ブ グ ル ー プ の 設 定 は 行 わ ず 、 対 照 技 術 は 、。

2.1 分析対象とする集団
2019 年月日に実施された費用対効果評価専門組織において、決定された分析対象は下記のとおりである。以下、分析枠組みに関する厚生労働省からの通知資料の抜粋。

【B-ALL】
対象とする疾患

再発又は難治性の CD19 陽性の B 細胞性急性リンパ芽球性白血病。
ただし、25 歳以下（治療時）の、以下のいずれかの場合に限る。
•

初発の患者では標準的な化学療法を 2 回以上施行したが寛解が得られない場合•再発の患者では化学療法を 1 回以上施行したが寛解が得られない場合•

同種造血幹細胞移植の適応とならない又は同種造血幹細胞移植
後に再発した場合

サブグループ解析•

15 歳未満の集団•

15 歳以上 25 歳以下の集団【DLBCL】
対象とする疾患

再発又は難治性の CD19 陽性のびまん性大細胞型 B 細胞リンパ腫。
ただし、以下のいずれかの場合であって、自家造血幹細胞移植の適応とならない又は自家造血幹細胞移植後に再発した患者に限る。
•

初発の患者では化学療法を 2 回以上、再発の患者では再発後に化学療法を 1 回以上施行し、化学療法により完全奏効が得られなかった又は完全奏効が得られたが再発した場合

34

•

濾胞性リンパ腫が形質転換した患者では通算 2 回以上の化学療法を施行し、形質転換後には化学療法を 1 回以上施行したが、形質転換後の化学療法により完全奏効が得られなかった又は完全奏効が得られたが再発した場合

サブグループ解析

70 歳未満の患者及び 70 歳以上の患者のサブグループに分けて分析を実施する。

2.2 比較対照
2019 年月日に実施された費用対効果評価専門組織において、決定された比較対照技術は下記のとおりである。以下、分析枠組みに関する厚生労働省からの通知資料の抜粋。

【B-ALL】
比較対照技術名

15 歳未満の集団においては「ブリナツモマブ（同種 HSCT を含む）」、
15 歳以上 25 歳以下の集団においては効果が同程度と考えられる「ブリナツモマブ（同種 HSCT を含む）」、「イノツズマブ オゾガマイシン（同種 HSCT を含む）」の両者を比較対照とする。

比較対照技術を選定

いずれの集団においても、日本における診療実態、あるいは米国した理由

NCCN ガイドラインを参照すると、現在実施されている標準治療は（再発後）2 次化学療法（同種 HSCT を含む）である。
化学療法としては、「中央社会保険医療協議会における費用対効果評
価の分析ガイドライン第 2 版」に従い、候補となり得るものの中で、寛解率が高いと考えられる 15 歳未満の集団においては「ブリナツモマブ（同種 HSCT を含む）」、15 歳以上 25 歳以下の集団においては効果が同程度と考えられる「ブリナツモマブ（同種 HSCT を含む）」、「イノツ
ズマブ オゾガマイシン（同種 HSCT を含む）」の両者を比較対照とす
ることが適当である。なお、イノツズマブ イゾガマイシンは添付文書上で、「低出生体重児、新生児、乳児、幼児又は小児に対する安全性及び有効性は確立していない」とされることから、成人（15 歳以上）のみ
比較対照技術として含めることとした。

比較対照技術の使用

ブリナツモマブ（ビーリンサイト 点滴静注用 35μｇ）

方法

効能・効果：再発又は難治性の B 細胞性急性リンパ性白血病（添付文書より一部

用法及び用量：通常、ブリナツモマブ（遺伝子組換え）として以下の投抜粋）

与量を 28 日間持続点滴静注した後、14 日間休薬する。これを 1 サ
イクルとし、最大 5 サイクル繰り返す。その後、ブリナツモマブ（遺伝子35組換え）として以下の投与量を 28 日間持続点滴静注した後、56 日間休薬する。これを 1 サイクルとし、最大 4 サイクル繰り返す。なお、患者の状態により適宜減量する。
○ 体重が 45 kg 以上の場合：1 サイクル目の 1～7 日目は 1 日 9
μg、それ以降は 1 日 28 μg とする。
○ 体重が 45 kg 未満の場合：1 サイクル目の 1～7 日目は 1 日 5
μg/m2（体表面積）、それ以降は 1 日 15 μg/m2（体表面積）とする。
ただし、体重が 45 kg 以上の場合の投与量を超えないこと。
＜用法・用量に関連する使用上の注意＞(1) 本品投与によりサイトカイン放出症候群が発現する可能性があるため、本品投与前及び増量前はデキサメタゾンを投与すること。

イノツズマブ イゾガマイシン
効能・効果：再発又は難治性の CD22 陽性の急性リンパ性白血病［効能・効果に関連する使用上の注意］
1. フローサイトメトリー法等の検査によって、CD22 抗原が陽性であることが確認された患者に使用すること
用法及び用量：通常、成人にはイノツズマブ オゾガマイシン（遺伝子組換え）として 1 日目は 0.8mg/m2（体表面積）、8 及び 15 日目は0.5mg/m2（体表面積）を 1 日 1 回、1 時間以上かけて点滴静脈内投与した後、休薬する。1 サイクル目は 21～28 日間、2 サイクル目以
降は 28 日間を 1 サイクルとし、投与を繰り返す。投与サイクル数は造血幹細胞移植の施行予定を考慮して決定する。なお、患者の状態により適宜減量する。
［用法・用量に関連する使用上の注意］
1. 1 サイクル目の期間は原則 21 日間とするが、寛解（血球数の回復の有無を問わない）が得られた場合は、28 日間まで延長できる。また、寛解（血球数の回復の有無を問わない）が得られた場合、2 サイクル目以降の 1 日目の投与量は、イノツズマブ オゾガマイシン（遺伝子組換え）として 0.5mg/m2（体表面積）とすること。なお、骨髄中の芽球が 5％未満で、末梢血中の白血病芽球及び髄外病変が消失した場
合に、寛解（血球数の回復の有無を問わない）が得られたと判断すること。
2.本品の投与サイクル数は、以下のとおりとする。
⑴HSCT の施行を予定している場合
36投与サイクル数の増加に応じて HSCT 施行後の VOD/SOS の発現リスクが高まるおそれがあるので、本品の効果が得られる最小限のサイクル数とすること。治療上やむを得ないと判断される場合を除き、3サイクル終了までに投与を中止すること。［「警告」、「効能・効果に関連する使用上の注意」、「慎重投与」、「重要な基本的注意」、「副作用」、「高齢者への投与」及び「その他の注意」の項参照］⑵HSCT の施行を予定していない場合
6 サイクルまで投与を繰り返すことができる。ただし、3 サイクル終了ま
でに本品の効果が得られない場合には、投与を中止すること。
3. 本品を 7 サイクル以上投与した際の有効性及び安全性は確立していない。
［小児等への投与］
低出生体重児、新生児、乳児、幼児又は小児に対する安全性及び有効性は確立していない。［使用経験がない。］【DLBCL】
比較対照技術名•

70 歳未満の患者：サルベージ化学療法+/-同種 HSCT•

70 歳以上の患者：サルベージ化学療法

比較対照技術を選定

治療効果の大きい治療法はサルベージ化学療法+/-同種 HSCT であした理由

るが、70 歳以上のサブグループについては、同種 HSCT が積極的には実施されないことから、上記の集団ごとに、比較対照技術を設定し、それぞれ分析する。

比較対照技術の使用

造血器腫瘍診療ガイドライン（2018 年版日本血液学会ガイドライン)

方法に示された salvage chemotherapy のレジメンは下記のとおりである。その中で本邦の実臨床における使用度合い、保険償還された医薬品を使用したレジメンを考慮して比較対照技術に含めるレジメンを決定した。[15]救援化学療法DHAP 療法（DEX, CDDP, AraC）（＋R）（R-）ESHAP 療法（mPSL, ETP, AraC, CDDP）（R-）ICE 療法（IFM, CBDCA, ETP）
CHASE（R）療法（CPA, AraC, DEX, ETP）
Dose adjusted（DA）-EPOCH（-R）療法（ETP, PSL, VCR, CPA,
DXR）

37

MINE 療法（MIT, IFM,メスナ，ETP）
GDP 療法（Gem, DEX, CDDP）
2.3 分析の立場と費用の範囲【B-ALL】
基本分析では公的医療費支払者の立場から、公的医療費のみを含めた分析を行う。ただし、本品が長期間のベネフィットを患者にもたらす可能性があること、対象疾患が小児および若年性であること等を考慮し、生産性損失を含めた分析も補助的に実施する。

【DLBCL】
基本分析では公的医療費支払者の立場から、公的医療費のみを含めた分析を行う。ただし本品は既存の治療方法と異なり、持続的な有効性と Social functioning ability の改善が期待できる。そのため本治療法による患者の生産性への影響は大きいと考えられることから、生産性損失を含めた分析も補助的に実施する。
2.4 効果指標【B-ALL&DLBCL】
両疾患ともに効果の指標として質調整生存年（QALYs）を用いる。また参考値として、生存年（LYs）の推計結果も表示する。
2.5 分析期間
【B-ALL&DLBCL】
両疾患ともに分析期間は生涯に設定する。これは、中央社会保険医療協議会における費用対効
果評価の分析ガイドライン第 2 版（以降、分析ガイドライン）7.1 の記載、「評価対象技術の費用や効果におよぼす影響を評価するのに十分に長い分析期間を用いる」とも合致する。
第一回分析前協議でも弊社意見として生涯の分析期間を提示しており、2019 年月日に実施した分析の進め方に関する会議においても、C2H 側から生涯の分析期間を提示されている。
補助的な分析として、分析期間を短縮 (ALL：年

年、DLBCL年)した結果も表示する。
2.6 割引率【B-ALL&DLBCL】
両疾患ともに分析ガイドラインに従い、費用･効果ともに年率 2%で割引を行うこととする。感度分
析では費用･効果を同率で年率 0%から 4%の範囲で変化させる。
38

2.7 分析条件の設定の要約【B-ALL】
分析対象とする集団再発又は難治性の CD19 陽性の B 細胞性急性リンパ芽球性白血病。ただし、25 歳以下（治療時）の、以下のいずれかの場合に限る。
・ 初発の患者では標準的な化学療法を 2 回以上施行したが寛解が得られない場合・ 再発の患者では化学療法を 1 回以上施行したが寛解が得られない場合
・ 同種造血幹細胞移植の適応とならない又は同種造血幹細胞移
植後に再発した場合

比較対照

15 歳未満の集団においては「ブリナツモマブ（同種 HSCT を含む）」、15 歳以上 25 歳以下の集団においては効果が同程度と考えられる「ブリナツモマブ（同種 HSCT を含む）」、「イノツズマブ オ
ゾガマイシン（同種 HSCT を含む）」の両者を比較対照とする。

比較対照を選定した理いずれの集団においても、日本における診療実態、あるいは米国

由NCCN ガイドラインを参照すると、現在実施されている標準治療は（再発後）2 次化学療法（同種 HSCT を含む）である。
化学療法としては、「中央社会保険医療協議会における費用対効
果評価の分析ガイドライン第 2 版」に従い、候補となり得るものの中で、寛解率が高いと考えられる 15 歳未満の集団においては「ブリナツモマブ（同種 HSCT を含む）」、15 歳以上 25 歳以下の集団に お い ては 効果 が 同程度 と考 えられ る「 ブリナ ツモ マブ （同 種
HSCT を含む）」、「イノツズマブ オゾガマイシン（同種 HSCT を含む）」の両者を比較対照とすることが適当である。なお、イノツズマ
ブ イゾガマイシンは添付文書上で、「低出生体重児、新生児、乳児、幼児又は小児に対する安全性及び有効性は確立していない」とされることから、成人（15 歳以上）のみ比較対照技術として含めることとした。

分析の立場と費用の範ベースケースは公的医療費支払者の立場（公的医療費のみ）

囲

追加的な分析において生産性損失を考慮する

効果指標

QALY、参考値：生存年

分析期間

生涯

割引率

費用･効果ともに年率 2%39感度分析 0%-4%【DLBCL】
分析対象とする集団再発又は難治性の CD19 陽性のびまん性大細胞型 B 細胞リンパ腫。ただし、以下のいずれかの場合であって、自家造血幹細胞移
植の適応とならない又は自家造血幹細胞移植後に再発した患者に限る。
・ 初発の患者では化学療法を 2 回以上、再発の患者では再発後に化学療法を 1 回以上施行し、化学療法により完全奏効が得られなかった又は完全奏効が得られたが再発した場合
・ 濾胞性リンパ腫が形質転換した患者では通算 2 回以上の化学療法を施行し、形質転換後には化学療法を 1 回以上施行したが、形質転換後の化学療法により完全奏効が得られなかった又は完全奏効が得られたが再発した場合

比較対照

・

70 歳未満の患者：サルベージ化学療法+/-同種 HSCT・

70 歳以上の患者：サルベージ化学療法

比較対照を選定した理

治療効果の大きい治療法はサルベージ化学療法+/-同種 HSCT

由であるが、70 歳以上のサブグループについては、同種 HSCT が積
極的には実施されないことから、上記の集団ごとに、比較対照技術を設定し、それぞれ分析する。

分析の立場と費用の範ベースケースは公的医療費支払者の立場（公的医療費のみ）

囲

追加的な分析において生産性損失を考慮する

効果指標

QALY、参考値：生存年

分析期間

生涯

割引率

費用･効果ともに年率 2%
感度分析 0%-4%40

3. 追加的有用性
3.1 クリニカルクエスチョン
B-ALL 及び DLBCL の両疾患について、クリニカルクエスチョンを下記の通り PICO の形式で設定した。
3.1.1 B-ALL
海外文献 SLR における CQ：
Children and young adults (patients under 26 years of age)with r/r ALL after transplantation or second or further
対象集団

relapses
Share of the relevant patient population in the study
population at least 80% B-cell ALLa
Tisagenlecleucel, single infusion, as approved.

介入

Previously available treatment options licensed orrecommended for ALL or related oncology indications (e.g.,stem cell transplantation, chemotherapy)

比較対照

Any comparator therapy
Mortality:•

Overall survival

Morbidity:

アウトカム

•

Event-free survival•

Disease-free survival•

Progression-free survival•

Response rate•

Remission duration•

Recurrence rate•

Frequency and timing of stem cell transplants•

Adverse events

Health-related quality of life:•

Disease-specific or general validated survey
instruments

Randomized controlled trials
研究デザイン

Controlled clinical trials
Uncontrolled single-arm clinical studies
Observational studies

41

All studies include in the EMA historical comparison
文献検索期間From January 1, 1946 to July 30, 2019a. Studies in which B-cell lineage was not reported were assumed to have amajority of patients with B-cell ALL since that is the most common
immunophenotype in the population
国内文献 SLR における CQ：
再発または難治性の B 細胞性急性リンパ芽球性白血病（B-ALL）の患
対象集団者
ただし、造血幹細胞移植後または 2 回目以降に再発後で 26 歳未満の
患者に限る

介入
比較対照
アウトカム
研究デザイン

対象集団の適応症に対する以下の療法•

チサゲンレクルユーセル

制限なし
以下のいずれかのアウトカム：
生存（期間）、有効性、安全性、健康に関する QOL
ランダム化比較試験（RCT）、比較臨床試験(CCT)

文献検索期間

年

月

日から

年

月

日まで

3.1.2 DLBCL
海外文献 SLR における CQ：•

Adult patients with relapsed or refractory disease after≥2 lines of therapies, and either having failed
autologous hematopoietic stem cell transplantation(ASCT), or being ineligible for or not consenting to
ASCT

対象集団

•

Histology of interest included DLBCL not otherwise
specified, primary mediastinal large B-cell lymphoma,
high grade B-cell lymphoma, and DLBCL arising fromfollicular lymphoma•

If other histologies were included, and the DLBCL
subgroup results were not reported, share of therelevant patient population in the study population had

42・ 自家造血幹細胞移植（ASCT）が不適格である患者
・ 少なくとも過去 2 つ以上の治療に成功しなかった再発患者
介入
比較対照
アウトカム
研究デザイン
文献検索期間対象集団の適応症に対する以下の療法•

チサゲンレクルユーセル

制限なし
以下のいずれかのアウトカム：
生存（期間）、有効性、安全性、健康に関する QOL
ランダム化比較試験（RCT）、比較臨床試験(CCT)
年

月

日から

年

月

日まで

B-ALL と DLBCL の両疾患について、患者数が限られるなどの理由からこれまで臨床試験として本品のランダム化比較試験（RCT）は実施されておらず、いずれも単群試験である。本製品と比較対照技術の RCT が抽出される可能性は極めて低いため、クリニカルクエスチョンの「研究デザイン」に単群試験を含めることにした。
国内外で公開されているエビデンスを網羅するため、両疾患について英語及び日本語によるシス
テマティックレビューを実施した。
分析ガイドラインには、文献検索終了時点について「分析枠組みが決定された後から製造販売業
者による分析提出までの一時点に決める」と規定されている。しかし分析枠組みの合意に時間を要し、製造販売業者による分析提出までの期間が限られていたことから、既に一定以上の質を有するエビデンスが検出されていることを鑑み、英語によるシステマティックレビューについては文献検索終了時点を分析枠組みの決定以前に設定した（具体的な文献検索終了時点については上述の表を参照）。これらについて 2019 年

月日に実施された C2H 及び厚生労働省との協議の中で提案したところ、特に反対意見は出なかった。なお国内の文献を対象としたシステマティ
ックレビューについては、対象となるデータベースが比較的少数であるなどの理由から、分析ガイ
ドラインの規定に従い、文献検索終了時点を分析枠組みの決定後に設定した。以上より、今回の文献検索時点の設定は分析ガイドラインと照らし合わせて適切であると考える。
3.2 システマティックレビュー
3.2.1 B-ALL
海外文献 SLR：
Data Source and Search Terms
MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials(CENTRAL) were searched to identify English-language studies published fromthe start of database indexing (since. Searches were conducted using a combination of search
44Extraction
Data from the included studies were captured into an extraction template
created in Microsoft Excel®. Each article was extracted by one researcher
familiar with the subject area and validated by a second, independent
researcher.
Trial quality and a risk of bias assessments were assessed at extraction for eachstudy considered similar to the ELIANA trial. To assess risk of bias/quality, weapplied the following questions to each trial:
1. Was the allocation sequence adequately generated?
2. Was allocation adequately concealed?
3. Was knowledge of the allocated interventions adequately prevented during
the trial (blinded)?
4. Was a power calculation conducted?
5. Were the groups similar at baseline in terms of prognostic factors?
6. Were there fewer than

withdrawals?

7. Was there a balanced percentage of dropouts between groups?
8. Was intention to treat (ITT) analysis conducted?
9. Were subgroup analyses defined a priori?
Result
The electronic database searches yielded 12,935 titles and abstracts. Afterremoving duplicate references across the databases, 9,595 unique studies
remained for screening. Of these, 8,697 abstracts were excluded and 898
references remained for further full-text review. Following full-text screening,
714 of the 89 studies were excluded and 184 studies were included. Exclusions
were primarily because studies did not report outcomes separately for patientsof interest (206 studies). In addition 17 conference abstracts identified EMA
submission for tisagenlecleucel. The PRISMA flow diagram for the SLR ispresented in Figure 5. Ultimately, 14 of the included studies had populations thatwere similar to the ELIANA trial and 9 of those were deemed eligible for inclusion
in statistical analysis. Details on the 9 studies are presented in Table 5.

49

Figure5.

PRISMAflow

diagramfortheSystematic

Review

50

Table 5. List of clinical studies (papers) identified
NameofInterventio
Comparisonsclinica nl trialNR,
Retrospecti
ve
cohor
t
MT10
3-205
NCT0
1471
782

inotuzumabozogamicinblinatumo
mab

RIALT
O
NCT0
2187
354

blinatumo
mab

NR,
Phase
II
trial

Clofarabinemonothera
py

None

None

None

None

Sa
m
pl
e
siz
e

51

70

40

61

Statistic

Univariable and multivariable logistic regression was used to examine
associations between patient and disease characteristics and theprobability of achieving CR. Univariable and multivariable Cox
regression analysis was used to assess the associations between
EFS/OS and patient/disease characteristics. Estimates of EFS or OS
probability were based on the product limit estimator with Greenwood
SE. Reported p-values are all two-sided.
A minimum of 40 patients (first stage, n = 21; second stage, n = 19)
was estimated to be needed to provide 80% power to test the null
hypothesis, with two-sided p=0.05, that achievement of CR within thefirst two cycles was 10% versus the alternative hypothesis of 27.5%.
The proportion of responders with exact 95% CIs was calculated. RFS
and OS (time from enrollment to first relapse or death, respectively)
were estimated using the Kaplan-Meier method.

Reference

Bhojwani et al.
2019
[16]
von
Stackelberg et
al.
2016
[17]

NR

Locatelli et al.
2018[18]

The study’s primary objective was to estimate the overall remissionrate, which was defined as patients who achieved CR or CR without
platelet recovery divided by the number of treated patients. KaplanMeier methods were used to summarize duration of remission andoverall survival. Patients who were in remission or alive at last followup were censored at that point. In addition, patient performance

Jeha et
al.
2006
[19]
51

Name
of
Interventio
Comparisonsclinica nl trial

NR,
NCT0
0315
705

NR,
Prosp
ective
cohor
t
NR,
Phase
II
trial
NR,
Retro
spective
cohor

Clofarabine,cyclophosp
Nonehamide,andetoposide
Clofarabine,cyclophosp
Nonehamide,andetoposide
Clofarabine,cyclophosp
Nonehamide,andetoposide
Palliative care
Salvageor Supportive
chemother care (noapyantileukemic
therapy)

Sa
m
pl
e
siz
e

25

24

25

93

Statistic

status on study as well as transplantations that occurred after
clofarabine were analyzed.
The primary efficacy analysis included all patients who received atleast one dose of clofarabine. All patients who received any amount ofstudy drug were included in the safety analysis. Descriptive statistics
were used to describe response rates. Time-to-event outcomes, suchas DOR and OS, were described using Kaplan-Meier estimates. DOR
was calculated censoring patients known to be in remission at last
follow-up, and separately with censoring at the time of alternative
therapy or HSCT.
Qualitative data were reported in terms of absolute frequencies andpercentages, and quantitative data in terms of medians with minimum
and maximum values. The probability of OS was estimated using the
Kaplan–Meier method. The log-rank test was used to compare survival
curves. A p-value less than 0.05 was considered statisticallysignificant.
Quantitative variables were reported as median and range. Patientand disease-related variables were analysed for their prognostic value
on probability of obtaining CR or CRp. The probability of OS wasestimated by the Kaplan–Meier method, and expressed as 18-monthprobability, with the corresponding 95% CI. P-values < 0.05 wereconsidered significant.
Differences in the distribution of variables among subgroups wereassessed by the Mann–Whitney U- or Kruskal–Wallis test forcontinuous variables. Exact Fischer-test was used to analyze theindependency of two, Pearson-test of more than two qualitative
variables. Kaplan–Meier life-table-analysis was performed to present

Reference

Hijiyaet al.
2011
[20]

Miano
et al.
2012[21]
Locatelli et al.
2009
[22]
von
Stackelberg et
al.
2011
52

Name
of
Interventio
Comparisonsclinica nl trial
t

NR,
Prosp
ectivecohortSalvagechemotherapy

Salvagechemotherap
y + SCT

Sa
m
pl
e
siz
e

24
2

Statistic

survival data of the total cohort and subgroups only considering
disease- or treatment-related deaths as subsequent events.
Subgroups were compared by the two-sided log-rank-test. In all tests,
two-sided p≥0.05 or higher was regarded as not significant.
Multivariate Cox stepwise- forward-conditional–regression-analysis
was done to determine statistically significant independent indicatorsof outcome
The OS and EFS probabilities were calculated using the Kaplan–Meiermethod and groups were compared using the log-rank test. The
median follow-up time was estimated using the reverse Kaplan–Meiermethod. The impact of prognostic factors on EFS and OS wasevaluated in a univariate and multivariate manner by using the Cox
proportional hazards model.

Reference[23]

Kuhlen
2018
[24]

53

conducted for the time span ofto
The time
frame covered studies published over a decade, since rituximab’s approval for
DLBCL by both the European Medicines Agency (EMA) (approved in 2002) andthe US Food and Drug Administration (FDA) (approved in 2006). The following
databases were searched:• EMBASE (https://www.embase.com)• MEDLINE (inclusive “in-process & other non-indexed citations”)(https://www.ncbi.nlm.nih.gov/pubmed)• Cochrane Controlled Trials Register (CCTR) (Cochrane Library)To capture results from the most recent trials that might not have been published
as a full text, additional searches were performed for clinical trials in trial
registries. The registry search was conducted on
without any
limit to the time frame of the trials. Publications or other data associated withincluded trials specified in the registries were also leveraged to capture additional
results, including full text articles, conference abstracts, and regulatory
documents. The following trial registries were included in the search:• Clinicaltrials.gov (https://www.clinicaltrials.gov/)• European Union Clinical Trials Register (EU-CTR)(https://www.clinicaltrialsregister.eu/)• World Health Organization (WHO) and International Clinical Trials Registry
Platform (ICTRP) (http://apps.who.int/trialsearch/)
The search strategies for databases via Ovid were developed in accordance withthe best practices for systematic literature search including those published by
the Cochrane Collaboration, and health technology assessment (HTA) agencies,
and incorporated the PICOS elements to identify publications relevant to theresearch questions. Search terms comprised of combinations of keywords (freetext), subject headings (e.g., Medical Subject Headings [MeSH]) and therelationship between the search terms (e.g., Boolean logic). Additional criteria
were added (where appropriate/possible depending on the search interface used)
to restrict the search results to English publications in human studies publishedinor later. The search strategies for studies on three databases are provided
in Appendix B. Duplicate citations within databases were excluded.
Manual searches were performed on trial registries' websites to identify relevant
records. The search strategies for clinical trials in registries are delineated inAppendix B. All records identified from the database and registry searches were
electronically downloaded from the database for screening.
Screening (Inclusion/Exclusion Criteria)
A two-level screening was conducted on all records from the database search.
The detailed inclusion/exclusion criteria provided in Table 7 were used as a
guideline for the study selection to ensure that all decisions regarding theinclusion and exclusion of studies were consistent.
For all records identified from the database search, two-level screening (level I
and level II screening) were conducted by two reviewers independently as
follows:• Level I screening based on title and abstract
Studies identified from the databases were screened initially based on the title
and abstract exported from the databases. Studies that did not meet the inclusion
criteria or met the exclusion criteria were excluded at level I. When decisions toinclude or exclude studies could not be made based on title and abstract alone,full-text articles were obtained and assessed at level II.
55Table 8. List of clinical studies (papers) identified from Ovid search (N=3)
Nameof Interve
clinical trial
ntion

Compa
risonsCORAL
extension
study 1

Salvagetherapy

N/A

CORAL
extension
study 2

Salvagetherapy

N/A

SCHOLAR-1

Salvagetherapy

N/A

Sample size
• Full analysis set (baselinecharacteristics reported): N = 75
• Patients evaluated for response: N= 75• Patients evaluated for survival: N= 73• Full analysis set (baselinecharacteristics reported): N = 203• Patients evaluated for response: N= 203• Patients evaluated for survival: N= 193• Primary abstraction: N=861•
Analysisset(baseline
characteristics reported): N=636• Patients evaluated for response:
N=523• Patients evaluated for survival:
N=603

Statistic

Reference• Number of patients (%) Van Den Neste etachieving ORR, CR, PR
al. 2017[12]• Median OS• Number of patients (%)
Van Den Neste etachieving ORR, CR, PR
al. 2016[11]• Median OS• Number of patients (%)
Crump
etachieving ORR, CR, PR
2017[13]• Median OSal60

A multivariable Cox regression model adjusting for cross-trial differences inpatient characteristics was used to compare OS. Patient characteristics that wereconsistently reported in tisagenlecleucel and blinatumomab trials were adjusted
including:・Age (years)
・AlloHSCT and number of prior relapses
・With prior alloHSCT・Without prior alloHSCT and 0 or 1 relapse
・Without prior alloHSCT and 2 or more relapses
The multivariable Cox regression model provided an estimated conditional HR
comparing tisagenlecleucel vs. blinatumomab, accounting for cross-trial
heterogeneities in patient characteristics. The conditional HR contrasted thehazards of death in patients with a given set of patient characteristics (i.e., atindividual patient level) if treated with tisagenlecleucel vs. blinatumomab.
Results(a) Patients aged under 15 years old
The analysis included
tisagenlecleucel patients aged <15 from the threetisagenlecleucel trials and 62 blinatumomab patients aged <15 from the Gore2018 study. The unadjusted HR of death between two treatments was
(95%
CI: [
In the adjusting for patient characteristics using a multivariable
Cox regression model, tisagenlecleucel was associated with% lower hazard ofdeath compared to blinatumomab ([(b) Patients aged 15 years old or above
The analysis included
tisagenlecleucel patients aged ≥15 from the threetisagenlecleucel trials, and a total of 70 patients of all ages from the Gore 2018
study. All the patients from the Gore 2018 study were included because only 8
patients were aged ≥15. The unadjusted HR of death between two treatmentswas(95% CI:In the adjusting for patient characteristics using a multivariable Cox regression
model, tisagenlecleucel was associated with% lower hazard of death
compared to blinatumomab ([]).
Limitation• The current study adjusted patient characteristics that were consistently
reported in the trials of both treatments. However, some factors were notable to be adjusted due to inconsistent definitions across trials (e.g.,
refractory to the last line of treatment). In addition, there may be unobservedor unmeasurable differences between the tisagenlecleucel trials and the Gore2018 study that could confound the comparison results.
• The analyses using pooled data from three tisagenlecleucel trials (B2202,
B2205J, and B2101J) ensured a sufficient sample size and statistical power
to detect the difference between treatments. However, the potential
heterogeneities across the three tisagenlecleucel trials (B2202, B2205J, andB2101J) were not adjusted for in the analyses.
• The Gore 2018 study included an extremely small number of patients aged
≥15. All patients in the Gore 2018 study were used in the comparisons oftreatment effects on OS for patients aged ≥15. The comparison results relyon the assumption that blinatumomab patients had similar survival as theoverall pediatric patient population.
64

•

Since the primary goal of treatment is to cure the cancer, OS should beconsidered as one of the primary endpoints to evaluate the treatment efficacy.
In addition, survival is considered the most reliable cancer endpoint, andwhen studies can be conducted to adequately assess survival, it is usually thepreferred endpoint. The other outcomes were not compared due to data
unavailability in Gore 2018 study (e.g., PFS) or inconsistent definition
between the tisagenlecleucel trials and Gore 2018 study (e.g., complete
remission and minimal residual disease).

3.7.2 B-ALL: Kymriah (tisagenlecleucel) vs. Inotuzumab
Data Sources
Patient-level data from three tisagenlecleucel trials (B2202, B2205J, andB2101J)As same as ITC vs Blinatumoma, Patient-level data on patient characteristics andOS for patients treated with tisagenlecleucel from the B2202 (ELIANA;
NCT02435849), B2205J (ENSIGN; NCT02228096), and B2101J (NCT01626495)
trials were pooled and 15-25 age sub-group used in the analyses.[25]–[27]Published aggregate data from a Inotuzumab trial (Bhojwani 2019)[16]A retrospective cohort reported on the results for Intuzumab in a compassionate
use program of heavily pretreated patients ≤21 years of age. The study
population was comprised mainly of those refractory to prior treatment (80%)
and 71% of patients had received 4 or more prior treatment regimens. In addition,
43% of patients had received prior treatment with blinatumomab, and 29% had
been treated with CAR-T therapy. At 12 months, the OS and EFS rates were
36.3% and 23.4%, respectively. Median duration of survival was not reported.
Methods
We conducted an indirect comparison for the two datasets, using matching
indirect comparisons (MAICs). MAICs adjust for the differences in selectedbaseline characteristics by assigning balancing weights to the tisagenlecleucelpatients so that their re-weighted baseline matches the comparator patient
baseline. In order to prioritize the characteristics to adjust, the available
matching characteristics were assessed on their relative predictive value on
outcomes in this heavily pre-treated r/r pALL population based on clinician input
and the literature.
Although prior lines of therapy was ranked high as a matching characteristic,
there was a large imbalance between the trials. Matching on previous relapses,
disease status, prior lines of therapy, and prior HSCT did not converge. Therefore,
we only matched on previous relapses, disease status, and prior HSCT in themain analyses.
Results
The analysis included
tisagenlecleucel patients aged ≥15 from the threetisagenlecleucel trials, and a total of 51 patients of all ages from the Bhojwani2019 study. Before matching, tisagenlecleucel was associated with a%lower hazard of death than inotuzumab (log-rank p-value<0.01; HR [95% CI] =[After matching, the hazard of death remained significantly
lower with tisagenlecleucel vs. salvage chemotherapies (weighted log-rank pvalue<0.01; HR [95% CI] =
[

65

and
patients were infused with tisagenlecleucel (i.e., mITT population,
inthe Main Cohort andin Cohort A, which comprised the FAS). The EAS includes
patients who received a tisagenlecleucel infusion) prior to data cutoff. In the current data, all FAS patientsare included in the EAS (N=), which consisted ofpatients from the Main
Cohort andpatients from Cohort A. The following patient sets were used in
the comparisons with historical controls: mITT patients in both cohorts (FAS) for
OS analysis.
Published aggregate data from the CORAL extension studies
CORAL is a phase III, multi-center, randomized trial that compared the efficacyof three cycles of rituximab, ifosfamide, carboplatin, and etoposide (R-ICE) or
rituximab, dexamethasone, high-dose cytarabine, and cisplatin (R-DHAP) as
second-line therapy, followed by ASCT with or without rituximab maintenance,in patients with relapsed DLBCL.[11], [12]Among the 477 patients randomized to R-ICE or R-DHAP, 255 patients whoachieved CR, PR, or stable disease (SD) after the third cycle of salvage treatment
with adequate stem cell collection received consolidation with BEAM (carmustine,
etoposide, cytarabine, and melphalan), followed by ASCT; 75 patients relapsed
thereafter and received mixed third-line salvage chemotherapies. The remaining
222 patients did not proceed to planned ASCT according to the protocol becauseof an event leading to withdrawal between cycle 1 of R-ICE or R-DHAP andscheduled ASCT. Among these 222 patients, 6 withdrew their consent, and 13
died before planned ASCT. All patients in the CORAL extension studies were underage 70. CORAL patients enrolled in the following two extension studies were
included in the current analysis:o CORAL extension study 1: 75 patients in the CORAL observational followup phase who relapsed after ASCTo CORAL extension study 2: 203 patients in the CORAL observational followup phase who failed to proceed to ASCT
Methods
When comparing outcomes between JULIET and historical control groups deemedsuitably similar, additional steps were undertaken to account for any differencesin patient baseline characteristics via statistical adjustment when possible. These
adjustments were accomplished using the MAIC approach, which is an extensionof propensity score weighting to settings in which only aggregate data are
available for external controls. In particular, each patient in the study withavailable IPD (patients from JULIET, in this case) is re-weighted based on apropensity score model such that after re-weighting, the average baselinecharacteristics among these patients match those reported for the external
control group.
The following three sets of analyses were performed:(a) Comparison of OS in overall population: JULIET mITT patients in both cohortsof the FAS vs. pooled CORAL patients(b) Comparison of OS in age <70 group: JULIET mITT patients under the age of
70 in both cohorts of the FAS vs. pooled CORAL patients (all CORAL patients werewith age < 70 years)
In each comparison, JULIET patients with missing values in the baselinecharacteristics to be matched were excluded from the analysis. Variables includedin the matching adjustment were:
67

•

in the CORAL extension study were required to be candidates for third-line
chemotherapy by design. As patients who received more prior therapies are
expected to have worse efficacy outcomes with chemotherapies compared topatients who received fewer prior therapies, this difference in populations
would be expected to bias the comparison of outcomes against the JULIET
population. Additionally, in the CORAL extension study where patients failed
to proceed to ASCT, 26 (out of 203) patients achieved CR/CRu to second-line
regimen, and 30 (out of 203) patients achieved PR to second-line regimen.
Those patients who had responses to the second-line might be more likely torespond to the third-line regimen. However, given that more than half of thepatients in the JULIET study had at least three lines of prior treatment, it is
not feasible to adjust for such differences, which may bias the comparison
results. JULIET patients had either failed ASCT or were ineligible for ASCT atenrollment, and the JULIET trial inclusion criteria required patients to havefailed at least two prior lines of therapies with the majority (%) failingthree of more lines of treatment, while all patients in CORAL extensions
received only two prior lines of therapy. In addition, approximately 30% of
patients in CORAL extensions received SCT during the follow up. These factors
could favor bias toward historical controls from CORAL extensions over JULIET,
as SCT has been shown to extend survival. Lastly, IPI data were only available
for 115 (out of 203) patients who failed to proceed to ASCT and 67 (out of75) patients who relapsed after ASCT in the CORAL extension studies, which
may result in residual confounding due to inadequate adjustment for baseline
IPI. As with any comparison of non-randomized treatment groups, thiscomparison was subject to potential bias due to unobserved or unmeasurable
confounding.
The analysis of OS comparison among patients aged ≥70 years was not
feasible between JULIET and CORAL patients, as no patients in the CORAL
extension studies were aged ≥70 years, and only( %) JULIET patientswere aged ≥70 years.

3.8 追加的有用性の有無に関する評価【B-ALL】
対象集団

15 歳未満の B-ALL

介入

キムリア点滴静注

比較対照

ブリナツモマブ +/- 同種 HSCT

アウトカム

Overall Survival

追加的有用性の有無
判断の根拠となった
データ
追加的有用性の有無を判断した理由■ 追加的有用性あり □ 「追加的有用性なし」あるいは「ありとは判断できない」□ RCT のメタアナリシス □ 単一の RCT□ 前向きの比較観察研究 □ RCT の間接比較■ 単群試験の比較 □ 臨床データなし
Pooled trial data(B2101J、ELIANA/B2202、ENSIGN/B2205)の
15 歳未満集団と Gore 2018 の 15 歳未満集団との間接比較（OS）において、conditional HR は(95% CI: [)であった。

70このことから、本製品は比較対照技術に対して追加的有用性を有すると
判断した。
対象集団

15 歳以上 25 歳未満の B-ALL

介入

キムリア点滴静注

比較対照

ブリナツモマブ +/- 同種 HSCT
イノツズマブ +/- 同種 HSCT

アウトカム

Overall Survival

追加的有用性の有無
判断の根拠となった
データ

追加的有用性の有無を判断した理由■ 追加的有用性あり □ 「追加的有用性なし」あるいは「ありとは判断できない」□ RCT のメタアナリシス □ 単一の RCT□ 前向きの比較観察研究 □ RCT の間接比較■ 単群試験の比較 □ 臨床データなし
ブリナツモマブを比較対照にした場合、Pooled trial data（B2101J、
ELIANA/B2202、ENSIGN/B220）の 15 歳以上集団と Gore 2018の全体集団との MAIC 分析（OS）において、conditional HR は
（95%CI: [であった。
イノツズマブを比較対照にした場合、Pooled trial data（B2101J、
ELIANA/B2202、ENSIGN/B2205）の 15 歳以上集団と Bhojwani2019 の全体集団との MAIC 分析（OS）において、conditional HR は
（95%CI: [であった。このことから、本製品は比較対
照技術に対して追加的有用性を有すると判断した。

【DLBCL】
対象集団

70 歳未満の DLBCL

介入

キムリア点滴静注

比較対照

救援化学療法 +/- 同種 HSCT

アウトカム

Overall Survival

追加的有用性の有無
判断の根拠となった
データ
追加的有用性の有無を判断した理由

対象集団■ 追加的有用性あり □ 「追加的有用性なし」あるいは「ありとは判断できない」□ RCT のメタアナリシス □ 単一の RCT□ 前向きの比較観察研究 □ RCT の間接比較■ 単群試験の比較 □ 臨床データなし
JULIET 試験の 70 歳未満集団と CORAL extention studies（すべての患者が 70 歳以下）との MAIC 分析（OS）において、conditional HR
は（95% CI: [であった。このことから、本製品は比較対照技術に対して追加的有用性を有すると判断した。
70 歳以上の DLBCL

71

介入

キムリア点滴静注

比較対照

救援化学療法アウトカム

Overall Survival

追加的有用性の有無
判断の根拠となった
データ

追加的有用性の有無を判断した理由■ 追加的有用性あり □ 「追加的有用性なし」あるいは「ありとは判断できない」□ RCT のメタアナリシス □ 単一の RCT□ 前向きの比較観察研究 □ RCT の間接比較■ 単群試験の比較 □ 臨床データなし
介入群（tisagenlecleucel）の有効性データについて、JULIET 試験において本製品が投与された患者のうち、本対象集団に該当する 70 歳以上の患者は症例に限られる。また、全生存期間や無増悪生存期間の解
析上の情報量（生存時間解析手法におけるイベント数）は 例である。
もともと JULIET 試験は年齢別の解析を想定せずにデザインされており、年齢で層別化した場合のサンプルサイズが極めて小さくなり、統計的検出力は低下する。それゆえ間接比較における比較可能性の検討や、統計的手法による調整も困難になる。以上より、JULIET 試験の 70 歳以上の症例のみを抽出した結果をもとに追加的有用性のみを判断することは極めて困難である。
2019 年月 日に開催された第 3 回費用対効果評価専門組織において C2H より、元々想定されていないサブ集団を構築したことによって追加的有用性を示すことが困難になった場合には、切り分け前の全体集
団、この場合であれば年齢の区切りのない全体集団の結果を参照することを容認する旨のコメントを得ている。
JULIET 試験の全体集団と CORAL extention studies（すべての患者が 70 歳以下）との MAIC 分析（OS）において、conditional HR は（95% CI: [）であった。全体集団の間接比較で追加的有用性が確認されていることから、本患者集団についても本製品は比較対照技術に対して追加的有用性を有すると判断した。

72

4. 分析方法の詳細
4.1 分析方法
4.1.1 費用対効果の算出方法
4.1.1.1 B-ALL
・医療経済評価モデル（マルコフモデル）の概要
The cost-effectiveness model was developed in Microsoft Excel®. The analysis
used a decision tree approach to determine the proportion of patients initiallyassigned to tisagenlecleucel who continued to infusion (Figure 9).
After the initial decision-tree partition, patients on tisagenlecleucel enter into thepartitioned survival model. Patients on the comparators directly enter into thepartitioned survival model. The model comprised of three mutually exclusive
health states: (i) event-free survival (EFS), (ii) progressive disease (PD) and (iii)
death (Figure 10). EFS was defined as the time from the date of treatment
initiation to the earliest date of death, relapse, or treatment failure. All patientsbegan in EFS at the model start. The proportion of patients in the EFS healthstate of the model was set to be equal to the EFS curve of each treatment. The
PD state included alive patients who progressed or relapsed. The proportion ofpatients in the PD health state was set to be equal to the difference between the
proportion of living patients, which was based on the OS curve, and the
proportion of EFS patients. During each cycle, patients were redistributed among
the three health states, with death being the absorbing state. A monthly model
cycle was used for estimating the proportion of patients in each heath state overtime.
Figure 9. Tisagenlecleucel decision tree structure

Figure 10. Partitioned survival model structure73Subsequent HSCT was considered in the model since subsequent HSCT is an
important treatment option in the clinical pathway of r/r pALL patients.
Subsequent HSCT was not modelled as a distinct health state, but the efficacy
benefit of subsequent HSCT was captured in the OS and EFS estimates of eachtreatment arm, and the cost and disutility of subsequent HSCT was added
separately for each treatment arm using age-group specific HSCT rate data if
available.
Half-cycle correction was applied, in order to account for the real-world in which
patients transition to the subsequent health state continuously throughout agiven cycle. It did this by assuming that patients transition, on average, halfway
through a cycle. This correction was applied to avoid an over- or under-estimationof the results that might occur without the correction (i.e., assuming patients
only transition at the beginning or end of a cycle). Treatment costs before
maintenance therapy initiation (if applicable) were applied as one-time costs inthe model, which were not affected by the half-cycle correction.
4.1.1.2 DLBCL
・医療経済評価モデル（マルコフモデル）の概要
The cost-effectiveness model was developed in Microsoft Excel®. The analysis
used a decision tree approach to determine the proportion of patients initiallyassigned to tisagenlecleucel who continued to infusion (Figure 11).
After the initial decision-tree partition, patients on tisagenlecleucel enter into thepartitioned survival model. Patients on salvage chemotherapy directly enter into
the partitioned survival model. The model comprised of three mutually exclusive
health states: (i) PFS, (ii) PD/RL and (iii) death (Figure 12). PFS was defined as
the time from the date of tisagenlecleucel infusion or treatment initiation to thedate of first documented progression or death due to any cause. All patientsbegan in PFS at the model start. The proportion of patients in the PFS healthstate of the model was set to be equal to the PFS curve of each treatment. The
PD/RL state included alive patients who progressed or relapsed. The proportionof patients in the PD/RL health state was set to be equal to the difference between
the proportion of living patients, which was based on the OS curve, and the
proportion of PFS patients. During each cycle, patients were redistributed among
the three health states, with death being the absorbing state. A monthly model
cycle was used for estimating the proportion of patients in each heath state overtime.
Figure 11. Tisagenlecleucel decision tree structure74

Figure 12. Partitioned survival model structure

Subsequent SCT, including both allo SCT and auto SCT, was considered only inthe < 70 model. The efficacy benefit of subsequent SCT was captured in the OS
and PFS estimates of each treatment arm. The cost and disutility of subsequent
SCT were added separately for the proportion of patients who received the SCT
treatment based on trial observation for tisagenlecleucel and literature for thecomparator.
Half-cycle correction was applied, in order to account for the real-world in which
patients transition to the subsequent health state continuously throughout agiven cycle. It does this by assuming that patients transition, on average, halfway
through a cycle. This correction was applied to avoid an over- or under-estimationof the results that may occur without the correction (i.e., assuming patients onlytransition at the beginning or end of a cycle). Treatment costs were applied as
one-time costs in the model, which were not affected by the half-cycle correction.
4.1.2 モデルで使用した仮定
B-ALL
Parameter
Assumption
Health states• Utilities of health states were assumed to be
and utilities bydependent only on health states and independent on
health statestreatment arms
• At the start of each model cycle, patients wereredistributed among the 3 health states (EFS, PD anddeath), with death being the absorbing state
Disutility• Treatment disutilities for comparators were considered
for the duration of the treatment; Treatment
disutilities for tisagenlecleucel were considered for theduration of hospitalization after the infusion• These treatment disutilities included disutilities of AEs
during the treatment period, except for CRS (cytokine
release syndrome). Disutilities of CRS were added
separately

75

Parameter
Subsequent
HSCT

Efficacy

Medical costs
and AE costs

Discontinuation
prior totisagenlecleucel
infusion

Societal Costs

Assumption• Subsequent HSCTs after the initial treatment wereconsidered in the model to reflect the natural
treatment course patients experienced• Efficacy benefit of subsequent HSCT were captured in
the EFS and OS estimations• Cost and disutility of subsequent HSCTs wereconsidered for the proportion of patients who received
subsequent HSCT• In the base-case, the observed data was used during
the trial period. Afterwards, parametric survival
models were used to project OS and EFS fortisagenlecleucel and ITC analysis result was used toproject OS and EFS for comparators using
tisagenlecleucel as the reference arm up to year 5.
After year 5, the model estimated the OS based onlong-term ALL survivors and assumed there was nodifference in mortality risk across treatment arms.
• EFS data were not reported for blinatumomab arm in
the publications; EFS for blinatumomab were
estimated based on the OS data assuming a constantcumulative HR over time between EFS and OS. Afteryear 5, the model assumed that was no additional
events beyond death in the base-case• In addition to treatment and AE costs, the model
considered additional medical costs including follow-up
costs, post-progression costs and terminal care costs• AE costs are only considered for tisagenlecleucel andblinatumomab to be conservative, which composes ofcosts for treating CRS and B-cell aplasia. Costs ofother AEs are reflected in the hospitalization costs.
• All patients incur one-time terminal care costs beforedeath• A proportion of patients in the clinical trials oftisagenlecleucel did not go on to receive
tisagenlecleucel due to manufacture failure orwithdrawal due to adverse events or death in the
period post-leukapheresis and pre-infusion• It was assumed that these patients would therefore
instead receive the blinatumomab comparator, andhave the same efficacy, cost, and disutility as thecomparator treatment• Societal costs were not considered in the base-casemodel, but were considered in the DSA. Employment
rates by age and the average wage were used to
calculate the societal costs

76

DLBCL
Parameter
Health states
and utilities byhealth states
Disutility

Subsequent
SCT ( for aged
less than 70)

Efficacy

Medical costs
and AE costs

Assumption• Utilities of health states were assumed to depend only
on health state and be independent on treatment arm• At the start of each cycle, patients were redistributed
among the 3 health states, PFS, PD/RL, and death,with death being the absorbing state• Treatment disutilities for chemotherapies wereconsidered for the duration of the treatment;
Treatment disutilities for tisagenlecleucel wereconsidered for the duration of hospitalization after theinfusion• These treatment disutilities included disutilities of AEs
during the treatment period, except for CRS.
Disutilities of CRS were added separately• Subsequent SCTs after the initial treatment wereconsidered in the model to reflect the natural
treatment course patients experienced. Both auto SCT
and allo SCT could be feasible as subsequent SCT, andboth were considered• Efficacy benefit of subsequent SCT were captured in
the PFS and OS estimations• Cost and disutility of subsequent SCT were considered
for the proportion of patients who received subsequent
SCT• In the base-case analysis, the observed OS data fromtisagenlecleucel trial and CORAL extension studies
were used directly until year 3. Afterwards, the model
used literature for DLBCL long-term survivors to informthe mortality risk and assumed there was no difference
in mortality risk across treatments.
• Observed PFS data for tisagenlecleucel was used until
year 3. PFS data are not reported for salvage
chemotherapy in the literature and is estimated basedon the OS data assuming a constant cumulative hazard
ratio (HR) over time. After year 3, the model assumed
no additional progression in the base-case• In addition to treatment and AE costs, the model
considered additional medical costs including follow-up
costs, post-progression costs and terminal care costs• AE costs were only considered for tisagenlecleucel tobe conservative, which composes of costs for treating
CRS and B-cell aplasia. Costs of other AEs are reflectedin the hospitalization costs• All patients incur one-time terminal care costs before
death

77

Parameter
Discontinuation
prior totisagenlecleucel
infusion

Societal Costs

Assumption• A proportion of patients in the clinical trial oftisagenlecleucel did not receive tisagenlecleucel due tomanufacture failure, or withdrawal due to AEs or deathin the period post-leukapheresis and pre-infusion• It was assumed that these patients would therefore
instead receive the comparator treatment (i.e., salvage
chemotherapy), and have the same efficacy, cost, anddisutility as patients with the comparator treatment• Societal costs were not considered in the base-casemodel, but were considered in the DSA. Employment
rates by age and the average wage were used to
calculate the societal costs

78(該当
する場
合)
95%
CI

分布[該
当する場
合]

35.71%

NA

NA

Gore et al., 2019[28]41.18%

NA

NA

Bhojwani et al., 2019[16]

0.91
0.75

NA
NA

NA
NA

ELIANA, ENSIGN, B2101J[25]–[27]

-0.42

NA

NA

-0.42
-0.57
Age <25: 0.97
Age 25-34: 0.96
Age 35-44: 0.97
Age 45-54: 0.94
Age 55-64: 0.91

NA
NA

NA
NA

Sung et al., 2003[31]NANA

Janssen 2014[32]

NA

NA

変数名

Subsequent HSCT rate forblinatumomab
Subsequent HSCT rate for
inotuzumab
Utility (4.2.2)
Utility for EFS
Utility for PD
Disutility fortisagenlecleucel (infused
patients)
Disutility for comparator
HSCT disutility
Age-related utility (absolutevalue)
Cost (4.2.3)
Pre-treatment cost(tisagenlecleucel only)

Tisagenlecleucel treatment(infused patients)

値

Leukapheresis: ¥174,400
Bridging chemotherapy:¥
Lymphodepleting regimen:¥
Tisagenlecleucel infusion:¥34,113,655
Administration: ¥308,500
Hospitalization: ¥設定根拠

Sung et al., 2003[31]See Section 4.2.3
NA

NA

83

(該当
する場
合)
95%
CI

分布[該当す
る場合]

0.83
0.39

NA
NA

NA
NA

-0.15

NA

NA

-0.15
-0.30

NA
NA

NA
NA

NA

NA

変数名

Utility (4.2.2)
Utility for PFS
Utility for PD
Disutility for tisagenlecleucel(infused patients)
Disutility for comparator
HSCT disutility
Cost (4.2.3)

Pre-treatment cost(tisagenlecleucel only)

Tisagenlecleucel treatment(infused patients)

Salvage Chemotherapy

値

Leukapheresis:¥174,400
Bridging
chemotherapy:¥
Lymphodepleting
regimen: ¥Tisagenlecleucel
infusion: ¥34,113,655
Administration:
Hospitalization:
ICU: ¥
Drug: ¥1,301,260
Administration:¥98,480
Hospitalization:¥266,068

NA

NA

NA

NA

設定根拠

Chen et al. 2017[33]Guadagnolo et al. 2006[34]Guadagnolo et al. 2006[34]See Section 4.2.3

86

変数名
Mean weight (kg)
Proportion receiving infusion(tisagenlecleucel arm only)
Efficacy & Safety (4.2.1)
OS (tisagenlecleucel)EFS(tisagenlecleucel)
OS (comparator)
PFS(comparator)
Utility (4.2.2)
Utility for PFS
Utility for PD
Disutility for tisagenlecleucel(infused patients)
Disutility for comparator
Cost (4.2.3)

Pre-treatment cost(tisagenlecleucel only)

値

%

(該当す
る場合)
95%
CI
NA

分布[該当す
る場合]
NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

0.83
0.39

NA
NA

NA
NA

-0.15

NA

NA

-0.15

NA

NA

Leukapheresis:¥174,400
Bridging
chemotherapy:

NA

NA

Observed followed bylong-term survivor
data
Observed followed byassumption
Observed followed bylong-term survivor
data
PFS estimated based
on OS

設定根拠

JULIET trial data among patients >=70
years and CORAL extension studies
w/o HSCT[11], [12], [29]Chen et al. 2017[33]Guadagnolo et al. 2006[34]See Section 4.2.3

Lymphodepleting
regimen:88Figure 18. Base-case OS estimation diagram for tisagenlecleucel andcomparators (age < 15 years)

Figure 19. Base-case OS estimation diagram for tisagenlecleucel andcomparators (age 15-25 years)

94who survived 5 years
or more after diagnosis

ALL patients:
429

survivors:
9.05

Abbreviations: ALL, acute lymphoblastic leukemia; SMR, standardizedmortality ratio
生存曲線の推計（PFS）
The EFS of tisagenlecleucel infused patients was based on the IPD pooled from 3
clinical trials of tisagenlecleucel: ELIANA (data cut-off:), ENSIGN
clinical trials (data cut-off:) and B2101J (data cut-off:) trials.[25]–[27] Similar to OS, the EFS was defined among infused
population and was evaluated from the time of infusion. The EFS for patients inthe tisagenlecleucel arm but not infused was the same as that of theblinatumomab comparator. No EFS data was available for the blinatumomab
comparator, and was estimated based on OS assuming a constant cumulative HR.
EFS data was also available for the inotuzumab comparator and was reported in
Bhojwani et al 2019.[16] Age group-specific data were used whenever feasible
to inform the EFS among patients aged < 15 years and aged 15-25 years,
respectively.
Parametric function and ITC method was used to inform and project EFS
estimates in the CEA model after the end of trial observation. Parameter
estimates and goodness-of-fit criteria were estimated for EFS using the same
approach as described above for OS, and each survival distribution was described.
Due to the limited number of events over the long-term in subgroup analysis(tisagenlecleucel arm among patients aged 15-25 years), some spline models for
the EFS parametric estimation could not converge. A weighted distribution basedon various parametric survival curves was then derived and applied in the basecase analysis. A visual comparison of the survival data based on the observed
data, all considered distributions, and the weighted distribution are reported in
Figure 22-24, by age groups. The summary of AIC values and the weights
considered for each survival distribution are presented in Appendix C.

97Tisagenlecleucel(infused
patients)
Blinatumomab
Inotuzumab
Other utility/disutility

SGNA

ICU stay not due to CRS

NA

NA

Grade3/4 CRS disutility

NA

NA

HSCT disutility

SG

NA

EQ-5D

NA

Age-related utility

Sung et al.,
2003[31]
Assumption:utility=0 during ICU
admission
Assumption:utility=0 during ICU
admission
Sung et al.,
2003[31]
Janssen 2014[32]Health states utility
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 based on
published studies and trial-based utility inputs were used in the sensitivity
analysis.
Kelly et al., 2015 used a decision analysis to evaluate cranial radiation therapy
for pediatric T-cell ALL patients and performed a systematic literature review(SLR) of utility studies as part of the analysis.[30] While the study focused on Tcell 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 andCHRIs) 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 wereconsidered relevant for the CEA model and was used to inform the utility value
for the PD and EFS states respectively in the base-case model.
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 forall short-term AEs associated with the treatment, with the exception for thecytokine release syndrome (CRS).
Additional treatment disutilities associated with CRS were considered for patientswith grades 3 or 4 CRS. The CRS rate for tisagenlecleucel was derived from the
ELIANA trial data and the rate for blinatumomab was derived from vonStackelberg et al., 2016.[17] No patients from the inotuzumab arm experienced
grades 3 or 4 CRS. Patients were assumed to have a utility of 0 (a disutility of
0.91 based on EFS utility) for the duration of the CRS ICU based on the ELIANA
trial. For the tisagenlecleucel arm, an additional treatment disutility was also
considered for ICU stays not due to CRS by assuming that patients in the ICU
would have a utility value of 0. The treatment and adverse events disutility
considered in the model are summarized in Section 4.2.
Subsequent HSCT disutility
The model assumed patients could receive subsequent HSCT after initial
treatment. Patients receiving subsequent HSCT were assumed to have additional
106

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-group specific data was used forthe rate of subsequent HSCT where feasible. The subsequent HSCT disutility
considered in the model are summarized in Section 4.2.
Age-related utility
Because the utility inputs for the model were estimated based on a pediatric andadolescent 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 healthutilities of healthy populations by different age groups using the EQ-5D index
population norms based on the Japan time-trade-off value sets.[32] Age-related
utility decrements were estimated based on the absolute utility values reported
for each age group (e.g. adjustment for age 25-34 was calculated as
and were applied to all alive patients over the modelled time horizon.
4.2.2.2 DLBCL使用した尺度
測定者数
変数名
reference
Health states utility (base-case)
PFS
EQ-5D
NA
Chen et al. 2017a[33]
PD/RL
EQ-5D
NA
Treatment disutility
Tisagenlecleucel
Guadagnolo et al. 2006b[34](infused patients),
NA
NA
Salvagechemotherapy,
Other utility/disutility
HSCT disutility
NANA
Guadagnolo et al. 2006b[34]Grade3/4
CRS
Assumption: utility=0 duringNANA
disutility
ICU admission
a. Micro-simulation models were developed to study the cost-effectiveness of
precision treatment strategies for DLBCL patientsb. A decision-analytical model to evaluate follow-up strategies for patients with
Hodgkin's disease
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 target population. The utility inputs used in the base-case were obtained
from Chen et al. 2017, where micro-simulation models were developed 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 forthe adult lymphoma population developed by the Institute for Clinical andEconomic Review. In the DSA, an alternative set of utility values were consideredbased on SF-36 data collected from the JULIET data. A mapping algorithm wasused to convert the SF-36 data to derive the utility measures.

107

Treatment disutility
Inputs for treatment disutility were obtained from Guadagnolo et al. 2006.[34]
Guadagnolo et al. 2006 developed a decision-analytical model to evaluate followup strategies for patients with Hodgkin's disease. Utility and disutility inputs forpatients with Hodgkin's disease were consolidated from prior published studies
and used in the analysis. A decrement of 0.15 for patients undergoing
conventional dose salvage chemotherapy was reported and assumed to capture
the utility decrements for all short-term AEs associated with the tisagenlecleucel
or salvage chemotherapy, with the exception of the CRS.
For the tisagenlecleucel arm, additional treatment disutilities were considered forgrade 3 or 4 CRS and intensive care unit (ICU) stays not due to CRS. For both
events, the patients were assumed to have a utility of 0 (a disutility of -0.83
based on PFS utility).
HSCT disutility
The model assumed patients could receive subsequent auto SCT or allo SCT after
initial treatment. The efficacy of subsequent SCT was captured in the PFS and OS
estimations. Patients receiving either subsequent auto SCT or allo SCT wereassumed to have additional SCT disutility, derived from Guadagnolo et al.
2006.[34]4.2.3 費用のパラメータの詳細
本品の対象疾患となる B-ALL および DLBCL は、いずれも患者数が少ないことから、レセプトデータを用いた費用の分析は不確実性が大きくなると判断し、標準治療モデルをベースにした推計を実施した。
B-ALL と DLBCL の両疾患について、原則として 2019 年 10 月時点の診療報酬点数表、薬価基準に基づき、積み上げ方式により分析対象技術及び比較対照技術にかかる費用を推計した。
資源消費量の推計に関しては、本品は臨床試験で使用されたレジメンの実績を、比較対照技術
は診療ガイドラインで規定された標準的な用法を用いた。有害事象の治療費は、臨床試験の発症率に、予め設定した個別の有害事象治療フローのコストを乗じて、期待費用を計算した。なお、本邦では、DLBCL 患者の増悪後の統一された治療方針やコストに関するデータが存在しない。そのため、DLBCL の増悪後のコストは、海外データを日本円に換算して使用している。海外データの外挿は大きな不確実性を伴うため、感度分析での考慮を行った。以下に費用の各構成要素における詳細について記載する。
4.2.3.1 B-ALL
Tisagenlecleucel cost
For tisagenlecleucel arm, the model used a decision-tree approach to partition
patients based on the infusion status to assign different effectiveness, cost anddisutility inputs. For patients who proceeded with infusion, they were assumed
to incur the cost related to tisagenlecleucel treatment. For patients who
discontinued before infusion, they were assumed to incur the costs related to theblinatumomab comparator. The model considered% and% proceededwith infused for patients aged < 15 years and patients aged 15-25 years
respectively, based on the observed infusion rate from the pooled trial data of
ELIANA, ENSIGN, and B2101J.[25]–[27] Regardless of infusion, patients on
tisagenlecleucel arm will incur pre-treatment leukapheresis cost. Table 14
summarizes how different cost components were attributed to patients in thetisagenlecleucel arm based on their infusion status.

108

Table 14. Attribution of cost for tisagenlecleucel arm based on patients’
infusion status
Cost component
Pre-treatment:
leukapheresis
Pre-treatment:
bridging
chemotherapy
Pre-treatment:
lymphodepleting
regimenTreatment cost:tisagenlecleucel orcomparator
treatment
Adverse event
Subsequent HSCT
Follow-up

Infused patients
Non-infused patients
Same leukapheresis cost for all patients regardless of
infusion status
Only considered for infused NA
patients
Only considered for infused
patients

NA

Drug, administration, andhospitalization costassociated withtisagenlecleucel infusion
Adverse event associatedwith tisagenlecleucel
Subsequent HSCT rate
based on tisagenlecleuceltrialsTisagenlecleucel-specificfollow-up cost by healthstatesDrug, administration, andhospitalization costassociated withblinatumomab
Adverse event associatedwith blinatumomab
Subsequent HSCT rate
based on blinatumomab
Blinatumomab-specificfollow-up cost by healthstatesPre-treatment cost
Prior to tisagenlecleucel infusion, patients have to undergo three pre-treatment
phases:leukapheresis, bridging chemotherapy, andlymphodepleting
chemotherapy. The costs associated with each of these pre-treatment phases
were applied in the first cycle of the model. The proportion of patients attributed
the costs of each of three pre-treatment phases were specified in Table 15.
•Leukapheresis: collection of T-cells from the patients and consisted ofleukapheresis and cryopreservation procedures.The cost of leukapheresis andcryopreservation was estimated to be ¥174,400 based on official gazette releasedby Ministry of Health, Labour and Welfare, and assumed to be the same acrossboth age groups.[45] All patients in the tisagenlecleucel arm were assumed toincur the cost of leukapheresis and cryopreservation procedures, regardless ofwhether they received tisagenlecleucel infusion or not.
•Bridging chemotherapy: chemotherapy administered to stabilize disease whilst
waitingfortisagenlecleucel
manufacturingandinfusion.Withinthetisagenlecleucel clinical trials, the provision of bridging chemotherapy was left toinvestigator discretion and therefore a wide range of bridging chemotherapy
regimens were received by patients in all three trials. As such, the costs ofbridging chemotherapy (i.e., drug acquisition costs and administration costs)
were assumed to be the average costs of the salvage chemotherapy regimens
following the Children's Oncology Group AALL01P2 protocol.[46] Specifically, a
total of ¥was estimated for patients aged <15 years and ¥wasestimated for patients aged 15-25 years as the average BSA and weight profile
differs between age groups. For patients who received tisagenlecleucel infusion,
the model assumed% of patients would receive bridging chemotherapy,
based on pooled data from ELIANA, ENSIGN and B2101J, which was assumed to109

be the same across age groups.[25]–[27] For patients who discontinued prior totisagenlecleucel infusion, they were assumed to be managed by blinatumomab
comparator, and would not need any bridging chemotherapy treatment.
•Lymphodepleting regimen: treatment administered to facilitate the engraftment
and homeostatic expansion of tisagenlecleucel cells
In tisagenlecleucel trials, lymphodepleting regimen was administered to patientsdays prior to the infusion. It was assumed that the cost of this regimen was
only applied to the proportion of patients who received tisagenlecleucel infusion(% for patients aged <15 years and% for patients aged 15-25 years).
The lymphodepleting regimens and resource use as observed in the ELIANA trial
was used to model the cost associated with lymphodepleting. Drug costs for
lymphodepleting regimens were calculated as a function of unit drug costs,
dosing, and proportion of patients receiving each regimen. The unit costs of thetreatment agent and the administration costs were based on the official gazettereleased by Ministry of Health, Labour and Welfare.[47] Two lymphodepleting
regimens were available. The dosing and proportion of patients receiving eachlymphodepleting regimen were based on ELIANA trial data.[26] Vial sharing was
not considered when estimating the drug cost in the base-case. The
hospitalization cost for lymphodepleting period was calculated separately basedon ELIANA trial data.[26] An estimated% of patients were hospitalized
during lymphodepleting chemotherapy, with an average duration ofdays.
The total hospitalization cost during the pre-treatment period of tisagenlecleucel
was estimated to be, using daily costs reported by the points ofNotification Related to Reimbursement released by Ministry of Health, Labour andWelfare.[47]110Table 15. Dosing schedule, drug acquisition cost, and administration cost for lymphodepleting regimen
Treatment

Regimen 1
Fludarabine

Cost perpackage,package size

Dosingschedule¥33,203, 50 mg

30 mg/m
intravenous(IV) daily for 4
doses
500 mg/m2 IV
daily for 2
doses

Cyclophosphamide ¥1,254, 500 mg
Regimen 2

2

Daily
administration
cost

Total
treatment
costa¥8,520Age < 15:
Age 1525:

Cytarabine

Distributionof patientsperregimen(%)%%

SourceELIANA (dosing
and patient
distribution)[26];The official
gazette releasedby Ministry of
Health, Labourand Welfare (unitdrug cost;administrationcost)[47]¥5,156, 1,000 mg

500 mg/m2 IV ¥8,520
daily for 2
days
Etoposide¥4,172, 100 mg
150 mg/m2 IV
daily for 3
days
Abbreviations: IV, intravenous; mg, milligrams
a The treatment costs for regimen 2 differ as the BSA is different across age groups

111

Table 16. Hospitalization cost for lymphodepleting regimen% patients require
hospitalization before
infusion%

Daily hospitalization/
administration cost
The first 14 days:¥23,240;
After 14 days: ¥20,660

Number ofdays

Total cost

SourceELIANA(resource use)[26]; The
official gazette released by
Ministry of Health, Labourand Welfare (hospitalizationcost)[47]112Treatment cost
After the lymphodepleting chemotherapy, a one-time acquisition cost of¥34,113,655 was considered for patients who received tisagenlecleucel
infusion.[45] The administration cost of tisagenlecleucel was ¥308,500, which
was obtained from the points of Notification Related to Reimbursement releasedby Ministry of Health, Labour and Welfare.[47] Hospitalization and ICU stayassociated with tisagenlecleucel treatment were estimated based on ELIANA trial
data.[26] In the ELIANA trial, all hospitalization and ICU stays initiated withindays after tisagenlecleucel infusion were assessed. Based on ELIANA trial data,
an estimated% of patients were ever hospitalized post tisagenlecleucel
infusion for an average duration ofdays. The calculated total
hospitalization cost was ¥, based on daily costs of ¥23,240 and ¥20,660
for the first 14 days of hospitalization and for the hospitalization after 14 days,
respectively, obtained from the official gazette released by Ministry of Health,Labour and Welfare.[47] On average, tisagenlecleucel patients haddays ofICU stay due to reasons other than CRS. The total ICU cost was estimated to be¥, based on a daily ICU cost of ¥specific to pediatric patientsfrom the official gazette released by Ministry of Health, Labour and Welfare.[47]The cost of ICU stays due to CRS was calculated separately as part of the AE
costs later/
For patients who discontinued prior to tisagenlecleucel infusion, the same drug,
administration, and hospitalization cost as the blinatumomab comparator
treatment was considered. The detailed cost inputs are described in the next
section.
Comparator cost
Blinatumomab (for age < 15 years and age 15-25 years)
Drug acquisition costs were calculated as a function of unit drug costs, dosing,and treatment duration. The dosing schedule and the number of treatment cyclesof blinatumomab were obtained from von Stackelberg et al., 2016, the same trial
used for the efficacy input of blinatumomab in the model, and were considered
the same for both age groups.[17] The model assumed 9 days of hospitalizationin cycle 1 and 2 days in cycle 2 in accordance with the hospitalization
recommendation in blinatumomab NICE submission ID804.[48] Accounting forthe proportion of patients on each cycle shown in Table 17, the average
LOS(length of stay) was estimated asdays. Thus, the total hospitalization
cost was estimated to be, based on a daily cost of ¥23,240 for the first
14 days of hospitalization, obtained from the official gazette released by Ministryof Health, Labour and Welfare.[47] Detailed inputs for the cost of blinatumomab
are presented in Table 17.
Inotuzumab (for age 15-25 years)
Drug acquisition costs were calculated as a function of unit drug costs, dosing,and treatment duration. The dosing schedule and the number of treatment cyclesof blinatumomab was obtained from Bhojwani 2019, the same publication used
for the efficacy input of inotuzumab in the model.[16] The model assumed 9.5
days of hospitalization per cycle in accordance with the hospitalization
recommendation in inotuzumab adult ALL NICE submission TA541.[49]Accounting for the proportion of patients on each cycle shown in Table 18, theaverage LOS was estimated asdays. Thus, the total hospitalization cost wasestimated to be, based on a daily cost of ¥23,240 for the first 14 days113

of hospitalization and ¥20,660 after 14 days of hospitalization, obtained from theofficial gazette released by Ministry of Health, Labour and Welfare.[47] Detailed
inputs for the cost of inotuzumab are presented in Table 18.

114

Table 17. Dosing schedule, drug acquisition cost, and administration cost for blinatumomab

Treatment

Cost perpackage orvial,
package size

Dosing scheduleDailyadministration
cost

Distributionof patients
per cycle ornumber ofcyclesTotaltreatmentcost

von Stackelberg
er al., 2016
(dosingschedule)[17];The official
gazettereleased by
Ministry of
Health, Labourand Welfare(unit drug cost;administrationcost)[47]Blinatumomab
Blinatumomab
cycle 1

¥281,345, 35
mcg

Blinatumomab
cycle 2
Blinatumomab
cycle 3¥281,345, 35
mcg¥281,345, 35
mcg

5 mcg/m2/day Day
1-7;
15 mcg/m2/day
Day 8-28
15 mcg/m2/day
Day 1-28
15 mcg/m2/day
Day 1-28

Blinatumomab
cycle 4 and 5¥281,345, 35
mcg

15 mcg/m2/day
Day 1-28¥9,650%¥¥9,650¥9,650¥9,650Source%Abbreviations: mcg, micrograms
Table 18. Dosing schedule, drug acquisition cost, and administration cost for inotuzumab

Treatment

Cost perpackage orvial, package
size

Inotuzumab
Inotuzumab
cycle 1¥1,307,092, 1
mg

Dosing schedule

0.8 mg/m2 Week 1;
0.5 mg/m2 Week 2
and 3

Daily
administration
cost¥8,520Distributionof patients
per cycle ornumber ofcycles%Totaltreatment
cost

SourceBhojwani, et al2019 (dosing
schedule)[16];The official
115

Inotuzumab
cycle 2

¥1,307,092, 1
mg

0.5 mg/m2 Day 1,8, 15¥8,520%Inotuzumab
cycle 3-5

¥1,307,092, 1
mg

0.5 mg/m2 Day 1,8, 15¥8,520%Abbreviations: mg, milligrams

gazette releasedby Ministry of
Health, Labourand Welfare(unit drug cost;administrationcost)[47]116Subsequent HSCT costs
The model assumed patients could receive subsequent HSCT after initial
treatment. The cost and disutility of subsequent HSCT were added separately forthe proportion of patients who received subsequent HSCT for each arm. The rates
of subsequent HSCT were obtained from the same clinical trial study used for theefficacy estimation and are described in Section 4.2.
HSCT costs were considered in two parts: HSCT procedure cost, HSCT follow-up
cost up to 24 months (Table 19). In the base-case, the HSCT procedure andfollow-up costs were derived from an observational study using claims data inJapan, and considered, inpatient, outpatient, prescribed drug, and test costs. The
costs specific to pediatric patients with a diagnosis of ALL were considered to bealigned with the target population. Based on the study, the HSCT procedure cost
was estimated to be ¥, and the total follow-up cost up to 24 months
after HSCT procedure was estimated to be ¥.
Table 19. HSCT costs
Component
Cost
SourceTotal cost¥
HSCT procedure +¥pALL-specific HSCT cost based on
harvesting cost
JMDC claim data (relavant study:
HSCT follow-up cost
Wakase et al., 2018[50])(up to 24 months)
Abbreviations: HSCT, hematopoietic stem cell transplantation
Follow-up costs
Follow-up costs consisted of the costs of the outpatient visits and laboratory tests
and procedures (e.g., full blood count, electrocardiogram, and bone marrowbiopsy). The costs were assumed to vary by treatment, health state, and thetime horizon. The follow-up schedules and unit costs are summarized in Table 20
and Table 21. Table 22 summarizes the follow-up costs for each arm by healthstates and follow-up year.
For patients receiving blinatumomab and inotuzumab who remained in the EFS
state, the frequency of follow-up was obtained from the National Comprehensive
Cancer Network (NCCN) guideline.[9] For patients receiving tisagenlecleucel
infusion who remain in the EFS state, the frequency of follow-up was derived
from the ELIANA trial protocol.[26] The frequency of follow-up was assumed tobe the same for PD state across all comparator arms, and was assumed to be thesame as the EFS state of comparators during year 1, except that frequency offollow-up for cerebrospinal fluid and bone marrow aspirate was based onassumptions. Unit costs per provider visit and per test/procedure were collectedfrom the official gazette released by Ministry of Health, Labour and Welfare.[47]117Parameter

Unit
cost

Yearlyfrequency(Year 1)aYearlyfrequency(Year 2)aYearlyfrequency(Years 35)aYearlyfrequency(Years5+)aCode for unit cost

Coagulation panel¥180

Chemistry panel (including liverfunction test)
Cerebrospinal fluid (CSF)¥170

D007-3(AST,ALT etc)

¥5,000

D401

Serum test

¥3,900D011-10

B cell and T cell test

¥2,040D016-4

Electrocardiogram (ECG)¥1,300

D208

Bone marrow aspirate¥2,600

D404

Bone marrow biopsy¥7,300D404-2

Echocardiogram¥5,300

D215

Liver function test

¥110

D007

D006-2Abbreviations: CSF, cerebrospinal fluid; ECG, electrocardiogram
a. Follow up frequencies for tisagenlecleucel were derived from ELIANA. Follow up frequencies for chemotherapy regimens
were based on NCCN guideline.
Table 21. Follow-up schedule and unit cost inputs for PD patientsParameter
SourceConsultant visit

Unit cost
Yearly frequencya
Code for unit cost
Unit cost: the official gazette released by Ministry of Health, Labour and Welfare[47];Frequencies: assumed to be the same as the EFS state of comparators during year 1,
except that cerebrospinal fluid, bone marrow aspirate and echocardiogram were basedon assumptions
¥720
A002

Hematology panel¥210

D005-5(R,W,Hb,Ht,PI)
119societal benefit associated with productivity gain for both tisagenlecleucel andcomparators. Patients in the PFS state were assumed to incur work productivity
benefit one year after treatment initiation based on the monthly wage and agespecific employment rate in Japan. The specific inputs used for the productivity
gain estimation are presented in Table 25. The total societal benefit associatedwith productivity gain was calculated for each treatment over the modelled time
horizon, and was subtracted from the total direct medical cost to estimate thetotal societal costs.
Table 25. Inputs for productivity losses
Parameter
Monthly Wage
Age-specificemployment rate
15-24
25-54
55-59
60-64
65 +

Input value¥427,877.33

Source/notes
Wage level data inJapan[53]43.50%
84.90%
74.90%
74.90%
24.10%

2018 Mar, Historical
data 1 b-6
Employment rate [byage group] - Whole
Japan, Monthly
Data[54]4.2.3.2 DLBCL
Tisagenlecleucel cost
For tisagenlecleucel arm, the model used a decision-tree approach to partition
patients based on the infusion status to assign different effectiveness, cost anddisutility inputs. For patients who proceeded with infusion, they were assumed
to incur the cost related to tisagenlecleucel treatment. For patients who
discontinued before infusion, they were assumed to incur the costs related to thecomparator treatment (i.e., salvage chemotherapy). For the population less than
70 years, the model considered% of patients proceeded with infused basedon the observed infusion rate from the JULIET trial data among patients aged <70 years. For the population aged 70 years or older, the model considered%of patients proceeded with infused based on the observed infusion rate from the
JULIET trial data among patients aged ≥70 years. Regardless of infusion, patientson tisagenlecleucel arm will incur pre-treatment leukapheresis cost. Table 26
summarized how different cost components were attributed to patients in thetisagenlecleucel arm based on their infusion status.
Table 26. Attribution of cost for tisagenlecleucel arm based on patients’
infusion status
Cost component
Pre-treatment:
leukapheresis
Pre-treatment:
bridging
chemotherapy
Pre-treatment:

Infused patients
Non-infused patients
Same leukapheresis cost for all patients regardless of
infusion status
Only considered for infused
patients

NA

Only considered for infusedNA123lymphodepleting
regimenTisagenlecleucel orcomparator
treatment
AE
Subsequent SCT(only for <70
years)
Follow-up

patients
Drug, administration, andhospitalization costassociated withtisagenlecleucel infusion
AE associated withtisagenlecleucel
Subsequent SCT rates
based on tisagenlecleuceltrialsTisagenlecleucel-specificfollow-up cost by healthstatesDrug, administration, andhospitalization costassociated with salvage
chemotherapy
AE associated with salvage
chemotherapy
Subsequent SCT rates
based on salvage
chemotherapy trials
Salvage chemotherapyspecific follow-up cost byhealth states

Pre-treatment cost
Prior to tisagenlecleucel infusion, patients have to undergo three pre-treatment
phases:leukapheresis, bridging chemotherapy, andlymphodepleting
chemotherapy. The costs associated with each of these pre-treatment phases
were applied in the first cycle of the model. The subgroups of patients based on
infusion status attributed the costs of each of three pre-treatment phases were
specified in Table 26.
• Leukapheresis: collection of T-cells from the patients and consisted ofleukapheresis and cryopreservation procedures
The cost of leukapheresis and cryopreservation were estimated to be ¥174,400
based on the points of Notification Related to Reimbursement released by MHLW.
All patients in the tisagenlecleucel arm were assumed to incur the cost ofleukapheresis and cryopreservation procedures, regardless of whether theyreceived tisagenlecleucel infusion or not.
• Bridging chemotherapy: chemotherapy administered to stabilize disease
whilst waiting for tisagenlecleucel manufacturing and infusion
In the tisagenlecleucel clinical trial, the provision of bridging chemotherapy wasleft to investigator discretion and therefore a wide range of bridging
chemotherapy regimens were received by patients in JULIET trial. As such, thecosts of bridging chemotherapy were assumed to be equal to one cycle of drug
and administration costs of salvage chemotherapy for DLBCL. For patients aged
less than 70 years, the one cycle of drug acquisition and administration costs ofsalvage chemotherapy were calculated as the weighted average of different
chemotherapy regimens, which wereand, respectively. For
patients aged 70 years and above, the one cycle of drug acquisition andadministration costs of salvage chemotherapy were calculated as the weighted
average of different chemotherapy regimens, which wereand, respectively. For patients who received tisagenlecleucel infusion, themodel assumed% of patients would receive bridging chemotherapy, basedon JULIET data. For patients who discontinued prior to tisagenlecleucel infusion,
they were assumed to be managed by the comparator treatment (i.e., salvage
chemotherapy), and would not need any bridging chemotherapy treatment.
• Lymphodepleting regimen: treatment administered to facilitate theengraftment and homeostatic expansion of tisagenlecleucel cells
In tisagenlecleucel trial, lymphodepleting regimen was administered to patients1242-14 days prior to the infusion. It was assumed that the cost of this regimen was
only applied to the proportion of patients who received tisagenlecleucel infusion% for <70 years,% for ≥70 years). The lymphodepleting regimens
and resource use as observed in the JULIET trial were used to model the costs
associated with lymphodepleting. Drug costs for lymphodepleting chemotherapy
were included in the model and were calculated as a function of unit drug costs,
dosing, administration costs, and proportion of patients receiving each regimen(Table 27). The unit costs and administration costs of the treatment agent werebased on official gazette released by MHLW. Two lymphodepleting regimens wereavailable. The dosing and proportion of patients receiving each lymphodepleting
regimen were based on the JULIET trial data. Vial sharing was not consideredwhen estimating the drug cost in the base-case.

125Gemcitabine¥8,495,1000 mg

Dexamethaso
ne

¥314,
6.6 mgCisplatin¥7,099,50 mg1000 mg/m² ondays 1 and 8
40 mg (oral)
daily on days 14
75 mg/m² on
day 1

Rituximab¥157,855,
500 mg

375 mg/m² on
day 1(R)-ESHAP
Etoposide
Methylprednis
olone acetate
Cytarabine
Cisplatin¥6,680¥4,172,
100 mg¥1,769,1000 mg¥5,156,1000 mg¥7,099,40 mg/m² ondays 1-4
500 mg on days
1-5
2000 mg/m² on
day 5
25 mg/m² on

2004(dosingschedule,cycles)[56];
The
officialgazettereleased by
Ministry of
Health,LabourandWelfare
(unit
drug
cost;
administrationcost)[47]Martin2008,
National
Guideline
Alliance
2016(dosing129

Rituximab¥157,855,
500 mg

375 mg/m² on
day 1(R)-EPOCH
Doxorubixin
Vincristine
Etoposide
Cyclophospha
mide¥6,560¥4,351,50 mg¥2,638,
1 mg¥4,172,
100 mg¥1,254,500 mgPrednisone

¥167,
20 mg

Rituximab¥157,855,
500 mg

15 mg/m² ondays 2-4
0.5 mg on days
2-4
65 mg/m² ondays 2-4
750 mg/m² on
day 5
60 mg/m²(oral) on days
1-14
375 mg/m² onday 1

released by
Ministry of
Health,LabourandWelfare
(unit
drug
cost;
administrationcost)[47]Jermann 2004(dosingschedule,cycles)[59];
The
officialgazettereleased by
Ministry of
Health,LabourandWelfare131

Abbreviations: mg, milligrams

(unit
drug
cost;
administrationcost)[47]132

DLBCL patients in progressive/relapsed disease state.[64] The costs wereassumed to be the same for tisagenlecleucel and salvage chemotherapy.
Table 31 summarizes the monthly pre-progression and post-progression costs bytreatment, health states, and follow-up year.

1345. 分析結果
5.1 基本分析(費用対効果評価専門組織で決定された分析枠組みによる分析)の結果
2019 年
月 日開催の費用対効果評価専門組織で決定された分析枠組み 4 つすべてに対して、増分費用効果比を算出する費用効果分析を実施した。
【B-ALL: 15 歳未満】
･ 実施した分析■ 費用効果分析 （増分費用効果比を算出する）□ 費用最小化分析 （効果は同等として費用を比較する）【B-ALL: 15～25 歳】･ 実施した分析■ 費用効果分析 （増分費用効果比を算出する）□ 費用最小化分析 （効果は同等として費用を比較する）【DLBCL: 70 歳未満】
･ 実施した分析■ 費用効果分析 （増分費用効果比を算出する）□ 費用最小化分析 （効果は同等として費用を比較する）【DLBCL: 70 歳以上】･ 実施した分析■ 費用効果分析 （増分費用効果比を算出する）□ 費用最小化分析 （効果は同等として費用を比較する）
5.1.1 基本分析の増分費用、増分効果、増分費用効果比
2019 年
月 日開催の費用対効果評価専門組織で決定された分析枠組み 4 つの基本分析は下記のとおりである。
B-ALL：15 歳未満･ 分析結果の要約

評価対象技術
比較対照技術効果(QALY)
11.11
2.07

増分効果
(QALY)
9.05

評価対象技術
比較対照技術

効果
(LY)
12,69
2.74

増分効果
(LY)
9.95

費用 (円)

増分費用 (円)¥40,448,386¥21,565,737¥18,882,649

費用 (円)

増分費用 (円)¥40,448,386¥21,565,737¥18,882,649

ICER(円/QALY)¥2,087,581

ICER(円/LY)¥1,898,514

139

･ 費用の内訳の詳細

B-ALL：15～25 歳･ 分析結果の要約
効果(QALY)

増分効果(QALY)

評価対象技術11.58

比較対照技術Blinatumomab
比較対照技術
Inotuzumab

3.01

8.56

2.03

9.55

効果
(LY)

増分効果
(LY)

評価対象技術13.62

比較対照技術Blinatumomab
比較対照技術
Inotuzumab

3.88

9.74

2.63

10.99

費用 (円)

増分費用 (円)¥40,245,19
2¥22,988,92
4¥21,196,01
2¥17,256,268

費用 (円)

増分費用 (円)¥40,245,19
2¥22,988,92
4¥21,196,01
2¥17,256,268¥19,049,180¥19,049,180

ICER(円/QALY)¥2,015,34
9¥1,994,59
2
ICER(円/LY)¥1,772,15
3¥1,733,33
3140

DLBCL：70 歳未満･ 分析結果の要約

評価対象技術
比較対照技術効果(QALY)
5.70
2.46

増分効果
(QALY)
3.23

評価対象技術
比較対照技術

効果
(LY)
7.65
4.23

増分効果
(LY)
3.42

費用 (円)

増分費用 (円)¥37,362,788¥19,713,646¥17,649,143

費用 (円)

増分費用 (円)¥37,362,788¥19,713,646¥17,649,143

費用 (円)

増分費用 (円)¥21,450,349¥8,516,144¥12,934,205

ICER(円/QALY)¥5,459,234

ICER(円/LY)¥5,167,633･ 費用の内訳の詳細

DLBCL：70 歳以上･ 分析結果の要約

評価対象技術
比較対照技術効果(QALY)
3.64
1.16

増分効果
(QALY)
2.47

ICER(円/QALY)¥5,231,584141評価対象技術
比較対照技術

効果
(LY)
4.59
1.95

増分効果
(LY)
2.65

費用 (円)

増分費用 (円)¥21,450,349¥8,516,144¥12,934,205

ICER(円/LY)¥4,887,933･ 費用の内訳の詳細

5.1.2 感度分析
5.1.2.1 DSA: B-ALL
B-ALL の基本分析の limitation は下記のとおりである。
The model presented in this document, while comprehensive, had some
limitations. First, because the efficacy and safety data were sourced from singlearm trials of study treatments, there were inherent differences in patient
populations across trials. Second, most of the studies used for the efficacy
estimation had limited follow-up times. Thirdly, there is no reported efficacy of
blinatumomab and inotuzumab in 15-25 years age group. The efficacy of thesetreatments from a broader age group (age<18 years for blinatumomab and 2-21
years for inotuzumab) were used as proxy for the efficacy in the 15-25 years age
group. Finally, detailed hospitalization data was observed for tisagenlecleucelfrom the ELIANA trial but such information was not available for comparators.
Therefore, it is likely the hospitalization duration for the comparator treatments(i.e., blinatumomab and inotuzumab) might not reflect the exact hospitalization
duration incurred by patients and underestimate the resource use for thecomparators.
B-ALL: age < 15 years
Table 34. DSA inputs – model parameters (age < 15 years)
Parameter
Efficacy inputs
HR for comparator vs.
tisagenlecleucel
SMR of long-term ALL
survivor
EFS/OS cumulative HR
for comparators
without EFS input
Subsequent SCT
Subsequent HSCT rate

Base-case Input

DSA Input

Blinatumomab:

95% CI:

9.05

95% CI: 7.69-10.42±10% of base-caseTisagenlecleucel (infused

95% CI:%142Parameter
Efficacy estimation forcomparators before
year 5

ITC approach toestimate HR between
blinatumomab vs.
tisagenlecleucel
Long-term survival
Proportion of patientsassigned totisagenlecleucel toreceive infusion
Alternative efficacy
input source fortisagenlecleucel(infused patients)
Vial sharing

Base-case Input
Observed withintrial period and ITCadjusted curves
based ontisagenlecleucel
after trial period
Use multivariable
Cox regression toestimate HR (HR =)Use SMR-adjusted
survival to estimate
OS after year 5% based ontrial observation

DSA Input
Observed within trial period
and weighted average ofparametric estimates based on
AIC afterwards;
Use ITC-adjusted curves fromthe beginning
Use stabilized inverse
probability of treatment
weighting approach toestimate HR (HR =)Use SMR-adjusted survival toestimate OS after year 3

Estimate OS andEFS using pooled
trial data[25]–[27]Estimate OS and EFS using
ELIANA trial alone[26]Assume 100% patientsassigned to tisagenlecleucel
receive infusion

Do not consider vial Consider vial sharing
sharing
Productivity gain
Do not consider
Consider productivity gain
productivity gain
Abbreviations: OS, overall survival; EFS, event-free survival; ALL, acutelymphoblastic leukemia; SMR, standardized mortality ratio; AIC, Akaike
information criterion; HSCT, hematopoietic stem cell transplantation; EQ5D, EuroQol-5D
DSA 結果については、下記のとおり、トルネードダイアグラムを示す。

147

Figure 32. Top 20 DSA results ranked by impact on ICER values(tisagenlecleucel vs. blinatumomab, age 15-25 years)

Figure 33. Top 20 DSA results ranked by impact on ICER values(tisagenlecleucel vs. inotuzumab, age 15-25 years)

以上より、仮定に基づき設定したパラメータに関しては DSA を実施した場合に ICER が閾値で設定されている 750 万を超えることはなかった。
148

5.1.2.2 DSA: DLBCLDLBCL の基本分析の limitation は下記のとおりである。
This CEA was subject to a few limitations, some of which are characteristic ofeconomic modelling studies. First, because the efficacy and safety data weresourced from single-arm trials of study treatments, there were inherent
differences in patient populations across trials. To the extent feasible, clinical trial
publications with similar inclusion or exclusion criteria as the JULIETtisagenlecleucel trial were chosen to inform the efficacy of salvage chemotherapy.
However, differences still exist. For example, for salvage chemotherapy, inputs
were based on DLBCL patients that either failed an auto SCT or failed 2 priorregimens. The JULIET trial enrolled r/r DLBCL patients who failed or were noteligible for auto SCT and failed an average of 3 regimens.
Second, the clinical trial data used for the efficacy estimation for tisagenlecleucel
had limited follow-up. To mitigate the longer-term uncertainties from theextrapolation of data, the model assumed that all patients who remained alivefrom year 3 onward would experience a mortality risk profile similar to that of along-term survivor of DLBCL. The long-term survival was estimated using an SMR
approach. Due to limited data, the identified SMR study reported the SMR ofpatients who are progression free at 24 months following initial diagnosis.Patientsevaluated in this publication had newly diagnosed DLBCL and the impact ofmanagement after relapse were not assessed, therefore they may have been
healthier than 3-year survivors considered in the model. To address thisuncertainty, extensive sensitivity analyses were performed to vary the time point
to introduce the long-term DLBCL survivor mortalities. The model results were
not sensitive to these inputs.
Third, the OS definition was different in JULIET vs. CORAL extension studies.
JULIET trial evaluated OS from time of infusions, whereas CORAL extension
studies evaluated OS survival from time of last relapse and before the initiationof 3rd-line treatment. This might create a bias against tisagenlecleucel given
there might be a gap between relapse from 2nd-line treatment to the initiationof 3rd-line therapy and the CORAL extension studies might overestimate thesurvival of salvage chemotherapy in target population.
Lastly, despite the best efforts to select the most accurate model inputs basedon the existing literature, different data sources were used to describe resource
utilization for each treatment arm. Detailed hospitalization data were observed
for tisagenlecleucel from the JULIET trial, where such information was notavailable for salvage chemotherapy. Therefore, it is likely that the hospitalization
duration for the salvage chemotherapy might not reflect the exact hospitalization
duration incurred by patients treated with salvage chemotherapy. However, these
inputs represented the best available sources, and the impact of these inputs on
the model's results were extensively tested in the DSA and PSA. The results fromthe DSA and PSA generally supported the robustness of the model's results.

149

DLBCL: age < 70 years
Table 38. DSA inputs – model parameters (age <70 years)
Parameter
Efficacy inputs
PFS/OS cumulative HR
for salvage
chemotherapy
SMR of long term
survivors
Subsequent SCT
Subsequent SCT rate
for tisagenlecleucel(infused patients)
Subsequent SCT rate
for salvage
chemotherapy
Cost
Pre-treatment cost
Hospitalization andadministration cost for
tisagenlecleucel
Treatment cost forcomparators
CRS cost for
tisagenlecleucel(infused patients)
IVIG dose fortisagenlecleucel(infused patients)
Pre-progression costBase-case Input

DSA Input±10% of base-case

1.09

95% CI: 0.69-1.74

Allo SCT rate:%
Auto SCT rate:%
Allo SCT rate:
7.55%
Auto SCT rate:
21.22%

Allo SCT rate 95% CI:%
Auto SCT rate 95% CI:%±25% of base-caseTisagenlecleucel(infused patients):±25% of base-caseTisagenlecleucel(infused patients):¥
Salvagechemotherapy:¥1,665,809±25% of base-case±25% of base-case±25% of base-case
95% CI:

Tisagenlecleucel(infused patients):±25% of base-case

Salvagechemotherapy:
Post-progression cost
±25% of base-case
Terminal care cost
¥747,787±25% of base-case
Subsequent allo SCT±25% of base-casecost
Subsequent auto SCT±25% of base-casecost
Utility and disutility (upper utility limit capped at 1)
Utility for PFS
0.83±10% of base-caseUtility for PD
0.39±10% of base-case150

Treatment disutility

Tisagenlecleucel(infused patients):-0.02
Salvagechemotherapy: 0.01
-0.30

±10% of base-case

Subsequent SCT±10% of base-case
disutility
Patient characteristics
BSA
95% CI:
Discount rate
Cost and effectiveness
2.0%
0% and 4.0%
Abbreviations: AE, adverse events; BSA, body surface area; DSA,
deterministic sensitivity analysis; OS, overall survival; PFS, progression-freesurvival; SCT, stem cell transplantation; allo SCT, allogeneic stem celltransplantation; auto SCT, autologous stem cell transplantation; CRS,
cytokine release syndrome; PD, progressive disease; HR, hazard ratio; CI,
confidence interval.
Table 39. DSA inputs – model scenarios (age <70 years)
Parameter
Utility
Health state utilities

Base-case Input

Based on Chen etal. 2017[33]Alternative cost scenarios
Salvage chemotherapy Consider thecostweighted average
cost of five common
regimens: (R)-ICE,(R)-GDP, (R)ESHAP, (R)-DHAP,and (R)-EPOCH
Salvage chemotherapy Consider thecostweighted average
cost of five common
regimens: (R)-ICE,(R)-GDP, (R)ESHAP, (R)-DHAP,and (R)-EPOCH
Salvage chemotherapy Do not consider
costs
radiotherapy cost
Alternative time horizon scenarios
Time horizon
Different modelling scenarios
Model starting age
based on JULIET
trial data
Proportion of patients% based on
assigned totrial observation
tisagenlecleucel

DSA Input
Based on EQ-5D from JULIET
trial data[29]Consider the cost based on(R)-GDP (cheapest)

Consider the cost based on(R)-DHAP (most expensive)

Consider radiotherapy cost

Assume 100% patientsassigned to tisagenlecleucel
receive infusion
151

Parameterreceive infusion
Long-term survival andmodel extrapolation

Base-case Input

DSA Input

Use SMR-adjusted
survival to estimate
OS after year 3

Use SMR-adjusted survival toestimate OS after year 5 andparametric function approachfor OS extrapolation after trial
period and before year 5;
Use SMR-adjusted survival toestimate OS after year 5 andMAIC approach for OS
extrapolation after trial period
and before year 5;
Use SMR-adjusted survival toestimate OS after year 4 andMAIC approach for OS
extrapolation after trial period
and before year 4;

Efficacy estimation fortisagenlecleucel(infused patients)
before year 3

Estimate OS using
observed JULIET
trial data before
year 3[29]Alternative OS input
source for salvage
chemotherapy

CORAL extension
studies[11], [12]Use SMR-adjusted survival toestimate OS after year 4 andparametric function approachfor OS extrapolation after trial
period and before year 4;
Use MAIC-adjusted curvefrom the beginning toestimate tisagenlecleucel
efficacy using salvage
chemotherapy as thereference arm. The MAIC wasconducted to compare
tisagenlecleucel with salvage
chemotherapy, adjusting fordifferences in baselinecharacteristics between
studies
Overall patient populationfrom SCHOLAR-1 study5

Subsequent SCT rate
for salvage
chemotherapy

Subsequent allo
SCT:
Subsequent auto
SCT:

The subgroup of SCHOLAR-1
patient population excluding
patients who are primaryrefractory and with ECOG
performance status>1, which
was deemed to be moresimilar to the JULIET
populations
Consider 20% subsequent
SCT rate for salvage
chemotherapy and reestimate the efficacy using
152

Parameter

Vial sharing

Base-case Input

DSA Input
survival curves stratified by
SCT status and specified SCT
rate. Cost and disutility is reestimated based on thespecified SCT rate
Consider vial sharing

Do not consider vial
sharing
Productivity gain
Do not consider
Consider productivity gain
productivity gain
Abbreviations: AE, adverse events; allo SCT, allogeneic stem celltransplantation; auto SCT, autologous stem cell transplantation; DSA,
deterministic sensitivity analysis; ECOG, Eastern Cooperative Oncology
Group; HR, hazard ratio; OS, overall survival; PFS, progression-free survival;
SMR, standardized mortality ratio; SCT, stem cell transplantation; CRS,
cytokine release syndrome; PD/RL, progressive/relapsed disease; AIC, Akaike
information criterion; MAIC, matching adjusted indirect comparison.
DSA 結果については、下記のとおり、トルネードダイアグラムを示す。
Figure 34. Top 20 DSA results ranked by impact on ICER values (age <70
years)

153

DLBCL: age >= 70 years
Table 40. DSA inputs – model parameters (age >=70 years)
Parameter
Efficacy inputs
PFS/OS cumulative HR
for salvage
chemotherapy
SMR of long term
survivors
Cost
Pre-treatment cost
Hospitalization andadministration cost for
tisagenlecleucel
Treatment cost forcomparators
CRS cost for
tisagenlecleucel(infused patients)
IVIG dose fortisagenlecleucel(infused patients)
Pre-progression costBase-case Input

DSA Input±10% of base-case

1.09

95% CI: 0.69-1.74

Tisagenlecleucel(infused patients):¥
Tisagenlecleucel(infused patients):±25% of base-case

Salvagechemotherapy:¥1,663,111±25% of base-case±25% of base-case±25% of base-case
95% CI:

Tisagenlecleucel±25% of base-case(infused patients):¥
Salvagechemotherapy:¥5,496
Post-progression cost
¥525,220±25% of base-case
Terminal care cost
¥747,787±25% of base-caseUtility and disutility (upper utility limit capped at 1)
Utility for PFS
0.83±10% of base-caseUtility for PD
0.39±10% of base-caseTreatment disutility
Tisagenlecleucel±10% of base-case(infused patients):-0.02
Salvagechemotherapy: 0.01
Patient characteristics
BSA
95% CI:
Discount rate
Cost and effectiveness
2.0%
0% and 4.0%
Abbreviations: AE, adverse events; BSA, body surface area; DSA,
deterministic sensitivity analysis; OS, overall survival; PFS, progression-freesurvival; CRS, cytokine release syndrome; PD, progressive disease; HR,154

hazard ratio; CI, confidence interval.
Table 41. DSA inputs – model scenarios (age >=70 years)
Parameter
Utility
Health state utilities

Base-case Input

DSA Input

Based on Chen etal. 2017[33]Alternative cost scenarios
Salvage chemotherapy
Consider thecostweighted average
cost of fivecommonregimens: (R)-ICE,(R)-GDP, (R)ESHAP, (R)-DHAP,and (R)-EPOCH
Salvage chemotherapy
Consider thecostweighted average
cost of fivecommonregimens: (R)-ICE,(R)-GDP, (R)ESHAP, (R)-DHAP,and (R)-EPOCH
Salvage chemotherapy
Do not consider
costs
radiotherapy cost
Alternative time horizon scenarios
Time horizon
Different modelling scenarios
Model starting age
based onJULIET trial data

Based on EQ-5D from JULIET
trial data[29]Proportion of patientsassigned totisagenlecleucel receive
infusionLong-term survival andmodel extrapolation% based ontrial observation

Assume 100% patientsassigned to tisagenlecleucel
receive infusion

Use SMR-adjusted
survival toestimate OS after
year 3Use SMR-adjusted survival toestimate OS after year 5 andparametric function approachfor OS extrapolation after trial
period and before year 5;

Consider the cost based on(R)-GDP (cheapest)

Consider the cost based on(R)-DHAP (most expensive)

Consider radiotherapy cost

70 based on suggestion fromC2H at a meeitng on

Use SMR-adjusted survival toestimate OS after year 4 andparametric function approachfor OS extrapolation after trial
period and before year 4;
Alternative OS input

CORAL extension

Overall patient population
155

conducted. In each iteration, the model inputs were randomly drawn from thespecified distributions, as summarized in Table 42. The efficacy inputs weremodelled using parametric estimates of bootstrapped samples of the original IPD
or proxy IPD data used for OS and EFS estimation in the base-case. For each PSA
iteration, all 10 parametric functions and their associated AIC values for eacharm were estimated based on one bootstrapped sample, and were weighted using
AIC to form the weighted average.
Whenever available, the standard error (SE) of the model input was obtained
directly from the same data source that informed the mean value. In the absenceof data on the variability around health state cost values, the SE for each cost
parameter was assumed to be equal to the mean value divided by ten for efficacy
and utility parameters and mean value divided by four for cost parameters.
In the PSA, the threshold of ¥7,500,000 per QALY gained was used as it is acommonly referenced the threshold for CEE evaluation in Japan.[66] Comparedwith blinatumomab, the probability of tisagenlecleucel being cost-effective at the
specified threshold of ¥7,500,000 per QALY gained was 100%. The average
probabilistic ICER for this comparison was ¥2,125,514 per QALY gained.
Table 42. PSA inputs
Parameter

Description

Parametricsurvivalfunctions
OS for tisagenlecleucel

The efficacy inputs were modelled usingparametric estimates of bootstrapped samplesof the original patient-level data or proxypatient-level data used for OS and EFS
estimation in the base-case. For each PSA
iteration, all ten parametric functions and theirassociated AIC values for each treatment arm
were estimated based on one bootstrappedsample and are weighted using AIC to form theweighted average to be used in the model.
Hazard ratio is modelled using lognormal
distribution with the mean value as specified in
the base-case model. Standard error (SE) was
obtained from ITC analyses.
Utilities were modelled using beta distributions
with the mean values as specified in the basecase model and SEs based on the same source
for the base-case input. It was assumed that theutility of PD health state should not exceed theutility of the EFS health state and vice versa.
Treatment disutilities for each comparator weremodelled using beta distributions with the meanvalues as specified in the base-case model. SEs
were assumed to be 1/10 of mean.

EFS for tisagenlecleucel

Hazardratiostisagenlecleucelcomparator

for
vs.

Utility for health states
EFS
PD

Treatment disutility
Treatment disutility for eachtreatment
Additional AE disutility fortisagenlecleucel
andblinatumomab
Subsequent HSCT
Subsequent HSCT rate ofeach treatment

Subsequent HSCT rates and disutility weremodelled using beta distributions with the meanvalues as specified in the base-case model. SEs
157

Parameter

Description

Subsequent HSCT cost
Subsequent HSCT disutilityof subsequent SCT rates were based on thesame source for the base-case input. SE ofsubsequent SCT disutility was assumed to be
1/10 of mean. Subsequent HSCT costs weremodelled using gamma distributions with themean values as specified in the base-casemodel. SEs were assumed to be 1/4 of mean.
Pre-treatment costs were modelled using
gamma distributions with the mean values as
specified in the base-case model. SEs wereassumed to be 1/4 of mean.

Pre-treatment costs
Drug and administrationand hospitalization costs for
lymphodepleting,leukapheresis, and bridging
chemotherapy
Treatment costs
Drug
cost
for
all
comparators
Hospitalization
andoutpatient
administration
cost for all treatments
Follow-up
andother
medical costs
EFS follow-up cost
PD follow-up cost
Terminal care cost
AE costTreatment costs were modelled using gamma
distributions with the mean values as specified
in the base-case model. SEs were assumed to be
1/4 of mean.

Follow-up costs associated with each healthstate and terminal care costs were modelledusing gamma distributions with the mean values
as specified in the base-case model. SEs wereassumed to be 1/4 of mean.
AE costs were modelled using gamma
distributions with the mean values as specified
in the base-case model. SEs were assumed to be
1/4 of mean.
Patient characteristics
Age, weight and BSA were modelled using
normal distributions with the mean values as
Age
specified in the base-case model. SEs were
Weightobtained from the pooled data from three trials
BSA(ELIANA, ENSIGN, and B2101J). Gender was
Gendermodelled using a beta distribution with the meanvalue as specified in the base-case model and SE
based on the same source for the base-case
input.
Tisagenlecleucel infusion Tisagenlecleucel infusion rate was modelledrateusing beta distributions with the mean values as
specified in the base-case model. SE was
obtained from the pooled data from three trials(ELIANA, ENSIGN, and B2101J).
SMR for long-term ALL SMR was modelled using lognormal distribution
survivors
with the mean value as specified in the basecase model. SEs were obtained from the same
literature used for the base-case input.
Abbreviations: AE, adverse event; HSCT, hematopoietic
stem celltransplantation; BSA, body surface area; PD, progressive disease; SMR,
standardized mortality ratio; ALL, acute lymphoblastic leukemia; SE, standard
158

Parameter

Description

error; OS, overall survival; EFS, event-free survival; PSA, probabilistic
sensitivity analysis
Table 43. PSA results for tisagenlecleucel vs. blinatumomab (age < 15years)
Average
MedianIncremental cost
¥18,930,135¥19,078,680
Incremental QALY
8.91
9.01
Probabilistic ICER
¥2,125,514
Abbreviations: QALY, quality-adjusted life year; ICER, incremental costeffectiveness ratio
Figure 36. Cost-effectiveness acceptability curve: tisagenlecleucel vs.
blinatumomab (age < 15 years)

159

Figure 37. Cost-effectiveness plane: tisagenlecleucel vs. blinatumomab(age < 15 years)

B-ALL：15～25 歳
Probabilistic sensitivity analysis (PSA) was conducted to estimate the probability
for tisagenlecleucel to be cost-effective compared to comparator treatments,
based on different thresholds. A Monte-Carlo simulation with 5,000 iterations was
conducted. Detailed information regarding PSA inputs are described in Table 42.
The PSA results are presented in Table 44, Figure 38, Figure 39, Figure 40, andFigure 41. Compared with blinatumomab, the probability of tisagenlecleucel
being cost-effective at the specified threshold of ¥7,500,000 per QALY gained
was 100.0%. The average probabilistic ICER for this comparison was ¥2,122,818
per QALY gained. Compared with inotuzumab, the probability of tisagenlecleucel
being cost-effective at the specified threshold of ¥7,500,000 per QALY gained
was 100.0%, and the average probabilistic ICER for this comparison was¥2,084,237 per QALY gained.
Table 44. PSA results for tisagenlecleucel vs. comparator treatments(age 15-25 years)
AverageTisagenlecleucel vs. blinatumomab
Incremental cost
¥17,334,847

MedianIncremental QALY
8.17
Probabilistic ICER
¥2,122,818
Tisagenlecleucel vs. inotuzumab
Incremental cost
¥19,038,834
Incremental QALY
9.13

8.18

¥17,447,077¥19,278,346
9.21
160

Probabilistic ICER
¥2,084,237
Abbreviations: QALY, quality-adjusted life year; ICER, incremental costeffectiveness ratio
Figure 38. Cost-effectiveness acceptability curve: tisagenlecleucel vs.
blinatumomab (age 15-25 years)

161

Figure 39. Cost-effectiveness plane: tisagenlecleucel vs. blinatumomab(age 15-25 years)

Figure 40. Cost-effectiveness acceptability curve: tisagenlecleucel vs.
inotuzumab (age 15-25 years)

162

Figure 41. Cost-effectiveness plane: tisagenlecleucel vs. inotuzumab(age 15-25 years)

5.1.2.4 PSA: DLBCLDLBCL：70 歳未満
PSA was conducted to estimate the probability for tisagenlecleucel to be costeffective compared to comparator treatments, based on different thresholds. A
Monte-Carlo simulation with 5,000 iterations was conducted. In each iteration,
the model inputs were randomly drawn from the specified distributions, assummarized in Table 44. The efficacy inputs were modelled using parametricestimates of bootstrapped samples of the original IPD or proxy IPD data used for
OS and PFS estimation in PSA. For each PSA iteration, all 10 parametric functions
and their associated Akaike information criterion (AIC) values for each arm were
estimated based on one bootstrapped sample, and were weighted using AIC toform the weighted average.
Whenever available, the stand error (SE) of the selected distribution was obtained
directly from the same data source that informed the mean value. In the absenceof data on the variability around health state cost values, the standard error foreach cost and efficacy parameter was assumed to be equal to the mean value
divided by four and ten, respectively.
Thethreshold was specified at ¥7,500,000 per QALY because, in addition to thedisease rarity of r/r DLBCL, tisagenlecleucel is an innovative therapy that brings
significant survival and quality of life benefit for terminally ill patients without
good alternative options.
The PSA results are presented in Table 45, Figure 42 and Figure 43. Comparedwith salvage chemotherapy, the probability of tisagenlecleucel being costeffective for patients aged < 70 years at the specified threshold of ¥7,500,000
per QALY gained was 97.6%. The average probabilistic ICER for this comparison
was ¥5,478,296 per QALY gained.
163

Table 45. PSA inputs
Parameter

Description

Parametricsurvival The efficacy inputs were modelled using
functionsparametric estimates of bootstrapped samples ofthe original patient-level data used for OS and PFS
OS for all treatments
estimation if parametric estimations are selected in
the base-case. For each PSA iteration, all ten
PFS for all treatments
parametric functions and their associated AIC
values for each treatment arm were estimatedbased on one bootstrapped sample and areweighted using AIC to form the weighted average
to be used in the model.
Pre-treatment costs
Pre-treatment costs were modelled using gamma
Drug and administration distributions with the mean values as specified incosts
for the base-case model. SEs were assumed to be 1/4
of mean.
lymphodepleting,leukapheresis,
andbridging chemotherapy
Treatment costs
Treatment costs were modelled using gamma
Drug
cost
for
all distributions with the mean values as specified in
the base-case model. SEs were assumed to be 1/4
comparators
Hospitalizationand of mean.
outpatient administration
cost for all treatments
Utility for health states Utilities were modelled using beta distributions
with the mean values as specified in the base-case
PFS
model and SEs were assumed to be 1/10 of mean.
PD
It is assumed that the utility of progressive disease
health state should not exceed the utility of the
progression-free survival health state.
Treatment disutility
Treatment disutilities for each comparator were
Treatment disutility for modelled using beta distributions with the meanvalues as specified in the base-case model. SEseach comparator
Additional AE disutility for were assumed to be 1/10 of mean.
tisagenlecleucel
Follow-up and other Follow-up costs associated with each health states
medical costs
and other medical costs are modelled using
Follow-up cost during PFS gamma distributions with the mean values as
Post-progression follow- specified in the base-case model. SEs wereassumed to be 1/4 of mean.
up costTerminal care cost
Patient characteristics Age, weight and BSA were modelled using normal
distributions with the mean values as specified inAgethe base-case model. SEs were obtained from theWeightJULIET trial.2 Gender was modelled using a beta
BSA
distribution with the mean value as specified in the
Genderbase-case model and SE based on the same source
for the base-case input.
Subsequent SCT
Subsequent SCT rates and disutility were modelled
164

Parameter

Description

Subsequent SCT rate ofeach comparator
Subsequent SCT costusing beta distributions with the mean values as
specified in the base-case model; SEs were basedon the same source for base-case input whereavailable, and assumed to be 1/4 of mean where
Subsequent SCT disutility not available. Subsequent SCT costs weremodelled using gamma distributions with the meanvalues as specified in the base-case model. SEs
were assumed to be 1/4 of mean.
AE costAE costs were modelled using gamma distributions
with the mean values as specified in the base-casemodel. SEs were assumed to be 1/4 of mean.
Tisagenlecleucel
Tisagenlecleucel infusion rate was modelled using
infusion rate
beta distributions with the mean values as
specified in the base-case model. SE was obtained
from the JULIET trial.
SMR
forlong-term SMR was modelled using a lognormal distribution
DLBCL survivors
with the mean value as specified in the base-casemodel. SEs were assumed to be 1/10 of mean.
Abbreviations: AE, adverse event; SCT, stem cell transplantation; auto SCT,
autologous stem cell transplantation; BSA, body surface area; DLBCL, diffuse
large B-cell lymphoma; PD/RL, progressive/relapsed disease; SE, standard
error; AIC, Akaike information criterion; OS, overall survival; PFS, progressionfree survival; PD, progressed disease; HR, hazard ratio; MAIC, matchingadjusted indirect comparison; PSA, probabilistic sensitivity analysis; SMR,
standardized mortality ratio
Table 46. PSA results for tisagenlecleucel vs. salvage chemotherapy
Average
MedianIncremental cost

¥17,673,612¥17,687,621

Incremental QALY

3.23

3.25

Probabilistic ICER

¥5,478,296

Abbreviations: QALY, quality-adjusted life year; ICER, incremental costeffectiveness ratio; PSA, probabilistic sensitivity analysis

165

Figure 42. Cost-effectiveness acceptability curve: tisagenlecleucel vs.
salvage chemotherapy

Figure 43. Cost-effectivenesschemotherapy

plane:

tisagenlecleucelvs.

salvage

166

DLBCL：70 歳以上
PSA was conducted to estimate the probability for tisagenlecleucel to be costeffective compared to comparator treatments, based on different thresholds. A
Monte-Carlo simulation with 5,000 iterations was conducted. In each iteration,
the model inputs were randomly drawn from the specified distributions, assummarized in Table 47. The efficacy inputs were modelled using parametricestimates of bootstrapped samples of the original IPD or proxy IPD data used for
OS and PFS estimation in PSA. For each PSA iteration, all 10 parametric functions
and their associated Akaike information criterion (AIC) values for each arm were
estimated based on one bootstrapped sample, and were weighted using AIC toform the weighted average.
Whenever available, the stand error (SE) of the selected distribution was obtained
directly from the same data source that informed the mean value. In the absenceof data on the variability around health state cost values, the standard error foreach cost and efficacy parameter was assumed to be equal to the mean value
divided by four and ten, respectively.
The threshold was specified at ¥7,500,000 per QALY because, in addition to thedisease rarity of r/r DLBCL, tisagenlecleucel is an innovative therapy that brings
significant survival and quality of life benefit for terminally ill patients without
good alternative options.
The PSA results are presented in Table 48, Figure 44 and Figure 45. Comparedwith salvage chemotherapy, the probabilities of tisagenlecleucel being costeffective for patients aged ≥70 years at the specified threshold of ¥7,500,000
per QALY gained was 98.0%. The average probabilistic ICER for this comparison
was ¥5,300,340 per QALY gained.
Table 47. PSA inputs
Parameter

Description

Parametricsurvival The efficacy inputs were modelled using
functionsparametric estimates of bootstrapped samples ofthe original patient-level data used for OS and PFS
OS for all treatments
estimation if parametric estimations are selected in
the base-case. For each PSA iteration, all ten
PFS for all treatments
parametric functions and their associated AIC
values for each treatment arm were estimatedbased on one bootstrapped sample and areweighted using AIC to form the weighted average
to be used in the model.
Pre-treatment costs
Pre-treatment costs were modelled using gamma
Drug and administration distributions with the mean values as specified incosts
for the base-case model. SEs were assumed to be 1/4
of mean.
lymphodepleting,leukapheresis,
andbridging chemotherapy
Treatment costs
Treatment costs were modelled using gamma
Drug
cost
for
all distributions with the mean values as specified in
the base-case model. SEs were assumed to be 1/4
comparators
Hospitalizationand of mean.
outpatient administration
cost for all treatments
167

Parameter

Description

Utility for health states
PFS
PD

Utilities were modelled using beta distributions
with the mean values as specified in the base-casemodel and SEs were assumed to be 1/10 of mean.
It is assumed that the utility of progressive disease
health state should not exceed the utility of the
progression-free survival health state.
Treatment disutilities for each comparator weremodelled using beta distributions with the meanvalues as specified in the base-case model. SEs
were assumed to be 1/10 of mean.

Treatment disutility
Treatment disutility foreach comparator
Additional AE disutility fortisagenlecleucel
Follow-up and othermedical costs
Follow-up cost during PFS
Post-progression followup cost
Terminal care cost
Patient characteristics
Age
WeightBSA
GenderFollow-up costs associated with each health statesand other medical costs are modelled using
gamma distributions with the mean values as
specified in the base-case model. SEs wereassumed to be 1/4 of mean.

Age, weight and BSA were modelled using normal
distributions with the mean values as specified in
the base-case model. SEs were obtained from the
JULIET trial.2 Gender was modelled using a beta
distribution with the mean value as specified in thebase-case model and SE based on the same source
for the base-case input.
AE costAE costs were modelled using gamma distributions
with the mean values as specified in the base-casemodel. SEs were assumed to be 1/4 of mean.
Tisagenlecleucel
Tisagenlecleucel infusion rate was modelled using
infusion rate
beta distributions with the mean values as
specified in the base-case model. SE was obtained
from the JULIET trial.
SMR
forlong-term SMR was modelled using a lognormal distribution
DLBCL survivors
with the mean value as specified in the base-casemodel. SEs were assumed to be 1/10 of mean.
Abbreviations: AE, adverse event; BSA, body surface area; DLBCL, diffuse
large B-cell lymphoma; PD/RL, progressive/relapsed disease; SE, standard
error; AIC, Akaike information criterion; OS, overall survival; PFS, progressionfree survival; PD, progressed disease; HR, hazard ratio; PSA, probabilistic
sensitivity analysis; SMR, standardized mortality ratio
Table 48. PSA results for tisagenlecleucel vs. salvage chemotherapy
Average
MedianIncremental cost

¥13,059,645¥13,017,239

Incremental QALY

2.46

2.47

Probabilistic ICER

¥5,300,340

Abbreviations: QALY, quality-adjusted life year; ICER, incremental costeffectiveness ratio; PSA, probabilistic sensitivity analysis
168

Figure 44. Cost-effectiveness acceptability curve: tisagenlecleucel vs.
salvage chemotherapy

Figure 45. Cost-effectivenesschemotherapy

plane:

tisagenlecleucelvs.

salvage169

years, the base-case model prediction OS at 2, 3, 4, and 5 years were
. In addition, the extrapolation assumption thatpatients were considered cured after year 5 to follow the mortality risk of longterm ALL survivors were also validated by the experts. This assumption
conservatively assumes that there is no additional clinical benefit for
tisagenlecleucel compared to existing treatments after year 5, which will makethe ICER estimate from the current model being conservative against
tisagenlecleucel. Given the uncertainty surrounding long-term OS extrapolation,
scenario analyses were conducted varying the SMR input by 95% CI and varying
the time point to introduce the long-term ALL survivor mortalities. The model
was not sensitive to these parameters. The model also explored costs and utilities.
The literature and data sources used for these inputs were valid and relevant to
the population of interest.
5.1.3.2 DLBCL
Patients aged <70 years
The CAR-T therapy tisagenlecleucel is a highly effective treatment for adultpatients with r/r DLBCL, and its introduction has altered the treatment landscapeof this disease by extending life as well as improving quality of life. The current
model assessed cost-effectiveness of tisagenlecleucel in terms of LYs and QALYs
in comparison with salvage chemotherapy among patients aged < 70 years. The
comparator was selected to reflect existing standard of care for r/r DLBCL
patients aged <70 years in Japanese clinical practice, which were validated byclinical input. R/R DLBCL patients after two round of treatments or after auto SCT
have very few treatment options and a poor prognosis. If left untreated, theestimated life expectancy for a patient with r/r DLBCL after at least twotreatments is only three to four months.[67] Compared to salvage chemotherapy,
tisagenlecleucel showed promising efficacy results. The current model predicted
incremental LYs of 3.42 years and incremental QALYs of 3.23 years (vs. salvage
chemotherapy) over the lifetime horizon for patients < 70 years. As a patientspecific, single infusion therapy, tisagenlecleucel is the first in this class of CART therapy for the treatment of r/r DLBCL and represents a paradigm-shift in thetreatment approach for this aggressive disease in adults in Japan.
The current model used clinical trial data of tisagenlecleucel and salvage
chemotherapy to simulate the disease course of r/r DLBCL over a lifetime horizon
for patients < 70 years. The clinical trials explored in this model were the key
clinical trials for each treatment. The population evaluated in the JULIET clinical
trial is representative of the target population of tisagenlecleucel in Japan. To theextent feasible, age-group specific inputs were derived to be consistent with themodeled population. In the model, the predicted median OS of patients in thetisagenlecleucel and salvage chemotherapy arms wereand 5.8 months,
respectively. They are the same as that those observed among patients aged <70
in JULIET and extended CORAL studies. Additionally, the median OS of patientswith salvage chemotherapy in the model was close to the median OS observedin SCHOLAR-1 (6.3 months). The clinical trial has limited follow-up (maximum
follow-up ofmonths), while the impact of the treatments on the disease is
lifetime. Therefore, the use of modelling approach to evaluate the long-termvalue of the treatments is necessary. Survival extrapolation is essential toquantify the survival benefit beyond the trial period. In the current model,
followed by the observed trial data, patients who were alive at the end of three
years were assumed to be long-term survivors and follow the mortality risk of171to evaluate the long-term value of the treatments is necessary. Survival
extrapolation is essential to quantify the survival benefit beyond the trial period.
In the current model, followed by the observed trial data, patients who were aliveat the end of three years were assumed to be long-term survivors and follow themortality risk of long-term DLBCL survivors as reported in the literature. The
NICE committee believed a cure point between 2 and 5 years was the mostclinically plausible scenario with the former to be optimistic while the latter to be
pessimistic. Therefore, 3-year cure point was considered in the base-case modelas the midpoint between year 2 and year 5. This assumption conservatively
assumed that there was no additional clinical benefit for tisagenlecleucelcompared to salvage treatment after year 3, which will make the ICER estimate
from the current model being conservative against tisagenlecleucel. Given theuncertainty surrounding long-term OS extrapolation, scenario analyses wereconducted varying the time point to introduce the long-term DLBCL survivor
mortality. The model was not sensitive to this parameter. The model also explored
costs and utilities. The literature and data sources used for these inputs werevalid and relevant to the population of interest.

5.1.4 分析結果の解釈
5.1.1 から 5.1.3 に記載した内容について、下記のとおりまとめる。
また本品は、下記 3 つの条件すべてを満たすことから、価格調整における配慮を行うべき製品であり、ICER の閾値は 750 万円となる。
ア 適用症の一部に治療方法が十分に存在しない疾病が含まれるものであって、当該疾病を分析対象集団として分析を行ったもの
イ 小児に係る用法・用量等が承認された医薬品等又は医療機器等（小児のみに用いるものを除く。）であって、その小児に係る適用症を分析対象集団として分析を行ったものウ 承認された効能又は効果において悪性腫瘍が対象となっており、当該悪性腫瘍を分析対象集団として分析を行ったもの（通知より抜粋）

対象集団

15 歳未満の B-ALL

比較対照

ブリナツモマブ +/- 同種移植

ICER の基準値□ 通常の品目 ■ 配慮が必要な品目□ 費用削減あるいはドミナント ■ 500 万円以下 (750 万円以下)□ 500 万円超 (750 万円超)かつ 750 万円以下 (1125 万円以下)
ICER の所属する確□ 750 万円超 (1125 万円超)かつ 1000 万円以下 (1500 万円以率が最も高いと考え下)る区間□ 1000 万円超 (1500 万円超)
□ 効果が同等（あるいは劣り）、かつ費用が高い
本対象集団における ICER は¥2,087,581 であり、これは価格調整の閾
そのように判断した理値である 750 万円を下回り、DSA においても基本分析と大きく結果が異由なることはなかった。
173

また、確率論的感度分析（PSA）においては、ICER が 750 万円以下となる確率は 100%であった。以上より、「750 万円以下」が ICER の所属する区間として妥当と判断する。
対象集団

15 歳以上 25 歳未満の B-ALL

比較対照

ブリナツモマブ +/- 同種移植
イノツズマブ +/- 同種移植

ICER の基準値□ 通常の品目 ■ 配慮が必要な品目

ICER の所属する確率が最も高いと考える区間□ 費用削減あるいはドミナント ■ 500 万円以下 (750 万円以下)□ 500 万円超 (750 万円超)かつ 750 万円以下 (1125 万円以下)□ 750 万円超 (1125 万円超)かつ 1000 万円以下 (1500 万円以
下)□ 1000 万円超 (1500 万円超)
□ 効果が同等（あるいは劣り）、かつ費用が高い【比較対照】ブリナツモマブ
本対象集団における ICER は¥2,015,349 であり、これは価格調整の閾値である 750 万円を下回り、DSA においても基本分析と大きく結果が異なることはなかった。
また、確率論的感度分析（PSA）においては、ICER が 750 万円以下となる確率は 100%であった。

そのように判断した理 【比較対照】イノツズマブ
本対象集団における ICER は¥1,994,592 であり、これは価格調整の閾由値である 750 万円を下回り、DSA においても基本分析と大きく結果が異なることはなかった。
また、確率論的感度分析（PSA）においては、ICER が 750 万円以下となる確率は 100%であった。
以上より、両比較対照群の分析結果を考慮すると、「750 万円以下」がICER の所属する区間として妥当と判断する。
対象集団

70 歳未満の r/r DLBCL

比較対照

Salvage Chemotherapy +/- HSCTICER の基準値□ 通常の品目 ■ 配慮が必要な品目□ 費用削減あるいはドミナント ■ 500 万円以下 (750 万円以下)□ 500 万円超 (750 万円超)かつ 750 万円以下 (1125 万円以下)
ICER の所属する確□ 750 万円超 (1125 万円超)かつ 1000 万円以下 (1500 万円以率が最も高いと考え下)る区間□ 1000 万円超 (1500 万円超)
□ 効果が同等（あるいは劣り）、かつ費用が高い
本対象集団における ICER は¥5,459,234 であり、これは価格調整の閾
そのように判断した理値である 750 万円を下回り、DSA においても、ほぼ全ての場合において
由ICER が 750 万円を下回っており、750 万円を超えるのは割引率を 4%
174サンプルサイズ
実査期間
3. 価格調整率の重み
1 及び 2 より対象集団別の価格調整率の重みは以下の通りである。「5.1.4 分析結果の解釈」に記載の通り、70 歳以上集団の分析結果については価格調整に用いるべきでないと考える。な
お 2 で算出した年齢集団別の患者処方割合を用いた場合、対象集団全体に占める DLBCL の70 歳未満患者の割合は% (=%)、70 歳以上患者の割合は%(%) となる。
対象集団
B-ALL
15 歳未満15 歳～25 歳
DLBCL 70 歳未満
70 歳以上
合計

患者割合

計算式

NA
NA

NA
100%

5.1.6 価格の引き上げ [該当する場合のみ]該当せず
5.2 公的介護費用や生産性損失を含めた分析 [該当する場合のみ]
既存の治療方法とは異なり、本製品の投与により持続的な有効性が期待できる。本製品の投与による患者の生産性への影響は大きいため、生産性損失を考慮した分析を実施する。分析における主要なインプットを Table 51 に示す。
Table 51. Inputs for productivity gain
Parameter
Monthly Wage
Age-specificemployment rate

15-24
25-54
55-59
60-64
65 +

Input Value¥427,877.33
43.50%
84.90%
74.90%
74.90%
24.10%

Source/Notes
Wage level data in Japan[53]2018 Mar, Historical data 1
b-6
Employment rate [by age
group] - Whole Japan,
Monthly Data[54]【B-ALL：15 歳未満】
生産性損失を含めた分析において、介入群の費用が比較対照群の費用を下回るため、ICER はドミナントとなる。
比較対照技術：Blinatumomab
増分効果
増分費用 (円)(QALY)
生産性損失を
9.05-¥9,897,380
含めた分析
基本分析
9.05
¥18,882,649

ICER(円/QALY)
Dominant¥2,087,581【B-ALL：15 歳以上 25 歳未満】
生産性損失を含めた分析において、Blinatumomab と Inotuzumab の両比較対照技術につ1787. 実施体制
【社内メンバー】
所属
氏名【社外専門家】
氏名

所属

役割

187

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[4]

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[6]

[7]
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[9]
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[12]

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192−Had ECOG performance status of 0 or 1

Exclusion criteria for the CORAL trial14:• CNS or meningeal involvement by lymphoma
Major
exclusion• Burkitt, mantle cell, T-cell lymphoma
criteria• History of HIV infection• Prior transplantation at CORAL enrolment
Detailsof • Chemotherapy (e.g., +/- rituximab and ICE, DHAP, CHOP-like, etc.)
interventions• ASCT or Allo-SCT
Detailsofthe
N/A
comparison
Study Design• Extension study of CORAL, a randomized, multi-center, multi-country, phase III trial

Blinding method

None (open label)• ORR• CR/CRu• PR• OS

Primary endpoint
Key
endpoints

secondary

N/A• Kaplan–Meier method was used to estimate OS• Wilcoxon's signed rank test was used to compare patient characteristics
Statistical methods• Cox regression analysis was used to calculate the hazard ratio (HR) between
different patient categories• Full analysis set (baseline characteristics reported): N = 75
Sample size
• Patients evaluated for response: N = 75
• Patients evaluated for survival: N = 73
Follow-up period
Median 32.8 months (range: 24.3-45.8 months)• Age: median 56 years
Major
background • Sex: 68% male
factors of subjects• Predominant histology: 100% DLBCL• IPI risk classification: 72% 0-2, 28% >2201• ORR: 44%
Results of the primary • CR/CRu: 32%
endpoint• PR: 12%
• Median OS: 10.0 (95% CI: [6.6, 12.6]) months
Results
of
major
N/A
secondary endpoints
Limitation of the study Not reported
Abbreviations: allo-SCT: allogenic stem cell transplant; ASCT: autologous stem cell transplant; CHOP: cyclophosphamide,
doxorubicin, vincristine, prednisone; CI: confidence interval; CNS: central nervous system; CR/CRu: complete
response/complete response unconfirmed; DHAP: dexamethasone, cytarabine, cisplatinum; DLBCL: diffuse large B-cell
lymphoma; ECOG: Eastern Cooperative Oncology Group; HIV: human immunodeficiency virus; HR: hazard ratio; ICE:
ifosfamide, carboplatinum, etoposide; IPI: International Prognosis Index; N/A: not applicable; NHL: non-Hodgkin lymphoma;
ORR: overall response rate; OS: overall; PR: partial response
CORAL extension study 2
Location where theMultiple countries (e.g., US, UK, Germany, Australia, etc.)
test was performed
Participant
July 2003-June 2008
recruitment period• Patients included in the CORAL trial who did not proceed to per-protocol ASCT because of anevent leading to withdrawal between cycle 1 and scheduled ASCT and who were candidates forthird-line regimen were included in the extension study 2
Population

Major

Patients enrolled in the CORAL trial14− Were with age 18 to 65 years− Were with aggressive CD20+ B-cell NHL, including DLBCL. Before enrolment, CD20+
aggressive B-cell lymphoma was histologically confirmed in all patients− Had experienced relapse or did not achieve CR with a standard anthracycline-based regimen
composed of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)− Had ECOG performance status of 0 or 1
exclusion Exclusion criteria for the CORAL trial14:202criteria

Details
interventions
Detailsofcomparison• CNS or meningeal involvement by lymphoma• Burkitt, mantle cell, T-cell lymphoma• History of HIV infection• Prior transplantation at CORAL enrolment• Chemotherapy (+/- rituximab and ICE-type, DHAP-type, gemcitabine-containing, CHOP-like,ofetc.)• ASCT or allo-SCT
the
N/A

Study Design• Extension study of CORAL, a randomized, multi-center, multi-country, phase III trial

Blinding method

None (open label)• ORR• CR/CRu• PR• OS

Primary endpoint
Key
endpoints

secondary

N/A• Kaplan–Meier method was used to estimate OS• Wilcoxon's signed rank test was used to compare patient characteristics
Statistical methods• Cox regression analysis was used to calculate the hazard ratio (HR) between
different patient categories• Full analysis set (baseline characteristics reported): N = 203
Sample size
• Patients evaluated for response: N = 203• Patients evaluated for survival: N = 193
Follow-up period
Median 30.1 months• Age: median 55 years
Major
background • Sex: 61% male
factors of subjects• Predominant histology: 100% DLBCL• IPI risk classification: 30% 0-1, 52% 2-3, 17% 4-5
Results of the primary • ORR: 39%
endpoint• CR/CRu: 27%
203

• PR: 12%• Median OS: 4.4 months (95% CI: not reported)

Results
of
major
N/A
secondary endpoints
Even with the limitation of missing data, this cohort is the largest ever described in that situation
Limitation of the study and provides interesting parameters, which can be validated in future studies to better describe
who could be eligible for experimental third-line salvage regimens.
Abbreviations: allo-SCT: allogenic stem cell transplant; ASCT: autologous stem cell transplant; CHOP: cyclophosphamide,
doxorubicin, vincristine, prednisone; CI: confidence interval; CNS: central nervous system; CR/CRu: complete
response/complete response unconfirmed; DHAP: dexamethasone, cytarabine, cisplatinum; DLBCL: diffuse large B-cell
lymphoma; ECOG: Eastern Cooperative Oncology Group; HIV: human immunodeficiency virus; N/A: not applicable; ICE:
ifosfamide, carboplatinum, etoposide; IPI: International Prognosis Index; NHL: non-Hodgkin lymphoma; NR: not reported;
ORR: overall response rate; OS: overall; PR: partial response
SCHOLAR-1
Location where the test wasMultiple countries (e.g., US, Canada, UK, etc.)
performed
Participant recruitment period 2001-2014• All patients from each data source who met criteria for refractory DLBCL, including tFL
and primary mediastinal B-cell lymphoma (PMBCL), who went on to receive subsequent
therapy were considered for analysis; tFL and PMBCL were included because they arehistologically similar and clinically treated as large cell lymphoma
Population• Refractory DLBCL, defined as progressive disease or stable disease as best response to
chemotherapy (received ≥4 cycles of first-line therapy or 2 cycles of later-line therapy,
respectively) or relapse ≤12 months (365 days) post-ASCT

Major exclusion criteria• Patients must have received an anti-CD20 monoclonal antibody and an anthracycline as
one of their prior regimens• Patients with primary central nervous system lymphoma were excluded

Details of interventions

Chemotherapies (e.g., +/- rituximab and GDP, DHAP, ICE, etc.)

204

Details of the comparison

N/A
Retrospective meta-analysis of four studies (multi-country):• 2 phase III randomized controlled trials- Lymphoma Academic Research Organization-CORAL
Study Design- Canadian Cancer Trials Group study LY.12• 2 observational cohorts- MDACC- IA/MC
Blinding method
None (open label)
• ORR
• CR
Primary endpoint
• PR
• OS
Key secondary endpoints
N/A• Higgin’s Q statistic was used to assess the heterogeneity of response rate between thesource databases• Response rates were estimated from the pooled data with a random effects model
Statistical methods• Covariates for response were evaluated with a Cochran-Mantel-Haenszel test stratified
by institution• Survival was estimated, and covariates were assessed by a Cox proportional hazards
model stratified by data source• Primary abstraction: N=861• Analysis set (baseline characteristics reported): N=636- MDACC: N=165 (out of 191)
- IA/MC: N=82 (out of 107)
Sample size
- LY.12: N=219 (out of 353)
- CORAL: N=170 (out of 210)
• Patients evaluated for response: N=523• Patients evaluated for survival: N=603
Follow-up period
Range: 1-14 years
Major background factors of • Age: median 55 years
subjects• Sex: 64% male205• Predominant histology: 87% DLBCL, 4% tFL, 2% PMBCL, 7% missing• ECOG performance status: 73% 0-1, 14% 2-4, 13% missing• Disease stage: 27% I-II, 72% III-IV, <1% missing• Number of lines of prior chemotherapy and ASCT: 28% 1, 49% 2-3, <1% ≥4• IPI risk classification: 25% low risk, 57% intermediate-high risk , 18% missing or
incompletely assessed• ORR: 26%
Resultsoftheprimary • CR: 7%
endpoint• PR: 18%
• Median OS: 6.3 (95% CI: [5.9, 7.0]) months
Results of major secondary
N/A
endpoints
Limitation of the study

As a retrospective study, limitations of the direct applicability of the results to future studies
may exist.

Abbreviations: ASCT: autologous stem cell transplant; CI: confidence interval; CR: complete response; DHAP:
dexamethasone, cytarabine, cisplatinum; DLBCL: diffuse large B-cell lymphoma; ECOG: Eastern Cooperative Oncology
Group; GDP: Gemcitabine, Cisplatin, and Dexamethasone; IA/MC: Molecular Epidemiology Resource of the University of
Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence; ICE: ifosfamide, carboplatinum, etoposide; IPI:International Prognosis Index; MDACC: MD Anderson Cancer Center; N/A: not applicable; PMBCL: primary mediastinal B-cell
lymphoma; tFL: transformed follicular lymphoma; ORR: overall response rate; OS: overall; PR: partial response206Appendix C. Summary of goodness of fit statistics and weights forsurvival distributions
C-1. B-ALL: OS
Summary of goodness of fit statistics and weights for OS survival
distributions (age < 15 years)
Distribution
AICb
AIC based weightc
Tisagenlecleucel
Exponential
Weibull
Gompertz
Log-Normal
Log-Logistic
Gamma
Spline with single knota
Spline with two knotsa
Spline with three knots
Spline with four knotsa
BlinatumomabExponential
309.73
2.0%
Weibull
310.23
1.6%
Gompertz
305.9713.1%
Log-Normal
304.3329.9%
Log-Logistic
305.0720.6%
Gamma
306.02
12.8%
Spline with single knota
306.03
12.8%
Spline with two knotsa
308.094.6%
aSpline with three knots
309.77
2.0%
Spline with four knotsa
311.900.7%
Abbreviation: AIC, Akaike information criterion
a. Cubic spline models with one, two, three, and four knots expressed on the
proportional hazard scale were fitted based on the method developed by
Royston 2002.
b. A smaller AIC value represents a better goodness of fit.
c. The weights were calculated based on AIC scores using the method outlined
in Jackson 2009. The weights represent the adequacy of each distribution inpredicting the efficacy and are used in the calculation for the weighted
distribution.
Summary of goodness of fit statistics and weights for OS survival
distributions (age 15-25 years)
Distribution
AICb
AIC based weightc
Tisagenlecleucel
Exponential
Weibull
Gompertz
Log-Normal
Log-Logistic
Gamma
Spline with single knota
216

Distribution
AICb
AIC based weightc
Spline with two knotsa
Spline with three knotsa
Spline with four knotsa%
BlinatumomabExponential
349.27
0.7%
Weibull
348.91
0.9%
Gompertz
343.2314.7%
Log-Normal
341.8928.6%
Log-Logistic343.0815.8%
Gamma
343.15
15.3%
Spline with single knota
343.11
15.6%
Spline with two knotsa
345.205.5%aSpline with three knots
346.95
2.3%
Spline with four knotsa
349.120.8%
Inotuzumab
Exponential
280.94
0.5%
Weibull
281.580.4%
Gompertz
274.47
13.4%
Log-Normal
274.06
16.5%
Log-Logistic274.1715.6%
Gamma
274.91
10.7%
Spline with single knota
274.30
14.6%
Spline with two knotsa
273.7818.9%
aSpline with three knots
276.23
5.6%
Spline with four knotsa
276.983.8%Abbreviation: AIC, Akaike information criterion
a. Cubic spline models with one, two, three, and four knots expressed on the
proportional hazard scale were fitted based on the method developed by
Royston 2002.
b. A smaller AIC value represents a better goodness of fit.
c. The weights were calculated based on AIC scores using the method outlined
in Jackson 2009. The weights represent the adequacy of each distribution inpredicting the efficacy and are used in the calculation for the weighted
distribution.
C-2. B-ALL: EFS
Summary of goodness of fit statistics and weights for tisagenlecleucel
EFS survival distributions (age < 15 years)
Distribution
AICb
AIC based weightc
Tisagenlecleucel
Exponential
Weibull
Gompertz
Log-Normal
Log-Logistic
Gamma
Spline with single knot
Spline with two knotsa
217